Journal: PLoS Med

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Abstract

Correlates of attendance at community engagement meetings held in advance of bio-behavioral research studies: A longitudinal, sociocentric social network study in rural Uganda.

Kakuhikire B, Satinsky EN, Baguma C, Rasmussen JD, ... Bangsberg DR, Tsai AC
Background
Community engagement is central to the conduct of health-related research studies as a way to determine priorities, inform study design and implementation, increase recruitment and retention, build relationships, and ensure that research meets the goals of the community. Community sensitization meetings, a form of community engagement, are often held prior to the initiation of research studies to provide information about upcoming study activities and resolve concerns in consultation with potential participants. This study estimated demographic, health, economic, and social network correlates of attendance at community sensitization meetings held in advance of a whole-population, combined behavioral, and biomedical research study in rural Uganda.
Methods and findings
Research assistants collected survey data from 1,630 adults participating in an ongoing sociocentric social network cohort study conducted in a rural region of southwestern Uganda. These community survey data, collected between 2016 and 2018, were linked to attendance logs from community sensitization meetings held in 2018 and 2019 before the subsequent community survey and community health fair. Of all participants, 264 (16%) attended a community sensitization meeting before the community survey, 464 (28%) attended a meeting before the community health fair, 558 (34%) attended a meeting before either study activity (survey or health fair), and 170 (10%) attended a meeting before both study activities (survey and health fair). Using multivariable Poisson regression models, we estimated correlates of attendance at community sensitization meetings. Attendance was more likely among study participants who were women (adjusted relative risk [ARR]health fair = 1.71, 95% confidence interval [CI], 1.32 to 2.21, p < 0.001), older age (ARRsurvey = 1.02 per year, 95% CI, 1.01 to 1.02, p < 0.001; ARRhealth fair = 1.02 per year, 95% CI, 1.01 to 1.02, p < 0.001), married (ARRsurvey = 1.74, 95% CI, 1.29 to 2.35, p < 0.001; ARRhealth fair = 1.41, 95% CI, 1.13 to 1.76, p = 0.002), and members of more community groups (ARRsurvey = 1.26 per group, 95% CI, 1.10 to 1.44, p = 0.001; ARRhealth fair = 1.26 per group, 95% CI, 1.12 to 1.43, p < 0.001). Attendance was less likely among study participants who lived farther from meeting locations (ARRsurvey = 0.54 per kilometer, 95% CI, 0.30 to 0.97, p = 0.041; ARRhealth fair = 0.57 per kilometer, 95% CI, 0.38 to 0.86, p = 0.007). Leveraging the cohort\'s sociocentric design, social network analyses suggested that information conveyed during community sensitization meetings could reach a broader group of potential study participants through attendees\' social network and household connections. Study limitations include lack of detailed data on reasons for attendance/nonattendance at community sensitization meetings; achieving a representative sample of community members was not an explicit aim of the study; and generalizability may not extend beyond this study setting.
Conclusions
In this longitudinal, sociocentric social network study conducted in rural Uganda, we observed that older age, female sex, being married, membership in more community groups, and geographical proximity to meeting locations were correlated with attendance at community sensitization meetings held in advance of bio-behavioral research activities. Information conveyed during meetings could have reached a broader portion of the population through attendees\' social network and household connections. To ensure broader input and potentially increase participation in health-related research studies, the dissemination of research-related information through community sensitization meetings may need to target members of underrepresented groups.



PLoS Med: 15 Jul 2021; 18:e1003705
Kakuhikire B, Satinsky EN, Baguma C, Rasmussen JD, ... Bangsberg DR, Tsai AC
PLoS Med: 15 Jul 2021; 18:e1003705 | PMID: 34270581
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Abstract

Estimating the effect of moving meat-free products to the meat aisle on sales of meat and meat-free products: A non-randomised controlled intervention study in a large UK supermarket chain.

Piernas C, Cook B, Stevens R, Stewart C, ... Scarborough P, Jebb SA
Background
Reducing meat consumption could bring health and environmental benefits, but there is little research to date on effective interventions to achieve this. A non-randomised controlled intervention study was used to evaluate whether prominent positioning of meat-free products in the meat aisle was associated with a change in weekly mean sales of meat and meat-free products.
Methods and findings
Weekly sales data were obtained from 108 stores: 20 intervention stores that moved a selection of 26 meat-free products into a newly created meat-free bay within the meat aisle and 88 matched control stores. The primary outcome analysis used a hierarchical negative binomial model to compare changes in weekly sales (units) of meat products sold in intervention versus control stores during the main intervention period (Phase I: February 2019 to April 2019). Interrupted time series analysis was also used to evaluate the effects of the Phase I intervention. Moreover, 8 of the 20 stores enhanced the intervention from August 2019 onwards (Phase II intervention) by adding a second bay of meat-free products into the meat aisle, which was evaluated following the same analytical methods. During the Phase I intervention, sales of meat products (units/store/week) decreased in intervention (approximately -6%) and control stores (-5%) without significant differences (incidence rate ratio [IRR] 1.01 [95% CI 0.95-1.07]. Sales of meat-free products increased significantly more in the intervention (+31%) compared to the control stores (+6%; IRR 1.43 [95% CI 1.30-1.57]), mostly due to increased sales of meat-free burgers, mince, and sausages. Consistent results were observed in interrupted time series analyses where the effect of the Phase II intervention was significant in intervention versus control stores.
Conclusions
Prominent positioning of meat-free products into the meat aisle in a supermarket was not effective in reducing sales of meat products, but successfully increased sales of meat-free alternatives in the longer term. A preregistered protocol (https://osf.io/qmz3a/) was completed and fully available before data analysis.



PLoS Med: 14 Jul 2021; 18:e1003715
Piernas C, Cook B, Stevens R, Stewart C, ... Scarborough P, Jebb SA
PLoS Med: 14 Jul 2021; 18:e1003715 | PMID: 34264943
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Abstract

Mortality and concurrent use of opioids and hypnotics in older patients: A retrospective cohort study.

Ray WA, Chung CP, Murray KT, Malow BA, Daugherty JR, Stein CM
Background
Benzodiazepine hypnotics and the related nonbenzodiazepine hypnotics (z-drugs) are among the most frequently prescribed medications for older adults. Both can depress respiration, which could have fatal cardiorespiratory effects, particularly among patients with concurrent opioid use. Trazodone, frequently prescribed in low doses for insomnia, has minimal respiratory effects, and, consequently, may be a safer hypnotic for older patients. Thus, for patients beginning treatment with benzodiazepine hypnotics or z-drugs, we compared deaths during periods of current hypnotic use, without or with concurrent opioids, to those for comparable patients receiving trazodone in doses up to 100 mg.
Methods and findings
The retrospective cohort study in the United States included 400,924 Medicare beneficiaries 65 years of age or older without severe illness or evidence of substance use disorder initiating study hypnotic therapy from January 2014 through September 2015. Study endpoints were out-of-hospital (primary) and total mortality. Hazard ratios (HRs) were adjusted for demographic characteristics, psychiatric and neurologic disorders, cardiovascular and renal conditions, respiratory diseases, pain-related diagnoses and medications, measures of frailty, and medical care utilization in a time-dependent propensity score-stratified analysis. Patients without concurrent opioids had 32,388 person-years of current use, 260 (8.0/1,000 person-years) out-of-hospital and 418 (12.9/1,000) total deaths for benzodiazepines; 26,497 person-years,150 (5.7/1,000) out-of-hospital and 227 (8.6/1,000) total deaths for z-drugs; and 16,177 person-years,156 (9.6/1,000) out-of-hospital and 256 (15.8/1,000) total deaths for trazodone. Out-of-hospital and total mortality for benzodiazepines (respective HRs: 0.99 [95% confidence interval, 0.81 to 1.22, p = 0.954] and 0.95 [0.82 to 1.14, p = 0.513] and z-drugs (HRs: 0.96 [0.76 to 1.23], p = 0.767 and 0.87 [0.72 to 1.05], p = 0.153) did not differ significantly from that for trazodone. Patients with concurrent opioids had 4,278 person-years of current use, 90 (21.0/1,000) out-of-hospital and 127 (29.7/1,000) total deaths for benzodiazepines; 3,541 person-years, 40 (11.3/1,000) out-of-hospital and 64 (18.1/1,000) total deaths for z-drugs; and 2,347 person-years, 19 (8.1/1,000) out-of-hospital and 36 (15.3/1,000) total deaths for trazodone. Out-of-hospital and total mortality for benzodiazepines (HRs: 3.02 [1.83 to 4.97], p < 0.001 and 2.21 [1.52 to 3.20], p < 0.001) and z-drugs (HRs: 1.98 [1.14 to 3.44], p = 0.015 and 1.65 [1.09 to 2.49], p = 0.018) were significantly increased relative to trazodone; findings were similar with exclusion of overdose deaths or restriction to those with cardiovascular causes. Limitations included composition of the study cohort and potential confounding by unmeasured variables.
Conclusions
In US Medicare beneficiaries 65 years of age or older without concurrent opioids who initiated treatment with benzodiazepine hypnotics, z-drugs, or low-dose trazodone, study hypnotics were not associated with mortality. With concurrent opioids, benzodiazepines and z-drugs were associated with increased out-of-hospital and total mortality. These findings indicate that the dangers of benzodiazepine-opioid coadministration go beyond the documented association with overdose death and suggest that in combination with opioids, the z-drugs may be more hazardous than previously thought.



PLoS Med: 14 Jul 2021; 18:e1003709
Ray WA, Chung CP, Murray KT, Malow BA, Daugherty JR, Stein CM
PLoS Med: 14 Jul 2021; 18:e1003709 | PMID: 34264928
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Abstract

Evaluating the impact of the nationwide public-private mix (PPM) program for tuberculosis under National Health Insurance in South Korea: A difference in differences analysis.

Yu S, Sohn H, Kim HY, Kim H, ... Chung H, Choi H
Background
Public-private mix (PPM) programs on tuberculosis (TB) have a critical role in engaging and integrating the private sector into the national TB control efforts in order to meet the End TB Strategy targets. South Korea\'s PPM program can provide important insights on the long-term impact and policy gaps in the development and expansion of PPM as a nationwide program.
Methods and findings
Healthcare is privatized in South Korea, and a majority (80.3% in 2009) of TB patients sought care in the private sector. Since 2009, South Korea has rapidly expanded its PPM program coverage under the National Health Insurance (NHI) scheme as a formal national program with dedicated PPM nurses managing TB patients in both the private and public sectors. Using the difference in differences (DID) analytic framework, we compared relative changes in TB treatment outcomes-treatment success (TS) and loss to follow-up (LTFU)-in the private and public sector between the 2009 and 2014 TB patient cohorts. Propensity score matching (PSM) using the kernel method was done to adjust for imbalances in the covariates between the 2 population cohorts. The 2009 cohort included 6,195 (63.0% male, 37.0% female; mean age: 42.1) and 27,396 (56.1% male, 43.9% female; mean age: 45.7) TB patients in the public and private sectors, respectively. The 2014 cohort included 2,803 (63.2% male, 36.8% female; mean age: 50.1) and 29,988 (56.5% male, 43.5% female; mean age: 54.7) patients. In both the private and public sectors, the proportion of patients with transfer history decreased (public: 23.8% to 21.7% and private: 20.8% to 17.6%), and bacteriological confirmed disease increased (public: 48.9% to 62.3% and private: 48.8% to 58.1%) in 2014 compared to 2009. After expanding nationwide PPM, absolute TS rates improved by 9.10% (87.5% to 93.4%) and by 13.6% (from 70.3% to 83.9%) in the public and private sectors. Relative to the public, the private saw 4.1% (95% confidence interval [CI] 2.9% to 5.3%, p-value < 0.001) and -8.7% (95% CI -9.7% to -7.7%, p-value <0.001) higher rates of improvement in TS and reduction in LTFU. Treatment outcomes did not improve in patients who experienced at least 1 transfer during their TB treatment. Study limitations include non-longitudinal nature of our original dataset, inability to assess the regional disparities, and verify PPM program\'s impact on TB mortality.
Conclusions
We found that the nationwide scale-up of the PPM program was associated with improvements in TB treatment outcomes in the private sector in South Korea. Centralized financial governance and regulatory mechanisms were integral in facilitating the integration of highly diverse South Korean private sector into the national TB control program and scaling up of the PPM intervention nationwide. However, TB care gaps continued to exist for patients who transferred at least once during their treatment. These programmatic gaps may be improved through reducing administrative hurdles and making programmatic amendments that can help facilitate management TB patients between institutions and healthcare sectors, as well as across administrative regions.



PLoS Med: 13 Jul 2021; 18:e1003717
Yu S, Sohn H, Kim HY, Kim H, ... Chung H, Choi H
PLoS Med: 13 Jul 2021; 18:e1003717 | PMID: 34260579
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Abstract

Psychological distress, resettlement stress, and lower school engagement among Arabic-speaking refugee parents in Sydney, Australia: A cross-sectional cohort study.

Baker JR, Silove D, Horswood D, Al-Shammari A, ... Rees S, Eapen V
Background
Schools play a key role in supporting the well-being and resettlement of refugee children, and parental engagement with the school may be a critical factor in the process. Many resettlement countries have policies in place to support refugee parents\' engagement with their children\'s school. However, the impact of these programs lacks systematic evaluation. This study first aimed to validate self-report measures of parental school engagement developed specifically for the refugee context, and second, to identify parent characteristics associated with school engagement, so as to help tailor support to families most in need.
Methods and findings
The report utilises 2016 baseline data of a cohort study of 233 Arabic-speaking parents (77% response rate) of 10- to 12-year-old schoolchildren from refugee backgrounds across 5 schools in Sydney, Australia. Most participants were born in Iraq (81%) or Syria (11%), and only 25% spoke English well to very well. Participants\' mean age was 40 years old, and 83% were female. Confirmatory factor analyses were run on provisional item sets identified from a literature review and separate qualitative study. The findings informed the development of 4 self-report tools assessing parent engagement with the school and school community, school belonging, and quality of the relationship with the schools\' bilingual cultural broker. Cronbach alpha and Pearson correlations with an established Teacher-Home Communication subscale demonstrated adequate reliability (α = 0.67 to 0.80) and construct and convergent validity of the measures (p < 0.01), respectively. Parent characteristics were entered into respective least absolute shrinkage and selection operator (LASSO) regression analyses. The degree of parents\' psychological distress (as measured by the Kessler10 self-report instrument) and postmigration living difficulties (PLMDs) were each associated with lower school engagement and belonging, whereas less time lived in Australia, lower education levels, and an unemployed status were associated with higher ratings in relationship quality with the schools\' cultural broker. Study limitations include the cross-sectional design and the modest amount of variance (8% to 22%) accounted for by the regression models.
Conclusions
The study offers preliminary refugee-specific measures of parental school engagement. It is expected they will provide a resource for evaluating efforts to support the integration of refugee families into schools. The findings support the need for initiatives that identify and support parents with school-attending children from refugee backgrounds who are experiencing psychological distress or resettlement stressors. At the school level, the findings suggest that cultural brokers may be effective in targeting newly arrived families.



PLoS Med: 11 Jul 2021; 18:e1003512
Baker JR, Silove D, Horswood D, Al-Shammari A, ... Rees S, Eapen V
PLoS Med: 11 Jul 2021; 18:e1003512 | PMID: 34252076
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Abstract

Changes in the calorie and nutrient content of purchased fast food meals after calorie menu labeling: A natural experiment.

Petimar J, Zhang F, Rimm EB, Simon D, ... Roberto CA, Block JP
Background
Calorie menu labeling is a policy that requires food establishments to post the calories on menu offerings to encourage healthy food choice. Calorie labeling has been implemented in the United States since May 2018 per the Affordable Care Act, but to the best of our knowledge, no studies have evaluated the relationship between calorie labeling and meal purchases since nationwide implementation of this policy. Our objective was to investigate the relationship between calorie labeling and the calorie and nutrient content of purchased meals after a fast food franchise began labeling in April 2017, prior to the required nationwide implementation, and after nationwide implementation of labeling in May 2018, when all large US chain restaurants were required to label their menus.
Methods and findings
We obtained weekly aggregated sales data from 104 restaurants that are part of a fast food franchise for 3 national chains in 3 US states: Louisiana, Mississippi, and Texas. The franchise provided all sales data from April 2015 until April 2019. The franchise labeled menus in April 2017, 1 year prior to the required nationwide implementation date of May 2018 set by the US Food and Drug Administration. We obtained nutrition information for items sold (calories, fat, carbohydrates, protein, saturated fat, sugar, dietary fiber, and sodium) from Menustat, a publicly available database with nutrition information for items offered at the top revenue-generating US restaurant chains. We used an interrupted time series to find level and trend changes in mean weekly calorie and nutrient content per transaction after franchise and nationwide labeling. The analytic sample represented 331,776,445 items purchased across 67,112,342 transactions. Franchise labeling was associated with a level change of -54 calories/transaction (95% confidence interval [CI]: -67, -42, p < 0.0001) and a subsequent 3.3 calories/transaction increase per 4-week period (95% CI: 2.5, 4.1, p < 0.0001). Nationwide implementation was associated with a level decrease of -82 calories/transaction (95% CI: -88, -76, p < 0.0001) and a subsequent -2.1 calories/transaction decrease per 4-week period (95% CI: -2.9, -1.3, p < 0.0001). At the end of the study, the model-based predicted mean calories/transaction was 4.7% lower (change = -73 calories/transaction, 95% CI: -81, -65), and nutrients/transaction ranged from 1.8% lower (saturated fat) to 7.0% lower (sugar) than what we would expect had labeling not been implemented. The main limitations were potential residual time-varying confounding and lack of individual-level transaction data.
Conclusions
In this study, we observed that calorie labeling was associated with small decreases in mean calorie and nutrient content of fast food meals 2 years after franchise labeling and nearly 1 year after implementation of labeling nationwide. These changes imply that calorie labeling was associated with small improvements in purchased meal quality in US chain restaurants.



PLoS Med: 11 Jul 2021; 18:e1003714
Petimar J, Zhang F, Rimm EB, Simon D, ... Roberto CA, Block JP
PLoS Med: 11 Jul 2021; 18:e1003714 | PMID: 34252088
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Abstract

Adipose tissue biomarkers and type 2 diabetes incidence in normoglycemic participants in the MESArthritis Ancillary Study: A cohort study.

Pishgar F, Shabani M, Quinaglia A C Silva T, Bluemke DA, ... Lima JAC, Demehri S
Background
Given the central role of skeletal muscles in glucose homeostasis, deposition of adipose depots beneath the fascia of muscles (versus subcutaneous adipose tissue [SAT]) may precede insulin resistance and type 2 diabetes (T2D) incidence. This study was aimed to investigate the associations between computed tomography (CT)-derived biomarkers for adipose tissue and T2D incidence in normoglycemic adults.
Methods and findings
This study was a population-based multiethnic retrospective cohort of 1,744 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with normoglycemia (baseline fasting plasma glucose [FPG] less than 100 mg/dL) from 6 United States of America communities. Participants were followed from April 2010 and January 2012 to December 2017, for a median of 7 years. The intermuscular adipose tissue (IMAT) and SAT areas were measured in baseline chest CT exams and were corrected by height squared (SAT and IMAT indices) using a predefined measurement protocol. T2D incidence, as the main outcome, was based on follow-up FPG, review of hospital records, or self-reported physician diagnoses. Participants\' mean age was 69 ± 9 years at baseline, and 977 (56.0%) were women. Over a median of 7 years, 103 (5.9%) participants were diagnosed with T2D, and 147 (8.4%) participants died. The IMAT index (hazard ratio [HR]: 1.27 [95% confidence interval [CI]: 1.15-1.41] per 1-standard deviation [SD] increment) and the SAT index (HR: 1.43 [95% CI: 1.16-1.77] per 1-SD increment) at baseline were associated with T2D incidence over the follow-up. The associations of the IMAT and SAT indices with T2D incidence were attenuated after adjustment for body mass index (BMI) and waist circumference, with HRs of 1.23 (95% CI: 1.09-1.38) and 1.29 (95% CI: 0.96-1.74) per 1-SD increment, respectively. The limitations of this study include unmeasured residual confounders and one-time measurement of adipose tissue biomarkers.
Conclusions
In this study, we observed an association between IMAT at baseline and T2D incidence over the follow-up. This study suggests the potential role of intermuscular adipose depots in the pathophysiology of T2D.
Trial registration
ClinicalTrials.gov NCT00005487.



PLoS Med: 08 Jul 2021; 18:e1003700
Pishgar F, Shabani M, Quinaglia A C Silva T, Bluemke DA, ... Lima JAC, Demehri S
PLoS Med: 08 Jul 2021; 18:e1003700 | PMID: 34242221
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Abstract

Evaluating the use of the QUiPP app and its impact on the management of threatened preterm labour: A cluster randomised trial.

Watson HA, Carlisle N, Seed PT, Carter J, ... Tribe RM, Shennan AH
Background
Preterm delivery (before 37 weeks of gestation) is the single most important contributor to neonatal death and morbidity, with lifelong repercussions. However, the majority of women who present with preterm labour (PTL) symptoms do not deliver imminently. Accurate prediction of PTL is needed in order ensure correct management of those most at risk of preterm birth (PTB) and to prevent the maternal and fetal risks incurred by unnecessary interventions given to the majority. The QUantitative Innovation in Predicting Preterm birth (QUIPP) app aims to support clinical decision-making about women in threatened preterm labour (TPTL) by combining quantitative fetal fibronectin (qfFN) values, cervical length (CL), and significant PTB risk factors to create an individualised percentage risk of delivery.
Methods and findings
EQUIPTT was a multi-centre cluster randomised controlled trial (RCT) involving 13 maternity units in South and Eastern England (United Kingdom) between March 2018 and February 2019. Pregnant women (n = 1,872) between 23+0 and 34+6 weeks\' gestation with symptoms of PTL in the analysis period were assigned to either the intervention (762) or control (1,111). The mean age of the study population was 30.2 (+/- SD 5.93). A total of 56.0% were white, 19.6% were black, 14.2% were Asian, and 10.2% were of other ethnicities. The intervention was the use of the QUiPP app with admission, antenatal corticosteroids (ACSs), and transfer advised for women with a QUiPP risk of delivery >5% within 7 days. Control sites continued with their conventional management of TPTL. Unnecessary management for TPTL was a composite primary outcome defined by the sum of unnecessary admission decisions (admitted and delivery interval >7 days or not admitted and delivery interval ≤7 days) and the number of unnecessary in utero transfer (IUT) decisions/actions (IUT that occurred or were attempted >7 days prior to delivery) and ex utero transfers (EUTs) that should have been in utero (attempted and not attempted). Unnecessary management of TPTL was 11.3% (84/741) at the intervention sites versus 11.5% (126/1094) at control sites (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.66-1.42, p = 0.883). Control sites frequently used qfFN and did not follow UK national guidance, which recommends routine treatment below 30 weeks without testing. Unnecessary management largely consisted of unnecessary admissions which were similar at intervention and control sites (10.7% versus 10.8% of all visits). In terms of adverse outcomes for women in TPTL <36 weeks, 4 women from the intervention sites and 12 from the control sites did not receive recommended management. If the QUiPP percentage risk was used as per protocol, unnecessary management would have been 7.4% (43/578) versus 9.9% (134/1,351) (OR 0.72, 95% CI 0.45-1.16). Our external validation of the QUiPP app confirmed that it was highly predictive of delivery in 7 days; receiver operating curve area was 0.90 (95% CI 0.85-0.95) for symptomatic women. Study limitations included a lack of compliance with national guidance at the control sites and difficulties in implementation of the QUiPP app.
Conclusions
This cluster randomised trial did not demonstrate that the use of the QUiPP app reduced unnecessary management of TPTL compared to current management but would safely improve the management recommended by the National Institute for Health and Care Excellence (NICE). Interpretation of qfFN, with or without the QUiPP app, is a safe and accurate method for identifying women most likely to benefit from PTL interventions.
Trial registration
ISRCTN Registry ISRCTN17846337.



PLoS Med: 05 Jul 2021; 18:e1003689
Watson HA, Carlisle N, Seed PT, Carter J, ... Tribe RM, Shennan AH
PLoS Med: 05 Jul 2021; 18:e1003689 | PMID: 34228735
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Abstract

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

Tea F, Ospina Stella A, Aggarwal A, Ross Darley D, ... Brilot F, Turville SG
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.



PLoS Med: 05 Jul 2021; 18:e1003656
Tea F, Ospina Stella A, Aggarwal A, Ross Darley D, ... Brilot F, Turville SG
PLoS Med: 05 Jul 2021; 18:e1003656 | PMID: 34228725
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Prediction of risk of prolonged post-concussion symptoms: Derivation and validation of the TRICORDRR (Toronto Rehabilitation Institute Concussion Outcome Determination and Rehab Recommendations) score.

Langer LK, Alavinia SM, Lawrence DW, Munce SEP, ... Comper P, Bayley MT
Background
Approximately 10% to 20% of people with concussion experience prolonged post-concussion symptoms (PPCS). There is limited information identifying risk factors for PPCS in adult populations. This study aimed to derive a risk score for PPCS by determining which demographic factors, premorbid health conditions, and healthcare utilization patterns are associated with need for prolonged concussion care among a large cohort of adults with concussion.
Methods and findings
Data from a cohort study (Ontario Concussion Cohort study, 2008 to 2016; n = 1,330,336) including all adults with a concussion diagnosis by either primary care physician (ICD-9 code 850) or in emergency department (ICD-10 code S06) and 2 years of healthcare tracking postinjury (2008 to 2014, n = 587,057) were used in a retrospective analysis. Approximately 42.4% of the cohort was female, and adults between 18 and 30 years was the largest age group (31.0%). PPCS was defined as 2 or more specialist visits for concussion-related symptoms more than 6 months after injury index date. Approximately 13% (73,122) of the cohort had PPCS. Total cohort was divided into Derivation (2009 to 2013, n = 417,335) and Validation cohorts (2009 and 2014, n = 169,722) based upon injury index year. Variables selected a priori such as psychiatric disorders, migraines, sleep disorders, demographic factors, and pre-injury healthcare patterns were entered into multivariable logistic regression and CART modeling in the Derivation Cohort to calculate PPCS estimates and forward selection logistic regression model in the Validation Cohort. Variables with the highest probability of PPCS derived in the Derivation Cohort were: Age >61 years ([Formula: see text] = 0.54), bipolar disorder ([Formula: see text] = 0.52), high pre-injury primary care visits per year ([Formula: see text] = 0.46), personality disorders ([Formula: see text] = 0.45), and anxiety and depression ([Formula: see text] = 0.33). The area under the curve (AUC) was 0.79 for the derivation model, 0.79 for bootstrap internal validation of the Derivation Cohort, and 0.64 for the Validation model. A limitation of this study was ability to track healthcare usage only to healthcare providers that submit to Ontario Health Insurance Plan (OHIP); thus, some patients seeking treatment for prolonged symptoms may not be captured in this analysis.
Conclusions
In this study, we observed that premorbid psychiatric conditions, pre-injury health system usage, and older age were associated with increased risk of a prolonged recovery from concussion. This risk score allows clinicians to calculate an individual\'s risk of requiring treatment more than 6 months post-concussion.



PLoS Med: 29 Jun 2021; 18:e1003652
Langer LK, Alavinia SM, Lawrence DW, Munce SEP, ... Comper P, Bayley MT
PLoS Med: 29 Jun 2021; 18:e1003652 | PMID: 34237056
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Evaluation of a package of risk-based pharmaceutical and lifestyle interventions in patients with hypertension and/or diabetes in rural China: A pragmatic cluster randomised controlled trial.

Wei X, Zhang Z, Chong MKC, Hicks JP, ... Upshur REG, Yu M
Background
Primary prevention of cardiovascular disease (CVD) requires adequate control of hypertension and diabetes. We designed and implemented pharmaceutical and healthy lifestyle interventions for patients with diabetes and/or hypertension in rural primary care, and assessed their effectiveness at reducing severe CVD events.
Methods and findings
We used a pragmatic, parallel group, 2-arm, controlled, superiority, cluster trial design. We randomised 67 township hospitals in Zhejiang Province, China, to intervention (34) or control (33). A total of 31,326 participants were recruited, with 15,380 in the intervention arm and 15,946 in the control arm. Participants had no known CVD and were either patients with hypertension and a 10-year CVD risk of 20% or higher, or patients with type 2 diabetes regardless of their CVD risk. The intervention included prescription of a standardised package of medicines, individual advice on lifestyle change, and adherence support. Control was usual hypertension and diabetes care. In both arms, as usual in China, most outpatient drug costs were out of pocket. The primary outcome was severe CVD events, including coronary heart disease and stroke, during 36 months of follow-up, as recorded by the CVD surveillance system. The study was implemented between December 2013 and May 2017. A total of 13,385 (87%) and 14,745 (92%) participated in the intervention and control arms, respectively. Their mean age was 64 years, 51% were women, and 90% were farmers. Of all participants, 64% were diagnosed with hypertension with or without diabetes, and 36% were diagnosed with diabetes only. All township hospitals and participants completed the 36-month follow-up. At 36 months, there were 762 and 874 severe CVD events in the intervention and control arms, respectively, yielding a non-significant effect on CVD incidence rate (1.92 and 2.01 per 100 person-years, respectively; crude incidence rate ratio = 0.90 [95% CI: 0.74, 1.08; P = 0.259]). We observed significant, but small, differences in the change from baseline to follow-up for systolic blood pressure (-1.44 mm Hg [95% CI: -2.26, -0.62; P < 0.001]) and diastolic blood pressure (-1.29 mm Hg [95% CI: -1.77, -0.80; P < 0.001]) in the intervention arm compared to the control arm. Self-reported adherence to recommended medicines was significantly higher in the intervention arm compared with the control arm at 36 months. No safety concerns were identified. Main study limitations include all participants being informed about their high CVD risk at baseline, non-blinding of participants, and the relatively short follow-up period available for judging potential changes in rates of CVD events.
Conclusions
The comprehensive package of pharmaceutical and healthy lifestyle interventions did not reduce severe CVD events over 36 months. Improving health system factors such as universal coverage for the cost of essential medicines is required for successful risk-based CVD prevention programmes.
Trial registration
ISRCTN registry ISRCTN58988083.



PLoS Med: 29 Jun 2021; 18:e1003694
Wei X, Zhang Z, Chong MKC, Hicks JP, ... Upshur REG, Yu M
PLoS Med: 29 Jun 2021; 18:e1003694 | PMID: 34197452
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Impact:
Abstract

Rotavirus vaccine efficacy up to 2 years of age and against diverse circulating rotavirus strains in Niger: Extended follow-up of a randomized controlled trial.

Isanaka S, Langendorf C, McNeal MM, Meyer N, ... Ciglenecki I, Grais RF
Background
Rotavirus vaccination is recommended in all countries to reduce the burden of diarrhea-related morbidity and mortality in children. In resource-limited settings, rotavirus vaccination in the national immunization program has important cost implications, and evidence for protection beyond the first year of life and against the evolving variety of rotavirus strains is important. We assessed the extended and strain-specific vaccine efficacy of a heat-stable, affordable oral rotavirus vaccine (Rotasiil, Serum Institute of India, Pune, India) against severe rotavirus gastroenteritis (SRVGE) among healthy infants in Niger.
Methods and findings
From August 2014 to November 2015, infants were randomized in a 1:1 ratio to receive 3 doses of Rotasiil or placebo at approximately 6, 10, and 14 weeks of age. Episodes of gastroenteritis were assessed through active and passive surveillance and graded using the Vesikari score. The primary endpoint was vaccine efficacy of 3 doses of vaccine versus placebo against a first episode of laboratory-confirmed SRVGE (Vesikari score ≥ 11) from 28 days after dose 3, as previously reported. At the time of the primary analysis, median age was 9.8 months. In the present paper, analyses of extended efficacy were undertaken for 3 periods (28 days after dose 3 to 1 year of age, 1 to 2 years of age, and the combined period 28 days after dose 3 to 2 years of age) and by individual rotavirus G type. Among the 3,508 infants included in the per-protocol efficacy analysis (mean age at first dose 6.5 weeks; 49% male), the vaccine provided significant protection against SRVGE through the first year of life (3.96 and 9.98 cases per 100 person-years for vaccine and placebo, respectively; vaccine efficacy 60.3%, 95% CI 43.6% to 72.1%) and over the entire efficacy follow-up period up to 2 years of age (2.13 and 4.69 cases per 100 person-years for vaccine and placebo, respectively; vaccine efficacy 54.7%, 95% CI 38.1% to 66.8%), but the difference was not statistically significant in the second year of life. Up to 2 years of age, rotavirus vaccination prevented 2.56 episodes of SRVGE per 100 child-years. Estimates of efficacy against SRVGE by individual rotavirus genotype were consistent with the overall protective efficacy. Study limitations include limited generalizability to settings with administration of oral polio virus due to low concomitant administration, limited power to assess vaccine efficacy in the second year of life owing to a low number of events among older children, potential bias due to censoring of placebo children at the time of study vaccine receipt, and suboptimal adapted severity scoring based on the Vesikari score, which was designed for use in settings with high parental literacy.
Conclusions
Rotasiil provided protection against SRVGE in infants through an extended follow-up period of approximately 2 years. Protection was significant in the first year of life, when the disease burden and risk of death are highest, and against a changing pattern of rotavirus strains during the 2-year efficacy period. Rotavirus vaccines that are safe, effective, and protective against multiple strains represent the best hope for preventing the severe consequences of rotavirus infection, especially in resource-limited settings, where access to care may be limited. Studies such as this provide valuable information for the planning of national immunization programs and future vaccine development.
Trial registration
ClinicalTrials.gov NCT02145000.



PLoS Med: 29 Jun 2021; 18:e1003655
Isanaka S, Langendorf C, McNeal MM, Meyer N, ... Ciglenecki I, Grais RF
PLoS Med: 29 Jun 2021; 18:e1003655 | PMID: 34214095
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Abstract

Conflict violence reduction and pregnancy outcomes: A regression discontinuity design in Colombia.

Buitrago G, Moreno-Serra R
Background
The relationship between exposure to conflict violence during pregnancy and the risks of miscarriage, stillbirth, and perinatal mortality has not been studied empirically using rigorous methods and appropriate data. We investigated the association between reduced exposure to conflict violence during pregnancy and the risks of adverse pregnancy outcomes in Colombia.
Methods and findings
We adopted a regression discontinuity (RD) design using the July 20, 2015 cease-fire declared during the Colombian peace process as an exogenous discontinuous change in exposure to conflict events during pregnancy, comparing women with conception dates before and after the cease-fire date. We constructed the cohorts of all pregnant women in Colombia for each day between January 1, 2013 and December 31, 2017 using birth and death certificates. A total of 3,254,696 women were followed until the end of pregnancy. We measured conflict exposure as the total number of conflict events that occurred in the municipality where a pregnant woman lived during her pregnancy. We first assessed whether the cease-fire did induce a discontinuous fall in conflict exposure for women with conception dates after the cease-fire to then estimate the association of this reduced exposure with the risks of miscarriage, stillbirth, and perinatal mortality. We found that the July 20, 2015 cease-fire was associated with a reduction of the average number of conflict events (from 2.64 to 2.40) to which women were exposed during pregnancy in their municipalities of residence (mean differences -0.24; 95% confidence interval [CI] -0.35 to -0.13; p < 0.001). This association was greater in municipalities where Fuerzas Armadas Revolucionarias de Colombia (FARC) had a greater presence historically. The reduction in average exposure to conflict violence was, in turn, associated with a decrease of 9.53 stillbirths per 1,000 pregnancies (95% CI -16.13 to -2.93; p = 0.005) for municipalities with total number of FARC-related violent events above the 90th percentile of the distribution of FARC-related conflict events and a decrease of 7.57 stillbirths per 1,000 pregnancies (95% CI -13.14 to -2.00; p = 0.01) for municipalities with total number of FARC-related violent events above the 75th percentile of FARC-related events. For perinatal mortality, we found associated reductions of 10.69 (95% CI -18.32 to -3.05; p = 0.01) and 6.86 (95% CI -13.24 to -0.48; p = 0.04) deaths per 1,000 pregnancies for the 2 types of municipalities, respectively. We found no association with miscarriages. Formal tests support the validity of the key RD assumptions in our data, while a battery of sensitivity analyses and falsification tests confirm the robustness of our empirical results. The main limitations of the study are the retrospective nature of the information sources and the potential for conflict exposure misclassification.
Conclusions
Our study offers evidence that reduced exposure to conflict violence during pregnancy is associated with important (previously unmeasured) benefits in terms of reducing the risk of stillbirth and perinatal deaths. The findings are consistent with such beneficial associations manifesting themselves mainly through reduced violence exposure during the early stages of pregnancy. Beyond the relevance of this evidence for other countries beset by chronic armed conflicts, our results suggest that the fledgling Colombian peace process may be already contributing to better population health.



PLoS Med: 29 Jun 2021; 18:e1003684
Buitrago G, Moreno-Serra R
PLoS Med: 29 Jun 2021; 18:e1003684 | PMID: 34228744
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Abstract

Development and validation of a risk prediction model of preterm birth for women with preterm labour symptoms (the QUIDS study): A prospective cohort study and individual participant data meta-analysis.

Stock SJ, Horne M, Bruijn M, White H, ... Norman JE, Norrie J
Background
Timely interventions in women presenting with preterm labour can substantially improve health outcomes for preterm babies. However, establishing such a diagnosis is very challenging, as signs and symptoms of preterm labour are common and can be nonspecific. We aimed to develop and externally validate a risk prediction model using concentration of vaginal fluid fetal fibronectin (quantitative fFN), in combination with clinical risk factors, for the prediction of spontaneous preterm birth and assessed its cost-effectiveness.
Methods and findings
Pregnant women included in the analyses were 22+0 to 34+6 weeks gestation with signs and symptoms of preterm labour. The primary outcome was spontaneous preterm birth within 7 days of quantitative fFN test. The risk prediction model was developed and internally validated in an individual participant data (IPD) meta-analysis of 5 European prospective cohort studies (2009 to 2016; 1,783 women; mean age 29.7 years; median BMI 24.8 kg/m2; 67.6% White; 11.7% smokers; 51.8% nulliparous; 10.4% with multiple pregnancy; 139 [7.8%] with spontaneous preterm birth within 7 days). The model was then externally validated in a prospective cohort study in 26 United Kingdom centres (2016 to 2018; 2,924 women; mean age 28.2 years; median BMI 25.4 kg/m2; 88.2% White; 21% smokers; 35.2% nulliparous; 3.5% with multiple pregnancy; 85 [2.9%] with spontaneous preterm birth within 7 days). The developed risk prediction model for spontaneous preterm birth within 7 days included quantitative fFN, current smoking, not White ethnicity, nulliparity, and multiple pregnancy. After internal validation, the optimism adjusted area under the curve was 0.89 (95% CI 0.86 to 0.92), and the optimism adjusted Nagelkerke R2 was 35% (95% CI 33% to 37%). On external validation in the prospective UK cohort population, the area under the curve was 0.89 (95% CI 0.84 to 0.94), and Nagelkerke R2 of 36% (95% CI: 34% to 38%). Recalibration of the model\'s intercept was required to ensure overall calibration-in-the-large. A calibration curve suggested close agreement between predicted and observed risks in the range of predictions 0% to 10%, but some miscalibration (underprediction) at higher risks (slope 1.24 (95% CI 1.23 to 1.26)). Despite any miscalibration, the net benefit of the model was higher than \"treat all\" or \"treat none\" strategies for thresholds up to about 15% risk. The economic analysis found the prognostic model was cost effective, compared to using qualitative fFN, at a threshold for hospital admission and treatment of ≥2% risk of preterm birth within 7 days. Study limitations include the limited number of participants who are not White and levels of missing data for certain variables in the development dataset.
Conclusions
In this study, we found that a risk prediction model including vaginal fFN concentration and clinical risk factors showed promising performance in the prediction of spontaneous preterm birth within 7 days of test and has potential to inform management decisions for women with threatened preterm labour. Further evaluation of the risk prediction model in clinical practice is required to determine whether the risk prediction model improves clinical outcomes if used in practice.
Trial registration
The study was approved by the West of Scotland Research Ethics Committee (16/WS/0068). The study was registered with ISRCTN Registry (ISRCTN 41598423) and NIHR Portfolio (CPMS: 31277).



PLoS Med: 29 Jun 2021; 18:e1003686
Stock SJ, Horne M, Bruijn M, White H, ... Norman JE, Norrie J
PLoS Med: 29 Jun 2021; 18:e1003686 | PMID: 34228732
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Abstract

Investigating associations between COVID-19 mortality and population-level health and socioeconomic indicators in the United States: A modeling study.

Kandula S, Shaman J
Background
With the availability of multiple Coronavirus Disease 2019 (COVID-19) vaccines and the predicted shortages in supply for the near future, it is necessary to allocate vaccines in a manner that minimizes severe outcomes, particularly deaths. To date, vaccination strategies in the United States have focused on individual characteristics such as age and occupation. Here, we assess the utility of population-level health and socioeconomic indicators as additional criteria for geographical allocation of vaccines.
Methods and findings
County-level estimates of 14 indicators associated with COVID-19 mortality were extracted from public data sources. Effect estimates of the individual indicators were calculated with univariate models. Presence of spatial autocorrelation was established using Moran\'s I statistic. Spatial simultaneous autoregressive (SAR) models that account for spatial autocorrelation in response and predictors were used to assess (i) the proportion of variance in county-level COVID-19 mortality that can explained by identified health/socioeconomic indicators (R2); and (ii) effect estimates of each predictor. Adjusting for case rates, the selected indicators individually explain 24%-29% of the variability in mortality. Prevalence of chronic kidney disease and proportion of population residing in nursing homes have the highest R2. Mortality is estimated to increase by 43 per thousand residents (95% CI: 37-49; p < 0.001) with a 1% increase in the prevalence of chronic kidney disease and by 39 deaths per thousand (95% CI: 34-44; p < 0.001) with 1% increase in population living in nursing homes. SAR models using multiple health/socioeconomic indicators explain 43% of the variability in COVID-19 mortality in US counties, adjusting for case rates. R2 was found to be not sensitive to the choice of SAR model form. Study limitations include the use of mortality rates that are not age standardized, a spatial adjacency matrix that does not capture human flows among counties, and insufficient accounting for interaction among predictors.
Conclusions
Significant spatial autocorrelation exists in COVID-19 mortality in the US, and population health/socioeconomic indicators account for a considerable variability in county-level mortality. In the context of vaccine rollout in the US and globally, national and subnational estimates of burden of disease could inform optimal geographical allocation of vaccines.



PLoS Med: 29 Jun 2021; 18:e1003693
Kandula S, Shaman J
PLoS Med: 29 Jun 2021; 18:e1003693 | PMID: 34255766
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Abstract

Preventing microalbuminuria with benazepril, valsartan, and benazepril-valsartan combination therapy in diabetic patients with high-normal albuminuria: A prospective, randomized, open-label, blinded endpoint (PROBE) study.

Ruggenenti P, Cortinovis M, Parvanova A, Trillini M, ... Remuzzi G, VARIETY Study Organization
Background
Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) prevent microalbuminuria in normoalbuminuric type 2 diabetic patients. We assessed whether combined therapy with the 2 medications may prevent microalbuminuria better than ACE inhibitor or ARB monotherapy.
Methods and findings
VARIETY was a prospective, randomized, open-label, blinded endpoint (PROBE) trial evaluating whether, at similar blood pressure (BP) control, combined therapy with benazepril (10 mg/day) and valsartan (160 mg/day) would prevent microalbuminuria more effectively than benazepril (20 mg/day) or valsartan (320 mg/day) monotherapy in 612 type 2 diabetic patients with high-normal albuminuria included between July 2007 and April 2013 by the Istituto di Ricerche Farmacologiche Mario Negri IRCCS and 8 diabetology or nephrology units in Italy. Time to progression to microalbuminuria was the primary outcome. Analyses were intention to treat. Baseline characteristics were similar among groups. During a median [interquartile range, IQR] follow-up of 66 [42 to 83] months, 53 patients (27.0%) on combination therapy, 57 (28.1%) on benazepril, and 64 (31.8%) on valsartan reached microalbuminuria. Using an accelerated failure time model, the estimated acceleration factors were 1.410 (95% CI: 0.806 to 2.467, P = 0.229) for benazepril compared to combination therapy, 0.799 (95% CI: 0.422 to 1.514, P = 0.492) for benazepril compared to valsartan, and 1.665 (95% CI: 1.007 to 2.746, P = 0.047) for valsartan compared to combination therapy. Between-group differences in estimated acceleration factors were nonsignificant after adjustment for predefined confounders. BP control was similar across groups. All treatments were safe and tolerated well, with a slight excess of hyperkalemia and hypotension in the combination therapy group. The main study limitation was the lower than expected albuminuria at inclusion.
Conclusions
Risk/benefit profile of study treatments was similar. Dual renin-angiotensin system (RAS) blockade is not recommended as compared to benazepril or valsartan monotherapy for prevention of microalbuminuria in normoalbuminuric type 2 diabetic patients.
Trial registration
EudraCT 2006-005954-62; ClinicalTrials.gov NCT00503152.



PLoS Med: 29 Jun 2021; 18:e1003691
Ruggenenti P, Cortinovis M, Parvanova A, Trillini M, ... Remuzzi G, VARIETY Study Organization
PLoS Med: 29 Jun 2021; 18:e1003691 | PMID: 34260595
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Abstract

Obesity and revision surgery, mortality, and patient-reported outcomes after primary knee replacement surgery in the National Joint Registry: A UK cohort study.

Evans JT, Mouchti S, Blom AW, Wilkinson JM, ... Beswick A, Judge A
Background
One in 10 people in the United Kingdom will need a total knee replacement (TKR) during their lifetime. Access to this life-changing operation has recently been restricted based on body mass index (BMI) due to belief that high BMI may lead to poorer outcomes. We investigated the associations between BMI and revision surgery, mortality, and pain/function using what we believe to be the world\'s largest joint replacement registry.
Methods and findings
We analysed 493,710 TKRs in the National Joint Registry (NJR) for England, Wales, Northern Ireland, and the Isle of Man from 2005 to 2016 to investigate 90-day mortality and 10-year cumulative revision. Hospital Episodes Statistics (HES) and Patient Reported Outcome Measures (PROMs) databases were linked to the NJR to investigate change in Oxford Knee Score (OKS) 6 months postoperatively. After adjustment for age, sex, American Society of Anaesthesiologists (ASA) grade, indication for operation, year of primary TKR, and fixation type, patients with high BMI were more likely to undergo revision surgery within 10 years compared to those with \"normal\" BMI (obese class II hazard ratio (HR) 1.21, 95% CI: 1.10, 1.32 (p < 0.001) and obese class III HR 1.13, 95% CI: 1.02, 1.26 (p = 0.026)). All BMI classes had revision estimates within the recognised 10-year benchmark of 5%. Overweight and obese class I patients had lower mortality than patients with \"normal\" BMI (HR 0.76, 95% CI: 0.65, 0.90 (p = 0.001) and HR 0.69, 95% CI: 0.58, 0.82 (p < 0.001)). All BMI categories saw absolute increases in OKS after 6 months (range 18-20 points). The relative improvement in OKS was lower in overweight and obese patients than those with \"normal\" BMI, but the difference was below the minimal detectable change (MDC; 4 points). The main limitations were missing BMI particularly in the early years of data collection and a potential selection bias effect of surgeons selecting the fitter patients with raised BMI for surgery.
Conclusions
Given revision estimates in all BMI groups below the recognised threshold, no evidence of increased mortality, and difference in change in OKS below the MDC, this large national registry shows no evidence of poorer outcomes in patients with high BMI. This study does not support rationing of TKR based on increased BMI.



PLoS Med: 29 Jun 2021; 18:e1003704
Evans JT, Mouchti S, Blom AW, Wilkinson JM, ... Beswick A, Judge A
PLoS Med: 29 Jun 2021; 18:e1003704 | PMID: 34270557
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Abstract

Telmisartan use and risk of dementia in type 2 diabetes patients with hypertension: A population-based cohort study.

Liu CH, Sung PS, Li YR, Huang WK, ... Chen TH, Wei YC
Background
Angiotensin receptor blockers (ARBs) may have protective effects against dementia occurrence in patients with hypertension (HTN). However, whether telmisartan, an ARB with peroxisome proliferator-activated receptor γ (PPAR-γ)-modulating effects, has additional benefits compared to other ARBs remains unclear.
Methods and findings
Between 1997 and 2013, 2,166,944 type 2 diabetes mellitus (T2DM) patients were identified from the National Health Insurance Research Database of Taiwan. Patients with HTN using ARBs were included in the study. Patients with a history of stroke, traumatic brain injury, or dementia were excluded. Finally, 65,511 eligible patients were divided into 2 groups: the telmisartan group and the non-telmisartan ARB group. Propensity score matching (1:4) was used to balance the distribution of baseline characteristics and medications. The primary outcome was the diagnosis of dementia. The secondary outcomes included the diagnosis of Alzheimer disease and occurrence of symptomatic ischemic stroke (IS), any IS, and all-cause mortality. The risks between groups were compared using a Cox proportional hazard model. Statistical significance was set at p < 0.05. There were 2,280 and 9,120 patients in the telmisartan and non-telmisartan ARB groups, respectively. Patients in the telmisartan group had a lower risk of dementia diagnosis (telmisartan versus non-telmisartan ARBs: 2.19% versus 3.20%; HR, 0.72; 95% CI, 0.53 to 0.97; p = 0.030). They also had lower risk of dementia diagnosis with IS as a competing risk (subdistribution HR, 0.70; 95% CI, 0.51 to 0.95; p = 0.022) and with all-cause mortality as a competing risk (subdistribution HR, 0.71; 95% CI, 0.53 to 0.97; p = 0.029). In addition, the telmisartan users had a lower risk of any IS (6.84% versus 8.57%; HR, 0.79; 95% CI, 0.67 to 0.94; p = 0.008) during long-term follow-up. Study limitations included potential residual confounding by indication, interpretation of causal effects in an observational study, and bias caused by using diagnostic and medication codes to represent real clinical data.
Conclusions
The current study suggests that telmisartan use in hypertensive T2DM patients may be associated with a lower risk of dementia and any IS events in an East-Asian population.



PLoS Med: 29 Jun 2021; 18:e1003707
Liu CH, Sung PS, Li YR, Huang WK, ... Chen TH, Wei YC
PLoS Med: 29 Jun 2021; 18:e1003707 | PMID: 34280191
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Abstract

Resistance exercise, alone and in combination with aerobic exercise, and obesity in Dallas, Texas, US: A prospective cohort study.

Brellenthin AG, Lee DC, Bennie JA, Sui X, Blair SN
Background
Obesity is a significant and growing public health problem in high-income countries. Little is known about the relationship between resistance exercise (RE), alone and in combination with aerobic exercise (AE), and the risk of developing obesity. The purpose of this prospective cohort study was to examine the associations between different amounts and frequencies of RE, independent of AE, and incident obesity.
Methods and findings
Participants were 11,938 healthy adults ages 18-89 years with a BMI < 30 kg/m2 at baseline who completed at least 2 clinical examinations during 1987-2005 as part of the Aerobics Center Longitudinal Study. Self-reported RE participation in minutes/week and days/week was collected from a standardized questionnaire. Incident obesity was defined as a BMI ≥ 30 kg/m2 at follow-up. Incident obesity was also defined by waist circumference (WC) > 102/88 cm for men/women and percent body fat (PBF) ≥ 25%/30% for men/women at follow-up in participants who were not obese by WC (n = 9,490) or PBF (n = 8,733) at baseline. During the average 6-year follow-up, 874 (7%), 726 (8%), and 1,683 (19%) developed obesity defined by BMI, WC, or PBF, respectively. Compared with no RE, 60-119 min/wk of RE was associated with 30%, 41%, and 31% reduced risk of obesity defined by BMI (hazard ratio [95% CI], 0.70 [0.54-0.92], p = 0.008), WC (0.59 [0.44-0.81], p < 0.001), and PBF (0.69 [0.57-0.83], p < 0.001), respectively, after adjusting for confounders including age, sex, examination year, smoking status, heavy alcohol consumption, hypertension, hypercholesterolemia, diabetes, and AE. Compared with not meeting the RE guidelines of ≥2 d/wk, meeting the RE guidelines was associated with 18%, 30%, and 30% reduced risk of obesity defined by BMI (hazard ratio [95% CI], 0.82 [0.69-0.97], p = 0.02), WC (0.70 [0.57-0.85], p < 0.001), and PBF (0.70 [0.62-0.79], p < 0.001), respectively. Compared with meeting neither guideline, meeting both the AE and RE guidelines was associated with the smallest hazard ratios for obesity. Limitations of this study include limited generalizability as participants were predominantly white men from middle to upper socioeconomic strata, use of self-reported RE, and lack of detailed diet data for the majority of participants.
Conclusions
In this study, we observed that RE was associated with a significantly reduced risk of obesity even after considering AE. However, meeting both the RE and AE guidelines was associated with the lowest risk of obesity.



PLoS Med: 30 May 2021; 18:e1003687
Brellenthin AG, Lee DC, Bennie JA, Sui X, Blair SN
PLoS Med: 30 May 2021; 18:e1003687 | PMID: 34161329
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Abstract

Association between exercise habits and stroke, heart failure, and mortality in Korean patients with incident atrial fibrillation: A nationwide population-based cohort study.

Ahn HJ, Lee SR, Choi EK, Han KD, ... Oh S, Lip GYH
Background
There is a paucity of information about cardiovascular outcomes related to exercise habit change after a new diagnosis of atrial fibrillation (AF). We investigated the association between exercise habits after a new AF diagnosis and ischemic stroke, heart failure (HF), and all-cause death.
Methods and findings
This is a nationwide population-based cohort study using data from the Korea National Health Insurance Service. A retrospective analysis was performed for 66,692 patients with newly diagnosed AF between 2010 and 2016 who underwent 2 serial health examinations within 2 years before and after their AF diagnosis. Individuals were divided into 4 categories according to performance of regular exercise, which was investigated by a self-reported questionnaire in each health examination, before and after their AF diagnosis: persistent non-exercisers (30.5%), new exercisers (17.8%), exercise dropouts (17.4%), and exercise maintainers (34.2%). The primary outcomes were incidence of ischemic stroke, HF, and all-cause death. Differences in baseline characteristics among groups were balanced considering demographics, comorbidities, medications, lifestyle behaviors, and income status. The risks of the outcomes were computed by weighted Cox proportional hazards models with inverse probability of treatment weighting (IPTW) during a mean follow-up of 3.4 ± 2.0 years. The new exerciser and exercise maintainer groups were associated with a lower risk of HF compared to the persistent non-exerciser group: the hazard ratios (HRs) (95% CIs) were 0.95 (0.90-0.99) and 0.92 (0.88-0.96), respectively (p < 0.001). Also, performing exercise any time before or after AF diagnosis was associated with a lower risk of mortality compared to persistent non-exercising: the HR (95% CI) was 0.82 (0.73-0.91) for new exercisers, 0.83 (0.74-0.93) for exercise dropouts, and 0.61 (0.55-0.67) for exercise maintainers (p < 0.001). For ischemic stroke, the estimates of HRs were 10%-14% lower in patients of the exercise groups, yet differences were statistically insignificant (p = 0.057). Energy expenditure of 1,000-1,499 MET-min/wk (regular moderate exercise 170-240 min/wk) was consistently associated with a lower risk of each outcome based on a subgroup analysis of the new exerciser group. Study limitations include recall bias introduced due to the nature of the self-reported questionnaire and restricted external generalizability to other ethnic groups.
Conclusions
Initiating or continuing regular exercise after AF diagnosis was associated with lower risks of HF and mortality. The promotion of exercise might reduce the future risk of adverse outcomes in patients with AF.



PLoS Med: 30 May 2021; 18:e1003659
Ahn HJ, Lee SR, Choi EK, Han KD, ... Oh S, Lip GYH
PLoS Med: 30 May 2021; 18:e1003659 | PMID: 34101730
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Abstract

Integrated treatment of hepatitis C virus infection among people who inject drugs: A multicenter randomized controlled trial (INTRO-HCV).

Fadnes LT, Aas CF, Vold JH, Leiva RA, ... Johansson KA, INTRO-HCV Study Group
Background
The standard pathways of testing and treatment for hepatitis C virus (HCV) infection in tertiary healthcare are not easily accessed by people who inject drugs (PWID). The aim of this study was to evaluate the efficacy of integrated treatment of chronic HCV infection among PWID.
Methods and findings
INTRO-HCV is a multicenter, randomized controlled clinical trial. Participants recruited from opioid agonist therapy (OAT) and community care clinics in Norway over 2017 to 2019 were randomly 1:1 assigned to the 2 treatment approaches. Integrated treatment was delivered by multidisciplinary teams at opioid agonist treatment clinics or community care centers (CCCs) for people with substance use disorders. This included on-site testing for HCV, liver fibrosis assessment, counseling, treatment, and posttreatment follow-up. Standard treatment was delivered in hospital outpatient clinics. Oral direct-acting antiviral (DAA) medications were administered in both arms. The study was not completely blinded. The primary outcomes were time-to-treatment initiation and sustained virologic response (SVR), defined as undetectable HCV RNA 12 weeks after treatment completion, analyzed with intention to treat, and presented as hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals. Among 298 included participants, 150 were randomized to standard treatment, of which 116/150 (77%) initiated treatment, with 108/150 (72%) initiating within 1 year of referral. Among those 148 randomized to integrated care, 145/148 (98%) initiated treatment, with 141/148 (95%) initiating within 1 year of referral. The HR for the time to initiating treatment in the integrated arm was 2.2 (1.7 to 2.9) compared to standard treatment. SVR was confirmed in 123 (85% of initiated/83% of all) for integrated treatment compared to 96 (83% of initiated/64% of all) for the standard treatment (OR among treated: 1.5 [0.8 to 2.9], among all: 2.8 [1.6 to 4.8]). No severe adverse events were linked to the treatment.
Conclusions
Integrated treatment for HCV in PWID was superior to standard treatment in terms of time-to-treatment initiation, and subsequently, more people achieved SVR. Among those who initiated treatment, the SVR rates were comparable. Scaling up of integrated treatment models could be an important tool for elimination of HCV.
Trial registration
ClinicalTrials.gov.no NCT03155906.



PLoS Med: 30 May 2021; 18:e1003653
Fadnes LT, Aas CF, Vold JH, Leiva RA, ... Johansson KA, INTRO-HCV Study Group
PLoS Med: 30 May 2021; 18:e1003653 | PMID: 34061883
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Abstract

Association between industry payments and prescriptions of long-acting insulin: An observational study with propensity score matching.

Inoue K, Tsugawa Y, Mangione CM, Duru OK
Background
The rapidly increased spending on insulin is a major public health issue in the United States. Industry marketing might be one of the upstream determinants of physicians\' prescription of long-acting insulin-the most commonly used and costly type of insulin, but the evidence is lacking. We therefore aimed to investigate the association between industry payments to physicians and subsequent prescriptions of long-acting insulin.
Methods and findings
Using the databases of Open Payments and Medicare Part D, we examined the association between the receipt of industry payments for long-acting insulin in 2016 and (1) the number of claims; (2) the costs paid for all claims; and (3) the costs per claim of long-acting insulin in 2017. We also examined the association between the receipt of payments and the change in these outcomes from 2016 to 2017. We employed propensity score matching to adjust for the physician-level characteristics (sex, years in practice, specialty, and medical school attended). Among 145,587 eligible physicians treating Medicare beneficiaries, 51,851 physicians received industry payments for long-acting insulin worth $22.3 million. In the propensity score-matched analysis including 102,590 physicians, we found that physicians who received the payments prescribed a higher number of claims (adjusted difference, 57.8; 95% CI, 55.8 to 59.7), higher costs for total claims (adjusted difference, +$22,111; 95% CI, $21,387 to $22,836), and higher costs per claim (adjusted difference, +$71.1; 95% CI, $69.0 to $73.2) of long-acting insulin, compared with physicians who did not receive the payments. The association was also found for changes in these outcomes from 2016 to 2017. Limitations to our study include limited generalizability, confounding, and possible reverse causation.
Conclusions
Industry marketing payments to physicians for long-acting insulin were associated with the physicians\' prescriptions and costs of long-acting insulin in the subsequent year. Future research is needed to assess whether policy interventions on physician-industry financial relationships will help to ensure appropriate prescriptions and limit overall costs of this essential drug for diabetes care.



PLoS Med: 30 May 2021; 18:e1003645
Inoue K, Tsugawa Y, Mangione CM, Duru OK
PLoS Med: 30 May 2021; 18:e1003645 | PMID: 34061852
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Abstract

Associations of obesity and malnutrition with cardiac remodeling and cardiovascular outcomes in Asian adults: A cohort study.

Chien SC, Chandramouli C, Lo CI, Lin CF, ... Hung CL, Lam CSP
Background
Obesity, a known risk factor for cardiovascular disease and heart failure (HF), is associated with adverse cardiac remodeling in the general population. Little is known about how nutritional status modifies the relationship between obesity and outcomes. We aimed to investigate the association of obesity and nutritional status with clinical characteristics, echocardiographic changes, and clinical outcomes in the general community.
Methods and findings
We examined 5,300 consecutive asymptomatic Asian participants who were prospectively recruited in a cardiovascular health screening program (mean age 49.6 ± 11.4 years, 64.8% male) between June 2009 to December 2012. Clinical and echocardiographic characteristics were described in participants, stratified by combined subgroups of obesity and nutritional status. Obesity was indexed by body mass index (BMI) (low, ≤25 kg/m2 [lean]; high, >25 kg/m2 [obese]) (WHO-recommended Asian cutoffs). Nutritional status was defined primarily by serum albumin (SA) concentration (low, <45 g/L [malnourished]; high, ≥45 g/L [well-nourished]), and secondarily by the prognostic nutritional index (PNI) and Global Leadership Initiative on Malnutrition (GLIM) criteria. Cox proportional hazard models were used to examine a 1-year composite outcome of hospitalization for HF or all-cause mortality while adjusting for age, sex, and other clinical confounders. Our community-based cohort consisted of 2,096 (39.0%) lean-well-nourished (low BMI, high SA), 1,369 (25.8%) obese-well-nourished (high BMI, high SA), 1,154 (21.8%) lean-malnourished (low BMI, low SA), and 681 (12.8%) obese-malnourished (high BMI, low SA) individuals. Obese-malnourished participants were on average older (54.5 ± 11.4 years) and more often women (41%), with a higher mean waist circumference (91.7 ± 8.8 cm), the highest percentage of body fat (32%), and the highest prevalence of hypertension (32%), diabetes (12%), and history of cardiovascular disease (11%), compared to all other subgroups (all p < 0.001). N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were substantially increased in the malnourished (versus well-nourished) groups, to a similar extent in lean (70.7 ± 177.3 versus 36.8 ± 40.4 pg/mL) and obese (73.1 ± 216.8 versus 33.2 ± 40.8 pg/mL) (p < 0.001 in both) participants. The obese-malnourished (high BMI, low SA) group also had greater left ventricular remodeling (left ventricular mass index, 44.2 ± 1.52 versus 33.8 ± 8.28 gm/m2; relative wall thickness 0.39 ± 0.05 versus 0.38 ± 0.06) and worse diastolic function (TDI-e\' 7.97 ± 2.16 versus 9.87 ± 2.47 cm/s; E/e\' 9.19 ± 3.01 versus 7.36 ± 2.31; left atrial volume index 19.5 ± 7.66 versus 14.9 ± 5.49 mL/m2) compared to the lean-well-nourished (low BMI, high SA) group, as well as all other subgroups (p < 0.001 for all). Over a median 3.6 years (interquartile range 2.5 to 4.8 years) of follow-up, the obese-malnourished group had the highest multivariable-adjusted risk of the composite outcome (hazard ratio [HR] 2.49, 95% CI 1.43 to 4.34, p = 0.001), followed by the lean-malnourished (HR 1.78, 95% CI 1.04 to 3.04, p = 0.034) and obese-well-nourished (HR 1.41, 95% CI 0.77 to 2.58, p = 0.27) groups (with lean-well-nourished group as reference). Results were similar when indexed by other anthropometric indices (waist circumference and body fat) and other measures of nutritional status (PNI and GLIM criteria). Potential selection bias and residual confounding were the main limitations of the study.
Conclusions
In our cohort study among asymptomatic community-based adults in Taiwan, we found that obese individuals with poor nutritional status have the highest comorbidity burden, the most adverse cardiac remodeling, and the least favorable composite outcome.



PLoS Med: 30 May 2021; 18:e1003661
Chien SC, Chandramouli C, Lo CI, Lin CF, ... Hung CL, Lam CSP
PLoS Med: 30 May 2021; 18:e1003661 | PMID: 34061848
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Abstract

Risk of prostate cancer in relatives of prostate cancer patients in Sweden: A nationwide cohort study.

Xu X, Kharazmi E, Tian Y, Mukama T, ... Brenner H, Fallah M
Background
Evidence-based guidance for starting ages of screening for first-degree relatives (FDRs) of patients with prostate cancer (PCa) to prevent stage III/IV or fatal PCa is lacking in current PCa screening guidelines. We aimed to provide evidence for risk-adapted starting age of screening for relatives of patients with PCa.
Methods and findings
In this register-based nationwide cohort study, all men (aged 0 to 96 years at baseline) residing in Sweden who were born after 1931 along with their fathers were included. During the follow-up (1958 to 2015) of 6,343,727 men, 88,999 were diagnosed with stage III/IV PCa or died of PCa. The outcomes were defined as the diagnosis of stage III/IV PCa or death due to PCa, stratified by age at diagnosis. Using 10-year cumulative risk curves, we calculated risk-adapted starting ages of screening for men with different constellations of family history of PCa. The 10-year cumulative risk of stage III/IV or fatal PCa in men at age 50 in the general population (a common recommended starting age of screening) was 0.2%. Men with ≥2 FDRs diagnosed with PCa reached this screening level at age 41 (95% confidence interval (CI): 39 to 44), i.e., 9 years earlier, when the youngest one was diagnosed before age 60; at age 43 (41 to 47), i.e., 7 years earlier, when ≥2 FDRs were diagnosed after age 59, which was similar to that of men with 1 FDR diagnosed before age 60 (41 to 45); and at age 45 (44 to 46), when 1 FDR was diagnosed at age 60 to 69 and 47 (46 to 47), when 1 FDR was diagnosed after age 69. We also calculated risk-adapted starting ages for other benchmark screening ages, such as 45, 55, and 60 years, and compared our findings with those in the guidelines. Study limitations include the lack of genetic data, information on lifestyle, and external validation.
Conclusions
Our study provides practical information for risk-tailored starting ages of PCa screening based on nationwide cancer data with valid genealogical information. Our clinically relevant findings could be used for evidence-based personalized PCa screening guidance and supplement current PCa screening guidelines for relatives of patients with PCa.



PLoS Med: 30 May 2021; 18:e1003616
Xu X, Kharazmi E, Tian Y, Mukama T, ... Brenner H, Fallah M
PLoS Med: 30 May 2021; 18:e1003616 | PMID: 34061847
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Abstract

Inequities in access to primary care among opioid recipients in Ontario, Canada: A population-based cohort study.

Gomes T, Campbell TJ, Martins D, Paterson JM, ... Mamdani M, Glazier RH
Background
Stigma and high-care needs can present barriers to the provision of high-quality primary care for people with opioid use disorder (OUD) and those prescribed opioids for chronic pain. We explored the likelihood of securing a new primary care provider (PCP) among people with varying histories of opioid use who had recently lost access to their PCP.
Methods and findings
We conducted a retrospective cohort study using linked administrative data among residents of Ontario, Canada whose enrolment with a physician practicing in a primary care enrolment model (PEM) was terminated between January 2016 and December 2017. We assigned individuals to 3 groups based upon their opioid use on the date enrolment ended: long-term opioid pain therapy (OPT), opioid agonist therapy (OAT), or no opioid. We fit multivariable models assessing the primary outcome of primary care reattachment within 1 year, adjusting for demographic characteristics, clinical comorbidities, and health services utilization. Secondary outcomes included rates of emergency department (ED) visits and opioid toxicity events. Among 154,970 Ontarians who lost their PCP, 1,727 (1.1%) were OAT recipients, 3,644 (2.4%) were receiving long-term OPT, and 149,599 (96.5%) had no recent prescription opioid exposure. In general, OAT recipients were younger (median age 36) than those receiving long-term OPT (59 years) and those with no recent prescription opioid exposure (44 years). In all exposure groups, the majority of individuals had their enrolment terminated by their physician (range 78.1% to 88.8%). In the primary analysis, as compared to those not receiving opioids, OAT recipients were significantly less likely to find a PCP within 1 year (adjusted hazard ratio [aHR] 0.55, 95% confidence interval [CI] 0.50 to 0.61, p < 0.0001). We observed no significant difference between long-term OPT and opioid unexposed individuals (aHR 0.96; 95% CI 0.92 to 1.01, p = 0.12). In our secondary analysis comparing the period of PCP loss to the year prior, we found that rates of ED visits were elevated among people not receiving opioids (adjusted rate ratio (aRR) 1.20, 95% CI 1.18 to 1.22, p < 0.0001) and people receiving long-term OPT (aRR 1.37, 95% CI 1.28 to 1.48, p < 0.0001). We found no such increase among OAT recipients, and no significant increase in opioid toxicity events in the period following provider loss for any exposure group. The main limitation of our findings relates to their generalizability outside of PEMs and in jurisdictions with different financial incentives incorporated into primary care provision.
Conclusions
In this study, we observed gaps in access to primary care among people who receive prescription opioids, particularly among OAT recipients. Ongoing efforts are needed to address the stigma, discrimination, and financial disincentives that may introduce barriers to the healthcare system, and to facilitate access to high-quality, consistent primary care services for chronic pain patients and those with OUD.



PLoS Med: 30 May 2021; 18:e1003631
Gomes T, Campbell TJ, Martins D, Paterson JM, ... Mamdani M, Glazier RH
PLoS Med: 30 May 2021; 18:e1003631 | PMID: 34061846
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Abstract

Global economic costs due to vivax malaria and the potential impact of its radical cure: A modelling study.

Devine A, Battle KE, Meagher N, Howes RE, ... Price RN, Lubell Y
Background
In 2017, an estimated 14 million cases of Plasmodium vivax malaria were reported from Asia, Central and South America, and the Horn of Africa. The clinical burden of vivax malaria is largely driven by its ability to form dormant liver stages (hypnozoites) that can reactivate to cause recurrent episodes of malaria. Elimination of both the blood and liver stages of the parasites (\"radical cure\") is required to achieve a sustained clinical response and prevent ongoing transmission of the parasite. Novel treatment options and point-of-care diagnostics are now available to ensure that radical cure can be administered safely and effectively. We quantified the global economic cost of vivax malaria and estimated the potential cost benefit of a policy of radical cure after testing patients for glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Methods and findings
Estimates of the healthcare provider and household costs due to vivax malaria were collated and combined with national case estimates for 44 endemic countries in 2017. These provider and household costs were compared with those that would be incurred under 2 scenarios for radical cure following G6PD screening: (1) complete adherence following daily supervised primaquine therapy and (2) unsupervised treatment with an assumed 40% effectiveness. A probabilistic sensitivity analysis generated credible intervals (CrIs) for the estimates. Globally, the annual cost of vivax malaria was US$359 million (95% CrI: US$222 to 563 million), attributable to 14.2 million cases of vivax malaria in 2017. From a societal perspective, adopting a policy of G6PD deficiency screening and supervision of primaquine to all eligible patients would prevent 6.1 million cases and reduce the global cost of vivax malaria to US$266 million (95% CrI: US$161 to 415 million), although healthcare provider costs would increase by US$39 million. If perfect adherence could be achieved with a single visit, then the global cost would fall further to US$225 million, equivalent to $135 million in cost savings from the baseline global costs. A policy of unsupervised primaquine reduced the cost to US$342 million (95% CrI: US$209 to 532 million) while preventing 2.1 million cases. Limitations of the study include partial availability of country-level cost data and parameter uncertainty for the proportion of patients prescribed primaquine, patient adherence to a full course of primaquine, and effectiveness of primaquine when unsupervised.
Conclusions
Our modelling study highlights a substantial global economic burden of vivax malaria that could be reduced through investment in safe and effective radical cure achieved by routine screening for G6PD deficiency and supervision of treatment. Novel, low-cost interventions for improving adherence to primaquine to ensure effective radical cure and widespread access to screening for G6PD deficiency will be critical to achieving the timely global elimination of P. vivax.



PLoS Med: 30 May 2021; 18:e1003614
Devine A, Battle KE, Meagher N, Howes RE, ... Price RN, Lubell Y
PLoS Med: 30 May 2021; 18:e1003614 | PMID: 34061843
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Abstract

Blood pressure-lowering treatment for the prevention of cardiovascular events in patients with atrial fibrillation: An individual participant data meta-analysis.

Pinho-Gomes AC, Azevedo L, Copland E, Canoy D, ... Rahimi K, Blood Pressure Lowering Treatment Trialists’ Collaboration
Background
Randomised evidence on the efficacy of blood pressure (BP)-lowering treatment to reduce cardiovascular risk in patients with atrial fibrillation (AF) is limited. Therefore, this study aimed to compare the effects of BP-lowering drugs in patients with and without AF at baseline.
Methods and findings
The study was based on the resource provided by the Blood Pressure Lowering Treatment Trialists\' Collaboration (BPLTTC), in which individual participant data (IPD) were extracted from trials with over 1,000 patient-years of follow-up in each arm, and that had randomly assigned patients to different classes of BP-lowering drugs, BP-lowering drugs versus placebo, or more versus less intensive BP-lowering regimens. For this study, only trials that had collected information on AF status at baseline were included. The effects of BP-lowering treatment on a composite endpoint of major cardiovascular events (stroke, ischaemic heart disease or heart failure) according to AF status at baseline were estimated using fixed-effect one-stage IPD meta-analyses based on Cox proportional hazards models stratified by trial. Furthermore, to assess whether the associations between the intensity of BP reduction and cardiovascular outcomes are similar in those with and without AF at baseline, we used a meta-regression. From the full BPLTTC database, 28 trials (145,653 participants) were excluded because AF status at baseline was uncertain or unavailable. A total of 22 trials were included with 188,570 patients, of whom 13,266 (7%) had AF at baseline. Risk of bias assessment showed that 20 trials were at low risk of bias and 2 trials at moderate risk. Meta-regression showed that relative risk reductions were proportional to trial-level intensity of BP lowering in patients with and without AF at baseline. Over 4.5 years of median follow-up, a 5-mm Hg systolic BP (SBP) reduction lowered the risk of major cardiovascular events both in patients with AF (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.83 to 1.00) and in patients without AF at baseline (HR 0.91, 95% CI 0.88 to 0.93), with no difference between subgroups. There was no evidence for heterogeneity of treatment effects by baseline SBP or drug class in patients with AF at baseline. The findings of this study need to be interpreted in light of its potential limitations, such as the limited number of trials, limitation in ascertaining AF cases due to the nature of the arrhythmia and measuring BP in patients with AF.
Conclusions
In this meta-analysis, we found that BP-lowering treatment reduces the risk of major cardiovascular events similarly in individuals with and without AF. Pharmacological BP lowering for prevention of cardiovascular events should be recommended in patients with AF.



PLoS Med: 30 May 2021; 18:e1003599
Pinho-Gomes AC, Azevedo L, Copland E, Canoy D, ... Rahimi K, Blood Pressure Lowering Treatment Trialists’ Collaboration
PLoS Med: 30 May 2021; 18:e1003599 | PMID: 34061831
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Abstract

Association of APOE ε4 genotype and lifestyle with cognitive function among Chinese adults aged 80 years and older: A cross-sectional study.

Jin X, He W, Zhang Y, Gong E, ... Zeng Y, Yan LL
Background
Apolipoprotein E (APOE) ε4 is the single most important genetic risk factor for cognitive impairment and Alzheimer disease (AD), while lifestyle factors such as smoking, drinking, diet, and physical activity also have impact on cognition. The goal of the study is to investigate whether the association between lifestyle and cognition varies by APOE genotype among the oldest old.
Methods and findings
We used the cross-sectional data including 6,160 oldest old (aged 80 years old or older) from the genetic substudy of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) which is a national wide cohort study that began in 1998 with follow-up surveys every 2-3 years. Cognitive impairment was defined as a Mini-Mental State Examination (MMSE) score less than 18. Healthy lifestyle profile was classified into 3 groups by a composite measure including smoking, alcohol consumption, dietary pattern, physical activity, and body weight. APOE genotype was categorized as APOE ε4 carriers versus noncarriers. We examined the associations of cognitive impairment with lifestyle profile and APOE genotype using multivariable logistic regressions, controlling for age, sex, education, marital status, residence, disability, and numbers of chronic conditions. The mean age of our study sample was 90.1 (standard deviation [SD], 7.2) years (range 80-113); 57.6% were women, and 17.5% were APOE ε4 carriers. The mean MMSE score was 21.4 (SD: 9.2), and 25.0% had cognitive impairment. Compared with those with an unhealthy lifestyle, participants with intermediate and healthy lifestyle profiles were associated with 28% (95% confidence interval [CI]: 16%-38%, P < 0.001) and 55% (95% CI: 44%-64%, P < 0.001) lower adjusted odds of cognitive impairment. Carrying the APOE ε4 allele was associated with 17% higher odds (95% CI: 1%-31%, P = 0.042) of being cognitively impaired in the adjusted model. The association between lifestyle profiles and cognitive function did not vary significantly by APOE ε4 genotype (noncarriers: 0.47 [0.37-0.60] healthy versus unhealthy; carriers: 0.33 [0.18-0.58], P for interaction = 0.30). The main limitation was the lifestyle measurements were self-reported and were nonspecific. Generalizability of the findings is another limitation because the study sample was from the oldest old in China, with unique characteristics such as low body weight compared to populations in high-income countries.
Conclusions
In this study, we observed that healthier lifestyle was associated with better cognitive function among the oldest old regardless of APOE genotype. Our findings may inform the cognitive outlook for those oldest old with high genetic risk of cognitive impairment.



PLoS Med: 30 May 2021; 18:e1003597
Jin X, He W, Zhang Y, Gong E, ... Zeng Y, Yan LL
PLoS Med: 30 May 2021; 18:e1003597 | PMID: 34061824
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Abstract

Cervical intraepithelial neoplasia and the risk of spontaneous preterm birth: A Dutch population-based cohort study with 45,259 pregnancy outcomes.

Loopik DL, van Drongelen J, Bekkers RLM, Voorham QJM, ... van Kemenade FJ, Siebers AG
Background
Excisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased risk is due to the excision procedure itself, to the underlying CIN, or to secondary risk factors that are associated with both preterm birth and CIN. The aim of this study is to assess the risk of spontaneous preterm birth in women with treated and untreated CIN and examine possible associations by making a distinction between the excised volume of cervical tissue and having cervical disease.
Methods and findings
This Dutch population-based observational cohort study identified women aged 29 to 41 years with CIN between 2005 and 2015 from the Dutch pathology registry (PALGA) and frequency matched them with a control group without any cervical abnormality based on age at and year of pathology outcome (i.e., CIN or normal cytology) and urbanization (<100,000 inhabitants or ≥100,000 inhabitants). All their 45,259 subsequent singleton pregnancies with a gestational age ≥16 weeks between 2010 and 2017 were identified from the Dutch perinatal database (Perined). Nineteen potential confounders for preterm birth were identified. Adjusted odds ratios (ORs) were calculated for preterm birth comparing the 3 different groups of women: (1) women without CIN diagnosis; (2) women with untreated CIN; and (3) women with treated CIN prior to each childbirth. In total, 29,907, 5,940, and 9,412 pregnancies were included in the control, untreated CIN, and treated CIN group, respectively. The control group showed a 4.8% (1,002/20,969) proportion of spontaneous preterm birth, which increased to 6.9% (271/3,940) in the untreated CIN group, 9.5% (600/6,315) in the treated CIN group, and 15.6% (50/321) in the group with multiple treatments. Women with untreated CIN had a 1.38 times greater odds of preterm birth compared to women without CIN (95% confidence interval (CI) 1.19 to 1.60; P < 0.001). For women with treated CIN, these odds 2.07 times increased compared to the control group (95% CI 1.85 to 2.33; P < 0.001). Treated women had a 1.51 times increased odds of preterm birth compared to women with untreated CIN (95% CI 1.29 to 1.76; P < 0.001). Independent from cervical disease, a volume excised from the cervix of 0.5 to 0.9 cc increased the odds of preterm birth 2.20 times (37/379 versus 1,002/20,969; 95% CI 1.52 to 3.20; P < 0.001). These odds further increased 3.13 times and 5.93 times for women with an excised volume of 4 to 8.9 cc (90/724 versus 1,002/20,969; 95% CI 2.44 to 4.01; P < 0.001) and ≥9 cc (30/139 versus 1,002/20,969; 95% CI 3.86 to 9.13; P < 0.001), respectively. Limitations of the study include the retrospective nature, lack of sufficient information to calculate odds of preterm birth <24 weeks, and that the excised volume could only be calculated for a select group of women.
Conclusions
In this study, we observed a strong correlation between preterm birth and a volume of ≥0.5 cc excised cervical tissue, regardless of the severity of CIN. Caution should be taken when performing excisional treatment in women of reproductive age as well as prudence in case of multiple biopsies. Fertile women with a history of performing multiple biopsies or excisional treatment for CIN may benefit from close surveillance during pregnancy.



PLoS Med: 30 May 2021; 18:e1003665
Loopik DL, van Drongelen J, Bekkers RLM, Voorham QJM, ... van Kemenade FJ, Siebers AG
PLoS Med: 30 May 2021; 18:e1003665 | PMID: 34086680
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Abstract

Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial.

Miles LF, Burt C, Arrowsmith J, McKie MA, ... De Silva R, Falter F
Background
The dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio.
Methods and findings
We undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: NCT03532594). Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78-1.14] vs. 0.75 [IQR 0.57-0.99]; p < 0.001). We found no evidence of a difference in median mediastinal/pleural drainage at 4 hours postoperatively (140 [IQR 75-245] vs. 135 [IQR 94-222] mL; p = 0.85) or requirement (as a binary outcome) for packed red blood cell transfusion at 24 hours postoperatively (19 [15.8%] vs. 14 [13.1%] p = 0.69). Those in the model group had a lower median protamine dose (180 [IQR 160-210] vs. 280 [IQR 250-300] mg; p < 0.001). Important limitations of this study include an unblinded design and lack of generalisability to certain populations deliberately excluded from the study (specifically children, patients with a total body weight >120 kg, and patients requiring therapeutic hypothermia to <28°C).
Conclusions
Using a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients.
Trial registration
ClinicalTrials.gov Unique identifier NCT03532594.



PLoS Med: 30 May 2021; 18:e1003658
Miles LF, Burt C, Arrowsmith J, McKie MA, ... De Silva R, Falter F
PLoS Med: 30 May 2021; 18:e1003658 | PMID: 34097705
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Abstract

Human papillomavirus seroprevalence in pregnant women following gender-neutral and girls-only vaccination programs in Finland: A cross-sectional cohort analysis following a cluster randomized trial.

Gray P, Kann H, Pimenoff VN, Eriksson T, ... Dillner J, Lehtinen M
Background
Cervical cancer elimination through human papillomavirus (HPV) vaccination programs requires the attainment of herd effect. Due to its uniquely high basic reproduction number, the vaccination coverage required to achieve herd effect against HPV type 16 exceeds what is attainable in most populations. We have compared how gender-neutral and girls-only vaccination strategies create herd effect against HPV16 under moderate vaccination coverage achieved in a population-based, community-randomized trial.
Methods and findings
In 2007-2010, the 1992-1995 birth cohorts of 33 Finnish communities were randomized to receive gender-neutral HPV vaccination (Arm A), girls-only HPV vaccination (Arm B), or no HPV vaccination (Arm C) (11 communities per trial arm). HPV16/18/31/33/35/45 seroprevalence differences between the pre-vaccination era (2005-2010) and post-vaccination era (2011-2016) were compared between all 8,022 unvaccinated women <23 years old and resident in the 33 communities during 2005-2016 (2,657, 2,691, and 2,674 in Arms A, B, and C, respectively). Post- versus pre-vaccination-era HPV seroprevalence ratios (PRs) were compared by arm. Possible outcome misclassification was quantified via probabilistic bias analysis. An HPV16 and HPV18 seroprevalence reduction was observed post-vaccination in the gender-neutral vaccination arm in the entire study population (PR16 = 0.64, 95% CI 0.10-0.85; PR18 = 0.72, 95% CI 0.22-0.96) and for HPV16 also in the herpes simplex virus type 2 seropositive core group (PR16 = 0.64, 95% CI 0.50-0.81). Observed reductions in HPV31/33/35/45 seroprevalence (PR31/33/35/45 = 0.88, 95% CI 0.81-0.97) were replicated in Arm C (PR31/33/35/45 = 0.79, 95% CI 0.69-0.90).
Conclusions
In this study we only observed herd effect against HPV16/18 after gender-neutral vaccination with moderate vaccination coverage. With only moderate vaccination coverage, a gender-neutral vaccination strategy can facilitate the control of even HPV16. Our findings may have limited transportability to other vaccination coverage levels.
Trial registration
ClinicalTrials.gov number NCT00534638, https://clinicaltrials.gov/ct2/show/NCT00534638.



PLoS Med: 30 May 2021; 18:e1003588
Gray P, Kann H, Pimenoff VN, Eriksson T, ... Dillner J, Lehtinen M
PLoS Med: 30 May 2021; 18:e1003588 | PMID: 34097688
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Abstract

Selective serotonin reuptake inhibitors, and serotonin and norepinephrine reuptake inhibitors for anxiety, obsessive-compulsive, and stress disorders: A 3-level network meta-analysis.

Gosmann NP, Costa MA, Jaeger MB, Motta LS, ... Pine DS, Salum GA
Background
Anxiety, obsessive-compulsive, and stress-related disorders frequently co-occur, and patients often present symptoms of several domains. Treatment involves the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), but data on comparative efficacy and acceptability are lacking. We aimed to compare the efficacy of SSRIs, SNRIs, and placebo in multiple symptom domains in patients with these diagnoses over the lifespan through a 3-level network meta-analysis.
Methods and findings
We searched for published and unpublished randomized controlled trials that aimed to assess the efficacy of SSRIs or SNRIs in participants (adults and children) with diagnosis of any anxiety, obsessive-compulsive, or stress-related disorder in MEDLINE, PsycINFO, Embase, and Cochrane Library from inception to 23 April 2015, with an update on 11 November 2020. We supplemented electronic database searches with manual searches for published and unpublished randomized controlled trials registered in publicly accessible clinical trial registries and pharmaceutical companies\' databases. No restriction was made regarding comorbidities with any other mental disorder, participants\' age and sex, blinding of participants and researchers, date of publication, or study language. The primary outcome was the aggregate measure of internalizing symptoms of these disorders. Secondary outcomes included specific symptom domains and treatment discontinuation rate. We estimated standardized mean differences (SMDs) with 3-level network meta-analysis with random slopes by study for medication and assessment instrument. Risk of bias appraisal was performed using the Cochrane Collaboration\'s risk of bias tool. This study was registered in PROSPERO (CRD42017069090). We analyzed 469 outcome measures from 135 studies (n = 30,245). All medications were more effective than placebo for the aggregate measure of internalizing symptoms (SMD -0.56, 95% CI -0.62 to -0.51, p < 0.001), for all symptom domains, and in patients from all diagnostic categories. We also found significant results when restricting to the most used assessment instrument for each diagnosis; nevertheless, this restriction led to exclusion of 72.71% of outcome measures. Pairwise comparisons revealed only small differences between medications in efficacy and acceptability. Limitations include the moderate heterogeneity found in most outcomes and the moderate risk of bias identified in most of the trials.
Conclusions
In this study, we observed that all SSRIs and SNRIs were effective for multiple symptom domains, and in patients from all included diagnostic categories. We found minimal differences between medications concerning efficacy and acceptability. This three-level network meta-analysis contributes to an ongoing discussion about the true benefit of antidepressants with robust evidence, considering the significantly larger quantity of data and higher statistical power when compared to previous studies. The 3-level approach allowed us to properly assess the efficacy of these medications on internalizing psychopathology, avoiding potential biases related to the exclusion of information due to distinct assessment instruments, and to explore the multilevel structure of transdiagnostic efficacy.



PLoS Med: 30 May 2021; 18:e1003664
Gosmann NP, Costa MA, Jaeger MB, Motta LS, ... Pine DS, Salum GA
PLoS Med: 30 May 2021; 18:e1003664 | PMID: 34111122
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Abstract

Direct maternal morbidity and the risk of pregnancy-related deaths, stillbirths, and neonatal deaths in South Asia and sub-Saharan Africa: A population-based prospective cohort study in 8 countries.

Aftab F, Ahmed I, Ahmed S, Ali SM, ... Zaidi AK, Alliance for Maternal and Newborn Health Improvement (AMANHI) maternal morbidity study group
Background
Maternal morbidity occurs several times more frequently than mortality, yet data on morbidity burden and its effect on maternal, foetal, and newborn outcomes are limited in low- and middle-income countries. We aimed to generate prospective, reliable population-based data on the burden of major direct maternal morbidities in the antenatal, intrapartum, and postnatal periods and its association with maternal, foetal, and neonatal death in South Asia and sub-Saharan Africa.
Methods and findings
This is a prospective cohort study, conducted in 9 research sites in 8 countries of South Asia and sub-Saharan Africa. We conducted population-based surveillance of women of reproductive age (15 to 49 years) to identify pregnancies. Pregnant women who gave consent were include in the study and followed up to birth and 42 days postpartum from 2012 to 2015. We used standard operating procedures, data collection tools, and training to harmonise study implementation across sites. Three home visits during pregnancy and 2 home visits after birth were conducted to collect maternal morbidity information and maternal, foetal, and newborn outcomes. We measured blood pressure and proteinuria to define hypertensive disorders of pregnancy and woman\'s self-report to identify obstetric haemorrhage, pregnancy-related infection, and prolonged or obstructed labour. Enrolled women whose pregnancy lasted at least 28 weeks or those who died during pregnancy were included in the analysis. We used meta-analysis to combine site-specific estimates of burden, and regression analysis combining all data from all sites to examine associations between the maternal morbidities and adverse outcomes. Among approximately 735,000 women of reproductive age in the study population, and 133,238 pregnancies during the study period, only 1.6% refused consent. Of these, 114,927 pregnancies had morbidity data collected at least once in both antenatal and in postnatal period, and 114,050 of them were included in the analysis. Overall, 32.7% of included pregnancies had at least one major direct maternal morbidity; South Asia had almost double the burden compared to sub-Saharan Africa (43.9%, 95% CI 27.8% to 60.0% in South Asia; 23.7%, 95% CI 19.8% to 27.6% in sub-Saharan Africa). Antepartum haemorrhage was reported in 2.2% (95% CI 1.5% to 2.9%) pregnancies and severe postpartum in 1.7% (95% CI 1.2% to 2.2%) pregnancies. Preeclampsia or eclampsia was reported in 1.4% (95% CI 0.9% to 2.0%) pregnancies, and gestational hypertension alone was reported in 7.4% (95% CI 4.6% to 10.1%) pregnancies. Prolonged or obstructed labour was reported in about 11.1% (95% CI 5.4% to 16.8%) pregnancies. Clinical features of late third trimester antepartum infection were present in 9.1% (95% CI 5.6% to 12.6%) pregnancies and those of postpartum infection in 8.6% (95% CI 4.4% to 12.8%) pregnancies. There were 187 pregnancy-related deaths per 100,000 births, 27 stillbirths per 1,000 births, and 28 neonatal deaths per 1,000 live births with variation by country and region. Direct maternal morbidities were associated with each of these outcomes.
Conclusions
Our findings imply that health programmes in sub-Saharan Africa and South Asia must intensify their efforts to identify and treat maternal morbidities, which affected about one-third of all pregnancies and to prevent associated maternal and neonatal deaths and stillbirths.
Trial registration
The study is not a clinical trial.



PLoS Med: 30 May 2021; 18:e1003644
Aftab F, Ahmed I, Ahmed S, Ali SM, ... Zaidi AK, Alliance for Maternal and Newborn Health Improvement (AMANHI) maternal morbidity study group
PLoS Med: 30 May 2021; 18:e1003644 | PMID: 34181649
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Abstract

Trends in HIV incidence between 2013-2019 and association of baseline factors with subsequent incident HIV among gay, bisexual, and other men who have sex with men attending sexual health clinics in England: A prospective cohort study.

Hanum N, Cambiano V, Sewell J, Rodger AJ, ... Lampe FC, AURAH2 Study Group
Background
Prospective cohort studies of incident HIV and associated factors among gay, bisexual, and other men who have sex with men (GBMSM) in the United Kingdom are lacking. We report time trends in and factors associated with HIV incidence between 2013 and 2019 among a cohort of GBMSM: the AURAH2 prospective study.
Methods and findings
Participants were recruited through 1 of 3 sexual health clinics in London and Brighton (July 2013 to April 2016) and self-completed a baseline paper questionnaire and subsequent 4-monthly and annual online questionnaires (March 2015 to March 2018), including information on sociodemographics, lifestyle, health and well-being, HIV status, sexual/HIV-related behaviours, and preexposure prophylaxis and postexposure prophylaxis (PrEP/PEP). Incident HIV was ascertained by linkage with national HIV surveillance data from Public Health England (PHE). We investigated the associations of HIV incidence with (1) baseline factors using mixed-effects Weibull proportional hazard models, unadjusted and adjusted for age, country of birth and ethnicity, sexuality, and education level; and (2) time-updated factors, using mixed-effects Poisson regression models. In total, 1,162 men (mean age 34 years, 82% white, 94% gay, 74% university-educated) were enrolled in the study. Thirty-three HIV seroconversions occurred over 4,618.9 person-years (PY) of follow-up: an overall HIV incidence rate (IR) of 0.71 (95% confidence interval (CI) 0.51 to 1.00) per 100 PY. Incidence declined from 1.47 (95% CI 0.48 to 4.57) per 100 PY in 2013/2014 to 0.25 (95% CI 0.08 to 0.78) per 100 PY in 2018/2019; average annual decline was 0.85-fold (p < 0.001). Baseline factors associated with HIV acquisition included the following: injection drug use (6/38 men who reported injection drug-acquired HIV; unadjusted conditional hazard ratio (HR) 27.96, 95% CI 6.99 to 111.85, p < 0.001), noninjection chemsex-related drug use (13/321; HR 6.45, 95% CI 1.84 to 22.64, p < 0.001), condomless anal sex (CLS) (26/741; HR 3.75, 95% CI 1.31 to 10·74, p = 0.014); higher number of CLS partners (HRs >10 partners [7/57]; 5 to 10 partners [5/60]; and 2 to 4 partners [11/293]: 14.04, 95% CI 4.11 to 47.98; 9.60, 95% CI 2.58 to 35.76; and 4.05, 95% CI 1.29 to 12.72, respectively, p < 0.001); CLS with HIV-positive partners (14/147; HR 6.45, 95% CI 3.15 to 13.22, p < 0.001), versatile CLS role (21/362; HR 6.35, 95% CI 2.18 to 18.51, p < 0.001), group sex (64/500; HR 8.81, 95% CI 3.07 to 25.24, p < 0.001), sex for drugs/money (4/55, HR 3.27, 95% CI 1.14 to 9.38, p = 0.027) (all in previous 3 months); previous 12-month report of a bacterial sexually transmitted infection (STI) diagnoses (21/440; HR 3.95, 95% CI 1.81 to 8.63, p < 0.001), and more than 10 new sexual partners (21/471, HRs 11 to 49, 50 to 99, and >100 new partners: 3.17, 95% CI 1.39 to 7.26; 4.40, 95% CI 1.35 to 14.29; and 4.84, 95% CI 1.05 to 22.4, respectively, p < 0.001). Results were broadly consistent for time-updated analysis (n = 622 men). The study\'s main limitation is that men may not be representative of the broader GBMSM population in England.
Conclusions
We observed a substantial decline in HIV incidence from 2013 to 2019 among GBMSM attending sexual health clinics. Injection drug use, chemsex use, and measures of high-risk sexual behaviour were strongly associated with incident HIV. Progress towards zero new infections could be achieved if combination HIV prevention including Test and Treat strategies and routine commissioning of a PrEP programme continues across the UK and reaches all at-risk populations.



PLoS Med: 30 May 2021; 18:e1003677
Hanum N, Cambiano V, Sewell J, Rodger AJ, ... Lampe FC, AURAH2 Study Group
PLoS Med: 30 May 2021; 18:e1003677 | PMID: 34143781
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Abstract

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.

Celum C, Hosek S, Tsholwana M, Kassim S, ... Rooney J, Delany-Moretlwe S
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.



PLoS Med: 30 May 2021; 18:e1003670
Celum C, Hosek S, Tsholwana M, Kassim S, ... Rooney J, Delany-Moretlwe S
PLoS Med: 30 May 2021; 18:e1003670 | PMID: 34143779
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Abstract

Effectiveness of Group Problem Management Plus, a brief psychological intervention for adults affected by humanitarian disasters in Nepal: A cluster randomized controlled trial.

Jordans MJD, Kohrt BA, Sangraula M, Turner EL, ... Luitel NP, van Ommeren M
Background
Globally, 235 million people are impacted by humanitarian emergencies worldwide, presenting increased risk of experiencing a mental disorder. Our objective was to test the effectiveness of a brief group psychological treatment delivered by trained facilitators without prior professional mental health training in a disaster-prone setting.
Methods and findings
We conducted a cluster randomized controlled trial (cRCT) from November 25, 2018 through September 30, 2019. Participants in both arms were assessed at baseline, midline (7 weeks post-baseline, which was approximately 1 week after treatment in the experimental arm), and endline (20 weeks post-baseline, which was approximately 3 months posttreatment). The intervention was Group Problem Management Plus (PM+), a psychological treatment of 5 weekly sessions, which was compared with enhanced usual care (EUC) consisting of a family psychoeducation meeting with a referral option to primary care providers trained in mental healthcare. The setting was 72 wards (geographic unit of clustering) in eastern Nepal, with 1 PM+ group per ward in the treatment arm. Wards were eligible if they were in disaster-prone regions and residents spoke Nepali. Wards were assigned to study arms based on covariate constrained randomization. Eligible participants were adult women and men 18 years of age and older who met screening criteria for psychological distress and functional impairment. Outcomes were measured at the participant level, with assessors blinded to group assignment. The primary outcome was psychological distress assessed with the General Health Questionnaire (GHQ-12). Secondary outcomes included depression symptoms, posttraumatic stress disorder (PTSD) symptoms, \"heart-mind\" problems, social support, somatic symptoms, and functional impairment. The hypothesized mediator was skill use aligned with the treatment\'s mechanisms of action. A total of 324 participants were enrolled in the control arm (36 wards) and 319 in the Group PM+ arm (36 wards). The overall sample (N = 611) had a median age of 45 years (range 18-91 years), 82% of participants were female, 50% had recently experienced a natural disaster, and 31% had a chronic physical illness. Endline assessments were completed by 302 participants in the control arm (36 wards) and 303 participants in the Group PM+ arm (36 wards). At the midline assessment (immediately after Group PM+ in the experimental arm), mean GHQ-12 total score was 2.7 units lower in Group PM+ compared to control (95% CI: 1.7, 3.7, p < 0.001), with standardized mean difference (SMD) of -0.4 (95% CI: -0.5, -0.2). At 3 months posttreatment (primary endpoint), mean GHQ-12 total score was 1.4 units lower in Group PM+ compared to control (95% CI: 0.3, 2.5, p = 0.014), with SMD of -0.2 (95% CI: -0.4, 0.0). Among the secondary outcomes, Group PM+ was associated with endline with a larger proportion attaining more than 50% reduction in depression symptoms (29.9% of Group PM+ arm versus 17.3% of control arm, risk ratio = 1.7, 95% CI: 1.2, 2.4, p = 0.002). Fewer participants in the Group PM+ arm continued to have \"heart-mind\" problems at endline (58.8%) compared to the control arm (69.4%), risk ratio = 0.8 (95% CI, 0.7, 1.0, p = 0.042). Group PM+ was not associated with lower PTSD symptoms or functional impairment. Use of psychosocial skills at midline was estimated to explain 31% of the PM+ effect on endline GHQ-12 scores. Adverse events in the control arm included 1 suicide death and 1 reportable incidence of domestic violence; in the Group PM+ arm, there was 1 death due to physical illness. Study limitations include lack of power to evaluate gender-specific effects, lack of long-term outcomes (e.g., 12 months posttreatment), and lack of cost-effectiveness information.
Conclusions
In this study, we found that a 5-session group psychological treatment delivered by nonspecialists modestly reduced psychological distress and depression symptoms in a setting prone to humanitarian emergencies. Benefits were partly explained by the degree of psychosocial skill use in daily life. To improve the treatment benefit, future implementation should focus on approaches to enhance skill use by PM+ participants.
Trial registration
ClinicalTrials.gov NCT03747055.



PLoS Med: 30 May 2021; 18:e1003621
Jordans MJD, Kohrt BA, Sangraula M, Turner EL, ... Luitel NP, van Ommeren M
PLoS Med: 30 May 2021; 18:e1003621 | PMID: 34138875
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Abstract

Multi-morbidity and blood pressure trajectories in hypertensive patients: A multiple landmark cohort study.

Tran J, Norton R, Canoy D, Ayala Solares JR, ... Rodgers A, Rahimi K
Background
Our knowledge of how to better manage elevated blood pressure (BP) in the presence of comorbidities is limited, in part due to exclusion or underrepresentation of patients with multiple chronic conditions from major clinical trials. We aimed to investigate the burden and types of comorbidities in patients with hypertension and to assess how such comorbidities and other variables affect BP levels over time.
Methods and findings
In this multiple landmark cohort study, we used linked electronic health records from the United Kingdom Clinical Practice Research Datalink (CPRD) to compare systolic blood pressure (SBP) levels in 295,487 patients (51% women) aged 61.5 (SD = 13.1) years with first recorded diagnosis of hypertension between 2000 and 2014, by type and numbers of major comorbidities, from at least 5 years before and up to 10 years after hypertension diagnosis. Time-updated multivariable linear regression analyses showed that the presence of more comorbidities was associated with lower SBP during follow-up. In hypertensive patients without comorbidities, mean SBP at diagnosis and at 10 years were 162.3 mm Hg (95% confidence interval [CI] 162.0 to 162.6) and 140.5 mm Hg (95% CI 140.4 to 140.6), respectively; in hypertensive patients with ≥5 comorbidities, these were 157.3 mm Hg (95% CI 156.9 to 157.6) and 136.8 mm Hg (95% 136.4 to 137.3), respectively. This inverse association between numbers of comorbidities and SBP was not specific to particular types of comorbidities, although associations were stronger in those with preexisting cardiovascular disease. Retrospective analysis of recorded SBP showed that the difference in mean SBP 5 years before diagnosis between those without and with ≥5 comorbidities was -9 mm Hg (95% CI -9.7 to -8.3), suggesting that mean recorded SBP already differed according to the presence of comorbidity before baseline. Within 1 year after the diagnosis, SBP substantially declined, but subsequent SBP changes across comorbidity status were modest, with no evidence of a more rapid decline in those with more or specific types of comorbidities. We identified factors, such as prescriptions of antihypertensive drugs and frequency of healthcare visits, that can explain SBP differences according to numbers or types of comorbidities, but these factors only partly explained the recorded SBP differences. Nevertheless, some limitations have to be considered including the possibility that diagnosis of some conditions may not have been recorded, varying degrees of missing data inherent in analytical datasets extracted from routine health records, and greater measurement errors in clinical measurements taken in routine practices than those taken in well-controlled clinical study settings.
Conclusions
BP levels at which patients were diagnosed with hypertension varied substantially according to the presence of comorbidities and were lowest in patients with multi-morbidity. Our findings suggest that this early selection bias of hypertension diagnosis at different BP levels was a key determinant of long-term differences in BP by comorbidity status. The lack of a more rapid decline in SBP in those with multi-morbidity provides some reassurance for BP treatment in these high-risk individuals.



PLoS Med: 30 May 2021; 18:e1003674
Tran J, Norton R, Canoy D, Ayala Solares JR, ... Rodgers A, Rahimi K
PLoS Med: 30 May 2021; 18:e1003674 | PMID: 34138851
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Abstract

Development and validation of the CHIME simulation model to assess lifetime health outcomes of prediabetes and type 2 diabetes in Chinese populations: A modeling study.

Quan J, Ng CS, Kwok HHY, Zhang A, ... Eggleston K, Leung GM
Background
Existing predictive outcomes models for type 2 diabetes developed and validated in historical European populations may not be applicable for East Asian populations due to differences in the epidemiology and complications. Despite the continuum of risk across the spectrum of risk factor values, existing models are typically limited to diabetes alone and ignore the progression from prediabetes to diabetes. The objective of this study is to develop and externally validate a patient-level simulation model for prediabetes and type 2 diabetes in the East Asian population for predicting lifetime health outcomes.
Methods and findings
We developed a health outcomes model from a population-based cohort of individuals with prediabetes or type 2 diabetes: Hong Kong Clinical Management System (CMS, 97,628 participants) from 2006 to 2017. The Chinese Hong Kong Integrated Modeling and Evaluation (CHIME) simulation model comprises of 13 risk equations to predict mortality, micro- and macrovascular complications, and development of diabetes. Risk equations were derived using parametric proportional hazard models. External validation of the CHIME model was assessed in the China Health and Retirement Longitudinal Study (CHARLS, 4,567 participants) from 2011 to 2018 for mortality, ischemic heart disease, cerebrovascular disease, renal failure, cataract, and development of diabetes; and against 80 observed endpoints from 9 published trials using 100,000 simulated individuals per trial. The CHIME model was compared to United Kingdom Prospective Diabetes Study Outcomes Model 2 (UKPDS-OM2) and Risk Equations for Complications Of type 2 Diabetes (RECODe) by assessing model discrimination (C-statistics), calibration slope/intercept, root mean square percentage error (RMSPE), and R2. CHIME risk equations had C-statistics for discrimination from 0.636 to 0.813 internally and 0.702 to 0.770 externally for diabetes participants. Calibration slopes between deciles of expected and observed risk in CMS ranged from 0.680 to 1.333 for mortality, myocardial infarction, ischemic heart disease, retinopathy, neuropathy, ulcer of the skin, cataract, renal failure, and heart failure; 0.591 for peripheral vascular disease; 1.599 for cerebrovascular disease; and 2.247 for amputation; and in CHARLS outcomes from 0.709 to 1.035. CHIME had better discrimination and calibration than UKPDS-OM2 in CMS (C-statistics 0.548 to 0.772, slopes 0.130 to 3.846) and CHARLS (C-statistics 0.514 to 0.750, slopes -0.589 to 11.411); and small improvements in discrimination and better calibration than RECODe in CMS (C-statistics 0.615 to 0.793, slopes 0.138 to 1.514). Predictive error was smaller for CHIME in CMS (RSMPE 3.53% versus 10.82% for UKPDS-OM2 and 11.16% for RECODe) and CHARLS (RSMPE 4.49% versus 14.80% for UKPDS-OM2). Calibration performance of CHIME was generally better for trials with Asian participants (RMSPE 0.48% to 3.66%) than for non-Asian trials (RMPSE 0.81% to 8.50%). Main limitations include the limited number of outcomes recorded in the CHARLS cohort, and the generalizability of simulated cohorts derived from trial participants.
Conclusions
Our study shows that the CHIME model is a new validated tool for predicting progression of diabetes and its outcomes, particularly among Chinese and East Asian populations that has been lacking thus far. The CHIME model can be used by health service planners and policy makers to develop population-level strategies, for example, setting HbA1c and lipid targets, to optimize health outcomes.



PLoS Med: 30 May 2021; 18:e1003692
Quan J, Ng CS, Kwok HHY, Zhang A, ... Eggleston K, Leung GM
PLoS Med: 30 May 2021; 18:e1003692 | PMID: 34166382
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Abstract

Mycophenolate mofetil versus azathioprine in kidney transplant recipients on steroid-free, low-dose cyclosporine immunosuppression (ATHENA): A pragmatic randomized trial.

Ruggenenti P, Cravedi P, Gotti E, Plati A, ... Peraro F, Remuzzi G
Background
We compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression.
Methods and findings
ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design.
Conclusions
In this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression.
Trial registration
ClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.



PLoS Med: 30 May 2021; 18:e1003668
Ruggenenti P, Cravedi P, Gotti E, Plati A, ... Peraro F, Remuzzi G
PLoS Med: 30 May 2021; 18:e1003668 | PMID: 34166370
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Abstract

Separating parental and treatment contributions to perinatal health after fresh and frozen embryo transfer in assisted reproduction: A cohort study with within-sibship analysis.

Westvik-Johari K, Romundstad LB, Lawlor DA, Bergh C, ... Pinborg A, Opdahl S
Background
Compared to naturally conceived children, adverse perinatal outcomes are more common among children born after assisted reproductive technology with fresh embryo transfer (fresh-ET) or frozen embryo transfer (frozen-ET). However, most previous studies could not adequately control for family confounding factors such as subfertility. We compared birth size and duration of pregnancy among infants born after fresh-ET or frozen-ET versus natural conception, using a within-sibship design to account for confounding by maternal factors.
Methods and findings
This registry-based cohort study with nationwide data from Denmark (1994-2014), Norway (1988-2015), and Sweden (1988-2015) consisted of 4,510,790 live-born singletons, 4,414,703 from natural conception, 78,095 from fresh-ET, and 17,990 from frozen-ET. We identified 33,056 offspring sibling groups with the same mother, conceived by at least 2 different conception methods. Outcomes were mean birthweight, small and large for gestational age, mean gestational age, preterm (<37 weeks, versus ≥37), and very preterm birth (<32 weeks, versus ≥32). Singletons born after fresh-ET had lower mean birthweight (-51 g, 95% CI -58 to -45, p < 0.001) and increased odds of small for gestational age (odds ratio [OR] 1.20, 95% CI 1.08 to 1.34, p < 0.001), while those born after frozen-ET had higher mean birthweight (82 g, 95% CI 70 to 94, p < 0.001) and increased odds of large for gestational age (OR 1.84, 95% CI 1.56 to 2.17, p < 0.001), compared to naturally conceived siblings. Conventional population analyses gave similar results. Compared to naturally conceived siblings, mean gestational age was lower after fresh-ET (-1.0 days, 95% CI -1.2 to -0.8, p < 0.001), but not after frozen-ET (0.3 days, 95% CI 0.0 to 0.6, p = 0.028). There were increased odds of preterm birth after fresh-ET (OR 1.27, 95% CI 1.17 to 1.37, p < 0.001), and in most models after frozen-ET, versus naturally conceived siblings, with somewhat stronger associations in population analyses. For very preterm birth, population analyses showed increased odds for both fresh-ET (OR 2.03, 95% CI 1.90 to 2.12, p < 0.001) and frozen-ET (OR 1.66, 95% CI 1.42 to 1.94, p < 0.001) compared with natural conception, but results were notably attenuated within siblings (OR 1.18, 95% CI 1.0 to 1.41, p = 0.059, and OR 0.92, 95% CI 0.67 to 1.27, p = 0.6, for fresh-ET and frozen-ET, respectively). Sensitivity analyses in full siblings, in siblings born within 3-year interval, by birth order, and restricting to single embryo transfers and blastocyst transfers were consistent with the main analyses. Main limitations were high proportions of missing data on maternal body mass index and smoking.
Conclusions
We found that infants conceived by fresh-ET had lower birthweight and increased odds of small for gestational age, and those conceived by frozen-ET had higher birthweight and increased odds of large for gestational age. Conception by either fresh-ET or frozen-ET was associated with increased odds of preterm birth. That these findings were observed within siblings, as well as in conventional multivariable population analyses, reduces the likelihood that they are explained by confounding or selection bias.
Trial registration
ClinicalTrials.gov ISRCTN11780826.



PLoS Med: 30 May 2021; 18:e1003683
Westvik-Johari K, Romundstad LB, Lawlor DA, Bergh C, ... Pinborg A, Opdahl S
PLoS Med: 30 May 2021; 18:e1003683 | PMID: 34170923
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Impact:
Abstract

Evaluation of a package of continuum of care interventions for improved maternal, newborn, and child health outcomes and service coverage in Ghana: A cluster-randomized trial.

Shibanuma A, Ansah EK, Kikuchi K, Yeji F, ... Jimba M, Ghana EMBRACE Implementation Research Project Team
Background
In low- and middle-income countries (LMICs), the continuum of care (CoC) for maternal, newborn, and child health (MNCH) is not always complete. This study aimed to evaluate the effectiveness of an integrated package of CoC interventions on the CoC completion, morbidity, and mortality outcomes of woman-child pairs in Ghana.
Methods and findings
This cluster-randomized controlled trial (ISRCTN: 90618993) was conducted at 3 Health and Demographic Surveillance System (HDSS) sites in Ghana. The primary outcome was CoC completion by a woman-child pair, defined as receiving antenatal care (ANC) 4 times or more, delivery assistance from a skilled birth attendant (SBA), and postnatal care (PNC) 3 times or more. Other outcomes were the morbidity and mortality of women and children. Women received a package of interventions and routine services at health facilities (October 2014 to December 2015). The package comprised providing a CoC card for women, CoC orientation for health workers, and offering women with 24-hour stay at a health facility or a home visit within 48 hours after delivery. In the control arm, women received routine services only. Eligibility criteria were as follows: women who gave birth or had a stillbirth from September 1, 2012 to September 30, 2014 (before the trial period), from October 1, 2014 to December 31, 2015 (during the trial period), or from January 1, 2016 to December 31, 2016 (after the trial period). Health service and morbidity outcomes were assessed before and during the trial periods through face-to-face interviews. Mortality was assessed using demographic surveillance data for the 3 periods above. Mixed-effects logistic regression models were used to evaluate the effectiveness as difference in differences (DiD). For health service and morbidity outcomes, 2,970 woman-child pairs were assessed: 1,480 from the baseline survey and 1,490 from the follow-up survey. Additionally, 33,819 cases were assessed for perinatal mortality, 33,322 for neonatal mortality, and 39,205 for maternal mortality. The intervention arm had higher proportions of completed CoC (410/870 [47.1%]) than the control arm (246/620 [39.7%]; adjusted odds ratio [AOR] for DiD = 1.77; 95% confidence interval [CI]: 1.08 to 2.92; p = 0.024). Maternal complications that required hospitalization during pregnancy were lower in the intervention (95/870 [10.9%]) than in the control arm (83/620 [13.4%]) (AOR for DiD = 0.49; 95% CI: 0.29 to 0.83; p = 0.008). Maternal mortality was 8/6,163 live births (intervention arm) and 4/4,068 live births during the trial period (AOR for DiD = 1.60; 95% CI: 0.40 to 6.34; p = 0.507) and 1/4,626 (intervention arm) and 9/3,937 (control arm) after the trial period (AOR for DiD = 0.11; 95% CI: 0.11 to 1.00; p = 0.050). Perinatal and neonatal mortality was not significantly reduced. As this study was conducted in a real-world setting, possible limitations included differences in the type and scale of health facilities and the size of subdistricts, contamination for intervention effectiveness due to the geographic proximity of the arms, and insufficient number of cases for the mortality assessment.
Conclusions
This study found that an integrated package of CoC interventions increased CoC completion and decreased maternal complications requiring hospitalization during pregnancy and maternal mortality after the trial period. It did not find evidence of reduced perinatal and neonatal mortality.
Trial registration
The study protocol was registered in the International Standard Randomised Controlled Trial Number Registry (90618993).



PLoS Med: 30 May 2021; 18:e1003663
Shibanuma A, Ansah EK, Kikuchi K, Yeji F, ... Jimba M, Ghana EMBRACE Implementation Research Project Team
PLoS Med: 30 May 2021; 18:e1003663 | PMID: 34170904
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Impact:
Abstract

Ethnic differences in guideline-indicated statin initiation for people with type 2 diabetes in UK primary care, 2006-2019: A cohort study.

Eastwood SV, Mathur R, Sattar N, Smeeth L, Bhaskaran K, Chaturvedi N
Background
Type 2 diabetes is 2-3 times more prevalent in people of South Asian and African/African Caribbean ethnicity than people of European ethnicity living in the UK. The former 2 groups also experience excess atherosclerotic cardiovascular disease (ASCVD) complications of diabetes. We aimed to study ethnic differences in statin initiation, a cornerstone of ASCVD primary prevention, for people with type 2 diabetes.
Methods and findings
Observational cohort study of UK primary care records, from 1 January 2006 to 30 June 2019. Data were studied from 27,511 (88%) people of European ethnicity, 2,386 (8%) people of South Asian ethnicity, and 1,142 (4%) people of African/African Caribbean ethnicity with incident type 2 diabetes, no previous ASCVD, and statin use indicated by guidelines. Statin initiation rates were contrasted by ethnicity, and the number of ASCVD events that could be prevented by equalising prescribing rates across ethnic groups was estimated. Median time to statin initiation was 79, 109, and 84 days for people of European, South Asian, and African/African Caribbean ethnicity, respectively. People of African/African Caribbean ethnicity were a third less likely to receive guideline-indicated statins than European people (n/N [%]: 605/1,142 [53%] and 18,803/27,511 [68%], respectively; age- and gender-adjusted HR 0.67 [95% CI 0.60 to 0.76], p < 0.001). The HR attenuated marginally in a model adjusting for total cholesterol/high-density lipoprotein cholesterol ratio (0.77 [95% CI 0.69 to 0.85], p < 0.001), with no further diminution when deprivation, ASCVD risk factors, comorbidity, polypharmacy, and healthcare usage were accounted for (fully adjusted HR 0.76 [95% CI 0.68, 0.85], p < 0.001). People of South Asian ethnicity were 10% less likely to receive a statin than European people (1,489/2,386 [62%] and 18,803/27,511 [68%], respectively; fully adjusted HR 0.91 [95% CI 0.85 to 0.98], p = 0.008, adjusting for all covariates). We estimated that up to 12,600 ASCVD events could be prevented over the lifetimes of people currently affected by type 2 diabetes in the UK by equalising statin prescribing across ethnic groups. Limitations included incompleteness of recording of routinely collected data.
Conclusions
In this study we observed that people of African/African Caribbean ethnicity with type 2 diabetes were substantially less likely, and people of South Asian ethnicity marginally less likely, to receive guideline-indicated statins than people of European ethnicity, even after accounting for sociodemographics, healthcare usage, ASCVD risk factors, and comorbidity. Underuse of statins in people of African/African Caribbean or South Asian ethnicity with type 2 diabetes is a missed opportunity to prevent cardiovascular events.



PLoS Med: 30 May 2021; 18:e1003672
Eastwood SV, Mathur R, Sattar N, Smeeth L, Bhaskaran K, Chaturvedi N
PLoS Med: 30 May 2021; 18:e1003672 | PMID: 34185782
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Impact:
Abstract

Taxed and untaxed beverage intake by South African young adults after a national sugar-sweetened beverage tax: A before-and-after study.

Essman M, Taillie LS, Frank T, Ng SW, Popkin BM, Swart EC
Background
In an effort to prevent and reduce the prevalence rate of people with obesity and diabetes, South Africa implemented a sugar-content-based tax called the Health Promotion Levy in April 2018, one of the first sugar-sweetened beverage (SSB) taxes to be based on each gram of sugar (beyond 4 g/100 ml). This before-and-after study estimated changes in taxed and untaxed beverage intake 1 year after the tax, examining separately, to our knowledge for the first time, the role of reformulation distinct from behavioral changes in SSB intake.
Methods and findings
We collected single-day 24-hour dietary recalls from repeat cross-sectional surveys of adults aged 18-39 years in Langa, South Africa. Participants were recruited in February-March 2018 (pre-tax, n = 2,459) and February-March 2019 (post-tax, n = 2,489) using door-to-door sampling. We developed time-specific food composition tables (FCTs) for South African beverages before and after the tax, linked with the diet recalls. By linking pre-tax FCTs only to dietary intake data collected in the pre-tax and post-tax periods, we calculated changes in beverage intake due to behavioral change, assuming no reformulation. Next, we repeated the analysis using an updated FCT in the post-tax period to capture the marginal effect of reformulation. We estimated beverage intake using a 2-part model that takes into consideration the biases in using ordinary least squares or other continuous variable approaches with many individuals with zero intake. First, a probit model was used to estimate the probability of consuming the specific beverage category. Then, conditional on a positive outcome, a generalized linear model with a log-link was used to estimate the continuous amount of beverage consumed. Among taxed beverages, sugar intake decreased significantly (p < 0.0001) from 28.8 g/capita/day (95% CI 27.3-30.4) pre-tax to 19.8 (95% CI 18.5-21.1) post-tax. Energy intake decreased (p < 0.0001) from 121 kcal/capita/day (95% CI 114-127) pre-tax to 82 (95% CI 76-87) post-tax. Volume intake decreased (p < 0.0001) from 315 ml/capita/day (95% CI 297-332) pre-tax to 198 (95% CI 185-211) post-tax. Among untaxed beverages, sugar intake increased (p < 0.0001) by 5.3 g/capita/day (95% CI 3.7 to 6.9), and energy intake increased (p < 0.0001) by 29 kcal/capita/day (95% CI 19 to 39). Among total beverages, sugar intake decreased significantly (p = 0.004) by 3.7 (95% CI -6.2 to -1.2) g/capita/day. Behavioral change accounted for reductions of 24% in energy, 22% in sugar, and 23% in volume, while reformulation accounted for additional reductions of 8% in energy, 9% in sugar, and 14% in volume from taxed beverages. The key limitations of this study are an inability to make causal claims due to repeat cross-sectional data collection, and that the magnitude of reduction in taxed beverage intake may not be generalizable to higher income populations.
Conclusions
Using a large sample of a high-consuming, low-income population, we found large reductions in taxed beverage intake, separating the components of behavioral change from reformulation. This reduction was partially compensated by an increase in sugar and energy from untaxed beverages. Because policies such as taxes can incentivize reformulation, our use of an up-to-date FCT that reflects a rapidly changing food supply is novel and important for evaluating policy effects on intake.



PLoS Med: 29 Apr 2021; 18:e1003574
Essman M, Taillie LS, Frank T, Ng SW, Popkin BM, Swart EC
PLoS Med: 29 Apr 2021; 18:e1003574 | PMID: 34032809
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Impact:
Abstract

Sexual and reproductive health information and referrals for resettled refugee women: A survey of resettlement agencies in the United States.

Katcher T, Thimmesch R, Spitz A, Kulkarni L, ... Weiner A, Woodford Martin M
Background
Refugee resettlement offices are the first point of contact for newly arrived refugees and play a significant role in helping refugees acclimate and settle into life in the United States. Available literature suggests that refugee women are vulnerable to poor sexual and reproductive health (SRH) outcomes, including sexually transmitted infections and HIV infections as well as adverse pregnancy outcomes, but little is known about the role that refugee resettlement offices play in supporting refugee women\'s SRH. This study examines the capacity and interest of resettlement offices in providing SRH information and referrals to newly arrived refugees.
Methods and findings
The research team conducted an online survey of staff members at refugee resettlement offices throughout the US in 2018 to determine (1) available SRH resources and workshops; (2) referrals to and assistance with making appointments for SRH and primary care appointments; (3) barriers to addressing SRH needs of clients; and (4) interest in building the capacity of office staff to address SRH issues. The survey was created for this study and had not been previously used or validated. Survey data underwent descriptive analysis. A total of 236 resettlement offices were contacted, with responses from 100 offices, for a total response rate of 42%. Fifteen percent (N = 15) of refugee resettlement agencies (RRAs) who responded to the survey provide materials about SRH to clients, and 49% (N = 49) incorporate sexual health into the classes they provide to newly arrived refugee clients. Moreover, 12% (N = 12) of responding RRAs screen clients for pregnancy intention, and 20% (N = 20) directly refer to contraceptive care and services. This study is limited by the response rate of the survey; no conclusions can be drawn about those offices that did not respond. In addition, the survey instrument was not validated against any other sources of information about the practices of refugee resettlement offices.
Conclusions
In this study, we observed that many resettlement offices do not routinely provide information or referrals for SRH needs. Responding offices cite lack of time and competing priorities as major barriers to providing SRH education and referrals to clients.



PLoS Med: 29 Apr 2021; 18:e1003579
Katcher T, Thimmesch R, Spitz A, Kulkarni L, ... Weiner A, Woodford Martin M
PLoS Med: 29 Apr 2021; 18:e1003579 | PMID: 33939705
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Impact:
Abstract

Tranexamic acid and bleeding in patients treated with non-vitamin K oral anticoagulants undergoing dental extraction: The EXTRACT-NOAC randomized clinical trial.

Ockerman A, Miclotte I, Vanhaverbeke M, Vanassche T, ... Politis C, Verhamme P
Background
Oral bleeding after dental extraction in patients on non-vitamin K oral anticoagulants (NOACs) is a frequent problem. We investigated whether 10% tranexamic acid (TXA) mouthwash decreases post-extraction bleeding in patients treated with NOACs.
Methods and findings
The EXTRACT-NOAC study is a randomized, double-blind, placebo-controlled, multicenter, clinical trial. Patients were randomly assigned to 10% TXA or placebo mouthwash and were instructed to use the mouthwash once prior to dental extraction, and thereafter for 3 times a day for 3 days. The primary outcome was the number of patients with any post-extraction oral bleeding up to day 7. Secondary outcomes included periprocedural, early, and delayed bleeding, and the safety outcomes included all thrombotic events. The first patient was randomized on February 9, 2018 and the last patient on March 12, 2020. Of 222 randomized patients, 218 patients were included in the full analysis set, of which 106 patients were assigned to TXA (74.8 (±8.8) years; 81 men) and 112 to placebo (72.7 (±10.7) years; 64 men). Post-extraction bleeding occurred in 28 (26.4%) patients in the TXA group and in 32 (28.6%) patients in the placebo group (relative risk, 0.92; 95% confidence interval [CI], 0.60 to 1.42; P = 0.72). There were 46 bleeds in the TXA group and 85 bleeds in the placebo group (rate ratio, 0.57; 95% CI, 0.31 to 1.05; P = 0.07). TXA did not reduce the rate of periprocedural bleeding (bleeding score 4 ± 1.78 versus 4 ± 1.82, P = 0.80) and early bleeding (rate ratio, 0.76; 95% CI, 0.42 to 1.37). Delayed bleeding (rate ratio, 0.32; 95% CI, 0.12 to 0.89) and bleeding after multiple extractions (rate ratio, 0.40; 95% CI, 0.20 to 0.78) were lower in the TXA group. One patient in the placebo group had a transient ischemic attack while interrupting the NOAC therapy in preparation for the dental extraction. Two of the study limitations were the premature interruption of the trial following a futility analysis and the assessment of the patients\' compliance that was based on self-reported information during follow-up.
Conclusions
In patients on NOACs undergoing dental extraction, TXA does not seem to reduce the rate of periprocedural or early postoperative oral bleeding compared to placebo. TXA appears to reduce delayed bleeds and postoperative oral bleeding if multiple teeth are extracted.
Trial registration
ClinicalTrials.gov NCT03413891 EudraCT; EudraCT number:2017-001426-17; EudraCT Public website: eudract.ema.europa.eu.



PLoS Med: 29 Apr 2021; 18:e1003601
Ockerman A, Miclotte I, Vanhaverbeke M, Vanassche T, ... Politis C, Verhamme P
PLoS Med: 29 Apr 2021; 18:e1003601 | PMID: 33939696
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Impact:
Abstract

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

Tie J, Wang Y, Cohen J, Li L, ... Vogelstein B, Gibbs P
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.



PLoS Med: 29 Apr 2021; 18:e1003620
Tie J, Wang Y, Cohen J, Li L, ... Vogelstein B, Gibbs P
PLoS Med: 29 Apr 2021; 18:e1003620 | PMID: 33939694
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Impact:
Abstract

Financial incentives and deposit contracts to promote HIV retesting in Uganda: A randomized trial.

Chamie G, Kwarisiima D, Ndyabakira A, Marson K, ... Kamya MR, Thirumurthy H
Background
Frequent retesting for HIV among persons at increased risk of HIV infection is critical to early HIV diagnosis of persons and delivery of combination HIV prevention services. There are few evidence-based interventions for promoting frequent retesting for HIV. We sought to determine the effectiveness of financial incentives and deposit contracts in promoting quarterly HIV retesting among adults at increased risk of HIV.
Methods and findings
In peri-urban Ugandan communities from October to December 2018, we randomized HIV-negative adults with self-reported risk to 1 of 3 strategies to promote HIV retesting: (1) no incentive; (2) cash incentives (US$7) for retesting at 3 and 6 months (total US$14); or (3) deposit contracts: participants could voluntarily deposit US$6 at baseline and at 3 months that would be returned with interest (total US$7) upon retesting at 3 and 6 months (total US$14) or lost if participants failed to retest. The primary outcome was retesting for HIV at both 3 and 6 months. Of 1,482 persons screened for study eligibility following community-based recruitment, 524 participants were randomized to either no incentive (N = 180), incentives (N = 172), or deposit contracts (N = 172): median age was 25 years (IQR: 22 to 30), 44% were women, and median weekly income was US$13.60 (IQR: US$8.16 to US$21.76). Among participants randomized to deposit contracts, 24/172 (14%) made a baseline deposit, and 2/172 (1%) made a 3-month deposit. In intent-to-treat analyses, HIV retesting at both 3 and 6 months was significantly higher in the incentive arm (89/172 [52%]) than either the control arm (33/180 [18%], odds ratio (OR) 4.8, 95% CI: 3.0 to 7.7, p < 0.001) or the deposit contract arm (28/172 [16%], OR 5.5, 95% CI: 3.3 to 9.1, p < 0.001). Among those in the deposit contract arm who made a baseline deposit, 20/24 (83%) retested at 3 months; 11/24 (46%) retested at both 3 and 6 months. Among 282 participants who retested for HIV during the trial, three (1%; 95%CI: 0.2 to 3%) seroconverted: one in the incentive group and two in the control group. Study limitations include measurement of retesting at the clinic where baseline enrollment occurred, only offering clinic-based (rather than community-based) HIV retesting and lack of measurement of retesting after completion of the trial to evaluate sustained retesting behavior.
Conclusions
Offering financial incentives to high-risk adults in Uganda resulted in significantly higher HIV retesting. Deposit contracts had low uptake and overall did not increase retesting. As part of efforts to increase early diagnosis of HIV among high-risk populations, strategic use of incentives to promote retesting should receive greater consideration by HIV programs.
Trial registration
clinicaltrials.gov: NCT02890459.



PLoS Med: 29 Apr 2021; 18:e1003630
Chamie G, Kwarisiima D, Ndyabakira A, Marson K, ... Kamya MR, Thirumurthy H
PLoS Med: 29 Apr 2021; 18:e1003630 | PMID: 33945526
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Impact:
Abstract

Components of clean delivery kits and newborn mortality in the Zambia Chlorhexidine Application Trial (ZamCAT): An observational study.

Park JH, Hamer DH, Mbewe R, Scott NA, ... Yeboah-Antwi K, Semrau KEA
Background
Neonatal infection, a leading cause of neonatal death in low- and middle-income countries, is often caused by pathogens acquired during childbirth. Clean delivery kits (CDKs) have shown efficacy in reducing infection-related perinatal and neonatal mortality. However, there remain gaps in our current knowledge, including the effect of individual components, the timeline of protection, and the benefit of CDKs in home and facility deliveries.
Methods and findings
A post hoc secondary analysis was performed using nonrandomized data from the Zambia Chlorhexidine Application Trial (ZamCAT), a community-based, cluster-randomized controlled trial of chlorhexidine umbilical cord care in Southern Province of Zambia from February 2011 to January 2013. CDKs, containing soap, gloves, cord clamps, plastic sheet, razor blade, matches, and candle, were provided to all pregnant women. Field monitors made a home-based visit to each participant 4 days postpartum, during which CDK use and newborn outcomes were ascertained. Logistic regression was used to study the association between different CDK components and neonatal mortality rate (NMR). Of 38,579 deliveries recorded during the study, 36,996 newborns were analyzed after excluding stillbirths and those with missing information. Gloves, cord clamps, and plastic sheets were the most frequently used CDK item combination in both home and facility deliveries. Each of the 7 CDK components was associated with lower NMR in users versus nonusers. Adjusted logistic regression showed that use of gloves (odds ratio [OR] 0.33, 95% CI 0.24-0.46), cord clamp (OR 0.51, 95% CI 0.38-0.68), plastic sheet (OR 0.46, 95% CI 0.34-0.63), and razor blade (OR 0.69, 95% CI 0.53-0.89) were associated with lower risk of newborn mortality. Use of gloves and cord clamp were associated with reduced risk of immediate newborn death (<24 hours). Reduction in risk of early newborn death (1-6 days) was associated with use of gloves, cord clamps, plastic sheets, and razor blades. In examining perinatal mortality (stillbirth plus neonatal death in the first 7 days of life), similar patterns were observed. There was no significant reduction in risk of late newborn mortality (7-28 days) with CDK use. Study limitations included potential recall bias of CDK use and inability to establish causality, as this was a secondary observational study.
Conclusions
CDK use was associated with reductions in early newborn mortality at both home and facility deliveries, especially when certain kit components were used. While causality could not be established in this nonrandomized secondary analysis, given these beneficial associations, scaling up the use of CDKs in rural areas of sub-Saharan Africa may improve neonatal outcomes.
Trial registration
Name of trial: Zambia Chlorhexidine Application Trial (ZamCAT) Name of registry: Clinicaltrials.gov Trial number: NCT01241318.



PLoS Med: 29 Apr 2021; 18:e1003610
Park JH, Hamer DH, Mbewe R, Scott NA, ... Yeboah-Antwi K, Semrau KEA
PLoS Med: 29 Apr 2021; 18:e1003610 | PMID: 33951036
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Impact:
Abstract

Digital adherence technology for tuberculosis treatment supervision: A stepped-wedge cluster-randomized trial in Uganda.

Cattamanchi A, Crowder R, Kityamuwesi A, Kiwanuka N, ... Dowdy D, Katamba A
Background
Adherence to and completion of tuberculosis (TB) treatment remain problematic in many high-burden countries. 99DOTS is a low-cost digital adherence technology that could increase TB treatment completion.
Methods and findings
We conducted a pragmatic stepped-wedge cluster-randomized trial including all adults treated for drug-susceptible pulmonary TB at 18 health facilities across Uganda over 8 months (1 December 2018-31 July 2019). Facilities were randomized to switch from routine (control period) to 99DOTS-based (intervention period) TB treatment supervision in consecutive months. Patients were allocated to the control or intervention period based on which facility they attended and their treatment start date. Health facility staff and patients were not blinded to the intervention. The primary outcome was TB treatment completion. Due to the pragmatic nature of the trial, the primary analysis was done according to intention-to-treat (ITT) and per protocol (PP) principles. This trial is registered with the Pan African Clinical Trials Registry (PACTR201808609844917). Of 1,913 eligible patients at the 18 health facilities (1,022 and 891 during the control and intervention periods, respectively), 38.0% were women, mean (SD) age was 39.4 (14.4) years, 46.8% were HIV-infected, and most (91.4%) had newly diagnosed TB. In total, 463 (52.0%) patients were enrolled on 99DOTS during the intervention period. In the ITT analysis, the odds of treatment success were similar in the intervention and control periods (adjusted odds ratio [aOR] 1.04, 95% CI 0.68-1.58, p = 0.87). The odds of treatment success did not increase in the intervention period for either men (aOR 1.24, 95% CI 0.73-2.10) or women (aOR 0.67, 95% CI 0.35-1.29), or for either patients with HIV infection (aOR 1.51, 95% CI 0.81-2.85) or without HIV infection (aOR 0.78, 95% CI 0.46-1.32). In the PP analysis, the 99DOTS-based intervention increased the odds of treatment success (aOR 2.89, 95% CI 1.57-5.33, p = 0.001). The odds of completing the intensive phase of treatment and the odds of not being lost to follow-up were similarly improved in PP but not ITT analyses. Study limitations include the likelihood of selection bias in the PP analysis, inability to verify medication dosing in either arm, and incomplete implementation of some components of the intervention.
Conclusions
99DOTS-based treatment supervision did not improve treatment outcomes in the overall study population. However, similar treatment outcomes were achieved during the control and intervention periods, and those patients enrolled on 99DOTS achieved high treatment completion. 99DOTS-based treatment supervision could be a viable alternative to directly observed therapy for a substantial proportion of patients with TB.
Trial registration
Pan-African Clinical Trials Registry (PACTR201808609844917).



PLoS Med: 29 Apr 2021; 18:e1003628
Cattamanchi A, Crowder R, Kityamuwesi A, Kiwanuka N, ... Dowdy D, Katamba A
PLoS Med: 29 Apr 2021; 18:e1003628 | PMID: 33956802
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Impact:
Abstract

A framework for prospective, adaptive meta-analysis (FAME) of aggregate data from randomised trials.

Tierney JF, Fisher DJ, Vale CL, Burdett S, ... White IR, Parmar MKB
Background
The vast majority of systematic reviews are planned retrospectively, once most eligible trials have completed and reported, and are based on aggregate data that can be extracted from publications. Prior knowledge of trial results can introduce bias into both review and meta-analysis methods, and the omission of unpublished data can lead to reporting biases. We present a collaborative framework for prospective, adaptive meta-analysis (FAME) of aggregate data to provide results that are less prone to bias. Also, with FAME, we monitor how evidence from trials is accumulating, to anticipate the earliest opportunity for a potentially definitive meta-analysis.
Methodology
We developed and piloted FAME alongside 4 systematic reviews in prostate cancer, which allowed us to refine the key principles. These are to: (1) start the systematic review process early, while trials are ongoing or yet to report; (2) liaise with trial investigators to develop a detailed picture of all eligible trials; (3) prospectively assess the earliest possible timing for reliable meta-analysis based on the accumulating aggregate data; (4) develop and register (or publish) the systematic review protocol before trials produce results and seek appropriate aggregate data; (5) interpret meta-analysis results taking account of both available and unavailable data; and (6) assess the value of updating the systematic review and meta-analysis. These principles are illustrated via a hypothetical review and their application to 3 published systematic reviews.
Conclusions
FAME can reduce the potential for bias, and produce more timely, thorough and reliable systematic reviews of aggregate data.



PLoS Med: 29 Apr 2021; 18:e1003629
Tierney JF, Fisher DJ, Vale CL, Burdett S, ... White IR, Parmar MKB
PLoS Med: 29 Apr 2021; 18:e1003629 | PMID: 33956789
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Impact:
Abstract

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

Jeong J, Franchett EE, Ramos de Oliveira CV, Rehmani K, Yousafzai AK
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.



PLoS Med: 29 Apr 2021; 18:e1003602
Jeong J, Franchett EE, Ramos de Oliveira CV, Rehmani K, Yousafzai AK
PLoS Med: 29 Apr 2021; 18:e1003602 | PMID: 33970913
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Abstract

Risk of miscarriage in women with chronic diseases in Norway: A registry linkage study.

Magnus MC, Morken NH, Wensaas KA, Wilcox AJ, Håberg SE
Background
Increased risk of miscarriage has been reported for women with specific chronic health conditions. A broader investigation of chronic diseases and miscarriage risk may uncover patterns across categories of illness. The objective of this study was to study the risk of miscarriage according to various preexisting chronic diseases.
Methods and findings
We conducted a registry-based study. Registered pregnancies (n = 593,009) in Norway between 2010 and 2016 were identified through 3 national health registries (birth register, general practitioner data, and patient registries). Six broad categories of illness were identified, comprising 25 chronic diseases defined by diagnostic codes used in general practitioner and patient registries. We required that the diseases were diagnosed before the pregnancy of interest. Miscarriage risk according to underlying chronic diseases was estimated as odds ratios (ORs) using generalized estimating equations adjusting for woman\'s age. The mean age of women at the start of pregnancy was 29.7 years (SD 5.6 years). We observed an increased risk of miscarriage among women with cardiometabolic diseases (OR 1.25, 95% CI 1.20 to 1.31; p-value <0.001). Within this category, risks were elevated for all conditions: atherosclerosis (2.22; 1.42 to 3.49; p-value <0.001), hypertensive disorders (1.19; 1.13 to 1.26; p-value <0.001), and type 2 diabetes (1.38; 1.26 to 1.51; p-value <0.001). Among other categories of disease, risks were elevated for hypoparathyroidism (2.58; 1.35 to 4.92; p-value 0.004), Cushing syndrome (1.97; 1.06 to 3.65; p-value 0.03), Crohn\'s disease (OR 1.31; 95% CI: 1.18 to 1.45; p-value 0.001), and endometriosis (1.22; 1.15 to 1.29; p-value <0.001). Findings were largely unchanged after mutual adjustment. Limitations of this study include our inability to adjust for measures of socioeconomic position or lifestyle characteristics, in addition to the rareness of some of the conditions providing limited power.
Conclusions
In this registry study, we found that, although risk of miscarriage was largely unaffected by maternal chronic diseases, risk of miscarriage was associated with conditions related to cardiometabolic health. This finding is consistent with emerging evidence linking cardiovascular risk factors to pregnancy complications.



PLoS Med: 29 Apr 2021; 18:e1003603
Magnus MC, Morken NH, Wensaas KA, Wilcox AJ, Håberg SE
PLoS Med: 29 Apr 2021; 18:e1003603 | PMID: 33970911
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Abstract

Associations of treated and untreated human papillomavirus infection with preterm delivery and neonatal mortality: A Swedish population-based study.

Wiik J, Nilsson S, Kärrberg C, Strander B, Jacobsson B, Sengpiel V
Background
Treatment of cervical intraepithelial neoplasia (CIN) is associated with an increased risk of preterm delivery (PTD) although the exact pathomechanism is not yet understood. Women with untreated CIN also seem to have an increased risk of PTD. It is unclear whether this is attributable to human papillomavirus (HPV) infection or other factors. We aimed to investigate whether HPV infection shortly before or during pregnancy, as well as previous treatment for CIN, is associated with an increased risk of PTD and other adverse obstetric and neonatal outcomes.
Methods and findings
This was a retrospective population-based register study of women with singleton deliveries registered in the Swedish Medical Birth Register 1999-2016 (n = 1,044,023). The study population had a mean age of 30.2 years (SD 5.2) and a mean body mass index of 25.4 kg/m2 (SD 3.0), and 44% of the women were nulliparous before delivery. Study groups were defined based on cervical HPV tests, cytology, and histology, as registered in the Swedish National Cervical Screening Registry. Women with a history of exclusively normal cytology (n = 338,109) were compared to women with positive HPV tests (n = 2,550) or abnormal cytology (n = 11,727) within 6 months prior to conception or during the pregnancy, women treated for CIN3 before delivery (n = 23,185), and women with CIN2+ diagnosed after delivery (n = 33,760). Study groups were compared concerning obstetric and neonatal outcomes by logistic regression, and comparisons were adjusted for socioeconomic and health-related confounders. HPV infection was associated with PTD (adjusted odds ratio [aOR] 1.19, 95% CI 1.01-1.42, p = 0.042), preterm prelabor rupture of membranes (pPROM) (aOR 1.52, 95% CI 1.18-1.96, p < 0.001), prelabor rupture of membranes (PROM) (aOR 1.24, 95% CI 1.08-1.42, p = 0.002), and neonatal mortality (aOR 2.69, 95% CI 1.25-5.78, p = 0.011). Treatment for CIN was associated with PTD (aOR 1.85, 95% CI 1.76-1.95, p < 0.001), spontaneous PTD (aOR 2.06, 95% CI 1.95-2.17, p < 0.001), pPROM (aOR 2.36, 95% CI 2.19-2.54, p < 0.001), PROM (aOR 1.11, 95% CI 1.05-1.17, p < 0.001), intrauterine fetal death (aOR 1.35, 95% CI 1.05-1.72, p = 0.019), chorioamnionitis (aOR 2.75, 95% CI 2.33-3.23, p < 0.001), intrapartum fever (aOR 1.24, 95% CI 1.07-1.44, p = 0.003), neonatal sepsis (aOR 1.55, 95% CI 1.37-1.75, p < 0.001), and neonatal mortality (aOR 1.79, 95% CI 1.30-2.45, p < 0.001). Women with CIN2+ diagnosed within 3 years after delivery had increased PTD risk (aOR 1.18, 95% CI 1.10-1.27, p < 0.001). Limitations of the study include the retrospective design and the fact that because HPV test results only became available in 2007, abnormal cytology was used as a proxy for HPV infection.
Conclusions
In this study, we found that HPV infection shortly before or during pregnancy was associated with PTD, pPROM, PROM, and neonatal mortality. Previous treatment for CIN was associated with even greater risks for PTD and pPROM and was also associated with PROM, neonatal mortality, and maternal and neonatal infectious complications.



PLoS Med: 29 Apr 2021; 18:e1003641
Wiik J, Nilsson S, Kärrberg C, Strander B, Jacobsson B, Sengpiel V
PLoS Med: 29 Apr 2021; 18:e1003641 | PMID: 33970907
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Abstract

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

Le LK, Esturas AC, Mihalopoulos C, Chiotelis O, ... Chatterton ML, Engel L
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.



PLoS Med: 29 Apr 2021; 18:e1003606
Le LK, Esturas AC, Mihalopoulos C, Chiotelis O, ... Chatterton ML, Engel L
PLoS Med: 29 Apr 2021; 18:e1003606 | PMID: 33974641
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Abstract

Effect of community-led delivery of HIV self-testing on HIV testing and antiretroviral therapy initiation in Malawi: A cluster-randomised trial.

Indravudh PP, Fielding K, Kumwenda MK, Nzawa R, ... Terris-Prestholt F, Corbett EL
Background
Undiagnosed HIV infection remains substantial in key population subgroups including adolescents, older adults, and men, driving ongoing transmission in sub-Saharan Africa. We evaluated the impact, safety, and costs of community-led delivery of HIV self-testing (HIVST), aiming to increase HIV testing in underserved subgroups and stimulate demand for antiretroviral therapy (ART).
Methods and findings
This cluster-randomised trial, conducted between October 2018 and July 2019, used restricted randomisation (1:1) to allocate 30 group village head clusters in Mangochi district, Malawi to the community-led HIVST intervention in addition to the standard of care (SOC) or the SOC alone. The intervention involved mobilising community health groups to lead the design and implementation of 7-day HIVST campaigns, with cluster residents (≥15 years) eligible for HIVST. The primary outcome compared lifetime HIV testing among adolescents (15 to 19 years) between arms. Secondary outcomes compared: recent HIV testing (in the last 3 months) among older adults (≥40 years) and men; cumulative 6-month incidence of ART initiation per 100,000 population; knowledge of the preventive benefits of HIV treatment; and HIV testing stigma. Outcomes were measured through a post-intervention survey and at neighboring health facilities. Analysis used intention-to-treat for cluster-level outcomes. Community health groups delivered 24,316 oral fluid-based HIVST kits. The survey included 90.2% (3,960/4,388) of listed participants in the 15 community-led HIVST clusters and 89.2% (3,920/4,394) of listed participants in the 15 SOC clusters. Overall, the proportion of men was 39.0% (3,072/7,880). Most participants obtained primary-level education or below, were married, and reported a sexual partner. Lifetime HIV testing among adolescents was higher in the community-led HIVST arm (84.6%, 770/910) than the SOC arm (67.1%, 582/867; adjusted risk difference [RD] 15.2%, 95% CI 7.5% to 22.9%; p < 0.001), especially among 15 to 17 year olds and boys. Recent testing among older adults was also higher in the community-led HIVST arm (74.5%, 869/1,166) than the SOC arm (31.5%, 350/1,111; adjusted RD 42.1%, 95% CI 34.9% to 49.4%; p < 0.001). Similarly, the proportions of recently tested men were 74.6% (1,177/1,577) and 33.9% (507/1,495) in the community-led HIVST and SOC arms, respectively (adjusted RD 40.2%, 95% CI 32.9% to 47.4%; p < 0.001). Knowledge of HIV treatment benefits and HIV testing stigma showed no differences between arms. Cumulative incidence of ART initiation was respectively 305.3 and 226.1 per 100,000 population in the community-led HIVST and SOC arms (RD 72.3, 95% CI -36.2 to 180.8; p = 0.18). In post hoc analysis, ART initiations in the 3-month post-intervention period were higher in the community-led HIVST arm than the SOC arm (RD 97.7, 95% CI 33.4 to 162.1; p = 0.004). HIVST uptake was 74.7% (2,956/3,960), with few adverse events (0.6%, 18/2,955) and at US$5.70 per HIVST kit distributed. The main limitations include the use of self-reported HIV testing outcomes and lack of baseline measurement for the primary outcome.
Conclusions
In this study, we found that community-led HIVST was effective, safe, and affordable, with population impact and coverage rapidly realised at low cost. This approach could enable community HIV testing in high HIV prevalence settings and demonstrates potential for economies of scale and scope.
Trial registration
Clinicaltrials.gov NCT03541382.



PLoS Med: 29 Apr 2021; 18:e1003608
Indravudh PP, Fielding K, Kumwenda MK, Nzawa R, ... Terris-Prestholt F, Corbett EL
PLoS Med: 29 Apr 2021; 18:e1003608 | PMID: 33974621
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Abstract

Adverse childhood experiences, adult depression, and suicidal ideation in rural Uganda: A cross-sectional, population-based study.

Satinsky EN, Kakuhikire B, Baguma C, Rasmussen JD, ... Bangsberg DR, Tsai AC
Background
Depression is recognized globally as a leading cause of disability. Early-life adverse childhood experiences (ACEs) have been shown to have robust associations with poor mental health during adulthood. These effects may be cumulative, whereby a greater number of ACEs are progressively associated with worse outcomes. This study aimed to estimate the associations between ACEs and adult depression and suicidal ideation in a cross-sectional, population-based study of adults in Uganda.
Methods and findings
Between 2016 and 2018, research assistants visited the homes of 1,626 adult residents of Nyakabare Parish, a rural area in southwestern Uganda. ACEs were assessed using a modified version of the Adverse Childhood Experiences-International Questionnaire, and depression symptom severity and suicidal ideation were assessed using the Hopkins Symptom Checklist for Depression (HSCL-D). We applied a validated algorithm to determine major depressive disorder diagnoses. Overall, 1,458 participants (90%) had experienced at least one ACE, 159 participants (10%) met criteria for major depressive disorder, and 28 participants (1.7%) reported suicidal ideation. We fitted regression models to estimate the associations between cumulative number of ACEs and depression symptom severity (linear regression model) and major depressive disorder and suicidal ideation (Poisson regression models). In multivariable regression models adjusted for age, sex, primary school completion, marital status, self-reported HIV status, and household asset wealth, the cumulative number of ACEs was associated with greater depression symptom severity (b = 0.050; 95% confidence interval [CI], 0.039-0.061, p < 0.001) and increased risk for major depressive disorder (adjusted relative risk [ARR] = 1.190; 95% CI, 1.109-1.276; p < 0.001) and suicidal ideation (ARR = 1.146; 95% CI, 1.001-1.311; p = 0.048). We assessed the robustness of our findings by probing for nonlinearities and conducting analyses stratified by age. The limitations of the study include the reliance on retrospective self-report as well as the focus on ACEs that occurred within the household.
Conclusions
In this whole-population, cross-sectional study of adults in rural Uganda, the cumulative number of ACEs had statistically significant associations with depression symptom severity, major depressive disorder, and suicidal ideation. These findings highlight the importance of developing and implementing policies and programs that safeguard children, promote mental health, and prevent trajectories toward psychosocial disability.



PLoS Med: 29 Apr 2021; 18:e1003642
Satinsky EN, Kakuhikire B, Baguma C, Rasmussen JD, ... Bangsberg DR, Tsai AC
PLoS Med: 29 Apr 2021; 18:e1003642 | PMID: 33979329
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Abstract

Outcomes and costs of publicly funded patient navigation interventions to enhance HIV care continuum outcomes in the United States: A before-and-after study.

Shade SB, Kirby VB, Stephens S, Moran L, ... Steward WT, Myers JJ
Background
In the United States, patients with HIV face significant barriers to linkage to and retention in care which impede the necessary steps toward achieving the desired clinical outcome of viral suppression. Individual-level interventions, such as patient navigation, are evidence based, effective strategies for improving care engagement. In addition, use of surveillance and clinical data to identify patients who are not fully engaged in care may improve the effectiveness and cost-effectiveness of these programs.
Methods and findings
We employed a pre-post design to estimate the outcomes and costs, from the program perspective, of 5 state-level demonstration programs funded under the Health Resources and Services Administration\'s Special Projects of National Significance Program (HRSA/SPNS) Systems Linkages Initiative that employed existing surveillance and/or clinical data to identify individuals who had never entered HIV care, had fallen out of care, or were at risk of falling out of care and navigation strategies to engage patients in HIV care. Outcomes and costs were measured relative to standard of care during the first year of implementation of the interventions (2013 to 2014). We followed patients to estimate the number and proportion of additional patients linked, reengaged, retained, and virally suppressed by 12 months after enrollment in the interventions. We employed inverse probability weighting to adjust for differences in patient characteristics across programs, missing data, and loss to follow-up. We estimated the additional costs expended during the first year of each intervention and the cost per outcome of each intervention as the additional cost per HIV additional care continuum target achieved (cost per patient linked, reengaged, retained, and virally suppressed) 12 months after enrollment in each intervention. In this study, 3,443 patients were enrolled in Louisiana (LA), Massachusetts (MA), North Carolina (NC), Virginia (VA), and Wisconsin (WI) (147, 151, 2,491, 321, and 333, respectively). Patients were a mean of 40 years old, 75% male, and African American (69%) or Caucasian (22%). At baseline, 24% were newly diagnosed, 2% had never been in HIV care, 45% had fallen out of care, and 29% were at risk of falling out of care. All 5 interventions were associated with increases in the number and proportion of patients with viral suppression [percent increase: LA = 90.9%, 95% confidence interval (CI) = 88.4 to 93.4; MA = 78.1%, 95% CI = 72.4 to 83.8; NC = 47.5%, 95% CI = 45.2 to 49.8; VA = 54.6, 95% CI = 49.4 to 59.9; WI = 58.4, 95% CI = 53.4 to 63.4]. Overall, interventions cost an additional $4,415 (range = $3,746 to $5,619), $2,009 (range = $1,516 to $2,274), $920 (range = $627 to $941), $2,212 (range = $1,789 to $2,683), and $3,700 ($2,734 to $4,101), respectively per additional patient virally suppressed. The results of this study are limited in that we did not have contemporaneous controls for each intervention; thus, we are only able to assess patients against themselves at baseline and not against standard of care during the same time period.
Conclusions
Patient navigation programs were associated with improvements in engagement of patients in HIV care and viral suppression. Cost per outcome was minimized in states that utilized surveillance data to identify individuals who were out of care and/or those that were able to identify a larger number of patients in need of improvement at baseline. These results have the potential to inform the targeting and design of future navigation-type interventions.



PLoS Med: 29 Apr 2021; 18:e1003418
Shade SB, Kirby VB, Stephens S, Moran L, ... Steward WT, Myers JJ
PLoS Med: 29 Apr 2021; 18:e1003418 | PMID: 33983925
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Abstract

Assessment of the causal relevance of ECG parameters for risk of atrial fibrillation: A mendelian randomisation study.

Gajendragadkar PR, Von Ende A, Ibrahim M, Valdes-Marquez E, ... Casadei B, Hopewell JC
Background
Atrial electrical and structural remodelling in older individuals with cardiovascular risk factors has been associated with changes in surface electrocardiographic (ECG) parameters (e.g., prolongation of the PR interval) and higher risks of atrial fibrillation (AF). However, it has been difficult to establish whether altered ECG parameters are the cause or a consequence of the myocardial substrate leading to AF. This study aimed to examine the potential causal relevance of ECG parameters on risk of AF using mendelian randomisation (MR).
Methods and findings
Weighted genetic scores explaining lifelong differences in P-wave duration, PR interval, and QT interval were constructed, and associations between these ECG scores and risk of AF were estimated among 278,792 UK Biobank participants (mean age: 57 years at recruitment; 19,132 AF cases). The independent genetic variants contributing to each of the separate ECG scores, and their corresponding weights, were based on published genome-wide association studies. In UK Biobank, genetic scores representing a 5 ms longer P-wave duration or PR interval were significantly associated with lower risks of AF (odds ratio [OR] 0.91; 95% confidence interval [CI]: 0.87-0.96, P = 2 × 10-4 and OR 0.94; 95% CI: 0.93-0.96, P = 2 × 10-19, respectively), while longer QT interval was not significantly associated with AF. These effects were independently replicated among a further 17,931 AF cases from the AFGen Consortium. Investigation of potential mechanistic pathways showed that differences in ECG parameters associated with specific ion channel genes had effects on risk of AF consistent with the overall scores, while the overall scores were not associated with changes in left atrial size. Limitations of the study included the inherent assumptions of MR, restriction to individuals of European ancestry, and possible restriction of results to the normal ECG ranges represented in UK Biobank.
Conclusions
In UK Biobank, we observed evidence suggesting a causal relationship between lifelong differences in ECG parameters (particularly PR interval) that reflect longer atrial conduction times and a lower risk of AF. These findings, which appear to be independent of atrial size and concomitant cardiovascular comorbidity, support the relevance of varying mechanisms underpinning AF and indicate that more individualised treatment strategies warrant consideration.



PLoS Med: 29 Apr 2021; 18:e1003572
Gajendragadkar PR, Von Ende A, Ibrahim M, Valdes-Marquez E, ... Casadei B, Hopewell JC
PLoS Med: 29 Apr 2021; 18:e1003572 | PMID: 33983917
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Abstract

Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study.

Varma VR, Wang Y, An Y, Varma S, ... Gadalla SM, Thambisetty M
Background
While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis.
Methods and findings
We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer\'s Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = <0.001-0.013) in males in BLSA. In ADNI, we found a modest sex-specific effect indicating that lower serum concentrations of CA and CDCA were associated with faster brain atrophy (FDR p = 0.049) in males.Step 2: In the Clinical Practice Research Datalink (CPRD) dataset, covering >4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings.
Conclusions
We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.



PLoS Med: 29 Apr 2021; 18:e1003615
Varma VR, Wang Y, An Y, Varma S, ... Gadalla SM, Thambisetty M
PLoS Med: 29 Apr 2021; 18:e1003615 | PMID: 34043628
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Abstract

The sugar content of foods in the UK by category and company: A repeated cross-sectional study, 2015-2018.

Bandy LK, Scarborough P, Harrington RA, Rayner M, Jebb SA
Background
Consumption of free sugars in the UK greatly exceeds dietary recommendations. Public Health England (PHE) has set voluntary targets for industry to reduce the sales-weighted mean sugar content of key food categories contributing to sugar intake by 5% by 2018 and 20% by 2020. The aim of this study was to assess changes in the sales-weighted mean sugar content and total volume sales of sugar in selected food categories among UK companies between 2015 and 2018.
Methods and findings
We used sales data from Euromonitor, which estimates total annual retail sales of packaged foods, for 5 categories-biscuits and cereal bars, breakfast cereals, chocolate confectionery, sugar confectionery, and yoghurts-for 4 consecutive years (2015-2018). This analysis includes 353 brands (groups of products with the same name) sold by 99 different companies. These data were linked with nutrient composition data collected online from supermarket websites over 2015-2018 by Edge by Ascential. The main outcome measures were sales volume, sales-weighted mean sugar content, and total volume of sugar sold by category and company. Our results show that between 2015 and 2018 the sales-weighted mean sugar content of all included foods fell by 5.2% (95% CI -9.4%, -1.4%), from 28.7 g/100 g (95% CI 27.2, 30.4) to 27.2 g/100 g (95% CI 25.8, 28.4). The greatest change seen was in yoghurts (-17.0% [95% CI -26.8%, -7.1%]) and breakfast cereals (-13.3% [95% CI -19.2%, -7.4%]), with only small reductions in sugar confectionery (-2.4% [95% CI -4.2%, -0.6%]) and chocolate confectionery (-1.0% [95% CI -3.1, 1.2]). Our results show that total volume of sugars sold per capita fell from 21.4 g/d (95% CI 20.3, 22.7) to 19.7 g/d (95% CI 18.8, 20.7), a reduction of 7.5% (95% CI -13.1%, -2.8%). Of the 50 companies representing the top 10 companies in each category, 24 met the 5% reduction target set by PHE for 2018. The key limitations of this study are that it does not encompass the whole food market and is limited by its use of brand-level sales data, rather than individual product sales data.
Conclusions
Our findings show there has been a small reduction in total volume sales of sugar in the included categories, primarily due to reductions in the sugar content of yoghurts and breakfast cereals. Additional policy measures may be needed to accelerate progress in categories such as sugar confectionery and chocolate confectionery if the 2020 PHE voluntary sugar reduction targets are to be met.



PLoS Med: 29 Apr 2021; 18:e1003647
Bandy LK, Scarborough P, Harrington RA, Rayner M, Jebb SA
PLoS Med: 29 Apr 2021; 18:e1003647 | PMID: 34003863
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Abstract

Effects of psychosocial support interventions on survival in inpatient and outpatient healthcare settings: A meta-analysis of 106 randomized controlled trials.

Smith TB, Workman C, Andrews C, Barton B, ... Petersen D, Holt-Lunstad J
Background
Hospitals, clinics, and health organizations have provided psychosocial support interventions for medical patients to supplement curative care. Prior reviews of interventions augmenting psychosocial support in medical settings have reported mixed outcomes. This meta-analysis addresses the questions of how effective are psychosocial support interventions in improving patient survival and which potential moderating features are associated with greater effectiveness.
Methods and findings
We evaluated randomized controlled trials (RCTs) of psychosocial support interventions in inpatient and outpatient healthcare settings reporting survival data, including studies reporting disease-related or all-cause mortality. Literature searches included studies reported January 1980 through October 2020 accessed from Embase, Medline, Cochrane Library, CINAHL, Alt HealthWatch, PsycINFO, Social Work Abstracts, and Google Scholar databases. At least 2 reviewers screened studies, extracted data, and assessed study quality, with at least 2 independent reviewers also extracting data and assessing study quality. Odds ratio (OR) and hazard ratio (HR) data were analyzed separately using random effects weighted models. Of 42,054 studies searched, 106 RCTs including 40,280 patients met inclusion criteria. Patient average age was 57.2 years, with 52% females and 48% males; 42% had cardiovascular disease (CVD), 36% had cancer, and 22% had other conditions. Across 87 RCTs reporting data for discrete time periods, the average was OR = 1.20 (95% CI = 1.09 to 1.31, p < 0.001), indicating a 20% increased likelihood of survival among patients receiving psychosocial support compared to control groups receiving standard medical care. Among those studies, psychosocial interventions explicitly promoting health behaviors yielded improved likelihood of survival, whereas interventions without that primary focus did not. Across 22 RCTs reporting survival time, the average was HR = 1.29 (95% CI = 1.12 to 1.49, p < 0.001), indicating a 29% increased probability of survival over time among intervention recipients compared to controls. Among those studies, meta-regressions identified 3 moderating variables: control group type, patient disease severity, and risk of research bias. Studies in which control groups received health information/classes in addition to treatment as usual (TAU) averaged weaker effects than those in which control groups received only TAU. Studies with patients having relatively greater disease severity tended to yield smaller gains in survival time relative to control groups. In one of 3 analyses, studies with higher risk of research bias tended to report better outcomes. The main limitation of the data is that interventions very rarely blinded personnel and participants to study arm, such that expectations for improvement were not controlled.
Conclusions
In this meta-analysis, OR data indicated that psychosocial behavioral support interventions promoting patient motivation/coping to engage in health behaviors improved patient survival, but interventions focusing primarily on patients\' social or emotional outcomes did not prolong life. HR data indicated that psychosocial interventions, predominantly focused on social or emotional outcomes, improved survival but yielded similar effects to health information/classes and were less effective among patients with apparently greater disease severity. Risk of research bias remains a plausible threat to data interpretation.



PLoS Med: 29 Apr 2021; 18:e1003595
Smith TB, Workman C, Andrews C, Barton B, ... Petersen D, Holt-Lunstad J
PLoS Med: 29 Apr 2021; 18:e1003595 | PMID: 34003832
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Abstract

Effects of community-based antiretroviral therapy initiation models on HIV treatment outcomes: A systematic review and meta-analysis.

Eshun-Wilson I, Awotiwon AA, Germann A, Amankwaa SA, ... Baral S, Geng EH
Background
Antiretroviral therapy (ART) initiation in the community and outside of a traditional health facility has the potential to improve linkage to ART, decongest health facilities, and minimize structural barriers to attending HIV services among people living with HIV (PLWH). We conducted a systematic review and meta-analysis to determine the effect of offering ART initiation in the community on HIV treatment outcomes.
Methods and findings
We searched databases between 1 January 2013 and 22 February 2021 to identify randomized controlled trials (RCTs) and observational studies that compared offering ART initiation in a community setting to offering ART initiation in a traditional health facility or alternative community setting. We assessed risk of bias, reporting of implementation outcomes, and real-world relevance and used Mantel-Haenszel methods to generate pooled risk ratios (RRs) and risk differences (RDs) with 95% confidence intervals. We evaluated heterogeneity qualitatively and quantitatively and used GRADE to evaluate overall evidence certainty. Searches yielded 4,035 records, resulting in 8 included studies-4 RCTs and 4 observational studies-conducted in Lesotho, South Africa, Nigeria, Uganda, Malawi, Tanzania, and Haiti-a total of 11,196 PLWH. Five studies were conducted in general HIV populations, 2 in key populations, and 1 in adolescents. Community ART initiation strategies included community-based HIV testing coupled with ART initiation at home or at community venues; 5 studies maintained ART refills in the community, and 4 provided refills at the health facility. All studies were pragmatic, but in most cases provided additional resources. Few studies reported on implementation outcomes. All studies showed higher ART uptake in community initiation arms compared to facility initiation and refill arms (standard of care) (RR 1.73, 95% CI 1.22 to 2.45; RD 30%, 95% CI 10% to 50%; 5 studies). Retention (RR 1.43, 95% CI 1.32 to 1.54; RD 19%, 95% CI 11% to 28%; 4 studies) and viral suppression (RR 1.31, 95% CI 1.15 to 1.49; RD 15%, 95% CI 10% to 21%; 3 studies) at 12 months were also higher in the community-based ART initiation arms. Improved uptake, retention, and viral suppression with community ART initiation were seen across population subgroups-including men, adolescents, and key populations. One study reported no difference in retention and viral suppression at 2 years. There were limited data on adherence and mortality. Social harms and adverse events appeared to be minimal and similar between community ART initiation and standard of care. One study compared ART refill strategies following community ART initiation (community versus facility refills) and found no difference in viral suppression (RD -7%, 95% CI -19% to 6%) or retention at 12 months (RD -12%, 95% CI -23% to 0.3%). This systematic review was limited by few studies for inclusion, poor-quality observational data, and short-term outcomes.
Conclusions
Based on data from a limited set of studies, community ART initiation appears to result in higher ART uptake, retention, and viral suppression at 1 year compared to facility-based ART initiation. Implementation on a wider scale necessitates broader exploration of costs, logistics, and acceptability by providers and PLWH to ensure that these effects are reproducible when delivered at scale, in different contexts, and over time.



PLoS Med: 29 Apr 2021; 18:e1003646
Eshun-Wilson I, Awotiwon AA, Germann A, Amankwaa SA, ... Baral S, Geng EH
PLoS Med: 29 Apr 2021; 18:e1003646 | PMID: 34048443
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Abstract

Adherence at 2 years with distribution of essential medicines at no charge: The CLEAN Meds randomized clinical trial.

Persaud N, Bedard M, Boozary A, Glazier RH, ... Laupacis A, Carefully seLected and Easily Accessible at No Charge Medications (CLEAN Meds) study team
Background
Adherence to medicines is low for a variety of reasons, including the cost borne by patients. Some jurisdictions publicly fund medicines for the general population, but many jurisdictions do not, and such policies are contentious. To our knowledge, no trials studying free access to a wide range of medicines have been conducted.
Methods and findings
We randomly assigned 786 primary care patients who reported not taking medicines due to cost between June 1, 2016 and April 28, 2017 to either free distribution of essential medicines (n = 395) or to usual medicine access (n = 391). The trial was conducted in Ontario, Canada, where hospital care and physician services are publicly funded for the general population but medicines are not. The trial population was mostly female (56%), younger than 65 years (83%), white (66%), and had a low income from wages as the primary source (56%). The primary outcome was medicine adherence after 2 years. Secondary outcomes included control of diabetes, blood pressure, and low-density lipoprotein (LDL) cholesterol in patients taking relevant treatments and healthcare costs over 2 years. Adherence to all appropriate prescribed medicines was 38.7% in the free distribution group and 28.6% in the usual access group after 2 years (absolute difference 10.1%; 95% confidence interval (CI) 3.3 to 16.9, p = 0.004). There were no statistically significant differences in control of diabetes (hemoglobin A1c 0.27; 95% CI -0.25 to 0.79, p = 0.302), systolic blood pressure (-3.9; 95% CI -9.9 to 2.2, p = 0.210), or LDL cholesterol (0.26; 95% CI -0.08 to 0.60, p = 0.130) based on available data. Total healthcare costs over 2 years were lower with free distribution (difference in median CAN$1,117; 95% CI CAN$445 to CAN$1,778, p = 0.006). In the free distribution group, 51 participants experienced a serious adverse event, while 68 participants in the usual access group experienced a serious adverse event (p = 0.091). Participants were not blinded, and some outcomes depended on participant reports.
Conclusions
In this study, we observed that free distribution of essential medicines to patients with cost-related nonadherence substantially increased adherence, did not affect surrogate health outcomes, and reduced total healthcare costs over 2 years.
Trial registration
ClinicalTrials.gov NCT02744963.



PLoS Med: 29 Apr 2021; 18:e1003590
Persaud N, Bedard M, Boozary A, Glazier RH, ... Laupacis A, Carefully seLected and Easily Accessible at No Charge Medications (CLEAN Meds) study team
PLoS Med: 29 Apr 2021; 18:e1003590 | PMID: 34019540
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Abstract

SMS messaging to improve retention and viral suppression in prevention of mother-to-child HIV transmission (PMTCT) programs in Kenya: A 3-arm randomized clinical trial.

Kinuthia J, Ronen K, Unger JA, Jiang W, ... Richardson BA, John-Stewart G
Background
Pregnant and postpartum women living with HIV (WLWH) need support for HIV and maternal child health (MCH) care, which could be provided using short message service (SMS).
Methods and findings
We compared 2-way (interactive) and 1-way SMS messaging to no SMS in a 3-arm randomized trial in 6 MCH clinics in Kenya. Messages were developed using the Health Belief Model and Social Cognitive Theory; HIV messages were integrated into an existing MCH SMS platform. Intervention participants received visit reminders and prespecified weekly SMS on antiretroviral therapy (ART) adherence and MCH, tailored to their characteristics and timing. Two-way participants could message nurses as needed. Clinic attendance, viral load (VL), and infant HIV results were abstracted from program records. Primary outcomes were viral nonsuppression (VL ≥1,000 c/ml), on-time clinic attendance, loss to follow-up from clinical care, and infant HIV-free survival. Among 824 pregnant women randomized between November 2015 and May 2017, median age was 27 years, gestational age was 24.3 weeks, and time since initiation of ART was 1.0 year. During follow-up to 2 years postpartum, 9.8% of 3,150 VL assessments and 19.6% of women were ever nonsuppressed, with no significant difference in 1-way versus control (11.2% versus 9.6%, adjusted risk ratio (aRR) 1.02 [95% confidence interval (CI) 0.67 to 1.54], p = 0.94) or 2-way versus control (8.5% versus 9.6%, aRR 0.80 [95% CI 0.52 to 1.23], p = 0.31). Median ART adherence and incident ART resistance did not significantly differ by arm. Overall, 88.9% (95% CI 76.5 to 95.7) of visits were on time, with no significant differences between arms (88.2% in control versus 88.6% in 1-way and 88.8% in 2-way). Incidence of infant HIV or death was 3.01/100 person-years (py), with no significant difference between arms; risk of infant HIV infection was 0.94%. Time to postpartum contraception was significantly shorter in the 2-way arm than control. Study limitations include limited ability to detect improvement due to high viral suppression and visit attendance and imperfect synchronization of SMS reminders to clinic visits.
Conclusions
Integrated HIV/MCH messaging did not improve HIV outcomes but was associated with improved initiation of postpartum contraception. In programs where most women are virally suppressed, targeted SMS informed by VL data may improve effectiveness. Rigorous evaluation remains important to optimize mobile health (mHealth) interventions.
Trial registration
ClinicalTrials.gov number NCT02400671.



PLoS Med: 29 Apr 2021; 18:e1003650
Kinuthia J, Ronen K, Unger JA, Jiang W, ... Richardson BA, John-Stewart G
PLoS Med: 29 Apr 2021; 18:e1003650 | PMID: 34029338
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Abstract

California and federal school nutrition policies and obesity among children of Pacific Islander, American Indian/Alaska Native, and Filipino origins: Interrupted time series analysis.

Matsuzaki M, Sánchez BN, Rebanal RD, Gittelsohn J, Sanchez-Vaznaugh EV
Background
Obesity prevalence remains high among children of Pacific Islander (PI) origin, Filipino (FI), and American Indian/Alaska Native (AIAN) origins in the United States. While school nutrition policies may help prevent and reduce childhood obesity, their influences specifically among PI, FI, and AIAN children remain understudied. We evaluated the association of the California (CA) state school nutrition policies for competitive food and beverages and the federal policy for school meals (Healthy, Hunger-Free Kids Act of 2010 (HHFKA 2010)) with overweight/obesity among PI, FI, and AIAN students.
Methods and findings
We used an interrupted time series (ITS) design with FitnessGram data from 2002 to 2016 for PI (78,841), FI (328,667), AIAN (97,129), and White (3,309,982) students in fifth and seventh grades who attended CA public schools. Multilevel logistic regression models estimated the associations of the CA school nutrition policies (in effect beginning in academic year 2004 to 2005) and HHFKA 2010 (from academic year 2012 to 2013) with overweight/obesity prevalence (above the 85 percentile of the age- and sex-specific body mass index (BMI) distribution). The models were constructed separately for each grade and sex combination and adjusted for school district-, school-, and student-level characteristics such as percentage of students eligible for free and reduced price meals, neighborhood income and education levels, and age. Across the study period, the crude prevalence of overweight/obesity was higher among PI (39.5% to 52.5%), FI (32.9% to 36.7%), and AIAN (37.7% to 45.6%) children, compared to White (26.8% to 30.2%) students. The results generally showed favorable association of the CA nutrition policies with overweight/obesity prevalence trends, although the magnitudes of associations and strengths of evidence varied among racial/ethnic subgroups. Before the CA policies went into effect (2002 to 2004), overweight/obesity prevalence increased for White, PI, and AIAN students in both grades and sex groups as well as FI girls in seventh grade. After the CA policies took place (2005 to 2012), the overweight/obesity rates decreased for almost all subgroups who experienced increasing trends before the policies, with the largest decrease seen among PI girls in fifth grade (before: log odds ratio = 0.149 (95% CI 0.108 to 0.189; p < 0.001); after: 0.010 (-0.005 to 0.025; 0.178)). When both the CA nutrition policies and HHFKA 2010 were in effect (2013 to 2016), declines in the overweight/obesity prevalence were seen among White girls and FI boys in fifth grade. Despite the evidence of the favorable association of the school nutrition policies with overweight/obesity prevalence trends, disparities between PI and AIAN students and their White peers remained large after the policies took place. As these policies went into effect for all public schools in CA, without a clear comparison group, we cannot conclude that the changes in prevalence trends were solely attributable to these policies.
Conclusions
The current study found evidence of favorable associations of the state and federal school nutrition policies with overweight/obesity prevalence trends. However, the prevalence of overweight/obesity continued to be high among PI and AIAN students and FI boys. There remain wide racial/ethnic disparities between these racial/ethnic minority subgroups and their White peers. Additional strategies are needed to reduce childhood obesity and related disparities among these understudied racial/ethnic populations.



PLoS Med: 29 Apr 2021; 18:e1003596
Matsuzaki M, Sánchez BN, Rebanal RD, Gittelsohn J, Sanchez-Vaznaugh EV
PLoS Med: 29 Apr 2021; 18:e1003596 | PMID: 34029318
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Abstract

Positron emission tomography and magnetic resonance imaging in experimental human malaria to identify organ-specific changes in morphology and glucose metabolism: A prospective cohort study.

Woodford J, Gillman A, Jenvey P, Roberts J, ... Anstey NM, McCarthy JS
Background
Plasmodium vivax has been proposed to infect and replicate in the human spleen and bone marrow. Compared to Plasmodium falciparum, which is known to undergo microvascular tissue sequestration, little is known about the behavior of P. vivax outside of the circulating compartment. This may be due in part to difficulties in studying parasite location and activity in life.
Methods and findings
To identify organ-specific changes during the early stages of P. vivax infection, we performed 18-F fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) at baseline and just prior to onset of clinical illness in P. vivax experimentally induced blood-stage malaria (IBSM) and compared findings to P. falciparum IBSM. Seven healthy, malaria-naive participants were enrolled from 3 IBSM trials: NCT02867059, ACTRN12616000174482, and ACTRN12619001085167. Imaging took place between 2016 and 2019 at the Herston Imaging Research Facility, Australia. Postinoculation imaging was performed after a median of 9 days in both species (n = 3 P. vivax; n = 4 P. falciparum). All participants were aged between 19 and 23 years, and 6/7 were male. Splenic volume (P. vivax: +28.8% [confidence interval (CI) +10.3% to +57.3%], P. falciparum: +22.9 [CI -15.3% to +61.1%]) and radiotracer uptake (P. vivax: +15.5% [CI -0.7% to +31.7%], P. falciparum: +5.5% [CI +1.4% to +9.6%]) increased following infection with each species, but more so in P. vivax infection (volume: p = 0.72, radiotracer uptake: p = 0.036). There was no change in FDG uptake in the bone marrow (P. vivax: +4.6% [CI -15.9% to +25.0%], P. falciparum: +3.2% [CI -3.2% to +9.6%]) or liver (P. vivax: +6.2% [CI -8.7% to +21.1%], P. falciparum: -1.4% [CI -4.6% to +1.8%]) following infection with either species. In participants with P. vivax, hemoglobin, hematocrit, and platelet count decreased from baseline at the time of postinoculation imaging. Decrements in hemoglobin and hematocrit were significantly greater in participants with P. vivax infection compared to P. falciparum. The main limitations of this study are the small sample size and the inability of this tracer to differentiate between host and parasite metabolic activity.
Conclusions
PET/MRI indicated greater splenic tropism and metabolic activity in early P. vivax infection compared to P. falciparum, supporting the hypothesis of splenic accumulation of P. vivax very early in infection. The absence of uptake in the bone marrow and liver suggests that, at least in early infection, these tissues do not harbor a large parasite biomass or do not provoke a prominent metabolic response. PET/MRI is a safe and noninvasive method to evaluate infection-associated organ changes in morphology and glucose metabolism.



PLoS Med: 29 Apr 2021; 18:e1003567
Woodford J, Gillman A, Jenvey P, Roberts J, ... Anstey NM, McCarthy JS
PLoS Med: 29 Apr 2021; 18:e1003567 | PMID: 34038421
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Abstract

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

Kho S, Qotrunnada L, Leonardo L, Andries B, ... Buffet PA, Anstey NM
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.



PLoS Med: 29 Apr 2021; 18:e1003632
Kho S, Qotrunnada L, Leonardo L, Andries B, ... Buffet PA, Anstey NM
PLoS Med: 29 Apr 2021; 18:e1003632 | PMID: 34038413
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This program is still in alpha version.