Journal articles on the topic '621.317.4, 537.6'

Abstract Background Respiratory syncytial virus (RSV) is a major cause of hospitalizations in young children. We estimated the burden of community-onset RSV-associated hospitalizations among US children aged <2 years by extrapolating rates of RSV-confirmed hospitalizations in 4 surveillance states and using probabilistic multipliers to adjust for ascertainment biases. Methods From October 2014 through April 2015, clinician-ordered RSV tests identified laboratory-confirmed RSV hospitalizations among children aged <2 years at 4 influenza hospitalization surveillance network sites. Surveillance populations were used to estimate age-specific rates of RSV-associated hospitalization, after adjusting for detection probabilities. We extrapolated these rates using US census data. Results We identified 1554 RSV-associated hospitalizations in children aged <2 years. Of these, 27% were admitted to an intensive care unit, 6% needed mechanical ventilation, and 5 died. Most cases (1047/1554; 67%) had no underlying condition. Adjusted age-specific RSV hospitalization rates per 100 000 population were 1970 (95% confidence interval [CI],1787 to 2177), 897 (95% CI, 761 to 1073), 531 (95% CI, 459 to 624), and 358 (95% CI, 317 to 405) for ages 0–2, 3–5, 6–11, and 12–23 months, respectively. Extrapolating to the US population, an estimated 49 509–59 867 community-onset RSV-associated hospitalizations among children aged <2 years occurred during the 2014–2015 season. Conclusions Our findings highlight the importance of RSV as a cause of hospitalization, especially among children aged <2 months. Our approach to estimating RSV-related hospitalizations could be used to provide a US baseline for assessing the impact of future interventions.

Background:Most of the patients suffering from autoimmune and rheumatic diseases (AIRD) are on immunomodulator or immunosuppressive therapies and they are susceptible to infections including COVID19.Objectives:To assess the risk factors for hospitalization with COVID-19 in patients with AIRDMethods:A single centre retrospective observational study including patients with AIRD who had contracted COVID-19. Data was collected from all patients attending our clinic from September 2020 to January 2021. Patients with COVID-19 were divided into hospitalized and non-hospitalized groups. Clinical, demographic, ongoing medications, comorbidities and post COVID flare data were collected and analysed using crosstabs-chi square and Mann-Whitney U test.Results:520 patients with AIRD were screened over the study duration, of which 52 patients who had contracted COVID-19 were included in the study. Amongst them, 19 patients (36.5%) required hospitalization. The common symptoms in the hospitalized patients over non-hospitalized were fever (63.2% vs 57.6), fatigue (42.1% vs 21.2%), headache (36.8% vs 18.2%), abdominal pain (26.3% vs 6.1%), myalgias (36.8 vs 18.2%) and dyspnea (31.6% vs 18.2%). The most common rheumatic conditions seen in both the groups were RA (42.1% vs 30.3%), SPA (26.3% vs 36.4%), and SLE with other CTD’s (15.8% vs 24.2%). 6 patients (11.5%) required ICU stay, 3 patients (5.7%) were ventilated, and 2 (3.8%) patients died.Patients requiring hospitalization were aged >50 years (p=0.018), had DM type II (p=0.003), HTN (p=0.035), multimorbidity (p=0.021), and a higher CORAD score (p<0.001). Usage of CsDMARDS, bDMARDS, TsDMARDS, corticosteroids did not show a significant difference between both the groups. Patients with >2 years of disease duration required hospitalization in comparison to <2 years of duration but this was not statistically significant.84.2% of hospitalized and 69.7% of non-hospitalized patients stopped anti-rheumatic treatment and disease flare was seen in 47.4% and 39.4% patients respectively.Conclusion:The rheumatic disease and their medications did not increase the risk of COVID-19 hospitalization in this study. However, higher age, DM II, HTN, and high CORAD score were found to be associated with hospitalization in AIRD patients. The findings of this study are limited by a small sample size.Table 1.Demographic and Rheumatic disease specific data of COVID-19 patientsAll patients (n=52)Hospitalized (n=19)Non-hospitalized (n=33)p-valueAll patients (n=52)Hospitalized (n=19)Non-hospitalized (n=33)p-valueAge– n (%)45.73 (10.829)50.53 (10.905)42.97 (9.923)0.018Duration– n (%)>2 years14(26.9)3(15.8)11(33.3)0.147>2 years38(73.1)16(84.2)22(66.7)Gender (Male/Female)21 (40.4)/ 31 (59.6)7 (36.8) / 12 (63.2)14 (42.4)/ 19 (57.6)0.462Corticosteroids – n (%)No steroids18(34.6)5(26.3)13(39.4)0.294Low dose steroids33(63.5)13(68.4)20(60.6)BMI– n (%)Normal27 (51.9)8 (42.1)19 (57.6)0.528Moderate dose steroids1(1.9)1(5.3)0(0.0)Pre-obese19 (36.5)8 (42.1)11 (33.3)DMARDS (CS) – n (%)MTX25 (48.1)8 (42.1)17 (51.5)0.358Obesity6 (11.5)3 (15.8)3 (9.1)HCQ13 (25)5 (26.3)8 (24.2)0.560Disease– n (%)RA18(34.6)8(42.1)10(30.3)0.287LEF4 (7.7)3 (15.8)1 (3)0.132SPA17(32.7)5(26.3)12(36.4)0.335SSZ10 (19.2)6 (31.6)4 (12.1)0.090SLE and other CTD’S11(21.2)3(15.8)8(24.2)0.364Azathioprine2 (3.8)2 (10.5)0 (0)Others6(11.5)3(15.8)3(9.1)0.380Iguratimod3 (5.8)1 (5.3)2 (6.1)0.129Comorbidities-n (%)DM212(23.1)9(47.4)3.(9.1)0.003Combination13 (25.0)6 (31.6)7 (21.2)0.701DMARDS(B)– n (%)Adalimumab1 (20.0)0 (0)1 (25.0)0.659HTN13(25)8(42.1)5(15.2)0.035Etanercept1 (20.0)0 (0)1 (25.0)Rituximab3 (60.0)1 (100.0)2 (50.0)CKD2 (3.8)2 (10.5)0 (0)0.129CO RADS-n (%)011 (21.2)0 (0)11 (33.3)<0.00119 (17.3)0 (0)9 (27.3)Hypothyroidism12 (23.1)4 (21.1)8 (24.2)0.53723 (5.8)0 (0)3 (9.1)33 (5.8)2 (10.5)1 (3)Multimorbidity8(15.4)6(31.6)2(6.1)0.021411 (21.2)7 (36.8)4 (12.1)515 (28.8)10 (52.6)5 (15.2)Disclosure of Interests:None declared

ABSTRACT Escherichia coli O157 and six non-O157 Shiga toxin–producing E. coli (STEC) serotypes (O26, O45, O103, O111, O121, and O145, colloquially referred to as the “big 6”) have been classified as adulterants of raw nonintact beef products in the United States. While beef cattle are a known reservoir for the prototype STEC serotype, E. coli O157, less is known about the dissemination of non-O157 STEC serotypes in Australian cattle. In the present study, 1,500 fecal samples were collected at slaughter from adult (n =628) and young (n =286) beef cattle, adult (n =128) and young (n =143) dairy cattle, and veal calves (n = 315) across 31 Australian export-registered processing establishments. Fecal samples were enriched and tested for E. coli O157 and the big 6 STEC serotypes using BAX System PCR and immunomagnetic separation methods. Pathogenic STEC (pSTEC; isolates that possess stx, eae, and an O antigen marker for O157 or a big 6 serotype) were isolated from 115 samples (7.7%), of which 100 (6.7%) contained E. coli O157 and 19 (1.3%) contained a big 6 serotype. Four of the 115 samples contained multiple pSTEC serotypes. Among samples confirmed for big 6 pSTEC, 15 (1%) contained E. coli O26 and 4 (0.3%) contained E. coli O111. pSTEC of serotypes O45, O103, O121, and O145 were not isolated from any sample, even though genes indicative of E. coli belonging to these serotypes were detected by PCR. Analysis of animal classes revealed a higher pSTEC prevalence in younger animals, including veal (12.7%), young beef (9.8%), and young dairy (7.0%), than in adult animals, including adult beef (5.1%) and adult dairy (3.9%). This study is the largest of its kind undertaken in Australia. In contrast to E. coli O157 and consistent with previous findings, this study reports a relatively low prevalence of big 6 pSTEC serotypes in Australian cattle populations.

Background: To investigate the efficacy and safety of supplementation with a fixed combination of magnesium, vitamin B2, feverfew, andrographis paniculata and coenzyme Q10 in episodic migraine (EM) prevention. Methods: A pilot, single-arm, open-label study was conducted. After a one-month baseline period, the above-described supplementation was introduced in 113 EM Greek patients, who were prospectively followed-up for three months. The primary endpoint was the change in monthly migraine days between baseline period (BSL) and the third month of supplementation (T3). Secondary endpoints included changes in mean intensity of migraine and in days with use of acute migraine medications. Changes in scores of Migraine Disability Assessment questionnaire (MIDAS), Headache Impact Test-6 (HIT-6), Migraine Therapy Assessment questionnaire (MTAQ), Migraine-Specific Quality-of-life questionnaire (MSQ-QOL), Hospital Anxiety and Depression Scale (HADS) were also evaluated. Those with ≥50% reduction in monthly migraine days at T3, compared to BSL were considered supplementation-responders. Results: The mean number of migraine days was significantly decreased between BSL and T3 (9.4 ± 3.7 vs. 6.1 ± 3.5; p < 0.001). Likewise, days with peak headache intensity of >4/10 (5.7 ± 3.4 vs. 4.9 ± 3.1; p < 0.001) as well as days using acute headache medications per month (8.9 ± 3.6 vs. 5.7 ± 3.4; p < 0.001) were significantly reduced. At T3, 64 patients (56.6%) were classified as responders. The beneficial effect of supplementation was also associated with significant changes in HIT-6, MIDAS, MTAQ and MSQ-QOL scores. There were no safety concerns. Conclusions: The supplementation we have tested appears to be an effective and well-tolerated preventive approach against EM. A randomized, placebo-controlled study is needed to confirm our results.

The aim of this paper was to identify which psycholinguistic variables are better predictors of performance for healthy participants in a picture naming task and in a picture categorization task. A correlation analysis and a Path analysis were carried out. The correlation analysis showed that naming accuracy and naming latency are significant and positively correlated with lexical frequency and conceptual familiarity variables, whereas they are negatively correlated with H index. Reaction times in the categorization task were negatively correlated with lexical frequency and conceptual familiarity variables and positively correlated with visual complexity variable. The Path analysis showed that subjective lexical frequency and H index are the better predictors for picture naming task. In picture categorization task, for reaction times, the better predictor variables were subjective lexical frequency, conceptual familiarity and visual complexity. 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Liveweight and age at first and second oestrus of Hereford, highgrade Simmental, and Belmont Red heifers were measured over 4 cohorts born from 1979 to 1982. Heifers were observed for standing oestrus or chin-ball markings by vasectomised bulls from about 7 months of age (May) to about 26 months (December). During this period they grazed predominantly improved pastures growing on cleared brigalow country in a subtropical environment. Hereford heifers demonstrated first and second oestrus at lower (P<0.05) liveweights (277 and 301 kg) than Belmont Reds (293 and 319 kg), which were lighter (P<0.05) than highgrade Simmentals (322 and 345 kg). Belmont Red heifers were younger (P<0.05) at first oestrus (527 days) than either Hereford (565 days) or highgrade Simmental (550 days), which were not significantly different. There was a similar pattern for age at second oestrus, except that only Belmont Red (583 days) and Hereford (617 days) differed significantly (P<0.05). However, 13% of heifers did not record a second oestrus during the observation period, in addition to the 7% that failed to record first oestrus by the end of the experiment. There was no difference between cohorts for liveweight at which heifers expressed first oestrus, but the cohort born in 1981 had higher liveweights at second oestrus than the 1979 and 1980 cohorts. Average age ranged from 476 to 613 days at first oestrus and 542 to 620 days at second oestrus over the 4 cohorts. This variation was a reflection of seasonal conditions, particularly during the period May-October following weaning at about 7 months of age. Only 6% of Hereford, 19% of highgrade Simmental, and 16% of Belmont Red heifers had reached puberty in time for seasonal mating as yearlings (about 15 months), and 88% of these were from the 1982 cohort.

The syntheses and room-temperature single-crystal X-ray structural characterization of 1 : 3 adducts formed between silver(I) (pseudo-) halides, AgX, and triphenylstibine, SbPh3, are described for X = Cl, I, SCN, NCS, CN, NO3 (1)-(6). The chloride, as its methanol solvate (1a), is isomorphous with the arsine analogue: triclinic, P-1, a 13·373(4), b 14·48(6), c 14·702(3) Å, α 83·49(3), β 87·76(2), γ 76·45(3)°; Z = 2, conventional R on F being 0·046 for No 5514 independent ‘observed’ reflections (I > 3σ(I )). A new form (1b) of the chloride has also been authenticated: monoclinic, P 21/c, a 12·832(2), b 54·24(1), c 18·519(8) Å, β 129·68(3)°; Z = 8 (R 0·065 for No 5672). No bromide has been obtained; the iodide (2) is described as monoclinic, P 21/n, a 19·611(4), b 14·473(6), c 17·74(1) Å, β 98·28(3)°; Z = 4 (R 0·036 for No 6769). The thiocyanate crystallizes from acetonitrile or pyridine as an S-bonded form (3) isomorphous with the arsine analogue: monoclinic, P 21/n, a 19·143(7), b 14·288(5), c 18·694(6) Å, β 98·81(2)°; Z = 4 (R 0·037 for No 4482). From 2-methylpyridine, remarkably, a solvate is obtained in which the thiocyanate is N-bonded (4): triclinic, P-1, a 27·261(5), b 14·767(3), c 13·319(1) Å, α 91·53(1), β 101·58(1), γ 92·29(2)°; Z = 4 (R 0·045 for No 6900). The cyanide is also monoclinic, P 21/n, a 19·442(7), b 14·267(3), c 17·741(6) Å, β 97·63(3)°, z = 4; R 0·057 for No 2487. The unsolvated 1 : 3 nitrate complex (6a) is monoclinic, P 21/n, a 19·602(5), b 14·455(1), c 17·727(2) Å, β 97·19(2)°, Z = 4; R was 0·034 for No 6522. The complex is isomorphous with the arsenic and phosphorus analogues, being mononuclear [(Ph3Sb)3Ag(O2NO)]. The ethanol solvate (6b) is triclinic, P-1, a 13·352(5), b 14·548(9), c 14·701(4) Å, α 81·64(4), β 84·45(3), γ 75·32(4)°, Z = 2; R was 0·058 for No 4702. Ag-Sb range between 2·6980(8) and 2·843(3) Å in the precise determinations; Ag-X are 2·481(4) and 2·52(1) Å (the two chlorides), 2·757(1) (I), 2·533(3) (SCN), 2·21(1) (NCS), 2· 09(3) (CN), 2·377(7) Å (unidentate ONO2)

Abstract Introduction In Colombia Breast cancer (BC), is the most frequent and has the highest mortality rate among all types of cancer. There are few studies of the genomic profile in unselected affected population by BC in Colombia. Some of these studies have only tested the presence of variants reported as founders named “Colombian Profile”.We conducted a large-scale genomic analysis using Whole Exome Sequencing (WES) to evaluate germline mutations in unselected BC patients. Methods This trial included 299 unselected BC female patients aged over 18 years old, without personal and family history of germline BC risk mutations.The protocol was approved by the IRC and EC of Fundación Cardioinfantil (FCI). All patients signed informed consent before recruitment.Genomic DNA was extracted from peripheral blood samples and was used to WES (Novogene Inc. Beijing, China). The variants were filtered using VarSeq v2.1.1 software, following the criteria: missense, non-sense, frameshift, and intronic variants, we additionally considered a MAF ≤0.01 for ATM, CHEK2, and PALB2 genes.Clinical significance of each variant was annotated according to the ACMG/AMP and ENIGMA guidelines.MLPA was assessed using the commercial kit SALSA MLPA Probemix P002-D1 for BRCA1 and P090-C1 for BRCA2 (MRC-Holland, Amsterdam).This study was financially supported by an unrestricted grant from Pfizer. Results This abstract is the first report from 299 patients. To determine the presence of germline variants in the patients a WES was performed. Here we describe the pathogenic and probably pathogenic mutations in BRCA1, BRCA2, ATM, CHEK2, PALB2. We found BRCA1/2 alterations were found in 3.7% of the patients (11 patients, IC 95% 1.7-5.6%), 5 patients in BRCA1 and 6 patients in BRCA2 (1.7% IC 95% 0.7-4%, and 2% IC 95% 0.9-4.4% respectively). We found 29 patients had mutations unrelated to BRCA1/2 (9.5% IC 95% 5.8-11.7%). The most frequently affected gene was ATM (17 patients, 5.7% IC95% 3.6-9%). Discussion and conclusion We found that 12.2% of the population of the study were carriers of a pathogenic/likely pathogenic variant in the evaluated genes, and interestingly 9.5% of them corresponded to non-BRCA1/2 genes. ATM variants have a prevalence of 5.7% in the whole population and represent 42% of all the variants. Other mutations in genes like BRCA2, ATM and CHEK2 were exclusive in non-TNBC. Meanwhile, BRCA1 and PALB2 mutations had higher frequencies in TNBC. We identified five novel mutations.We demonstrate that LGRs are not an important molecular cause in non-hereditary cases of BC.27% of the carriers of mutations in BRCA1/2 did not fulfilled NCCN criteria and 82% of the mutations are not described in “Colombian Profile”. These findings demonstrate the particular genetic profile in an unselected population with breast cancer, and this highlights the importance of WES as a molecular diagnostic tool. We think that universal germline testing in cancer should be considered. Baseline demographic and clinical characteristics Demographic and clinical characteristics of patients with pathogenic and likely pathogenic mutationsVariableBRCA1 n (%, IC 95%)BRCA2 n (%, IC 95%)ATM n (%, IC 95%)PALB2 n (%, IC 95%)CHEK2 n (%, IC 95%)Median age37.4 (22.4 – 54.3)45.5 (36.2 – 54.7)53.1 (45.4 – 60.7)55.8 (27.9 – 83.5)NA*Age≤ 50 years4 (80, 11.1 – 99.2%)4 (66.7, 14.8 – 95.8%)8 (47.1, 23.5 – 80%)2 (50, 24.7 – 97.5)NA*&gt; 50 years1 (20, 0.7 – 88.9%)2 (33.3, 4 – 85%)9 (52.9, 28 – 76.5%)2 (50, 24.7 – 97.5)OverweightYes4 (80, 11 – 99-2%)(33.3, 4 – 85%)9 (52.9, 28 – 76.5%) 3 (75, 0.4 – 99.5%)NA*No1 (20, 0.8 – 88.9%)(66.7, 14.9 – 94.8%)8 (47, 23.5 – 80%)1 (25, 0.4 – 95.9%)Estrogen receptor(+)2 (0.9%, 0.2 – 3.5%)5 (2.2%, 0.9 – 5.3%)16 (7.1%, 4.4 – 11.3%)3 (1.3%, 0.4 – 4.1%)3 (1.3%, 0.4 – 4.1%)(-)3 (4.3%, 1.4 – 12.6%)1 (1.4%, 0.2 – 9.6%)1 (1.4%, 0,2 – 9.6%)1 (1.4%, 0.2 – 9.6%)1 (1.4%, 0.2 – 9.6%)Progesterone receptor(+)2 (0.9%, 0.2 – 3.5%)5 (2.2%, 0.9 – 5.3%)13 (6%, 3.7 – 10.5%)3 (1.3%, 0.4 – 4.1%)4 (1.9%, 0.7 – 5%)(-)3 (4.3%, 1.4 – 12.6%)1 (1.4%, 0,2 – 9.6%)4 (4%, 1.7 – 11.7%)1 (1.4%, 0.2 – 9.6%)0HER-2 3+Yes1 (1.3%, 0.2 – 8.5%)1 (1.3%, 0.2 – 8.5%)4 (5%, 1.9 – 12.7%)1 (1.3%, 0.2 – 8.5%)2 (2.5%, 0.6 – 9.6%)No4 (1.9%, 0.7 – 4.9%)5 (2.3, 0.1 – 5.5%)13 (6%, 3.5- 10.2%)3 (1.4%, 0.4 – 4.3%)2 (0.9%, 0.2 – 3.7%)ER/Pgr y HER-2 negativeYes2 (5.1, 1.3 – 18.7%)001 (2.5%, 0-3 – 16.5%)0No3 (1.2%, 0.4 – 3.6%)6 (2.3%, 1 – 5.1%)17 (6.6%, 4-2 – 10.4%)3 (1.2%, 0.4 – 3.6%)4 (1.6%, 0.6 – 4.1%)Ki67&lt;20%0 1 (16.7, 0.9 – 81%) 5 (29.4, 11.5 – 57.1)0NA*≥20%5 (100%)5 (83.3, 18.6 – 99%)12 (70.6, 42.8 – 88.5%)4 (100%)Median tumoral size mm (min-max)24 (19.6 – 47.8)21 (12.5 – 29.5)24.9 (19.6 – 30.3)27.6 (0 – 59)NA* Lymph nodes involvementYes1 (0.7%, 0.1 – 4.6%)2 (1.3%, 0.3 – 5.2%)10 (6.7%, 3.6 – 12.1%)3 (2%, 0.6 – 6.1%)4 (2.7%, 1 – 7%)1No4 (2.7%, 1 – 7%)4 (2.7%, 1 – 7%)7 (4.7%, 2.2 – 9.5%)1 (0.7%, 0.1 – 4.6%)0MetastasisYes00001 (9%, 1.1 – 46.6%)2No5 (1.9%, 0.8 – 4.5%)6 (2.3%, 1 – 5%)17 (5.7%, 3.5 – 9.3%)4 (1.5 – 0.5 – 4%)3 (1.1%, 0.4 – 3.5%)Clinical stage (AJCC)I2 (40, 3.7 – 91.9%)1 (16.7, 0.9 – 81.3%)4 (23.5, 81 – 51.8%)0NA*II2(40 3.7 – 91.9%)4 (66.7, 14.8 – 95.8%)7 (41.2, 19.3 – 67.3%)4 (100%)III1 (20, 0.7 – 88.9%)1 (16.7, 0.9 – 81.3%)6 (23-3, 15.2 – 62.3%)0IV0000Family history for cancerYes4 (80, 11.1 – 99.2%)5 (83.3, 9 – 81.4%)13 (76.5 – 48.2 – 91.9%)2 (50, 2- 97.5%)NA*No1 (20, 0.7 – 88-9)1 (16.7, 0.9 – 81.4%)4 (23, 8 – 51.8%)2 (50, 2- 97.5%)NCCN criteriaYes4 (2.4%, 0.9 – 6.3%)4 (2.4%, 0.9 – 6.3%)NA*NA*NA*No1 (0.8%, 0.1 – 5.9%)2 (1.7%, 0.4 – 6.6%)Colombian profileYes1 (50%, 19 – 98%)31(50%, 19 – 98%)3NA*NA*NA*No4 (13.5%, 5 – 35.5%)5 (17%, 7 – 40%) Citation Format: Diana Carolina Sierra-Díaz, Adrien Morel, Dora Janeth Fonseca, Nora Contreras, Mariana Angulo-Aguado, Valentina Balaguera, Kevin Llinás-Caballero, Isabel Munevar, Mariana Borras, Mauricio Lema, Henry Idrobo, Daniela Trujillo, Norma Serrano, Ana Isabel Orduz, Diego Lopera, Jaime Gonzalez, Gustavo Rojas, Paula Londoño, Ray Manneh, Catalina Quintero, Paul Laissue, Rodrigo Cabrera, Carlos M Restrepo, William Mantilla. Genetic profile of germline mutations in unselected women with breast cancer in a Colombian population [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-05.

Trastuzumab deruxtecan (T-DXd) has shown promising efficacy against HER2-positive advanced gastric cancer (AGC). However, data on its real-world efficacy in AGC patients are insufficient, and the predictive marker of T-DXd is unclear. In this multi-center retrospective study, we collected clinical information of 18 patients with HER2-positive AGC who received T-DXd after intolerant or refractory responses to at least two prior regimens and analyzed predictive factors. The median age was 71 years (range: 51–85), 13 men were included, and ECOG performance status (PS): 0/1/2/3 was 9/6/2/1. A total of 11 patients (61%) received prior immune checkpoint inhibitors (ICIs), 14 patients were HER2 3+, and 4 patients were HER2 2+/FISH positive. The median trastuzumab (Tmab)-free interval was 7.7 months (range: 2.8–28.6). The overall response rate was 41%, and the disease control rate was 76%. Median progression-free survival (PFS) was 3.9 months (95% CI: 2.6–6.5), and median overall survival (OS) was 6.1 months (95% CI: 3.7–9.4). PFS (6.5 vs. 2.9 months, p = 0.0292) and OS (9.2 vs. 3.7 months, p = 0.0819) were longer in patients who received prior ICIs than in those who had not. PFS (6.5 vs. 3.4 months, p = 0.0249) and OS (9.4 vs. 5.7 months, p = 0.0426) were longer in patients with an 8 month or longer Tmab-free interval. In patients with ascites, PFS (6.5 vs. 2.75 months, p = 0.0139) and OS (9.4 vs. 3.9 months, p = 0.0460) were shorter. T-DXd showed promising efficacy in HER2-positive AGC patients in a real-world setting. Pre-administration of ICIs and a sufficient Tmab-free interval may be predictive factors of T-DXd efficacy.

ABSTRACTBacteriophages UAB_Phi20, UAB_Phi78, and UAB_Phi87 were encapsulated in liposomes, and their efficacy in reducingSalmonellain poultry was then studied. The encapsulated phages had a mean diameter of 309 to 326 nm and a positive charge between +31.6 and +35.1 mV (pH 6.1). In simulated gastric fluid (pH 2.8), the titer of nonencapsulated phages decreased by 5.7 to 7.8 log units, whereas encapsulated phages were significantly more stable, with losses of 3.7 to 5.4 log units. The liposome coating also improved the retention of bacteriophages in the chicken intestinal tract. When cocktails of the encapsulated and nonencapsulated phages were administered to broilers, after 72 h the encapsulated phages were detected in 38.1% of the animals, whereas the nonencapsulated phages were present in only 9.5%. The difference was significant. In addition, in anin vitroexperiment, the cecal contents of broilers promoted the release of the phages from the liposomes. In broilers experimentally infected withSalmonella, the daily administration of the two cocktails for 6 days postinfection conferred similar levels of protection againstSalmonellacolonization. However, once treatment was stopped, protection by the nonencapsulated phages disappeared, whereas that provided by the encapsulated phages persisted for at least 1 week, showing the enhanced efficacy of the encapsulated phages in protecting poultry againstSalmonellaover time. The methodology described here allows the liposome encapsulation of phages of different morphologies. The preparations can be stored for at least 3 months at 4°C and could be added to the drinking water and feed of animals.

Aim. To evaluate patients’ (pts.) compliance with Ventavis inhaled treatment. Secondary aim: to study pts. characteristics; reason for low compliance; changes in 6-minute walking distance (6MWD) test and dyspnea score; changes in the parameters of pulmonary hemodynamics; pulmonary function changes; quality of life (QOL) according to compliance with Ventavis use; to assess frequency, severity and other characteristics of AE. Materials and methods. Prospective, multicenter, single cohort non-interventional IV phase study IVENT (NCT01971450). The study lasted 12 month. Pts. evaluation was scheduled as follows: initial visit done at baseline (pts. inclusion) - iV, 6 (follow-up visit 1) - V1, and 12 (follow-up visit 2, final) month - V2 thereafter. Evaluation of basic demographic and functional characteristics using needed armamentarium was planned at these time points. Treatment compliance was analyzed at 1 (6 month) and 2 (12 month) follow-up visits (ITT population). Results. As many as 82 pts. averages (mean±SD) 47.6±14.2 years with mean PH syndrome duration 3.2±5.7 years were included. Substantial number of pts. presented with severe disorders in anamnesis, i.e. pulmonary embolism, heart defect, arterial hypertension, heart failure in 35.4; 14.6; 36.6 and 70.7% of pts., respectively. PH syndrome verification methods varied with right heart catheterization (RHC) being the most prevalent one in 45.1% of pts., following by echocardiography (EchoCG) in 30.5%. At the iV EchoCG was performed in all the pts; and at the final visit in 82.9%; RHC - in 62.2% and 7.3%, respectively. Study population mean 6MWD estimated to be 257.7±109.6 m at the time of inclusion with Borg index score 6.4±4.2. All 82 pts. were being treated with iloprost inhaled [average daily dose 8.0±7.9 (95% CI 6.2-9.7) mcg] at the iV. 53 and 29 pts. of ITT population formed ‘sufficient-compliant’ (SC) and ‘low-compliant’ (LC) subgroups (sbgr.), respectively. Patients’ compliance of inhaled treatment with Ventavis in the overall population was shown to be 82.3±27.7% at the V1 and 81.8±28.4% at the V2; in SC sbgr. - 96.9±5.4 and 96.6±5.8%, respectively; in LC sbgr. - 49.1±29.1 and 46.4±29.9%, respectively. AE, lack of the drug or drug ineffectiveness, patient preferences not to receive the drug were demonstrated to be the main reasons for treatment discontinuation in both sbgr. At 6 month mean daily dose of iloprost was 7.7±5.5 mcg; at 12 month 7.2±4.9 mcg. At the iV 63.4% of pts. was receiving inhalations 6 times in a days at month 6 and 12 - 58.5% and 48.8%, respectively. Mean number of inhalations per day was estimated to be 5.9±1.3 at the iV and 6.1±1.3 at V1 and V2. Ventavis treatment interruptions were registered in 37.8% of pts. at the end of observation period (22.6% SC sbgr.; 65.5% LC sbgr.). Premature discontinuation of the drug treatment was noted in 8.5% of pts. at V1 and 20.7% at the V2. Dose correction took place in 4.9% and 1.2% of pts. at V1 and final visit, accordingly. SC sbgr. of pts. at baseline was characterized by 6MWD of 266.9±114.23 vs. 240.5±100.2 m in LC one. At 12 month 6MWD had increased up to 307.1±115.4 vs. 263.5±107.4 m in SC and LC sbgr., respectively. Baseline Borg dyspnea score in SC sbgr. was 6.1±3.8 vs. 6.9±4.9 in LC pts. At the end of the study, Borg dyspnea score for SC and LC pts. estimated to be 6.3±3.6 and 7.7±5.7, respectively. Thus, in SC sbgr. was achieved positive changes in 6MWD with persistent dyspnea, but in LC sbgr. dyspnea severity had increased. In ITT population systolic PAP (SPAP) measured by EchoCG was slightly decreased from 83.2±27.9 to 76.6±29.7 mmHg at the final visit; in SC sbgr. - from 82.5±24.1 to 76.5±26.7 mmHg; in LC sbgr. - from 84.5±34.5 to 76.8±35.7 mmHg. Due to the fact RHC data is available only for several pts., it is impossible to analyze changes in hemodynamic variables. Patients’ QoL according to SF-12 questioner showed positive changes from mean score 30.8±7.7 to 35.1±9.3 in SC pts. at the end of observation. QoL in LC sbgr. did not change substantially. Same trend could be revealed when evaluating psychological component: 41.7±10.6 and 46.3±10.9 in SC sbgr.; 40.6±11.4 and 40.2±11.7 in LC sbgr. During the study 64 AE in 24.4% of pts. were registered, 37 AE in 17.1% of pts. judged to be drug-related. Iloprost dose was remaining unchanged in 13.4% of pts., whereas in 2.4% of pts. dose decreased; in 8.5% of pts. drug intake was discontinued. At the end of the study, 35 AE in 15.9% of pts. successfully resolved. The most frequent AE became cough (9.8%), dysphonia (3.7%), headache (6.1%), dizziness (4.9%), syncope (3.7%), asthenia (2.4%), edema (2.4%). Overall 24 serious AE (SAE) had occurred in 20.7 of pts. 17 (out of 24) SAE in 11 (37.9%) pts. emerged in LC sbgr. None of the SAE were considered to be drug-related. Iloprost dose remained unchanged in 6.1% of pts. (8 SAE cases), treatment paused in 1.2% of pts., and treatment was discontinued in a single case. 13 SAE in 11 (13.4%) pts. were fatal, 4 SAE in 4 (4.9%) pts. had resolved, 3 SAE in 2 (2.4%) pts. was resolving, 4 SAE in 2 (2.4%) pts. were continuing at the end of observation. In 8 cases in 6 (7.3%) pts. dose correction measures were not undertaken; in 6 SAE cases in 5 (6.1%) pts. there is no information available. Conclusion. In general population studied, it’s been demonstrated sufficient PH patients’ compliance of Ventavis inhaled treatment.

The low number of oocytes collected from unstimulated donors by ovum pick-up means that embryos produced from each female have to be cultured in very small groups. Because embryo quality and development rates are reduced in individual and small group culture, several methods to culture embryos individually but sharing the same medium have been designed. However, these systems prevent embryo movements, interfering with paracrine factors transmission and gradient changes. Here, we present an alternative in vitro culture method to allow the co-culture of embryos from different origins, without movement restriction and preserving their pedigree, by labelling the zygotes with polysilicon barcodes attached to the outer surface of the zona pellucida (ZP). Barcodes (10 × 6 × 1 µm) with 8 rectangular bits of binary codification (256 possible combinations), which can be read under a standard inverted microscope, were fabricated using silicon microtechnologies. To provide the barcodes with a ZP-binding capacity, they were biofunctionalized by self-assembled monolayers with the wheat germ agglutinin (WGA) lectin, which recognizes specific saccharides highly abundant in the ZP of most mammalian species. As a proof of concept, the culture method was tested on bovine zygotes produced from slaughterhouse-derived cow oocytes matured and fertilized in vitro. Using a mouth-controlled pipette, presumptive zygotes were individually rolled over WGA-biofunctionalized barcodes (8 barcodes/embryo) previously placed at the bottom of a drop of manipulation media. Four different barcodes, each one with a different codification, were used to encode 25 embryos (6–7 embryos/barcode codification), which were then cultured together in the same drop of medium. Day 7 (D7) and Day 8 (D8) blastocyst, and barcode retention rates were assessed. In addition, D7 expanded blastocysts were vitrified by the cryotop method and post-warming survival was determined as re-expansion rate at 24 h in culture. Finally, the quality of D8 blastocysts was assessed by differential staining and counting of inner cell mass (ICM) and trophectoderm (TE) cells. In all the experiments, a control group without barcodes was cultured and vitrified-warmed. Data were analyzed by chi-square and Mann–Whitney tests. The presence of barcodes attached to the ZP did not affect in vitro embryo development (D8 blastocysts: 29.7% control n = 309, 36.2% encoded n = 315), post-warming survival (86.4% control n = 66, 80.5% encoded n = 82), or blastocyst quality (IMC/TE: 22.1 ± 1.4/64.5 ± 5.7 control n = 18, 22.2 ± 1.7/64.1 ± 6.1 encoded n = 23). The labelling system was effective until D8 of culture, as all the embryos maintained barcodes attached (4 ± 1.8 barcodes/embryo) and could be identified, even after undergoing vitrification and warming. In conclusion, identification of co-cultured embryos by biofunctionalized barcodes attached to the ZP is feasible and will allow to culture embryos from different donors in the same drop, keeping the benefits of collective culture. Support was provided by Spanish MEC (TEC2011-29140-C03; RZ2010-00015-0-00; AGL2010-19069), Generalitat Catalunya (2009 SGR 282 and 621), and PIF-UAB Fellowship.

Abstract BACKGROUND: Pulmonary hypertension is a potentially life threatening complication described in adults with sickle cell disease and other hemolytic disorders. There has been little to no information on the occurrence of this condition in pediatric patients. METHODS: Retrospective case review of sickle cell patients at Children’s Hospital of Pittsburgh to determine the clinical characteristics and co-morbidities of patients previously diagnosed with pulmonary hypertension, as detected by tricuspid regurgitant (TR) jet velocity of ≥ 2.5 m/sec on Doppler echocardiography. RESULTS: Nine patients with sickle cell disease (all HbSS) were diagnosed with pulmonary hypertension, with an initial mean TR jet velocity of 2.98±0.19 m/sec. All had some history of respiratory disease, 4 had a cerebrovascular disease, and 4 were previously on a chronic transfusion program. Laboratory results reveal low hemoglobin, reticulocytosis, and elevated total bilirubin and lactate dehydrogenase in a majority of patients, suggesting clinically significant chronic hemolysis. Therapy initiated for these patients included increasing transfusion therapy, oxygen supplementation, hydroxyurea, and tonsillectomy when indicated. These interventions resulted in a reduction in mean post-therapy TR Jet to 2.61±0.21 m/sec (p=0.0015) in 8 of 9 patients. CONCLUSIONS: Pulmonary hypertension occurs in children with sickle cell disease and is associated with manifestations of increased hemolysis and co-morbid respiratory or cerebrovascular diseases. Aggressive sickle cell-directed therapy and management of co-morbidities reduces the degree of pulmonary hypertension. Table I Pt #/Age/Sex Complications/Co-morbidities Hemoglobin % Reticulocytes Ferritin Total Bilirubin LDH Therapies/Intervention Abbreviations: LDH, lactate dehydrogenase; MCA, middle cerebral artery; OSA, obstructive sleep apnea; TRX, transfusion therapy; O2, oxygen; ACS, acute chest syndrome; VOC, vasoocclusive crisis 1: 13/F Asthma, OSA, MCA stenosis, pneumonia/ACS, iron overload 8.7 14.4 2010 8.1 n/a Chronic TRX, asthma therapy, Tonsillectomy 2: 18/M ACS (multiple), hyperhemolysis, allosensitization, aplastic crises, central hypopnea, cor pulmonale 5.8 34 774 6.4 527 Chronic TRX, O2 at night, initiation of hydroxyurea 3: 14/M Asthma, nocturnal enuresis, constipation, OSA, ACS, recurrent VOC 8.8 11.1 4330 2 657 Periodic TRX, O2 at night, hydroxyurea, asthma therapy 4: 18/M Asthma, Hepatitis C, silent stroke, Moya-Moya syndrome, priaprism, sepsis (multiple), aplastic crises, iron overload 9.1 7.3 4385 2.6 n/a Chronic TRX, O2 at night, asthma therapy 5: 17/F Hepatitis C, asthma, restrictive lung disease, chronic dyspnea, blain gliosis, silent stroke, ACS, cardiomegaly, allosensitization 7.1 19.7 n/a 5.7 n/a Infrequent TRX (due to allosensitization), O2, asthma therapy 6: 12/M Asthma, nocturnal enuresis, sepsis 7.9 17 310 5.1 485 Increased frequency TRX, asthma therapy 7: 16/M ACS, stroke, intracranial hemorrhage 8.2 9.5 2012 3.5 440 Chronic TRX, O2 at night 8: 14/F ACS, cardiomegaly 8.8 14 n/a 3.9 n/a Initiaion of TRX, O2 at night 9: 9/M Tonsillar hypertrophy, possible OSA, cardiomegaly 6.1 20.7 n/a 4.1 667 Increased frequency TRX Table II Patient # Maximum TR Jet TR Jet Post-Therapy TR Jet: tricuspid regurgitant jet velocity (m/sec) 1 2.6 2.4 2 3 2.7 3 3 2 4 2.8 2.6 5 3.3 2.8 6 3.5 3 7 3 2.7 8 3 2.7 9 2.65 n/a yet

Abstract Introduction: Augmented post-induction (IND) intensification therapy improved event free (EFS) and overall survival (OS) among patients (pts) 1-20 years (yr) with NCI high-risk (HR) B- and T-ALL on CCG-1961 (Seibel, Blood 2008) but was associated with significant ON (Mattano, Lancet Oncol 2012). Successor COG trials for HR B-ALL (AALL0232) and T-ALL (AALL0434) have investigated modifications of augmented therapy to further improve outcome and reduce ON risk. HD-MTX delivered during interim maintenance (IM) provided an EFS advantage over escalating dose (Capizzi) MTX/ASNase on AALL0232 (Larsen, ASCO 2011) and confirmed a lower ON incidence with alternate-week (AWD) vs continuous (CD) dexamethasone (DEX) during delayed intensification (DI) (Mattano, ASH 2012). Additionally, ON incidence was lower among pts 10+ yr receiving IND prednisone (PDN) vs DEX, especially those randomized to HD-MTX. We now report results for ON incidence among T-ALL pts receiving comparable therapy on AALL0434. Methods: AALL0434 opened 1/2007 and completed accrual 7/2014, with 1155 evaluable T-ALL pts 1-30 yr included in this report (data freeze 6/30/2014). All pts received standard 4-drug IND (vincristine, PDN 60 mg/M2 days 1-28, pegaspargase, daunorubicin, intrathecal MTX). Following IND, pts received augmented therapy with a 2x2 randomization to HD-MTX vs C-MTX/ASNase (during a single IM phase) with or without six 5-day (d) courses of nelarabine (NEL) (during consolidation (CON), DI, and MTC cycles 1-3). Pts meeting low-risk (LR) criteria (age 1-9 yr, WBC <50,000/microliter, no central nervous system or testicular leukemia, and rapid marrow response (<5% blasts by d15 and end-IND minimal residual disease <0.1%)) were not eligible for the NEL randomization. Initially, pts 1-9 yr received CD (10 mg/M2 d1-21) during DI, and all pts received DEX pulses (6 mg/M2 d1-5) every 28d during MTC. After 9/2008, based on AALL0232 ON interim analyses, all pts received AWD (d1-7,15-21) during DI and PDN pulses (40 mg/M2 d1-5) during MTC. To accommodate drug scheduling, pegaspargase dose intervals were increased on NEL regimens during CON and DI by 7-14d, CON was extended by 21d, and 3 fewer steroid pulses were given during MTC cycles 1-3. MTC duration was 1 yr longer for males. Results: Among 1155 evaluable pts (617 with 36+ months follow-up), 69 (6%) developed imaging-confirmed ON (58/527 (11%) 10+ yr, 11/628 (2%) 1-9 yr; 54/861 (6%) males, 15/294 (5%) females). Symptom onset was pre-MTC in 13%, during MTC in 86%, after therapy completion in 1%, and within 36 months in 93%. Maximum reported ON clinical severity (CTCAE v4.0) was 11.6% grade 1, 60.9% grade 2, 27.5% grade 3. The overall 36-month ON cumulative incidence was 8.0±1.2% and was higher for pts 10+ yr (14.6±2.3 vs 2.6±1.0%, RHR 5.7, p<0.0001). Males 10+ yr had a numerically higher ON incidence that was not statistically significant (15.5±2.7 vs 10.9±4.8, RHR 1.4, p=0.4). Higher ON rates were seen among pts randomized to C-MTX/ASNase or HD-MTX without NEL (Table). Among pts 13+ yr treated without NEL, ON rates for C-MTX/ASNase (26.4±5.8%) and HD-MTX (23.0±6.2%) were similar to those seen in comparably treated B-ALL pts on AALL0232 regimens PC (18.9±2.7%) and PH (17.3±2.5%). Conclusions: T- and B-lineage ALL pts are at similar overall risk for developing ON when given comparable therapy, particularly those age 10+ yr. Increased pegaspargase exposure likely contributes to the increased ON rates seen with C-MTX/ASNase in both populations, whereas longer intervals between pegaspargase doses and fewer steroid pulses during early MTC appear associated with significantly lower rates for T-ALL pts on NEL regimens. Unlike B-ALL, the observed higher rate among males may be due to the expected T-ALL gender imbalance and resulting low numbers of female pts. AWD during DI is now considered standard care for all ALL populations on COG ALL trials. ON will continue to be closely monitored through completion of this trial. Table: Randomized Regimens, 36-Month Cumulative Incidence Rate (% ± SE) Without Nelarabine With Nelarabine Age (yr) C-MTX/ASNase HD-MTX C-MTX/ASNase HD-MTX P* 1-30 11.6±2.2 8.2±1.9 5.2±4.0 3.2±3.5 0.04 n=363 n=442 n=138 n=171 10-30 20.6±4.0 16.0±3.7 10.2±7.7 6.1±6.2 0.07 n=158 n=185 n=71 n=93 *P value for 4-way comparison of regimens by age cohort Disclosures Hunger: Sigma Tau Pharmaceuticals: Honoraria; Jazz Pharmaceuticals: Honoraria.

Abstract Host dendritic cells (DC) are thought to be essential in the induction of acute GVHD after allogeneic HSCT. Human peripheral blood contains various circulating DC precursors including CD11c+ myeloid preDC (mDC), CD14+ monocytic DC precursors (CD14+ preDC) and plasmacytoid preDC (pDC). In this study we employed flow cytometry to enumerate both mDC (lin-, HLA-DR+ and CD11c+), mono-DC (CD14+, CD45 bright) and pDC (lin-, HLA-DR+ and CD123+) numbers in the blood of patients receiving an allogeneic HSCT. Fifty consecutive patients undergoing HSCT from HLA-matched either related (n=28) or unrelated (n=22) donors were enrolled in the study. The stem cell source was bone marrow in all unrelated donors, and G-CSF mobilized PBSC in related donors. Indications to transplant were AML (n=12), ALL (n=11), MM (n=10), CML (n=7), NHL (n=6) and HD (n=4). 13 patients (26%) received reduced dose conditioning regimens (RIC). All patients received CsA and MTX as GVHD prophylaxis. Moreover, 26 patients (52%) received ATG before transplant. mDC and pDC PB counts were significantly lower in patients as compared to 28 age-matched healthy controls [8.8 cells/microL (25th to 75th percentile 3.5–14.5) mDC, and 2.8 (1.3–5.5) pDC, vs 15.5 (12.1–25.1) and 8.6 (5.6–13.1), respectively] (p&lt;0.001). However the mDC/pDC ratio was significantly higher in the patient group [3.5 (1.6–6.2) vs 1.7 (1.3–2.6), p=0.002], indicating a preferential decrease of pDC. CD14+ preDC counts were not significantly different. Among 46 patients evaluable, 12 (26%) developed acute GVHD grade II–IV. Risk factors significantly associated with acute GVHD were older age (p=0.01), PBSC transplants (p=0.02) and the absence of ATG in the conditioning regimen (p=0.01). Patients with acute GVHD had significantly higher pre-transplant mDC:pDC ratio [5.7 (3.3–16.4) vs 3.1 (1.6–5.5)] (p=0.03) and CD14+ preDC counts [395 (326–625) vs 284 (187–395] (p=0.02). A subset analysis was performed in PBSC patients, only 3 of whom had received ATG before transplant. Among 26 evaluable patients, 10 (38%) developed acute GVHD grade II–IV. Besides older age (p=0.02), the only risk factors significantly associated with acute GVHD in PBSC patients were the pre-transplant mDC:pDC ratio [5.7 (4.1–13.1) vs 1.7 (1.2–2.9)](p=0.008) and CD14+ preDC counts [395 (352–710) vs 259 (199–314)](p=0.004). In multivariate analysis, only older age (p=0.04) and pretransplant circulating CD14+ preDC numbers (p=0.04) were significantly associated with acute GVHD in PBSC transplants. Patients with pretransplant CD14+ preDC counts &gt; 310/mL (median value) had a higher actuarial probability of developing acute GVHD grade II–IV than patients with lower CD14+ preDC counts (61% vs 15%). No correlation was observed between pretransplant recipient PB mDC, pDC or CD14+ preDC counts and chronic GVHD. These findings demonstrate that blood levels of DC precursors may represent an important biomarker correlating with a higher risk of developing aGVHD. Based on these results, future studies will exploit clinical strategies aimed at depleting or inactivating host preDC before allotransplant as a means of GVHD prophylaxis.

Abstract Introduction Benign neutropenia (BN) is an asymptomatic condition observed in individuals of African descent. Patients with BN tend to have normal myeloid maturation within the bone marrow but release fewer neutrophils into the peripheral circulation. Previous studies of BN in pediatrics have reported no evidence of increased infections but otherwise lacked a detailed clinical description. The purpose of this study is to identify individuals with BN and better characterize the clinical findings seen in patients with this condition. Methods A single institution retrospective study from 2008-2013 was conducted at an urban tertiary care children’s hospital in Washington, DC. Potential patients were initially identified by searching for ICD9 codes 288.0 (neutropenia) and 288.09 (neutropenia, not otherwise specified). Absolute neutrophil count (ANC) less than1500 was required for inclusion. Exclusion criteria included other hematologic disorder, pregnancy, low B12 or folate levels, prior cancer diagnosis, or concurrent immunosuppressant therapy. Demographic, laboratory, and clinical information on all included patients was recorded. All outpatient visits with a hematologist with a documented ANC were evaluated and recorded as encounters. Results Searching by ICD9 codes yielded 136 potential patients. 99 were excluded: 43 had antibody positive autoimmune neutropenia, 26 had transient or self-resolved neutropenia, 22 had concurrent malignancy, while 4 were receiving other immunosuppressant medications, and 4 had other known causes of neutropenia. The remaining 37 patients were included as BN, and were seen in a total of 130 encounters in the outpatient hematology clinic. Median age at evaluation was 5.3 years; 19 were males and 18 females. 22 (59.5%) patients were of African descent, 4 (10.8%) Caucasian, 3 (8.1%) Hispanic, 2 (5.4%) Asian, and 6 (16.2%) ethnicity was not documented. A summary of patient reported symptoms is in Table 1. Table 1. Key clinical findings from BN individuals Finding Patients % Reporting Upper respiratory infection 8 21.6 Rash 6 16.2 Poor weight gain or weight loss 4 10.8 Headache 3 8.1 Oral ulcers 3 8.1 Bone or joint pain 2 5.4 Cervical lymphadenopathy 2 5.4 Gingivitis 1 2.7 Dental problems 1 2.7 Night sweats or chills 1 2.7 Delayed wound healing and dyspnea were not reported during by any patients. There were 2 patients with drug allergies and 1 with a food allergy. No first degree relatives of any of the patients were noted to have a history of neutropenia. For all patients in the study there were 5 total hospitalizations: 2 for febrile neutropenia, 1 each for mastoiditis, weight loss and neutropenia, and pneumonia. None of these hospitalizations required ICU management. 5 patients had bone marrow biopsies, 3 of which were normal and the others had focal/mild hypocellularity. In terms of laboratory findings, BN individuals had a median ANC of 893 x 10^6 cells per L. Additional laboratory statistical information can be seen in Table 2. Table 2. Key laboratory results from BN individuals Result Units Minimum 25th Quartile Median 75th Quartile Maximum White blood cell cells*109/L 2.3 3.4 4.8 6.1 10.4 ANC cells*106/L 158 628 893 1255 3614 Neutrophils % 7 13 17.3 28.7 50.7 Lymphocytes % 37.4 53.7 67.4 70.7 81.1 Monocytes % 2 8.2 10.1 11.8 18 Eosinophils % 0 1.6 2.7 4 12.4 Hemoglobin gm/dL 9.4 11.3 11.8 12.7 14.1 Hematocrit % 26.4 32.7 35 36.8 42.4 Platelets cells*109/L 170 220 265 316 472 Immunoglobulin G mg/dL 445 672 1049 1351 1851 Immunoglobulin A mg/dL 29 50 106 152 203 Immunoglobulin M mg/dL 22 64 86 112 156 Discussion Compared to reported ANC values from patients with congenital neutropenias, BN patients in our sample rarely had ANCs < 500 and were hospitalized infrequently. The gender and racial characteristics of our study sample were atypical. BN has been previously reported to have a male predilection. A quarter of patients self-reported Caucasian, Hispanic, or Asian heritage – three backgrounds to which this clinical entity is quite atypical. Conclusion BN is often considered as a normal variant that does not confer increased risk of morbidity or mortality. Larger, prospective studies are needed to further elucidate the clinical course of this condition as well as to better understand molecular genetics. Disclosures No relevant conflicts of interest to declare.

691 Background: In metastatic renal cell carcinoma (mRCC), immune-oncology (IO), alone or in combination, (IO-IO or IO-TKI) has changed the therapeutic scenario. Few real-world data are available about safety and outcome after IO progression. Methods: Baseline characteristics, outcome data including progression-free survival (PFS) and toxicities were retrospectively collected from 162 eligible pts treated in 16 Italian referral centers adhering to the Meet-Uro group and progressing to IO. Results: 111 pts (68,5%) were treated after progression to IO. 142 (87.6%) pts received IO as second line, 5 pts as first line and 16 pts as further line. Subsequent therapy included cabozantinib (n = 79, 48.0%), everolimus (n = 11, 6.7%), sunitinib (n = 6, 3.7%) and others (n = 15, 9.25%). Median IO-PFS was 4 months (95%CI 3.1-4.8) with no difference in pts pretreated with pazopanib or sunitinib (4 months (95%CI 2.4-5.5) vs 3,9 months (95%CI 2.9-4.9) p = 0.5). PFS tends to be longer in pts reporting adverse events of any grade (5.03 (95%CI 3.8-6.1) vs 2,99 (95%CI 2.4-3.5) months p = 0.004) or without nephrectomy (4.1 vs 2.9 months p = 0.071). Median PFS, in pts treated post-IO, was 6.5 months (95%CI 5.1-7.8). In term of best response, 55 pts (49%) had stability of disease/partial response and 29 pts (26%) had progressive disease, for the other pts treatment is still ongoing. Pts with ECOG PS 0 at progression to IO, had longer PFS, 11 months (95%CI 5.7-17.5) as well as those treated with cabozantinib (7.6 months, 95%CI 5.2-10.1) compared to everolimus, (3.2 months, 95%CI 1.8-4.5) or other drugs (4.3 months, 95%CI 1.3-7.4) p = 0.001. All grade adverse events were reported in 83 pts (74%) with G3-G4 adverse events in 39 pts (35%). Median overall survival, from first line, was 41,1 months (95%CI 30.4-51.8). Conclusions: In our real world experience after progression to IO, most pts received VEGF-TKI and mTOR inhibitors that showed to be active and safe choices. Cabozantinib was associated with a longer mPFS.

Aims/Objectives/BackgroundGlobally, injuries cause more than 5 million deaths annually. Children and young people are a particularly vulnerable group and injuries are the leading cause of death in people aged 5–24 years globally and a leading cause of disability.In most low and middle-income countries where the majority of global child injury burden occurs, systems for routinely collecting injury data are limited. There is a continuing need for better data on childhood injuries and for injury surveillance.The aim of our study was to introduce a hospital-based injury surveillance tool – the first of its kind in Nepal and explore its feasibility. We undertook prospective collection of data on all injuries/trauma presenting to 2 hospital emergency departments to describe the epidemiology of paediatric hospital injury presentations and associated risk factors.Methods/DesignA new injury surveillance system for use in emergency departments in Nepal was designed and used to collect data on patients presenting with injuries. Data were collected prospectively in two hospitals 24 h a day over 12 months (April 2019 - March 2020) by trained data collectors using tablet computers.Abstract 432 Table 1Socio-demographic profile and characteristics of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020 (N=2696)CharacteristicsFrequencyGender Male 1778 Female 918 Age groups 0–4 years 653 5–9 years 866 10–14 years 680 15–17 years 497 Median year (IRQ) 8 (5 – 13) Ethnicity/caste Janajati 1384 Brahmin/Chhetri 892 Dalit 148 Madhesi 146 Muslim 74 Others 50 Unknown 2 Place where injury occurred Home/Compound 1576 Highway/road/street 636 School 233 Recreational area 138 Workplace 76 Other 37 Activities at the time injury occurred Leisure/Play 1889 Travelling (other than to/from school/work) 296 Work 202 Travelling (to/from school/work) 184 Education 42 Organised sports 11 Other 52 Unknown 20 Intent of injury Unintentional 2560 Intentional (self-harm) 61 Intentional (assault) 75 Unintentional (n=2560) Fall 912 Animal or insect related 728 Road traffic injury 356 Injured by a blunt force 201 Stabbed, cut or pierced 176 Fire, burn or scald 65 Poisoning 52 Suffocation/choking 36 Electrocution 12 Drowning and submersion 7 Other 13 Unknown 2 Self-harm (n=61) Poisoning 38 Hanging, strangulation, suffocation 12 Stabbed, cut or pierced 6 Injured by blunt object 4 Other 1 Assault (n=75) Bodily force (physical violence) 43 Injured by blunt object 18 Stabbed, cut or pierced 8 Pushing from a high place 2 Poisoning 2 Sexual assault 1 Other 1 Nature of injury (one most severe) Cuts, bites or open wound 1378 Bruise or superficial injury 383 Fracture 299 Sprain, strain or dislocation 243 Internal injury 124 Head Injury/Concussion 83 Burns 67 Other 115 Unknown 2 Not recorded 2 Severity of injury No apparent injury 125 Minor 1645 Moderate 813 Severe 111 Not recorded 2 Disposition Discharged 2317 Admitted to hospital 164 Transferred to another hospital 179 Died 21 Leave Against Medical Advice (LAMA) 11 Unknown 2 Not recorded 2 Note:Not recorded = missing cases95% CI calculated using one proportion test and normal approximation method in Minitab.Abstract 432 Table 2Distribution of injuries by age-group, sex and mechanism of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Age groups & Sex0 - 4 years5 - 9 years10–14 years15–17 yearsMaleFemaleTotalIntent & mechanismsn (%)n (%)n (%)n (%)n (%)n (%)n (%)Unintentional Fall 239 (26.2) 328 (36.0) 249 (27.3) 96 (10.5) 636 (69.7) 276 (30.3) 912 (100) Animal or insect related 175 (24.0) 260 (35.7) 190 (26.1) 103 (14.1) 470 (64.6) 258 (35.4) 728 (100) Road traffic injury 49 (13.8) 108 (30.3) 86 (24.2) 113 (31.7) 223 (62.6) 133 (37.4) 356 (100) Injured by a blunt force 54 (26.9) 74 (36.8) 49 (24.4) 24 (11.9) 150 (74.6) 51 (25.4) 201 (100) Stabbed, cut or pierced 20 (11.4) 56 (31.8) 49 (27.8) 51 (29.0) 127 (72.2) 49 (27.8) 176 (100) Fire, burn or scald 42 (64.6) 10 (15.4) 9 (13.8) 4 (6.2) 27 (41.5) 38 (58.5) 65 (100) Poisoning 33 (63.5) 6 (11.5) 5 (9.6) 8 (15.4) 26 (50.0) 26 (50.0) 52 (100) Suffocation/choking 24 (66.7) 5 (13.9) 2 (5.6) 5 (13.9) 20 (55.6) 16 (44.4) 36 (100) Electrocution 2 (15.7) 0 (0.0) 3 (25.0) 7 (58.3) 10 (83.3) 2 (16.7) 12 (100) Drowning and submersion 1 (14.3) 1 (14.3) 3 (42.9) 2 (28.6) 3 (42.9) 4 (57.1) 7 (100) Other 6 (46.2) 4 (30.8) 3 (23.1) 0 (0.0) 10 (76.9) 3 (23.1) 13 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) 2 (100) Total 647 (25.3) 852 (33.3) 648 (25.3) 413 (16.1) 1702 (66.5) 858 (33.5) 2560 (100) Self-harm Poisoning 0 (0.0) 0 (0.0) 6 (15.8) 32 (84.2) 7 (18.4) 31 (81.6) 38 (100) Hanging 0 (0.0) 0 (0.0) 3 (25.0) 9 (75.0) 4 (33.3) 8 (66.7) 12 (100) Stabbed, cut or pierced 0 (0.0) 0 (0.0) 2 (33.3) 4 (66.7) 1 (16.7) 5 (83.3) 6 (100) Injured by blunt object 0 (0.0) 2 (50.0) 2 (50.0) 0 (0.0) 4 (100) 0 (0.0) 4 (100) Other 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) 1 (100) 0 (0.0) 1 (100) Total 0 (0.0) 2 (3.3) 13 (21.3) 46 (75.4) 17 (27.9) 44 (72.1) 61 (100) Assault Bodily force (physical violence) 3 (7.0) 1 (2.3) 11 (25.6) 28 (65.1) 37 (86.0) 6 (14.0) 43 (100) Injured by blunt object 2 (11.1) 8 (44.4) 4 (22.2) 4 (22.2) 13 (72.2) 5 (27.8) 18 (100) Stabbed, cut or pierced 1 (12.5) 0 (0.0) 2 (25.0) 5 (62.5) 7 (87.5) 1 (12.5) 8 (100) Pushing from a high place 0 (0.0) 1 (50.0) 1 (50.0) 0 (0.0) 1 (50.0) 1 (50.0) 2 (100) Poisoning 0 (0.0) 1 (50.0) 0 (0.0) 1 (50.0) 1 (50.0) 1 (50.0) 2 (100) Sexual assault 0 (0.0) 0 (0.0) 1 (100) 0 (0.0) 0 (0.0) 1 (100) 1 (100) Other 0 (0.0) 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) 1 (100) Total 6 (8.0) 12 (16.0) 19 (25.3) 38 (50.7) 59 (78.7) 16 (21.3) 75 (100) Abstract 432 Table 3Association of injury location, nature and severity with age among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Age groups0 – 4 years5 – 9 years10–14 years15–17 yearsTotalChi-SquareInjury characteristicsn (%)n (%)n (%)n (%)n (%)P valueLocation of injury sustained Home/Compound 537 (34.1) 504 (32.0) 319 (20.2) 216 (13.7) 1576 (100) <0.001 Highway/road/street 85 (13.4) 196 (30.8) 190 (29.9) 165 (25.9) 636 (100) School 15 (6.4) 107 (45.9) 85 (36.5) 26 (11.2) 233 (100) Recreational area 9 (6.5) 44 (31.9) 55 (39.9) 30 (21.7) 138 (100) Workplace 1 (1.3) 4 (5.3) 19 (25.0) 52 (68.4) 76 (100) Other 6 (16.2) 11 (29.7) 12 (32.4) 8 (21.6) 37 (100) Total 653 (24.2) 866 (32.1) 680 (25.2) 497 (18.4) 2696 (100) Nature of injury Cuts, bites or open wound 328 (23.8) 506 (36.7) 314 (22.8) 230 (16.7) 1378 (100) <0.001 Bruise or superficial injury 81 (21.1) 99 (25.8) 118 (30.8) 85 (22.2) 383 (100) Fracture 48 (16.1) 101 (33.8) 112 (37.5) 38 (12.7) 299 (100) Sprain, strain or dislocation 48 (19.8) 78 (32.1) 72 (29.6) 45 (18.5) 243 (100) Internal injury 44 (35.5) 8 (6.5) 18 (14.5) 54 (43.5) 124 (100) Head Injury/Concussion 18 (21.7) 26 (31.3) 18 (21.7) 21 (25.3) 83 (100) Burns 42 (62.7) 9 (13.4) 10 (14.9) 6 (9.0) 67 (100) Other 41 (35.7) 38 (33.0) 18 (15.7) 18 (15.7) 115 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Total 652 (24.2) 865 (32.1) 680 (25.2) 497 (18.4) 2694 (100) Severity of injury No apparent injury 39 (31.2) 45 (36.0) 26 (20.8) 15 (12.0) 125 (100) <0.001 Minor 419 (25.5) 535 (32.5) 406 (24.7) 285 (17.3) 1645 (100) Moderate 171 (21.0) 262 (32.2) 225 (27.7) 155 (19.1) 813 (100) Severe 23 (20.7) 23 (20.7) 23 (20.7) 42 (37.8) 111 (100) Total 652 (24.2) 865 (32.1) 680 (25.2) 497 (18.4) 2694 (100) Abstract 432 Table 4Association of injury location, nature and severity with sex among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020SexMaleFemaleTotalChi-SquareInjury characteristicsn (%)n (%)n (%)P valueLocation of injury sustained Home/Compound 979 (62.1) 597 (37.9) 1576 (100) <0.001 Highway/road/street 421 (66.2) 215 (33.8) 636 (100) School 176 (75.5) 57 (24.5) 233 (100) Recreational area 111 (80.4) 27 (19.6) 138 (100) Workplace 62 (81.6) 14 (18.4) 76 (100) Other 29 (78.4) 8 (21.6) 37 (100) Total 1778 (65.9) 918 (34.1) 2696 (100) Nature of injury Cuts, bites or open wound 959 (69.6) 419 (30.4) 1378 (100) <0.001 Bruise or superficial injury 246 (64.2) 137 (35.8) 383 (100) Fracture 200 (66.9) 99 (33.1) 299 (100) Sprain, strain or dislocation 154 (63.4) 89 (36.6) 243 (100) Internal injury 50 (40.3) 74 (59.7) 124 (100) Head Injury/Concussion 59 (71.1) 24 (28.9) 83 (100) Burns 27 (40.3) 40 (59.7) 67 (100) Other 79 (68.7) 36 (31.3) 115 (100) Unknown 2 (100) 0 (0.0) 2 (100) Total 1776 (65.9) 918 (34.1) 2694 (100) Severity of injury No apparent injury 81 (64.8) 44 (35.2) 125 (100) 0.048 Minor 1102 (67.0) 543 (33.0) 1645 (100) Moderate 533 (65.6) 280 (34.4) 813 (100) Severe 60 (54.1) 51 (45.9) 111 (100) Total 1776 (65.9) 918 (34.1) 2694 (100) Abstract 432 Table 5Distribution of injuries by outcome and mechanism of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Outcome of injuryDischargedAdmittedTransferredDiedLAMAUnknownTotalIntent & mechanismsn (%)n (%)n (%)n (%)n (%)n (%)n (%)Unintentional Fall 787 (86.5) 65 (7.1) 53 (5.8) 0 (0.0) 4 (0.4) 1 (0.1) 910 (100) Animal/insect bite/sting 704 (96.7) 3 (0.4) 19 (2.6) 0 (0.0) 1 (0.1) 1 (0.1) 728 (100) Road traffic injury 260 (73.0) 47 (13.2) 44 (12.4) 5 (1.4) 0 (0.0) 0 (0.0) 356 (100) Injured by a blunt force 190 (94.5) 4 (2.0) 6 (3.0) 0 (0.0) 1 (0.5) 0 (0.0) 201 (100) Stabbed, cut or pierced 165 (93.8) 8 (4.5) 3 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 176 (100) Fire, burn or scald 52 (80.0) 12 (18.5) 1 (1.5) 0 (0.0) 0 (0.0) 0 (0.0) 65 (100) Poisoning 30 (57.7) 4 (7.7) 16 (30.8) 1 (1.9) 1 (1.9) 0 (0.0) 52 (100) Suffocation/choking/asphyxia 24 (66.7) 4 (11.1) 6 (16.7) 1 (2.8) 1 (2.8) 0 (0.0) 36 (100) Electrocution 7 (58.3) 2 (16.7) 2 (16.7) 1 (8.3) 0 (0.0) 0 (0.0) 12 (100) Drowning and submersion 4 (57.1) 0 (0.0) 0 (0.0) 3 (42.9) 0 (0.0) 0 (0.0) 7 (100) Other 12 (92.3) 1 (7.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 13 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Total 2237 (87.5) 150 (5.9) 150 (5.9) 11 (0.4) 8 (0.3) 2 (0.1) 2558 (100) Self-harm Poisoning 5 (13.2) 8 (21.1) 23 (60.5) 0 (0.0) 2 (5.3) 0 (0.0) 38 (100) Hanging 1 (8.3) 0 (0.0) 1 (8.3) 10 (83.3) 0 (0.0) 0 (0.0) 12 (100) Stabbed, cut or pierced 6 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 6 (100) Injured by blunt object 4 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 4 (100) Other 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Total 17 (27.9) 8 (13.1) 24 (39.3) 10 (16.4) 2 (3.3) 0 (0.0) 61 (100) Assault Bodily force (physical violence) 34 (79.1) 5 (11.6) 3 (7.0) 0 (0.0) 1 (2.3) 0 (0.0) 43 (100) Injured by blunt object 18 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 18 (100) Stabbed, cut or pierced 6 (75.0) 1 (12.5) 1 (12.5) 0 (0.0) 0 (0.0) 0 (0.0) 8 (100) Pushing from a high place 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Poisoning 1 (50) 0 (0.0) 1 (50.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Sexual assault 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Other 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Total 63 (84.0) 6 (8.0) 5 (6.7) 0 (0.0) 1 (1.3) 0 (0.0) 75 (100) Abstract 432 Figure 1Seasonal variation of injuries identified by the injury surveillance system over a year among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Results/ConclusionsThe total number of ED patients with injury in the study was 10,154.2,696 were patients aged <18 years. Most injuries in children were unintentional and over half of children presenting with injuries were <10 years of age. Falls, animal bites/stings and road traffic injuries accounted for nearly 75% of all injuries with some (drowning, poisonings and burns) under-represented. Over half of injuries were cuts, bites and open wounds. The next most common injury types were superficial injuries (14.2%); fractures (11.1%); sprains/dislocations (9.0%). Child mortality was 1%.This is the biggest prospective injury surveillance study in a low or middle country in recent years and supports the use of injury surveillance in Nepal for reducing child morbidity and mortality through improved data.CHILD PAPER: RESULTS SECTIONTotal number of ED patients: 33046Total number of ED patient with injury: 10154 (adult=7458 & children=2696)8.2% (n=2696) patients with injury were children aged <18 yearsHetauda hospital: 2274 (84.3%)Chure hill hospital: 422 (15.7%)

Background:Sjogren’s syndrome is one of the most common autoimmune diseases, with a prevalence of 0.33% to 0.77% in Chinese people, characterized by focal infiltration of lymphocytes in glands and the production of multiple autoantibodies. Studies have shown that virus infection may play a crucial role in the occurrence and development of this disease.Objectives:It has been shown that airway stimulation with poly(I:C) can mimic respiratory tract viral infection to some extent. Thus, this study was aimed to investigate the dynamic immune responses in salivary gland after respiratory tract poly(I:C) stimulation in NOD mice.Methods:The 5-week-old NOD mice were given respiratory tract poly(I:C) stimulation to mimic the respiratory virus infection once every other day for a total of 5 times (the total dose is 100μg), and the control group were given the same dose of sterile PBS. After 8 weeks, the mice were sacrificed to obtain and analyze the salivary gland tissues.Results:We found that the salivary gland flow rate was decreased and the blood glucose was influenced by the Viroid stimulation during the early stage in poly(I:C) stimulated group compared with that in PBS group. Accordingly, the pathological injury of salivary gland tissues in poly(I:C) stimulated group was more serious, including decreased volumes of the salivary glands, increased number of pathological focus score and the increased area of lymphocyte infiltration. Furthermore, we found that the expression of IL-33 in salivary glands of poly(I:C) stimulated NOD mice was increased, especially the expression of IL-33 in the acini and ducts. Moreover, the expression of IFN-I and IFN-II is up-regulated in salivary glands.Conclusion:The results of this study suggest that respiratory tract poly(I:C) stimulation accelerates salivary gland immune dysfunction in spontaneous sjogren’s syndrome NOD mice, which mechanisms need to be further investigated.References:[1] Pathogenetic mechanisms in the initiation and perpetuation of Sjogren’s syndrome. Nat Rev Rheumatol 2010; 6: 529-537.[2]Primary Sjögren’s Syndrome. N Engl J Med.2018 378(10):931-939.[3]Epidemiology of primary Sjögren’s syndrome: a systematic review and meta-analysis. Ann Rheum Dis 2015; 74: 1983-9.[4]Vitamin D insufficiency in a large MCTD population. Autoimmun Rev 10:317–324.[5]Epstein-Barr virus persistence and infection of autoreactive plasma cells in synovial lymphoid structures in rheumatoid arthritis. Ann Rheum Dis 72:1559–1568[6]Liew, F., Girard, J. & Turnquist, H. Interleukin-33 in health and disease. Nat Rev Immunol 16, 676–689 (2016) doi:10.1038/nri.2016.95[7]Interleukin-33 and the function of innate lymphoid cells. Trends in Immunology, August 2012, Vol. 33, No. 8[8]Increased Levels of Interleukin 33 in Sera and Synovial Fluid from Patients with Active Rheumatoid Arthritis YASUSHI MATSUYAMA et al The Journal of Rheumatology January 2010, 37 (1) 18-25[9]Potential involvement of the IL-33-ST2 axis in the pathogenesis of primary Sjogren’s syndrome, Ann Rheum Dis, 2014, 73(6): 1259-1263.[10]The Interleukin 33/ST2 axis in patients with primary Sjogren syndrome: expression in serum and salivary glands, and the clinical association, J Rheumatol, 2015, 42(2): 264-271.[11]Kok MR, Baum BJ, Tak PP, et al Use of localised gene transfer to develop new treatment strategies for the salivary component of Sjögren’s syndrome Annals of the Rheumatic Diseases 2003;62:1038-1046.Acknowledgments:NODisclosure of Interests:None declared

Background:Psoriatic arthritis (PsA) is characterised by musculoskeletal symptoms, and patients (pts) with PsA usually experience psoriasis concurrently. Real-world data reflecting impact of skin symptoms on PsA disease burden are limited.Objectives:Analyse effectiveness of ustekinumab (UST) and tumour necrosis factor inhibitor (TNFi) therapy on extent of skin involvement, and the impact this has on PsA disease burden and drug persistence.Methods:PsABio (NCT02627768) is a prospective, observational study of 1st/2nd/3rd-line UST or TNFi treatment in PsA in 8 European countries. Extent of skin involvement was categorised as body surface area (BSA): clear/almost clear; <3% but not clear/almost clear; 3–10%; or >10%. Pt-reported disease impact was evaluated by PsAID-12, including assessment of two skin-related domains (D): D3 (skin problems, including itching) and D10 (embarrassment and/or shame because of appearance). Estimated persistence at 1 year was assessed across baseline (BL) BSA categories.Results:At BL, significantly more pts receiving UST than TNFi had BSA >10% (Figure 1). BL disease impact (PsAID-12) was worse in pts with BSA >10% than <3% in D3, D10 and total (non-overlapping 95% CIs suggest significance) (Table 1). BSA improved from BL to 1 year with both treatments. At 1 year, 64% of pts in both groups had clear/almost clear skin and only 3% had BSA >10% (Figure 1). At 1 year, both treatments significantly reduced disease impact (PsAID-12 total), and D3 and D10 scores, irrespective of BL BSA category, but most markedly in pts with higher BL BSA (Table 1). Worse BL psoriasis was generally associated with longer persistence for both treatments; however, at 1 year, pts with BSA >10% had significantly shorter persistence with TNFi (mean [95% CI]: 361 [336; 387] days) than with UST (410 [394; 426] days).Conclusion:In PsA, interleukin-12/23 inhibition (UST) and TNFi therapy in routine care rapidly and substantially reduced extent of skin involvement and related disease impact. Pts with highest BL skin involvement had significantly longer drug persistence with UST than with TNFi. Together, PsABio data suggest that successful treatment of skin involvement in PsA with biologics reduces disease burden and may improve persistence, especially in pts with worse BL psoriasis.Figure 1Table 1.PsAID-12 scores at BL and change from BL scores at 6 months and 1 year, by BL BSA categoryMean (95% CI)Domain 3(skin problems, including itching)Domain 10(embarrassment and/orshame because of appearance)Total PsAID-12USTTNFiUSTTNFiUSTTNFiPsAID-12 score at BL by BL BSA <3%4.2 (3.7; 4.8)3.1 (2.7; 3.6)3.9 (3.3; 4.4)3.1(2.6; 3.6)5.7(5.3; 6.0)5.0 (4.6; 5.3) 3–10%6.4 (5.9; 6.8)5.8 (5.3; 6.3)4.1 (3.5; 4.7)4.5 (3.9; 5.1)5.4 (5.1; 5.8)5.8 (5.4; 6.1) >10%7.9 (7.5; 8.3)6.7 (6.0; 7.5)6.1 (5.4; 6.8)5.8 (4.8; 6.8)6.2 (5.7; 6.6)6.1 (5.6; 6.7)Change from BL in PsAID-12 score at 6 months by BL BSA <3%-1.5 (-2.1; -0.9)-0.8 (-1.3; -0.3)-1.5 (-2.0; -0.9)-1.2 (-1.6; -0.7)-1.6 (-2.0; -1.2)-1.9 (-2.2; -1.5) 3–10%-3.2 (-3.8; -2.7)-2.4 (-3.0; -1.9)-1.9 (-2.5; -1.3)-2.0 (-2.5; -1.5)-2.0 (-2.4; -1.6)-2.4 (-2.8; -2.0) >10%-4.2 (-4.9; -3.6)-2.5 (-3.2; -1.9)-2.9 (-3.5; -2.2)-1.6 (-2.4; -0.8)-2.4 (-2.8; -2.0)-2.2 (-2.7; -1.7)Change from BL in PsAID-12 score at 1 year (LOCF) by BL BSA <3%-1.5 (-2.1; -0.9)-0.8 (-1.3; -0.3)-1.6 (-2.2; -1.1)-1.2 (-1.7; -0.7)-1.6 (-2.0; -1.2)-1.9 (-2.3; -1.5) 3–10%-3.5 (-4.0; -2.9)-3.2(-3.7; -2.7)-2.0 (-2.6; -1.4)-2.5 (-3.0; -2.0)-2.2 (-2.6; -1.7)-3.0 (-3.4; -2.6) >10%-4.9 (-5.5; -4.3)-3.1 (-4.0; -2.3)-3.5 (-4.2; -2.8)-2.7 (-3.7; -1.8)-2.9 (-3.4; -2.4)-2.9 (-3.5; -2.2)PsAID-12 total score ≤4 is considered a patient-acceptable symptom state.BL, baseline; BSA, body surface area; CI, confidence interval; LOCF, last observation carried forward; PsAID-12, 12-item Psoriatic Arthritis Impact of Disease questionnaire; TNFi, tumour necrosis factor inhibitor; UST, ustekinumabAcknowledgements:This study was funded by Janssen.Disclosure of Interests:Josef S. Smolen Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis- Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, Grant/research support from: AbbVie, AstraZeneca, Lilly, Novartis, Roche, Tatiana Korotaeva Speakers bureau: AbbVie, Amgen, Biocad, Janssen, Lilly, MSD, Novartis, Novartis-Sandoz, Pfizer, UCB, Consultant of: AbbVie, Amgen, Biocad, Janssen, Lilly, MSD, Novartis, Novartis-Sandoz, Pfizer, UCB, Grant/research support from: Pfizer, Michael Nurmohamed Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Menarini, MSD, Mundipharma, Pfizer, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Janssen, Menarini, MSD, Mundipharma, Pfizer, Roche, Sanofi, UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Menarini, MSD, Mundipharma, Pfizer, Roche, Sanofi, UCB, Stefan Siebert Speakers bureau: AbbVie, Amgen (previously Celgene), Biogen, Janssen, Novartis, UCB, Consultant of: AbbVie, Janssen, UCB, Grant/research support from: Amgen (previously Celgene), Boehringer Ingelheim, Bristol-Myers Squibb, GSK, Janssen, Novartis, Pfizer, UCB, Paul Bergmans Shareholder of: Johnson & Johnson, Employee of: Janssen, Kurt de Vlam Speakers bureau: AbbVie, Amgen, Eli Lilly, Novartis, UCB, Paid instructor for: Amgen, Galapagos, UCB, Consultant of: Eli Lilly, Galapagos, Johnson & Johnson, Novartis, UCB, Grant/research support from: Celgene, Elisa Gremese: None declared., Beatriz Joven-Ibáñez Speakers bureau: AbbVie, Celgene, Janssen, Novartis, MSD, Pfizer, Wim Noel Employee of: Janssen, Petros Sfikakis Consultant of: AbbVie, Actelion, Boehringer Ingelheim, Enorasis, Farmaserv-Lilly, Genesis, Gilead, MSD, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Faran, Janssen, Pfizer, Roche, Elke Theander Employee of: Janssen, Laure Gossec Consultant of: AbbVie, Amgen, Bioepis, Biogen, Bristol-Myers Squibb, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Sanofi-Aventis, UCB, Grant/research support from: Amgen, Galapagos, Janssen, Lilly, Pfizer, Sandoz, Sanofi.

Abstract Abstract 4393 Background: YM150, a potent oral direct factor Xa (FXa) inhibitor, is in development for the prevention of venous thromboembolism after major surgery and of thromboembolic events in subjects with atrial fibrillation. After administration, YM150 is rapidly and extensively metabolized into YM-222714, which predominantly determines antithrombotic effect. Naproxen, a non-steroidal anti-inflammatory drug with antiplatelet properties that inhibits cyclooxygenase (COX)-1 and COX-2 isoenzymes, and similar mode of action drugs will likely be co-prescribed with YM150 in clinical practice. This study assessed the interaction of YM150 and naproxen following co-administration in healthy males. Methods: A Phase I, randomized, open-label, 3-period crossover study (≥14-day washout between periods) compared the pharmacodynamic (PD) and pharmacokinetic (PK) properties of YM150 and naproxen given alone and in combination. Subjects received YM150 60 mg once daily and/or naproxen 500 mg twice daily for 6 and 4 days, respectively. Primary endpoint was change in skin bleeding time (SBT); assessors were blinded to treatment. Change from baseline (BL; pre-dose on Day 1) to 3 h post final dose in SBT was calculated to Day 4 for naproxen alone and Day 6 for YM150 alone and the combination group, thereby reflecting the respective times to achieve steady state (SS). Secondary PD endpoints included minimum FXa activity (FXamin), maximum prothrombin time (PTmax), maximum activated partial thromboplastin time (aPTTmax) and platelet aggregation. Blood and urine PK parameters (maximum concentration [Cmax], time to maximum concentration [tmax], area under the curve [AUC] and renal clearance [CLR]) and safety were also assessed. Blood samples for PK and PD variables were taken at SS on the final day of dosing (pre-dose and up to 24 h post-dose). Data are presented as arithmetic means. Results: 26 subjects were randomized and received treatment (mean age, 30.4 yrs); 6 subjects prematurely discontinued (consent withdrawal, n=3; adverse event [AE], n=2; protocol violation, n=1). Co-administration of YM150 and naproxen did not result in additive increases in SBT (Table). From BL to SS, mean (standard deviation [SD]) SBT (sec) increased from 317 (89.2) to 430 (111) after YM150 alone, from 306 (79.0) to 621 (230) after naproxen alone and from 332 (84.1) to 721 (259) after combination treatment. YM150 inhibited FXa activity and increased PTmax and aPTTmax; co-administration with naproxen did not influence these outcomes (Table). Naproxen decreased collagen-induced platelet aggregation, with no additive effect when co-administered with YM150 (Table). The PK of YM-222714 was generally unchanged when YM150 was administered alone or with naproxen (tmax 1.70 vs 1.45 h; Cmax 1535 vs 1497 ng/mL; AUCtau 11,644 vs 11,369 ng·h/mL; CLR 2.39 vs 3.42 L/h); the PK profile of YM150 itself was similarly unchanged (tmax 1.43 vs 1.17 h; Cmax 7.94 vs 8.23 ng/mL; AUCtau 79.8 vs 66.6 ng·h/mL; CLR 4.91 vs 6.67 L/h). Naproxen PK were also unchanged when co-administered with YM150. Overall, YM150 alone, naproxen alone and combination treatment were safe and well tolerated. Only one subject experienced AEs considered related to treatment (gingival bleeding and epistaxis); combination treatment was discontinued. One other subject discontinued due to an AE unrelated to study drug (gastroenteritis). No clinically relevant changes in laboratory parameters, vital signs or physical assessments were observed. Conclusions: Co-administration of YM150 with naproxen did not result in additive increases in SBT or clinically relevant changes in the PD or PK profiles of either agent; the combination was generally safe and well tolerated. Observed changes in FXa activity, PT and aPTT confirm the antithrombotic potency of YM150 and YM-222714, which was unaltered upon co-administration with naproxen. YM150 has no clinically relevant interaction with naproxen. Disclosures: Heeringa: Astellas Pharma Global Development Europe: Employment. Garcia-Hernandez:Astellas Pharma Global Development Europe: Employment. Kadokura:Astellas Pharma Inc.: Employment. Groenendaal – van de Meent:Astellas Pharma Global Development Europe: Employment. Mol:Astellas Pharma Global Development Europe: Employment. Eltink:Astellas Pharma Global Development Europe: Employment. Heinzerling:Astellas Pharma Global Development Europe: Employment.

Abstract Abstract 3125 Poster Board III-62 VTE is the most frequent complication of OS and it can be prevented through anticoagulant prophylaxis. Numerous studies have evaluated different agents for this purpose and there are new agents currently under development or recently approved for this indication. We conducted a systematic review of randomized controlled trials (RCT) evaluating administration of anticoagulants for VTE prophylaxis in OS and performed a MA of proportions to estimate the overall incidence of major VTE (proximal VTE, pulmonary embolism (PE), or death from PE), total VTE (proximal and distal VTE, PE or death from PE), symptomatic VTE and major bleeding episodes (as defined by the International Society on Thrombosis and Hemostasis). We included RCT comparing currently approved anticoagulants (head-to-head or placebo-controlled) for VTE prophylaxis in OS (hip and knee arthroplasty and hip fracture surgery) using systematic evaluation of VTE (ultrasound or venography, pulmonary angiography, CT pulmonary angiography, or ventilation perfusion scan). Heterogeneity of proportions was evaluated using a chi2 test and pooled estimates of proportions were obtained using either a fixed or a random effects model in which the weights were estimated as proposed by Laird and Mosteller. We retrieved 74 studies including180 research arms and enrolling 71,012 patients. The total number of events and evaluable patients, percentage of events and 95% CI, and number of study arms included are shown in the table. We found differences in the percentage of VTE and bleeding events associated with the use of different anticoagulants for VTE prophylaxis after OS. Due to the nature of the analysis no effect measure can be estimated. These estimates might help to design future studies. Major VTE Total VTE Symptomatic VTE Major Bleeding Cases / Evaluable Pts. (N) Percentage (95% CI) Study arms (N) Cases / Evaluable Pts. (N) Percentage (95% CI) Study arms (N) Cases / Evaluable Pts. (N) Percentage (95% CI) Study arms (N) Cases / Evaluable Pts. (N) Percentage (95% CI) Study arms (N) All patients LMWH 993/23692 5.96 (5.81, 6.11) 72 4068/22610 20.29 (20.04, 20.55) 80 193/19431 1.32 (1.27, 1.37) 35 476/28725 1.98 (1.93, 2.02) 70 UFH 234/2407 13.39 (12.86, 13.93) 14 596/2537 22.54 (22, 23.08) 17 11/339 3.24 (3.06, 3.43) 4 70/2849 2.75 (2.61, 2.89) 16 Warfarin 269/5677 6.28 (6.09, 6.46) 12 1317/4203 31.05 (30.44, 31.66) 12 71/4146 1.95 (1.83, 2.08) 6 96/6751 1.78 (1.69, 1.87) 12 Fonda 96/3673 3.81 (3.53, 4.09) 7 223/3477 6.82 (6.57, 7.07) 6 69/6398 1.06 (1.01, 1.1) 8 121/6576 1.63 (1.55, 1.71) 9 Riva 50/5025 2.02 (1.86, 2.19) 8 242/4595 13.05 (12.16, 13.94) 8 29/6252 0.46 (0.45, 0.48) 6 31/6643 0.63 (0.59, 0.68) 8 Dabi 149/4091 3.64 (3.59, 3.69) 6 834/4051 22.96 (21.91, 24.01) 6 26/3664 0.71 (0.67, 0.75) 4 67/5419 1.21 (1.17, 1.26) 6 Placebo 193/710 24.26 (23.17, 25.34) 10 379/816 49.35 (48.08, 50.62) 11 19/198 12.02 (10.32, 13.72) 3 12/753 1.59 (1.5, 1.68) 7 Total 1984/45275 129 7659/42289 140 418/40428 66 873/57716 128 Total Hip Arthroplasty LMWH 653/15978 6 (5.85, 6.16) 50 1817/14480 15.58 (15.35, 15.82) 55 81/11552 0.7 (0.69, 0.72) 19 306/18010 1.97 (1.92, 2.02) 45 UFH 187/1739 14.3 (13.64, 14.96) 11 354/1836 20.13 (19.46, 20.8) 13 11/246 4.47 (4.21, 4.73) 3 52/1451 3.2 (3.01, 3.39) 11 Warfarin 77/2758 4.28 (4.08, 4.48) 6 265/1273 20.82 (20.59, 21.04) 6 32/1833 1.75 (1.69, 1.81) 2 47/2856 2.23 (2.09, 2.37) 5 Fonda 28/1799 2.96 (2.58, 3.33) 3 85/1695 5.01 (4.91, 5.12) 2 15/2255 0.67 (0.63, 0.7) 2 69/2349 2.94 (2.87, 3.01) 3 Riva 25/2938 2.21 (1.95, 2.46) 5 73/2749 9.72 (8.92, 10.53) 5 10/3468 0.29 (0.27, 0.31) 3 14/3795 0.49 (0.44, 0.54) 5 Dabi 72/1803 3.99 (3.88, 4.11) 2 124/1766 7.02 (6.77, 7.27) 2 21/2293 0.92 (0.91, 0.93) 2 38/2309 1.65 (1.58, 1.72) 2 Placebo 105/414 26.01 (24.76, 27.27) 7 174/418 45.43 (43.74, 47.13) 7 4/147 2.72 (2.46, 2.98) 2 3/388 0.77 (0.69, 0.86) 5 Total 1147/27429 84 2892/24217 90 174/21794 33 529/31158 76 Total Knee Arthroplasty LMWH 277/6916 4.45 (4.34, 4.55) 25 2062/7326 30.72 (30.37, 31.07) 32 83/4902 1.69 (1.66, 1.73) 11 89/7808 1.14 (1.12, 1.16) 26 UFH 42/638 6.58 (6.39, 6.78) 3 226/638 35.42 (35.05, 35.79) 3 0/93 NE 1 3/318 0.94 (0.84, 1.05) 2 Warfarin 192/2919 8.1 (7.88, 8.32) 9 1052/2930 39.36 (38.69, 40.02) 9 39/2056 1.9 (1.84, 1.96) 3 28/3407 0.82 (0.79, 0.85) 8 Fonda 23/452 9.3 (7.93, 10.67) 2 45/361 12.47 (12.12, 12.81) 1 3/517 0.58 (0.51, 0.65) 1 12/601 2 (1.88, 2.11) 2 Riva 25/2087 1.2 (1.15, 1.24) 3 169/1846 18.55 (16.47, 20.63) 3 19/2784 0.68 (0.65, 0.71) 3 17/2848 0.6 (0.57, 0.63) 3 Dabi 77/2288 3.37 (3.32, 3.41) 4 710/2285 30.98 (30.42, 31.55) 4 5/1371 0.36 (0.32, 0.41) 2 29/3110 0.93 (0.89, 0.98) 4 Placebo 88/296 27.12 (24.54, 29.7) 4 205/398 55.19 (53.53, 56.84) 5 15/51 29.41 (28.16, 30.66) 1 9/365 2.47 (2.31, 2.62) 4 Total 724/15596 50 4469/15784 57 164/11774 22 187/18457 49 LMWH Low molecular weight heparin, UFH unfractionated heparin, Riva Rivaroxaban, Dabi Dabigatran etexilate Disclosures Lazo-Langner: Boehringer Ingelheim: Honoraria. Rodger:Bayer: Research Funding; Leo Pharma: Research Funding; Pfizer: Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Biomerieux: Research Funding; GTC Therapeutics: Research Funding.

Commercial embryo transfer programs require frequent superovulation of embryo donors. Although early reports suggested that donor cows require 60 to 90 days to recover from superovulation, recent information suggests that this interval could be reduced to 25 to 30 days. Because donor cows reovulate at variable intervals after embryo collection, some donors do not have an ultrasonically detectable corpus luteum (CL) when frequent superovulation programs are initiated. A retrospective study was performed to evaluate the influence of the presence of a CL at the time of initiating treatments on superovulatory response of beef donors that had been previously collected once and then were collected every 28 to 35 days 2 or 3 times. The data were from 190 collections performed in 48 Angus, 36 in 10 Brangus and 74 in 20 Bonsmara donors. On Day 0, all cows were ultrasonically examined for the presence of a CL (Falco 100 Vet, 8-MHz transducer, Pie Medical, the Netherlands) and were treated with 5 mg of oestradiol-17β and 50 mg of progesterone IM and a progesterone-releasing intravaginal device (Cue-Mate, Bioniche Animal Health, Belleville, Ontario, Canada). On Day 4, donors were superstimulated with Folltropin-V (Bioniche Animal Health), in twice-daily injections over 4 days or diluted in 20 mg mL–1 hyaluronan and given by a single IM injection. Folltropin-V dosages used were 300 or 400 mg (Angus), 260 or 300 mg (Brangus), or 200 or 300 mg (Bonsmara). On Day 6, all cows received 2 doses of PGF2α 12 h apart and Cue-Mates were removed in the p.m. In the a.m. of Day 8, cows received 12.5 mg pLH (Lutropin-V; Bioniche Animal Health) and were inseminated 12 and 24 h later. Ova/embryos were collected nonsurgically on Day 15 and evaluated following IETS guidelines. For each breed, superovulatory response (i.e. mean number of CL) and embryo data were evaluated by ANOVA for mixed models, using CL, FSH dose and treatment as fixed variables and cow identification as a random variable. Forty-six (24.2%) Angus donors, 4 (11.1%) Brangus donors and 5 (6.8%) Bonsmara donors did not have a CL at the time of initiating FSH treatment. There was no significant effect of FSH dose or treatment protocol on superovulatory response and the presence or absence of a CL did not influenced embryo production (P > 0.31). Mean (± SEM) number of CL, ova/embryos and transferable embryos were 13.2 ± 0.5, 12.4 ± 0.7 and 6.1 ± 0.4 in Angus donors with a CL vs 13.0 ± 0.7, 11.5 ± 0.9 and 5.6 ± 0.7 for those without a CL (P > 0.37); 14.8 ± 1.2, 14.2 ± 1.6 and 8.4 ± 1.1 for Brangus donors with a CL vs 15.2 ± 3.1; 11.2 ± 3.3 and 5.7 ± 2.8 for those without a CL (P > 0.34); and 13.2 ± 0.8, 11.2 ± 1.0 and 7.4 ± 0.5 for Bonsmara donors with a CL vs 17.4 ± 3.7, 13.6 ± 6.5 and 9.2 ± 4.3 for those without a CL (P > 0.16). In summary, the presence or absence of a CL did not affect embryo production in donor cows superstimulated every 28 to 35 days using a progesterone-releasing device and FSH. Study was supported by Bioniche Animal Health, Belleville, Ontario, Canada.

Abstract Introduction Post-transplant lymphoproliferative disorders (PTLD) are mostly Epstein-Barr virus (EBV) positive lymphoid proliferations resulting from immunosuppression following allogeneic stem cell or solid organ transplantation (SOT). Despite this strong association, there is a lack of data evaluating the risk of PTLD in SOT patients (pts) with (w/) EBV viremia. The significance of EBV detection remains unclear and can lead to unwarranted preemptive treatments in SOT pts. The aim of this study is to assess the association between peripheral blood EBV viral load and risk of PTLD post SOT. Methods We identified 6468 adult and pediatric pts from the Cleveland Clinic SOT database who underwent SOT from 2002-2016. We included pts who had ≥1 EBV viral load test by PCR, and excluded pts w/ first EBV test at or after PTLD diagnosis. EBV viral load was quantified by polymerase chain reaction (PCR) of whole blood samples and expressed as log copies/mL. Lower detection limits varied from 2.00 to 2.70 log copies/mL. EBV monitoring post SOT was done at the physician's discretion. Potential risk factors for PTLD were assessed using Fine and Gray competing risk regression. Stepwise analysis was used to identify multivariable risk factors. Landmark analyses at 2 and 6 months post SOT (LM-2 and LM-6) were performed based on pts' peak pre-landmark EBV levels. Pts were excluded if they died, lost follow-up (f/u) or developed PTLD prior to the landmark. Two multivariable models were assessed at each landmark using EBV level cutoffs of 3.00 and 4.00 log. Results Of 6324 pts w/ available f/u data, 3348 (52%) had ≥1 quantitative EBV PCR test and were included in this analysis w/ a total of 91,067 tests performed. Median age at SOT was 54 years (range 0.3-79) and 63% were male. The most common SOT was kidney (38%) followed by lung (37%), liver (18%), heart (7%), pancreas (6%) and intestine (2%), w/ 7% receiving >1 organ type (Table 1). Of 3348 pts included, 1503 (45%) developed EBV viremia and 68 (2%) developed PTLD; 45/1503 (3.0%) and 23/1845 (1.2%) of pts w/ and without (w/o) EBV viremia, respectively. EBV was detected in 44% of pts w/o PTLD and 66% of pts w/ PTLD. Median age at PTLD diagnosis was 58 years (range 1-75), with a median time from SOT to PTLD of 33 months (range 2-146). PTLD morphology was DLBCL (n=39), polymorphic (n=9) Burkitt (n=5), other (n=10) and unknown (n=5). EBV-encoded RNA (EBER) testing in tumor was positive in 47%, negative in 44% and unknown in 9% of cases. In pts w/ and w/o PTLD, tacrolimus was the most common immunosuppressant used at 1 month (99% and 89%), 1 year (94% and 88%) and 2 years (81% and 74%) post SOT, respectively. First EBV was checked at a median of 54 days (range 0-5090) in pts w/o PTLD and 28 days (range 0-4308) in pts w/ PTLD. The median number of EBV tests/pt before PTLD or last f/u was 4 (range 1-214) in pts w/o PTLD and 6 (range 1-123) in pts w/ PTLD. Peak EBV levels ≥3.00 and ≥4.00 log were detected in 36% and 13% of pts w/o PTLD, and 60% and 40% of pts w/ PTLD, respectively. Median f/u in both cohorts for pts who were alive was 6.1 years. In multivariable analysis (MVA) for non-EBV risk factors for PTLD, liver (HR 2.19, 95% CI 1.31 - 3.66, p=.003) and intestine SOT (HR 4.62, 95% CI 1.84 - 11.6, p=.001) were the only factors associated w/ higher PTLD risk; age, years since SOT, gender, race, other types of SOT and >1 SOT were not significant. 1685 pts were eligible for LM-2 (43 w/ PTLD) and 2093 for LM-6 (36 w/ PTLD). In univariable analysis at LM-2 and LM-6, peak EBV levels ≥4.00 log (LM-2: HR 2.72, p=.016; LM-6: HR 7.08, p<.001) and ≥5.00 log (LM-2: HR 8.64, p=.006; LM-6: HR 7.06, p=.002) were associated w/ increased risk for PTLD (Table 2 and Figure). Additionally, at LM-6, peak EBV level ≥3 was predictive for PTLD development (HR 2.18, p=.018). MVA at LM-2 was significant using cutoff ≥4 log (HR 2.90, p=.011), and at LM-6 using ≥3 (HR 2.21, p=.02) and ≥4 log (HR 6.91, p<.001). The cumulative incidence rate (CIR) for PTLD was 2.4% at 6 months and 4.9% at 1 and 2 years post SOT in pts w/ EBV ≥4 log by LM-2. By LM-6, EBV value of ≥4 log resulted in a CIR of 3.7% and 5.7% at 1 and 2 years, respectively. Conclusion In this large cohort of SOT pts, <50% had EBV viremia post SOT with only 3% of pts with EBV viremia developing PTLD. EBV viral load of ≥4 log copies/mL at 2 and 6 months was associated with increased risk of PTLD. EBV monitoring post-transplant may benefit a subset of pts, and prospective studies are warranted to evaluate if preemptive treatment can reduce PTLD risk in high-risk pts. Figure. Figure. Disclosures Hill: Pharmacyclics: 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; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pharmacyclics: 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; Seattle Genetics: 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.

Abstract Background Serum Beta-2 microglobulin (B2M) has been proposed as a potential prognostic factor for Non Hodgkin Lymphomas, including diffuse large B cell lymphoma (DLBCL). However, its prognostic value in DLBCL is not well known in rituximab era. We aimed to investigate its role as a prognostic factor in patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) Method Between January 2004 and April 2014, 940 patients with DLBCL, newly diagnosed and treated with R-CHOP, were identified in a single center lymphoma registry. Baseline serum B2M was available in 834 of these patients. Progression-free survival (PFS) and Overall survival (OS) was compared according to the levels of B2M using log-rank test. Result Median B2M value was 2.1 (range, 0.67-29.6 mg/L) and baseline value was elevated (> 2.5 mg/L) in 269 patients (32%). Elevated serum B2M was significantly associated with poor prognostic factors, as summarizedin table 1. In univariate analysis, elevated B2MG was significantly associated with poor PFS (hazard ratio [HR]=3.0, 95% confidence interval [CI]: 2.4-3.9; P <0.001) and OS (HR=3.5, 95% CI: 2.6-4.6; P <0.001). Each elements of IPI, high intermediate or high risk group of IPI, accompanying B symptoms, and bone marrow (BM) involvement were associated with shorter PFS and OS, also. We performed multivariate analyses to establish the prognostic role of B2M with confounding variables inlucidng sex, existence of B symptoms, Han's classification, BM involvement, bulky disease, risk groups according to IPI, revised IPI and National Comprehensive Cancer Network (NCCN)-IPI using three different models to avoid multicollinearity problem, each including IPI, revised IPI and NCCN-IPI. With adjustment for IPI, elevated B2M was demonstrated as a significant prognostic factor for PFS (HR=1.9, 95% CI: 1.3-2.6; p<0.001) and OS (HR=2.1, 95% CI: 1.4-3.0; p<0.001). After adjustment for revised IPI and NCCN-IPI with above confounding factors, elevated B2M still maintained statistical significance in PFS and OS, respectively (Table 2). The relevance of prognostic value of serum B2M in different risk groups by IPI was shown in subgroup analysis. Serum B2M was significantly associated with PFS and OS in both lower-risk group (IPI, 0-2) and higher-risk group (IPI, 3-5) (Figure 1) Conclusion In conclusion, elevated serum B2M seems to be an independent prognostic factor in patients with DLBCL who were treated with R-CHOP, which warrants further validation. Table 1. Relationship between B2M and baseline patient characteristics Characteristics B2MG¡Â2.5 mg/L, N (%) B2MG>2.5 mg/L, N (%) P value Age. Years <60 ¡Ã60 363 (44)202 (24) 100 (12)169 (20) <0.001 Sex Male Female 303 (36)262 (31) 174 (21)95 (11) 0.003 ECOG 0 – 1 2 – 4 545 (65)20 (2) 216 (26)53 (6) <0.001 Serum LDH Normal Elevated 367 (44)198 (24) 64 (8)205 (25) <0.001 Ann Arbor stage I - II III – IV 339 (41)225 (27) 53 (6)216 (26) <0.001 Number of extranodal sites0-1¡Ã2 417 (50)148 (18) 113 (13)156 (19) <0.001 B symptoms Yes No 76 (9)109 (13) 489 (59)160 (19) <0.001 Han's classification Germinal center B cell-likeActivated B cell-like 165 (20)302 (36) 62 (7)162 (19) 0.045 BM involvementNoYes 512 (61)51 (6) 192 (23)77 (9) <0.001 Bulky diseaseNoYes (> 10 cm) 530 (64)35 (4) 241 (29)28 (3) 0.031 IPILow/low-intermediate (0-1)/(2)High-intermediate/high (3)/(4-5) 445 (53)120 (14) 88 (11)181 (22) <0.001 Revised IPI Very good (0) Good (1-2) Poor (3-5) 188 (23)257 (31)120 (14) 6 (1)82 (10)181 (22) <0.001 NCCN-IPILow (0-1)Low-intermediate (2-3)High-intermediate (4-5)High (¡Ã6) 144 (17)286 (34)104 (12)31 (4) 6 (1)65 (8)122 (15)76 (9) <0.001 Table 2. Multivatiate analysis for the association with serum B2M with PFS and OS Variables PFSHR (95% CI ) P value OSHR (95% CI) P value B2MG (>2.5 mg/dL) 1.9 (1.3-2.6) <0.001 2.1 (1.4-3.0) <0.001 IPI0-23-5 1.03.0 (2.1-4.1) <0.001 1.03.4 (2.3-5.0) <0.001 B2MG (>2.5 mg/dL) 1.7 (1.2-2.3) 0.002 1.9 (1.3-2.8) <0.001 Revised IPI 01-24-5 1.03.1 (1.6-6.0)7.5 (3.8-14.8) 0.001<0.001 1.02.5 (1.2-5.4)7.1 (3.3-15.4) 0.019<0.001 B2MG (>2.5 mg/dL) 1.6 (1.2-2.3) 0.003 1.8 (1.3-2.7) 0.002 NCCN-IPI0-12-34-5¡Ã6 1.01.9 (1.0-3.7)3.3 (1.7-6.5)8.7 (4.4-17.9) 0.048<0.001<0.001 1.02.6 (1.1-6.1)5.0 (2.1-12.0)12.3 (5.0-30.4) 0.032<0.001<0.001 Figure 1. Impact B2M in lower-risk and higher-risk group of patients with DLBCL by IPI Figure 1. Impact B2M in lower-risk and higher-risk group of patients with DLBCL by IPI Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Numerous recurrent chromosomal abnormalities have been described in adult Ph-negative ALL, often observed in small patient cohorts. In the largest MRC/ECOG study (Moorman, Blood 2007), t(4;11)(q21;q23), 14q32 involvement, complex karyotype (≥5 abnormalities), and low hypodiploidy/near triploidy (Ho-Tr) were associated with shorter event-free survival (EFS), while patients with high hyperdiploidy or del(9p) had a better outcome. We aimed to confirm these observations in 955 adult patients (15-60y; median, 35y) with Ph-negative ALL treated in the pediatric-inspired GRAALL-2003/2005 trials. Patients and Methods: Overall, a karyotype was performed for 946 (611 BCP-ALL, and 335 T-ALL), successful for 811 (523 BCP-ALL and 288 T-ALL) and abnormal in 590 patients (387 BCP-ALL and 203 T-ALL). FISH and/or PCR screening for relevant abnormalities and DNA index were also performed, finally allowing for the identification of cytogenetic abnormalities in 677/955 patients (71%). All were centrally reviewed. Ultimately, 857/955 patients (90%; 542 BCP-ALL and 315 T-ALL) could be classified in 18 exclusive primary cytogenetic subsets as detailed below. Endpoints were cumulative incidence of failure (CIF, including primary refractoriness and relapse) and EFS. With a median follow-up of 4 years, 5-year CIF and EFS were estimated in these patients at 31% and 51%, respectively. As some abnormalities, including MLL rearrangements, Ho/Tr, t(1;19)(q23;p13)/TCF3 and complex karyotypes were used to stratify allogeneic stem cell transplantation (SCT) in GRAALL trials, some comparisons were repeated after censoring patients transplanted in first CR at SCT time. Results: The 542 informative BCP-ALL patients were classified as: t(4;11)(q21;q23)/MLL-AFF1 (n=72; 13%); other MLL+ 11q23 abnormalities (n=11; 2%); t(1;19)(q23;p13)/TCF3-PBX1 (#28; 5%); Ho/Tr (n=33; 6%); high hyperdiploidy (n=36; 7%); abnormal 14q32/IGH translocation (n=27; 5%); t(12;21)(p13;q22)/ETV6-RUNX1 (n=2; 0.4%); iAMP21 (n=3; 0.6%); other abnormalities (n=210; 39%); and no abnormality (n=120; 22%). The 315 informative T-ALL patients were classified as: t(10;14)(q24;q11)/TLX1 (n=64; 20%); other 14q11 or 7q34/TCR (n=31; 10%); t(5;14)(q35;q32)/TLX3 (n=29; 9%); t(10;11)(p12;q14)/PICALM-MLLT10 (n=14; 4%); deletion 1p32/SIL-TAL (n=18; 6%); MLL+ 11q23 abnormalities (n=6; 2%); other abnormalities (n=93; 30%); and no abnormalities (n=60; 19%). A complex karyotype was observed in 27/527 (5%) BCP-ALL and 21/298 (7%) T-ALL patients and a monosomal karyotype (as per Breems, JCO 2008) in 82/518 (16%) BCP-ALL and 26/286 (9%) T-ALL patients. In BCP-ALL, trends towards higher CIF and shorter EFS were observed in t(4;11) patients, with or without SCT censoring (HRs, 1.34 to 1.64; p values <0.10). Shorter EFS was observed in 3 subsets: 14q32 (HR, 2.10; p=0.002), Ho/Tr (HR, 1.45; p=0.10), and monosomal karyotype (HR, 1.42; p=0.029), but CIF were not different. This might be related to the older age of patients in these subsets (medians, 43y, 53y and 44y; p=0.029, <0.001 and <0.001, respectively) and worse treatment tolerance. For instance, higher incidences of non ALL-related deaths were observed in patients with 14q32 abnormalities or monosomal karyotype (p=0.031 and 0.067, respectively). Patients with high hyperdiploidy only tended to have lower CIF and longer EFS. Complex karyotype did not impact CIF and EFS, even after SCT censoring. Conversely, in T-ALL, complex karyotypes were associated with shorter EFS (HR, 2.20; p=0.004), even if the difference in CIF did not reach significance. A worse outcome was also observed in patients with t(10;11)(p12;q14)/PICALM-MLLT10 (HR, 2.45 and 2.14; p=0.016 and 0.021, for CIF and EFS respectively). A longer EFS was observed in patients with t(10;14)(q24;q11)/TLX1 (HR, 0.55; p=0.014), with a trend for lower CIF (HR, 0.59; p=0.070), while no inferior outcome was observed in t(5;14)(q35;q32)/TLX3 patients. Conclusion: These results show that, in the context of an intensified pediatric-inspired protocol designed for adult Ph-negative ALL patients, few cytogenetic subsets remained reliably predictive of response to therapy. Differences observed in EFS might partly be due to treatment-related mortality. Combining cytogenetics, molecular genetics and minimal residual disease monitoring could allow for better individual risk assessment (Beldjord, Blood 2014). Disclosures No relevant conflicts of interest to declare.

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.

Background and Objectives: To compare the accuracy of multimodality imaging (myocardial perfusion imaging with single-photon emission computed tomography (SPECT MPI), 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), and cardiovascular magnetic resonance (CMR) in the evaluation of left ventricle (LV) myocardial viability for the patients with the myocardial infarction (MI) and symptomatic heart failure (HF). Materials and Methods: 31 consecutive patients were included in the study prospectively, with a history of previous myocardial infarction, symptomatic HF (NYHA) functional class II or above, reduced ejection fraction (EF) ≤ 40%. All patients had confirmed atherosclerotic coronary artery disease (CAD), but conflicting opinions regarding the need for percutaneous intervention due to the suspected myocardial scar tissue. All patients underwent transthoracic echocardiography (TTE), SPECT MPI, 18F-FDG PET, and CMR with late gadolinium enhancement (LGE) examinations. Quantification of myocardial viability was assessed in a 17-segment model. All segments that were described as non-viable (score 4) by CMR LGE and PET were compared. The difference of score between CMR and PET we named reversibility score. According to this reversibility score, patients were divided into two groups: Group 1, reversibility score > 10 (viable myocardium with a chance of functional recovery after revascularization); Group 2, reversibility score ≤ 10 (less viable myocardium when revascularisation remains questionable). Results: 527 segments were compared in total. A significant difference in scores 1, 2, 3 group, and score 4 group was revealed between different modalities. CMR identified “non-viable” myocardium in 28.1% of segments across all groups, significantly different than SPECT in 11.8% PET in 6.5% Group 1 (viable myocardium group) patients had significantly higher physical tolerance (6 MWT (m) 3892 ± 94.5 vs. 301.4 ± 48.2), less dilated LV (LVEDD (mm) (TTE) 53.2 ± 7.9 vs. 63.4 ± 8.9; MM (g) (TTE) 239.5 ± 85.9 vs. 276.3 ± 62.7; LVEDD (mm) (CMR) 61.7 ± 8.1 vs. 69.0 ± 6.1; LVEDDi (mm/m2) (CMR) 29.8 ± 3.7 vs. 35.2 ± 3.1), significantly better parameters of the right heart (RV diameter (mm) (TTE) 33.4 ± 6.9 vs. 38.5 ± 5.0; TAPSE (mm) (TTE) 18.7 ± 2.0 vs. 15.2 ± 2.0), better LV SENC function (LV GLS (CMR) −14.3 ± 2.1 vs. 11.4 ± 2.9; LV GCS (CMR) −17.2 ± 4.6 vs. 12.7 ± 2.6), smaller size of involved myocardium (infarct size (%) (CMR) 24.5 ± 9.6 vs. 34.8 ± 11.1). Good correlations were found with several variables (LVEDD (CMR), LV EF (CMR), LV GCS (CMR)) with a coefficient of determination (R2) of 0.72. According to the cut-off values (LVEDV (CMR) > 330 mL, infarct size (CMR) > 26%, and LV GCS (CMR) < −15.8), we performed prediction of non-viable myocardium (reversibility score < 10) with the overall percentage of 80.6 (Nagelkerke R2 0.57). Conclusions: LGE CMR reveals a significantly higher number of scars, and the FDG PET appears to be more optimistic in the functional recovery prediction. Moreover, using exact imaging parameters (LVEDV (CMR) > 330 mL, infarct size (CMR) > 26% and LV GCS (CMR) < −15.8) may increase sensitivity and specificity of LGE CMR for evaluation of non-viable myocardium and lead to a better clinical solution (revascularization vs. medical treatment) even when viability is low in LGE CMR, and FDG PET is not performed.

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Background:BAFF, APRIL and BAFFR are genes that encode cytokines with a key role in the development and survival of B-lymphocytes [1-4]: The B cell-activating factor (BAFF, also known as BLyS), a proliferation-inducing ligand (APRIL) and BAFF receptor (BAFF-R), respectively. Previous genetic studies have revealed that the BAFF-APRIL-BAFFR pathway is implicated in the genetic predisposition to several immune-mediated diseases [5].Objectives:To determine whether the BAFF-APRIL-BAFFR pathway represents a novel genetic risk factor for the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory disease in which IgA deposits and B-lymphocytes are crucial [6, 7].Methods:A functional BAFF polymorphism (rs374039502) and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients (the largest series of Caucasian patients with IgAV ever assessed for genetic studies) and 806 sex and ethnically matched healthy controls by TaqMan assays.Results:No statistically significant differences in the genotype and allele frequencies between patients with IgAV and healthy controls were observed when each genetic variant of BAFF APRIL and BAFFR was analyzed independently (Table 1). Likewise, no statistically significant differences in genotype and allele frequencies of BAFF APRIL or BAFFR were found when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. Similar results were disclosed when haplotype frequencies of APRIL and BAFFR were compared between patients with IgAV and healthy controls as well as patients with IgAV stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations.Conclusion:Our results suggest that the BAFF-APRIL-BAFFR pathway does not contribute to the genetic network underlying IgAV.References:[1]J Exp Med 1999;190:1697-710; [2] Science 1999;285:260-3; [3] Nat Genet 2005;37:829-34; [4] Nat Immunol 2002;3:822-9; [5] N Engl J Med 2017;376:1615-26; [6] N Engl J Med 2013;368:2402-14; [7] Autoimmun Rev 2018;17:301-315.Table 1.Genotype and allele frequencies of BAFF, APRIL and BAFFR genes in patients with IgA vasculitis and healthy controls.PolymorphismLocus1/2Data set1/11/22/212rs374039502BAFFT/APatients91.9 (353)8.1 (31)095.9 (737)4.1 (31)Controls91.5 (733)8.1 (65)0.4 (3)95.6 (1531)4.4 (71)rs11552708APRILG/APatients78.1 (299)20.6 (79)1.3 (5)88.4 (677)11.6 (89)Controls77.9 (625)20.4 (1641.6 (13)88.1 (1414)11.9 (190)rs6608APRILC/TPatients71.9 (277)26.0 (100)2.1 (8)84.9 (654)15.1 (116)Controls70.0 (561)27.6 (221)2.5 (20)83.7 (1343)16.3 (261)rs7290134BAFFRA/GPatients58.0 (224)36.3 (140)5.7 (22)76.2 (588)23.8 (184)Controls57.2 (459)36.4 (292)6.5 (52)75.3 (1210)24.6 (396)rs77874543BAFFRG/CPatients82.7 (316)16.0 (61)1.3 (5)90.7 (693)9.3 (71)Controls83.0 (666)16.6 (133)0.4 (3)91.3 (1465)8.7 (139)Acknowledgements:This study was supported by European Union FEDER funds and “Fondo de Investigaciones Sanitarias” (grant PI18/00042) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). DP-P is a recipient of a Río Hortega programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) [grant number CM20/00006]; SR-M is supported by funds of the RETICS Program co-funded by the European Regional Development Fund (ERDF) [grant number RD16/0012/0009]; VP-C is supported by a pre-doctoral grant from IDIVAL [grant number PREVAL 18/01]; BA-M is a recipient of a `López Albo´ Post-Residency Programme funded by Servicio Cántabro de Salud; LL-G is supported by funds of IDIVAL [grant number INNVAL20/06]; RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) [grant number CP16/00033].Disclosure of Interests:Diana Prieto-Peña Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD and Roche, Sara Remuzgo Martinez: None declared, Fernanda Genre: None declared, Verónica Pulito-Cueto: None declared, Belén Atienza-Mateo: None declared, Belén Sevilla: None declared, Javier Llorca: None declared, Norberto Ortego: None declared, Leticia Lera-Gómez: None declared, Maite Leonardo: None declared, Ana Peñalba: None declared, J. Narváez: None declared, Luis Martín-Penagos: None declared, Jose Alberto Miranda-Filloy: None declared, LUIS CAMINAL MONTERO: None declared, PAZ COLLADO: None declared, Javier Sanchez Perez: None declared, Diego de Argila: None declared, Esteban Rubio-Romero: None declared, MANUEL LEON LUQUE: None declared, Juan María Blanco-Madrigal: None declared, E. Galindez: None declared, Javier Martin Ibanez: None declared, Santos Castañeda: None declared, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD and Roche, Miguel A González-Gay Speakers bureau: Pfizer, Abbvie, MSD, Grant/research support from: Pfizer, Abbvie, MSD, Raquel López-Mejías: None declared

Abstract Background: The addition of venetoclax to a hypomethylating agent (HMA) backbone has been shown to augment responses when compared to HMA monotherapy or to low-dose cytarabine in the treatment of acute myeloid leukemia (AML). The aim of this retrospective analysis was to characterize venetoclax-based regimens in both the first-line and relapsed/refractory settings to determine efficacy and safety outcomes. Patients & Methods: We retrospectively analyzed 74 patients treated with venetoclax in combination with decitabine, azacitidine, or low-dose cytarabine treated from June 2018 to December 2020. This analysis included 41 patients in the upfront setting and 33 patients in the relapsed/refractory setting. Baseline patient demographics were obtained alongside ECOG performance status at diagnosis, cytogenetics and molecular profiling, dates and doses of induction, toxicity, responses, MRD analysis, and allogeneic hematopoietic stem cell transplant (HSCT) outcomes. The event for calculating the overall survival was the date of death and patients were otherwise censored at the date of last contact. Results: In the upfront setting of 41 patients, 25 (61%) were male and 16 (39%) were female, the median age was 72 (range: 37 - 85), the median ECOG score was 2 (range: 0 - 3), and the median Charlson Comorbidity Index (CCI) score was 6 (range: 3 - 12). There were four patients with favorable-risk cytogenetics (9.8%), six (14.6%) with intermediate cytogenetics, and 29 (70.7%) with adverse cytogenetics. Two (4.9%) patients had cytogenetics unknown at diagnosis. Eight (19.5%) had mutations in TP53. Thirty-three (80.5%) received venetoclax with 5-day decitabine, one (2.4%) with 10-day decitabine, six (14.6%) with azacitidine, and one (2.4%) with low-dose cytarabine. In the entire cohort, 37 (90.2%) experienced at least one grade 1 non-hematological toxicity during induction. Non-hematological adverse events were infection (58.5%), neutropenic fever (53.7%), and acute kidney injury (26.8%). Six (14.6%) patients had tumor lysis syndrome defined by Cairo-Bishop criteria and all six were spontaneous rather than therapy-induced. One (2.4%) died within 30 days of induction, nine (22.0%) died within 60 days, and 29 (70.7%) had no death during induction. Three (7.3%) achieved CR and 13 (31.7%) achieved CRi for an ORR of 39.0%. Two patients (4.9%) went on to receive HSCT. The median OS was 416 days (13.7 months) in the intermediate category and 281 days (9.2 months) in the adverse category. In the relapsed/refractory setting, 20 (60.6%) were male and 13 (39.4%) were female. The median age was 63 (range: 23 - 76), the median ECOG score was 1 (range: 0 - 4), and the median CCI score was 5 (range: 2 - 11). At the time of initial diagnosis, two patients (6.1%) had favorable cytogenetics, three (9.1%) had intermediate cytogenetics, 27 (81.8%) had adverse cytogenetics, and one had unknown cytogenetics. Seven (21.2%) patients had a TP53 mutation at initial diagnosis. Twenty-five (75.8%) received venetoclax with 5-day decitabine, 6 (18.2%) with azacitidine, one (3.0%) with low-dose cytarabine, and one with an unknown duration of decitabine. Common non-hematological toxicities included 13 (39.4%) with infection, 11 (33.3%) with neutropenic fever, and 3 (9.1%) with acute kidney injury. Five patients (15.2%) achieved CR and 5 (15.2%) achieved CRi for an ORR of 30.3%. Four (12.1%) died within 30 days, 3 (9.1%) within 60 days, and 25 (75.8%) with no death during induction. The median OS was 251 days (8.25 months). Conclusion: The combination of venetoclax with decitabine, azacitidine, or low-dose cytarabine demonstrates an ORR of 39.0% in the upfront setting and the OS was 13.7 months and 9.2 months in the intermediate and adverse categories, respectively. The relapsed/refractory setting featured a shorter OS at 8.25 months and an ORR of 30.3%, which does not appear to be substantially different from historical data with HMA monotherapy in relapsed disease (mOS = 6.7 months). These findings raise the question regarding the benefit of venetoclax in the relapsed setting for selected patients. Additionally, our findings augment the small sample of available data on the utility of HMA/venetoclax, particularly in the treatment of relapsed disease, with recent retrospective data showing a CR/CRi rate of 24% and a mOS of 6.1 months. Prospective trial designs are needed to confirm these findings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background:The efficacy and safety of upadacitinib (UPA), a selective Janus kinase inhibitor, has been evaluated in the SELECT rheumatoid arthritis (RA) clinical program,1–6 but its real-world effectiveness remains to be investigated. The UPwArds study will assess the association of C-reactive protein (CRP) level with remission and other efficacy outcomes in patients with RA treated with UPA in German real-world practice.Objectives:To describe the baseline characteristics of patients enrolled in the UPwArds study.Methods:The prospective, open-label, multicenter, non-interventional, post-marketing UPwArds study included adult patients with moderate-to-severe RA (swollen joint count [SJC28] ≥3 and inadequate response or intolerance to ≥1 disease-modifying antirheumatic drug [DMARD]). Patients were treated with UPA 15 mg once daily, as monotherapy or in combination with methotrexate (MTX; 50:50 mono:combo enrollment planned), according to the German label. Variables assessed included medical history (disease duration, previous RA therapy, and vaccination status), CRP level, and disease activity (disease activity score [DAS28(CRP)], tender joint count [TJC28], and SJC28). There was no recruitment restriction regarding CRP level. This descriptive interim analysis reports patient baseline characteristics after enrollment was complete. All data were analyzed as observed, with no imputation of missing data.Results:533 patients (UPA monotherapy: 257 [48%]; UPA plus MTX: 276 [52%]) were included. Mean patient age was 58 years; mean disease duration was 9 years (Table 1). Despite having active RA, almost half the population (44%; n=237) did not have elevated CRP at the start of UPA treatment. Mean DAS28(CRP) was 4.6; mean TJC28 and SJC28 were 7.7 and 5.6, respectively. Overall, 39% of patients had not been treated with any biologic (b) DMARD or targeted synthetic (ts) DMARD before enrollment; 25% and 36% had previously been treated with 1 or ≥2 bDMARDs or tsDMARDs, respectively (Figure 1). 8.7% of patients had previously received a herpes zoster vaccination (8.1% Shingrix; 0.6% Zostavax).Conclusion:In German clinical practice, the population of patients with RA in the UPwArds study was predominantly treatment-refractory. Half of these patients had no elevated CRP despite active disease; future analyses will assess the impact of CRP on efficacy outcomes.References:[1]Smolen JS, et al. Lancet 2019;393:2303–11;[2]Burmester GR, et al. Lancet 2018;391:2503–12;[3]Genovese MC, et al. Lancet 2018;391:2513–24;[4]van Vollenhoven R, et al. Arthritis Rheumatol 2020;72:1607–20;[5]Fleischmann R, et al. Arthritis Rheumatol 2019;71:1788–800;[6]Rubbert-Roth A, et al. N Engl J Med 2020;383:1511–21.Table 1.Baseline characteristicsAge, yearsUPAUPA + MTXTotal57.7 (13.2)n=25758.1 (11.4)n=27657.9 (12.3)n=533Disease duration, years9.4 (8.3)8.5 (7.7)9.0 (8.0)n=253n=272n=525CRP, mg/dL1.3 (1.9)1.1 (1.7)1.2 (1.8)n=257n=276n=533CRP >ULN, n (%)137 (53.3)159 (57.6)296 (55.5)n=257n=276n=533TJC287.4 (6.0)7.9 (6.4)7.7 (6.2)n=257n=276n=533SJC285.5 (3.7)5.6 (4.1)5.6 (3.9)n=257n=276n=533Patient’s Global Assessment6.2 (1.9)6.3 (1.8)6.3 (1.8)n=257n=276n=533Physician’s Global Assessment5.8 (1.5)5.9 (1.6)5.9 (1.6)n=257n=276n=533DAS28(CRP)4.6 (1.0)4.6 (1.0)4.6 (1.0)n=257n=276n=533DAS28(ESR)4.8 (1.1)4.9 (1.2)4.9 (1.1)n=224n=239n=463CDAI24.9 (10.2)25.7 (10.8)25.4 (10.5)n=257n=276n=533SDAI26.2 (10.5)26.9 (11.3)26.6 (10.9)n=257n=276n=533RAID5.7 (2.0)5.7 (2.0)5.7 (2.0)n=255n=275n=530Pain (RAID-1)6.2 (2.2)6.1 (2.3)6.2 (2.2)n=255n=275n=530SF-12 Physical Component Summary32.6 (8.5)33.9 (8.6)33.3 (8.6)n=245n=262n=507SF-12 Mental Component Summary42.4 (11.6)42.6 (11.3)42.5 (11.5)n=245n=262n=507HAQ-DI1.3 (0.7)1.3 (0.6)1.3 (0.6)n=250n=270n=520PHQ-98.9 (5.3)8.6 (5.3)8.7 (5.3)n=252n=272n=524Erosions, n (%)87 (33.9)95 (34.4)182 (34.1)n=257n=276n=533Data are mean (SD), n unless otherwise statedAcknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and in the writing, review, and approval of the abstract. AbbVie and the authors thank all study investigators for their contributions and the patients who participated in this study. No honoraria or payments were made for authorship. Medical writing support was provided by Grant Thomas Kirkpatrick, MSc, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Torsten Witte Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Chugai, Gilead, Janssen, Lilly, MSD, Mylan, Novartis, Pfizer, Roche, and UCB., Uta Kiltz Consultant of: AbbVie, Biocad, Eli Lilly and Company, Grünenthal, Hexal, Janssen, MSD, Novartis, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Amgen, Biogen, Fresenius, GSK, Hexal, Novartis, and Pfizer, Florian Haas Consultant of: AbbVie, Celgene, Novartis, and Pfizer, Grant/research support from: AbbVie, BMS, Celgene, Chugai, MSD, Novartis, Pfizer, Roche, and Sanofi Genzyme, Elke Riechers Consultant of: AbbVie, Chugai, Novartis, and UCB, Grant/research support from: AbbVie, Chugai, Lilly, Janssen, Novartis, Pfizer, Roche, and UCB, Ulrich Prothmann Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Glaxo Smith Kline, Novartis, Pfizer, Roche, Sanofi, SOBI, and UCB, Daniela Adolf Employee of: Employee of StatConsult and may own stock or options, Carsten Holland Employee of: Employee of AbbVie and may own stock or options, Rouven Hecht Employee of: Employee of AbbVie and may own stock or options, Alexander Roessler Employee of: Employee of AbbVie and may own stock or options, Kirsten Famulla Employee of: Employee of AbbVie and may own stock or options, Klaus Krueger Grant/research support from: AbbVie, Biogen, BMS, Celltrion, Gilead, Hexal, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche, and UCB.

Background:Elderly rheumatoid arthritis (RA) patients are generally at increased risk of serious infections (SI). At the same time, treatment with bDMARDs has been associated with a higher SI risk than treatment with csDMARDs (1). However, long-term use of bDMARDs did not increase the risk of SI in a small group of elderly patients over 65 (2). The extent to which elderly patients are exposed to a higher SI risk when treated with JAK inhibitors (JAKi) is an open question.Objectives:To assess the effects of bDMARDs and specifically JAKi on the risk of SI in elderly patients with RA.Methods:The German register RABBIT is a prospective, longitudinally followed cohort of RA patients enrolled with a new start of a DMARD after at least one csDMARD failure. This analysis comprises patients over 70 years of age who were enrolled between 01/2007 and 04/2020 and had at least one follow-up.Results:Of 13,491 patients followed-up in RABBIT, 2274 with an age > 70 years were included in the analysis. 626 SI were observed in 425 of these patients. Baseline characteristics at start of the respective DMARD are shown in Table 1. In most characteristics, patients on JAKi were more comparable to patients under bDMARDs than to those on csDMARDs. JAKi patients received glucocorticoids (GC) less frequently than patients on other treatments. The HR for SI was lower than 1 in patients receiving bDMARDs or JAKi compared to csDMARDs, but without statistical significance (Figure 1). GC use (HR 1.6, 95% CI: 1.2 – 2.2 for ≤ 10 mg/d), higher DAS28-ESR values (HR 1.1, 95% CI: 1.0 – 1.2 per 1 point increase), COPD or pulmonary fibrosis (HR 1. 8, 95% CI: 1.3 – 2.4), chronic kidney disease (HR 1.5, 95% CI: 1.2 – 1.9) and diabetes mellitus (HR 1.3, 95% CI: 1.0 – 1.7) were associated with an increased risk of SI. Better physical capacity was associated with a decreased risk of SI (HR 0.9, 95% CI: 0.88 – 0.98 for a 10 point increase).Table 1.Patient characteristics by treatment at baselineParametercsDMARDsTNFiRTXABAIL-6iJAKiN=758N=840N=209N=147N=212N=108Age (years)75.9 (3.9)75.5 (3.6)74.8 (3.6)76.1 (3.9)75.9 (3.7)76.7 (3.7)Male sex184 (24.3)220 (26.2)50 (23.9)36 (24.5)46 (21.7)28 (25.9)Ever smoker249 (32.8)287 (34.2)77 (36.8)50 (34)73 (34.4)39 (36.1)Disease duration (years)7.9 (8.8)12.3 (11.4)17 (11.1)12.8 (10)13.8 (11.7)11.9 (10.9)Seropositivity487 (64.3)671 (79.9)201 (96.2)126 (85.4)182 (85.8)79 (73.5)Number of previous DMARDs1.4 (0.7)2.5 (1.3)4.2 (1.8)3.6 (1.9)3.3 (1.8)2.6 (1.5)DAS28-ESR4.6 (1.2)5.1 (1.2)5.4 (1.3)5.3 (1.3)5.3 (1.3)5 (1.2)Proportion of full physical function64.8 (23.1)57.1 (23.6)50.4 (23.7)52.9 (23.5)55.3 (24.1)55.2 (23.7)Number of comorbidities3.1 (2.5)3.8 (2.6)4.2 (2.6)4.6 (2.9)3.6 (2.4)3.8 (2.2)No comorbidity52 (6.9)29 (3.5)4 (1.9)4 (2.7)9 (4.2)5 (4.6)Three and more comorbidities385 (50.8)528 (62.9)147 (70.3)107 (72.8)131 (61.8)76 (70.4)COPD or pulmonary fibrosis69 (9.1)89 (10.6)29 (13.9)26 (17.7)12 (5.7)11 (10.2)Chronic kidney disease94 (12.4)151 (18)28 (13.4)21 (14.3)39 (18.4)22 (20.4)Diabetes mellitus151 (19.9)172 (20.5)31 (14.8)23 (15.6)42 (19.8)25 (23.1)GCs (last 6 months)347 (45.8)526 (62.6)143 (68.8)82 (56.2)127 (59.9)44 (40.7)GCs (<5mg)447 (58.9)384 (45.7)101 (48.2)88 (60)118 (55.8)72 (66.7)GCs (5-9mg)252 (33.3)375 (44.6)81 (38.7)43 (29)72 (34.2)27 (25.1)GCs (>=10mg)59 (7.8)82 (9.8)274 (13.1)16 (11)21 (10)9 (8.2)Results are presented as mean ± SD for continuous variables and number (percentage) for discrete variables.Figure 1.Hazard ratios for serious infections with 95% confidence intervalsConclusion:Treatment with JAKi as well as treatment with bDMARDs was not associated with an increased risk of SI in elderly patients above 70 years of age. Key comorbidities such as diabetes mellitus, chronic pulmonary and kidney diseases were associated with increased risk, as was concomitant GC use and higher disease activity.References:[1] Listing J et al., Rheumatology 2013; 52 (1): 53-61.[2] Kawashima H. et al., Rheum. Intern. 2017; 37: 369-376.Acknowledgements:RABBIT is supported by a joint, unconditional grant from AbbVie, Amgen, BMS, Celltrion, Fresenius-Kabi, Gilead, Hexal, Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, UCB, and Viatris.Disclosure of Interests:None declared

Abstract Introduction: Prophylaxis of venous thromboembolism (VTE) in patients undergoing total knee replacement (TKR) most often entails anticoagulation, yet minimization of excessive postoperative bleeding and wound complications is critical to attain an excellent functional result. Ximelagatran (Exanta®, AstraZeneca), the first oral alternative to warfarin, has a rapid onset of action and requires no coagulation monitoring or dose adjustment. Three randomized, double-blind trials of VTE prophylaxis after TKR comparing ximelagatran 24 and 36 mg BID with well-controlled warfarin (target INR 2.5) were completed: Study 236 (n=680), EXULT A (n=2301), and EXULT B (n=2303). When administered for 7–12 days, ximelagatran 36 mg BID was superior to well-controlled warfarin, while 24 mg yielded numerically better but not statistically superior efficacy over warfarin. Adjudicated bleeding rates did not differ significantly. Objective: To assess the postoperative bleeding complications and overall surgical wound appearance during anticoagulation after TKR. Methods: Two comparison pools were created: 36-mg pool (ximelagatran 36 mg and corresponding warfarin groups from EXULT A and B) and 24-mg pool (ximelagatran 24 mg and corresponding warfarin groups from Study 236 and EXULT A). Bleeding indicators, i.e., postoperative wound drainage, bleeding index, and transfusion requirements, were compared. A prespecified subjective assessment of the surgical wound was performed on postoperative Day 3, end of treatment (Day 7–12), and at follow-up (4–6 weeks). If wound appearance was rated “worse than expected” at any time point, wound characteristics of swelling, drainage, erythema, and bleeding were assessed. Intra-articular bleeding, unusual bruising or hematoma, and bleeding requiring an intervention were also recorded. Results: 36-mg Pool (n=3810) 24-mg Pool (n=2178) Bleeding Indicators Ximelagatran Warfarin Ximelagatran Warfarin Post-op wound drainage, mean in mL (95% CI) 697 (675, 718) 704 (682, 725) 659 (632, 686) 654 (626, 682) Bleeding Index, mean (95% CI) 3.4 (3.3, 3.4) 3.3 (3.2, 3.4) 3.2 (3.1, 3.3) 3.1 (3.0, 3.2) Transfusions Unplanned, % of Pts 8.9 8.1 Not Assessed Not Assessed Total, % of Pts 33.5 33.6 37.6 34.3 Vol. Transfused/Pt, mean (95% CI) 630 mL (602, 659) 606 mL (578, 635) 1.7 U (1.6, 1.8) 1.7 U (1.6, 1.8) Overall wound appearance (worse than expected), % 9.2 8.7 8.9 8.2 Wound characteristics (worse than expected) Swelling, % 5.1 4.5 5.7 4.6 Drainage, % 3.6 2.4 2.7 1.8 Erythema, % 3.9 3.7 2.8 3.5 Bleeding, % 1.7 1.2 Not Assessed Not Assessed In the 36- and 24-mg pools the wound was assessed as “expected” or “better than expected” for ≥90% of the patients in the ximelagatran and warfarin groups. For the small number of patients with “worse than expected” wounds, the differences between the ximelagatran and warfarin groups were not statistically significant. Bleeding complications of the surgical wound, including intra-articular bleeding (<3.5%), unusual bruising or hematoma (<5.0%), and bleeding requiring an intervention (<0.9%), were few and comparable between treatment groups. Conclusions: Analysis of bleeding indicators and complications of the surgical wound revealed no significant differences between treatment groups, supporting the safety of 36 mg for all patients undergoing TKR.

Abstract Background Adolescents and young adults (AYAs) with sickle cell disease (SCD) are at increased risk for disease complications and mortality, particularly during transition to adult care. Little is known about the disease course that might be contributing to the increase in morbidity and mortality during transition. This study provides a longitudinal description of the clinical characteristics and disease severity among AYAs with SCD during transition to adult care. Methods We conducted a longitudinal analysis of the electronic health records of 339 AYAs (ages 12-27 years) with SCD (97% black, 56% male, 69% hemoglobin SS) who received care at a comprehensive SCD center in the Southeast US between 1989 and 2015. Measures included sociodemographics, transfer, complications, comorbidities, and severity of SCD (using a modification of the pediatric SCD severity index). We used group-based trajectory modeling to identify subgroups of AYAs with distinct severity trajectories. AYAs who were in care for at least 10 years were included (n=133). We used chi-square and unpaired student t-test to explore subgroup differences among (1) AYAs who died compared to AYAs who were still alive during the study; (2) AYAs who were eligible to transfer (i.e., ≥ 19 years) (n=293) and transferred compared to AYAs who were eligible to transfer and did not transfer; and (3) AYAs with different severity trajectories. Statistical significance was set at p=0.05 and 95% CI. Results Common complications among AYAs (n=339) included vaso-occlusive crises (80%), acute chest syndrome (41%), chronic pain (35%), and cerebral infarcts (22%). Comorbidities included depression (19%) and anxiety (14%). Most AYAs who were eligible to transfer transferred (n=220, 75%) at a mean age of 19 years (SD=1.3). Fourteen AYAs died, 10 (71%) after transfer at a mean of 7.3 years (SD=3.1) from transfer. SCD Severity Trajectories (Figure 1): Group-based trajectory modeling identified both stable and increasing severity trajectory groups: stable-low (n=31, 23%), stable-medium (n= 61, 46%), stable-high (n=6, 5%), low-increasing (n=13, 10%), and medium-increasing (n= 22,17%) severity trajectory groups. Most AYAs (74%) had stable severity over time, whereas 26% had increased severity with increasing age. Subgroup Differences in Care and Mortality: AYAs who died (n=14) spent less time in pediatric care (mean=4.6 years, 95%CI 3.7-5.6), however, had a higher mean number of pediatric annual visits (mean=9.3 visits; 95%CI 6.3-12.3) compared to those who were alive (n=324, mean=6 years in pediatric care, 95%CI 5.7-6.1; mean number of pediatric annual visits=5.4, 95%CI 4.8-6.1). There were no differences in demographics, SCD complications, or morbidity. Subgroup Differences in Transfer to Adult Care (Tables 1 and 2): Compared to AYAs who did not transfer, AYAs who transferred were older and lived closer to the SCD clinic. AYAs who transferred were at higher risk for SCD complications and comorbidities. They were more likely to be receiving hydroxyurea. They had higher mean annual pediatric SCD clinic visits, especially during older adolescence, and were in pediatric care for a longer duration. Subgroup Differences in Disease Severity (Tables 3 and 4). Compared to AYAs in stable severity trajectory groups (Figure 1: Groups 1, 3, and 5), AYAs in unstable disease severity trajectory groups (Figure 1: Groups 2 and 4) were more likely to be married, older, and lived closer to the SCD clinic. AYAs in unstable groups were also at higher risk for SCD complications and comorbidities. They were less likely to be receiving treatments and had less pediatric SCD clinic visits by age 18. However, they were more likely to transfer to adult care, have had more adult SCD visits overall, and remained longer in adult SCD care after transfer. Conclusions Whereas most AYAs with SCD had stable disease severity, nearly a quarter had increasing disease severity, over time. AYAs with increasing severity lived closer to the SCD clinic, were more likely to transfer to adult care, and demonstrated higher and longer use of adult SCD care compared to AYAs with stable disease severity. Genotype was not associated with disease severity trajectory groups, underscoring the importance of clinical care for AYAs, over time. Disclosures Kayle: Department of Health and Human Services, Administration for Community Living, NIDILRR Advanced Rehabilitation Research Training Health and Function Grant #90AR5019 (PI Heinemann): Other: post-doctoral fellowship; Department of Health and Human Services, Administration for Community Living, NIDILRR Advanced Rehabilitation Research Training Health and Function Grant # 90ARHF0003 (PI Heinemann): Other: Postdoctoral fellowship. Tanabe:Duke University: Employment; NIH and AHRQ: Research Funding; Alliant Health: Consultancy. Maslow:The Crohn's and Colitis Foundation and the American Gastroenterological Association, in collaboration with Pfizer, Inc: Research Funding. Holl:Before Brands, Inc: Research Funding; NIH: Research Funding; Branstad Family Foundation: Research Funding; AHRQ: Research Funding. Shah:Novartis: Research Funding, Speakers Bureau.

Introduction: The utility of amyloidosis staging systems has been validated for newly diagnosed patients, but their role in restaging after starting treatment has not been explored. Given the high early mortality in this disease, restaging remote from the diagnosis may have clinical value. We designed this study to evaluate whether the currently used staging systems are prognostic when applied at 3 and 6 months from starting first-line treatment, and whether stage migration impacts survival. Methods: This is a retrospective study including patients with systemic light chain amyloidosis diagnosed between January, 1st 2006 and June, 30th 2019 and were seen in Mayo Clinic, Rochester, MN within 90 days of diagnosis; the analysis included 535 and 301 patients who had restaging data available for at least one of the staging systems at 3 and 6 months, respectively. Patients were grouped into 4 stages using the 2015 European modification of the Mayo 2004 staging system based on values of cardiac biomarkers (cardiac troponin T and NTproBNP), and using the Mayo 2012 staging system based on cardiac biomarkers and the difference in serum free light chain concentration (dFLC). Overall survival (OS) was calculated from the time of re-staging until death or last follow up. Results: Using the modified Mayo 2004 staging system at 3 months from starting first-line treatment, median OS was 11.8 [95%CI: 11.4-not reached (NR)], 10.8 (95%CI: 9.4-NR), 4.6 (95%CI: 2.8-6.7), and 1.1 (95%CI: 0.7-2.6) years in patients with stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012 staging at 3 months, OS was 11.8 (95%CI: 10.9-NR), 9.0 (95%CI: 6.2-NR), 5.2 (95%CI: 3.3-6.1), and 0.8 (95%CI: 0.7-1.1) years in patients with stage I, II, III, and IV, respectively (Figure 1a &b). Using the modified Mayo 2004 staging system at 6 months from starting first-line treatment, median OS was NR (95%CI: NR-NR), 9.8 (95%CI: 6.2-NR), 5.4 (95%CI: 3.2-9.0) and 0.9 (95%CI: 0.6-3.7) years in patients with stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012 staging at 6 months, OS was NR (95%CI: 8.4-NR), NR (95%CI: 7.9-NR), 4.6 (95%CI: 3.0-6.5), and 0.9 (95%CI: 0.2-1.8) years in patients with stage I, II, III, and IV, respectively (Figure 1c &d). On multivariate analysis, advanced (stage &gt; 2) modified Mayo 2004 stage (HR: 1.6, P=0.004) and advanced (stage &gt; 2) Mayo 2012 stage (HR: 2.4, P&lt;0.001) at 3 months were associated with decreased survival independent of cardiac response, hematologic response, and transplantation status. Although advanced Mayo 2004 stage at 6 months was associated with decreased survival, it was not statistically significant (HR: 1.5, P=0.09). In contrast, advanced Mayo 2012 stage at 6 months was independently associated with decreased survival (HR: 2.1, P=0.02). For both systems, worsening stage at 3 months or at 6 months was associated with a worse survival than retaining the original stage. In contrast, improving stage as compared to remaining in same stage was not associated with better survival at 3 or 6 months (Table 1). When the analysis was restricted to patients who had an advanced stage at diagnosis, improving stage at 3 months was associated with longer survival compared to retaining the original stage, with both modified Mayo 2004 (10.8 vs. 3.3 years, P&lt;0.001) and Mayo 2012 (8.1 vs. 2.6 years, P&lt;0.001) staging systems. At 6 months, stage improvement was associated with longer survival than retaining the original stage when the modified Mayo 2004 staging system was used (NR vs. 5.0 years, P=0.02), but it was not statistically significant when the Mayo 2012 staging system was used (5.9 vs. 3.7 years, P=0.12). Conclusion: The modified Mayo 2004 and the Mayo 2012 staging systems have independent prognostic value when used for restaging after 3 and 6 months from initiation of first-line treatment. Migration to a higher stage from diagnosis predicts decreased survival, compared to retaining the same stage. Stage improvement is associated with a better OS in patients with advanced stage at diagnosis. Disclosures Dispenzieri: Alnylam, Intellia, Janssen, Takeda, Pfizer, Prothena, Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:GlaxoSmithKline: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Celgene: Honoraria; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Cellectar: Consultancy. Dingli:Rigel: Consultancy; Millenium: Consultancy; Sanofi-Genzyme: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Janssen: Consultancy; Alexion: Consultancy; Apellis: Consultancy. Lin:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gamida Cells: Consultancy; Takeda: Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Janssen: Consultancy, Research Funding; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Gertz:Alnylam: Consultancy; NCI SPORE MM: Research Funding; Ionis/Akcea: Consultancy; Amyloidosis Foundation: Research Funding; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy; Springer Publishing: Patents & Royalties; Prothena: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; International Waldenstrom Foundation: Research Funding. Kumar:Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genecentrix: Consultancy; Cellectar: Other; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; MedImmune: Research Funding; Carsgen: Other, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Karyopharm: Consultancy; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Novartis: Research Funding; Adaptive Biotechnologies: Consultancy; Tenebio: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; Sanofi: Research Funding.

Abstract Background: Elotuzumab (elo) is a humanized monoclonal antibody, which has been approved by the FDA for use in combination with lenalidomide (lena) and dexamethasone (dexa) in patients (pts) with relapsed and refractory multiple myeloma (RRMM). Elotuzumab is effective as a single agent, as well as in combination for multiple myeloma treatments, supporting the use of elo in pts with RRMM and newly diagnosed multiple myeloma (NDMM) pts. Method: After review of literature using database searches was done on 6/27/18 (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), 9 prospective and 1 retrospective study with 1128 enrolled pts met the inclusion criteria to date in RRMM and 2 clinical trials including 123 pts in NDMM (Table 1). CMA software v.3 was used for meta-analysis. A random-effect model was applied. Result: Regimens used in RRMM: Based on pooled analysis (95% CI), an overall response rate (ORR) of 66% (54-76.2) was calculated in 685 evaluable pts treated with elo based regimens in RRMM (Figure 1). Most common grade (G) ≥ 3 hematological adverse events (HAE) and non-hematological adverse events (NHAE) based on regimen were calculated using pooled analysis in RRMM pts (Table 2). Anemia was noted in 12.1% ( 7.7-18.6) in 559 pts, while neutropenia in 14.5% (7.5-26.4) out of 591 pts and thrombocytopenia (tcp) in 11.9% (7.9-17.4) in 198 evaluable pts. Diarrhea 5.5% (3.6-8.3), pyrexia 2.4% (1.5-4), peripheral neuropathy (PN) 8.4% (3.8-17.8) were measured in 626, 668 and 143 pts respectively. Elotuzumab as monotherapy: 1 study (n=34) evaluated the efficacy of elo as single agent in RRMM. The median age, time from diagnosis and number of prior therapies were 64.5 years (y) (46-87), 4.4 y (0.9-12.8) and 4.5 y (2-10) respectively. It produced an ORR of 1.4% (0.1-19.1 95% CI) in 34 evaluable pts. Adverse events recorded were pyrexia and fatigue in 17.6% and 8.8% pts respectively. Elotuzumab in two drug regimen: In RRMM, 2 clinical trials (n=49) evaluated the efficacy (95% CI) of elo, ORR of 25% (4.1-72.3) was calculated. The best PFS (progression free survival) produced was in combination of elo 20 mg with bortezumib (bort) 1.3mg/m2 of 9.46 months as compared to 1.8 months when elo10mg/kg + dexamethasone (dexa) 28mg was used. In our analysis for safety, common G≥ 3 HAE calculated were, thrombocytopenia 8.7% (3.3-21.1) n=49, neutropenia 10.7 % (3.5-28.4) n=28 pts and anemia 7.1% (1.8-24.5) n=28 pts. NHAE included diarrhea 1.7% (0.1-22.3), PN 10.7% (3.5-28.4), pyrexia 1.7% (0.1-22.3) in 28 evaluable pts each. Elotuzumab in three drug regimen: In RRMM, 10 clinical trials including 602 pts evaluated the efficacy of elo as a part of triple drug regimen, producing an ORR of 72.2% (54-76.2). The best results were produced with the combination of elo 10-20mg/kg + lenalidomide (lena) 25mg + dexa 40mg producing a PFS of 32.2 mo and 28.62 mo in its phase I and II cohorts respectively. Based on pooled analysis (95% CI) common HAE calculated were neutropenia 17.5% (7.6-35.4) in n=563, thrombocytopenia 12.7% (8.2-19.4) in n=149 and anemia 13% (8-20.5) in n=531 pts. Common G ≥ 3 NHAE estimated were diarrhea 5.7% (3.7-8.6), PN 6.6% (2-19.2), pyrexia 2.5% (1.5-4.1) in 598, 115 and 640 pts respectively. Elotuzumab based regimen in NDMM: A currently ongoing clinical trial NCT02272803 has produced promising results in NDMM pts. As a part of three drug regimen with dose of elo 10mg/kg-20mg/kg, lena 25mg, dexa 20mg in 40 pts produced an ORR of 87.5% (73.2-95.8) versus control group of lena 25mg plus dexa 40mg in 42 pts with an ORR of 73.8% (58-86.1). The PFS rate recorded at 1 year was 93% (79-98%) and 91% (73-97%) respectively. The HAE G ≥ 3 included, neutropenia 18% and leukopenia 15%. In another study with 41 pts, elo was used in combination with lena, bort and dexa producing an ORR of 100% and greater than grade 3 adverse events including Tcp 15%, PN 2%. Conclusion: Results produced in our study suggest that elotuzumab is highly effective when used in pts with RRMM and NDMM. Combination regimens for elo produces an ORR ranging from 79-83% with elo + lena+ dexa, proving that the best results were produced by three drug regimens. Large prospective studies are required to evaluate efficacy and safety of elotuzumab in combination therapies. Disclosures No relevant conflicts of interest to declare.

Abstract INTRODUCTION: Most clinical trials exclude patients with poor performance, organ dysfunction, and presence of other active malignancies or comorbidities. Although some of these criteria are based on clinical reasoning, patients with such clinical features have dismal expected outcomes and limited therapeutic options and could therefore have a more favorable risk/benefit ratio if treated with a low intensity investigational intervention. The current study was designed to test whether it is feasible to treat patients not eligible for conventional studies in a clinical trial. METHODS: We conducted an initial Bayesian designed single-arm study and a subsequent randomized study for patients with AML or higher-risk MDS (intermediate-2 or high risk by IPSS) with either ECOG performance status (PS) ≥3, creatinine or bilirubin ≥2mg/dL, presence of other malignancy or other comorbidities. Primary endpoint was survival at day 60. The study included stopping rules for survival, response and toxicity. All patients received azacitidine 75mg/m2 sc daily for 5 days. Patients in the single-arm study and in the combination arm of the randomized study also received vorinostat 200mg tid for 5 days. Cycles could be repeated every 3-8 weeks. Responses were evaluated following the revised 2006 IWG criteria for patients with MDS and the IWG 2003 recommendations for patients with AML. Comorbidities were evaluated using the Adult Comorbidity Evaluation-27 (ACE-27) index. Adverse events (AEs) were assessed and graded according to the CTCAE v4 criteria. Overall survival (OS) was censored at the time of transplant. Event-free survival (EFS) was defined as the time interval between treatment start and date of resistance, progression or death. RESULTS: A total of 30 patients (16 with MDS, 14 with AML) were enrolled in the initial single-arm study. Patient characteristics and inclusion criteria are detailed in Table 1. Median age was 73 years (44-83). Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. Median number of cycles administered was 3.5 (1-12). The overall response rate (ORR) was 40% with 8 (27%) patients achieving CR, 4 with AML and 4 with MDS. Median OS was 7.8 months (0.3-29, CI 7.54-8.03) (Figure 1A) and median EFS was 5.1 months (0.3-15.9, CI 4.87-5.37) (Figure 1B). Stopping rules for survival and response were not met. Main adverse events (AEs) where grade 1-2 gastrointestinal toxicities. Mortality at 4 and 8 weeks was 10 and 20% respectively. A total of 79 patients were enrolled in the subsequent randomized study: 27 to azacitidine (A) and 52 to azacitidine and vorinostat (A+V). Patient characteristics and inclusion criteria are also shown in Table 1. Median age was 70 years (30-90). Forty-seven (59%) patients had MDS and 32 (41%) had AML. Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rates were 67% (A) and 85% (A+V), respectively (p=0.07). No differences in ORR (48% vs 46%, p=0.87), OS (6.1 vs 7.6 months, p=0.49) (Figure 1C) or EFS (3 vs 5.5 months, p=0.05) (Figure 1D) were observed between groups. Main AEs included grade 1-2 gastrointestinal toxicities with a higher proportion of AEs with A+V (81 vs 56%). Mortality at 4 and 8 weeks was 10% (A: 4, A+V: 4) and 19% (A: 9, A+V: 6) respectively. By univariate analysis neither PS ≥3, creatinine or bilirubin ≥2mg/dL nor presence of other malignancy were predictive for 60-day survival, OS or EFS. There were no significant differences in survival between patients with ACE-27 scores of 0-1 compared to 2-3 both in the single-arm (6.3 vs 7 months, HR=0.88, 95% CI 0.41-1.91, p=0.75) and the randomized phase of the study (A: 13.5m vs 6.1m, HR 0.93, 95% CI 0.27-3.17, p=0.9 and A+V: 12.1m vs 7.4m, HR 1.38, 95% CI 0.61-3.14, p=0.4). CONCLUSION: Most enrolled patients met the study's primary endpoint of survival at 60 days without major toxicity. Patients obtained clinical benefit with acceptable responses and survival despite their high comorbidity burden. Our results support the feasibility of treating patients with MDS or AML not eligible to other clinical trials due to poor performance status, comorbidities or organ dysfunction, with low intensity therapies within a clinical trial. These findings suggest relaxation of such criteria may likely increase the pool of clinical trial patient candidates and allow access to potential beneficial therapies for patients with otherwise dismal prognosis. Table 1 Table 1. Figure 1 Figure 1. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. DiNardo:Abbvie: Research Funding; Novartis: Research Funding; Agios: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Wierda:Genentech: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Abbvie: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Jain:Novimmune: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; BMS: Research Funding; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria.

Abstract Introduction: Clinical characteristics of post-essential thrombocythemia/polycythemia vera myelofibrosis "post ET/PV-MF" are not well defined as for primary myelofibrosis "MF". Objective: We aimed to identify morphological, clinical and prognostic characteristics of patients with post ET/PV-MF seen at our center. Methods: Retrospective chart review of 1120 patients with MF - 766 primary MF, 354 post ET/PV-MF, who were referred to our institution between years 1984-2013 was performed; 92% presented after the year of 2000. Fisher's exact and Mann-Whitney test were used for categorical and continuous variables; Cox proportional hazard model and Kaplan-Meier curves with log rank test for correlation between the variables and survival. Survival analysis were calculated after censoring patients for stem cell transplantation "SCT" (n=92). Results: Overall median follow up was 36 months (0-411), 51% (n=573) patients had died. Progression to AML after median time of 32 months was not different between groups and occurred in 9.5% (n=106) patients over observation period of 5180 persons-years. Incidence rate was 3.4 cases per 100 persons-year. Causes of death were known in 55% of patients, and included progression of MF in 38% (n=122), infection in 27% (n=86), and other reasons with less than 10% occurrence (complications post SCT; secondary malignancy; other medical conditions). Demographics and disease characteristics are depicted in a table. 92% of patients were evaluable for karyotype; abnormalities were detected in 39% (n=404), of which 53% were unfavorable with monosomal (23%), complex (43%) and trisomy 8 (18%) being the most common. Molecularly high risk mutations "MHR" in genes ASXL1, EZH2, and IDH1/2 were positive in 35% of tested patients (n=161) regardless of presence of driver mutation. IPSS and DIPSS plus scores were similar between MF and post ET/PV-MF (with IPSS low in 8.7%, intermediate 1 in 19%, intermediate 2 in 28%, and high in 44%). By multivariate analysis, higher risk categories of IPSS and DIPSSplus predicted shorter overall survival "OS" for both cohorts (by DIPSSplus - high risk: HR 2.7, 95% CI 2.1-3.5; int-2: HR 1.6; 95% CI 1.3-2.0). Median OS stratified by IPSS was 160 (HR 1.8, 95%CI 1.0-3.0), 116 (HR 1.5, 95%CI 1.0 -1.5), 78 (HR 1.4, 95%CI 1.2-1.7) and 54 months, p=0.001. Univariate analysis identified age over 65, anemia, trombocytopenia, leukopenia, increased blasts, splenomegaly, constitutional symptoms, unfavorable karyotype, JAK2 mutation and triple negativity as predictors for inferior survival. Age over 65; hemoglobin below 10, platelets below 100 and peripheral blasts ≥1% showed significance for predicting OS by multivariate analysis. When stratified according to diagnosis, higher age, anemia, thrombocytopenia, high blasts, JAK2 positivity and triple negativity retained prognostic significance for MF whereas anemia, thrombocytopenia, and JAK2 mutation for post ET/PV-MF. Median OS was 73 months (range, 0.1-210) without difference between MF and post ET/PV-MF. Conclusion: Post ET/PV-MF does not appear to have substantial different clinical characteristics than primary MF. Table. Characteristics Total, number or median (% or range) MF, number or median (% or range) PET/PV-MF, number or median (% or range) Age 65 (20-89) 64 (20-88) 64 (27-89) Age > 65 552 (49) 367 (48) 185 (53) Males 675 (60%) 494 (65) 181 (51)* WBC 9.6 (0.4-361) 17.3 (5-19) 16.7 (5-18) WBC > 24 203 (18) 133 (18) 70 (20) WBC < 4 160 (14) 130 (17) 30 (8.5)* Plt 204 (3-2690) 237 (1-1364) 354 (6-2690)* Plt < 100 276 (25) 220 (29) 56 (16)* Hgb 10.5 (5-18) 10 (5-18) 11 (5-19)* Hgb < 10 462 (42) 329 (43) 133 (38)* Transfusion dependency 265 (24) 203 (27) 62 (18)* Blasts ≥ 1% 523 (47) 371 (49) 152 (43) Splenomegaly 668 (60) 459 (63) 209 (65) Symptoms 793 (71) 537 (70) 256 (73) LDH 1246 (189-10343) 1248 (189-10353) 1261 (205-8476) LDH > 620 958 (86) 640 (85) 318 (90)* JAK2 positive 586 (57) 371 (63) 215 (37)* MPL positive 19 (1.9) 16 (84) 3 (16)* CARL positive 53 (5) 27 (51) 26 (49)* Triple negative 26 (2.5) 21 (81) 5 (19)* *statistically significant differences (p<0.05) Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding.

Compulsory notification provides a valuable means to monitor population health and indicate priorities for health policies and allocation of financial resources. Thus, it is also evident the need to stimulate adequate training, either at graduation or during professional practice. This study aimed to present the process of constructing an open educational resource on Compulsory Notification, created as a result of the lack of knowledge of the vast majority of students and health professionals and deficiency in teaching by higher education institutions on the subject. Materials and methods: this is an exploratory and descriptive study, which approach was qualitative, carried out in November 2018, from a discipline attended in a stricto sensu post - graduation course. Results: the construction of the resource occurred through six distinct steps presented throughout this article and which final product was the e-book about Compulsory Notification. Conclusion: The process of building the open educational resource presented in this article, along with the other information about Compulsory Notification, supports the learning of health professionals and students, who often need to overcome difficulties in their own knowledge and contribute to promotion and prevention strategies of the health of the Brazilian population.ResumoA Notificação Compulsória oferece um meio valioso para monitorar a saúde populacional e indicar prioridades para as políticas de saúde e alocação de recursos financeiros. Deste modo, evidencia-se também a necessidade de estimulação de uma formação adequada seja ainda na graduação ou durante o exercício profissional. Este estudo objetivou apresentar o processo de construção de um Recurso Educacional Aberto sobre Notificação Compulsória, criado em decorrência da falta de conhecimento da maioria dos estudantes e profissionais da saúde e da deficiência no ensino pelas Instituições de Ensino Superior sobre o tema. Materiais e métodos: Trata-se de um estudo exploratório, descritivo, cuja abordagem foi qualitativa, realizado no mês de novembro de 2018, a partir de uma disciplina cursada em uma pós-graduação stricto sensu. Resultados: A construção do recurso ocorreu através de seis etapas distintas apresentadas ao longo deste artigo e cujo produto final foi o e-book acerca da Notificação Compulsória. Conclusão: O processo de construção do recurso educacional aberto apresentado neste artigo, juntamente com as demais informações sobre Notificação Compulsória oferecem suporte para aprendizagem de profissionais e estudantes da saúde, que muitas vezes precisam superar as dificuldades no próprio conhecimento e contribuir com as estratégias de promoção e prevenção da saúde da população brasileira.Palavras-chave: Ensino, Saúde, Recurso educacional aberto, Notificação compulsóriaKeywords: Teaching, Health, Open educational resource, Compulsory notificationReferencesAMANCIO FILHO, Antenor. Dilemas e desafios da formação profissional em saúde. Interface (Botucatu), Botucatu, v. 8, n. 15, p. 375-380, Ago. 2004. Disponível em <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1414-32832004000200019&lng=en&nrm=iso>. Acesso em: 3 jul. 2019.BELMIRO, Celia Abicalil. A imagem e suas formas de visualidade nos livros didáticos de Português. Educ. Soc., Campinas, v. 21, n. 72, p. 11-31, Ago. 2000. Disponível em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0101-73302000000300002&lng=en&nrm=iso>. Acesso em: 19 nov. 2018.BRASIL. Lei nº 6.259, de 30 de outubro de 1975. Dispõe sobre a organização das ações de Vigilância Epidemiológica, sobre o Programa Nacional de Imunizações, estabelece normas relativas à notificação compulsória de doenças, e dá outras providências. Diário Oficial da União, Brasília, DF, 07 nov. 1975. p. 14.785. Disponível em: <http://www2.camara.leg.br/legin/fed/lei/1970-1979/lei-6259-30-outubro-1975-357094-norma-pl.html>. Acesso em: 4 jul. 2018.BRASIL. Lei nº 6.437, de 20 de agosto de 1977. Configura infrações à legislação sanitária federal, estabelece as sanções respectivas, e dá outras providências. Diário Oficial da União, Brasília, DF, 24 ago. 1977. p. 11.145. Disponível em: <http:// www2.camara.leg.br/legin/fed/lei/1970-1979/lei-6437-20-agosto-1977-357206-norma-pl.html>. Acesso em: 4 jul. 2018.BRASIL. Ministério da Saúde. Gabinete do Ministro. Portaria nº 204, de 17 de fevereiro de 2016. Define a Lista Nacional de Notificação Compulsória de doenças, agravos e eventos de saúde pública nos serviços de saúde públicos e privados em todo o território nacional, nos termos do anexo, e dá outras providências. Diário Oficial da União, Brasília, DF, 18 fev. 2016. Disponível em: <http://bvsms.saude.gov.br/bvs/saudelegis/gm/2016/prt0204_17_02_2016.html>. Acesso em: 14 nov. 2018.BRASIL. Secretaria de Gestão do Trabalho e da Educação na Saúde. Departamento de Gestão e da Regulação do Trabalho em Saúde. Câmara de Regulação do Trabalho em Saúde / Ministério da Saúde, Secretaria de Gestão do Trabalho e da Educação na Saúde. Departamento de Gestão e da Regulação do Trabalho em Saúde. Resolução nº 287 de 8 de outubro de 1998. Brasília; 2006. Disponível em: <http://bvsms.saude.gov.br/bvs/publicacoes/cart_camara_regulacao.pdf>. Acesso em: 14 nov. 2018.CARVALHO, Carolina Novaes; DOURADO, Ines; BIERRENBACH, Ana Luiza. Subnotificação da comorbidade tuberculose e aids: uma aplicação do método de linkage. Rev. Saúde Pública, São Paulo, v. 45, n. 3, p. 548-555, Jun. 2011. Disponível em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0034-89102011000300013&lng=en&nrm=iso>. Acesso em: 4 jul. 2019.CATANI, Afrânio Mendes; OLIVEIRA, João Ferreira de; DOURADO, Luiz Fernandes. Política educacional, mudanças no mundo do trabalho e reforma curricular dos cursos de graduação no Brasil. Educ. Soc., Campinas, v. 22, n. 75, p. 67-83, Ago. 2001. Disponível em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0101-73302001000200006&lng=en&nrm=iso>. Acesso em: 19 nov. 2018.CAVALCANTE, Maria Tereza Leal; VASCONCELLOS, Miguel Murat. Tecnologia de informação para a educação na saúde: duas revisões e uma proposta. Ciênc. saúde coletiva, Rio de Janeiro, v. 12, n. 3, p. 611-622, Jun. 2007. Disponível em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1413-81232007000300011&lng=en&nrm=iso>. Acesso em: 17 jul. 2019.CRUZ, Marly Marques da; TOLEDO, Luciano Medeiros de; SANTOS, Elizabeth Moreira dos. O sistema de informação de AIDS do Município do Rio de Janeiro: suas limitações e potencialidades enquanto instrumento da vigilância epidemiológica. Cad. Saúde Pública, Rio de Janeiro, v.19, n. 1, p. 81-89, Fev. 2003. Disponível em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0102-311X2003000100009&lng=en&nrm=iso>. Acesso em: 26 jun. 2019.SCOSTEGUY, Claudia Caminha; PEREIRA, Alessandra Gonçalves Lisbôa; MEDRONHO, Roberto de Andrade. Três décadas de epidemiologia hospitalar e o desafio da integração da Vigilância em Saúde: reflexões a partir de um caso. Ciênc. saúde coletiva, Rio de Janeiro , v. 22, n. 10, p. 3365-3379, Oct. 2017 Disponível em <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1413-81232017021003365&lng=en&nrm=iso>. Acesso em: 17 jul. 2019.FERREIRA, Giselle Martins dos Santos; SA, Jaciara Carvalho de. recursos educacionais abertos como tecnologias educacionais: considerações críticas. Educ. Soc., Campinas, v. 39, n. 144, p. 738-755, Set. 2018. Disponível em <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0101-73302018000300738&lng=pt&nrm=iso>. Acesso em: 17 jul. 2019.GIRIANELLI, Vania Reis; FERREIRA, Aldo Pacheco; VIANNA, Marcos Besserman; TELES, Nair; ERTHAL, Regina Maria de Carvalho; OLIVEIRA, Maria Helena Barros de. Qualidade das notificações de violências interpessoal e autoprovocada no Estado do Rio de Janeiro, Brasil, 2009-2016. Cad. saúde colet., Rio de Janeiro, v. 26, n. 3, p. 318-326, Jul. 2018. Disponível em <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1414-462X2018000300318&lng=en&nrm=iso>. Acesso em: 2 jul. 2019.GONSALES, Priscila. Recursos educacionais abertos (REA) e novas práticas sociais. Revista Eletrônica de Comunicação, Informação e Inovação em Saúde, [S.l.], v. 10, n. 1, Mar. 2016. ISSN 1981-6278. Disponível em: <https://www.reciis.icict.fiocruz.br/index.php/reciis/article/view/1078>. Acesso em: 17 jul. 2019.HEREDIA, Jimena de Mello; RODRIGUES, Rosângela Schwarz; VIEIRA, Eleonora Milano Falcão. Produção científica sobre Recursos Educacionais Abertos. Transinformação, Campinas, v. 29, n. 1, p. 101-113, Abr. 2017. Disponível em <http://www.scielo.br/scielo.php?pid=S0103-37862017000100101&script=sci_abstract&tlng=pt>. Acesso em: 15 jul. 2019.JURDI, Andrea Perosa Saigh et al. Revisitar processos: revisão da matriz curricular do curso de Terapia Ocupacional da Universidade Federal de São Paulo. Interface (Botucatu), Botucatu, v. 22, n. 65, p. 527-538, Abr. 2018. Disponível em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1414-32832018000200527&lng=en&nrm=iso>. Acesso em: 19 nov. 2018.LIMA, Romênia Kelly Soares de; EVANGELISTA, Aline Luiza de Paulo; MAIA, Jéssica Karen de Oliveira; TRAVASSOS, Priscila Nunes da Silva; PINTO, Francisco José Maia; MOREIRA, Francisco José Maia. Notificação compulsória de acidentes de trabalho: dificuldades e sugestões dos profissionais de saúde em Fortaleza, Ceará. Rev Bras Med Trab. v. 16, n. 2, p. 192-198, 2018. Disponível em: <http://www.rbmt.org.br/details/315/pt-BR>. Acesso em: 1 jul. 2019.MACEDO, Kelly Dandara da Silva; ACOSTA, Beatriz Suffer; SILVA, Ethel Bastos da; SOUZA, Neila Santini de; BECK, Carmem Lúcia Colomé; SILVA, Karla Kristiane Dames da. Active learning methodologies: possible paths to innovation in health teaching. Esc. Anna Nery. v. 22, n. 3, e20170435, 2018. Disponível em: <http://www.revenf.bvs.br/scielo.php?script=sci_arttext&pid=S1414-81452018000300704>. Acesso em: 17 jul. 2019.MIRANDA, Fernanda Moura D’Almeida; PURIM, Kátia Sheylla Malta; SARQUIS, Leila Maria Mansano; SHWETZ, Ana Claudia Athanasio; DELATORRE, Letícia Schlichting; SAALFELD, Rosangela Maria. Dermatoses ocupacionais registradas em sistema de notificação na região Sul do Brasil (2007 a 2016). Rev Bras Med Trab. V. 16, N. 4, p. 442-450. 2018. Disponível em: < http://www.rbmt.org.br/details/384/en-US>. Acesso em: 20 jun. 2019.OLIVEIRA, Magda Lúcia Felix de; SILVA, Adaelson Alves; BALLANI, Tanimária Silva Lira; BELLASALMA, Ana Carolina Manna. Sistema de notificação de intoxicações desafios e dilemas. Rio de Janeiro: FIOCRUZ, 2003. Disponível em: http://books.scielo.org/id/sg3mt/pdf/peres-9788575413173-15.pdf. Acesso em: 16 jul. 2019.PEREIRA, Teresa Avalos et al. Uso das Tecnologias de Informação e Comunicação por Professores da Área da Saúde da Universidade Federal de São Paulo. Rev. bras. educ. med., Rio de Janeiro, v. 40, n. 1, p. 59-66, Mar. 2016. Disponível em:<http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-55022016000100059&lng=en&nrm=iso>. Acesso em: 19 nov. 2018.Prüss-Üstün, Annette et al. Safer water, better health: costs, benefits and sustainability of interventions to protect and promote health. Geneva: World Health Organization, 2008. Disponível em: <http://apps.who.int/iris/bitstream/handle/10665/43840/9789241596435_eng.pdf;jsessionid=488714A30C7AC39333E5080F15DCF420?sequence=1>. Acesso em: 14 nov. 2018.REBERTE, Luciana Magnoni; HOGA, Luiza Akiko Komura; GOMES, Ana Luisa Zaniboni. O processo de construção de material educativo para a promoção da saúde da gestante. Rev. Latino-Am. Enfermagem, Ribeirão Preto, v. 20, n. 1, p. 101-108, Fev. 2012. Disponível em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0104-11692012000100014&lng=en&nrm=iso>. Acesso em: 14 nov. 2018.SCHMIDT, Rosana Andreatta Carvalho. A questão ambiental na promoção da saúde: uma oportunidade de ação multiprofissional sobre doenças emergentes. Physis, Rio de Janeiro, v. 17, n. 2, p. 373-392, 2007. Disponível em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-73312007000200010&lng=en&nrm=iso>. Acesso em: 14 nov. 2018.SILVA, Geraedson Aristides da. Enfoque sobre a leptospirose na região nordeste do Brasil entre os anos de 2000 a 2013. Acta Biomedica Brasiliensia. v. 6, n. 1, p. 101-108, Jul. 2015. Disponível em: <http://www.actabiomedica.com.br/index.php/acta/article/view/105/78>. Acesso em: 14 nov. 2018.SILVA, Geraedson Aristides da; OLIVEIRA, Cilmery Marly Gabriel de. O registro das doenças de notificação compulsória: a participação dos profissionais da saúde e da comunidade. Rev Epidemiol Control Infect. v.4, n. 3, p. 215-220, Jul-Set. 2014. Disponível em: <https://online.unisc.br/seer/index.php/epidemiologia/article/view/4578>. Acesso em: 14 nov. 2018.SIQUEIRA FILHA, Noêmia Teixeira de; VANDERLEI, Lygia Carmen de Moraes; MENDES, Marina Ferreira de Medeiros. Avaliação do Subsistema Nacional de Vigilância Epidemiológica em Âmbito Hospitalar no Estado de Pernambuco, Brasil. Epidemiol. Serv. Saúde, Brasília, v. 20, n. 3, p. 307-316, Set. 2011. Disponível em <http://scielo.iec.gov.br/scielo.php?script=sci_arttext&pid=S1679-49742011000300005&lng=pt&nrm=iso>. Acesso em: 1jul. 2019.ZANIN, Alice Aquino. Recursos educacionais abertos e direitos autorais: análise de sítios educacionais brasileiros. Rev. Bras. Educ., Rio de Janeiro, v. 22, n. 71, e227174, 2017. Disponível em <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1413-24782017000400230&lng=en&nrm=iso>. Acesso em: 26 jul. 2019.e3743016

Abstract Abstract 2970 Evaluating real life outcomes in Multiple Myeloma (MM) pts in order to understand treatment outcome in clinical practice is very important. The introduction of novel agents (Bortezomib, Thalidomide, Lenalidomide) has been shown to increase overall survival (OS). Can MM be regarded as a chronic disease, defined as a similar OS as a matched normal population at diagnosis, after the introduction of novel agents? All pts diagnosed with MM since earliest Jan 2000 until latest Jun 2011 from 6 university clinics, 3 regional centers and 4 local hospitals in Sweden were included. Near complete response (nCR) was defined as an immeasurable M-protein in the blood and urine by standard electrophoresis. Partial response (PR) was defined as a 50% reduction in M-protein, no response (NR) as less than 50% reduction and progress was considered when the increase was ≥ 25%. The Swedish population (n = 9 340 682 in 2009) was used to select a gender and 5-yrs age strata matched cohort based on 2008–2010 observed death rates. In the total MM population n=1 843, 201 (11%) pts were excluded due to non treatment demanding disease setting the study population to n=1 642. The median follow up of pts still alive was 30 months. The median age was 70 yrs and 45% women. The most common subtype was IgG (59%) followed by IgA (22%), BJ (15%) and Other (4%). High dose treatment (HDT) was given to 517 (32%) pts. The median number of given treatment lines in both the HDT and the non-HDT population was two but the number of pts receiving more treatment lines were declining rapidly. The response distribution for the HDT population nCR/PR/NR was 47/41/12% in 1st line (induction and high-dose melphalan) and 25/42/33% in 2nd line. In the non-HDT population the response distribution was 14/42/44% in 1st line and 11/31/58% in 2nd line. Non-HDT pts receiving novel agents in 1st line had significantly higher nCR rates compared to pts receiving older drugs, 22% vs. 12% as well as pts receiving novel agents in 2nd line with nCR rates of 16% vs. 6%. In the HDT population the median time to progression/time to next treatment (TTP/TTNT) was 21.0/29.7 months in 1st line and 8.1/12.7 in 2nd line. In the non-HDT population the median TTP/TTNT was 11.0/16.8 months in 1st line and 7.3/11.4 in 2nd line. There was a significantly increased TTP/TTNT in 1st and 2nd line depending on the increased depth of the response for both the HDT and non-HDT populations. The median OS for HDT pts was 6.7 yrs 95% CI[6.1;7.6] and correlated with 1st line response (nCR 7.6, PR 6.1 and NR 6.2 yrs). When comparing HDT pts to the matched normal population the 1-year survival was 97% vs. 99%, 3-year survival 86% vs. 98% and 5-year survival 66% vs. 95%. The median OS for non-HDT pts (n=1080) was 2.7 yrs 95% CI[2.5;3.0] and increased with better response in 1st line; nCR 3.4, PR 3.0 and NR 1.9 yrs. Kaplan-Mayer analysis showed that the use of novel agents in 1st line (n=316, median age 72.1 yrs) predicted a significantly longer OS compared to conventional treatment (n=764, median age 75.4), median 4.9 vs 2.3 yrs. When comparing pts that received at least two lines of treatment, pts treated with novel agents in 1st line followed by novel agents in 2nd had not reached the median survival but had a lower CI of 6.3 yrs, novel agents in 1st line followed by old agents in 2nd line had a median OS of 4.3 yrs old agents in 1st line followed by novel agents in 2nd line had a median of OS 3.3 yrs and old agents in 1st line followed by old agents in 2nd line had a median of OS 3.0 yrs. Compared to the matched normal population non-HDT pts receiving novel agents in both 1st and 2nd line the 1-year survival was 90 % vs. 96%, 3-year survival 71% vs. 86% and 5-year survival 67% vs. 77%. The number of pts receiving 2nd and 3rd line treatment declined rapidly. Non-HDT pts treated with novel agents in 1st line had a superior response and OS compared to the group treated with standard chemotherapy. Pts treated with novel agents in 2nd line as well seem to have a further improved survival compared to other alternatives. In comparison to a normal population, matched for gender and age at diagnosis, the survival is still shorter. However, if novel agents were used in an optimal treatment sequence the survival could potentially be higher. There is still a need for further development in MM treatment before one can call it a chronic disease. Figure 1: HDT treated pts compared to a matched normal population Figure 1:. HDT treated pts compared to a matched normal population Figure 2: Non-HDT pts receiving old or novel agents in 1st line compared to a matched normal population. Figure 2:. Non-HDT pts receiving old or novel agents in 1st line compared to a matched normal population. Disclosures: Liwing: Janssen-Cilag: Employment, Equity Ownership. Mellqvist:Janssen, Celgene: Honoraria. Näsman:Janssen-Cilag: Consultancy. Aschan:Janssen-Cilag: Employment, Equity Ownership.

Abstract Abstract 1876 Carfilzomib (CFZ), a next-generation proteasome inhibitor that selectively and irreversibly binds to its target, resulting in sustained inhibition absent of off-target effects relative to bortezomib, is being evaluated in MM patients. The selectivity of CFZ for the proteasome may explain the low rates of peripheral neuropathy (PN) relative to historical data for bortezomib (BTZ). Safety data have been compiled for >700 patients who received CFZ in 9 Phase (Ph) 1 or 2 trials, 4 of which are completed. The majority of patients had relapsed and refractory (R/R) MM, and many had comorbidities including baseline PN and renal insufficiency. This abstract updates and summarizes mature safety data for single-agent CFZ in 526 patients with R/R MM who took part in 1 of 3 Ph 2 studies and is a follow-up with more mature data compared with those presented at ASH 2010. Patients enrolled and treated with CFZ in the following trials are included in this analysis: PX-171-003 (conducted in 2 parts, a pilot study, PX-171-003-A0 [R/R MM], followed by PX-171-003-A1 [R/R MM]), PX-171-004 (relapsed MM), and PX-171-005 (R/R MM with varying degrees of renal function). In all studies, CFZ was dosed on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C). Doses were 20 mg/m2 in C1, escalating to 27 mg/m2 in C2 for all studies with the exception of 005 (15 mg/m2 in C1, 20 mg/m2 in C2, and 27 mg/m2 in C3). Overall, CFZ had a favorable safety profile in these studies. The most frequently reported adverse events (AEs) occurring in ≥30% of patients included fatigue (55%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%). The most common (≥10% of patients overall) ≥G3 AEs were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), pneumonia (11%), and neutropenia (10%). The assessment of PN was based on a pooled aggregate of PN preferred terms, including neuropathy peripheral, neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. PN was reported infrequently (14% overall) across all studies. Although 378 (72%) patients had baseline PN (≤G 2), only 13% reported treatment-emergent symptoms during the study. PN was generally mild to moderate in severity (1.3% G3 PN with no G4 PN), and only 5 patients (1%) required dose modification or discontinuation due to PN. Renal AEs (mainly ≤G2) were reported in 174 (33%) patients, and CFZ was discontinued because of a renal AE in only 21 patients (4%). A summary of CFZ exposure and discontinuation rates is reported in the table. There were a total of 37 (7%) deaths on study, including within 30 days of the last dose of study drug. The primary cause of death was due to disease progression in 22/37 patients (4.2%); however, AEs, including in order of frequency, cardiac events, hepatic failure, and infection, contributed to 14 of these deaths.No. of Patients (%) in Ph 2 MM Studies Who Received Carfilzomib003-A0 (N = 46)003-A1 (N = 266)004 (N = 164)005 (N = 50)All Patients (N = 526)Cycles, mean, n (SD)4.4 (3.4)5.3 (4.1)7.0 (4.4)5.5 (3.7)5.7 (4.2)Completed ≥12 cycles4 (8.7)40 (15.0)47 (28.7)3 (6.0)94 (17.9)Reason for not completing 12 cycles Progressive Disease23 (50.0)157 (59.0)64 (39.0)24 (48.0)268 (51.0) Adverse Event13 (28.3)33 (12.4)26 (15.9)6 (12.0)78 (14.8) Withdrew Consent2 (4.3)22 (8.3)9 (5.5)4 (8.0)37 (7.0) Other4 (8.7)14 (5.3)10 (6.1)028 (5.3) Of the 526 patients included in these analyses, >50% were treated on the 003-A1 dose and schedule (20/27 mg/m2), and fewer than 10% required dose reduction. 18% of patients completed ≥12 cycles (∼1 y) and were eligible to participate in an ongoing, multicenter, open-label Ph 2 study (PX-171-010) to monitor long-term single-agent CFZ safety. To date, patients in this extension trial have not shown evidence of cumulative toxicity. In summary, these data confirm and extend results that were previously presented, namely that single-agent CFZ has an acceptable safety profile in heavily pretreated patients with R/R MM, including those with pre-existing renal dysfunction and PN. Disclosures: Singhal: Onyx Pharmaceuticals: Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Celgene: Speakers Bureau. Siegel:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Martin:Celgene: Honoraria; Onyx Pharmaceuticals: Consultancy. Vij:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau. Wang:Onyx Pharmaceuticals: Research Funding. Jakubowiak:Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx Pharmaceuticals: Consultancy; Merck: Consultancy. Kukreti:Celgene: Honoraria. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. McCulloch:Onyx Pharmaceuticals: Employment. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding; Seattle Genetics Inc: Research Funding, Speakers Bureau. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kotlovker:Onyx Pharmaceuticals: Employment. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; OrthoBiotec. Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees.

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. 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In the last few decades, the studies in second language acquisition have not answered the question what mechanisms a human’s brain uses to make acquisition of language(s) possible. A neurocognitive model which tries to address SLA from such a perspective was suggested by Ullman (2005; 2015), according to which, “both first and second languages are acquired and processed by well-studied brain systems that are known to subserve particular nonlanguage functions” (Ullman, 2005: 141). The brain systems in question have analogous roles in their language and nonlanguage functions. This article is meant to critically analyse the suggested DP model within the context of neurocognitive studies of L2; and evaluate its contribution to the field of SLA studies. References Aboitiz, F. (1995). Working memory networks and the origin of language areas in the human brain. Medical Hypothesis, 25, 504-506. Aboitiz, F. & Garcia, R. (1977). The anatomy of language revisited. 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The pandemic of COVID-19 has afflicted every individual and has initiated a cascade of directly or indirectly involved events in precipitating mental health issues. The human species is a wanderer and hunter-gatherer by nature, and physical social distancing and nationwide lockdown have confined an individual to physical isolation. The present review article was conceived to address psychosocial and other issues and their aetiology related to the current pandemic of COVID-19. The elderly age group has most suffered the wrath of SARS-CoV-2, and social isolation as a preventive measure may further induce mental health issues. Animal model studies have demonstrated an inappropriate interacting endogenous neurotransmitter milieu of dopamine, serotonin, glutamate, and opioids, induced by social isolation that could probably lead to observable phenomena of deviant psychosocial behavior. Conflicting and manipulated information related to COVID-19 on social media has also been recognized as a global threat. Psychological stress during the current pandemic in frontline health care workers, migrant workers, children, and adolescents is also a serious concern. Mental health issues in the current situation could also be induced by being quarantined, uncertainty in business, jobs, economy, hampered academic activities, increased screen time on social media, and domestic violence incidences. The gravity of mental health issues associated with the pandemic of COVID-19 should be identified at the earliest. Mental health organization dedicated to current and future pandemics should be established along with Government policies addressing psychological issues to prevent and treat mental health issues need to be developed. References World Health Organization (WHO) Coronavirus Disease (COVID-19) Dashboard. 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Tulip (Tulipa gesneriana L.) is an important and highly valuable flower of the cut flower industry. The most critical step in its cultivation is to break dormancy in order to initiate the growth, especially in tropical and sub-tropical areas of the world. Therefore, the current research was conducted to break bulb dormancy and foster the growth of tulip in Potohar region with the help of different primers. The objective of this study was the selection of best primer at appropriate concentration level to enhance growth, yield and vase life of the flower. Tulip bulbs were treated with different primers: T0 (distilled water), T1 (chitosan @ 5 g/L), T2 (gibberellic acid @ 0.15 g/L), T3 (humic acid 160 g/L), T4 (imidacloprid 19 g/L) and T5 (salicylic acid 0.1 g/L) for 24 hours, respectively. The experiment was laid out using Complete Randomized Design (CRD) with three replications. Statistical results revealed that characteristics including early germination, plant height, number of leaves, stalk length, fresh and dry weight of flower, weight of bulbs, diameter of bulbs and number of daughter bulbs were significantly increased in T2. Whereas, leaf area, diameter of stem and flower was maximum in T0. Plants under T3 showed an increase in chlorophyll content of leaves. While floral characteristics like early formation and opening of flower bud, more number of flowers and vase life were improved in T1. Thus, statistical results showed that priming can effectively help to improve morpho-physiological attributes of tulip.Key wordTulip, primers, dormancy, chitosan, gibberellic acid, humic acid, imidacloprid, salicylic acid.INTRODUCTIONTulip (Tulips gesneriana L.) is the most popular and lucrative spring blooming bulbous plant of Liliacae family. It is famous for its distinctive flower shape; size and vibrant color range that make it stand out aesthetically among other ornamental flowers. There are about 150 to 160 species of tulip that can be grown in gardens. In addition to this, they are also used as cut flowers. In cut flower industry, it is ranked as 3rd most desirable flower after rose and chrysanthemum (Singh, 2006; Ahmad et al., 2014). This flower holds a significant importance on societal events like Valentine’s Day, Easter, New Year and Mother’s Day. Along with ornamental uses, its bulb can be used for cooking purposes in place of onions and petals can be used to treat rough skin. As a result of its immense beauty and multiple uses, it is day by day becoming more eminent and favorite among people globally (Buschman, 2004; Jhon and Neelofar, 2006). The demand for cut flowers in Pakistan is also gaining popularity. In Pakistan, where floriculture industry is still struggling to make its way towards development, the annual production of cut flowers is estimated to be 10,000 to 12,000 tons per annum (Younis et al., 2009). Main cut flower crops produced includes: rose, carnation, gerbera, statice, tuberose, narcissus, gladiolus, freesia and lilies (Ahsan et al., 2012). Despite of tulip’s high demand, it is not among the few cut flowers that are produced at commercial level in Pakistan. However, some of the wild species of tulip (Tulipa stellate) are found in the country, as they wildly grow in West and North West Himalayan region of the world. (Nasir et al., 1987). This perennial plant needs several weeks of low temperature (temperature < 50C) to break its dormancy for producing beautiful flowers, as a result, its cultivation is restricted to temperate areas (Koksal et al., 2011). It is widely grown in areas with 5-100C night and 17-200C day temperature throughout the growing season (Singh, 2006). Although, it has high demand worldwide but there are only 15 tulips producing countries in the world. Among few tulip producing countries, Netherlands tops the list due to her favorable climatic conditions. The total production area of tulips in Netherlands is 10,800 hectares that contributes 60% of the world’s total production. The reason behind its limited production in the world is the inability of tulip bulbs to break dormancy under unfavorable climatic conditions. Dormancy is a state in which flower bulbs do not show any physical growth due to physical and physiological barriers. Therefore, dormancy breaking is the utmost important step while growing tulips anywhere in the world (De Klerk et al., 1992). Thus, aforementioned restrictions and sensitivity of crop towards its growth requirements has also affected its production in Pakistan. Its cultivation is restricted to Murree, Abottabad and Swat only. Some other parts of the country, including the Potohar region have great potential to grow tulip by putting in a little effort to cope with the challenge of dormancy breaking due to relatively high temperature. The winter period in Potohar region is from November to March. Moreover, December, January and February are the coldest months with a mean annual temperature between 100C to 150C. As a result, the time of planting is very critical for dormancy breaking and fast growth in such areas, as late planting would cause an abortion of flowers due to a raised field temperature at the time of flowering. In order to grow tulips in areas with mild winters different techniques are adopted that includes: pre- chilling, seed priming and protected cultivation method to achieve early growth and high yield of flowers before the temperature rises. Out of all additional efforts, seed priming can be an effective method for growing tulips in open fields because it promotes early growth and good yield (Anjum et al., 2010; Benschop et al., 2010; Kumar et al., 2013; Ramzan et al., 2014; Sarfaraz et al., 2014; Khan, 2019). Seed priming is a method of soaking seeds in solution with high osmotic potential which provides optimum level of hydration and aggravates the germination process, but don’t show the radical emergence by prolonging the lag phase. Lag phase makes the seed metabolically active and helps to convert the stored food reserves into the available form to be used during germination (Taylor et al., 1998; Reid et al., 2011; Nawaz et al., 2013). Application of different chemicals as primmer including salts (chitosan), growth regulator (gibberellic acid), plant hormone (salicylic acid), organic compounds (humic acid) and insecticides (imidacloprid) can result in a reduced forcing period, enhanced growth, early flowering and high flower yield. Therefore, careful selection of variety and use of priming as dormancy breaking technique is the essential step of Tulip cultivation in the Potohar area (Horii et al., 2007; Shakarami et al., 2013; Nakasha et al., 2014; Baldotto et al., 2016).OBJECTIVES Keeping in view that tulip is an excellent cut flower and its demand is increasing globally, present study was designed to analyze and study the effects of best concentration of different primers on early growth (vegetative and reproductive), yield and vase life of tulip in the Potohar region of Northern Punjab, Pakistan. MATERIALS AND METHODSExperimental site and planting material: The experiment on Tulipa gesneriana L. was conducted at the experimental area, Department of Horticulture, PMAS-Arid Agriculture University, Rawalpindi with longitude 73.070 E and latitude 33.60 N, during the year 2017-2018. Tulipa gesneriana L. was established through bulbs. Tulip bulbs were purchased from reliable sources and were planted by the end of November in pots after priming treatment in open field conditions.Maintenance practice: Regular watering and fortnightly fertilizer application of NPK (Grow more (17:17:17) @ 10g/m2 was done to maintain plant health.Priming treatments: Tulip bulbs were treated with different primers including: T0 (distilled water), T1 (chitosan @ 5 g/L), T2 (gibberellic acid @ 0.15 g/L), T3 (humic acid 160 g/L), T4 (Imidacloprid 19 g/L) and T5 (salicylic acid 0.1 g/L) for 24 hours, respectively.Parameters: Both vegetative and reproductive parameters were analyzed to determine the efficacy of primers including days to sprouting of bulbs (days), plant height (cm), leaf area (cm2), number of leaves, diameter of flower stem (mm), days to flower bud formation (days), days to flower opening stage (days), diameter of flower (mm), number of flowers per plant, stalk length (cm), fresh weight of flower (g), dry weight of flower (g), diameter of bulbs (mm), weight of bulbs (g), number of daughter bulbs per plant and vase life (days).Statistical analysis: Experiment was laid out randomly using Complete Randomized Design (CRD).The collected data was analyzed through appropriate statistical package i.e. MSTAT-C. Statistical significance was compared with LSD test at 5% level of significance (Steel et al., 1997).RESULTS AND DISCUSSIONEffect of priming on vegetative growth attributes: Results were exhibiting significant difference among vegetative growth attributes of the treated plants (table 1). The 0.15 g/L of gibberellic acid treated plants showed early sprouting (25 days) and maximum increase in plant height (33cm), number of leaves (6), stalk length (29.05cm) and diameter of flower stem (9.66mm), followed by 5 g/L of chitosan, 160g/L of humic acid and 19 g/L of Imidacloprid, respectively. Minimum plant height (15.6cm), number of leaves (4), stalk length (12.33cm) diameter of flower stem (6.04mm) and delayed bulb sprouting (31 days) was observed in 0.1 g/L of salicylic acid. Improvement in vegetative characteristics shown by T2 plants revealed that gibberellic acid helped in dormancy breaking, cell division and elongation in actively growing plant parts (Kumar et al., 2013). As further result confirmed that the maximum leaf area (39.07cm2) was observed in control plants and treated plants didn’t show significant increase in leaf area, because of the use of energy in increasing plant height and number of leaves. Previous studies also showed that plants with more number of leaves had a less leaf area and color of the leaves was also lighter (Khangoli, 2001; Janowska and Jerzy, 2004). Moreover, the maximum amount of chlorophyll content (62) was observed in 160 g/L of humic acid followed by 5 g/L of chitosan, 0.15 g/L of gibberellic acid and 19 g/L of Imidacloprid, respectively. Whereas, minimum amount of chlorophyll content was observed in 0.1 g/L of salicylic acid (58). Tulip bulbs treated with Humic acid effectively increased photosynthetic activity of the plant which in result increased the chlorophyll content of the leaves and produced more plant food. Leaf area of the humic acid treated plants was also increased as compared to other treatments that also caused an increase in the chlorophyll content of the leaves (Chanprasert et al., 2012; Salachna and Zawadzińska, 2014). Furthermore, bulb characteristics were also improved under the influence of priming. Maximum diameter (41mm) and weight of bulbs (26g) was observed in 0.15g/L of Gibberellic acid followed by 0.1g/L of salicylic acid, 5 g/L of chitosan, 19 g/L of Imidacloprid and 160 g/L of humic acid respectively. Whereas, minimum diameter (36mm) and weight (21g) of bulbs was observed in control treatment which proved the efficacy of primers in enhancing characteristics of tulip bulbs. Bulb diameter and weight was increased because of the presence of good amount of food in the bulb which helped in its growth (Arteca, 2013). Furthermore the number of daughter bulbs were maximum in 0.15 g/L of gibberellic acid (4.22) and 5 g/L of Chitosan (4.22) followed by 0.1 g/L of salicylic acid and 160 g/L of Humic acid respectively. Minimum number of bulb-lets was observed in 19 g/l of Imidacloprid (3.11). Increased rate of cell division and multiplication, plus availability of good nutrition in bulbs helped to increase the number of daughter bulbs in the treated plants (Shakarami et al., 2013). Thus, results confirmed that 0.15 g/L of gibberellic acid effectively improved both plant (figure 1) and bulb (figure 2) characteristics. Effect of priming on reproductive growth attributes: Results showed significant differences in plants for reproductive growth attributes in response to priming (table 2). Minimum days of bud formation (122 days) and flower opening stage (124 days) were showed by 5 g/L of chitosan followed by 0.15 g/L of gibberellic acid, 160g/L of humic acid and 19 g/L of Imidacloprid, respectively. Whereas, 0.15 g/L of salicylic acid took maximum days in the formation (127 days) and opening (129 days) of flower buds. Chitosan helps plant in maintaining its vegetative and reproductive growth under stress conditions like drought and high temperature. As a result, the plant maintains its growth under stress conditions and give early flowers, because its reproductive growth attributes remain unaffected under any abiotic stress, as previously studied in orchid as well (Saniewska, 2001; Uthairatanakij et al., 2007). Moreover, the number of flowers per plant were maximum in 5 g/L of Chitosan (3.33) and 0.15 g/L of gibberellic acid (3.33), followed by 160 g/L of humic acid. Whereas, 19 g/L of Imidacloprid (2.33) and 0.1 g/L of Salicylic acid (1.44) gave minimum flower yield. Along with enhancing the defense mechanism, chitosan also helped in increasing flower number in Freesia and other flowers, previously (Salachna and Zawadzińska, 2014). Furthermore, maximum fresh weight (33g) and dry weight of flower (2g) were observed in 0.15 g/L, of gibberellic acid followed by 5 g/L of chitosan, 160 g/L of humic acid and 19 g/L of imidacloprid, respectively. Minimum fresh weight of flower (12 g) and dry weight of flower (0.98 g) was observed in 0.1 g/L of salicylic acid. Gibberellic acid effectively increases plant height and diameter of stem that caused an increase in fresh and dry weight of flower due to presence of more plant nutrients and maintenance of turgidity. Diameter of the flower was maximum (40mm) in control plants, this showed priming of tulip bulbs didn’t have any effect on increasing flower size due to increase in flower number (Rashad et al., 2009; Hashemabadi, 2010). Thus, the aforementioned results confirmed that 5 g/L chitosan was most effective in improving floral attributes (figure 3) of tulip.Effect of priming on vase life: According to results (table 3), 5 g/L of Chitosan and 0.1 g/L of salicylic acid showed maximum vase life (8 days) followed by 19 g/L of imidacloprid, 0.15 g/L of gibberellic acid and 160 g/L of humic acid, respectively. Flowers under control treatment showed minimum vase life (6) as compared to treated plants. Chitosan improved the quality of flower by maintaining its size, color and freshness, but most importantly, it provided protection against many pathogenic fungi that can attack tulip and cause senescence of the flower. As a result of fungal protection and resistance against abiotic stresses, Tulip flower showed increased post-harvest quality and vase life (Saniewska, 2001). In Lilium flower it helped to decrease the production of ethylene and respiration rate and helped in increasing its vase life (Kim et al., 2004).CONCLUSIONPresent research proved that treatment of tulip bulbs with different primers at their best selected concentration levels was an effective method of enhancing early growth and yield in an area with relatively high temperature as compared to temperate region. The Tulip plants showed improvement in sprouting, plant height, number of leaves, chlorophyll content of leaf, leaf area, early flowering, flower size, number of flowers, stalk length, stem diameter, bulbs weight and diameter, number of bulb-lets and vase life. Thus, this method can be used in future for the production of Tulips under tropical and sub-tropical areas.CONFLICT OF INTERESTAuthors have no conflict of interest.REFERENCESAhmad, A., H. Rashid, R. Sajjad, S. Mubeen, B. Ajmal and M. Khan, 2014. 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Background: Recent evidence suggests that LDL levels alone may be an incomplete assessment of cardiovascular risk, given the emerging importance of LDL density. Specifically, an excess of low-density LDL (Pattern B vs. A/B or A) has been shown in primary prevention cohorts to be particularly atherogenic. To date, however, the prevalence of Pattern B profiles among patients presenting with an MI has not been described. Methods: The TRIUMPH registry enrolled acute MI patients from 24 US centers between 4/05 and 12/08. We excluded patients with prior MI or missing LDL levels; leaving 1,975 patients for analysis. Patients were stratified by LDL patterns, using the VAP method, to compare their demographic and clinical characteristics. As a secondary analysis, we examined changes in LDL pattern from baseline in patients newly on statins at 6 months. Results: Pattern B LDL profiles were present in 644 (32.6%) of patients. These patients were younger and more likely to be male, obese, have larger waist circumferences, higher triglycerides, and lower HDL levels ( Table ). Blood pressure, fasting glucose, and Lp-a levels did not differ across groups. Among 311 MI patients started on a statin, their LDL patterns became more atherogenic in 99 (31.8%) and less atherogenic in 43 (13.8%), suggesting little improvement with statins. Of the 113 patients with Pattern B at baseline, 84 (74.3%) patients did not improve, while the remaining 29 (25.7%) changed to a more favorable pattern. Conclusion: Patients with LDL Pattern B were younger and had more risk factors for metabolic syndrome. Statins did not markedly improve particle size patterns over time, suggesting that other approaches may be needed to further modify risk. Patient characteristics and 6-month LDL patterns according to LDL Density Pattern at baseline Patient characteristics and 6 month LDL patterns Variable Pattern A (n=777) Pattern A/B (n=554) Pattern B (n=644) p-value Age (yrs.) 59.9 ± 12.8 58.2 ± 12.1 55.3 ± 10.7 <0.001 Male 473 (60.9%) 383 (69.1%) 482 (74.8%) <0.001 Caucasian 475 (61.3%) 378 (68.2%) 495 (77.1%) <0.001 MI type: <0.001 STEMI 303 (39.0%) 275 (49.6%) 326 (50.6%) NSTEMI 468 (60.2%) 273 (49.3%) 315 (48.9%) DM 224 (28.8%) 175 (31.6%) 180 (28.0%) 0.359 LDL-C (mg/dL) 94.4 ± 32.2 95.8 ± 31.7 100.0 ± 31.9 0.004 Triglycerides (mg/dL) 132.4 ± 65.2 133.8 ± 60.3 200.1 ± 149.0 <0.001 HDL (mg/dL) 42.6 ± 11.4 40.9 ± 10.3 36.6 ± 8.1 <0.001 BMI (kg/m 2 ) 28.5 ± 6.1 29.9 ± 6.7 30.8 ± 6.6 < 0.001 Waist circumference (in) 37.6 ± 5.6 38.9 ± 5.7 39.3 ± 5.3 < 0.001 hsCRP (mg/L) 4.2 ± 6.0 3.7 ± 4.6 3.2 ± 4.0 <0.001 Home statin use (%) 191(24.6%) 165(29.8%) 218(33.9%) <0.001 Initial systolic BP (mmHg) 141.9 ± 31.7 143.1 ± 27.3 144.9 ± 29.1 0.171

Abstract Xerostomia and salivary gland hypofunction are prevalent conditions in older people and may adversely influence the intake of certain foods, notably fruit and vegetables. Here, we aimed to investigate whether xerostomia and salivary gland hypofunction were associated with a lower intake of fruit and vegetables. The study included 621 community-dwelling adults, mean age 75⋅2 ± 6⋅4 years, 58⋅9 % female, who had participated in the Copenhagen City Heart Study follow-up, and undergone interviews regarding food intake (preceding month), oral and general health (xerostomia, taste alterations, diseases, medication, alcohol consumption and smoking), clinical oral examination and measurements of unstimulated and chewing-stimulated whole saliva flow rates. The average total energy intake (8⋅4 ± 2⋅7 MJ) and protein energy percentage (14⋅8 ± 3⋅1 %) were slightly below recommendations. The average fruit (234⋅7 ± 201⋅2 g/d) and vegetables (317⋅3 ± 157⋅4 g/d) intakes were within recommendations. Xerostomia and hyposalivation were more prevalent in women than in men (16⋅4 v. 7⋅1 %, P < 0⋅001 and 40⋅7 v. 27⋅5 %, P < 0⋅001). Multiple linear regression analyses revealed that older age (β −0⋅009, se 0⋅003, P = 0⋅005), smoking (β −0⋅212, se 0⋅060, P = 0⋅0005) and wearing complete dentures/being partially or fully edentulous (β −0⋅141, se 0⋅048, P = 0⋅003), but neither xerostomia nor salivary flow rates were associated with an inadequate fruit and vegetable intake, after adjustment for covariates. Older age, smoking, tooth loss and denture-wearing were stronger determinants of low fruit and vegetable intakes than xerostomia and salivary hypofunction supporting the importance of dietary counselling and maintenance of oral health and an adequate masticatory performance.

Objetivo. Determinar la concentración de glucosa no activadora de la movilidad espermática como componente de futuros diluyentes para la crioconservación de semen de Prochilodus magdalenae. Materiales y métodos. Se analizó semen inactivo de tres machos obtenido por inducción hormonal. Una submuestra de 0.25 μL de semen de cada macho fue depositada sobre una cámara de Makler y evaluada usando diferentes concentraciones de glucosa (0, 1, 2, 3, 4, 5, 6, 7, 8, 9 y 10%) mediante la adición de 75 μL de cada solución sobre el semen (n=3). De cada solución se determinó la osmolaridad, siendo de 0, 62, 124, 186, 250, 310, 360, 410, 472, 536 y 620 mOsm/kg, respectivamente, así como la del plasma seminal (~250–300 mOsm/kg). Mediante el software Sperm Class Analyzer (SCA) se determinó la velocidad curvilínea (VCL) y recta (VSL) (μm/seg), movilidad rápida (%), media (%) y lenta (%) y el porcentaje de espermatozoides inmóviles. El tiempo de activación de la movilidad (segundos) se obtuvo por cronometraje y visualización bajo microscopio de campo claro. Resultados. Concentraciones de 0 a 5% de glucosa produjeron activación de la movilidad espermática, no obstante, a partir de glucosa al 6% no fue detectada activación visual; sin embargo, SCA detectó movilidad total (7.2%), VCL (5.1 μm/seg) y VSL (1.7 μm/seg). A partir de glucosa al 7% el SCA detectó 100% de inmovilidad, no adquirida posteriormente con agua destilada. Conclusiones. La concentración de glucosa tiene efecto determinante en la viabilidad y activación de semen fresco. Una concentración de 6% de glucosa puede ser utilizada como solución no activadora de la movilidad espermática en futuros diluyentes para la crioconservación de semen de esta especie.