Pragmatic approaches to handling practice effects in longitudinal cognitive aging research.

INTRODUCTION: The challenge of accounting for practice effects (PEs) when modeling cognitive change was amplified by the COVID-19 pandemic, which introduced period and mode effects that may bias the estimation of cognitive trajectory. METHODS: In three Kaiser Permanente Northern California prospective cohorts, we compared predicted cognitive trajectories and the association of grip strength with cognitive decline using three approaches: (1) no acknowledgment of PE, (2) inclusion of a wave indicator, and (3) constraining PE based on a preliminary model (APM) fit using a subset of the data. RESULTS: APM-based correction for PEs based on balanced, pre-pandemic data, and with current age as the timescale produced the smallest discrepancy between within-person and between-person estimated age effects. Estimated associations between grip strength and cognitive decline were not sensitive to the approach used. DISCUSSION: Constraining PEs based on a preliminary model is a flexible, pragmatic approach allowing for meaningful interpretation of cognitive change. HIGHLIGHTS: The magnitude of practice effects (PEs) varied widely by study. When PEs were present, the three PE approaches resulted in divergent estimated age-related cognitive trajectories. Estimated age-related cognitive trajectories were sometimes implausible in models that did not account for PEs. The associations between grip strength and cognitive decline did not differ by the PE approach used. Constraining PEs based on estimates from a preliminary model allows for a meaningful interpretation of cognitive change.

Sex-Specific Neurodevelopmental Outcomes Among Offspring of Mothers With SARS-CoV-2 Infection During Pregnancy.

Importance: Prior studies using large registries have suggested a modest increase in risk for neurodevelopmental diagnoses among children of mothers with immune activation during pregnancy, and such risk may be sex-specific. Objective: To determine whether in utero exposure to SARS-CoV-2 is associated with sex-specific risk for neurodevelopmental disorders up to 18 months after birth, compared with unexposed offspring born during or prior to the COVID-19 pandemic period. Design, Setting, and Participants: This retrospective cohort study included the live offspring of all mothers who delivered between January 1 and December 31, 2018 (born and followed up before the COVID-19 pandemic), between March 1 and December 31, 2019 (born before and followed up during the COVID-19 pandemic), and between March 1, 2020, and May 31, 2021 (born and followed up during the COVID-19 pandemic). Offspring were born at any of 8 hospitals across 2 health systems in Massachusetts. Exposures: Polymerase chain reaction evidence of maternal SARS-CoV-2 infection during pregnancy. Main Outcomes and Measures: Electronic health record documentation of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnostic codes corresponding to neurodevelopmental disorders. Results: The COVID-19 pandemic cohort included 18 355 live births (9399 boys [51.2%]), including 883 (4.8%) with maternal SARS-CoV-2 positivity during pregnancy. The cohort included 1809 Asian individuals (9.9%), 1635 Black individuals (8.9%), 12 718 White individuals (69.3%), and 1714 individuals (9.3%) who were of other race (American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, more than 1 race); 2617 individuals (14.3%) were of Hispanic ethnicity. Mean maternal age was 33.0 (IQR, 30.0-36.0) years. In adjusted regression models accounting for race, ethnicity, insurance status, hospital type (academic center vs community), maternal age, and preterm status, maternal SARS-CoV-2 positivity was associated with a statistically significant elevation in risk for neurodevelopmental diagnoses at 12 months among male offspring (adjusted OR, 1.94 [95% CI 1.12-3.17]; P = .01) but not female offspring (adjusted OR, 0.89 [95% CI, 0.39-1.76]; P = .77). Similar effects were identified using matched analyses in lieu of regression. At 18 months, more modest effects were observed in male offspring (adjusted OR, 1.42 [95% CI, 0.92-2.11]; P = .10). Conclusions and Relevance: In this cohort study of offspring with SARS-CoV-2 exposure in utero, such exposure was associated with greater magnitude of risk for neurodevelopmental diagnoses among male offspring at 12 months following birth. As with prior studies of maternal infection, substantially larger cohorts and longer follow-up will be required to reliably estimate or refute risk.

Reduction in Long-term Mortality after Sleeve Gastrectomy and Gastric Bypass Compared to Non-surgical Patients with Severe Obesity.

OBJECTIVE: To separately compare the long-term risk of mortality among bariatric surgical patients undergoing either RYGB or SG to large, matched, population-based cohorts of patients with severe obesity who did not undergo surgery. BACKGROUND: Bariatric surgery has been associated with reduced long-term mortality compared to usual care for severe obesity which is particularly relevant in the COVID-19 era. Most prior studies involved the Roux-en-Y gastric bypass (RYGB) operation and there is less long-term data on the sleeve gastrectomy (SG). METHODS: In this retrospective, matched cohort study, patients with a body mass index ≥35 kg/m2 who underwent bariatric surgery from January 2005 to September 2015 in three integrated health systems in the United States were matched to nonsurgical patients on site, age, sex, body mass index, diabetes status, insulin use, race/ethnicity, combined Charlson/Elixhauser comorbidity score, and prior health care utilization, with follow-up through September 2015. Each procedure (RYGB, SG) was compared to its own control group and the two surgical procedures were not directly compared to each other. Multivariable-adjusted Cox regression analysis investigated time to all-cause mortality (primary outcome) comparing each of the bariatric procedures to usual care. Secondary outcomes separately examined the incidence of cardiovascular-related death, cancer related-death, and diabetes related-death. RESULTS: Among 13,900 SG, 17,258 RYGB, and 87,965 nonsurgical patients, the 5-year follow-up rate was 70.9%, 72.0%, and 64.5%, respectively. RYGB and SG were each associated with a significantly lower risk of all-cause mortality compared to nonsurgical patients at 5-years of follow-up (RYGB: HR = 0.43; 95% CI: 0.35,0.54; SG: HR = 0.28; 95% CI: 0.13,0.57) Similarly, RYGB was associated with a significantly lower 5-year risk of cardiovascular- (HR = 0.27; 95% CI: 0.20, 0.37), cancer- (HR = 0.54; 95% CI: 0.39, 0.76), and diabetes-related mortality (HR = 0.23; 95% CI:0.15, 0.36). There was not enough follow-up time to assess 5-year cause-specific mortality in SG patients, but at 3-years follow up, there was significantly lower risk of cardiovascular- (HR = 0.33; 95% CI:0.19, 0.58), cancer- (HR = 0.26; 95% CI:0.11, 0.59), and diabetes-related (HR = 0.15; 95% CI:0.04, 0.53) mortality for SG patients. CONCLUSION: This study confirms and extends prior findings of an association with better survival following bariatric surgery in RYGB patients compared to controls and separately demonstrates that the SG operation also appears to be associated with lower mortality compared to matched control patients with severe obesity that received usual care. These results help to inform the trade-offs between long-term benefits and risks of bariatric surgery.

Peer Review in a General Medical Research Journal Before and During the COVID-19 Pandemic.

Importance: Although peer review is an important component of publication for new research, the viability of this process has been questioned, particularly with the added stressors of the COVID-19 pandemic. Objective: To characterize rates of peer reviewer acceptance of invitations to review manuscripts, reviewer turnaround times, and editor-assessed quality of reviews before and after the start of the COVID-19 pandemic at a large, open-access general medical journal. Design, Setting, and Participants: This retrospective, pre-post cohort study examined all research manuscripts submitted to JAMA Network Open between January 1, 2019, and June 29, 2021, either directly or via transfer from other JAMA Network journals, for which at least 1 peer review of manuscript content was solicited. Measures were compared between the period before the World Health Organization declaration of a COVID-19 pandemic on March 11, 2020 (14.3 months), and the period during the pandemic (15.6 months) among all reviewed manuscripts and between pandemic-period manuscripts that did or did not address COVID-19. Main Outcomes and Measures: For each reviewed manuscript, the number of invitations sent to reviewers, proportions of reviewers accepting invitations, time in days to return reviews, and editor-assessed quality ratings of reviews were determined. Results: In total, the journal sought review for 5013 manuscripts, including 4295 Original Investigations (85.7%) and 718 Research Letters (14.3%); 1860 manuscripts were submitted during the prepandemic period and 3153 during the pandemic period. Comparing the prepandemic with the pandemic period, the mean (SD) number of reviews rated as high quality (very good or excellent) per manuscript increased slightly from 1.3 (0.7) to 1.5 (0.7) (P < .001), and the mean (SD) time for reviewers to return reviews was modestly shorter (from 15.8 [7.6] days to 14.4 [7.0] days; P < .001), a difference that persisted in linear regression models accounting for manuscript type, study design, and whether the manuscript addressed COVID-19. Conclusions and Relevance: In this cohort study, the speed and editor-reported quality of peer reviews in an open-access general medical journal improved modestly during the initial year of the pandemic. Additional study will be necessary to understand how the pandemic has affected reviewer burden and fatigue.

Evaluation of a cluster-randomized controlled trial: Communities for Healthy Living, family-centered obesity prevention program for Head Start parents and children.

BACKGROUND: This study reports the outcomes of Communities for Healthy Living (CHL), a cluster randomized obesity prevention trial implemented in partnership with Head Start, a federally-funded preschool program for low-income families. METHODS: Using a stepped wedge design, Head Start programs (n = 16; Boston, MA, USA) were randomly assigned to one of three intervention start times. CHL involved a media campaign and enhanced nutrition support. Parents were invited to join Parents Connect for Healthy Living (PConnect), a 10-week wellness program. At the beginning and end of each school year (2017-2019), data were collected on the primary outcome of child Body Mass Index z-score (BMIz) and modified BMIz, and secondary outcomes of child weight-related behaviors (diet, physical activity, sleep, media use) and parents' weight-related parenting practices and empowerment. Data from 2 years, rather than three, were utilized to evaluate CHL due to the COVID-19 pandemic. We used mixed effects linear regression to compare relative differences during intervention vs. control periods (n = 1274 vs. 2476 children) in (1) mean change in child BMIz and modified BMIz, (2) the odds of meeting child health behavior recommendations, (3) mean change in parenting practices, and (4) mean change in parent empowerment. We also compared outcomes among parents who chose post-randomization to participate in PConnect vs. not (n = 55 vs. 443). RESULTS: During intervention periods (vs. control), children experienced greater increases in BMIz and modified BMIz (b = 0.06, 95% CI = 0.02,0.10; b = 0.07, 95% CI = 0.03, 0.12), yet were more likely to meet recommendations related to three of eight measured behaviors: sugar-sweetened beverage consumption (i.e., rarely consume; Odds Ratio (OR) = 1.5, 95% CI = 1.2,2.3), water consumption (i.e., multiple times per day; OR = 1.6, 95% CI = 1.2,2.3), and screen time (i.e., ≤1 hour/day; OR = 1.4, 95% CI = 1.0,1.8). No statistically significant differences for intervention (vs. control) periods were observed in parent empowerment or parenting practices. However, parents who enrolled in PConnect (vs. not) demonstrated greater increases in empowerment (b = 0.17, 95% CI = 0.04,0.31). CONCLUSIONS: Interventions that emphasize parent engagement may increase parental empowerment. Intervention exposure was associated with statistically, but not clinically, significant increases in BMIz and increased odds of meeting recommendations for three child behaviors; premature trial suspension may explain mixed results. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03334669 , Registered October 2017.

Duration of viral shedding and culture positivity with postvaccination SARS-CoV-2 delta variant infections.

Isolation guidelines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are largely derived from data collected prior to the emergence of the delta variant. We followed a cohort of ambulatory patients with postvaccination breakthrough SARS-CoV-2 infections with longitudinal collection of nasal swabs for SARS-CoV-2 viral load quantification, whole-genome sequencing, and viral culture. All delta variant infections in our cohort were symptomatic, compared with 64% of non-delta variant infections. Symptomatic delta variant breakthrough infections were characterized by higher initial viral load, longer duration of virologic shedding by PCR, greater likelihood of replication-competent virus at early stages of infection, and longer duration of culturable virus compared with non-delta variants. The duration of time since vaccination was also correlated with both duration of PCR positivity and duration of detection of replication-competent virus. Nonetheless, no individuals with symptomatic delta variant infections had replication-competent virus by day 10 after symptom onset or 24 hours after resolution of symptoms. These data support US CDC isolation guidelines as of November 2021, which recommend isolation for 10 days or until symptom resolution and reinforce the importance of prompt testing and isolation among symptomatic individuals with delta breakthrough infections. Additional data are needed to evaluate these relationships among asymptomatic and more severe delta variant breakthrough infections.

Genome-wide association analysis of COVID-19 mortality risk in SARS-CoV-2 genomes identifies mutation in the SARS-CoV-2 spike protein that colocalizes with P.1 of the Brazilian strain.

SARS-CoV-2 mortality has been extensively studied in relation to host susceptibility. How sequence variations in the SARS-CoV-2 genome affect pathogenicity is poorly understood. Starting in October 2020, using the methodology of genome-wide association studies (GWAS), we looked at the association between whole-genome sequencing (WGS) data of the virus and COVID-19 mortality as a potential method of early identification of highly pathogenic strains to target for containment. Although continuously updating our analysis, in December 2020, we analyzed 7548 single-stranded SARS-CoV-2 genomes of COVID-19 patients in the GISAID database and associated variants with mortality using a logistic regression. In total, evaluating 29,891 sequenced loci of the viral genome for association with patient/host mortality, two loci, at 12,053 and 25,088 bp, achieved genome-wide significance (p values of 4.09e-09 and 4.41e-23, respectively), though only 25,088 bp remained significant in follow-up analyses. Our association findings were exclusively driven by the samples that were submitted from Brazil (p value of 4.90e-13 for 25,088 bp). The mutation frequency of 25,088 bp in the Brazilian samples on GISAID has rapidly increased from about 0.4 in October/December 2020 to 0.77 in March 2021. Although GWAS methodology is suitable for samples in which mutation frequencies varies between geographical regions, it cannot account for mutation frequencies that change rapidly overtime, rendering a GWAS follow-up analysis of the GISAID samples that have been submitted after December 2020 as invalid. The locus at 25,088 bp is located in the P.1 strain, which later (April 2021) became one of the distinguishing loci (precisely, substitution V1176F) of the Brazilian strain as defined by the Centers for Disease Control. Specifically, the mutations at 25,088 bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Since the mutations alter amino acid coding sequences, they potentially imposing structural changes that could enhance viral infectivity and symptom severity. Our analysis suggests that GWAS methodology can provide suitable analysis tools for the real-time detection of new more transmissible and pathogenic viral strains in databases such as GISAID, though new approaches are needed to accommodate rapidly changing mutation frequencies over time, in the presence of simultaneously changing case/control ratios. Improvements of the associated metadata/patient information in terms of quality and availability will also be important to fully utilize the potential of GWAS methodology in this field.

Correction: Social distancing to slow the US COVID-19 epidemic: Longitudinal pretest-posttest comparison group study.

[This corrects the article DOI: 10.1371/journal.pmed.1003244.].

Social distancing to slow the US COVID-19 epidemic: Longitudinal pretest-posttest comparison group study.

BACKGROUND: Social distancing measures to address the US coronavirus disease 2019 (COVID-19) epidemic may have notable health and social impacts. METHODS AND FINDINGS: We conducted a longitudinal pretest-posttest comparison group study to estimate the change in COVID-19 case growth before versus after implementation of statewide social distancing measures in the US. The primary exposure was time before (14 days prior to, and through 3 days after) versus after (beginning 4 days after, to up to 21 days after) implementation of the first statewide social distancing measures. Statewide restrictions on internal movement were examined as a secondary exposure. The primary outcome was the COVID-19 case growth rate. The secondary outcome was the COVID-19-attributed mortality growth rate. All states initiated social distancing measures between March 10 and March 25, 2020. The mean daily COVID-19 case growth rate decreased beginning 4 days after implementation of the first statewide social distancing measures, by 0.9% per day (95% CI -1.4% to -0.4%; P < 0.001). We did not observe a statistically significant difference in the mean daily case growth rate before versus after implementation of statewide restrictions on internal movement (0.1% per day; 95% CI -0.04% to 0.3%; P = 0.14), but there is substantial difficulty in disentangling the unique associations with statewide restrictions on internal movement from the unique associations with the first social distancing measures. Beginning 7 days after social distancing, the COVID-19-attributed mortality growth rate decreased by 2.0% per day (95% CI -3.0% to -0.9%; P < 0.001). Our analysis is susceptible to potential bias resulting from the aggregate nature of the ecological data, potential confounding by contemporaneous changes (e.g., increases in testing), and potential underestimation of social distancing due to spillover effects from neighboring states. CONCLUSIONS: Statewide social distancing measures were associated with a decrease in the COVID-19 case growth rate that was statistically significant. Statewide social distancing measures were also associated with a decrease in the COVID-19-attributed mortality growth rate beginning 7 days after implementation, although this decrease was no longer statistically significant by 10 days.