Artículos de revistas sobre el tema "Metamorphoses 12,1-13,622"

Abstract The Kozani earthquake (Ms = 6.6) of 13 May 1995 is the strongest event of the decade in Greece and occurred in a region of low seismic activity. Using regional data and the strong-motion record at the Kozani station, we relocate the mainshock at 40.183° N and 21.660° E, beneath the Vourinos massif at a depth of 14.2 km. We also compute a focal mechanism by body-waveform modeling at teleseismic distance, which confirms a normal mechanism. The most likely plane strikes 240° ± 1° N and dips 40° ± 1° N with a centroid depth of 11 ± 1 km. Modeling of the strong-motion record at Kozani confirms that nucleation started at the eastern termination of the bottom of the fault. Six days after the mainshock, we installed a network of 40 portable seismological stations for one week around the epicentral region. Several thousand aftershocks were recorded, among which we locate 622 with a precision better than 1 km. We compute 181 focal mechanisms that mostly show normal faulting. The aftershock seismicity is restricted between 5 and 15 km depth and defines a plane dipping north at an angle of about 35°, consistent with the mainshock mechanism. Seismic activity with the same pattern of normal fault mechanisms is also seen on an antithetic fault connected to the main one at 12 km depth, which cuts the ground surface north of the Vourinos ophiolite massif in the Siatista valley. These results suggest two possibilities for the active fault plane; either it is the Deskati fault that is flat and dips with a constant angle, and therefore the surface breaks are secondary features, or, more likely, it is the Paleohori fault that is new, of listric shape, and located ahead of the Deskati fault, which was not active during the earthquake.

Background CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Overexpression of CD47 serves as a mechanism of immune surveillance evasion, and is found to be associated with poor prognosis in both hematologic and solid malignancies. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. Importantly, unlike many CD47-blocking agents, TTI-622 does not bind to human red blood cells. Methods TTI-622-01 is an ongoing multicenter, Phase 1 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of TTI-622 in adult patients with relapsed/refractory (R/R) lymphoma (NCT03530683). Based on a modified 3+3 scheme, weekly doses are escalated through pre-planned dose levels ranging from 0.05 to 8 mg/kg. The observation period for dose limiting toxicity (DLT) is the initial 3 weeks of treatment. Safety monitoring includes weekly clinical laboratories and assessments of adverse events (AEs) based on CTCAE v 4.03. Blood samples are collected for PK analysis and assessment of receptor occupancy on normal peripheral T cells. Disease assessments are performed per Lugano criteria every 8 weeks within the first 6 months, every 3 months up to two years, and every 6 months thereafter until the end of treatment. Results As of the July 16, 2020 cutoff, 25 patients (12M/13F) with a median age of 68 years (range 24-86) have received dose levels of 0.05−8 mg/kg with testing at 8 mg/kg ongoing. Patients with the following histologies have been enrolled: diffuse large B-cell lymphoma (DLBCL; n=13), Hodgkin lymphoma (n=5), follicular lymphoma (FL; n=2), peripheral T-cell lymphoma (PTCL; n=2), cutaneous T-cell lymphoma with CD30 negative large cell transformation (CTCL-LCT, n=2), and mantle cell lymphoma (n=1). Disease stages at entry have been III or IV in 23 patients; patients had received a median of 3 (range 1-9) prior systemic therapies including CAR-T in 5 patients and HSCT in 6 patients. Treatment-related AEs have been reported in 12 (48%) patients. Most AEs have been grade 1 or 2. The most frequent treatment-related AEs include thrombocytopenia (n=4; 1 grade ≥3), neutropenia (n=3; 3 grade ≥3) and fatigue (n=3; 0 grade ≥3). Grade 4 thrombocytopenia occurred in 1 patient in the 8 mg/kg cohort and accounted for the only DLT and treatment-related serious AE reported to date. This event that occurred on Day 8 was not associated with bleeding and resolved within 1 day after prophylactic platelet transfusion. Mild to moderate platelet decreases seen in the majority of patients generally occurred on dosing days and recovered quickly to baseline levels. No other grade ≥3 thrombocytopenia have been observed in the 4 other DLT evaluable patients dosed with 8 mg/kg to date. Preliminary PK results suggest dose-dependent increases in exposure following both single and repeated TTI-622 infusions. PD results indicate that end-of-infusion CD47 receptor occupancy (RO) is above 60% at doses ≥2 mg/kg and that RO is more sustained with TTI-622 doses ≥1 mg/kg compared to lower doses. Objective responses have been achieved in 5 patients, including 1 complete response (CR) in DLBCL (0.8 mg/kg) and 4 partial responses (PR) in PTCL (2 mg/kg), DLBCL (4 mg/kg), CTCL-LCT and FL (8 mg/kg). Initial responses were achieved at the first disease assessment (week 8) in all 5 responders including initial PR in the patient who subsequently achieved CR at week 36 (See Figure 1). In the dose range of 0.8-8 mg/kg, objective responses occurred in 31% (5/16) of patients with ≥1 post-treatment response assessment (See Table 1). Two of 4 response evaluable patients in the ongoing 8 mg/kg cohort achieved a PR, and 2 other patients have been on treatment for <8 weeks. Conclusions Results to date from this ongoing Phase 1 study in patients with R/R lymphomas indicate that weekly doses of TTI-622 up to 4 mg/kg are well tolerated with dose-dependent increases in exposure and RO. TTI-622 has shown activity in R/R lymphoma with objective responses across a broad dose range (0.8-8 mg/kg) and in multiple histologies. The study is currently evaluating the 8 mg/kg dose level. Disclosures Patel: Pharmacyclics: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Kite: Consultancy; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy. Ramchandren:Seattle Genetics, Sandoz-Novartis, Pharmacyclics/Janssen, Bristol-Myers Squibb: Consultancy; Merck, Seattle Genetics, Janssen, Genentech: Research Funding. Lesokhin:Juno: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Takeda: Consultancy, Honoraria. von Keudell:Pharmacyclics: Research Funding; Genentech: Research Funding; Bayer: Research Funding. Cheson:Symbio: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; TG Therapeutics: Speakers Bureau; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Research Funding; Kite: Consultancy; Parexel: Consultancy. Zonder:Intellia, Amgen, Takeda, Janssen, Regeneron, Alnylam, Caelum, Oncopeptides: Consultancy; BMS, Celgene: Research Funding. Seymour:Seattle Genetics: Research Funding; Merck: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding. Catalano:Trillium Therapeutics Inc.: Current Employment. Lin:Trillium Therapeutics Inc.: Current Employment. Uger:Trillium Therapeutics Inc.: Current Employment. Petrova:Trillium Therapeutics Inc.: Current Employment. Roberge:Trillium Therapeutics Inc.: Current Employment. Shou:Trillium Therapeutics Inc.: Current Employment. Iyer:Target Oncology: Honoraria; Seattle Genetics, Inc.: Research Funding; Rhizen: Research Funding; CRISPR: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Spectrum: Research Funding; Merck: Research Funding; Afffimed: Research Funding.

BackgroundGPs are crucial in adequately diagnosing and initiating appropriate management for patients with psychological problems, but face many challenges and require support.AimTo determine the effects of the e-tool PsyScan.Design and settingA randomised controlled trial with a 1-year follow-up, comparing care using PsyScan with usual care for psychological problems, was undertaken in 10 multidisciplinary primary healthcare centres in Eindhoven, the Netherlands.MethodBetween consultations with their GP, participants in the intervention group could complete PsyScan. The e-tool consists of a distress screener and Four-Dimensional Symptom Questionnaire to differentiate between stress, depression, anxiety, and somatisation symptoms, and to explore symptom severity. PsyScan generated diagnostic and therapeutic advice for GPs and participants that was automatically transferred to each patient’s electronic medical record. The primary outcome was the proportion of participants that achieved a successful treatment result; namely, a decrease of ≥50% on the Symptom Checklist-90-Revised, after 1 year.ResultsThere were 176 participants in the intervention group and 160 in the control group. After multiple imputation, the participants in the intervention group had higher chances of achieving a successful treatment result compared with those in the control group (odds ratio [OR] 2.7, 95% confidence interval [CI] = 1.5 to 4.8, P = 0.002). Quality of life was higher in the intervention group at 12 months (mean difference in EuroQol 5 Dimensions 5 Levels index values was 0.076, 95% CI = 0.015 to 0.136, P = 0.01). The mean 1-year costs per participant were similar (€13 622 in intervention group, €12 487 in control group [β = −0.03, P = 0.71, R2 = 0.05]).ConclusionPsyScan generated clinically relevant and statistically significant effects, and could be useful in offering effective individualised care to patients.

Background and purpose: In the past decade, a shift occurred in surgical total hip arthroplasty (THA) approaches to the posterolateral (PLA) and direct anterior approach (DAA). Comparisons of postoperative activities and participation between surgical approaches for THA are sparse. We therefore investigated the association between PLA and DAA for THA regarding the construct “activity and participation” (ICF model) during the first postoperative year.Patients and methods: This was an observational cohort study on osteoarthritis patients scheduled for primary THA in 2 hospitals. Questionnaires to assess the ICF domain “activity and participation” were completed preoperatively, and 3, 6, and 12 months postoperatively (HOOS Activities of daily living (ADL) and Sport and Recreation Function (SR), Hospital for Special Surgery Hip Replacement Expectations Survey, and questions regarding return to work). Each hospital exclusively performed one approach (PLA [Alloclassic-Zweymüller stem] or DAA [Taperloc Complete stem]) for uncemented THA. Hospital was included as instrumental variable, thereby addressing bias by (un)measured confounders. Adjusted mixed-effect models were used, stratified by employment.Results: Total population: 238 PLA (24% employed) and 622 DAA (26% employed) patients. At 12 months, the PLA group had a lower ADL score (–7, 95% CI –12 to –2 points). At 6 months, significantly fewer PLA patients had fulfillment of the expectation sports-performance (OR = 0.3, CI 0.2–0.7]. Other outcomes were comparable.Employed population: At 6 and 12 months, PLA patients scored clinically lower on ADL (respectively –10, CI –19 to 0 and –9, CI –19 to 0 points) and SR (respectively –13, CI –21 to –4 and –9, CI –18 to –1 points). At 6 months, fewer PLA patients fulfilled the expectation joining recreational activities (OR = 0.2, CI 0.1–0.7]. Fulfillment of other expectations was comparable between groups. PLA patients less often returned to work within 3 months (31% vs. 45%), but rates were comparable at 12 months (86% vs. 87%).Interpretation: Overall, functional recovery regarding “activity and participation” was comparable for PLA and DAA. Among employed patients, DAA resulted in better functional recovery and more fulfillment of expectations compared with PLA patients. DAA might also facilitate faster return to work.

To date there have been few reports on the impact of dietary intervention on the clinical course of acute shigellosis. Current management of acute shigellosis is primarily focused on antibiotic therapy with less emphasis on nutritional management. In a randomised clinical trial, we examined the role of an energy-dense diet on the clinical outcome in malnourished children with acute dysentery due to shigellosis. Seventy-five children aged 12–48 months with acute dysentery randomly received either a milk–cereal formula with an energy density of 4960 kJ/l (test group) or a milk–cereal formula with energy of 2480 kJ/l (control group) for 10 d in hospital. In both milk–cereal formulas, protein provided 11 % energy. In addition, the standard hospital diet was offered to all children and all children received an appropriate antibiotic for 5 d. The mean food intakes (g/kg per d) in the test and control groups were: 112 (SE 2·28) AND 116 (se 3·48) (P=0·16) on day 1; 118 (se 2·72) and 107 (se 3·13) (P=0·04) on day 5; 120 (se 2·25) and 100 (se 3·83) (P=0·04) on day 10. The mean energy intakes (kJ/kg per d) in the test and control groups respectively were: 622 (se 13·2) and 315 (se 11·3) (P<0·05) on day 1; 655 (se 15·1) and 311 (se 7·98) (P<0·05) on day 5; 672 (se 14·7) and 294 (se 11·1) (P<0·05) on day 10. The food and energy intakes were mostly from the milk–cereal diet. There was no difference between two groups in resolution of fever, dysenteric (bloody and or mucoid) stools, stool frequency and tenesmus. However, vomiting was more frequently observed among the test-group children during the first 5 d of intervention (67 % v. 41 %, P=0·04). There was an increase in the mean weight-for-age (%) in the test group compared with the control group after the 10 d of dietary intervention (6·2 (se 0·6) v. 2·7 (se 0·4), P<0·01). In addition, resolution of rectal prolapse was better (26 % v. 8 %, P=0·04) in the test group v. control group after 5 d, and 13 % v. 6 %, (P=0·08) after 10 d of dietary intervention. Supplementation with a high-energy diet does not have any adverse effect on clinical course of acute shigellosis and reduces the incidence of rectal prolapse in malnourished children.

Room-temperature single-crystal X-ray studies are recorded for 2- and 4-nitrophenoxide salts of silver(I) and thallium(I), M(2-np) and Tl(4-np) (anhydrous), and Ag(4-np).H2O. Ag(2-np) is monoclinic, P21/c, a 9·012(4), b 5·743(5), c 12·594(5) Å, β 104·34(4)°, Z = 4; conventional R on |F| was 0·042 for No 1378 independent ‘observed’ (I > 3σ(I)) reflections. Tl(2-np) is monoclinic, C2/c, a 27·250(3), b 3·712(1), c 15·147(3) Å, β 114·41(1)°, Z = 8, R 0·025 for No 1346. Ag(4-np).H2O is monoclinic, P21/a, a 5·613(6), b 13·191(7), c 9·844(5) Å, β 92·50(6)°, Z = 4, R 0 ·033 for No 622. Tl(4-np) is tetragonal, I 41/a, a 18·037(8), c 8·979(8) Å, Z = 16, R 0·043 for No 924. An acid salt of the latter, Tl(4-np).(4-npH)3, triclinic, P-1, a 11·861(8), b 11·45(1), c 11· 423(1) Å, α 114·00(6), β 109·78(5), γ 96·87(7)°, Z = 2, R 0·042 for No 3814, is isomorphous with its rubidium analogue. These comprise a novel array of structures: although the structures of the silver(I) complexes are two-dimensional sheets with familiar head-tail connecting ligands, a strong silver-aromatic carbon interaction is found in Ag(2-np) (Ag–C 2·496(5) Å). Tl(2-np) and Tl(4-np) both present unusual forms related to the stair-polymer and cubane adducts found in 1 : 1 coinage metal(I)/halide-unidentate nitrogen base adducts; Tl(2-np) is a double-stranded stair-polymer array, with the phenoxide oxygen atoms incorporated in the stair and the nitro oxygen atoms linking successive thallium atoms. The structure of Tl(4-np) is based on a tetranuclear cubane motif of -4 symmetry, [Tl(O-phenoxide)]4, these being linked into a three-dimensional network by further Tl · · · O-nitro interactions from adjacent units. The structure of silver(I) picrate monohydrate, isomorphous with its sodium counterpart, is also recorded: monoclinic, C 2/m, a 12·818(7), b 20·208(8), c 3· 741(1) Å, β 88·25(3)°, Z = 4, R 0·047 for No 1042, void of any significant Ag · · · C contacts.

Epidemiological studies show that adherence to a Mediterranean diet (MD) increases longevity; however, few studies are restricted to Mediterranean populations or explore the effect of a MD pattern that directly incorporates olive oil. Therefore the relationship between adherence to the MD and mortality was studied within the the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). The EPIC-Spain analysis included 40 622 participants (37·7 % males) aged 29–69 years who were recruited from five Spanish regions in 1992–1996. During a mean follow-up of 13·4 years, 1855 deaths were documented: 913 from cancer, 399 from CVD, 425 from other causes and 118 from unknown causes of death. Risk of all-cause and cause-specific mortality was assessed according to the level of adherence to a relative MD (rMED) score, measured using an 18-unit scale incorporating nine selected dietary components. A high compared with a low rMED score was associated with a significant reduction in mortality from all causes (hazard ratio (HR) 0·79; 95 % CI 0·69, 0·91), from CVD (HR 0·66; 95 % CI 0·49, 0·89), but not from overall cancer (HR 0·92; 95 % CI 0·75, 1·12). A 2-unit increase in rMED score was associated with a 6 % (P < 0·001) decreased risk of all-cause mortality. A high olive oil intake and moderate alcohol consumption contributed most to this association. In this Spanish cohort, following an olive oil-rich MD was related to a significant reduction in all-cause mortality, and reduced the risk of mortality from CVD. These results support the important role that the MD pattern has on reducing mortality in Mediterranean countries.

This paper explores the effect of using regional data for livestock attributes on estimation of greenhouse gas (GHG) emissions for the northern beef industry in Australia, compared with using state/territory-wide values, as currently used in Australia’s national GHG inventory report. Regional GHG emissions associated with beef production are reported for 21 defined agricultural statistical regions within state/territory jurisdictions. A management scenario for reduced emissions that could qualify as an Emissions Reduction Fund (ERF) project was used to illustrate the effect of regional level model parameters on estimated abatement levels. Using regional parameters, instead of state level parameters, for liveweight (LW), LW gain and proportion of cows lactating and an expanded number of livestock classes, gives a 5.2% reduction in estimated emissions (range +12% to –34% across regions). Estimated GHG emissions intensity (emissions per kilogram of LW sold) varied across the regions by up to 2.5-fold, ranging from 10.5 kg CO2-e kg–1 LW sold for Darling Downs, Queensland, through to 25.8 kg CO2-e kg–1 LW sold for the Pindan and North Kimberley, Western Australia. This range was driven by differences in production efficiency, reproduction rate, growth rate and survival. This suggests that some regions in northern Australia are likely to have substantial opportunities for GHG abatement and higher livestock income. However, this must be coupled with the availability of management activities that can be implemented to improve production efficiency; wet season phosphorus (P) supplementation being one such practice. An ERF case study comparison showed that P supplementation of a typical-sized herd produced an estimated reduction of 622 t CO2-e year–1, or 7%, compared with a non-P supplemented herd. However, the different model parameters used by the National Inventory Report and ERF project means that there was an anomaly between the herd emissions for project cattle excised from the national accounts (13 479 t CO2-e year–1) and the baseline herd emissions estimated for the ERF project (8 896 t CO2-e year–1) before P supplementation was implemented. Regionalising livestock model parameters in both ERF projects and the national accounts offers the attraction of being able to more easily and accurately reflect emissions savings from this type of emissions reduction project in Australia’s national GHG accounts.

BackgroundReports of an impaired humoral response after COVID-19 vaccination in patients treated with rituximab (RTX) have raised particular concern for patients with inflammatory rheumatic diseases (IRD) receiving RTX (1). This calls for strategies to enhance a humoral response in RTX-treated patients. At present, there is no data on whether it is best to increase the humoral response with a third vaccine dose (a booster) or with a third and fourth dose (re-vaccination).ObjectivesIn IRD patients treated with RTX, without a detectable humoral response after the first vaccination course (two shots), we aimed to investigate the difference of either a booster vaccine (dose 3) or a new re-vaccination course (dose 3 + 4) on the serological response of the COVID-19 mRNA vaccines.MethodsWe included 84 patients with IRD treated with RTX, all without measurable total SARS-CoV-2 antibodies after a full primary COVID-19 vaccination course (2 doses three weeks apart). All patients were offered a new re-vaccination course with the mRNA vaccine not used primarily (Pfizer/Biontec or Moderna). A small number of patients declined the revaccination, and recieved a booster with the mRNA vaccine used initially. Serum total antibodies were measured before and six weeks after the last dose against recombinant SARS-CoV-2 spike S1 protein (VITROS). In addition, CD19+ B-cells were measured at inclussion.ResultsPatient characteristics are in Table 1. The median age was 64 years; 68% were female with a disease duration of 5 years. Sixty-nine out of 84 were re-vaccinated (3 + 4 dose). Details previous exposure to RTX are given in Table 1. CD19+ B-cells were measurable in 12/81 at inclusion.Table 1.Patient CharacteristicsBooster, n=15Revaccination, n=69Age, years median (IQR)60 (45 - 69)65 (54 - 70)Female47%72%Disease duration, years (IQR)5 (2-8)6(2 - 13) ANCA-vasculitis47 %45 % Rheumatoid Arthritis47 %17 % Poly- Dermatomyositis6 %19 % SLE, Scleroderma, other diagnoses-19 %No DMARD treatment27 %35 %Prednisone33 %46 %Methotrexate40 %16 %Azathioprine7 %12 %Mycophenolate7 %7 %Other20 %9 %Rituximab treatment, (IQR) Months from last RTX to vaccination3.9 (1.3 - 9.3)5.4 (4.2 - 7.3) Number of infusions6 (4 - 8)7 (5 - 12) Cummulativ total dose, gram4 (2.5 - 7.5)6 (3.5 - 10) Total treatment time with RTX, months15 (9 - 54)27 (13 - 63)Patients with measurable CD19+ B-cells in peripheral blood at the time of booster or re-vaccination (positive/total)3/149/67We found a combined seroconversion rate of 33% six weeks after the last shot. There was no statistical difference between the booster (38,5%) and the re-vaccination group (32,3%), p=0.67 (Pearson’s chi-squared). IRD patients with a humoral response in the re-vaccination group had significantly higher levels of total SARS-CoV-2 antibodies (median(IQR) 306(49-464) AU/ml) compared to the booster group (14(4-15) AU/ml) p=0.02, Figure 1A. In multiple logistic regression model, we found that levels of CD19+ B-cells were the only variable able to predict a humoral response, Figure 1B. However, only 39% of the patients with a humoral response to vaccination had measurable CD19+ B-cells before vaccination. We found no effect of age, sex, diagnosis, treatment, and RTX exposure on the chance of seroconversion in multiple logistic regression models when corrected for CD19+ B-cells.Figure 1.ConclusionWe found that re-vaccination (dose 3 + 4) with COVID-19 mRNA vaccines favored a high humoral response in patients with IRD treated with RTX, who did not have a detectable humoral response after the first two vaccine doses, compared to a booster shot (dose 3). A detectable humoral response after re-vaccination was seen in more than half of the patients with no measurable CD19+ B-cells before vaccination. Presence of circulating CD19+ B-cells are a significant predictor of humoral response to mRNA COVID-19 vaccination.References[1]Ammitzbøll et al. ACR Open Rheum. 2021 Sep;3(9):622-628. doi: 10.1002/acr2.11299.AcknowledgementsThe Danish Rheumatism Association - Gigtforeningen for funding the study.Disclosure of InterestsNone declared

White alder (Alnus rhombifolia) is a fast-growing tree native to the western United States and is planted frequently in landscapes. In September 2010, mature leaves of white alder with small, orange-yellow pustules were collected in a commercial nursery in Santa Cruz County, CA. Approximately 25 white alder trees were affected. Collected leaves were sent to the California Department of Food and Agriculture Plant Pest Diagnostics Laboratory. Young uredinial pustules were bullate, with urediniospores emerging from a single pore in the pustule. Spiny cells lined the ostiole. With age, pustules broke open to release more spores. Urediniospores were obovate to oval and measured from 14 to 20 × 27 to 41 μm (17.1 × 32.2 μm average, n = 62). Spores were uniformly echinulate and contained a nearly hyaline cell wall measuring from 1 to 2 μm (1.5 μm average) in thickness. A portion of the 28S ribosomal subunit (GenBank Accession No. KC313888) and the internal transcribed spacer regions (KC313889) were amplified and sequenced from DNA extracted from urediniospores using primers LR6 and rust2inv (1) and ITS1-F and ITS4-B (2), respectively. Our ITS sequence had 99% identity to GenBank accession EF564164, Melampsoridium hiratsukanum. In September 2011, white alder leaves with similar symptoms were collected from a commercial nursery in Santa Barbara County, CA. The spore morphology matched the white alder sample previously collected in Santa Cruz County, CA, in 2010. At that time, pathogenicity assays were conducted on three 1-year-old, 61-cm white alder trees planted in 3.8-liter pots. Six detached leaves with visible rust pustules were rubbed gently onto both the apical and distal side of moistened leaves of the healthy alders. Each infected leaf was used to inoculate a total of 6 to 10 healthy leaves by rubbing two leaves per tree before moving to the next tree. Leaves on three additional white alder trees were rubbed with healthy leaves as controls. Trees were incubated in a dew chamber for 3 days in darkness at 24°C, then placed in a growth chamber at 22°C with a 12-h photoperiod. Twelve days after inoculation, small lesions were visible on a few of the leaf undersides of each inoculated tree. Not all inoculated leaves developed pustules. No lesions developed on the control trees. M. hiratsukanum has been reported in Canada, Europe, and eastern Asia (3). There are no published reports of this rust in the United States, but there is an unpublished specimen from white alder in the USDA Systematic Mycology Herbarium (BPI 028048) collected from California in 1931, which was identified as M. hiratsukanum by G. B. Cummins using morphological criteria. We are unaware if older specimens of this rust exist because we were unable to search other herbaria in the United States. To the best of our knowledge, this rust has been present in California since 1931, but has only recently been found causing disease in nursery plants. There have been no reports of the serious foliar disease symptoms on trees in California wild lands as have been reported in Europe, presumably due to dry summer and fall seasons in white alder's natural habitat. References: (1) M. C. Aime. Mycoscience 47:112, 2006. (2) M. Gardes and T. D. Bruns. Mol. Ecol. 2:113, 1993. (3) J. Hatula et al. Mycologia 101:622, 2009.

BackgroundSystemic sclerosis (SSc) is a chronic autoimmune multisystemic disease characterized by fibrosis and vasculopathy.[1]Mortality in patients with systemic sclerosis who present with interstitial lung disease can be up to 3x healthy population.[2]It is estimated that 70-90% have interstitial lung disease.[3]High resolution computed tomography (HRCT) of chest is recognized as a sensitive imaging method for evaluating pulmonary involvement.[4,5]Presentation patterns are also described: NSIP (non specific interstitial pneumonia), UIP (usual interstitial pneumonia), COP (cryptogenic organizing pneumonia), LIP (Lymphocytic interstitial pneumonitis). Capillaroscopy allows the study of the microcirculation. Changes are classified into “early,” “active,” and “late” scleroderma patterns.[6]ObjectivesTo relate between high resolution chest tomography and capillaroscopic findings in Systemic sclerosis.MethodsDescriptive, observational, cross-sectional study. Capillaroscopy with Optilia CapiScope 2.0/5.0MP and lung ultrasound with Siemmens Acuson X150 were performed in patients with SSc in the outpatient clinic of the rheumatology service from August-November 2021. Inclusion criteria: > 18 years old, meet criteria for classification of SSc according to ACR/EULAR 2013. Exclusion criteria: history of pre-existing lung disease.Results22 patients met inclusion criteria. 80% were female. Diffuse SSc 81.8% (18), limited SSc 18.2% (4). Mean age 54±17 years, disease duration 58.1% (13) >5 years and 40.9% (9) < 5 years, mean diagnosis 15.3±9.2 years, mean mRSS 19.4 + 13.2 mRSS Mild: 22.7% (5), moderate 18.2% (4), severe 27.3% (6), terminal 31.8% (7). ANA+ 45.5% (10), Topo IA 18.2% (4). Treatment: RTX 77.3% (17), Ca+ antagonists 68.2% (15), Bosentan 36.4% (8), MMF 36.4% (8), Colchicine 31.8% (7), Sildenafil 27.3% (6). Capillaroscopy: normal pattern 59% (13), early scleroderma pattern 9.1% (2), active scleroderma pattern 4.5% (1), late scleroderma pattern 22.7% (5), nonspecific abnormalities 4.5% (1). TACAR: 54.5% (12) normal, pathological findings 45.4% (10): NSIP pattern 80% (8), UIP 20% (2). TACAR/Capillaroscopy correlation: UIP pattern and early scleroderma pattern 4.5% (1) rp=.112, NSIP pattern and active scleroderma pattern 4.5% (1) rp=.769, NSIP pattern and normal capillaroscopy 4.5% (1) rp=. 518, NSIP pattern and late scleroderma pattern 27.2% (6) rp=1, normal TACAR and capillaroscopy with nonspecific abnormalities 4.5% (1) rp=1, UIP pattern and early pattern 4.5% (1) rp=.622, normal TACAR and normal capillaroscopy 27.2% (6).ConclusionWe found in this study that capillaroscopic findings of active and late patterns correlated with greater pulmonary involvement. It is recommended to follow patients with early patterns and the existence or not of interstitial pattern and to evaluate response to medication.References[1]Morrisroe K, Stevens W, Sahhar J. The clinical and economic burden of systemic sclerosis related interstitial lung disease. Rheumatology. 2019;0(1):1-11.[2]Volkmann E, Tashkin D, Sim M, Kim G, Goldin J, Clements P. Determining progression of scleroderma-related interstitial lung disease. Journal of Scleroderma and Related Disorders. 2018;4(1):62-70.[3]Simeón-Aznar C, Fonollosa-Plá V, et al. Registry of the Spanish Network forSystemic Sclerosis. Medicine. 2015;94(43):e1728.[4]Hussein, K., Shaaban, L. and Mohamed, E., 2016. Correlation of high resolution CT patterns with pulmonary function tests in patients with interstitial lung diseases. Egyptian Journal of Chest Diseases and Tuberculosis, 65(3), pp.681- 688.[5]Chung JH, Walker CM, Hobbs S. Imaging Features of Systemic Sclerosis- Associated Interstitial Lung Disease. J Vis Exp. 2020[6]Man, M., Dantes, E., Domokos Hancu, B., Bondor, C., Ruscovan, A., Parau, A., Motoc, N. and Marc, M., 2019. Correlation between Transthoracic Lung Ultrasound Score and HRCT Features in Patients with Interstitial Lung Diseases. Journal of Clinical Medicine, 8(8), p.1199.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Abstract. The new mineral zvěstovite-(Fe), ideally Ag6(Ag4Fe2)As4S13, has been found in the small abandoned Ulatayskoe Ag–Cu–Co occurrence, Ovyurskiy District, Tuva Republic, eastern Siberia, Russia. It occurs as anhedral grains, up to 1 × 0.4 mm in size but usually much smaller, closely intergrown with native silver, in Mg-bearing siderite–quartz gangue. Other associated minerals include acanthite, cobaltite, As-rich members of the tetrahedrite group (kenoargentotennantite-(Fe), tennantite-(Zn), zvěstovite-(Zn)), gersdorffite, jalpaite, krutovite, löllingite, pearceite, safflorite, skutterudite, Br-bearing chlorargyrite, malachite, and muscovite. Zvěstovite-(Fe) is iron black and opaque and has a black streak and metallic lustre. It is brittle and has a conchoidal fracture. No cleavage or parting is observed. The Vickers micro-indentation hardness (Vickers hardness number, VHN; 25 g load) is 169 kg mm−2 (range of 149–187 kg mm−2, n=4), corresponding to a Mohs hardness of 3–3.5. The calculated density is 4.979 g cm−3. In reflected light, zvěstovite-(Fe) is light grey with a greenish tint and isotropic. Internal reflections are ubiquitous and deep red in colour. The reflectance values for wavelengths recommended by the Commission on Ore Mineralogy of the International Mineralogical Association are (R, %): 32.5 (470 nm), 31.1 (546 nm), 30.1 (589 nm), and 28.8 (650 nm). The chemical composition (wt %, electron microprobe data, mean of eight spot analyses) is as follows: Cu 1.81, Ag 56.02, Fe 4.60, Zn 0.01, As 13.85, Sb 2.63, S 21.50, total 100.42. The empirical formula, calculated on the basis of 16 atoms per formula unit, is Ag9.93Cu0.54Fe1.58As3.54Sb0.41S12.83. Zvěstovite-(Fe) is cubic and has a space group of I4‾3m, with a=10.8601(3), V=1280.86(11) Å3, and Z=2. The strongest lines of the X-ray powder diffraction pattern (d, Å (I, %) hkl) are 7.68 (11) 110, 3.136 (100) 222, 2.717 (12) 400, 1.984 (8) 521, 1.921 (23) 440, and 1.638 (11) 622. The crystal structure of zvěstovite-(Fe) was refined to R1=0.0551 for 400 unique reflections with Fo>4σ (Fo). The possible ordering of the split M(2) sites is discussed. The new mineral is the Fe isotype of zvěstovite-(Zn). Both these minerals form the zvěstovite series within the tetrahedrite group.

Abstract. Male Wistar rats were castrated and implantated with testosterone-filled silastic depots (in vitro release rate: 60 μg/24 h) prior to treatment with 10 mg cyproterone acetate (CyAc) on day 1, and 5 mg on days 4, 7, 10 and 13. Animals were sacrificed on day 14. Control animals were treated identically, with the exception of CyAc administration. Blood was collected and the ventral prostates of 6–8 animals were pooled, homogenized and processed into cytosol and purified nuclei. Steroid determinations (CyAc, testosterone, 5α-dihydrotestosterone (DHT), 5α-androstane-3α,17β-diol (3α-diol)) were performed by RIA. Specifically bound DHT (charcoal resistant DHT = CR-DHT) represents DHT values (RIA) following treatment of cytosol or nuclear extract with dextran coated charcoal. The androgen receptor was determined in cytosol and nuclear extract by 'exchange assay' using [3H]methyltrienolone (MT) (18 h, 15°C). The main results were: 1) The steroid levels in plasma (testosterone, DHT, 3α-diol) were in the range of untreated adult animals and not significantly influenced by the CyAc treatment. Final CyAc levels were 305 ± 58 nmol/l (mean ± sd, n = 5). 2) Significantly lower DHT, CR-DHT and testosterone levels (P at least < 0.01) were found in cytosol and in nuclei in the CyAc-treated group (cytosol (fmol/mg protein): DHT 305 ± 61 (n = 5), CR-DHT 54 ± 37 (n = 8), testosterone ≤ 8 (n = 5); nuclei (pmol/mg DNA): DHT 0.4 ± 0.2 (n = 5), CR-DHT 0.7 ± 0.2 (n = 3), testosterone ≤ 0.2 (n = 5)) when compared to controls (cytosol: DHT 645 ± 232 (n = 15), CR-DHT 204 ± 49 (n = 8), testosterone 24 ± 12 (n = 10); nuclei: DHT 5.0 ± 2.5 (n = 12), CR-DHT 3.1 ± 0.7 (n = 5), testosterone 0.9 ± 0.6 (n = 7)). 3α-diol was similar in the cytosol of both groups and could not be detected in the nuclei. 3) The androgen receptor concentration was increased in the cytosol of the CyAc-treated group (216 ± 17 (n = 4), control group 98 ± 10 (n = 5) fmol/mg protein, P < 0.001)) and decreased in the nuclear extract (0.61 ± 0.25 (n = 4), control 1.75 ± 0.25 (n = 5) pmol/mg DNA, P < 0.001). 4) The weight and DNA content of the prostate were reduced following CyAc treatment (weight 191 ± 11 mg (n = 9), DNA 622 ± 61 μg/organ (n = 8), controls 312 ± 9 (n = 8) and 838 ± 103 (n = 8), respectively). The data demonstrate that an approximate 40-fold excess of CyAc over testosterone in plasma led to a distinct but partial reduction of nuclear DHT and androgen receptor values coinciding with partial effects on prostate weight and DNA content. These results reflect the ability of the prostate to maintain significant androgen stimulation in the presence of low nuclear DHT and androgen receptor values.

BackgroundImmune checkpoint inhibitor associated arthritis (ICI-A) commonly persists for months to years, even after ICI cessation.[1]ObjectivesTo compare the safety and effectiveness of biologic and conventional disease modifying anti-rheumatic drugs (DMARDs) for ICI-A.MethodsRetrospective multicenter observational study. Inclusion: 1) diagnosis of ICI-A and 2) treatment with a tumor necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX). Exclusion: preexisting autoimmune disease. The primary outcome was time to cancer progression from ICI initiation. Patients whose cancer progressed prior to DMARD initiation were excluded from this analysis. The secondary outcome was time to arthritis control from DMARD initiation, defined as grade 1 arthritis and prednisone ≤10mg/day. Cox proportional hazard models were generated, adjusting for confounders. A sensitivity analysis was performed incorporating a time dependent variable “time from ICI initiation to DMARD initiation.”Results147 patients were included, mean (SD) age 60.3 (11.9) years, 66 (45%) females. Sixty percent had received PD1/PDL1 monotherapy, 30% received combination CTLA4/PD1. Eighty percent had stage IV cancer. ICI-A treatment was TNFi in 33 (22%), IL6Ri 42 (29%), MTX 72 (49%) (Table 1). A Kaplan-Meier curve showing time to cancer progression by DMARD is shown inFigure 1. In an unadjusted Cox model with MTX as the reference, time to cancer progression with a TNFi was HR 2.51 (95% CI 0.91-6.93, p=0.075) and for IL6Ri HR 2.36 (95% CI 0.91-6.12, p=0.078). After adjustment for the time dependent variable, time to cancer progression was significantly shorter for TNFi-treated patients compared to MTX, HR 3.27 (95% CI 1.21-8.84, p=0.019). The result for IL6Ri was HR 2.31 (95% CI 0.98-5.41, p=0.055). Time to arthritis control was significantly faster for TNFi compared to MTX, HR 1.91 (95% CI 1.06-3.45, p=0.032) in an adjusted Cox model. Results for IL6Ri were HR 1.66 (95% CI 0.93-2.97, p=0.089). Results for cancer progression and arthritis control were similar in the subset of patients with melanoma.ConclusionTreatment of ICI-A with biologic DMARDs is associated with more rapid arthritis control than with MTX but may be associated with a shorter time to cancer progression. A prospective randomized controlled trial is needed to verify these findings and to identify the optimal approach to managing patients with high grade ICI-A.Reference[1] Braaten TJ, et al Ann Rheum Dis. 2020 Mar;79(3):332-338.Table 1.Patient characteristicsTotalTNFiIL6RMTXp-valueN147 (100%)33 (22%)42 (29%)72 (49%)Age, mean (SD)60.3 (11.9)56.3 (14.0)61.5 (12.5)61.5 (10.1)0.085Sex (female)66 (45%)13 (39%)15 (36%)38 (53%)0.17Race (white)136 (92%)30 (91%)40 (95%)66 (92%)0.18Cancer type0.068Melanoma63 (43%)16 (48%)21 (50%)26 (36%)Non-small cell lung cancer15 (10%)1 (3%)0 (0%)14 (19%)Renal cell carcinoma24 (16%)5 (15%)12 (29%)7 (10%)Bladder cancer7 (5%)1 (3%)3 (7%)1 (4%)Other38 (25%)10 (30%)6 (14%)22 (31%)Cancer stage0.34III26 (18%)7 (21%)6 (14%)13 (18%)IV118 (80%)24 (73%)36 (86%)58 (81%)Checkpoint inhibitor0.91PD1/PDL1 monotherapy101 (69%)24 (73%)28 (67%)49 (68%)Combination (CTLA4/PD1)44 (30%)9 (27%)13 (31%)22 (31%)ICI discontinued for arthritis58 (40%)12 (36%)17 (40%)29 (40%)0.92ICI initiation to DMARD start (days), median (IQR)403 (258,638)411 (284, 622)300 (170, 435)486(258, 675)0.020Duration of DMARD treatment, median (IQR)278 (77, 546)92 (45, 149)309 (63, 483)420 (138, 765)<0.001Maximum glucocorticoid dose, mean (SD)40 (27)53 (27)42 (28)33 (23)0.002Figure 1.Kaplan-Meier curve showing time to cancer progression from time of immune checkpoint inhibitor initiationAcknowledgements:NIL.Disclosure of InterestsAnne Bass: None declared, Noha Abdel-Wahab Speakers bureau: ChemoCentryx, Consultant of: ChemoCentryx, Pankti Reid: None declared, Jeffrey Sparks Consultant of: Bristol Myers Squibb, AbbVie, Amgen, Boehringer Ingelheim, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, Grant/research support from: Bristol Myers Squibb, cassandra calabrese Speakers bureau: Sanofi, Consultant of: Astazenica, Deanna Jannat-Khah: None declared, Nilasha Ghosh: None declared, Divya Rajesh: None declared, Carlos Aude: None declared, Lydia Gedmintas: None declared, Lindsey MacFarlane: None declared, Senada Arabelovic: None declared, Adewunmi Falohun: None declared, Komal Mushtak: None declared, Farah Al Haj: None declared, Adi Diab: None declared, Ami Shah Grant/research support from: Eicos Sciences, Medpace LLC, Arena Pharmaceuticals, Kadmon Corporation, Clifton Bingham Consultant of: Bristol Myers Squibb,: Abbvie, Janssen, Lilly, Pfizer, Sanofi, Moderna, Grant/research support from: Bristol Myers Squibb, Karmela Kim Chan: None declared, Laura Cappelli Consultant of: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb.

BackgroundRheumatoid arthritis (RA) patients are at higher risk of developing cardiovascular (CV) diseases, both ischemic and non-ischemic, than the general population [1]. Inflammatory status and fibrotic changes at cardiac valves in these patients predispose them to a higher risk of valve diseases, which could be detected by echocardiography [2].ObjectivesTo determine the prevalence of valvular regurgitation, according to the time of disease evolution in RA patients.MethodsDescriptive, comparative, and cross-sectional study. We enrolled RA patients between 40 and 75 years old who fulfilled ACR/EULAR 2010 classification criteria and recruited in the Rheumatology service from tertiary care hospital. Patients were divided by time of disease evolution into quartiles. A transthoracic echocardiogram performed by a certified cardiologist blinded to clinical data. Normality was assesed by Kolmogorov-Smirnov test. Variables with normal and non-normal distribution were described by media and standard deviation, such as median and interquartile range (p25-p75), respectively. Differences between groups was analyzed by ANOVA, Kruskal-Wallis test or Chi-squared, accordingly.ResultsWe included 151 RA patients. Demographic characteristics are in Table 1. Overweight/obesity was found between 62-87% of patients, hypertension between 26-34%, and Type 2 Diabetes mellitus between 8-26%. The tricuspid valve was the most affected (73-84%). There was no differences in prevalence of valvular regurgitation.ConclusionRA patients have a high prevalence of valvular regurgitation, which could predispose them to develop heart failure, therefore it is important to consider echocardiography in the approach of this population, despite not showing an increase.References[1] Crowson CS, Liao KP, Davis JM, Solomon DH, Matteson EL, Knutson KL, et al. Rheumatoid arthritis and cardiovascular disease. Am Heart J. 2013 Oct;166(4):622-628.e1.[2] Maksimowicz-McKinnon K, Mandell BF. Understanding valvular heart disease in patients with systemic autoimmune diseases. Cleve Clin J Med. 2004 Nov 1;71(11):881–5Table 1.Demographic characteristics (n= 151)Variable1st Quartile (n= 38)2nd Quartile (n=38)3rd Quartile (n=38)4th Quartile (n=37)pDuration of disease, years. median (p25-p75)1.5 (1.0-2.0)5.0 (3.9-6.0)10.6 (9.4-12.6)20.5 (16.5-25.2)Women, (n)%37 (97)34 (89)36 (94)35 (94)NSAge, years. mean (±SD)54 (9.6)56 (8.5)55 (8.8)56 (8.0)NSComorbidities, n (%)Overweight/Obesity28 (73.7)33 (86.8)31 (81.6)23 (62.2)NSHypertension13 (34.2)13 (34.2)10 (26.3)12 (32.4)NST2DM6 (15.8)10 (26.3)8 (21.1)3 (8.1)NSValvular regurgitation, n (%)Aortic valve3 (7.9)7 (18.4)2 (5.3)8 (21.6)NSMitral valve26 (68.4)21 (55.3)17 (44.7)20 (54.1)NSPulmonary valve9 (23.7)7 (18.4)9 (23.7)8 (21.6)NSTricuspid valve28 (73.7)31 (81.6)31 (81.6)31 (83.8)NSAny of valves32 (84.2)33 (86.8)33 (86.8)31 (83.8)NSThis table shows demographic and clinical characteristics. Quartiles were divided according to rheumatoid arthritis duration, meanwhile, each variable was described individually. T2DM Type 2 Diabetes Mellitus.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Abstract Introduction The clinical manifestations of pituitary apoplexy (PA) are highly variable and are caused by a rapid increase in the size of intrasellar contents, leading to an increase in intrasellar pressure. Headache, visual disturbances, cranial nerve palsies, and pituitary insufficiency are the most frequent symptoms. Cerebral ischemia and hemorrhage are rare complications of PA. Here we present a case of a young male who presented with left basal ganglia hemorrhagic stroke and pituitary apoplexy. Case Presentation 39-year-old male presented to emergency department for acute onset of nausea, vomiting and right sided weakness for past 2-3 days. Soon after, patient became acutely confused. On examination, he was hypertensive, tachycardiac, tachypneic and obtunded. His pupils were 3 mm, equal, sluggish. He was moving left side but no movements on the right side of his body. In view of rapidly deteriorating mental status, he was intubated for airway protection. Computed tomography (CT) of the head was performed which showed acute left basal ganglia hemorrhage measuring 4.2 cm with vasogenic edema and midline shift of 4 mm. Also noted was markedly expanded sella with a cystic mass containing fluid level measuring up to 4.3 cm. Complete blood count, coagulation profile and liver function tests were unremarkable. His sodium levels were 140 mmol/L, potassium 2.9mmol/L, chloride 101mmol/L and bicarbonate 22 mmol/L. Endocrine workup revealed free T4 0.7 ng/dl, TSH 2.32 mIU/L, FSH 3.0 mIU/ml, LH 4.9 mIU/ml, estradiol 7 pg/ml, testosterone 59 ng/dl, random cortisol 8 ug/dl, ACTH 5.1 pg/ml, growth hormone &lt;0.05 ng/ml, IGF-2 249 ng/ml and prolactin 10,470 ng/ml. MRI brain confirmed hemorrhagic pituitary macroadenoma and left basal ganglia parenchymal hematoma with mass effect and midline shift. Patient was diagnosed with hemorrhagic pituitary macroadenoma causing PA. He was started on intravenous steroids, levothyroxine, cabergoline and hypertonic saline. External ventricular drain was placed for obstructive hydrocephalus followed by left frontal burr hole for hematoma evacuation. Pathology was negative for infection, inflammation, neoplasm and amyloid angiopathy. CT angiography was negative for intracranial aneurysm, arteriovenous malformation, dural arteriovenous fistula, or tumor blushes. He subsequently underwent tracheostomy and gastrostomy placement and transferred to rehabilitation facility. Patient continued to improve neurologically, was subsequently decannulated. Discussion PA is reported to occurs in 2-12% of pituitary adenoma.1 Corticotropic deficiency is common and can be life threatening if left untreated. Empiric steroids should be administered to all patients with signs of PA without waiting for diagnostic confirmation. Intraparenchymal hemorrhage is an extremely rare complication of PA and thought to be related to vasospasm of the cerebral arteries. Reference 1. Briet C, Salenave S, Bonneville JF, et. Al. Pituitary Apoplexy. Endocr Rev. 2015 Dec;36(6): 622-45. doi: 10.1210/er.2015-1042. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Abstract Background: Daratumumab (Dara) was recently FDA approved for the treatment of relapsed/refractory multiple myeloma (RRMM). We evaluated a real-world single-center experience of Dara salvage therapy for RRMM. Methods: Patients treated at the University of Florida with Dara for RRMM between January 2016 and February 2018 were included. Data was collected by chart review and analyzed for patient demographics, disease characteristics, treatment, and outcomes. Results: 25 patients (13 as monotherapy and 12 in combination) were included, with a median age of 63 (range, 42-86) years. Median time from MM diagnosis to Dara initiation was 51.3 (range, 8.4 -162.3) months. The median duration of Dara therapy was 72 days (range, 7 - 622). The median number of Dara doses was 7 (range, 2- 49). The best response to DARA was Very Good Partial Response (VGPR) in 1 (4%), Partial Response (PR) in 17 (68%), while 7 (28%) had Progressive Disease (PD). Overall Response Rate (ORR) to Dara was 72%. By the end of the study period, another 11 (44%) patients progressed while on DARA with a total of 18 (72%) patients having PD at the time of analysis. Estimated median progression free survival (PFS) after starting Dara was 155 days (95% CI: 21 - 289) and estimated median overall survival (OS) in the entire cohort was 11.7 months (95% CI: 4.2 - 19.2). Post DARA, 1 (4%) patient with VGPR underwent ASCT, while 9 (36%) went on to have other therapies which included HyperCVAD, Melphalan, and clinical trials, and 8 (32%) were treated with only best supportive care. Of 18 patients who had PD, 10 (40%) patients had a progressive extramedullary disease (EMD), of whom 6 (24%) had EMD prior to starting Dara, while another 4 (16%) patients developed new EMD while on Dara. PFS in the EMD cohort was 63 days (95% CI: 23 - 103), which was shorter than patients with no EMD (333 days; 95% CI: 42 - 624) (P= 0.08). Estimated median OS in patients with EMD was 5.4 months while in patients with no EMD was 16.1 months (p =0.16). Conclusions: DARA therapy does have good ORR (72%) in RRMM, however, there was an unusually high incidence of progressive or newly diagnosed EMD in RRMM patients treated with Dara/Dara-containing regimens, suggesting that Dara may not be effective in treating or preventing EMD. Moreover, we noticed patients who have EMD or develop new EMD tends to have worse outcomes. The underlying escape mechanism for EMD remains unknown and warrants further investigation. Table. Table. Disclosures No relevant conflicts of interest to declare.

Abstract Molecular classification of acute myeloid leukemia (AML) has identified several candidate genes that could potentially define prognosis and response to therapy. One such candidate, identified from microarray studies, is the Class I homeobox gene HOXA9. The HOX gene network encodes master regulators of developmental processes including hemopoiesis. To quantify the contribution of this network of genes in AML, we carried out specific RQ-PCR analysis on twenty-four de novo patient samples using a subset of genes (12 HOX and MEIS1) selected on the basis of their recently reported expression in AML. HOXA6 was ranked, as the most highly expressed gene (range 1 x 103 – 2 x 107 copies per 50 ng RNA), substantially higher than HOXA9 (see Table). Further analysis identified high expression of HOXA6 in both human myeloid cell lines and CD34+ enriched primary progenitors. Parallel studies with murine progenitors (c-Kit+, Lin−) and cell lines also showed a preponderance of Hoxa6 expression over other family members including Hoxa9 and Hoxb4. Several hemopoietic cell lines, namely Ba/F3, EML, FDCP-Mix A4 and 32Dcl3 were subsequently used to investigate Hoxa6 regulation following differentiation or growth factor stimuli. Hoxa6 expression decreased with cell differentiation and growth factor depletion/replenishment studies indicated a cell-cycle component for Hoxa6 regulation. Direct evaluation of cell-cycle status, using Hoechst 33342 staining and cell sorting, identified peak expression of Hoxa6 during S-phase. Gene deletion studies involving Hox tend to result in either a moderate or no phenotype, presumably due to intrinsic compensatory mechanisms. We therefore overexpressed HOXA6 in the Ba/F3 cell line to gain functional insights. Ba/F3-A6 cells were compared to mock-transfected and vector controls on the basis of proliferation, maturation, cell-cycle status, growth factor-dependence and apoptosis. The Ba/F3-A6 cells displayed a growth advantage over normal cells in the presence of IL-3 and maturation was not impaired. Cell-cycle analysis showed a reduction in the number of cells in both G2M and S-phase, associated with accumulation in the pre G1-phase, indicative of increased apoptosis. IL-3 depletion studies of Ba/F3-A6 cells indicated substantial factor-independent growth compared to controls, implying oncogenic potential for HOXA6. In support of this, a recent report (Mamo et al, Blood. 2006 Jul 15;108(2):622–9) indicated Hoxa6 as a potential collaborator in a Meis1-induced model of AML. Taken together these findings identify Hoxa6 as a novel candidate gene in AML with the capacity to alter growth and survival of hemopoietic cells. Gene Expression Ranking of HOX and MEIS1 in AML. GENE EXPRESSION RANGE MEAN RANK S.D. OVERALL RANK Expression values (copies per 50 ng RNA) compiled from primary AML patient samples (n=24) or * (n=12). S.D = standard deviation. HOXA6 1.2 x 103 – 1.7 x 107 2.2 1.6 1 HOXB3 9.3 x 101 – 8.4 x 106 3.2 2.5 2 HOXB2* 7.9 x 102 – 5.4 x 106 3.4 2.0 3 HOXA9 4.0 x 101 – 5.3 x 106 5.3 2.4 4 MEIS1 0.6 x 101 – 8.4 x 106 5.4 2.7 5 HOXA10* 2.4 x 102 – 1.7 x 105 5.5 3.2 6 HOXB4 1.5 x 102 – 7.8 x 105 5.5 3.2 7 HOXA7* 5.3 x 103 – 1.8 x 106 5.7 1.7 8 HOXB6 2.3 x 101 – 8.8 x 105 6.6 2.8 9 HOXA4 4.1 x 101 – 1.1 x 105 7.9 3.4 10 HOXA5* 3.4 x 101 – 4.3 x 104 9.3 2.8 11 HOXC6 1.0 x 101 – 3.2 x 103 9.7 2.3 12 HOXA11* 4.0 x 101 – 6.1 x 103 10.6 2.2 13

Abstract Background: Platelet transfusion practice in neonates is not evidence-based and there is a lack of data relating transfusion to clinical outcome. To inform the design of clinical trials, we conducted a prospective multicentre observational study of platelet transfusion in thombocytopenic neonates to describe: transfusion practice, including reason for transfusion; clinically-related outcomes, including minor and major bleeding and mortality. Methods: Neonates with platelets &lt;60x109/l were studied at 7 UK neonatal intensive care units Mar 05-Jun 06. With parental consent, daily data were collected on minor bleeding (blood staining of oral/nasogastric/endotracheal secretions and stool; microscopic haematuria; petechial rash; oozing from puncture sites - scored 0–7), and major bleeding (intraventricular (IVH), intra-abdominal, pulmonary or renal). Surviving neonates were studied for 7 days or until platelets were ≥60x109/l. Blood counts and all transfusions were directed by the attending neonatologist, with reason for transfusion and its effect on bleeding prospectively documented. Results: 145 of 167 (87%) eligible neonates were enrolled; 123 (85%) were &lt; 37 weeks gestational age (GA), 89 (61%) were male. The study documented 186 episodes of thrombocytopenia (1606 study days) and 309 platelet transfusions given to 91 (63%) neonates. GA, birth weight and age at thrombocytopenic episode were: 27 (24–32) weeks; 825 (675–1370) grams; 5 (2–16) days, respectively [all data median (IQR)]. 21/145 babies (14%) had major IVH (Grade 3/4) at study entry. Platelets (x 109/l) at study entry, and at platelet nadir, and duration of count &lt;60x109/l were: 44 (33–54); 31 (19–42); 2 (1–5) days respectively. In transfused neonates, platelets (x109/l) pre- and post-transfusion, and number of transfusions were: 27 (19–36); 84 (46–138); 2 (1–4) respectively. The principal indications for transfusion were:- platelet count below threshold of unit guideline: 265/309 (86%); deteriorating clinical condition: 17/309 (6%); and significant bleeding: 7/309 (2%). At least 1 episode of minor bleeding was recorded on 622/1606 (39%) of study days. Minor bleeding scores recorded for 12 hours pre- and post each transfusion were [median (IQR)]: 1 (0–2) and 0 (0–1) respectively. New or extension of IVH bleeding to Grade 3/4 occurred in 7 neonates and other major haemorrhage in 9 neonates (4 pulmonary, 3 GI). A total of 20/145 (14%) neonates died, 13 with major IVH bleeding (of which 10 had Grade 3/4 IVH at study entry); all received platelet transfusions [total 87; median 3 (2 to 7). Conclusion: This study confirms that most neonates with severe thrombocytopenia are preterm, most episodes develop after 72 hours of life (median 5 days) and are of short duration (median 2 days). Minor haemorrhage is common and may be reduced by platelet transfusion. Major haemorrhage is uncommon (11%), is associated with mortality (82%) and affected patients receive a large number of platelet transfusions. There is a clear distinction between the majority of thrombocytopenic neonates who receive one or two transfusions as prophylaxis with a good outcome, and the minority who suffer adverse outcomes despite transfusion. Many neonates are transfused with platelets at thresholds below those suggested in guidelines without apparent clinical detriment. These data will be invaluable for planning the randomised trials necessary for rationalising platelet transfusion in these vulnerable patients.

Lr19, a resistance gene originally transferred from Agropyron elongatum to wheat (Triticum aestivum L.), has remained effective worldwide against leaf rust (Puccinia triticina Eriks.) except in Mexico (1). This report records a new pathotype of P. triticina virulent on Lr19 from India. From 2003 to 2004, 622 wheat leaf rust samples from 14 states were subjected to pathotype analysis. Samples were established on susceptible wheat cv. Agra Local, and pathotypes were identified on three sets of differentials following binomial nomenclature (3). Virulence on Lr19 (Agatha T4 line) was observed in approximately 2% of samples. These samples were picked from Lr19 (NIL), cvs. Ajit, Lal Bahadur, Local Red, Lok1, and Nirbhay from Karnataka and Gujarat states. All Lr19 virulent isolates were identical. The reference culture is being maintained on susceptible wheat cv. Agra Local and has also been put under long-term storage in a national repository at Flowerdale. From 2004 to 2005, this pathotype was detected in 6.3% of samples from central and peninsular India. There is no wheat variety with Lr19 under cultivation in India, however, it is being used in wheat breeding programs targeted at building resistance against leaf and stem rusts. NIL's Lr19/Sr25 (LC25) and Lr19/Sr25 (82.2711) were also susceptible to this isolate, whereas Lr19/Sr25 (spring accession) was resistant. The new isolate, designated as 253R31 (77-8), appears to be close to the pathotype 109R31 (4) with additional virulence for Lr19. The avirulence/virulence formula of pathotype 253R31 is Lr9, 23, 24, 25, 26, 27+31, 28, 29, 32, 36, 39, 41, 42, 43, 45/Lr1, 2a, 2b, 2c, 3, 10, 11, 12, 13, 14a, 14b, 14ab, 15, 16, 17, 18, 20, 21, 22a, 22b, 30, 33, 34, 35, 37, 38, 40, 44, 48, and 49. To our knowledge, this is the first report of virulence on Lr19 from two states of India. On international rust differentials, it is designated as TGTTQ (2), and is different from CBJ/QQ (1), the other isolate reported virulent on Lr19 from Mexico. The Mexican isolate is avirulent on Lr1, 2a, 2b, 2c, 3ka, 16, 21, and 30 to which the Indian isolate is virulent. However, both isolates are avirulent on Lr9, 24, 26, 36, and Lr42. Among the wheat cultivars identified during the last 6 years, HD2824, HD2833, HD2864, HI1500, HS375, HUW 510, HW 2044, HW 5001, Lok 45, MACS 6145, MP4010, NW 2036, PBW 443, PBW 498, PBW 502, PBW 524, Raj 4037, UP 2565, VL 804, VL 829, and VL 832 and lines of wheat possessing Lr9, Lr23, Lr24, and Lr26 showed resistance to this pathotype. PBW 343, which occupies more than 5 million ha in India, is also resistant to this pathotype along with PBW 373. An integrated strategy using a combination of diverse resistance genes, deployment of cultivars by using pathotype distribution data, slow rusting, and adult plant resistance is in place to curtail selection of new pathotypes and prevent rust epiphytotics. References: (1) J. Huerta-Espino and R. P. Singh. Plant Dis. 78:640,1994. (2) D. V. Mc Vey et al. Plant Dis. 88:271, 2004. (3) S. Nagarajan et al. Curr. Sci. 52:413, 1983. (4) S. K. Nayar et al. Curr. Sci. 44:742, 1975.

1515 Background: Precision oncology clinical trials often struggle to accrue due to the difficulty of identifying patients whose tumors meet complex tumor genomic matching criteria at propitious moments when they need new treatment. We conducted a pilot of deploying an artificial-intelligence (AI) model to find such patients and facilitate clinical trial matching workflows at a large academic cancer center. Methods: An AI model was trained to predict initiation of new palliative intent systemic therapy within 30 days of a given imaging report (CT, MRI, bone scan, or PET-CT), using the text of that report and prior reports for each patient. The model architecture and performance were previously published (Kehl et al, JCO-CCI 2021 5:622-630). From April to December 2022, the model was applied prospectively each time patients with solid tumors that had undergone next-generation sequencing underwent an imaging study. Model output was linked to the MatchMiner tool, which matches patients to clinical trials using tumor genomics (Klein et al, NPJ Precis Oncol 2022 6(1):69). The output consisted of lists of patients with tumor genomic matches to specific trials, sorted in order of the likelihood of changing treatment within 30 days. This information was provided to an oncology nurse navigator (ONN) charged with coordinating recruitment to early-phase targeted and immunotherapy trials. For 9 high priority trials, the ONN reviewed records for each patient flagged as likely to change treatment and contacted treating oncologists when patients appeared potentially eligible. The proportions of records leading to oncologist contact, and reasons for oncologist non-contact, were analyzed. Results: 2093 patients had tumors with genomic matches to the 9 trials of interest; 492 patients (24%) were deemed “likely” to change treatment by our AI model at least once during the pilot. The treating oncologist for 66 patients (3% of the total; 13% of 492 “likely” patients) was contacted after ONN review for potential eligibility. Reasons for not contacting treating oncologists included cases where they had already decided to continue current treatment (21%); the trial had no slots at the time (14%); or the patient was ineligible on nurse navigator review (12%); or had already been evaluated for the trial (7%), started new treatment (18%), or enrolled in hospice (5%). Of the 66 patients whose oncologists were contacted, 9 patients had a consult regarding early phase trials; 4 consented to participate; and all 4 received protocol treatment. Conclusions: Identifying potential precision clinical trial candidates by using AI to find patients likely to change treatment is feasible, but many other factors also impact potential trial enrollment. A prospective study is planned to evaluate the impact of sharing clinical trial information directly with treating oncologists when our model predicts a high probability of treatment change.

Abstract Abstract 2575 Introduction: Few research studies have investigated the nutritional status of children with acute lymphoblastic leukemia (ALL). Preliminary studies have found that malnutrition is associated with lower 5-year survival, increased relapse rates and more frequent reductions in chemotherapy dose. The extent of malnutrition has not been well characterized. Results of a prospective multi-institution study investigating dietary micronutrient intake over the course of treatmentfor ALL are reported. Methods: Assessment of dietary intake was collected for participants enrolled on the DFCI ALL Consortium Protocol 05-001 from 2005–2011. Institutional review board approval was obtained by each of the 9 participating centers. Dietary intake was assessed at three timepoints in therapy: diagnosis (T1), Day 32 (end) of induction therapy (T2), and 15 months post-diagnosis (T3) (during maintenance therapy) with the Harvard Service Food Frequency Questionnaire for children ages 1–5 years and the Youth and Adolescent Harvard Food Frequency Questionnaire for children ages 5–18 years. Questionnaires were self-administered and were completed by parents or primary care takers when children were below age 6 years. Dietary intake was examined by comparing energy and nutrient specific consumption above and below recommended intake using age specific values for Dietary Reference Intake (DRI). Results: Among 794 patients with ALL registered on the 05-001 Protocol, dietary intake questionnaires were availablefor 622, 564, and 423 patients at T1, T2, and T3, respectively. Median age of participants at T1 was 5 yrs (range 1–17.9 yrs) and 272 (44%) were female, 350 (56%) were male. Initial leukemia risk classification included 363 standard risk (58%) and 259 (42%) high risk. At diagnosis, the majority of children reported consuming more than the age and gender specific DRI. For 388 children (62%), reported caloric intake was >25% the DRI, while another 81 (13%) reported caloric consumption >10% the DRI. In contrast, only 116 (19%) did not meet the DRI. At T2, similar findings were observed, despite administration of a 32 day prednisone course which would have been expected to result in a higher proportion of children exceeding recommended caloric intake. Of those responding at T2, 128 (23%) were not meeting the DRI, while 65 (12%) and 335 (59%) exceeded the recommended caloric intake by >10% and >25% respectively. During maintenance therapy (T3), total caloric intake declined with a greater proportion of participating children reporting intake below the DRI (30%) and a smaller proportion reporting intake >25%DRI (49%), while the proportion consuming recommended intake or >10% DRI remained stable. Distribution of children reporting nutrient consumption below, at, or above age and gender specific DRI values for key micronutrients is summarized in Figure 1. The majority of patients did not meet the DRI for vitamin E and vitamin D at all 3 time points, while nearly half the participants exceeded the DRI for zinc and folate. Conclusions: The majority of children with newly diagnosed ALL have evidence of overnutrition or malnutrition, as demonstrated by overconsumption of calories, or deficiency or overconsumption of key micronutrients, which may be associated with increased risk for treatment related toxicities. Increased consumption of folate during the maintenance phase in which methotrexate is a major component of treatment also needs further study. Additional analyses are underway to explore these relationships. Disclosures: No relevant conflicts of interest to declare.

Cellulose is the main raw material for the production of paper. Companies that produce it present in their production line the cutting of the cellulose sheet. This failure is sporadic and has a high economic impact since it paralyzes the production line for several hours, incurring unproductive hours and a large deployment of human and financial resources. In this research, the use of Data Mining is proposed to define a machine learning algorithm that allows predicting the cutting of the cellulose sheet in a production line of a cellulose plant in Chile. The results show that by applying this technique it is possible to predict the cutting of the cellulose sheet well in advance to take corrective actions to avoid cutting and thus minimize the economic impact associated with the failure. Keywords: Data Mining, machine learning, cellulose, productivity. References [1]B. Ranaganth y G. Viswanath, «Application of artificial neural network for optimizing cutting variables in laser cutting of 304 grade stainless steel,» International Journal of Applied Engineering and Technology, vol. 1, nº 1, pp. 106-112, 2011. [2]M. Durica, J. Frnda y L. Svabova, «Decision tree based model of business failure prediction for Polish companies,» Oeconomia Copernicana, vol. 10, nº 3, pp. 453-469, 2019. [3]G. Köksal, İ. Batmaz y M. C. Testik, «A review of data mining applications for quality improvement in manufacturing industry,» Expert systems with Applications, vol. 38, nº 10, pp. 13448-13467, 2011. [4]H. Poblete y R. Vargas, «Relacion entre densidad y propiedades de tableros HDF producidos por un proceso seco,» Maderas. Ciencia y tecnología, vol. 8, nº 3, pp. 169-182, 2006. [5]B. Kovalerchuk y E. Vityaev, «Data mining for financial applications,» Data Mining and Knowledge Discovery Handbook, pp. 1203-1224, 2005. [6]U. Fayyad, G. Piatetsky-Shapiro, P. Smyth y R. Uthurusamy, «Advances in knowledge discovery and data mining,» American Association for Artificial Intelligence, 1996. [7]A. K. Pandey y A. K. Dubey, «Neuro fuzzy modeling of laser beam cutting process,» Applied Mechanics and Materials, vol. 110, pp. 4109-4117, 2012. [8]M. Németh y G. Michaľčonok, «Preparation and cluster analysis of data from the industrial production process for failure prediction,» Research Papers Faculty of Materials Science and Technology Slovak University of Technology, vol. 24, nº 39, pp. 111-116, 2016. [9]S. Ballı, «A data mining approach to the diagnosis of failure modes for two serial fastened sandwich composite plates,» Journal of Composite Materials, vol. 51, nº 20, pp. 2853-2862, 2017. [10]S. Dindarloo y E. Siami-Irdemoosa, «Data mining in mining engineering: results of classification and clustering of shovels failures data,» International Journal of Mining, Reclamation and Environment, vol. 31, nº 2, pp. 105-118, 2017. [11]E. e Oliveira, V. Miguéis, L. Guimarães y J. L. Borges, «Power Transformer Failure Prediction: Classification in Imbalanced Time Series,» U. Porto Journal of Engineering, vol. 3, nº 2, pp. 34-48, 2017. [12]A. Taghizadeh y N. Demirel, «Application of Machine Learning for Dragline Failure Prediction,» E3S Web of Conferences, vol. 15, p. 03002, 2017. [13]W. Chang, Z. Xu, M. You, S. Zhou, Y. Xiao y Y. Cheng, «A Bayesian Failure Prediction Network Based on Text Sequence Mining and Clustering,» Entropy, vol. 20, nº 12, p. 923, 2018. [14]K. Halteh, K. Kumar y A. Gepp, «Financial distress prediction of Islamic banks using tree-based stochastic techniques,» Managerial Finance, vol. 44, nº 6, pp. 759-773, 2018. [15]C.-H. Liu, C.-J. Lin, Y.-H. Hu y Z.-H. You, «Predicting the failure of dental implants using supervised learning techniques,» Applied Sciences, vol. 8, nº 5, p. 698, 2018. [16]B. Mohammed, I. Awan, H. Ugail y M. Younas, «Failure prediction using machine learning in a virtualised HPC system and application,» Cluster Computing, vol. 22, nº 2, pp. 471-485, 2019. [17]O. Sukhbaatar, T. Usagawa y L. Choimaa, «An artificial neural network based early prediction of failure-prone students in blended learning course,» International Journal of Emerging Technologies in Learning (iJET)}, vol. 14, nº 19, pp. 77-92, 2019. [18]Z. Wang, W. Zhao y X. Hu, «Analysis of prediction model of failure depth of mine floor based on fuzzy neural network,» Geotechnical and Geological Engineering, vol. 37, nº 1, pp. 71-76, 2019. [19]V. S. Gujre y R. Anand, «Machine learning algorithms for failure prediction and yield improvement during electric resistance welded tube manufacturing,» Journal of Experimental \& Theoretical Artificial Intelligence, vol. 32, nº 4, pp. 601-622, 2020. [20]P. du Jardin, «Forecasting corporate failure using ensemble of self-organizing neural networks,» European Journal of Operational Research, vol. 288, nº 3, pp. 869-885, 2021. [21]R. Brachman y T. Anand, «The process of knowledge discovery in databases,» Advances in knowledge discovery and data mining, pp. 37-57, 1996. [22]W. Frawley, G. Piatetsky-Shapiro y C. Matheus, «Knowledge discovery in databases: An overview,» AI magazine, vol. 13, nº 3, p. 57, 1992. [23]F. H. Troncoso Espinosa y J. V. Ruiz Tapia, «Predicción de fuga de clientes en una empresa de distribución de gas natural mediante el uso de minería de datos,» Universidad Ciencia y Tecnología, vol. 24, nº 106, pp. 79-87, 2020. [24]F. H. Troncoso, «Prediction of Recidivism in Thefts and Burglaries Using Machine Learning,» Indian Journal of Science and Technology, vol. 13, nº 6, pp. 696-711, March 2020. [25]M. Kantardzic, Data mining: concepts, models, methods, and algorithms, John Wiley & Sons, 2011. [26]F. H. Troncoso Espinosa, P. G. Fuentes Figueroa y I. R. Belmar Arriagada, «Predicción de fraudes en el consumo de agua potable mediante el uso de Minería de Datos,» Universidad Ciencia y Tecnología, vol. 24, nº 104, pp. 58-66, 2020. [27]C. Romero y S. Ventura, «Data mining in education,» Wiley Interdisciplinary Reviews: Data Mining and Knowledge Discovery, vol. 3, nº 1, pp. 12-27, 2013. [28]D. Larose y C. Larose, Discovering knowledge in data: an introduction to data mining, John Wiley & Sons, 2014.

Background Prospective cohort studies of incident HIV and associated factors among gay, bisexual, and other men who have sex with men (GBMSM) in the United Kingdom are lacking. We report time trends in and factors associated with HIV incidence between 2013 and 2019 among a cohort of GBMSM: the AURAH2 prospective study. Methods and findings Participants were recruited through 1 of 3 sexual health clinics in London and Brighton (July 2013 to April 2016) and self-completed a baseline paper questionnaire and subsequent 4-monthly and annual online questionnaires (March 2015 to March 2018), including information on sociodemographics, lifestyle, health and well-being, HIV status, sexual/HIV-related behaviours, and preexposure prophylaxis and postexposure prophylaxis (PrEP/PEP). Incident HIV was ascertained by linkage with national HIV surveillance data from Public Health England (PHE). We investigated the associations of HIV incidence with (1) baseline factors using mixed-effects Weibull proportional hazard models, unadjusted and adjusted for age, country of birth and ethnicity, sexuality, and education level; and (2) time-updated factors, using mixed-effects Poisson regression models. In total, 1,162 men (mean age 34 years, 82% white, 94% gay, 74% university-educated) were enrolled in the study. Thirty-three HIV seroconversions occurred over 4,618.9 person-years (PY) of follow-up: an overall HIV incidence rate (IR) of 0.71 (95% confidence interval (CI) 0.51 to 1.00) per 100 PY. Incidence declined from 1.47 (95% CI 0.48 to 4.57) per 100 PY in 2013/2014 to 0.25 (95% CI 0.08 to 0.78) per 100 PY in 2018/2019; average annual decline was 0.85-fold (p < 0.001). Baseline factors associated with HIV acquisition included the following: injection drug use (6/38 men who reported injection drug-acquired HIV; unadjusted conditional hazard ratio (HR) 27.96, 95% CI 6.99 to 111.85, p < 0.001), noninjection chemsex-related drug use (13/321; HR 6.45, 95% CI 1.84 to 22.64, p < 0.001), condomless anal sex (CLS) (26/741; HR 3.75, 95% CI 1.31 to 10·74, p = 0.014); higher number of CLS partners (HRs >10 partners [7/57]; 5 to 10 partners [5/60]; and 2 to 4 partners [11/293]: 14.04, 95% CI 4.11 to 47.98; 9.60, 95% CI 2.58 to 35.76; and 4.05, 95% CI 1.29 to 12.72, respectively, p < 0.001); CLS with HIV–positive partners (14/147; HR 6.45, 95% CI 3.15 to 13.22, p < 0.001), versatile CLS role (21/362; HR 6.35, 95% CI 2.18 to 18.51, p < 0.001), group sex (64/500; HR 8.81, 95% CI 3.07 to 25.24, p < 0.001), sex for drugs/money (4/55, HR 3.27, 95% CI 1.14 to 9.38, p = 0.027) (all in previous 3 months); previous 12-month report of a bacterial sexually transmitted infection (STI) diagnoses (21/440; HR 3.95, 95% CI 1.81 to 8.63, p < 0.001), and more than 10 new sexual partners (21/471, HRs 11 to 49, 50 to 99, and >100 new partners: 3.17, 95% CI 1.39 to 7.26; 4.40, 95% CI 1.35 to 14.29; and 4.84, 95% CI 1.05 to 22.4, respectively, p < 0.001). Results were broadly consistent for time-updated analysis (n = 622 men). The study’s main limitation is that men may not be representative of the broader GBMSM population in England. Conclusions We observed a substantial decline in HIV incidence from 2013 to 2019 among GBMSM attending sexual health clinics. Injection drug use, chemsex use, and measures of high-risk sexual behaviour were strongly associated with incident HIV. Progress towards zero new infections could be achieved if combination HIV prevention including Test and Treat strategies and routine commissioning of a PrEP programme continues across the UK and reaches all at-risk populations.

Maddox Dairy, located in Riverdale, CA, USA, is a Holstein herd that milks 3500 cows with a 305-day mature-equivalent milk production of 12 800 kg, and they have been producing high genetic animals by embryo transfer (ET) since the early 1980s. Invivo-derived embryos from Holstein donors were transferred fresh (grade 1 or 2) or frozen (grade 1), at morula (4), early blastocyst (5), or blastocyst (6) stage, to virgin heifers (VH, natural oestrus, 13-15 months old) or lactating cows (LC, Presynch-Ovsynch, 86 days in milk, first or second lactation) 6 to 9 days after oestrus. Pregnancy diagnosis was done by transrectal ultrasonography at 32-46 days in VH and by the IDEXX PAG test at 30 days in LC. June, July, August, September, and October were called critical months (first service AI conception rate drops below 44%) and compared with the other months. The data from 32 503 ETs between January 2008 and December 2018 are summarised on Table 1. Pregnancy rates (PR) are lower for LC recipients than for VH. Embryo transfers performed 7 or 8 days after oestrus had higher PR in both types of recipients and embryos, but Day 6 and 9 oestrus are also used with fair results. The season does not seem to affect PR. There is not enough difference in the combination of stage and days from oestrus for invivo-derived embryos. These numbers do not belong to a planned experiment. Several management changes during the years were made, which make it very difficult to apply statistical methods to analyse the data correctly. They are used as a tool to make decisions in an attempt to improve future results. Table 1.Pregnancy rate (PR) of virgin heifers (top) and lactating cows (bottom)-fresh (SH) and frozen (OZ) invivo-derived embryo transfer1 Heat-months SH-ST4 SH-ST5 SH-ST6 SH-All OZ-ST4 OZ-ST5 OZ-ST6 OZ-All PR% n PR% n PR% n PR% n PR% n PR% n PR% n PR% n Heifers 6 d-CM 62 934 66 243 68 69 63 1246 56 473 58 219 62 42 57 734 6 d-OM 62 1623 67 489 69 211 64 2323 56 600 55 296 48 137 55 1033 6 d-T 62 2557 67 732 69 280 63 3569 56 1073 57 515 51 179 56 1767 7 d-CM 64 1506 68 495 67 221 65 2222 60 822 62 340 63 156 61 1318 7 d-OM 66 2723 68 1021 69 510 67 4254 57 1120 59 581 57 231 58 1932 7 d-T 66 4229 68 1516 69 731 67 6476 58 1942 60 921 60 387 59 3250 8 d-CM 65 1348 64 518 67 322 65 2188 59 595 64 258 63 108 61 961 8 d-OM 66 2166 68 886 70 510 67 3562 61 770 60 364 51 130 60 1264 8 d-T 66 3514 67 1404 69 832 66 5750 60 1365 62 622 56 238 60 2225 9 d-CM 60 109 56 43 70 20 60 172 60 5 33 6 50 4 47 15 9 d-OM 58 129 63 57 60 40 60 226 63 16 50 18 75 4 58 38 9 d-T 59 238 60 100 63 60 60 398 62 21 46 24 63 8 55 53 All-CM 64 3897 66 1299 67 632 65 5828 58 1895 61 823 63 310 60 3028 All-OM 65 6641 67 2453 69 1271 66 10 365 58 2506 58 1259 53 502 58 4267 All-T 65 10 538 67 3752 69 1903 66 16 193 58 4401 60 2082 57 812 59 7295 Lactating cows 6 d-CM 54 265 48 86 50 12 53 363 38 141 31 77 50 10 36 228 6 d-OM 49 463 52 203 45 56 50 723 46 101 48 54 59 27 48 182 6 d-T 51 728 51 289 46 68 51 1086 41 242 38 131 57 37 42 410 7 d-CM 54 755 59 274 56 103 55 1137 43 928 48 450 43 192 45 1570 7 d-OM 55 914 66 367 54 109 58 1393 46 1052 45 564 47 353 46 1969 7 d-T 55 1669 63 641 55 212 57 2530 45 1980 46 1014 46 545 45 3539 8 d-CM 63 252 68 82 76 33 65 368 48 219 56 80 42 33 50 332 8 d-OM 61 257 64 161 53 47 61 466 50 191 53 77 56 16 51 284 8 d-T 62 509 65 243 63 80 63 834 49 410 55 157 47 49 50 616 All-CM 56 1272 58 442 60 148 57 1868 44 1288 47 607 43 235 45 2130 All-OM 55 1634 62 731 51 212 56 2582 47 1344 46 695 48 396 47 2435 All-T 55 2906 60 1173 55 360 57 4450 45 2632 47 1302 46 631 46 4565 1ST=stage; CM=critical months (June, July, August, September, and October); OM=other months.

Abstract Abstract 622 Background: Lenalidomide is an oral IMiD® compound with a dual mechanism of action, namely tumoricidal and immunomodulatory activity, and has proven efficacy in patients with MM. The current study (MM-015) is a prospective, randomized phase 3 trial designed to evaluate the efficacy and safety of continuous lenalidomide treatment (MPR-R: melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance) vs fixed-duration regimens of melphalan and prednisone (MP) or melphalan, prednisone, and lenalidomide (MPR) in transplant-ineligible patients with NDMM. Methods: 459 patients aged ≥ 65 years with NDMM, stratified by age and International Staging System (ISS) stage were randomized to receive MPR-R, MPR, or MP. During double-blind treatment, patients received melphalan 0.18 mg/kg (D1-4), prednisone 2 mg/kg (D1-4), with or without lenalidomide 10 mg/day (D1-21) for nine 28-day cycles. Following 9 cycles of MPR, patients received maintenance lenalidomide (10 mg/day; D1-21) or placebo until progression; MP patients received placebo until progression. Patients with progressive disease (PD) could enroll in the open-label extension phase (OLEP) and receive lenalidomide at 25 mg/day (D1-21) with or without dexamethasone at 40 mg/day (D1-4, 9–12, and 17–20). The primary comparison for this trial was MPR-R vs MP. Updated data from a pre-planned interim analysis at 70% of events (median follow-up of 21 months) are presented. Results: MPR-R compared with MP resulted in a higher overall response rate (ORR; 77% vs 50%, P <.001) as well as higher rates of complete response (16% vs 4%, P < .001) and very good partial response (VGPR) or better (32% vs 12%, P < .001). Responses were more rapid in patients receiving MPR-R compared with MP (median 2 vs 3 months, P < .001), and improved over time. Overall, MPR-R reduced the risk of disease progression by 58% compared with MP (hazard ratio [HR] = 0.423, P < .001) with a higher 2-year progression-free survival (PFS) rate (55% vs 16%). PFS was extended in patients receiving continuous lenalidomide therapy vs fixed-duration MP regardless of gender, ISS stage (stage I/II vs III), kidney function (creatinine clearance ≥ 60 vs < 60 mL/min), or baseline β2-microglobulin (≤ 5.5 vs > 5.5 mg/L). A landmark analysis comparing MPR-R and MPR initiated at the beginning of cycle 10 demonstrated that maintenance lenalidomide resulted in a 69% reduced risk of progression compared with placebo (HR = 0.314, P < .001). In addition, regardless of induction response (≥ VGPR or PR), patients who received maintenance lenalidomide had longer PFS compared with placebo. Importantly, patients relapsing during MPR-R had similar second-line treatment duration (median 55 weeks) compared with those relapsing while on placebo following MPR or MP (median 68 and 54 weeks, respectively). Additionally, PD rates during the OLEP were similar across all treatments (13% for each). Thus, outcomes of patients who relapse following continuous lenalidomide are similar to those who relapse following fixed-duration regimens, suggesting maintenance lenalidomide is not associated with more aggressive relapse. Follow-up remains too short to identify significant overall survival differences between the 3 groups. MPR-R had a manageable safety profile with minimal cumulative toxicities. Discontinuation rates due to adverse events (AEs) for patients treated with MPR-R and MP were 20% and 8%, respectively. Grade 3/4 neutropenia, thrombocytopenia, and anemia occurred in 71%, 38%, and 24% of patients receiving MPR-R and 30%, 14%, and 17% of those receiving MP; no grade 3/4 peripheral neuropathy was observed. Importantly, maintenance lenalidomide was as well tolerated as placebo, with few grade 3/4 AEs. During maintenance, low rates of thrombocytopenia (3% vs 2%, respectively), neutropenia (2% vs 0%), deep vein thrombosis (1% vs 0%), and fatigue (1% vs 0%) were observed. Conclusions: MPR-R achieved a higher ORR, as well as better quality and more rapid responses vs MP. Furthermore, MPR-R compared with fixed-duration regimens of MP and MPR resulted in an unprecedented reduction in the risk of progression with a manageable safety profile, and similar rates of PD in subsequent OLEP treatment. These data suggest that continuous lenalidomide therapy with MPR-R is superior to regimens of limited duration by providing sustained disease control in transplant-ineligible patients with NDMM. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide is not approved for first line use in multiple myeloma. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho-Biotech: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants. Hajek:Celgene: Honoraria; Janssen-Cilag: Honoraria. Kropff:OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Petrucci:Celgene: Honoraria; Janssen-Cilag: Honoraria. Yu:Celgene: Employment. Herbein:Celgene: Employment. Mei:Celgene: Employment. Jacques:Celgene: Employment. Dimopoulos:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Parents play an important role in the development of their children. This research reflects the role of parents in developing children. Through four stages of identification, screening, eligibility, and acceptable results, this method uses a systematic literature review using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) method. The findings from the fourteen articles examined show that parenting skills play an important role in a child's growth and development from birth to death. The determining factor in the development of physical, motoric, moral, language, social-emotional, and life skills aspects is the role of both parents as important teachers for children from birth to adulthood. Parents can also use a variety of parenting strategies and skills, many of which they have learned throughout their lives and passed on to their children, to help their children grow. Keywords: Role of Parents, Child Development, first education for children References: Albanese, A. M., Russo, G. R., & Geller, P. A. (2019). The role of parental self‐efficacy in parent and child well‐being. Child Care Health Dev, 45(3), 333–363. https://doi.org/10.1111/cch.12661. Almås, I., Cappelen, A. W., Sørensen, E. Ø., Tungodden, B., Alm, I., & Tungodden, B. (2010). Fairness and the Development of Inequality Acceptance Supporting materials for “ Fairness and the development of inequality acceptance .” Science, 328(5982), 1176–1178. https://doi.org/10.1126/science.1187300. Ahmadi, Abu. 2004. Psikologi Belajar. Jakarta : Rineka Cipta. Ahmetoglu, E., Acar, I. H., & Ozturk, M. A. (2022). Parental involvement and children’s peer interactions. Current Psychology, 41(7), 4447–4456. https://doi.org/10.1007/s12144-020-00965-0. Andhika, M. R. (2021). Peran Orang Tua Sebagai Sumber Pendidikan Karakter Bagi Anak Usia Dini. At-Ta’Dib: Jurnal Ilmiah Prodi Pendidikan Agama Islam, 13(1), 73. https://doi.org/10.47498/tadib.v13i01.466. Arthur, A. E., Bigler, R. S., Liben, L. S., Gelman, S. A., & Ruble, D. N. (2008). Gender stereotyping and prejudice in young children. In S. R. Levy & M. Killen (Eds.), Intergroup attitudes and relations in childhood through adulthood (pp. 66–86). New York, NY: Oxford University Press. Aydin, G., Margerison, C., Worsley, A., & Booth, A. (2021). Parents’ and teachers’ views of the promotion of healthy eating in Australian primary schools. BMC Public Health, 21(1), 1–12. https://doi.org/10.1186/s12889-021-11813-6. Baumard, N., Mascaro, O., & Chevallier, C. (2012). Preschoolers Are Able to Take Merit into Account When Distributing Goods. 48(2), 492–498. https://doi.org/10.1037/a0026598. Benozio, A., & Diesendruck, G. (2015). Parochialism in preschool boys ’ resource allocation. Evolution and Human Behavior, 36(4), 256–264. https://doi.org/10.1016/j.evolhumbehav.2014.12.002. Berthelot, N., Lemieux, R., Garon-Bissonnette, J., Lacharité, C., & Muzik, M. (2019). The protective role of mentalizing: Reflective functioning as a mediator between child maltreatment, psychopathology and parental attitude in expecting parents. Child Abuse and Neglect, 95(April). https://doi.org/10.1016/j.chiabu.2019.104065. Bigler, R. S., & Liben, L. S. (2006). A Developmental Intergroup Theory Of Social Stereotypes And Prejudice. Advances in Child Development and Behavior, 16, 162–166. https://doi.org/https://doi.org/10. 1111/j.1467-8721.2007.00496.x. Bigler, R. S., & Liben, L. S. (2007). Developmental Intergroup Theory: Explaining and reducing children’s social stereotyping and prejudice. Association for Psychological Science, 16(3), 162–166. https://doi.org/https://doi.org/10. 1111/j.1467-8721.2007.00496.x. Blair, C., & Diamond, A. (2008). Biological processes in prevention and intervention: The promotion of self-regulation as a means of preventing school failure. Development and Psychopathology, 20(3), 899–911. https://doi.org/10.1017/S0954579408000436. Chacko, A., Jensen, S. A., Lowry, L. S., Cornwell, M., Chimklis, A., Chan, E., Lee, D., & Pulgarin, B. (2016). Engagement in Behavioral Parent Training: Review of the Literature and Implications for Practice. Clinical Child and Family Psychology Review, 19(3), 204–215. https://doi.org/10.1007/s10567-016-0205-2 Cheal, D. J. (1988). In Intergenerational Transfers. Int’l. J. Aging And Human Development, 26(4), 261–273. https://doi.org/10.2190/V2E8-UEAT-5MJ7-UQ6F. Chernyak, N., & Kushnir, T. (2013). Giving Preschoolers Choice Increases Sharing Behavior. Psychological Science, 24(10), 1971–1979. https://doi.org/10.1177/0956797613482335. Coleman, M., Ganong, L. H., Hans, J. D., Sharp, E. A., & Rothrauff, T. C. (2005). Filial Obligations in Post-Divorce Stepfamilies Filial Obligations in Post-Divorce Stepfamilies. Journal of Divorce & Remarriage, 43(3/4), 37–41. https://doi.org/10.1300/J087v43n03. Cvencek, D., & Meltzoff, A. N. (2015). Developing Implicit Social Cognition In Early Childhood : Methods, phenomena, prospects. The Routledge International Handbook of Young Children’s Thinking and Understanding, 43–53. https://www.researchgate.net/publication/343658204_4_Developing_implicit_social_cognition_in_early_childhood_Methods_phenomena_prospects. Davis-Kean, P. E., Tighe, L. A., & Waters, N. E. (2021). The Role of Parent Educational Attainment in Parenting and Children’s Development. Current Directions in Psychological Science, 30(2), 186–192. https://doi.org/10.1177/0963721421993116. Damon, W. (1977). The social world of the child. San Francisco, CA: Jossey-Bass. Dunfield, K. A., Kuhlmeier, V. A., & Murphy, L. (2013). Children ’ s Use of Communicative Intent in the Selection of Cooperative Partners. PLoS ONE, 8(4), 1–6. https://doi.org/10.1371/journal.pone.0061804. Eagly, A. H., & Wood, W. (2017). Social Role Theory (Issue January 2012). https://doi.org/10.4135/9781446249222.n49. Fadillah, M. (2012). Desain Pembelajaran PAUD Tinjauan Teoritik & Praktik. Ar-Ruzz Media. Fan, R., Ruoyu, L., Chang, G., Yongling, H., Haiyan, H., Chunyan, P., Xinzhu, W., & Yuhui, W. (2022). Association of mothers’ adverse childhood experiences and parenting styles with emotional behavior problems in preschool children. Sch. Health China, 43(8), 1134–1138. https://doi.org/10.16835/j.cnki.1000-9817.2022.08.004. Fardiansyah, H. (2022). Manajemen Pendidikan (Tinjaun Pada Pendidikan Formal). Bandung: Widina Media Utama. Feng, L., Zhang, L., & Zhong, H. (2021). Perceived parenting styles and mental health: The multiple mediation effect of perfectionism and altruistic behavior. Psychology Research and Behavior Management, 14, 1157–1170. https://doi.org/10.2147/PRBM.S318446. Fikriyah, S., Mayasari, A., Ulfah, U., & Arifudin, O. (2022). Peran Orang Tua Terhadap Pembentukan Karakter Anak Dalam Menyikapi Bullying. Jurnal Tahsinia, 3(1), 11–19. https://doi.org/10.57171/jt.v3i1.306. Finch, J. (1989). Family Obligations and Social Change. Cambridge: Polity Press. Fiske, S. T., Cuddy, A. J. C., & Glick, P. (2002). A Model of ( Often Mixed ) Stereotype Content : Competence and Warmth Respectively Follow From Perceived Status and Competition. Of Personality and Social Psychology, 82(6), 878–902. https://doi.org/10.1037//0022-3514.82.6.878. Florean, I. S., Dobrean, A., Păsărelu, C. R., Georgescu, R. D., & Milea, I. (2020). The Efficacy of Internet-Based Parenting Programs for Children and Adolescents with Behavior Problems: A Meta-Analysis of Randomized Clinical Trials. Clinical Child and Family Psychology Review, 23(4), 510–528. https://doi.org/10.1007/s10567-020-00326-0. Ganong, L., & Coleman, M. (2006). Patterns of exchange and intergenerational responsibilities after divorce and remarriage. Journal of Aging Studies, 20, 265–278. https://doi.org/10.1016/j.jaging.2005.09.005. Hapsari, D. I., Dewi, R. R. K., & Selviana. (2019). Determinan Kejadian Stunting Pada Balita Di Wilayah 3T (Tertinggal , Terdepan, dan Terluar). Jurnal Publikasi Kesehatan Masyarakat Indonesia, 6(2), 72–78. https://doi.org/10.20527/jpkmi.v6i2.7456. Hartman, K. M., Ratner, N. B., & Newman, R. S. (2016). Infant-directed speech ( IDS ) vowel clarity and child language outcomes *. Child. Lang, 44, 1140–1162. https://doi.org/10.1017/S0305000916000520. Hofmann, V., & Müller, C. M. (2021). Learning , Culture and Social Interaction Language skills and social contact among students with intellectual disabilities in special needs schools. Learning, Culture and Social Interaction, 30(PA), 100534. https://doi.org/10.1016/j.lcsi.2021.100534. Houdt, K. Van, Kalmijn, M., & Ivanova, K. (2018). Family Complexity and Adult Children ’ s Obligations : The Role of Divorce and Co-Residential History in Norms to Support Parents and Step-Parents. European Sociological Review, 34(2), 169–183. https://doi.org/10.1093/esr/jcy007. House, B. R., Silk, J. B., Henrich, J., Barrett, H. C., Scelza, B. A., Boyette, A. H., Hewlett, B. S., Mcelreath, R., & Laurence, S. (2013). Ontogeny of prosocial behavior across diverse societies. Proceedings of the National Academy of Sciences, 110(36), 14586–14591. https://doi.org/https://doi.org/10.1073/pnas.1221217110. Irma, C. N., Nisa, K., & Sururiyah, S. K. (2019). Keterlibatan Orang Tua dalam Pendidikan Anak Usia Dini di TK Masyithoh 1 Purworejo. Jurnal Obsesi : Jurnal Pendidikan Anak Usia Dini, 3(1), 214. https://doi.org/10.31004/obsesi.v3i1.152. Jackson, L. A., Witt, E. A., Fitzgerald, H. E., VonEye, A., & Zhao, Y. (2011). Perceptions of parent behavior and children’s information technology use. In T. Bastiaens, & M. Ebner (Eds.). Proceedings of ED-MEDIA 2011–World Conference on Educational Multimedia, Hypermedia & Telecommunications (pp. 3864–3869). Lisbon, Portugal: Association for the Advancement of Computing in Education (AACE). Jatiningsih, O., Habibah, S. M., Wijaya, R., & Sari, M. M. K. (2021). Peran Orang Tua Dalam Pemenuhan Hak Pendidikan Anak Pada Masa Belajar Dari Rumah. Jurnal Ilmu Sosial Dan Humaniora, 10(1), 147. https://doi.org/10.23887/jish-undiksha.v10i1.29943. Jeon, H. J., Peterson, C. A., Luze, G., Carta, J. J., & Clawson Langill, C. (2020). Associations between parental involvement and school readiness for children enrolled in Head Start and other early education programs. Children and Youth Services Review, 118(April), 105353. https://doi.org/10.1016/j.childyouth.2020.105353. Juniarti, Y., & Nurlaeni. (2017). Peran Orang Tua Dalam Mengembangkan Kemampuan Bahasa Pada Anak Usia 4-6 Tahun. Jurnal Pelita PAUD, 2(1), 51–62. https://doi.org/https://doi.org/10.33222/pelitapaud.v2i1.196. Kanngiesser, P., & Warneken, F. (2012). Young Children Consider Merit when Sharing Resources with Others. PLoS ONE, 7(8), 1–5. https://doi.org/10.1371/journal.pone.0043979. Kienbaum, J., & Wilkening, F. (2009). European Journal of Children ’ s and adolescents ’ intuitive judgements about distributive justice : Integrating need , effort , and luck. European Journal of Developmental Psychology, 6(4), 481–498.https://doi.org/10.1080/17405620701497299. Koenig, A. M., & Eagly, A. H. (2014). Evidence for the Social Role Theory of Stereotype Content : Observations of Groups ’ Roles Shape Stereotypes. Journal of Personality and Social Psychology, 107(3), 371–392. https://doi.org/10.1037/a0037215. Latifa, U. (2017). Perkembangan pada Anak Sekolah Dasar: Masalah dan Perkembangannya. Academica: Journal of Multidisciplinary Studies, 1(2), 185–196. https://ejournal.uinsaid.ac.id/index.php/academica/article/download/1052/297. Lee, E. J., & Sun, H. (2018). Gender Differences in Smartphone Addiction Behaviors Associated With Parent Y Child Bonding , Parent Y Child Communication , and Parental Mediation Among Korean Elementary School Students. Journal of Addictions Nursing, 29(4), 244–254. https://doi.org/10.1097/JAN.0000000000000254. Lilawati, A. (2020). Peran Orang Tua dalam Mendukung Kegiatan Pembelajaran di Rumah pada Masa Pandemi. Jurnal Obsesi : Jurnal Pendidikan Anak Usia Dini, 5(1), 549. https://doi.org/10.31004/obsesi.v5i1.630. Lin, X., Liao, Y., & Li, H. (2022). Parenting Styles and Social Competence in Chinese Preschoolers: A Moderated Mediation Model of Singleton and Self-regulation. Early Education and Development, 33(3), 437–451. https://doi.org/10.1080/10409289.2021.1940643. Maifani. (2016). Peranan Orang Tua dalam Pembentukan Karakter Anak Sejak Dini di Desa Lampoh Tarom Kecamatan Kuta Baro Kabupaten Aceh Besar. Aceh: UIN Ar-Raniry Banda Aceh. Malti, T., Gummerum, M., Ongley, S., Chaparro, M., Nola, M., & Bae, N. Y. (2016). ‘“ Who is worthy of my generosity ?”’ Recipient characteristics and the development of children ’ s sharing. International Journal of Behavioral Development, 40(1), 31–40. https://doi.org/10.1177/0165025414567007. Martin, C. L., & Ruble, D. (2004). Current Directions in Psychological Science Children ’ s Search for Gender Cues Cognitive Perspectives on Gender Development. Current Directions in Psychological Science, 13(2), 67–70. https://doi.org/10.1111/j.0963-7214.2004.00276.x. Morgan, G., Curtin, M., & Botting, N. (2021). Infant Behavior and Development The interplay between early social interaction , language and executive function development in deaf and hearing infants. Infant Behavior and Development, 64(June), 101591. https://doi.org/10.1016/j.infbeh.2021.101591. Niu, G., Chai, H., Li, Z., Wu, L., & Sun, X. (2019). Online Parent-Child Communication and Left-Behind Children ’ s Subjective Well-Being : the Effects of Parent-Child Relationship and Gratitude. Child Indicators Research, 13(6). https://doi.org/https://doi.org/10.1007/s12187-019-09657-z. Ong, M. Y., Eilander, J., Saw, S. M., Xie, Y., Meaney, M. J., & Broekman, B. F. P. (2018). The influence of perceived parenting styles on socio-emotional development from pre-puberty into puberty. European Child and Adolescent Psychiatry, 27(1), 37–46. https://doi.org/10.1007/s00787-017-1016-9. Paulus, M. (2014). The early origins of human charity : developmental changes in preschoolers ’ sharing with poor and wealthy individuals. Frontiers in Psychology, 5, 1–10. https://doi.org/10.3389/fpsyg.2014.00344. Piotrowska, P. J., Tully, L. A., Lenroot, R., Kimonis, E., Hawes, D., Moul, C., Frick, P. J., Anderson, V., & Dadds, M. R. (2017). Mothers, Fathers, and Parental Systems: A Conceptual Model of Parental Engagement in Programmes for Child Mental Health—Connect, Attend, Participate, Enact (CAPE). Clinical Child and Family Psychology Review, 20(2), 146–161. https://doi.org/10.1007/s10567-016-0219-9. Popov, L. M., & Ilesanmi, R. A. (2015). Parent-Child Relationship : Peculiarities and Outcome. Review of European Studies, 7(5), 21–27. https://doi.org/10.5539/res.v7n5p253. Prabhawani, S. W. (2016). Pelibatan Orang Tua dalam Program Sekolah di TK Khalifah. Pendidikan Guru PAUD S-1, 5(2), 205–218. http://journal.student.uny.ac.id/ojs/index.php/pgpaud/article/view/1217. Procentese, F., Gatti, F., & Di Napoli, I. (2019). Families and social media use: The role of parents’ perceptions about social media impact on family systems in the relationship between family collective efficacy and open communication. International Journal of Environmental Research and Public Health, 16(24). https://doi.org/10.3390/ijerph16245006. Ratiwi, R. D., & Sumarni, W. (2020). Peran Orang Tua Dalam Pendampingan Belajar Daring. Cetta: Jurnal Ilmu Pendidikan,3(ISSN: 2686 6404), 304–309. https://proceeding.unnes.ac.id/index.php/snpasca/article/view/600/518. Rizzo, M. T., Elenbaas, L., Cooley, S., & Killen, M. (2016). Children’s Recognition of Fairness and Others’ Welfare in a Resource Allocation Task: Age Related Changes. Developmental Psychology, 52(8), 1307–1317. https://doi.org/https://doi.org/10.1037/dev0000134. Rossi, P. H. and Rossi, A. S. (1990). Of Human Bonding: Parent-Child Relations across the Life Course. New York: Aldine de Gruyter. Ruli, E. (2020). Tugas Dan Peran Orang Tua Dalam Mendidk Anak. Jurnal Edukasi Nonformal, vol.1(No.1), hlm.145. https://ummaspul.e-journal.id/JENFOL/article/view/428. Sabani, F. (2019). Perkembangan Anak - Anak Selama Masa Sekolah Dasar (6 - 7 Tahun). Didakta: Jurnal Kependidikan, 8(2), 89–100. https://doi.org/https://doi.org/10.58230/27454312.71. Salwiah, S., & Asmuddin, A. (2022). Membentuk Karakter Anak Usia Dini melalui Peran Orang Tua. Jurnal Obsesi : Jurnal Pendidikan Anak Usia Dini, 6(4), 2929–2935. https://doi.org/10.31004/obsesi.v6i4.1945. Schmidt, M. F. H., & Sommerville, J. A. (2011). Fairness Expectations and Altruistic Sharing in 15-Month-Old Human Infants. PLoS ONE, 6(10). https://doi.org/10.1371/journal.pone.0023223. Scott-phillips, T. C. (2016). Pragmatics and the aims of language evolution. Psychonomic Bulletin & Review, 24(2), 186–189. https://doi.org/10.3758/s13423-016-1061-2. Shaw, A., Descioli, P., & Olson, K. R. (2012). Fairness versus favoritism in children ☆. Evolution and Human Behavior, 33(6), 736–745. https://doi.org/10.1016/j.evolhumbehav.2012.06.001. Shutts, K., Brey, E. L., Dornbusch, L. A., & Slywotzky, N. (2016). Children Use Wealth Cues to Evaluate Others. PLoS ONE, 11(3), 1–21. https://doi.org/10.1371/journal.pone.0149360. Smetana, J. G., & Rote, W. M. (2019). Adolescent – Parent Relationships : Progress , Processes , and Prospects. Annual Review of Developmental Psychology, 1, 41–68. https://doi.org/https://doi.org/10.1146/annurev-devpsych-121318-084903. Smith, C. E., Blake, P. R., & Harris, P. L. (2013). I Should but I Won ’ t : Why Young Children Endorse Norms of Fair Sharing but Do Not Follow Them. 8(3). https://doi.org/10.1371/journal.pone.0059510. Spilt, J. L., & Harrison, L. J. (2015). Language Development in the Early School Years : The Importance of Close Relationships With Teachers. Developmental Psychology, 51(2), 185–196. https://doi.org/10.1037/a0038540. Sri Asri, A. (2018). Hubungan Pola Asuh Terhadap Perkembangan Anak Usia Dini. Jurnal Ilmiah Sekolah Dasar, 2(1), 1. https://doi.org/10.23887/jisd.v2i1.13793. Stein, C. H., Wemmerus, V. A., Ward, M., Gaines, M. E., Freeberg, A. L., Jewell, T. C., Ward, M., Gaines, M. E., Freeberg, A. L., & Jewell, T. C. (1998). “Because They’re My Parents”: An Intergenerational Study of Felt Obligation and Parental Caregiving. Journal of Marriage and the Fam, 60(3), 611–622. https://doi.org/https://doi.org/10.2307/353532. Sugiyanto, W. P. (2015). Pengaruh Pola Asuh Orang Tua Terhadap Perilaku Prososial Siswa Kelas V Sd Se Gugus Ii Kecamatan Pengasih Kabupaten Kulon Progo Tahun Ajaran 2014/2015. Pendidikan Guru Sekolah Dasar, 15(4), 1–27. https://doi.org/10.31004/aulad.v3i1.53. Syahailatua, J., & Kartini, K. (2020). Pengetahuan ibu tentang tumbuh kembang berhubungan dengan perkembangan anak usia 1-3 tahun. Jurnal Biomedika Dan Kesehatan, 3(2), 77–83. https://doi.org/10.18051/jbiomedkes.2020.v3.77-83. Talango, S. R. (2020). Konsep Perkembangan Anak Usia Dini. Early Childhood Islamic Education Journal, 1(1), 92–105. https://doi.org/10.54045/ecie.v1i1.35. Taubah, M. (2016). Pendidikan Anak Dalam Keluarga Perspektif Islam Mufatihatut Taubah (Dosen STAIN Kudus Prodi PAI). JUrnal Pendidikan Agama Islam, 3(1), 109–136. https://doi.org/https://doi.org/10.15642/jpai.2015.3.1.109-136. Tocaimaza-Hatch, C. C., & Santo, J. (2020). Social interaction in the Spanish classroom : How proficiency and linguistic background impact vocabulary learning. Language Teaching Research, 27(5), 1–25. https://doi.org/10.1177/1362168820971468. Triandis, H. C. (2001). Individualism-Collectivism and Personality. Journal of Personality, 69(6), 907–924. https://doi.org/https://doi. org/10.1111/1467-6494.696169. Vieira, J. M., Matias, M., Ferreira, T., Lopez, F. G., & Matos, P. M. (2016). Parents ’ Work-Family Experiences and Children ’ s Problem Behaviors : The Mediating Role of the Parent – Child Relationship. Journal of Family Psychology, 30(4), 419–430. https://doi.org/http://dx.doi.org/10.1037/fam0000189. Wahidin. (2019). Peran Orang Tua Dalam Menumbuhkan Motivasi Belajar Anak Sekolah Dasar. Pancar, 3(1), 232–245. https://ejournal.unugha.ac.id/index.php/pancar/article/view/291. Wang, M., Wang, J., Deng, X., & Chen, W. (2019). Why are empathic children more liked by peers? The mediating roles of prosocial and aggressive behaviors. Personality and Individual Differences, 144(September 2018), 19–23. https://doi.org/10.1016/j.paid.2019.02.029. Wiresti, R. D., & Na’imah, N. (2020). Aspek Perkembangan Anak : Urgensitas Ditinjau dalam Paradigma Psikologi Perkembangan Anak. Aulad : Journal on Early Childhood, 3(1), 36–44. https://doi.org/10.31004/aulad.v3i1.53. Wood, W., & Eagly, A. H. (2012). Biosocial Construction of Sex Differences and Similarities in Behavior. In Advances in Experimental Social Psychology (1st ed., Vol. 46). Elsevier Inc. https://doi.org/10.1016/B978-0-12-394281-4.00002-7. Xia, X. (2023). Parenting style and Chinese preschool children’s pre-academic skills: A moderated mediation model of approaches to learning and family socioeconomic status. Frontiers in Psychology, 14(February), 1–9. https://doi.org/10.3389/fpsyg.2023.1089386. Xie, X., Chen, W., Zhu, X., & He, D. (2019). Parents’ phubbing increases Adolescents’ Mobile phone addiction: Roles of parent-child attachment, deviant peers, and gender. Children and Youth Services Review, 105(April), 104426. https://doi.org/10.1016/j.childyouth.2019.104426. Xie, Y., Shi, Z., Yin, L., & Lan, L. (2022). A Meta-Analysis of the Relationships between Chinese Parenting Styles and Child Academic Achievement. Best Evidence in Chinese Education, 12(1), 1589–1595. https://doi.org/10.15354/bece.22.ab009. Yang, N., Shi, J., Lu, J., & Huang, Y. (2021). Language Development in Early Childhood : Quality of Teacher-Child Interaction and Children ’ s Receptive Vocabulary Competency. Frontiers in Psychology, 12(July), 1–12. https://doi.org/10.3389/fpsyg.2021.649680. Zhang, W., Yu, G., Fu, W., & Li, R. (2022). Parental Psychological Control and Children’s Prosocial Behavior: The Mediating Role of Social Anxiety and the Moderating Role of Socioeconomic Status. International Journal of Environmental Research and Public Health, 19(18). https://doi.org/10.3390/ijerph191811691.

Can Gio mangrove forest (CGM) is located downstream of Ho Chi Minh City (HCMC), situated between an estuarine system of Dong Nai - Sai Gon river and a part of Vam Co river. The CGM is the largest restored mangrove forest in Vietnam and the UNESCO’s Mangrove Biosphere Reserve. The CGM has been gradually facing to numeric challenges of global climate change, environmental degradation and socio-economic development for the last decades. To evaluate sediment quality in the CGM, we collected 13 cores to analyze for sediment grain size, organic matter content, and trace element concentration of Cd, Cr, Cu, Ni, Pb, Zn. Results showed that trace element concentrations ranged from uncontaminated (Cd, Cu, and Zn) to very minor contaminated (Cr, Ni, and Pb). The concentrations were gradually influenced by suspended particle size and the mangrove plants.ReferencesAnh M.T., Chi D.H., Vinh N.N., Loan T.T., Triet L.M., Slootenb K.B.-V., Tarradellas J., 2003. Micropollutants in the sediment of Sai Gon – Dong Nai rivers: Situation and ecological risks. Chimia International Journal for Chemistry, 57, 09(0009–4293), 537–541.Baruddin N.A., Shazili N.A., Pradit S., 2017. Sequential extraction analysis of heavy metals in relation to bioaccumulation in mangroves, Rhizophora mucronata from Kelantan delta, Malaysia. AACL Bioflux, 10(2), 172-181. Retrieved from www.bioflux.com/aacl.Bravard J.-P., Goichot M., Tronchere H., 2014. An assessment of sediment transport processes in the lower Mekong river based on deposit grain size, the CM technique and flow energy data. Geomorphology, 207, 174-189.Cang L.T., Thanh N.C. 2008. Importing and exporting sediment to and from mangrove forest at Dong Trang estuary, Can Gio district, Ho Chi Minh city. Science & Technology Development, 11(04), 12-18.Carignan J., Hild P., Mevelle G., Morel J., Yeghicheyan D., 2001. Routine analyses of trace elements in geological samples using flow injection and low-pressure on-line liquid chromatography coupled to ICP-MS: A study of geochemical reference materials BR, DR-N, UB-N, AN-G and GH. The Journal of Geo standard and Geoanalysis, 187-198.Carlson P.R., Yarbro L.A., Zimmermann C.F., Montgomery J.R., 1983. Pore water chemistry of an overwash mangrove island. Academy Symposium: Future of the Indian River System, 46(3/4), 239-249. https://www.jstor.org/stable/24320336.Chatterjee M., Canário J., Sarkar S.K., Branco V., Godhantaraman N., Bhattacharya B.D., Bhattacharya A., 2012. Biogeochemistry of mercury and methylmercury in sediment cores from Sundarban mangrove wetland, India—a UNESCO World Heritage Site. Environ Monit Assess, 184, 5239–5254.Claudia R., Huy N.V., 2004. Water allocation policies for the Dong Nai river basin in Viet Nam: An integrated perspective. EPTD Discussion Paper, 127, 01-52.Folk R.L., Ward W.C., 1957. Brazos River bar: A study in the significance of grain size parameters. Journal of Sedimentary Petrology, 27(1), 3-26.Furukawaa K., Wolanski E., Mueller H., 1997. Currents and sediment transport in mangrove forests. Estuarine, Coastal and Shelf Science, 44, 301-310.Hai H.Q., Tuyen N.N., 2011. Coastal Erosion of Can Gio district Ho Chi Minh City due to the global climate change. The journal of development of technology and science, 14, 17-28.HCM SO S.O., 2015. Annual statistic data in 2015 for HCM city. Ho Chi Minh city: Statistic office of HCM city.HCMC, 2017. Decision No. 3901 on approving the areas of forest and land in HCM city in 2016. Ho Chi Minh: The people's committee of HCM city.Herut B., Sandler A., 2006. Normalization methods for pollutants in marine sediments: review and recommendations for the Mediterranean. Haifa 31080: Israel Oceanographic & Limnological Research: IOLR Report H18/2006.Hong P.N., San H.T., 1993. Mangroves of Vietnam: Chapter VI Human impacts on the mangrove ecosystem. Bangkok 10501: IUCN - The International Union for Conservation of Nature, ISBN: 2-8317-0166-x.Hubner R., Astin K.B., Herbert R.J., 2009. Comparison of sediment quality guidelines (SQGs) for the assessment of metal contamination in marine and estuarine environments. Journal of Environmental Monitoring, 11, 713–722.IAEA, 2003. Collection and preparation of bottom sediment samples for analysis of radionuclides and trace elements. Vienna, Austria: International Atomic Energy Agency, IAEA-TECDOC-1360, ISBN 92–0–109003–X.Jingchun L., Chongling Y., Ruifeng Z., Haoliang L., Guangqiu Q., 2008. Speciation changes of Cd in mangrove (Kandelia Candel L.) rhizosphere sediments. Bull Environ Contam Toxicol, 231-236. Doi:10.1007/s00128-007-9351-z.Kalaivanan R., Jayaprakash M., Nethaji S., Arya V., Giridharan L., 2017. Geochemistry of Core Sediments from Tropical Mangrove Region of Tamil Nadu: Implications on Trace Metals. Journal of Earth Science & Climatic Change, ISSN: 2157-7617., 8(1.1000385), 1-10. Doi:10.4172/2157-7617.1000385.Kathiresan K., Saravanakumar K., Mullai P., 2014. Bioaccumulation of trace elements by Avicennia marina. Journal of Coastal Life Medicine, 2(11), 888-894.Kitazawa T., Nakagawa T., Hashimoto T., Tateishi M., 2006. Stratigraphy and optically stimulated luminescence (OSL) dating of a Quaternary sequence along the Dong Nai River, southern Vietnam. Journal of Asian Earth Sciences, 27, 788–804.Lacerda L.D., 1998. Trace metals of biogeochemistry and diffuse pollution in mangrove (M. Vannucci, Ed.) Mangrove ecosystem occassional papers (ISSN: 0919-1348), 2, 1-72.Laura H., Probsta A., Probsta J.L., Ulrich E., 2003. Heavy metal distribution in some French forest soils: evidence for atmospheric contamination. The Science of Total Environment, 195-210.Li R., Li R., Chai M., Shen X., Xu H., Qiu G., 2015. Heavy metal contamination and ecological risk in Futian mangrove forest sediment in Shenzhen Bay, South China. Marine Pollution Bulletin, 101, 448–456.Long E., Morgan L.G., 1990. The potential for biological effects of sediment-sorted contaminants tested in the national status and trends program. Seattle, Washington: NOAA Technical Memorandum NOS OMA 52.Long E.R., Field L.J., MacDonald D.D., 1998. Predicting toxicity in marine sediments with numerical sediment quality guidelines. Environmental Toxicology and Chemistry, 17, 714–727. http://onlinelibrary.wiley.com/doi/10.1002/etc.5620170428/abstract;jsessionid=C5264A1AD0.7ACCA9B4EF9A088BE2EDE9.f04t04Long E.R., MacDonald D.D., Smith S.L., Calder F.D., 1995. Incidence of adverse biological effects within ranges of chemical concentration in marine and estuarine sediments. Environmental management, 19, 81-97.Maiti S.K., Chowdhury A., 2013. Effects of Anthropogenic Pollution on Mangrove Biodiversity: A Review. Journal of Environmental Protection, 4, 1428-1434.Marchand C., Allenbach M., Lallier-Verges E., 2011. Relation between heavy metal distribution and organic matter cycling in mangrove sediments (Conception Bay, New Caledonia). Geoderma, Elsevier, 160 (3-4), 444-456.Mohd F.N., Nor R.H., 2010. Heavy metal concentrations in an important mangrove species, Sonneratia caseolaris, in Peninsular Malaysia. Environment Asia, 3, 50-53.Muller G., 1979. Schwermetalle in den Sedimenten des Rheins - Veränderungen seit 1971. Umschau, 778-783.Nam V.N., 2007. Restoration of Can Gio mangrove forest: Its structure and function in comparison between the ecosytems of plantion and nature mangrove forest. Workshop on the thesis between Germany and Vietnam.Nickerson N.H., Thibodeau F.R., 1985. Association between pore water sulfide concentrations and the distribution of mangroves. Biogeochemistry, 1, 183-192.Ong Che R.G., 1999. Concentration of 7 Heavy Metals in Sediments and Mangrove Root Samples from Mai Po, Hong Kong. Marine Pollution Bulletin, 39, 269-279.Passega R., 1957. Texture as characteristics of clastic deposition. Publisher: American Association of Petroleum Geologists.Passega R., 1964. Grain size representation by CM patterns as a geological tool. J Sediment Petrol, 34, 830–847.Phuoc V.L., An D.T., Cang L.T., Chung B.N., Tien N.V., 2010. Study the sediment dynamics in Can Gio mangrove forest (Nang Hai site, Ho Chi Minh city). Ho Chi Minh city: The final report of National University Ho Chi Minh city, No. B2009-18-36.Pumijumnong N., Danpradit S., 2016. Heavy metal accumulation in sediments and mangrove forest stems from Surat Thani province, Thailand. The Malaysian forester, 79(1&2), 212-228.QCVN43:2012/BTNMT, 2012. QCVN43:2012/BTNMT: National technical regulation on the sediment quality, Ha Noi: Ministry of natural resources and environment of Vietnam.Qiao S., Shi X., Fang X., Liu S., Kornkanitnan N., Gao J., Yu Y., 2015. Heavy metal and clay mineral analyses in the sediments of Upper Gulf of Thailand and their implications on sedimentary provenance and dispersion pattern. Journal of Asian Earth Sciences, 114, 488–496.Rollinson H. R., 1993. Using geochemical data for evaluation, presentation and interpretation. UK: Longman Group UK Limited ISBN-0-582-06701-4.Spalding M., Blasco F., Field C., 2010. World atlas of mangrove. Cambridge: Earthscan in UK and US, ISBN: 978-1-84407-657-4.Strady E., Dang V.B., Némery J., Guédron S., Dinh Q.T., Denis H., Nguyen P.D., 2016. Baseline seasonal investigation of nutrients and trace metals in surface waters and sediments along the Saigon River basin impacted by the megacity of HCM, Viet Nam. Environ Sci Pollut Res, 1-18. doi:10.1007/s11356-016-7660-7.Tam N.F., Wong Y.S., 1996. Retention and distribution of heavy metals in mangrove soils receiving wastewater. Environment pollution, 94(5), 283-291.Thomas N., Lucas R., Bunting P., Hardy A., Rosenqvist A., Simard M., 2017. Distribution and drivers of global mangrove forest change, 1996– 2010. PLoS ONE, 12(6): e0179302, 1-14. Doi:10.1371/journal.pone.0179302.Thuy H.T., Loan T.T., Vy N.N., 2007. Study on environmental geochemistry of heavy metals in urban canal sediments of Ho Chi Minh city. Science and Technology Development, 10(01), 1-9.Toan T.T., Bay N.T., 2006. A study on the tendency of accretion and erosion in Can Gio coastal zone. Vietnam-Japan estuary workshop, 184-194.Tri N.H., Hong P.N., Cuc L.T., 2000. Can Gio Mangrove Biosphere Reserve Ho Chi Minh city, Ha Noi, Viet Nam. Ha Noi: Hanoi University Publisher.Truong T.V., 2007. Planning for water source of Dong Nai river basin. Retrieved from Water Resources Planning: http://siwrp.org.vn/tin-tuc/quy-hoach-tai-nguyen-nuoc-luu-vuc-song-dong-nai_143.html.Tuan L.D., Oanh T.T., Thanh C.V., Quy N.D., 2002. Can Gio mangrove biosphere reserve. HCM city, Vietnam: Agriculture Publisher.Tue N.T., Quy T.D., Amono A., 2012. Historical profiles of trace element concentrations in Mangrove sediments from the Ba Lat estuary, Red river, Vietnam. Water, Air & Soil Pollution, ISSN 0049-6979, 223(3), 1315-1330.Twilley R., Chen R., Hargis T., 1992. Carbon sinks in mangroves and their implications to carbon budget of tropical coastal ecosystems. Water, Air & Soil pollution, Netherland, 64, 265-288.UN Environment Program, 2006. Methods for sediment sampling and analysis. Palermo (Sicily), Italy: United Nation Environment Program.UNESCO, 2000. List of Biosphere reserves approved by MAB committee belonging to UNESCO. Retrieved from United Nations, Educational, Scientific, Cultural Organization (UNESCO): http://www.unesco.org/new/en/natural-sciences/environment/ecological-sciences/biosphere-reserves/asia-and-the-pacific.Vandenberghe N., 1975. An evaluation of CM patterns for grain size studies of fine grained sediments. Sedimentology, 22, 615-622.Vinh B.T., Ichiro D., 2012. Erosion mechanism of cohesive river bank and bed of Soai Rap river (Ho Chi Minh city). J. Sci. of the Earth, 34(2), 153-161.Wang J., Du H., Xu Y., Chen K., Liang J., Ke H., Cai M., 2016. Environmental and Ecological Risk Assessment of Trace Metal Contamination in Mangrove Ecosystems. BioMed Research International, Article ID 2167053, 1-14. Doi:10.1155/2016/2167053.Wedepohl K.H., 1995. The composition of the continental crust. Geochimica et Cosmochimica Acta, 59(7), 1217-1232.Woodroffe C., Rogers K., McKee K., Lovelock C., Mendelssohn I., Saintilan N., 2016. Mangrove sedimentation and response to relative sea level rise. The Annual Review of Marine Science, 8, 243-266.Zhang J., Liu C.L., 2002. Riverine Composition and Estuarine Geochemistry of Particulate Metals in China-Weathering Features, Anthropogenic Impact and Chemical Fluxes. Estuarine, Coastal and Shelf Science, 54(6), 1051-1070.Zhang W., Feng H., Chang J., Qu J., Xie H., Yu L., 2009. Heavy metal contamination in surface sediments of Yangtze River intertidal zone: An assessment from different indexes. Environmental Pollution, 157, 1533-1543.Zheng W.-j., Xiao-yong C., Peng L., 1997. Accumulation and biological cycling of heavy metal elements in Rhizophora stylosa mangroves in Yingluo Bay, China. Marine ecology progress series, 159, 293-301.

Abstract Background In myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) achievement of complete remission (CR) is a prerequisite for potential cure. In AML, CR/CR with incomplete recovery (CRi) is deemed the major outcome associated with improved overall survival (OS); patients (pts) without CR/CRi are considered non-responders, and hematologic improvement (HI) without (assessment of) bone marrow (BM) blast clearance is considered treatment (trt) failure. Achievement of CR may not be necessary for prolonged OS in pts treated with azacitidine (AZA) (Pleyer L, Annals Hematol 2014, 1825; Schuh AC, ASH 2015, P575). Outside of clinical trials, BM evaluations (BME) are only performed in ~50% of pts (Dinmohamed, Leuk Res 2015, 177) when either response or progression are obvious from peripheral blood (PB) values, or when pts are unable or unwilling to have BME. Aims To assess of the impact of response type on AZA trt outcomes in multivariate adjusted analyses (MVA). Methods 1441 pts included in the Austrian Azacitidine Registry were analyzed (NCT01595295). Data cut-off was 1 July 21. Marrow response was assessed for MDS/CMML and AML at each BME; HI was assessed on day 1 of each AZA cycle (Döhner H, Blood 2017, 424; Cheson BD, Blood 2006, 419; Pleyer L, ASH 2019, P3821); peripheral blood complete remission (PB-CR) was defined as hemoglobin ³11 g/dL, platelet count ≥100 G/L, neutrophil count ³1.0 G/L, white blood cell count &lt;15 G/L, PB blasts =0%, and no transfusions. Response types were calculated from electronic case report form data. To identify which response type achieved by which AZA cycle had the highest impact on time-to-event endpoints, likelihood ratios (LR) of the Cox-regression model for OS or time to next treatment (TTNT) were calculated using the respective response types as covariates. Baseline characteristics with univariate p&lt;0·10 (n=23) for association with OS were included in the multivariate regression. After stepwise selection n=17 variables remained and were used for MVA. Assign Data Management and Biostatistics GmbH performed statistical analyses with SAS® 9.4. Results In total, 521, 135, and 785 pts had MDS, CMML and AML. Median year of initial diagnosis was 2012, median time to AZA start was 3·0 (IQR 1·0-13·2) months (mo), median follow-up time from AZA start was 10.6 (IQR 4·0-21·1) mo, 894 pts received AZA as first line trt, median age at AZA start was 73 (range 23-99) years. In total, 13956 AZA cycles were applied, median duration of AZA trt was 5·0 (IQR 1·9-12·1) mo, median AZA dose was 875 (IQR 700-1000) mg/cycle, AZA was applied for a median of 7 (IQR 5-7) days. Median time to best response was 3·7 (IQR 2·0-5·9) months. Early mortality was 5.5% within 30 days. During AZA trt 1225 BM evaluations (BME) were performed in 697 (48·4%) of pts. Of these, 204 achieved CR/CRi. Irrespective of BME, 622 (43%) of 1441 pts achieved an HI and 264 (18·3%) of 1441 pts achieved a PB-CR. Pts achieving CR had longer adjusted OS (23·7 vs 19·7 mo, p=0·0227; HR=0·621 [0·413-0·936]) and TTNT (19·4 vs 15·7 mo, p=0·0262; HR=0·644 [0·436-0·949]) than pts achieving CRi. Among pts achieving CR, those additionally achieving PB-CR had longer adjusted OS (24·8 vs 16·3; p=0·0040; HR=0·256 [0·101-0·647]; Fig 1A) and TTNT (21·2 vs 11·0; p=0·0005; HR=0·219 [0·094-0·513]; Fig 1B) than those who did not. Among pts not achieving CR, those additionally achieving PB-CR had longer adjusted OS (20·8 vs 14·1; p&lt;0·0001; HR=0·510 [0·397-0·657]; Fig 1A) and TTNT (17·7 vs 10·9; p&lt;0·0001; HR=0·485 [0·357-0·589]; Fig 1B) than those who did not. Among all pts, irrespective of BM blast count, achievement of PB-CR resulted in longer adjusted OS (21·7 vs 10·0 mo; p&lt;·0001; HR 0·363; Fig 1C) and TTNT (18.5 vs 7.8 mo; p&lt;0.0001; HR=0.346; Fig 1D) and provided added value to CR and CR/CRi. Among all response types and after MVA, the highest prognostic impact on both OS and TTNT was observed when achieving PB-CR or CR/CRi by cycle 9 or 10 (Fig 2A-B). Conclusions Above data indicate that achievement of PB-CR is a strong predictor of OS and TTNT that provides additional information to current response criteria. Inclusion of PB-CR in updated response criteria of pts with MDS, CMML or AML receiving non-intensive trt should be considered. The greatest advantage of PB-CR is that it can be easily, nearly painlessly and quickly assessed. Inclusion of PB-CR as an endpoint in clinical trials would be desirable for validation of these results. Figure 1 Figure 1. Disclosures Pleyer: AbbVie, BMS, Novartis: Honoraria, Other: Travel Sport. Pfeilstocker: BMS: Honoraria. Stauder: Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heibl: BMS: Honoraria. Sill: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hartmann: Celgene, Amgene, Janssen, AbbVie: Honoraria. Petzer: Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Saegen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Geissler: BMS: Honoraria. Sperr: AbbVie, BMS-Celgene, Daiichi Sankyo, Deciphera, Incyte, Jazz, Novartis, Pfizer, StemLine, Thermo Fisher: Honoraria, Research Funding. Leisch: Honoraria from BMS, Celgene, Gilead, Takeda and Novartis; Travel support: Celgene and Novartis: Honoraria, Other: Travel support. Melchardt: Abbvie, Celgene, Novartis: Honoraria. Zebisch: Novartis: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Honoraria. Machherndl-Spandl: AbbVie, Celgene, BMS, Pfizer: Honoraria. Wolf: Roche: Honoraria, Research Funding; MSD: Honoraria, Research Funding; BMS-Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Gilead: Honoraria; Incyte: Honoraria; GEMOAB: Honoraria. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. OffLabel Disclosure: Azacitidine is approved for all types of MDS and CMML as well as low blast count AML by FDA, but not for all subtypes of MDS and CMML by EMA.

Early childhood emotional dysregulation is critical in recognizing and preventing psychological well-being disorders, laying the groundwork for developing healthy emotional behaviors early on. This study aims to determine the direct influence of smartphone addiction, executive function, and the mother-child relationship on emotional dysregulation in early childhood in West Sumatra. This research method is a quantitative survey. The data collection technique in this research uses a questionnaire design on 309 parents who were selected using a simple random sampling method. This data processing tool uses the SmartPLS software. The results of the study indicate that smartphone addiction has a significant impact on emotional dysregulation in early childhood, executive function has a positive and significant effect on emotional dysregulation in early childhood, and the mother-child relationship has a positive and significant influence on emotional dysregulation in early childhood. The findings of this research can offer valuable insights into improving the understanding of the factors that influence emotional dysregulation in early childhood and intervention strategies to address the issues that arise as a result. Keywords: smartphone addiction, executive function, mother-child relationship, emotional dysregulation, early childhood References: Aisyah, Salehudin, M., Yatun, S., Yani, Komariah, D. L., Aminda, N. E. R., Hidayati, P., & Latifah, N. (2021). Persepsi Orang Tua Dalam Pendidikan karakter Anak Usia Dini Pada Pembelajaran Online di Masa Pandemi Covid-19. PEDAGOGI: Jurnal Anak Usia Dini Dan Pendidikan Anak Usia Dini, 7(1), 60–75. https://doi.org/http://dx.doi.org/10.30651/pedagogi.v7i1.6593 Allison, S. Z. (2023). Islamic Educational Provisions in South Korea and Indonesia : A Comparison. Journal of Islamic Education Students, 3, 50–61. https://doi.org/10.31958/jies.v3i1.8772 Anggraini, E. (2019). Mengatasi Kecanduan Gadget Pada Anak. Serayu Publishing. Annisa, N., Padilah, N., Rulita, R., & Yuniar, R. (2022). Dampak Gadget Terhadap Perkembangan Anak Usia Dini. Jurnal Pendidikan Indonesia, 3(9), 837–849. https://doi.org/10.36418/japendi.v3i9.1159 Annisavitry, Y., & Budiani, M. S. (2006). Hubungan antara Kematangan Emosi dengan Agresivitas pada Remaja. 1–6. Anzani, R. W., & Intan Khairul Insan. (2020). Perkembangan sosial emosi pada anak usia prasekolah. Jurnal Pendidikan Dan Dakwah, 02, 180–193. APJII. (2019). Pengguna Internet Indonesia Hampir Tembus 200 Juta di 2019. Asosiasi Pengguna Jasa Internet Indonesia (APJII). https://blog.apjii.or.id/index.php/2020/11/09/siaran-pers-pengguna-internet-indonesia-hampir-tembus-200-juta-di-2019-q2-2020/ Aryanti, Z. (2017). Kelekatan dalam perkembangan anak. Arbawiyah: Jurnal Ilmiah Pendidikan. Ashari, L. F., & Anwar, F. (2022). Moral Problems and Mothers’ Efforts to Educate Children in Single Parent Families. Journal of Islamic Education Students (JIES), 2(1), 12. https://doi.org/10.31958/jies.v2i1.4367 Ayomi, A. T. R., Widyorini, E., & Roswita, M. Y. (2021). Hubungan Inteligensi dengan Fungsi Eksekutif pada Anak Gifted Relationship between Intelligence and Executive Function to Gifted Children. Jurnal Ilmiah Psikologi Candrajiwa, 6(2), 136. Bachtiar, M. A., & Faletehan, A. F. (2021). Self-Healing sebagai Metode Pengendalian Emosi. Journal An-Nafs: Kajian Penelitian Psikologi, 6(1), 41–54. https://doi.org/10.33367/psi.v6i1.1327 Baptista, J., Osório, A., Martins, E. C., Verissimo, M., & Martins, C. (2016). Does social-behavioral adjustment mediate the relation between executive function and academic readiness? Journal of Applied Developmental Psychology, 46, 22–30. https://doi.org/10.1016/j.appdev.2016.05.004 Bassett, H. H., Denham, S., Wyatt, T. M., & Warren-Khot, H. K. (2012). Refining the Preschool Self-regulation Assessment for Use in Preschool Classrooms. Infant and Child Development, 21(6), 596–616. https://doi.org/10.1002/icd.1763 Bell, M. A., & Wolfe, C. D. (2004). Emotion and Cognition: An Intricately Bound Developmental Process. Child Development, 75(2), 366–370. https://doi.org/10.1111/j.1467-8624.2004.00679.x Bocknek, E. L., Brophy-Herb, H. E., Fitzgerald, H., Burns-Jager, K., & Carolan, M. T. (2012). Maternal Psychological Absence and Toddlers’ Social-Emotional Development: Interpretations From the Perspective of Boundary Ambiguity Theory. Family Process, 51(4), 527–541. https://doi.org/10.1111/j.1545-5300.2012.01411.x Brock, R. L., & Kochanska, G. (2019). Anger in infancy and its implications: History of attachment in mother–child and father–child relationships as a moderator of risk. Development and Psychopathology, 31(04), 1353–1366. https://doi.org/10.1017/S0954579418000780 Cacioppo, J. T., & Berntson, G. G. (2019). The Affect System structure: architecture and operating characteristics. Current Directions in Psychological Science, 8(5), 133–137. https://doi.org/10.1111/1467-8721.00031 Calkins, S. D., & Marcovitch, S. (2015). Emotion regulation and executive functioning in early development: Integrated mechanisms of control supporting adaptive functioning. In Child development at the intersection of emotion and cognition. (pp. 37–57). American Psychological Association. https://doi.org/10.1037/12059-003 Carlson, S. M. (2005). Developmentally Sensitive Measures of Executive Function in Preschool Children. Developmental Neuropsychology, 28(2), 595–616. https://doi.org/10.1207/s15326942dn2802_3 Chang, F.-C., Chiu, C.-H., Chen, P.-H., Chiang, J.-T., Miao, N.-F., Chuang, H.-Y., & Liu, S. (2019). Children’s use of mobile devices, smartphone addiction and parental mediation in Taiwan. Computers in Human Behavior, 93, 25–32. https://doi.org/10.1016/j.chb.2018.11.048 Chiu, S.-I. (2014). The relationship between life stress and smartphone addiction on taiwanese university student: A mediation model of learning self-Efficacy and social self-Efficacy. Computers in Human Behavior, 34, 49–57. https://doi.org/10.1016/j.chb.2014.01.024 Cholik, C. A. (2021). Perkembangan Teknologi Informasi Komunikasi / Ict Dalam Berbagai Bidang. Jurnal Fakultas Teknik, 14, 1–13. Chusna, P. A. (2017). Pengaruh Media Gadget pada Perkembangan Karakter Anak. 315–330. Cole, P. M., Martin, S. E., & Dennis, T. A. (2004). Emotion Regulation as a Scientific Construct: Methodological Challenges and Directions for Child Development Research. Child Development, 75(2), 317–333. https://doi.org/10.1111/j.1467-8624.2004.00673.x Denham, S. A., Ferrier, D. E., Howarth, G. Z., Herndon, K. J., Bassett, H. H., Denham, S. A., Ferrier, D. E., Howarth, G. Z., & Herndon, K. J. (2016). Key considerations in assessing young children ’ s emotional competence. Cambridge Journal of Education ISSN:, 3577(April). https://doi.org/10.1080/0305764X.2016.1146659 Eliasa, E. I. (2011). Pentingnya kelekatan orangtua dalam internal working model untuk pembentukan karakter anak (kajian berdasarkan teori kelekatan dari john bowlby). Yogyakarta: Inti Media Yogyakarta Bekerjasama Dengan Pusat Studi Pendidikan Anak Usia Dini Lembaga Penelitian Universitas Negeri Yogyakarta. Evy Clara, A. A. D. W. (2020). Sosiologi Keluarga. In UNJ PRESS. Unj Press. Fatwikiningsih, N. (2016). Rehabilitasi Neuropsikologi Dalam Upaya Memperbaiki Defisit Executive Function (Fungsi Eksekutif) Klien Gangguan Mental. Journal An-Nafs: Kajian Penelitian Psikologi, 1(2), 320–335. https://doi.org/10.33367/psi.v1i2.296 Ferrier, D. E., Bassett, H. H., & Denham, S. A. (2014). Relations between executive function and emotionality in preschoolers: Exploring a transitive cognition–emotion linkage. Frontiers in Psychology, 5. https://doi.org/10.3389/fpsyg.2014.00487 Ferrier, D. E., Karalus, S. P., Denham, S. A., Hideko, H., Ferrier, D. E., Karalus, S. P., Denham, S. A., & Bassett, H. H. (2018). Indirect effects of cognitive self-regulation on the relation between emotion knowledge and emotionality between emotion knowledge and emotionality. Early Child Development and Care, 0(0), 1–14. https://doi.org/10.1080/03004430.2018.1445730 Flannery, D. D., Gouma, S., Dhudasia, M. B., Mukhopadhyay, S., Pfeifer, M. R., Woodford, E. C., Triebwasser, J. E., Gerber, J. S., Morris, J. S., Weirick, M. E., McAllister, C. M., Bolton, M. J., Arevalo, C. P., Anderson, E. M., Goodwin, E. C., Hensley, S. E., & Puopolo, K. M. (2021). Assessment of Maternal and Neonatal Cord Blood SARS-CoV-2 Antibodies and Placental Transfer Ratios. JAMA Pediatrics, 175(6), 594. https://doi.org/10.1001/jamapediatrics.2021.0038 Gio, P. U. (2019). Covariance-Based Structural Equation Modeling(CB-SEM) dengan Disertai Perbandingan Hasil dengan Software LISREL dan Amos. In STATCAL (pp. 1–56). Statkomat. www.statcal.org Gioia, G. A., Isquith, P. K., Guy, S. C., & Kenworthy, L. (2000). TEST REVIEW Behavior Rating Inventory of Executive Function. Child Neuropsychology, 6(3), 235–238. https://doi.org/10.1076/chin.6.3.235.3152 Goleman, D. (2015). Emotional Intelligence. PT. Main Library Gramedia. Groves, N. B., Wells, E. L., Soto, E. F., Marsh, C. L., Jaisle, E. M., Harvey, T. K., & Kofler, M. J. (2022). Executive Functioning and Emotion Regulation in Children with and without ADHD. Research on Child and Adolescent Psychopathology, 50(6), 721–735. https://doi.org/10.1007/s10802-021-00883-0 Guswani, A. M. (2011). Perilaku agresi pada mahasiswa ditinjau dari kematangan emosi. I(2), 86–92. Hadi, S. (2011). Pembelajaran Sosial Emosional Sebagai Dasar Pendidikan Karakter Anak Usia Dini. Jurnal Teknodik, 15(2), 227–240. Hadi, S. (2013). Pembelajaran Sosial Emosional Sebagai Dasar Pendidikan Karakter Anak Usia Dini. Jurnal Teknodik, 227–240. https://doi.org/10.32550/teknodik.v0i0.104 Handayani, S., Sumarno, S., & Haryati, Y. (2017). UpayaMeningkatkan Kemampuan Kognitif Dalam Memperkenalkan Konsep Pengukuran Anak Usia Dini Melalui Metode Bermain Peran. Jurnal Karya Pendidikan Matematika, 4(1), 43. https://doi.org/10.1017/CBO9781107415324.004 Hapsari. (2016). Psikologi Perkembangan Anak. PT Index. Hasanah, M. (2017). Pengaruh Gadget terhadap Kesehatan Mental Anak. 2(2), 207–214. Hermawati, N. S., & Sugito, S. (2021). Peran Orang Tua dalam Menyediakan Home Literacy Environment (HLE) pada Anak Usia Dini. Jurnal Obsesi : Jurnal Pendidikan Anak Usia Dini, 6(3), 1367–1381. https://doi.org/10.31004/obsesi.v6i3.1706 Herndon, K. J., Bailey, C. S., Shewark, E. A., Denham, S. A., & Bassett, H. H. (2013). Preschoolers’ Emotion Expression and Regulation: Relations with School Adjustment. The Journal of Genetic Psychology, 174(6), 642–663. https://doi.org/10.1080/00221325.2012.759525 Holley, S. R., Ewing, S. T., Stiver, J. T., & Bloch, L. (2015). The Relationship Between Emotion Regulation , Executive Functioning , and Aggressive Behaviors. Journal of Interpersonal Violence, 15(3), 1–16. https://doi.org/10.1177/0886260515592619 Imron, R. I. (2017). Hubungan Penggunaan Gadget Dengan Perkembangan Sosial Dan Emosional Anak Prasekolah Di Kabupaten Lampung Selatan. XIII(2), 148–154. Islamiah, A. (2018). Dampak teknologi informasi terhadap perilaku keagamaan bagi remaja di menganti gresik. Skrispi, Universita(Surabaya), 48. Ita, E., & Fono, Y. M. (2021). Pendampingan Kesulitan Belajar Pada Smartphone Addiction Child di PAUD Terpadu Citra Bakti. Jurnal Abdimas Ilmiah Citra Bakti, 2(2), 149–156. https://doi.org/10.38048/jailcb.v2i2.377 Jahromi, L. B., & Stifter, C. A. (2008). Individual Differences in Preschoolers’ Self-Regulation and Theory of Mind. Merrill-Palmer Quarterly, 54(1), 125–150. https://doi.org/10.1353/mpq.2008.0007 Joormann, J., & Quinn, M. E. (2014). Cognitive Processes And Emotion Regulation in Depression. Depression and Anxiety, 31(4), 308–315. https://doi.org/10.1002/da.22264 Jumrianti, F., Nugroho, S., & Arief, Y. (2022). Hubungan Antara Kecanduan Smartphone Dengan Psychological Well-being Pada Remaja. Journal of Islamic and Contemporary Psychology (JICOP), 2(1), 49–57. https://doi.org/10.25299/jicop.v2i1.10263 Kabali, H. K., Irigoyen, M. M., Nunez-Davis, R., Budacki, J. G., Mohanty, S. H., Leister, K. P., & Bonner, R. L. (2015). Exposure and Use of Mobile Media Devices by Young Children. Pediatrics, 136(6), 1044–1050. https://doi.org/10.1542/peds.2015-2151 Katz, E. (2019). Coercive Control, Domestic Violence, and a Five-Factor Framework: Five Factors That Influence Closeness, Distance, and Strain in Mother–Child Relationships. Violence Against Women, 25(15), 1829–1853. https://doi.org/10.1177/1077801218824998 Khoshgoftar, M., Khodabakhshi-Koolaee, A., & Sheikhi, M. R. (2022). Analysis of the early mother-child relationship in schizophrenic patients. International Journal of Social Psychiatry, 68(3), 548–554. https://doi.org/10.1177/0020764021991186 Kominfo. (2018). Indonesia Raksasa teknologi Digital Asia. Kominfo.Go.Id. https://www.kominfo.go.id/content/detail/6095/indonesia-raksasa-teknologi-digital-asia/0/sorotan_media Kujawa, A., Arfer, K. B., Finsaas, M. C., Kessel, E. M., Mumper, E., & Klein, D. N. (2020). Effects of Maternal Depression and Mother–Child Relationship Quality in Early Childhood on Neural Reactivity to Rejection and Peer Stress in Adolescence: A 9-Year Longitudinal Study. Clinical Psychological Science, 8(4), 657–672. https://doi.org/10.1177/2167702620902463 Kusdemawati, J. (2021). Dampak Attachment Ibu-Anak Bagi Perkembangan Dampak Attachment Ibu-Anak Bagi Perkembangan Psikososial Anak Di Masa Remaja Anak Di Masa Remaja. ROSYADA: Islamic Guidance and Counseling, 2(2), 141–148. https://doi.org/10.21154/rosyada.v2i2.3539 Kusramadhanty, M., Hastuti, D., & Herawati, T. (2019). Temperamen dan praktik pengasuhan orang tua menentukan perkembangan sosial emosi anak usia prasekolah. Persona:Jurnal Psikologi Indonesia, 8(2), 258–277. https://doi.org/10.30996/persona.v8i2.2794 Kusuma, T. C. (2015). Peningkatan Kemampuan Pengukuran Dalam Matematika Awal Melalui Metode Discovery Learning (Penelitian Tindakan Di Tk B Pertiwi I Kantor Gubernur Padang Tahun 2015). Jurnal Tumbuh Kembang, 4(1), 76–84. https://doi.org/https://doi.org/10.36706/jtk.v4i1.8242 Kwon, M., Lee, J.-Y., Won, W.-Y., Park, J.-W., Min, J.-A., Hahn, C., Gu, X., Choi, J.-H., & Kim, D.-J. (2013). Development and Validation of a Smartphone Addiction Scale (SAS). PLoS ONE, 8(2), e56936. https://doi.org/10.1371/journal.pone.0056936 Laible, D., Davis, A., Karahuta, E., & Van Norden, C. (2020). Does corporal punishment erode the quality of the mother–child interaction in early childhood? Social Development, 29(3), 674–688. https://doi.org/10.1111/sode.12427 Lauricella, A. R., Wartella, E., & Rideout, V. J. (2015). Young children’s screen time: The complex role of parent and child factors. Journal of Applied Developmental Psychology, 36, 11–17. https://doi.org/10.1016/j.appdev.2014.12.001 Lintuuran, rifo mario warouw. (2015). Hubungan antara Kadar Seng dalam Serum dengan Fungsi Eksekutif pada Anak dengan Gangguan Pemusatan Perhatian dan Hiperaktivitas (GPPH) Correlation between Serum Zinc Level and Executive Function in Children with Attention Deficit/Hyperactivity Disorder (A. 17(4), 285–291. Mansur, A. R. (2019). Tumbuh kembang anak usia prasekolah. In 1 (Ed.), Andalas University Pres. Martí, M., Bonillo, A., Jané, M. C., Fisher, E. M., & Duch, H. (2016). Cumulative Risk, the Mother–Child Relationship, and Social-Emotional Competence in Latino Head Start Children. Early Education and Development, 27(5), 590–622. https://doi.org/10.1080/10409289.2016.1106202 Martin, R. E., & Ochsner, K. N. (2016). The neuroscience of emotion regulation development : implications for education. Current Opinion in Behavioral Sciences, 10, 142–148. https://doi.org/10.1016/j.cobeha.2016.06.006 Martins, E. C., Mărcuș, O., Leal, J., Visu-petra, L., Costa, E., Mărcuș, O., Leal, J., Visu-petra, L., & Martins, E. C. (2018). Assessing hot and cool executive functions in preschoolers : affective flexibility predicts emotion regulation a ff ective fl exibility predicts emotion regulation. Early Child Development and Care, 0(0), 1–15. https://doi.org/10.1080/03004430.2018.1545765 Mawarpury, M. (2020). Kecenderungan Adiksi Smartphone ditinjau dari jenis kelamin dan usia. 05, 24–37. Miller, J. G., Vrtička, P., Cui, X., Shrestha, S., Hosseini, S. M. H., Baker, J. M., & Reiss, A. L. (2019). Inter-brain synchrony in mother-child dyads during cooperation: An fNIRS hyperscanning study. Neuropsychologia, 124, 117–124. https://doi.org/10.1016/j.neuropsychologia.2018.12.021 Miyake, A., Friedman, N. P., Emerson, M. J., Witzki, A. H., Howerter, A., & Wager, T. D. (2020). The Unity and Diversity of Executive Functions and Their Contributions to Complex “Frontal Lobe” Tasks: A Latent Variable Analysis. Cognitive Psychology, 41(1), 49–100. https://doi.org/10.1006/cogp.1999.0734 Mu’min, S. A. (2013). Teori Pengembangan Kognitif Jian Piaget. Jurnal AL-Ta’dib, 6(1), 89–99. Nikken, P., & Schols, M. (2015). How and Why Parents Guide the Media Use of Young Children. Journal of Child and Family Studies, 24(11), 3423–3435. https://doi.org/10.1007/s10826-015-0144-4 Nisak, F. F., Munawaroh, H., & Abbas, S. (2022). The Effect of “ Kids Moderations ” Interactive Multimedia on Religious Moderation Attitudes in Early Childhood. Indonesian Journal of Early Childhood Education Research, 1(1), 38–47. https://doi.org/10.31958/ijecer.v1i1.5811 Novitasari, W., & Khotimah, N. (2013). Dampak Penggunaan Gadget Terhadap Interksi Sosial Anak Usia 5-6 Tahun. 05(03), 182–186. Nurjannah, N. (2017). Mengembangkan Kecerdasan emosiaonal Anak Usia Dini Melalui Keteladanan. Hisbah: Jurnal Bimbingan Konseling Dan Dakwah Islam, 14(1), 50–61. https://doi.org/10.14421/hisbah.2017.141-05 Pangastuti, R. (2017). Fenomena Gadget dan Perkembangan Sosial bagi Anak Usia Dini. Ijiece, 2(2), 165–174. Park, C., & Park, Y. R. (2014). The Conceptual Model on Smart Phone Addiction among Early Childhood. International Journal of Social Science and Humanity, 4(2), 147–150. https://doi.org/10.7763/IJSSH.2014.V4.336 Peñacoba, C., & Catala, P. (2019). Associations Between Breastfeeding and Mother–Infant Relationships: A Systematic Review. Breastfeeding Medicine, 14(9), 616–629. https://doi.org/10.1089/bfm.2019.0106 Pérez-Salas, C. P., Ramos, C., Oliva, K., & Ortega, A. (2016). Bifactor modeling of the behavior rating inventory of executive function (BRIEF) in a Chilean sample. Perceptual and Motor Skills, 122(3), 757–776. https://doi.org/10.1177/0031512516650441 Pianta, R. C. (2001). Student-teacher relationship scale: Professional manual. Psychological Assessment Resources. Priyanti, N., & Jhoni Warmansyah. (2021). The Effect of Loose Parts Media on Early Childhood Naturalist Intelligence. JPUD - Jurnal Pendidikan Usia Dini, 15(2), 239–257. https://doi.org/10.21009/jpud.152.03 Putri, A. R. H., & Rahmasari, D. (2021). Disregulasi Emosi pada Perempuan Dewasa Awal yang Melakukan Self Injury. Character: Jurnal Penelitian Psikologi, 1–16. Putri, C. I. H., & Primana, L. (2018). Gambaran Perilaku Disregulasi Emosi Anak Prasekolah Usia 3-4 Tahun. Jurnal Ilmiah Psikologi Terapan, 6(1), 102. https://doi.org/10.22219/jipt.v6i1.5113 Rachmat, I. F., Hartati, S., & Erdawati. (2021a). Pengaruh Kecanduan Gawai Terhadap Disregulasi Emosi Anak Usia Dini. Journal of Chemical Information and Modeling, 53(9), 1689–1699. https://ojs3.umc.ac.id/index.php/JJB/article/view/1726 Rachmat, I. F., Hartati, S., & Erdawati, E. (2021b). Family Cohesion, Interpersonal Communication, and Smartphone Addiction: Does It Affect Children’s Emotional Dysregulation? Jurnal Cakrawala Pendidikan, 40(2), 279–291. https://doi.org/10.21831/cp.v40i2.34214 Radliya, N. R., Apriliya, S., & Zakiyyah, T. R. (2017). Pengaruh Penggunaan Gawai Terhadap Perkembangan Sosial Emosional Anak Usia Dini. Jurnal Paud Agapedia, 1(1), 1–12. https://doi.org/10.17509/jpa.v1i1.7148 Riggs, N. R., Jahromi, L. B., Razza, R. P., Dillworth-Bart, J. E., & Mueller, U. (2016). Executive function and the promotion of social–emotional competence. Journal of Applied Developmental Psychology, 27(4), 300–309. https://doi.org/10.1016/j.appdev.2006.04.002 Roberts, M. Z., Flagg, A. M., & Lin, B. (2022). Context matters: How smartphone (mis)use may disrupt early emotion regulation development. New Ideas in Psychology, 64, 100919. https://doi.org/10.1016/j.newideapsych.2021.100919 Rubinsztein, D. C., Gestwicki, J. E., Murphy, L. O., & Klionsky, D. J. (2007). Potential therapeutic applications of autophagy. Nature Reviews Drug Discovery, 6(4), 304–312. https://doi.org/10.1038/nrd2272 Safitri, N. D., Hasanah, U., & Masruroh, F. (2023). The Development of Thematic Board Educational Game Tools to Train The Literacy Skills of Children 5-6 Years Old. Indonesian Journal of Early Childhood Educational Research, 1(2), 75–86. https://doi.org/10.31958/ijecer.v1i2.8156 Salsabilafitri, N., & Izzati, I. (2022). Pelaksanaan Pengembangan Sosial Anak di Taman Kanak-kanak Pertiwi 1 Kantor Gubernur Padang. Jurnal Pendidikan AURA (Anak Usia Raudhatul Atfhal). https://doi.org/10.37216/aura.v3i1.591 Sandoval, J., & Echandia, A. (1994). Behavior assessment system for children. Journal of School Psychology, 32(4), 419–425. https://doi.org/10.1016/0022-4405(94)90037-X Santrock, J. W. (2008). Psikologi Pendidikan (terjemahan). Kencana Prenada Media Group. Saraswati, S. W. E., Setiawan, D., & Hilyana, F. S. (2021). Dampak Penggunaan Smartphone pada Perilaku Anak Di Desa Muktiharjo Kabupaten Pati. WASIS : Jurnal Ilmiah Pendidikan, 2(2), 96–102. https://doi.org/10.24176/wasis.v2i2.6432 Sari, I. P., Warmansyah, J., Yuningsih, R., & Sari, M. (2023). The Effect of Realistic Mathematics Education ( RME ) Learning Approach on the Ability to Recognize Number Concepts in Children Aged 4-5 Years. Journal of Islamic Education Students, 3, 38–49. https://doi.org/10.31958/jies.v3i1.8654 Schmeichel, B. J., & Tang, D. (2015). Individual Differences in Executive Functioning and Their Relationship to Emotional Processes and Responses. Current Directions in Psychological Science, 24(2). https://doi.org/10.1177/0963721414555178 Setianingsih, Ardani, A. W., & Khayati, F. N. (2018). Dampak Penggunaan Gadget Pada Anak Usia Prasekolah Dapat Meningkatan Resiko Gangguan Pemusatan Perhatian Dan Hiperaktivitas. XVI(2), 191–205. Shaffer, A. (2017). Unique Contributions of Emotion Regulation and Executive Functions in Predicting the Quality of Parent – Child Interaction Behaviors. Journal of Family Psychology, 31(2), 150–159. Shah, P. E., Weeks, H. M., Richards, B., & Kaciroti, N. (2018). Early childhood curiosity and kindergarten reading and math academic achievement. Pediatric Research, 84(3), 380–386. https://doi.org/10.1038/s41390-018-0039-3 Sirois, M.-S., Bernier, A., & Lemelin, J.-P. (2019). Child temperamental anger, mother–child interactions, and socio-emotional functioning at school entry. Early Childhood Research Quarterly, 47, 30–38. https://doi.org/10.1016/j.ecresq.2018.10.005 Siskawati & Herawati. (2021). Efektivitas Media Loose Parts di PAUD Kelompok A Pada Masa Belajar Dari Rumah. Jurnal Pendidikan Luar Sekolah, 15(1), 41–47. https://doi.org/10.32832/jpls.v14i2.4629 Smith-Donald, R., Raver, C. C., Hayes, T., & Richardson, B. (2007). Preliminary construct and concurrent validity of the Preschool Self-regulation Assessment (PSRA) for field-based research. Early Childhood Research Quarterly, 22(2), 173–187. https://doi.org/10.1016/j.ecresq.2007.01.002 Smith-Etxeberria, K., & Eceiza, A. (2021). Mother-Child and Father-Child Relationships in Emerging Adults from Divorced and Non-Divorced Families. Social Sciences, 10(10), 382. https://doi.org/10.3390/socsci10100382 Soetjiningsih. (2018). Seri Psikologi Perkembangan : Perkembangan Anak Sejak Pembuahan Sampai dengan Kanak-Kanak Akhir. Kencana. Solfiah, Y. S., Risma, D., Hukmi, & Kurnia, R. (2020). Early Childhood Disaster Management Media Through Picture Story Books. JPUD - Jurnal Pendidikan Usia Dini, 14(1), 141–155. https://doi.org/10.21009/141.10 Sucipto, & Huda, N. (2016). Pola Bermain Anak Usia Dini di Era Gadget Siswa PAUD Mutiara Bunda Sukodono Sidoarjo (pp. 274–347). Sundus. (2017). The Impact of using Gadgets on Children. Journal of Depression and Anxiety, 07(01). https://doi.org/10.4172/2167-1044.1000296 Susanti, D., & Hasmira, M. S. P. (2023). Peran fungsi eksekutif otak pada perkembangan anak. 4(01), 22–32. Trinika, Y. (2015). Pengaruh Penggunaan Gadgetterhadap Perkembangan Psikososial Anak Usia Prasekolah (3- 6 Tahun) Di Tk Swasta Kristen Immanuel Tahun Ajaran 2014-2015. Turk, C. L., Heimberg, R. G., Luterek, J. A., Mennin, D. S., & Fresco, D. M. (2005). Emotion dysregulation in generalized anxiety disorder: A comparison with social anxiety disorder. Cognitive Therapy and Research, 29(1), 89–106. https://doi.org/10.1007/s10608-005-1651-1 Ulfah, M. (2020). DIGITAL PARENTING: Bagaimana Orang Tua Melindungi Anak-anak dari Bahaya Digital? Edu Publisher. Ulya, L., Sucipto, S., & Fathurohman, I. (2021). Analisis Kecanduan Game Online Terhadap Kepribadian Sosial Anak. Jurnal Educatio FKIP UNMA, 7(3), 1112–1119. https://doi.org/10.31949/educatio.v7i3.1347 Unde, A. A., Fatimah, J. M., & Hasanuddin, U. (2023). Komunikasi orang tua pekerja dalam menjaga kesehatan mental anak. 4, 39–51. Ursache, A., Blair, C., & Raver, C. C. (2012). The Promotion of Self-Regulation as a Means of Enhancing School Readiness and Early Achievement in Children at Risk for School Failure. Child Development Perspectives, 6(2), 122–128. https://doi.org/10.1111/j.1750-8606.2011.00209.x Ursache, A., Blair, C., Stifter, C., & Voegtline, K. (2013). Emotional reactivity and regulation in infancy interact to predict executive functioning in early childhood. Developmental Psychology, 49(1), 127–137. https://doi.org/10.1037/a0027728 Valiente, C., Swanson, J., & Eisenberg, N. (2012). Linking Students’ Emotions and Academic Achievement: When and Why Emotions Matter. Child Development Perspectives, 6(2), 129–135. https://doi.org/10.1111/j.1750-8606.2011.00192.x Vgontzas, A. N., Lin, H.-M., Papaliaga, M., Calhoun, S., Vela-Bueno, A., Chrousos, G. P., & Bixler, E. O. (2008). Short sleep duration and obesity: the role of emotional stress and sleep disturbances. International Journal of Obesity, 32(5), 801–809. Wahyuni, A. S., Siahaan, F. B., Arfa, M., Alona, I., & Nerdy, N. (2019). The Relationship between the Duration of Playing Gadget and Mental Emotional State of Elementary School Students. Open Access Macedonian Journal of Medical Sciences, 7(1), 148–151. https://doi.org/10.3889/oamjms.2019.037 Warmansyah, J., Zulhendri, Z., & Amalina, A. (2021). The Effectiveness of Lore Traditional Games Towards The Ability to Recognize The Concept of Numbers on Early Childhood. Ta’dib, 24(2), 79. https://doi.org/10.31958/jt.v24i2.2685 Wilson, D., & Gross, D. (2018). Parents ’ Executive Functioning and Involvement in Their Child ’ s Education : An. Journal of School Health, 88(4), 322–329. Wulandani, C., & Putri, M. A. (2022). Implementing Project-Based Steam Instructional Approach in Early Childhood Education in 5 . 0 Industrial Revolution Era. 1(1), 29–37. https://doi.org/10.31958/ijecer.v1i1.5819 Yan, J., Schoppe-Sullivan, S. J., & Feng, X. (2019). Trajectories of mother-child and father-child relationships across middle childhood and associations with depressive symptoms. Development and Psychopathology, 31(04), 1381–1393. https://doi.org/10.1017/S0954579418000809 Yansyah, Y., Hamidah, J., & Ariani, L. (2021). Pengembangan Big Book Storytelling Dwibahasa untuk Meningkatkan Literasi Anak Usia Dini. Jurnal Obsesi : Jurnal Pendidikan Anak Usia Dini, 6(3), 1449–1460. https://doi.org/10.31004/obsesi.v6i3.1779 Yunianggraeni. (2019). Pengawasan Orang Tua Dalam Penggunaan Gadget Pada Anak Di Ra Yapsisumberjaya Lampung Barat. Skripsi, 561(3), S2–S3. Zaini, M., & Soenarto, S. (2019). Persepsi Orangtua Terhadap Hadirnya Era Teknologi Digital di Kalangan Anak Usia Dini. Jurnal Obsesi : Jurnal Pendidikan Anak Usia Dini, 3(1), 254. https://doi.org/10.31004/obsesi.v3i1.127 Zelazo, Z., Blair, P. D., B.W, C., & Illoughby, M. (2016). Executive Function: Implications for Education. NCER 2017-2000. National Center for Education Research, 1(2).

FAKTOR-FAKTOR YANG MEMPENGARUHI MORTALITAS PADA PASIEN DENGAN FRAKTUR COSTA: Literature Review Anna Tri Wahyuni1), Masfuri2), Liya Arista3)1,2,3 Fakultas Ilmu Keperawatan Universitas Indonesia ABSTRAK Cedera paling umum yang terjadi pada trauma tumpul adalah fraktur costa (patah tulang iga/rusuk) dimana mekanisme cedera berpotensi mengancam jiwa. Pasien fraktur costa yang menunjukkan tingkat keparahan trauma lebih dari 90% melibatkan kepala, perut dan ekstremitas. Nyeri yang dirasakan akibat dari fraktur costa berkontribusi pada gangguan pernafasan, peningkatan resiko pneumonia dan gagal nafas yang meningkatkan angka morbiditas dan mortalitas. Pedoman penanganan fraktur costa sangat dibutuhkan untuk terjadinya komplikasi. Studi literature ini bertujuan menganalisis faktor-faktor yang mempengaruhi mortalitas pada pasien fraktur costa. Metode penulisan artikel ini menggunakan literature review yang didapat melalui 5 online database yaitu Sage Publishing, Science Direct, SpringerLink, Pub Med dan Google Scholar. Kriteria inklusi jurnal terkait meliputi: free fulltext, berbahasa Indonesia atau Bahasa asing lainnya, metode penelitian prospective, retrospective, case-control, cohort dan terbit antara tahun 2004-2021. Kata kunci yang yang digunakan dalam pencarian adalah “Respiratory depression OR Respiratory failure AND fraktur ribs AND Mortality”. Dari pencarian artikel diperoleh hasil akhir sebanyak 7 artikel yang relevan dan dilakukan proses review. Artikel tersebut menunjukkan hasil bahwa angka mortalitas dipengaruhi oleh faktor usia, skor keparahan cedera, jumlah patah tulang rusuk, dan implementasi penanganan infeksi. Faktor usia, tingkat keparahan cedera dan jumlah tulang rusuk yang patah menentukan tinggi rendahnya angka mortalitas pasien fraktur costa. Penanganan yang tepat dan manajemen nyeri yang sesuai dapat mempengaruhi penurunan angka morbiditas dan mortalitas pasien dengan fraktur costa. Pengembangan intervensi perawatan pasien fraktur costa terkait manajemen nyeri dan kontrol infeksi menjadi penelitian menarik selanjutnya.Kata kunci : Depresi pernafasan, gagal nafas, fraktur iga, angka kematian, angka kesakitanABSTRACT The most common injury in blunt trauma is a rib fracture, where the mechanism of injury is potentially life-threatening. Patients with rib fracture whose severity of the injury is greater than 90% are associated with damage to the head, abdomen, and extremities. Pain from rib fractures contributes to respiratory failure, increasing the risk of pneumonia and respiratory failure, which increases morbidity and mortality. Recommendations are needed for the treatment of complicated rib fractures. This literature study aims to analyze the factors that influence mortality in rib fracture patients. The method of writing this article uses a literature review sourced from 5 online databases, namely Sage Publishing, Science Direct, SpringerLink, Pub Med, and Google Scholar. The inclusion criteria for related journals included: free full text, in Bahasa or another foreign language, prospective, retrospective, case-control, cohort study method, and published between 2004 and 2021. Keywords used in the search were: "respiratory depression OR respiratory failure AND rib fractures AND death." From the article search results, we obtained 7 relevant articles which are the final results and a review process is carried out. The article showed that mortality was influenced by age, injury severity score, number of rib fractures, and infection control practices. The mortality rate of patient with rib fracture is determined by Factors such as age, severity of injury, and number of rib fractures. Appropriate care and adequate pain management can help reduce morbidity and mortality in patients with rib fractures. Another interesting research is the development of interventions in the treatment of rib fracture patients related to pain management and infection control.Key words: respiratory depression; respiratory failure; rib fracture; mortality; morbidity. Alamat korespondensi: RSUD Dr.Kanujoso Djatiwibowo Jalan MT.Haryono No 656 Ringroad BalikpapanEmail: annazahra30@gmail.com PENDAHULUAN Fraktur costa adalah cedera pada dada karena trauma tumpul, tajam atau kondisi patologis angka morbiditas dan mortilitas. Berdasarkan Western Trauma Association (WTA) sekitar 10% kematian pada orang dewasa muda disebabkan oleh cedera patah tulang rusuk yang melibatkan kepala, perut dan ekstremitas. Sebaliknya, pasien lanjut usia dengan patah tulang rusuk memiliki setidaknya 20% kematian yang secara langsung menyebabkan gagal napas progresif dan pneumonia (Brasel et al., 2017). Risiko pneumonia meningkat sebesar 27%, dan kematian meningkat sebesar 19% untuk setiap fraktur costa lebih dari 2 pada kelompok lanjut usia (Wanek & Mayberry, 2004). Pasien dengan trauma dada atau fraktur costa harusnya dilakukan pemantauan ketat sejak masuk rumah sakit, 24 jam pertama merupakan identifikasi awal adanya komplikasi yang menyebabkan depresi pernafasan. Menurut penelitian Coary, et.al (2020) fraktur costa adalah cedera paling serius pada 55% pasien berusia di atas 60 tahun yang menyebabkan kematian karena 90% dari patah tulang rusuk menunjukkan cedera tambahan pada pemeriksaan sistemik. Trauma langsung dan hipoventilasi yang diinduksi nyeri menyebabkan komplikasi pernafasan sehingga menjadi beban morbiditas dan mortalitas. Komplikasi yang sering terjadi adalah pneumotoraks diikuti hemothoraks, kontusio paru dan flail chest.Nyeri adalah suatu pengalaman sensorik yang multidimensional dengan fenomena yang berbeda dalam intensitas (ringan,sedang, berat), kualitas (tumpul, seperti terbakar, tajam), durasi (transien, intermiten,persisten), dan penyebaran (superfisial atau dalam, terlokalisir atau difus) (Bahrudin, 2018). Induksi nyeri pada pasien dengan fraktur costa menyebabkan pasien kesulitan bernafas dimana keparahan memar paru yang mendasarinya signifikan dengan terjadinya hipoksemia atau gangguan pernafasan. Hal ini menyebabkan pasien cenderung membatasi pergerakan dan menjadi tirah baring lama. Kondisi tirah baring lama menyebabkan tubuh mengalami penurunan berbagai fungsi secara sistematis, yang disebut dengan sindroma dekondisi dan rentan terjadinya infeksi (Hashem, Nelliot, & Needham, 2016; Hunter, Johnson, & Coustasse, 2014; Phelan, Lin, Mitchell, & Chaboyer, 2018 dalam Ananta & Fitri, 2020).Fraktur costa atau patah tulang rusuk secara klinis penting disebabkan tiga hal yaitu: sebagai penanda penyakit serius cedera intrathoraks dan perut, sebagai sumber rasa sakit yang signifikan, dan sebagai prediktor untuk kerusakan paru, terutama pada pasien usia lanjut. Organ perut yang paling sering terluka adalah hati dan limpa. Pasien dengan patah tulang rusuk kanan, memiliki 19% hingga 56% kemungkinan cedera hati, sedangkan patah tulang sisi kiri memiliki 22% hingga 28% kemungkinan cedera limpa (Wanek & Mayberry, 2004). Kematian pada orang dewasa dan lansia cenderung terjadi kemudian (≥72 jam setelah masuk) dan biasanya sebagai akibat dari kegagalan multi-organ yang dipicu oleh insufisiensi pernapasan dan pneumonia sehingga tingkat kematian secara keseluruhan, tanpa memandang usia, diperkirakan antara 10 dan 12% (Wanek & Mayberry, 2004). Tingkat mortalitas untuk pasien trauma usia lanjut yang mengalami patah tulang rusuk lebih besar daripada mereka yang tidak mengalami cedera toraks (Coary, et.al, 2020). Penelitian yang dilakukan Marini, et.al, (2021) menyatakan indikator penyebab kematian pada pasien fraktur costa dengan atau tanpa trauma kepala dan cedera organ adalah usia, jenis kelamin, ISS (Injury Severe Score), dan GCS (Glasglow Coma Scale).Berdasarkan uraian diatas maka peneliti ingin menganalisis faktor-faktor yang mempengaruhi angka morbiditas dan mortalitas pada pasien dengan fraktur costa untuk meningkatkan pemahaman tentang penanganan fraktur costa serta mengidentifikasi dari beberapa artikel terkini dalam mengurangi mortalitas. METODE PENELITIAN Metode penulisan artikel ini menggunakan literature review yaitu studi yang berfokus pada hasil penulisan yang berkaitan dengan topik, tema atau variabel penulisan.dan dipakai untuk menghimpun data atau sebuah sintesa sumber-sumber yang berhubungan dengan topik penelitian (Nursalam, 2017). Didapatkan 5 database yang dilakukan melalui pencarian elektronik dari yaitu Sage Publishing, Science Direct, SpringerLink, Pub Med dan Google Scholar. Kriteria inklusi telaah jurnal ini adalah free fulltext, berbahasa Indonesia atau bahasa asing lainnya, dengan metode penelitian prospective, retrospective, case-control, cohort dan terbit tahun 2004-2021. Kata kunci yang yang digunakan dalam pencarian adalah “Respiratory depression OR Respiratory failure AND fraktur ribs AND Mortality”. HASIL DAN PEMBAHASAN Berdasarkan hasil studi literature terdapat banyak faktor yang mempengaruhi terjadinya depresi pernafasan pada pasien fraktur costa yang dapat menyebabkan kematian. Terdapat 17.500 artikel yang muncul setelah dilakukan telusur berdasarkan kata kunci dalam google scholar, 10.000 artikel tidak masuk kriteria inklusi, 350 artikel duplikat dengan database yang lain. Kemudian sisanya disaring kembali berdasarkan hasil abstrak, metode dan hasil temuan sesuai topik peneliti yang diinginkan dan diperoleh 7 artikel yang relevan dan tersedia dalam bentuk fulltext. Beberapa penelitian terkait pencegahan depresi pernafasan pada fraktur costa berfokus pada manajemen nyeri baik secara farmakologis maupun non farmakologis. Penanganan dan pemantauan yang ketat dapat mengurangi komplikasi yang menyebabkan terjadinya depresi pernafasan. Berikut faktor-faktor yang mempengaruhi angka morbiditas dan mortalitas pada fraktur costa menurut Coary, et.al (2020) yaitu: (1) Usia, pasien berusia > 65 tahun memiliki kematian 2-5 kali lebih tinggi dibandingkan usia dibawahnya pada kondisi fraktur costa lebih dari dua. Pasien dengan komorbid sering menjadi faktor penyulit ditambah dengan kondisi paru-paru yang buruk (misal: perokok). Faktor pemulihan menjadi terhambat disebabkan osteoporosis, sistem pernafasan yang buruk, gangguan pertukaran gas dan tergambar dari lama rawat inap. (2) Jumlah patah tulang, dari beberapa penelitian meta-analisis diperoleh hasil jumlah absolut fraktur tulang rusuk yang berjumlah >2 maka dua kali lebih mungkin meninggal dunia dibandingkan pasien dengan 1-2 patah tulang rusuk. (3) Posisi anatomi patah tulang, Fraktur costa bilateral memiliki resiko kematian lebih tinggi dimana segmen flail chest menghasilkan gerak paradox yang menyebabkan pergerakan dinding dada mengarah kedalam saat inspirasi sedangkan tulang rusuk yang sehat bergerak keluar sehingga ventilasi tidak adekuat dan terjadi depresi pernafasan dan kematian. Berbeda dengan penelitian yang dilakukan Brasel et al., (2006) faktor yang paling mempengaruhi kematian adalah faktor usia ditandai dengan Injury Severity Score (ISS) jika dikaitkan dengan peningkatan terjadinya pneumonia. Analisis yang menyatakan komorbiditas mempengaruhi kematian hal ini disertai dengan faktor usia bukan karena faktor komorbiditas murni. Komorbiditas yang biasanya menyertai fraktur costa menurut penelitian adalah komorbiditas yang spesifik seperti gagal jantung kongestif, aritmia, gagal ginjal, penyakit hati, kanker metastatik dan penyakit neurologis.Pada penelitian Bulger et al dalam Wanek & Mayberry, (2004), membandingkan pasien yang berusia minimal 65 tahun keatas dengan usia 18-64 tahun dengan metode cohort pada kasus fraktur costa pada kelompok >65 tahun memiliki dua kali mortalitas dan morbiditas yang tinggi. Risiko pneumonia meningkat sebesar 27%, dan kematian meningkat sebesar 19% untuk setiap fraktur tulang rusuk tambahan pada kelompok lanjut usia.Nyeri adalah keluhan yang paling dirasakan oleh pasien dengan fraktur costa. Oleh sebab itu penanganan manajemen nyeri untuk mengontrol nyeri terus-menerus dan mencegah depresi pernafasan harus diberikan terapi yang agresif dengan pendekatan multimodalitas. Penelitian yang dilakukan oleh Peek, et.al, (2019) dengan membandingkan pemberian analgesik dengan 4 metode yaitu analgesia epidural, analgesia intravena, blok paravertebral dan blok intercostal, diperoleh hasil berdasarkan systematic review dan meta-analysis analgesia epidural signifikan mengurangi rasa sakit dibandingkan intervensi yang lain. Intervensi keperawatan sendiri menekankan pada terapi non farmakologis untuk kontrol nyeri pada pasien fraktur. Terapi nonfarmakologis dengan guided imagery dapat mengurangi intensitas dan skala nyeri pada pasien fraktur. Guided imagery mempengaruhi hampir semua fisiologis sistem kontrol tubuh yaitu pernapasan, denyut jantung, tekanan darah, tingkat metabolisme dalam sel, mobilitas dan sekresi gastrointestinal, fungsi seksual, dan bahkan respon imun (Rossman, 2000). Intervensi ini juga dapat mempercepat penyembuhan pasien dan mengurangi hari rawat inap (Forward et.al, 2015) Gambar 1. Algorithma fraktur costa (Brasel K.J, et.al, 2016).Western Trauma Association (WTA) menyatakan algorithma penanganan fraktur costa sebagai suatu observasi atau pemantauan ketat pada fraktur costa lebih dari 2 patah tulang (Brasel et.al, 2017). Berdasarkan algoritma diatas maka pasien dengan patah tulang rusuk >2 dengan usia lebih dari 65 tahun jika pada observasi kurang dari 24 jam menunjukkan peningkatan pada depresi pernafasan maka segera pindahkan ke ICU dan pertimbangkan penggunaan ventilator dan operasi rib fixaxion. Penggunaan terapi analgesia epidural digunakan untuk kontrol nyeri dilanjutkan batuk efektif, tehnik relaksasi nafas dalam dan mobilisasi dini (Brasel et.al, 2017). Analisis terkait studi literatur untuk memperkuat hasil analisis terdapat pada masing-masing artikel dibawah ini. Tabel 1. Artikel terkait faktor-faktor yang mempengaruhi terjadinya depresi pernafasan pada pasien dengan fraktur costa.Study citationMetode penelitian Desain PenelitianSampel dan Jumlah sampelHasil temuanA multidisciplinary clinical pathway decreases rib fracture–associated infectious morbidity and mortality in high-risk trauma patientsTodd,et.al,(2006)prospective cohort study Non eksperimental150 pasien dari Februari 2002-Oktober 2004 dengan > 45 tahun dan>4 patah tulang rusuk.Diperoleh hasil usia, skor keparahan cedera, dan jumlah patah tulang rusuk, jalur klinis menurunkan mekanisme hari tergantung ventilator, lama rawat inap, morbiditas infeksi, dan mortalitas dengan (interval kepercayaan 95% [CI] P<0.01).Predicting outcome of patients with chest wall injuryPressley, et.al, (2012)retrospectively reviewedNon eksperimental649 pasien (Juni 2008 hingga Februari 2010) termasuk usia, jumlah patah tulang, cedera bilateral, adanya kontusio paru, klasifikasi memar, LOS, masuk ICU, ventilasi mekanikSebuah sistem penilaian sederhana memprediksi kemungkinan bahwa pasien akan memerlukan ventilasi mekanik dan perawatan yang berkepanjangan. Skor 7 atau 8 memprediksi peningkatan risiko kematian, penerimaanke ICU, dan intubasi. Skor 5 memprediksi lama tinggal yang lebih lama dan periode ventilasi yang lebih lama. Factors Affecting Pneumonia Occurring to Patients with Multiple Rib FracturesByun & Kim., (2013).retrospectively reviewedNon eksperimentalData rekam medis 327 pasien laki-laki rata-rata usia 53 tahun dengan fraktur costa akibat kecelakaan dari Januari 2002- Desember 2008.Faktor yang mempengaruhi pneumonia pada pasien dengan fraktur tulang rusuk multipel dalam analisis multivariat termasuk usia (p=0,004), ISS (p＜0,001), dan skor tulang rusuk(p=0,038). Penggunaan antibiotik tidak berhubungan dengan kejadian pneumonia (p=0,28).Determinants of Mortality in Chest Trauma PatientsEkpe & Eyo, (2014)Retrospective and prospective Non eksperimental149 pasien dengan trauma thoraks 121 laki-laki, 28 perempuan dari Januari 2007-Desember 2011Variabel bebas, umur, jenis kelamin dan jenis cedera dada tidak terbukti berkorelasi dengan mortalitas dengan nilai P >0,05. Namun adanya cedera organ ekstra toraks terkait, skor MEWS saat masuk tinggi> 9, cedera pada interval presentasi lebih dari 24 jam, dan cedera dada yang parah ditandai dengan keterlibatan dada bilateral yang berkorelasi positif dengan mortalitas dengan nilai P <0,05.The number of displaced rib fractures is more predictive for complications in chest trauma patientsChien et.al, (2017)retrospectively reviewedNon eksperimentalJanuari 2013 -Mei 2015 diperoleh data di rumah sakit dengan total pasien 3151. Pasien yang dirawat dengan trauma dada dan patah tulang rusuk, termasuk cedera otak, limpa, panggul atau hatiJumlah patah tulang rusuk yang bergeser bisa menjadi prediktor kuat untuk berkembangnya penyakit paru-paru komplikasi. Untuk pasien dengan kurang dari tiga patah tulang rusuk tanpa perpindahan tulang rusuk dan paru-paru awal atau cedera organ lainnya, manajemen rawat jalan bisa aman dan efisien.Is the number of rib fractures a risk factor for delayed complications? Flores-Funes, et.al, (2020)Retrospective case–control studyNon eksperimentalPasien yang dirawat dengan diagnosis patah tulang rusuk antara 2010 dan 2014, diperoleh 141 pasien.Tidak ada perbedaan dalam karakteristik dasar pasien (usia, jenis kelamin dan Indeks Komorbiditas Charlson) antara kedua kelompok. Perbedaan ditemukan pada jumlah fraktur pada kelompok tanpa komplikasi p>0,05 (tidak signifikan) pada kelompok dengan komplikasi, (p=0,05) dan pada penurunan kadar hemoglobin (p=0,01). Hari rawat inap bervariasi pada setiap kelompok tetapi tanpa signifikansi statistik (p=0,11). Kesimpulan: Jumlah fraktur iga yang paling baik memprediksi munculnya komplikasi (delayed pleuro-pulmonary) dan perdarahan yang lebih besar) adalah patah tulang rusuk 3 atau lebihPredictors of mortality in patients with rib fracturesMarini, et.al, (2021) Retrospective review Non eksperimental1188 pasien patah tulang rusuk dan cedera tambahan yang dirawat selama Januari 2013-Desember 2014; 800 laki-laki dan 388 perempuan Usia, GCS, jenis kelamin laki-laki, dan Injury Severity Score (ISS) tetapi tidak jumlah patah tulang rusuk dan/atau Pulmonary contusion merupakan prediksi kematian. Peningkatan mortalitas pada pasien patah tulang rusuk dimulai pada usia 65-80 tahun tanpa peningkatan lebih lanjut. Jumlah patah tulang rusuk bukan faktor independen peningkatan mortalitas terlepas dari usia. Severe traumatic brain injury adalah penyebab kematian paling umum pada pasien usia 16-65 tahun, dibandingkan dengan komplikasi pernapasan pada pasien berusia 80 tahun atau lebih. Banyak penelitian yang telah dilakukan untuk menentukan faktor prediktor kematian pada pasien fraktur costa. Dari 7 artikel di atas terdapat berbagai bukti yang mempengaruhi kematian akibat fraktur costa dengan metode penelitian yang berbeda.Penelitian Chien, et.al, (2017) dan Flores-Funes, et.al, (2020) menunjukkan hasil yang hampir sama dimana jumlah fraktur costa yang >2 akan meningkatkan angka morbiditas dan mortalitas dikarenakan faktor komplikasi pada paru. Berbeda dengan penelitian yang dilakukan Marini, et.al, (2021) yang menyatakan jumlah dari fraktur costa tidak memprediksi peningkatan mortalitas terlepas dari usia. Menurut peneliti faktor usia menjadi prediktor utama dalam menentukan angka mortalitas pada pasien dengan fraktur costa, dimana peningkatan mortalitas pada pasien patah tulang rusuk dimulai pada usia 65-80 tahun ke atas.Penelitian yang dilakukan Todd et.al,(2006) menghasilkan hipotesa bahwa usia, skor keparahan cedera, dan jumlah patah tulang rusuk, dan implementasi jalur klinis signifikan dengan penurunan lama perawatan di unit perawatan intensif, lama rawat inap di rumah sakit, infeksi pneumonia, dan mortalitas. Maka semakin lanjut usia, tingkat keparahan yang tinggi dan jumlah patah tulang rusuk bilateral atau >2 dapat meningkatkan angka morbiditas dan mortalitas pasien dengan fraktur costa.Penelitian Pressley et.al, (2012) dilakukan dengan melakukan analisis dengan menggunakan trauma dada scoring system dimana skor >7 memprediksi peningkatan risiko kematian, penerimaan ke ICU, dan intubasi. Penilaian scoring system ini dapat digunakan untuk memprediksi kemungkinan pasien akan memerlukan ventilasi mekanik dan perawatan yang berkepanjangan sehingga dapat memperparah penyakit, menimbulkan infeksi oportunistik dan menyebabkan resiko mortalitas.Penelitian Ekpe & Eyo, (2014) menggunakan system MEWS (modified early warning signs) untuk menganalis faktor prognosis pada pasien dengan trauma dada. Sebagai variabel bebas, umur, jenis kelamin dan jenis cedera dada tidak terbukti berkorelasi dengan mortalitas dengan nilai P >0,05. Namun adanya cedera organ ekstra toraks terkait, skor MEWS saat masuk tinggi> 9, dimana interval presentasi lebih dari 24 jam dengan cedera dada yang parah ditandai dengan keterlibatan dada bilateral, berkorelasi positif pada mortalitas. Berbeda dengan penelitian sebelumnya Byun & Kim., (2013) dimana faktor umur berpengaruh pada terjadinya infeksi pneumonia dan meningkatkan angka mortilitas dengan atau tanpa diikuti tingkat keparahan pada trauma dada.Berdasarkan analisis diatas terdapat persamaan hasil penelitian dimana rata-rata metode penelitian yang dilakukan dengan menggunakan retrospective review non eksperimental. Peneliti mengamati data rekam medis dari beberapa rentang waktu dengan kriteria inklusi menderita patah tulang rusuk lebih dari dua. Namun, terdapat kriteria yang berbeda-beda pula dimana peneliti memasukkan trauma tambahan seperti brain injury dan cedera pada organ yang lain. Jumlah sampel antara penelitian satu dengan yang lain juga berbeda dari ratusan hingga ribuan data yang dianalisis. Hal ini menyebabkan hasil penelitian yang diperoleh sedikit berbeda antara satu dengan yang lain.Manajemen fraktur costa berfokus pada manajemen nyeri yang adekuat, batuk efektif, relaksasi nafas dalam dan mobilisasi dini (Brasel et al., 2017). Berdasarkan beberapa penelitian manajemen nyeri pada pasien orthopedic terutama pasca operasi adalah dengan guided imagery. The American Holistic Nurses Association menyatakan guided imagery adalah modalitas holistik yang membantu klien dalam menghubungkan pengetahuan batin mereka pada pemikiran, perasaan, dan tingkat penginderaan, mempromosikan penyembuhan bawaan mereka dengan kemampuan bersama-sama memandu klien mengatasi stres; resolusi konflik; masalah pemberdayaan diri; dan persiapan medis-bedah (Integrative & Review, 2016). Oleh sebab itu, guided imagery tepat jika digunakan pada managemen nyeri non farmakologis yang diterapkan dalam intervensi keperawatan.Dalam teori keperawatan Jean Watson tentang Transpersonal Caring mendefinisikan hubungan manusia yang bersifat caring, bersatu dengan orang lain dengan menghargai klien seutuhnya termasuk keberadaannya di dunia (Alligood, 2014). Watson menyatakan kepedulian transpersonal caring adalah dasar dari teori kepedulian manusia dimana fokus dari kepedulian transpersonal adalah pada peduli, penyembuhan, dan keutuhan, bukan pada penyakit, sakit dan patologi yang mencakup 10 faktor karatif dalam konsep utamanya (Integrative & Review, 2016). Sesuai dengan teori Watson, Guided Imagery (GI) menggabungkan kedua sains (melalui praktik berbasis bukti) dan seni (melalui aplikasi untuk berlatih) untuk mengobati rasa sakit pasien menggunakan imaginasi terbimbing dan teknik relaksasi nafas dalam. Kombinasi dengan terapi obat, GI menyediakan rezim pengobatan holistik untuk manajemen nyeri untuk menenangkan pikiran dan merilekskan tubuh mereka, memberikan kesempatan bagi klien untuk menciptakan lingkungan penyembuhan internalnya sendiri (Integrative & Review, 2016).Intervensi keperawatan untuk batuk efektif dan mobilisasi dini termasuk poin penting dalam manajemen perawatan pasien fraktur costa. Batuk efektif adalah suatu metode batuk dengan benar dan pasien dapat mengeluarkan dahak secara maksimal untuk mengeluarkan sekret dari saluran pernapasan bawah (Potter dan Perry, 2006). Mobilisasi sendiri dapat menghasilkan outcome yang baik bagi pasien seperti meningkatkan pertukaran gas, mengurangi angka Ventilator Associated Pneumoia (VAP), mengurangi durasi penggunaan ventilator, dan meningkatkan kemampuan fungsional jangka panjang (Green, Marzano, Leditschke, Mitchell, & Bissett, 2016 dalam Ananta & Fitri, 2020). Oleh sebab itu, kedua intervensi ini perlu diteliti lebih lanjut guna mengembangkan riset terkait manajemen pasien fraktur costa. SIMPULAN Pasien dengan usia lanjut dengan patah tulang rusuk atau fraktur costa biasanya menunjukkan tingkat kelemahan, multi-morbiditas, dan kompleksitas medis yang tinggi (Coary, et.al, 2020). Hal ini tentu menjadi penghambat dalam faktor penyembuhan tulang dan dapat meningkatkan angka mortalitas. Pemaparan hasil analisis menggambarkan faktor usia, cedera tulang rusuk atau costa bilateral lebih dari 2, terjadinya komplikasi dan cedera pada organ lain menyebabkan pasien harus dirawat di ruang ICU lebih lama karena resiko infeksi dan komplikasi yang dapat meningkatkan angka morbiditas dan mortalitas.Terlepas dari faktor usia, tingkat keparahan cedera dan jumlah tulang rusuk yang patah menentukan haluaran pasien yang lebih baik. Penanganan fraktur costa yang tepat yang berfokus pada kontrol kerusakan, manajemen nyeri, fiksasi seleksi, dan kualitas hidup mempengaruhi penurunan angka morbiditas dan mortalitas pasien dengan fraktur costa. Kedudukan dan peran perawat spesialis dalam tugas mengatur asuhan klien dengan kompleksitas tinggi menjadi sangat penting (Masfuri, et.all, 2019) SARAN Penelitian klinis terkait implementasi keperawatan berbasis kasus masih jarang dilakukan. Implementasi keperawatan pada pasien dengan fraktur costa terkait manajemen nyeri dan kontrol infeksi menjadi penelitian yang menarik untuk dilakukan karena hal ini menjadi indikator faktor yang mempengaruhi angka mortalitas pasien dengan fraktur costa. DAFTAR PUSTAKA Alligood Raile Martha,2014, Nursing Theorits and their Work, 8th edition, by Mosby, an imprint of Elsevier IncAnanta Tanujiarso, B., & Fitri Ayu Lestari, D. (2020). Mobilisasi Dini Pada Pasien Kritis Di Intensive Care Unit (Icu): Case Study. Jurnal Keperawatan Widya Gantari Indonesia, 4(1), 59–66.Bahrudin, M. (2018). Patofisiologi Nyeri (Pain). Saintika Medika, 13(1), 7. https://doi.org/10.22219/sm.v13i1.5449Brasel, K. J., Guse, C. E., Layde, P., & Weigelt, J. A. (2006). Rib fractures: Relationship with pneumonia and mortality. Critical Care Medicine, 34(6), 1642–1646. https://doi.org/10.1097/01.CCM.0000217926.40975.4BBrasel, K. J., Moore, E. E., Albrecht, R. A., De Moya, M., Schreiber, M., Karmy-Jones, R., Rowell, S., Namias, N., Cohen, M., Shatz, D. V., & Biffl, W. L. (2017). Western trauma association critical decisions in trauma: Management of rib fractures. Journal of Trauma and Acute Care Surgery, 82(1), 200–203. https://doi.org/10.1097/TA.0000000000001301Byun, J. H., & Kim, H. Y. (2013). Factors affecting pneumonia occurring to patients with multiple rib fractures. Korean Journal of Thoracic and Cardiovascular Surgery, 46(2), 130–134. https://doi.org/10.5090/kjtcs.2013.46.2.130Chien, C. Y., Chen, Y. H., Han, S. T., Blaney, G. N., Huang, T. S., & Chen, K. F. (2017). The number of displaced rib fractures is more predictive for complications in chest trauma patients. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, 25(1), 19. https://doi.org/10.1186/s13049-017-0368-yCoary, R., Skerritt, C., Carey, A., Rudd, S., & Shipway, D. (2020). New horizons in rib fracture management in the older adult. Age and Ageing, 49(2), 161–167. https://doi.org/10.1093/ageing/afz157Ekpe, E. E., & Eyo, C. (2014). Determinants of mortality in chest trauma patients. Nigerian Journal of Surgery : Official Publication of the Nigerian Surgical Research Society, 20(1), 30–304. https://doi.org/10.4103/1117-6806.127107Forward, J. B., Greuter, N. E., Crisall, S. J., & Lester, H. F. (2015). Effect of Structured Touch and Guided Imagery for Pain and Anxiety in Elective Joint Replacement Patients--A Randomized Controlled Trial: M-TIJRP. The Permanente Journal, 19(4), 18–28. https://doi.org/10.7812/TPP/14-236Flores-Funes, D., Lluna-Llorens, A. D., Jiménez-Ballester, M. Á., Valero-Navarro, G., Carrillo-Alcaráz, A., Campillo-Soto, Á., & Aguayo-Albasini, J. L. (2020). Is the number of rib fractures a risk factor for delayed complications? A case–control study. European Journal of Trauma and Emergency Surgery, 46(2), 435–440. https://doi.org/10.1007/s00068-018-1012-xIntegrative, A., & Review, L. (2016). jhn. 1–10.Marini, C. P., Petrone, P., Soto-Sánchez, A., García-Santos, E., Stoller, C., & Verde, J. (2021). Predictors of mortality in patients with rib fractures. European Journal of Trauma and Emergency Surgery, 47(5), 1527–1534. https://doi.org/10.1007/s00068-019-01183-5Masfuri Masfuri, Agung Waluyo, Yati Afiyanti, Achir Yani S. Hamid (2019) Educational background and clinical nursing tasks performed by nurses in Indonesian hospitals. Enfermería Clínica. 29 (2), 418-423. https://doi.org/10.1016/j.enfcli.2019.04.061.Nursalam. (2017). Metodologi Penelitian Ilmu Keperawatan: Pendekatan Praktis. (P. P. Lestari, Ed.) (4th ed.). Jakarta: Salemba Medika.Peek, J., Smeeing, D. P. J., Hietbrink, F., Houwert, R. M., Marsman, M., & de Jong, M. B. (2019). Comparison of analgesic interventions for traumatic rib fractures: a systematic review and meta-analysis. European Journal of Trauma and Emergency Surgery, 45(4), 597–622. https://doi.org/10.1007/s00068-018-0918-7Potter&Perry. (2006). Buku ajar Fundamental Keperawatan Konsep, Proses, dan Praktik. Jakarta: Penerbit Buku Kedokteran, EGC.Pressley, C. M., Fry, W. R., Philp, A. S., Berry, S. D., & Smith, R. S. (2012). Predicting outcome of patients with chest wall injury. American Journal of Surgery, 204(6), 910–914. https://doi.org/10.1016/j.amjsurg.2012.05.015Rossman, M. L. (2000). G uided I magery and I nteractive G uided I magery. M. L. Guided Imagery for Self Healing: An Essential for Anyone Seeking Wellness, 930.Simon, B. J., Cushman, J., Barraco, R., Lane, V., Luchette, F. A., Miglietta, M., Roccaforte, D. J., & Spector, R. (2005). Pain management guidelines for blunt thoracic trauma. Journal of Trauma - Injury, Infection and Critical Care, 59(5), 1256–1267. https://doi.org/10.1097/01.ta.0000178063.77946.f5Todd, S. R., McNally, M. M., Holcomb, J. B., Kozar, R. A., Kao, L. S., Gonzalez, E. A., Cocanour, C. S., Vercruysse, G. A., Lygas, M. H., Brasseaux, B. K., & Moore, F. A. (2006). A multidisciplinary clinical pathway decreases rib fracture-associated infectious morbidity and mortality in high-risk trauma patients. American Journal of Surgery, 192(6), 806–811. https://doi.org/10.1016/j.amjsurg.2006.08.048Wanek, S., & Mayberry, J. C. (2004). Blunt thoracic trauma: Flail chest, pulmonary contusion, and blast injury. Critical Care Clinics, 20(1), 71–81. https://doi.org/10.1016/S0749-0704(03)00098-8

Mycological investigations have been made since 2001 in all characteristic forest types in Central Börzsöny Mts., North Hungary. Among the near 500 macrolungi species documented 8 protected and 32 rare taxa occurred. Present paper concerns 13 of these taxa: 3 critically endangered, 7 endangered and 3 vulnerable in Hungary. Near the summarisation of the European habitat preference a Hungarian habitat characterisation were made for each species based on all Hungarian documented occurrence data. Majority of the species have similar habitat preference in Hungary to the European one, but some exceptions were noted. Boletus pinophilus is a typical species of deciduous forests with acidic soil, not documented from coniferous stands. Pluteo.v umbrosus prefers undisturbed forest stands with high quantity of dead wood in Hungary and did not occur in parks. Trichoma psammopus fructified in lower altitude in deciduous and mixed forest stands (always connected with Larix). Sonic species were rarer in Hungary, than in other European countries, caused by lack of their original habitats: Boletus pinophilus, 11rclJrclloin concrescens, Tremella encephala, Tricholoma aurantium, Iwo species — Boleros torosus anti Amanita lirielopallescens — were touch common in Hungary than in Europe. Two taxa —Amanita vaginata var. alba, Tremella encephala — are new From Hungary.

Abstract Aims The characteristics and clinical course of hospitalized patients with Coronavirus disease 2019 (COVID-19) have been widely described, while long-term data are still poor. The aim of this study was to evaluate the long-term clinical outcome and its association with right ventricular (RV) dysfunction in hospitalized patients with COVID-19. Methods and results This was a retrospective multicentre study of consecutive COVID-19 patients hospitalized at seven Italian Hospitals from 28 February to 20 April 2020. The study population was divided into two groups according to echocardiographic evidence of RV dysfunction defined by tricuspid annular plane systolic excursion (TAPSE) value &lt;17 mm in accordance with the current guidelines. The primary study outcome was 1-year mortality. The study population consisted of 224 patients (mean age 69 ± 14, male sex 62%); RV dysfunction was diagnosed in 63 cases (28%). Patients with RV dysfunction were older (75 vs. 67 years, P &lt; 0.001) and showed a higher prevalence of coronary artery disease (27% vs. 11%, P = 0.003), heart failure (5% vs. 22%; P &lt; 0.001), chronic obstructive pulmonary disease (13% vs. 38%; P &lt; 0.001), and chronic kidney disease (12% vs. 39%; P &lt; 0.001). Left ventricular ejection fraction (LVEF) was significantly lower in patients with RV dysfunction that in those without (55% vs. 50%; P &lt; 0.001). The rate of mortality at 1-year was significantly higher in patients with RV dysfunction as compared with those without (67% vs. 28%; P ≤ 0.001). After propensity score matching, patients with RV dysfunction showed a significantly lower long-term survival than patients without RV dysfunction (62% vs. 29%, P &lt; 0.001). At multivariable Cox regression analysis, TAPSE, LVEF and acute respiratory distress syndrome during the hospitalization were independently associated with 1-year mortality (Table). Conclusions RV dysfunction is a relatively common finding in hospitalized patients with COVID-19 and is independently associated with an higher risk of mortality at one-year follow-up.

Relevance. The prevalence of caries in permanent teeth of 6-year-old children in Russia reaches 13%. In view of tooth enamel mineralization completion within a few years after the eruption, the role of primary prevention is especially significant. Fissure sealing is one of the preventive measures. At the same time, the effectiveness of dental caries prevention in children within the first year after tooth eruption reaches sufficiently high rates.Material and methods. The study involved 58 children. The experimental group included 30 children (105 teeth) who had the fissures sealed by air abrasion with additional water supply using a "Rondoflex plus 360" handpiece ("KaVo", Germany). The control group included 28 children (89 teeth) who underwent standard non-invasive sealing. Sealing effectiveness was assessed in 3, 6, 12, 18, and 24 months using the E.M. Melnichenko formula modified by the authors. Statistical data were represented by percentage; the χ2 test identified inter-group differences.Results. The experimental group showed the best sealant retention (up to 76.19% after 24 months). In the control group, the percentage of retained sealant was 48.31% by the end of the follow-up period. After 1 and 2 years, the total sealant loss was 11.24% and 22.48%, respectively. This fact may be associated with the failure of the sealant adhesion to the tooth enamel under the influence of a constant chewing load.Conclusion. Analyzing two-year follow-up results, we found that caries developed in 3.81% of cases in the main group, and the control group revealed caries in 12.37%. Thus, the effectiveness of fissure sealing using air abrasion with additional water supply is 63.4% higher compared to the non-invasive technique (χ2 =16.638, p<0.001).

Abstract Background the assessment of myocardial work (MW) by pressure-strain loops is a recently introduced tool for the assessment of myocardial performance. Aim of the present study is to evaluate the relationship between myocardial work and exercise tolerance in patients with dilated cardiomyopathy (DCM) Methods 51 patients with DCM (mean age 57 ± 13 years, left entricular ejection fraction : 32 ± 9%) underwent cardiopulmonary exercise test (CPET) to assess exercise performance. Trans-thoracic echocardiography (TTE) was performed CPET. The following indices of myocardial work (MW) were measured regionally and globally: constructive work (CW), wasted work (WW), and work efficiency (WE). Left ventricular (LV) dyssynchrony (DYS) was defined by the presence of septal flash or apical rocking at TTE. Results LV-DYS was observed in 16 (31%) patients and associated with lower LV ejection fraction (LVEF), GLS, global and septal WE, and higher global and septal WW (Table 1). In patients with LV-DYS, septal WE was the only predictor of exercise peak VO2max at multivariable analysis (Figure 1), whereas LVEF (β=0.47, p = 0.05) and age (β=-0.42, 47, p= 0.04) were predictors of exercise capacity in patients without LV-DYS. Conclusions In patients with DCM, LV-DYS is associated with an heterogeneous distribution of myocardial work. Septal WE is the best predictor of exercise performance in these patients. Table 1 All n = 51 No-dyssynchrony n = 35 (69%) LV-Dyssynchrony n = 16 (31%) p-value LVEF, % 32 ± 9 34 ± 10 28 ± 7 0.04 GLS, % -12 ± 3 -13 ± 3 -10 ± 3 0.001 GCW, mmHg% 1325 ± 398 1342 ± 354 1287 ± 491 0.65 GWW, mmHg% 201 ± 147 154 ± 95 304 ±191 &lt;0.0001 GWE, % 85 ± 9 88 ± 7 78 ±10 &lt;0.0001 CWsept, mmHg% 1172 ± 459 1274 ± 398 949 ± 516 0.017 CWlat, mmHg% 1518 471 1472 ± 386 1620 ± 622 0.30 WWsept, mmHg% 283 ± 275 174 ± 98 522 ±376 &lt;0.0001 WWlat, mmHg% 135 ± 88 117 ± 81 176 ± 92 0.02 WEsept, % 78 ± 16 84 ± 9 62± 18* &lt;0.0001 WElat, % 90 ± 7 91 ± 7 88 ± 7 0.16 Abstract P1779 Figure.

INTRODUCTION: Diseases of the gallbladder commonly manifest as gallstones and gallbladder cancer. To identify risk factors in a given 1 population, epidemiological studies must rst dene the frequency of disease. Studies employing necropsy surveys or healthcare databases carry biases by their implicit nature: being postmortem or requiring biliary symptoms/complications, respectively. AIMS & OBJECTIVE:To assess the relevant sociodemographic characteristics, relevant history and clinical prole of the study population. METHODOLOGY: Study Area: The study was conducted DEPARTMENT OF GENERAL SURGERY, PARAS GLOBAL HOSPITAL, DARBHANGA. It is having a capacity of 252 indoor beds in the Department of Surgery and associated academic section, catering to people of several districts. The study shall be done in the Surgery Indoor of his hospital. Duration of Study:Twelve Months RESULTAND ANALYSIS:We found in our study 37(5.9%) patients had GB Wall thickness. 12(1.9%) patients had GB Commet tail appearencel, 8(1.3%) patients had GB Mass and 1(0.2%) patients had GB Mass fundus. 52(8.4%) patients had CBD stone. 1(0.2%) patient had Irregular wall thickening GB body and 407(65.3%) patients had MRCP. 52(8.4%) patients had CT. 1(0.2%) patient had GB Thickening and 1(0.2%) patient had EUS. 34(5.5%) patients had Conservative. 17(2.7%) patients had ERCPand 1(0.2%) patient had failed ESRCPon 14/3/18. SUMMARY AND CONCLUSION:We found that 22(3.5%) patients had post-operative jaundice. 8(1.3%) patients had post-operative pancreatitis. 622(100.0%) patients had no post-operative cases of retained stone. 13(2.1%) patients had post-operative signicant pain abdomen. It was found that 611(98.1%) patients had monthly. 10(1.6%) patients had lost follow-up. We concluded that symptomatic gallstone diseases were more common in > 35 Years with a female predominance.

Abstract Background An improved understanding of childhood pneumonia aetiology is required to inform prevention and treatment strategies. Lung aspiration is the gold standard specimen for pneumonia diagnostics. We report findings from analyses of lung and pleural aspirates collected in the Pneumonia Etiology Research for Child Health (PERCH) study. Methods The PERCH study enrolled children aged 1–59 months hospitalized with World Health Organization defined severe or very severe pneumonia in 7 countries in Africa and Asia. Percutaneous trans-thoracic lung (LA) and pleural fluid (PF) aspiration was performed on a sample of pneumonia cases with radiological consolidation and/or pleural fluid in 4 countries. Venous blood and nasopharyngeal/oropharyngeal swabs were collected from all cases. Multiplex quantitative PCR and routine microbiologic culture were applied to clinical specimens. Results Of 44 LAs performed within 3 days of admission on 622 eligible cases, 13 (30%) had a pathogen identified by either culture (5/44) or by PCR (11/29). A pathogen was identified in 12/14 (86%) PF specimens tested by either culture (9/14) or PCR (9/11). Bacterial pathogens were identified more frequently than viruses. All but one of the cases with a virus identified were co-infected with bacterial pathogens. Streptococcus pneumoniae (9/44 [20%]) and Staphylococcus aureus (7/14 [50%]) were the predominant pathogen identified in LA and PF, respectively. Conclusions Bacterial pathogens predominated in this selected subgroup of PERCH participants drawn from those with radiological consolidation or pleural fluid, with S. pneumoniae and S. aureus the leading pathogens identified.

Background: Previous retrospective studies have shown that CAR-T cell therapy may be associated with major adverse cardiovascular events (MACE) especially in context of cytokine release syndrome (CRS) events. Objectives. The aim of this prospective observational study was to define the occurrence of MACE in adults undergoing treatment with CAR-T cell therapy and identify associated risk factors. Methods: Vital signs, blood samples and an echocardiogram were collected prior to, two days, one week, one month, and six months after CAR-T cell infusion, and chart consulted at 12 months. In the event of CRS, an echocardiogram was repeated within 72 hours. MACE were defined as cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke, and de novo cardiac arrhythmia. Results: A total of 44 patients were enrolled (58 ±11 years-old, 77 % male). The median follow-up was 487 days (258-622 days). There were 24 episodes of CRS in 23 patients (52%) (13 with grade 1, 10 with grade 2, and one with grade 3) with a median time to CRS of 4 days. Two patients had MACE (HFpEF and atrial fibrillation) within one year, six and seven days after CAR-T cell infusion respectively. There was no change in left ventricular ejection fraction (LVEF), however, a modest decrease in global longitudinal strain (GLS) was noted. Conclusions: There were few cardiac effects associated with contemporary CAR-T cell therapy. A small decline in LV mechanics was detected. As MACE occurred after CRS episodes, aggressive treatment and close follow-up during CRS events are essential.

Abstract Background Quality indicators (QIs) are used to monitor quality of care and adherence to osteoarthritis (OA) standards of care. Patient reported QIs can identify the most important gaps in quality of care and the most vulnerable patient groups. The aim of this study was to capture the perspective of people with knee OA (KOA) in the Netherlands on the quality of care received, and explore determinants related to lower achievement rates. Methods We sent an online survey to all members of The Dutch Knee Panel (n = 622) of the Sint Maartenskliniek Nijmegen, the Netherlands between September and October 2019. The survey consisted of a slightly adapted version of the “OsteoArthritis Quality Indicator” (OA-QI) questionnaire (18 items; yes, no, N/A); a rating of quality of KOA care on a 10-point scale; a question on whether or not one wanted to see change in the care for KOA; and an open-ended question asking recommendations for improvement of OA care. Furthermore, sociodemographic and disease related characteristics were collected. Pass rates for separate QIs and pass rates on patient level were calculated by dividing the number of times the indicator was achieved by the number of eligible persons for that particular indicator. Results A total of 434 participants (70%) completed the survey. The mean (SD) pass rate (those answering “Yes”) for separate QIs was 49% (20%); ranging from 15% for receiving referral for weight reduction to 75% for patient education on how to manage knee OA. The mean (SD) pass rate on patient level was 52% (23%). Presence of OA in other joints, comorbidities, and having a knee replacement were associated with higher pass rates. On average, a score of 6.5 (1.6) was given for the quality of care received, and the majority of respondents (59%) wanted change in the care for KOA. Of 231 recommendations made, most often mentioned were the need for tailoring of care (14%), more education (13%), and more empathy and support from healthcare providers (12%). Conclusion This study found patients are only moderately satisfied with the OA care received, and showed substantial gaps between perceived quality of care for OA and internationally accepted standards. Future research should focus on the underlying reasons and provide strategies to bridge these gaps.

Abstract Background Mycotic aneurysms are a serious complication of infective endocarditis and bloodstream infection with high mortality and morbidity. Computed tomography (CT) and magnetic resonance (MRI) play major roles in detecting mycotic aneurysms, but their accuracy is not well established warranting this meta-analysis. Purpose We aimed to assess the diagnostic performance of CT and MRI for mycotic aneurysms in this meta-analysis. Methods Pubmed, Cochrane and Embase were searched from 1 January 1980–30 June 2019 for diagnostic studies reporting both sensitivity and specificity of CT and/or MRI for detecting mycotic aneurysms, and pooled using random effects models and Meta-DiSc 1.4 software. Results Amongst 1507 articles searched, 15 studies with 622 scans for 249 mycotic aneurysms included. CT was performed in 13 studies and MRI in 5 studies, looking at aortic and cerebral mycotic aneurysm in 12 and 3 studies respectively. The pooled sensitivities and specificities for all mycotic aneurysms with 95% confidence intervals were for CT 0.82 (0.77–0.87) and 0.93 (0.89–0.95) respectively, and for MRI 0.79 (0.61–0.91) and 0.89 (0.81–0.95) (Figure). CT or MRI had pooled sensitivities and specificities of 0.84 (0.78–0.89) and 0.92 (0.89–0.95) for aortic and 0.71 (0.54–0.85) and 0.90 (0.83–0.95) for cerebral mycotic aneurysms. Heterogeneity and publication bias was observed in some pooled analysis. Conclusion CT and MRI had moderately high diagnostic accuracy for mycotic aneurysms. Sensitivity was numerically higher for detecting aortic than cerebral mycotic aneurysms, with similar specificity. Study heterogeneity, publication bias and modest sample size from the literature were important limitations, warranting larger and higher quality studies. Forrest plots for CT and MRI pooled data Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Heart Foundation of New Zealand - Overseas Clinical and Research Fellowship

What we wear signals our membership within groups, be theyorganised by gender, class, ethnicity or religion. Simultaneously our clothing signifies hierarchies and power relations that sustain dominant power structures. How we dress is an expression of our identity. For Veblen, how we dress expresses wealth and social stratification. In imitating the fashion of the wealthy, claims Simmel, we seek social equality. For Barthes, clothing is embedded with systems of meaning. For Hebdige, clothing has modalities of meaning depending on the wearer, as do clothes for gender (Davis) and for the body (Entwistle). For Maynard, “dress is a significant material practice we use to signal our cultural boundaries, social separations, continuities and, for the present purposes, political dissidences” (103). Clothing has played a central role in historical and contemporary forms of political dissent. During the French Revolution dress signified political allegiance. The “mandated costumes, the gold-braided coat, white silk stockings, lace stock, plumed hat and sword of the nobility and the sober black suit and stockings” were rejected as part of the revolutionary struggle (Fairchilds 423). After the storming of the Bastille the government of Paris introduced the wearing of the tricolour cockade, a round emblem made of red, blue and white ribbons, which was a potent icon of the revolution, and a central motif in building France’s “revolutionary community”. But in the aftermath of the revolution divided loyalties sparked power struggles in the new Republic (Heuer 29). In 1793 for example anyone not wearing the cockade was arrested. Specific laws were introduced for women not wearing the cockade or for wearing it in a profane manner, resulting in six years in jail. This triggered a major struggle over women’s abilities to exercise their political rights (Heuer 31).Clothing was also central to women’s political struggles in America. In the mid-nineteenth century, women began wearing the “reform dress”—pants with shortened, lightweight skirts in place of burdensome and restrictive dresses (Mas 35). The wearing of pants, or bloomers, challenged gender norms and demonstrated women’s agency. Women’s clothes of the period were an "identity kit" (Ladd Nelson 22), which reinforced “society's distinctions between men and women by symbolizing their natures, roles, and responsibilities” (Ladd Nelson 22, Roberts 555). Men were positioned in society as “serious, active, strong and aggressive”. They wore dark clothing that “allowed movement, emphasized broad chests and shoulders and presented sharp, definite lines” (Ladd Nelson 22). Conversely, women, regarded as “frivolous, inactive, delicate and submissive, dressed in decorative, light pastel coloured clothing which inhibited movement, accentuated tiny waists and sloping shoulders and presented an indefinite silhouette” (Ladd Nelson 22, Roberts 555). Women who challenged these dress codes by wearing pants were “unnatural, and a perversion of the “true” woman” (Ladd Nelson 22). For Crane, the adoption of men’s clothing by women challenged dominant values and norms, changing how women were seen in public and how they saw themselves. The wearing of pants came to “symbolize the movement for women's rights” (Ladd Nelson 24) and as with women in France, Victorian society was forced to consider “women's rights, including their right to choose their own style of dress” (Ladd Nelson 23). As Yangzom (623) puts it, clothing allows groups to negotiate boundaries. How the “embodiment of dress itself alters political space and civic discourse is imperative to understanding how resistance is performed in creating social change” (Yangzom 623). Fig. 1: 1850s fashion bloomersIn a different turn is presented in Mahatma Gandhi’s Khadi movement. Khadi is a term used for fabrics made on a spinning wheel (or charkha) or hand-spun and handwoven, usually from cotton fibre. Khadi is considered the “fabric of Indian independence” (Jain). Gandhi recognised the potential of the fabric to a self-reliant, independent India. Gandhi made the struggle for independence synonymous with khadi. He promoted the materials “simplicity as a social equalizer and made it the nation’s fabric” (Sinha). As Jain notes, clothing and in this case fabric, is a “potent sign of resistance and change”. The material also reflects consciousness and agency. Khadi was Gandhi’s “own sartorial choices of transformation from that of an Englishman to that of one representing India” (Jain). For Jain the “key to Khadi becoming a successful tool for the freedom struggle” was that it was a “material embodiment of an ideal” that “represented freedom from colonialism on the one hand and a feeling of self-reliance and economic self-sufficiency on the other”. Fig. 2: Gandhi on charkha The reappropriating of Khadi as a fabric of political dissent echoes the wearing of blue denim by the Student Nonviolent Coordinating Committee (SNCC) at the 1963 National Mall Washington march where 250,000 people gather to hear Martin Luther King speak. The SNCC formed in 1960 and from then until the 1963 March on Washington they developed a “style aesthetic that celebrated the clothing of African American sharecroppers” (Ford 626). A critical aspect civil rights activism by African America women who were members of the SNCC was the “performance of respectability”. With the moral character of African American women under attack (as a way of delegitimising their political activities), the female activists “emphasized the outward display of their respectability in order to withstand attacks against their characters”. Their modest, neat “as if you were going to church” (Chappell 96) clothing choices helped them perform respectability and this “played an important performative role in the black freedom struggle” (Ford 626). By 1963 however African American female civil rights activists “abandoned their respectable clothes and processed hairstyles in order to adopt jeans, denim skirts, bib-and-brace overalls”. The adoption of bib-and-brace overalls reflected the sharecropper's blue denim overalls of America’s slave past.For Komar the blue denim overalls “dramatize[d] how little had been accomplished since Reconstruction” and the overalls were practical to fix from attack dog tears and high-pressure police hoses. The blue denim overalls, according to Komar, were also considered to be ‘Negro clothes’ purchased by “slave owners bought denim for their enslaved workers, partly because the material was sturdy, and partly because it helped contrast them against the linen suits and lace parasols of plantation families”. The clothing choice was both practical and symbolic. While the ‘sharecropper’ narrative is problematic as ‘traditional’ clothing (something not evident in the case of Ghandi’s Khandi Movement, there is an emotion associated with the clothing. As Barthes (6-7) has shown, what makes ‘traditional clothing,’ traditional is that it is part of a normative system where not only does clothing have its historical place, but it is governed by its rules and regimentation. Therefore, there is a dialectical exchange between the normative system and the act of dressing where as a link between the two, clothing becomes the conveyer of its meanings (7). Barthes calls this system, langue and the act of dressing parole (8). As Ford does, a reading of African American women wearing what she calls a “SNCC Skin” “the uniform [acts] consciously to transgress a black middle-class worldview that marginalised certain types of women and particular displays of blackness and black culture”. Hence, the SNCC women’s clothing represented an “ideological metamorphosis articulated through the embrace and projection of real and imagined southern, working-class, and African American cultures. Central to this was the wearing of the blue denim overalls. The clothing did more than protect, cover or adorn the body it was a conscious “cultural and political tool” deployed to maintain a movement and build solidarity with the aim of “inversing the hegemonic norms” via “collective representations of sartorial embodiment” (Yangzom 622).Fig. 3: Mississippi SNCC March Coordinator Joyce Ladner during the March on Washington for Jobs and Freedom political rally in Washington, DC, on 28 Aug. 1963Clothing in each of these historical examples performs an ideological function that can bridge, that is bring diverse members of society together for a cause, or community cohesion or clothing can act as a fence to keep identities separate (Barnard). This use of clothing is evident in two indigenous examples. For Maynard (110) the clothes worn at the 1988 Aboriginal ‘Long March of Freedom, Justice and Hope’ held in Australia signalled a “visible strength denoted by coherence in dress” (Maynard 112). Most noted was the wearing of colours – black, red and yellow, first thought to be adopted during protest marches organised by the Black Protest Committee during the 1982 Commonwealth Games in Brisbane (Watson 40). Maynard (110) describes the colour and clothing as follows:the daytime protest march was dominated by the colours of the Aboriginal people—red, yellow and black on flags, huge banners and clothing. There were logo-inscribed T-shirts, red, yellow and black hatband around black Akubra’s, as well as red headbands. Some T-shirts were yellow, with images of the Australian continent in red, others had inscriptions like 'White Australia has a Black History' and 'Our Land Our Life'. Still others were inscribed 'Mourn 88'. Participants were also in customary dress with body paint. Older Indigenous people wore head bands inscribed with the words 'Our Land', and tribal elders from the Northern Territory, in loin cloths, carried spears and clapping sticks, their bodies marked with feathers, white clay and red ochres. Without question, at this most significant event for Aboriginal peoples, their dress was a highly visible and cohesive aspect.Similar is the Tibetan Freedom Movement, a nonviolent grassroots movement in Tibet and among Tibet diaspora that emerged in 2008 to protest colonisation of Tibet. It is also known as the ‘White Wednesday Movement’. Every Wednesday, Tibetans wear traditional clothes. They pledge: “I am Tibetan, from today I will wear only Tibetan traditional dress, chuba, every Wednesday”. A chuba is a colourful warm ankle-length robe that is bound around the waist by a long sash. For the Tibetan Freedom Movement clothing “symbolically functions as a nonverbal mechanism of communication” to “materialise consciousness of the movement” and functions to shape its political aims (Yangzom 622). Yet, in both cases – Aboriginal and Tibet protests – the dress may “not speak to single cultural audience”. This is because the clothing is “decoded by those of different political persuasions, and [is] certainly further reinterpreted or reframed by the media” (Maynard 103). Nevertheless, there is “cultural work in creating a coherent narrative” (Yangzom 623). The narratives and discourse embedded in the wearing of a red, blue and white cockade, dark reform dress pants, cotton coloured Khadi fabric or blue denim overalls is likely a key feature of significant periods of political upheaval and dissent with the clothing “indispensable” even if the meaning of the clothing is “implied rather than something to be explicated” (Yangzom 623). On 21 January 2017, 250,000 women marched in Washington and more than two million protesters around the world wearing pink knitted pussy hats in response to the remarks made by President Donald Trump who bragged of grabbing women ‘by the pussy’. The knitted pink hats became the “embodiment of solidarity” (Wrenn 1). For Wrenn (2), protests such as this one in 2017 complete with “protest visuals” which build solidarity while “masking or excluding difference in the process” indicates “a tactical sophistication in the social movement space with its strategic negotiation of politics of difference. In formulating a flexible solidarity, the movement has been able to accommodate a variety of races, classes, genders, sexualities, abilities, and cultural backgrounds” (Wrenn 4). In doing so they presented a “collective bodily presence made publicly visible” to protest racist, sexist, homophobic, Islamophobic, and xenophobic white masculine power (Gokariksel & Smith 631). The 2017 Washington Pussy Hat March was more than an “embodiment tactic” it was an “image event” with its “swarms of women donning adroit posters and pink pussy hats filling the public sphere and impacting visual culture”. It both constructs social issues and forms public opinion hence it is an “argumentative practice” (Wrenn 6). Drawing on wider cultural contexts, as other acts of dissent note here do, in this protest with its social media coverage, the “master frame” of the sea of pink hats and bodies posited to audiences the enormity of the anger felt in the community over attacks on the female body – real or verbal. This reflects Goffman’s theory of framing to describe the ways in which “protestors actively seek to shape meanings such that they spark the public’s support and encourage political openings” (Wrenn 6). The hats served as “visual tropes” (Goodnow 166) to raise social consciousness and demonstrate opposition. Protest “signage” – as the pussy hats can be considered – are a visual representation and validation of shared “invisible thoughts and emotions” (Buck-Coleman 66) affirming Georg Simmel’s ideas about conflict; “it helps individuals define their differences, establish to which group(s) they belong, and determine the degrees to which groups are different from each other” (Buck-Coleman 66). The pink pussy hat helped define and determine membership and solidarity. Further embedding this was the hand-made nature of the hat. The pattern for the hat was available free online at https://www.pussyhatproject.com/knit/. The idea began as one of practicality, as it did for the reform dress movement. This is from the Pussy Hat Project website:Krista was planning to attend the Women’s March in Washington DC that January of 2017 and needed a cap to keep her head warm in the chill winter air. Jayna, due to her injury, would not be able to attend any of the marches, but wanted to find a way to have her voice heard in absentia and somehow physically “be” there. Together, a marcher and a non-marcher, they conceived the idea of creating a sea of pink hats at Women’s Marches everywhere that would make both a bold and powerful visual statement of solidarity, and also allow people who could not participate themselves – whether for medical, financial, or scheduling reasons — a visible way to demonstrate their support for women’s rights. (Pussy Hat Project)In the tradition of “craftivism” – the use of traditional handcrafts such as knitting, assisted by technology (in this case a website with the pattern and how to knit instructions), as a means of community building, skill-sharing and action directed towards “political and social causes” (Buszek & Robertson 197) –, the hand-knitted pink pussy hats avoided the need to purchase clothing to show solidarity resisting the corporatisation of protest clothing as cautioned by Naomi Klein (428). More so by wearing something that could be re-used sustained solidarity. The pink pussy hats provided a counter to the “incoherent montage of mass-produced clothing” often seen at other protests (Maynard 107). Everyday clothing however does have a place in political dissent. In late 2018, French working class and middle-class protestors donned yellow jackets to protest against the government of French President Emmanuel Macron. It began with a Facebook appeal launched by two fed-up truck drivers calling for a “national blockade” of France’s road network in protest against rising fuel prices was followed two weeks later with a post urging motorist to display their hi-vis yellow vests behind their windscreens in solidarity. Four million viewed the post (Henley). Weekly protests continued into 2019. The yellow his-vis vests are compulsorily carried in all motor cars in France. They are “cheap, readily available, easily identifiable and above all representing an obligation imposed by the state”. The yellow high-vis vest has “proved an inspired choice of symbol and has plainly played a big part in the movement’s rapid spread” (Henley). More so, the wearers of the yellow vests in France, with the movement spreading globally, are winning in “the war of cultural representation. Working-class and lower middle-class people are visible again” (Henley). Subcultural clothing has always played a role as heroic resistance (Evans), but the coloured dissent dressing associated with the red, blue and white ribboned cockades, the dark bloomers of early American feminists, the cotton coloured natural fabrics of Ghandi’s embodiment of resistance and independence, the blue denim sharecropper overalls worn by African American women in their struggles for civil rights, the black, red and orange of Aboriginal protestors in Australia and the White Wednesday performances of resistance undertaken by Tibetans against Chinese colonisation, the Washington Pink Pussy Hat marches for gender respect and equality and the donning of every yellow hi-vis vests by French protestors all posit the important role of fabric and colour in protest meaning making and solidarity building. It is in our rage we consciously wear the colours and fabrics of dissent dress. ReferencesBarnard, Malcolm. Fashion as Communication. New York: Routledge, 1996. Barthes, Roland. “History and Sociology of Clothing: Some Methodological Observations.” The Language of Fashion. Eds. Michael Carter and Alan Stafford. UK: Berg, 2006. 3-19. Buck-Coleman, Audra. “Anger, Profanity, and Hatred.” Contexts 17.1 (2018): 66-73.Buszek, Maria Elena, and Kirsty Robertson. “Introduction.” Utopian Studies 22.1 (2011): 197-202. Chappell, Marisa, Jenny Hutchinson, and Brian Ward. “‘Dress Modestly, Neatly ... As If You Were Going to Church’: Respectability, Class and Gender in the Montgomery Bus Boycott and the Early Civil Rights Movement.” Gender and the Civil Rights Movement. Eds. Peter J. Ling and Sharon Monteith. New Brunswick, N.J., 2004. 69-100.Crane, Diana. Fashion and Its Social Agendas. Chicago: University of Chicago Press, 2000. Davis, Fred. Fashion, Culture, and Identity. Chicago: University of Chicago Press, 1992.Entwistle, Joanne. The Fashioned Body: Fashion, Dress, and Modern Social Theory. Cambridge: Polity Press, 2000.Evans, Caroline. “Dreams That Only Money Can Buy ... Or the Shy Tribe in Flight from Discourse.” Fashion Theory 1.2 (1997): 169-88.Fairchilds, Cissie. “Fashion and Freedom in the French Revolution.” Continuity and Change 15.3 (2000): 419-33.Ford, Tanisha C. “SNCC Women, Denim, and the Politics of Dress.” The Journal of Southern History 79.3 (2013): 625-58.Gökarıksel, Banu, and Sara Smith. “Intersectional Feminism beyond U.S. Flag, Hijab and Pussy Hats in Trump’s America.” Gender, Place & Culture 24.5 (2017): 628-44.Goodnow, Trischa. “On Black Panthers, Blue Ribbons, & Peace Signs: The Function of Symbols in Social Campaigns.” Visual Communication Quarterly 13 (2006): 166-79.Hebdige, Dick. Subculture: The Meaning of Style. London: Routledge, 2002. Henley, Jon. “How Hi-Vis Yellow Vest Became Symbol of Protest beyond France: From Brussels to Basra, Gilets Jaunes Have Brought Visibility to People and Their Grievances.” The Guardian 21 Dec. 2018. <https://www.theguardian.com/world/2018/dec/21/how-hi-vis-yellow-vest-became-symbol-of-protest-beyond-france-gilets-jaunes>.Heuer, Jennifer. “Hats On for the Nation! Women, Servants, Soldiers and the ‘Sign of the French’.” French History 16.1 (2002): 28-52.Jain, Ektaa. “Khadi: A Cloth and Beyond.” Bombay Sarvodaya Mandal & Gandhi Research Foundation. ND. 19 Dec. 2018 <https://www.mkgandhi.org/articles/khadi-a-cloth-and-beyond.html>. Klein, Naomi. No Logo. London: Flamingo, London, 2000. Komar, Marlen. “What the Civil Rights Movement Has to Do with Denim: The History of Blue Jeans Has Been Whitewashed.” 30 Oct. 2017. 19 Dec. 2018 <https://www.racked.com/2017/10/30/16496866/denim-civil-rights-movement-blue-jeans-history>.Ladd Nelson, Jennifer. “Dress Reform and the Bloomer.” Journal of American and Comparative Cultures 23.1 (2002): 21-25.Maynard, Margaret. “Dress for Dissent: Reading the Almost Unreadable.” Journal of Australian Studies 30.89 (2006): 103-12. Pussy Hat Project. “Design Interventions for Social Change.” 20 Dec. 2018. <https://www.pussyhatproject.com/knit/>.Roberts, Helene E. “The Exquisite Slave: The Role of Clothes in the Making of the Victorian Woman.” Signs (1977): 554-69.Simmel, Georg. “Fashion.” American Journal of Sociology 62 (1957): 541–58.Sinha, Sangita. “The Story of Khadi, India's Signature Fabric.” Culture Trip 2018. 18 Jan. 2019 <https://theculturetrip.com/asia/india/articles/the-story-of-khadi-indias-fabric/>.Yangzom, Dicky. “Clothing and Social Movements: Tibet and the Politics of Dress.” Social Movement Studies 15.6 (2016): 622-33. Veblen, Thorstein. The Theory of the Leisure Class: An Economic Study of Institutions. New York: Dover Thrift, 1899. Watson, Lilla. “The Commonwealth Games in Brisbane 1982: Analysis of Aboriginal Protests.” Social Alternatives 7.1 (1988): 1-19.Wrenn, Corey. “Pussy Grabs Back: Bestialized Sexual Politics and Intersectional Failure in Protest Posters for the 2017 Women’s March.” Feminist Media Studies (2018): 1-19.

Abstract Background Multimodality imaging approach is becoming more and more common in evaluating the severity and outcome of aortic stenosis (AS). Aim To assess the outcome of asymptomatic AS and the usefulness of aortic calcium score (CS) by computed tomography (CT) for solving the dilemma of low flow, low gradients (LFLG) severe AS. Methods 70 (81.4±8.4 years) prospective asymptomatic patients with AS were followed for 2.77±2.01 years with a trans-thoracic echo (TTE) every 6 months. End-points were all cause mortality, aortic valve replacement (AVR or TAVR), aortic velocity and gradients progression and symptoms occurrence. Prevalence of LFLG-AS was investigated and these patients underwent CT for CS calculation at the end of follow-up (FU), Figure 1. Results Baseline TTE results from the 70 pts were: peak velocity 3.1±0.8m/sec; peak gradient 44±21mmHg; mean gradient 26±14 mmHg; AVA 1±0.3 cm2; DVI 0.31±0.1; Svi 33.8±18 ml/m2; EF: 55±9% with an AS being mild in 32.9%, moderate in 28.4%, severe in 27.1%; 36.8% of severe AS were LFLG. During FU, 23 (32.8%) pts died (5.7% LFLG) and 13 (18.5%) underwent AVR/TAVR. Predictors of mortality were aortic gradients (p=0.03), AVA (p=0.008), DVI (p&lt;0.001), pulse pressure (p=0.005) and dilated ascending aorta (p&lt;0001). Predictors of AVR/TAVR were: gradients (p=0.003), peak aortic velocity (p=0.02) and dilated ascendent aorta (p=0.01). The best cut-off to predict survival was AVA = 1 cm2 (100% sensitivity and 80% specificity). In 34 pts ending FU we found an overall progression of AS severity (peak velocity 3.6±0.9m/sec; peak gradient 50±24 mmHg; mean gradient 33±15 mmHg; AVA 0.7±0.3 cm2; DVI 0.25±0.08; Svi 36±10 ml/m2; EF 54±10%; p&lt;0.05 for all vs baseline) with 24 (70.5%) pts with severe AS and 10 (29.5%) with not severe AS. 18 (75%) of progressive severe AS were LFLG, 12 asymptomatic and 6 symptomatic and all underwent CS revealing that AS was not severe in 6 (1233±1123 AU; 622±55 AU/m2) and true severe in 12 (3388±1188 AU; 1858±795 AU/m2; p=0.005 and p=0.002, respectively). Symptomatic severe LFLG AS were all true severe according to CS (Figure 1). Table 1 shows the main CS correlations. Conclusions Asymptomatic AS in elderly people is associated with high mortality risk and rapid progression. AVA remains the best predictor of outcome. In severe LFLG AS, calcium score correlates with symptoms occurrence, progression of valve disease, LV hypertrophy and function and also with RV function. Funding Acknowledgement Type of funding sources: None.

Abstract Background Management of asymptomatic severe aortic stenosis is controversial and the decision to intervene requires careful assessment of the benefits and risks in an individual patient. Multimodality imaging approach is becoming an important tool to evaluate the severity and outcome of aortic stenosis (AS). Aim To assess the outcome of asymptomatic AS and the usefulness of aortic calcium score (CS) by computed tomography (CT) for solving the dilemma of low-flow, low-gradients (LFLG) severe AS. Methods 70 (81.4±8.4yrs) prospective asymptomatic patients with AS were followed for 2.77±2.01yrs with a trans-thoracic echo (TTE) every 6 months. End-points were all cause mortality, aortic valve replacement (AVR or TAVR), aortic velocity and gradients progression and symptoms occurrence. Prevalence of LFLG-AS was investigated and these patients underwent CT for CS calculation at the end of follow-up (FU), Figure 1. Results Baseline TTE results from the 70 pts were: peak velocity 3.1±0.8m/sec; peak gradient 44±21mmHg; mean gradient 26±14 mmHg; AVA 1±0.3 cm2; DVI 0.31 ±0.1; Svi 33.8±18 ml/m2; EF: 55±9% with an AS being mild in 32.9%, moderate in 28.4%, severe in 27.1%; 36.8% of severe AS were LFLG. During FU, 23 (32.8%) pts died (5.7% LFLG) and 13(18.5%) underwent AVR/TAVR. Predictors of mortality were aortic gradients (p=0.03), AVA (p=0.008), DVI (p&lt;0.001), pulse pressure (p=0.005) and dilated ascending aorta (p&lt;0001). Predictors of AVR/TAVR were: gradients (p=0.003), peak aortic velocity (p=0.02) and dilated ascendent aorta (p=0.01). The best cut-off to predict survival was AVA =1cm2 (100% sensitivity and 80% specificity). In 34 pts ending FU we found an overall progression of AS severity (peak velocity 3.6±0.9m/sec; peak gradient 50±24mmHg; mean gradient 33±15 mmHg; AVA 0.7±0.3 cm2; DVI 0.25±0.08; Svi 36±10 ml/m2; EF 54±10%; p&lt;0.05 for all vs baseline) with 24 (70.5%) pts with severe AS and 10 (29.5%) with not severe AS. 18 (75%) of progressive severe AS were LFLG, 12 asymptomatic and 6 symptomatic and all underwent CS revealing that AS was not severe in 6 (1233±1123 AU; 622±55AU/m2) and true severe in 12 (3388±1188 AU;1858 ±795 AU/m2; p=0.005 and p=0.002, respectively). Symptomatic severe LFLG AS were all true severe according to CS (Figure 1). Table 1 shows the main CS correlations. Conclusions Asymptomatic AS in elderly people is associated with high mortality risk and rapid progression. AVA remains the best predictor of outcome. In severe LFLG AS, calcium score correlates with symptoms occurrence, progression of valve disease, LV hypertrophy and function and also with RV function.

ImportanceMelanoma treatment has evolved during the past decade with the adoption of adjuvant and palliative immunotherapy and targeted therapies, with an unclear impact on health care costs and outcomes in routine practice.ObjectiveTo examine changes in health care costs, overall survival (OS), and time toxicity associated with primary treatment of melanoma.Design, Setting, and ParticipantsThis cohort study assessed a longitudinal, propensity score (PS)–matched, retrospective cohort of residents of Ontario, Canada, aged 20 years or older with stages II to IV cutaneous melanoma identified from the Ontario Cancer Registry from January 1, 2018, to March 31, 2019. A historical comparison cohort was identified from a population-based sample of invasive melanoma cases diagnosed from the Ontario Cancer Registry from January 1, 2007, to December 31, 2012. Data analysis was performed from October 17, 2022, to March 13, 2023.ExposuresEra of melanoma diagnosis (2007-2012 vs 2018-2019).Main Outcomes and MeasuresThe primary outcomes were mean per-capita health care and systemic therapy costs (Canadian dollars) during the first year after melanoma diagnosis, time toxicity (days with physical health care contact) within 1 year of initial treatment, and OS. Standardized differences were used to compare costs and time toxicity. Kaplan-Meier methods and Cox proportional hazards regression were used to compare OS among PS-matched cohorts.ResultsA PS-matched cohort of 731 patients (mean [SD] age, 67.9 [14.8] years; 437 [59.8%] male) with melanoma from 2018 to 2019 and 731 patients (mean [SD] age, 67.9 [14.4] years; 440 [60.2%] male) from 2007 to 2012 were evaluated. The 2018 to 2019 patients had greater mean (SD) health care (including systemic therapy) costs compared with the 2007 to 2012 patients ($47 886 [$55 176] vs $33 347 [$31 576]), specifically for stage III ($67 108 [$57 226] vs $46 511 [$30 622]) and stage IV disease ($117 450 [$79 272] vs $47 739 [$37 652]). Mean (SD) systemic therapy costs were greater among 2018 to 2019 patients: stage II ($40 823 [$40 621] vs $10 309 [$12 176]), III ($55 699 [$41 181] vs $9764 [$12 771]), and IV disease ($79 358 [$50 442] vs $9318 [$14 986]). Overall survival was greater for the 2018 to 2019 cohort compared with the 2007 to 2012 cohort (3-year OS: 74.2% [95% CI, 70.8%-77.2%] vs 65.8% [95% CI, 62.2%-69.1%], hazard ratio, 0.72 [95% CI, 0.61-0.85]; P &amp;lt; .001). Time toxicity was similar between eras. Patients with stage IV disease spent more than 1 day per week (&amp;gt;52 days) with physical contact with the health care system by 2018 to 2019 (mean [SD], 58.7 [43.8] vs 44.2 [26.5] days; standardized difference, 0.40; P = .20).Conclusions and RelevanceThis cohort study found greater health care costs in the treatment of stages II to IV melanoma and substantial time toxicity for patients with stage IV disease, with improvements in OS associated with the adoption of immunotherapy and targeted therapies. These health system–wide data highlight the trade-off with adoption of new therapies, for which there is a greater economic burden to the health care system and time burden to patients but an associated improvement in survival.

Abstract Disclosure: T. Prodanov: None. A. Jha: None. S. Talvacchio: None. M. Nazari, MD: None. K. Pacak, MD, PhD: None. Background: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrinetumors arising from chromaffin cells in adrenal or extra-adrenal locations,respectively. PPGLs are characterized by an excessive production ofcatecholamines and/or metanephrines. Most of the symptoms of PPGLs, likehypertension, headaches, palpitation, sweating, and anxiety are an effect ofoverproduction of catecholamines and/or metanephrines. Metastatic PPGLs mayoccur in as many as 35% of patients, with higher metastatic potential observed in succinatedehydrogenase subunit B (SDHB)-related tumors (up to 90%). ClinicalCase: A retrospective analysis of 422patients with metastatic PPGL diagnosed and treated from 2000 to 2023 at theNational Institutes of Health, in Bethesda, Maryland, was conducted. We found42 patients with extremely elevated free plasma normetanephrine levels.Extremely elevated level was defined if the value was 100 times or more higherthan the upper reference limit. Free plasma normetanephrine and metanephrinewere measured. Therelated descriptive analyses of this cohort are as follows: 18 (42.8%) werefemales, 24 (57.2%) were males. The average age of patients at the time of theprimary tumor diagnosis was 39.3 ± 44 years. At theirinitial presentation, there were 29 (69.1%) patients with solitary tumors; and13 (30.9%) with metastatic tumors. In 20 (47.6%) patients, primary tumor waslocated in the adrenal gland, 19 (45.3%) had extra-adrenal PGL and head andneck PGL was seen in 3 (7.1%) patients. The average time interval to metastaticdisease was 5.7 ± 20 years. Thirteen(30.9%) patients had metastatic disease at the initial presentation. Theelevated plasma normetanephrine values ranged from 11407 to 69697 pg/mL (normalrange 18-112 pg/mL). The highest level was 622 times above upper referencelimit. None of the patients were found with elevated metanephrine 100 timesthat of upper reference limit.Genetictesting showed pathogenic variants in SDHB in 22 (52.4%), SDHA in2 (4.7%), NF1 in 2 (4.7%), VHL in 1 (2.3%), IDH1 in 1 (2.3%),and apparently sporadic disease in 12 (28.6%) patients, respectively. Overallsurvival, defined as time from diagnosis until last follow up/death was 11.47 ± 22.5 years.Twentypatients received CVD therapy, 13 patients received 131I-MIBGtherapy, 4 patients received 177Lu-DOTATATE therapy, 9 receivedlocalized radiation therapy. Thirty-nine out of 42 (92.8%) patients died due tometastatic PPGL most likely related to cardiovascular complications. Conclusion:Patients presented with extremely elevatednormetanephrine levels were found to have poorer prognosis as 92.8% (39/42) ofpatients died due to complications associated with their disease. Patients whopresent with extremely elevated plasma metanephrines should be carefullymonitored and managed. Presentation: Saturday, June 17, 2023

Human preeclampsia (PE) is associated with elevated secretion of arginine vasopressin (AVP), and chronic infusion of AVP into pregnant mice is sufficient to model PE by causing hypertension, renal glomerular endotheliosis, proteinuria, fetal placental hypoxia, and growth restriction. Early stages of PE are associated with defective trophoblast invasion of maternal spiral arteries, leading to decreased artery diameter and placental oxygenation. AVP infusion (24 ng/hr, sc) into pregnant mice caused placental hypoxia (chromatin-bound HIF1α on gestational day (GD)17.5; saline n=5, 0.31±0.01; AVP n=5, 0.34±0.01 AU, p<0.05) and reduced placental growth factor mRNA (n=18, 1.0 (0.7-1.3) vs n=21, 0.3 (0.2-0.4) fold (1 se), p<0.05). Therefore, we performed histological analyses of placentas collected from mice at GD12.5 infused with saline or AVP, with the hypothesis that AVP leads to early placental PE phenotypes. Similar to effects on GD17.5, this preliminary cohort demonstrated increased urine protein content (n=7, 27±3 vs n=13, 44±3, g/L p<0.05) and mid-gestational systolic blood pressure (-7.6±3.1 vs +3.5±2.2, mmHg p<0.05), similar fetal (75±7 vs 78±4 mg, p=0.75) and placental (83±10 vs 81±4 mg, p=0.80) masses, and similar changes in heart rate (+37±16 vs +39±12 bpm, p=0.93). GD12.5 placentas were then stained with haemotoxylin and eosin or immunostained for cytokeratin-8 to examine morphological changes induced by AVP. AVP infusion had no significant effects on labyrinth (saline n=3, 647±25 vs AVP n=7, 602±35 um, p=0.45), spongiotrophoblast (342±19 vs 363±24 um, p=0.61), or decidua (622±47 vs 520±47 um, p=0.24) layer thicknesses. AVP caused a reduction in average maximum spiral artery diameter (171±28 vs 121±8 um, p<0.05) and a trend toward reduced total spiral artery number (8.4±2.9 vs 4.9±0.7, p=0.13), but no difference in the maximum invasion depth of CK8-positive trophoblasts (310±50 vs 286±37 um, p=0.72). We conclude that AVP infusion is sufficient to induce cardinal mid-gestational features of PE in pregnant mice, including reduced spiral artery diameter. Such morphological changes may be associated with the placental hypoxia and reduced placental growth factor expression in model.

Abstract: This study aimed to establish a reasonable population pharmacokinetic model for rifampicin taken orally by patients with pulmonary tuberculosis, estimate pharmacokinetic parameters as well as influencing covariates. Blood samples of patients were collected at day 10 – 14 after commencing treatment. Time – concentration data were handled using non-linear mixed-effect model with Monolix 2018. An one-compartment, linear elimination, absorption with transit compartments model was found to be the most suitable for rifampicin. Volume of distribution (33,5 L) and clearance (9,62 L) were found to be influenced by fat-free mass (calculated using Janmahasatian’s method). Absorption-related parameters (Ktr, mean transit time and Ka) were found to have high inter-individual variability. Keywords Rifampicin, population pharmacokinetics, pulmonary tuberculosis. References [1] Christian Lienhardt et al, Target regimen profiles for treatment of tuberculosis: a WHO document (2017).[2] J.G. Pasipanodya et al, Serum drug concentrations predictive of pulmonary tuberculosis outcomes, The Journal of infectious diseases 208(9) (2013) 1464-1473. https://doi.org/10.1093/infdis/jit352[3] Jonathan Reynolds, Scott K Heysell (2014), Understanding pharmacokinetics to improve tuberculosis treatment outcome, Expert opinion on drug metabolism & toxicology 10(6) (2014) 813-823. https://doi.org/10.1517/17425255.2014.895813[4] E.F. Egelund, A.B. Barth, C.A. Peloquin (2011), Population pharmacokinetics and its role in anti-tuberculosis drug development and optimization of treatment, Current pharmaceutical design 17(27) (2017) 2889-2899. https://doi.org/10.2174/138161211797470246.[5] J.F. Murray, D.E. Schraufnagel, P.C. Hopewell, Treatment of tuberculosis. A historical perspective, Annals of the American Thoracic Society 12(12) (2015) 1749-1759. https://doi.org/10.1513/AnnalsATS.201509-632PS[6] K.E. Stott, et al, Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis, Journal of Antimicrobial Chemotherapy 73(9) (2018) 2305-2313. https://doi.org/10.1093/jac/dky152.[7] Le Thi Luyen, Ta Manh Hung et al, Simultaneous Determination of Pyrazinamide, Rifampicin, Ethambutol, Isoniazid and Acetyl Isoniazid in Human Plasma by LC-MS/MS Method, Journal of Applied Pharmaceutical Science 8(09) (2018) 061-073. https://doi.org/ 10.7324/JAPS.2018.8910.[8] M.T. Chirehwa et al, Model-based evaluation of higher doses of rifampin using a semimechanistic model incorporating autoinduction and saturation of hepatic extraction, Antimicrobial agents and chemotherapy 60(1) (2016) 487-494. https://doi.org/10.1128/AAC.01830-15.[9] Paolo Denti et al, A population pharmacokinetic model for rifampicin auto-induction, The 3rd international workshop on clinical pharmacology of TB drugs (2010).[10] Y. Jing et al, Population pharmacokinetics of rifampicin in Chinese patients with pulmonary tuberculosis, The Journal of Clinical Pharmacology 56(5) (2016) 622-627. https://doi.org/10.1002/jcph.643.[11] S.R.C. Milán et al, Population pharmacokinetics of rifampicin in Mexican patients with tuberculosis, Journal of clinical pharmacy and therapeutics 38(1) (2013) 56-61. https://doi.org/10.1111/jcpt.12016.[12] Anushka Naidoo et al, Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis, Pharmacogenomics(00) (2013). https://doi.org/10.2217/pgs-2018-0166.[13] Neesha Rockwood et al, HIV-1 coinfection does not reduce exposure to rifampin, isoniazid, and pyrazinamide in South African tuberculosis outpatients, Antimicrobial agents and chemotherapy 60(10) (2016) 6050-6059. https://doi.org/10.1128/AAC.00480-16.[14] Alessandro Schipani et al, A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children, British Journal of Clinical Pharmacology 81(4) (2016) 679-687. https://doi.org/10.1111/bcp.12848.[15] Kok-Yong Seng et al, Population pharmacokinetics of rifampicin and 25-deacetyl-rifampicin in healthy Asian adults, Journal of Antimicrobial Chemotherapy 70(12) (2015) 3298-3306. https://doi.org/10.1093/jac/dkv268.[16] J.J. Wilkins et al, Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption, Antimicrobial agents and chemotherapy 52(6) (2008)2138-2148. https://dx.doi.org/10.1128%2FAAC.00461-07.[17] Sylvain Goutelle et al, Population modeling and Monte Carlo simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of rifampin in lungs, Antimicrobial agents and chemotherapy 53(7) (2009) 2974-2981. https://doi.org/10.1128/AAC.01520-08.[18] R.M. Savic et al, Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies, Journal of pharmacokinetics and pharmacodynamics 34(5) (2007) 711-726. https://doi.org/10.1007/s10928-007-9066-0.[19] B.J. Anderson, N.H.G. Holford, Mechanism-based concepts of size and maturity in pharmacokinetics, Annu. Rev. Pharmacol. Toxicol 48 (2008) 303-332. https://doi.org/10.1146/annurev.pharmtox.48.113006.094708.[20] Kok-Yong Seng et al, Population pharmacokinetic analysis of isoniazid, acetyl-isoniazid and isonicotinic acid in healthy volunteers, Antimicrobial agents and chemotherapy, pp. AAC. (2015) 01244-15. https://doi.org/10.1128/AAC.01244-15.[21] Sarayut Janmahasatian et al, Quantification of lean bodyweight, Clinical pharmacokinetics 44(10), (2005) 1051-1065. https://doi.org/10.2165/00003088-200544100-00004.[22] Kidola Jeremiah et al, Nutritional supplementation increases rifampin exposure among tuberculosis patients coinfected with HIV, Antimicrobial agents and chemotherapy 58(6) (2014) 3468-3474. https://doi.org/10.1128/AAC.02307-13

Abstract Background Ambulatory management of heart failure (HF) patients require the ability to identify when patients are at highest risk of impending HF events (HFE). The risk stratification ability based on diagnostic parameters measured by implantable cardiac monitors may differ depending on the left ventricular ejection fraction (LVEF) of HF patients. Objective The purpose of this study was to evaluate the difference in risk stratification performance of individual diagnostic parameters currently available in ICMs in identifying patients at increasing risk of HFE in patients with reduced versus preserved LVEF. Methods Patients with history of HFE who were implanted with an ICM was identified from the aggregated and de-identified electronic health record (EHR) database during 2007-2021. The device collected data were merged with the EHR data to create a de-identified database of real-world patients. Currently approved ICMs measure nighttime heart rate (NHR), heart rate variability (HRV), atrial fibrillation (AF) burden, ventricular rate during AF, and activity duration (ACT) daily and stores and transmits this information for the lifetime of the device. Each diagnostic parameter was categorized into high, medium, or low risk using a combination of features predefined in earlier studies. HFEs were defined as inpatient stay with a primary diagnosis of HF or HF related observation unit or emergency visit with IV diuresis administration. Patients were divided into two cohorts of patients with (1) median LVEF ≤ 40% (HFrEF), and (2) median LVEF &gt; 40% (HFpEF). Performance evaluation was performed by simulating monthly follow-ups which consisted of looking at the individual parameter risk states in the last 30 days and evaluating the occurrence of HF events in the following 30 days. A marginal Cox proportional hazards model was used to compare HF events for different risk groups (high, medium, and low) for each individual diagnostic parameter. Results There was a total of 267 patients with median LVEF ≤ 40% (64±13 years old, 67% male) and 622 patients with LVEF&gt;40% (69 ±12 years old, 47% male). For the reduced LVEF cohort, there was a total of 4,867 follow-up months with 65 monthly evaluations (1.3%) had an HF event in the next 30 days. For the preserved LVEF cohort, there was a total of 11,057 follow-up months with 224 monthly evaluations (2.0%) had an HF event in the next 30 days. The event rate comparisons between the risk groups for each individual diagnostic parameter are shown in Figure. As compared to ICM patients with HFrEF, ICM patients with HFpEF had higher absolute event rate across all risk groups, thus lowering the relative risk stratification between risk groups. Conclusion ICM patients with HFpEF showed a higher event rate and hence a higher absolute risk for each risk group, however relative risk between risk groups and hence the risk stratification performance for identifying risk for worsening HF was better in patients with HFrEF.

Zinc oxide (ZnO) has been widely deployed as electron conducting layer in emerging photovoltaics including quantum dot, perovskite and organic solar cells. Reducing the curing temperature of ZnO layer to below 200 oC is an essential requirement to reduce the cell fabrication cost enabled by large-scale processes such as ink-jet printing, spin coating or roll-roll printing. Herein, we present a novel water-based ZnO precursor stabilized with labile NH3, which allow us to spin coat crystalline ZnO thin films with temperatures below 200 oC. Thin film transistors (TFTs) and diode-type quantum dot solar cells (QD SCs) were fabricated using ZnO as electron conduction layer. In the QD SCs, a p-type 1,2-ethylenedithiol treated PbS QDs with a bandgap of 1.4 eV was spin-coated on top of ZnO layer by a layer-by-layer solid state ligand exchange process. Electron mobility of ZnO was about 0.1 cm2V-1s-1 as determined from TFT measurements. Power conversion efficiency of solar cells: FTO/ZnO/PbS/Au-Ag was 3.0% under AM1.5 irradiation conditions. The possibility of deposition of ZnO at low temperatures demonstrated herein is of important for solution processed electronic and optoelectronic devices. Keywords ZnO, low-temperature, quantum dots, solar cells, TFTs References [1] A. Janotti, A. Janotti, C.G. Van De Walle-fundamental of ZnO as a semiconductor, Reports on Progress in Physics, 72 (2009) 126501.[2] H. You, Y. Lin-investigation of the sol-gel method on the flexible ZnO device, International Journal of Electrochemical Science, 7 (2012) 9085–9094.[3] Y. Lin, C. Hsu, M. Tseng, J. Shyue, F. Tsai-stable and high-performance flexible ZnO thin-film transistors by atomic layer deposition, Applied Materials &Interfaces, 7(40) (2015) 22610–22617.[4] C. Lin, S. Tsai, M. Chang-Spontaneous growth by sol-gel process of low temperature ZnO as cathode buffer layer in flexible inverted organic solar cells, Organic Electronics, 46 (2017) 218-255.[5] H. Park, I. Ryu, J. Kim, S. Jeong, S. Yim, S. Jang-PbS quantum dot solar cells integrated with sol−gel-derived ZnO as an n‑type charge-selective layer, Journal of Physical Chemistry C, 118(2014) 17374−17382.[6] Y. Sun, J.H. Seo, C.J. Takacs, J. Seifter, A.J. Heeger-inverted polymer solar cells integrated with a low- temperature-annealed sol-gel-derived ZnO film as an electron transport layer Advanced Materials, 23(2011) 1679–1683.[7] V.A. Online, R. Suriano, C. Bianchi, M. Levi, S. Turri, G. Griffini-the role of sol-gel chemistry in low-temperature formation of ZnO buffer layers for polymer solar cells with improved performance, RSC Advances, 6(2016) 46915-46924.[8] X. D. Mai, J. An, H. Song, J. Jang-inverted Schottky quantum dot solar cells with enhanced carrier extraction and air-stability, Journal of Materials Chemistry A, 2 (2014) 20799–20805.[9] H. Choi, J. Lee, X.D. Mai, M.C. Beard, S.S. Yoon, S. Jeong - supersonically spray-coated colloidal quantum dot ink solar cells, Scientific Report, 7(2017) 622.[10] C.R. Newman, C.D. Frisbie, A. Demetrio, S. Filho, J. Bre- introduction to organic thin film transistors and design of n-channel organic semiconductors, Chemistry Materials, 16(2004) 4436-4451.[11] M. Asad, N. Abdul, Chapter 9: Sol-Gel-Derived Doped ZnO Thin Films: Processing, Properties, and Applications, in Recent Applications in Sol-Gel Synthesis, Edt:C. Usha. InTech, Rijeka, Croatia, 2017. [12] D. Guo, K. Sato, S. Hibino, T. Takeuchi, H. Bessho, K. Kato, Low-temperature preparation of (002)-oriented ZnO thin films by sol–gel method, Thin Solid Films, 550 (2014), 250-258. [13] S. T. Meyers, J. T. Anderson, C. M. Hung, J. Thompson, J. F. Wager, D. A. Keszler, Aqueous Inorganic Inks for Low-Temperature Fabrication of ZnO TFTs, J. Am. Chem. Soc, 130 (2008), 17603-17609.

BackgroundMany cancer patients initiated supplement use after cancer diagnosis and yet the effect of supplement use on survival has not been established. The trend of and factors associated with dietary supplement use in cancer survivors warrant further investigation.MethodsWe examined the trend of dietary supplemental use in 1,902 adult cancer survivors who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2012, and compared the frequency of supplement use in cancer survivors to that of 3,804 individuals with no history of cancer who were matched to the cancer survivors by age, sex, and race/ethnicity. The use of any supplements and individual supplements in the past 30 days was assessed based on self‐report. We further evaluated factors associated with supplement use in cancer survivors.ResultsAdult cancer survivors reported a significantly higher frequency of using any supplements (58% vs. 54%, p=0.0009) and individual supplements such as folic acid (26% vs. 23%, p=0.01), vitamin D (21% vs. 17%, p=0.0002), vitamin C (19% vs. 16%, p=0.01), and magnesium (12% vs. 10%, p=0.03) than non‐cancer individuals. Cancer survivors also reported an increasing trend of using vitamin D (11% in 1999–2000 vs. 41% in 2011–2012, p for trend<0.0001) and fish oil (1% in 1999–2000 vs. 15% in 2011–2012, p for trend<0.0001) but a decreasing trend of using calcium (18% in 1999–2000 vs. 10% in 2011–2012, p for trend=0.002). Compared to survivors who reported no supplement use, those who reported any supplement use were older (60 vs. 56 years of age, p<0.0001) and more likely to be non‐Hispanic Whites (86% vs. 76%, p<0.0001), college graduates (62% vs. 46%, p<0.0001), nonsmokers (42% vs. 38%, p<0.0001), and moderate alcohol drinkers defined as <=1 drink/d for women and <=2 drinks/d for men (41% vs. 31%, p=0.004), having a diagnosis of breast cancer (22% vs.14%, p=0.004), and being diagnosed with cancer at an older (49 vs. 45 years of age, p<0.0001). Gender, weight status, and years since diagnosis were not associated with supplement use in cancer survivors.ConclusionsIn a national sample of US adults, cancer survivors reported a higher frequency of supplement use than non‐cancer individuals. Supplement use in cancer survivors has been increasing for vitamin D and fish oil but decreasing for calcium.Support or Funding InformationNIH/NCI 1R03CA199516 Supplement Use in Adult Cancer Survivors and Individuals without Cancer in NHANES 1999–2012 Supplement Use Cancer Survivors (n=1,902) Individuals without Cancer (n=3,804) P value N (%) N (%) Any supplement use1 1,111 (58.4) 2046 (53.8) 0.0009 Multivitamin and mineral (MVM) supplement use2 Multivitamin with mineral 182 (9.6) 336 (8.8) 0.36 Multivitamin without mineral 75 (3.9) 111(2.9) 0.04 Single supplement use 444 (23.3) 877 (23.1) 0.81 Vitamins Folic Acid 492 (25.9) 862 (22.7) 0.01 Vitamin D 393 (20.7) 631 (16.6) 0.0002 Vitamin C 362 (19.0) 622 (16.4) 0.01 Vitamin E 331 (17.4) 609 (16.0) 0.18 Vitamin B12 212 (11.2} 385 (10.1) 0.23 Vitamin B6 181 (9.5) 327 (8.6) 0.25 Vitamin A 177 (9.3) 364 (9.6) 0.75 Vitamin B3 161 (8.5) 303 (8.0) 0.52 Vitamin K 54 (2.8) 118 (3.1) 0.58 Minerals Calcium 274 (14.4) 551 (14.5) 0.94 Magnesium 225 (11.8) 377 (9.9) 0.03 Zinc 153 (8.0) 311 (8.2) 0.86 Iron 130 (6.8) 242 (6.4) 0.49 Selenium 118 (6.2) 214 (5.6) 0.38 Potassium 114 (6.0) 212 (5.6) 0.52 Copper 93 (4.9) 201 (5.3) 0.53 Phosphorus 56 (2.9) 109 (2.9) 0.87 Others Fish Oil 116 (6.1) 218 (5.7) 0.58 Glucosamine 43 (2.3) 88 (2.3) 0.90 Garlic 40 (2.1) 82 (2.2) 0.90 Fiber 27 (1.4) 60 (1.6) 0.65 Glutamine 4 (0.2) 7 (0.2) 0.83 Echinacea 8 (0.4) 22 (0.6) 0.44 Any supplement use was defined as the use of the selected vitamins, minerals, non‐vitamin non‐mineral supplements. Multivitamin/mineral (MVM) supplemental use was defined as containing 3 or more vitamins with or without minerals. B‐complex vitamin is considered as a multivitamin supplement. Factors Associated with Supplemental Use in Adult Cancer Survivors1 Characteristics Survivors who reported supplemental use (N=1,111) Survivors who did not report supplemental use (N=791) P value OR (95% CI) Age, years, mean (SEM) 59.8 (0.5) 55.6 (0.6) <.000l Gender, N (%) Men 450 (34.9) 348 (37.0) 0.50 1.0 (ref.) Women 661 (65.1) 443 (63.0) 1.1 (0.8–1.4) Race/ethnicity, N (%) Non‐Hispanic White 747 (86.4) 410 (76.1) < 0001 1.0 (ref.) Non‐Hispanic Black 179 (6.0) 209 (12.2) 0.4 (0.3–0.6) Other 185 (7.6) 172 (11.7) 0.6 (0.4–0.8) Education, N (%) Grades 0–12 242 (14.3) 289 (25.1) <.000l 1.0 (ref.) Some post high school 265 (23.3) 206 (29.2) 1.4 (1.0–1.9) College graduate 602 (62.4) 296 (45.7) 2.4 (1.8–3.2) Smoking, N (%) Nonsmokers 481 (42.2) 308 (38.0) <.0001 1.0 (ref.) Former smokers 472 (42.7) 272 (31.9) 1.2 (0.9–1.6) Current smokers 157 (15.1) 210 (30.1) 0.5 (0.3–0.6) Alcohol, drink/week, N (%) Nondrinkers 414 (33.3) 345 (40.6) 0.004 1.0 (ref.) Moderate drinkers 421 (41.4) 215 (30.8) 1.6 (1.2–2.2) Heavy Drinkers 219 (25.4) 164 (28.6) 1.1 (0.8–1.5) Body mass index (BMI), kg/m2, mean (SEM) 28.9 (0.2) 29.4 (0.3) 0.13 Weight status, N (%) Normal weight (BMI=18.5–24.9) 308 (31.1) 186 (28.1) 0.60 1.0 (ref.) Overweight (BMI=25–29.9) 374 (31.8) 276 (33.2) 0.9 (0.6–1.2) Obese (BMI≥30) 429 (37.1) 329 (38.7) 0.9 (0.6–1.2) Primary diagnosis, N (%) Breast cancer 233 (22.0) 114 (14.3) 0.004 1.7 (1.2–2.4) Prostate cancer 184 (11.6) 162 (12.9) 0.45 0.9 (0.7–1.2) Colon cancer 94 (6.7) 77 (7.5) 0.54 0.9 (0.6–1.3) Lung cancer 33 (3.0) 20 (2.4) 0.40 1.3 (0.7–2.1) Other 500 (50.0) 381 (57.0) 0.02 0.8 (0.6–0.9) Multiple 67 (6.7) 37 (5.8) 0.60 1.2 (0.7–2.1) Age at diagnosis, years, mean (SEM) 49.0 (0.6) 44.6 (0.7) <.0001 Time from diagnosis, years, mean (SEM) 10.8 (0.5) 11.0 (0.4) 0.76 Time from diagnosis, N (%) >10 453 (42.0) 324 (43.0) 0.98 1.0 (ref) 5–9 279 (24.4) 196 (24.4) 1.1 (0.6–1.9) 1–4 331 (28.6) 230 (27.9) 1.1 (0.8–1.4) <1 48 (5.0) 41 (4.7) 1.0 (0.8–1.3) Frequencies, odds ratio, and 95% confidence intervals presented were weighted. Trend of Supplemental Use in Adult Cancer Survivors and Individuals without Cancer1 Supplement Use Cancer Survivors (n=1,902) p trend Individuals Without Cancer (n=3,804) p trend 99–00 01–02 03–04 05–06 07–08 09–10 11–12 99–00 01–02 03–04 05–06 07–08 09–10 11–12 Any supplement use2 125 (62.1) 133 (62.9) 156 (64.2) 131 (63.3) 192 (60.0) 197 (62.6) 177 (67.3) 0.95 239 (55.0) 286 (56.9) 313 (61.0) 260 (59.8) 352 (59.1) 332 (54.7) 264 (57.2) 0.44 Folic Acid 39 (20.7) 69 (31.5) 78 (33.0) 66 (31.3) 95 (30.4) 75 (27.9) 70 (24.5) 0.26 85 (19.3) 124 (23.9) 129 (25.3) 130 (28.2) 155 (26.7) 139 (24.6) 100 (22.0) 0.49 Vitamin D 21 (11.3) 30 (15.3) 44 (18.7) 38 (19.9) 68 (21.7) 96 (33.7) 96 (41.3) <.0001 38 (10.2) 53 (11.1) 78 (15.8) 71 (16.1) 125 (21.8) 134 (24.9) 132 (27.4) <.0001 Vitamin C 45 (22.2) 43 (26.3) 68 (29.9) 43 (21.8) 59 (18.0) 58 (19.3) 46 (16.5) 0.08 71 (17.4) 103 (22.1) 92 (16.9) 86 (20.6) 105 (19.0) 85 (15.9) 80 (19.0) 0.48 Calcium 34 (17.6) 41 (22.4) 46 (20.3) 37 (19.1) 40 (12.6) 43 (14.5) 33 (10.3) 0.002 65 (16.4) 79 (15.5) 86 (16.3) 89 (21.2) 87 (15.0) 70 (12.8) 75 (17.9) 0.02 Magnesium 28 (14.0) 23 (12.1) 36 (13.1) 26 (13.9) 36 (12.0) 41 (14.0) 35 (16.5) 0.89 45 (13.3) 55 (10.2) 50 (9.8) 53 (13.7) 67 (11.4) 59 (10.7) 48 (14.1) 0.45 Zinc 13 (6.5) 15 (7.9) 18 (7.0) 23 (12.7) 28 (7.8) 30 (11.8) 26 (11.8) 0.34 25 (6.6) 54 (10.6) 42 (7.9) 48 (9.8) 57 (9.9) 42 (8.0) 43 (10.8) 0.54 Fish Oil 1 (0.7) 4 (1.6) 6 (2.8) 13 (7.6) 26 (6.6) 32 (8.8) 34 (15.8) <.0001 3 (1.4) 10 (2.7) 19 (4.3) 59 (9.7) 66 (13.1) 66 (13.1) 44 (6.6) <.0001 Frequencies presented were weighted frequencies. Any supplement use was defined as the use of the selected vitamins, minerals, non‐vitamin non‐mineral supplements.