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The dosing interval of a primary vaccination series can significantly impact on vaccine immunogenicity and efficacy. The current study compared 3 dosing intervals for the primary vaccination series of the BNT162b2 mRNA COVID-19 vaccine, on humoral immune response and durability against SARS-CoV-2 ancestral and Beta variants up to 9 months post immunization. Three groups of age- and sex-matched healthcare workers (HCW) who received 2 primary doses of BNT162b2 separated by 35-days, 35-42 days or >42-days were enrolled. Vaccine induced antibody titers at 3 weeks, 3 and 6-9 months post-second dose were assessed. There were 309 age- and sex-matched HCW (mean age 43 [sd 13], 58% females) enrolled. Anti-SARS-CoV-2 binding (IgG, IgM, IgA) and neutralizing antibody titers showed significant waning in levels beyond 35 days post first dose. The second dose induced a significant rise in antibody titers, which peaked at 3 weeks and then declined at variable rates across groups. The magnitude, consistency and durability of response was greater for anti-Spike than anti-RBD antibodies; and for IgG than IgA or IgM. Compared to the shorter schedules, a longer interval of >42 days offered the highest binding and neutralizing antibody titers against SARS-CoV-2 ancestral and Beta (B1.351) variants beyond 3 months post-vaccination. This is the first comprehensive study to compare 3 dosing intervals for the primary vaccination of BNT162b2 mRNA COVID-19 vaccine implemented in the real world. These findings suggest that delaying the second dose beyond 42 days can potentiate and prolong the humoral response against ancestral and Beta variants of SARS-CoV-2 up to 9 months post-vaccination.

Frequent SARS-CoV-2 vaccination in vulnerable populations has raised concerns that this may contribute to T cell exhaustion, which could negatively affect the quality of immune protection. Herein, we examined the impact of repeated SARS-CoV-2 vaccination on T cell phenotypic and functional exhaustion in frail older adults in long-term care ( n  = 23), individuals on immunosuppressive drugs ( n  = 10), and healthy adults ( n  = 43), in Canada. Spike-specific CD4 + and CD8 + T cell levels did not decline in any cohort following repeated SARS-CoV-2 vaccination, nor did the expression of exhaustion markers on spike-specific or total T cells increase. T cell production of multiple cytokines (i.e. polyfunctionality) in response to the spike protein of SARS-CoV-2 did not decline in any cohort following repeated vaccination. None of the cohorts displayed elevated levels of terminally differentiated T cells following multiple SARS-CoV-2 vaccinations. Thus, repeated SARS-CoV-2 vaccination was not associated with increased T cell exhaustion in older frail adults, immunosuppressed individuals, or healthy adults. Repeated vaccination is needed to maintain high levels of SARS-CoV-2 immunity in vulnerable populations, but there is concern that it could lead to immune exhaustion. Here, the authors assess the evidence for immune exhaustion following multiple SARS-CoV-2 vaccination three vulnerable population cohorts in Canada.

The dosing interval of a primary vaccination series can significantly impact on vaccine immunogenicity and efficacy. The current study compared 3 dosing intervals for the primary vaccination series of the BNT162b2 mRNA COVID-19 vaccine, on humoral immune response and durability against SARS-CoV-2 ancestral and Beta variants up to 9 months post immunization. Three groups of age- and sex-matched healthcare workers (HCW) who received 2 primary doses of BNT162b2 separated by 35-days, 35-42 days or >42-days were enrolled. Vaccine induced antibody titers at 3 weeks, 3 and 6-9 months post-second dose were assessed. There were 309 age- and sex-matched HCW (mean age 43 [sd 13], 58% females) enrolled. Anti-SARS-CoV-2 binding (IgG, IgM, IgA) and neutralizing antibody titers showed significant waning in levels beyond 35 days post first dose. The second dose induced a significant rise in antibody titers, which peaked at 3 weeks and then declined at variable rates across groups. The magnitude, consistency and durability of response was greater for anti-Spike than anti-RBD antibodies; and for IgG than IgA or IgM. Compared to the shorter schedules, a longer interval of >42 days offered the highest binding and neutralizing antibody titers against SARS-CoV-2 ancestral and Beta (B1.351) variants beyond 3 months post-vaccination. This is the first comprehensive study to compare 3 dosing intervals for the primary vaccination of BNT162b2 mRNA COVID-19 vaccine implemented in the real world. These findings suggest that delaying the second dose beyond 42 days can potentiate and prolong the humoral response against ancestral and Beta variants of SARS-CoV-2 up to 9 months post-vaccination.

This study aimed to identify the interaction of depression and diets on cardiovascular diseases (CVD) incident and death in China and key subpopulations. We included 40,925 participants from the Prospective Urban Rural Epidemiology (PURE)-China cohort which recruited participants aged 35–70 years from 45 urban and 70 rural communities. Depression was measured by the adapted Short-Form (CIDI-SF). The unhealthy diet was considered when the score of Alternative Healthy Eating Index was below the lowest tertile. The primary outcome was a composite outcome of incident CVD and all-cause mortality. Cox frailty models were used to examine the associations. During a median follow-up of 11.9 years (IQR: 9.6–12.6 years), depression significantly increased the risk of the composite outcome (HR = 2.00; 95% CI, 1.16–3.27), major CVD (HR = 1.82; 95% CI, 1.48–2.23), and all-cause mortality (HR = 2.21; 95% CI, 1.51–3.24) for the unhealthy diet group, but not for the healthy diet group. The interaction between depression and diet for the composite outcome was statistically significant (RERI = 1.19; 95% CI, 0.66–1.72; AP = 0.42, 95% CI, 0.27–0.61; SI = 3.30, 95% CI, 1.42–7.66; multiplicative-scale = 1.74 95% CI, 1.27–2.39), even in the subgroup and sensitivity analyses. In addition, the intake of vegetable and polyunsaturated fatty acids contributed most to the interaction of diets and depression. Depressive participants should focus on healthy diets, especially vegetables and polyunsaturated fatty acids, to avoid premature death and CVD.

Importance Cardiometabolic parameters are established risk factors for COVID-19 severity. The identification of causal or protective biomarkers for COVID-19 severity may facilitate the development of novel therapies. Objective To identify protein biomarkers that promote or reduce COVID-19 severity and that mediate the association of cardiometabolic risk factors with COVID-19 severity. Design, Setting, and Participants This genetic association study using 2-sample mendelian randomization (MR) was conducted in 2022 to investigate associations among cardiometabolic risk factors, circulating biomarkers, and COVID-19 hospitalization. Inputs for MR included genetic and proteomic data from 4147 participants with dysglycemia and cardiovascular risk factors collected through the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial. Genome-wide association study summary statistics were obtained from (1) 3 additional independent plasma proteome studies, (2) genetic consortia for selected cardiometabolic risk factors (including body mass index [BMI], type 2 diabetes, type 1 diabetes, and systolic blood pressure; all n >10 000), and (3) the COVID-19 Host Genetics Initiative (n = 5773 hospitalized and 15 497 nonhospitalized case participants with COVID-19). Data analysis was performed in July 2022. Exposures Genetically determined concentrations of 235 circulating proteins assayed with a multiplex biomarker panel from the ORIGIN trial for the initial analysis. Main Outcomes and Measures Hospitalization status of individuals from the COVID-19 Host Genetics Initiative with a positive COVID-19 test result. Results Among 235 biomarkers tested in samples totaling 22 101 individuals, MR analysis showed that higher kidney injury molecule-1 (KIM-1) levels reduced the likelihood of COVID-19 hospitalization (odds ratio [OR] per SD increase in KIM-1 levels, 0.86 [95% CI, 0.79-0.93]). A meta-analysis validated the protective association with no observed directional pleiotropy (OR per SD increase in KIM-1 levels, 0.91 [95% CI, 0.88-0.95]). Of the cardiometabolic risk factors studied, only BMI was associated with KIM-1 levels (0.17 SD increase in biomarker level per 1 kg/m2[95% CI, 0.08-0.26]) and COVID-19 hospitalization (OR per 1-SD biomarker level, 1.33 [95% CI, 1.18-1.50]). Multivariable MR analysis also revealed that KIM-1 partially mitigated the association of BMI with COVID-19 hospitalization, reducing it by 10 percentage points (OR adjusted for KIM-1 level per 1 kg/m2, 1.23 [95% CI, 1.06-1.43]). Conclusions and Relevance In this genetic association study, KIM-1 was identified as a potential mitigator of COVID-19 severity, possibly attenuating the increased risk of COVID-19 hospitalization among individuals with high BMI. Further studies are required to better understand the underlying biological mechanisms.

Introduction. Switching from polluting (e.g. wood, crop waste, coal) to clean (e.g. gas, electricity) cooking fuels can reduce household air pollution exposures and climate-forcing emissions. While studies have evaluated specific interventions and assessed fuel-switching in repeated cross-sectional surveys, the role of different multilevel factors in household fuel switching, outside of interventions and across diverse community settings, is not well understood. Methods. We examined longitudinal survey data from 24 172 households in 177 rural communities across nine countries within the Prospective Urban and Rural Epidemiology study. We assessed household-level primary cooking fuel switching during a median of 10 years of follow up (∼2005-2015). We used hierarchical logistic regression models to examine the relative importance of household, community, sub-national and national-level factors contributing to primary fuel switching. Results. One-half of study households (12 369) reported changing their primary cooking fuels between baseline and follow up surveys. Of these, 61% (7582) switched from polluting (wood, dung, agricultural waste, charcoal, coal, kerosene) to clean (gas, electricity) fuels, 26% (3109) switched between different polluting fuels, 10% (1164) switched from clean to polluting fuels and 3% (522) switched between different clean fuels. Among the 17 830 households using polluting cooking fuels at baseline, household-level factors (e.g. larger household size, higher wealth, higher education level) were most strongly associated with switching from polluting to clean fuels in India; in all other countries, community-level factors (e.g. larger population density in 2010, larger increase in population density between 2005 and 2015) were the strongest predictors of polluting-to-clean fuel switching. Conclusions. The importance of community and sub-national factors relative to household characteristics in determining polluting-to-clean fuel switching varied dramatically across the nine countries examined. This highlights the potential importance of national and other contextual factors in shaping large-scale clean cooking transitions among rural communities in low- and middle-income countries.

Objectives The dosing interval of a primary vaccination series can significantly impact on vaccine immunogenicity and efficacy. The current study compared 3 dosing intervals for the primary vaccination series of the BNT162b2 mRNA COVID-19 vaccine, on humoral immune response and durability against SARS-CoV-2 ancestral and Beta variants up to 9 months post immunization. Methods Three groups of age- and sex-matched healthcare workers (HCW) who received 2 primary doses of BNT162b2 separated by 35-days, 35–42 days or >42-days were enrolled. Vaccine induced antibody titers at 3 weeks, 3 and 6–9 months post-second dose were assessed. Results There were 309 age- and sex-matched HCW (mean age 43 [sd 13], 58% females) enrolled. Anti-SARS-CoV-2 binding (IgG, IgM, IgA) and neutralizing antibody titers showed significant waning in levels beyond 35 days post first dose. The second dose induced a significant rise in antibody titers, which peaked at 3 weeks and then declined at variable rates across groups. The magnitude, consistency and durability of response was greater for anti-Spike than anti-RBD antibodies; and for IgG than IgA or IgM. Compared to the shorter schedules, a longer interval of >42 days offered the highest binding and neutralizing antibody titers against SARS-CoV-2 ancestral and Beta (B1.351) variants beyond 3 months post-vaccination. Conclusions This is the first comprehensive study to compare 3 dosing intervals for the primary vaccination of BNT162b2 mRNA COVID-19 vaccine implemented in the real world. These findings suggest that delaying the second dose beyond 42 days can potentiate and prolong the humoral response against ancestral and Beta variants of SARS-CoV-2 up to 9 months post-vaccination.

Objective Duchenne muscular dystrophy (DMD) is a rare X-linked neurodegenerative disorder caused by mutations in the DMD gene. This study examined the efficacy and safety of ataluren, the first oral treatment for DMD with nonsense mutations (nmDMD), in patients in the Middle East. Methods This retrospective longitudinal study assessed the outcomes of seven boys with nmDMD who received treatment with ataluren and follow-up at a single center since 2016. Results The median patient age at treatment initiation was 8.04 years (range: 3.3–9.92), and the median duration of exposure was 3.95 years (interquartile range = 4.42 years). Five patients were still ambulatory at the last follow-up. Ataluren was more effective in individuals with baseline 6-min walking distance (6MWD) ≥300 m, as these patients had smaller declines in 6MWD and North Star Ambulatory Assessment scores. Pulmonary function was well preserved in all patients, with no patients having forced vital capacity <60% at their last follow-up. Six patients maintained normal cardiac function, whereas one patient developed heart failure before starting ataluren treatment. Conclusions Our results demonstrated both the efficacy and safety of ataluren. Early initiation of ataluren treatment delayed the loss of ambulation and cardiorespiratory milestones.