The BCL6 Corepressor (BCOR) is a component of a variant Polycomb repressive complex 1 (PRC1) that is essential for normal development. Recurrent mutations in the BCOR gene have been identified in ...acute myeloid leukaemia and myelodysplastic syndrome among other cancers; however, its function remains poorly understood. Here we examine the role of BCOR in haematopoiesis in vivo using a conditional mouse model that mimics the mutations observed in haematological malignancies. Inactivation of Bcor in haematopoietic stem cells (HSCs) results in expansion of myeloid progenitors and co-operates with oncogenic Kras
in the initiation of an aggressive and fully transplantable acute leukaemia. Gene expression analysis and chromatin immunoprecipitation sequencing reveals differential regulation of a subset of PRC1-target genes including HSC-associated transcription factors such as Hoxa7/9. This study provides mechanistic understanding of how BCOR regulates cell fate decisions and how loss of function contributes to the development of leukaemia.
Mucosal-associated invariant T (MAIT) cells are T cells that recognise vitamin-B derivative Ag presented by the MHC-related-protein 1 (MR1) antigen-presenting molecule. While MAIT cells are highly ...abundant in humans, their role in tumour immunity remains unknown. Here we have analysed the frequency and function of MAIT cells in multiple myeloma (MM) patients. We show that MAIT cell frequency in blood is reduced compared to healthy adult donors, but comparable to elderly healthy control donors. Furthermore, there was no evidence that MAIT cells accumulated at the disease site (bone marrow) of these patients. Newly diagnosed MM patient MAIT cells had reduced IFNγ production and CD27 expression, suggesting an exhausted phenotype, although IFNγ-producing capacity is restored in relapsed/refractory patient samples. Moreover, immunomodulatory drugs Lenalidomide and Pomalidomide, indirectly inhibited MAIT cell activation. We further show that cell lines can be pulsed with vitamin-B derivative Ags and that these can be presented via MR1 to MAIT cells in vitro, to induce cytotoxic activity comparable to that of natural killer (NK) cells. Thus, MAIT cells are reduced in MM patients, which may contribute to disease in these individuals, and moreover, MAIT cells may represent new immunotherapeutic targets for treatment of MM and other malignancies.
Abstract
Introduction
Active duty Navy women participate in biannual Physical Fitness Assessments (PFAs), which include height and weight measurements and a Physical Readiness Test (PRT). PFAs are ...waived during pregnancy and resume the cycle after 6 months following maternity leave. The purpose of this study was to compare changes in PFA results over time between women who had or did not have a live birth during the follow-up period, and identify characteristics of women with lower PFA results postpartum.
Materials and Methods
This longitudinal study included 14,142 active duty Navy women, aged 19–40 years, with PFA results during July 2011–June 2015. Multivariable logistic regression, Stuart-Maxwell tests, and mixed effects modeling were used to examine changes in PRT scores and body mass index over time between women with and without a live birth during follow-up. All data were analyzed in 2017. This study was approved by the institutional review boards at the Uniformed Services University Office of Research and the Naval Health Research Center, and informed consent was waived in accordance with 32 CFR § 219.116(d).
Results
Postpartum women had increased odds of PRT failures (AOR = 3.88, 95% CI: 1.44–10.40) and lower PRT scores (AOR = 1.47, 95% CI: 1.12–1.92) up to 2.5 years postpartum, versus women without a live birth. Being enlisted, obese/overweight prepregnancy, and younger were risk factors for suboptimal PFA outcomes. Mean core strength and cardiovascular endurance, but not upper body strength, scores were significantly lower in postpartum women at 1 year postpartum versus women without a live birth.
Conclusions
Our findings show that additional interventions may be needed to assist women in returning to prepregnancy fitness up to 1 year postpartum. Future studies should examine additional factors that may improve postpartum fitness in addition to enhancing maternity leave policies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Surveillance of circulating microbial populations is critical for monitoring the performance of a molecular diagnostic test. In this study, we characterized 31 isolates of
(group B
GBS) from several ...geographic locations in the United States and Ireland that contain deletions in or adjacent to the region of the chromosome that encodes the hemolysin gene
, the region targeted by the Xpert GBS and GBS LB assays. PCR-negative, culture-positive isolates were recognized during verification studies of the Xpert GBS assay in 12 laboratories between 2012 and 2018. Whole-genome sequencing of 15 GBS isolates from 11 laboratories revealed four unique deletions of chromosomal DNA ranging from 181 bp to 49 kb. Prospective surveillance studies demonstrated that the prevalence of GBS isolates containing deletions in the convenience sample was <1% in three geographic locations but 7% in a fourth location. Among the 15 isolates with chromosomal deletions, multiple pulsed-field gel electrophoresis types were identified, one of which appears to be broadly dispersed across the United States.
Intestinal malrotation is a rare congenital condition with potentially devastating consequences due to potential volvulus and massive intestinal necrosis. Diagnosis is often delayed and long-term ...symptoms following surgical correction are poorly characterized. We developed the Intestinal Malrotation Patient Outcomes and WEllness Registry (IMPOWER), a national patient-generated registry (PGR), to capture data related to presenting symptoms, testing, diagnosis, treatment, and follow-up of individuals diagnosed with malrotation. IMPOWER captures patient-reported information from adult patients and parents/caregivers of children diagnosed with malrotation at the time of enrollment and at ongoing 6-month intervals. We present baseline characteristics of patients enrolled during the first two months of the registry.
Within the first two months, 354 patients with malrotation enrolled in IMPOWER, and 191 (53.9%) completed all baseline assessments. Nearly 90% of the 119 pediatric participants and 37.7% of the 72 adult participants experienced symptoms prior to diagnosis. Vomiting was the predominant symptom for pediatric participants compared to abdominal pain in adults. Yellow bilious emesis was more commonly reported than green, and volvulus at diagnosis occurred in 70% of pediatric and 27% of adult participants. One-third of pediatric participants had a bowel resection as part of their initial surgical procedure, resulting in 23.4% with diagnosed short bowel syndrome. More than 60% of pediatric and 80% of adult registrants reported gastrointestinal symptoms that persisted throughout the first year following their initial operation. Approximately 25% of registrants reported visiting four or more gastroenterologists for management of ongoing symptoms.
Fewer than half of pediatric patients presented with the "classic" presentation of green bilious colored emesis. Yellow bilious emesis was more commonly reported, and chronic gastrointestinal symptoms (i.e., abdominal pain, reflux, constipation, diarrhea) and feeding intolerance were common following surgical procedures for malrotation. This novel PGR highlights the need for a multicenter prospective registry to characterize the natural history and develop consistent standards of care related to the diagnosis, treatment, and long-term care for patients with malrotation.
ABSTRACT
Introduction
Surveillance systems have become a valuable tool to capture epidemiological data at multi-sport events, with findings serving to predict and prevent injury, reduce illness, and ...guide efficient utilization of medical resources. In 2016, the first injury and illness surveillance tool for the Department of Defense (DoD) Warrior Games was established to inform the required medical footprint. The purpose of this paper is to describe the methods and findings from the 2016 DoD Warrior Games surveillance system, which included a database of injuries and illness.
Materials and Methods
A total of 245 wounded warrior (WW) athletes were followed over 19 days, to include train-up and competition periods, as they competed for their respective teams of Army, Navy, Air Force, Marines, Special Operations, and United Kingdom. Medical personnel recorded injuries and illnesses treated utilizing a standardized surveillance form and data were entered into a daily tracker to examine patterns or areas for prevention. Reports included sex, age, event discipline, previous injury or illness, reason for presentation, and treatment provided.
Results
From June 3 to June 21, 2016, 114 individual encounters were recorded on the standard form and entered into the surveillance database. Athletes accounted for 67% of all encounters. Illness accounted for 30.7% of all visits, while injuries accounted for 69.2%. The incident proportion of injuries in athletes was 23.3 injuries per 100 athletes (95% CI 17.6, 30.1) and incident rate of 12.2 injuries per 1000 athlete days. Integrative medicine treatments including acupuncture, osteopathic manipulative treatment (OMT), massage therapy, and gua sha accounted for the largest forms of treatment (31%).
Conclusions
From the surveillance data, staff levels and treatment supplies can be adjusted. In addition an improved surveillance tool can be created. Continuous surveillance is required to provide information on trends in injury and illness to support prevention strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
ObjectivesTo describe the incidence of adverse events (AEs), reactogenicity symptoms, menstrual changes and overall self-rated improvement in health and well-being after COVID-19 ...vaccination.DesignVAC4COVID is an ongoing prospective, active observational, post-authorisation cohort safety study (PASS) of UK-approved vaccines for COVID-19 disease.SettingThe study is conducted through a secure website (www.vac4covid.com) by MEMO Research, University of Dundee, UK.Participants16 265 adult (18 years or older) UK residents with a valid email address and internet access.InterventionsAny UK-authorised COVID-19 vaccination.Main outcome measuresThe outcomes reported in this interim analysis include AEs, reactogenicity-type AEs (headache, fatigue, muscle or joint pain, fever, nausea, dizziness or local vaccine reaction), menstrual changes and reported improvement in overall health and well-being.Results11 475 consented participants (mean age 54.8 years) provided follow-up data between 2 February and 5 October 2021 (mean follow-up duration 184 days), by which date 89.2% of participants had received two vaccine doses. 89.8% of 5222 participants who completed a follow-up questionnaire in the 7 days after any COVID-19 vaccination reported no AEs. The risk of experiencing any event (not necessarily vaccine-related) requiring hospitalisation was less than 0.2%. 43.7% of post-vaccination follow-up records reported improvement in health and well-being. Reactogenicity-type reactions were more common in the week after the first dose of ChAdOx1 than BNT162b2 (7.8% vs 1.6%), but this relationship was reversed after the second dose (1.3% vs 3.1%). 0.3% of women reported menstrual symptoms after vaccination; no differences between vaccine type or dose order were detected.ConclusionsThe study provides reassuring data on low rates of AEs after COVID-19 vaccination. Differences in reactogenicity-type AE profiles between ChAdOx1 and BNT162b2 and between first and second doses of these vaccines were observed.Trial registration numberISRCTN95881792; Pre-results.
Approximately 20% of acute myeloid leukemia (AML) patients carry mutations in IDH1 or IDH2 that result in over-production of the oncometabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors ...that block 2-HG synthesis can induce complete morphological remission; however, almost all patients eventually acquire drug resistance and relapse. Using a multi-allelic mouse model of IDH1-mutant AML, we demonstrate that the clinical IDH1 inhibitor AG-120 (ivosidenib) exerts cell-type-dependent effects on leukemic cells, promoting delayed disease regression. Although single-agent AG-120 treatment does not fully eradicate the disease, it increases cycling of rare leukemia stem cells and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitizes IDH1-mutant AML to azacitidine, with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide a mechanistic rationale for the observed combinatorial effect of AG-120 and azacitidine in patients.
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•Inhibition of mutant IDH1 promotes exhaustion of the leukemic hierarchy•Resistance to the IDH1 inhibitor AG-120 can arise through transcriptional reprogramming•The differentiation state of AML cells affects their response to IDH1 inhibition•The response of LSCs to AG-120 sensitizes them to azacitidine
IDH1-mutant acute myeloid leukemia cells accumulate the oncometabolite D-2-hydroxyglutarate (2-HG). Gruber et al. demonstrate that pharmacological 2-HG blockade sensitizes rare leukemia stem cells to the cytosine analogue azacitidine by promoting cycling and upregulating pyrimidine salvage.
Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid and is used to prevent acute gout flares in patients with gout. Observational and small interventional studies have suggested ...beneficial cardiovascular effects of allopurinol.
To determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease.
Prospective, randomised, open-label, blinded endpoint multicentre clinical trial.
Four hundred and twenty-four UK primary care practices.
Aged 60 years and over with ischaemic heart disease but no gout.
Participants were randomised (1 : 1) using a central web-based randomisation system to receive allopurinol up to 600 mg daily that was added to usual care or to continue usual care.
The primary outcome was the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes were non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, all-cause mortality, hospitalisation for heart failure, hospitalisation for acute coronary syndrome, coronary revascularisation, hospitalisation for acute coronary syndrome or coronary revascularisation, all cardiovascular hospitalisations, quality of life and cost-effectiveness. The hazard ratio (allopurinol vs. usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis.
From 7 February 2014 to 2 October 2017, 5937 participants were enrolled and randomised to the allopurinol arm (
= 2979) or the usual care arm (
= 2958). A total of 5721 randomised participants (2853 allopurinol; 2868 usual care) were included in the modified intention-to-treat analysis population (mean age 72.0 years; 75.5% male). There was no difference between the allopurinol and usual care arms in the primary endpoint, 314 (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years), hazard ratio 1.04 (95% confidence interval 0.89 to 1.21);
= 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, hazard ratio 1.02 (95% confidence interval 0.87 to 1.20);
= 0.77. The pre-specified health economic analysis plan was to perform a 'within trial' cost-utility analysis if there was no statistically significant difference in the primary endpoint, so NHS costs and quality-adjusted life-years were estimated over a 5-year period. The difference in costs between treatment arms was +£115 higher for allopurinol (95% confidence interval £17 to £210) with no difference in quality-adjusted life-years (95% confidence interval -0.061 to +0.060). We conclude that there is no evidence that allopurinol used in line with the study protocol is cost-effective.
The results may not be generalisable to younger populations, other ethnic groups or patients with more acute ischaemic heart disease. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment, but an on-treatment analysis gave similar results to the main analysis.
The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve cardiovascular outcomes compared to usual care in patients with ischaemic heart disease. We conclude that allopurinol should not be recommended for the secondary prevention of cardiovascular events in patients with ischaemic heart disease but no gout.
The effects of allopurinol on cardiovascular outcomes in patients with ischaemic heart disease and co-existing hyperuricaemia or clinical gout could be explored in future studies.
This trial is registered as EU Clinical Trials Register (EudraCT 2013-003559-39) and ISRCTN (ISRCTN 32017426).
This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/36/41) and is published in full in
; Vol. 28, No. 18. See the NIHR Funding and Awards website for further award information.
For most chronic medical conditions, multiple medications are available and prescribers often have limited evidence about which therapy is likely to be the most effective and safe for an individual ...patient. As many patients are exposed every day to medicines that may be less effective than available alternatives, this is of public health importance. Cluster randomised trials of prescribing policy offer an opportunity to rapidly obtain evidence of comparative effectiveness and safety. These trials can pose a low risk to patients and cause minimal disruption to usual care. Despite the potential scientific value of this approach, there remain valid concerns about consent, medication switching and the use of routinely collected data in research. We discuss these concerns with reference to an ongoing pilot study (Evaluating Diuretics in Normal Care (EVIDENCE) - a cluster randomised evaluation of hypertension prescribing policy, ISRCTN 46635087, registered 11 August 2017).
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