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ObjectivesTo evaluate whether SARS-CoV-2 infection in residents of long-term care (LTC) facilities is associated with higher mortality after the acute phase of infection, and to estimate survival in uninfected residents.DesignExtended follow-up of a previous, propensity score-matched, retrospective cohort study based on the Swedish Senior Alert register.SettingLTC facilities in Sweden.Participantsn=3604 LTC residents with documented SARS-CoV-2 until 15 September 2020 matched to 3604 uninfected controls using time-dependent propensity scores on age, sex, health status, comorbidities, prescription medications, geographical region and Senior Alert registration time. In a secondary analysis (n=3731 in each group), geographical region and Senior Alert registration time were not matched for in order to increase the follow-up time in controls and allow for an estimation of median survival.Primary outcome measuresAll-cause mortality until 24 October 2020, tracked using the National Cause of Death Register.ResultsMedian age was 87 years and 65% were women. Excess mortality peaked at 5 days after documented SARS-CoV-2-infection (HR 21.5, 95% CI 15.9 to 29.2), after which excess mortality decreased. From the second month onwards, mortality rate became lower in infected residents than controls. The HR for death during days 61–210 of follow-up was 0.76 (95% CI 0.62 to 0.93). The median survival of uninfected controls was 1.6 years, which was much lower than the national life expectancy in Sweden at age 87 (5.05 years in men, 6.07 years in women).ConclusionsThe risk of death after SARS-CoV-2 infection in LTC residents peaked after 5 days and decreased after 2 months, probably because the frailest residents died during the acute phase, leaving healthier residents remaining. The limited life expectancy in this population suggests that LTC resident status should be accounted for when estimating years of life lost due to COVID-19.

Reproducibility is a highly desired feature of scientific investigation in general, and it has special connotations for research in pharmacokinetics, a vibrant field with over 500,000 publications to-date. It is important to be able to differentiate between genuine heterogeneity in pharmacokinetic parameters from heterogeneity that is due to errors and biases. This overview discusses efforts and opportunities to diminish the latter type of undesirable heterogeneity. Several reporting and research guidance documents and standards have been proposed for pharmacokinetic studies, but their adoption is still rather limited. Quality problems in the methods used and model evaluations have been examined in some empirical studies of the literature. Standardization of statistical and laboratory tools and procedures can be improved in the field. Only a small fraction of pharmacokinetic studies become pre-registered and only 9995 such studies have been registered in ClinicalTrials.gov as of August 2018. It is likely that most pharmacokinetic studies remain unpublished. Publication bias affecting the results and inferences has been documented in case studies, but its exact extent is unknown for the field at-large. The use of meta-analyses in the field is still limited. Availability of raw data, detailed protocols, software and codes is hopefully improving with multiple ongoing initiatives. Several research practices can contribute to greater transparency and reproducibility for pharmacokinetic investigations.

Introduction: Three previous individual participant data meta-analyses (IPDMAs) reported that, compared to the Structured Clinical Interview for the DSM (SCID), alternative reference standards, primarily the Composite International Diagnostic Interview (CIDI) and the Mini International Neuropsychiatric Interview (MINI), tended to misclassify major depression status, when controlling for depression symptom severity. However, there was an important lack of precision in the results. Objective: To compare the odds of the major depression classification based on the SCID, CIDI, and MINI. Methods: We included and standardized data from 3 IPDMA databases. For each IPDMA, separately, we fitted binomial generalized linear mixed models to compare the adjusted odds ratios (aORs) of major depression classification, controlling for symptom severity and characteristics of participants, and the interaction between interview and symptom severity. Next, we synthesized results using a DerSimonian-Laird random-effects meta-analysis. Results: In total, 69,405 participants (7,574 [11%] with major depression) from 212 studies were included. Controlling for symptom severity and participant characteristics, the MINI (74 studies; 25,749 participants) classified major depression more often than the SCID (108 studies; 21,953 participants; aOR 1.46; 95% confidence interval [CI] 1.11–1.92]). Classification odds for the CIDI (30 studies; 21,703 participants) and the SCID did not differ overall (aOR 1.19; 95% CI 0.79–1.75); however, as screening scores increased, the aOR increased less for the CIDI than the SCID (interaction aOR 0.64; 95% CI 0.52–0.80). Conclusions: Compared to the SCID, the MINI classified major depression more often. The odds of the depression classification with the CIDI increased less as symptom levels increased. Interpretation of research that uses diagnostic interviews to classify depression should consider the interview characteristics.

PURPOSE: Although ~25% of colorectal cancer or polyps (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. METHODS: We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. RESULTS: We found a significant enrichment of PDVs in cases versus controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR=1.9, p=0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p=0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p=0.0001), BRCA2 (p=0.01) and BRIP1 (p=0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. CONCLUSION: These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.

Background: Recent GWAS revealed single nucleotide polymorphisms (SNPs) that cumulatively increase risk of CHD in those of European ancestry. We quantified the magnitude of preventive effects of healthy lifestyle against the countervailing effects of genetic risk on incident CHD, and assessed potential interactions. Methods: We extracted SNPs of genome-wide significance (-8 ) for CHD from CARDIoGRAMplusC4 GWAS, and created a weighted 57-SNP genetic risk score (GRS). Baseline covariates, healthy lifestyle score (including diet pattern, physical activity, smoking and BMI), and incident CHD were harmonized across 4 US cohorts (WHI, ARIC, CHS, and MESA) using dbGaP data. Pooled analyses were run using one-step individual participant data multivariate regressions in Caucasians without prevalent CVD. Results: Among 22,412 adults, the GRS was associated with incident CHD (n = 3001 cases) across each cohort (pooled GRS quintile (Q)5 vs Q1, RR (95% CI): 1.59 (1.41-1.79)), independent of all demographic and lifestyle variables. The lifestyle score was more strongly associated with CHD (pooled Q1 vs Q5, RR: 1.94 (1.71-2.20)) than the GRS, and better discriminated those who had a CHD event ( P =0.025 for difference in AUROC curves). When compared to population-level analysis, joint effects analysis revealed significant heterogeneity within quartiles of lifestyle score on risk of incident CHD ( Table ). Interactions between the GRS and diet pattern ( P =0.022) and trans fats ( P =0.046) were observed. Effects of trans fats on CHD risk appear to be concentrated in those with a higher GRS: for trans fats >2.4% of energy, RRs for increasing GRS quartiles are 0.92 (0.62-1.36), 1.13 (0.79-1.62), 1.43 (1.01-2.01), and 1.84 (1.30-2.61), compared to those in the lowest quartile of trans fat ( Conclusion: A joint effects approach reveals significant inter-individual variability in lifestyle on CHD risk by underlying genetic risk that is obscured by a conventional population-level effects approach.

Introduction: Both genetic and environmental factors contribute to triglyceride, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) levels. While genome-wide association studies test the genetic factors systematically, testing and reporting a few factors may lead to fragmented literature for environmental correlates. Hypothesis: We hypothesize that one may systematically screen environmental factors to discover and replicate robust correlations with serum lipid levels. To address this hypothesis, we conduct an environment-wide association study (EWAS) to comprehensively and systematically associate multiple environmental factors with serum lipid levels. Methods: We utilized four independent surveys from the National Health and Nutrition Examination Survey (NHANES), collected between 1999 and 2006. 322 urine and blood markers of environmental factors were assayed in 500 to 7000 individuals. We used linear regression to associate each standardized environmental factor (mean subtracted and divided by the standard deviation) to triglycerides, LDL-C, and HDL-C adjusting for age, age-squared, sex, ethnicity, socioeconomic status (SES), and body mass index (BMI). Final estimates were additionally adjusted for waist circumference, diabetes status, blood pressure, and cohort. Multiple comparisons were controlled for the false discovery rate (the estimated ratio of false positives among statistically significant findings). Significant findings were tentatively validated across surveys. Finally, we conducted sensitivity analyses adjusting for 62 questionnaire-based variables in order to assess the degree of bias. Results: We identified and validated 22, 8, and 17 environmental factors correlated with triglycerides, LDL-C and HDL-C levels, respectively. Novel associations include markers of air pollution associated with lower HDL-C (p=0.006, 3% lower, N=2000) and vitamin E (-tocopherol) associated with unfavorable lipid levels (triglycerides: p=10 -17 , 17% higher, N=3000; LDL-C: p=3x10 -14 , 6% higher, N=3,000; HDL-C: p=6x10 -6 , 3% lower, N=7000). We also confirmed many known or previously speculated associations, such as lower levels in HDL-C with a marker of nicotine, cotinine, and higher triglycerides and lower HDL-C with levels of persistent fat-soluble contaminants, and lower triglycerides and higher HDL-C levels with nutrient markers such as iron, folate, vitamin C, and vitamin D, and enterolactone. Conclusions: EWAS is a way to create hypothesis regarding the association of environmental factors to serum lipids. Due to the cross-sectional nature of the surveys, findings may be biased by confounders or may be reverse causal. Nonetheless, we document a wide array of both known and novel associations, such as nutrients, vitamins, and persistent pollutants, with lipid levels that should be examined in depth in longitudinal studies.

Introduction For any health intervention, accurate knowledge of both benefits and harms is needed. Systematic reviews often compound poor reporting of harms in primary studies by failing to report harms or doing so inadequately. While the PRISMA statement (Preferred Reporting Items for Systematic reviews and MetaAnalyses) helps systematic review authors ensure complete and transparent reporting, it is focused mainly on efficacy. Thus, a PRISMA harms checklist has been developed to improve harms reporting in systematic reviews, promoting a more balanced assessment of benefits and harms. Methods A development strategy, endorsed by the EQUATOR Network and existing reporting guidelines (including the PRISMA statement, PRISMA for abstracts, and PRISMA for protocols), was used. After the development of a draft checklist of items, a modified Delphi process was initiated. The Delphi consisted of three rounds of electronic feedback followed by an in-person meeting. Results The PRISMA harms checklist contains four essential reporting elements to be added to the original PRISMA statement to improve harms reporting in reviews. These are reported in the title (“Specifically mention ‘harms’ or other related terms, or the harm of interest in the review”), synthesis of results (“Specify how zero events were handled, if relevant”), study characteristics (“Define each harm addressed, how it was ascertained (eg, patient report, active search), and over what time period”), and synthesis of results (“Describe any assessment of possible causality”). Additional guidance regarding existing PRISMA items was developed to demonstrate relevance when synthesising information about harms. Conclusions The PRISMA harms checklist identifies a minimal set of items to be reported when reviewing adverse events. This guideline extension is intended to improve harms reporting in systematic reviews, whether harms are a primary or secondary outcome.

To examine temporal variation in the effects of CCR5-Delta32 and CCR2-64I chemokine receptor gene polymorphisms on HIV-1 disease progression.Pooled analysis of individual patient data from 10 cohorts of HIV-1 seroconverters from the United States, Europe, and Australia.We studied HIV-1 seroconverters of European (n = 1635) or African (n = 215) ancestry who had been genotyped for CCR5-Delta32 and CCR2-64I. We used Cox proportional hazards models with time-varying coefficients to determine whether the genetic protection against AIDS (1987 case definition) and death varied with time since seroconversion.Protection against AIDS conferred by CCR5-Delta32 held constant at a 31% (RH 0.69, 95% CI 0.54, 0.88) reduction in risk over the course of HIV-1 infection, whereas protection against death held constant at a 39% reduction in risk (RH 0.61, 95% CI 0.45, 0.88). When the period from AIDS to death was isolated, the survival benefit of CCR5-Delta32 diminished 2 years after AIDS. Protection against AIDS conferred by CCR2-64I was greatest early in the disease course. Compared with individuals without CCR5-Delta32 or CCR2-64I, individuals with one or two copies of CCR2-64I had a 58% lower risk of AIDS during the first 4 years after seroconversion (RH 0.42, 95% CI 0.23, 0.76), a 19% lower risk during the subsequent 4 years (RH 0.81, 95% CI 0.59, 1.12), and no significant protection thereafter.The protection against AIDS provided by CCR5-Delta32 is continuous during the course of infection. In contrast, the protection provided by CCR2-64I is greatest early in the course of infection.