Journal: PLoS Med

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<div><h4>Outcome of COVID-19 in hospitalised immunocompromised patients: An analysis of the WHO ISARIC CCP-UK prospective cohort study.</h4><i>Turtle L, Thorpe M, Drake TM, Swets M, ... Semple MG, Docherty AB</i><br /><b>Background</b><br />Immunocompromised patients may be at higher risk of mortality if hospitalised with Coronavirus Disease 2019 (COVID-19) compared with immunocompetent patients. However, previous studies have been contradictory. We aimed to determine whether immunocompromised patients were at greater risk of in-hospital death and how this risk changed over the pandemic.<br /><b>Methods and findings</b><br />We included patients > = 19 years with symptomatic community-acquired COVID-19 recruited to the ISARIC WHO Clinical Characterisation Protocol UK prospective cohort study. We defined immunocompromise as immunosuppressant medication preadmission, cancer treatment, organ transplant, HIV, or congenital immunodeficiency. We used logistic regression to compare the risk of death in both groups, adjusting for age, sex, deprivation, ethnicity, vaccination, and comorbidities. We used Bayesian logistic regression to explore mortality over time. Between 17 January 2020 and 28 February 2022, we recruited 156,552 eligible patients, of whom 21,954 (14%) were immunocompromised. Approximately 29% (n = 6,499) of immunocompromised and 21% (n = 28,608) of immunocompetent patients died in hospital. The odds of in-hospital mortality were elevated for immunocompromised patients (adjusted OR 1.44, 95% CI [1.39, 1.50], p < 0.001). Not all immunocompromising conditions had the same risk, for example, patients on active cancer treatment were less likely to have their care escalated to intensive care (adjusted OR 0.77, 95% CI [0.7, 0.85], p < 0.001) or ventilation (adjusted OR 0.65, 95% CI [0.56, 0.76], p < 0.001). However, cancer patients were more likely to die (adjusted OR 2.0, 95% CI [1.87, 2.15], p < 0.001). Analyses were adjusted for age, sex, socioeconomic deprivation, comorbidities, and vaccination status. As the pandemic progressed, in-hospital mortality reduced more slowly for immunocompromised patients than for immunocompetent patients. This was particularly evident with increasing age: the probability of the reduction in hospital mortality being less for immunocompromised patients aged 50 to 69 years was 88% for men and 83% for women, and for those >80 years was 99% for men and 98% for women. The study is limited by a lack of detailed drug data prior to admission, including steroid doses, meaning that we may have incorrectly categorised some immunocompromised patients as immunocompetent.<br /><b>Conclusions</b><br />Immunocompromised patients remain at elevated risk of death from COVID-19. Targeted measures such as additional vaccine doses, monoclonal antibodies, and nonpharmaceutical preventive interventions should be continually encouraged for this patient group.<br /><b>Trial registration</b><br />ISRCTN 66726260.<br /><br />Copyright: © 2023 Turtle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 31 Jan 2023; 20:e1004086</small></div>
Turtle L, Thorpe M, Drake TM, Swets M, ... Semple MG, Docherty AB
PLoS Med: 31 Jan 2023; 20:e1004086 | PMID: 36719907
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<div><h4>Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A mendelian randomisation study.</h4><i>Hamilton FW, Thomas M, Arnold D, Palmer T, ... Ghazal P, Timpson NJ</i><br /><b>Background</b><br />Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis.<br /><b>Methods and findings</b><br />We performed a mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade.<br /><b>Conclusions</b><br />IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.<br /><br />Copyright: © 2023 Hamilton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 30 Jan 2023; 20:e1004174</small></div>
Hamilton FW, Thomas M, Arnold D, Palmer T, ... Ghazal P, Timpson NJ
PLoS Med: 30 Jan 2023; 20:e1004174 | PMID: 36716318
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<div><h4>Age-specific population attributable risk factors for all-cause and cause-specific mortality in type 2 diabetes: An analysis of a 6-year prospective cohort study of over 360,000 people in Hong Kong.</h4><i>Wu H, Lau ESH, Yang A, Zhang X, ... Chan JCN, Luk AOY</i><br /><b>Background</b><br />The prevalence of type 2 diabetes has increased in both young and old people. We examined age-specific associations and population attributable fractions (PAFs) of risk factors for all-cause and cause-specific mortality in people with type 2 diabetes.<br /><b>Methods and findings</b><br />We analysed data from 360,202 Chinese with type 2 diabetes who participated in a territory-wide diabetes complication screening programme in Hong Kong between January 2000 and December 2019. We compared the hazard ratios and PAFs of eight risk factors, including three major comorbidities (cardiovascular disease [CVD], chronic kidney disease [CKD], all-site cancer) and five modifiable risk factors (suboptimal HbA1c, suboptimal blood pressure, suboptimal low-density lipoprotein cholesterol, smoking, and suboptimal weight), for mortality across four age groups (18 to 54, 55 to 64, 65 to 74, and ≥75 years). During a median 6.0 years of follow-up, 44,396 people died, with cancer, CVD, and pneumonia being the leading causes of death. Despite a higher absolute mortality risk in older people (crude all-cause mortality rate: 59.7 versus 596.2 per 10,000 person-years in people aged 18 to 54 years versus those aged ≥75 years), the relative risk of all-cause and cause-specific mortality associated with most risk factors was higher in younger than older people, after mutually adjusting for the eight risk factors and other potential confounders including sex, diabetes duration, lipid profile, and medication use. The eight risk factors explained a larger proportion of mortality events in the youngest (PAF: 51.6%, 95% confidence interval [CI] [39.1%, 64.0%], p < 0.001) than the oldest (PAF: 35.3%, 95% CI [27.2%, 43.4%], p < 0.001) age group. Suboptimal blood pressure (PAF: 16.9%, 95% CI [14.7%, 19.1%], p < 0.001) was the leading attributable risk factor for all-cause mortality in the youngest age group, while CKD (PAF: 15.2%, 95% CI [14.0%, 16.4%], p < 0.001) and CVD (PAF: 9.2%, 95% CI [8.3%, 10.1%], p < 0.001) were the leading attributable risk factors in the oldest age group. The analysis was restricted to Chinese, which might affect the generalisability to the global population with differences in risk profiles. Furthermore, PAFs were estimated under the assumption of a causal relationship between risk factors and mortality. However, reliable causality was difficult to establish in the observational study.<br /><b>Conclusions</b><br />Major comorbidities and modifiable risk factors were associated with a greater relative risk for mortality in younger than older people with type 2 diabetes and their associations with population mortality burden varied substantially by age. These findings highlight the importance of early control of blood pressure, which could reduce premature mortality in young people with type 2 diabetes and prevent the onset of later CKD and related mortality at older ages.<br /><br />Copyright: © 2023 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 30 Jan 2023; 20:e1004173</small></div>
Abstract
<div><h4>Risk of fracture in adults with type 2 diabetes in Sweden: A national cohort study.</h4><i>Axelsson KF, Litsne H, Kousoula K, Franzén S, Eliasson B, Lorentzon M</i><br /><b>Background</b><br />Type 2 diabetes mellitus (T2DM) is considered a risk factor for fracture but the evidence regarding the impact of T2DM on fracture risk is conflicting. The objective of the study was to determine if patients with T2DM have increased fracture risk and if T2DM-related risk factors could be identified.<br /><b>Methods and findings</b><br />In this national cohort study in Sweden, we investigated the risk of fracture in 580,127 T2DM patients, identified through the national diabetes register including from both primary care and hospitals, and an equal number of population-based controls without diabetes matched for age, sex, and county from 2007 to 2017. The mean age at entry was 66.7 years and 43.6% were women. During a median follow-up time of 6.6 (interquartile range (IQR) 3.1 to 9.8) years, patients with T2DM had a marginally but significantly increased risk of major osteoporotic fracture (MOF) (hazard ratio (HR) 1.01 (95% confidence interval [CI] 1.00 to 1.03)) and hip fracture (HR 1.06 (95% CI 1.04 to 1.08)) compared to controls, associations that were only minimally affected (HR 1.05 (95% CI 1.03 to 1.06) and HR 1.11 (95% CI 1.09 to 1.14), respectively) by multivariable adjustment (age, sex, marital status, and an additional 20 variables related to general morbidity, cardiovascular status, risk of falls, and fracture). In a multivariable-adjusted Cox model, the proportion of the risk for all fracture outcomes (Heller\'s R2) explained by T2DM was below 0.1%. Among the T2DM patients, important risk factors for fracture were a low BMI (<25 kg/m2), long diabetes duration (≥15 years), insulin treatment, and low physical activity. In total, 55% of the T2DM patients had none of these risk factors and a significantly lower fracture risk than their respective controls. The relatively short mean duration of T2DM and lack of bone density data, constitute limitations of the analysis.<br /><b>Conclusion</b><br />In this study, we observed only a marginally increased fracture risk in T2DM, a condition that explained less than 0.1% of the fracture risk. Consideration of the herein identified T2DM-related risk factors could be used to stratify T2DM patients according to fracture risk.<br /><br />Copyright: © 2023 Axelsson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 26 Jan 2023; 20:e1004172</small></div>
Axelsson KF, Litsne H, Kousoula K, Franzén S, Eliasson B, Lorentzon M
PLoS Med: 26 Jan 2023; 20:e1004172 | PMID: 36701363
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<div><h4>Mpox virus and transmission through sexual contact: Defining the research agenda.</h4><i>Low N, Bachmann LH, Ogoina D, McDonald R, ... Quilter LAS, Cevik M</i><br /><AbstractText>In a Policy Forum piece, Dr. Nicola Low and colleagues define the research agenda for Mpox virus and transmission through sexual contact.</AbstractText><br /><br />Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.<br /><br /><small>PLoS Med: 17 Jan 2023; 20:e1004163</small></div>
Low N, Bachmann LH, Ogoina D, McDonald R, ... Quilter LAS, Cevik M
PLoS Med: 17 Jan 2023; 20:e1004163 | PMID: 36649325
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<div><h4>Essential childhood immunization in 43 low- and middle-income countries: Analysis of spatial trends and socioeconomic inequalities in vaccine coverage.</h4><i>Dimitrova A, Carrasco-Escobar G, Richardson R, Benmarhnia T</i><br /><b>Background</b><br />Globally, access to life-saving vaccines has improved considerably in the past 5 decades. However, progress has started to slow down and even reverse in recent years. Understanding subnational heterogeneities in essential child immunization will be critical for closing the global vaccination gap.<br /><b>Methods and findings</b><br />We use vaccination information for over 220,000 children across 1,366 administrative regions in 43 low- and middle-income countries (LMICs) from the most recent Demographic and Health Surveys. We estimate essential immunization coverage at the national and subnational levels and quantify socioeconomic inequalities in such coverage using adjusted concentration indices. Within- and between-country variations are summarized via the Theil index. We use local indicator of spatial association (LISA) statistics to identify clusters of administrative regions with high or low values. Finally, we estimate the number of missed vaccinations among children aged 15 to 35 months across all 43 countries and the types of vaccines most often missed. We show that national-level vaccination rates can conceal wide subnational heterogeneities. Large gaps in child immunization are found across West and Central Africa and in South Asia, particularly in regions of Angola, Chad, Nigeria, Guinea, and Afghanistan, where less than 10% of children are fully immunized. Furthermore, children living in these countries consistently lack all 4 basic vaccines included in the WHO\'s recommended schedule for young children. Across most countries, children from poorer households are less likely to be fully immunized. The main limitations include subnational estimates based on large administrative divisions for some countries and different periods of survey data collection.<br /><b>Conclusions</b><br />The identified heterogeneities in essential childhood immunization, especially given that some regions consistently are underserved for all basic vaccines, can be used to inform the design and implementation of localized intervention programs aimed at eliminating child suffering and deaths from existing and novel vaccine-preventable diseases.<br /><br />Copyright: © 2023 Dimitrova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 17 Jan 2023; 20:e1004166</small></div>
Dimitrova A, Carrasco-Escobar G, Richardson R, Benmarhnia T
PLoS Med: 17 Jan 2023; 20:e1004166 | PMID: 36649359
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<div><h4>The association between perinatal factors and cardiometabolic risk factors in children and adolescents with overweight or obesity: A retrospective two-cohort study.</h4><i>Prinz N, Putri RR, Reinehr T, Danielsson P, ... Holl RW, Hagman E</i><br /><b>Background</b><br />Children with obesity have an increased risk of cardiometabolic risk factors, but not all children carry a similar risk. Perinatal factors, i.e., gestational age (GA) and birth weight for GA, may affect the risk for metabolic complications. However, there are conflicting data whether the association between birth size and cardiometabolic risk factors is independent among children with obesity. Moreover, differential effects of GA and birth weight for GA on cardiometabolic risk factors in pediatric obesity are still unexplored. We aimed to investigate the association between birth weight for GA and cardiometabolic risk factors in children and adolescents with overweight or obesity and to assess whether the association is modified by prematurity.<br /><b>Methods and findings</b><br />We conducted a retrospective study of 2 cohorts, using data from the world\'s 2 largest registers of pediatric obesity treatment-The Swedish childhood obesity treatment register (BORIS) and The Adiposity Patients Registry (APV) (1991 to 2020). Included were individuals with overweight or obesity between 2 to 18 years of age who had data of birth characteristics and cardiometabolic parameters. Birth data was collected as exposure variable and the first reported cardiometabolic parameters during pediatric obesity treatment as the main outcome. The median (Q1, Q3) age at the outcome measurement was 11.8 (9.4, 14.0) years. The main outcomes were hypertensive blood pressure (BP), impaired fasting glucose, elevated glycated hemoglobin (HbA1c), elevated total cholesterol, elevated low-density lipoprotein (LDL) cholesterol, elevated triglycerides, decreased high-density lipoprotein (HDL) cholesterol, and elevated transaminases. With logistic regression, we calculated the odds ratio (OR) and its 95% confidence interval (CI) for each cardiometabolic parameter. All the analyses were adjusted for sex, age, degree of obesity, migratory background, and register source. In total, 42,760 (51.9% females) individuals were included. Small for GA (SGA) was prevalent in 10.4%, appropriate for GA (AGA) in 72.4%, and large for GA (LGA) in 17.2%. Most individuals (92.5%) were born full-term, 7.5% were born preterm. Median (Q1, Q3) body mass index standard deviation score at follow-up was 2.74 (2.40, 3.11) units. Compared with AGA, children born SGA were more likely to have hypertensive BP (OR = 1.20 [95% CI 1.12 to 1.29], p < 0.001), elevated HbA1c (1.33 [1.06 to 1.66], p = 0.03), and elevated transaminases (1.21 [1.10 to 1.33], p < 0.001) as well as low HDL (1.19 [1.09 to 1.31], p < 0.001). On the contrary, individuals born LGA had lower odds for hypertensive BP (0.88 [0.83 to 0.94], p < 0.001), elevated HbA1c (0.81 [0.67 to 0.97], p < 0.001), and elevated transaminases (0.88 [0.81 to 0.94], p < 0.001). Preterm birth altered some of the associations between SGA and outcomes, e.g., by increasing the odds for hypertensive BP and by diminishing the odds for elevated transaminases. Potential selection bias due to occasionally missing data could not be excluded.<br /><b>Conclusions</b><br />Among children and adolescents with overweight/obesity, individuals born SGA are more likely to possess cardiometabolic risk factors compared to their counterparts born AGA. Targeted screening and treatment of obesity-related comorbidities should therefore be considered in this high-risk group of individuals.<br /><br />Copyright: © 2023 Prinz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 13 Jan 2023; 20:e1004165</small></div>
Prinz N, Putri RR, Reinehr T, Danielsson P, ... Holl RW, Hagman E
PLoS Med: 13 Jan 2023; 20:e1004165 | PMID: 36638094
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<div><h4>Regional and country-level trends in cervical cancer screening coverage in sub-Saharan Africa: A systematic analysis of population-based surveys (2000-2020).</h4><i>Yang L, Boily MC, Rönn MM, Obiri-Yeboah D, ... Delany-Moretlwe S, Maheu-Giroux M</i><br /><b>Background</b><br />Sub-Saharan Africa (SSA) has the highest cervical cancer (CC) burden globally-worsened by its HIV epidemics. In 2020, the World Health Organization (WHO) introduced a CC elimination strategy with goals for vaccination, screening, and treatment. To benchmark progress, we examined temporal trends in screening coverage, percent screened at least twice by the age of 45, screening coverage among women living with HIV (WLHIV), and pre-cancer treatment coverage in SSA.<br /><b>Methods and findings</b><br />We conducted a systematic analysis of cross-sectional population-based surveys. It included 52 surveys from 28 countries (2000 to 2020) with information on CC screening among women aged 25 to 49 years (N = 151,338 women). We estimated lifetime and past 3-year screening coverage by age, year, country, and HIV serostatus using a Bayesian multilevel model. Post-stratification and imputations were done to obtain aggregate national, regional, and SSA-level estimates. To measure re-screening by age 45, a life table model was developed. Finally, self-reported pre-cancer treatment coverage was pooled across surveys using a Bayesian meta-analysis. Overall, an estimated 14% (95% credible intervals [95% CrI]: 11% to 21%) of women aged 30 to 49 years had ever been screened for CC in 2020, with important regional and country-level differences. In Eastern and Western/Central Africa, regional screening coverages remained constant from 2000 to 2020 and WLHIV had greater odds of being screened compared to women without HIV. In Southern Africa, however, screening coverages increased and WLHIV had equal odds of screening. Notably this region was found to have higher screening coverage in comparison to other African regions. Rescreening rates were high among women who have already been screened; however, it was estimated that only 12% (95% CrI: 10% to 18%) of women had been screened twice or more by age 45 in 2020. Finally, treatment coverage among 4 countries with data was 84% (95% CrI: 70% to 95%). Limitations of our analyses include the paucity of data on screening modality and the few countries that had multiple surveys.<br /><b>Conclusion</b><br />Overall, CC screening coverage remains sub-optimal and did not improve much over the last 2 decades, outside of Southern Africa. Action is needed to increase screening coverage if CC elimination is to be achieved.<br /><br />Copyright: © 2023 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 12 Jan 2023; 20:e1004143</small></div>
Yang L, Boily MC, Rönn MM, Obiri-Yeboah D, ... Delany-Moretlwe S, Maheu-Giroux M
PLoS Med: 12 Jan 2023; 20:e1004143 | PMID: 36634119
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<div><h4>Effectiveness of mRNA boosters after homologous primary series with BNT162b2 or ChAdOx1 against symptomatic infection and severe COVID-19 in Brazil and Scotland: A test-negative design case-control study.</h4><i>Cerqueira-Silva T, Shah SA, Robertson C, Sanchez M, ... Sheikh A, Barral-Netto M</i><br /><b>Background</b><br />Brazil and Scotland have used mRNA boosters in their respective populations since September 2021, with Omicron\'s emergence accelerating their booster program. Despite this, both countries have reported substantial recent increases in Coronavirus Disease 2019 (COVID-19) cases. The duration of the protection conferred by the booster dose against symptomatic Omicron cases and severe outcomes is unclear.<br /><b>Methods and findings</b><br />Using a test-negative design, we analyzed national databases to estimate the vaccine effectiveness (VE) of a primary series (with ChAdOx1 or BNT162b2) plus an mRNA vaccine booster (with BNT162b2 or mRNA-1273) against symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and severe COVID-19 outcomes (hospitalization or death) during the period of Omicron dominance in Brazil and Scotland compared to unvaccinated individuals. Additional analyses included stratification by age group (18 to 49, 50 to 64, ≥65). All individuals aged 18 years or older who reported acute respiratory illness symptoms and tested for SARS-CoV-2 infection between January 1, 2022, and April 23, 2022, in Brazil and Scotland were eligible for the study. At 14 to 29 days after the mRNA booster, the VE against symptomatic SARS-CoV-2 infection of ChAdOx1 plus BNT162b2 booster was 51.6%, (95% confidence interval (CI): [51.0, 52.2], p < 0.001) in Brazil and 67.1% (95% CI [65.5, 68.5], p < 0.001) in Scotland. At ≥4 months, protection against symptomatic infection waned to 4.2% (95% CI [0.7, 7.6], p = 0.02) in Brazil and 37.4% (95% CI [33.8, 40.9], p < 0.001) in Scotland. VE against severe outcomes in Brazil was 93.5% (95% CI [93.0, 94.0], p < 0.001) at 14 to 29 days post-booster, decreasing to 82.3% (95% CI [79.7, 84.7], p < 0.001) and 98.3% (95% CI [87.3, 99.8], p < 0.001) to 77.8% (95% CI [51.4, 89.9], p < 0.001) in Scotland for the same periods. Similar results were obtained with the primary series of BNT162b2 plus homologous booster. Potential limitations of this study were that we assumed that all cases included in the analysis were due to the Omicron variant based on the period of dominance and the limited follow-up time since the booster dose.<br /><b>Conclusions</b><br />We observed that mRNA boosters after a primary vaccination course with either mRNA or viral-vector vaccines provided modest, short-lived protection against symptomatic infection with Omicron but substantial and more sustained protection against severe COVID-19 outcomes for at least 3 months.<br /><br />Copyright: © 2023 Cerqueira-Silva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 11 Jan 2023; 20:e1004156</small></div>
Cerqueira-Silva T, Shah SA, Robertson C, Sanchez M, ... Sheikh A, Barral-Netto M
PLoS Med: 11 Jan 2023; 20:e1004156 | PMID: 36630477
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<div><h4>Booster vaccination protection against SARS-CoV-2 infections in young adults during an Omicron BA.1-predominant period: A retrospective cohort study.</h4><i>Wan J, Cazer CL, Clarkberg ME, Henderson SG, ... Shmoys DB, Frazier PI</i><br /><b>Background</b><br />While booster vaccinations clearly reduce the risk of severe Coronavirus Disease 2019 (COVID-19) and death, the impact of boosters on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections has not been fully characterized: Doing so requires understanding their impact on asymptomatic and mildly symptomatic infections that often go unreported but nevertheless play an important role in spreading SARS-CoV-2. We sought to estimate the impact of COVID-19 booster doses on SARS-CoV-2 infections in a vaccinated population of young adults during an Omicron BA.1-predominant period.<br /><b>Methods and findings</b><br />We implemented a cohort study of young adults in a college environment (Cornell University\'s Ithaca campus) from a period when Omicron BA.1 was the predominant SARS-CoV-2 variant on campus (December 5 to December 31, 2021). Participants included 15,800 university students who completed initial vaccination series with vaccines approved by the World Health Organization for emergency use, were enrolled in mandatory at-least-weekly surveillance polymerase chain reaction (PCR) testing, and had no positive SARS-CoV-2 PCR test within 90 days before the start of the study period. Robust multivariable Poisson regression with the main outcome of a positive SARS-CoV-2 PCR test was performed to compare those who completed their initial vaccination series and a booster dose to those without a booster dose. A total of 1,926 unique SARS-CoV-2 infections were identified in the study population. Controlling for sex, student group membership, date of completion of initial vaccination series, initial vaccine type, and temporal effect during the study period, our analysis estimates that receiving a booster dose further reduces the rate of having a PCR-detected SARS-CoV-2 infection relative to an initial vaccination series by 56% (95% confidence interval [42%, 67%], P < 0.001). While most individuals had recent booster administration before or during the study period (a limitation of our study), this result is robust to the assumed delay over which a booster dose becomes effective (varied from 1 day to 14 days). The mandatory active surveillance approach used in this study, under which 86% of the person-days in the study occurred, reduces the likelihood of outcome misclassification. Key limitations of our methodology are that we did not have an a priori protocol or statistical analysis plan because the analysis was initially done for institutional research purposes, and some analysis choices were made after observing the data.<br /><b>Conclusions</b><br />We observed that boosters are effective, relative to completion of initial vaccination series, in further reducing the rate of SARS-CoV-2 infections in a college student population during a period when Omicron BA.1 was predominant; booster vaccinations for this age group may play an important role in reducing incidence of COVID-19.<br /><br />Copyright: © 2023 Wan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 10 Jan 2023; 20:e1004153</small></div>
Wan J, Cazer CL, Clarkberg ME, Henderson SG, ... Shmoys DB, Frazier PI
PLoS Med: 10 Jan 2023; 20:e1004153 | PMID: 36626376
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<div><h4>Improving cascade outcomes for active TB: A global systematic review and meta-analysis of TB interventions.</h4><i>Marley G, Zou X, Nie J, Cheng W, ... Ong J, Tang W</i><br /><b>Background</b><br />To inform policy and implementation that can enhance prevention and improve tuberculosis (TB) care cascade outcomes, this review aimed to summarize the impact of various interventions on care cascade outcomes for active TB.<br /><b>Methods and findings</b><br />In this systematic review and meta-analysis, we retrieved English articles with comparator arms (like randomized controlled trials (RCTs) and before and after intervention studies) that evaluated TB interventions published from January 1970 to September 30, 2022, from Embase, CINAHL, PubMed, and the Cochrane library. Commentaries, qualitative studies, conference abstracts, studies without standard of care comparator arms, and studies that did not report quantitative results for TB care cascade outcomes were excluded. Data from studies with similar comparator arms were pooled in a random effects model, and outcomes were reported as odds ratio (OR) with 95% confidence interval (CI) and number of studies (k). The quality of evidence was appraised using GRADE, and the study was registered on PROSPERO (CRD42018103331). Of 21,548 deduplicated studies, 144 eligible studies were included. Of 144 studies, 128 were from low/middle-income countries, 84 were RCTs, and 25 integrated TB and HIV care. Counselling and education was significantly associated with testing (OR = 8.82, 95% CI:1.71 to 45.43; I2 = 99.9%, k = 7), diagnosis (OR = 1.44, 95% CI:1.08 to 1.92; I2 = 97.6%, k = 9), linkage to care (OR = 3.10, 95% CI = 1.97 to 4.86; I2 = 0%, k = 1), cure (OR = 2.08, 95% CI:1.11 to 3.88; I2 = 76.7%, k = 4), treatment completion (OR = 1.48, 95% CI: 1.07 to 2.03; I2 = 73.1%, k = 8), and treatment success (OR = 3.24, 95% CI: 1.88 to 5.55; I2 = 75.9%, k = 5) outcomes compared to standard-of-care. Incentives, multisector collaborations, and community-based interventions were associated with at least three TB care cascade outcomes; digital interventions and mixed interventions were associated with an increased likelihood of two cascade outcomes each. These findings remained salient when studies were limited to RCTs only. Also, our study does not cover the entire care cascade as we did not measure gaps in pre-testing, pretreatment, and post-treatment outcomes (like loss to follow-up and TB recurrence).<br /><b>Conclusions</b><br />Among TB interventions, education and counseling, incentives, community-based interventions, and mixed interventions were associated with multiple active TB care cascade outcomes. However, cost-effectiveness and local-setting contexts should be considered when choosing such strategies due to their high heterogeneity.<br /><br />Copyright: © 2023 Marley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 03 Jan 2023; 20:e1004091</small></div>
Marley G, Zou X, Nie J, Cheng W, ... Ong J, Tang W
PLoS Med: 03 Jan 2023; 20:e1004091 | PMID: 36595536
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<div><h4>Metacognitive therapy home-based self-help for anxiety and depression in cardiovascular disease patients in the UK: A single-blind randomised controlled trial.</h4><i>Wells A, Reeves D, Heal C, Fisher P, ... Heagerty A, Capobianco L</i><br /><b>Background</b><br />Anxiety and depression in cardiac rehabilitation (CR) are associated with greater morbidity, mortality, and increased healthcare costs. Current psychological interventions within CR have small effects based on low-quality studies of clinic-based interventions with limited access to home-based psychological support. We tested the effectiveness of adding self-help metacognitive therapy (Home-MCT) to CR in reducing anxiety and depression in a randomised controlled trial (RCT).<br /><b>Methods and findings</b><br />We ran a single-blind, multi-centre, two-arm RCT. A total of 240 CR patients were recruited from 5 NHS-Trusts across North West England between April 20, 2017 and April 6, 2020. Patients were randomly allocated to Home-MCT+CR (n = 118, 49.2%) or usual CR alone (n = 122, 50.8%). Randomisation was 1:1 via randomised blocks within hospital site, balancing arms on sex and baseline Hospital Anxiety and Depression Scale (HADS) scores. The primary outcome was the HADS total score at posttreatment (4-month follow-up). Follow-up data collection occurred between August 7, 2017 and July 20, 2020. Analysis was by intention to treat. The 4-month outcome favoured the MCT intervention group demonstrating significantly lower end of treatment scores (HADS total: adjusted mean difference = -2.64 [-4.49 to -0.78], p = 0.005, standardised mean difference (SMD) = 0.38). Sensitivity analysis using multiple imputation (MI) of missing values supported these findings. Most secondary outcomes also favoured Home-MCT+CR, especially in reduction of post-traumatic stress symptoms (SMD = 0.51). There were 23 participants (19%) lost to follow-up in Home-MCT+CR and 4 participants (3%) lost to follow-up in CR alone. No serious adverse events were reported. The main limitation is the absence of longer term (e.g., 12-month) follow-up data.<br /><b>Conclusion</b><br />Self-help home-based MCT was effective in reducing total anxiety/depression in patients undergoing CR. Improvement occurred across most psychological measures. Home-MCT was a promising addition to cardiac rehabilitation and may offer improved access to effective psychological treatment in cardiovascular disease (CVD) patients.<br /><b>Trial registration</b><br />NCT03999359.<br /><br />Copyright: © 2023 Wells et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004161</small></div>
Wells A, Reeves D, Heal C, Fisher P, ... Heagerty A, Capobianco L
PLoS Med: 01 Jan 2023; 20:e1004161 | PMID: 36719886
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<div><h4>Associations between β-blockers and psychiatric and behavioural outcomes: A population-based cohort study of 1.4 million individuals in Sweden.</h4><i>Molero Y, Kaddoura S, Kuja-Halkola R, Larsson H, ... D\'Onofrio BM, Fazel S</i><br /><b>Background</b><br />β-blockers are widely used for treating cardiac conditions and are suggested for the treatment of anxiety and aggression, although research is conflicting and limited by methodological problems. In addition, β-blockers have been associated with precipitating other psychiatric disorders and suicidal behaviour, but findings are mixed. We aimed to examine associations between β-blockers and psychiatric and behavioural outcomes in a large population-based cohort in Sweden.<br /><b>Methods and findings</b><br />We conducted a population-based longitudinal cohort study using Swedish nationwide high-quality healthcare, mortality, and crime registers. We included 1,400,766 individuals aged 15 years or older who had collected β-blocker prescriptions and followed them for 8 years between 2006 and 2013. We linked register data on dispensed β-blocker prescriptions with main outcomes, hospitalisations for psychiatric disorders (not including self-injurious behaviour or suicide attempts), suicidal behaviour (including deaths from suicide), and charges of violent crime. We applied within-individual Cox proportional hazards regression to compare periods on treatment with periods off treatment within each individual in order to reduce possible confounding by indication, as this model inherently adjusts for all stable confounders (e.g., genetics and health history). We also adjusted for age as a time-varying covariate. In further analyses, we adjusted by stated indications, prevalent users, cardiac severity, psychiatric and crime history, individual β-blockers, β-blocker selectivity and solubility, and use of other medications. In the cohort, 86.8% (n = 1,215,247) were 50 years and over, and 52.2% (n = 731,322) were women. During the study period, 6.9% (n = 96,801) of the β-blocker users were hospitalised for a psychiatric disorder, 0.7% (n = 9,960) presented with suicidal behaviour, and 0.7% (n = 9,405) were charged with a violent crime. There was heterogeneity in the direction of results; within-individual analyses showed that periods of β-blocker treatment were associated with reduced hazards of psychiatric hospitalisations (hazard ratio [HR]: 0.92, 95% confidence interval [CI]: 0.91 to 0.93, p < 0.001), charges of violent crime (HR: 0.87, 95% CI: 0.81 to 0.93, p < 0.001), and increased hazards of suicidal behaviour (HR: 1.08, 95% CI: 1.02 to 1.15, p = 0.012). After stratifying by diagnosis, reduced associations with psychiatric hospitalisations during β-blocker treatment were mainly driven by lower hospitalisation rates due to depressive (HR: 0.92, 95% CI: 0.89 to 0.96, p < 0.001) and psychotic disorders (HR: 0.89, 95% CI: 0.85 to 0.93, p < 0.001). Reduced associations with violent charges remained in most sensitivity analyses, while associations with psychiatric hospitalisations and suicidal behaviour were inconsistent. Limitations include that the within-individual model does not account for confounders that could change during treatment, unless measured and adjusted for in the model.<br /><b>Conclusions</b><br />In this population-wide study, we found no consistent links between β-blockers and psychiatric outcomes. However, β-blockers were associated with reductions in violence, which remained in sensitivity analyses. The use of β-blockers to manage aggression and violence could be investigated further.<br /><br />Copyright: © 2023 Molero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004164</small></div>
Molero Y, Kaddoura S, Kuja-Halkola R, Larsson H, ... D'Onofrio BM, Fazel S
PLoS Med: 01 Jan 2023; 20:e1004164 | PMID: 36719888
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<div><h4>The association between multimorbidity and osteoporosis investigation and treatment in high-risk fracture patients in Australia: A prospective cohort study.</h4><i>Bliuc D, Tran T, Chen W, Alarkawi D, ... Blank RD, Center JR</i><br /><b>Background</b><br />Multimorbidity is common among fracture patients. However, its association with osteoporosis investigation and treatment to prevent future fractures is unclear. This limited knowledge impedes optimal patient care. This study investigated the association between multimorbidity and osteoporosis investigation and treatment in persons at high risk following an osteoporotic fracture.<br /><b>Methods and findings</b><br />The Sax Institute\'s 45 and Up Study is a prospective population-based cohort of 267,153 people in New South Wales, Australia, recruited between 2005 and 2009. This analysis followed up participants until 2017 for a median of 6 years (IQR: 4 to 8). Questionnaire data were linked to hospital admissions (Admitted Patients Data Collection (APDC)), emergency presentations (Emergency Department Data Collection (EDDC)), Pharmaceutical Benefits Scheme (PBS), and Medicare Benefits Schedule (MBS). Data were linked by the Centre for Health Record Linkage and stored in a secured computing environment. Fractures were identified from APDC and EDDC, Charlson Comorbidity Index (CCI) from APDC, Dual-energy X-ray absorptiometry (DXA) investigation from MBS, and osteoporosis treatment from PBS. Out of 25,280 persons with index fracture, 10,540 were classified as high-risk based on 10-year Garvan Fracture Risk (age, sex, weight, prior fracture and falls) threshold ≥20%. The association of CCI with likelihood of investigation and treatment initiation was determined by logistic regression adjusted for education, socioeconomic and lifestyle factors). The high-risk females and males averaged 77 ± 10 and 86 ± 5 years, respectively; >40% had a CCI ≥2. Only 17% of females and 7% of males received a DXA referral, and 22% of females and 14% males received osteoporosis medication following fracture. A higher CCI was associated with a lower probability of being investigated [adjusted OR, females: 0.73 (95% CI, 0.61 to 0.87) and 0.43 (95% CI, 0.30 to 0.62); males: 0.47 (95% CI, 0.33 to 0.68) and 0.52 (0.31 to 0.85) for CCI: 2 to 3, and ≥4 versus 0 to 1, respectively] and of receiving osteoporosis medication [adjusted OR, females: 0.85 (95% CI, 0.74 to 0.98) and 0.78 (95% CI, 0.61 to 0.99); males: 0.75 (95% CI, 0.59 to 0.94) and 0.37 (95% CI, 0.23 to 0.53) for CCI: 2 to 3, and ≥4 versus 0 to 1, respectively]. The cohort is relatively healthy; therefore, the impact of multimorbidity on osteoporosis management may have been underestimated.<br /><b>Conclusions</b><br />Multimorbidity contributed significantly to osteoporosis treatment gap. This suggests that fracture risk is either underestimated or underprioritized in the context of multimorbidity and highlights the need for extra vigilance and improved fracture care in this setting.<br /><br />Copyright: © 2023 Bliuc et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004142</small></div>
Bliuc D, Tran T, Chen W, Alarkawi D, ... Blank RD, Center JR
PLoS Med: 01 Jan 2023; 20:e1004142 | PMID: 36649234
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<div><h4>School-age outcomes among IVF-conceived children: A population-wide cohort study.</h4><i>Kennedy AL, Vollenhoven BJ, Hiscock RJ, Stern CJ, ... Tong S, Lindquist AC</i><br /><b>Background</b><br />In vitro fertilisation (IVF) is a common mode of conception. Understanding the long-term implications for these children is important. The aim of this study was to determine the causal effect of IVF conception on primary school-age childhood developmental and educational outcomes, compared with outcomes following spontaneous conception.<br /><b>Methods and findings</b><br />Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The study cohort comprised statewide linked maternal and childhood administrative data. Participants included singleton infants conceived spontaneously or via IVF, born in Victoria, Australia between 2005 and 2014 and who had school-age developmental and educational outcomes assessed. The exposure examined was conception via IVF, with spontaneous conception the control condition. Two outcome measures were assessed. The first, childhood developmental vulnerability at school entry (age 4 to 6), was assessed using the Australian Early Developmental Census (AEDC) (n = 173,200) and defined as scoring <10th percentile in ≥2/5 developmental domains (physical health and wellbeing, social competence, emotional maturity, language and cognitive skills, communication skills, and general knowledge). The second, educational outcome at age 7 to 9, was assessed using National Assessment Program-Literacy and Numeracy (NAPLAN) data (n = 342,311) and defined by overall z-score across 5 domains (grammar and punctuation, reading, writing, spelling, and numeracy). Inverse probability weighting with regression adjustment was used to estimate population average causal effects. The study included 412,713 children across the 2 outcome cohorts. Linked records were available for 4,697 IVF-conceived cases and 168,503 controls for AEDC, and 8,976 cases and 333,335 controls for NAPLAN. There was no causal effect of IVF-conception on the risk of developmental vulnerability at school-entry compared with spontaneously conceived children (AEDC metrics), with an adjusted risk difference of -0.3% (95% CI -3.7% to 3.1%) and an adjusted risk ratio of 0.97 (95% CI 0.77 to 1.25). At age 7 to 9 years, there was no causal effect of IVF-conception on the NAPLAN overall z-score, with an adjusted mean difference of 0.030 (95% CI -0.018 to 0.077) between IVF- and spontaneously conceived children. The models were adjusted for sex at birth, age at assessment, language background other than English, socioeconomic status, maternal age, parity, and education. Study limitations included the use of observational data, the potential for unmeasured confounding, the presence of missing data, and the necessary restriction of the cohort to children attending school.<br /><b>Conclusions</b><br />In this analysis, under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children. These findings provide important reassurance for current and prospective parents and for clinicians.<br /><br />Copyright: © 2023 Kennedy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004148</small></div>
Kennedy AL, Vollenhoven BJ, Hiscock RJ, Stern CJ, ... Tong S, Lindquist AC
PLoS Med: 01 Jan 2023; 20:e1004148 | PMID: 36693021
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<div><h4>Dietary exposure to nitrites and nitrates in association with type 2 diabetes risk: Results from the NutriNet-Santé population-based cohort study.</h4><i>Srour B, Chazelas E, Druesne-Pecollo N, Esseddik Y, ... Deschasaux-Tanguy M, Touvier M</i><br /><b>Background</b><br />Nitrites and nitrates occur naturally in water and soil and are commonly ingested from drinking water and dietary sources. They are also used as food additives, mainly in processed meats, to increase shelf life and to avoid bacterial growth. Experimental studies suggested both benefits and harmful effects of nitrites and nitrates exposure on type 2 diabetes (T2D) onset, but epidemiological and clinical data are lacking. We aimed to study these associations in a large population-based prospective cohort study, distinguishing foods and water-originated nitrites/nitrates from those from food additives.<br /><b>Methods and findings</b><br />Overall, 104,168 adults from the French NutriNet-Santé cohort study (2009 to 2021, 79.1% female, mean age [SD] = 42.7 [14.5]) were included. Associations between self-reported exposure to nitrites and nitrates (evaluated using repeated 24-h dietary records, linked to a comprehensive food composition database and accounting for commercial names/brands details of industrial products) and risk of T2D were assessed using cause-specific multivariable Cox proportional hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). During a median follow-up duration of 7.3 years (interquartile range: [3.2; 10.1] years), 969 incident T2D cases were ascertained. Total nitrites and foods and water-originated nitrites were both positively associated with a higher T2D risk (HRtertile 3 vs.1 = 1.27 (95% CI 1.04 to 1.54), Ptrend = 0.009 and 1.26 (95% CI 1.03 to 1.54), Ptrend = 0.02, respectively). Participants with higher exposure to additives-originated nitrites (i.e., above the sex-specific median) and specifically those having higher exposure to sodium nitrite (e250) had a higher T2D risk compared with those who were not exposed to additives-originated nitrites (HR higher consumers vs. non-consumers = 1.53 (95% CI 1.24 to 1.88), Ptrend < 0.001 and 1.54 (95% CI 1.26 to 1.90), Ptrend < 0.001, respectively). There was no evidence for an association between total, foods and water-originated, or additives-originated nitrates and T2D risk (all Ptrend = 0.7). No causal link can be established from this observational study. Main limitations include possible exposure measurement errors and the lack of validation versus specific nitrites/nitrates biomarkers; potential selection bias linked to the healthier behaviors of the cohort\'s participants compared to the general population; potential residual confounding linked to the observational design, as well as a self-reported, yet cross-checked, case ascertainment.<br /><b>Conclusions</b><br />The findings of this large prospective cohort did not support any potential benefits for dietary nitrites and nitrates. They suggested that a higher exposure to both foods and water-originated and additives-originated nitrites was associated with higher T2D risk in the NutriNet-Santé cohort. This study provides a new piece of evidence in the context of current debates about updating regulations to limit the use of nitrites as food additives. The results need to be replicated in other populations.<br /><b>Trial registration</b><br />ClinicalTrials.gov NCT03335644 (https://clinicaltrials.gov/ct2/show/NCT03335644).<br /><br />Copyright: © 2023 Srour et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004149</small></div>
Srour B, Chazelas E, Druesne-Pecollo N, Esseddik Y, ... Deschasaux-Tanguy M, Touvier M
PLoS Med: 01 Jan 2023; 20:e1004149 | PMID: 36649248
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<div><h4>Comorbidity and health-related quality of life in people with a chronic medical condition in randomised clinical trials: An individual participant data meta-analysis.</h4><i>Butterly EW, Hanlon P, Shah ASV, Hannigan LJ, ... Welton NJ, McAllister DA</i><br /><b>Background</b><br />Health-related quality of life metrics evaluate treatments in ways that matter to patients, so are often included in randomised clinical trials (hereafter trials). Multimorbidity, where individuals have 2 or more conditions, is negatively associated with quality of life. However, whether multimorbidity predicts change over time or modifies treatment effects for quality of life is unknown. Therefore, clinicians and guideline developers are uncertain about the applicability of trial findings to people with multimorbidity. We examined whether comorbidity count (higher counts indicating greater multimorbidity) (i) is associated with quality of life at baseline; (ii) predicts change in quality of life over time; and/or (iii) modifies treatment effects on quality of life.<br /><b>Methods and findings</b><br />Included trials were registered on the United States trials registry for selected index medical conditions and drug classes, phase 2/3, 3 or 4, had ≥300 participants, a nonrestrictive upper age limit, and were available on 1 of 2 trial repositories on 21 November 2016 and 18 May 2018, respectively. Of 124 meeting these criteria, 56 trials (33,421 participants, 16 index conditions, and 23 drug classes) collected a generic quality of life outcome measure (35 EuroQol-5 dimension (EQ-5D), 31 36-item short form survey (SF-36) with 10 collecting both). Blinding and completeness of follow up were examined for each trial. Using trials where individual participant data (IPD) was available from 2 repositories, a comorbidity count was calculated from medical history and/or prescriptions data. Linear regressions were fitted for the association between comorbidity count and (i) quality of life at baseline; (ii) change in quality of life during trial follow up; and (iii) treatment effects on quality of life. These results were then combined in Bayesian linear models. Posterior samples were summarised via the mean, 2.5th and 97.5th percentiles as credible intervals (95% CI) and via the proportion with values less than 0 as the probability (PBayes) of a negative association. All results are in standardised units (obtained by dividing the EQ-5D/SF-36 estimates by published population standard deviations). Per additional comorbidity, adjusting for age and sex, across all index conditions and treatment comparisons, comorbidity count was associated with lower quality of life at baseline and with a decline in quality of life over time (EQ-5D -0.02 [95% CI -0.03 to -0.01], PBayes > 0.999). Associations were similar, but with wider 95% CIs crossing the null for SF-36-PCS and SF-36-MCS (-0.05 [-0.10 to 0.01], PBayes = 0.956 and -0.05 [-0.10 to 0.01], PBayes = 0.966, respectively). Importantly, there was no evidence of any interaction between comorbidity count and treatment efficacy for either EQ-5D or SF-36 (EQ-5D -0.0035 [95% CI -0.0153 to -0.0065], PBayes = 0.746; SF-36-MCS (-0.0111 [95% CI -0.0647 to 0.0416], PBayes = 0.70 and SF-36-PCS -0.0092 [95% CI -0.0758 to 0.0476], PBayes = 0.631.<br /><b>Conclusions</b><br />Treatment effects on quality of life did not differ by multimorbidity (measured via a comorbidity count) at baseline-for the medical conditions studied, types and severity of comorbidities and level of quality of life at baseline, suggesting that evidence from clinical trials is likely to be applicable to settings with (at least modestly) higher levels of comorbidity.<br /><b>Trial registration</b><br />A prespecified protocol was registered on PROSPERO (CRD42018048202).<br /><br />Copyright: © 2023 Butterly et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004154</small></div>
Butterly EW, Hanlon P, Shah ASV, Hannigan LJ, ... Welton NJ, McAllister DA
PLoS Med: 01 Jan 2023; 20:e1004154 | PMID: 36649256
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<div><h4>Association between genetically proxied PCSK9 inhibition and prostate cancer risk: A Mendelian randomisation study.</h4><i>Fang S, Yarmolinsky J, Gill D, Bull CJ, ... Gaunt TR, Richardson TG</i><br /><b>Background</b><br />Prostate cancer (PrCa) is the second most prevalent malignancy in men worldwide. Observational studies have linked the use of low-density lipoprotein cholesterol (LDL-c) lowering therapies with reduced risk of PrCa, which may potentially be attributable to confounding factors. In this study, we performed a drug target Mendelian randomisation (MR) analysis to evaluate the association of genetically proxied inhibition of LDL-c-lowering drug targets on risk of PrCa.<br /><b>Methods and findings</b><br />Single-nucleotide polymorphisms (SNPs) associated with LDL-c (P < 5 × 10-8) from the Global Lipids Genetics Consortium genome-wide association study (GWAS) (N = 1,320,016) and located in and around the HMGCR, NPC1L1, and PCSK9 genes were used to proxy the therapeutic inhibition of these targets. Summary-level data regarding the risk of total, advanced, and early-onset PrCa were obtained from the PRACTICAL consortium. Validation analyses were performed using genetic instruments from an LDL-c GWAS conducted on male UK Biobank participants of European ancestry (N = 201,678), as well as instruments selected based on liver-derived gene expression and circulation plasma levels of targets. We also investigated whether putative mediators may play a role in findings for traits previously implicated in PrCa risk (i.e., lipoprotein a (Lp(a)), body mass index (BMI), and testosterone). Applying two-sample MR using the inverse-variance weighted approach provided strong evidence supporting an effect of genetically proxied inhibition of PCSK9 (equivalent to a standard deviation (SD) reduction in LDL-c) on lower risk of total PrCa (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.76 to 0.96, P = 9.15 × 10-3) and early-onset PrCa (OR = 0.70, 95% CI = 0.52 to 0.95, P = 0.023). Genetically proxied HMGCR inhibition provided a similar central effect estimate on PrCa risk, although with a wider 95% CI (OR = 0.83, 95% CI = 0.62 to 1.13, P = 0.244), whereas genetically proxied NPC1L1 inhibition had an effect on higher PrCa risk with a 95% CI that likewise included the null (OR = 1.34, 95% CI = 0.87 to 2.04, P = 0.180). Analyses using male-stratified instruments provided consistent results. Secondary MR analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR = 0.90 per SD reduction in PCSK9 expression, 95% CI = 0.86 to 0.95, P = 5.50 × 10-5) and circulating plasma levels of PCSK9 (OR = 0.93 per SD reduction in PCSK9 protein levels, 95% CI = 0.87 to 0.997, P = 0.04) on PrCa risk. Colocalization analyses identified strong evidence (posterior probability (PPA) = 81.3%) of a shared genetic variant (rs553741) between liver-derived PCSK9 expression and PrCa risk, whereas weak evidence was found for HMGCR (PPA = 0.33%) and NPC1L1 expression (PPA = 0.38%). Moreover, genetically proxied PCSK9 inhibition was strongly associated with Lp(a) levels (Beta = -0.08, 95% CI = -0.12 to -0.05, P = 1.00 × 10-5), but not BMI or testosterone, indicating a possible role for Lp(a) in the biological mechanism underlying the association between PCSK9 and PrCa. Notably, we emphasise that our estimates are based on a lifelong exposure that makes direct comparisons with trial results challenging.<br /><b>Conclusions</b><br />Our study supports a strong association between genetically proxied inhibition of PCSK9 and a lower risk of total and early-onset PrCa, potentially through an alternative mechanism other than the on-target effect on LDL-c. Further evidence from clinical studies is needed to confirm this finding as well as the putative mediatory role of Lp(a).<br /><br />Copyright: © 2023 Fang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1003988</small></div>
Fang S, Yarmolinsky J, Gill D, Bull CJ, ... Gaunt TR, Richardson TG
PLoS Med: 01 Jan 2023; 20:e1003988 | PMID: 36595504
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<div><h4>Effectiveness of a peer educator-coordinated preference-based differentiated service delivery model on viral suppression among young people living with HIV in Lesotho: The PEBRA cluster-randomized trial.</h4><i>Kopo M, Lejone TI, Tschumi N, Glass TR, ... Labhardt ND, Amstutz A</i><br /><b>Background</b><br />Southern and Eastern Africa is home to more than 2.1 million young people aged 15 to 24 years living with HIV. As compared with other age groups, this population group has poorer outcomes along the HIV care cascade. Young people living with HIV and the research team co-created the PEBRA (Peer Educator-Based Refill of ART) care model. In PEBRA, a peer educator (PE) delivered services as per regularly assessed patient preferences for medication pick-up, short message service (SMS) notifications, and psychosocial support. The cluster-randomized trial compared PEBRA model versus standard clinic care (no PE and ART refill done by nurses) in 3 districts in Lesotho.<br /><b>Methods and findings</b><br />Individuals taking antiretroviral therapy (ART) aged 15 to 24 years at 20 clinics (clusters) were eligible. In the 10 clinics randomized to the intervention arm, participants were offered the PEBRA model, coordinated by a trained PE and supported by an eHealth application (PEBRApp). In the 10 control clusters, participants received standard nurse-coordinated care without any service coordination by a PE. The primary endpoint was 12-month viral suppression below 20 copies/mL. Analyses were intention-to-treat and adjusted for sex. From November 6, 2019 to February 4, 2020, we enrolled 307 individuals (150 intervention, 157 control; 218 [71%] female, median age 19 years [interquartile range, IQR, 17 to 22]). At 12 months, 99 of 150 (66%) participants in the intervention versus 95 of 157 (61%) participants in the control arm had viral suppression (adjusted odds ratio (OR) 1.27; 95% confidence interval [CI] [0.79 to 2.03]; p = 0.327); 4 of 150 (2.7%) versus 1 of 157 (0.6%) had died (adjusted OR 4.12; 95% CI [0.45 to 37.62]; p = 0.210); and 12 of 150 (8%) versus 23 of 157 (14.7%) had transferred out (adjusted OR 0.53; 95% CI [0.25 to 1.13]; p = 0.099). There were no significant differences between arms in other secondary outcomes. Twenty participants (11 in intervention and 9 in control) were lost to follow-up over the entire study period. The main limitation was that the data collectors in the control clusters were also young peers; however, they used a restricted version of the PEBRApp to collect data and thus were not able to provide the PEBRA model. The trial was prospectively registered on ClinicalTrials.gov (NCT03969030).<br /><b>Conclusions</b><br />Preference-based peer-coordinated care for young people living with HIV, compared to nurse-based care only, did not lead to conclusive evidence for an effect on viral suppression.<br /><b>Trial registration</b><br />clinicaltrials.gov, NCT03969030, https://clinicaltrials.gov/ct2/show/NCT03969030.<br /><br />Copyright: © 2023 Kopo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004150</small></div>
Abstract
<div><h4>Gestational age at birth and body size from infancy through adolescence: An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies.</h4><i>Vinther JL, Cadman T, Avraam D, Ekstrøm CT, ... Lawlor DA, Nybo Andersen AM</i><br /><b>Background</b><br />Preterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence.<br /><b>Methods and findings</b><br />We conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child\'s birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positively associated with BMI in the first decade of life, with the greatest increase in mean BMI z-score during early infancy (0.02, 95% confidence interval (CI): 0.00; 0.05, p < 0.05) per week of increase in GA, while in adolescence, preterm individuals reached similar levels of BMI (0.00, 95% CI: -0.01; 0.01, p 0.9) as term counterparts. The association between GA and overweight revealed a similar pattern of association with an increase in odds ratio (OR) of overweight from late infancy through mid-childhood (OR 1.01 to 1.02) per week increase in GA. By adolescence, however, GA was slightly negatively associated with the risk of overweight (OR 0.98 [95% CI: 0.97; 1.00], p 0.1) per week of increase in GA. Although based on only four cohorts (n = 32,089) that reached the age of adolescence, data suggest that individuals born very preterm may be at increased odds of overweight (OR 1.46 [95% CI: 1.03; 2.08], p < 0.05) compared with term counterparts. Findings were consistent across cohorts and sensitivity analyses despite considerable heterogeneity in cohort characteristics. However, residual confounding may be a limitation in this study, while findings may be less generalisable to settings in low- and middle-income countries.<br /><b>Conclusions</b><br />This study based on data from infancy through adolescence from 16 cohort studies found that GA may be important for body size in infancy, but the strength of association attenuates consistently with age. By adolescence, preterm individuals have on average a similar mean BMI to peers born at term.<br /><br />Copyright: © 2023 Vinther et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004036</small></div>
Vinther JL, Cadman T, Avraam D, Ekstrøm CT, ... Lawlor DA, Nybo Andersen AM
PLoS Med: 01 Jan 2023; 20:e1004036 | PMID: 36701266
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<div><h4>Associations between trajectories of obesity prevalence in English primary school children and the UK soft drinks industry levy: An interrupted time series analysis of surveillance data.</h4><i>Rogers NT, Cummins S, Forde H, Jones CP, ... White M, Adams J</i><br /><b>Background</b><br />Sugar-sweetened beverages (SSBs) are the primary source of dietary added sugars in children, with high consumption commonly observed in more deprived areas where obesity prevalence is also highest. Associations between SSB consumption and obesity in children have been widely reported. In March 2016, a two-tier soft drinks industry levy (SDIL) on drinks manufacturers to encourage reformulation of SSBs in the United Kingdom was announced and then implemented in April 2018. We examined trajectories in the prevalence of obesity at ages 4 to 5 years and 10 to 11 years, 19 months after the implementation of SDIL, overall and by sex and deprivation.<br /><b>Methods and findings</b><br />Data were from the National Child Measurement Programme and included annual repeat cross-sectional measurement of over 1 million children in reception (4 to 5 years old) and year 6 (10 to 11 years old) in state-maintained English primary schools. Interrupted time series (ITS) analysis of monthly obesity prevalence data from September 2013 to November 2019 was used to estimate absolute and relative changes in obesity prevalence compared to a counterfactual (adjusted for temporal variations in obesity prevalence) estimated from the trend prior to SDIL announcement. Differences between observed and counterfactual estimates were examined in November 2019 by age (reception or year 6) and additionally by sex and deprivation quintile. In year 6 girls, there was an overall absolute reduction in obesity prevalence (defined as >95th centile on the UK90 growth charts) of 1.6 percentage points (PPs) (95% confidence interval (CI): 1.1, 2.1), with greatest reductions in the two most deprived quintiles (e.g., there was an absolute reduction of 2.4 PP (95% CI: 1.6, 3.2) in prevalence of obesity in the most deprived quintile). In year 6 boys, there was no change in obesity prevalence, except in the least deprived quintile where there was a 1.6-PP (95% CI: 0.7, 2.5) absolute increase. In reception children, relative to the counterfactual, there were no overall changes in obesity prevalence in boys (0.5 PP (95% CI: 1.0, -0.1)) or girls (0.2 PP (95% CI: 0.8, -0.3)). This study is limited by use of index of multiple deprivation of the school attended to assess individual socioeconomic disadvantage. ITS analyses are vulnerable to unidentified cointerventions and time-varying confounding, neither of which we can rule out.<br /><b>Conclusions</b><br />Our results suggest that the SDIL was associated with decreased prevalence of obesity in year 6 girls, with the greatest differences in those living in the most deprived areas. Additional strategies beyond SSB taxation will be needed to reduce obesity prevalence overall, and particularly in older boys and younger children.<br /><b>Trial registration</b><br />ISRCTN18042742.<br /><br />Copyright: © 2023 Rogers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004160</small></div>
Abstract
<div><h4>The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: A modeling study.</h4><i>Portnoy A, Clark RA, Quaife M, Weerasuriya CK, ... White RG, Menzies NA</i><br /><b>Background</b><br />Tuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMICs) for a range of product characteristics and delivery strategies.<br /><b>Methods and findings</b><br />We developed a system of epidemiological and economic models, calibrated to demographic, epidemiological, and health service data in 105 LMICs. For each country, we assessed the likely future course of TB-related outcomes under several vaccine introduction scenarios, compared to a \"no-new-vaccine\" counterfactual. Vaccine scenarios considered 2 vaccine product profiles (1 targeted at infants, 1 at adolescents/adults), both assumed to prevent progression to active TB. Key economic inputs were derived from the Global Health Cost Consortium, World Health Organization (WHO) patient cost surveys, and the published literature. We estimated the incremental impact of vaccine introduction for a range of health and economic outcomes. In the base-case, we assumed a vaccine price of $4.60 and used a 1× per-capita gross domestic product (GDP) cost-effectiveness threshold (both varied in sensitivity analyses). Vaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, adolescent/adult vaccination was cost-effective in 64 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), adolescent/adult vaccination was projected to be cost-effective in 73 of 105 LMICs and cost-saving in 58 of 105 LMICs, including 96% of countries with higher TB burden. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $283 to 474 billion in economic benefits by 2050. Limited data availability required assumptions and extrapolations that may omit important country-level heterogeneity in epidemiology and costs.<br /><b>Conclusions</b><br />TB vaccination would be highly impactful and cost-effective in most LMICs. Further efforts are needed for future development, adoption, and implementation of novel TB vaccines.<br /><br />Copyright: © 2023 Portnoy et al. This is an open access article distributed under the Creative Commons Attribution IGO License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/3.0/igo/. In any use of this article, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article’s original URL.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004155</small></div>
Portnoy A, Clark RA, Quaife M, Weerasuriya CK, ... White RG, Menzies NA
PLoS Med: 01 Jan 2023; 20:e1004155 | PMID: 36693081
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<div><h4>US and EU Free Trade Agreements and implementation of policies to control tobacco, alcohol, and unhealthy food and drinks: A quasi-experimental analysis.</h4><i>Barlow P, Allen LN</i><br /><b>Background</b><br />Identifying and tackling the factors that undermine regulation of unhealthy commodities is an essential component of effective noncommunicable disease (NCD) prevention. Unhealthy commodity producers may use rules in US and EU Free Trade Agreements (FTAs) to challenge policies targeting their products. We aimed to test whether there was a statistical relationship between US and EU FTA participation and reduced implementation of WHO-recommended policies.<br /><b>Methods and findings</b><br />We performed a statistical analysis assessing the probability of at least partially implementing 10 tobacco, alcohol, and unhealthy food and drink policies in 127 countries in 2014, 2016, and 2019. We assessed differences in implementation of these policies in countries with and without US/EU FTAs. We used matching to conduct 48 covariate-adjusted quasi-experimental comparisons across 27 matched US/EU FTA members (87 country-years) and performed additional analyses and robustness checks to assess alternative explanations for our results. Out of our 48 tests, 19% (9/48) identified a statistically significant decrease in the predicted probability of at least partially implementing the unhealthy commodity policy in question, while 2% (1/48) showed an increase. However, there was marked heterogeneity across policies. At the level of individual policies, US FTA participation was associated with a 37% reduction (95%CI: -0.51 to -0.22) in the probability of fully implementing graphic tobacco warning policies, and a 53% reduction (95%CI: -0.63 to -0.43) in the probability of at least partially implementing smoke-free place policies. EU FTA participation was associated with a 28% reduction (95%CI: -0.45 to -0.10) in the probability of fully implementing graphic tobacco warning policies, and a 25% reduction (95%CI: -0.47 to -0.03) in the probability of fully implementing restrictions on child marketing of unhealthy food and drinks. There was a positive association with implementing fat limits and bans, but this was not robust. Associations with other outcomes were not significant. The main limitations included residual confounding, limited ability to discern precise mechanisms of influence, and potentially limited generalisability to other FTAs.<br /><b>Conclusions</b><br />US and EU FTA participation may reduce the probability of implementing WHO-recommended tobacco and child food marketing policies by between a quarter and a half-depending on the FTA and outcome in question. Governments negotiating or participating in US/EU FTAs may need to establish robust health protections and mitigation strategies to achieve their NCD mortality reduction targets.<br /><br />Copyright: © 2023 Barlow, Allen. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004147</small></div>
Abstract
<div><h4>Correction: Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: A nationwide prospective cohort study.</h4><i>Hensley KS, Jongkees MJ, Geers D, GeurtsvanKessel CH, ... Roukens AHE, Rokx C</i><br /><AbstractText>[This corrects the article DOI: 10.1371/journal.pmed.1003979.].</AbstractText><br /><br />Copyright: © 2023 Hensley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004159</small></div>
Hensley KS, Jongkees MJ, Geers D, GeurtsvanKessel CH, ... Roukens AHE, Rokx C
PLoS Med: 01 Jan 2023; 20:e1004159 | PMID: 36608645
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<div><h4>Healthy lifestyle choices and microvascular complications: New insights into diabetes management.</h4><i>Chudasama YV, Khunti K</i><br /><AbstractText>Yogini Chudasama and Kamlesh Khunti discuss new evidence, published in PLOS Medicine, highlighting the importance of healthy lifestyle behaviours in diabetes management.</AbstractText><br /><br />Copyright: © 2023 Chudasama, Khunti. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004152</small></div>
Chudasama YV, Khunti K
PLoS Med: 01 Jan 2023; 20:e1004152 | PMID: 36626355
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<div><h4>Healthy lifestyle behaviors, mediating biomarkers, and risk of microvascular complications among individuals with type 2 diabetes: A cohort study.</h4><i>Geng T, Zhu K, Lu Q, Wan Z, ... Pan A, Liu G</i><br /><b>Background</b><br />The influence of overall lifestyle behaviors on diabetic microvascular complications remains unknown. In addition, the potential mediating biomarkers underlying the association is unclear. This study aimed to examine the associations of the combined lifestyle factors with risks of total and individual microvascular complications among patients with type 2 diabetes (T2D) and to explore the potential mediation effects of metabolic biomarkers.<br /><b>Methods and findings</b><br />This retrospective cohort study included 15,104 patients with T2D free of macro- and microvascular complications at baseline (2006 to 2010) from the UK Biobank. Healthy lifestyle behaviors included noncurrent smoking, recommended waist circumference, regular physical activity, healthy diet, and moderate alcohol drinking. Outcomes were ascertained using electronic health records. Over a median of 8.1 years of follow-up, 1,296 cases of the composite microvascular complications occurred, including 558 diabetic retinopathy, 625 diabetic kidney disease, and 315 diabetic neuropathy, with some patients having 2 or 3 microvascular complications simultaneously. After multivariable adjustment for sociodemographic characteristics, history of hypertension, glycemic control, and medication histories, the hazard ratios (95% confidence intervals (CIs)) for the participants adhering 4 to 5 low-risk lifestyle behaviors versus 0 to 1 were 0.65 (0.46, 0.91) for diabetic retinopathy, 0.43 (0.30, 0.61) for diabetic kidney disease, 0.46 (0.29, 0.74) for diabetic neuropathy, and 0.54 (0.43, 0.68) for the composite outcome (all Ps-trend ≤0.01). Further, the population-attributable fraction (95% CIs) of diabetic microvascular complications for poor adherence to the overall healthy lifestyle (<4 low-risk factors) ranged from 25.3% (10.0%, 39.4%) to 39.0% (17.7%, 56.8%). In addition, albumin, HDL-C, triglycerides, apolipoprotein A, C-reactive protein, and HbA1c collectively explained 23.20% (12.70%, 38.50%) of the associations between overall lifestyle behaviors and total diabetic microvascular complications. The key limitation of the current analysis was the potential underreporting of microvascular complications because the cases were identified via electronic health records.<br /><b>Conclusions</b><br />Adherence to overall healthy lifestyle behaviors was associated with a significantly lower risk of microvascular complications in patients with T2D, and the favorable associations were partially mediated through improving biomarkers of glycemic control, systemic inflammation, liver function, and lipid profile.<br /><br />Copyright: © 2023 Geng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004135</small></div>
Geng T, Zhu K, Lu Q, Wan Z, ... Pan A, Liu G
PLoS Med: 01 Jan 2023; 20:e1004135 | PMID: 36626356
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<div><h4>Mandatory, voluntary, repetitive, or one-off post-migration follow-up for tuberculosis prevention and control: A systematic review.</h4><i>Wahedi K, Zenner D, Flores S, Bozorgmehr K</i><br /><b>Background</b><br />Post-migration follow-up of migrants identified to be at-risk of developing tuberculosis during the initial screening is effective, but programmes vary across countries. We aimed to review main strategies applied to design follow-up programmes and analyse the effect of key programme characteristics on reported coverage (i.e., proportion of migrants screened among those eligible for screening) or yields (i.e., proportion of active tuberculosis among those identified as eligible for follow-up screening).<br /><b>Methods and findings</b><br />We performed a systematic review and meta-analysis of studies reporting yields of follow-up screening programmes. Studies were included if they reported the rate of tuberculosis disease detected in international migrants through active case finding strategies and applied a post-migration follow-up (defined as one or more additional rounds of screening after finalising the initial round). For this, we retrieved all studies identified by Chan and colleagues for their systematic review (in their search until January 12, 2017) and included those reporting from active follow-up programmes. We then updated the search (from January 12, 2017 to September 30, 2022) using Medline and Embase via Ovid. Data were extracted on reported coverage, yields, and key programme characteristics, including eligible population, mode of screening, time intervals for screening, programme providers, and legal frameworks. Differences in follow-up programmes were tabulated and synthesised narratively. Meta-analyses in random effect models and exploratory analysis of subgroups showed high heterogeneity (I2 statistic > 95.0%). We hence refrained from pooling, and estimated yields and coverage with corresponding 95% confidence intervals (CIs), stratified by country, legal character (mandatory versus voluntary screening), and follow-up scheme (one-off versus repetitive screening) using forest plots for comparison and synthesis. Of 1,170 articles, 24 reports on screening programmes from 7 countries were included, with considerable variation in eligible populations, time intervals of screening, and diagnostic protocols. Coverage varied, but was higher than 60% in 15 studies, and tended to be lower in voluntary compared to compulsory programmes, and higher in studies from the United States of America, Israel, and Australia. Yield varied within and between countries and ranged between 53.05 (31.94 to 82.84) in a Dutch study and 5,927.05 (4,248.29 to 8,013.71) in a study from the United States. Of 15 estimates with narrow 95% CIs for yields, 12 were below 1,500 cases per 100,000 eligible migrants. Estimates of yields in one-off follow-up programmes tended to be higher and were surrounded by less uncertainty, compared to those in repetitive follow-up programmes. Yields in voluntary and mandatory programmes were comparable in magnitude and uncertainty. The study is limited by the heterogeneity in the design of the identified screening programmes as effectiveness, coverage and yields also depend on factors often underreported or not known, such as baseline incidence in the respective population, reactivation rate, educative and administrative processes, and consequences of not complying with obligatory measures.<br /><b>Conclusion</b><br />Programme characteristics of post-migration follow-up screening for prevention and control of tuberculosis as well as coverage and yield vary considerably. Voluntary programmes appear to have similar yields compared with mandatory programmes and repetitive screening apparently did not lead to higher yields compared with one-off screening. Screening strategies should consider marginal costs for each additional round of screening.<br /><br />Copyright: © 2023 Wahedi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004030</small></div>
Wahedi K, Zenner D, Flores S, Bozorgmehr K
PLoS Med: 01 Jan 2023; 20:e1004030 | PMID: 36719863
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<div><h4>Inequities in COVID-19 vaccine and booster coverage across Massachusetts ZIP codes after the emergence of Omicron: A population-based cross-sectional study.</h4><i>Bor J, Assoumou SA, Lane K, Diaz Y, ... Raifman J, Levy JI</i><br /><b>Background</b><br />Inequities in Coronavirus Disease 2019 (COVID-19) vaccine and booster coverage may contribute to future disparities in morbidity and mortality within and between Massachusetts (MA) communities.<br /><b>Methods and findings</b><br />We conducted a population-based cross-sectional study of primary series vaccination and booster coverage 18 months into the general population vaccine rollout. We obtained public-use data on residents vaccinated and boosted by ZIP code (and by age group: 5 to 19, 20 to 39, 40 to 64, 65+) from MA Department of Public Health, as of October 10, 2022. We constructed population denominators for postal ZIP codes by aggregating census tract population estimates from the 2015-2019 American Community Survey. We excluded nonresidential ZIP codes and the smallest ZIP codes containing 1% of the state\'s population. We mapped variation in ZIP code-level primary series vaccine and booster coverage and used regression models to evaluate the association of these measures with ZIP code-level socioeconomic and demographic characteristics. Because age is strongly associated with COVID-19 severity and vaccine access/uptake, we assessed whether observed socioeconomic and racial/ethnic inequities persisted after adjusting for age composition and plotted age-specific vaccine and booster coverage by deciles of ZIP code characteristics. We analyzed data on 418 ZIP codes. We observed wide geographic variation in primary series vaccination and booster rates, with marked inequities by ZIP code-level education, median household income, essential worker share, and racial/ethnic composition. In age-stratified analyses, primary series vaccine coverage was very high among the elderly. However, we found large inequities in vaccination rates among younger adults and children, and very large inequities in booster rates for all age groups. In multivariable regression models, each 10 percentage point increase in \"percent college educated\" was associated with a 5.1 (95% confidence interval (CI) 3.9 to 6.3, p < 0.001) percentage point increase in primary series vaccine coverage and a 5.4 (95% CI 4.5 to 6.4, p < 0.001) percentage point increase in booster coverage. Although ZIP codes with higher \"percent Black/Latino/Indigenous\" and higher \"percent essential workers\" had lower vaccine coverage (-0.8, 95% CI -1.3 to -0.3, p < 0.01; -5.5, 95% CI -7.3 to -3.8, p < 0.001), these associations became strongly positive after adjusting for age and education (1.9, 95% CI 1.0 to 2.8, p < 0.001; 4.8, 95% CI 2.6 to 7.1, p < 0.001), consistent with high demand for vaccines among Black/Latino/Indigenous and essential worker populations within age and education groups. Strong positive associations between \"median household income\" and vaccination were attenuated after adjusting for age. Limitations of the study include imprecision of the estimated population denominators, lack of individual-level sociodemographic data, and potential for residential ZIP code misreporting in vaccination data.<br /><b>Conclusions</b><br />Eighteen months into MA\'s general population vaccine rollout, there remained large inequities in COVID-19 primary series vaccine and booster coverage across MA ZIP codes, particularly among younger age groups. Disparities in vaccination coverage by racial/ethnic composition were statistically explained by differences in age and education levels, which may mediate the effects of structural racism on vaccine uptake. Efforts to increase booster coverage are needed to limit future socioeconomic and racial/ethnic disparities in COVID-19 morbidity and mortality.<br /><br />Copyright: © 2023 Bor et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2023; 20:e1004167</small></div>
Bor J, Assoumou SA, Lane K, Diaz Y, ... Raifman J, Levy JI
PLoS Med: 01 Jan 2023; 20:e1004167 | PMID: 36719864
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<div><h4>The effect of population-based blood pressure screening on long-term cardiometabolic morbidity and mortality in Germany: A regression discontinuity analysis.</h4><i>Pedron S, Hanselmann M, Burns J, Rich A, ... Bärnighausen T, Laxy M</i><br /><b>Background</b><br />Hypertension represents one of the major risk factors for cardiovascular morbidity and mortality globally. Early detection and treatment of this condition is vital to prevent complications. However, hypertension often goes undetected, and even if detected, not every patient receives adequate treatment. Identifying simple and effective interventions is therefore crucial to fight this problem and allow more patients to receive the treatment they need. Therefore, we aim at investigating the impact of a population-based blood pressure (BP) screening and the subsequent \"low-threshold\" information treatment on long-term cardiovascular disease (CVD) morbidity and mortality.<br /><b>Methods and findings</b><br />We examined the impact of a BP screening embedded in a population-based cohort study in Germany and subsequent personalized \"light touch\" information treatment, including a hypertension diagnosis and a recommendation to seek medical attention. We pooled four waves of the KORA study, carried out between 1984 and 1996 (N = 14,592). Using a sharp multivariate regression discontinuity (RD) design, we estimated the impact of the information treatment on CVD mortality and morbidity over 16.9 years. Additionally, we investigated potential intermediate outcomes, such as hypertension awareness, BP, and behavior after 7 years. No evidence of effect of BP screening was observed on CVD mortality (hazard ratio (HR) = 1.172 [95% confidence interval (CI): 0.725, 1.896]) or on any (fatal or nonfatal) long-term CVD event (HR = 1.022 [0.636, 1.641]) for individuals just above (versus below) the threshold for hypertension. Stratification for previous self-reported diagnosis of hypertension at baseline did not reveal any differential effect. The intermediate outcomes, including awareness of hypertension, were also unaffected by the information treatment. However, these results should be interpreted with caution since the analysis might not be sufficiently powered to detect a potential intervention effect.<br /><b>Conclusions</b><br />The study does not provide evidence of an effect of the assessed BP screening and subsequent information treatment on BP and behavior, but also on long-term CVD mortality and morbidity. Future studies should consider larger datasets to detect possible effects and a shorter follow-up for the intermediate outcomes (i.e., BP and behavior) to detect short-, medium-, and long-term effects of the intervention along the causal pathway.<br /><br />Copyright: © 2022 Pedron et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 27 Dec 2022; 19:e1004151</small></div>
Pedron S, Hanselmann M, Burns J, Rich A, ... Bärnighausen T, Laxy M
PLoS Med: 27 Dec 2022; 19:e1004151 | PMID: 36574446
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<div><h4>Care cascades for hypertension and diabetes: Cross-sectional evaluation of rural districts in Tanzania.</h4><i>Osetinsky B, Mhalu G, Mtenga S, Tediosi F</i><br /><b>Background</b><br />Noncommunicable diseases (NCDs), especially hypertension and diabetes, are rapidly rising in sub-Saharan Africa, necessitating health systems transformations. In Tanzania, current policies aim to improve control of hypertension and diabetes, but information is still needed to assess the gaps in treatment.<br /><b>Methods and findings</b><br />We conducted a cross-sectional household survey of 784 adults in two districts in Tanzania from December 2020 to January 2021, capturing the cascade-of-care for hypertension and diabetes. The ages of the respondents ranged from 18 to 89 years. Of those screened positive for these conditions, we measured the proportion in each step of the cascades: awareness, care engagement, treatment, and control. We conducted multivariable logistic regression analyses for all four steps along the hypertension care cascade with the independent variables of social health protection schemes, and prior diagnosis of comorbid diabetes, and demographic information. In our sample, of the 771 who had their blood pressure measured, 41% (95% confidence interval (CI): 38% to 44%) were screened positive for hypertension, and of the 707 who had their blood sugar measured, 6% (95% CI: 4% to 8%) were screened positive for diabetes. Of those with hypertension, 43% (95% CI: 38% to 49%) had a prior diagnosis, 25% (95% CI: 21% to 31%) were engaged in care, 21% (95% CI: 3% to 25%) were on treatment, and 11% (95% CI: 8% to 15%) were controlled. Of the 42 respondents with diabetes, 80% (95% CI: 69% to 93%) had a prior diagnosis. The diabetes care cascade had much less drop-off, so 66% of those with diabetes (95% CI: 52% to 82%) were engaged in care and on treatment, and 48% (95% CI: 32% to 63%) had their diabetes controlled at the point of testing. Healthcare fee exemptions were independently associated with higher odds of being previously diagnosed (OR 5.81; 95% CI [1.98 to 17.10] p < 0.005), engaged in care (OR 4.71; 95% CI [1.59 to 13.90] p 0.005), and retained in treatment (OR 2.93; 95% CI [1.03 to 8.35] p < 0.05). Prior diagnosis of comorbid diabetes was highly associated with higher odds of being engaged in care for hypertension (OR 3.26; 95% CI [1.39 to 7.63] p < 0.005). The two primary limitations of this study were reliance on screening at a single time point only of people available at the village at the time of the sample and dependence on self-report for to inform the three cascade steps of prior diagnosis, healthcare visits for engagement in care, and treatment use.<br /><b>Conclusions</b><br />The high burden of hypertension and low levels of control in our study underscores the importance of improving the awareness and treatment of hypertension. The differences in the care cascades for hypertension and diabetes demonstrates that chronic NCD treatment is possible in this setting, but efforts will be needed across the entire care cascade to improve hypertension control.<br /><br />Copyright: © 2022 Osetinsky et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 05 Dec 2022; 19:e1004140</small></div>
Osetinsky B, Mhalu G, Mtenga S, Tediosi F
PLoS Med: 05 Dec 2022; 19:e1004140 | PMID: 36469527
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<div><h4>Understanding ethnic inequalities in mental healthcare in the UK: A meta-ethnography.</h4><i>Bansal N, Karlsen S, Sashidharan SP, Cohen R, Chew-Graham CA, Malpass A</i><br /><b>Background</b><br />Evidence regarding the presence and persistence of ethnic inequalities in mental healthcare is well established. The reasons for these inequalities and lack of progress in diminishing them are less understood. This meta-ethnography aims to provide a new conceptual understanding of how ethnic inequalities are created and sustained; this is essential to develop effective interventions. Specifically, we sought to understand why people from ethnic minority groups are underrepresented in primary care mental health service provision and overrepresented in crisis pathways and detention.<br /><b>Methods and findings</b><br />Following eMERGe guidelines for meta-ethnographies, we searched OpenGrey, Kings Fund, CINAHL, Medline, PsycINFO, and Social Care Online databases for qualitative articles published from database inception until October 2, 2022, using broad categories of search terms relating to \"ethnicity AND (mental illness/mental health/emotional distress) AND (help-seeking/service utilisation/experience/perception/view).\" We included all conceptually rich articles that used qualitative methods of data collection and analysis and excluded non-UK studies and those that focused solely on causation of mental illness. Our patient, public, and practitioner lived experience advisory group provided feedback and input on key stages of the project including search terms, research questions, data analysis, and dissemination. A total of 14,142 articles were identified; 66 met the inclusion criteria. We used reciprocal, refutational, and line of argument analytical approaches to identify convergence and divergence between studies. The synthesis showed that current models of statutory mental healthcare are experienced as a major barrier to the delivery of person-centred care to those in ethnic minority groups due to the perceived dominance of monocultural and reductionist frameworks of assessment and treatment (described as \"medical\" and \"Eurocentric\") and direct experiences of racist practice. The lack of socially oriented and holistic frameworks of knowledge and understanding in medical training and services is experienced as epistemic injustice, particularly among those who attribute their mental illness to experiences of migration, systemic racism, and complex trauma. Fear of harm, concerns about treatment suitability, and negative experiences with health providers such as racist care and medical neglect/injury contribute to avoidance of, and disengagement from, mainstream healthcare. The lack of progress in tackling ethnic inequalities is attributed to failures in coproduction and insufficient adoption of existing recommendations within services. Study limitations include insufficient recording of participant characteristics relating to generational status and social class in primary studies, which prevented exploration of these intersections.<br /><b>Conclusions</b><br />In this study, we found that the delivery of safe and equitable person-centred care requires a model of mental health that is responsive to the lived experiences of people in ethnic minority groups. For the people considered in this review, this requires better alignment of mental health services with social and anti-racist models of care. Our findings suggest that intersections related to experiences of racism, migration, religion, and complex trauma might be more relevant than crude ethnic group classifications. Strategies to tackle ethnic inequalities in mental healthcare require an evaluation of individual, systemic, and structural obstacles to authentic and meaningful coproduction and implementation of existing community recommendations in services.<br /><br />Copyright: © 2022 Bansal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Dec 2022; 19:e1004139</small></div>
Bansal N, Karlsen S, Sashidharan SP, Cohen R, Chew-Graham CA, Malpass A
PLoS Med: 01 Dec 2022; 19:e1004139 | PMID: 36512523
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<div><h4>Discontinuation and tapering of prescribed opioids and risk of overdose among people on long-term opioid therapy for pain with and without opioid use disorder in British Columbia, Canada: A retrospective cohort study.</h4><i>Kennedy MC, Crabtree A, Nolan S, Mok WY, ... Slaunwhite A, Ti L</i><br /><b>Background</b><br />The overdose crisis in North America has prompted system-level efforts to restrict opioid prescribing for chronic pain. However, little is known about how discontinuing or tapering prescribed opioids for chronic pain shapes overdose risk, including possible differential effects among people with and without concurrent opioid use disorder (OUD). We examined associations between discontinuation and tapering of prescribed opioids and risk of overdose among people on long-term opioid therapy for pain, stratified by diagnosed OUD and prescribed opioid agonist therapy (OAT) status.<br /><b>Methods and findings</b><br />For this retrospective cohort study, we used a 20% random sample of residents in the provincial health insurance client roster in British Columbia (BC), Canada, contained in the BC Provincial Overdose Cohort. The study sample included persons aged 14 to 74 years on long-term opioid therapy for pain (≥90 days with ≥90% of days on therapy) between October 2014 and June 2018 (n = 14,037). At baseline, 7,256 (51.7%) persons were female, the median age was 55 years (quartile 1-3: 47-63), 227 (1.6%) persons had been diagnosed with OUD (in the past 3 years) and recently (i.e., in the past 90 days) been prescribed OAT, and 483 (3.4%) had been diagnosed with OUD but not recently prescribed OAT. The median follow-up duration per person was 3.7 years (quartile 1-3: 2.6-4.0). Marginal structural Cox regression with inverse probability of treatment weighting (IPTW) was used to estimate the effect of prescribed opioid treatment for pain status (discontinuation versus tapered therapy versus continued therapy [reference]) on risk of overdose (fatal or nonfatal), stratified by the following groups: people without diagnosed OUD, people with diagnosed OUD receiving OAT, and people with diagnosed OUD not receiving OAT. In marginal structural models with IPTW adjusted for a range of demographic, prescription, comorbidity, and social-structural exposures, discontinuing opioids (i.e., ≥7-day gap[s] in therapy) was associated with increased overdose risk among people without OUD (adjusted hazard ratio [AHR] = 1.44; 95% confidence interval [CI] 1.12, 1.83; p = 0.004), people with OUD not receiving OAT (AHR = 3.18; 95% CI 1.87, 5.40; p < 0.001), and people with OUD receiving OAT (AHR = 2.52; 95% CI 1.68, 3.78; p < 0.001). Opioid tapering (i.e., ≥2 sequential decreases of ≥5% in average daily morphine milligram equivalents) was associated with decreased overdose risk among people with OUD not receiving OAT (AHR = 0.31; 95% CI 0.14, 0.67; p = 0.003). The main study limitations are that the outcome measure did not capture overdose events that did not result in a healthcare encounter or death, medication dispensation may not reflect medication adherence, residual confounding may have influenced findings, and findings may not be generalizable to persons on opioid therapy in other settings.<br /><b>Conclusions</b><br />Discontinuing prescribed opioids was associated with increased overdose risk, particularly among people with OUD. Prescribed opioid tapering was associated with reduced overdose risk among people with OUD not receiving OAT. These findings highlight the need to avoid abrupt discontinuation of opioids for pain. Enhanced guidance is needed to support prescribers in implementing opioid therapy tapering strategies with consideration of OUD and OAT status.<br /><br />Copyright: © 2022 Kennedy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Dec 2022; 19:e1004123</small></div>
Abstract
<div><h4>Association between primary or booster COVID-19 mRNA vaccination and Omicron lineage BA.1 SARS-CoV-2 infection in people with a prior SARS-CoV-2 infection: A test-negative case-control analysis.</h4><i>Lind ML, Robertson AJ, Silva J, Warner F, ... Hitchings MDT, Schulz WL</i><br /><b>Background</b><br />The benefit of primary and booster vaccination in people who experienced a prior Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection remains unclear. The objective of this study was to estimate the effectiveness of primary (two-dose series) and booster (third dose) mRNA vaccination against Omicron (lineage BA.1) infection among people with a prior documented infection.<br /><b>Methods and findings</b><br />We conducted a test-negative case-control study of reverse transcription PCRs (RT-PCRs) analyzed with the TaqPath (Thermo Fisher Scientific) assay and recorded in the Yale New Haven Health system from November 1, 2021, to April 30, 2022. Overall, 11,307 cases (positive TaqPath analyzed RT-PCRs with S-gene target failure [SGTF]) and 130,041 controls (negative TaqPath analyzed RT-PCRs) were included (median age: cases: 35 years, controls: 39 years). Among cases and controls, 5.9% and 8.1% had a documented prior infection (positive SARS-CoV-2 test record ≥90 days prior to the included test), respectively. We estimated the effectiveness of primary and booster vaccination relative to SGTF-defined Omicron (lineage BA.1) variant infection using a logistic regression adjusted for date of test, age, sex, race/ethnicity, insurance, comorbidities, social venerability index, municipality, and healthcare utilization. The effectiveness of primary vaccination 14 to 149 days after the second dose was 41.0% (95% confidence interval (CI): 14.1% to 59.4%, p 0.006) and 27.1% (95% CI: 18.7% to 34.6%, p < 0.001) for people with and without a documented prior infection, respectively. The effectiveness of booster vaccination (≥14 days after booster dose) was 47.1% (95% CI: 22.4% to 63.9%, p 0.001) and 54.1% (95% CI: 49.2% to 58.4%, p < 0.001) in people with and without a documented prior infection, respectively. To test whether booster vaccination reduced the risk of infection beyond that of the primary series, we compared the odds of infection among boosted (≥14 days after booster dose) and booster-eligible people (≥150 days after second dose). The odds ratio (OR) comparing boosted and booster-eligible people with a documented prior infection was 0.79 (95% CI: 0.54 to 1.16, p 0.222), whereas the OR comparing boosted and booster-eligible people without a documented prior infection was 0.54 (95% CI: 0.49 to 0.59, p < 0.001). This study\'s limitations include the risk of residual confounding, the use of data from a single system, and the reliance on TaqPath analyzed RT-PCR results.<br /><b>Conclusions</b><br />In this study, we observed that primary vaccination provided significant but limited protection against Omicron (lineage BA.1) infection among people with and without a documented prior infection. While booster vaccination was associated with additional protection against Omicron BA.1 infection in people without a documented prior infection, it was not found to be associated with additional protection among people with a documented prior infection. These findings support primary vaccination in people regardless of documented prior infection status but suggest that infection history may impact the relative benefit of booster doses.<br /><br />Copyright: © 2022 Lind et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Dec 2022; 19:e1004136</small></div>
Lind ML, Robertson AJ, Silva J, Warner F, ... Hitchings MDT, Schulz WL
PLoS Med: 01 Dec 2022; 19:e1004136 | PMID: 36454733
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<div><h4>Associations of genetically predicted fatty acid levels across the phenome: A mendelian randomisation study.</h4><i>Zagkos L, Dib MJ, Pinto R, Gill D, ... Dehghan A, Tzoulaki I</i><br /><b>Background</b><br />Fatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes.<br /><b>Methods and findings</b><br />The UK Biobank (UKB) is a large study involving over 500,000 participants aged 40 to 69 years at recruitment from 2006 to 2010. We used summary-level data for 117,143 UKB samples (base dataset), to extract genetic associations of fatty acids, and individual-level data for 322,232 UKB participants (target dataset) to conduct our discovery analysis. We studied potentially causal relationships of circulating fatty acids with 845 clinical diagnoses, using mendelian randomisation (MR) approach, within a phenome-wide association study (PheWAS) framework. Regression models in PheWAS were adjusted for sex, age, and the first 10 genetic principal components. External summary statistics were used for replication. When several fatty acids were associated with a health outcome, multivariable MR and MR-Bayesian method averaging (MR-BMA) was applied to disentangle their causal role. Genetic predisposition to higher docosahexaenoic acid (DHA) was associated with cholelithiasis and cholecystitis (odds ratio per mmol/L: 0.76, 95% confidence interval: 0.66 to 0.87). This was supported in replication analysis (FinnGen study) and by the genetically predicted omega-3 fatty acids analyses. Genetically predicted linoleic acid (LA), omega-6, polyunsaturated fatty acids (PUFAs), and total fatty acids (total FAs) showed positive associations with cardiovascular outcomes with support from replication analysis. Finally, higher genetically predicted levels of DHA (0.83, 0.73 to 0.95) and omega-3 (0.83, 0.75 to 0.92) were found to have a protective effect on obesity, which was supported using body mass index (BMI) in the GIANT consortium as replication analysis. Multivariable MR analysis suggested a direct detrimental effect of LA (1.64, 1.07 to 2.50) and omega-6 fatty acids (1.81, 1.06 to 3.09) on coronary heart disease (CHD). MR-BMA prioritised LA and omega-6 fatty acids as the top risk factors for CHD. Although we present a range of sensitivity analyses to the address MR assumptions, horizontal pleiotropy may still bias the reported associations and further evaluation in clinical trials is needed.<br /><b>Conclusions</b><br />Our study suggests potentially protective effects of circulating DHA and omega-3 concentrations on cholelithiasis and cholecystitis and on obesity, highlighting the need to further assess them as prevention treatments in clinical trials. Moreover, our findings do not support the supplementation of unsaturated fatty acids for cardiovascular disease prevention.<br /><br />Copyright: © 2022 Zagkos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Dec 2022; 19:e1004141</small></div>
Zagkos L, Dib MJ, Pinto R, Gill D, ... Dehghan A, Tzoulaki I
PLoS Med: 01 Dec 2022; 19:e1004141 | PMID: 36580444
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<div><h4>A peer-facilitated psychological group intervention for perinatal women living with HIV and depression in Tanzania-Healthy Options: A cluster-randomized controlled trial.</h4><i>Kaaya S, Siril H, Fawzi MCS, Aloyce Z, ... Sudfeld CR, Larson E</i><br /><b>Background</b><br />Perinatal women living with HIV (PWLH) have a greater risk of depression compared to other women; however, there are limited specialized mental health services available to them. We aimed to determine whether a stepped-care intervention facilitated by trained lay providers can improve mental health outcomes postpartum for PWLH.<br /><b>Methods and findings</b><br />Healthy Options is a cluster-randomized controlled study conducted in 16 government-managed antenatal care clinics that provided HIV care for pregnant women in urban Tanzania. Recruitment occurred from May 2015 through April 2016, with the final round of data collection completed in October 2017. Participants included a consecutive sample of pregnant women under 30 weeks of gestation, living with HIV and depression, and attending the study clinics. Control sites received enhanced usual care for depression (EUDC). Intervention sites received EUDC plus the Healthy Options intervention, which includes prenatal group sessions of problem-solving therapy (PST) plus cognitive behavioral therapy (CBT) sessions for individuals showing depressive symptoms at 6 weeks postdelivery. We assessed depressive symptoms comparable to major depressive disorder (MDD) using the Patient Health Questionnaire-9 (PHQ-9) with a locally validated cutoff at 9 months and 6 weeks postpartum. The primary time point is 9 months postpartum. We examined differences in outcomes using an intent-to-treat analysis with a complete case approach, meaning those with data at the relevant time point were included in the analysis. We used generalized estimating equations accounting for clustering. Of 818 women screened using the PHQ-9, 742 were determined eligible and enrolled (395 intervention; 347 control); 649 women (87.5%) participated in the first follow-up and 641 women (86.4%) in the second. A majority (270, 74.6%) of women in the intervention arm attended 5 or more PST sessions. Women enrolled in Healthy Options demonstrated a 67% (RR 0.33; 95% CI: 0.22, 0.51; p-value: <0.001; corresponding to a 25.7% difference in absolute risk) lower likelihood of depressive symptoms than women in control clusters at 6 weeks postpartum. At 9 months postpartum, women enrolled in Healthy Options demonstrated a nonsignificant 26% (RR 0.74; 95% CI: 0.42, 1.3; p-value: 0.281; corresponding to a 3.2% difference in absolute risk) lower likelihood of depressive symptoms than women in control clusters. Study limitations include not using diagnostic interviews to measure depression and not blinding data collectors to intervention status during follow-up.<br /><b>Conclusions</b><br />The Healthy Options intervention did not demonstrate reduction in depressive symptoms at 9 months postpartum, the primary outcome. Significant reductions were seen in depression symptoms at 6 weeks postpartum, the secondary outcome. Stepped-care interventions may be relevant for improving outcomes in the critical early postpartum window.<br /><b>Trial registration</b><br />Clinical Trial registration number (closed to new participants) NCT02039973.<br /><br />Copyright: © 2022 Kaaya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Dec 2022; 19:e1004112</small></div>
Kaaya S, Siril H, Fawzi MCS, Aloyce Z, ... Sudfeld CR, Larson E
PLoS Med: 01 Dec 2022; 19:e1004112 | PMID: 36512631
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<div><h4>Addressing the diagnostic gap in hypertension through possible interventions and scale-up: A microsimulation study.</h4><i>Koeppel L, Dittrich S, Brenner Miguel S, Carmona S, ... Denkinger CM, HPACC Consortium</i><br /><b>Background</b><br />Cardiovascular diseases (CVDs) are the leading cause of mortality globally with almost a third of all annual deaths worldwide. Low- and middle-income countries (LMICs) are disproportionately highly affected covering 80% of these deaths. For CVD, hypertension (HTN) is the leading modifiable risk factor. The comparative impact of diagnostic interventions that improve either the accuracy, the reach, or the completion of HTN screening in comparison to the current standard of care has not been estimated.<br /><b>Methods and findings</b><br />This microsimulation study estimated the impact on HTN-induced morbidity and mortality in LMICs for four different scenarios: (S1) lower HTN diagnostic accuracy; (S2) improved HTN diagnostic accuracy; (S3) better implementation strategies to reach more persons with existing tools; and, lastly, (S4) the wider use of easy-to-use tools, such as validated, automated digital blood pressure measurement devices to enhance screening completion, in comparison to the current standard of care (S0). Our hypothetical population was parametrized using nationally representative, individual-level HPACC data and the global burden of disease data. The prevalence of HTN in the population was 31% out of which 60% remained undiagnosed. We investigated how the alteration of a yearly blood pressure screening event impacts morbidity and mortality in the population over a period of 10 years. The study showed that while improving test accuracy avoids 0.6% of HTN-induced deaths over 10 years (13,856,507 [9,382,742; 17,395,833]), almost 40 million (39,650,363 [31,34,233, 49,298,921], i.e., 12.7% [9.9, 15.8]) of the HTN-induced deaths could be prevented by increasing coverage and completion of a screening event in the same time frame. Doubling the coverage only would still prevent 3,304,212 million ([2,274,664; 4,164,180], 12.1% [8.3, 15.2]) CVD events 10 years after the rollout of the program. Our study is limited by the scarce data available on HTN and CVD from LMICs. We had to pool some parameters across stratification groups, and additional information, such as dietary habits, lifestyle choice, or the blood pressure evolution, could not be considered. Nevertheless, the microsimulation enabled us to include substantial heterogeneity and stochasticity toward the different income groups and personal CVD risk scores in the model.<br /><b>Conclusions</b><br />While it is important to consider investing in newer diagnostics for blood pressure testing to continuously improve ease of use and accuracy, more emphasis should be placed on screening completion.<br /><br />Copyright: © 2022 Koeppel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Dec 2022; 19:e1004111</small></div>
Koeppel L, Dittrich S, Brenner Miguel S, Carmona S, ... Denkinger CM, HPACC Consortium
PLoS Med: 01 Dec 2022; 19:e1004111 | PMID: 36472973
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<div><h4>Estimated economic burden of genital herpes and HIV attributable to herpes simplex virus type 2 infections in 90 low- and middle-income countries: A modeling study.</h4><i>Silva S, Ayoub HH, Johnston C, Atun R, Abu-Raddad LJ</i><br /><b>Background</b><br />Economic losses due to herpes simplex infections in low- and middle-income countries (LMICs) are unknown. We estimated economic and quality-of-life losses due to genital herpes in 2019, in 90 LMICs, and from 2020 to 2030 in 45 countries in the World Health Organization (WHO) Africa. We additionally estimated economic losses due to human immunodeficiency virus (HIV) attributable to herpes simplex virus type 2 (HSV-2) infections.<br /><b>Methods and findings</b><br />We estimated genital herpes-related spending on treatment, wage losses due to absenteeism, and reductions in quality of life, for individuals aged 15 to 49 years, living with genital herpes. Had HSV-2 had contributed to the transmission of HIV, we estimated the share of antiretroviral treatment costs and HIV-related wage losses in 2019 that can be attributed to incident and prevalent HSV-2 infections in 2018. For the former, we used estimates of HSV-2 incidence and prevalence from the global burden of disease (GBD) study. For the latter, we calculated population attributable fractions (PAFs), using the classic (Levin\'s) epidemiological formula for polytomous exposures, with relative risks (RRs) reported in literature. To extend estimates from 2020 to 2030, we modeled the transmission of HSV-2 in 45 African countries using a deterministic compartmental mathematical model, structured by age, sex, and sexual activity, which was fitted to seroprevalence gathered from a systematic review and meta-regression analysis. In the 90 LMICs, genital herpes contributed to US$813.5 million in treatment and productivity losses in 2019 (range: US$674.4 to US$952.2 million). Given observed care-seeking and absenteeism, losses are in the range of US$29.0 billion (US$25.6 billion to US$34.5 billion). Quality-of-life losses in the amount of 61.7 million quality-adjusted life years (QALYs) are also possible (50.4 million to 74.2 million). The mean annual cost of treatment and wage losses per infection is US$183.00 (95% CI: US$153.60 to US$212.55); the mean annual cost of quality-of-life losses is US$343.27 (95% CI: 272.41 to 414.14). If HSV-2 has fueled the transmission of HIV, then seroprevalent HSV-2 cases in 2018 can account for 33.2% of the incident HIV infections in 2019, with an associated antiretroviral therapy (ART) cost of US$186.3 million (range: US$163.6 to US$209.5 million) and 28.6% of HIV-related wage losses (US$21.9 million; range: US$19.2 to US$27.4 million). In the WHO Africa region, the 3.9 million seroprevalent genital herpes cases from 2020 to 2030 contributed to US$700.2 million in treatment and productivity losses. Additionally, quality-of-life losses in the range of 88 million to 871 million QALYs are also possible. If HSV-2 has contributed to the transmission of HIV, then in 2020, the PAF of HIV due to prevalent HSV-2 will be 32.8% (95% CI: 26.7% to 29.9%) and due to incident infections will be 4.2% (95% CI: 2.6% to 3.4%). The PAF due to prevalent infections will decline to 31.0% by 2030 and incident infections to 3.6%. Though we have accounted for the uncertainty in the epidemiological and economic parameter values via the sensitivity analysis, our estimates still undervalue losses due to limiting to the 15- to 49-year-old population.<br /><b>Conclusions</b><br />Economic losses due to genital herpes in LMICs can be large, especially when considering the lifelong nature of the disease. Quality-of-life losses outweigh spending on treatment and reductions in productivity. If HSV-2 has contributed to the spread of HIV in LMICs, then nearly one third of antiretroviral costs and HIV-related wage losses can be attributed to HSV-2. Given the magnitude of the combined losses, a vaccine against HSV-2 must be a global priority.<br /><br />Copyright: © 2022 Silva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Dec 2022; 19:e1003938</small></div>
Silva S, Ayoub HH, Johnston C, Atun R, Abu-Raddad LJ
PLoS Med: 01 Dec 2022; 19:e1003938 | PMID: 36520853
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<div><h4>Infection and transmission risks of COVID-19 in schools and their contribution to population infections in Germany: A retrospective observational study using nationwide and regional health and education agency notification data.</h4><i>Heinsohn T, Lange B, Vanella P, Rodiah I, ... Dötsch J, Krause G</i><br /><b>Background</b><br />School-level infection control measures in Germany during the early Coronavirus Disease 2019 (COVID-19) pandemic differed across the 16 federal states and lacked a dependable evidence base, with available evidence limited to regional data restricted to short phases of the pandemic. This study aimed to assess the (a) infection risks in students and staff; (b) transmission risks and routes in schools; (c) effects of school-level infection control measures on school and population infection dynamics; and (d) contribution of contacts in schools to population cases.<br /><b>Methods and findings</b><br />For this retrospective observational study, we used German federal state (NUTS-2) and county (NUTS-3) data from public health and education agencies from March 2020 to April 2022. We assessed (a) infection risk as cumulative risk and crude risk ratios and (b) secondary attack rates (SARs) with 95% confidence interval (CI). We used (c) multiple regression analysis for the effects of infection control measures such as reduced attendance, mask mandates, and vaccination coverage as absolute reduction in case incidence per 100,000 inhabitants per 14 days and in percentage relative to the population, and (d) infection dynamic modelling to determine the percentage contribution of school contacts to population cases. We included (a) nationwide NUTS-2 data from calendar weeks (W) 46-50/2020 and W08/2021-W15/2022 with 3,521,964 cases in students and 329,283 in teachers; (b) NUTS-3 data from W09-25/2021 with 85,788 student and 9,427 teacher cases; and (c) detailed data from 5 NUTS-3 regions from W09/2020 to W27/2021 with 12,814 cases (39% male, 37% female; median age 14, range 5 to 63), 43,238 contacts and 4,165 secondary cases for students (for teachers, 14,801 [22% male, 50% female; median age 39, range 16 to 75], 5,893 and 472). Infection risk (a) for students and teachers was higher than the population risk in all phases of normal presence class and highest in the early 2022 omicron wave with 30.6% (95% CI 30.5% to 32.6%) of students and 32.7% (95% CI 32.6% to 32.8%) of teachers infected in Germany. SARs (b) for students and staff were below 5% in schools throughout the study period, while SARs in households more than doubled from 13.8% (95% CI 10.6% to 17.6%) W21-39/2020 to 28.7% (95% CI 27% to 30.4%) in W08-23/2021 for students and 10.9% (95% CI 7% to 16.5%) to 32.7% (95% CI 28.2% to 37.6%) for staff. Most contacts were reported for schools, yet most secondary cases originated in households. In schools, staff predominantly infected staff. Mandatory surgical mask wearing during class in all schools was associated with a reduction in the case incidence of students and teachers (c), by 56/100,000 persons per 14 days (students: 95% CI 47.7 to 63.4; teachers: 95% CI 39.6 to 71.6; p < 0.001) and by 29.8% (95% CI 25% to 35%, p < 0.001) and 24.3% (95% CI 13% to 36%, p < 0.001) relative to the population, respectively, as were reduced attendance and higher vaccination coverage. The contribution of contacts in schools to population cases (d) was 2% to 20%, lowest during school closures/vacation and peaked during normal presence class intervals, with the overall peak early during the omicron wave. Limitations include underdetection, misclassification of contacts, interviewer/interviewee dependence of contact-tracing, and lack of individual-level confounding factors in aggregate data regression analysis.<br /><b>Conclusion</b><br />In this study, we observed that open schools under hygiene measures and testing strategies contributed up to 20% of population infections during the omicron wave early 2022, and as little as 2% during vacations/school closures; about a third of students and teachers were infected during the omicron wave in early 2022 in Germany. Mandatory mask wearing during class in all school types and reduced attendance models were associated with a reduced infection risk in schools.<br /><br />Copyright: © 2022 Heinsohn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Dec 2022; 19:e1003913</small></div>
Abstract
<div><h4>Association between antidementia medication use and mortality in people diagnosed with dementia with Lewy bodies in the UK: A retrospective cohort study.</h4><i>Chen S, Price AC, Cardinal RN, Moylett S, ... Stewart R, O\'Brien JT</i><br /><b>Background</b><br />Dementia with Lewy bodies (DLBs) is a common cause of dementia but has higher mortality than Alzheimer\'s disease (AD). The reasons for this are unclear, but antidementia drugs (including acetylcholinesterase inhibitors [AChEIs] and memantine) symptomatically benefit people with DLB and might improve outcomes. We investigated whether AChEIs and/or memantine were associated with reduced hospital admissions and mortality.<br /><b>Methods and findings</b><br />We performed a retrospective cohort study of those diagnosed with DLB between 1 January 2005 and 31 December 2019, using data from electronic clinical records of secondary care mental health services in Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), United Kingdom (catchment area population approximately 0.86 million), as well as linked records from national Hospital Episode Statistics (HES) data. Eligible patients were those who started AChEIs or memantine within 3 months of their diagnosis (cases) and those who never used AChEIs or memantine (controls). Outcomes included admission, length of stay, and mortality. Cox proportional hazard and linear regression models were used. Of 592 patients with DLB, 219 never took AChEIs or memantine, 100 took AChEIs only, and 273 took both AChEIs and memantine. The cohorts were followed up for an average of 896 days, 981 days, and 1,004 days, respectively. There were no significant differences in the cohorts\' baseline characteristics, except for socioeconomic status that was lower in patients who never took AChEIs or memantine (χ2 = 23.34, P = 0.003). After controlling for confounding by sociodemographic factors (age, sex, marital status, ethnicity, socioeconomic status), antipsychotic use, antidepressant use, cognitive status, physical comorbidity, anticholinergic burden, and global health performance, compared with patients who never took AChEIs or memantine, patients taking AChEIs only or taking both had a significantly lower risk of death (adjusted hazard ratio (HR) = 0.67, 95% CI = 0.48 to 0.93, p = 0.02; adjusted HR = 0.64, 95% CI = 0.50 to 0.83, P = 0.001, respectively). Those taking AChEIs or both AChEIs and memantine had significantly shorter periods of unplanned hospital admission for physical disorders (adjusted coefficient -13.48, 95% CI = [-26.87, -0.09], P = 0.049; adjusted coefficient -14.21, 95% CI = [-24.58, -3.85], P = 0.007, respectively), but no difference in length of stay for planned admissions for physical disorders, or for admissions for mental health disorders. No significant additional associations of memantine on admission, length of stay, and mortality were found (all P > 0.05). The main limitation was that this was a naturalistic study and possible confounds cannot be fully controlled, and there may be selection bias resulting from nonrandom prescription behaviour in clinical practice. However, we mimicked the intention-to-treat design of clinical trials, and the majority of baseline characters were balanced between cohorts. In addition, our series of sensitivity analyses confirmed the consistency of our results.<br /><b>Conclusion</b><br />In this study, we observed that use of AChEIs with or without memantine in DLB was associated with shorter duration of hospital admissions and decreased risk of mortality. Although our study was naturalistic, it supports further the use of AChEIs in DLB.<br /><br />Copyright: © 2022 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Dec 2022; 19:e1004124</small></div>
Chen S, Price AC, Cardinal RN, Moylett S, ... Stewart R, O'Brien JT
PLoS Med: 01 Dec 2022; 19:e1004124 | PMID: 36472984
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<div><h4>Scaling-up a pharmacist-led information technology intervention (PINCER) to reduce hazardous prescribing in general practices: Multiple interrupted time series study.</h4><i>Rodgers S, Taylor AC, Roberts SA, Allen T, ... Siriwardena AN, Avery AJ</i><br /><b>Background</b><br />We previously reported on a randomised trial demonstrating the effectiveness and cost-effectiveness of a pharmacist-led information technology intervention (PINCER). We sought to investigate whether PINCER was effective in reducing hazardous prescribing when rolled out at scale in UK general practices.<br /><b>Methods and findings</b><br />We used a multiple interrupted time series design whereby successive groups of general practices received the PINCER intervention between September 2015 and April 2017. We used 11 prescribing safety indicators to identify potentially hazardous prescribing and collected data over a maximum of 16 quarterly time periods. The primary outcome was a composite of all the indicators; a composite for indicators associated with gastrointestinal (GI) bleeding was also reported, along with 11 individual indicators of hazardous prescribing. Data were analysed using logistic mixed models for the quarterly event numbers with the appropriate denominator, and calendar time included as a covariate. PINCER was implemented in 370 (94.1%) of 393 general practices covering a population of almost 3 million patients in the East Midlands region of England; data were successfully extracted from 343 (92.7%) of these practices. For the primary composite outcome, the PINCER intervention was associated with a decrease in the rate of hazardous prescribing of 16.7% (adjusted odds ratio (aOR) 0.83, 95% confidence interval (CI) 0.80 to 0.86) at 6 months and 15.3% (aOR 0.85, 95% CI 0.80 to 0.90) at 12 months postintervention. The unadjusted rate of hazardous prescribing reduced from 26.4% (22,503 patients in the numerator/853,631 patients in the denominator) to 20.1% (11,901 patients in the numerator/591,364 patients in the denominator) at 6 months and 19.1% (3,868 patients in the numerator/201,992 patients in the denominator). The greatest reduction in hazardous prescribing associated with the intervention was observed for the indicators associated with GI bleeding; for the GI composite indicator, there was a decrease of 23.9% at both 6 months (aOR 0.76, 95% CI 0.73 to 0.80) and 12 months (aOR 0.76, 95% CI 0.70 to 0.82) postintervention. The unadjusted rate of hazardous prescribing reduced from 31.4 (16,185 patients in the numerator/515,879 patients in the denominator) to 21.2% (7,607 patients in the numerator/358,349 patients in the denominator) at 6 months and 19.5% (2,369 patients in the numerator/121,534 patients in the denominator). We adjusted for calendar time and practice, but since this was an observational study, the findings may have been influenced by unknown confounding factors or behavioural changes unrelated to the PINCER intervention. Data were also not collected for all practices at 6 months and 12 months postintervention.<br /><b>Conclusions</b><br />The PINCER intervention, when rolled out at scale in routine clinical practice, was associated with a reduction in hazardous prescribing by 17% and 15% at 6 and 12 months postintervention. The greatest reductions in hazardous prescribing were for indicators associated with risk of GI bleeding. These findings support the wider national rollout of PINCER in England.<br /><br />Copyright: © 2022 Rodgers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 16 Nov 2022; 19:e1004133</small></div>
Rodgers S, Taylor AC, Roberts SA, Allen T, ... Siriwardena AN, Avery AJ
PLoS Med: 16 Nov 2022; 19:e1004133 | PMID: 36383560
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<div><h4>Risk and symptoms of COVID-19 in health professionals according to baseline immune status and booster vaccination during the Delta and Omicron waves in Switzerland-A multicentre cohort study.</h4><i>Babouee Flury B, Güsewell S, Egger T, Leal O, ... Kohler P, SURPRISE Study Group</i><br /><b>Background</b><br />Knowledge about protection conferred by previous Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and/or vaccination against emerging viral variants allows clinicians, epidemiologists, and health authorities to predict and reduce the future Coronavirus Disease 2019 (COVID-19) burden. We investigated the risk and symptoms of SARS-CoV-2 (re)infection and vaccine breakthrough infection during the Delta and Omicron waves, depending on baseline immune status and subsequent vaccinations.<br /><b>Methods and findings</b><br />In this prospective, multicentre cohort performed between August 2020 and March 2022, we recruited hospital employees from ten acute/nonacute healthcare networks in Eastern/Northern Switzerland. We determined immune status in September 2021 based on serology and previous SARS-CoV-2 infections/vaccinations: Group N (no immunity); Group V (twice vaccinated, uninfected); Group I (infected, unvaccinated); Group H (hybrid: infected and ≥1 vaccination). Date and symptoms of (re)infections and subsequent (booster) vaccinations were recorded until March 2022. We compared the time to positive SARS-CoV-2 swab and number of symptoms according to immune status, viral variant (i.e., Delta-dominant before December 27, 2021; Omicron-dominant on/after this date), and subsequent vaccinations, adjusting for exposure/behavior variables. Among 2,595 participants (median follow-up 171 days), we observed 764 (29%) (re)infections, thereof 591 during the Omicron period. Compared to group N, the hazard ratio (HR) for (re)infection was 0.33 (95% confidence interval [CI] 0.22 to 0.50, p < 0.001) for V, 0.25 (95% CI 0.11 to 0.57, p = 0.001) for I, and 0.04 (95% CI 0.02 to 0.10, p < 0.001) for H in the Delta period. HRs substantially increased during the Omicron period for all groups; in multivariable analyses, only belonging to group H was associated with protection (adjusted HR [aHR] 0.52, 95% CI 0.35 to 0.77, p = 0.001); booster vaccination was associated with reduction of breakthrough infection risk in groups V (aHR 0.68, 95% CI 0.54 to 0.85, p = 0.001) and H (aHR 0.67, 95% CI 0.45 to 1.00, p = 0.048), largely observed in the early Omicron period. Group H (versus N, risk ratio (RR) 0.80, 95% CI 0.66 to 0.97, p = 0.021) and participants with booster vaccination (versus nonboosted, RR 0.79, 95% CI 0.71 to 0.88, p < 0.001) reported less symptoms during infection. Important limitations are that SARS-CoV-2 swab results were self-reported and that results on viral variants were inferred from the predominating strain circulating in the community at that time, rather than sequencing.<br /><b>Conclusions</b><br />Our data suggest that hybrid immunity and booster vaccination are associated with a reduced risk and reduced symptom number of SARS-CoV-2 infection during Delta- and Omicron-dominant periods. For previously noninfected individuals, booster vaccination might reduce the risk of symptomatic Omicron infection, although this benefit seems to wane over time.<br /><br />Copyright: © 2022 Babouee Flury et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 07 Nov 2022; 19:e1004125</small></div>
Babouee Flury B, Güsewell S, Egger T, Leal O, ... Kohler P, SURPRISE Study Group
PLoS Med: 07 Nov 2022; 19:e1004125 | PMID: 36342956
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This program is still in alpha version.