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BACKGROUND: Low muscle mass increases the risk of developing type 2 diabetes mellitus (DM 2) and prediabetes. Nutrition is an important factor in the study of the relationship between low muscle mass and the development of glucose metabolic disorders.AIM: The present study was conducted to assess the relationship between prediabetes and low muscle mass on the basis of serum creatinine levels, taking into account patient nutrition.MATERIALS AND METHODS: The study included 551 patients aged 18–69 years without DM 2. The glucose level was determined based on fasting glucose and after an oral glucose tolerance test (OGTT). Hyperglycemia is assessed according to the classification of the World Health Organization. The MedDietScore questionnaire was used to assess the nutritional factor, which determines the adherence of patients to the Mediterranean diet. In order to assess odds ratios (OR) and 95% confidence interval (CI), a binary logistic regression was performed.RESULTS: The prevalence of prediabetes in the group with the lowest and highest blood creatinine level was 31.9% and 17.5% respectively (p=0.016). As a result of the conducted regression analysis, a statistically significant relationship was found between low creatinine levels and the chances of having prediabetes (crude OR 2,07, 95% CI 1,21; 3,56), which persisted after adjusting for socio-demographic, anthropometric factors, stress level and physical activity as well as muscle strength. After adding the data on MedDietScore to the statistical model, the revealed relationship was lost (p = 0.187).CONCLUSION: Low serum creatinine increases the chances of the presence of prediabet regardless of gender, age, body weight index, the volume of the hips, the ratio of the volume of the waist to growth, as well as physical activity, the level of stress and muscular power. However, the chances of the presence of prediabet do not differ in persons with low creatinine blood depending on the commitment to the Mediterranean diet among the population of those living in the Turkestan region.

International audience; Objectives: Our aim was to assess if switching from a protease inhibitors (PI)-based regimen to a PI-free one is associated with an increased risk of Kaposi Sarcoma (KS) relapse among patients living with HIV (PLHIV) with history of KS and controlled HIV replication.Methods: In a retrospective analysis of the prospectively collected Dat'AIDS database we selected patients who both had a past KS history and a HIV-1 viral load below 200 copies/mL while being PI-treated. We searched for KS relapses while persistent virological success was maintained for at least 6 months, whether patients kept taking the PI, or switched to PI-free regimen.Results: Among the 216 patients with past KS event and a history of HIV-1 infection efficiently treated by a PI-based regimen, 148 patients (68.5%) later switched to a PI-sparing regimen. Their baseline characteristics were not different from non-switching patients. We described 7 cases of relapse (3.2% of the 216 patients). Five cases of relapse occurred in switching patients (3.4%). The remaining two relapses occurred in PI-treated patients (2.9%). At KS relapse, CD4 cell count was 459 cells/μL (range 225-560) for switching patients, compared with 362 and 136 cells/μL for the other two patients.Conclusions: In this large cohort of PLHIV with a history of KS and ART-controlled HIV replication, KS relapses were described in 3.2% of the patients, and were not more frequent when a PI-containing ART regimen has been switched to a PI-free regimen. Our results do not support a specific effect of PI on KS.

Clonal cytogenetic abnormalities (CCA) in donor-derived cells after stem cell transplant (SCT) are typically reported in donor-derived cell neoplasms, but CCA also may reflect a constitutional abnormality in the donor or may be present in a recipient without overt hematological malignancy. We reviewed 8515 tests on 2035 patients, who had allogenic sex mismatched SCT and underwent serial cytogenetic analysis between 2006 and 2020 in our institution. A constitutional CCA was observed in 3 patients: inv(10), t(1;5), and t(13;14). A somatic CCA without overt neoplasia was detected in 12 patients: del(7q) (n = 6), del(20q) (n = 3), der(11)t(11;11) (n = 1), t(1;9) (n = 1), dup(6p)(n = 1). In this group, four patients with cytopenia had del(7q), and an association between del(7q) and an adverse overall survival (OS) was observed [HR:5.99; 95%CI 1.23–29.92). Four patients had a donor-derived cell neoplasm: myelodysplastic syndrome (n = 3) and acute myeloid leukemia (n = 1), and all four neoplasms had loss of 7q. In our cohort, ∼1% of the patients (19/2,035) had CCA in donor-derived cells. Balanced constitutional CCA can pose a reproductive risk to donor. Loss of 7q is the most common somatic CCA, in donor-derived cells.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined. METHODS We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration. RESULTS The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm ( P = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; P = .003). The survival benefit was seen across all subgroups examined. CONCLUSION We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS.

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive hematological malignancy; however, some patients achieve durable remission with allogeneic hematopoietic cell transplantation (allo-HCT). We report on all 17 patients with BPDCN who underwent allo-HCT at our center between 2000 and 2020. The median age was 39 (18-67) years. All (n = 16, 94%), except one patient, had systemic disease involving bone marrow and/or other organs. Ten patients (59%) were in first complete remission (CR1) at allo-HCT. The donor source was matched related or unrelated in ten (59%) and alternate donor in seven (41%) patients. Five (31%) patients developed acute graft-versus-host disease (GVHD), all grade I-II. The cumulative incidence (CI) of chronic GVHD at five-year was 34%. The CI of non-relapse mortality at one-year was 29%. Progression-free survival (PFS) rates at two-year and five-year were 49% (95% CI = 22-71%) and 39% (95% CI = 14-64%), respectively. The two-year and five-year overall survival (OS) rates were 65% (95% CI = 38-82%) and 40% (95% CI = 12-68%), respectively. The five-year rate for both PFS and OS was 80% in CR1 patients versus 0% in patients not in CR1. In conclusion, allo-HCT provides long-lasting remissions in BPDCN patients, particularly when performed in CR1.

Relapse after allogeneic hematopoietic cell transplantation (HCT) leads to poor survival in patients with acute myeloid leukemia (AML). A second HCT (HCT2) may achieve durable remission. To determine the outcomes of patients who received an HCT2 for relapsed AML and to evaluate the predictors of overall survival (OS) and progression-free survival (PFS). We retrospectively reviewed medical records of adult patients who underwent an HCT2 for relapsed AML at our institution during 2000 to 2019. Ninety-one patients were identified with a median age of 44 years (range 18-73) at HCT2. Donor types were HLA-identical sibling (n = 37 [41%]), HLA-matched–unrelated (n = 34 [37%]), haploidentical (n = 19 [21%]), and cord blood (n=1 [1%]). Donors were different at HCT2 in 53% of patients. The majority of patients received reduced intensity conditioning (n = 71 [78%]) and were in remission (n = 56 [61%]) at HCT2. The median remission duration after HCT1 was 8.4 months (range 1-70) and the median time between transplants was 14 months (range 3-73). The median follow-up of surviving patients after HCT2 was 66 months (range 2-171), with 32% alive at time of analysis. The most common cause of death was disease recurrence (n = 45 [73%]). At 2 years, the rates of OS, PFS, progression, and nonrelapse mortality were 36%, 27%, 42%, and 18%, respectively. The development of chronic graft-versus-host disease (GVHD) after first HCT and HCT comorbidity index (HCT-CI) ≥2 at HCT2 were associated with inferior PFS and OS after HCT2. A second HCT is feasible in selected patients with AML who have relapsed after HCT1. Long-term survival benefit is possible in patients without chronic GVHD after HCT1 and HCT-CI

Clonal hematopoiesis (CH) is associated with older age and an increased risk of myeloid malignancies and cardiovascular complications. We analyzed donor DNA samples in patients with AML/MDS who underwent first allogeneic stem cell transplant (SCT) to investigate the association between donor CH and transplant outcomes. We performed targeted deep sequencing of 300 genes on donor blood samples and identified CH with the minimum variant allele frequency of 2%. Among 363 donors, 65 (18%) had CH. The most frequently mutated genes were DNMT3A (31 of 65; 48%), TET2 (16 of 65; 25%), PPM1D (5 of 65, 8%), and ASXL1 (7 of 65; 11%). Transplant outcomes: time to neutrophil and platelet recovery, relapse incidence, transplant-related mortality and progression-free survival, were comparable by donor CH. However, risk of grade II-IV and III-IV acute graft versus host disease (aGvHD) at 6 months after transplant was higher with donor CH vs. without donor CH (hazard ratio (HR) = 2.4, 95% Confidence Interval (CI) = 1.6-3.6, p < 0.001 and HR = 3.8, 95% CI = 1.6-8.9, p = 0.003). In this homogenous population of AML/MDS patients, donor CH was associated with increased risk of grade II-IV and III-IV aGvHD. Further studies to investigate the mechanisms of increased aGvHD and therapeutic interventions to improve aGvHD in the context of donor CH are warranted.

Massively parallel sequencing (MPS) has become a viable diagnostic tool to interrogate genetic profiles of numerous tumors but has yet to be routinely adopted in the setting of lymphoma. Here, we report the empirical application of a targeted 40-gene panel developed for use in mature lymphoid neoplasms (MLNs) and report our experience on over 500 cases submitted for MPS during the first year of its clinical use. MPS was applied to both fresh and fixed specimens. The most frequent diagnoses were diffuse large B-cell lymphoma (116), chronic lymphocytic leukemia/small lymphocytic lymphoma (60), marginal zone lymphoma (52), and follicular lymphoma (43), followed by a spectrum of mature T-cell neoplasms (40). Of 534 cases submitted, 471 generated reportable results in MLNs, with disease-associated variants (DAVs) detected in 241 cases (51.2%). The most frequent DAVs affected TP53 (30%), CREBBP (14%), MYD88 (14%), TNFRSF14 (10%), TNFAIP3 (10%), B2M (7%), and NOTCH2 (7%). The bulk of our findings confirm what is reported in the scientific literature. While a substantial majority of mutations did not directly impact diagnosis, MPS results were utilized to either change, refine, or facilitate the final diagnosis in ~10.8% of cases with DAVs and 5.5% of cases overall. In addition, we identified preanalytic variables that significantly affect assay performance highlighting items for specimen triage. We demonstrate the technical viability and utility of the judicious use of a targeted MPS panel that may help to establish general guidelines for specimen selection and diagnostic application in MLNs in routine clinical practice.

Despite low nonrelapse mortality (NRM) at day 100 after allogeneic hematopoietic cell transplantation (HCT), NRM at 1 year remains substantial. In this study, we retrospectively analyzed 199 patients who were treated on a phase II clinical trial assessing safety and efficacy of myeloablative fractionated busulfan and fludarabine conditioning regimen for hematologic malignancies. The goal of the study was to identify factors associated with NRM occurring between days 101 and 365 post-HCT and generate a hypothesis for future studies to reduce the risk of NRM at 1 year. We found that a vast majority (83%) of patients who experienced NRM between days 101 and 365 had prior grade II-IV acute graft-versus-host disease (GVHD), which was the leading cause of death either by itself (33.3%) or complicated by infections (37.5%). In multivariate analysis, grade II-IV acute GVHD (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3–6.6, p = 0.01) was the only significant predictor of NRM between days 101 and 365. Measures to reduce the risk of acute GVHD could lower the risk of NRM at 1 year and improve overall survival.

Background A myeloablative conditioning regimen can be safely given to older patients and those with comorbidities without increasing nonrelapse mortality (NRM) by fractionating the dose of intravenous busulfan. How this approach compares in efficacy with traditional, nonfractionated, lower dose regimens is unknown. Methods Outcomes were compared in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received either myeloablative, fractionated busulfan (f-Bu) dosed to achieve an area under the curve of 20,000 μmol per minute (f-Bu20K) over 2 weeks (n = 84) or a standard, nonfractionated, lower busulfan dose regimen of 16,000 μmol per minute (Bu16K) over 4 days (n = 78). Both groups also received fludarabine 40 mg/m2 intravenously for 4 days. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Patients in the Bu16K group who had unrelated donors also received antithymocyte globulin. The primary endpoint was progression-free survival. Results Roughly one-half of the patients were aged >65 years, approximately 40% had poor-risk cytogenetics, approximately 40% of those with AML were not in complete remission, and approximately 40% had a comorbidity index >3. At 2 years, progression-free survival was significantly improved in the f-Bu20K group compared with the Bu16K group (45% vs 24%, respectively; hazard ratio [HR], 0.6; 95% CI, 0.4-0.8; P = .004). This was because of a significant reduction in progression (34% vs 59%, respectively; HR, 0.5; 95% CI, 0.3-0.8; P = .003) without any increase in NRM (21% vs 15%, respectively; HR, 1.4; 95% CI, 0.7-3; P = .3), which resulted in improved overall survival (51% vs 31%, respectively; HR, 0.6; 95% CI, 0.3-0.9; P = .01). Conclusions A myeloablative, fractionated busulfan regimen reduces relapse and improves survival without increasing NRM in older patients with AML and myelodysplastic syndrome.

Steroids remain the initial therapy for acute graft-vs.-host disease (AGVHD). Strategies to improve response and minimize steroid exposure are needed. We report results of a randomized, adaptive, Bayesian-designed, phase II trial of prednisone with or without extracorporeal photopheresis (ECP) as an initial therapy for patients with newly diagnosed AGVHD. The primary endpoint was success at day 56 defined as: alive, in remission, achieving AGVHD response without additional therapy, and on

The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consisting of both transplant and nontransplant experts, was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by the American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate- and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.

Diabetes mellitus and obesity are very similar in terms of pathogenesis and pathophysiology. Most obese patients have adipose tissue dysfunction caused by genetic and environmental factors. Adipose tissue is the source of adipokines secreted from adipocytes. Vaspin, Visfatin and Chemerin are adipokines discovered in recent years. The study consists of 43 non-diabetic obese and 51 diabetic obese individuals. The PCR-RFLP method and agarose gel electrophoresis techniques were used to detect gene polymorphisms of Chemerin rs17173608, Vaspin rs2236242 and Visfatin rs2110385 from DNA samples. In our study, when diabetic obese and non-diabetic obese patient groups were examined in terms of Vaspin gene polymorphism, statistically significant results were obtained (22% → 7%, p=0.048, respectively). The distribution of Chemerin or Visfatin gene variants were not different in study groups (p>0.05). Our results indicate that Chemerin rs17173608 and Visfatin rs2110385 gene polymorphisms were not risk factors for development of diabetes in obese individuals, however, Vaspin rs2236242 gene polymorphism may be a contributory risk of development of diabetes in obese individuals.

Objective: Iron deficiency (ID) is a frequent complication in end stage renal insufficiency. These patients have to be diagnosed and treated to reduce the prevalence of anemia. Functional iron deficiency (FID) is a situation that can disrupt biochemical iron tests and mask an eventual association with ID. In this study, we tried to prove the ability of extended parameters of red cells and reticulocytes to diagnose ID without being influenced by FID. Design and methods: 164 chronic hemodialysis patients (CHP) in end stage renal disease were enrolled. Research parameters of red cells and reticulocytes determined on ADVIA 2120i were studied in the diagnosis of ID associated or not with chronic inflammation. Results: Parameters such as corpuscular hemoglobin of mature red cells (CHm), corpuscular hemoglobin of reticulocytes (CHr), cellular concentration of hemoglobin in mature red cells (CHCMm), cellular concentration of hemoglobin in reticulocytes (CHCMr) and percentage of microcytic and hypochromic red cells (HYMI) showed a high sensitivity to diagnose ID. However, the distinction of combined iron deficiency (CID) from other entities was not possible with all parameters. In chronic inflammatory states, the decrease of CHm, CHCMm and CHCMr with the rise of percentage hypochromic mature red cells (HYPOm) and reticulocytes (HYPOr) is in favor of CID. So, determination of inflammatory state is needed to complete research parameters of blood count in CHP. Conclusion: Extended erythrocyte and reticulocyte parameters can be useful to check iron status in CHP.

This study investigated the efficacy and safety of azacitidine maintenance in the posttransplant setting based on the encouraging phase 1/2 reports for azacitidine maintenance in patients with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). Between 2009 and 2017, a total of 187 patients aged 18 to 75 years were entered into a randomized controlled study of posttransplant azacitidine if they were in complete remission. Patients randomized to the treatment arm (n = 93) were scheduled to receive azacitidine, given as 32 mg/m2 per day subcutaneously for 5 days every 28 days for 12 cycles. The control arm (n = 94) had no intervention. Eighty-seven of the 93 patients started azacitidine maintenance. The median number of cycles received was 4; a total of 29 patients relapsed on study, and 23 patients withdrew from the study due to toxicity, patient’s preference, or logistical reasons. Median relapse-free survival (RFS) was 2.07 years in the azacitidine group vs 1.28 years in the control group (P = .43). There was also no significant difference for overall survival, with a median of 2.52 years vs 2.56 years in the azacitidine and control groups (P = .85), respectively. Multivariate Cox regression analysis revealed no improvement in RFS or overall survival with the use of azacitidine as maintenance compared with the control group (hazard ratios of 0.73 [95% confidence interval, 0.49-1.1; P = .14] and 0.84 [95% confidence interval, 0.55-1.29; P = .43]). This randomized trial with azacitidine maintenance showed that a prospective trial in the posttransplant setting was feasible and safe but challenging. Although RFS was comparable between the 2 arms, we believe the strategy of maintenance therapy merits further study with a goal to reduce the risk of relapse in patients with AML/MDS. This trial was registered at www.clinicaltrials.gov as #NCT00887068.

In recent decades, the prevalence of diabetes has rapidly increased worldwide. Medical nutrition therapy has been identified as a major therapeutic support for diabetic patients, while preventive strategies in prediabetic or high-risk individuals have mainly focused on supplementation with bioactive compounds. Recently, meal-based interventions have been investigated as novel and safe long-term strategies for improving glucose regulation. However, evaluation of meal-based interventions is difficult since it requires analysis of sensitive markers. Biomarkers can also be used to identify individuals at risk for diabetes, which is important for disease prevention. In this review, we summarize current evidence from meal-based intervention studies conducted with the aim of improving glucose homeostasis in individuals at risk of diabetes using clinical biomarkers currently used to assess diabetic risk. Very low-calorie diets have significantly improved glucose regulation in obese adults and in adults with type 2 diabetes mellitus. In particular, changing the ratios of macronutrients through calorie restriction reduces fasting glucose level and hemoglobin A1c levels in patients with diabetes mellitus. However, this effect is limited in both obese and healthy adults. To date, multiple glucose-related markers have been identified as clinical biomarkers of diabetes. Additional clinical biomarkers include cholesterol levels, hematological markers, and inflammatory markers. Taken together, the evidence presented in this review may help for selection of clinical biomarkers for meal-based preventive approaches for non- or pre-diabetic individuals to prevent onset of diabetes.

The optimal conditioning regimen for older patients with acute myeloid leukemia (AML) remains unclear. In this study, we compared outcomes of AML patients >60 years of age undergoing allogenic hematopoietic stem cell transplantation at our institution. All 404 consecutively treated patients received 1 of the following conditioning regimens: (1) fludarabine+melphalan 100 mg/m2 (FM100), (2) fludarabine+melphalan 140 mg/m2 (FM140), (3) fludarabine+IV busulfan AUC ≥ 5000/d × 4 d (Bu≥20000), and (4) fludarabine+IV busulfan AUC 4000/d × 4 d (Bu16000). A propensity score analysis (PSA) was used to compare outcomes between these 4 groups. Among the 4 conditioning regimens, the FM100 group had a significantly better long-term survival with 5-year progression-free survival of 49% vs 30%, 34%, and 23%, respectively. The benefit of the FM100 regimen resulted primarily from the lower nonrelapse mortality associated with this regimen, an effect more pronounced in patients with lower performance status. The PSA confirmed that FM100 was associated with better posttransplantation survival, whereas no significant differences were seen between the other regimen groups. In summary, older patients with AML benefited from a reduced-intensity conditioning regimen with lower melphalan doses (FM100), which was associated with better survival, even though it was primarily used in patients who could not receive a more intense conditioning regimen.

BACKGROUND AND PURPOSE: Vascular devices generating high shear stress can cause type 2A acquired von Willebrand disease, which is characterized by low von Willebrand factor activity accompanied by hemorrhagic complications. The braided mesh structure of flow-diverting stents with a relatively small strut size can create abnormally high shear stress while arterial blood flows through the stent struts into the aneurysm, and flow-diverting stent may be associated with reduced von Willebrand factor activity. MATERIALS AND METHODS: Aneurysmal morphologic parameters and patient data were examined retrospectively among patients who had an unruptured intracranial aneurysm treated with a flow-diverting stent. The RISTOtest (test for whole blood ristocetin-induced platelet aggregation) for von Willebrand factor activity, as well as tests for aspirin and clopidogrel/prasugrel effectiveness, were performed immediately before the endovascular procedure and 24 hours later by multiple electrode aggregometry. RESULTS: A total of 39 patients with 56 aneurysms were recruited, and statistical analyses were performed in 32 patents with 49 aneurysms. Compared with the baseline values, von Willebrand factor activity was reduced in 16 patients but increased in 23 patients. Aneurysmal variables (eg, neck area, volume, volume-to-neck area ratio, size ratio, and morphologic index) clearly distinguished patients with reduced von Willebrand factor activity from those with nonreduced von Willebrand factor activity. The receiver operating characteristic curve showed that the morphologic index and volume had the highest discriminative power, with an area under the curve of 0.99. CONCLUSIONS: In high-volume/large-neck aneurysms, flow-diverting stent implantation can cause reduced von Willebrand factor activity, which may be linked causally to acquired von Willebrand disease.

Background Maintenance ART with dolutegravir-based dual regimens have proved their efficacy among HIV-1-infected subjects in randomized trials. However, real-life data are scarce, with limited populations and follow-up. Objectives We assessed virological failure (VF) and resistance-associated mutations (RAMs) on dolutegravir maintenance regimens in combination with rilpivirine or with lamivudine or emtricitabine (xTC) and analysed the factors associated with VF. Methods Between 2014 and 2018, all HIV-1-infected adults included in the Dat’AIDS cohort and starting dolutegravir/rilpivirine or dolutegravir/xTC as a maintenance dolutegravir-based dual regimen were selected. VF was defined as two consecutive HIV RNA values >50 copies/mL or a single value >400 copies/mL. We compared cumulative genotypes before initiation of a maintenance dolutegravir-based dual regimen with genotype at VF. Results We analysed 1374 subjects (799 on dolutegravir/rilpivirine and 575 on dolutegravir/xTC) with a median follow-up of 20 months (IQR = 11–31) and 19 months (IQR = 11–31), respectively. VF occurred in 3.8% (n = 30) of dolutegravir/rilpivirine subjects and 2.6% (n = 15) of dolutegravir/xTC subjects. Among subjects receiving dolutegravir/rilpivirine, two genotypes harboured emerging RAMs at VF: E138K on NNRTI (n = 1); and E138K+K101E on NNRTI and N155H on INSTI (n = 1). Among subjects receiving dolutegravir/xTC, no new RAM was detected. The only predictive factor of VF on dolutegravir/rilpivirine was the history of failure on an NNRTI-based regimen (adjusted HR = 2.97, 95% CI = 1.28–6.93). No factor was associated with VF on dolutegravir/xTC. Conclusions In this large real-life cohort, dolutegravir/rilpivirine and dolutegravir/xTC sustained virological suppression and were associated with a low rate of VF and RAM emergence. Careful virological screening is essential before switching to dolutegravir/rilpivirine in virologically suppressed patients with a history of NNRTI therapy.

Background Increased oxidative stress has been shown to lead to muscle damage and reduced physical performance. The antioxidant mechanism is most likely to reduce these relationships, but in the context of the action of carotenoids, more research is needed. This cross-sectional study aims to investigate whether carotenoids modify the association between plasma malondialdehyde (MDA) and physical performance in Korean adolescents. Methods The study sample consisted of 381 participants (164 boys, 217 girls) aged 13−18, who participated in the 2018 National Fitness Award Project. We quantified α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, lycopene, and MDA levels in plasma using HPLC with photodiode array detection. Physical performance was measured by determining the absolute and relative hand grip strength, 20-m progressive aerobic cardiovascular endurance run, estimated maximal oxygen consumption, curl-up, and sit-and-reach. Results In boys, the multiple linear regression model adjusted for age, BMI, smoking, drinking, and physical activity showed that the MDA level was negatively associated with absolute hand grip strength; this association was observed only in groups with α-carotene, β-cryptoxanthin, zeaxanthin, and total carotenoid values below the median. Conclusion These results suggest that carotenoids may act as an effect modifier of the association between MDA and physical performance in Korean male adolescents.

Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the 2 most commonly used RIC regimens, i.v. fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in patients with myelodysplastic syndrome (MDS). Through the Center for International Blood and Marrow Transplant Research (CIBMTR), we identified 1045 MDS patients age >= 60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using an RIC regimen. The CIBMTR's definition of RIC was used: a regimen that incorporated an i.v. busulfan total dose

Short sleep duration or poor sleep quality has been associated with an increased risk of obesity. Although the underlying mechanism remains unclear, one proposed pathway is poor diet quality. This cross-sectional study investigated whether diet quality modifies the association between sleep status and obesity in Korean adults. We used the baseline data and samples of 737 men and 428 women (n = 1165) aged 19–64, who participated in the prospective Ewha–Boramae cohort study. Sleep duration was dichotomized into ≥7 h (adequate) and &lt, 7 h (insufficient). Pittsburgh Sleep Quality Index (PSQI) values, reflecting sleep quality, were dichotomized into &gt, 5 (poor quality) and ≤5 (good quality). Diet quality was evaluated by the Recommended Food Score (RFS). Obesity was associated with higher rates of insufficient sleep and poor sleep quality in women, but not in men. After adjustment for covariates, women with poor sleep quality had a higher risk of obesity than women with good sleep quality (OR = 2.198, 95% CI = 1.027–4.704), this association occurred only in the group with RFS ≤ median score. Our findings support a significant association between sleep quality and obesity, and this association has been potentially modified by dietary quality in women.

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan over a longer period (fractionated busulfan regimen) than the standard four-day regimen (Popat et al Lancet Haematology 2018). This longer duration of conditioning regimen allows addition of targeted agents like Venetoclax, which may be synergistic with conditioning chemotherapy and may further improve disease control with this regimen. We therefore added Venetoclax to our ongoing prospective clinical trial with f-Bu-Flu-Cladribine conditioning (NCT02250937). After enrolling 83 patients, the study was amended and venetoclax was added for the next 33 patients. Here we report the safety and preliminary efficacy of venetoclax and fractionated busulfan regimen. Methods: Between 2/2019 and 3/2021, 33 patients with AML (n=21) or MDS (n=10) up to 70 years of age with adequate organ function and 8/8-HLA matched related or unrelated donor were enrolled on a prospective trial. The conditioning regimen was f-Bu to target an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min given over a period of 2-3 weeks. The first two doses of busulfan (80 mg/m2 IV each) were administered either consecutively (days -13 and -12) or with further fractionation, one week apart (days -20 and -13) on outpatient basis. Then, inpatient fludarabine 10 mg/m 2, and cladribine 10 mg/m 2 were given followed by Bu on days -6 to -3. Venetoclax 400mg daily was given from day -22 to -3. Azoles were avoided during this period. GVHD prophylaxis was PTCy 50mg/kg on days 3 and 4 and tacrolimus from day 5. Results: The median age was 59 years (range, 23-69); High or very high disease risk index was present in 21%; Comorbidity index score of >3 was present in 45%; Donor was a sibling in 39%; and peripheral blood stem cells was the graft source in 100%. The median follow up was 8 months. At 1-year, overall survival was 84% (95% confidence interval, 71-100), progression-free survival 77% (64-94), relapse 13% (1-25), and non-relapse mortality 10% (0-20) [Table 1, Figure 1]. Incidence of acute GVHD grade 2-4 was 28% (12-43) and grade 3-4 acute GVHD was 3% (0-9) at day 100. All patients engrafted. The median time to neutrophil engraftment was 15 days (13 -19) and median time to platelet engraftment was 23 days (11-85). Full donor chimerism at day 30 was noted in 76%. Common grade 3 or 4 toxicity were neutropenic fever (58%), mucositis (18%) and pulmonary toxicity in 21%. Conclusion: Venetoclax can be safely added to the fractionated busulfan regimen. Early data on efficacy appear promising. Figure 1 Figure 1. Disclosures Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Mehta: CSLBehring: Research Funding; Syndax: Research Funding; Incyte: Research Funding; Kadmon: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Gulbis: EUSA Pharma: Other: Advisory board participation. Rezvani: AvengeBio: Other: Scientific Advisory Board ; Pharmacyclics: Other: Educational grant, Research Funding; GemoAb: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; Bayer: Other: Scientific Advisory Board ; Caribou: Other: Scientific Advisory Board; Takeda: Other: License agreement and research agreement, Patents & Royalties; Virogin: Other: Scientific Advisory Board ; GSK: Other: Scientific Advisory Board ; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding. Qazilbash: Bristol-Myers Squibb: Other: Advisory Board; Oncopeptides: Other: Advisory Board; Amgen: Research Funding; Angiocrine: Research Funding; NexImmune: Research Funding; Biolline: Research Funding; Janssen: Research Funding. Kadia: Cure: Speakers Bureau; Novartis: Consultancy; Dalichi Sankyo: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Sanofi-Aventis: Consultancy; Genentech: Consultancy, Other: Grant/research support; Astellas: Other; Liberum: Consultancy; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; Pfizer: Consultancy, Other; AstraZeneca: Other; AbbVie: Consultancy, Other: Grant/research support; Pulmotech: Other; Jazz: Consultancy. Konopleva: Calithera: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Ascentage: Other: grant support, Research Funding; Cellectis: Other: grant support; Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AstraZeneca: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; KisoJi: Research Funding. Shpall: Axio: Consultancy; Magenta: Consultancy; Novartis: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Adaptimmune: Consultancy; Navan: Consultancy; Takeda: Patents & Royalties; Novartis: Honoraria; Affimed: Patents & Royalties; Magenta: Honoraria.

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan (Bu) over a longer period (fractionated (f)-Bu) with fludarabine (Flu) than the standard four-day regimen. (Popat et al Lancet Haematology 2018). We added thiotepa (Thio) to this f-Bu/Flu regimen in patients with haploidentical (haplo) donors to promote engraftment and to reduce relapse. With encouraging results, Thio was then added in matched unrelated (MUD) and sibling (MSD) donor recipients also. However, the optimal doses of Thio and Bu were undefined. To further optimize the regimen, we tested two different f-Bu/Flu/Thio regimens in parallel prospective cohorts: (a) higher dose Bu with lower dose Thio, and (b) lower dose Bu with a higher dose Thio. Patients were enrolled on these cohorts based on age and co-morbidity index (HCT-CI). Herein, we report on the safety and preliminary efficacy of these regimens (NCT02861417). Methods: Patients 60 years with HCT-CI 3, or >60 years with HCT-CI >2, or >70 years irrespective of HCT-CI received f-BU to target AUC of 16,000 with Thio 5mg/kg (Bu16K/Thio5; Cohort 2). In both cohorts, the first two doses of Bu (80 mg/m2 IV each) were given as outpatient on days -20 and -13. The last four Bu doses were given as inpatient following each dose of Flu 40 mg/m2 on days -6 through -3. Thio was given on day -7. GVHD prophylaxis was post-transplant cyclophosphamide (PTCy) 50mg/kg on days 3 and 4, tacrolimus and MMF. Results: 66 patients were enrolled - 25 in cohort 1 and 41 in cohort 2, with a median age 60 years (range, 22-69) vs 62 years (range, 30-74), respectively (P=0.14). Diagnoses were AML/MDS (64% vs 54%), CML/MPD (24% vs 22%), ALL (12% vs 22%) and 1 myeloma; P=0.24. Most had intermediate disease risk index (80% vs 73%, P=0.57); median HCT-CI was 1 (range, 0-6) vs 3 (range, 0-9); P Primary graft failure occurred in 1 patient in cohort 1 and none in cohort 2. The median time to neutrophil engraftment was 17.5 days (range, 14-26) vs 18 days (range, 12-26); P=0.12, respectively; platelet engraftment > 20K was 30 days in both groups; P=0.75. Median donor chimerism at day 30 was 100% in both groups. The incidence of acute GVHD grade III-IV was 4% vs 5%; P=0.88 at day 100; extensive chronic GVHD at 1 year was 13% vs 10%; P=0.83. At 1-year overall survival was 72% vs 78%; P=0.95; relapse was 12% each; non-relapse mortality was 20% vs 17%; P=0.97 [Table 1, Fig 1]. Common grade >3 toxicities were neutropenic fever (64% vs 42%; P=0.13), bacterial infection (44% vs 34%; P=0.45), nausea (12% vs 2%; P=0.15), mucositis (8% vs 5%; P=0.63), pneumonitis (12% vs 7%; P=0.67), hemorrhagic cystitis (8% vs 5%) and sinusoidal obstructive syndrome (8% vs 2.4%). Conclusion: In this population of older patients and/or high co-morbidities, both myeloablative regimens with f-Bu/Flu with thiotepa and PTCy were well tolerated and led to low NRM, low risk of relapse and encouraging survival. Although both regimens led to similar outcomes, the f-Bu/Flu/Thio regimen with Bu16K and thiotepa 5 mg/kg dose may be preferred as this was used in patients who were older and/or had high co-morbidities. Figure 1 Figure 1. Disclosures Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Mehta: CSLBehring: Research Funding; Kadmon: Research Funding; Syndax: Research Funding; Incyte: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rezvani: Caribou: Other: Scientific Advisory Board; Virogin: Other: Scientific Advisory Board ; AvengeBio: Other: Scientific Advisory Board ; GSK: Other: Scientific Advisory Board ; Bayer: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; GemoAb: Other: Scientific Advisory Board ; Takeda: Other: License agreement and research agreement, Patents & Royalties; Pharmacyclics: Other: Educational grant, Research Funding; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding. Qazilbash: Oncopeptides: Other: Advisory Board; Janssen: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Amgen: Research Funding; Angiocrine: Research Funding; Biolline: Research Funding. Shpall: Affimed: Patents & Royalties; Adaptimmune: Consultancy; Novartis: Consultancy; Magenta: Consultancy; Magenta: Honoraria; Axio: Consultancy; Takeda: Patents & Royalties; Navan: Consultancy; Novartis: Honoraria; Bayer HealthCare Pharmaceuticals: Honoraria.

Background The arrival of highly effective, well-tolerated, direct-acting antiviral agents (DAA) led to a dramatic decrease in hepatitis C virus (HCV) prevalence. Human immunodeficiency virus (HIV)-HCV–coinfected patients are deemed a priority population for HCV elimination, while a rise in recently acquired HCV infections in men who have sex with men (MSM) has been described. We describe the variations in HIV-HCV epidemiology in the French Dat’AIDS cohort. Methods This was a retrospective analysis of a prospective cohort of persons living with HIV (PLWH) from 2012 to 2018. We determined HCV prevalence, HCV incidence, proportion of viremic patients, treatment uptake, and mortality rate in the full cohort and by HIV risk factors. Results From 2012 to 2018, 50 861 PLWH with a known HCV status were followed up. During the period, HCV prevalence decreased from 15.4% to 13.5%. HCV prevalence among new HIV cases increased from 1.9% to 3.5% in MSM but remained stable in other groups. Recently acquired HCV incidence increased from 0.36/100 person-years to 1.25/100 person-years in MSM. The proportion of viremic patients decreased from 67.0% to 8.9%. MSM became the first group of viremic patients in 2018 (37.9%). Recently acquired hepatitis represented 59.2% of viremic MSM in 2018. DAA treatment uptake increased from 11.4% to 61.5%. More treatments were initiated in MSM in 2018 (41.2%) than in intravenous drug users (35.6%). In MSM, treatment at the acute phase represented 30.0% of treatments in 2018. Conclusions A major shift in HCV epidemiology was observed in PLWH in France from 2012 to 2018, leading to a unique situation in which the major group of HCV transmission in 2018 was MSM. Clinical Trials Registration. NCT02898987.

The decline in skeletal muscle mass and strength, also called sarcopenia, accelerates with age, leading to negative health outcomes and poor quality of life. Diet is important to promote health and plays a key role in muscle aging. Plant-based foods have recently received attention as sources of phytochemical components to attenuate loss of muscle mass and strength in older adults. This systematic review and meta-analysis evaluated the benefits of botanical extracts and their phytochemical compounds for muscle health in older adults. Randomized controlled trials were identified via systematic searches of four electronic databases (PubMed, Cochrane Library, Web of Science, and KoreaMed) up to June 2021 and were quality assessed. The results of muscle strength, mass, and physical performance were pooled using a random-effects model. Fourteen studies involving 528 subjects aged between 50 and 80 years met the inclusion criteria. Dietary phytochemicals significantly increased handgrip strength [0.90 kg; 95% confidence interval (CI) 0.26–1.53, p = 0.01] and physical performance (timed up-and-go test: − 0.5 s, 2.73 times; 95% CI − 0.84 to − 0.15, p p p p > 0.05). The findings of this systematic review and meta-analysis suggest that phytochemicals are a potential nutritional strategy to improve muscle health in older adults.

The homeostatic challenge may provide unique opportunities for quantitative assessment of the health-promoting effects of nutritional interventions in healthy individuals. Objective. The present study is aimed at characterizing and validating the use of acute aerobic exercise (AAE) on a treadmill at 60% of VO2max for 30 min, in assessing the antioxidative and anti-inflammatory effects of a nutritional intervention. In a controlled, randomized, parallel trial of Korean black raspberry (KBR) (n=24/group), fasting blood and urine samples collected before and following the AAE load at either baseline or 4-week follow-up were analyzed for biochemical markers, 1H-NMR metabolomics, and transcriptomics. The AAE was characterized using the placebo data only, and either the placebo or the treatment data were used in the validation. The AAE load generated a total of 50 correlations of 44 selected markers, based on Pearson’s correlation coefficient analysis of 105 differential markers. Subsequent mapping of selected markers onto the KEGG pathway dataset showed 127 pathways relevant to the AAE load. Of these, 54 pathways involving 18 key targets were annotated to be related to oxidative stress and inflammation. The biochemical responses were amplified with the AAE load as compared to those with no load, whereas, the metabolomic and transcriptomic responses were downgraded. Furthermore, target-pathway network analysis revealed that the AAE load provided more explanations on how KBR exerted antioxidant effects in healthy subjects (29 pathways involving 12 key targets with AAE vs. 12 pathways involving 2 key targets without AAE). This study provides considerable insight into the molecular changes incurred by AAE and furthers our understanding that AAE-induced homeostatic perturbation could magnify oxidative and inflammatory responses, thereby providing a unique opportunity to test functional foods for antioxidant and anti-inflammatory purposes in clinical settings with healthy subjects.

Osteoarthritis (OA) is a degenerative joint disorder in which progressive articular cartilage loss occurs alongside pathological changes in subchondral bone and other joint tissues. The pathophysiological role of bone in OA has been a point of interest for many years and has resurfaced again in recent years as a potential target for new treatments. Articular cartilage and subchondral bone together form the osteochondral unit. Its homeostasis and integrity are reliant on biochemical crosstalk and biomechanical interplay between the two. Subchondral bone, with its relatively greater stiffness and strength, provides mechanical support to the overlying cartilage and absorbs much of the mechanical force transmitted through the joint. Mechanical instability in osteoarthritic joints is thought to be a significant risk-factor in joint disease, due to the mechano-sensitive nature of many of its native tissues. Although the progression of joint disease remains incompletely understood, significant changes in subchondral bone remodelling, structure, composition, and mechanical properties have been documented in animal and human studies of OA. The purpose of this review is to explore and discuss these bony changes associated with disease and, in particular, contextualise the basic science and clinical literature on the role of subchondral bone in OA.

There is limited data on the outcomes of autologous hematopoietic cell transplantation (auto-HCT) in myeloma patients, 75 or older. We retrospectively analyzed all myeloma patients (n = 72)...

Although bortezomib and rituximab have synergistic activity in patients with lymphoma, and can both attenuate graft-versus-host disease (GVHD), the drugs have not been used together in patients undergoing allogeneic stem-cell transplantation (alloSCT). In this phase 1/2 trial, we assessed the safety and activity of bortezomib added to the rituximab (R) plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen in patients with relapsed lymphoma undergoing alloSCT. Primary GVHD prophylaxis consisted of tacrolimus and methotrexate. Bortezomib (1 – 1.3 mg/m(2) per dose) was administered intravenously on days −13, −6, −1, and +2. We performed inverse probability weighting analysis to compare GVHD and survival results to a historical control group that received R-BEAM without bortezomib. Thirty-nine patients were assessable for toxic effects and response. The median age was 54 years. The most common diagnosis was diffuse large B-cell lymphoma (41%). Twenty-two patients (56%) and 17 patients (44%) received their transplants from matched related and unrelated matched donors, respectively. The maximum tolerated bortezomib dose was 1 mg/m(2). The weighted cumulative incidences of grade II-IV and grade III or IV acute GVHD were 50% and 34%, respectively; these incidences and survival rates were not significantly different from those of the control group. Median survival has not been reached in patients age ≤50 years and who had a long follow-up time of 60.7 months. The R-BEAM regimen has a survival benefit in lymphoma patients age ≤50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD.

Objective The aim of ths study was to investigate the combined association of overall diet quality and physical activity (PA) on the risk for metabolic syndrome (MetS) in Korean adults. Methods This cross-sectional study extracted the data on 1008 adults (384 men and 624 women) 20 to 64 y of age. Dietary quality was assessed using a recommended food score (RFS) modified for a Korean diet. The total PA was summed to obtain a metabolic equivalent task score. Participants were classified according to the recommended levels of PA and RFS. Multiple logistic regression analysis was applied to determine the associations of RFS and PA with the prevalence of MetS after adjustment for potential confounders. Results About 21% of men and 19% of women were reported to have MetS. Nearly 5% of both sexes reached the recommended level of diet quality and PA. In men, a significantly reduced odds ratio (OR) for MetS (OR, 0.16; 95% confidence interval [CI], 0.09–0.93) and hypertriglyceridemia (OR, 0.25; 95% CI, 0.04–0.99) was found in those with better diet quality, within the strata of high PA. In women, compared with inactive individuals with poor diet quality, the OR for abdominal obesity in those with a better diet quality and who were active was 0.21 (95% CI, 0.05–0.86). Conclusions Both diet quality and PA are associated with a lower risk for hypertriglyceridemia in men and abdominal obesity in women. These findings suggest that a sex-specific pattern of association between MetS and lifestyle factors (diet and PA) should be considered in clinical practice.

It is important to understand the association between oxidative stress-related parameters and to evaluate their status in advance of chronic disease development. Further development towards disease can then be prevented by dietary antioxidants. The present study was aimed at assessing the relationship between diet quality, blood antioxidants, and oxidative damage to determine whether the association between these markers differs by oxidative stress status. For a cross-sectional analysis, we used data and samples of baseline information from a prospective cohort study. A total of 1229 eligible adults were classified into apparently healthy subjects (66.5%) and those with oxidative stress conditions (35.5%). Diet quality was assessed using the recommended food score (RFS). Plasma carotenoids (blood antioxidants) and blood/urinary malondialdehyde (MDA; oxidative damage) were determined by high-performance liquid chromatography. We found that the healthy group was younger, and they had a lower RFS and plasma MDA level and higher plasma carotenoids compared to the oxidative stress condition group. This result is probably due to the quenching of the oxidative response in the tissues of those people. A positive association of RFS with plasma carotenoids (total andβ-carotene) was found in both groups, suggesting that carotenoids are a robust reflection of diet quality. Negative associations were observed between plasma MDA and RFS in the oxidative stress condition group and between urinary MDA and plasma zeaxanthin in the healthy group. Erythrocyte MDA was positively associated with plasma carotenoids (total, lutein, zeaxanthin,β-cryptoxanthin, andα- andβ-carotene), regardless of health condition, probably also as a result of the use of carotenoids as antioxidants. In conclusion, these results indicate that the above three factors may be associated with the oxidative stress response and depend on the oxidative status. Furthermore, it was also suggested that erythrocytes are important in the oxidative stress response and the quenching of this response is represented in plasma carotenoids.

BackgroundIvermectin, an anti-parasitic agent, also has anti-viral properties. Our aim was to assess whether ivermectin can shorten the viral shedding in patients at an early-stage of COVID-19 infection.MethodsThe double-blinded trial compared patients receiving ivermectin 0·2 mg/kg for 3 days vs. placebo in non-hospitalized COVID-19 patients. RT-PCR from a nasopharyngeal swab was obtained at recruitment and then every two days. Primary endpoint was reduction of viral-load on the 6th day (third day after termination of treatment) as reflected by Ct level>30 (non-infectious level). The primary outcome was supported by determination of viral culture viability.ResultsEighty-nine patients were eligible (47 in ivermectin and 42 in placebo arm). Their median age was 35 years. Females accounted for 21·6%, and 16·8% were asymptomatic at recruitment. Median time from symptom onset was 4 days. There were no statistical differences in these parameters between the two groups.On day 6, 34 out of 47 (72%) patients in the ivermectin arm reached the endpoint, compared to 21/ 42 (50%) in the placebo arm (OR 2·62; 95% CI: 1·09-6·31). In a multivariable logistic-regression model, the odds of a negative test at day 6 was 2.62 time higher in the ivermectin group (95% CI: 1·06–6·45). Cultures at days 2 to 6 were positive in 3/23 (13·0%) of ivermectin samples vs. 14/29 (48·2%) in the placebo group (p=0·008).ConclusionsThere were significantly lower viral loads and viable cultures in the ivermectin group, which could lead to shortening isolation time in these patients.The study is registered at ClinicalTrials.gov NCT 044297411.

BACKGROUND Esophageal cancer represents a global challenge. Despite significant evolution of treatment protocols in the past decade, recurrence rates are still high and survival rates are poor. Current treatment paradigm for localized gastroesophageal junction (GEJ) carcinoma remains to be further elucidated as for the role of neoadjuvant chemoradiation versus perioperative chemotherapy. AIM To identify biomarkers for response to chemoradiation in esophageal and gastroesophageal cancer, we performed an in-depth proteomic analysis of esophageal and gastroesophageal tumors, to describe differences in pathway activation between patients with favorable and poor prognosis following neoadjuvant chemoradiation. METHODS Patients with locally advanced esophageal and gastroesophageal cancer following neoadjuvant chemoradiation were included in the cohort. The study cohort was dichotomized into two groups of patients, named "favorable prognosis" and "poor prognosis" according to the postoperative disease-free interval. We performed a mass spectrometry analysis of proteins extracted from the malignant regions of surgical specimens and analyzed data from electronic medical records. Clinical data was correlated with differences in protein expression between patient with a favorable and poor prognosis using validated gene expression pathways. RESULTS The study included 35 patients with adenocarcinoma. All patients in this cohort had esophageal adenocarcinoma. Patients median age was 62 years. Twenty-five (71.3%) patients underwent neoadjuvant chemoradiation, and 28.7% underwent neoadjuvant chemotherapy only. A proteomic analysis of our cohort identified 2885 proteins. Enrichment levels of 98 of these proteins differed significantly between favorable and poor prognosis cohorts in patients who underwent neoadjuvant chemoradiation (p

HLA-DPB1 mismatches between donor and recipient are commonly seen in allogeneic hematopoietic stem cell transplantation from an unrelated donor. HLA-DPB1 mismatch, conventionally determined by the similarity of the T-cell epitope (TCE), is associated with an increased risk of acute graft-versus-host disease (GVHD) and a decreased risk of disease relapse. We investigated the clinical impact of HLA-DPB1 molecular mismatch quantified by mismatched eplets (ME) and the Predicted Indirectly Recognizable HLA Epitopes Score (PS) in a cohort of 1,514 patients receiving hematopoietic stem cell transplants from unrelated donors matched at HLA-A, -B, -C, -DRB1/3/4/5, and - DQB1 loci. HLA-DPB1 alloimmunity in the graft-versus-host direction, determined by high graft-versus-host ME/PS, was associated with a reduced risk of relapse (hazard ratio [HR]=0.83, P=0.05 for ME) and increased risk of grade 2-4 acute GVHD (HR=1.44, P

Chronic excessive alcohol consumption is associated with multiple liver defects, such as steatosis and cirrhosis, mainly attributable to excessive reactive oxygen species (ROS) production. Barley sprouts (Hordeum vulgare L.) contain high levels of polyphenols that may serve as potential antioxidants. This study aimed to investigate whether barley sprouts extract powder (BSE) relieves alcohol-induced oxidative stress and related hepatic damages in habitual alcohol drinkers with fatty liver. In a 12-week randomized controlled trial with two arms (placebo or 480 mg/day BSE, n = 76), we measured clinical markers and metabolites at the baseline and endpoint to understand the complex molecular mechanisms. BSE supplementation reduced the magnitude of ROS generation and lipid peroxidation and improved the glutathione antioxidant system. Subsequent metabolomic analysis identified alterations in glutathione metabolism, amino acid metabolism, and fatty acid synthesis pathways, confirming the role of BSE in glutathione-related lipid metabolism. Finally, the unsupervised machine learning algorithm indicated that subjects with lower glutathione reductase at the baseline were responders for liver fat content, and those with higher fatigue and lipid oxidation were responders for γ-glutamyl transferase. These findings suggest that BSE administration may protect against hepatic injury by reducing oxidative stress and changing the metabolism in habitual alcohol drinkers with fatty liver.

Context Fractionated busulfan/fludarabine (Bu-Flu) myeloablative conditioning yields low non-relapse mortality (NRM) in older patients and those with comorbidities after matched sibling (MSD) or unrelated (MUD) donor transplant (HCT). [Popat et al, Lancet Haematology 2018]. This has not been tested in haploidentical patients, and safety of post-transplant cyclophosphamide (PTCy) GVHD prophylaxis with this approach is unknown; both aims were assessed in the current trial. Objective Primary objective/endpoints were safety/NRM. Design Open label, non-randomized, phase II. Participants Eligibility criteria included any hematologic malignancy, age Interventions Patients received busulfan 80 mg/m2 i.v. either on days -13 and -12 (n=45) or with further fractionation (days -20 and -13; n=10) and fludarabine 40 mg/m2 i.v. plus busulfan (days -6 to -2) dosed to achieve target AUC 20,000 pmol/min per pharmacokinetic studies. Haploidentical patients received thiotepa 5 mg/kg i.v on day -7. GVHD prophylaxis included PTCy 50 mg/kg i.v. and tacrolimus. Haploidentical and later MUD recipients also received mycophenolate mofetil. Results Fifty-five patients were enrolled between 08/2016 and06/2018; median follow-up was 37.6 months (range, 25.3–47.8). Diagnoses were AML/MDS (n=30), CML/MPN (n=9), ALL (n=6), and lymphoma/myeloma (n=10). Donors were haploidentical (n=26, 47%), MUD (n=18, 33%), or MSD (n=11, 20%) with PB (n=33, 60%) or BM graft. DRI was intermediate/high (n=50, 91%); 40% (n=22) had HCT-CI >3. There was no graft failure. Median time to neutrophil and platelet engraftment was 17 days (range, 13–39) and 25 days (range, 11–167). Day 100 NRM was 16.4% (95% CI 6.5–26.2%) and 24.6% (12.6–36.6%) at 3-years. Day 100 grade II–IV and III–IV acute GVHD was 38.2% (95% CI 25.2–51.2%) and 9.1% (95% CI 1.4–16.8%), 3-year chronic GVHD (all extensive) was 15.2% (95% CI 5.3–25.1%). Relapse was 25.5% (95% CI 13.8–37.1%), PFS 50% (95% CI 38.1–65.6%), OS 60.7% (95% CI 48.7–75.6%). Conclusions Myeloablative fractionated Bu-Flu with PTCy is safe and effective in MSD, MUD, and haploidentical HCT. It appears to reduce the severe acute/chronic GVHD without an apparent increase in relapse.

Asymptomatic infection seems to be a notable feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the prevalence is uncertain. This review summarizes available evidence to estimate the proportion of persons infected with SARS-CoV-2 who never develop symptoms., Background: Asymptomatic infection seems to be a notable feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19), but the prevalence is uncertain. Purpose: To estimate the proportion of persons infected with SARS-CoV-2 who never develop symptoms. Data Sources: Searches of Google News, Google Scholar, medRxiv, and PubMed using the keywords antibodies, asymptomatic, coronavirus, COVID-19, PCR, seroprevalence, and SARS-CoV-2. Study Selection: Observational, descriptive studies and reports of mass screening for SARS-CoV-2 that were either cross-sectional or longitudinal in design; were published through 17 November 2020; and involved SARS-CoV-2 nucleic acid or antibody testing of a target population, regardless of current symptomatic status, over a defined period. Data Extraction: The authors collaboratively extracted data on the study design, type of testing performed, number of participants, criteria for determining symptomatic status, testing results, and setting. Data Synthesis: Sixty-one eligible studies and reports were identified, of which 43 used polymerase chain reaction (PCR) testing of nasopharyngeal swabs to detect current SARS-CoV-2 infection and 18 used antibody testing to detect current or prior infection. In the 14 studies with longitudinal data that reported information on the evolution of symptomatic status, nearly three quarters of persons who tested positive but had no symptoms at the time of testing remained asymptomatic. The highest-quality evidence comes from nationwide, representative serosurveys of England (n = 365 104) and Spain (n = 61 075), which suggest that at least one third of SARS-CoV-2 infections are asymptomatic. Limitation: For PCR-based studies, data are limited to distinguish presymptomatic from asymptomatic infection. Heterogeneity precluded formal quantitative syntheses. Conclusion: Available data suggest that at least one third of SARS-CoV-2 infections are asymptomatic. Longitudinal studies suggest that nearly three quarters of persons who receive a positive PCR test result but have no symptoms at the time of testing will remain asymptomatic. Control strategies for COVID-19 should be altered, taking into account the prevalence and transmission risk of asymptomatic SARS-CoV-2 infection. Primary Funding Source: National Institutes of Health.

Background: SARS-CoV-2 variant Beta (B.1.351) was designated as a Variant of Concern (VoC) after becoming the dominant strain in South Africa and spreading internationally. BNT162b2 showed lower levels of neutralizing antibodies against Beta than against other strains raising concerns about effectiveness of vaccines against infections caused by Beta. We estimated BNT162b2 effectiveness against Beta infections in Israel, a country with high vaccine uptake. Methods: The Ministry of Health (MoH) identified Beta cases through mandatory reporting of SARS-CoV-2 cases and whole genome sequencing (WGS) of specimens from vaccination-breakthrough infections, reinfections, arriving international travelers, and a selection of other infected persons. A cohort analysis was conducted of exposure events of contacts of primary Beta cases. WGS was conducted on available PCR-positive specimens collected from contacts. VE estimates with 95% confidence intervals (CIs) against confirmed and probable Beta infections were determined by comparing infection risk between unvaccinated and fully-vaccinated ( > 7 days after the second dose) contacts, and between unvaccinated and partially-vaccinated ( 16 years, were identified. 343/552 (62%) contacts were interviewed and tested. 71/343 (21%) contacts were PCR-positive. WGS was performed on 7/71 (10%) PCR-positive specimens; all were Beta. Among SARS-CoV-2-infected contacts, 48/71 (68%) were symptomatic, 10/71 (14%) hospitalized, and 2/71 (3%) died. Fully-vaccinated VE against confirmed or probable Beta infections was 72% (95% CI -5 - 97%; p =0.04) and against symptomatic confirmed or probable Beta infections was 100% (95% CI 19 - 100%; p =0.01). There was no evidence of protection in partially-vaccinated contacts. Interpretation: Two doses of BNT162b2 conferred protection against Beta infections and disease. Introductions of Beta did not interrupt control of the pandemic in Israel. Funding: None to declare. Declaration of Interest: Frederick Angulo, David Swerdlow, John McLaughlin, Farid Khan, Gabriel Mircus, Kaijie Pan, Jo Southern, and Luis Jodar hold stock and stock options in Pfizer Inc. Marc Lipsitch has provided advice on COVID-19 free of charge to Janssen, Astra-Zeneca, Pfizer, and COVAXX (United Biomedical), as well as to the nonprofit One Day Sooner and has received consulting income or honoraria from Merck, Pfizer, Bristol Meyers Squibb, Janssen, and Sanofi, and institutional research support from Pfizer. He is on the Scientific Advisory Committee of the Coalition for Epidemic Preparedness and Innovations (CEPI). All other authors report no conflicts. Ethical Approval: This study was approved by MoH’s Institutional Review Board (CoR-MoH-080-2021).

Previously considered rare, inherited hematologic malignancies are increasingly identified. Germline mutations in the RNA helicase DDX41 predispose to increased lifetime risks of myeloid neoplasms with disease often occurring later in life which presents challenges for germline recognition. To improve identification of germline DDX41, individuals presenting with ≥1 DDX41 alteration on an institutional MDS/AML next-generation sequencing based panel with at least one at >40% variant allele frequency were flagged for review and genetic counseling referral. Of 5,801 individuals, 90 (1.5%) had ≥1 DDX41 mutation(s) identified. Thirty-eight (42%) patients with a median age of 66 years were referred for genetic counseling; thirty-one were male (81.5%). Thirty-five (92%) referred patients elected to pursue germline evaluation and in 33/35 (94%) a germline DDX41 variant was confirmed. Twenty-two patients (66%) with germline variants reported antecedent cytopenias, seven (21%) had a prior history of malignancy, and twenty-seven (82%) reported a family history of cancer. Predictive genetic testing for healthy family members under consideration as stem cell transplant donors was successfully performed in 11 family members, taking an average of 15 days. Near-heterozygous DDX41 mutations identified on next-generation sequencing, particularly nonsense/frameshift variants or those at recurrent germline “hot spots” are highly suggestive of a germline mutation. Next-generation sequencing screening is a feasible tool to screen unselected myeloid neoplasms for germline DDX41 mutations, enabling timely and appropriate care.

Ischemia-modified albumin (IMA) is assumed “N-terminal modified” albumin which is generated immediately following myocardial ischemia. The diagnosis of IMA is based on reduced cobalt binding affinity to albumin which is attributed mainly to incapability of cobalt to bind at albumin’s modified N-terminus. Although the albumin cobalt binding test was accepted as a potentially powerful marker for discriminating acute coronary syndrome from nonischemic chest pain, its usefulness has been brought into question in recent years. Patients with acutely ischemic myocardium exhibit a rapid increase in serum levels of fatty acids (FAs). Almost all released FAs are strongly bound to albumin which create conformational changes in the protein with resultant reduced cobalt binding affinity. There is a clear metabolic and temporal relationship between IMA measured via albumin cobalt binding testing and serum levels of FAs. In line with what has been suggested recently in the literature, we conclude that a shift from the concept of “N-terminal modified” to “FA-occupied” albumin is required, as this better describes IMA in patients with acute coronary syndrome. We also offer “oxidation modified albumin, OMA,” which is conceptually different from the “FA-occupied” IMA, to describe modification of albumin in chronic disease associated with increased oxidative stress.

Steroid-refractory (SR) lower gastrointestinal (LGI) acute graft-versus-host disease (aGVHD) has poor prognosis, and novel drugs are needed. We describe outcomes of patients with SR-LGI aGVHD treated with vedolizumab. The primary objective was to determine overall response rate (ORR) at days 14, 28, and 56. Secondary outcomes included overall survival (OS), non-relapse mortality and toxicities. Twenty patients, median age 46 years (range, 23-71), were included. All but 2 patients (90%) had grade 3 to 4 aGVHD (45% stage 4, 40% stage 3 LGI). Median time to vedolizumab was 21 days (range, 5-1031) and 13 days (range, 0-533) after diagnosis of LGI aGVHD and SR-LGI aGVHD, respectively. It was given as ≥3rd line (median 3; range 2-6) in 75% after failure of steroids, and additional treatments including ruxolitinib (n = 12) and others. Median follow-up was 17 months (range, 10-34). The days 14, 28 and 56 ORRs were 45% (9/20; complete response [CR] 25%), 35% (7/20; CR 20%), and 25% (5/20; CR 20%), respectively. Among ruxolitinib failures, it was 50% (6/12; CR 25%), 50% (6/12; CR 25%) and 25% (3/12; CR 16.7%), respectively. Fifteen patients died (14 GVHD, 1 leukemia relapse). The actuarial 6-month OS was 35% (95% confidence interval 16-55). No progressive multifocal leukoencephalopathy or infusion reaction occurred. Forty-four infection events (22 viral, 18 bacterial, and 4 fungal) were noted in 16 patients. Vedolizumab was well tolerated and demonstrated potential efficacy even after ruxolitinib failure for SR-LGI aGVHD. Yet the responses were suboptimal, and its use requires further investigation.

BackgroundIntegrase strand transfer inhibitors (INSTIs) are increasingly used in patients living with HIV due to their safety, effectiveness and high genetic barrier. However, an association with weight gain has recently been suggested and several cases of diabetes mellitus have been reported with raltegravir and dolutegravir. The long-time metabolic impact of these recent molecules remains unclear.ObjectivesTo assess if an INSTI as a third agent is statistically associated with new-onset diabetes mellitus compared with an NNRTI or a PI.Patients and methodsPatients undergoing first-line combined ART (cART) without diabetes at baseline were retrospectively included from the Dat’AIDS French cohort study (ClinicalTrials.gov NCT02898987). Incident diabetes mellitus was defined as a notification of new diabetes in the medical history, a glycated haemoglobin (HbA1c) level superior to 7.5% or the start of a diabetes therapy following the initiation of ART.ResultsFrom 2009 to 2017, 19 462 patients were included, among which 265 cases of diabetes mellitus occurred. Multivariate and survival analyses did not highlight an increase in new-onset diabetes in patients undergoing cART with an INSTI as a third agent compared with an NNRTI or a PI. BMI >30 kg/m2, age >37 years old (in survival analysis), black race or Hispanic ethnicity, arterial hypertension and AIDS were associated with a higher proportion of incident diabetes.ConclusionsINSTIs were not statistically associated with new-onset diabetes. However, clinicians should remain aware of this possible metabolic comorbidity, particularly in patients with a high BMI and older patients.

This randomized controlled study aimed to assess the efficacy and safety of an extract mixture of kudzu flower and mandarin peel (KM) on hot flashes (HFs) and markers of bone turnover in women during the menopausal transition. Healthy women aged 45&ndash, 60 years with the menopausal HFs were randomly assigned in a 1:1 ratio to either KM (1150 mg/day) or placebo arms for 12 weeks (n = 84). The intent-to-treat analysis found that compared with the placebo, the KM significantly attenuated HF scores (p = 0.041) and HF severities (p &lt, 0.001), with a mean difference from baseline to week 12. The KM also improved bone turnover markers, showing a significant reduction in bone resorption CTx (p = 0.027) and a tendency of increasing bone formation OC relative to the placebo. No serious adverse events and hormonal changes were observed in both groups. These findings suggest that KM consumption may improve the quality of life in ways that are important to symptomatic menopausal women.

SESSION TITLE: Pulmonary Vascular Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Novel coronavirus disease 2019 (COVID-19) is associated with significant morbidity and high mortality, however, 70-81% of all cases are classified as non-severe COVID-19 disease is being increasingly recognized as a prothrombotic state with a high incidence of coagulopathy Up to 30% of intensive care unit patients with COVID-19 develop a venous thromboembolism (VTE) Limited studies of non-ICU and non-mechanically ventilated patients have suggested a 5 to 10% risk of VTE However, these studies have been limited in scope and may not be generalizable to patients seen in the United States The goal of this study is to further characterize non-critically ill COVID-19 patients at our institution who develop VTEs METHODS: This is a retrospective cohort study using data from the electronic medical record It examined all adult inpatients diagnosed with COVID-19 based on a positive nasopharyngeal/oropharyngeal swab who were not mechanically ventilated during hospitalization and who were discharged alive from three hospitals comprising an integrated health system in Bronx, NY between March 11, 2020 and May 2, 2020 Patients were eligible for study inclusion if an upper or lower extremity duplex or Computerized Tomography (CT) imaging with contrast to rule out PE was performed during admission or within 14 days of discharge Summary statistics were used to characterize patients with and without VTE based on imaging findings Unpaired two-tailed t-test, Wilcoxon rank sum test or test of proportion were used to compare the groups RESULTS: Of the 2671 adult inpatients with COVID-19 who were not mechanically ventilated and survived to discharge, 313 (11 7%) completed CT or duplex imaging to identify VTE, and 72 patients (72/2671, 2 7%) were found to have a confirmed VTE Out of the 72 VTE identified, 31 were located in peripheral veins, 38 were in pulmonary veins, and 3 were in both peripheral and pulmonary veins Compared to patients without VTE on imaging, patients with VTE were of similar age (60 3 vs 61 5 years, p=0 55) and body mass index (30 8 vs 30 2, p=0 56) Patients who developed a VTE had a longer length of stay (10 vs 8 days, p=0 02) and a more elevated admission white blood cell count (10 3 vs 8 4 k/uL, p=0 002), d-dimer (4 37 vs 1 67 ug/mL, p

BACKGROUND BK polymavirus (BKPyV), a member of the family Polyomaviridae, is associated with increased morbidity and mortality in allogeneic stem cell transplant recipients. METHODS In our previous retrospective study of 2477 stem cell transplant patients, BKPyV replication independently predicted chronic kidney disease and poor survival. In this study, using the same cohort, we derived and validated a risk grading system to identify patients at risk of BKPyV replication after transplantation in a user-friendly modality. We used 3 baseline variables (conditioning regimen, HLA match status, and underlying cancer diagnosis) that significantly predicted BKPyV replication in our initial study in a subdistribution hazard model with death as a competing risk. We also developed a nomogram of the hazard model as a visual aid. The AUC of the ROC of the risk-score-only model was 0.65. We further stratified the patients on the basis of risk score into low-, moderate-, and high-risk groups. RESULTS The total risk score was significantly associated with BKPyV replication (P