Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

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

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

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

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

A comparison of three established age estimation methods on an adult Spanish sample.

Most current methods for adult skeletal age-at-death estimation are based on American samples comprising individuals of European and African ancestry. Our limited understanding of population variability hampers our efforts to apply these techniques to various skeletal populations around the world, especially in global forensic contexts. Further, documented skeletal samples are rare, limiting our ability to test our techniques. The objective of this paper is to test three pelvic macroscopic methods (1-Suchey-Brooks; 2- Lovejoy; 3- Buckberry and Chamberlain) on a documented modern Spanish sample. These methods were selected because they are popular among Spanish anthropologists and because they never have been tested in a Spanish sample. The study sample consists of 80 individuals (55 ♂ and 25 ♀) of known sex and age from the Valladolid collection. Results indicate that in all three methods, levels of bias and inaccuracy increase with age. The Lovejoy method performs poorly (27%) compared with Suchey-Brooks (71%) and Buckberry and Chamberlain (86%). However, the levels of correlation between phases and chronological ages are low and comparable in the three methods (< 0.395). The apparent accuracy of the Suchey-Brooks and Buckberry and Chamberlain methods is largely based on the broad width of the methods" estimated intervals. This study suggests that before systematic application of these three methodologies in Spanish populations, further statistical modeling and research into the co-variance of chronological age with morphological change is necessary. Future methods should be developed specific to various world populations, and should allow for both precision and flexibility in age estimation

The persistence of epiphyseal scars in the adult tibia

Estimation of chronological age from skeletal material is dependent upon estimation of maturational stage observed. Following completion of epiphyseal fusion, a transverse radio-opaque line, termed "epiphyseal scar", may be observed in the region of the former growth plate. According to the literature, this line is likely to become obliterated shortly after completion of epiphyseal fusion. Consequently, presence of an epiphyseal scar has been interpreted as an indication of recent epiphyseal fusion; however, this has not been validated by quantitative research. A study was undertaken to determine persistence of the epiphyseal scars in a cross-sectional population of adults between 20 and 50 years of age. This study examined 1,216 radiographs of proximal and distal tibiae from both sexes and sides of the body. This study suggested that 98.05 % of females and 97.74 % of males retained some remnant of the epiphyseal scar at the proximal tibia whilst 92.72 % of females and 92.95 % of males retained some remnant of the epiphyseal scar at the distal tibia. General linear model (GLM) analysis determined that chronological age accounted for 2.7 % and 7.6 % of variation in persistence of the epiphyseal scar at the proximal and distal tibiae, respectively. This study suggests that obliteration of the epiphyseal scar is not as dependent on chronological age as previously thought. It is, therefore, recommended that this feature not be used as an indicator of chronological age during forensic age assessment

Nephrogenic diabetes insipidus in children

Congenital nephrogenic diabetes insipidus (NDI) is a disorder associated with mutations in either the AVP2R or AQP2 gene, causing the inability of patients to concentrate their pro-urine, which leads to a high risk of dehydration. In this chapter, the clinical aspects as well as the current knowledge regarding the cell biological aspects of congenital X-linked, autosomal recessive and autosomal dominant NDI will be discussed, specifically addressing the latest developments within the field. Based on deepened mechanistic understanding, new therapeutic strategies are currently being explored, which we also describe here

Comparative analysis of metazoan chromatin organization.

Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function