Circulating proteins to predict COVID-19 severity.

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict COVID-19 severity in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different COVID-19 severity were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of COVID-19 severity. Further research is needed to understand how to incorporate protein measurement into clinical care.

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity.

Obesity is a major risk factor for Coronavirus disease (COVID-19) severity; however, the mechanisms underlying this relationship are not fully understood. As obesity influences the plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity in humans. Here, we screened 4,907 plasma proteins to identify proteins influenced by body mass index using Mendelian randomization. This yielded 1,216 proteins, whose effect on COVID-19 severity was assessed, again using Mendelian randomization. We found that an s.d. increase in nephronectin (NPNT) was associated with increased odds of critically ill COVID-19 (OR = 1.71, P = 1.63 × 10-10). The effect was driven by an NPNT splice isoform. Mediation analyses supported NPNT as a mediator. In single-cell RNA-sequencing, NPNT was expressed in alveolar cells and fibroblasts of the lung in individuals who died of COVID-19. Finally, decreasing body fat mass and increasing fat-free mass were found to lower NPNT levels. These findings provide actionable insights into how obesity influences COVID-19 severity.

Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.

Despite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA), low receptor binding domain­specific immunoglobulin G and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers were strongly associated with mortality, including in patients on mechanical ventilation. A three-variable model of vRNA, with predefined adjustment by age and sex, robustly identified patients with fatal outcome (adjusted hazard ratio for log-transformed vRNA = 3.5). This model remained robust in independent validation and confirmation cohorts. Since plasma vRNA's predictive accuracy was maintained at earlier time points, its quantitation can help us understand disease heterogeneity and identify patients who may benefit from new therapies.

Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study.

BACKGROUND: Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity. METHODS AND FINDINGS: Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency. CONCLUSIONS: In this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.

A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity.

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10-8), hospitalization (OR = 0.61, P = 8 × 10-8) and susceptibility (OR = 0.78, P = 8 × 10-6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.

Patient-reported reasons for and predictors of noncompliance with compression stockings in a randomized trial of stockings to prevent postthrombotic syndrome.

INTRODUCTION: Elastic compression stockings (ECSs) are used to treat symptoms of venous insufficiency. However, lack of patient compliance can limit their effectiveness. In a secondary analysis of the SOX Trial, a randomized trial of active vs. placebo ECSs worn for 2 years to prevent postthrombotic syndrome after deep vein thrombosis, we aimed to describe patient-reported reasons for nondaily use of ECS and to identify predictors of noncompliance during follow-up. METHODS: At each follow-up visit of the SOX Trial, patients were asked how many days per week they wore study stockings, and if not worn daily, to specify the reason(s). Reasons for nondaily use of ECSs were tabulated. Multiple logistic regression modeling was used to identify predictors of stocking noncompliance during follow-up (defined as use <3 days per week). RESULTS: Among the 776 patients who attended at least 1 follow-up visit, daily use of stockings at each visit was similar in the active and placebo ECS groups. Reasons for nondaily use of stockings was most frequently related to aversive aspects of stockings (~three-fourths of patients) and less often related to patient behaviors (~one-fourth of patients). In multivariate analyses, behavior-related and aversive aspect-related reasons for nondaily use of ECSs at the 1-month visit were significant predictors of noncompliance during follow-up (odds ratio [OR] = 4.41 [95% confidence interval, 2.12-9.17] and OR = 3.99 [2.62-6.08], respectively). CONCLUSIONS: Aversive aspects of ECSs and patient behaviors are important reasons for noncompliance. Improving the appeal and tolerability of ECS and education directed at modifying patient behaviors may improve compliance.

Effectiveness of interventions for the implementation of thromboprophylaxis in hospitalised patients at risk of venous thromboembolism: an updated abridged Cochrane systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To assess the effectiveness of system-wide interventions designed to increase the implementation of thromboprophylaxis and decrease the incidence of venous thromboembolism (VTE) in hospitalised medical and surgical patients at risk of VTE. DESIGN: Systematic review and meta-analysis of randomised controlled trials (RCTs). DATA SOURCES: Medline, PubMed, Embase, BIOSIS, CINAHL, Web of Science, CENTRAL, DARE, EED, LILACS and clinicaltrials.gov without language restrictions from inception to 7 January 2017, as well as the reference lists of relevant review articles. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: RCTs that evaluated the effectiveness of system-wide interventions such as alerts, multifaceted, education, and preprinted orders when compared with no intervention, existing policy or another intervention. RESULTS: We included 13 RCTs involving 35 997 participants. Eleven RCTs had data available for meta-analysis. Compared with control, we found absolute increase in the prescription of prophylaxis associated with alerts (21% increase, 95% CI [15% to 275%]) and multifaceted interventions (4% increase, 95% CI [3% to 11%]), absolute increase in the prescription of appropriate prophylaxis associated with alerts (16% increase, 95% CI [12% to 20%]) and relative risk reductions (risk ratio 64%, 95% CI [47% to 86%]) in the incidence of symptomatic VTE associated with alerts. Computer alerts were found to be more effective than human alerts, and multifaceted interventions with an alert component appeared to be more effective than multifaceted interventions without, although comparative pooled analyses were not feasible. The quality of evidence for improvement in outcomes was judged to be low to moderate certainty. CONCLUSIONS: Alerts increased the proportion of patients who received prophylaxis and appropriate prophylaxis, and decreased the incidence of symptomatic VTE. Multifaceted interventions increased the proportion of patients who received prophylaxis but were found to be less effective than alerts interventions. TRIAL REGISTRATION NUMBER: CD008201.

Looking Further When Symptoms Are Disproportionate to Physical Findings.

A 36-yr-old man presents with left ulnar-side wrist pain during an ice hockey game that prevented him from playing hockey or golf. There was no acute mechanism of injury. The usual clinical examination revealed only minimal tenderness and minimal pain with resisted wrist extension. Careful attention to precipitating factors led to testing resisted wrist extension with the forearm fully supinated, which reliably reproduced the intensity of the patient's symptoms, and a diagnosis of extensor carpi ulnaris tendinopathy. A literature review suggested three additional special tests (two were positive) and management. However, a standard of care has yet been established because neither the tests nor the management has been properly validated through research, thus leaving the management of this condition as an art.

Interventions for implementation of thromboprophylaxis in hospitalized patients at risk for venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in hospitalized patients. While numerous randomized controlled trials (RCTs) have shown that the appropriate use of thromboprophylaxis in hospitalized patients at risk for VTE is safe, effective, and cost-effective, thromboprophylaxis remains underused or inappropriately used. Our previous review suggested that system-wide interventions, such as education, alerts, and multifaceted interventions were more effective at improving the prescribing of thromboprophylaxis than relying on individual providers' behaviors. However, 47 of the 55 included studies in our previous review were observational in design. Thus, an update to our systematic review, focused on the higher level of evidence of RCTs only, was warranted. OBJECTIVES: To assess the effects of system-wide interventions designed to increase the implementation of thromboprophylaxis and decrease the incidence of VTE in hospitalized adult medical and surgical patients at risk for VTE, focusing on RCTs only. SEARCH METHODS: Our research librarian conducted a systematic literature search of MEDLINE Ovid, and subsequently translated it to CENTRAL, PubMed, Embase Ovid, BIOSIS Previews Ovid, CINAHL, Web of Science, the Database of Abstracts of Reviews of Effects (DARE; in the Cochrane Library), NHS Economic Evaluation Database (EED; in the Cochrane Library), LILACS, and clinicaltrials.gov from inception to 7 January 2017. We also screened reference lists of relevant review articles. We identified 12,920 potentially relevant records. SELECTION CRITERIA: We included all types of RCTs, with random or quasi-random methods of allocation of interventions, which either randomized individuals (e.g. parallel group, cross-over, or factorial design RCTs), or groups of individuals (cluster RCTs (CRTs)), which aimed to increase the use of prophylaxis or appropriate prophylaxis, or decrease the occurrence of VTE in hospitalized adult patients. We excluded observational studies, studies in which the intervention was simply distribution of published guidelines, and studies whose interventions were not clearly described. Studies could be in any language. DATA COLLECTION AND ANALYSIS: We collected data on the following outcomes: the number of participants who received prophylaxis or appropriate prophylaxis (as defined by study authors), the occurrence of any VTE (symptomatic or asymptomatic), mortality, and safety outcomes, such as bleeding. We categorized the interventions into alerts (computer or human alerts), multifaceted interventions (combination of interventions that could include an alert component), educational interventions (e.g. grand rounds, courses), and preprinted orders (written predefined orders completed by the physician on paper or electronically). We meta-analyzed data across RCTs using a random-effects model. For CRTs, we pooled effect estimates (risk difference (RD) and risk ratio (RR), with 95% confidence interval (CI), adjusted for clustering, when possible. We pooled results if three or more trials were available for a particular intervention. We assessed the certainty of the evidence according to the GRADE approach. MAIN RESULTS: From the 12,920 records identified by our search, we included 13 RCTs (N = 35,997 participants) in our qualitative analysis and 11 RCTs (N = 33,207 participants) in our meta-analyses. PRIMARY OUTCOME: Alerts were associated with an increase in the proportion of participants who received prophylaxis (RD 21%, 95% CI 15% to 27%; three studies; 5057 participants; I² = 75%; low-certainty evidence). The substantial statistical heterogeneity may be in part explained by patient types, type of hospital, and type of alert. Subgroup analyses were not feasible due to the small number of studies included in the meta-analysis.Multifaceted interventions were associated with a small increase in the proportion of participants who received prophylaxis (cluster-adjusted RD 4%, 95% CI 2% to 6%; five studies; 9198 participants; I² = 0%; moderate-certainty evidence). Multifaceted interventions with an alert component were found to be more effective than multifaceted interventions that did not include an alert, although there were not enough studies to conduct a pooled analysis. SECONDARY OUTCOMES: Alerts were associated with an increase in the proportion of participants who received appropriate prophylaxis (RD 16%, 95% CI 12% to 20%; three studies; 1820 participants; I² = 0; moderate-certainty evidence). Alerts were also associated with a reduction in the rate of symptomatic VTE at three months (RR 64%, 95% CI 47% to 86%; three studies; 5353 participants; I² = 15%; low-certainty evidence). Computer alerts were associated with a reduction in the rate of symptomatic VTE, although there were not enough studies to pool computer alerts and human alerts results separately. AUTHORS' CONCLUSIONS: We reviewed RCTs that implemented a variety of system-wide strategies aimed at improving thromboprophylaxis in hospitalized patients. We found increased prescription of prophylaxis associated with alerts and multifaceted interventions, and increased prescription of appropriate prophylaxis associated with alerts. While multifaceted interventions were found to be less effective than alerts, a multifaceted intervention with an alert was more effective than one without an alert. Alerts, particularly computer alerts, were associated with a reduction in symptomatic VTE at three months, although there were not enough studies to pool computer alerts and human alerts results separately.Our analysis was underpowered to assess the effect on mortality and safety outcomes, such as bleeding.The incomplete reporting of relevant study design features did not allow complete assessment of the certainty of the evidence. However, the certainty of the evidence for improvement in outcomes was judged to be better than for our previous review (low- to moderate-certainty evidence, compared to very low-certainty evidence for most outcomes). The results of our updated review will help physicians, hospital administrators, and policy makers make practical decisions about adopting specific system-wide measures to improve prescription of thromboprophylaxis, and ultimately prevent VTE in hospitalized patients.

Interventions for implementation of thromboprophylaxis in hospitalized medical and surgical patients at risk for venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in hospitalized patients. Numerous randomized controlled trials (RCTs) show that using thromboprophylaxis in hospitalized patients at risk for VTE is safe, effective and cost-effective. Despite this, prophylactic therapies for VTE are underutilized. System-wide interventions may be more effective to improve the use of VTE prophylaxis than relying on individual providers' prescribing behaviors. OBJECTIVES: To assess the effects of interventions designed to increase the implementation of thromboprophylaxis in hospitalized adult medical and surgical patients at risk for venous thromboembolism (VTE), assessed in terms of: 1. Increase in the proportion of patients who receive prophylaxis and appropriate prophylaxis 2. Reduction in risk of symptomatic VTE3. Reduction in risk of asymptomatic VTE4. Safety of the intervention. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Group's Specialised Register (last searched July 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) 2010, Issue 3. We searched the PubMed, EMBASE, and SCOPUS databases (19 April 2010) as well as the reference lists of relevant review articles. SELECTION CRITERIA: We included all studies whose interventions aimed to increase the use of prophylaxis and/or appropriate prophylaxis, decrease the proportion of symptomatic VTE, or decrease the proportion of asymptomatic VTE in hospitalized adult patients. We excluded studies that simply distributed published guidelines and studies whose interventions were not clearly described. DATA COLLECTION AND ANALYSIS: We collected the following outcomes: the proportion of patients who received prophylaxis (RP), the proportion of patients who received appropriate prophylaxis (RAP) (primary outcomes), and the occurrence of symptomatic VTE, asymptomatic VTE, and safety outcomes such as bleeding. We categorized interventions into education, alerts, and multifaceted interventions. We meta-analyzed RCTs and non-randomized studies (NRS) separately by random effects meta-analysis, and assessed heterogeneity using the I(2)statistic and subgroup analyses. Before analysis, we decided that results would be pooled if three or more studies were available for a particular intervention. We assessed publication bias using funnel plots and cumulative meta-analysis. MAIN RESULTS: We included a total of 55 studies. One of these reported data in patient-days and could not be quantitatively analyzed with the others. The 54 remaining studies (8 RCTs and 46 NRS) eligible for inclusion in our quantitative synthesis enrolled a total of 78,343 participants. Among RCTs, there were sufficient data to pool results for one primary outcome (received prophylaxis) for the 'alert' intervention. Alerts, such as computerized reminders or stickers on patients' charts, were associated with a risk difference (RD) of 13%, signifying an increase in the proportion of patients who received prophylaxis (95% confidence interval (CI) 1% to 25%). Among NRS, there were sufficient data to pool both primary outcomes for each intervention type. Pooled risk differences for received prophylaxis ranged from 8% to 17%, and for received appropriate prophylaxis ranged from 11% to 19%. Education and alerts were associated with statistically significant increases in prescription of appropriate prophylaxis, and multifaceted interventions were associated with statistically significant increases in prescription of any prophylaxis and appropriate prophylaxis. Multifaceted interventions had the largest pooled effects. I(2) results showed substantial statistical heterogeneity which was in part explained by patient types and type of hospital. A subgroup analysis showed that multifaceted interventions which included an alert may be more effective at improving rates of prophylaxis and appropriate prophylaxis than those without an alert. Results for VTE and safety outcomes did not show substantial benefits or harms, although most studies were underpowered to assess these outcomes. AUTHORS' CONCLUSIONS: We reviewed a large number of studies which implemented a variety of system-wide strategies aimed to improve thromboprophylaxis rates in many settings and patient populations. We found statistically significant improvements in prescription of prophylaxis associated with alerts (RCTs) and multifaceted interventions (RCTs and NRS), and improvements in prescription of appropriate prophylaxis in NRS with the use of education, alerts and multifaceted interventions. Multifaceted interventions with an alert component may be the most effective. Demonstrated sources of heterogeneity included patient types and type of hospital. The results of our review will help physicians, nurses, pharmacists, hospital administrators and policy makers make practical decisions about local adoption of specific system-wide measures to improve prevention of VTE, an important public health issue. We did not find a significant benefit for VTE outcomes; however, earlier RCTs assessing the efficacy of thromboprophylaxis which were powered to address these outcomes have demonstrated the benefit of prophylactic therapies and a favourable balance of benefits versus the increased risk of bleeding events.

Definition of immobility in studies of thromboprophylaxis in hospitalized medical patients: a systematic review.

BACKGROUND: Venous thromboembolism (VTE) is a common, serious and preventable complication in hospitalized patients. Thromboprophylaxis in medical patients is safe, effective, and cost saving, but remains underutilized. Although immobility plays an important role in determining VTE risk in medical patients, no clear criteria exist to guide clinicians in assessing immobility when making decisions about thromboprophylaxis. OBJECTIVES: A systematic review was conducted to determine how immobility is defined and operationalized in randomized controlled trials (RCTs) of thromboprophylaxis in medical inpatients. METHODS: PubMed database was searched until September 2008 for RCTs of thromboprophylaxis in medical patients. Articles retrieved were further hand-searched to identify additional RCTs. Definitions of "immobility" were assessed. RESULTS: Twenty-one RCTs were retrieved, 18 were retained and 17 of these defined, to varying degrees, "immobility." Studies used several definition criteria, including the patient's degree of activity (14 studies), time spent immobile or mobile (13 studies), distance walked (4 studies) and underlying reason for immobility (4 studies); 14 studies used a combination of criteria. Definitions were clearly operationalized in 15 studies. The concept of "immobility" was utilized in study introductions (4 studies), inclusion/exclusion criteria (16 studies), as a stratification variable before randomization (1 study), in ongoing patient assessment (1 study), in treatment decisions (5 studies), as part of the study intervention (2 studies), as standard of care (2 studies), and in the results, discussion or conclusions (12 studies). CONCLUSIONS: There is a marked lack of consistency in how the concept of immobility is defined and utilized in RCTs of thromboprophylaxis in medical inpatients. This circumstance may contribute to the underutilization of thromboprophylaxis in clinical practice with medical inpatients.