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Anterior shoulder instability is a complex spectrum of pathology characterized by excessive translation of the humeral head across the glenoid, leading to apprehension, subluxation, and dislocation. Diagnosis and classification require a thorough clinical history, physical examination, and imaging to appropriately determine the severity of instability. Depending on the individual patient anatomy and severity of instability, there exist many management options that are well-positioned to successfully treat this pathology and allow patients to return to prior functional levels. Treatment options available are conservative management, arthroscopic or open Bankart repair, remplissage, open or arthroscopic Latarjet, and glenoid bone grafting. Each of these options provides unique advantages for the surgeon in treating a subset of patients along the spectrum of disease. Selection of treatment modality depends upon the number of instability events, appropriate quantification, classification bone loss, presence of associated soft tissue injuries, and patient-specific goals regarding return of function. The purpose of this review was to present an evidence-based approach to the investigation, treatment selection, and follow-up of anterior shoulder instability. Individualized patient care is required to optimally address intra-articular pathology, restore stability and function, and preserve joint health for all.

Abstract Vascular smooth muscle cell (VSMC) proliferation, migration, and apoptosis play important roles in many physiological processes and pathological conditions. To identify genetic influences on VSMC behavior, we measured these traits and undertook genome-wide association studies in primary umbilical artery-derived VSMCs from >2000 individuals. Although there were no genome-wide significant associations for VSMC proliferation or migration, genetic variants at two genomic loci (7p15.3 and 7q32.3) showed highly significant associations with VSMC apoptosis (P = 1.95 × 10−13 and P = 7.47 × 10−9, respectively). The lead variant at the 7p51.3 locus was associated with increased expression of the GSDME and PALS2 genes in VSMCs. Knockdown of GSDME or PALS2 in VSMCs attenuated apoptotic cell death. A protein co-immunoprecipitation assay indicated that GSDME complexed with PALS2. PALS2 knockdown attenuated activated caspase-3 and GSDME fragmentation, whilst GSDME knockdown also reduced activated caspase-3. These findings provide new insights into the genetic regulation of VSMC apoptosis, with potential utility for therapeutic development.

Purpose: To determine the prevalence of spin in systematic reviews (SRs) and meta-analyses of clinical studies of the remplissage procedure. Methods: Two reviewers independently performed a literature search of the PubMed, Scopus, and Embase databases using the search term “remplissage” in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The full article of each included SR was assessed for the presence of the 15 most common types of spin. Methodologic quality was assessed using the second version of A Measurement Tool to Assess Systematic Reviews (AMSTAR 2). Results: A total of 15 SRs (8 accompanied by meta-analyses; 6 Level III and 9 Level IV) were included. Overall, 13 SRs (86.7%) contained at least 1 form of spin, with 33 unique instances of spin recorded; the mean frequency was 2.2 ± 1.3 (range, 0-4). The most prevalent form of spin, present in 11 studies (73%), was type 9 (“conclusion claims the beneficial effect of the experimental treatment despite reporting bias”). There were 14 uses of spin classified as misleading reporting, 16 classified as misleading interpretation, and 3 classified as inappropriate extrapolation. The mean 5-year impact factor of the publishing journals was 4.4 ± 0.9 (range, 0-6.1), the mean number of citations per SR was 33.3 ± 24.9 (range, 0-55), and the mean number of citations per month since publication was 0.68 ± 0.44 (range, 0-1.48). According to the AMSTAR 2 assessment, confidence in the results of the SRs was rated as critically low for 20% of reviews, low for 33.3%, and moderate for 46.7%. Conclusions: Most SRs of the remplissage procedure are affected by the presence of spin. Favorable reporting was observed in the absence of definite findings, as was minimization of drawbacks for certain populations. Level of Evidence: Level IV, systematic review of Level III and IV studies.

Research on positional segregation in sport focuses on mechanisms perpetuating discrepancies in integrated contexts, including in majority-minority sports. However, theoretical explanations for positional segregation should apply to other status groups, such as ethnicity, that may be more salient in monoracial or nearly monoracial settings. We use 2018 to 2019 data on 790 NHL players and executives along with descriptive models previously applied to questions of racial segregation in sport to evaluate if stereotypes have led to ethnicity-based differences in athletes’ outcomes, using on-ice positions, leadership positions, team management positions, and penalty minutes related to stereotypes in playing style. Results show no evidence for ethnic stacking nor barriers to player leadership in the NHL but substantial differences in team management positions and penalty minutes. Our findings illuminate the degree to which theories concerning racial stereotyping mechanisms might be extended to apply in monoracial settings.

Globally, work is being undertaken to preserve biodiversity and prevent further species extinctions. Yet, without adequate data about the presence of species within ecosystems, hidden extinctions can occur without our knowledge. Given that poleward range retractions are projected for bull kelp (Durvillaea amatheiae) in southeastern Australia, there is the potential for hidden extinctions to occur in associated macrofaunal species. However, this risk cannot be assessed due to the limited data on the invertebrate macrofauna associated with D. amatheiae. We documented macrofauna within D. amatheiae holdfasts, with the objective of establishing a first analysis of the holdfast fauna for this kelp and identifying, where possible, any host-specific taxa. Holdfasts were collected at six locations, spanning most of the range of D. amatheiae on the southeastern Australian mainland. Macrofauna were removed from holdfasts and identified to the lowest possible taxonomic level. Modelling was applied to determine factors correlated with patterns of assemblages among locations. Holdfast assemblages were found to vary significantly among locations and exhibited a latitudinal gradient in assemblage structure. The northernmost location (Aragunnu), which has the highest risk of D. amatheiae range retractions, was found to have distinct species assemblages and generally higher diversity and abundance than locations further south. However, no host-specific taxa were identified in samples, indicating that there is a low risk of multiple hidden species extinctions occurring in holdfast macrofauna, due to future range retractions of D. amatheiae. Rather, most of the macrofauna taxa in D. amatheiae holdfasts were found to also occur in association with the sympatric golden kelp Ecklonia radiata, which is not expected to undergo range retractions at the latitudes where losses of D. amatheiae are projected. Overall, there is an urgent need to develop strategies to combat projected future range retractions of D. amatheiae to reduce impacts on the species that rely on D. amatheiae for habitat.

Although many interventions for acute spinal cord injury (SCI) appear promising in experimental models, translation directly from experimental animals to human patients is a large step that can be problematic. Acute SCI occurs frequently in companion dogs and may provide a model to ease translation. Recently, incision of the dura has been highlighted in both research animals and human patients as a means of reducing intraspinal pressure, with a view to improving perfusion of the injured tissue and enhancing functional recovery. Observational clinical data in humans and dogs support the notion that it may also improve functional outcome. Here, we report the results of a multi-center randomized controlled trial of durotomy as an adjunct to traditional decompressive surgery for treatment of severe thoracolumbar SCI caused by acute intervertebral disc herniation in dogs. Sample-size calculation was based on the proportion of dogs recovering ambulation improving from an expected 55% in the traditional surgery group to 70% in the durotomy group. Over a 3.5-year period, we enrolled 140 dogs, of which 128 had appropriate duration of follow-up. Overall, 65 (51%) dogs recovered ambulation. Recovery in the traditional decompression group was 35 of 62 (56%) dogs, and in the durotomy group 30 of 66 (45%) dogs, associated with an odds ratio of 0.643 (95% confidence interval: 0.320?1.292) and z-score of ?1.24. This z-score indicates trial futility to reach the target 15% improvement over traditional surgery, and the trial was terminated at this stage. We conclude that durotomy is ineffective in improving functional outcome for severe acute thoracolumbar SCI in dogs. In the future, these data can be compared with similar data from clinical trials on duraplasty in human patients and will aid in determining the predictive validity of the ?companion dog model? of acute SCI.

Background: Excellent short-term outcomes after reverse shoulder arthroplasty (RSA) have been reported, but longer term outcomes in the existing literature are sparse and vary widely. The purpose of this study is to systematically assess the existing literature to quantify functional outcomes and complication rates after RSA at a minimum of five years of follow-up. Methods: A Preferred Reporting Items for Systematic Reviews and Meta-analyses-compliant systematic literature search of the PubMed and Embase databases was undertaken. Studies reporting outcomes after primary RSA for nontrauma-related indications with a minimum of 5-year follow-up were included. Results: Overall, 20 studies satisfied all inclusion criteria. This represented 1591 shoulders in 1556 patients (32.1% males), with a mean age of 70.2 ± 5.0 years and mean follow-up of 8.8 years, or 106.2 ± 30.1 months (60-243). At final follow-up, the mean reported Constant Murley score was 62.1 ± 5.0 (49.0-83.0). The mean adjusted Constant Murley score was 83.5 ± 12.5 (58-111.9). The mean American Shoulder and Elbow Surgeons score was 81.8 ± 4.6, while the mean subjective shoulder value was 74.6 ± 6.4. Overall, 88% of patients rated their satisfaction as either good or very good. The range of active forward flexion, abduction, external, and internal rotation were respectively, 126° ± 13°, 106° ± 11°, 22° ± 11°, and 6° ± 2°. The overall rate of revision surgery was 4.9% (0%-45.5%). Regarding complications, the rate of prosthetic joint infection was 4.3% (0%-26.7%), shoulder dislocation was 3.7% (0%-20.4%), and acromial fracture was 2.0% (0%-8.8%). At final follow-up, 30.9% of shoulders had some degree of scapular notching. Conclusion: This systematic review shows that RSA results in high satisfaction rates, good clinical outcomes, as well as modest complication and revision rates at minimum 5-year follow-up.

IntroductionChocolate spot, caused by the ascomycete fungus Botrytis fabae, is a devastating foliar disease and a major constraint on the quality and yield of faba beans (Vicia faba). The use of fungicides is the primary strategy for controlling the disease. However, high levels of partial genetic resistance have been identified and can be exploited to mitigate the disease.MethodsThe partially resistant V. faba cultivar Maris Bead and susceptible Egyptian accession ig70726 were crossed, and a genetic mapping population of 184 individuals was genotyped in the F2 generation and screened for resistance to B. fabae infection in the F3, F5, and F6 generations in a series of field experiments. A high-density linkage map of V. faba containing 3897 DArT markers spanning 1713.7 cM was constructed.ResultsMultiple candidate quantitative trait loci (QTLs) in 11 separate regions of the V. faba genome were identified; some on chromosomes 2, 3, and 6 overlapped with loci previously linked to resistance to Ascochyta leaf and pod blight caused by the necrotrophic fungus Ascochyta fabae. A transcriptomics experiment was conducted at 18 h post-inoculation in seedlings of both parents of the mapping population, identifying several differentially expressed transcripts potentially involved in early stage defence against B. fabae, including cell-wall associated protein kinases, NLR genes, and genes involved in metabolism and response to reactive oxygen species.DiscussionThis study identified several novel candidate QTLs in the V. faba genome that contribute to partial resistance to chocolate spot, but differences between growing seasons highlighted the importance of multi-year phenotyping experiments when searching for candidate QTLs for partial resistance.

Abstract The amphibian‐infecting chytrid fungus, Batrachochytrium dendrobatidis (Bd), is widespread throughout Africa and is linked to declines of populations and species across the continent. While it is well established that the lineage of Bd encodes traits which determine disease severity, knowledge around how lineages are distributed according to environmental envelope is unclear. We here studied the distribution of Bd in South Africa based on the two lineages found, BdGPL and BdCAPE, in terms of their genome and environmental envelope statistically associated with their distribution. We used Bd surveillance data from published studies, as well as data collected during fieldwork from across South Africa, Lesotho, and eSwatini with samples collected along a transect spanning most of South Africa from Lesotho to the west coast. We utilized lineage‐typing qPCR to resolve the spatial distribution of BdGPL and BdCAPE across South Africa and used the resulting surveillance data to create a predictive ecological niche model for Bd lineages in South Africa. Phylogenomic analyses were performed on isolates sourced from across the transect. We show that BdGPL demonstrates a strong isolation by distance suggestive of stepping‐stone dispersal, while BdCAPE showed two distinct clusters within their genomic structure that appear geographically and temporally clustered, indicating two separate invasions. Our predictive niche model revealed that the two lineages tended to occur in different ecotypes; BdGPL was associated with lower altitude, arid regions while BdCAPE occurred across cooler, higher altitude environs. Niche predictions identified a zone of lineage contact, where genomics identified inter‐lineage recombinants. We argue that this zone of recombination should be prioritized for disease surveillance as it is a potential hotspot for the evolution of variants of amphibian chytrid with novel traits that may be epidemiologically relevant.

Abstract Background Ketone bodies (KBs) are an alternative energy supply for brain functions when glucose is limited. The most abundant ketone metabolite, 3-β-hydroxybutyrate (BOHBUT), has been suggested to prevent or delay cognitive impairment, but the evidence remains unclear. We triangulated observational and Mendelian randomization (MR) studies to investigate the association and causation between KBs and cognitive function. Methods In observational analyses of 5506 participants aged ≥ 45 years from the Whitehall II study, we used multiple linear regression to investigate the associations between categorized KBs and cognitive function scores. Two-sample MR was carried out using summary statistics from an in-house KBs meta-analysis between the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium and Kettunen et al. (N = 45,031), and publicly available summary statistics of cognitive performance and Alzheimer’s disease (AD) from the Social Science Genetic Association Consortium (N = 257,841), and the International Genomics of Alzheimer’s Project (N = 54,162), respectively. Both strong (P

Reverse shoulder arthroplasty (RSA) is used in the treatment of traumatic and arthritic pathologies, with expanding clinical indications and as a result there has been an increase in clinical research on the topic. The purpose of this study was to examine the statistical fragility of randomized control trials (RCTs) reporting outcomes from RSA. A systematic search was undertaken to find RCTs investigating RSA. The Fragility Index (FI) was calculated using Fisher’s exact test, by sequentially altering the number of events until there was a reversal of significance. The Fragility Quotient (FQ) was calculated by dividing the FI by the trial population. Each trial was assigned an overall FI and FQ calculated as the median result of its reported findings. Overall, 19 RCTs warranted inclusion in the review, representing 1146 patients, of which 41.2% were male, with a mean age of 74.2 ± 4.3 years and mean follow-up of 22.1 ± 9.9 months. The median RCT population was 59, with a median of 9 patients lost to follow-up. The median FI was 4.5, and median FQ was 0.083, indicating more patients did not complete the trial than the number of outcomes which would have to change to reverse the finding of significance. This review found that the RCT evidence for RSA management may be vulnerable to statistical fragility, with a handful of events required to reverse a finding of significance.

Abstract Objective Survival models are used extensively in biomedical sciences, where they allow the investigation of the effect of exposures on health outcomes. It is desirable to use diverse data sets in survival analyses, because this offers increased statistical power and generalisability of results. However, there are often challenges with bringing data together in one location or following an analysis plan and sharing results. DataSHIELD is an analysis platform that helps users to overcome these ethical, governance and process difficulties. It allows users to analyse data remotely, using functions that are built to restrict access to the detailed data items (federated analysis). Previous works have provided survival modelling functionality in DataSHIELD (dsSurvival package), but there is a requirement to provide functions that offer privacy enhancing survival curves that retain useful information. Results We introduce an enhanced version of the dsSurvival package which offers privacy enhancing survival curves for DataSHIELD. Different methods for enhancing privacy were evaluated for their effectiveness in enhancing privacy while maintaining utility. We demonstrated how our selected method could enhance privacy in different scenarios using real survival data. The details of how DataSHIELD can be used to generate survival curves can be found in the associated tutorial.

Abstract Embedding knowledge graphs into low-dimensional spaces is a popular method for applying approaches, such as link prediction or node classification, to these databases. This embedding process is very costly in terms of both computational time and space. Part of the reason for this is the optimisation of hyperparameters, which involves repeatedly sampling, by random, guided, or brute-force selection, from a large hyperparameter space and testing the resulting embeddings for their quality. However, not all hyperparameters in this search space will be equally important. In fact, with prior knowledge of the relative importance of the hyperparameters, some could be eliminated from the search altogether without significantly impacting the overall quality of the outputted embeddings. To this end, we ran a Sobol sensitivity analysis to evaluate the effects of tuning different hyperparameters on the variance of embedding quality. This was achieved by performing thousands of embedding trials, each time measuring the quality of embeddings produced by different hyperparameter configurations. We regressed the embedding quality on those hyperparameter configurations, using this model to generate Sobol sensitivity indices for each of the hyperparameters. By evaluating the correlation between Sobol indices, we find substantial variability in the hyperparameter sensitivities between knowledge graphs with differing dataset characteristics as the probable cause of these inconsistencies. As an additional contribution of this work we identify several relations in the UMLS knowledge graph that may cause data leakage via inverse relations, and derive and present UMLS-43, a leakage-robust variant of that graph.

Animals actively sample their environment through orienting actions such as saccadic eye movements. Saccadic targets are selected based both on sensory evidence immediately preceding the saccade, and a "salience map" or prior built-up over multiple saccades. In the primate cortex, the selection of each individual saccade depends on competition between target-selective cells that ramp up their firing rate to saccade release. However, it is less clear how a cross-saccade prior might be implemented, either in neural firing or through an activity-silent mechanism such as modification of synaptic weights on sensory inputs. Here, we present evidence from magnetoencephalography for 2 distinct processes underlying the selection of the current saccade, and the representation of the prior, in human parietal cortex. While the classic ramping decision process for each saccade was reflected in neural firing rates (measured in the event-related field), a prior built-up over multiple saccades was implemented via modulation of the gain on sensory inputs from the preferred target, as evidenced by rapid frequency tagging. A cascade of computations over time (initial representation of the prior, followed by evidence accumulation and then an integration of prior and evidence) provides a mechanism by which a salience map may be built up across saccades in parietal cortex. It also provides insight into the apparent contradiction that inactivation of parietal cortex has been shown not to affect performance on single-trials, despite the presence of clear evidence accumulation signals in this region.

Abstract Background Preterm birth and low birthweight have been associated with increased risk of heart failure and cardiovascular disease in young adulthood. However, results from clinical studies of myocardial function are not consistent. Echocardiographic strain analyses allow detection of early stages of cardiac dysfunction, and non-invasive estimates of myocardial work can provide additional information on cardiac function. We aimed to evaluate left ventricular (LV) myocardial function including measures of myocardial work in young adults born very preterm (gestational age -16%, but 22% had borderline impaired GLS between − 16% and − 18%. Mean GLS in PB/ELBW (-19.4% (95% confidence interval (CI) -20.0, -18.9)) was impaired compared to controls (-20.6% (95% CI -21.1, -20.1)), p = 0.003. Lower birthweight was associated to more impaired GLS (Pearson correlation coefficient − 0.2). Means of EF, measures of diastolic function including left atrial reservoir strain, global constructive and wasted work, global work index and global work efficiency was similar in PB/ELBW and controls. Conclusion The young adults born very preterm or with extremely low birthweight had impaired LV-GLS compared to controls, although systolic function mainly within normal range. Lower birthweight was associated with more impaired LV-GLS. These findings could indicate an elevated lifetime risk of developing heart failure in preterm born individuals. Measures of diastolic function and myocardial work were similar compared to controls.

Abstract People vary both in their embrace of their society’s traditions, and in their perception of hazards as salient and necessitating a response. Over evolutionary time, traditions have offered avenues for addressing hazards, plausibly resulting in linkages between orientations toward tradition and orientations toward danger. Emerging research documents connections between traditionalism and threat responsivity, including pathogen-avoidance motivations. Additionally, because hazard-mitigating behaviors can conflict with competing priorities, associations between traditionalism and pathogen avoidance may hinge on contextually contingent tradeoffs. The COVID-19 pandemic provides a real-world test of the posited relationship between traditionalism and hazard avoidance. Across 27 societies (N = 7844), we find that, in a majority of countries, individuals’ endorsement of tradition positively correlates with their adherence to costly COVID-19-avoidance behaviors; accounting for some of the conflicts that arise between public health precautions and other objectives further strengthens this evidence that traditionalism is associated with greater attention to hazards.

Abstract Background The identification of effective dementia prevention strategies is a major public health priority, due to the enormous and growing societal cost of this condition. Consumption of a Mediterranean diet (MedDiet) has been proposed to reduce dementia risk. However, current evidence is inconclusive and is typically derived from small cohorts with limited dementia cases. Additionally, few studies have explored the interaction between diet and genetic risk of dementia. Methods We used Cox proportional hazard regression models to explore the associations between MedDiet adherence, defined using two different scores (Mediterranean Diet Adherence Screener [MEDAS] continuous and Mediterranean diet Pyramid [PYRAMID] scores), and incident all-cause dementia risk in 60,298 participants from UK Biobank, followed for an average 9.1 years. The interaction between diet and polygenic risk for dementia was also tested. Results Higher MedDiet adherence was associated with lower dementia risk (MEDAS continuous: HR = 0.77, 95% CI = 0.65–0.91; PYRAMID: HR = 0.86, 95% CI = 0.73–1.02 for highest versus lowest tertiles). There was no significant interaction between MedDiet adherence defined by the MEDAS continuous and PYRAMID scores and polygenic risk for dementia. Conclusions Higher adherence to a MedDiet was associated with lower dementia risk, independent of genetic risk, underlining the importance of diet in dementia prevention interventions.

Glacial lake outburst floods (GLOFs) are a major hazard to downstream populations. Here, the authors show that 15 million people globally are potentially exposed to GLOF impacts, with more than half of these living in India, Pakistan, Peru and China.

Feminine honor dictates that women should cultivate a reputation for sexual purity via behaviors such as dressing modestly and maintaining virginity before marriage. The dominant explanation for people's support for feminine honor is that female infidelity threatens male partners’ honor. Beyond this, the literature affords little understanding of the evolutionary and psychological origins of feminine honor. We propose that feminine honor functions as an ideological form of mate guarding that is shaped by sexual jealousy and mating strategy. Two correlational studies ( N = 892) revealed support for predictions derived from this ideological mate-guarding account. In Study 1, dispositional jealousy and mating strategy (more monogamous orientation) predicted male participants’ support for a mate's (especially a long-term mate's) feminine honor. Moving beyond mate preferences, in Study 2 male and female participants’ dispositional jealousy and mating strategy predicted support for feminine honor of women in general. Results applied beyond masculine honor norms, religiosity, political conservativism, and age. These findings enhance the understanding of the origins and maintenance of feminine honor and related norms and ideologies that enable control over women's socio-sexual behavior.

Summary: Background: Metformin shows beneficial effects on cardiometabolic health in diabetic individuals. However, the beneficial effects in the general population, especially in non-diabetic individuals are unclear. We aim to estimate the effects of perturbation of seven metformin targets on cardiometabolic health using Mendelian randomization (MR). Methods: Genetic variants close to metformin-targeted genes associated with expression of the corresponding genes and glycated haemoglobin (HbA1c) level were used to proxy therapeutic effects of seven metformin-related drug targets. Eight cardiometabolic phenotypes under metformin trials were selected as outcomes (average N = 466,947). MR estimates representing the weighted average effects of the seven effects of metformin targets on the eight outcomes were generated. One-sample MR was applied to estimate the averaged and target-specific effects in 338,425 non-diabetic individuals in UK Biobank. Findings: Genetically proxied averaged effects of five metformin targets, equivalent to a 0.62% reduction of HbA1c level, was associated with 37.8% lower risk of coronary artery disease (CAD) (odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.46–0.84), lower levels of body mass index (BMI) (β = −0.22, 95% CI = −0.35 to −0.09), systolic blood pressure (SBP) (β = −0.19, 95% CI = −0.28 to −0.09) and diastolic blood pressure (DBP) levels (β = −0.29, 95% CI = −0.39 to −0.19). One-sample MR suggested that the seven metformin targets showed averaged and target-specific beneficial effects on BMI, SBP and DBP in non-diabetic individuals. Interpretation: This study showed that perturbation of seven metformin targets has beneficial effects on BMI and blood pressure in non-diabetic individuals. Clinical trials are needed to investigate whether similar effects can be achieved with metformin medications. Funding: Funding information is provided in the Acknowledgements.

Objective To scope the potential for (semi)-automated triangulation of Mendelian randomisation (MR) and randomised controlled trials (RCTs) evidence since the two methods have distinct assumptions that make comparisons between their results invaluable.Methods We mined ClinicalTrials.Gov, PubMed and EpigraphDB databases and carried out a series of 26 manual literature comparisons among 54 MR and 77 RCT publications.Results We found that only 13% of completed RCTs identified in ClinicalTrials.Gov submitted their results to the database. Similarly low coverage was revealed for Semantic Medline (SemMedDB) semantic triples derived from MR and RCT publications –36% and 12%, respectively. Among intervention types that can be mimicked by MR, only trials of pharmaceutical interventions could be automatically matched to MR results due to insufficient annotation with Medical Subject Headings ontology. A manual survey of the literature highlighted the potential for triangulation across a number of exposure/outcome pairs if these challenges can be addressed.Conclusions We conclude that careful triangulation of MR with RCT evidence should involve consideration of similarity of phenotypes across study designs, intervention intensity and duration, study population demography and health status, comparator group, intervention goal and quality of evidence.

Abstract Climate change has driven contemporary decline and loss of kelp forests globally with an accompanying loss of their ecological and economic values. Kelp populations at equatorward-range edges are particularly vulnerable to climate change as these locations are undergoing warming at or beyond thermal tolerance thresholds. Concerningly, these range-edge populations may contain unique adaptive or evolutionary genetic diversity that is vulnerable to warming. We explore haplotype diversity by generating a Templeton–Crandall–Sing (TCS) network analysis of 119 Cytochrome C Oxidase (COI) sequences among four major population groupings for extant and putatively extinct populations only known from herbarium specimens of the dominant Laminarian kelp Ecklonia radiata in the south-western Pacific, a region warming at 2–4 times the global average. Six haplotypes occurred across the region with one being widespread across most populations. Three unique haplotypes were found in a deep-water range-edge population off Moreton Island, Queensland, which likely represents both a contemporary and historic refuge during periods of climatic change. Hindcasting E. radiata cover estimates using extant data, we reveal that this region likely supported the highest kelp cover in eastern Australia during the last glacial maximum. The equatorward range edge, deep-water kelp populations off Moreton Island represent a genetically diverse evolutionary refuge that is currently threatened by warming and requires prompt ex-situ conservation measures.

Schmidt et al. evaluate the effects of elevated circulating concentrations of cholesterol-containing lipoproteins and apolipoproteins. Effects are seen on measures of atherosclerosis, blood pressure, c-reactive protein, coronary heart disease, heart failure, Alzheimer’s disease, type 2 diabetes and inflammatory bowel disease.

Genome-wide and epigenome-wide association studies both link genomic regions to human traits, but here the authors demonstrate that these study types are capturing different genes and biological aspects of complex traits.

There is a need for improved understanding of how climate-change driven rises in sea level and increased ocean temperatures will affect fish assemblages in rocky shore tidal pools. Rising sea levels are predicted to alter habitat availability and increasing ocean temperatures will drive tropicalisation, both of which are likely to alter tidal pool fish assemblages. Consequently, we examined changes in fish assemblages in tidal pools at four sites in Coffs Harbour, Australia, using baited video sampling. Data were collected seasonally at each site, in pools at differing tidal elevations. We identified significant differences in tidal pool fish assemblages among elevations and found that assemblages exhibited cyclic seasonal patterns. Modelling identified that ocean temperature was the most powerful factor for explaining variations in assemblages, followed by pool area and pool elevation. Results highlight that distinct fish assemblages occur in tidal pools at different elevations and indicate that assemblages at higher elevations could be squeezed out by rising sea levels and by increased competition from tropical fish species. Future conservation assessments are needed to determine whether latitudinal and vertical range shifts for tidal pool fishes are possible, with facilitation of these range shifts needed to address displacement of tidal pool fishes by rising sea levels and ocean temperatures.

Plant-parasitic nematodes are a threat to crop production. Combining bioinformatics, genetic and biochemical approaches, the authors show that the plant pathogen beet cyst nematode possesses an incomplete vitamin B5 synthesis pathway, of potential prokaryotic origin, complemented by its plant host.

Summary: Background: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. Methods: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. Findings: Genetically elevated PUFA desaturase activity was associated (P

Objectives The renal nephrometry score uses imaging characteristics such as lesion diameter, location, and proximity to hilar vessels to categorize renal masses by complexity for preoperative planning. These characteristics may also be used to determine the best approach to targeted renal biopsy. This study was conducted to investigate the impact of renal lesion characteristics as measured by the renal nephrometry score on the choice of modality used for performing a targeted renal lesion biopsy and increasing the chance of yielding a diagnostic biopsy. Materials and Methods All targeted computed tomography (CT)/ultrasound-guided renal biopsies performed by our radiology department from January 2017 to February 2020 were reviewed. Radiological characteristics and pathological outcomes were recorded with data on lesion size/ side, location in craniocaudal/anterior–posterior planes, endophytic/exophytic/mixed nature, and skin-lesion distance. Statistical Analysis Chi-squared tests, multivariate analysis, and t-tests were used in this study. Results Of the 145 consecutive patients included in the study, 86.2% (125/145) biopsies were diagnostic. About 54.5% (79/145) biopsies were ultrasound-guided, while 45.5% (66/145) were CT-guided. About 62.1% (90/145) biopsies revealed renal cell carcinoma. The highest rate of diagnostic biopsy was in the exophytic, laterally positioned mass either entirely below lower polar or above upper polar line. Ultrasound was preferred for lesions under 4cm and 4 to 7cm (p = 0.06). CT was used for anterior lesions and ultrasound for posterior and lateral lesions (p

Abstract Objective Platforms such as DataSHIELD allow users to analyse sensitive data remotely, without having full access to the detailed data items (federated analysis). While this feature helps to overcome difficulties with data sharing, it can make it challenging to write code without full visibility of the data. One solution is to generate realistic, non-disclosive synthetic data that can be transferred to the analyst so they can perfect their code without the access limitation. When this process is complete, they can run the code on the real data. Results We have created a package in DataSHIELD (dsSynthetic) which allows generation of realistic synthetic data, building on existing packages. In our paper and accompanying tutorial we demonstrate how the use of synthetic data generated with our package can help DataSHIELD users with tasks such as writing analysis scripts and harmonising data to common scales and measures.

Abstract Objective Achieving sufficient statistical power in a survival analysis usually requires large amounts of data from different sites. Sensitivity of individual-level data, ethical and practical considerations regarding data sharing across institutions could be a potential challenge for achieving this added power. Hence we implemented a federated meta-analysis approach of survival models in DataSHIELD, where only anonymous aggregated data are shared across institutions, while simultaneously allowing for exploratory, interactive modelling. In this case, meta-analysis techniques to combine analysis results from each site are a solution, but an analytic workflow involving local analysis undertaken at individual studies hinders exploration. Thus, the aim is to provide a framework for performing meta-analysis of Cox regression models across institutions without manual analysis steps for the data providers. Results We introduce a package (dsSurvival) which allows privacy preserving meta-analysis of survival models, including the calculation of hazard ratios. Our tool can be of great use in biomedical research where there is a need for building survival models and there are privacy concerns about sharing data.

Summary: Background: Amino acids are key to protein synthesis, energy metabolism, cell signaling and gene expression; however, the contribution of specific maternal amino acids to fetal growth is unclear. Methods: We explored the effect of maternal circulating amino acids on fetal growth, proxied by birthweight, using two-sample Mendelian randomisation (MR) and summary data from a genome-wide association study (GWAS) of serum amino acids levels (sample 1, n = 86,507) and a maternal GWAS of offspring birthweight in UK Biobank and Early Growth Genetics Consortium, adjusting for fetal genotype effects (sample 2, n = 406,063 with maternal and/or fetal genotype effect estimates). A total of 106 independent single nucleotide polymorphisms robustly associated with 19 amino acids (p

Environmental sensors are crucial for monitoring weather conditions and the impacts of climate change. However, it is challenging to place sensors in a way that maximises the informativeness of their measurements, particularly in remote regions like Antarctica. Probabilistic machine learning models can suggest informative sensor placements by finding sites that maximally reduce prediction uncertainty. Gaussian process (GP) models are widely used for this purpose, but they struggle with capturing complex non-stationary behaviour and scaling to large datasets. This paper proposes using a convolutional Gaussian neural process (ConvGNP) to address these issues. A ConvGNP uses neural networks to parameterise a joint Gaussian distribution at arbitrary target locations, enabling flexibility and scalability. Using simulated surface air temperature anomaly over Antarctica as training data, the ConvGNP learns spatial and seasonal non-stationarities, outperforming a non-stationary GP baseline. In a simulated sensor placement experiment, the ConvGNP better predicts the performance boost obtained from new observations than GP baselines, leading to more informative sensor placements. We contrast our approach with physics-based sensor placement methods and propose future steps towards an operational sensor placement recommendation system. Our work could help to realise environmental digital twins that actively direct measurement sampling to improve the digital representation of reality.

BackgroundProstate cancer (PrCa) is the second most prevalent malignancy in men worldwide. Observational studies have linked the use of low-density lipoprotein cholesterol (LDL-c) lowering therapies with reduced risk of PrCa, which may potentially be attributable to confounding factors. In this study, we performed a drug target Mendelian randomisation (MR) analysis to evaluate the association of genetically proxied inhibition of LDL-c-lowering drug targets on risk of PrCa.Methods and findingsSingle-nucleotide polymorphisms (SNPs) associated with LDL-c (P < 5 × 10-8) from the Global Lipids Genetics Consortium genome-wide association study (GWAS) (N = 1,320,016) and located in and around the HMGCR, NPC1L1, and PCSK9 genes were used to proxy the therapeutic inhibition of these targets. Summary-level data regarding the risk of total, advanced, and early-onset PrCa were obtained from the PRACTICAL consortium. Validation analyses were performed using genetic instruments from an LDL-c GWAS conducted on male UK Biobank participants of European ancestry (N = 201,678), as well as instruments selected based on liver-derived gene expression and circulation plasma levels of targets. We also investigated whether putative mediators may play a role in findings for traits previously implicated in PrCa risk (i.e., lipoprotein a (Lp(a)), body mass index (BMI), and testosterone). Applying two-sample MR using the inverse-variance weighted approach provided strong evidence supporting an effect of genetically proxied inhibition of PCSK9 (equivalent to a standard deviation (SD) reduction in LDL-c) on lower risk of total PrCa (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.76 to 0.96, P = 9.15 × 10-3) and early-onset PrCa (OR = 0.70, 95% CI = 0.52 to 0.95, P = 0.023). Genetically proxied HMGCR inhibition provided a similar central effect estimate on PrCa risk, although with a wider 95% CI (OR = 0.83, 95% CI = 0.62 to 1.13, P = 0.244), whereas genetically proxied NPC1L1 inhibition had an effect on higher PrCa risk with a 95% CI that likewise included the null (OR = 1.34, 95% CI = 0.87 to 2.04, P = 0.180). Analyses using male-stratified instruments provided consistent results. Secondary MR analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR = 0.90 per SD reduction in PCSK9 expression, 95% CI = 0.86 to 0.95, P = 5.50 × 10-5) and circulating plasma levels of PCSK9 (OR = 0.93 per SD reduction in PCSK9 protein levels, 95% CI = 0.87 to 0.997, P = 0.04) on PrCa risk. Colocalization analyses identified strong evidence (posterior probability (PPA) = 81.3%) of a shared genetic variant (rs553741) between liver-derived PCSK9 expression and PrCa risk, whereas weak evidence was found for HMGCR (PPA = 0.33%) and NPC1L1 expression (PPA = 0.38%). Moreover, genetically proxied PCSK9 inhibition was strongly associated with Lp(a) levels (Beta = -0.08, 95% CI = -0.12 to -0.05, P = 1.00 × 10-5), but not BMI or testosterone, indicating a possible role for Lp(a) in the biological mechanism underlying the association between PCSK9 and PrCa. Notably, we emphasise that our estimates are based on a lifelong exposure that makes direct comparisons with trial results challenging.ConclusionsOur study supports a strong association between genetically proxied inhibition of PCSK9 and a lower risk of total and early-onset PrCa, potentially through an alternative mechanism other than the on-target effect on LDL-c. Further evidence from clinical studies is needed to confirm this finding as well as the putative mediatory role of Lp(a).

ABSTRACT Introduction: The current recommendation for systemic to pulmonary artery shunt (SPS) patients requiring extracorporeal life support (ECLS) is to keep the shunt open, maintaining a higher pump flow. The practice in our center is to totally occlude the shunt while on ECLS, and we are presenting the outcome of this strategy. Methods: This is a retrospective analysis of patients who underwent SPS for cyanotic congenital heart disease with decreased pulmonary blood flow and required postoperative ECLS between January 2016 and December 2020. ECLS indication was excessive pulmonary blood flow, leading to either refractory low cardiac output syndrome (LCOS) or cardiac arrest. All patients had their shunts totally occluded soon after ECLS establishment. Results: Of the 27 SPS patients who needed postoperative ECLS (13 refractory LCOS, 14 extracorporeal cardiopulmonary resuscitation), wherein the strategy of occluding the shunt on ECLS initiation was followed, 16 (59.3 %) survived ECLS weaning and eight (29.6%) survived to discharge. Conclusion: Increased flow to maintain systemic circulation for a SPS patient while on ECLS is an accepted strategy, but it should not be applied universally. A large subset of SPS patients, who require ECLS either due to cardiac arrest or refractory LCOS due to excessive pulmonary flow, might benefit from complete occlusion of the shunt soon after commencement of ECLS, especially in cases with frank pulmonary edema or haemorrhage in the pre-ECLS period. A prospective randomized trial could be ethically justified for the subset of patients receiving ECLS for the indication of excessive pulmonary blood flow.

Summary: Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era.

Abstract Background An Informatics Consult has been proposed in which clinicians request novel evidence from large scale health data resources, tailored to the treatment of a specific patient. However, the availability of such consultations is lacking. We seek to provide an Informatics Consult for a situation where a treatment indication and contraindication coexist in the same patient, i.e., anti-coagulation use for stroke prevention in a patient with both atrial fibrillation (AF) and liver cirrhosis. Methods We examined four sources of evidence for the effect of warfarin on stroke risk or all-cause mortality from: (1) randomised controlled trials (RCTs), (2) meta-analysis of prior observational studies, (3) trial emulation (using population electronic health records (N = 3,854,710) and (4) genetic evidence (Mendelian randomisation). We developed prototype forms to request an Informatics Consult and return of results in electronic health record systems. Results We found 0 RCT reports and 0 trials recruiting for patients with AF and cirrhosis. We found broad concordance across the three new sources of evidence we generated. Meta-analysis of prior observational studies showed that warfarin use was associated with lower stroke risk (hazard ratio [HR] = 0.71, CI 0.39–1.29). In a target trial emulation, warfarin was associated with lower all-cause mortality (HR = 0.61, CI 0.49–0.76) and ischaemic stroke (HR = 0.27, CI 0.08–0.91). Mendelian randomisation served as a drug target validation where we found that lower levels of vitamin K1 (warfarin is a vitamin K1 antagonist) are associated with lower stroke risk. A pilot survey with an independent sample of 34 clinicians revealed that 85% of clinicians found information on prognosis useful and that 79% thought that they should have access to the Informatics Consult as a service within their healthcare systems. We identified candidate steps for automation to scale evidence generation and to accelerate the return of results. Conclusion We performed a proof-of-concept Informatics Consult for evidence generation, which may inform treatment decisions in situations where there is dearth of randomised trials. Patients are surprised to know that their clinicians are currently not able to learn in clinic from data on ‘patients like me’. We identify the key challenges in offering such an Informatics Consult as a service.

Drug target Mendelian randomization (MR) uses genetic variation in or near a gene encoding a drug target to anticipate the effect of drug action on the same target. Using drug target MR, the authors prioritized 30 targets that might elicit beneficial effects in the prevention or treatment of coronary heart disease.

Despite being studied in clinical trials, CETP inhibitors are not yet an approved treatment for coronary heart disease. Here, by analyzing results from clinical trials and drug target mendelian randomization studies, the authors demonstrate that previous failure of CETP inhibitors are likely compound and not drug target-related.

The soybean cyst nematode Heterodera glycines is the most economically devastating pathogen of soybean in the United States and threatens to become even more damaging through the selection of virulent nematode populations in the field that can overcome natural resistance mechanisms in soybean cultivars. This pathogen, therefore, demands intense transcriptomic/genomic research inquiries into the biology of its parasitic mechanisms. H. glycines delivers effector proteins that are produced in specialized gland cells into the soybean root to enable infection. The study of effector proteins, thus, is particularly promising when exploring novel management options against this pathogen. Here, we announce the availability of a gland cell–specific RNA-seq resource. These data represent an expression snapshot of gland cell activity during early soybean infection of a virulent and an avirulent H. glycines population, providing a unique and highly valuable resource for scientists examining effector biology and nematode virulence.[Graphic: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract The inferior vena cava (IVC) is the largest vein in the body, draining blood from the abdomen, pelvis and lower extremities. This pictorial review summarises normal anatomy and embryological development of the IVC. In addition, we highlight a wide range of anatomical variants, acquired pathologies and a common pitfall in imaging of the IVC. This information is essential for clinical decision making and to reduce misdiagnosis.

Accurate seasonal forecasts of sea ice are highly valuable, particularly in the context of sea ice loss due to global warming. A new machine learning tool for sea ice forecasting offers a substantial increase in accuracy over current physics-based dynamical model predictions.

Background: Polygenic scores (PGS) are becoming an increasingly popular approach to predict complex disease risk, although they also hold the potential to develop insight into the molecular profiles of patients with an elevated genetic predisposition to disease. Methods: We sought to construct an atlas of associations between 125 different PGS derived using results from genome-wide association studies and 249 circulating metabolites in up to 83,004 participants from the UK Biobank. Results: As an exemplar to demonstrate the value of this atlas, we conducted a hypothesis-free evaluation of all associations with glycoprotein acetyls (GlycA), an inflammatory biomarker. Using bidirectional Mendelian randomization, we find that the associations highlighted likely reflect the effect of risk factors, such as adiposity or liability towards smoking, on systemic inflammation as opposed to the converse direction. Moreover, we repeated all analyses in our atlas within age strata to investigate potential sources of collider bias, such as medication usage. This was exemplified by comparing associations between lipoprotein lipid profiles and the coronary artery disease PGS in the youngest and oldest age strata, which had differing proportions of individuals undergoing statin therapy. Lastly, we generated all PGS–metabolite associations stratified by sex and separately after excluding 13 established lipid-associated loci to further evaluate the robustness of findings. Conclusions: We envisage that the atlas of results constructed in our study will motivate future hypothesis generation and help prioritize and deprioritize circulating metabolic traits for in-depth investigations. All results can be visualized and downloaded at http://mrcieu.mrsoftware.org/metabolites_PRS_atlas. Funding: This work is supported by funding from the Wellcome Trust, the British Heart Foundation, and the Medical Research Council Integrative Epidemiology Unit.

BackgroundHand transcribing nutrient composition data from websites requires extensive human resources and is prone to error. As a result, there are limited nutrient composition data on food prepared out of the home in the United Kingdom. Such data are crucial for understanding and monitoring the out-of-home food environment, which aids policy making. Automated data collection from publicly available sources offers a potential low-resource solution to address this gap. ObjectiveIn this paper, we describe the first UK longitudinal nutritional database of food prepared out of the home, MenuTracker. As large chains will be required to display calorie information on their UK menus from April 2022, we also aimed to identify which chains reported their nutritional information online in November 2021. In a case study to demonstrate the utility of MenuTracker, we estimated the proportions of menu items exceeding recommended energy and nutrient intake (eg, >600 kcal per meal). MethodsWe have collated nutrient composition data of menu items sold by large chain restaurants quarterly since March 2021. Large chains were defined as those with 250 employees or more (those covered by the new calorie labeling policy) or belonging to the top 100 restaurants based on sales volume. We developed scripts in Python to automate the data collection process from business websites. Various techniques were used to harvest web data and extract data from nutritional tables in PDF format. ResultsAutomated Python programs reduced approximately 85% of manual work, totaling 500 hours saved for each wave of data collection. As of January 2022, MenuTracker has 76,405 records from 88 large out-of-home food chains at 4 different time points (ie, March, June, September, and December) in 2021. In constructing the database, we found that one-quarter (24.5%, 256/1043) of large chains, which are likely to be subject to the United Kingdom’s calorie menu labeling regulations, provided their nutritional information online in November 2021. Across these chains, 24.7% (16,391/66,295) of menu items exceeded the UK government’s recommendation of a maximum of 600 kcal for a single meal. Comparable figures were 46.4% (29,411/63,416) for saturated fat, 34.7% (21,964/63,388) for total fat, 17.6% (11,260/64,051) for carbohydrates, 17.8% (11,434/64,059) for sugar, and 35.2% (22,588/64,086) for salt. Furthermore, 0.7% to 7.1% of the menu items exceeded the maximum daily recommended intake for these nutrients. ConclusionsMenuTracker is a valuable resource that harnesses the power of data science techniques to use publicly available data online. Researchers, policy makers, and consumers can use MenuTracker to understand and assess foods available from out-of-home food outlets. The methods used in development are available online and can be used to establish similar databases elsewhere.

A male patient with a germline mutation in MEN1 presented at the age of 18 with classical features of gigantism. Previously, he had undergone resection of an insulin-secreting pancreatic neuroendocrine tumour (pNET) at the age of 10 years and had subtotal parathyroidectomy due to primary hyperparathyroidism at the age of 15 years. He was found to have significantly elevated serum IGF-1, GH, GHRH and calcitonin levels. Pituitary MRI showed an overall bulky gland with a 3 mm hypoechoic area. Abdominal MRI showed a 27 mm mass in the head of the pancreas and a 6 mm lesion in the tail. Lanreotide-Autogel 120 mg/month reduced GHRH by 45% and IGF-1 by 20%. Following pancreaticoduodenectomy, four NETs were identified with positive GHRH and calcitonin staining and Ki-67 index of 2% in the largest lesion. The pancreas tail lesion was not removed. Post-operatively, GHRH and calcitonin levels were undetectable, IGF-1 levels normalised and GH suppressed normally on glucose challenge. Post-operative fasting glucose and HbA1c levels have remained normal at the last check-up. While adolescent-onset cases of GHRH-secreting pNETs have been described, to the best of our knowledge, this is the first reported case of ectopic GHRH in a paediatric setting leading to gigantism in a patient with MEN1. Our case highlights the importance of distinguishing between pituitary and ectopic causes of gigantism, especially in the setting of MEN1, where paediatric somatotroph adenomas causing gigantism are extremely rare.