Participant recruitment and attrition in surgical randomised trials with placebo controls versus non-operative controls: a meta-epidemiological study and meta-analysis.

OBJECTIVE: To compare differences in recruitment and attrition between placebo control randomised trials of surgery, and trials of the same surgical interventions and conditions that used non-operative (non-placebo) controls. DESIGN: Meta-epidemiological study. DATA SOURCES: Randomised controlled trials were identified from an electronic search of MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials from their inception date to 21 November 2018. STUDY SELECTION: Placebo control trials evaluating efficacy of any surgical intervention and non-operative control trials of the same surgical intervention were included in this study. 25 730 records were retrieved from our systemic search, identifying 61 placebo control and 38 non-operative control trials for inclusion in analysis. OUTCOME MEASURES: Primary outcome measures were recruitment and attrition. These were assessed in terms of recruitment rate (number of participants enrolled, as a proportion of those eligible) and overall attrition rate (composite of dropout, loss to follow-up and cross-overs, expressed as proportion of total sample size). Secondary outcome measures included participant cross-over rate, dropout and loss to follow-up. RESULTS: Unadjusted pooled recruitment and attrition rates were similar between placebo and non-operative control trials. Study characteristics were not significantly different apart from time to primary timepoint which was shorter in studies with placebo controls (365 vs 274 days, p=0.006). After adjusting for covariates (follow-up duration and number of timepoints), the attrition rate of placebo control trials was almost twice as high compared with non-operative controlled-trials (incident rate ratio (IRR) (95% CI) 1.8 (1.1 to 3.0), p=0.032). The incorporation of one additional follow-up timepoint (regardless of follow-up duration) was associated with reduced attrition in placebo control surgical trials (IRR (95% CI) 0.64 (0.52 to 0.79), p<0.001). CONCLUSIONS: Placebo control trials of surgery have similar recruitment issues but higher attrition compared with non-operative (non-placebo) control trials. Study design should incorporate strategies such as increased timepoints for given follow-up duration to mitigate losses to follow-up and dropout. PROSPERO REGISTRATION NUMBER: CRD42019117364.

Cardiovascular Disease Risk Factor Interventions in Women With Prior Gestational Hypertensive Disorders or Diabetes in North America: A Rapid Review.

Women with previous hypertensive disorders of pregnancy (HDP) or gestational diabetes mellitus (GDM) have a 2- to 3-fold increased risk of cardiovascular disease (CVD). The goal of this rapid review was to summarize evidence of the effectiveness of CVD risk factor interventions for postpartum women with a history of HDP or GDM. A comprehensive search strategy was used to search articles published in 5 databases-Ovid MEDLINE, PubMed, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, and Embase). Observational and intervention studies that identified CVD prevention, screening, and/or risk factor management interventions among postpartum women with prior HDP or GDM in Canada and the US were included. The quality of observational and interventional studies, and their risk of bias, were assessed using appropriate critical appraisal checklists. Eight studies, including 4 observational cohorts, 3 randomized controlled trials, and 1 quasi-experimental study, merited inclusion for analysis. A total of 2449 participants were involved in the included studies. The most effective CVD risk factor intervention was comprised of postpartum transition and follow-up, CVD risk factor education, and advice on lifestyle changes. Most of the observational studies led to improvements in CVD risk factors, including improvements in CVD lifetime risk scores. However, none of the RCTs led to improvements in cardiometabolic risk factors. Few studies have investigated CVD risk factor interventions in the postpartum in women with previous HDP or GDM in North America. Further studies of higher quality are needed.

Les femmes ayant déjà souffert de troubles hypertensifs de la grossesse (THG) ou d'un diabète gestationnel (DG) présentent un risque de maladie cardiovasculaire (MCV) accru de 2 à 3 fois. Cette brève revue de littérature visait à colliger les évidences concernant l'efficacité des interventions se concentrant sur les facteurs de risque de MCV chez les femmes en post-partum ayant des antécédents de THG ou de DG. Une stratégie de recherche exhaustive a été employée pour rechercher des articles publiés dans 5 bases de données (Ovid MEDLINE, PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO et Embase). Les études d'observation et d'intervention qui ont identifié des interventions de prévention, de dépistage et/ou de gestion des facteurs de risque des MCV chez les femmes en post-partum ayant déjà souffert de THG ou de DG au Canada et aux États-Unis ont été incluses. La qualité des études observationnelles et interventionnelles, ainsi que leur risque de biais, ont été évalués à l'aide de listes de contrôle d'évaluation critique appropriées. Huit études, dont quatre cohortes observationnelles, trois essais contrôlés randomisés (ECR) et une étude quasi expérimentale, ont été incluses pour l'analyse, impliquant au total 2 449 participantes. L'intervention la plus efficace sur les facteurs de risque de MCV incluait une transition et un suivi post-partum, une sensibilisation aux facteurs de risque de MCV et des conseils sur les changements de mode de vie. La plupart des études observationnelles ont conduit à des améliorations concernant les facteurs de risque de MCV. Cependant, aucun des ECR n'a conduit à des améliorations des facteurs de risque cardiométabolique. Peu d'études ont examiné les interventions sur les facteurs de risque de MCV pendant le post-partum chez les femmes ayant déjà souffert de THG ou de DG en Amérique du Nord. D'autres études de meilleure qualité sont nécessaires.

Recent advances in polygenic scores: translation, equitability, methods and FAIR tools.

Polygenic scores (PGS) can be used for risk stratification by quantifying individuals' genetic predisposition to disease, and many potentially clinically useful applications have been proposed. Here, we review the latest potential benefits of PGS in the clinic and challenges to implementation. PGS could augment risk stratification through combined use with traditional risk factors (demographics, disease-specific risk factors, family history, etc.), to support diagnostic pathways, to predict groups with therapeutic benefits, and to increase the efficiency of clinical trials. However, there exist challenges to maximizing the clinical utility of PGS, including FAIR (Findable, Accessible, Interoperable, and Reusable) use and standardized sharing of the genomic data needed to develop and recalculate PGS, the equitable performance of PGS across populations and ancestries, the generation of robust and reproducible PGS calculations, and the responsible communication and interpretation of results. We outline how these challenges may be overcome analytically and with more diverse data as well as highlight sustained community efforts to achieve equitable, impactful, and responsible use of PGS in healthcare.

The Ontology of Biological Attributes (OBA)-computational traits for the life sciences.

Existing phenotype ontologies were originally developed to represent phenotypes that manifest as a character state in relation to a wild-type or other reference. However, these do not include the phenotypic trait or attribute categories required for the annotation of genome-wide association studies (GWAS), Quantitative Trait Loci (QTL) mappings or any population-focussed measurable trait data. The integration of trait and biological attribute information with an ever increasing body of chemical, environmental and biological data greatly facilitates computational analyses and it is also highly relevant to biomedical and clinical applications. The Ontology of Biological Attributes (OBA) is a formalised, species-independent collection of interoperable phenotypic trait categories that is intended to fulfil a data integration role. OBA is a standardised representational framework for observable attributes that are characteristics of biological entities, organisms, or parts of organisms. OBA has a modular design which provides several benefits for users and data integrators, including an automated and meaningful classification of trait terms computed on the basis of logical inferences drawn from domain-specific ontologies for cells, anatomical and other relevant entities. The logical axioms in OBA also provide a previously missing bridge that can computationally link Mendelian phenotypes with GWAS and quantitative traits. The term components in OBA provide semantic links and enable knowledge and data integration across specialised research community boundaries, thereby breaking silos.

The Ontology of Biological Attributes (OBA) - Computational Traits for the Life Sciences.

Existing phenotype ontologies were originally developed to represent phenotypes that manifest as a character state in relation to a wild-type or other reference. However, these do not include the phenotypic trait or attribute categories required for the annotation of genome-wide association studies (GWAS), Quantitative Trait Loci (QTL) mappings or any population-focused measurable trait data. Moreover, variations in gene expression in response to environmental disturbances even without any genetic alterations can also be associated with particular biological attributes. The integration of trait and biological attribute information with an ever increasing body of chemical, environmental and biological data greatly facilitates computational analyses and it is also highly relevant to biomedical and clinical applications. The Ontology of Biological Attributes (OBA) is a formalised, species-independent collection of interoperable phenotypic trait categories that is intended to fulfil a data integration role. OBA is a standardised representational framework for observable attributes that are characteristics of biological entities, organisms, or parts of organisms. OBA has a modular design which provides several benefits for users and data integrators, including an automated and meaningful classification of trait terms computed on the basis of logical inferences drawn from domain-specific ontologies for cells, anatomical and other relevant entities. The logical axioms in OBA also provide a previously missing bridge that can computationally link Mendelian phenotypes with GWAS and quantitative traits. The term components in OBA provide semantic links and enable knowledge and data integration across specialised research community boundaries, thereby breaking silos.

The effectiveness of naive optimization of the egress path for an active-shooter scenario.

There have been 130 mass shootings in the United States from 1982 to June, 2022 according to the Mother Jones database of active shooter events. In these critical scenarios, making the right decisions while evacuating can be the difference between life and death. However, emergency evacuation is intensely stressful, which along with lack of verifiable real-time information may lead to costly incorrect decisions. In this paper, we demonstrate the effectiveness of a non-homogeneous semi-Markov-Decision-Process (NHSMDP) based naive algorithm that relies on prior knowledge about the layout of a building and uses recurring updates of the shooter's location (based on automatic processing of images from a camera network) to provide an optimized egress plan for evacuees. While emergency evacuations due to fire and natural disasters are well researched, the novelty of this work is in the response to a threat that moves either purposefully or randomly through the building and in incorporating the ability for an evacuee to wait for danger to pass before beginning egress and during the process of evacuation. This ability to include sojourn times in the optimized scheme is due to the NHSMDP formulation and is a notable augmentation to the current state-of-the-art. We show that following this algorithm can reduce casualties by 56% and the time spent by evacuees in the shooter's line of sight by 52% compared to an intuitive natural response guided by expert advice.

Has the degree of outcome reporting bias in surgical randomized trials changed? A meta-regression analysis.

BACKGROUND: Outcome reporting bias in individual trials can compromise the validity of pooled estimates within systematic reviews. Recent strategies have attempted to address outcome reporting bias, which favours the full reporting of statistically significant outcomes over non-significant outcomes. We examined whether the association between full outcome reporting and statistical significance in surgical trials has changed from 2009 to 2019. METHODS: We systematically searched for 350 surgical randomized controlled trials (RCTs) from 2009 and 350 surgical RCTs from 2019. Outcomes were classified as fully reported, partially reported, qualitatively reported or unreported. For each outcome, a contingency table was populated with full outcome reporting (yes/no) and statistical significance (yes/no). We combined odds ratios in random effects meta-analysis to estimate the association between full outcome reporting and statistical significance in 2009 compared with 2019. RESULTS: Twenty-eight percent of outcomes in 2009 were incompletely reported, compared with 30% in 2019. In 2009, significant outcomes were more likely to be fully reported than non-significant outcomes (OR = 2.4, 95% CI 1.7-3.4, I2  = 35%), but the opposite association was seen in 2019 (OR = 0.51, 95% CI 0.34-0.77, I2  = 43%). RCTs from 2019 were less likely to demonstrate outcome reporting bias favouring significant outcomes (OR = 0.21, 95% CI 0.12-0.35, P < 0.001). CONCLUSION: Outcome reporting bias favouring the full reporting of significant over non-significant outcomes was demonstrated in 2009, but the opposite association was seen in 2019. There remains a high prevalence of incomplete outcome reporting. We recommend ongoing adherence to trial protocol guidelines to improve outcome reporting transparency and completeness.

The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource.

The NHGRI-EBI GWAS Catalog (www.ebi.ac.uk/gwas) is a FAIR knowledgebase providing detailed, structured, standardised and interoperable genome-wide association study (GWAS) data to >200 000 users per year from academic research, healthcare and industry. The Catalog contains variant-trait associations and supporting metadata for >45 000 published GWAS across >5000 human traits, and >40 000 full P-value summary statistics datasets. Content is curated from publications or acquired via author submission of prepublication summary statistics through a new submission portal and validation tool. GWAS data volume has vastly increased in recent years. We have updated our software to meet this scaling challenge and to enable rapid release of submitted summary statistics. The scope of the repository has expanded to include additional data types of high interest to the community, including sequencing-based GWAS, gene-based analyses and copy number variation analyses. Community outreach has increased the number of shared datasets from under-represented traits, e.g. cancer, and we continue to contribute to awareness of the lack of population diversity in GWAS. Interoperability of the Catalog has been enhanced through links to other resources including the Polygenic Score Catalog and the International Mouse Phenotyping Consortium, refinements to GWAS trait annotation, and the development of a standard format for GWAS data.

The Memphis Pandemic Health Informatics System (MEMPHI-SYS)-Creating a Metropolitan COVID-19 Data Registry Linked Directly to Community Testing to Enhance Population Health Surveillance.

The current coronavirus disease (COVID-19) pandemic has placed unprecedented strain on underfunded public health resources in the Southeastern United States. The Memphis, TN, metropolitan region has lacked infrastructure for health data exchange.This manuscript describes a multidisciplinary initiative to create a community-focused COVID-19 data registry, the Memphis Pandemic Health Informatics System (MEMPHI-SYS). MEMPHI-SYS leverages test result data updated directly from community-based testing sites, as well as a full complement of public health data sets and knowledge-based informatics. It has been guided by relationships with community stakeholders and is managed alongside the largest publicly funded community-based COVID-19 testing response in the Mid-South. MEMPHI-SYS has supported interactive Web-based analytic resources and informs federally funded COVID-19 outreach directed toward neighborhoods most in need of pandemic support.MEMPHI-SYS provides an instructive case study of how to collaboratively establish the technical scaffolding and human relationships necessary for data-driven, health equity-focused pandemic surveillance, and policy interventions.

Use of Placebo and Nonoperative Control Groups in Surgical Trials: A Systematic Review and Meta-analysis.

Importance: Nonspecific effects, particularly placebo effects, are thought to contribute significantly to the observed effect in surgical trials. Objective: To estimate the proportion of the observed effect of surgical treatment that is due to nonspecific effects (including the placebo effect). Data Sources: Published Cochrane reviews and updated, extended search of MEDLINE, Embase, and CENTRAL until March 2019. Study Selection: Published randomized placebo-controlled surgical trials and trials comparing the effect of the same surgical interventions with nonoperative controls (ie, no treatment, usual care, or exercise program). Data Extraction and Synthesis: Pairs of authors independently screened the search results, assessed full texts to identify eligible studies and the risk of bias of included studies, and extracted data. The proportion of all nonspecific effects was calculated as the change in the placebo control divided by the change in the active surgery and pooled in a random-effect meta-analysis. To estimate the magnitude of the placebo effect, we pooled the difference in outcome between placebo and nonoperative controls and used metaregression to estimate the association between the type of control group and the treatment effect (difference between the groups), adjusting for risk of bias, sample size, and type of outcome. Main Outcomes and Measures: Between- and within-group effect sizes expressed as Hedges g. Results: In this review, 100 trials were included comprising data from 62 trials with placebo controls (3 also included nonoperative controls), and 38 trials with nonoperative controls (32 interventions; 10 699 participants). Risk of bias across trials was comparable except for performance and detection bias, which was high in trials with nonoperative controls. The mean nonspecific effects accounted for 67% (95% CI, 61% to 73%) of the observed change after surgery; however, this varied widely between different procedures. The estimated surgical placebo effect had a standardized mean difference (SMD) of 0.13 (95% CI, -0.26 to 0.51). Trials with placebo and nonoperative controls found comparable treatment effects (SMD, -0.09 [95% CI, -0.35 to 0.18]; 15 interventions; 73 between-group effects; adjusted analysis: SMD, -0.11 [95% CI, -0.37 to 0.15]). Conclusions and Relevance: In this review, the change in health state after surgery was composed largely of nonspecific effects, but no evidence supported a large placebo effect. Placebo-controlled surgical trials may be redundant when trials with nonoperative controls consistently report no substantial association from surgery compared with nonoperative treatment.

Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson's disease.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factors for Parkinson's disease (PD). Increased LRRK2 kinase activity is thought to impair lysosomal function and may contribute to the pathogenesis of PD. Thus, inhibition of LRRK2 is a potential disease-modifying therapeutic strategy for PD. DNL201 is an investigational, first-in-class, CNS-penetrant, selective, ATP-competitive, small-molecule LRRK2 kinase inhibitor. In preclinical models, DNL201 inhibited LRRK2 kinase activity as evidenced by reduced phosphorylation of both LRRK2 at serine-935 (pS935) and Rab10 at threonine-73 (pT73), a direct substrate of LRRK2. Inhibition of LRRK2 by DNL201 demonstrated improved lysosomal function in cellular models of disease, including primary mouse astrocytes and fibroblasts from patients with Gaucher disease. Chronic administration of DNL201 to cynomolgus macaques at pharmacologically relevant doses was not associated with adverse findings. In phase 1 and phase 1b clinical trials in 122 healthy volunteers and in 28 patients with PD, respectively, DNL201 at single and multiple doses inhibited LRRK2 and was well tolerated at doses demonstrating LRRK2 pathway engagement and alteration of downstream lysosomal biomarkers. Robust cerebrospinal fluid penetration of DNL201 was observed in both healthy volunteers and patients with PD. These data support the hypothesis that LRRK2 inhibition has the potential to correct lysosomal dysfunction in patients with PD at doses that are generally safe and well tolerated, warranting further clinical development of LRRK2 inhibitors as a therapeutic modality for PD.

Looking beyond interaction: exploring meaning making through the windows of an art gallery.

How is meaning produced in and around the art gallery? Sociological answers to this question are limited by a narrow focus on inter-gallery group interaction and cognitive interpretation. I argue that such approaches would be strengthened by accounting for the diverting effects of gallery context and atmosphere, both in and beyond the gallery. Art gallery windows offer a lens through which to explore how issues of context and atmosphere are negotiated in and around an art gallery in everyday life. I trial this approach using data from a fourteen-month case study of Bluecoat, a city center art gallery in Liverpool, UK, which has a series of windows that mediate between the gallery and the neighboring shopping street. The windows partition zones of meaning; frame vision; contribute to the symbolic meanings of a gallery's exterior architecture; and modulate its interior atmosphere. The analysis models a meaning-centered sociology of the art gallery that moves beyond interpretation and towards a broader understanding of the currents of meaning in and around the art gallery.

Sequencing-based genome-wide association studies reporting standards.

Genome sequencing has recently become a viable genotyping technology for use in genome-wide association studies (GWASs), offering the potential to analyze a broader range of genome-wide variation, including rare variants. To survey current standards, we assessed the content and quality of reporting of statistical methods, analyses, results, and datasets in 167 exome- or genome-wide-sequencing-based GWAS publications published from 2014 to 2020; 81% of publications included tests of aggregate association across multiple variants, with multiple test models frequently used. We observed a lack of standardized terms and incomplete reporting of datasets, particularly for variants analyzed in aggregate tests. We also find a lower frequency of sharing of summary statistics compared with array-based GWASs. Reporting standards and increased data sharing are required to ensure sequencing-based association study data are findable, interoperable, accessible, and reusable (FAIR). To support that, we recommend adopting the standard terminology of sequencing-based GWAS (seqGWAS). Further, we recommend that single-variant analyses be reported following the same standards and conventions as standard array-based GWASs and be shared in the GWAS Catalog. We also provide initial recommended standards for aggregate analyses metadata and summary statistics.

Use and effectiveness of Pioneer re-entry device for subintimal true lumen re-entry: single-centre data and a review of the literature.

INTRODUCTION: During subintimal angioplasty (SIA), it is not always possible to re-enter the vessel lumen due to a variety of factors. Recanalization using hydrophilic wires and catheters alone, apart from its potential technical failure, is also limited by minimal control over the re-entry point. This is frequently well beyond the point of occlusion, thus often compromising important collaterals. In order to bypass the obstruction and attain controlled re-entry into the lumen of the diseased vessel, a re-entry device (RED) may be required. This paper assesses our centre's experience with the safety and efficacy of the Pioneer re-entry system and systematically reviews the pertinent literature. METHOD: A single centre retrospective study of subintimal angioplasty involving the use of the Pioneer Plus intravascular guided reentry catheter was performed. Patient demographics including age, gender, risk factors, comorbidities clinical indication and complications were recorded. Lesion characteristics, including location and severity of calcification were also assessed. A systematic literature review of all reported studies where the Pioneer RED was used for iliac and lower limb revascularization was conducted by 2 of the authors using the PubMed (MEDLINE) and EMBASE databases. RESULTS: The study comprised 30 cases. Technical success was 97%. A small, quickly resolved extravasation was the only device related complication. These results are in line with the systematic review which identified 16 studies using the Pioneer RED, reporting a technical success rate of 87.4-100% (median = 100%) and complication rate of 0-25.8% (median = 0%). However, due to heterogeneity in definitions of technical success, data was not pooled.

Gene Expression Meta-Analysis Reveals Interferon-Induced Genes Associated With SARS Infection in Lungs.

BACKGROUND: Severe Acute Respiratory Syndrome (SARS) corona virus (CoV) infections are a serious public health threat because of their pandemic-causing potential. This work is the first to analyze mRNA expression data from SARS infections through meta-analysis of gene signatures, possibly identifying therapeutic targets associated with major SARS infections. METHODS: This work defines 37 gene signatures representing SARS-CoV, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV2 infections in human lung cultures and/or mouse lung cultures or samples and compares them through Gene Set Enrichment Analysis (GSEA). To do this, positive and negative infectious clone SARS (icSARS) gene panels are defined from GSEA-identified leading-edge genes between two icSARS-CoV derived signatures, both from human cultures. GSEA then is used to assess enrichment and identify leading-edge icSARS panel genes between icSARS gene panels and 27 other SARS-CoV gene signatures. The meta-analysis is expanded to include five MERS-CoV and three SARS-CoV2 gene signatures. Genes associated with SARS infection are predicted by examining the intersecting membership of GSEA-identified leading-edges across gene signatures. RESULTS: Significant enrichment (GSEA p<0.001) is observed between two icSARS-CoV derived signatures, and those leading-edge genes defined the positive (233 genes) and negative (114 genes) icSARS panels. Non-random significant enrichment (null distribution p<0.001) is observed between icSARS panels and all verification icSARSvsmock signatures derived from human cultures, from which 51 over- and 22 under-expressed genes are shared across leading-edges with 10 over-expressed genes already associated with icSARS infection. For the icSARSvsmock mouse signature, significant, non-random significant enrichment held for only the positive icSARS panel, from which nine genes are shared with icSARS infection in human cultures. Considering other SARS strains, significant, non-random enrichment (p<0.05) is observed across signatures derived from other SARS strains for the positive icSARS panel. Five positive icSARS panel genes, CXCL10, OAS3, OASL, IFIT3, and XAF1, are found across mice and human signatures regardless of SARS strains. CONCLUSION: The GSEA-based meta-analysis approach used here identifies genes with and without reported associations with SARS-CoV infections, highlighting this approach's predictability and usefulness in identifying genes that have potential as therapeutic targets to preclude or overcome SARS infections.

Has the reporting of patient-important outcomes improved in surgical trials? A meta-epidemiological study.

BACKGROUND: Clinical trials should ideally use patient-important outcomes to ensure their results are clinically relevant. We aimed to determine if the proportion of patient-important outcomes in surgical trials has changed over the last decade, and to determine whether patient-important outcomes are more likely to be specified as primary outcomes. METHODS: The 350 most recent randomized controlled trials examining surgical interventions on humans and published in English were included. Outcomes were classified as patient-important, surrogate or laboratory using standardized definitions, along with either primary, secondary or unspecified. Mean proportions were calculated across all trials and a chi-squared test was used to detect the difference between time periods. Contingency tables were populated with each trial's outcomes, characterizing whether each outcome was patient-important or not, and whether it was specified as primary or secondary. Odds ratios were then combined in a random-effects meta-analysis to calculate a pooled odds ratio. RESULTS: A total of 64% of all outcomes were patient-important. The mean (standard deviation) proportion of patient-important outcomes per trial was 66% (31.4), which significantly increased over the last decade, from 60% (31.6) in 2009. The mean proportion of primary outcomes which were patient-important increased from 64% (46.0) in 2009 to 77% (40.6) in 2019. Patient-important outcomes were not significantly associated with being a primary outcome and this did not change significantly over the decade. CONCLUSION: Patient-important outcomes are still poorly represented as primary outcomes. The ongoing impact of updated reporting guidelines may improve the reporting of patient-important outcomes in surgical trials.

Workshop proceedings: GWAS summary statistics standards and sharing.

Genome-wide association studies (GWASs) have enabled robust mapping of complex traits in humans. The open sharing of GWAS summary statistics (SumStats) is essential in facilitating the larger meta-analyses needed for increased power in resolving the genetic basis of disease. However, most GWAS SumStats are not readily accessible because of limited sharing and a lack of defined standards. With the aim of increasing the availability, quality, and utility of GWAS SumStats, the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) GWAS Catalog organized a community workshop to address the standards, infrastructure, and incentives required to promote and enable sharing. We evaluated the barriers to SumStats sharing, both technological and sociological, and developed an action plan to address those challenges and ensure that SumStats and study metadata are findable, accessible, interoperable, and reusable (FAIR). We encourage early deposition of datasets in the GWAS Catalog as the recognized central repository. We recommend standard requirements for reporting elements and formats for SumStats and accompanying metadata as guidelines for community standards and a basis for submission to the GWAS Catalog. Finally, we provide recommendations to enable, promote, and incentivize broader data sharing, standards and FAIRness in order to advance genomic medicine.

An Educational Bioinformatics Project to Improve Genome Annotation.

Scientific advancement is hindered without proper genome annotation because biologists lack a complete understanding of cellular protein functions. In bacterial cells, hypothetical proteins (HPs) are open reading frames with unknown functions. HPs result from either an outdated database or insufficient experimental evidence (i.e., indeterminate annotation). While automated annotation reviews help keep genome annotation up to date, often manual reviews are needed to verify proper annotation. Students can provide the manual review necessary to improve genome annotation. This paper outlines an innovative classroom project that determines if HPs have outdated or indeterminate annotation. The Hypothetical Protein Characterization Project uses multiple well-documented, freely available, web-based, bioinformatics resources that analyze an amino acid sequence to (1) detect sequence similarities to other proteins, (2) identify domains, (3) predict tertiary structure including active site characterization and potential binding ligands, and (4) determine cellular location. Enough evidence can be generated from these analyses to support re-annotation of HPs or prioritize HPs for experimental examinations such as structural determination via X-ray crystallography. Additionally, this paper details several approaches for selecting HPs to characterize using the Hypothetical Protein Characterization Project. These approaches include student- and instructor-directed random selection, selection using differential gene expression from mRNA expression data, and selection based on phylogenetic relations. This paper also provides additional resources to support instructional use of the Hypothetical Protein Characterization Project, such as example assignment instructions with grading rubrics, links to training videos in YouTube, and several step-by-step example projects to demonstrate and interpret the range of achievable results that students might encounter. Educational use of the Hypothetical Protein Characterization Project provides students with an opportunity to learn and apply knowledge of bioinformatic programs to address scientific questions. The project is highly customizable in that HP selection and analysis can be specifically formulated based on the scope and purpose of each student's investigations. Programs used for HP analysis can be easily adapted to course learning objectives. The project can be used in both online and in-seat instruction for a wide variety of undergraduate and graduate classes as well as undergraduate capstone, honor's, and experiential learning projects.

Denser brain capillary network with preserved pericytes in Alzheimer's disease.

Pericytes are vascular mural cells that surround capillaries of the central nervous system (CNS). They are crucial for brain development and contribute to CNS homeostasis by regulating blood-brain barrier function and cerebral blood flow. It has been suggested that pericytes are lost in Alzheimer's disease (AD), implicating this cell type in disease pathology. Here, we have employed state-of-the-art stereological morphometry techniques as well as tissue clearing and two-photon imaging to assess the distribution of pericytes in two independent cohorts of AD (n = 16 and 13) and non-demented controls (n = 16 and 4). Stereological quantification revealed increased capillary density with a normal pericyte population in the frontal cortex of AD brains, a region with early amyloid ß deposition. Two-photon analysis of cleared frontal cortex tissue confirmed the preservation of pericytes in AD cases. These results suggest that pericyte demise is not a general hallmark of AD pathology.