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 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 NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019.

The GWAS Catalog delivers a high-quality curated collection of all published genome-wide association studies enabling investigations to identify causal variants, understand disease mechanisms, and establish targets for novel therapies. The scope of the Catalog has also expanded to targeted and exome arrays with 1000 new associations added for these technologies. As of September 2018, the Catalog contains 5687 GWAS comprising 71673 variant-trait associations from 3567 publications. New content includes 284 full P-value summary statistics datasets for genome-wide and new targeted array studies, representing 6 × 109 individual variant-trait statistics. In the last 12 months, the Catalog's user interface was accessed by ∼90000 unique users who viewed >1 million pages. We have improved data access with the release of a new RESTful API to support high-throughput programmatic access, an improved web interface and a new summary statistics database. Summary statistics provision is supported by a new format proposed as a community standard for summary statistics data representation. This format was derived from our experience in standardizing heterogeneous submissions, mapping formats and in harmonizing content. Availability: https://www.ebi.ac.uk/gwas/.

The Partnership to Improve Diabetes Education Trial: a Cluster Randomized Trial Addressing Health Communication in Diabetes Care.

BACKGROUND: Effective type 2 diabetes care remains a challenge for patients including those receiving primary care in safety net settings. OBJECTIVE: The Partnership to Improve Diabetes Education (PRIDE) trial team and leaders from a regional department of health evaluated approaches to improve care for vulnerable patients. DESIGN: Cluster randomized controlled trial. PATIENTS: Adults with uncontrolled type 2 diabetes seeking care across 10 unblinded, randomly assigned safety net clinics in Middle TN. INTERVENTIONS: A literacy-sensitive, provider-focused, health communication intervention (PRIDE; 5 clinics) vs. standard diabetes education (5 clinics). MAIN MEASURES: Participant-level primary outcome was glycemic control [A1c] at 12 months. Secondary outcomes included select health behaviors and psychosocial aspects of care at 12 and 24 months. Adjusted mixed effects regression models were used to examine the comparative effectiveness of each approach to care. KEY RESULTS: Of 410 patients enrolled, 364 (89%) were included in analyses. Median age was 51 years; Black and Hispanic patients represented 18% and 25%; 96% were uninsured, and 82% had low annual income level (< $20,000); adequate health literacy was seen in 83%, but numeracy deficits were common. At 12 months, significant within-group treatment effects occurred from baseline for both PRIDE and control sites: adjusted A1c (- 0.76 [95% CI, - 1.08 to - 0.44]; P < .001 vs - 0.54 [95% CI, - 0.86 to - 0.21]; P = .001), odds of poor eating (0.53 [95% CI, 0.33-0.83]; P = .01 vs 0.42 [95% CI, 0.26-0.68]; P < .001), treatment satisfaction (3.93 [95% CI, 2.48-6.21]; P < .001 vs 3.04 [95% CI, 1.93-4.77]; P < .001), and self-efficacy (2.97 [95% CI, 1.89-4.67]; P < .001 vs 1.81 [95% CI, 1.1-2.84]; P = .01). No significant difference was observed between study arms in adjusted analyses. CONCLUSIONS: Both interventions improved the participant's A1c and behavioral outcomes. PRIDE was not more effective than standard education. Further research may elucidate the added value of a focused health communication program in this setting.

Perceived stress and emotional social support among women who are denied or receive abortions in the United States: a prospective cohort study.

BACKGROUND: Examining women's stress and social support following denial and receipt of abortion furthers understanding of the effects of unwanted childbearing and abortion on women's well-being. This study investigated perceived stress and emotional social support over time among women who were denied wanted abortions and who received abortions, and compared outcomes between the groups. METHODS: The Turnaway Study is a prospective cohort study of women who sought abortions at 30 abortion facilities across the United States, and follows women via semiannual phone interviews for five years. Participants include 956 English or Spanish speaking women aged 15 and over who sought abortions between 2008 and 2010 and whose gestation in pregnancy fit one of three groups: women who presented up to three weeks beyond a facility's gestational age limit and were denied an abortion; women presenting within two weeks below the limit who received an abortion; and women who received a first trimester abortion. The outcomes were modified versions of the Perceived Stress Scale and the Multidimensional Scale of Perceived Social Support. Longitudinal mixed effects models were used to assess differences in outcomes between study groups over 30 months. RESULTS: Women denied abortions initially had higher perceived stress than women receiving abortions near gestational age limits (1.0 unit difference on 0-16 scale, P = 0.003). Women receiving first-trimester abortions initially had lower perceived stress than women receiving abortions near gestational age limits (0.6 difference, P = 0.045). By six months, all groups' levels of perceived stress were similar, and levels remained similar through 30 months. Emotional social support scores did not differ among women receiving abortions near gestational limits versus women denied abortions or women having first trimester abortions initially or over time. CONCLUSIONS: Soon after being denied abortions, women experienced higher perceived stress than women who received abortions. The study found no longer-term differences in perceived stress or emotional social support between women who received versus were denied abortions.

Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome.

Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia. We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome. We hypothesize that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors.

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.

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.

The Polygenic Score Catalog: new functionality and tools to enable FAIR research.

Polygenic scores (PGS) have transformed human genetic research and have multiple potential clinical applications, including risk stratification for disease prevention and prediction of treatment response. Here, we present a series of recent enhancements to the PGS Catalog (www.PGSCatalog.org), the largest findable, accessible, interoperable, and reusable (FAIR) repository of PGS. These include expansions in data content and ancestral diversity as well as the addition of new features. We further present the PGS Catalog Calculator (pgsc_calc, https://github.com/PGScatalog/pgsc_calc), an open-source, scalable and portable pipeline to reproducibly calculate PGS that securely democratizes equitable PGS applications by implementing genetic ancestry estimation and score normalization using reference data. With the PGS Catalog & calculator users can now quantify an individual's genetic predisposition for hundreds of common diseases and clinically relevant traits. Taken together, these updates and tools facilitate the next generation of PGS, thus lowering barriers to the clinical studies necessary to identify where PGS may be integrated into clinical practice.

An integrative review of the side effects related to the use of magnesium sulfate for pre-eclampsia and eclampsia management.

BACKGROUND: Pre-eclampsia/eclampsia is one of the most common causes of maternal and perinatal morbidity and mortality in low and middle income countries. Magnesium sulfate is the drug of choice for prevention of seizures as part of comprehensive management of the disease. Despite the compelling evidence for the effectiveness of magnesium sulfate, concern has been expressed about its safety and potential for toxicity, particularly among providers in low- and middle-income countries. The purpose of this review was to determine whether the literature published in these global settings supports the concerns about the safety of use of magnesium sulfate. METHODS: An integrative review of the literature was conducted to document the known incidences of severe adverse reactions to magnesium sulphate, and specific outcomes of interest related to its use. All types of prospective clinical studies were included if magnesium sulfate was used to manage pre-eclampsia or eclampsia, the study was conducted in a low- or middle-income country, and the study included the recording of the incidence of any adverse side effect resulting from magnesium sulfate use. RESULTS: A total of 24 studies that compared a magnesium sulfate regimen against other drug regimens and examined side effects among 34 subject groups were included. The overall rate of absent patellar reflex among all 9556 aggregated women was 1.6%, with a range of 0-57%. The overall rate of respiratory depression in 25 subject groups in which this outcome was reported was 1.3%, with a range of 0-8.2%. Delay in repeat administration of magnesium sulfate occurred in 3.6% of cases, with a range of 0-65%. Calcium gluconate was administered at an overall rate of less than 0.2%. There was only one maternal death that was attributed by the study authors to the use of magnesium sulfate among the 9556 women in the 24 studies. CONCLUSION: Concerns about safety and toxicity from the use of magnesium sulfate should be mitigated by findings from this integrative review, which indicates a low incidence of the most severe side effects, documented in studies that used a wide variety of standard and modified drug regimens. Adverse effects of concern to providers occur infrequently, and when they occurred, a delay of repeat administration was generally sufficient to mitigate the effect. Early screening and diagnosis of the disease, appropriate treatment with proven drugs, and reasonable vigilance for women under treatment should be adopted as global policy and practice.

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 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.

Proteomic analysis of the maternal protein restriction rat model for schizophrenia: identification of translational changes in hormonal signaling pathways and glutamate neurotransmission.

Previous studies have found that some first onset schizophrenia patients show signs of impaired insulin signaling. Also, epidemiological studies have shown that periods of suboptimal nutrition including protein deficiencies during pregnancy can lead to increased incidence of metabolic conditions and psychiatric disorders in the offspring. For these reasons, we have carried out a molecular profiling analysis of blood serum and brain tissues from adult offspring produced by the maternal low protein (LP) rat model. The results showed similar changes to those seen in schizophrenia. Multiplex immunoassay profiling identified changes in the levels of insulin, adiponectin, and leptin along with alterations in inflammatory and vascular system-related proteins such as osteopontin, macrophage colony-stimulating factor 1, and vascular cell adhesion molecule 1. LC-MS(E) proteomic profiling showed that glutamatergic pathways were altered in frontal cortex, while signaling pathways and cytoskeletal proteins involved in hormonal secretion and synaptic remodeling were altered in the hypothalamus. Taken together, these studies indicate that the LP rat model recapitulates several pathophysiological attributes seen in schizophrenia patients. We propose that the LP model may have utility for drug discovery efforts, especially to identify compounds that modulate the metabolic and glutamatergic systems.

Identification of targeted analyte clusters for studies of schizophrenia.

The search for biomarkers to diagnose psychiatric disorders such as schizophrenia has been underway for decades. Many molecular profiling studies in this field have focused on identifying individual marker signals that show significant differences in expression between patients and the normal population. However, signals for multiple analyte combinations that exhibit patterned behaviors have been less exploited. Here, we present a novel approach for identifying biomarkers of schizophrenia using expression of serum analytes from first onset, drug-naïve patients and normal controls. The strength of patterned signals was amplified by analyzing data in reproducing kernel spaces. This resulted in the identification of small sets of analytes referred to as targeted clusters that have discriminative power specifically for schizophrenia in both human and rat models. These clusters were associated with specific molecular signaling pathways and less strongly related to other neuropsychiatric disorders such as major depressive disorder and bipolar disorder. These results shed new light concerning how complex neuropsychiatric diseases behave at the pathway level and demonstrate the power of this approach in identification of disease-specific biomarkers and potential novel therapeutic strategies.

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.

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.

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.

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.