Canadian COVID-19 host genetics cohort replicates known severity associations.

The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic contributors to severe COVID-19 (considering 3,499 hospitalized cases and 4,975 non-hospitalized after quality control). We investigated the evidence for replication of loci reported by the International Host Genetics Initiative (HGI); analyzed the X chromosome; conducted rare variant gene-based analysis and polygenic risk score testing. Population stratification was adjusted for using meta-analysis across ancestry groups. We replicated two loci identified by the HGI for COVID-19 severity: the LZTFL1/SLC6A20 locus on chromosome 3 and the FOXP4 locus on chromosome 6 (the latter with a variant significant at P < 5E-8). We found novel significant associations with MRAS and WDR89 in gene-based analyses, and constructed a polygenic risk score that explained 1.01% of the variance in severe COVID-19. This study provides independent evidence confirming the robustness of previously identified COVID-19 severity loci by the HGI and identifies novel genes for further investigation.

Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer.

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.

Genome-wide association studies of brain imaging phenotypes in UK Biobank.

The genetic architecture of brain structure and function is largely unknown. To investigate this, we carried out genome-wide association studies of 3,144 functional and structural brain imaging phenotypes from UK Biobank (discovery dataset 8,428 subjects). Here we show that many of these phenotypes are heritable. We identify 148 clusters of associations between single nucleotide polymorphisms and imaging phenotypes that replicate at P < 0.05, when we would expect 21 to replicate by chance. Notable significant, interpretable associations include: iron transport and storage genes, related to magnetic susceptibility of subcortical brain tissue; extracellular matrix and epidermal growth factor genes, associated with white matter micro-structure and lesions; genes that regulate mid-line axon development, associated with organization of the pontine crossing tract; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide insights into the genetic architecture of the brain that are relevant to neurological and psychiatric disorders, brain development and ageing.

The UK Biobank resource with deep phenotyping and genomic data.

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.

Author Correction: Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.

In the originally published version of this Letter, the authors Arthur F. Kluge, Michael A. Patane and Ce Wang were inadvertently omitted from the author list. Their affiliations are: I-to-D, Inc., PO Box 6177, Lincoln, Massachusetts 01773, USA (A.F.K.); Mitobridge, Inc. 1030 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (M.A.P.); and China Novartis Institutes for BioMedical Research, No. 4218 Jinke Road, Zhangjiang Hi-Tech Park, Pudong District, Shanghai 201203, China (C.W.). These authors contributed to the interpretation of results and design of compounds. In addition, author 'Edward A. Kesicki' was misspelled as 'Ed Kesicki'. These errors have been corrected online.

Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.

The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.

Phenotypic variation and genome-wide association studies of main culm panicle node number, maximum node production rate, and degree-days to heading in rice.

BACKGROUND: Grain yield is a complex trait that results from interaction between underlying phenotypic traits and climatic, edaphic, and biotic variables. In rice, main culm panicle node number (MCPNN; the node number on which the panicle is borne) and maximum node production rate (MNPR; the number of leaves that emerge per degree-day > 10°C) are primary phenotypic plant traits that have significant positive direct effects on yield-related traits. Degree-days to heading (DDTH), which has a significant positive effect on grain yield, is influenced by the interaction between MCPNN and MNPR. The objective of this research is to assess the phenotypic variation of MCPNN, MNPR, and DDTH in a panel of diverse rice accessions, determine regions in the rice genome associated with these traits using genome-wide association studies (GWAS), and identify putative candidate genes that control these traits. RESULTS: Considerable variation was observed for the three traits in a 220-genotype diverse rice population. MCPNN ranged from 8.1 to 20.9 nodes in 2018 and from 9.9 to 21.0 nodes in 2019. MNPR ranged from 0.0097 to 0.0214 nodes/degree day > 10°C in 2018 and from 0.0108 to 0.0193 nodes/degree-day > 10°C in 2019. DDTH ranged from 713 to 2,345 degree-days > 10°C in 2018 and from 778 to 2,404 degree-days > 10°C in 2019. Thirteen significant (P < 2.91 x 10-7) trait-single nucleotide polymorphism (SNP) associations were identified using the multilocus mixed linear model for GWAS. Significant associations between MCPNN and three SNPs in chromosome 2 (S02_12032235, S02_11971745, and S02_12030176) were detected with both the 2018 and best linear unbiased prediction (BLUP) datasets. Nine SNPs in chromosome 6 (S06_1970442, S06_2310856, S06_2550351, S06_1968653, S06_2296852, S06_1968680, S06_1968681, S06_1970597, and S06_1970602) were significantly associated with MNPR in the 2019 dataset. One SNP in chromosome 11 (S11_29358169) was significantly associated with the DDTH in the BLUP dataset. CONCLUSIONS: This study identifies SNP markers that are putatively associated with MCPNN, MNPR, and DDTH. Some of these SNPs were located within or near gene models, which identify possible candidate genes involved in these traits. Validation of the putative candidate genes through expression and gene editing analyses are necessary to confirm their roles in regulating MCPNN, MNPR, and DDTH. Identifying the underlying genetic basis for primary phenotypic traits MCPNN and MNPR could lead to the development of fast and efficient approaches for their estimation, such as marker-assisted selection and gene editing, which is essential in increasing breeding efficiency and enhancing grain yield in rice. On the other hand, DDTH is a resultant variable that is highly affected by nitrogen and water management, plant density, and several other factors.

A trait-based model ensemble approach to design rice plant types for future climate.

Crop models are powerful tools to support breeding because of their capability to explore genotype × environment×management interactions that can help design promising plant types under climate change. However, relationships between plant traits and model parameters are often model specific and not necessarily direct, depending on how models formulate plant morphological and physiological features. This hinders model application in plant breeding. We developed a novel trait-based multi-model ensemble approach to improve the design of rice plant types for future climate projections. We conducted multi-model simulations targeting enhanced productivity, and aggregated results into model-ensemble sets of phenotypic traits as defined by breeders rather than by model parameters. This allowed to overcome the limitations due to ambiguities in trait-parameter mapping from single modelling approaches. Breeders' knowledge and perspective were integrated to provide clear mapping from designed plant types to breeding traits. Nine crop models from the AgMIP-Rice Project and sensitivity analysis techniques were used to explore trait responses under different climate and management scenarios at four sites. The method demonstrated the potential of yield improvement that ranged from 15.8% to 41.5% compared to the current cultivars under mid-century climate projections. These results highlight the primary role of phenological traits to improve crop adaptation to climate change, as well as traits involved with canopy development and structure. The variability of plant types derived with different models supported model ensembles to handle related uncertainty. Nevertheless, the models agreed in capturing the effect of the heterogeneity in climate conditions across sites on key traits, highlighting the need for context-specific breeding programmes to improve crop adaptation to climate change. Although further improvement is needed for crop models to fully support breeding programmes, a trait-based ensemble approach represents a major step towards the integration of crop modelling and breeding to address climate change challenges and develop adaptation options.

Estimation of SARS-CoV-2 antibody prevalence through serological uncertainty and daily incidence.

Serology tests for SARS-CoV-2 provide a paradigm for estimating the number of individuals who have had an infection in the past (including cases that are not detected by routine testing, which has varied over the course of the pandemic and between jurisdictions). Such estimation is challenging in cases for which we only have limited serological data and do not take into account the uncertainty of the serology test. In this work, we provide a joint Bayesian model to improve the estimation of the sero-prevalence (the proportion of the population with SARS-CoV-2 antibodies) through integrating multiple sources of data, priors on the sensitivity and specificity of the serological test, and an effective epidemiological dynamics model. We apply our model to the Greater Vancouver area, British Columbia, Canada, with data acquired during the pandemic from the end of January to May 2020. Our estimated sero-prevalence is consistent with previous literature but with a tighter credible interval.

Le dépistage sérologique du SRAS­CoV­2 permet d'estimer le nombre de personnes qui ont déjà été infectées (y compris les cas qui ne sont pas détectés au moyen de tests de dépistage réguliers, qui ont varié au cours de la pandémie et d'une province ou d'un territoire à l'autre). Une telle estimation est difficile lorsqu'il existe peu de données sérologiques et que l'incertitude du test sérologique n'est pas prise en compte. Nous proposons dans ce travail un modèle bayésien conjoint visant à améliorer l'estimation de la séroprévalence (la proportion de la population avec des anticorps SRAS­CoV­2) en intégrant de multiples sources de données, des lois a priori sur la sensibilité et la spécificité du test sérologique, et un modèle efficace des dynamiques épidémiologiques. Nous appliquons ce modèle à des données recueillies dans la région métropolitaine de Vancouver (Colombie­Britannique, Canada) pendant la pandémie de fin janvier à mai 2020. Notre estimation de la séroprévalence est cohérente avec la littérature antérieure tout en ayant un intervalle de crédibilité plus précis.

Design, Synthesis, and Biological Investigation of Thailanstatin A and Spliceostatin D Analogues Containing Tetrahydropyran, Tetrahydrooxazine, and Fluorinated Structural Motifs.

Thailanstatin A and spliceostatin D, two naturally occurring molecules endowed with potent antitumor activities by virtue of their ability to bind and inhibit the function of the spliceosome, and their natural siblings and designed analogues, constitute an appealing family of compounds for further evaluation and optimization as potential drug candidates for cancer therapies. In this article, the design, synthesis, and biological investigation of a number of novel thailanstatin A analogues, including some accommodating 1,1-difluorocyclopropyl and tetrahydrooxazine structural motifs within their structures, are described. Important findings from these studies paving the way for further investigations include the identification of several highly potent compounds for advancement as payloads for antibody-drug conjugates (ADCs) as potential targeted cancer therapies and/or small molecule drugs, either alone or in combination with other anticancer agents.

Long time frames to detect the impact of changing COVID-19 measures, Canada, March to July 2020.

BackgroundMany countries have implemented population-wide interventions to control COVID-19, with varying extent and success. Many jurisdictions have moved to relax measures, while others have intensified efforts to reduce transmission.AimWe aimed to determine the time frame between a population-level change in COVID-19 measures and its impact on the number of cases.MethodsWe examined how long it takes for there to be a substantial difference between the number of cases that occur following a change in COVID-19 physical distancing measures and those that would have occurred at baseline. We then examined how long it takes to observe this difference, given delays and noise in reported cases. We used a susceptible-exposed-infectious-removed (SEIR)-type model and publicly available data from British Columbia, Canada, collected between March and July 2020.ResultsIt takes 10 days or more before we expect a substantial difference in the number of cases following a change in COVID-19 control measures, but 20-26 days to detect the impact of the change in reported data. The time frames are longer for smaller changes in control measures and are impacted by testing and reporting processes, with delays reaching ≥ 30 days.ConclusionThe time until a change in control measures has an observed impact is longer than the mean incubation period of COVID-19 and the commonly used 14-day time period. Policymakers and practitioners should consider this when assessing the impact of policy changes. Rapid, consistent and real-time COVID-19 surveillance is important to minimise these time frames.

Hybrid Rice Outperforms Inbred Rice in Resistance to Sheath Blight and Narrow Brown Leaf Spot.

Sheath blight (ShB; caused by Rhizoctonia solani AG1-1A) and narrow brown leaf spot (NBLS; Cercospora janseana) are among the most important diseases affecting rice production in Texas and other southern parts of the United States. Because of the high yield potential, hybrid rice acreage is continually increasing. Understanding the relative levels of resistance to ShB and NBLS in hybrids compared to those of inbreds is important for effective disease management; however, this information remains largely unknown. A comparison of the performance of hybrid rice and inbred rice was performed involving 173 hybrid and 155 inbred genotypes (cultivars and elite breeding lines) over the course of five crop seasons (2016 to 2020) and two locations in Texas. The results showed that genotype, cultivar type (hybrid or inbred), location, and their interactions had significant effects on the severity of ShB and NBLS. The ShB severity in hybrid genotypes was significantly lower than that in inbred genotypes, with an average reduction of 27% in disease severity during the 5-year, two-location evaluation. Most (53%) of the hybrid genotypes were rated moderately resistant, whereas almost all (97%) of the inbred genotypes ranged from very susceptible to moderately susceptible. Similarly, NBLS severity in hybrid genotypes is significantly lower than that in inbred genotypes. All but four hybrid genotypes exhibit immune reactions to NBLS. In contrast, 77% of inbred genotypes exhibit NBLS symptoms, with disease resistance reactions ranging from susceptible to resistant. The results demonstrate that hybrid rice is generally less susceptible to sheath blight and has a higher level of resistance against NBLS compared with inbred rice.

Under-reporting of COVID-19 in the Northern Health Authority region of British Columbia.

Asymptomatic and pauci-symptomatic presentations of COVID-19 along with restrictive testing protocols result in undetected COVID-19 cases. Estimating undetected cases is crucial to understanding the true severity of the outbreak. We introduce a new hierarchical disease dynamics model based on the N-mixtures hidden population framework. The new models make use of three sets of disease count data per region: reported cases, recoveries and deaths. Treating the first two as under-counted through binomial thinning, we model the true population state at each time point by partitioning the diseased population into the active, recovered and died categories. Both domestic spread and imported cases are considered. These models are applied to estimate the level of under-reporting of COVID-19 in the Northern Health Authority region of British Columbia, Canada, during 30 weeks of the provincial recovery plan. Parameter covariates are easily implemented and used to improve model estimates. We compare two distinct methods of model-fitting for this case study: (1) maximum likelihood estimation, and (2) Bayesian Markov chain Monte Carlo. The two methods agreed exactly in their estimates of under-reporting rate. When accounting for changes in weekly testing volumes, we found under-reporting rates varying from 60.2% to 84.2%.

Le recours à des protocoles de tests restrictifs et l'existence de formes asymptomatiques et paucisymptomatiques de la COVID­19 contribuent à la non détection de cas COVID­19. Pour comprendre la véritable gravité de l'épidémie, il est primordial d'estimer correctement le nombre de cas non détectés. A cette fin, les auteurs de ce travail proposent un nouveau modèle hiérarchique des dynamiques de la maladie basé sur l'approche de N­mélanges de population cachée. Ces modèles utilisent trois types de données régionales, à savoir, les nombres de cas déclarés, guéris et décédés. En faisant appel à l'amincissement binomial (binomial thinning) et en traitant les nombres de cas déclarés et guéris comme étant sous­évalués, les auteurs proposent une modélisation de l'état réel de l'épidémie basée sur une partition de la population malade en trois catégories : cas actifs, cas guéris et cas décédés. Cette partition tient compte des cas de propagation intérieure et des cas importés. Les auteurs ont utilisé les données recueillies durant les trente semaines du plan de rétablissement provincial de la région de l'Autorité sanitaire du Nord de la Colombie­Britannique, Canada pour illustrer leur approche et estimer le niveau de sous­déclaration COVID­19 associé. Des covariables peuvent être facilement incorporées au modèle proposé et améliorer la qualité des estimations. Deux méthodes d'ajustement sont retenues: (1) l'estimation par maximum de vraisemblance, et (2) la méthode de Monte Carlo par chaînes de Markov. Les estimations du taux de sous­déclaration obtenues par ces deux méthodes concordent exactement et varient entre 60,2% et 84,2% après ajustement des variations des volumes de tests hebdomadaires.

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.

BACKGROUND AND PURPOSE: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. METHODS: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. RESULTS: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. CONCLUSIONS: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Peri-operative administration of tranexamic acid in lower limb arthroplasty: a multicentre, prospective cohort study.

In the UK, tranexamic acid is recommended for all surgical procedures where expected blood loss exceeds 500 ml. However, the optimal dose, route and timing of administration are not known. This study aimed to evaluate current practice of peri-operative tranexamic acid administration. Patients undergoing primary total hip arthroplasty, total knee arthroplasty or unicompartmental knee arthroplasty during a 2-week period were eligible for inclusion in this prospective study. The primary outcome was the proportion of patients receiving tranexamic acid in the peri-operative period. Secondary outcomes included: dose, route and timing of tranexamic acid administration; prevalence of pre- and postoperative anaemia; estimated blood loss; and red blood cell transfusion rates. In total, we recruited 1701 patients from 56 NHS hospitals. Out of these, 1523 (89.5%) patients received tranexamic acid and of those, 1052 (69.1%) received a single dose of 1000 mg intravenously either pre- or intra-operatively. Out of the 1701 patients, 571 (33.6%) and 1386 (81.5%) patients were anaemic (haemoglobin < 130 g.l-1 ) in the pre- and postoperative period, respectively. Mean (SD) estimated blood loss for all included patients was 792 (453) ml and 54 patients (3.1%) received a red blood cell transfusion postoperatively. The transfusion rate for patients with pre-operative anaemia was 6.5%, compared with 1.5% in patients without anaemia. Current standard of care in the UK is to administer 1000 mg of tranexamic intravenously either pre- or intra-operatively. Approximately one-third of patients present for surgery with anaemia, although the overall red blood cell transfusion rate is low. These data provide useful comparators when assessing the efficacy of tranexamic acid and other patient blood management interventions in future studies.

The role of intra-operative cell salvage in patient blood management for revision hip arthroplasty: a prospective cohort study.

Cell salvage is an important component of blood management in patients undergoing revision hip arthroplasty surgery. However concerns regarding efficacy and patient selection remain. The aims of this study were to describe intra-operative blood loss, cell salvage re-infusion volumes and red blood cell transfusion rates for revision hip procedures and to identify factors associated with the ability to salvage sufficient blood intra-operatively to permit processing and re-infusion. Data were collected from a prospective cohort of 664 consecutive patients undergoing revision hip surgery at a single tertiary centre from 31 March 2015 to 1 April 2018. Indications for revision surgery were aseptic (n = 393 (59%)) fracture (n = 160 (24%)) and infection (n = 111 (17%)). Salvaged blood was processed and re-infused when blood loss exceeded 500 ml. Mean (SD) intra-operative blood loss was 1038 (778) ml across all procedures. Salvaged blood was re-infused in 505 of 664 (76%) patients. Mean (SD) re-infusion volume was 253 (169) ml. In total, 246 of 664 (37%) patients received an allogeneic red blood cell transfusion within 72 h of surgery. Patients undergoing femoral component revision only (OR (95%CI) 0.41 (0.23-0.73)) or acetabular component revision only (0.53 (0.32-0.87)) were less likely to generate sufficient blood salvage volume for re-infusion compared with revision of both components. Compared with aseptic indications, patients undergoing revision surgery for infection (1.87 (1.04-3.36)) or fracture (4.43 (2.30-8.55)) were more likely to generate sufficient blood salvage volume for re-infusion. Our data suggest that cell salvage is efficacious in this population. Cases where the indication is infection or fracture and where both femoral and acetabular components are to be revised should be prioritised.

How sea level change mediates genetic divergence in coastal species across regions with varying tectonic and sediment processes.

Plate tectonics and sediment processes control regional continental shelf topography. We examine the genetic consequences of how glacial-associated sea level change interacted with variable nearshore topography since the last glaciation. We reconstructed the size and distribution of areas suitable for tidal estuary formation from the last glacial maximum, ~20 thousand years ago, to present from San Francisco, California, USA (~38°N) to Reforma, Sinaloa, Mexico (~25°N). We assessed range-wide genetic structure and diversity of three codistributed tidal estuarine fishes (California Killifish, Shadow Goby, Longjaw Mudsucker) along ~4,600 km using mitochondrial control region and cytB sequence, and 16-20 microsatellite loci from a total of 524 individuals. Results show that glacial-associated sea level change limited estuarine habitat to few, widely separated refugia at glacial lowstand, and present-day genetic clades were sourced from specific refugia. Habitat increased during postglacial sea level rise and refugial populations admixed in newly formed habitats. Continental shelves with active tectonics and/or low sediment supply were steep and hosted fewer, smaller refugia with more genetically differentiated populations than on broader shelves. Approximate Bayesian computation favoured the refuge-recolonization scenarios from habitat models over isolation by distance and seaway alternatives, indicating isolation at lowstand is a major diversification mechanism among these estuarine (and perhaps other) coastal species. Because sea level change is a global phenomenon, we suggest this top-down physical control of extirpation-isolation-recolonization may be an important driver of genetic diversification in coastal taxa inhabiting other topographically complex coasts globally during the Mid- to Late Pleistocene and deeper timescales.

Phylogeography and population genomics of a lotic water beetle across a complex tropical landscape.

The habitat template concept applied to a freshwater system indicates that lotic species, or those which occupy permanent habitats along stream courses, are less dispersive than lentic species, or those that occur in more ephemeral aquatic habitats. Thus, populations of lotic species will be more structured than those of lentic species. Stream courses include both flowing water and small, stagnant microhabitats that can provide refuge when streams are low. Many species occur in these microhabitats but remain poorly studied. Here, we present population genetic data for one such species, the tropical diving beetle Exocelina manokwariensis (Dytiscidae), sampled from six localities along a ~300 km transect across the Birds Head Peninsula of New Guinea. Molecular data from both mitochondrial (CO1 sequences) and nuclear (ddRAD loci) regions document fine-scale population structure across populations that are ~45 km apart. Our results are concordant with previous phylogenetic and macroecological studies that applied the habitat template concept to aquatic systems. This study also illustrates that these diverse but mostly overlooked microhabitats are promising study systems in freshwater ecology and evolutionary biology. With the advent of next-generation sequencing, fine-scale population genomic studies are feasible for small nonmodel organisms to help illuminate the effect of habitat stability on species' natural history, population structure and geographic distribution.

Identification of novel resistance mechanisms to NAMPT inhibition via the de novo NAD+ biosynthesis pathway and NAMPT mutation.

Cancer cells have an unusually high requirement for the central and intermediary metabolite nicotinamide adenine dinucleotide (NAD+), and NAD+ depletion ultimately results in cell death. The rate limiting step within the NAD+ salvage pathway required for converting nicotinamide to NAD+ is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). Targeting NAMPT has been investigated as an anti-cancer strategy, and several highly selective small molecule inhibitors have been found to potently inhibit NAMPT in cancer cells, resulting in NAD+ depletion and cytotoxicity. To identify mechanisms that could cause resistance to NAMPT inhibitor treatment, we generated a human fibrosarcoma cell line refractory to the highly potent and selective NAMPT small molecule inhibitor, GMX1778. We uncovered novel and unexpected mechanisms of resistance including significantly increased expression of quinolinate phosphoribosyl transferase (QPRT), a key enzyme in the de novo NAD+ synthesis pathway. Additionally, exome sequencing of the NAMPT gene in the resistant cells identified a single heterozygous point mutation that was not present in the parental cell line. The combination of upregulation of the NAD+ de novo synthesis pathway through QPRT over-expression and NAMPT mutation confers resistance to GMX1778, but the cells are only partially resistant to next-generation NAMPT inhibitors. The resistance mechanisms uncovered herein provide a potential avenue to continue exploration of next generation NAMPT inhibitors to treat neoplasms in the clinic.

Surfing parameter hyperspaces under climate change scenarios to design future rice ideotypes.

Growing food crops to meet global demand and the search for more sustainable cropping systems are increasing the need for new cultivars in key production areas. This study presents the identification of rice traits putatively producing the largest yield benefits in five areas that markedly differ in terms of environmental conditions in the Philippines, India, China, Japan and Italy. The ecophysiological model WARM and sensitivity analysis techniques were used to evaluate phenotypic traits involved with light interception, photosynthetic efficiency, tolerance to abiotic stressors, resistance to fungal pathogens and grain quality. The analysis involved only model parameters that have a close relationship with phenotypic traits breeders are working on, to increase the in vivo feasibility of selected ideotypes. Current climate and future projections were considered, in the light of the resources required by breeding programs and of the role of weather variables in the identification of promising traits. Results suggest that breeding for traits involved with disease resistance, and tolerance to cold- and heat-induced spikelet sterility could provide benefits similar to those obtained from the improvement of traits involved with canopy structure and photosynthetic efficiency. In contrast, potential benefits deriving from improved grain quality traits are restricted by weather variability and markedly affected by G × E interactions. For this reason, district-specific ideotypes were identified using a new index accounting for both their productivity and feasibility.