Showing papers in "PLOS Medicine in 2021"

The PRISMA 2020 statement: An updated guideline for reporting systematic reviews.

Abstract: Matthew Page and co-authors describe PRISMA 2020, an updated reporting guideline for systematic reviews and meta-analyses.

Accuracy of novel antigen rapid diagnostics for SARS-CoV-2: A living systematic review and meta-analysis.

Abstract: Background SARS-CoV-2 antigen rapid diagnostic tests (Ag-RDTs) are increasingly being integrated in testing strategies around the world. Studies of the Ag-RDTs have shown variable performance. In this systematic review and meta-analysis, we assessed the clinical accuracy (sensitivity and specificity) of commercially available Ag-RDTs. Methods and findings We registered the review on PROSPERO (registration number: CRD42020225140). We systematically searched multiple databases (PubMed, Web of Science Core Collection, medRvix, bioRvix, and FIND) for publications evaluating the accuracy of Ag-RDTs for SARS-CoV-2 up until 30 April 2021. Descriptive analyses of all studies were performed, and when more than 4 studies were available, a random-effects meta-analysis was used to estimate pooled sensitivity and specificity in comparison to reverse transcription polymerase chain reaction (RT-PCR) testing. We assessed heterogeneity by subgroup analyses, and rated study quality and risk of bias using the QUADAS-2 assessment tool. From a total of 14,254 articles, we included 133 analytical and clinical studies resulting in 214 clinical accuracy datasets with 112,323 samples. Across all meta-analyzed samples, the pooled Ag-RDT sensitivity and specificity were 71.2% (95% CI 68.2% to 74.0%) and 98.9% (95% CI 98.6% to 99.1%), respectively. Sensitivity increased to 76.3% (95% CI 73.1% to 79.2%) if analysis was restricted to studies that followed the Ag-RDT manufacturers’ instructions. LumiraDx showed the highest sensitivity, with 88.2% (95% CI 59.0% to 97.5%). Of instrument-free Ag-RDTs, Standard Q nasal performed best, with 80.2% sensitivity (95% CI 70.3% to 87.4%). Across all Ag-RDTs, sensitivity was markedly better on samples with lower RT-PCR cycle threshold (Ct) values, i.e., <20 (96.5%, 95% CI 92.6% to 98.4%) and <25 (95.8%, 95% CI 92.3% to 97.8%), in comparison to those with Ct ≥ 25 (50.7%, 95% CI 35.6% to 65.8%) and ≥30 (20.9%, 95% CI 12.5% to 32.8%). Testing in the first week from symptom onset resulted in substantially higher sensitivity (83.8%, 95% CI 76.3% to 89.2%) compared to testing after 1 week (61.5%, 95% CI 52.2% to 70.0%). The best Ag-RDT sensitivity was found with anterior nasal sampling (75.5%, 95% CI 70.4% to 79.9%), in comparison to other sample types (e.g., nasopharyngeal, 71.6%, 95% CI 68.1% to 74.9%), although CIs were overlapping. Concerns of bias were raised across all datasets, and financial support from the manufacturer was reported in 24.1% of datasets. Our analysis was limited by the included studies’ heterogeneity in design and reporting. Conclusions In this study we found that Ag-RDTs detect the vast majority of SARS-CoV-2-infected persons within the first week of symptom onset and those with high viral load. Thus, they can have high utility for diagnostic purposes in the early phase of disease, making them a valuable tool to fight the spread of SARS-CoV-2. Standardization in conduct and reporting of clinical accuracy studies would improve comparability and use of data.

Parenting interventions to promote early child development in the first three years of life: A global systematic review and meta-analysis

Abstract: Background Parents are the primary caregivers of young children. Responsive parent–child relationships and parental support for learning during the earliest years of life are crucial for promoting early child development (ECD). We conducted a global systematic review and meta-analysis to evaluate the effectiveness of parenting interventions on ECD and parenting outcomes. Methods and findings We searched MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and Global Health Library for peer-reviewed, published articles from database inception until November 15, 2020. We included randomized controlled trials (RCTs) of parenting interventions delivered during the first 3 years of life that evaluated at least 1 ECD outcome. At least 2 reviewers independently screened, extracted data, and assessed study quality from eligible studies. ECD outcomes included cognitive, language, motor, and socioemotional development, behavior problems, and attachment. Parenting outcomes included parenting knowledge, parenting practices, parent–child interactions, and parental depressive symptoms. We calculated intervention effect sizes as the standardized mean difference (SMD) and estimated pooled effect sizes for each outcome separately using robust variance estimation meta-analytic approaches. We used random-effects meta-regression models to assess potential effect modification by country-income level, child age, intervention content, duration, delivery, setting, and study quality. This review was registered with PROSPERO (CRD42018092458 and CRD42018092461). Of the 11,920 articles identified, we included 111 articles representing 102 unique RCTs. Pooled effect sizes indicated positive benefits of parenting interventions on child cognitive development (SMD = 0.32, 95% CI [confidence interval]: 0.23, 0.40, P < 0.001), language development (SMD = 0.28, 95% CI: 0.18 to 0.37, P < 0.001), motor development (SMD = 0.24, 95% CI: 0.15 to 0.32, P < 0.001), socioemotional development (SMD = 0.19, 95% CI: 0.10 to 0.28, P < 0.001), and attachment (SMD = 0.29, 95% CI: 0.18 to 0.40, P < 0.001) and reductions in behavior problems (SMD = −0.13, 95% CI: −0.18 to −0.08, P < 0.001). Positive benefits were also found on parenting knowledge (SMD = 0.56, 95% CI: 0.33 to 0.79, P < 0.001), parenting practices (SMD = 0.33, 95% CI: 0.22 to 0.44, P < 0.001), and parent–child interactions (SMD = 0.39, 95% CI: 0.24 to 0.53, P < 0.001). However, there was no significant reduction in parental depressive symptoms (SMD = −0.07, 95% CI: −0.16 to 0.02, P = 0.08). Subgroup analyses revealed significantly greater effects on child cognitive, language, and motor development, and parenting practices in low- and middle-income countries compared to high-income countries; and significantly greater effects on child cognitive development, parenting knowledge, parenting practices, and parent–child interactions for programs that focused on responsive caregiving compared to those that did not. On the other hand, there was no clear evidence of effect modification by child age, intervention duration, delivery, setting, or study risk of bias. Study limitations include considerable unexplained heterogeneity, inadequate reporting of intervention content and implementation, and varying quality of evidence in terms of the conduct of trials and robustness of outcome measures used across studies. Conclusions Parenting interventions for children during the first 3 years of life are effective for improving ECD outcomes and enhancing parenting outcomes across low-, middle-, and high-income countries. Increasing implementation of effective and high-quality parenting interventions is needed globally and at scale in order to support parents and enable young children to achieve their full developmental potential.

SARS-CoV-2 neutralizing antibodies: Longevity, breadth, and evasion by emerging viral variants.

Abstract: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antibody neutralization response and its evasion by emerging viral variants and variant of concern (VOC) are unknown, but critical to understand reinfection risk and breakthrough infection following vaccination. Antibody immunoreactivity against SARS-CoV-2 antigens and Spike variants, inhibition of Spike-driven virus-cell fusion, and infectious SARS-CoV-2 neutralization were characterized in 807 serial samples from 233 reverse transcription polymerase chain reaction (RT-PCR)-confirmed Coronavirus Disease 2019 (COVID-19) individuals with detailed demographics and followed up to 7 months. A broad and sustained polyantigenic immunoreactivity against SARS-CoV-2 Spike, Membrane, and Nucleocapsid proteins, along with high viral neutralization, was associated with COVID-19 severity. A subgroup of "high responders" maintained high neutralizing responses over time, representing ideal convalescent plasma donors. Antibodies generated against SARS-CoV-2 during the first COVID-19 wave had reduced immunoreactivity and neutralization potency to emerging Spike variants and VOC. Accurate monitoring of SARS-CoV-2 antibody responses would be essential for selection of optimal responders and vaccine monitoring and design.

Addressing power asymmetries in global health: Imperatives in the wake of the COVID-19 pandemic.

Abstract: Seye Abimbola and co-authors argue for a transformation in global health research and practice in the post-COVID-19 world.

COVID-19 and excess mortality in the United States: A county-level analysis.

Abstract: BACKGROUND: Coronavirus Disease 2019 (COVID-19) excess deaths refer to increases in mortality over what would normally have been expected in the absence of the COVID-19 pandemic. Several prior studies have calculated excess deaths in the United States but were limited to the national or state level, precluding an examination of area-level variation in excess mortality and excess deaths not assigned to COVID-19. In this study, we take advantage of county-level variation in COVID-19 mortality to estimate excess deaths associated with the pandemic and examine how the extent of excess mortality not assigned to COVID-19 varies across subsets of counties defined by sociodemographic and health characteristics. METHODS AND FINDINGS: In this ecological, cross-sectional study, we made use of provisional National Center for Health Statistics (NCHS) data on direct COVID-19 and all-cause mortality occurring in US counties from January 1 to December 31, 2020 and reported before March 12, 2021. We used data with a 10-week time lag between the final day that deaths occurred and the last day that deaths could be reported to improve the completeness of data. Our sample included 2,096 counties with 20 or more COVID-19 deaths. The total number of residents living in these counties was 319.1 million. On average, the counties were 18.7% Hispanic, 12.7% non-Hispanic Black, and 59.6% non-Hispanic White. A total of 15.9% of the population was older than 65 years. We first modeled the relationship between 2020 all-cause mortality and COVID-19 mortality across all counties and then produced fully stratified models to explore differences in this relationship among strata of sociodemographic and health factors. Overall, we found that for every 100 deaths assigned to COVID-19, 120 all-cause deaths occurred (95% CI, 116 to 124), implying that 17% (95% CI, 14% to 19%) of excess deaths were ascribed to causes of death other than COVID-19 itself. Our stratified models revealed that the percentage of excess deaths not assigned to COVID-19 was substantially higher among counties with lower median household incomes and less formal education, counties with poorer health and more diabetes, and counties in the South and West. Counties with more non-Hispanic Black residents, who were already at high risk of COVID-19 death based on direct counts, also reported higher percentages of excess deaths not assigned to COVID-19. Study limitations include the use of provisional data that may be incomplete and the lack of disaggregated data on county-level mortality by age, sex, race/ethnicity, and sociodemographic and health characteristics. CONCLUSIONS: In this study, we found that direct COVID-19 death counts in the US in 2020 substantially underestimated total excess mortality attributable to COVID-19. Racial and socioeconomic inequities in COVID-19 mortality also increased when excess deaths not assigned to COVID-19 were considered. Our results highlight the importance of considering health equity in the policy response to the pandemic.

Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis.

Abstract: Background Epidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses. Methods and findings We selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 × 10−8 from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m2; p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 × 10−5; UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m2, p = 2.1 × 10−5). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null. Conclusions In this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.

Mindfulness-based programmes for mental health promotion in adults in nonclinical settings: A systematic review and meta-analysis of randomised controlled trials

Abstract: Background There is an urgent need for mental health promotion in nonclinical settings. Mindfulness-based programmes (MBPs) are being widely implemented to reduce stress, but a comprehensive evidence synthesis is lacking. We reviewed trials to assess whether MBPs promote mental health relative to no intervention or comparator interventions. Methods and findings Following a detailed preregistered protocol (PROSPERO CRD42018105213) developed with public and professional stakeholders, 13 databases were searched to August 2020 for randomised controlled trials (RCTs) examining in-person, expert-defined MBPs in nonclinical settings. Two researchers independently selected, extracted, and appraised trials using the Cochrane Risk-of-Bias Tool 2.0. Primary outcomes were psychometrically validated anxiety, depression, psychological distress, and mental well-being questionnaires at 1 to 6 months after programme completion. Multiple testing was performed using p Conclusions Compared with taking no action, MBPs of the included studies promote mental health in nonclinical settings, but given the heterogeneity between studies, the findings do not support generalisation of MBP effects across every setting. MBPs may have specific effects on some common mental health symptoms. Other preventative interventions may be equally effective. Implementation of MBPs in nonclinical settings should be partnered with thorough research to confirm findings and learn which settings are most likely to benefit.

Social determinants of mortality from COVID-19: A simulation study using NHANES.

Abstract: Background The COVID-19 epidemic in the United States is widespread, with more than 200,000 deaths reported as of September 23, 2020. While ecological studies show higher burdens of COVID-19 mortality in areas with higher rates of poverty, little is known about social determinants of COVID-19 mortality at the individual level. Methods and findings We estimated the proportions of COVID-19 deaths by age, sex, race/ethnicity, and comorbid conditions using their reported univariate proportions among COVID-19 deaths and correlations among these variables in the general population from the 2017–2018 National Health and Nutrition Examination Survey (NHANES). We used these proportions to randomly sample individuals from NHANES. We analyzed the distributions of COVID-19 deaths by race/ethnicity, income, education level, and veteran status. We analyzed the association of these characteristics with mortality by logistic regression. Summary demographics of deaths include mean age 71.6 years, 45.9% female, and 45.1% non-Hispanic white. We found that disproportionate deaths occurred among individuals with nonwhite race/ethnicity (54.8% of deaths, 95% CI 49.0%–59.6%, p < 0.001), individuals with income below the median (67.5%, 95% CI 63.4%–71.5%, p < 0.001), individuals with less than a high school level of education (25.6%, 95% CI 23.4% –27.9%, p < 0.001), and veterans (19.5%, 95% CI 15.8%–23.4%, p < 0.001). Except for veteran status, these characteristics are significantly associated with COVID-19 mortality in multiple logistic regression. Limitations include the lack of institutionalized people in the sample (e.g., nursing home residents and incarcerated persons), the need to use comorbidity data collected from outside the US, and the assumption of the same correlations among variables for the noninstitutionalized population and COVID-19 decedents. Conclusions Substantial inequalities in COVID-19 mortality are likely, with disproportionate burdens falling on those who are of racial/ethnic minorities, are poor, have less education, and are veterans. Healthcare systems must ensure adequate access to these groups. Public health measures should specifically reach these groups, and data on social determinants should be systematically collected from people with COVID-19.

Polygenic risk scores in cardiovascular risk prediction: A cohort study and modelling analyses

Abstract: This work was supported by core funding from: the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946) and the National Institute for Health Research [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. LuanLuan Sun, Lisa Pennells, Stephen Kaptoge and Matt Arnold are funded by a British Heart Foundation Programme Grant (RG/18/13/33946). Scott Ritchie, Mike Inouye and Stephen Burgess are funded by the National Institute for Health Research [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust]. David Stevens was funded by the National Institute for Health Research [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust]. Thomas Bolton is funded by the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). Steven Bell was funded by the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). Angela Wood is supported by a BHF-Turing Cardiovascular Data Science Award and by the EC-Innovative Medicines Initiative (BigData@Heart). Professor John Danesh holds a British Heart Foundation Professorship and a National Institute for Health Research Senior Investigator Award

Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study

Abstract: Background Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity. Methods and findings Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency. Conclusions In this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.

Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial.

Abstract: Background Convalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression. Methods and findings The study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32-2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19-2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion. Conclusions In the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration. Trial registration NCT04375098.

Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study.

Abstract: Background In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Here, we performed a validation study to confirm the prognostic impact of postoperative ctDNA in resectable CRLM observed in a previous discovery study. Methods and findings We prospectively collected plasma samples from patients with resectable CRLM, including presurgical and postsurgical samples, serial samples during any pre- or postoperative chemotherapy, and serial samples in follow-up. Via targeted sequencing of 15 genes commonly mutated in CRC, we identified at least 1 somatic mutation in each patient’s tumor. We then designed a personalized assay to assess 1 mutation in plasma samples using the Safe-SeqS assay. A total of 380 plasma samples from 54 patients recruited from July 2011 to Dec 2014 were included in our analysis. Twenty-three (43%) patients received neoadjuvant chemotherapy, and 42 patients (78%) received adjuvant chemotherapy after surgery. Median follow-up was 51 months (interquartile range, 31 to 60 months). At least 1 somatic mutation was identified in all patients’ tumor tissue. ctDNA was detectable in 46/54 (85%) patients prior to any treatment and 12/49 (24%) patients after surgery. There was a median 40.93-fold (19.10 to 87.73, P < 0.001) decrease in ctDNA mutant allele fraction with neoadjuvant chemotherapy, but ctDNA clearance during neoadjuvant chemotherapy was not associated with a better recurrence-free survival (RFS). Patients with detectable postoperative ctDNA experienced a significantly lower RFS (HR 6.3; 95% CI 2.58 to 15.2; P < 0.001) and overall survival (HR 4.2; 95% CI 1.5 to 11.8; P < 0.001) compared to patients with undetectable ctDNA. For the 11 patients with detectable postoperative ctDNA who had serial ctDNA sampling during adjuvant chemotherapy, ctDNA clearance was observed in 3 patients, 2 of whom remained disease-free. All 8 patients with persistently detectable ctDNA after adjuvant chemotherapy have recurred. End-of-treatment (surgery +/− adjuvant chemotherapy) ctDNA detection was associated with a 5-year RFS of 0% compared to 75.6% for patients with an undetectable end-of-treatment ctDNA (HR 14.9; 95% CI 4.94 to 44.7; P < 0.001). Key limitations of the study include the small sample size and the potential for false-positive findings with multiple hypothesis testing. Conclusions We confirmed the prognostic impact of postsurgery and posttreatment ctDNA in patients with resected CRLM. The potential utility of serial ctDNA analysis during adjuvant chemotherapy as an early marker of treatment efficacy was also demonstrated. Further studies are required to define how to optimally integrate ctDNA analyses into decision-making regarding the use and timing of adjuvant therapy for resectable CRLM. Trial registration ACTRN12612000345886.

Different dose regimens of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373) in younger and older adults: A phase 2 randomized placebo-controlled trial.

Abstract: Background NVX-CoV2373 is a recombinant severe acute respiratory coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. Methods and findings The phase 2 component of our randomized, placebo-controlled, phase 1 to 2 trial was designed to identify which dosing regimen of NVX-CoV2373 should move forward into late-phase studies and was based on immunogenicity and safety data through Day 35 (14 days after the second dose). The trial was conducted at 9 sites in Australia and 8 sites in the United States. Participants in 2 age groups (aged 18 to 59 and 60 to 84 years) were randomly assigned to receive either 1 or 2 intramuscular doses of 5-μg or 25-μg NVX-CoV2373 or placebo, 21 days apart. Primary endpoints were immunoglobulin G (IgG) anti-spike protein response, 7-day solicited reactogenicity, and unsolicited adverse events. A key secondary endpoint was wild-type virus neutralizing antibody response. After enrollment, 1,288 participants were randomly assigned to 1 of 4 vaccine groups or placebo, with 1,283 participants administered at least 1 study treatment. Of these, 45% were older participants 60 to 84 years. Reactogenicity was predominantly mild to moderate in severity and of short duration (median Conclusions The study confirmed the phase 1 findings that the 2-dose regimen of 5-μg NVX-CoV2373 is highly immunogenic and well tolerated in younger adults. In addition, in older adults, the 2-dose regimen of 5 μg was also well tolerated and showed sufficient immunogenicity to support its use in late-phase efficacy studies. Trial registration ClinicalTrials.gov NCT04368988.

The prevalence of mental disorders among homeless people in high-income countries: An updated systematic review and meta-regression analysis.

Abstract: Background Homelessness continues to be a pressing public health concern in many countries, and mental disorders in homeless persons contribute to their high rates of morbidity and mortality. Many primary studies have estimated prevalence rates for mental disorders in homeless individuals. We conducted a systematic review and meta-analysis of studies on the prevalence of any mental disorder and major psychiatric diagnoses in clearly defined homeless populations in any high-income country. Methods and findings We systematically searched for observational studies that estimated prevalence rates of mental disorders in samples of homeless individuals, using Medline, Embase, PsycInfo, and Google Scholar. We updated a previous systematic review and meta-analysis conducted in 2007, and searched until 1 April 2021. Studies were included if they sampled exclusively homeless persons, diagnosed mental disorders by standardized criteria using validated methods, provided point or up to 12-month prevalence rates, and were conducted in high-income countries. We identified 39 publications with a total of 8,049 participants. Study quality was assessed using the JBI critical appraisal tool for prevalence studies and a risk of bias tool. Random effects meta-analyses of prevalence rates were conducted, and heterogeneity was assessed by meta-regression analyses. The mean prevalence of any current mental disorder was estimated at 76.2% (95% CI 64.0% to 86.6%). The most common diagnostic categories were alcohol use disorders, at 36.7% (95% CI 27.7% to 46.2%), and drug use disorders, at 21.7% (95% CI 13.1% to 31.7%), followed by schizophrenia spectrum disorders (12.4% [95% CI 9.5% to 15.7%]) and major depression (12.6% [95% CI 8.0% to 18.2%]). We found substantial heterogeneity in prevalence rates between studies, which was partially explained by sampling method, study location, and the sex distribution of participants. Limitations included lack of information on certain subpopulations (e.g., women and immigrants) and unmet healthcare needs. Conclusions Public health and policy interventions to improve the health of homeless persons should consider the pattern and extent of psychiatric morbidity. Our findings suggest that the burden of psychiatric morbidity in homeless persons is substantial, and should lead to regular reviews of how healthcare services assess, treat, and follow up homeless people. The high burden of substance use disorders and schizophrenia spectrum disorders need particular attention in service development. This systematic review and meta-analysis has been registered with PROSPERO (CRD42018085216). Trial registration PROSPERO CRD42018085216.

Global burden of influenza-associated lower respiratory tract infections and hospitalizations among adults: A systematic review and meta-analysis

Abstract: Background Influenza illness burden is substantial, particularly among young children, older adults, and those with underlying conditions. Initiatives are underway to develop better global estimates for influenza-associated hospitalizations and deaths. Knowledge gaps remain regarding the role of influenza viruses in severe respiratory disease and hospitalizations among adults, particularly in lower-income settings. Methods and findings We aggregated published data from a systematic review and unpublished data from surveillance platforms to generate global meta-analytic estimates for the proportion of acute respiratory hospitalizations associated with influenza viruses among adults. We searched 9 online databases (Medline, Embase, CINAHL, Cochrane Library, Scopus, Global Health, LILACS, WHOLIS, and CNKI; 1 January 1996–31 December 2016) to identify observational studies of influenza-associated hospitalizations in adults, and assessed eligible papers for bias using a simplified Newcastle–Ottawa scale for observational data. We applied meta-analytic proportions to global estimates of lower respiratory infections (LRIs) and hospitalizations from the Global Burden of Disease study in adults ≥20 years and by age groups (20–64 years and ≥65 years) to obtain the number of influenza-associated LRI episodes and hospitalizations for 2016. Data from 63 sources showed that influenza was associated with 14.1% (95% CI 12.1%–16.5%) of acute respiratory hospitalizations among all adults, with no significant differences by age group. The 63 data sources represent published observational studies (n = 28) and unpublished surveillance data (n = 35), from all World Health Organization regions (Africa, n = 8; Americas, n = 11; Eastern Mediterranean, n = 7; Europe, n = 8; Southeast Asia, n = 11; Western Pacific, n = 18). Data quality for published data sources was predominantly moderate or high (75%, n = 56/75). We estimate 32,126,000 (95% CI 20,484,000–46,129,000) influenza-associated LRI episodes and 5,678,000 (95% CI 3,205,000–9,432,000) LRI hospitalizations occur each year among adults. While adults <65 years contribute most influenza-associated LRI hospitalizations and episodes (3,464,000 [95% CI 1,885,000–5,978,000] LRI hospitalizations and 31,087,000 [95% CI 19,987,000–44,444,000] LRI episodes), hospitalization rates were highest in those ≥65 years (437/100,000 person-years [95% CI 265–612/100,000 person-years]). For this analysis, published articles were limited in their inclusion of stratified testing data by year and age group. Lack of information regarding influenza vaccination of the study population was also a limitation across both types of data sources. Conclusions In this meta-analysis, we estimated that influenza viruses are associated with over 5 million hospitalizations worldwide per year. Inclusion of both published and unpublished findings allowed for increased power to generate stratified estimates, and improved representation from lower-income countries. Together, the available data demonstrate the importance of influenza viruses as a cause of severe disease and hospitalizations in younger and older adults worldwide.

Accelerometer measured physical activity and the incidence of cardiovascular disease: Evidence from the UK Biobank cohort study.

Abstract: Background Higher levels of physical activity (PA) are associated with a lower risk of cardiovascular disease (CVD). However, uncertainty exists on whether the inverse relationship between PA and incidence of CVD is greater at the highest levels of PA. Past studies have mostly relied on self-reported evidence from questionnaire-based PA, which is crude and cannot capture all PA undertaken. We investigated the association between accelerometer-measured moderate, vigorous, and total PA and incident CVD. Methods and findings We obtained accelerometer-measured moderate-intensity and vigorous-intensity physical activities and total volume of PA, over a 7-day period in 2013-2015, for 90,211 participants without prior or concurrent CVD in the UK Biobank cohort. Participants in the lowest category of total PA smoked more, had higher body mass index and C-reactive protein, and were diagnosed with hypertension. PA was associated with 3,617 incident CVD cases during 440,004 person-years of follow-up (median (interquartile range [IQR]): 5.2 (1.2) years) using Cox regression models. We found a linear dose-response relationship for PA, whether measured as moderate-intensity, vigorous-intensity, or as total volume, with risk of incident of CVD. Hazard ratios (HRs) and 95% confidence intervals for increasing quarters of the PA distribution relative to the lowest fourth were for moderate-intensity PA: 0.71 (0.65, 0.77), 0.59 (0.54, 0.65), and 0.46 (0.41, 0.51); for vigorous-intensity PA: 0.70 (0.64, 0.77), 0.54 (0.49,0.59), and 0.41 (0.37,0.46); and for total volume of PA: 0.73 (0.67, 0.79), 0.63 (0.57, 0.69), and 0.47 (0.43, 0.52). We took account of potential confounders but unmeasured confounding remains a possibility, and while removal of early deaths did not affect the estimated HRs, we cannot completely dismiss the likelihood that reverse causality has contributed to the findings. Another possible limitation of this work is the quantification of PA intensity-levels based on methods validated in relatively small studies. Conclusions In this study, we found no evidence of a threshold for the inverse association between objectively measured moderate, vigorous, and total PA with CVD. Our findings suggest that PA is not only associated with lower risk for of CVD, but the greatest benefit is seen for those who are active at the highest level.

PrEP uptake, persistence, adherence, and effect of retrospective drug level feedback on PrEP adherence among young women in southern Africa: Results from HPTN 082, a randomized controlled trial.

Abstract: Background Pre-exposure prophylaxis (PrEP) is highly effective and an important prevention tool for African adolescent girls and young women (AGYW), but adherence and persistence are challenging. PrEP adherence support strategies for African AGYW were studied in an implementation study. Methods and findings HIV Prevention Trials Network (HPTN) 082 was conducted in Cape Town, Johannesburg (South Africa) and Harare (Zimbabwe) from October 2016 to October 2018 to evaluate PrEP uptake, persistence, and the effect of drug level feedback on adherence. Sexually active HIV-negative women ages 16-25 were offered PrEP and followed for 12 months; women who accepted PrEP were randomized to standard adherence support (counseling, 2-way SMS, and adherence clubs) or enhanced adherence support with adherence feedback from intracellular tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). PrEP uptake, persistence through 12 months (no PrEP hold or missed visits), and adherence were assessed. The primary outcome was high adherence (TFV-DP ≥700 fmol/punch) at 6 months, compared by study arm. Of 451 women enrolled, median age was 21 years, and 39% had curable sexually transmitted infections (STIs). Most (95%) started PrEP, of whom 55% had uninterrupted PrEP refills through 12 months. Of those with DBS, 84% had detectable TFV-DP levels at month 3, 57% at month 6, and 31% at month 12. At 6 months, 36/179 (21%) of AGYW in the enhanced arm had high adherence and 40/184 (22%) in the standard adherence support arm (adjusted odds ratio [OR] of 0.92; 95% confidence interval [CI] 0.55, 1.34; p = 0.76). Four women acquired HIV (incidence 1.0/100 person-years), with low or undetectable TFV-DP levels at or prior to seroconversion, and none of whom had tenofovir or emtricitabine resistance mutations. The study had limited power to detect a modest effect of drug level feedback on adherence, and there was limited awareness of PrEP at the time the study was conducted. Conclusions In this study, PrEP initiation was high, over half of study participants persisted with PrEP through month 12, and the majority of young African women had detectable TFV-DP levels through month 6 with one-fifth having high adherence. Drug level feedback in the first 3 months of PrEP use did not increase the proportion with high adherence at month 6. HIV incidence was 1% in this cohort with 39% prevalence of curable STIs and moderate PrEP adherence. Strategies to support PrEP use and less adherence-dependent formulations are needed for this population. Trial registration ClinicalTrials.gov NCT02732730.

Predictive symptoms for COVID-19 in the community: REACT-1 study of over 1 million people.

Abstract: Background Rapid detection, isolation, and contact tracing of community COVID-19 cases are essential measures to limit the community spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to identify a parsimonious set of symptoms that jointly predict COVID-19 and investigated whether predictive symptoms differ between the B.1.1.7 (Alpha) lineage (predominating as of April 2021 in the US, UK, and elsewhere) and wild type. Methods and findings We obtained throat and nose swabs with valid SARS-CoV-2 PCR test results from 1,147,370 volunteers aged 5 years and above (6,450 positive cases) in the REal-time Assessment of Community Transmission-1 (REACT-1) study. This study involved repeated community-based random surveys of prevalence in England (study rounds 2 to 8, June 2020 to January 2021, response rates 22%-27%). Participants were asked about symptoms occurring in the week prior to testing. Viral genome sequencing was carried out for PCR-positive samples with N-gene cycle threshold value Conclusions Where testing capacity is limited, it is important to use tests in the most efficient way possible. We identified a set of 7 symptoms that, when considered together, maximize detection of COVID-19 in the community, including infection with the B.1.1.7 lineage.

Sales of antibiotics and hydroxychloroquine in India during the COVID-19 epidemic: An interrupted time series analysis.

Abstract: BACKGROUND: We assessed the impact of the coronavirus disease 2019 (COVID-19) epidemic in India on the consumption of antibiotics and hydroxychloroquine (HCQ) in the private sector in 2020 compared to the expected level of use had the epidemic not occurred. METHODS AND FINDINGS: We performed interrupted time series (ITS) analyses of sales volumes reported in standard units (i.e., doses), collected at regular monthly intervals from January 2018 to December 2020 and obtained from IQVIA, India. As children are less prone to develop symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a predominant increase in non-child-appropriate formulation (non-CAF) sales. COVID-19-attributable changes in the level and trend of monthly sales of total antibiotics, azithromycin, and HCQ were estimated, accounting for seasonality and lockdown period where appropriate. A total of 16,290 million doses of antibiotics were sold in India in 2020, which is slightly less than the amount in 2018 and 2019. However, the proportion of non-CAF antibiotics increased from 72.5% (95% CI: 71.8% to 73.1%) in 2019 to 76.8% (95% CI: 76.2% to 77.5%) in 2020. Our ITS analyses estimated that COVID-19 likely contributed to 216.4 million (95% CI: 68.0 to 364.8 million; P = 0.008) excess doses of non-CAF antibiotics and 38.0 million (95% CI: 26.4 to 49.2 million; P < 0.001) excess doses of non-CAF azithromycin (equivalent to a minimum of 6.2 million azithromycin treatment courses) between June and September 2020, i.e., until the peak of the first epidemic wave, after which a negative change in trend was identified. In March 2020, we estimated a COVID-19-attributable change in level of +11.1 million doses (95% CI: 9.2 to 13.0 million; P < 0.001) for HCQ sales, whereas a weak negative change in monthly trend was found for this drug. Study limitations include the lack of coverage of the public healthcare sector, the inability to distinguish antibiotic and HCQ sales in inpatient versus outpatient care, and the suboptimal number of pre- and post-epidemic data points, which could have prevented an accurate adjustment for seasonal trends despite the robustness of our statistical approaches. CONCLUSIONS: A significant increase in non-CAF antibiotic sales, and particularly azithromycin, occurred during the peak phase of the first COVID-19 epidemic wave in India, indicating the need for urgent antibiotic stewardship measures.

Impact of color-coded and warning nutrition labelling schemes: A systematic review and network meta-analysis

Abstract: Background Suboptimal diets are a leading risk factor for death and disability. Nutrition labelling is a potential method to encourage consumers to improve dietary behaviour. This systematic review and network meta-analysis (NMA) summarises evidence on the impact of colour-coded interpretive labels and warning labels on changing consumers' purchasing behaviour. Methods and findings We conducted a literature review of peer-reviewed articles published between 1 January 1990 and 24 May 2021 in PubMed, Embase via Ovid, Cochrane Central Register of Controlled Trials, and SCOPUS. Randomised controlled trials (RCTs) and quasi-experimental studies were included for the primary outcomes (measures of changes in consumers' purchasing and consuming behaviour). A frequentist NMA method was applied to pool the results. A total of 156 studies (including 101 RCTs and 55 non-RCTs) nested in 138 articles were incorporated into the systematic review, of which 134 studies in 120 articles were eligible for meta-analysis. We found that the traffic light labelling system (TLS), nutrient warning (NW), and health warning (HW) were associated with an increased probability of selecting more healthful products (odds ratios [ORs] and 95% confidence intervals [CIs]: TLS, 1.5 [1.2, 1.87]; NW, 3.61 [2.82, 4.63]; HW, 1.65 [1.32, 2.06]). Nutri-Score (NS) and warning labels appeared effective in reducing consumers' probability of selecting less healthful products (NS, 0.66 [0.53, 0.82]; NW,0.65 [0.54, 0.77]; HW,0.64 [0.53, 0.76]). NS and NW were associated with an increased overall healthfulness (healthfulness ratings of products purchased using models such as FSAm-NPS/HCSP) by 7.9% and 26%, respectively. TLS, NS, and NW were associated with a reduced energy (total energy: TLS, -6.5%; NS, -6%; NW, -12.9%; energy per 100 g/ml: TLS, -3%; NS, -3.5%; NW, -3.8%), sodium (total sodium/salt: TLS, -6.4%; sodium/salt per 100 g/ml: NS: -7.8%), fat (total fat: NS, -15.7%; fat per 100 g/ml: TLS: -2.6%; NS: -3.2%), and total saturated fat (TLS, -12.9%; NS: -17.1%; NW: -16.3%) content of purchases. The impact of TLS, NS, and NW on purchasing behaviour could be explained by improved understanding of the nutrition information, which further elicits negative perception towards unhealthful products or positive attitudes towards healthful foods. Comparisons across label types suggested that colour-coded labels performed better in nudging consumers towards the purchase of more healthful products (NS versus NW: 1.51 [1.08, 2.11]), while warning labels have the advantage in discouraging unhealthful purchasing behaviour (NW versus TLS: 0.81 [0.67, 0.98]; HW versus TLS: 0.8 [0.63, 1]). Study limitations included high heterogeneity and inconsistency in the comparisons across different label types, limited number of real-world studies (95% were laboratory studies), and lack of long-term impact assessments. Conclusions Our systematic review provided comprehensive evidence for the impact of colour-coded labels and warnings in nudging consumers' purchasing behaviour towards more healthful products and the underlying psychological mechanism of behavioural change. Each type of label had different attributes, which should be taken into consideration when making front-of-package nutrition labelling (FOPL) policies according to local contexts. Our study supported mandatory front-of-pack labelling policies in directing consumers' choice and encouraging the food industry to reformulate their products. Protocol registry PROSPERO (CRD42020161877).

Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: A prospective human splenectomy study.

Abstract: Background A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival. Methods and findings We examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted. Conclusions Immature CD71+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen.

Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study

Abstract: Background Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD. Methods and findings The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p Conclusions Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD. Trial registration ClinicalTrials.gov NCT00799903.

Sugar-sweetened beverage taxes: Lessons to date and the future of taxation.

Abstract: We see at least 2 major health-related reasons to focus on SSBs. First, excess sugar consumption is a major cause of obesity and the increasing risk of type 2 diabetes, hypertension, liver and kidney damage, heart disease, and some cancers [2–4]. Second, high-caloric beverages offer little caloric compensation, so reducing their consumption lowers obesity risk [5,6]. Furthermore, we are beginning to understand the potential impacts of these beverages on stunting as well as obesity [7–11]. A less emphasized reason that deserves greater attention as we consider the links between our diets and planetary health is the environmental costs related to the production of sugary drinks, particularly in water use and carbon emissions. Estimates of total water lifecycle costs to produce a half-liter (or 17-ounce) regular soft drink range from 168 to 309 liters, depending on the sugar source and farm technology [12–14]. Finally, from a practical standpoint, SSB taxes have gained momentum because of their relative ease of implementation compared to other food/nutrition policy options. Taxes collected from manufacturers, bottlers, and distributors can often be built into existing taxation frameworks and collection systems, and these health taxes are a potential source of revenue.

Utility of ctDNA in predicting response to neoadjuvant chemoradiotherapy and prognosis assessment in locally advanced rectal cancer: A prospective cohort study.

Abstract: Background For locally advanced rectal cancer (LARC) patients who receive neoadjuvant chemoradiotherapy (nCRT), there are no reliable indicators to accurately predict pathological complete response (pCR) before surgery. For patients with clinical complete response (cCR), a “Watch and Wait” (WW however, its ability to predict pCR needs to be improved. In this prospective cohort study, we explored the value of circulating tumor DNA (ctDNA) in combination with MRI in the prediction of pCR before surgery and investigated the utility of ctDNA in risk stratification and prognostic prediction for patients undergoing nCRT and total mesorectal excision (TME). Methods and findings We recruited 119 Chinese LARC patients (cT3-4/N0-2/M0; median age of 57; 85 males) who were treated with nCRT plus TME at Fudan University Shanghai Cancer Center (China) from February 7, 2016 to October 31, 2017. Plasma samples at baseline, during nCRT, and after surgery were collected. A total of 531 plasma samples were collected and subjected to deep targeted panel sequencing of 422 cancer-related genes. The association among ctDNA status, treatment response, and prognosis was analyzed. The performance of ctDNA alone, MRI alone, and combining ctDNA with MRI was evaluated for their ability to predict pCR/non-pCR. Ranging from complete tumor regression (pathological tumor regression grade 0; pTRG0) to poor regression (pTRG3), the ctDNA clearance rate during nCRT showed a significant decreasing trend (95.7%, 77.8%, 71.1%, and 66.7% in pTRG 0, 1, 2, and 3 groups, respectively, P = 0.008), while the detection rate of acquired mutations in ctDNA showed an increasing trend (3.8%, 8.3%, 19.2%, and 23.1% in pTRG 0, 1, 2, and 3 groups, respectively, P = 0.02). Univariable logistic regression showed that ctDNA clearance was associated with a low probability of non-pCR (odds ratio = 0.11, 95% confidence interval [95% CI] = 0.01 to 0.6, P = 0.04). A risk score predictive model, which incorporated both ctDNA (i.e., features of baseline ctDNA, ctDNA clearance, and acquired mutation status) and MRI tumor regression grade (mrTRG), was developed and demonstrated improved performance in predicting pCR/non-pCR (area under the curve [AUC] = 0.886, 95% CI = 0.810 to 0.962) compared with models derived from only ctDNA (AUC = 0.818, 95% CI = 0.725 to 0.912) or only mrTRG (AUC = 0.729, 95% CI = 0.641 to 0.816). The detection of potential colorectal cancer (CRC) driver genes in ctDNA after nCRT indicated a significantly worse recurrence-free survival (RFS) (hazard ratio [HR] = 9.29, 95% CI = 3.74 to 23.10, P < 0.001). Patients with detectable driver mutations and positive high-risk feature (HR_feature) after surgery had the highest recurrence risk (HR = 90.29, 95% CI = 17.01 to 479.26, P < 0.001). Limitations include relatively small sample size, lack of independent external validation, no serial ctDNA testing after surgery, and a relatively short follow-up period. Conclusions The model combining ctDNA and MRI improved the predictive performance compared with the models derived from individual information, and combining ctDNA with HR_feature can stratify patients with a high risk of recurrence. Therefore, ctDNA can supplement MRI to better predict nCRT response, and it could potentially help patient selection for nonoperative management and guide the treatment strategy for those with different recurrence risks.

The revolving door of HIV care: Revising the service delivery cascade to achieve the UNAIDS 95-95-95 goals.

Abstract: Peter Ehrenkranz and co-authors present a cyclical cascade of care for people with HIV infection, aiming to facilitate assessment of outcomes.

Menopausal hormone therapy and women's health: An umbrella review.

Abstract: Background: There remains uncertainty about the impact of menopausal hormone therapy (MHT) on women’s health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes. Methods and findings: We searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p [less than] 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412). Conclusions: MHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.

Prevalence and determinants of healthcare avoidance during the COVID-19 pandemic: A population-based cross-sectional study.

Abstract: Background During the Coronavirus Disease 2019 (COVID-19) pandemic, the number of consultations and diagnoses in primary care and referrals to specialist care declined substantially compared to prepandemic levels. Beyond deferral of elective non-COVID-19 care by healthcare providers, it is unclear to what extent healthcare avoidance by community-dwelling individuals contributed to this decline in routine healthcare utilisation. Moreover, it is uncertain which specific symptoms were left unheeded by patients and which determinants predispose to healthcare avoidance in the general population. In this cross-sectional study, we assessed prevalence of healthcare avoidance during the pandemic from a patient perspective, including symptoms that were left unheeded, as well as determinants of healthcare avoidance. Methods and findings On April 20, 2020, a paper COVID-19 survey addressing healthcare utilisation, socioeconomic factors, mental and physical health, medication use, and COVID-19-specific symptoms was sent out to 8,732 participants from the population-based Rotterdam Study (response rate 73%). All questionnaires were returned before July 10, 2020. By hand, prevalence of healthcare avoidance was subsequently verified through free text analysis of medical records of general practitioners. Odds ratios (ORs) for avoidance were determined using logistic regression models, adjusted for age, sex, and history of chronic diseases. We found that 1,142 of 5,656 included participants (20.2%) reported having avoided healthcare. Of those, 414 participants (36.3%) reported symptoms that potentially warranted urgent evaluation, including limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). Determinants related to avoidance were older age (adjusted OR 1.14 [95% confidence interval (CI) 1.08 to 1.21]), female sex (1.58 [1.38 to 1.82]), low educational level (primary education versus higher vocational/university 1.21 [1.01 to 1.46), poor self-appreciated health (per level decrease 2.00 [1.80 to 2.22]), unemployment (versus employed 2.29 [1.54 to 3.39]), smoking (1.34 [1.08 to 1.65]), concern about contracting COVID-19 (per level increase 1.28 [1.19 to 1.38]) and symptoms of depression (per point increase 1.13 [1.11 to 1.14]) and anxiety (per point increase 1.16 [1.14 to 1.18]). Study limitations included uncertainty about (perceived) severity of the reported symptoms and potentially limited generalisability given the ethnically homogeneous study population. Conclusions In this population-based cross-sectional study, 1 in 5 individuals avoided healthcare during lockdown in the COVID-19 pandemic, often for potentially urgent symptoms. Healthcare avoidance was strongly associated with female sex, fragile self-appreciated health, and high levels of depression and anxiety. These results emphasise the need for targeted public education urging these vulnerable patients to timely seek medical care for their symptoms to mitigate major health consequences.

Obesity and the relation between joint exposure to ambient air pollutants and incident type 2 diabetes: A cohort study in UK Biobank.

Abstract: Background Air pollution has been related to incidence of type 2 diabetes (T2D). We assessed the joint association of various air pollutants with the risk of T2D and examined potential modification by obesity status and genetic susceptibility on the relationship. Methods and findings A total of 449,006 participants from UK Biobank free of T2D at baseline were included. Of all the study population, 90.9% were white and 45.7% were male. The participants had a mean age of 56.6 (SD 8.1) years old and a mean body mass index (BMI) of 27.4 (SD 4.8) kg/m2. Ambient air pollutants, including particulate matter (PM) with diameters ≤2.5 μm (PM2.5), between 2.5 μm and 10 μm (PM2.5–10), nitrogen oxide (NO2), and nitric oxide (NO) were measured. An air pollution score was created to assess the joint exposure to the 4 air pollutants. During a median of 11 years follow-up, we documented 18,239 incident T2D cases. The air pollution score was significantly associated with a higher risk of T2D. Compared to the lowest quintile of air pollution score, the hazard ratio (HR) (95% confidence interval [CI]) for T2D was 1.05 (0.99 to 1.10, p = 0.11), 1.06 (1.00 to 1.11, p = 0.051), 1.09 (1.03 to 1.15, p = 0.002), and 1.12 (1.06 to 1.19, p < 0.001) for the second to fifth quintile, respectively, after adjustment for sociodemographic characteristics, lifestyle factors, genetic factors, and other covariates. In addition, we found a significant interaction between the air pollution score and obesity status on the risk of T2D (p-interaction < 0.001). The observed association was more pronounced among overweight and obese participants than in the normal-weight people. Genetic risk score (GRS) for T2D or obesity did not modify the relationship between air pollution and risk of T2D. Key study limitations include unavailable data on other potential T2D-related air pollutants and single-time measurement on air pollutants. Conclusions We found that various air pollutants PM2.5, PM2.5–10, NO2, and NO, individually or jointly, were associated with an increased risk of T2D in the population. The stratified analyses indicate that such associations were more strongly associated with T2D risk among those with higher adiposity.

Cost-effectiveness evidence of mental health prevention and promotion interventions: A systematic review of economic evaluations.

Abstract: Background The prevention of mental disorders and promotion of mental health and well-being are growing fields. Whether mental health promotion and prevention interventions provide value for money in children, adolescents, adults, and older adults is unclear. The aim of the current study is to update 2 existing reviews of cost-effectiveness studies in this field in order to determine whether such interventions are cost-effective. Methods and findings Electronic databases (including MEDLINE, PsycINFO, CINAHL, and EconLit through EBSCO and Embase) were searched for published cost-effectiveness studies of prevention of mental disorders and promotion of mental health and well-being from 2008 to 2020. The quality of studies was assessed using the Quality of Health Economic Studies Instrument (QHES). The protocol was registered with PROSPERO (# CRD42019127778). The primary outcomes were incremental cost-effectiveness ratio (ICER) or return on investment (ROI) ratio across all studies. A total of 65 studies met the inclusion criteria of a full economic evaluation, of which, 23 targeted children and adolescents, 35 targeted adults, while the remaining targeted older adults. A large number of studies focused on prevention of depression and/or anxiety disorders, followed by promotion of mental health and well-being and other mental disorders. Although there was high heterogeneity in terms of the design among included economic evaluations, most studies consistently found that interventions for mental health prevention and promotion were cost-effective or cost saving. The review found that targeted prevention was likely to be cost-effective compared to universal prevention. Screening plus psychological interventions (e.g., cognitive behavioural therapy [CBT]) at school were the most cost-effective interventions for prevention of mental disorders in children and adolescents, while parenting interventions and workplace interventions had good evidence in mental health promotion. There is inconclusive evidence for preventive interventions for mental disorders or mental health promotion in older adults. While studies were of general high quality, there was limited evidence available from low- and middle-income countries. The review was limited to studies where mental health was the primary outcome and may have missed general health promoting strategies that could also prevent mental disorder or promote mental health. Some ROI studies might not be included given that these studies are commonly published in grey literature rather than in the academic literature. Conclusions Our review found a significant growth of economic evaluations in prevention of mental disorders or promotion of mental health and well-being over the last 10 years. Although several interventions for mental health prevention and promotion provide good value for money, the varied quality as well as methodologies used in economic evaluations limit the generalisability of conclusions about cost-effectiveness. However, the finding that the majority of studies especially in children, adolescents, and adults demonstrated good value for money is promising. Research on cost-effectiveness in low-middle income settings is required. Trial registration PROSPERO registration number: CRD42019127778 .