Vitamin K antagonists predispose to calciphylaxis in patients with end-stage renal disease.

BACKGROUND/AIMS: Calciphylaxis is associated with a poor prognosis in dialysis patients, and its pathogenesis remains incompletely understood. Although the use of vitamin K antagonists (VKA) has been implicated, previous reports are conflicting. We aimed to determine if vitamin K antagonists conferred an increased risk of calciphylaxis in patients on dialysis. METHODS: We performed a single-centre, retrospective cohort study of 2,234 patients receiving dialysis, and compared the characteristics of those with and without calciphylaxis. RESULTS: We identified 5 cases of calciphylaxis (all female) between January 2009 and December 2013. Overall, 142 patients (6.4%) were treated with VKA during the study period. Calciphylaxis was more common in the VKA group (4 of 142 patients, OR = 61, 95% CI 6.7-546, p = 0.0001). VKA was withdrawn in all cases and treatment instituted with sodium thiosulphate, cinacalcet and supportive measures. All patients recovered, although there was one sudden cerebrovascular death during follow-up. CONCLUSION: Treatment with VKA predisposes to the development of calciphylaxis.TFH is funded by the Cambridge BRC and NIHR.This is the accepted manuscript for a paper published in Nephron Clinical Practice, Vol. 129, No. 3, 2015, DOI:10.1159/00037144

PreImplantation Trial of Histopathology In renal Allografts (PITHIA): a stepped-wedge cluster randomised controlled trial protocol.

INTRODUCTION: Most potential kidney transplant donors in the UK are aged over 60 years, yet increasing donor age is associated with poorer graft survival and function. Urgent preimplantation kidney biopsy can identify chronic injury, and may aid selection of better 'quality' kidneys from this group. However, the impact of biopsy on transplant numbers remains unproven. The PreImplantation Trial of Histopathology In renal Allografts (PITHIA) study will assess whether the introduction of a national, 24 hours, digital histopathology service increases the number, and improves outcomes, of kidneys transplanted in the UK from older deceased donors. METHODS AND ANALYSIS: PITHIA is an open, multicentre, stepped-wedge cluster randomised study, involving all UK adult kidney transplant centres. At 4-monthly intervals, a group of 4-5 randomly selected clusters (transplant centres) will be given access to remote, urgent, digital histopathology (total intervention period, 24 months). The trial has two primary end points: it is powered for an 11% increase in the proportion of primary kidney offers from deceased donors aged over 60 years that are transplanted, and a 6 mL/min increase in the estimated glomerular filtration rate of recipients at 12 months post-transplant. This would equate to an additional 120 kidney transplants performed in the UK annually. Trial outcome data will be collected centrally via the UK Transplant Registry held by NHS Blood and Transplant (NHSBT) and will be analysed using mixed effects models allowing for clustering within centres and adjusting for secular trends. An accompanying economic evaluation will estimate the cost-effectiveness of the service to the National Health Service. ETHICS AND DISSEMINATION: The study has been given favourable ethical opinion by the Cambridge South Research Ethics Committee and is approved by the Health Research Authority. We will present our findings at key transplant meetings, publish results within 4 years of the trial commencing and support volunteers at renal patient groups to disseminate the trial outcome. TRIAL REGISTRATION NUMBER: ISRCTN11708741; Pre-results.nih

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Common variants of the <i>BRCA1</i> wild-type allele modify the risk of breast cancer in <i>BRCA1</i> mutation carriers

Mutations in the &lt;i&gt;BRCA1&lt;/i&gt; gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The &lt;i&gt;BRCA1&lt;/i&gt; protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of &lt;i&gt;BRCA1&lt;/i&gt; carried on the wild-type (non-mutated) copy of the &lt;i&gt;BRCA1&lt;/i&gt; gene would modify the risk of breast cancer in carriers of &lt;i&gt;BRCA1&lt;/i&gt; mutations. A total of 9874 &lt;i&gt;BRCA1&lt;/i&gt; mutation carriers were available in the Consortium of Investigators of Modifiers of &lt;i&gt;BRCA1/2&lt;/i&gt; (CIMBA) for haplotype analyses of &lt;i&gt;BRCA1&lt;/i&gt;. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of &lt;i&gt;BRCA1&lt;/i&gt; were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77–0.95, &lt;i&gt;P&lt;/i&gt; = 0.003). Promoter &lt;i&gt;in vitro&lt;/i&gt; assays of the major &lt;i&gt;BRCA1&lt;/i&gt; haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of &lt;i&gt;BRCA1&lt;/i&gt; modify risk of breast cancer among carriers of &lt;i&gt;BRCA1&lt;/i&gt; mutations, possibly by altering the efficiency of &lt;i&gt;BRCA1&lt;/i&gt; transcription