Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis.

OBJECTIVES: Treatments that prevent sepsis complications are needed. Circulating lipid and protein assemblies-lipoproteins play critical roles in clearing pathogens from the bloodstream. We investigated whether early inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) may accelerate bloodstream clearance of immunogenic bacterial lipids and improve sepsis outcomes. DESIGN: Genetic and clinical epidemiology, and experimental models. SETTING: Human genetics cohorts, secondary analysis of a phase 3 randomized clinical trial enrolling patients with cardiovascular disease (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402), and experimental murine models of sepsis. PATIENTS OR SUBJECTS: Nine human cohorts with sepsis (total n = 12,514) were assessed for an association between sepsis mortality and PCSK9 loss-of-function (LOF) variants. Incident or fatal sepsis rates were evaluated among 18,884 participants in a post hoc analysis of ODYSSEY OUTCOMES. C57BI/6J mice were used in Pseudomonas aeruginosa and Staphylococcus aureus bacteremia sepsis models, and in lipopolysaccharide-induced animal models. INTERVENTIONS: Observational human cohort studies used genetic PCSK9 LOF variants as instrumental variables. ODYSSEY OUTCOMES participants were randomized to alirocumab or placebo. Mice were administered alirocumab, a PCSK9 inhibitor, at 5 mg/kg or 25 mg/kg subcutaneously, or isotype-matched control, 48 hours prior to the induction of bacterial sepsis. Mice did not receive other treatments for sepsis. MEASUREMENTS AND MAIN RESULTS: Across human cohort studies, the effect estimate for 28-day mortality after sepsis diagnosis associated with genetic PCSK9 LOF was odds ratio = 0.86 (95% CI, 0.67-1.10; p = 0.24). A significant association was present in antibiotic-treated patients. In ODYSSEY OUTCOMES, sepsis frequency and mortality were infrequent and did not significantly differ by group, although both were numerically lower with alirocumab vs. placebo (relative risk of death from sepsis for alirocumab vs. placebo, 0.62; 95% CI, 0.32-1.20; p = 0.15). Mice treated with alirocumab had lower endotoxin levels and improved survival. CONCLUSIONS: PCSK9 inhibition may improve clinical outcomes in sepsis in preventive, pretreatment settings.

Common and rare variant associations with clonal haematopoiesis phenotypes.

Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes1-5. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes6, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.

ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma.

Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2-4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.

Germline Mutations in CIDEB and Protection against Liver Disease.

BACKGROUND: Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets. METHODS: We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations. RESULTS: The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in CIDEB, which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in CIDEB (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 U per liter; 95% confidence interval [CI], -1.66 to -0.83; P = 4.8×10-9) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P = 9.9×10-7). Rare coding variants in CIDEB were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, CIDEB small interfering RNA knockdown prevented the buildup of large lipid droplets. CONCLUSIONS: Rare germline mutations in CIDEB conferred substantial protection from liver disease. (Funded by Regeneron Pharmaceuticals.).

Exome sequencing and analysis of 454,787 UK Biobank participants.

A major goal in human genetics is to use natural variation to understand the phenotypic consequences of altering each protein-coding gene in the genome. Here we used exome sequencing1 to explore protein-altering variants and their consequences in 454,787 participants in the UK Biobank study2. We identified 12 million coding variants, including around 1 million loss-of-function and around 1.8 million deleterious missense variants. When these were tested for association with 3,994 health-related traits, we found 564 genes with trait associations at P ≤ 2.18 × 10-11. Rare variant associations were enriched in loci from genome-wide association studies (GWAS), but most (91%) were independent of common variant signals. We discovered several risk-increasing associations with traits related to liver disease, eye disease and cancer, among others, as well as risk-lowering associations for hypertension (SLC9A3R2), diabetes (MAP3K15, FAM234A) and asthma (SLC27A3). Six genes were associated with brain imaging phenotypes, including two involved in neural development (GBE1, PLD1). Of the signals available and powered for replication in an independent cohort, 81% were confirmed; furthermore, association signals were generally consistent across individuals of European, Asian and African ancestry. We illustrate the ability of exome sequencing to identify gene-trait associations, elucidate gene function and pinpoint effector genes that underlie GWAS signals at scale.

Comparing Clinical Characteristics of Influenza and Common Coronavirus Infections Using Electronic Health Records.

BACKGROUND: We compared outcomes in inpatients and outpatients, pre-COVID-19, who were infected with either coronavirus or influenza. METHODS: Using deidentified electronic health records data from the Geisinger-Regeneron partnership, we compared patients with RT-PCR-positive tests for the 4 common coronaviruses (229E, HKU1, NL63, OC43) or influenza (A and B) from June 2016 to February 2019. RESULTS: Overall, 52 833 patients were tested for coronaviruses and influenza. For patients ≥21 years old, 1555 and 3991 patient encounters had confirmed positive coronavirus and influenza tests, respectively. Both groups had similar intensive care unit (ICU) admission rates (7.2% vs 6.1%, P = .12), although patients with coronavirus had significantly more pneumonia (15% vs 7.4%, P < .001) and higher death rate within 30 days (4.9% vs 3.0%, P < .001). After controlling for other covariates, coronavirus infection still had a higher risk of death and pneumonia than influenza (odds ratio, 1.64 and 2.05, P < .001), with no significant difference in ICU admission rates. CONCLUSIONS: Common coronaviruses cause significant morbidity, with potentially worse outcomes than influenza. Identifying a subset of patients who are more susceptible to poor outcomes from common coronavirus infections may help plan clinical interventions in patients with suspected infections.

Implementation and early adaptation of patient-reported outcome measures into an electronic health record: A technical report.

We integrated and optimized patient-reported outcome measures into the electronic health record to provide quantitative, objective data regarding patients' health status, which is important for patient care, payer contracts, and research. With a multidisciplinary team from information technology, clinical informatics, population health, and physician champions, we used formal human-computer interaction techniques and user-centered design to integrate several technology platforms and computerized adaptive testing for the National Institutes of Health Patient-Reported Outcomes Measurement Information System. The patient-reported outcome measure system leverages software frequently used by health systems and provides data for research and clinical care via a mobile-responsive web application using Symfony, with REDCap for configuring assessments and de-identified data storage. The system incorporates Oracle databases and Epic flowsheets. Patients complete patient-reported outcome measures, with data viewable in MyChart and Epic Synopsis Reports. Researchers can access data portals. The highly usable, successful patient-reported outcome measures platform is acceptable to patients and clinicians and achieved 73 percent overall completion rates.

Partner meeting venue typology and sexual risk behaviors among French men who have sex with men.

Previous research has given considerable attention to venues where men who have sex with men (MSM) meet their sex partners. However, no previous study examined a vast range of sexual risk behaviors. The objective of this study was to examine the association between the types of venues for meeting sexual partners, condomless anal intercourse, engagement in group sex, and HIV and sexually transmitted infection (STI) risk among a sample of MSM. Users of a popular geosocial-networking app in Paris were provided an advertisement with text encouraging them to complete an anonymous web-based survey ( n = 580), which included questions about sex-seeking venues, condomless anal intercourse, HIV status and STI history, and sociodemographic characteristics. A log-binomial model was used to assess association between venues (i.e. public venues [gay clubs, bars, and discos], cruising venues [such as gay saunas, beaches, and parks], and internet-based venues [internet chat sites and geosocial-networking apps]), condomless anal intercourse, engagement in group sex, and HIV infection as well as infection with other STIs, after adjustment for sociodemographics. In multivariable models, attending cruising venues was associated with condomless receptive anal intercourse (adjusted relative risk [aRR] = 1.47; 95% confidence interval [CI] = 1.20-1.81), any kind of condomless anal intercourse (aRR = 1.34; 95% CI = 1.14-1.58), an STI (aRR = 1.50; 95% CI = 1.09-2.05), engagement in group sex (aRR = 1.42; 95% CI = 1.27-1.59), and multiple partners for both condomless insertive (aRR = 2.00; 95% CI = 1.38-2.88), and receptive (aRR = 1.70; 95% CI = 1.23-2.36) anal intercourse, STI infection (aRR = 1.50, 95% CI = 1.09-2.05) and HIV infection (aRR = 1.76; 95% CI = 1.05-2.96). No associations were found with other venue types and sexual risk behaviors, STIs, and HIV infection, except for group sex, which was associated with all venue types. Use of cruising where the primary aim is to have sex was found to be associated with risky sexual behavior. Risky behavior reduction strategies such as preexposure prophylaxis campaigns should be targeted to MSM who frequent cruising venues.

Measuring Patient and Staff Satisfaction Before and After Implementation of a Paperless Registration System.

EXECUTIVE SUMMARY: While many aspects of patient care have transitioned to digital technology, the patient registration process often is still paper based. Several studies have examined the effects of changes in clinic workflows and appointment scheduling on patient satisfaction, but few have investigated changes from a paper-based to a paperless registration process. The authors measured patient and staff satisfaction before and after implementation of a new, tablet-based registration process at NYU Langone Health's Center for Women's Health in New York City. Mean preimplementation patient satisfaction scores on the six questions related to the registration process (1-5 scale, with 5 being the highest score) ranged from 4.0 to 4.5. Postimplementation satisfaction scores on the nine questions (six premeasure questions and three additional questions related to the tablet-based process) ranged from 4.4 to 4.6, with four of the six premeasures showing statistically significant improvement in patient satisfaction. Staff satisfaction was generally lower (2.8-3.6 preimplementation and 2.8-4 postimplementation), with no statistically significant difference between time frames. Patient satisfaction was relatively high under the paper registration process, and it improved significantly in some respects under the paperless process, while staff satisfaction did not change. The convenience and ease of use of a paperless registration system can help maintain or increase patient and staff satisfaction while introducing new workflows and improving the efficiency of the outpatient registration process. In adopting technology that can lead to changing workflows, organizations should train staff members and support them during the process.

Integrating Data On Social Determinants Of Health Into Electronic Health Records.

As population health becomes more of a focus of health care, providers are realizing that data outside of traditional clinical findings can provide a broader perspective on potential drivers of a patient's health status and can identify approaches to improving the effectiveness of care. However, many challenges remain before data related to the social determinants of health, such as environmental conditions and education levels, are as readily accessible and actionable as medical data are. Key challenges are a lack of consensus on standards for capturing or representing social determinants of health in electronic health records and insufficient evidence that once information on them has been collected, social determinants can be effectively addressed through referrals or other action tools. To address these challenges and effectively use social determinants in health care settings, we recommend creating national standards for representing data related to social determinants of health in electronic health records, incentivizing the collection of the data through financial or quality measures, and expanding the body of research that measures the impact of acting on the information collected.

FACETS: using open data to measure community social determinants of health.

Objective: To develop a dataset based on open data sources reflective of community-level social determinants of health (SDH). Materials and Methods: We created FACETS (Factors Affecting Communities and Enabling Targeted Services), an architecture that incorporates open data related to SDH into a single dataset mapped at the census-tract level for New York City. Results: FACETS (https://github.com/mcantor2/FACETS) can be easily used to map individual addresses to their census-tract-level SDH. This dataset facilitates analysis across different determinants that are often not easily accessible. Discussion: Wider access to open data from government agencies at the local, state, and national level would facilitate the aggregation and analysis of community-level determinants. Timeliness of updates to federal non-census data sources may limit their usefulness. Conclusion: FACETS is an important first step in standardizing and compiling SDH-related data in an open architecture that can give context to a patient's condition and enable better decision-making when developing a plan of care.

Genome Sequence of Marinobacter sp. Strain MCTG268 Isolated from the Cosmopolitan Marine Diatom Skeletonema costatum.

Marinobacter sp. strain MCTG268 was isolated from the cosmopolitan marine diatom Skeletonema costatum and can degrade oil hydrocarbons as sole sources of carbon and energy. Here, we present the genome sequence of this strain, which is 4,449,396 bp with 4,157 genes and an average G+C content of 57.0%.

Genome Sequence of Arenibacter algicola Strain TG409, a Hydrocarbon-Degrading Bacterium Associated with Marine Eukaryotic Phytoplankton.

Arenibacter algicola strain TG409 was isolated from Skeletonema costatum and exhibits the ability to utilize polycyclic aromatic hydrocarbons as sole sources of carbon and energy. Here, we present the genome sequence of this strain, which is 5,550,230 bp with 4,722 genes and an average G+C content of 39.7%.

Repurposing historical control clinical trial data to provide safety context.

Billions of dollars spent, millions of subject-hours of clinical trial experience and an abundance of archived study-level data, yet why are historical data underutilized? We propose that historical data can be aggregated to provide safety, background incidence rate and context to improve the evaluation of new medicinal products. Here, we describe the development and application of the eControls database, which is derived from the control arms of studies of licensed products, and discuss the challenges and potential solutions to the proper application of historical data to help interpret product safety.