Spatial patterns and environmental constraints on ecosystem services at a catchment scale

Improved understanding and prediction of the fundamental environmental controls on ecosystem service supply across the landscape will help to inform decisions made by policy makers and land-water managers. To evaluate this issue for a local catchment case study, we explored metrics and spatial patterns of service supply for water quality regulation, agriculture production, carbon storage, and biodiversity for the Macronutrient Conwy catchment. Methods included using ecosystem models such as LUCI and JULES, integration of national scale field survey datasets, earth observation products and plant trait databases, to produce finely resolved maps of species richness and primary production. Analyses were done with both 1x1 km gridded and subcatchment data. A common single gradient characterised catchment scale ecosystem services supply with agricultural production and carbon storage at opposing ends of the gradient as reported for a national-scale assessment. Species diversity was positively related to production due to the below national average productivity levels in the Conwy combined with the unimodal relationship between biodiversity and productivity at the national scale. In contrast to the national scale assessment, a strong reduction in water quality as production increased was observed in these low productive systems. Various soil variables were tested for their predictive power of ecosystem service supply. Soil carbon, nitrogen, their ratio and soil pH all had double the power of rainfall and altitude, each explaining around 45% of variation but soil pH is proposed as a potential metric for ecosystem service supply potential as it is a simple and practical metric which can be carried out in the field with crowd-sourcing technologies now available. The study emphasises the importance of considering multiple ecosystem services together due to the complexity of covariation at local and national scales, and the benefits of exploiting a wide range of metrics for each service to enhance data robustness

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Global collaboration between platform trials in surgery and anaesthesia

Large, randomized trials are the bedrock of evidence-based medicine, but the resources required to complete such trials greatly limit the number of important clinical questions that can be addressed within a reasonable period of time. Adaptive platform trials can identify effective, ineffective, or harmful treatments faster. These trials have been shown to deliver rapid evidence through the COVID-19 pandemic and are now being adopted across surgery and anaesthesia, with many opportunities for surgeons, anaesthetists, and other perioperative physicians to conduct and collaborate in platform trials.</p

Global collaboration between platform trials in surgery and anaesthesia

Large, randomised trials are the bedrock of evidence-based medicine, but the resources required to complete such trials greatly limit the number of important clinical questions that can be addressed within a reasonable period of time. Adaptive platform trials can identify effective, ineffective, or harmful treatments faster. These trials have been shown to deliver rapid evidence through the COVID-19 pandemic and are now being adopted across surgery and anaesthesia, with many opportunities for surgeons, anaesthetists, and other perioperative physicians to conduct and collaborate in platform trials.</p

Partial Deletion of Chromosome 8 β-defensin Cluster Confers Sperm Dysfunction and Infertility in Male Mice

β-defensin peptides are a family of antimicrobial peptides present at mucosal surfaces, with the main site of expression under normal conditions in the male reproductive tract. Although they kill microbes in vitro and interact with immune cells, the precise role of these genes in vivo remains uncertain. We show here that homozygous deletion of a cluster of nine β-defensin genes (DefbΔ9) in the mouse results in male sterility. The sperm derived from the mutants have reduced motility and increased fragility. Epididymal sperm isolated from the cauda should require capacitation to induce the acrosome reaction but sperm from the mutants demonstrate precocious capacitation and increased spontaneous acrosome reaction compared to wild-types but have reduced ability to bind the zona pellucida of oocytes. Ultrastructural examination reveals a defect in microtubule structure of the axoneme with increased disintegration in mutant derived sperm present in the epididymis cauda region, but not in caput region or testes. Consistent with premature acrosome reaction, sperm from mutant animals have significantly increased intracellular calcium content. Thus we demonstrate in vivo that β-defensins are essential for successful sperm maturation, and their disruption leads to alteration in intracellular calcium, inappropriate spontaneous acrosome reaction and profound male infertility

Challenges to undertaking randomised trials with looked after children in social care settings.

BACKGROUND: Randomised controlled trials (RCTs) are widely viewed as the gold standard for assessing effectiveness in health research; however many researchers and practitioners believe that RCTs are inappropriate and un-doable in social care settings, particularly in relation to looked after children. The aim of this article is to describe the challenges faced in conducting a pilot study and phase II RCT of a peer mentoring intervention to reduce teenage pregnancy in looked after children in a social care setting. METHODS: Interviews were undertaken with social care professionals and looked after children, and a survey conducted with looked after children, to establish the feasibility and acceptability of the intervention and research design. RESULTS: Barriers to recruitment and in managing the intervention were identified, including social workers acting as informal gatekeepers; social workers concerns and misconceptions about the recruitment criteria and the need for and purpose of randomisation; resource limitations, which made it difficult to prioritise research over other demands on their time and difficulties in engaging and retaining looked after children in the study. CONCLUSIONS: The relative absence of a research infrastructure and culture in social care and the lack of research support funding available for social care agencies, compared to health organisations, has implications for increasing evidence-based practice in social care settings, particularly in this very vulnerable group of young people

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

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

An innovative in silico model of the oral mucosa reveals the impact of extracellular spaces on chemical permeation through epithelium

In pharmaceutical therapeutic design or toxicology, accurately predicting the permeation of chemicals through human epithelial tissues is crucial, where permeation is significantly influenced by the tissue's cellular architecture. Current mathematical models for multi-layered epithelium such as the oral mucosa only use simplistic 'bricks and mortar' geometries and therefore do not account for the complex cellular architecture of these tissues at the microscale level, such as the extensive plasma membrane convolutions that define the extracellular spaces between cells. Chemicals often permeate tissues via this paracellular route, meaning that permeation is underestimated. To address this, measurements of human buccal mucosal tissue were conducted to ascertain the width and tortuosity of extracellular spaces across the epithelium. Using mechanistic mathematical modelling, we show that the convoluted geometry of extracellular spaces significantly impacts chemical permeation and that this can be approximated, provided that extracellular tortuosity is accounted for. We next developed an advanced physically-relevant in silico model of oral mucosal chemical permeation using partial differential equations, fitted to chemical permeation in vitro assays on tissue-engineered human oral mucosa. Tissue geometries were measured and captured in silico, and permeation examined and predicted for chemicals with different physicochemical properties. The effect of altering the extracellular space to mimic permeation enhancers was also assessed by perturbing the in silico model. This novel in vitro-in silico approach has the potential to expedite pharmaceutical innovation for testing oromucosal chemical permeation, providing a more accurate, physiologically-relevant model which can reduce animal testing with early screening based on chemical properties

An advanced<i> in silico </i>model of the oral mucosa reveals the impact of extracellular spaces on chemical permeation

Accurately predicting the permeation of chemicals through human epithelial tissues is crucial for pharmaceutical therapeutic design and toxicology. Current mathematical models of multi-layered stratified squamous epithelium such as those in the oral cavity use simplistic ‘bricks and mortar’ geometries that do not fully account for the complex cellular architecture that may affect chemical permeation in these tissues. Here we aimed to develop a new, advanced mechanistic mathematical model of the human epithelium that more accurately represents chemical tissue permeation. Using measurements of cell size and tortuosity from micrograph images of both human oral (buccal) and tissue-engineered buccal mucosa along with mechanistic mathematical modelling, we show that the convoluted geometry of the extracellular spaces within the epithelium significantly impacts chemical permeation. We next developed an advanced histologically and physiologically-relevant in silico model of buccal mucosal chemical permeation using partial differential equations, fitted to chemical permeation from in vitro assay data derived from tissue-engineered buccal mucosal models and chemicals with known physiochemical properties. Our novel in silico model can predict epithelial permeation kinetics for chemicals with different physicochemical properties in the absence or presence of permeability enhancers. This in vitro − in silico approach constitutes a step-change in the modelling of chemical tissue permeation and has the potential to expedite pharmaceutical innovation by improved and more rapid screening of chemical entities whilst reducing the need for in vivo animal experiments.<p/