Reporting Compliance and Factors Influencing Timeliness of Stroke-Related Trial Results on ClinicalTrials.gov.

Since 2007, research groups are mandated by the Food and Drug Administration Amendments Act (FDAAA) to report clinical trial findings to ClinicalTrials.gov within 12 months of trial completion. This observational study aims to analyze compliance data of stroke-related randomized controlled trials subject to these mandates. Using a previously published algorithm, we identified clinical trials likely to be required to adhere to FDAAA mandates (highly likely applicable clinical trials, or HLACTs) from January 2008 to February 2023. We assessed the proportion of studies that reported results within 12 months of trial completion, as well as those that reported at any point within 5 years. Additionally, we utilized Kaplan-Meier and regression analysis to explore factors associated with on-time reporting. Among 357 stroke-related HLACTs on ClinicalTrials.gov that were terminated or completed between January 1, 2008, and February 1, 2023, 59 (16.5%) reported results within 12 months, while 320 (89.6%) reported results within 5 years. Median reporting times for industry funded, other government or academic institution funded, and National Institute of Health (NIH) funded studies were 18.5 months, 22 months, and 22.5 months, respectively. Open-label studies were less likely to report results by 12 months compared to double-blinded studies (p = 0.002). Biological trials exhibited a lower probability of reporting within 5 years compared to device and/or drug trials (p = 0.007). Clinical trial registries and FDAAA mandates aim to promote accountability and transparency in health sciences research. However, regardless of their funding source, only a minority of stroke-related randomized controlled trials comply with FDAAA's 12-month result reporting mandate.

Neuropsychological Profiles of Deployment-Related Mild Traumatic Brain Injury: A LIMBIC-CENC Study.

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is a concern for US service members and veterans (SMV), leading to heterogeneous psychological and cognitive outcomes. We sought to identify neuropsychological profiles of mild TBI (mTBI) and posttraumatic stress disorder (PTSD) among the largest SMV sample to date. METHODS: We analyzed cross-sectional baseline data from SMV with prior combat deployments enrolled in the ongoing Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium prospective longitudinal study. Latent profile analysis identified symptom profiles using 35 indicators, including physical symptoms, depression, quality of life, sleep quality, postconcussive symptoms, and cognitive performance. It is important to note that the profiles were determined independently of mTBI and probable PTSD status. After profile identification, we examined associations between demographic variables, mTBI characteristics, and PTSD symptoms with symptom profile membership. RESULTS: The analytic sample included 1,659 SMV (mean age 41.1 ± 10.0 years; 87% male); among them 29% (n = 480) had a history of non-deployment-related mTBI only, 14% (n = 239) had deployment-related mTBI only, 36% (n = 602) had both non-deployment and deployment-related mTBI, and 30% (n = 497) met criteria for probable PTSD. A 6-profile model had the best fit, with separation on all indicators (p < 0.001). The model revealed distinct neuropsychological profiles, representing a combination of 3 self-reported functioning patterns: high (HS), moderate (MS), and low (LS), and 2 cognitive performance patterns: high (HC) and low (LC). The profiles were (1) HS/HC: n=301, 18.1%; (2) HS/LC: n=294, 17.7%; (3) MS/HC: n=359, 21.6%; (4) MS/LC: n=316, 19.0%; (5) LS/HC: n=228, 13.7%; and (6) LS/LC: n=161, 9.7%. SMV with deployment-related mTBI tended to be grouped into lower functioning profiles and were more likely to meet criteria for probable PTSD. Conversely, SMV with no mTBI exposure or non-deployment-related mTBI were clustered in higher functioning profiles and had a lower likelihood of meeting criteria for probable PTSD. DISCUSSION: Findings suggest varied symptom and functional profiles in SMV, influenced by injury context and probable PTSD comorbidity. Despite diagnostic challenges, comprehensive assessment of functioning and cognition can detect subtle differences related to mTBI and PTSD, revealing distinct neuropsychological profiles. Prioritizing early treatment based on these profiles may improve prognostication and support efficient recovery.

Myositis and Its Mimics: Guideline Updates, MRI Characteristics, and New Horizons.

Myositis is defined as inflammation within skeletal muscle and is a subcategory of myopathy, which is more broadly defined as any disorder affecting skeletal muscle. Myositis may be encountered as a component of autoimmune and connective tissue disease, where it is described as idiopathic inflammatory myopathy. Myositis can also be caused by infections, as well as toxins and drugs, including newer classes of medications. MRI plays an important role in the diagnosis and evaluation of patients with suspected myositis, but many entities may have imaging features similar to myositis and can be considered myositis mimics. These include muscular dystrophies, denervation, deep venous thrombosis, diabetic myonecrosis, muscle injury, heterotopic ossification, and even neoplasms. In patients with suspected myositis, definitive diagnosis may require integrated analysis of imaging findings with clinical, laboratory, and pathology data. The objectives of this article are to review the fundamental features of myositis, including recent updates in terminology and consensus guidelines for idiopathic inflammatory myopathies, the most important MRI differential diagnostic considerations for myositis (i.e., myositis mimics), and new horizons, including the potential importance of artificial intelligence and multimodal integrated diagnostics in the evaluation of patients with muscle disorders.

Angular Momentum Fine Structure in InP/ZnSe Quantum Dots.

There is a large experimental and theoretical literature on the angular momentum fine structure of the lowest energy exciton in InP-based quantum dots. This literature is highly contradictory, and no clear picture of the fine structure accounting for all these results is available. This paper presents a quantitative analysis of recently published luminescence anisotropy results and presents an analysis of the different proposed fine structure models that compares radiative lifetimes calculated from those models with experimental values. These analyses show that the lowest energy (dark) state is the mj = ±2 state and the lowest energy bright state is a vibronically allowed phonon level. The splittings between the ±2/±1L states and the ±1U/0U states are the same, about 28 meV. We also find that the manifold of J = 1 states is about 60 meV above the manifold of J = 2 states.

The Effect of Intranasal Plus Transcranial Photobiomodulation on Neuromuscular Control in Individuals with Repetitive Head Acceleration Events.

Objective: This proof-of-concept study was to investigate the relationship between photobiomodulation (PBM) and neuromuscular control. Background: The effects of concussion and repetitive head acceleration events (RHAEs) are associated with decreased motor control and balance. Simultaneous intranasal and transcranial PBM (itPBM) is emerging as a possible treatment for cognitive and psychological sequelae of brain injury with evidence of remote effects on other body systems. Methods: In total, 43 (39 male) participants, age 18-69 years (mean, 49.5; SD, 14.45), with a self-reported history of concussive and/or RHAE and complaints of their related effects (e.g., mood dysregulation, impaired cognition, and poor sleep quality), completed baseline and posttreatment motor assessments including clinical reaction time, grip strength, grooved pegboard, and the Mini Balance Evaluation Systems Test (MiniBEST). In the 8-week interim, participants self-administered itPBM treatments by wearing a headset comprising four near-infrared light-emitting diodes (LED) and a near-infrared LED nasal clip. Results: Posttreatment group averages in reaction time, MiniBEST reactive control subscores, and bilateral grip strength significantly improved with effect sizes of g = 0.75, g = 0.63, g = 0.22 (dominant hand), and g = 0.34 (nondominant hand), respectively. Conclusion: This study provides a framework for more robust studies and suggests that itPBM may serve as a noninvasive solution for improved neuromuscular health.

Diazepam nasal spray administration is effective to control seizure clusters irrespective of time of day.

Introduction: Neurologic circadian influences, including sleep/wake transitions, processes (e.g., hormonal variation), and behavioral patterns (e.g., consumption of food and oral medications), may affect seizure patterns. Specific circadian patterns of seizures have been reported depending on type, onset location, and severity; however, data on patterns for patients with seizure clusters and effectiveness of rescue therapy by time of day are limited. Methods: We conducted post hoc analyses using patient diary data from the phase 3 safety study of diazepam nasal spray, which is indicated for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Patients were administered age- and weight-based doses; second doses could be administered if needed to control a seizure cluster. We assessed clock timing of seizure-cluster onset along with second-dose use as a proxy for effectiveness. Treatment-emergent adverse events were recorded. Results: Seizure-cluster onset was observed to be generally highest during mornings and late evenings and lowest in the early evening and middle of the night. Second-dose use was not consistently associated with a specific time of day. The safety profile was consistent with that expected from previous studies of diazepam nasal spray. Conclusion: These results suggest that diazepam nasal spray can be effectively administered at any time of day.

Inflammatory and bone remodelling related biomarkers following periodontal transplantation of the tissue engineered biocomplex.

OBJECTIVES: To assess gingival crevicular fluid (GCF) levels of inflammatory and bone remodelling related biomarkers following transplantation of a tissue-engineered biocomplex into intrabony defects at several time-points over 12-months. MATERIALS AND METHODS: Group-A (n = 9) received the Minimal Access Flap (MAF) surgical technique combined with a biocomplex of autologous clinical-grade alveolar bone-marrow mesenchymal stem cells in collagen scaffolds enriched with an autologous fibrin/platelet lysate (aFPL). Group-B (n = 10) received the MAF surgery, with collagen scaffolds enriched with aFPL and Group-C (n = 8) received the MAF surgery alone. GCF was collected from the osseous defects of subjects via paper strips/30 sec at baseline, 6-weeks, 3-, 6-, 9-, 12-months post-surgery. Levels of inflammatory and bone remodelling-related biomarkers in GCF were determined by ELISA. RESULTS: Group-A demonstrated significantly higher GCF levels of BMP-7 at 6-9 months than baseline, with gradually decreasing levels of pro-inflammatory and pro-osteoclastogenic markers (TNF-α, RANKL) over the study-period; and an overall decrease in the RANKL/OPG ratio at 9-12 months than baseline (all p < 0.001). In comparison, only modest interim changes were observed in Groups-B and -C. CONCLUSIONS: At the protein level, the approach of MAF and biocomplex transplantation provided greater tissue regeneration potential as cell-based therapy appeared to modulate inflammation and bone remodelling in residual periodontal defects. CLINICAL RELEVANCE: Transplantation of a tissue engineered construct into periodontal intrabony defects demonstrated a biochemical pattern for inflammatory control and tissue regeneration over 12-months compared to the control treatments. Understanding the biological healing events of stem cell transplantation may facilitate the design of novel treatment strategies. CLINICAL DATABASE REGISTRATION: ClinicalTrials.gov ID: NCT02449005.

T Cell Activators Exhibit Distinct Downstream Effects on Chimeric Antigen Receptor T Cell Phenotype and Function.

T cell activation is an essential step in chimeric Ag receptor (CAR) T (CAR T) cell manufacturing and is accomplished by the addition of activator reagents that trigger the TCR and provide costimulation. We explore several T cell activation reagents and examine their effects on key attributes of CAR T cell cultures, such as activation/exhaustion markers, cell expansion, gene expression, and transduction efficiency. Four distinct activators were examined, all using anti-CD3 and anti-CD28, but incorporating different mechanisms of delivery: Dynabeads (magnetic microspheres), TransAct (polymeric nanomatrix), Cloudz (alginate hydrogel), and Microbubbles (lipid membrane containing perfluorocarbon gas). Clinical-grade lentiviral vector was used to transduce cells with a bivalent CD19/CD22 CAR, and cell counts and flow cytometry were used to monitor the cells throughout the culture. We observed differences in CD4/CD8 ratio when stimulating with the Cloudz activator, where there was a significant skewing toward CD8 T cells. The naive T cell subset expressing CD62L+CCR7+CD45RA+ was the highest in all donors when stimulating with Dynabeads, whereas effector/effector memory cells were highest when using the Cloudz. Functional assays demonstrated differences in killing of target cells and proinflammatory cytokine secretion, with the highest killing from the Cloudz-stimulated cells among all donors. This study demonstrates that the means by which these stimulatory Abs are presented to T cells contribute to the activation, resulting in differing effects on CAR T cell function. These studies highlight important differences in the final product that should be considered when manufacturing CAR T cells for patients in the clinic.

Excess prevalence of preexisting chronic conditions in older adults with incident epilepsy.

OBJECTIVE: Prior studies have examined chronic conditions in older adults with prevalent epilepsy, but rarely among those with incident epilepsy. Identifying the chronic conditions with which older adults present at epilepsy incidence assists with the evaluation of disease burden in this patient population and informs coordinated care development. The aim of this study was to identify preexisting chronic conditions with excess prevalence in older adults with incident epilepsy compared to those without. METHODS: Using a random sample of 4 999 999 fee-for-service Medicare beneficiaries aged >65 years, we conducted a retrospective cohort study of epilepsy incidence in 2019. Non-Hispanic Black and Hispanic beneficiaries were oversampled. We identified preexisting chronic conditions from the 2016-2018 Medicare Beneficiary Summary Files and compared chronic condition prevalence between Medicare beneficiaries with and without incident epilepsy in 2019. We characterized variations in preexisting excess chronic condition prevalence by age, sex, and race/ethnicity, adjusting for the racial/ethnic oversampling. RESULTS: We observed excess prevalence of most preexisting chronic conditions in beneficiaries with incident epilepsy (n = 20 545, weighted n = 19 631). For stroke, for example, the adjusted prevalence rate ratio (APRR) was 4.82 (99% CI:4.60, 5.04), meaning that, compared to those without epilepsy, beneficiaries with incident epilepsy in 2019 had 4.82 times the stroke prevalence. Similarly, beneficiaries with incident epilepsy had a higher prevalence rate for preexisting neurological conditions (APRR = 3.17, 99% CI = 3.08-3.27), substance use disorders (APRR = 3.00, 99% CI = 2.81-3.19), and psychiatric disorders (APRR = 1.98, 99% CI = 1.94-2.01). For most documented chronic conditions, excess prevalence among beneficiaries with incident epilepsy in 2019 was larger for younger age groups compared to older age groups, and for Hispanic beneficiaries compared to both non-Hispanic White and non-Hispanic Black beneficiaries. SIGNIFICANCE: Compared to epilepsy-free Medicare beneficiaries, those with incident epilepsy in 2019 had a higher prevalence of most preexisting chronic conditions. Our findings highlight the importance of health promotion and prevention, multidisciplinary care, and elucidating shared pathophysiology to identify opportunities for prevention.

Creating elastase aneurysms in rabbits: a video primer.

The New Zealand rabbit elastase-induced arterial aneurysm of the right common carotid artery remains a widely used model for assessing the effectiveness and safety of new neuroendovascular devices.1 This model offers a simple and reliable platform for pre-clinical in vivo investigations, crucial for comprehending the biological processes underlying aneurysm healing after endovascular treatment.2 Notably, the induced aneurysm exhibits morphological, hemodynamic, and histological characteristics similar to human intracranial aneurysms. The creation of the aneurysm is performed using open and endovascular techniques. Each step of the procedure requires a meticulous and controlled gesture to ensure reproducibility of the aneurysm and minimize animal misuse. In video 1 we present a step-by-step procedural guide for aneurysm creation and follow-up. We hope this resource will help in promoting this model and provide useful guidance for researchers in the field.neurintsurg;jnis-2024-021912v1/V1F1V1Video 1Surgical procedure of creating elastase-induced aneurysms in rabbits.

PREDICT HF: Risk stratification in advanced heart failure using novel hemodynamic parameters.

BACKGROUND: Invasive hemodynamics are fundamental in assessing patients with advanced heart failure (HF). Several novel hemodynamic parameters have been studied; however, the relative prognostic potential remains ill-defined. HYPOTHESIS: Advanced hemodynamic parameters provide additional prognostication beyond the standard hemodynamic assessment. METHODS: Patients from the PRognostic Evaluation During Invasive CaTheterization for Heart Failure (PREDICT-HF) registry who underwent right heart catheterization (RHC) were included in the analysis. The primary endpoint was survival to orthotopic heart transplant (OHT) or durable left ventricular assist device (LVAD), or death within 6 months of RHC. RESULTS: Of 846 patients included, 176 (21%) met the primary endpoint. In a multivariate model that included traditional hemodynamic variables, pulmonary capillary wedge pressure (PCWP) (OR: 1.10, 1.04-1.15, p < .001), and cardiac index (CI) (OR: 0.86, 0.81-0.92, p < .001) were shown to be predictive of adverse outcomes. In a separate multivariate model that incorporated advanced hemodynamic parameters, cardiac power output (CPO) (OR: 0.76, 0.71-0.83, p < .001), aortic pulsatility index (API) (OR: 0.94, 0.91-0.96, p < .001), and pulmonary artery pulsatility index (OR: 1.02, 1.00-1.03, p .027) were all significantly associated with the primary outcome. Positively concordant API and CPO afforded the best freedom from the endpoint (94.7%), whilst negatively concordant API and CPO had the worst freedom from the endpoint (61.5%, p < .001). Those with discordant API and CPO had similar freedom from the endpoint. CONCLUSION: The advanced hemodynamic parameters API and CPO are independently associated with death or the need for OHT or LVAD within 6 months. Further prospective studies are needed to validate these parameters and elucidate their role in patients with advanced HF.

Genome-wide analysis to assess if heavy alcohol consumption modifies the association between SNPs and pancreatic cancer risk.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. METHODS: We conducted a genome-wide interaction analysis of single nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than 3 drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies (GWAS). Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed effect meta-analyses were conducted. RESULTS: A potential novel region of association on 10p11.22, lead SNP rs7898449 (Pinteraction = 5.1 x 10-8 in the meta-analysis, Pinteraction = 2.1x10-9 in the case-control studies, Pinteraction = 0.91 cohort studies) was identified. A SNP correlated with this lead SNP is an eQTL for the NRP1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). CONCLUSIONS: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an eQTL for the NRP1, a protein that plays an important role in the development and progression of pancreatic cancer Impact: This work can provide insight into the etiology of pancreatic cancer particularly in heavy drinkers.

A review of the use of numerical analysis in stomach modeling.

Food digestion is important for human health. Advances have been made using in vitro models to study food digestion, but there is considerable potential for numerical approaches in stomach modeling, as they can provide a comprehensive understanding of the complex flow and chemistry in the stomach. The focus of this study is to provide a concise review of the developed numerical stomach models over the past two decades. The gastric physiological parameters that are required for a computational model to represent the human gastric digestion process are discussed, including the stomach geometry, gastric motility, gastric emptying, and gastric secretions. Computational methods used to model gastric digestion are introduced and compared, including different computational fluid dynamics as well as solid mechanics methods. The challenges and limitations of current studies are discussed, as well as the areas for future research that need to be addressed. There has been progress in simulating gastric fluid flow with stomach wall motion, but much work remains to be done. The complex food breakdown mechanisms and a comprehensive chemical digestion process have not been implemented in any developed models. Numerical method that was once computationally expensive will be revolutionized as computing power continues to improve. Ultimately, the advancement of modeling of gastric food digestion will allow for additional hypothesis testing to streamline the development of food products that are beneficial to human health.

HSP70-mediated mitochondrial dynamics and autophagy represent a novel vulnerability in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer, is one of the deadliest forms of cancer with limited therapy options. Overexpression of the heat shock protein 70 (HSP70) is a hallmark of cancer that is strongly associated with aggressive disease and worse clinical outcomes. However, the underlying mechanisms by which HSP70 allows tumor cells to thrive under conditions of continuous stress have not been fully described. Here, we report that PDAC has the highest expression of HSP70 relative to normal tissue across all cancers analyzed. Furthermore, HSP70 expression is associated with tumor grade and is further enhanced in metastatic PDAC. We show that genetic or therapeutic ablation of HSP70 alters mitochondrial subcellular localization, impairs mitochondrial dynamics, and promotes mitochondrial swelling to induce apoptosis. Mechanistically, we find that targeting HSP70 suppresses the PTEN-induced kinase 1 (PINK1) mediated phosphorylation of dynamin-related protein 1 (DRP1). Treatment with the HSP70 inhibitor AP-4-139B was efficacious as a single agent in primary and metastatic mouse models of PDAC. In addition, we demonstrate that HSP70 inhibition promotes the AMP-activated protein kinase (AMPK) mediated phosphorylation of Beclin-1, a key regulator of autophagic flux. Accordingly, we find that the autophagy inhibitor hydroxychloroquine (HCQ) enhances the ability of AP-4-139B to mediate anti-tumor activity in vivo. Collectively, our results suggest that HSP70 is a multi-functional driver of tumorigenesis that orchestrates mitochondrial dynamics and autophagy. Moreover, these findings support the rationale for concurrent inhibition of HSP70 and autophagy as a novel therapeutic approach for HSP70-driven PDAC.

Associations of obesity, movement behaviors, and socioeconomic status with fundamental movement skills in children: Results from the REACT project.

OBJECTIVE: To investigate the relationship of biological characteristics (age, sex, and obesity), movement behaviors (physical activity and sedentary time), and family socioeconomic status with fundamental movement skills (FMS) in primary school children. METHODS: This cross-sectional study sampled 1014 children (537 girls) aged 6 to 10 years from 25 primary schools in Matosinhos, north of Portugal. Five object control skills (dribbling, kicking, catching, throwing, and underarm rolling) were assessed with a categorical scale using the Meu Educativo® platform. Body Mass Index (BMI) was calculated and transformed into z-scores. Moderate-to-vigorous physical activity (MVPA) and sedentary time were monitored with accelerometry (ActiGraph wGT3X-BT) for seven consecutive days. Family socioeconomic status (SES) was obtained from the Portuguese social support system. Ordinal multilevel logistic regression was used to analyze the associations of weight status, MVPA, sedentary time and SES with FMS, adjusted for sex and age. RESULTS: Boys (odds ratio (OR) = 6.54; 95% CI: 5.13-8.36) and older children (OR = 2.04; 95% CI: 1.85-2.26) were more likely to achieve higher FMS scores. Children with obesity (OR = 0.60; 95% CI: 0.45-0.80), those less active (OR = 0.56; 95% CI: 0.42-0.75) and children with more sedentary time (OR = 0.86; 95%CI: 0.77-0.97) were less likely to score high on FMS. Family SES was not significantly associated with FMS scores. CONCLUSION: Primary school children's FMS are significantly related to biological and behavioral factors but not to family SES. These findings highlight the need for suitable strategies to enhance children's FMS proficiency, considering differences in these characteristics. Fostering adequate motor skill proficiency levels will assist in establishing a robust foundation for healthy lifestyles of all children.

Establishing flood thresholds for sea level rise impact communication.

Sea level rise (SLR) affects coastal flood regimes and poses serious challenges to flood risk management, particularly on ungauged coasts. To address the challenge of monitoring SLR at local scales, we propose a high tide flood (HTF) thresholding system that leverages machine learning (ML) techniques to estimate SLR and HTF thresholds at a relatively fine spatial resolution (10 km) along the United States' coastlines. The proposed system, complementing conventional linear- and point-based estimations of HTF thresholds and SLR rates, can estimate these values at ungauged stretches of the coast. Trained and validated against National Oceanic and Atmospheric Administration (NOAA) gauge data, our system demonstrates promising skills with an average Kling-Gupta Efficiency (KGE) of 0.77. The results can raise community awareness about SLR impacts by documenting the chronic signal of HTF and providing useful information for adaptation planning. The findings encourage further application of ML in achieving spatially distributed thresholds.

ProtVar: mapping and contextualizing human missense variation.

Genomic variation can impact normal biological function in complex ways and so understanding variant effects requires a broad range of data to be coherently assimilated. Whilst the volume of human variant data and relevant annotations has increased, the corresponding increase in the breadth of participating fields, standards and versioning mean that moving between genomic, coding, protein and structure positions is increasingly complex. In turn this makes investigating variants in diverse formats and assimilating annotations from different resources challenging. ProtVar addresses these issues to facilitate the contextualization and interpretation of human missense variation with unparalleled flexibility and ease of accessibility for use by the broadest range of researchers. By precalculating all possible variants in the human proteome it offers near instantaneous mapping between all relevant data types. It also combines data and analyses from a plethora of resources to bring together genomic, protein sequence and function annotations as well as structural insights and predictions to better understand the likely effect of missense variation in humans. It is offered as an intuitive web server https://www.ebi.ac.uk/protvar where data can be explored and downloaded, and can be accessed programmatically via an API.