Journal articles on the topic 'Hm 1013'

Abstract. Identifying deep convection is of paramount importance, as it may be associated with extreme weather phenomena that have significant impact on the environment, property and populations. A new method, the hail detection tool (HDT), is described for identifying hail-bearing storms using multispectral Meteosat Second Generation (MSG) data. HDT was conceived as a two-phase method, in which the first step is the convective mask (CM) algorithm devised for detection of deep convection, and the second a hail mask algorithm (HM) for the identification of hail-bearing clouds among cumulonimbus systems detected by CM. Both CM and HM are based on logistic regression models trained with multispectral MSG data sets comprised of summer convective events in the middle Ebro Valley (Spain) between 2006 and 2010, and detected by the RGB (red-green-blue) visualization technique (CM) or C-band weather radar system of the University of León. By means of the logistic regression approach, the probability of identifying a cumulonimbus event with CM or a hail event with HM are computed by exploiting a proper selection of MSG wavelengths or their combination. A number of cloud physical properties (liquid water path, optical thickness and effective cloud drop radius) were used to physically interpret results of statistical models from a meteorological perspective, using a method based on these "ingredients". Finally, the HDT was applied to a new validation sample consisting of events during summer 2011. The overall probability of detection was 76.9 % and the false alarm ratio 16.7 %.

Abstract Background: The palliative care needs of children with cancer strongly depend on tumor entity and localization. However, little is known about the needs of children with hematologic malignancies (HM), as a much larger body of publications deals with the needs of children with solid tumors. Methods: Patient data were extracted from the database of one of the largest pediatric palliative care teams (PPCT) in Germany. Information included demographic data, diagnoses, patient contacts, symptoms, and medications. Children with HM were compared to other malignancies using bivariate analyses. Results: Between 01/2013 and 05/2016, the PPCT cared for a total of 178 patients. Of the 58 children with cancer (3 bone tumors, 25 brain tumors, 6 neuroblastomas, 9 soft tissue sarcomas, 9 other solid tumors), 6 (10.3%) had a hematologic malignancy (2 acute lymphoblastic leukemia, 2 acute myeloid leukemia, 1 T-cell lymphoma, 1 Burkitt lymphoma). Two patients underwent hematopoietic stem cell transplantation. Median age of patients with HM at the beginning of PCT was 12.1 years (range 5.4-18.9 years), 5 children were male. The number of children with HM cared for in the home setting was likely low due to the fact that most children with relapsed or refractory leukemia die during intensive chemotherapy and are thus still cared for in hospital. Time from start of palliative home care to death was the same in children with HM compared to non HM (54 vs. 53 days in care), although the range of days in palliative care was larger in children with non HM (1 to 226 days) compared to children with HM (10 to 116 days). The number of home visits was equal (9.7 vs. 9.4) as was the number of home visits per days in care (0.18 vs. 0.18). In both patient groups, most patients died at home or in hospice. The leading symptoms in children with HM were weakness and anxiety, whereas the most frequently reported symptom in patients with non HM was difficulty to move around (i.e. walk). Other frequently reported symptoms in non HM were neurological and gastrointestinal problems. In children with non HM, the occurring symptoms were much more variable. Mucosal bleeding, hematoma and/or petechiae were recurring problems in children with leukemia requiring platelet transfusions in the home setting, however, not a single child developed massive external hemorrhage. More children with non HM needed morphine-based pain medication (33% vs. 54%). Overall, less drugs for symptom control either regular or on demand medication were needed in children with HM. All patients with HM were continued on palliative chemotherapy. Although anti-infectious prophylaxis was discontinued at the beginning of palliative home care, sepsis did not occur in any child. Four of the HM patients died due to disease-related progressive weakness, one through an acute event (most likely intracranial hemorrhage), and one patient with a T-cell lymphoma and a large mediastinal mass died during palliative sedation. Conclusions: Children with hematologic malignancies who are referred to outpatient palliative care appear to have an equal length of care compared to other cancer patients. A lower number of medications (including morphine-based drugs) is necessary, however transfusion rates are higher. As might have been a fear of both parents and treating physicians, not a single child developed massive external hemorrhage. Better knowledge about the special symptoms and needs of children with hematologic malignancies will enable PPCTs to provide best possible care. Disclosures No relevant conflicts of interest to declare.

Abstract To date, the most reliable and environmentally friendly way to increase soil fertility and reduce the concentration of mobile forms of heavy metals is the use of organic fertilizers. The article discusses the results of field trials of compost composed of semi-rotted cattle manure, phosphogypsum and alfalfa hay. It was revealed that organic fertilization increases the concentration of organic matter in the upper layer of chernozem leached in the agrocenosis of maize. This enhances the sorption of the organic mineral complex of the soil and decreases the mass fraction of some heavy metals (HM). It is noted that the use of compost in doses of 40 and 60 t/ha helps to reduce the mass concentration of zinc, copper and manganese. The excess of the permissible concentration of highly toxic and dangerous for humans HM was not detected in any field variant.

A half-marathon (HM) is a vigorous high-intensity exercise, which could induce lower extremity musculoskeletal injury risks for recreational runners. They usually consume nonsteroidal anti-inflammatory drugs (NSAIDs) in order to shorten their return to play but ignore the side effects, such as peptic ulcers and renal and vascular disorders. Lactobacillus plantarum PS128 (PS128) could improve inflammation and oxidative stress by modulating the gut microbiota, thus potentially improving muscle damage and recovery. However, few studies have addressed the PS128 exercise capacity recovery 96 h after HM. Thus, this study aimed to investigate the effect of PS128 on exercise capacity and physiological adaptation after HM. A double-blind, randomized, placebo-controlled, counterbalanced, crossover trial was used for the experiment. HM was conducted at the beginning and end of the 4-week nutritional supplement administration. Eight recreational runners took two capsules (3 × 1010 CFU/capsule) of PS128 each morning and evening before meals for 4 weeks as the PS128 treatment (LT), or they took two capsules of placebo for 4 weeks as the placebo treatment (PT). In both treatments, an exercise capacity test (lower extremity muscle strength, anaerobic power, lower extremity explosive force, and aerobic capacity) and blood test (muscle fatigue, muscle damage, oxidative stress, and renal injury) were performed before the administration of the nutritional supplement (baseline), 48 h before HM (pre), and 0 h (0 h post), 3 h (3 h post), 24 h (24 h post), 48 h (48 h post), 72 h (72 h post), and 96 h (96 h post) after HM. There was no significant difference in the total duration of HM between PT and LT, but PT was found to be significantly higher than LT at Stage 4 (15,751–21,000 m) of HM (3394 ± 727 s vs. 2778 ± 551 s, p = 0.02). The lower extremity muscle strength measured using an isokinetic dynamometer in PT was significantly lower than that in LT at 72 h after HM. The lower extremity explosive force from the countermovement jump (CMJ) in PT was significantly decreased compared to 24 h prior. There was no significant difference between anaerobic power and aerobic capacity between the two treatments after HM. After HM, LT had lower muscle damage indices, such as myoglobin (3 h post-PT vs. -LT: 190.6 ± 118 ng/mL vs. 91.7 ± 68.6 ng/mL, p < 0.0001) and creatine phosphokinase (24 h post-PT vs. -LT: 875.8 ± 572.3 IU/L vs. 401 ± 295.7 IU/L, p < 0.0001). Blood urea nitrogen recovered in 24 h (24 h pre- vs. post-LT, p > 0.05) and higher superoxide dismutase was found in LT (96 h post-PT vs. -LT: 0.267 ± 0.088 U/mL vs. 0.462 ± 0.122 U/mL, p < 0.0001). In conclusion, PS128 supplementation was associated with an improvement in muscle damage, renal damage, and oxidative stress caused by HM through microbiota modulation and related metabolites but not in exercise capacity.

BACKGROUND: Head tracking movements are common in interceptive tasks. The benefits of these movements are unclear. The purpose of this study was to compare coincidence anticipation timing (CAT) responses for a simulated approaching object when the eyes were used in tracking the object and when the head was used in tracking the object.METHODS: A total of 29 subjects participated. A Bassin Anticipation Timer consisting of a track of sequentially illuminated lights was used to simulate an approaching object at velocities of 223 cm · s−1 to 894 cm · s−1. Each velocity was used 10 times under 2 conditions. In one condition, subjects were told to turn the eyes with the stimulus. In the other condition, subjects viewed the stimulus through apertures and were told to turn the head with the stimulus. Subjects pushed a button to coincide with illumination of the final light on the track.RESULTS: Signed CAT errors, unsigned CAT errors, and variable CAT errors were compared between the head movement (HM) and eye movement (EM) conditions. No significant differences were noted for the signed errors (mean signed error at 894 cm · s−1; 10.3 ± 75.4 ms (HM), −16.1 ± 51.0 ms (EM). However, the unsigned and variable errors were significantly larger at some stimulus velocities in the head movement condition [mean unsigned error at 894 cm · s−1: 82.6.0 ± 45.9 ms (HM), 59.0 ± 22.4 ms (EM); mean variable error at 894 cm · s−1; 78.0 ± 37.8 ms (HM), 49.2 ± 17.1ms (EM)].DISCUSSION: Head movement did not result in improved CAT performance compared to eye movements. Further work will be required to determine whether these results are generalizable to situations where head tracking is required but apertures are not worn.Ross E, Kinney M, Fogt N. Coincidence anticipation timing responses with head tracking and eye tracking. Aerosp Med Hum Perform. 2022; 93(2):79–88.

Abstract Background: Hepatitis B infection may be associated with an increased risk of non hodgkins lymphoma, especially diffuse large B cell lymphoma. Whether an intact immune system is required hepatitis B mediated lymphomagenesis and if factors such as other viral co infections and paraproteins may further compound this risk remains unclear. We retrospectively studied our large database of HBsAg positive patients for diagnoses of hematological malignancies or premalignant disorders (HM) and the risk factors for their development. Methods: Patients over the age of 18 with at least one positive HBsAg test between Jan 1st 2001 and Dec 31st 2011 were identified using the medical center database, clinical looking glass. Data were collected regarding demographics, HIV and hepatitis C status. Serum protein electrophoresis tests done after the HBsAg test were reviewed. Results of all biopsies performed for each patient, ICD9 and cancer registry diagnoses were reviewed for biopsy confirmed diagnoses of a HM. Liver biopsy results were reviewed for evidence of chronic hepatitis changes. Results: 3177 of 216,522 patients (1.5%) tested were HBsAg positive. Mean age of the HBsAg positive group was 43 years, 56% were male. 44% were black, 8% white and 7.4% were Asian. 33.6% of these patients had two positive HBsAg tests 6 months apart. 10.3% of patients underwent a liver biopsy and 9.4% of patients had biopsy changes consistent with chronic hepatitis. Of the 3177 patients, 4.9% (155 patients) had a biopsy of any lymphatic tissue or bone marrow performed. 2.2 % (71 patients) had a hematological malignancy or premalignant disorder diagnosed. 0.4% (12 patients) had an insufficient specimen for diagnosis and were excluded from further analysis. Of the 71 patients with a HM, 30 (42.3%) had a high grade B or T cell lymphoma; 12 (16.9%) had myeloma or smoldering myeloma; 11 (15.5%) had a low grade lymphoma; 6 (8.4%) had myelodysplasia, myeloproliferative disorder or acute leukemia and 11 (15.5%) had a premalignant disorder including multicentric castleman, MGUS or NK cell lymphocytosis. 47% of high grade lymphomas occurred in an extranodal location. Within the HBsAg positive population, HM positive patients (n=71) compared to HM negative controls (n=3094) were significantly older (52.5 vs 43 yrs, p<0.001) and more likely to be male (73.2% vs 55.5% p:0.003) HM positive patients were tested for other viral coinfections more often and were more likely to be seropositive for HIV (62.7% vs 31.4%, p<0.001) and Hepatitis C (20% vs 10.7%, p:0.014) . HM positive patients were also tested for paraprotein more frequently and had a significantly higher prevalence of paraproteinemia than their HM negative counterparts. (58.1% vs. 15.4%, p<0.0001) On multivariate analysis, male gender (OR: 2.4, 95% CI:1.1-4.9), paraprotein positivity (OR:16.3, 8.0-33.7) and HIV positivity (OR:2.6, 1.4-4.9) but not Hepatitis C positivity emerged as independent risk factors for development of HM. (Table 1) Of those patients with HBsAg positivity diagnosed with hematological malignancies, patients co-infected with HIV and hepatitis B had a significantly higher proportion of DLBCL cases as compared to those with hepatitis B alone (46.9% vs 10.5%, p:0.013). Conclusions: Concurrent HIV infection and paraproteinemia were associated with increased risk of HM in our HBsAg positive patients. Of those who develop HM, HIV and Hepatitis B co-infected patients have a higher proportion of DLBCL. These data suggest synergistic mechanisms of Hepatitis B and HIV in abnormal B cell proliferation. Being a retrospective study, inherent biases exist in terms of which patients get certain tests. Further work is required to confirm these findings and to elucidate the mechanisms of lymphomagenesis in this population. Abstract 5403. Table 1: Risk factors for the development of HM in HBsAg positive patients HM positive (n=71) HM negative (n=3094) p value Mean age in years (SE) 52.5 (12.9) 42.9 (13.6) <0.0001* Male gender (n,%) 52 (73.2%) 1716 (55.5%) 0.003* HIV serology or viral load tested (n,%) 51 (71.8%) 1787 (57.8%) 0.017* HIV positive of tested patients (n,%) 32/51 (62.7%) 561/1787 (31.4%) <0.0001* HCV serology done (n,%) 70 (98.6%) 2660 (86%) 0.001* HCV seropositive of those tested (n,%) 14 /70 (20%) 285 / 2660 (10.7%) 0.014* SPEP test done (n,%) 31 (43.6%) 311 (10.1%) 0.0001* SPEP positive of tested patients (n,%) 18/31 (58.1%) 48/311 (15.4%) <0.0001* Disclosures No relevant conflicts of interest to declare.

We consider the quasi-Ablowitz–Segur and quasi-Hastings–McLeod solutions of the inhomogeneous Painlevé II equation [Formula: see text] These solutions are obtained from the classical Ablowitz–Segur (AS) and Hastings–McLeod (HM) solutions via the Bäcklund transformation, and satisfy the same asymptotic behaviors when [Formula: see text]. For [Formula: see text], we show that the quasi-Ablowitz–Segur (qAS) and quasi-Hastings–McLeod (qHM) solutions possess [Formula: see text] simple poles on the real axis, which rigorously justifies the numerical results in Fornberg and Weideman (A computational exploration of the second Painlevé equation, Found. Comput. Math. 14(5) (2014) 985–1016).

In the current context, there is a growing interest in reducing the use of chemical fertilizers and pesticides to promote ecological agriculture. The use of biochar and plant growth-promoting rhizobacteria (PGPR) is an environmentally friendly alternative that can improve soil conditions and increase ecosystem productivity. However, the effects of biochar and PGPR amendments on forest plantations are not well known. The aim of this study is to investigate the effects of biochar and PGPR applications on soil nutrients and bacterial community. To achieve this goal, we applied amendments of (i) biochar at 20 t hm−2, (ii) PGPR at 5 × 1010 CFU mL−1, and (iii) biochar at 20 t hm−2 + PGPR at 5 × 1010 CFU mL−1 in a eucalyptus seedling plantation in Guangxi, China. Three months after applying the amendments, we collected six soil samples from each treatment and from control plots. From each soil sample, we analyzed several physicochemical properties (pH, electrical conductivity, total N, inorganic N, NO3−-N, NH4+-N, total P, total K, and soil water content), and we determined the bacterial community composition by sequencing the ribosomal 16S rRNA. Results indicated that co-application of biochar and PGPR amendments significantly decreased concentrations of soil total P and NH4+-N, whereas they increased NO3-N, total K, and soil water content. Biochar and PGPR treatments increased the richness and diversity of soil bacteria and the relative abundance of specific bacterial taxa such as Actinobacteria, Gemmatimonadetes, and Cyanobacteria. In general, the microbial composition was similar in the two treatments with PGPR. We also found that soil physicochemical properties had no significant influence on the soil composition of bacterial phyla, but soil NH4+-N was significantly related to the soil community composition of dominant bacterial genus. Thus, our findings suggest that biochar and PGPR amendments could be useful to maintain soil sustainability in eucalyptus plantations.

Abstract The majority of patients (pts) with hematologic malignancies (HM) are anemic and often have poor performance scores (Ludwig H et al. Blood.2002;100:234a). The correlation between increases in hemoglobin (Hb) with epoetin alfa and improvements in quality of life (QOL) was evaluated in this open-label, multicenter study that enrolled 736 adult pts with various solid tumors and HM (n = 122) who were receiving cytotoxic chemotherapy and had Hb levels <12 g/dL. Epoetin alfa was administered 150 IU/kg or 10,000 IU 3 times weekly (TIW) for a maximum 28 weeks (wks); dose was increased to 300 IU/kg or 20,000 IU TIW if Hb was not increased >1 g/dL above baseline within 4 wks. Results for pts with HM are compared to results from a similar 16-wk trial that included pts with HM (n = 488) and used the 40,000 IU once-weekly (QW) dose, increased to 60,000 IU QW if Hb did not increase ≥1 g/dL within 4 wks (Gabrilove J et al. Int J Hematol.2000;72:55). In the TIW study, the primary efficacy endpoint was change in QOL as measured by the Functional Assessment of Cancer Therapy-General (FACT-G), including subscales for anemia (FACT-An) and fatigue; the FACT was administered at study entry, at 8–9 wks, and at 12 wks. QOL was additionally measured by the Cancer Linear Analog Scale (CLAS; also known as the Linear Analog Scale Assessment [LASA]) administered at every study visit. Dose increases were similar in both studies (33.6% of pts in the TIW study; 36.7% of pts in the QW study). In the TIW study, mean baseline Hb was 9.6 g/dL; mean Hb increased at 4–6 wks (1.35 g/dL), 8–9 wks (2.09 g/dL) and 12 wks (2.46 g/dL) to a mean Hb of 12.0 g/dL. Almost half the HM patients in the TIW study (48.1%) had a complete response (Hb increase ≥2 g/dL without blood transfusion). Hematologic results are similar to those reported in the QW study where mean Hb increased 1.96 g/dL by end of study (P = .0001). QOL improvements were also similar between studies. Mean FACT-An scores for the total population in the TIW study increased 6.7 points after 12 wks, which is clinically significant (Patrick DL et al. Eur J Cancer.2003;39:335–345). The mean increase for overall FACT-G correlated significantly with increased Hb at 12 wks (P <.0001; r = .262). Mean CLAS scores for the total population increased steadily throughout the study. At 12 wks mean increases (based on the 100-mm scale) were clinically significant (Patrick et al): 10.9 mm for Energy, 11.2 mm for Daily Activity, and 10.3 mm for Overall QOL. Mean change for FACT-An for patients from the total population in the QW study (n = 2,230) was 6.0 points (P <.001), which is comparable to the mean changes in the TIW study and the HM population of the QW study (6.59 points, P <.0001). No unexpected adverse events were reported. Epoetin alfa TIW or QW was shown to steadily increase Hb, which significantly correlated with clinically significant improvements in QOL.

Background. Accurate delineation of tumor margin is essential for complete resection of early gastric cancer (EGC). The objective of this study is to assess the performance of magnifying endoscopy with narrow-band imaging (ME-NBI) for the accurate demarcation of EGC margins. Methods. We searched PubMed, EMBASE, Web of Science, and Cochrane Library databases up to March 2020 to identify eligible studies. The diagnostic accuracy of ME-NBI for EGC margins was calculated, and subgroup analyses were performed based on tumor size, depth of tumor invasion, tumor-occupied site, macroscopic type, histological type, Helicobacter pylori (H. pylori), and endoscopists’ experience. Besides, we also evaluated the negative and positive resection rates of the horizontal margin (HM) of EGC after endoscopic submucosal dissection (ESD) and surgery. Results. Ten studies comprising 1018 lesions were eligible in the databases. The diagnostic accuracy of ME-NBI for the demarcation of EGC margins was 92.4% (95% confidence interval (CI): 86.7%-96.8%). According to ME-NBI subgroup analyses, the rate of accurate evaluation of EGC margins was not associated with H. pylori infection status, tumor size, depth of tumor invasion, tumor-occupied site, macroscopic type, histological type, and endoscopists’ experience, and no statistical differences were found in subgroup analyses. Moreover, the negative and positive resection rates of HM after ESD and surgery were 97.4% (95% CI: 92.1%-100%) and 2.6% (95% CI: 0.02%-7.9%), respectively. Conclusions. ME-NBI enables a reliable delineation of the extent of EGC.

ABSTRACT Allergic fungal rhinosinusitis (AFRS) has always remained a topic of discussion at all rhinology meets. Despite so much of literature available, the nature of this disease, its diagnosis, pathogenesis, classification and appropriate management continue to generate debate and controversy even after three decades of research and investigation. AFRS is an endemic disease in North and South India. In spite of this, there has been no optimal management protocol for this disease being followed in India yet. To overcome this, a national panel was conducted on AFRS at the ENT Surgical Update 2011, held at Postgraduate Institute of Medical Education and Research, Chandigarh with experts from all over the country so that a consensus can be achieved regarding the workup and management of AFRS. How to cite this article Gupta AK, Shah N, Kameswaran M, Rai D, Janakiram TN, Chopra H, Nayar R, Soni A, Mohindroo NK, Rao CMS, Bansal S, Meghnadh KR, Vaid N, Patel HM, Sood S, Kanojia S, Charaya K, Pandhi SC, Mann SBS. Allergic Fungal Rhinosinusitis. Clin Rhinol An Int J 2012;5(2): 72-86.

Abstract Introduction: patients with hematologic malignancies (HM) admitted in intensive care units (ICU) have been traditionally seen as patients with very poor prognostic. Recently reports have informed that mortality has dropped and nowadays is in the order of 40-60 %, this is still high but closer to mortality in non-malignant patients admitted in an ICU. In an attempt to change this view we perform a study in order to evaluate the results and prognostic factors that contribute to mortality in HM patients who need critical care assistance. Methods: a retrospective study in 62 patients with HM who were admitted in ICU in the University Hospital, Hospital de Clinicas from Uruguay from 2003 to 2012. These 62 patients had 82 admissions, which are the population of our trial. Statistical analysis: Values are expressed as mean +/- standard deviation (SD), median and percentages. Comparison variable most used: discharge of ICU: dead or alive. Both groups were compared using Student's t test and Chi square. Multivariate logistic regression analysis was performed. Overall survival with Kaplan Meier. Significance p<0.05. Results: 50% of the episodes were in men. The median age was 56 years old (17-80). The distribution according to HM was: Non-Hodgkin Lymphoma 40.2%, Acute Myeloid Leukemia 23.2%, Multiple Myeloma 13.4%, Chronic Lymphocytic Leukemia 7.3%, Acute Lymphoblastic Leukemia 4.9%, Hodgkin Lymphoma 3.7%, other 3.7%, Myeloproliferative Neoplasm 2.4% and aplasia 1.2%. The mortality during ICU’s treatment was 47.6%. The causes of death in ICU were: septic shock: 74.4%; disease progression: 10.3%; Other: 7.7%; refractory respiratory failure: 5,1%; severe hemorrhage: 2.6%. Median days of overall survival in ICU were 11 days (CI 1.9 to 20.06). In table 1 we show the univariate analysis of prognostic factors. The parameters that showed a significant difference were; underlying diagnosis of ALL, presence of central catheter line prior to entering ICU; need for mechanical ventilation, diagnosis of septic shock, use and hours of vasopressors and the value of APACHE II. Of the 47 patients who required mechanical ventilation 33 died (70.2%), this is a risk factor for death, with an OR of 1.83 (CI: 1.1 to 3.02). The diagnosis on admission to ICU septic shock is a significant risk factor for death with an OR of 0.449 (CI: 0.351 to 0.574). In the multivariable analysis, admission to ICU for mechanical ventilation, use of mechanical ventilation at some point and use of vasopressors were statistically significant. TABLE 1. Univariate analysis of prognostic factors: Alive Death P value Diagnostic ALL Yes: 0 No: 43 Yes: 4 No: 35 0,03 Type of Chemotherapy Standard: 19High dose: 11Allogeneic SCT: 1Purine analogs: 1No Chemotherapy: 11 Standard: 19High dose: 11Allogeneic SCT: 0Purine analogs: 1No Chemotherapy: 8 0,920,430,340,940,58 Neutropenic No data: 8 Yes: 14 No: 29 Yes: 17 No: 14 0,304 Catheter No data: 2 Yes: 16 No: 26 Yes: 24 No: 14 0,025 Cretinine, mean (SD) 1,53 ±(1,55) 1,75 ±(1,17) 0,66 Urea, mean (SD) 68,2 ±(53,41) 89,27 ±(61,24) 0,09 Prothrombin time, mean (SD) 68,36 ±(21,37) 59,65 ±(20,67) 0,87 PAFI, mean (SD) 301,63 ±(110,41) 290,24 ±(123,25) 0,22 Bilirubin, mean (SD) 1,2 ±(1,78) 1,5 ±(2,49) 0,701 Use of mechanical Ventilatory Yes: 14 No: 29 Yes: 33 No: 6 <0,001 Septic Shock at admission Yes: 0 No: 43 Yes: 4 No: 35 0,032 Use of vasopressor Yes: 7 No: 36 Yes: 31 No: 8 < 0,001 Hours of vasopressors 46,29 86,63 0,023 Renal replacement Therapy Yes: 3 No: 40 Yes: 8 No: 31 0,074 APACHE II 17,05 ± (8,24) 20,66 ± (6,00) 0,042 SOFA at admission 4,99 ± (3,84) 7,32 ± (3,24) 0,35 SOFA at 48 hours 3,89 ± (3,83) 9,20 ± (4,43) 0,13 Conclusions: this is the first report on the impact of prognostic factors in the outcome of HM patients admitted to ICU in Hospital de Clinicas. HM patient’s acute complications are strong factors that contribute to prognostic in critically ill patients and not only the hematologic disease per se or presence of neutropenia or type of chemotherapy. The mortality rate in this series is similar to international reports and also in patients without HM admitted in ICU. Therefore, we support the idea that survival in critically ill HM patient is related with the intercurrent complication in a significant part, and we have to make more efforts to improve results in this area by working together with intensive care medicine physicians. Disclosures No relevant conflicts of interest to declare.

ImportanceClonal hematopoiesis (CH) with acquired pathogenic variants in myeloid leukemia driver genes is common in older adults but of unknown prognostic value.ObjectiveTo investigate the prevalence of CH and the utility of the CH risk score (CHRS) in estimating all-cause and disease-specific mortality in older adults with CH.Design, Setting, and ParticipantsThis population-based prospective cohort study involved community-dwelling older adults (aged 67-90 years) without hematologic malignant neoplasms (HMs) who were participants in the Atherosclerosis Risk in Communities Visit 5 at 4 US centers: Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland. Samples were collected from 2011 to 2013, sequencing was performed in 2022, and data analysis was completed in 2023.ExposureThe exposure was a diagnosis of CH. CHRS scores (calculated using 8 demographic, complete blood cell count, and molecular factors) were used to categorize individuals with CH into low-risk (CHRS ≤9.5), intermediate-risk (CHRS &amp;gt;9.5 to &amp;lt;12.5), and high-risk (CHRS ≥12.5) groups.Main Outcomes and MeasuresThe primary outcome was all-cause mortality, and secondary outcomes were HM mortality, cardiovascular disease mortality, and death from other causes.ResultsAmong 3871 participants without a history of HM (mean [SD] age, 75.7 [5.2] years; 2264 [58.5%] female individuals; 895 [23.1%] Black individuals; 2976 White individuals [76.9%]), 938 (24.2%) had CH. According to the CHRS, 562 (59.9%) were low risk, 318 (33.9%) were intermediate risk, and 58 (6.2%) were high risk. During a median (IQR) follow-up of 7.13 (5.63-7.78) years, 570 participants without CH (19.4%) and 254 participants with CH (27.1%) died. Mortality by CHRS risk group was 128 deaths (22.8%) for low risk, 93 (29.2%) for intermediate risk, and 33 (56.9%) for high risk. By use of multivariable competing risk regression, subdistribution hazard ratios (sHRs) for all-cause mortality were 1.08 (95% CI, 0.89-1.31; P = .42) for low-risk CH, 1.12 (95% CI, 0.89-1.41; P = .31) for intermediate-risk CH, and 2.52 (95% CI, 1.72-3.70; P &amp;lt; .001) for high-risk CH compared with no CH. Among individuals in the high-risk CH group, the sHR of death from HM (6 deaths [10.3%]) was 25.58 (95% CI, 7.55-86.71; P &amp;lt; .001) and that of cardiovascular death (12 deaths [20.7%]) was 2.91 (95% CI, 1.55-5.47; P &amp;lt; .001).Conclusions and RelevanceIn this cohort study, the CHRS was associated with all-cause, HM-related, and cardiovascular disease mortality in older adults with CH and may be useful in shared decision-making to guide clinical management and identify appropriate candidates for clinical trials.

Abstract CRE is the major concern in the patients suffering from hematological malignancy but the data on the impact of colonization in such patients is scarce. We conducted a prospective surveillance study of CRE on 225 patients of haematological malignancies (HM), who required hospital admission between October 2013 to January 2016. The median age of the cohort was 45 years(range,2-84). The cohort included a broad representation of diseases; AML (n=58), ALL(n=44), Lymphoma (n=76), Myeloma(n=22), CML(8) and Others (n=17). Rectal swabs were taken for cultures in all patients during first day of admission and repeated subsequently on weekly basis for continuous hospital stay or in subsequent admissions.47 (21%) patients were colonized with CRE on admission. This increased to 45% on prolonged hospital stay/ contact for more than 4 weeks with 72 (32%) patients being colonized overall. The highest number of patients colonized with CRE at diagnosis was those with AML (30%). The non-relapse mortality (NRM) of the cohort at 6 months was 10.3%. This was 14% in those with acute leukemia compared to 5.8% in others (p=0.02). Furthermore, this was highest in patients with AML (22.9% vs 6.1% in others; p=0.001). CRE related events accounted for 77% of mortality. NRM was 29.6% in those colonized with CRE during hospitalization compared to 10.5% in those colonized at admission with no NRM in those not colonized with CRE (p=0.0001). Amongst patients with AML, colonization with CRE during hospitalization was associated with a NRM of 54.9%(95%CI 32.4-67.4%) compared to those colonized at admission(11.8; 95%CI 4.0-19.6) and those not colonized(0%)(p=0.0001). This trend was true for patients without AML as well (27.3% vs 10.3% vs 0%; p=0.0001). On multivariate analysis, colonization with CRE during hospitalization was the most important risk factor for NRM in patients with hematological malignancies (HR-7.1; 95%CI 3.1-16.1). Our data demonstrates that a substantial proportion of patients with HM are colonized with CRE without prior hospitalisations but those with nosocomial colonization have the highest risk of mortality, particularly in those with AML. Figure Figure. Disclosures No relevant conflicts of interest to declare.

The objective of this study was to compare one- and two-step kinetic data analysis approaches to describe the growth of Staphylococcus aureus, Escherichia coli, and lactic acid bacteria Fresco 1010 starter culture in milk under isothermal conditions between 10 and 37 °C. The primary Huang model (HM) and secondary square root model were applied to lag times and growth rates of each of the population. The one-step approach for single cultures data enabled the direct construction of a tertiary model combining primary and secondary models to determine parameters from all growth data, thus minimizing the transfer of errors from one model to another. The statistical indices showed a significant improvement in the prediction capability provided by this approach. Then, a one-step approach combining the primary Huang, Giménez, and Dalgaard model (H-GD) with the secondary square root model was used to simultaneously model the growth of the populations mentioned above in co-culture under the same conditions. Independent isothermal data sets were chosen for validation of the growth description of single cultures (HM) and co-culture (H-GD) using validation factors, including the bias (Bf) and accuracy (Af). For example, the values of Af for the one-step approach range from 1.17 to 1.20 and 1.04 to 1.08 for single cultures and co-culture, respectively, demonstrating high accuracy. Thus, this approach may be used for co-culture growth description in general or specifically, e.g., in various types of lactic acid fermentation, including artisanal cheese-making technology.

Abstract. There is growing evidence that climate change will alter water availability in Europe. Here, we investigate how hydrological low flows are affected under different levels of future global warming (i.e. 1.5, 2, and 3 K with respect to the pre-industrial period) in rivers with a contributing area of more than 1000 km2. The analysis is based on a multi-model ensemble of 45 hydrological simulations based on three representative concentration pathways (RCP2.6, RCP6.0, RCP8.5), five Coupled Model Intercomparison Project Phase 5 (CMIP5) general circulation models (GCMs: GFDL-ESM2M, HadGEM2-ES, IPSL-CM5A-LR, MIROC-ESM-CHEM, NorESM1-M) and three state-of-the-art hydrological models (HMs: mHM, Noah-MP, and PCR-GLOBWB). High-resolution model results are available at a spatial resolution of 5 km across the pan-European domain at a daily temporal resolution. Low river flow is described as the percentile of daily streamflow that is exceeded 90 % of the time. It is determined separately for each GCM/HM combination and warming scenario. The results show that the low-flow change signal amplifies with increasing warming levels. Low flows decrease in the Mediterranean region, while they increase in the Alpine and Northern regions. In the Mediterranean, the level of warming amplifies the signal from −12 % under 1.5 K, compared to the baseline period 1971–2000, to −35 % under global warming of 3 K, largely due to the projected decreases in annual precipitation. In contrast, the signal is amplified from +22 (1.5 K) to +45 % (3 K) in the Alpine region due to changes in snow accumulation. The changes in low flows are significant for regions with relatively large change signals and under higher levels of warming. However, it is not possible to distinguish climate-induced differences in low flows between 1.5 and 2 K warming because of (1) the large inter-annual variability which prevents distinguishing statistical estimates of period-averaged changes for a given GCM/HM combination, and (2) the uncertainty in the multi-model ensemble expressed by the signal-to-noise ratio. The contribution by the GCMs to the uncertainty in the model results is generally higher than the one by the HMs. However, the uncertainty due to HMs cannot be neglected. In the Alpine, Northern, and Mediterranean regions, the uncertainty contribution by the HMs is partly higher than those by the GCMs due to different representations of processes such as snow, soil moisture and evapotranspiration. Based on the analysis results, it is recommended (1) to use multiple HMs in climate impact studies and (2) to embrace uncertainty information on the multi-model ensemble as well as its single members in the adaptation process.

In ferromagnetic semiconductors, the coupling of magnetic ordering with semiconductor character accelerates the quantum computing. The structural stability, Curie temperature (Tc), spin polarization, half magnetic ferromagnetism and transport properties of ZnX2Se4 (X = Ti, V, Cr) chalcogenides for spintronic and thermoelectric applications are studied here by density functional theory (DFT). The highest value of Tc is perceived for ZnCr2Se4. The band structures in both spin channels confirmed half metallic ferromagnetic behavior, which is approved by integer magnetic moments (2, 3, 4) μB of Ti, V and Cr based spinels. The HM behavior is further measured by computing crystal field energy ΔEcrystal, exchange energies Δx(d), Δx (pd) and exchange constants (Noα and Noβ). The thermoelectric properties are addressed in terms of electrical conductivity, thermal conductivity, Seebeck coefficient and power factor in within a temperature range 0–400 K. The positive Seebeck coefficient shows p-type character and the PF is highest for ZnTi2Se4 (1.2 × 1011 W/mK2) among studied compounds.

The molar enthalpies of mixing, Δmix Hm, of the liquid alkali metal iodide - neodymium iodide binary systems have been measured over the whole composition range at 1068 K with an accuracy of about 6%. The apparatus used was a Calvet - type high - temperature microcalorimeter. In all the systems under investigation the enthalpies of mixing are negative, with minimum values close to −1.1, −4.8, −10.3, −16.2, and −20.0 kJ mol−1 for LiI-NdI3, NaI-NdI3, KI-NdI3, RbI-NdI3, and CsI-NdI3, respectively, at the mole fractions xNdI3 ⋍ 0.30 - 0.40 except the LiI-NdI3 system, where it is at the NdI3-rich compositions. The molar enthalpies of formation ΔformHm at 1068 K for M = Li, Na, K, Rb, and Cs, arising from the reaction 3 MI(l) + NdI3(l), are found to be −4.5, −17.5, −39.1, −59.9, and −73.3 kJmol−1, respectively They are compared with the formation enthalpies determined previously for the (3MCl, NdCl3) and (3MBr,NdBr3) liquid mixtures. These enthalpies become less negative with increase of the radius of the halide ion.

BackgroundTocilizumab may be an alternative for patients with Behçet’s Syndrome (BS) refractory to conventional immunosuppressives and TNF inhibitors.ObjectivesWe aimed to report our experience with tocilizumab in patients with BS.MethodsWe identified BS patients who were treated with tocilizumab for eye, nervous system and arterial involvement, and amyloidosis, using our hospital’s electronic medical records. Demographic and clinical features, previous therapy, treatment response, outcomes, and adverse events were retrieved from patient charts.ResultsA total of 12 patients with BS (M/F: 9/3, mean age 44.4±10.3 years) were treated with tocilizumab for uveitis (n=6), parenchymal nervous system involvement (n=2), aortitis (n=2) and amyloidosis (n=2) between 2014-2022. Previous treatment modalities and treatment response for uveitis are shown in Table 1. Only 2 of the 6 patients with uveitis obtained remission with tocilizumab. Both patients with neurological involvement were refractory to tocilizumab treatment. They had previously used colchicine, steroids, azathioprine, interferon-alpha, infliximab, and adalimumab. Additionally, one had used cyclophosphamide and the other methotrexate and mycophenolate mofetil. One of the patients with amyloidosis was unresponsive and underwent kidney transplantation. The other had improvement in proteinuria, but she developed Crohn disease and infliximab was started. One patient with aortitis had used steroids, colchicine, azathioprine, cyclophosphamide, infliximab and the other had used steroids, colchicine, azathioprine, interferon-alpha and methotrexate. Both patients with aortitis obtained remission. One of them discontinued tocilizumab voluntarily, and the other due to dyslipidemia. Overall, tocilizumab was discontinued in 10/12 patients after 10.1±7.8 months. Adverse events were increased mucocutaneous lesions in one and dyslipidemia in another patient.ConclusionBS patients with aortitis benefitted from tocilizumab. However, our experience with tocilizumab in patients with eye and nervous system involvement was not as favorable as reported in previous case series. This may be partly due to the long disease duration before tocilizumab and the patient’s ‘being difficult-to-treat patients, refractory to several previous biologics including TNF inhibitors and interferon-alpha.References[1]Akiyama M, Kaneko Y, Takeuchi T. Effectiveness of tocilizumab in Behcet’s disease: A systematic literature review. Semin Arthritis Rheum. 2020 Aug;50(4):797-804.Table 1.Demographic and clinical features, previous and concomitant treatment in refractory Behçet’s uveitis patients treated with tocilizumab.NoSex/AgeUveitis duration before TCZ (year)Previous therapyIndicationsConcomitant medicationsNumber of attacksVA (before TCZ)VA (after TCZ)Response to TCZ treatmentRLRL1M/304cs, aza, CsA, ifn, inx, ada, czp, tacinductioncs, aza, CsA31/10CF at 3 mCF at 0.5 m2/10active2F/4415Cs, aza, CsA, ifn, inx, ada, mmf, czpinductioncs, CsA, mmf3TD4/10TD9/10active3*M/4518cs, aza, CsA, ifn, inxinductionAnti-tuberculosis01/101/101/102/10remission4¥M/351cs, aza, adaContraindication for TNF inhibitorscs, mmf010/1010/1010/1010/10remission5M/423cs, aza, CsA, ifn, inx, mmf, adainductioncs11/101/101/10HMactive6M/424colchicine, cs, aza, CsA, inx, anr, ifn, chlorambucilinductioncs55/10HM8/10LPactivecs: corticosteroids, aza: azathioprine, CsA: cyclosporine A, ifn: interferon alpha, inx: infliximab, ada: adalimumab, czp: certolizumab, tac: tacrolimus, mmf: mycophenolate mofetil, anr: anakinra, tcz: tocilizumab, VA: visual acuity, CF: counting fingers, m: meter, TD: terminal disease, HM: hand motion, LP: light perception, R: right, L: left*: The patient had pulmonary tuberculosis under infliximab treatment and was switched to tocilizumab. While uveitis was in remission, tocilizumab was discontinued due to the development of tuberculous lymphadenitis.¥: The patient had interstitial lung disease under infliximab treatment and was switched to tocilizumab.Acknowledgementsnone.Disclosure of InterestsNone Declared.

Abstract Background Information regarding infections caused by Aeromonas spp. is limited. The aim of this study was to describe the clinical and epidemiologic characteristics of infections by Aeromonas spp. during a 7-year period at a tertiary care hospital in Mexico. Methods We analyzed a retrospective cohort of adults with Aeromonas spp. clinical isolates, between January 1, 2010 and August 31, 2017 from the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. We analyzed demographic, clinical, microbial characteristics and antimicrobial susceptibility test. Risk factors for bacteremia and mortality were identified with logistic regression; adjustment for possible confounder factors was carried out. Data were analyzed with IBM SPSS Statistics version 21. Statistical significance was defined as the value for P < 0.05. Results We identified 387 patients with an infection by Aeromonas spp.; the median age was 55 years and 52% were women. 94 (24.3%) patients had an autoimmune disease; 74 (19.1%) had a solid tumor (ST); 51 (13.2%) had chronic kidney disease (CKD); 43 (11.1%) had chronic liver disease (CLD); 37 (9.6%) had a hematologic malignancy (HM); 23 (5.9%) were solid-organ recipients and 20 (5.2%) HIV infected. 41.6% (n = 161) of the infections were healthcare related. Stools were the most frequent isolation site (n = 299, 77%), followed by blood cultures (n = 29, 7.4%) and abscess (n = 19, 4.9%). The most common species was A. veronii. Aminoglycosides, quinolones, carbapenems, and trimethoprim/sulfamethoxazole were the most active antibiotics in vitro. The variables associated with bacteremia were CLD OR 5.647; diabetes OR 2.376 and nosocomial acquisition OR 4.08. 30-day mortality was 5.7%, while global mortality was 10.3%. Mortality was associated with sex (male) OR 1.753; HM OR 2.741; ST OR 2.576; polymicrobial infection OR 2.445; ICU admission OR 5.175 and bacteremia OR 3.881. Conclusion Infections by Aeromonas spp. have increased and have a greater incidence among individuals with chronic diseases and immunosuppressive states in this setting. Mortality described in this cohort was minor than previously stated by other series. Disclosures All authors: No reported disclosures.

Introduction. In patients with chronic heart failure (CHF), anemia is more common than in the general population, and its prevalence, according to various authors, ranges from 15 to 61%. Decreased hemoglobin levels are an independent factor contributing to mortality in this cohort. According to a retrospective analysis of the Val-HeFT study, patients with CHF with a decrease in hemoglobin during 12 months of follow-up had a higher rate of readmissions, complications and death compared with patients without a decrease in hemoglobin (Hb). The aim of our work was to study the clinical features and laboratory and instrumental manifestations in patients with CHF with low ejection fraction (CHFrEF) and anemia. Material and methods. We conducted a continuous sample and analyzed 105 case histories of patients for 2022, who were admitted with CHFlEF (EF < 40%) to the cardiology department of the City Clinical Hospital No. 3. The functional class (FC) of CHF was established according to the scale for assessing the clinical condition in CHF (SHOKS, modified by Mareeva V.Yu., 2000), stage - according to the Strazhesko-Vasilenko classification. The edematous syndrome was assessed by points (1 - feet, 2 - lower leg, 3 - scrotum / inguinal region, 4 - abdomen, 5 - chest wall). The presence of anemia was determined by the level of Hb: <130 g/l for men, <120 g/l for women. All patients underwent Holter monitoring of the electrocardiogram (HM ECG) and echocardiography (EchoCG). The indicators of patients with CHFrEF with and without anemia were studied and compared. For this purpose, the Mann–Whitney, Wilcoxon, and c2 tests were used for nonparametric data. The Statistica 12.0 software package (Statsoft, USA) was used. Results. The general group of patients with CHFrEF included 72.4% of men (n=76) and 27.6% of women (n=29), mean age 66.9±12.3. Of these, anemia was detected in 25.7% of cases (n=27), the proportion of men was 66.7% (n=18, mean age 69.1±9.4), women - 33.3% (n=9 , mean age 68.9±16.7). The mean age of patients with CHFrEF in the group with and without anemia did not differ significantly (69.0±12.0 and 66.1±12.3, respectively, р˃0.05). In patients with CHFrEF and anemia, hemoglobin values were significantly lower (106.9±12.7 and 151.6±15.8 g/l, respectively, p<0.001), mean hemoglobin content in erythrocytes (29.1±13, 2 and 31.2±7.7 pg, respectively, p<0.001), the number of erythrocytes (4.2±1.0 and 5.0±0.6 1012/l, respectively, p<0.001), serum iron ( 9.9±9.6 and 10.4±4.1 µmol/l, respectively, p<0.001), erythrocyte sedimentation rate (ESR) (20.9±13.7 and 8.8±8.8 mm/ hour, respectively, p<0.001). Patients with anemia had lower FC (10.3±2.2 and 8.9±2.7 points, respectively, p=0.022) and CHF stage (IIa - 19%, IIB - III - 81% versus IIa - 57 %, IIB - III - 43%, respectively, p=0.02), more pronounced edematous syndrome (2.3±1.0 and 1.8±1.1 points, respectively, p=0.039). According to HM ECG data, patients with anemia had a greater number of ventricular extrasystoles (3445.4±4439 versus 1727.4±3059.0, respectively, p=0.05). EchoCG parameters did not differ in both groups. Conclusion. Every fourth patient with CHFrEF has anemia, while there are no significant differences in age and gender. The combination of CHFrEF with anemia significantly aggravates the course of CHF (according to SHOKS, stage of CHF, severity of edematous syndrome).

O presente estudo teve como objetivo analisar a influência da expansão urbana aliada às características morfométricas nas ocorrências de inundações, no município de João Monlevade-MG. Para a mensuração e classificação das características morfométricas e a obtenção do mapa de uso e ocupação dentro da bacia foram utilizadas uma base de dados disponível no site da Agência Nacional de Águas (ANA) e imagens do satélite Alos Palsar. O uso e ocupação do solo foi dividido em 6 classes. A área de vegetação foi a queapresentoumaior porcentagem na bacia. Para a caracterização morfométrica da bacia, utilizando o software ArcGis 10.3, foi necessário a quantificação da área, perímetros, comprimento do canal principal da bacia e seu comprimento vetorial . De posse destes dados, calculou-se o coeficiente de compacidade (Kc), fator de forma (Kf), índice de circularidade (Ic), índices de declividade, índice de sinuosidade (Is), amplitude altimétrica (Hm), densidade de drenagem (Dd), hierarquia dos canais, número total de canais d’água na bacia e relação relevo (Rr). Diante dos resultados obtidos foi possível constatar que a bacia hidrográfica do córrego Carneirinhos possui uma suscetibilidade natural média ao desenvolvimento de inundações. Contudo, por meio da análise do uso e ocupação do solo foi constatado que os usos antrópicos prevaleceram e um aumento da expansão urbana foi observado, fato que tende a intensificar os processos de inundação na área.

Bone Marrow Aspiration (BMA) is a procedure that is often used to evaluate patients with haematological disorders including haematological malignancies (HMs) which account for about 6.5% of all cancers worldwide. There is paucity of data on the prevalence and pattern of HMs from BMA cytology in Nigeria. We carried out a retrospective review to determine the prevalence and distribution of HMs among adult patients who had BMA cytology at Benue State University Teaching Hospital (BSUTH) from June 2012 to July 2019. A total of 158 BMA reports extracted from the marrow and clinic medical records were reviewed. Out of 158 adult BMA cytology reports, HMs accounted for 78(49.4%) of all haematological disorders. There was no significant gender difference. The Male 38(48.7%) to Female 40(51.3%) ratio (M:F) was 1:1.1. Their ages ranged from 16 to 85 years with the median age of 54.0 years. Out of the 78 HMs, Lymphoid neoplasms were the most prevalent 47(60.3%), the leukaemias were higher 53/78(67.9%) compared to the non-leukaemic neoplasms. Of the 53 leukaemias, those of chronic lymphoid types were more 24/53(45.3%), followed by the chronic myeloid 15/53(28.3%). Chronic lymphocytic leukaemia (CLL) was the predominant leukaemia 24/53(45.3%) as well as the most prevalent HM 24/78(30.8%), followed by chronic myeloid leukaemia (CML) 19.2%(15/78). Others were myelodysplastic syndrome (MDS) 11.5%(9/78), acute lymphoblastic leukaemia (ALL) 10.3% (8/78), multiple myeloma (MM) 10.3%(8/78), acute myeloblastic leukaemia (AML) 7.7%(6/78), non-Hodgkin's lymphoma (NHL) 6.4%(5/78), Small lymphocytic lymphoma (SLL) 2.6%(2/78) and Hodgkin's lymphoma (HL) 1.3%(1/78). In conclusion, we established high prevalence of HMs among patients who had BMA cytology evaluation at BSUTH with the preponderance of lymphoid malignancies. We advocate for inclusion of HMs in the National Health Insurance Scheme (NHIS) for full implementation and to prioritise provision of modern diagnostic equipment and treatment options for quality and optimal management of leukaemias in the center.

e19225 Background: IVIG is used to replenish immunoglobulins in HG due to hematologic malignancies (HM) or their treatment (stem cell transplantation (ASCT) and chimeric antigen receptor T-cell therapy (CAR-T)), in an effort to reduce the risk of infections. There is limited high-level evidence to support this use, and IVIG supplies are limited with a recent shortage leading to restricted allotments. We report the results of a stewardship program designed to safely reduce IVIG usage. Methods: An IVIG stewardship plan (ISP) was implemented with the following requirements for IVIG administration: IgG level < 400 mg/dL (corrected for paraprotein) for post-ASCT and post-CAR-T patients, or IgG < 400 mg/dL with evidence of a bacterial infection within the last 3 months that required hospitalization or an emergency department encounter for those with HM. We evaluated the amount of IVIG administered, the incidence of infections, and antibiotic administration before and after implementation of an ISP. Results: In the 3 months pre-ISP, HG accounted for 38% (72/188) of total IVIG orders. 86 pts received IVIG for HG in the 3 months pre-ISP. The amount of IVIG given decreased from 1907 g/month pre-ISP to 670 g/month post-ISP; estimated cost savings in IVIG was $57,561/month. The pre-ISP median IgG level prior to dosing of IVIG was 550 (range 40-1189) mg/dL. Compared to pre-ISP, pts who stopped receiving IVIG post-ISP had lower median pre-dose IgG (444, range 93-819 mg/dL, p<0.05), infections/patient-months (14/141 vs 56/255, p<0.001), antibiotic usage (12/47 vs 44/86, p<0.05), and hospitalization rate for infection (4/55 vs 21/86, p<0.05); no deaths occurred. For those receiving IVIG post-ISP, adherence to guidelines was 64%. Compared to pre-ISP, median pre-dose IgG was lower (328, range 51-1011 mg/dL, p<0001), infections/patient-months decreased (27/163 vs 56/255, p<0.001), and antibiotic usage, hospitalization rate for infection, and deaths from infection all remained stable. Conclusions: An ISP for HG led to a dramatic and sustainable decrease in IVIG usage, primarily by selecting out patients who are low risk for infection after discontinuation of IVIG. Such an ISP is replicable and warrants adoption.

Abstract Background Blood stream infection (BSI) during neutropenia is associated with high risk for morbidity and mortality in patients with hematologic malignancies receiving chemotherapy or undergoing hematopoietic cell transplant (HCT). We sought to identify factors associated with increased risk for critical illness (CI) morbidities within 7 days of BSI with index FN following chemotherapy. Methods A prospective ongoing survey among 14 high-volume US cancer centers submitting clinical and microbiologic data from consecutive HM patients with blood stream infection (BSI) during first FN after cytotoxic chemotherapy or HCT. We evaluated factors influencing poor outcomes defined as critical illness (need for pressor support, mechanical ventilation, new pneumonia or new BSI) within 7 days of BSI with index FN. Concordance between antibiotic and BSI isolate was determined by investigator (AZ, AF) interpretation of susceptibility reports provided by each center compared with the initial antimicrobial regimen (IAR) used, for single organism bacteremias only. Results Among 294 FN bacteremic episodes (93 HCT) were 336 bacterial pathogens (48.5% Gram-negative [GN], 46.5% Gram-positive [GP], and 6% anaerobes). Death occurred in 11/294 (4%) and 41/294 (14%) had CI by day 8. At FN presentation, mean MASCC score of those with CI vs. those without was 16.9 vs. 18.6 (P = 0.03) and there was a trend toward higher mean PITT scores for patients with CI by day 8 vs. those without (1.54 vs. 0.82 (P = 0.08)). Among GN bacteremias, 15% developed CI vs. 14.5% in nonviridans group Streptococci (VGS) GP bacteremias, and 10.9% in VGS bacteremias (NS). Among patients with single organism bacteremias (88% of all BSI), mismatch of IAR coverage with isolate susceptibilities occurred in 16.7% (38/227). Among patients whom IAR was active vs. inactive against BSI isolate, 16% vs 14.3%, respectively, developed CI (P = 0.81). Conclusion These data indicate that the MASCC score applied to high-risk inpatients may be a predictor for CI in the first week after bacteremia FN. The PITT shows less correlation with poor outcomes. There was no association between isolate type (GN, GP, or VGS) and CI. Notably there was no association between mismatched BSI susceptibility and antimicrobial spectrum of the IAR and early CI. Disclosures A. G. Freifeld, Merck: Investigator, Research grant. A. Zimmer, Merck: Investigator, Research grant. S. Pergam, Merck: Consultant, Consulting fee. Chimerix: Consultant, Consulting fee. K. V. Rolston, Merck: Investigator, Research grant. JMI Laboratories: Investigator, Research grant. Shionogi (Japan): Investigator, Research grant. S. Shoham, Merck: Investigator and Scientific Advisor, Consulting fee and Grant recipient. Astellas: Investigator, Grant recipient. Shionogi (Japan): Investigator, Grant recipient. Gilead: Investigator, Grant recipient. Shire: Investigator, Grant recipient. T. J. Walsh, Merck: Grant Investigator, Research grant. Atellas: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Gilead: Scientific Advisor, Consulting fee. Allergan: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Scynexis: Grant Investigator, Research grant. Amplyx: Grant Investigator, Research grant. Shionogi: Scientific Advisor, Consulting fee. J. A. Young, GSK: Investigator, The University of Minnesota is reimbursed for contract costs associated with conducting clinical trials of vaccine. I receive no personal financial benefit. Y. Zhang, Merck: Investigator, Research grant. J. Meza, Merck: Investigator, Research grant.

Abstract Rational: Patients with t-AML are those previously treated for primary malignancy and are categorized with poor prognosis. t-AML treatment options include intensive chemotherapy (IC), hypomethylating agents (HMA) or low dose cytarabine (LDC). However, survival remains poor and allogeneic hematopoietic cell transplantation (Allo-HCT) could lead to better outcomes. The aim of this analysis is to assess the outcome of all consecutive t-AML pts from two regional centers in France, based on treatment intensity, and to identify prognostic factors. Patients and Methods: between January 2006 and December 2019, 112 adult pts diagnosed with t-AML occurring after treatment of solid tumors (ST; n=72), hematologic malignancies (HM; n=34) or autoimmune diseases (AID; n=6). Pts received chemotherapy and/or radiotherapy or high dose chemotherapy followed by autologous hematopoietic cell transplantation (Auto-HCT) in some. All eligible t-AML pts received intensive chemotherapy (IC, n=55) with the combination of anthracycline and cytarabine in 48 pts and CPX-351 in 7 pts. Unfit pts received non-IC (9 LDC, 24 HMA). The third study group (24 pts) received best supportive care (BSC). Fifteen pts underwent HSCT in first CR. Statistical analysis: We performed a descriptive analysis of the baseline characteristics and each treatment group was compared with a Kruskal-Wallis test and a Pearson's Chi-square test. Survival curves (Kaplan-Meier method) were compared with a log-rank test. Univariate and multivariate analyses on survival, relapse and NRM were done using Cox regression, Gray test, Fine & Gray regression. The bilateral level of significance was set at 5%. All analyses and graphics were made under the R program (v3.5.1). A pair-matched control analysis with de novo AML was performed only on pts who received IC matched for age, cytogenetics and ELN 2010 classification. Results: A total of 112 t-AML pts were identified, 56 were males (50%) with a median age of 68 yrs (19-87) at t-AML diagnosis. Before t-AML, 72 pts had ST (64.5%), 34 HM (30.5%) and 6 AID (5%). Forty-six pts (41%) received chemotherapy alone for their primary cancer, 17 (15%) radiotherapy alone, 49 (44%) radio chemotherapy, 17 (15%) auto-HCT and 6 (5%) long-term methotrexate for AID. Median interval from treatment of previous ST or HM to t-AML diagnosis was 4.7 years in ST, 6.6 years in HM and 21 years in AID (p=0.03). At t-AML diagnosis, 42% of pts presented an unfavorable karyotype and 44% an unfavorable ELN 2010 classification. Regarding molecular alterations, FLT3-ITD, FLT3-TKD, NPM1 and IDH1/2 mutations were observed in 6.9, 2.3, 11.5 and 2.3% of pts respectively. MECOM1 was overexpressed in 25.5% of cases. Among treated pts (n=88), 43 pts (49%) achieved CR: 4 from 33 (12%) in non-IC pts (3 in HMA and 1 in LDC) and 39 from 55 (71%) in IC pts. Fifteen pts (17%) underwent Allo-HCT with a median interval between AML diagnosis and Allo-HCT of 4.7 mo (2.6-17.5). The best response after transplantation was CR in 10 pts; at the last follow up, 4 pts are alive (3 in CR and 1 in relapse) and 11 died (5 from relapse, 5 from TRM causes and 1 from another subsequent malignancy). Overall, with a median follow up of 5.5 mo (0-144), the median OS and DFS were 9 mo (5.9-13.5) and 6.3 mo (5.3-10.3) respectively (Figure). There was a significant difference between the 3 treatment groups concerning OS (p&lt;0.001) and DFS (p&lt;0.001) with a significant difference in OS between IC and non-IC groups (p=0.02). In the 88 treated t-AML pts, with a median follow up of 8.2 mo (0.3-144), the median OS was 13.5 mo (10.3-19.6) and the median DFS was 8.2 mo (7-13.7). Multivariate analysis for total and treated populations showed no impact of all variables related to previous malignancies except for auto-HCT pre-t-AML (significant negative impact on OS, DFS, NRM), WBC at t-AML diagnosis (negative impact on OS, DFS) and chemotherapy (positive in total population on OS, DFS, NRM and negative impact of IC on OS and NRM in treated pts) . In IC treated pts, we showed, in a pair-matched analysis with de novo AML, no difference in term of OS and DFS due to a significant higher CI of NRM (p=0.045) at 24 mo (40% in t-AML versus 27.4% for de novo AML) and a lower CI of relapse (NS) at 24 mo (33% in t-AML versus 47.6% for de novo AML). Conclusion: The prognosis of t-AML remains poor and our study showed the advantage of using intensive chemotherapy whenever possible and, in comparison with de-novo AML, a higher NRM and a lower incidence relapse. Figure 1 Figure 1. Disclosures Nicolini: Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria.

PT Hamparan Mulya memiliki 2 pit, yaitu Pit Alfa dengan luas sebesar 8,4 Ha dan Pit Clara dengan luas sebesar 31,8 Ha. Sebelum melakukan suatu kegiatan penambangan, PT HM membuat perencanaan yang matang serta perancangan suatu sistem dan tata cara penambangan. Setelah itu perlu dilakukannya evaluasi dari perencanaan dan perancangan tersebut yang sudah terlaksana di lapangan untuk mengetahui ada atau tidaknya target produksi yang tidak tercapai dari data mine plan periode Mei 2017, sekaligus mencari faktor-faktor apa saja yang mempengaruhi ketidaktercapaian tersebut.Penelitian ini dilakukan dengan mengumpulkan data primer dan sekunder memakai dua cara, yaitu pengamatan lapangan dan penggunaan data perusahaan. Pengolahan data dilakukan dengan bantuan software Ms.Excel 2016, Map Source, ArcGIS ArcMap 10.3, dan Surpac 6.3 dengan melakukan penyusunan laporan yang menyajian peta, gambar, tabel, dan grafik. Analisis data dilakukan terhadap hasil pengolahan data dan analisa pembahasan dilakukan dengan cara mengkorelasikan hasil pengolahan data dengan masalah yang diteliti.Pembongkaran overburden (OB) pada Pit Alfa dan Pit Clara sudah tercapai sesuai target plan dengan total volume sebesar 341.079 BCM dan 96.063 BCM, sedangkan penggalian batubara (coal) pada Pit Alfa tidak tercapai sesuai target plan dengan total tonase sebesar 42.714,87 ton dan pada Pit Clara sudah tercapai sesuai target plan dengan total tonase sebesar 60.267,69 ton. Target produksi (gabungan kedua pit) untuk pembongkaran overburden (OB) sudah tercapai, sedangkan untuk penggalian batubara (coal) masih belum tercapai dikarenakan adanya ketidaktercapaian target plan perpit pada Pit Alfa. Luas area yang tergali pada kegiatan penambangan di Pit Alfa adalah seluas 7,4 Ha dan di Pit Clara adalah seluas 3,9 Ha. Kata-kata kunci: mine plan, penggalian, pit

e13532 Background: One of the most important cancer centers in Ohio experienced an explosive growth in the number of inpatient admissions, with numerous inpatient services created between 2010 and 2022. In this abstract, we present how some financial and quality measures performed during this rapid expansion. Methods: Slicer-Dicer aggregate data was used to compare financial performance and quality measures of oncologic and general medicine inpatient (IP) services over time. General medicine services do not include the cancer and the heart disease populations, but there might be a small overlap. The cancer population is served by 9 IP oncology services. The following SlicerDicer Filters were used. Population: IP admissions. Slices: populations include these study groups, 10 inpatient medical oncology (solid tumors) (MO), 6 inpatient malignant hematology (MH) (including 1 bone marrow transplant) services were compared to 10 general medicine (GM) services. Gynecologic and central nervous system tumors are served by other services and were excluded. Measures: number of admissions, median and total payments (actual payment received), median and total expected reimbursement (reimbursement expected for DRG), mortality, readmission rates, average length of stay (LOS), percentage of patients with Medicaid, percentage of patients with Medicare. Dates: from 2011 to 2022 data. For some measures, quarterly data is presented rather than yearly data for graph simplicity. Results: The number of inpatient admissions grew by 90.77%, 130.55%, and 105.58% for GM, MO, and MH, respectively. The total expected reimbursement increased by 6.22%, 13.56% and decreased by 17.14% for GM, MO and MH, respectively. The total payment received grew by 314.29%, 283.69%, 86.80%, for MO, MH, and GM, respectively. MO, GM, and HM had a median payment increase of 76.51%, 51.96%, 20.74%, respectively. Mortality dropped for MO by 32.11%, from 76.9% to 52.2%, for MH by 49.46%, from 55.6% to 28.1% and in GM by 73.80% from 35.5 % to 9.3%. The average length of stay was 1 to 2 days longer in the MH and GM (respectively) compared to MO, with an increase from 2011 to 2022 for GM and MO, but a decrease for MH. Readmission rates decreased from 17.4% to 15.1% for MO, 12.7% to 10.3% for MH, and 14.9 to 12.5% for GM. In 2014, the percentage of Medicaid population increased in GM, and decreased in the oncology services (MO and MH) reaching 35% and 14% of the admitted patient population in 2022, respectively. Percentage of Medicare patients increased from 36.9% to 52.9%, 39.6% to 44.9%, and remained stable for MO, HM, and GM, respectively. Hospice discharge fluctuated between 1.2-1.6%, 2.5-5%, 8-12.9% of the discharged patients in GM, MH, and MO, respectively. Conclusions: In this abstract, we present a decade-trend data of important measures of inpatient oncology units.

Введение. Профилактика внезапной сердечной смерти (ВСС), основанная на популяционных факторах риска, имеет низкую степень персонализации и недостаточную предиктивную точность 51,3–66,7%.Цель. Разработка информационной технологии первичной профилактики ВСС на основе ЭКГ-маркеров электрической нестабильности миокарда (ЭНМ), ориентированной на поликлиническое звено, где сконцентрирован основной поток кардиологических пациентов.Материалы и методы. Выполнен анализ ЭКГ высокого разрешения 1014 пациентов с коронарными и некоронарогенными заболеваниями, средний возраст 49,9±5,9 года. Первичные конечные точки: желудочковая тахикардия, успешная сердечно-легочная реанимация, разряды ИКД или ВСС. Период наблюдения 5,0 (2,1; 5,9) года. Контролировали ЭхоКГ, ХМ-ЭКГ и ЭКГ-маркеры ЭНМ: фрагментация QRS, угол QRS-T, длительность и дисперсия QRS, альтернация Т-волны, длительность и дисперсия QT, Tpeak-Tend, турбулентность и замедление сердечного ритма. Использовалась компьютерная программа «Интекард 7.3».Результаты. Среди ЭКГ-маркеров ЭНМ в фазе деполяризации наибольшей прогностической мощностью обладают фрагментация QRS – относительный риск (ОР) 4,3, 95% ДИ (3,5–6,3), p<0,001 и пространственный угол QRS-T – ОР=2,2, 95% ДИ (1,5–2,5), p<0,001. В фазе реполяризации наиболее высокие значения ОР имеют альтернация Т-волны – ОР=4,1, 95% ДИ (2,2–6,2), p<0,001 и дисперсия интервала QT – ОР=2,7, 95% ДИ (1,3–5,4), p<0,001. Маркеры дисфункции вегетативной регуляции турбулентность и замедление сердечного ритма имели ОР, равные 1,7, 95% ДИ (1,0–5,5) и 1,4, 95% ДИ (1,1–5,9) соответственно, p<0,05. Разработан персонифицированный алгоритм первичной профилактики ВСС на основе оценки ФВ, ХМ-ЭКГ и ЭКГ-маркеров ЭНМ. Риск стратифицируется на низкий, средний, высокий и критический. В соответствии с уровнем риска пациентам рекомендуется имплантация ритм-поддерживающих систем, медикаментозная терапия или мониторинг. При клинической апробации алгоритма у 52% пациентов зафиксирован низкий риск, у 42% – средний и у 6% – высокий риск ВСС.Заключение. Предложенная стратегия управления кардиоваскулярными рисками направлена на снижение преждевременной смертности от сердечно-сосудистых заболеваний. Неинвазивность, персонификация и высокая пропускная способность создают предпосылки для широкого внедрения программы первичной профилактики ВСС. Introduction. Prevention of sudden cardiac death (SCD) based on population risk factors has a low degree of personalization and, as a result, an insufficient predictive accuracy of 51.3–66.7%.Purpose. Development of information technology for primary prevention of SCD based on ECG-markers of electrical myocardial instability (EMI), focused on the polyclinics, where the main stream of cardiological patients is concentrated.Materials and methods. High-resolution ECG analysis was performed in 1014 patients with coronary and non-coronary heart diseases, mean age 49.9±5.9 years. Primary endpoints: ventricular tachycardia, successful cardiopulmonary resuscitation, ICD shocks or SCD. Follow-up period was 5.0 (2.1; 5.9) years. Controlled echoCG, HM-ECG and ECG- markers of the EMI: QRS fragmentation, QRS-T angle, QRS duration and dispersion, T-wave alternans, QT duration and dispersion, Tpeak-Tend, turbulence and deceleration of heart rate. The "Intecard 7.3" computer program was used.Results. Among the ECG-markers of EMI in the depolarization phase, QRS fragmentation has the highest predictive power – relative risk (RR)=4.3 95% CI (3.5–6.3), p<0.001 and QRS–T angle – RR=2.2 95% CI (1.5–2.5), p<0.001. In the repolarization phase, the highest RR values have T wave alternans – RR=4.1 95% CI (2.2–6.2), p<0.001 and QT interval dispersion – RR=2.7 95% CI (1.3–5.4), p<0.001. Autonomic regulation dysfunction markers heart rhythm turbulence and deceleration rate had RRs of 1.7 95% CI (1.0–5.5) and 1.4 95% CI (1.1–5.9), respectively, p<0.05. The personalized algorithm for the primary prevention of SCD based on the assessment of EF, HM-ECG and ECG-markers of EMI has been developed. The risk is stratified into low, medium, high and critical. According to the level of risk, implantation of rhythm-support systems, drug therapy or monitoring is recommended. In clinical testing of the algorithm, 52% of patients had a low risk, 42% – an average risk, and 6% – a high risk of SCD.Conclusion. The proposed strategy for managing cardiovascular risks is aimed at reducing premature mortality from cardiovascular diseases. Non-invasiveness, personalization and high throughput create the prerequisites for the widespread introduction of the SCD primary prevention program.

Abstract Background Patients with hematologic malignancies (HM) or hematopoietic stem cell transplant (HSCT) commonly receive broad-spectrum antimicrobials, often leading to the development of multidrug resistant organisms (MDRO). At our institution, rectal stool surveillance cultures (SSC) are done weekly on admitted adult patients with HMs or HSCT. The objective of this study is to determine the role of SSCs in predicting the development of a sterile site infection (StSI) with the same MDRO as identified in the SSC. Methods We retrospectively evaluated StSIs (blood, CSF, sputum/respiratory, pleural fluid, and urine) and SSC data from 242 adult patients admitted to the adult oncology ward at a large academic tertiary care center from 6/1/2017 to 2/28/2019. Demographics, SSC data, and StSIs in a 3-month period following the last SSC for each patient were collected from electronic medical records. SSCs were cultured on HardyCHROM ESBL™ media. MDRO similarity between SSC and StSI was determined by comparing susceptibility profiles. JMPÒ Pro 14.3.0 and RStudio were used for statistical analyses. Results Two hundred forty-two patients yielded 732 SSCs. We eliminated SSCs with incomplete (&lt; 3 months of follow up) data. Thus, 579 SSCs were included in the analyses. 64% of patients were male. Leukemias (55.4%), lymphomas (21.9%), and multiple myeloma (10.3%) were the most common HMs. HSCT recipients comprised 50.4%. SSCs were positive for a MDRO in 251 cases (vancomycin-resistant enterococci, 52.2%; extended-spectrum beta-lactamase (ESBL) producing organisms, 22.2%; and carbapenamase producing organisms, 4.4%). There were 54 StSIs documented where the MDRO was the same as the SSC MDRO. The NPV of the SSC was 95.1% (95%CI 0.93,0.97). The positive likelihood ratio of the SSC was 2.5 (95%CI 2.07,3.02). Conclusion Our results suggest that a negative SSC is associated with a lower probability of identifying a StSI with an MDRO. Clinically, this can be useful in providing the opportunity to judiciously guide antimicrobial therapy, thereby avoiding the unnecessary usage of broad-spectrum antimicrobials when no MDRO is identified in the SSC. Disclosures All Authors: No reported disclosures

e16121 Background: Colorectal cancer (CRC) is the second most common cancer in women and third in men. DNA damage repair (DDR) deficiency has emerged as a predictive biomarker for chemotherapy, PARP and immune checkpoint inhibitors. However, comprehensive molecular characteristics of DDR variants in Chinese CRC patients is lacking. Methods: Formalin fixed, paraffin embedded (FFPE) tumor tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) assay. The testing was carried out in a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Alterations of six functional gene sets involved in DDR pathways: homologous recombination (HR), mismatch repair (MMR), base excision repair (BER), nonhomologous end-joining (NHEJ), checkpoint factors (CPF) and Fanconi anemia (FA) were analyzed. The association of DDR gene mutations with TMB/MSI was assessed. Results: In total, 319 CRC patients were recruited, 127 female and 192 male with a median age of 59 (range 23-92). Over one third (36%,115/319) patients had at least one mutation in DDR genes. Mutation rates varied in different DDR pathway: HR (20.7%), CPF (15.1%), FA (11.3%), MMR (10.3%), BER (8.8%), and NHEJ (5.3%). The most frequently mutated DDR genes were ARID1A (13.4%), ATM (10.2%), BRCA2 (6.8%), MLH1 (5.6%), MSH6 (5.6%), POLE (5.0%). Germline mutations in MLH1 (2.5%), BRCA2 (1.2%), MSH2 (0.9%), MSH6 (0.9%), FANCA (0.9%), ATM (0.6%), BRCA1 (0.3%), and CHEK2 (0.3%) were detected in 24 patients. DDR variations were enriched in the right-side CRC compared to the left side CRC (50% vs. 32.8%, p= 0.024). Early stage (I-II) harbored more DDR variations. 20.1% of patients had high TMB (≥10 muts/Mb) with a median of 51 muts/Mb (10-326.7 mus/Mb). Patients with DDR mutations had a significantly higher TMB than patients with wild type DDR (8.5 vs. 4.6 muts/Mb, p< 0.001). All CRC tumors with high MSI harbored DDR mutations. Importantly, the mutations in “HM” (HR/MMR), but not BER/CPF/NHEJ/FA mutations, were significantly correlated with high MSI ( p< 0.001). Conclusions: DDR gene alterations occurred in 36% of Chinese CRC patients and were enriched in right sided tumors. DDR pathway alterations are relatively frequent in CRC and consideration for biomarker-enriched clinical trials with PARP, immune checkpoint inhibitors, and novel combinations are warranted.

Background:There is limited evidence regarding the impact of the Mediterranean Diet (Med Diet) on autoimmune diseases although it has been proposed that adherence to the Med Diet may decrease the risk of certain autoimmune diseases. However, the potential usefulness of the Med Diet as a high-quality dietary pattern for other autoimmune diseases such as SLE has not yet been investigated.Objectives:The aim of this study was to evaluate the potential association between the adherence to the Med Diet and disease activity, damage accrual and SLE-related clinical markers in a large cohort of women with SLE.Methods:In this cross-sectional study, we assessed Med Diet adherence through a 14-item questionnaire in 253 women with SLE (mean age 46.74 ± 12.70 years). The SLE Disease Activity Index (SLEDAI-2K) and the SDI Damage Index were used to asses disease activity and disease-related damage, respectively. Levels of C-reactive protein (CRP; mg/dL), homocysteine (Hcy; mol/L), anti-double stranded DNA antibodies (anti-dsDNA) (IU/mL), complement C3 (mg/dL), and complement C4 (mg/dL) were determined.Results:The Med Diet adherence score was classified as follows: low adherence (≤ 5 points); medium adherence (6–9 points) and good adherence (≥ 10 points). Only 50.2% of the SLE women had good adherence to the Med Diet. The ANCOVA models showed significant differences between patients with good adherence to the Med Diet and those with medium and low adherence in SLEDAI (p ≤ 0.001) and SDI (p ≤ 0.001). Age, medical treatment (immunosuppressors, corticoids, or antimalarials), smoking status, and body mass index (BMI) were included as confounding factors. The odds ratio (OR) for having active SLE (SLEDAI ≥ 5) or the presence of damage (SDI ≥ 1) was lower among patients whose Med Diet score was higher (p ≤ 0.001).Conclusion:Adherence to the Med Diet influences disease activity and damage accrual in SLE women. Thus, these patients would benefit from nutritional counselling and education on modification, to help adapt their lifestyles towards the Med Diet pattern. This would help slow the progression of SLE and the damage it causes.References:[1]Sedaghat F, Jessri M, Behrooz M, Mirghotbi M, Rashidkhani B. Mediterranean diet adherence and risk of multiple sclerosis: a case-control study. Asia Pac J Clin Nutr. 2016;25(2):377–84.[2]orsyth C, Kouvari M, D’Cunha NM, Georgousopoulou EN, Panagiotakos DB, Mellor DD, et al. The effects of the Mediterranean diet on rheumatoid arthritis prevention and treatment: a systematic review of human prospective studies. Rheumatol Int. 2018 May 18;38(5):737–47.[3]Minihane AM, Vinoy S, Russell WR, Baka A, Roche HM, Tuohy KM, et al. Low-grade inflammation, diet composition and health: current research evidence and its translation. Br J Nutr. 2015 Oct 14;114(7):999–1012.Acknowledgements:This research was supported by the grant PI0523-2016 from “Consejería de igualdad, salud y políticas sociales” (Junta de Andalucía) and is part of the research group LyDIMED “Lupus y Dieta Mediterránea”.Disclosure of Interests:None declared

Введение. Семейная природа дилатационной кардиомиопатии (ДКМП) часто неочевидна. В рутинной практике, если семейный анамнез тщательно не анализируют и не обследуют родственников пробандов, ДКМП ошибочно классифицируют как идиопатическую. Цель. Изучение диагностической значимости каскадного скрининга и генетического тестирования у пациентов с идиопатической ДКМП для выявления семейных форм заболевания. Материалы и методы. В исследование включили 259 неродственных пациентов с идиопатической формой ДКМП. Всем пациентам (возраст 46,5 [36; 57] года; 207 (79,9%) – мужчины; ФВ ЛЖ 29 [23; 36] %; КДД ЛЖ 67,7 [61; 74] мм; период наблюдения – 59 [42; 71] мес.) проведен комплекс клинико-инструментальных исследований (ЭКГ, ЭхоКГ, ХМ, МРТ) и каскадный семейный скрининг. По данным генеалогического и каскадного анализа когорты у 70 пробандов выявили критерии семейной ДКМП, у 56 лиц обнаружили признаки потенциально наследственного заболевания. В этой группе (n=126) проведены молекулярно-генетические исследования (секвенирование нового поколения с верификацией выявленных вариантов по методу Sanger) и косегрегационный анализ. Результаты. Патогенные и вероятно патогенные генетические варианты обнаружены у 61 (48,4%) из 126 пациентов с ДКМП. Доминирующими мутациями были укорачивающие варианты в гене титина, идентифицированные у 16 лиц (12,7%), и варианты ламина А/C, выявленные у 13 пробандов (10,3%), в других 19 генах мутации идентифицированы у 32 (25,4%) пациентов. В группе с семейной формой заболевания генетическая причина ДКМП определена в 45 (64,3%) случаях из 70, в то время как среди пациентов с предположительной наследственной составляющей патогенные мутации выявлены у 16 (28,6%) из 56 лиц. Детальное изучение семейного анамнеза и родословной пациентов с идиопатической ДКМП, каскадный скрининг с обследованием родственников пробандов, имеющих факторы генетического риска, позволили многократно улучшить диагностику семейной формы ДКМП и повысить частоту выявления наследственного заболевания в когорте «идиопатической» ДКМП с 5 (1,93%) до 70 (27%) случаев, а с учетом генетического теста – до 81 (31,3%). Результаты анализа Каплана – Мейера продемонстрировали значимо худший 5-летний прогноз и кумулятивную выживаемость пациентов с семейной формой заболевания (log rang χ2=38,5; р=0,0001) по сравнению с пациентами со спорадической ДКМП, однако значимых различий в достижении комбинированной конечной точки между генпозитивными и ген-негативными пациентами (log rang χ2=3,54; р=0,06) не выявлено. Заключение. Каскадный семейный скрининг (тщательная клиническая оценка родственников пробандов) и генетическое тестирование в когорте спорадической ДКМП позволили увеличить уровень диагностики семейных форм ДКМП с 1,93% до 31,3%. Introduction. The familial nature of dilated cardiomyopathy (DCM) is often not obvious. In routine clinical practice, if the family history is not carefully analyzed and relatives of the probands are not examined, DCM is erroneously classified as idiopathic. Purpose. To study the diagnostic value of cascade screening and genetic testing in patients with idiopathic DCM for the detection of familial forms of the disease. Materials and methods. The study included 259 unrelated patients (pts) with idiopathic DCM. All pts (aged 46.5 [36; 57] years; 207 (79.9%) male; LVEF 29 [23; 36] %; LV EDD 67.7 [61; 74] mm; follow-up median 59 [42; 71] months) a complex of clinical and instrumental studies (ECG, Echo, HM, MRI) and cascade family screening were performed. According to the genealogical and cascade analysis of the cohort, the criteria for familial DCM were identified in 70 probands, and signs of a potentially hereditary disease were found in 56 pts. This group (n=126) underwent molecular genetic studies (next generation sequencing followed by verification of identified variants using the Sanger method) and segregation analysis. Results. Pathogenic and likely pathogenic genetic variants were found in 61 (48.4%) of 126 DCM pts. The dominant mutations were truncating variants in the Titin gene, identified in 16 pts (12.7%), and Lamin A/C variants, identified in 13 probands (10.3%), in the other 19 genes, mutations were identified in 32 (25.4%) of pts. In the group with a familial disease, the genetic cause of DCM was identified in 45 (64.3%) of 70 pts, while in patients with a presumed hereditary component, pathogenic mutations were detected in 16 (28.6%) of 56 pts. A detailed study of the family history and pedigree of patients with idiopathic DCM, cascade screening with examination of relatives of probands with genetic risk factors, made it possible to significantly improve the diagnosis of the family form of DCM and increase the frequency of detection of a hereditary disease in the cohort of "idiopathic" DCM from 5 (1.93%) up to 70 (27%) pts, and taking into account the genetic test – up to 81 (31.3%). The results of Kaplan – Meier analysis showed a significantly worse 5-year prognosis and cumulative survival of pts with familial DCM (log χ2=38.5; p=0.0001) compared with sporadic DCM, however, there were significant differences in achieving the combined endpoint between gene-positive and gene-negative pts (log rang χ2=3.54; p=0.06) were not detected. Conclusion. Cascade family screening (detailed clinical assessment of proband relatives) and genetic testing in the cohort of sporadic DCM allowed to increase the level of diagnostics of familial DCM from 1.93% to 31.3%.

BackgroundFamilial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent attacks of fever, serositis, and musculoskeletal symptoms [1, 2]. Arthritis is the most common musculoskeletal symptom of attacks and also included in diagnostic criteria of FMF [3]. If it is specifically queried, myalgia may be detected in up to 20-25% of the patients with FMF. [4, 5].ObjectivesIn our study, we aim to assess the localization of attack-related myalgia and associated parameters in patients with FMF.MethodsA total of 349 consecutive patients followed by FMF in our clinic were enrolled in the study and asked for attack-induced myalgia and if present, localization of muscle groups on the mannequin body parts diagram.Attack frequency, duration, and disease activity were evaluated with the AutoInflammatory Diseases Activity Index (AIDAI) scoring system [6]. Patients were also asked for work/study day loss during attacks and patient acceptable symptom state (PASS) status [7].Results126 patients showed attack myalgia (36%); attack duration, frequency, severity were significantly higher in patients with attack-myalgia (p<0,005). Most common muscle groups were calves, lower back, and latissimus dorsi muscles in order. Myalgia was most commonly accompanied by arthritis (p<0,002). Patients with myalgia have a higher frequency of colchicine resistance and work/study day loss due to attacks.ConclusionOur results conclude that myalgia is an important domain of attacks and causes absenteeism and uncontrolled disease activity.References[1]El-Shanti H, Majeed HA, El-Khateeb M. Familial mediterranean fever in Arabs.Lancet. 2006;367(9515):1016–24.[2]Majeed HA, Al-Qudah AK, Qubain H, Shahin HM. The clinical patterns of myalgia in children with familial Mediterranean fever. Semin Arthritis Rheum. 2000;30(2):138–43.[3]Gattorno M, Hofer M, Federici S, Vanoni F et al. Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO). Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019 Aug;78(8):1025-1032. doi: 10.1136/annrheumdis-2019-215048.[4]Zemer D. Muscle pains in familial Mediterranean fever. Harefuah 1984; 106: 232-233.[5]Majeed HA. Differential diagnosis of fever of unknown origin in children. Curr Opin Rheumatol 2000; 12: 439-444.[6]Piram M, Frenkel J, Gattorno M et al. EUROFEVER and EUROTRAPS networks. A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference. Ann Rheum Dis. 2011 Feb;70(2):309-14. doi: 10.1136/ard.2010.132613.[7]Salaffi F, Carotti M, Gutierrez M, Di Carlo M, De Angelis R. (2015) Patient Acceptable Symptom State in Self-Report Questionnaires and Composite Clinical Disease Index for Assessing Rheumatoid Arthritis Activity: Identification of Cut-Off Points for Routine Care. Biomed Res Int. 2015:930756. doi: 10.1155/2015/930756.Table 1.Comparison of clinical and laboratory parameters between patients with /without myalgia attacksPatients with myalgia attackPatients without myalgia attackp valueAge (years)36,33 ±10, 6837,9±11, 48>0,05Sex (female/male)78/43138/87>0,05Follow-up time (years)16,117,6>0,05Dominant attack(number)Peritonitis4255>0,05Arthritis11390,012Pleuritis1310>0,05Only fever47>0,05AIDAI score (mean, 0-175)127,4080,68<0,05VAS score for pain (median score, during attack. 0-10)85<0,05Colchicine resistance (number of patients)69250,003Colchicine-resistantColchicine-sensitive29840,002PASS status (number)4160,016Need additional treatment Satisfied from treatment34740,010Work/study day loss (number)4860,003AcknowledgementsNo financial funding is received for this report. Informed consents for participating and publishing were obtained from all participantsDisclosure of InterestsNone declared

BackgroundFamilial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent attacks of fever, serositis, and musculoskeletal symptoms (1, 2). Arthritis is the most common musculoskeletal symptom of attacks and also included in diagnostic criteria of FMF (3). If it is specifically queried, myalgia may be detected in up to 20-25% of the patients with FMF.(4,5).ObjectivesIn our study, we aim to assess the localization of attack-related myalgia and associated parameters in patients with FMF.MethodsA total of 349 consecutive patients followed by FMF in our clinic were enrolled in the study and asked for attack-induced myalgia and if present, localization of muscle groups on the mannequin body parts diagram.Attack frequency, duration, and disease activity were evaluated with the AutoInflammatory Diseases Activity Index (AIDAI) scoring system (6). Patients were also asked for work/study day loss during attacks and patient acceptable symptom state (PASS) status (7).Results126 patients showed attack myalgia (36%); attack duration, frequency, severity were significantly higher in patients with attack-myalgia (p<0,005). Most common muscle groups were calves, lower back, and latissimus dorsi muscles in order. Myalgia was most commonly accompanied by arthritis (p<0,002). Patients with myalgia have a higher frequency of colchicine resistance and work/study day loss due to attacks.ConclusionOur results conclude that myalgia is an important domain of attacks and causes absenteeism and uncontrolled disease activity. Treatment of myalgia attacks may provide controlled disease activity, and prevent absenteeism from work/school.References[1]El-Shanti H, Majeed HA, El-Khateeb M. Familial mediterranean fever in Arabs.Lancet. 2006;367(9515):1016–24.[2]Majeed HA, Al-Qudah AK, Qubain H, Shahin HM. The clinical patterns of myalgia in children with familial Mediterranean fever. Semin Arthritis Rheum. 2000;30(2):138–43.[3]Gattorno M, Hofer M, Federici S, Vanoni F et al. Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO). Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019 Aug;78(8):1025-1032. doi: 10.1136/annrheumdis-2019-215048.[4]Zemer D. Muscle pains in familial Mediterranean fever. Harefuah 1984; 106: 232-233.[5]Majeed HA. Differential diagnosis of fever of unknown origin in children. Curr Opin Rheumatol 2000; 12: 439-444.[6]Piram M, Frenkel J, Gattorno M et al. EUROFEVER and EUROTRAPS networks. A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference. Ann Rheum Dis. 2011 Feb;70(2):309-14. doi: 10.1136/ard.2010.132613.[7]Salaffi F, Carotti M, Gutierrez M, Di Carlo M, De Angelis R. (2015) Patient Acceptable Symptom State in Self-Report Questionnaires and Composite Clinical Disease Index for Assessing Rheumatoid Arthritis Activity: Identification of Cut-Off Points for Routine Care. Biomed Res Int. 2015:930756. doi: 10.1155/2015/930756.Table 1.Comparison of clinical and laboratory parameters between patients with /without myalgia attacksPatients with myalgia attackPatients without myalgia attackp valueAge (years)36,33 ±10, 6837,9±11, 48>0,05Sex (female/male)78/43138/87>0,05Follow-up time (years)16,117,6>0,05Dominant attack(number)Peritonitis4255>0,05Arthritis11390,012Pleuritis1310>0,05Only fever47>0,05AIDAI score (mean, 0-175)127,4080,68<0,05VAS score for pain (median score, during attack. 0-10)85<0,05Colchicine resistance (number ofpatients)69250,003Colchicine-resistant29840,002Colchicine-sensitivePASS status (number)Need additional treatment4160,016Satisfied from treatment34740,010Work/study day loss (number)4860,003AcknowledgementsAll study population signed informed consent for both participation and publication. Local Ethical Committee of the university approved the study.Disclosure of InterestsNone declared

Introduction Methods Resuts Discussion Conclusions Acknowledgments Authors' contributions Competing interests Ethical approval References Effect of Methotrexate and Omega-3 Combination on Cytogenetic Changes of Bone Marrow and Some Enzymatic Antioxidants: An Experimental Study Inaam N. Ali1, Muthana M. Awad2, Alaa S. Mahmood2,* 1 Water and Environment Directorate, Ministry of Sciences and Technology, Baghdad, Iraq 2 Department of Biology, College of Science, University of Anbar, Anbar, Iraq * Corresponding author: A. S. Mahmood (alaashm91@gmail.com) Abstract: Objective: To assess the effect of methotrexate and omega-3 combination on cytogenetic changes of bone marrow and activities of some enzymatic antioxidants. Methods: Fifty-six mature male Wistar rats were divided into two experimental groups and a control group. The first experimental group was sub-divided into three sub-groups depending on the concentration of methotrexate (MTX): X1 (0.05 mg/kg MTX), X2 (0.125 mg/kg MTX) and X3 (0.250 mg/kg MTX), which were given intraperitoneally on a weekly basis for eight weeks. The second experimental group (MTX and omega-3 group) was also sub-divided into three sub-groups (Y1, Y2 and Y3), which were injected intraperitoneally with 0.05, 0.125 and 0.25 mg/kg MTX, respectively, weekly for eight weeks accompanied by the oral administration of 300 mg/kg omega-3. The rats of the control group were given distilled water. The enzymatic activity of catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR) were measured in the sera of rats. In addition, the mitotic index (MI) and chromosomal aberrations of bone marrow were also studied. Results: MTX resulted in a significant decrease in the activities of CAT, SOD and GR compared to the controls. It also increased the MI and chromosomal aberrations of rat bone marrows. On the other hand, omega-3 significantly increased the activities of the investigated enzymatic antioxidants and reduced the MI and chromosomal aberrations in treated mice when given in combination with MTX. Conclusions: MTX has a genotoxic effect on the bone marrow by increasing the MI and all types of chromosomal aberrations and decreasing the enzymatic activity of CAT, SOD and GR. The addition of omega-3 can lead to a protective effect by reducing the toxic and mutagenic effects of MTX. Keywords: Methotrexate, Omega-3, Antioxidant, Wistar rat, Chromosomal aberration, Mitotic index 1. Introduction Methotrexate (MTX) is a folic acid antagonist because of their chemical similarity [1]. Vezmar et al. [2] showed that MTX affects the synthesis of nucleic acids deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) by interfering with the biosynthesis of thymine and purines. It also directly affects the rapidly dividing and intact cells, especially those in the mucous membranes of the mouth, intestine and bone marrow [3]. Omega-3 is a type of unsaturated fats, which are classified as essential fatty acids that cannot be manufactured by the body and should be taken with food [4]. Sources of omega-3 include fish oils, such as salmon, sardines and tuna, as well as soybeans, walnuts, raisins and linseed, almonds and olive oils [5]. Omega-3 is used in the prevention of a number of diseases such as rheumatoid arthritis, ulcerative colitis, asthma, atherosclerosis, cancer, and cardiovascular diseases [6]. A large amount of evidence indicates that omega-3 fatty acids have significant health benefits, including anti-inflammatory and antioxidant properties besides their effect on blood cholesterol levels [7]. Antioxidants retard the oxidation process by different mechanisms such as the removal of free radicals [8]. Enzymatic antioxidants include catalase (CAT), which is the first line of defense in the cell that removes hydrogen peroxide formed during biological processes by converting it into an aldehyde, and superoxide dismutase (SOD). There are three major families of SOD enzymes: manganese SOD (Mn-SOD) in the mitochondria and peroxisomes, iron SOD (Fe-SOD) in prokaryote cells and copper/zinc SOD (Cu-Zn SOD) in the cytoplasm of eukaryote cells [9]. Therefore, changes in the metal co-factors (manganese, iron, copper and zinc) can alter the effectiveness of SOD and may lead to diseases as a result of oxidative stress [10]. Glutathione reductase (GR) is also an enzymatic antioxidant that converts the oxidized glutathione to the reduced glutathione in the presence of NADPH, which is oxidized to NADP [11]. Therefore, the aim of the present study was to assess the effects of MTX and omega-3 on the cytogenetic changes of bone marrow as well as the activities of CAT, SOD and GR enzymatic antioxidants in male rats. 2. Method 2.1. Laboratory animals and experimental design Fifty-six mature male Wistar rats (Rattus norvegicus), aged 10–12 weeks old and weighing 250–300 gm, were used in the present study. The rats were kept in separate cages, with natural 13- hour light and 11-hour dark periods in a contamination-free environment with a controlled temperature (28.0 ± 1.0°C). In addition, rats were maintained on a standard diet and tap water ad libitum. The rats were randomly allocated to two experimental groups and a control group. The first experimental group (MTX group) included 24 rats injected intraperitoneally with different MTX dilutions with distilled water [12]. It was sub-divided into three sub-groups (eight rats per sub-group) according to MTX concentration as follows: X1 (0.05 mg/kg MTX), X2 (0.125mg/kg MTX) and X3 (0.25 mg/kg MTX). All rats were given a single dose of the specified MTX concentration weekly for eight weeks. The second experimental group (MTX and omega-3 group) included 24 rats allocated to three sub-groups (Y1, Y2 and Y3), which were injected intraperitoneally with 0.05, 0.125 and 0.25 mg/kg MTX, respectively, weekly for eight weeks accompanied by the oral administration of 300 mg/kg omega-3. The control group included eight rats that were intraperitoneally injected with distilled water and given a single dose of distilled water orally weekly for eight weeks. 2.2. Blood collection and processing After the end of the dosing period, 5 ml of blood were withdrawn from the heart (by cardiac puncture) using a 5 cc disposable syringe. The collected blood was immediately poured into a clean sterile screw-capped tube (plain tube) and left for coagulation in a water bath at 37°C for 15 minutes. After coagulation of blood, the plain tube was centrifuged for 5 minutes at 1500 rpm. Then the samples were stored at -20°C for subsequent analysis. 2.3. Measurement of the activity of antioxidant enzymes The antioxidant activities of CAT, SOD and GR were measured using enzyme-linked immunosorbent assay kits purchased from Kamiya Biomedical Company (Seattle, WA, US), according to the manufacturer's instructions. 2.4. Cytogenetic study of bone marrow Rats were killed by cervical dislocation, and their hip bones were cleaned from surrounding muscles and then dissected by cutting both ends of the bone. Five milliliters of physiological buffered saline were injected inside the bone to withdraw bone marrow into a test tube. Tubes were centrifuged at 2000 rpm/10 minutes. The supernatant was then removed, and 10 ml of KCL solution (0.075 M) were added to the sediment. The mixture was then incubated at 37 °C in a water bath for 30 minutes, with shaking from time to time. The tubes were then centrifuged at 2000rpm/10 minutes to remove the supernatant. However, 5 ml of a freshly prepared fixative solution (methanol: glacial acetic acid 1:3) were added gradually in the form of droplets into the inner wall of the tube with constant mixing. After that, the tubes were placed at 4 °C for half an hour to fix the cells. This process was repeated for three times, and the cells were then suspended in 2 ml of the fixative solution. The tubes were centrifuged at 2000 rpm for 5 minutes, and the supernatant was then removed while the cells were re-suspended in 1-2 ml of cold fixative solution. After shaking the tubes, 4–5 drops were then taken from each tube onto a clean slide from a height of about three feet to provide an opportunity for the cells and nuclei to spread well. The slides were stained with acridine orange solution (0.01%) for 4–5 minutes, incubated in Sorensen’s buffer (0.06M, pH 6.5) for a minute. and then examined using a fluorescence microscope Olympus BX 51 America at a wavelength of 450–500 nm [13, 14]. A total of 1000 cells were examined, and both dividing and non-dividing cells were calculated [13]. Mitotic index (MI) was calculated according to the following formula [13]: MI= No. of dividing cells / 1000 × 100 2.5. Analysis of chromosomal aberrations of bone marrow cells A total of 1000 dividing cells were examined on the stained slides under a fluorescence microscope at a wavelength of 45–500 nm. The examined cells were at the first metaphase of the mitotic division, where chromosomal aberrations are clear and can be easily seen [13]. 2.6. Statistical analysis Data were analyzed using the Statistical Analysis System (SAS®) software, version 9.1 (Cary, NC, USA) [15]. Effects were expressed as mean ± standard error (SE) and statistically compared using a completely randomized design analysis of variance and least significant differences. Differences at P values <5 were considered statistically significant. 3. Results 3.1. Effects of MTX and MTX-omega-3 combination on antioxidant enzymatic activities Table (1) shows significantly lower SOD activities among rats treated with MTX or MTX-omega-3 compared to controls. Moreover, sera of rats receiving relatively high doses of MTX (sub-groups X2 and X3) showed the lowest enzymatic activities of 4.29 ± 0.01 IU and 3.93 ± 0.11 IU, respectively. On the other hand, CAT activity differed significantly between treated and control rats as well as among treated rats themselves, In this respect, the controls showed the highest activity of 39.38 ±0.02 IU, while those receiving the highest MTX concentration, either alone or in combination with omega-3 (sub-groups X3 and Y3), showed the lowest activities of 30.97 ± 0.03 IU and 32.12± 0.06 IU, respectively. Regarding GR activity, control rats showed a higher activity of 53.09± 0.05 IU compared to treated ones; however, the differences in GR activities in rats given low doses of MTX, either alone or in combination with omega-3 (sub-groups X1 and Y1), were not statistically significant. On the other hand, rats in sub-groups X3 and Y3 showed the lowest GR activities of 34.59 ± 0.63 IU and 37.15 ±0.01, respectively, with statistically significant differences from other sub-groups. 3.2. Effects of MTX and MTX-omega-3 combination on mitotic index of bone marrow cells Figure (1) shows a significant decrease in the MI in all treated groups compared to control. In addition, there was a reverse association between MTX concentration and MI, where rats treated with the highest dose of MTX (sub-group X3) showed a significant decrease in MI compared to all other treated rat sub-groups. In addition, rats in sub-groups treated with MTX and omega-3 (sub-groups Y1, Y2 and Y3) showed a significant increase in MI compared to their counterpart rats receiving MTX only. Table 1. Activity of antioxidant enzymes in rats treated with MTX and MTX-omega-3 Group Enzymatic activity (mean± SE) SOD (IU) CAT (IU) GR (µmol) Control 6.41±0.02 a 39.38±0.02 a 53.09±0.05 a X1 (0.05 mg MTX/ kg) 5.33±0.01 b 37.81±0.01 c 51.12±0.06 a Y1 (0.05 mg MTX + 300 mg omega-3/ kg) 6.08±0.04 a 38.40±0.02 b 51.97±0.03 a X2 (0.125 mg MTX/ kg) 4.29±0.01 cd 33.13±0.01 e 42.34±0.03 b Y2 (0.125 mg MTX + 300 mg omega-3/ kg) 4.99±0.40 b 36.68±0.02 d 43.02±3.04 b X3 (0.25 mg MTX/ kg) 3.93±0.11 d 30.97±0.03 g 34.59±0.63 c Y3 (0.25 mg MTX + 300 mg omega-3/ kg) 4.47±0.02 c 32.12±0.06 f 37.15±0.01 c SE, Standard error; IU, international unit; SOD, superoxide dismutase; CAT, catalase; GR, glutathione reductase; *statistically significant at P < 0.05; **statistically significant at P < 0.01. Means with different letters within the same column showed a statistically significant difference. 3.3. Effects of MTX and MTX-omega-3 combination on chromosomal aberrations of bone marrow cells Rats receiving higher concentrations of MTX (sub-group X3) showed a significant increase in all types of chromosomal aberrations, i.e., chromatid gaps, chromosome gaps, chromatid breaks, chromosome breaks, deletions and simple fragments (Figure 2 and Table 2) than those of the control group or other treated sub-groups. All rats treated with MTX-omega-3 combination showed a significant decrease in almost all types of chromosomal aberrations compared to their counterpart rats receiving MTX alone (Table 2). Figure 1. Effect of MTX and MTX-omega-3 on the MI of bone marrow cells of treated rats compared to the controls. The groups X1 (0.05 MTX), X2 (0.125 MTX) and X3 (0.250 MTX) were compared to the control group, while the groups Y1 (0.05 MTX+ omega-3), Y2 (0.125 MTX+ omega-3) and Y3 (0.25 MTX+ omega-3) were compared to X1, X2 and X3, respectively. Figure 2. Effect of MTX and MTX-omega-3 on chromosomal aberration as seen under fluorescence microscope after staining with acridine orange: (1) a simple fragment; (2) a chromatid gap; (3) a chromosomal gap (A) and a chromosomal break (B). 4. Discussion The present experiment reveals that the addition of omega-3 to MTX alleviates its effects on the activities of the antioxidant enzymes CAT, SOD and GR, and decreases the MI as well as all types of chromosomal aberrations in the bone marrow cells. Daham et al. [16] showed that the decline in antioxidants associated with chemotherapy is attributed to the increase in lipid peroxidation caused by these kinds of drugs, which increase the level of free radicals. In addition, Weijl et al. [17] showed that some chemotherapeutic drugs have a negative effect on the antioxidant levels such as GR, whose activity decreases as a result of its involvement in many cellular processes such as cell defenses against the toxicity of some compounds. Al-Dalawy et al. [18] found that the decrease in the level of SOD is an evidence of its increased activity due to the increased release of free radicals. MTX causes an increase in the release of free radicals, including the OH radical that causes direct damage to DNA [16]. Al-Helaly [19] showed that the amount of food taken has an effect on antioxidants, where nutritional deficiency decreases the antioxidant levels, thus increasing free radicals that cause damage to DNA. Table 2. Chromosomal aberrations of bone marrow cells in rats treated with MTX and MTX-omega-3 Group Type of chromosomal aberration(mean ± SE) Chromatid gap Chromosome Gap Chromatid breaks Chromosome breaks Deletion Simple Fragments Chromosomal aberration (%) Control 1.33±0.33 e 0.00±0.00 e 1.67±0.33 c 0.33±0.15 c 0.00±0.00 0.67±0.33 cd 0.04±0.005 f X1 2.75±0.47 cd 1.50±0.28 cd 2.50±0.64 bc 1.00±0.41 bc 0.50±0.28 bc 0.75±0.25 bcd 0.09±0.02 de Y1 1.75±0.47 de 0.75±0.25 de 1.50±0.28 c 1.00±0.00 bc 0.75±0.25 abc 0.75±0.25 abc 0.065±0.005 ef X2 4.67±0.33 b 2.67±0.33 ab 2.67±0.33 bc 1.67±0.33 ab 0.67±0.33 abc 1.67±0.33 ab 0.14±0.006 bc Y2 3.00±0.00 c 2.00±0.00 bc 3.00±0.057 bc 1.33±0.33 b 0.67±0.33 abc 0.33±0.15 d 0.106±0.003 cd X3 6.80±0.37 a 3.00±0.31 a 4.60±0.74 a 2.40±0.24 a 1.40±0.24 a 1.80±0.37 a 0.20±0.017 a Y3 5.60±0.40 ab 2.40±0.24 ab 3.60±0.24 ab 1.80±0.20 ab 1.20±0.20 ab 1.40±0.24 abc 0.16±0.003 b LSD 1.231** 0.814** 0.602** 0.841** 0.774* 0.941** 3.499* SE, Standard error; * statistically significant at P < 0.05; ** statistically significant at P < 0.01. Means with different letters within the same column showed a statistically significant difference. X1 (0.05 mg MTX/ kg); X2 (0.125 mg MTX/ kg); X3 (0.25 mg MTX/ kg); Y1 (0.05 mg MTX + 300 mg omega-3/ kg); Y2 (0.125 mg MTX + 300 mg omega-3/ kg); Y3 (0.25 mg MTX + 300 mg omega-3/ kg). In the present study, the intraperitoneal administration of MTX to rats also caused a decrease in the MI of bone marrow and a significant increase in the rate of abnormal chromosomal aberration compared to the control rats. This finding is consistent with those reported previously [20], [21]. The effect of MTX can be attributed to its ability to interfere with the genetic material, leading to the appearance of toxic and mutagenic consequences. Rushworth et al. [22] reported that MTX leads to a lack of dihydrofolate reductase, which is the key to the growth and cell division processes. This, in turn, leads to a reduction of the nucleotides involved in the building of DNA and, therefore, to a stop or obstruction of the repair mechanisms of the damaged DNA. In addition, Wong and Choi [23] concluded that MTX inhibits the action of enzymes controlling the purine metabolism, which leads to the accumulation of adenosine in addition to the damage of the molecule itself and to the occurrence of chromosomal aberrations. Jafer et al. [24] reported the ability of MTX to induce chromosomal aberration in humans or animals by preventing the repair of DNA and affecting the proteins found in chromosomes. These findings were also confirmed by Hussain et al. [25], who found that MTX causes an increase in chromosomal aberrations. In the present study, the MI showed a significant increase in rat sub-groups treated with MTX-omega-3 combination, but there was a decrease in the rate of chromosomal aberration, which confirms the role of omega-3 unsaturated fatty acids in protecting the cell from the impact of free radicals [26], [27]. Attia and Nasr [28] reported the antioxidant effect of omega-3, which was attributed to the reduction in lipid peroxidation and the increase in SOD and CAT or the stimulation of GR. It is noteworthy that GR leads to the synthesis of reduced glutathione, which is important in the defense of the cell against toxic substances and the prevention of the occurrence of mutations [29]. 5. Conclusions MTX significantly decreases the activity of enzymatic antioxidants, reduce the MI and increase the chromosomal aberrations of all types in bone marrow. This gives further evidence on the genotoxic effects of MTX on the bone marrow. On the other hand, omega-3 shows a protective effect by reducing the toxic and mutagenic effects of MTX. Acknowledgments The authors thank the staff of the Water and Environment Directorate, Ministry of Science and Technology, Baghdad, Iraq for their cooperation. They also thank Dr. Jasim Al-Niami for his technical and scientific guidance. Authors' contributions INA, MMA and ASM contributed to the study design and analyzed data. All authors contributed to the manuscript drafting and revising and approved the final submission. Competing interests The authors declare that they have no competing interests associated with this article. Ethical approval The ethical clearance of this study was obtained from the Ethics Committee of the College of Science, University of Anbar (Reference No. A. D. 51 in 30/8/2015). References Yuen CW, Winter ME. Methotrexate (MTX). In: Basic clinical pharmacokinetics, Winter ME, editor. Philadelphia, USA: Lippincott Williams & Wilkins; 2010. p.p. 304–25. Google Scholar Vezmar S, Becker A, Bode U, Jaehde U. Biochemical and clinical aspects of methotrexate neurotoxicity. Chemotherapy 2003; 49: 92–104. DOI PubMed - Google Scholar Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis 2007; 65: 168–73. PubMed - Google Scholar El-Khayat Z, Rasheed WI, Elias T, Hussein J, Oraby F, Badawi M, et al. Protective effect of either dietary or pharmaceutical n-3 fatty acids on bone loss in ovariectomized rats. Maced J Med Sci 2010; 3: 9–16. DOI - Google Scholar Kris-Etherton PM, Harris WS, Appel LJ; Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids and cardiovascular disease. Arterioscler Thromb Vasc Biol 2003; 23: e20–30. DOI - PubMed - Google Scholar Calder PC. Polyunsaturated fatty acids and inflammation. Prostaglandins Leukot Essent Fatty Acids 2006; 75: 197–202. DOI - PubMed - Google Scholar Begin ME, Ells G, Das UN, Horrobin DF. Differential killing of human carcinoma cells supplemented with n-3 and n-6 polyunsaturated fatty acids. J Natl Cancer Inst 1986; 77: 1053–62. DOI - PubMed - Google Scholar Shan B, Cai YZ, Sun M, Corke H. Antioxidant capacity of 26 spice extracts and characterization of their phenolic constituents. J Agric Food Chem. 2005; 53: 7749–59. DOI - PubMed - Google Scholar Matiax J, Quiles JL, Huertas JR, Battino M. Tissue specific interactions of exercise, dietary fatty acids, and vitamin E in lipid peroxidation. Free Radic Biol Med 1998; 24 : 511–21. DOI - PubMed - Google Scholar Dean RT, Fu S, Stocker R, Davies MJ. Biochemistry and pathology of radical-mediated protein oxidation. Biochem J 1997; 324: 1–8. PubMed - Google Scholar Bashir A, Perham RN, Scrutton NS, Berry A. Altering Kinetic mechanism and enzyme stability by mutagenesis of the dimmer interface of glutathione reductase. Biochem J 1995; 312: 527–33. PubMed - Google Scholar Perret-Gentil MI. Rat Biomethodology. Laboratory Animal Resources Center. The University of Texas at San Antonio. [Cited 1 Feb. 2015]. Available from: https://www.utdallas.edu/research/docs/rat_biomethodology/ Allen JW, Shuler CF, Menders RW, Olatt SA. A simplified technique for in vivo analysis of sister chromatid exchange using 50 bromodeoxyuridine tablets. Cytogenet Cell Genet 1977; 18: 231–7. DOI PubMed - Google Scholar Forsum U, Hallén A. Acridine orange staining of urethral and cervical smears for the diagnosis of gonorrhea. Acta Derm Venereol 1979; 59: 281–2. PubMed - Google Scholar Statistical Analysis System user's guide. Version 9.1. Cary, NC, USA: SAS Institute Inc.; 2012. Daham HH, Rahim SM, Al-Hmesh MJ. The effect of radiotherapy and chemotherapy in several physiological and biochemical parameters in cancer patients. Tikrit J Pure Sci 2012; 17: 83–91. Weijl N, Elseendoorm TJ, Lentjes EG, Hopman CD, Wipkink-Bakker A, Zwinderman AH, et al. Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double-blind placebo-controlled study. Eur J Cancer 2004; 40: 1713–23. DOI - PubMed - Google Scholar Al-Dalawy SS, Al-Salehy FK, Al-Sanafi AI. Efficient enzymatic antioxidants for oxidative stress syndrome in patients with hypertension. J Dhi Qar Sci 2008; 2: 32–3. Al-Helaly LA. Some antioxidant enzymes in workers exposed to pollutants. Raf J Sci 2011; 22: 29–38. Google Scholar Othman GO. Protective effects of linseed oil against methotrexate induced genotoxicity in bone marrow cells of albino mice Mus musculus. ZJPAS. 2016; 28: 49–53. Google Scholar Ashoka CH, Vijayalaxmi KK. Cytogenetic effects of methotrexate in bone marrow cells of Swiss albino mice. Int J Sci Res Edu 2016; 4: 4828–34. DOI - Google Scholar Rushworth D, Mathews A, Alpert A, Cooper Dihydrofolate reductase and thymidylate synthase transgenes resistant to methotrexate interact to permit novel transgene regulation. J Biol Chem 2015; 290: 22970–9. DOI - PubMed - Google Scholar Wong PT, Choi SK. Mechanisms and implications of dual-acting methotrexate in folate-targeted nanotherapeutic delivery. Int J Mol Sci 2015; 16: 1772–90. DOI - PubMed - Google Scholar Jafer ZMT, Shubber EK, Amash HS. Cytogenetic analysis of Chinese hamster lung fibroblasts spontaneously resistant to methotrexate. Nucleus 2001; 44: 28–35. Google Scholar Hussain ZK, AL-Mhdawi F, AL-Bakri N. Effect of methotrexate drug on some parameters of kidney in newborn mice. Iraqi J Sci 2014; 55: 968–73. Google Scholar Ghazi-Khansari M, Mohammadi-Bardbori A. Captopril ameliorates toxicity induced by paraquat in mitochondria isolated from the rat liver. Toxicol in Vitro 2007; 21: 403–7. DOI - PubMed - Google Scholar Dinic-olivira RJ, Sousa C, Remiao F, Durte JA, Navarro SA, Bastos L, et al. Full survival of paraquat-exposed rats after treatment with sodium salicylate. Free Radic Biol Med 2007; 42: 1017–28. DOI - PubMed - Google Scholar Attia AM, Nasr HM. Dimethoate-induced changes in biochemical parameters of experimental rat serum and its neutralization by black seed (Nigella sativa) oil. Slovak J Anim Sci 2009; 42: 87–94. Google Scholar Al-Rubaie AH.M. Effect of natural honey and mitomycin C on the effectiveness of the enzyme glutathione reductase in mice Mus musculus. Babylon Uni J 2008; 15: 1385–91.

Introduction Methods Resuts Discussion Conclusions Acknowledgments Authors' contributions Competing interests Ethical approval References Effect of Methotrexate and Omega-3 Combination on Cytogenetic Changes of Bone Marrow and Some Enzymatic Antioxidants: An Experimental Study Inaam N. Ali1, Muthana M. Awad2, Alaa S. Mahmood2,* 1 Water and Environment Directorate, Ministry of Sciences and Technology, Baghdad, Iraq 2 Department of Biology, College of Science, University of Anbar, Anbar, Iraq * Corresponding author: A. S. Mahmood (alaashm91@gmail.com) Abstract: Objective: To assess the effect of methotrexate and omega-3 combination on cytogenetic changes of bone marrow and activities of some enzymatic antioxidants. Methods: Fifty-six mature male Wistar rats were divided into two experimental groups and a control group. The first experimental group was sub-divided into three sub-groups depending on the concentration of methotrexate (MTX): X1 (0.05 mg/kg MTX), X2 (0.125 mg/kg MTX) and X3 (0.250 mg/kg MTX), which were given intraperitoneally on a weekly basis for eight weeks. The second experimental group (MTX and omega-3 group) was also sub-divided into three sub-groups (Y1, Y2 and Y3), which were injected intraperitoneally with 0.05, 0.125 and 0.25 mg/kg MTX, respectively, weekly for eight weeks accompanied by the oral administration of 300 mg/kg omega-3. The rats of the control group were given distilled water. The enzymatic activity of catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR) were measured in the sera of rats. In addition, the mitotic index (MI) and chromosomal aberrations of bone marrow were also studied. Results: MTX resulted in a significant decrease in the activities of CAT, SOD and GR compared to the controls. It also increased the MI and chromosomal aberrations of rat bone marrows. On the other hand, omega-3 significantly increased the activities of the investigated enzymatic antioxidants and reduced the MI and chromosomal aberrations in treated mice when given in combination with MTX. Conclusions: MTX has a genotoxic effect on the bone marrow by increasing the MI and all types of chromosomal aberrations and decreasing the enzymatic activity of CAT, SOD and GR. The addition of omega-3 can lead to a protective effect by reducing the toxic and mutagenic effects of MTX. Keywords: Methotrexate, Omega-3, Antioxidant, Wistar rat, Chromosomal aberration, Mitotic index 1. Introduction Methotrexate (MTX) is a folic acid antagonist because of their chemical similarity [1]. Vezmar et al. [2] showed that MTX affects the synthesis of nucleic acids deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) by interfering with the biosynthesis of thymine and purines. It also directly affects the rapidly dividing and intact cells, especially those in the mucous membranes of the mouth, intestine and bone marrow [3]. Omega-3 is a type of unsaturated fats, which are classified as essential fatty acids that cannot be manufactured by the body and should be taken with food [4]. Sources of omega-3 include fish oils, such as salmon, sardines and tuna, as well as soybeans, walnuts, raisins and linseed, almonds and olive oils [5]. Omega-3 is used in the prevention of a number of diseases such as rheumatoid arthritis, ulcerative colitis, asthma, atherosclerosis, cancer, and cardiovascular diseases [6]. A large amount of evidence indicates that omega-3 fatty acids have significant health benefits, including anti-inflammatory and antioxidant properties besides their effect on blood cholesterol levels [7]. Antioxidants retard the oxidation process by different mechanisms such as the removal of free radicals [8]. Enzymatic antioxidants include catalase (CAT), which is the first line of defense in the cell that removes hydrogen peroxide formed during biological processes by converting it into an aldehyde, and superoxide dismutase (SOD). There are three major families of SOD enzymes: manganese SOD (Mn-SOD) in the mitochondria and peroxisomes, iron SOD (Fe-SOD) in prokaryote cells and copper/zinc SOD (Cu-Zn SOD) in the cytoplasm of eukaryote cells [9]. Therefore, changes in the metal co-factors (manganese, iron, copper and zinc) can alter the effectiveness of SOD and may lead to diseases as a result of oxidative stress [10]. Glutathione reductase (GR) is also an enzymatic antioxidant that converts the oxidized glutathione to the reduced glutathione in the presence of NADPH, which is oxidized to NADP [11]. Therefore, the aim of the present study was to assess the effects of MTX and omega-3 on the cytogenetic changes of bone marrow as well as the activities of CAT, SOD and GR enzymatic antioxidants in male rats. 2. Method 2.1. Laboratory animals and experimental design Fifty-six mature male Wistar rats (Rattus norvegicus), aged 10–12 weeks old and weighing 250–300 gm, were used in the present study. The rats were kept in separate cages, with natural 13- hour light and 11-hour dark periods in a contamination-free environment with a controlled temperature (28.0 ± 1.0°C). In addition, rats were maintained on a standard diet and tap water ad libitum. The rats were randomly allocated to two experimental groups and a control group. The first experimental group (MTX group) included 24 rats injected intraperitoneally with different MTX dilutions with distilled water [12]. It was sub-divided into three sub-groups (eight rats per sub-group) according to MTX concentration as follows: X1 (0.05 mg/kg MTX), X2 (0.125mg/kg MTX) and X3 (0.25 mg/kg MTX). All rats were given a single dose of the specified MTX concentration weekly for eight weeks. The second experimental group (MTX and omega-3 group) included 24 rats allocated to three sub-groups (Y1, Y2 and Y3), which were injected intraperitoneally with 0.05, 0.125 and 0.25 mg/kg MTX, respectively, weekly for eight weeks accompanied by the oral administration of 300 mg/kg omega-3. The control group included eight rats that were intraperitoneally injected with distilled water and given a single dose of distilled water orally weekly for eight weeks. 2.2. Blood collection and processing After the end of the dosing period, 5 ml of blood were withdrawn from the heart (by cardiac puncture) using a 5 cc disposable syringe. The collected blood was immediately poured into a clean sterile screw-capped tube (plain tube) and left for coagulation in a water bath at 37°C for 15 minutes. After coagulation of blood, the plain tube was centrifuged for 5 minutes at 1500 rpm. Then the samples were stored at -20°C for subsequent analysis. 2.3. Measurement of the activity of antioxidant enzymes The antioxidant activities of CAT, SOD and GR were measured using enzyme-linked immunosorbent assay kits purchased from Kamiya Biomedical Company (Seattle, WA, US), according to the manufacturer's instructions. 2.4. Cytogenetic study of bone marrow Rats were killed by cervical dislocation, and their hip bones were cleaned from surrounding muscles and then dissected by cutting both ends of the bone. Five milliliters of physiological buffered saline were injected inside the bone to withdraw bone marrow into a test tube. Tubes were centrifuged at 2000 rpm/10 minutes. The supernatant was then removed, and 10 ml of KCL solution (0.075 M) were added to the sediment. The mixture was then incubated at 37 °C in a water bath for 30 minutes, with shaking from time to time. The tubes were then centrifuged at 2000rpm/10 minutes to remove the supernatant. However, 5 ml of a freshly prepared fixative solution (methanol: glacial acetic acid 1:3) were added gradually in the form of droplets into the inner wall of the tube with constant mixing. After that, the tubes were placed at 4 °C for half an hour to fix the cells. This process was repeated for three times, and the cells were then suspended in 2 ml of the fixative solution. The tubes were centrifuged at 2000 rpm for 5 minutes, and the supernatant was then removed while the cells were re-suspended in 1-2 ml of cold fixative solution. After shaking the tubes, 4–5 drops were then taken from each tube onto a clean slide from a height of about three feet to provide an opportunity for the cells and nuclei to spread well. The slides were stained with acridine orange solution (0.01%) for 4–5 minutes, incubated in Sorensen’s buffer (0.06M, pH 6.5) for a minute. and then examined using a fluorescence microscope Olympus BX 51 America at a wavelength of 450–500 nm [13, 14]. A total of 1000 cells were examined, and both dividing and non-dividing cells were calculated [13]. Mitotic index (MI) was calculated according to the following formula [13]: MI= No. of dividing cells / 1000 × 100 2.5. Analysis of chromosomal aberrations of bone marrow cells A total of 1000 dividing cells were examined on the stained slides under a fluorescence microscope at a wavelength of 45–500 nm. The examined cells were at the first metaphase of the mitotic division, where chromosomal aberrations are clear and can be easily seen [13]. 2.6. Statistical analysis Data were analyzed using the Statistical Analysis System (SAS®) software, version 9.1 (Cary, NC, USA) [15]. Effects were expressed as mean ± standard error (SE) and statistically compared using a completely randomized design analysis of variance and least significant differences. Differences at P values <5 were considered statistically significant. 3. Results 3.1. Effects of MTX and MTX-omega-3 combination on antioxidant enzymatic activities Table (1) shows significantly lower SOD activities among rats treated with MTX or MTX-omega-3 compared to controls. Moreover, sera of rats receiving relatively high doses of MTX (sub-groups X2 and X3) showed the lowest enzymatic activities of 4.29 ± 0.01 IU and 3.93 ± 0.11 IU, respectively. On the other hand, CAT activity differed significantly between treated and control rats as well as among treated rats themselves, In this respect, the controls showed the highest activity of 39.38 ±0.02 IU, while those receiving the highest MTX concentration, either alone or in combination with omega-3 (sub-groups X3 and Y3), showed the lowest activities of 30.97 ± 0.03 IU and 32.12± 0.06 IU, respectively. Regarding GR activity, control rats showed a higher activity of 53.09± 0.05 IU compared to treated ones; however, the differences in GR activities in rats given low doses of MTX, either alone or in combination with omega-3 (sub-groups X1 and Y1), were not statistically significant. On the other hand, rats in sub-groups X3 and Y3 showed the lowest GR activities of 34.59 ± 0.63 IU and 37.15 ±0.01, respectively, with statistically significant differences from other sub-groups. 3.2. Effects of MTX and MTX-omega-3 combination on mitotic index of bone marrow cells Figure (1) shows a significant decrease in the MI in all treated groups compared to control. In addition, there was a reverse association between MTX concentration and MI, where rats treated with the highest dose of MTX (sub-group X3) showed a significant decrease in MI compared to all other treated rat sub-groups. In addition, rats in sub-groups treated with MTX and omega-3 (sub-groups Y1, Y2 and Y3) showed a significant increase in MI compared to their counterpart rats receiving MTX only. Table 1. Activity of antioxidant enzymes in rats treated with MTX and MTX-omega-3 Group Enzymatic activity (mean± SE) SOD (IU) CAT (IU) GR (µmol) Control 6.41±0.02 a 39.38±0.02 a 53.09±0.05 a X1 (0.05 mg MTX/ kg) 5.33±0.01 b 37.81±0.01 c 51.12±0.06 a Y1 (0.05 mg MTX + 300 mg omega-3/ kg) 6.08±0.04 a 38.40±0.02 b 51.97±0.03 a X2 (0.125 mg MTX/ kg) 4.29±0.01 cd 33.13±0.01 e 42.34±0.03 b Y2 (0.125 mg MTX + 300 mg omega-3/ kg) 4.99±0.40 b 36.68±0.02 d 43.02±3.04 b X3 (0.25 mg MTX/ kg) 3.93±0.11 d 30.97±0.03 g 34.59±0.63 c Y3 (0.25 mg MTX + 300 mg omega-3/ kg) 4.47±0.02 c 32.12±0.06 f 37.15±0.01 c SE, Standard error; IU, international unit; SOD, superoxide dismutase; CAT, catalase; GR, glutathione reductase; *statistically significant at P < 0.05; **statistically significant at P < 0.01. Means with different letters within the same column showed a statistically significant difference. 3.3. Effects of MTX and MTX-omega-3 combination on chromosomal aberrations of bone marrow cells Rats receiving higher concentrations of MTX (sub-group X3) showed a significant increase in all types of chromosomal aberrations, i.e., chromatid gaps, chromosome gaps, chromatid breaks, chromosome breaks, deletions and simple fragments (Figure 2 and Table 2) than those of the control group or other treated sub-groups. All rats treated with MTX-omega-3 combination showed a significant decrease in almost all types of chromosomal aberrations compared to their counterpart rats receiving MTX alone (Table 2). Figure 1. Effect of MTX and MTX-omega-3 on the MI of bone marrow cells of treated rats compared to the controls. The groups X1 (0.05 MTX), X2 (0.125 MTX) and X3 (0.250 MTX) were compared to the control group, while the groups Y1 (0.05 MTX+ omega-3), Y2 (0.125 MTX+ omega-3) and Y3 (0.25 MTX+ omega-3) were compared to X1, X2 and X3, respectively. Figure 2. Effect of MTX and MTX-omega-3 on chromosomal aberration as seen under fluorescence microscope after staining with acridine orange: (1) a simple fragment; (2) a chromatid gap; (3) a chromosomal gap (A) and a chromosomal break (B). 4. Discussion The present experiment reveals that the addition of omega-3 to MTX alleviates its effects on the activities of the antioxidant enzymes CAT, SOD and GR, and decreases the MI as well as all types of chromosomal aberrations in the bone marrow cells. Daham et al. [16] showed that the decline in antioxidants associated with chemotherapy is attributed to the increase in lipid peroxidation caused by these kinds of drugs, which increase the level of free radicals. In addition, Weijl et al. [17] showed that some chemotherapeutic drugs have a negative effect on the antioxidant levels such as GR, whose activity decreases as a result of its involvement in many cellular processes such as cell defenses against the toxicity of some compounds. Al-Dalawy et al. [18] found that the decrease in the level of SOD is an evidence of its increased activity due to the increased release of free radicals. MTX causes an increase in the release of free radicals, including the OH radical that causes direct damage to DNA [16]. Al-Helaly [19] showed that the amount of food taken has an effect on antioxidants, where nutritional deficiency decreases the antioxidant levels, thus increasing free radicals that cause damage to DNA. Table 2. Chromosomal aberrations of bone marrow cells in rats treated with MTX and MTX-omega-3 Group Type of chromosomal aberration(mean ± SE) Chromatid gap Chromosome Gap Chromatid breaks Chromosome breaks Deletion Simple Fragments Chromosomal aberration (%) Control 1.33±0.33 e 0.00±0.00 e 1.67±0.33 c 0.33±0.15 c 0.00±0.00 0.67±0.33 cd 0.04±0.005 f X1 2.75±0.47 cd 1.50±0.28 cd 2.50±0.64 bc 1.00±0.41 bc 0.50±0.28 bc 0.75±0.25 bcd 0.09±0.02 de Y1 1.75±0.47 de 0.75±0.25 de 1.50±0.28 c 1.00±0.00 bc 0.75±0.25 abc 0.75±0.25 abc 0.065±0.005 ef X2 4.67±0.33 b 2.67±0.33 ab 2.67±0.33 bc 1.67±0.33 ab 0.67±0.33 abc 1.67±0.33 ab 0.14±0.006 bc Y2 3.00±0.00 c 2.00±0.00 bc 3.00±0.057 bc 1.33±0.33 b 0.67±0.33 abc 0.33±0.15 d 0.106±0.003 cd X3 6.80±0.37 a 3.00±0.31 a 4.60±0.74 a 2.40±0.24 a 1.40±0.24 a 1.80±0.37 a 0.20±0.017 a Y3 5.60±0.40 ab 2.40±0.24 ab 3.60±0.24 ab 1.80±0.20 ab 1.20±0.20 ab 1.40±0.24 abc 0.16±0.003 b LSD 1.231** 0.814** 0.602** 0.841** 0.774* 0.941** 3.499* SE, Standard error; * statistically significant at P < 0.05; ** statistically significant at P < 0.01. Means with different letters within the same column showed a statistically significant difference. X1 (0.05 mg MTX/ kg); X2 (0.125 mg MTX/ kg); X3 (0.25 mg MTX/ kg); Y1 (0.05 mg MTX + 300 mg omega-3/ kg); Y2 (0.125 mg MTX + 300 mg omega-3/ kg); Y3 (0.25 mg MTX + 300 mg omega-3/ kg). In the present study, the intraperitoneal administration of MTX to rats also caused a decrease in the MI of bone marrow and a significant increase in the rate of abnormal chromosomal aberration compared to the control rats. This finding is consistent with those reported previously [20], [21]. The effect of MTX can be attributed to its ability to interfere with the genetic material, leading to the appearance of toxic and mutagenic consequences. Rushworth et al. [22] reported that MTX leads to a lack of dihydrofolate reductase, which is the key to the growth and cell division processes. This, in turn, leads to a reduction of the nucleotides involved in the building of DNA and, therefore, to a stop or obstruction of the repair mechanisms of the damaged DNA. In addition, Wong and Choi [23] concluded that MTX inhibits the action of enzymes controlling the purine metabolism, which leads to the accumulation of adenosine in addition to the damage of the molecule itself and to the occurrence of chromosomal aberrations. Jafer et al. [24] reported the ability of MTX to induce chromosomal aberration in humans or animals by preventing the repair of DNA and affecting the proteins found in chromosomes. These findings were also confirmed by Hussain et al. [25], who found that MTX causes an increase in chromosomal aberrations. In the present study, the MI showed a significant increase in rat sub-groups treated with MTX-omega-3 combination, but there was a decrease in the rate of chromosomal aberration, which confirms the role of omega-3 unsaturated fatty acids in protecting the cell from the impact of free radicals [26], [27]. Attia and Nasr [28] reported the antioxidant effect of omega-3, which was attributed to the reduction in lipid peroxidation and the increase in SOD and CAT or the stimulation of GR. It is noteworthy that GR leads to the synthesis of reduced glutathione, which is important in the defense of the cell against toxic substances and the prevention of the occurrence of mutations [29]. 5. Conclusions MTX significantly decreases the activity of enzymatic antioxidants, reduce the MI and increase the chromosomal aberrations of all types in bone marrow. This gives further evidence on the genotoxic effects of MTX on the bone marrow. On the other hand, omega-3 shows a protective effect by reducing the toxic and mutagenic effects of MTX. Acknowledgments The authors thank the staff of the Water and Environment Directorate, Ministry of Science and Technology, Baghdad, Iraq for their cooperation. They also thank Dr. Jasim Al-Niami for his technical and scientific guidance. Authors' contributions INA, MMA and ASM contributed to the study design and analyzed data. All authors contributed to the manuscript drafting and revising and approved the final submission. Competing interests The authors declare that they have no competing interests associated with this article. Ethical approval The ethical clearance of this study was obtained from the Ethics Committee of the College of Science, University of Anbar (Reference No. A. D. 51 in 30/8/2015). References Yuen CW, Winter ME. Methotrexate (MTX). In: Basic clinical pharmacokinetics, Winter ME, editor. Philadelphia, USA: Lippincott Williams & Wilkins; 2010. p.p. 304–25. Google Scholar Vezmar S, Becker A, Bode U, Jaehde U. Biochemical and clinical aspects of methotrexate neurotoxicity. Chemotherapy 2003; 49: 92–104. DOI PubMed - Google Scholar Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis 2007; 65: 168–73. PubMed - Google Scholar El-Khayat Z, Rasheed WI, Elias T, Hussein J, Oraby F, Badawi M, et al. Protective effect of either dietary or pharmaceutical n-3 fatty acids on bone loss in ovariectomized rats. Maced J Med Sci 2010; 3: 9–16. DOI - Google Scholar Kris-Etherton PM, Harris WS, Appel LJ; Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids and cardiovascular disease. Arterioscler Thromb Vasc Biol 2003; 23: e20–30. DOI - PubMed - Google Scholar Calder PC. Polyunsaturated fatty acids and inflammation. Prostaglandins Leukot Essent Fatty Acids 2006; 75: 197–202. DOI - PubMed - Google Scholar Begin ME, Ells G, Das UN, Horrobin DF. Differential killing of human carcinoma cells supplemented with n-3 and n-6 polyunsaturated fatty acids. J Natl Cancer Inst 1986; 77: 1053–62. DOI - PubMed - Google Scholar Shan B, Cai YZ, Sun M, Corke H. Antioxidant capacity of 26 spice extracts and characterization of their phenolic constituents. J Agric Food Chem. 2005; 53: 7749–59. DOI - PubMed - Google Scholar Matiax J, Quiles JL, Huertas JR, Battino M. Tissue specific interactions of exercise, dietary fatty acids, and vitamin E in lipid peroxidation. Free Radic Biol Med 1998; 24 : 511–21. DOI - PubMed - Google Scholar Dean RT, Fu S, Stocker R, Davies MJ. Biochemistry and pathology of radical-mediated protein oxidation. Biochem J 1997; 324: 1–8. PubMed - Google Scholar Bashir A, Perham RN, Scrutton NS, Berry A. Altering Kinetic mechanism and enzyme stability by mutagenesis of the dimmer interface of glutathione reductase. Biochem J 1995; 312: 527–33. PubMed - Google Scholar Perret-Gentil MI. Rat Biomethodology. Laboratory Animal Resources Center. The University of Texas at San Antonio. [Cited 1 Feb. 2015]. Available from: https://www.utdallas.edu/research/docs/rat_biomethodology/ Allen JW, Shuler CF, Menders RW, Olatt SA. A simplified technique for in vivo analysis of sister chromatid exchange using 50 bromodeoxyuridine tablets. Cytogenet Cell Genet 1977; 18: 231–7. DOI PubMed - Google Scholar Forsum U, Hallén A. Acridine orange staining of urethral and cervical smears for the diagnosis of gonorrhea. Acta Derm Venereol 1979; 59: 281–2. PubMed - Google Scholar Statistical Analysis System user's guide. Version 9.1. Cary, NC, USA: SAS Institute Inc.; 2012. Daham HH, Rahim SM, Al-Hmesh MJ. The effect of radiotherapy and chemotherapy in several physiological and biochemical parameters in cancer patients. Tikrit J Pure Sci 2012; 17: 83–91. Weijl N, Elseendoorm TJ, Lentjes EG, Hopman CD, Wipkink-Bakker A, Zwinderman AH, et al. Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double-blind placebo-controlled study. Eur J Cancer 2004; 40: 1713–23. DOI - PubMed - Google Scholar Al-Dalawy SS, Al-Salehy FK, Al-Sanafi AI. Efficient enzymatic antioxidants for oxidative stress syndrome in patients with hypertension. J Dhi Qar Sci 2008; 2: 32–3. Al-Helaly LA. Some antioxidant enzymes in workers exposed to pollutants. Raf J Sci 2011; 22: 29–38. Google Scholar Othman GO. Protective effects of linseed oil against methotrexate induced genotoxicity in bone marrow cells of albino mice Mus musculus. ZJPAS. 2016; 28: 49–53. Google Scholar Ashoka CH, Vijayalaxmi KK. Cytogenetic effects of methotrexate in bone marrow cells of Swiss albino mice. Int J Sci Res Edu 2016; 4: 4828–34. DOI - Google Scholar Rushworth D, Mathews A, Alpert A, Cooper Dihydrofolate reductase and thymidylate synthase transgenes resistant to methotrexate interact to permit novel transgene regulation. J Biol Chem 2015; 290: 22970–9. DOI - PubMed - Google Scholar Wong PT, Choi SK. Mechanisms and implications of dual-acting methotrexate in folate-targeted nanotherapeutic delivery. Int J Mol Sci 2015; 16: 1772–90. DOI - PubMed - Google Scholar Jafer ZMT, Shubber EK, Amash HS. Cytogenetic analysis of Chinese hamster lung fibroblasts spontaneously resistant to methotrexate. Nucleus 2001; 44: 28–35. Google Scholar Hussain ZK, AL-Mhdawi F, AL-Bakri N. Effect of methotrexate drug on some parameters of kidney in newborn mice. Iraqi J Sci 2014; 55: 968–73. Google Scholar Ghazi-Khansari M, Mohammadi-Bardbori A. Captopril ameliorates toxicity induced by paraquat in mitochondria isolated from the rat liver. Toxicol in Vitro 2007; 21: 403–7. DOI - PubMed - Google Scholar Dinic-olivira RJ, Sousa C, Remiao F, Durte JA, Navarro SA, Bastos L, et al. Full survival of paraquat-exposed rats after treatment with sodium salicylate. Free Radic Biol Med 2007; 42: 1017–28. DOI - PubMed - Google Scholar Attia AM, Nasr HM. Dimethoate-induced changes in biochemical parameters of experimental rat serum and its neutralization by black seed (Nigella sativa) oil. Slovak J Anim Sci 2009; 42: 87–94. Google Scholar Al-Rubaie AH.M. Effect of natural honey and mitomycin C on the effectiveness of the enzyme glutathione reductase in mice Mus musculus. Babylon Uni J 2008; 15: 1385–91.

La Historia de las Matemáticas (HM) es una herramienta que puede ser muy útil en un contexto educativo. Sin embargo, la HM es un cuerpo de saber muy extenso y es necesario reflexionar cual HM debe ser enseñada en la formación inicial de los profesores en los primeros años de escolaridad. En este artículo hacemos esta reflexión tratando de justificar qué contenidos HM son realmente esenciales para los profesores y para sus futuras prácticas profesionales. En nuestra opinión, los contenidos de HM deben centrarse en los temas: sistemas de numeración de diversos pueblos, diferentes algoritmos para realizar operaciones aritméticas y resolver ecuaciones, tópicos de la geometría, así como el conocimiento de varios puntos de HM local/nacional. También damos una breve descripción de lo que son los cursos de Educación Básica en Portugal, prestando especial atención a las matemáticas que se enseñaban en estos cursos. Por otro lado, también presentamos varias referencias a estudios internacionales donde se atestigua la importancia de usar HM en el aula.Palabras clave: Educación básica Formación del profesorado, historia de las matemáticas, historia de las matemáticas como herramienta en un contexto educativo. HISTORY OF MATHEMATICS IN PORTUGUESE INITIAL BASIC TEACHER EDUCATION PROGRAMS: A REFLECTION FOR TEACHER TRAININGAbstractHistory of Mathematics (HM) is a tool that can be very useful in an educational context. However, HM is a very broad corpus of knowledge and it is necessary to reflect on what HM should be taught in the initial basic teacher education programs. In this paper, we make this reflection by trying to justify which HM contents are truly essential for teachers and their future professional practices. In our opinion, HM contents should focus on the following topics: diverse ancient peoples numbering systems, different algorithms for performing arithmetic operations and solving equations, geometry topics, as well as knowledge of various local/national HM aspects. We also give a brief description of Portuguese initial basic teacher education programs, giving special focus on the mathematics syllabus in these programs. And we present several references to international studies that show the importance of using HM in the classroom context.Keywords: Training of elementary school teachers, history of mathematics, history of mathematics as a tool in educational context. A HISTÓRIA DA MATEMÁTICA NOS CURSOS DE EDUCAÇÃO BÁSICA EM PORTUGAL: UMA REFLEXÃO PARA A FORMAÇÃO DE PROFESSORESResumoA História da Matemática (HM) é uma ferramenta que poderá ser muito útil em contexto educativo. Contudo, a HM é um corpo de saber muito extenso e é necessário refletir qual a HM que deverá ser ensinada na formação inicial de professores dos primeiros anos de escolaridade. Neste artigo fazemos essa reflexão tentando justificar quais os conteúdos de HM verdadeiramente essenciais para os professores e para as suas práticas profissionais futuras. Na nossa opinião, os conteúdos de HM deverão centrar-se nos temas: sistemas de numeração de diversos povos, diferentes algoritmos para realizar operações aritméticas e resolver equações, tópicos de geometria, bem como o conhecimento de vários pontos de HM local/nacional. Fazemos ainda uma breve descrição do que são os cursos de Educação Básica em Portugal, dando especial enfoque nas matemáticas lecionadas nesses cursos. Por outro lado, apresentamos também várias referências a estudos internacionais onde se atesta a importância da utilização da HM em contexto de sala de aula.Palavras- chave: Formação de professores do ensino básico, história da matemática, história da matemática como ferramenta em contexto educativo.

Abstract Background Knowledge about the prevalence, factors and mortality associated with subsequent carbapenem-resistant Enterobacterales (CRE) infection among hematological malignancies (HM) patients colonized with CRE is limited. Methods HM patients were screened for rectal CRE. A retrospective case–control study of subsequent CRE infection among HM patients colonized with CRE was conducted between January 1st, 2020 and January 31st, 2022. Cases were defined as CRE colonized patients with subsequent infection and controls were those without infection. Bacterial identification was performed using MALDI Biotyper and antimicrobial susceptibility testing of strains was carried out using the VITEK 2 system or standard broth microdilution method. Logistic analysis was used for analyzing associated factors and Kaplan–Meier method was used for survival estimates. Results A total of 953 HM patients were screened for rectal CRE and 98 (10.3%, 98/953) patients were colonized with CRE. Among the 98 colonized patients, 18 (18.4%, 18/98) patients developed subsequent infection. Most of the colonizing CRE isolates were Klebsiella pneumoniae (50.0%, 27/54), followed by Escherichia coli (27.8%, 15/54) and Enterobacter cloacae (9.3%, 5/54). As for the subsequent infecting CRE isolates, the dominated species was K. pneumoniae (55.6%, 10/18), followed by E. coli (33.3%, 6/18) and others (11.2%, 2/18). Receiving proton pump inhibitors and admission to ICU (P < 0.05) were the associated factors. Patients with subsequent CRE infection had significant higher mortality (33.3% vs 2.8%, P = 0.001) and shock was an associated factor (P = 0.008). Conclusions Klebsiella pneumoniae was the dominate colonizing species and subsequent infecting species among HM patients with CRE colonization. Receiving proton pump inhibitors and admission to ICU increased the risk of subsequent CRE infection among CRE colonized HM patients. Implementing strict infection control measures targeting those high- risk patients may prevent subsequent CRE infection.

This study aims to measure and analyze financial performance using the method of Economic Value Added (EVA) and Market Value Added (MVA) in cigarette companies namely PT HM Sampoerna Tbk, PT Gudang Garam Tbk and PT Wismilak Inti Makmur Tbk. This type of research is descriptive research with a quantitative approach. This study uses secondary data in the form of financial statements of PT HM Sampoerna Tbk, PT Gudang Garam Tbk and PT Wismilak Inti Makmur Tbk for the period 2012-2016 which are published on the Indonesia Stock Exchange and share prices on Okesaham. The research results of cigarette companies that are sampled generally show positive EVA and MVA values, meaning that these companies have been able to create added value or the resulting profits have been able to meet expectations for the company's shareholders (investors) and are able to create or increase capital values has been invested by funders. Except for MVA calculations at PT. Wismilak Inti Makmur Tbk., Although in the years 20012 - 2014 had a positive MVA value, but in 2015-1016 the company suffered a loss and had a negative MVA value. Penelitian ini bertujuan mengukur dan menganalisis kinerja keuangan dengan menggunakan metode Economic Value Added (EVA) dan Market Value Added (MVA) pada perusahaan rokok yakni PT HM Sampoerna Tbk, PT Gudang Garam Tbk dan PT Wismilak Inti Makmur Tbk. “Jenis penelitian ini adalah penelitian deskriptif dengan pendekatan kuantitatif. Penelitian ini menggunakan data sekunder berupa laporan keuangan PT HM Sampoerna Tbk, PT Gudang Garam Tbk dan PT Wismilak Inti Makmur Tbk periode 2012-2016 yang terpublikasi di Bursa Efek Indonesia” serta harga-harga saham pada Okesaham. “Hasil penelitian perusahaan rokok yang dijadikan sampel pada umumnya menunjukan nilai EVA dan MVA yang positif, artinya perusahaan – perusahaan tersebut telah mampu menciptakan nilai tambah atau laba yang dihasilkan telah mampu memenuhi harapan bagi pemegang saham perusahaan (investor) dan mampu menciptakan atau meningkatkan nilai modal yang telah diinvestasikan oleh penyandang dana”. Kecuali untuk perhitungan MVA pada PT. Wismilak Inti Makmur Tbk., meskipun pada tahun 20012 – 2014 memiliki nilai MVA yang positif, tetapi pada tahun 2015-1016 perusahaan tersebut mengalami kerugian dan memiliki nilai MVA yang negatif.

Zusammenfassung Ziel der Studie Bislang existieren in Deutschland nur wenige Daten zum Sterbeort von Patienten mit neurologischer Grunderkrankung. Methodik Im Rahmen der bis dato umfangreichsten Sterbeortstudie in Deutschland wurde in vorliegender Untersuchung der Sterbeort von neurologischen Patienten mit ausgewählten Erkrankungsentitäten (ALS (ALS), bösartige Neubildung des Gehirns (BNG), Hirnmetastase(n) (HM), hypoxischer Hirnschaden nach Reanimation (HHS), nichttraumatische SAB (SAB), Demenz älterer Menschen (≥65 Jahre) (DEM)) untersucht. Für die Analyse wurden sämtliche Todesbescheinigungen der Stadt Münster des Jahres 2017 ausgewertet. Patienten wurde durch die ärztliche Angabe zur Todesursache identifiziert. Ergebnisse Es verstarben 3844 Personen, hiervon neurologische Patienten mit folgenden Erkrankungsentitäten: ALS (6), BNG (29), HM (102), HHS (54), SAB (20), DEM (485). Der Sterbeort war wie folgt verteilt: (ALS, BNG, HM, HHS, SAB, DEM;%): Zuhause 50,0/10,3/13,7/1,9/0,0/12,0; Krankenhaus 33,3/48,3/38,2/90,7/100/23,1; Intensivstation 0,0/6,9/5,9/61,1/65,0/2,7; Palliativstation 33,3/0,0/6,9/0,0/0,0/1,4; Hospiz 16,7/27,6/43,1/0,0/0,0/1,2; Pflegeheim 0,0/13,8/4,9/7,4/0,0/63,7; sonstiger Ort 0,0/0,0/0,0/0,0/0,0/0,0. Schlussfolgerung Der häufigste Sterbeort von neurologischen Patienten mit ausgewählten Erkrankungsentitäten ist wie folgt: ALS>Zuhause, bösartiger Gehirntumor>Krankenhaus, Hirnmetastase(n)>Hospiz, hypoxischer Hirnschaden nach Reanimation>Krankenhaus, nichttraumatische SAB>Krankenhaus, Demenzpatienten (≥65 Jahre)>Pflegeheim.

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is common in older adults, but the prognostic significance is unknown. We studied the prevalence of CHIP and its mortality in older adults and investigated whether the CHIP risk score (CHRS) -tool to predict hematologic malignancies (HM)- is associated with mortality in this population. Method: In ARIC cohort, CHIP was identified using exome sequencing, and CHRS scores were calculated using demographic, blood parameters, and molecular features. Individuals with CHIP were categorized into low- (CHRS≤9.5), intermediate- (9.5<CHRS<12.5), and high-risk (CHRS ≥12.5) groups. The primary outcome was all-cause death, and secondary outcomes were death from HM and cardiovascular disease (CVD). Results: In 3871 participants without a history of HM (aged 75.7 ± 5.2 years, 58.5% female, 23.1% Black), we identified 938 (24.2%) with CHIP, of whom 562 (59.9%) were low risk, 318 (33.9%) intermediate risk, and 58 (6.2%) high risk by the CHRS. During a median follow-up of 7.13 years, 570 (19.4%) deaths occurred in participants without CHIP and 128 (22.8%), 93 (29.2%), and 33 (56.9%), in the CHRS groups, respectively. Using multivariable competing risk regression, the hazard ratio HR (95% confidence interval) for all-cause mortality was 1.09 (0.90-1.32, P = 0.35), 1.13 (0.90-1.42, P = 0.29), 2.57 (1.75-3.77, P <0.001), for low-, intermediate-, and high-risk CHIP, respectively. ( Fig. 1A ) Compared to those without CHIP, in the high-risk CHIP, the HR of death from HM (6 deaths of 58, 10.3%) was 25.92 (8.04-83.57, P <0.001) and from CVD (12 of 58, 20.7%) was 2.97 (1.59-5.53, P <0.001). ( Fig. 1B ). Conclusions: CHIP can be identified in one-fourth of older adults, and most were low-risk and had the same survival. However, individuals with high-risk CHIP face not only an elevated risk of death from HM but also a threefold higher risk of death from CVD. The latter was the most common cause of death in this group. Funding: NHLBI, NCI, NPCR

Objectives: Major therapeutic cardiac procedures include open heart surgery (e.g., coronary artery bypass graft, valv/septum repairs) (OPEN), insertion/repair of pacemakers, internal defibrillators, and related devices (PACE), and percutaneous coronary intervention (PCI). The use of these procedures among patients aged > 85 years has not been well-described. Methods: Inpatient records for adults aged > 85 years were obtained from a comprehensive all-payer hospital discharge database for Florida for 2006-2011. Major cardiac procedures were identified by ICD-9-CM codes. Patient race/ethnicity (non-Hispanic White, Hispanic, non-Hispanic Black), gender, payer, principal/secondary diagnoses, and in-hospital mortality were analyzed for each procedure type. Annual procedure rates were calculated using US Census population estimates. Results: There were 2,497,573 person-years at risk for the period 2006-2011, with a total of 1,355,308 inpatient hospitalizations in this very elderly population. Medicare coverage ranged from 88% in Hispanic men (HM) to 96% in White women (WW). Procedure rates were higher in Medicare patients vs. all other payers. PACE was the most common major cardiac procedure (n=32,338), followed by PCI (n=17,046) and OPEN (n=5,916). Population rates of each procedure varied significantly by race/ethnicity and gender (see Figure for PACE rates). In 2011, the rate of PCI for White men (WM) (89 per 10,000, 95% CI 84 to 94) was 20% higher compared to HM, 70% higher compared to Black men (BM), 80% higher than WW and Black women (BW), and 130% higher than Hispanic women (HW). The open heart surgery rate for WM (41 per 10,000, 95% CI 38 to 45) was significantly higher than all other groups: 1.6 times the rate for HM, 2.9 times the rate for WW, 4.1 times the rate for HW, 8.2 times the rate for BM and 10.3 times the rate for BW. In-hospital mortality rates were 1.4% for PACE, 4.3% for PCI, and 8.2% for OPEN. Temporal trends showed declining rates for all procedures over the study period. Conclusions: Major therapeutic cardiac interventions are common among the very elderly. Greater inclusion of very elderly patients in clinical trials and outcome studies is necessary to establish the survival and quality of life benefits of these procedures for patients near the end of life.

Abstract Study question Does embryo stage, hatching versus hatched blastocyst, affect ploidy status and implantation rates (IR)? Summary answer The embryo stage may influence ploidy status, but no correlation was made between embryo stage and IR. What is known already It is generally accepted that hatched embryos present increased vulnerability when handled and are often selected against. The literature on this varies with some reporting that the transfer of hatched blastocysts resulted in lower pregnancy rates compared to hatching or expanded blastocysts. Other studies have found no difference in clinical outcome with the transfer of hatched blastocysts compared to other stages. Reports defining the relationship between hatched or hatching blastocysts and ploidy rates are limited. Study design, size, duration Retrospective analysis of IR of 224 transferred euploid embryos and ploidy rate (P-Rt) of 1431 embryos produced in two IVF labs in the United States between 2019-2021. Embryos underwent assisted hatching on Day 3 and were subjected to preimplantation genetic testing (PGT) on Day 5 or Day 6 followed by vitrification. IR was defined as the presence of an intrauterine implantation sac with the detection of a fetal heartbeat on ultrasound. Participants/materials, setting, methods Trophectoderm biopsies were evaluated by NextGen Sequencing at the same genetics laboratory (Ovation Genetics, Nashville, TN). P-Rt included the following categories: Normal (N) or euploid, Abnormal (ABN) or aneuploid, Low-Mosaic (LM), and High-Mosaic (HM). Euploid embryos were transferred in subsequent frozen embryo transfer (FET) cycles and monitored by clinical ultrasound. Chi-square statistical analysis was performed to identify potential differences (p &lt; 0.05). Main results and the role of chance No significant difference was observed in IR after transferring euploid hatched blastocysts compared to euploid hatching blastocysts. The IR of hatched blastocysts was 40.3% compared to 50.3% for hatching blastocysts (p = 0.21). A significant difference in ABN and HM embryos was observed according to embryo stage (p = 0.02). The ABN rate was 21.2% for hatched blastocysts compared to 28.0% for hatching blastocyst and the HM rate of hatched blastocysts was 10.3% versus hatching blastocyst at 7.5%. No significant difference in Normal and LM ploidy rates were observed according to embryo stage. The N ploidy rate of hatched blastocysts was 58.1% versus 54.4% in hatching blastocysts, and LM rate for hatched blastocysts was 10.3% compared to 10.1% in hatching blastocysts. Limitations, reasons for caution The limited data set did not include fresh embryo transfers or the transfer of untested embryos. The inclusion of increased embryo numbers could strengthen the power of the evaluation and allow for more robust statistical analysis. Wider implications of the findings Embryo selection is a multifactorial process consisting of a wide range of parameters. Numerous advances in embryo production and evaluation have resulted in the need for an algorithm or guide to rank embryos for transfer. Further investigation is warranted to elucidate comprehensive recommendations for embryo selection. Trial registration number not applicable

In a study, field screening of 109 elite Indian and exotic lines was carried out under normal and waterlogged soil conditions for two consecutive years (2012-13 and 2013-14). Results revealed high GCV along with high heritability and genetic advance for plant height and 1000-grain weight and these two traits were found most desirable in germplasm characterization for waterlogging tolerance. The geometric mean productivity (GMP), harmonic mean (HM), stress tolerance index (STI) and mean productivity (MP) were positively correlated with grain yield under stress (Ys) and non-stress conditions (Yp). There was a negative association between stress susceptible index and yield under normal conditions (Yp), whereas tolerance index (TOL) was positively correlated with Yp and negatively with yield under waterlogged conditions (Ys) during both the years (2012-13 and 2013-14). The promising lines, viz. BH 1146, DBW 39, DBW 52, NW 1014, NW 1067, NW 4081, PBW 621, PBW 631, PBW 590, RW 3684, HD 2967, HD 2997 and NW 4083 were selected on the basis of GMP, STI, MP, HM, and STS and rated as highly tolerant for waterlogged soils. However, the lines identified on the basis of stress susceptible index (SSI) and tolerance index (TOL) only could be suitable for normal and waterlogged conditions. The lines thus identified included; Perenjori, PBW 343, PBW 636, KRL 268, RAJ 4201, RAJ 4205 and WH 1094. It is anticipated that these lines will be utilized as donors for incorporation of waterlogging tolerance genes. The research findings also imply that tolerant lines eventually would lead to higher production and productivity under, heavy rainfall and prolonged stagnant water situations (adversely affect the wheat crop). These lines may also be utilized in hybridization programme for developing next generation mapping (MAGIC and NAM) populations for fine QTLs scanning for waterlogging tolerance.

Abstract Background Cryptosporidium is a parasitic protozoan that causes severe and potentially life-threatening diarrheal disease in immunocompromised patients. Infections can be asymptomatic, cause self-limited disease, or chronic diarrhea and in some cases result in biliary and pulmonary disease Methods We performed a detailed retrospective analysis of patients that presented with diarrheal illness, and Cryptosporidium infection diagnosed by GI multiplex (Biofire) at UT MD Anderson Cancer Center between January 2017 and March 2023. Results We identified 51 patients aged 24 to 89 years with cryptosporidiosis. Hematological malignancies (HM) were present in 44% of patients, while non-hematological malignancies (NHM) in 55%. Thirty-seven percent of patients had received hematopoietic stem cell transplantation (HSCT), 8% chimeric antigen receptor T-cell (CAR-T) therapy, 18% immunosuppressive therapy, and 65% received chemotherapy in the last 90 days. Two patients had human immunodeficiency virus (HIV). All patients presented with diarrhea, 39% with nausea, 43% with abdominal pain, and 51% had fever. The median duration of symptoms was 3 days. About 41% were severely neutropenic, and 61% had severe lymphopenia. Computed tomography (CT) abdomen was normal in 43% of patients, 16% had colitis, 12% had enteritis, and 4% had enterocolitis. All patients were treated with Nitazoxanide, with a median duration of therapy (DOT) of 14 days. The DOT was longer in HM than in NHM (14 ± 7.9 vs. 9.9 ± 5.6, p= 0.016) and in HSCT/CAR-T patients than without HSCT/CAR-T (13.8 ± 6.1 vs. 10.3 ± 7.3, p = 0.009). About 18% of patients had co-infections with other enteropathogens. Death from other causes occurred in 13 of 51 (23%) of patients. All cause mortality between HM and NHM (p=0.207), HSCT/CAR-T and non-HSCT/CAR-T (p=0.52), or chemotherapy vs. without chemotherapy (p=0.34) was similar. Most infections were encountered in the month of October. Conclusion We observed a limited response to nitazoxanide at our center, contributing factors and confounders included co-infections with other pathogens, active chemotherapy, or HSCT/CAR-T induced intestinal epithelium injury. Controlled, double blinded studies with new agents are needed to determine the optimal management of cryptosporidiosis in this population. Disclosures Pablo C. Okhuysen, M.D., FACP, FIDSA, Astra Zeneca: Stocks/Bonds|Beam Therapeutics: Stocks/Bonds|Biontech: Stocks/Bonds|Deinove Pharmaceutucals: Grant/Research Support|Ferring: Advisor/Consultant|GSK PLC: Stocks/Bonds|Haleon: Stocks/Bonds|Johnson and Johnson: Stocks/Bonds|Melinta Pharmaceuticals: Grant/Research Support|Merk Sharp and Dohme: Grant/Research Support|Moderna: Stocks/Bonds|Napo Pharmaceuticals: Advisor/Consultant|Napo Pharmaceuticals: Grant/Research Support|Novavax: Stocks/Bonds|Pfizer: Stocks/Bonds|SNIPR Biome: Advisor/Consultant|Summit Pharmaceuticals: Grant/Research Support

The Baudet du Poitou is a vanishing donkey breed recognized for engendering robust working mules. In Chile, only two pure breed Poitou males exist, which belong to the Chilean army and are used for mule production. We performed an extensive sperm and seminal analysis of these two jackasses aged 3 and 6 years and investigated the use of a simple hypometabolic extender for sperm cryopreservation. Computer-assisted sperm analysis showed high motility, velocity, and linearity in sperm movement. The seminal plasma analysis revealed that sodium and chloride were the main electrolytes, and globulins were the main metabolites. Active and variable enzymatic activity was observed. New information is reported about gamma-glutamyltransferase, aspartate aminotransferase, zinc, and magnesium concentrations in seminal plasma of Poitou donkeys. Ejaculates among jackasses showed some variability due to individual variability and different stages in sexual maturation according to age. The freezability index analysis based in viability, total motility and progressive motility with Botucrio extender (57.1 ± 11.0%; 56.6 ± 20.0%; and 22.6 ± 10.3%, respectively) were significantly higher (p &lt; 0.05, p &lt; 0.0001, and p &lt; 0.0001, respectively) than with HM-0 extender (42,6 ± 11.4%; 14.9 ± 5.1%; and 1.0 ± 2.5%, respectively). We report new information on Poitou donkey semen and cryopreservation in the Southern Hemisphere that could be useful in donkey breeding and conservation programs to develop strategies that improve the effectiveness of population management of this breed.

Background: Heart failure disproportionately affects Black patients. Whether differences among race influence outcomes in advanced heart failure with use of a fully magnetically levitated continuous-flow left ventricular assist device remains uncertain. Methods: We included 515 IDE (Investigational Device Exemption) clinical trial patients and 500 Continued Access Protocol patients implanted with the HeartMate 3 left ventricular assist device in the MOMENTUM 3 study (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3). Outcomes were compared between Black and White left ventricular assist device recipients for the primary end point of survival free of disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years, overall survival, adverse events, 6-minute walk distance, and quality of life scores. Results: Of 1015 HeartMate 3 patients, 675 were self-identified as White and 285 as Black individuals. The Black patient cohort was younger, more obese and with a history of hypertension, and more nonischemic cause of heart failure, relative to the White patient group. Black and White patients did not experience a difference in the primary end point (81.1% versus 77.9%; hazard ratio, 1.08 [95% CI, 0.76–1.54], P =0.6568). Black patients were at higher risk of adverse events (calculated as events per 100 patient-years), including bleeding (75.4 versus 63.5; P <0.0001), stroke (9.5 versus 7.2; P =0.0183), and hypertension (10.1 versus 3.2; P <0.0001). The 6-minute walk distance was not different at baseline and 6 months between the groups, however, the absolute change from baseline was greater for White patients (median: +183.0 [interquartile range, 42.0–335.3] versus +163.8 [interquartile range, 42.3–315.0] meters, P =0.01). The absolute quality of life measurement (EuroQoL group, 5-dimension, 5-level instrument visual analog scale) at baseline and 6 months was better in the Black patient group, but relative improvement from baseline to 6 months was greater in White patients (median: +20.0 [interquartile range, 5.0–40.0] versus +25.0 [interquartile range, 10.0–45.0]; P =0.0298). Conclusions: Although the survival free of disabling stroke or reoperation to replace/remove a malfunctioning device at 2 years with the HM 3 left ventricular assist device did not differ by race, Black HeartMate 3 patients experienced a higher morbidity burden and smaller gains in functional capacity and quality of life when compared with White patients. These findings require efforts designed to better understand and overcome these gaps through systematic identification and tackling of putative factors. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02224755 and NCT02892955.

A osteoporose é responsável por causar condições devastadoras no tecido ósseo elevando o risco de fraturas, constituindo uma problemática importante de saúde pública. É comum o uso de medicamentos, como os bifosfonatos para o controle dessa patologia. Contudo, a associação do uso desse medicamento com a osteonecrose dos maxilares vem sendo amplamente discutido na literatura, assim como a dificuldade da reabilitação desses pacientes como implantes e do protocolo de tratamento dessa condição. Assim sendo, o objetivo do presente trabalho foi realizar uma revisão de literatura para discutir as principais falhas associadas a instalação de implantes em pacientes portadores de osteonecrose dos maxilares associada ao uso de bifosfonatos (OMAB), assim como as possibilidades de tratamento, e relatar um caso clínico. As informações obtidas na revisão nos permitiu concluir que o uso de bifosfonatos orais, como o alendronato, é capaz de levar ao desenvolvimento da OMAB sendo necessária bastante precaução na reabilitação oral com implantes dentários, tanto em pacientes que fazem uso, como pacientes que apresentam risco de futura utilização de bifosfonatos para o tratamento de desordens esqueléticas. Descritores: Osteoporose; Alendronato; Osteonecrose; Implantes Dentários.ReferênciasEsposito M, Hirsch JM, Lekholm U, Thomsen P. Biological factors contributing to failures of osseointegrated oral implants. (I). Success criteria and epidemiology. Eur J Oral Sci. 1998;106(1):527-51.Quirynen M, De Soete M, Van Steenberghe D. Infectious risks for oral implants: a review of the literature. Clin Oral Implants Res. 2002;13(1):1-19.Van Steenberghe D, Jacobs R, Desnyder M, Maffei G, Quirynen M. The relative impact of local and endogenous patient‐related factors on implant failure up to the abutment stage. Clin Oral Implants Res. 2002;13(6):617-22.Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol. 2003;21(22)4253-54.Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc. 2005;136(12):1658-68.Madrid C, Sanz M. What impact do systemically administrated bisphosphonates have on oral implant therapy? A systematic review. Clin Oral Implants Res. 2009;20(Suppl 4):87-95.Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296(24):2927-38.Schwartz AV, Bauer DC, Cummings SR, Cauley JA, Ensrud KE, Palermo L et al. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res. 2010;25(5):976-82.Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61(9):1115-17.Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. Journal of oral and maxillofacial surgery, 2004;62(5):527-34.Ruggiero SL. Guidelines for the diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Clin Cases Miner Bone Metab.2007;4(1):37-42.Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B et al. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg. 2009;67(5 Suppl):2-12.Ruggiero SL, Drew SJ. Osteonecrosis of the jaws and bisphosphonate therapy. J Dent Res. 2007;86(11):1013-21.Otto S, Abu-Id MH, Fedele S, Warnke PH, Becker ST, Kolk A et al. Osteoporosis and bisphosphonates-related osteonecrosis of the jaw: not just a sporadic coincidence–a multi-centre study. J Craniomaxillofac Surg. 2011;39(4):272-77.Yarom N, Yahalom R, Shoshani Y, Hamed W, Regev E, Elad S. Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int. 2007;18(10):1363-70.Sambrook P, Cooper C. Osteoporosis. Lancet. 2006;367(9527):2010-18.Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C. Meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev. 2002;23(4):570-78.Close P, Neuprez A, Reginster JY. Developments in the pharmacotherapeutic management of osteoporosis. Expert Opin Pharmacother. 2006;7(12):1603-15.Rodan GA, Fleisch HA. Bisphosphonates: mechanisms of action. J Clin Invest. 1996;97(12): 2692-96.Dannemann C, Grätz KW, Riener MO, Zwahlen RA. Jaw osteonecrosis related to bisphosphonate therapy: a severe secondary disorder. Bone. 2007;40(4):828-34.Kos M, Luczak K, Godzinski J, Klempous J. Treatment of monostotic fibrous dysplasia with pamidronate. J Craniomaxillofac Surg. 2004;32(1):10-15.Pastor-Zuazaga D, Garatea-Crelgo J, Martino-Gorbea R, Etayo-Pérez A, Sebastián-Lopez C. Osteonecrosis of the jaws and bisphosphonates. Report of three cases. Med Oral Patol Oral Cir Bucal. 2006;11(1):E76-9.Sato M, Grasser W, Endo N, Akins R, Simmons H, Thompson DD et al. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest. 1991;88(6):2095-2105.Sahni M, Guenther HL, Fleisch H, Collin P, Martin TJ. Bisphosphonates act on rat bone resorption through the mediation of osteoblasts. J Clin Invest.1993;91(5):2004-11.Merigo E, Manfredi M, Meleti M, Corradi D, Vescovi P. Jaw bone necrosis without previous dental extractions associated with the use of bisphosphonates (pamidronate and zoledronate): a four‐case report. J Oral Pathol Med. 2005;34(10):613-17.Olson KB, Hellie CM, Pienta KJ. Osteonecrosis of jaw in patient with hormonerefractory prostate cancer treated with zoledronic acid. Urology. 2005;66(3):658.Graziani F, Cei S, La Ferla F, Cerri E, Itro A, Gabriele M. Association between osteonecrosis of the jaws and chronic high-dosage intravenous bisphosphonates therapy. J Craniofac Surg. 2006;17(5):876-79.Greenberg MS. Comment in. Intravenous bisphosphonates and osteonecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;98(3):259-60.Gibbs SD, O'Grady J, Seymour JF, Prince HM. Bisphosphonate-induced osteonecrosis of the jaw requires early detection and intervention. Med J Aust. 2005;183(10):549-50.Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg. 2005;63(11)1567-75.Melo MD, Obeid G. Osteonecrosis of the jaws in patients with a history of receiving bisphosphonate therapy: strategies for prevention and early recognition. J Am Dent Assoc. 2005;136(12):1675-81.Purcell PM, Boyd IW. Bisphosphonates and osteonecrosis of the jaw. Med J Aust. 2005;182(8)417-18.Vannucchi AM, Ficarra G, Antonioli E, Bosi A. Osteonecrosis of the jaw associated with zoledronate therapy in a patient with multiple myeloma. Br J Haematol. 2005;128(6):738.Bilezikian JP. Osteonecrosis of the jaw - do bisphosphonates pose a risk? N Engl J Med. 2006;355(22):2278-81.Van Poznak C, Estilo C. Osteonecrosis of the jaw. J Oncol Pract. 2006;2(1):3-4.Santini D, Vincenzi B, Avvisati G, Dicuonzo G, Battistoni F, Gavasci M et al. Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res. 2002;8(5):1080-84.Wood J, Bonjean K, Ruetz S, Bellahcène A, Devy L, Foidart JM et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 2002;302(3):1055-61.Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol. 2006;24(6):945-52.Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med.2006;144(10):753-61.Cafro AM, Barbarano L, Nosari AM, D'avanzo G, Nichelatti M, Bibas M et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma. 2008;8(2):111-16.Mavrokokki T, Cheng A, Stein B, Goss A. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg. 2007;65(3):415-23.Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90(3):1294-301.Bedogni A, Blandamura S, Lokmic Z, Palumbo C, Ragazzo M, Ferrari F et al. Bisphosphonate-associated jawbone osteonecrosis: a correlation between imaging techniques and histopathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105(3):358-64.Khan AA, Sándor GK, Dore E, Morrison AD, Alsahli M, Amin F et al. Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw. J Rheumatol. 2008;35(7):1391-97.Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M et al.Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res. 2008;23(6):826-36.Assael LA. Oral bisphosphonates as a cause of bisphosphonate-related osteonecrosis of the jaws: clinical findings, assessment of risks, and preventive strategies. J Oral Maxillofac Surg. 2009;67(5 Suppl):35-43.Lazarovici TS, Yahalom R, Taicher S, Schwartz-Arad D, Peleg O, Yarom N. Bisphosphonate-related osteonecrosis of the jaw associated with dental implants. J Oral Maxillofac Surg. 2010;68(4):790-96.Jacobsen C, Metzler P, Rössle M, Obwegeser J, Zemann W, Grätz KW. Osteopathology induced by bisphosphonates and dental implants: clinical observations. Clin Oral Investig. 2013;17(1):167-75.López-Cedrún JL, Sanromán JF, García A, Peñarrocha M, Feijoo JF, Limeres J, Diz P. Oral bisphosphonate-related osteonecrosis of the jaws in dental implant patients: a case series. Br J Oral Maxillofac Surg. 2013;51(8):874-79.Kwon TG, Lee CO, Park JW, Choi SY, Rijal G, Shin HI. Osteonecrosis associated with dental implants in patients undergoing bisphosphonate treatment. Clin Oral Implants Res. 2014;25(5):632-40.Ramalho-Ferreira G, Faverani LP, Prado FB, Garcia IR, Okamoto R. Raloxifene enhances peri-implant bone healing in osteoporotic rats. Int J Oral Maxillofac Surg. 2015;44(6):798-805.Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350(12):1189-99.Lerner UH. Bone remodeling in post-menopausal osteoporosis. J Dent Res. 2006;85(7):584-95.Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282(7):637-45.Gallacher SJ, Dixon T. Impact of treatments for postmenopausal osteoporosis (bisphosphonates, parathyroid hormone, strontium ranelate, and denosumab) on bone quality: a systematic review. Calcif Tissue Int. 2010;87(6)469-84.

Introdução: A configuração das relações de saber-poder no contexto da Estratégia de Saúde da Família influencia fortemente na qualidade e capacidade cuidadora desse serviço. Objetivo: Analisar os reflexos da presença de relações de saber-poder no cuidado de saúde prestado pela Estratégia de Saúde da Família. Material e Método: Trata-se de um estudo de natureza qualitativa, desenvolvido junto a 20 profissionais assistencialistas que compõem o quadro de profissionais das três unidades de Estratégia de Saúde da Família do município paraibano de Nazarezinho, realizado mediante entrevista gravada norteada por formulário semiestruturado. Os dados coletados foram transcritos e analisados sob a luz da Análise da Ordem do Discurso, realizada após a construção de duas categorias temáticas. Resultados: No discurso dos entrevistados, observou-se a percepção do entrelaçamento entre saber e poder, o qual se relaciona à formação profissional, destacando determinados trabalhadores como superiores e resultando em relações desiguais de poder que favorecem a prestação de uma assistência de saúde verticalizada e a aproximação das práticas da Estratégia de Saúde da Família do modelo curativista. A presença de relações de saber-poder implica em uma distribuição desigual de poder no contexto estudado, interferindo na interdisciplinaridade entre os profissionais. Conclusão: Destaca-se a necessidade de promover o empoderamento dos profissionais de saúde, com vistas a estabelecer sua autonomia para que prestem uma assistência de saúde horizontalizada, com integralidade e desnuda de relações de poder.Descritores: Poder Público; Estratégia de Saúde da Família; Atenção Primária à Saúde; Equipe de Assistência ao Paciente.ReferênciasSilva IS, Arantes CIS. Relações de poder na equipe de saúde da família: foco na enfermagem. Rev Bras Enferm. 2017;70(3):607-15.Veloso ISC. Configurações das relações de poder no Serviço de Atendimento Móvel de Urgência de Belo Horizonte [tese]. Belo Horizonte: Universidade Federal de Minas Gerais;2011.Foucault M. Vigiar e punir: nascimento da prisão. 35. ed. Petrópolis: Vozes; 2008.Foucault M. Microfísica do poder. Rio de Janeiro: Edições Graal; 1979.Oliveira HM, Pires TO, Parente RCP. As relações de poder na Estratégia de Saúde da Família sob o enfoque da teoria de Hannah Arendt. Sau & Transf Soc. 2011;1(2):17-26.Goldstein RA, Barcellos C, Magalhães MAFM, Gracie R, Viacava F. A experiência de mapeamento participativo para a construção de uma alternativa cartográfica para a ESF. Ciênc saúde coletiva. 2013;18(1):45-56.Fortuna CM, Mishima SM, Matumoto S, Pereira MJB. O trabalho de equipe no programa de saúde da família: reflexões a partir de conceitos do processo grupal e de grupos operativos. Rev Latino-Am Enfermagem. 2005;13(2):262-68.Cavalcanti PB, Carvalho RF. A interdisciplinaridade no programa saúde da família: como articular os saberes num espaço de conflitos? Sociedade em Debate. 2010;16(2):191-208.Minayo MCS. Análise qualitativa: teoria, passos e fidedignidade. Ciênc saúde coletiva. 2012;17(3):621-26.Bardin L. Análise de Conteúdo. São Paulo: Edições 70;2011.Foucault M. A ordem do discurso. 5. ed. São Paulo: Edições Loyola;1999.Fischer RMB. Foucault e a análise do discurso em educação. Cad Pesqui. 2001(114):197-223.Oliveira LHS, Mattos RS, Castro JBP, Luz MT. Práticas corporais de saúde para pacientes com fibromialgia: acolhimento e humanização. Physis. 2017;27(4):1309-32.Tong A, Sainsbury P, Craig J. Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups. Int J Qual Health Care. 2007;19(6):349-57.Critical appraisal skills programme [Internet]. 10 questions to help you make sense of qualitative research. [Acesso em 2017 Ago 16]. Disponível em: http://www.cfkr.dk/images/file/CASP%20 instrumentet.pdf.Ferreirinha IMN, Raitz TR. As relações de poder em Michel Foucault: reflexões teóricas. Rev Adm Pública. 2010;44(2):367-83.Marques GS, Lima MADS. Organização tecnológica do trabalho em um pronto atendimento e a autonomia do trabalhador de enfermagem. Rev Esc Enferm USP. 2008;42(1):41-7.Baptista MKS, Santos RM, Duarte SJH, Comassetto I, Trezza MCSF. O paciente e as relações de poder-saber cuidar dos profissionais de enfermagem. Esc Anna Nery. 2017;21(4):1-7.Pires MRGM, Göttems LBD. Análise da gestão do cuidado no Análise da gestão do cuidado no Programa de Saúde da Família: referencial teórico-metodológico. Rev Bras Enferm. 2009;62(2):294-99.Costa DT, Martins MCF. Estresse em profissionais de enfermagem: impacto do conflito no grupo e do poder do médico. Rev Esc Enferm USP. 2011;45(5):1191-98.Villa EA, Aranha AVS, Silva LLT, Flôr CR. As relações de poder no trabalho da Estratégia Saúde da Família. Saúde Debate. 2015;39(107):1044-52.Matumoto S, Fortuna CM, Mishima SM, Pereira MJB, Domingos NAM. Supervisão de equipes no Programa de Saúde da Família: reflexões acerca do desafio da produção de cuidados. Interface (Botucatu). 2005;9(16):9-24.Silva JAM, Peduzzi M. Educação no trabalho na atenção primária à saúde: interfaces entre a educação permanente em saúde e o agir comunicativo. Saúde Soc. 2011;20(4):1018-32.Barreto SAP, Bertani IF. Rituais do poder nas organizações de saúde. Serv Soc & Saúde. 2005;4(4):39-54.Galavote HS, Franco TB, Lima RCD, Belizário AM. Alegrias e tristezas no cotidiano de trabalho do agente comunitário de saúde: cenários de paixões e afetamentos. Interface (Botucatu). 2013; 17(46):575-86.Lima L, Pires DEP, Forte ECN, Medeiros F. Satisfação e insatisfação no trabalho de profissionais de saúde da atenção básica. Esc Anna Nery. 2014;18(1):17-24.Ministério da Saúde (BRASIL). Política Nacional de Humanização. Brasília: Editora do Ministério da Saúde;2015.Sulti ADC, Lima RCD, Freitas PSS, Felsky CN, Galavote HS. O discurso dos gestores da Estratégia Saúde da Família sobre a tomada de decisão na gestão em saúde: desafio para o Sistema Único de Saúde. Saúde Debate. 2015;39(104):172-82.Ojeda BS. A tecedura das relações saber-poder em saúde: matizes de saberes e verdades [tese]. Porto Alegre: Pontifícia Universidade Católica do Rio Grande do Sul; 2004.Gaiva MAM, Scochi CGS. Processo de trabalho em saúde e enfermagem em uti neonatal. Rev Latino-Am Enfermagem. 2004;12(3):469-76.Oliveira HM, Moretti-Pires RO, Parente RCP. As relações de poder em equipe multiprofissional de Saúde da Família segundo um modelo teórico arendtiano. Interface Botucatu). 2011; 15(37):539-50.