PLOS Medicine recently published

by John P. Quattrochi, Kevin Croke, Caleb Dohou, Luca Stanus Ghib, Yannick Lokaya, Aidan Coville, Eric Mvukiyehe

Background

Diarrhea and growth faltering in early childhood reduce survival and impair neurodevelopment. We assessed whether a national program combining (i) funds for latrine and water upgrades; (ii) institutional strengthening; and (iii) behavior change campaigns reduced diarrhea and stunting, and strengthened local institutions.

Methods and Findings

We collaborated with program implementers to conduct a cluster-randomized controlled trial in four provinces of the Democratic Republic of Congo (DRC). Three hundred thirty-two rural villages were grouped into 121 clusters to minimize geographic spillovers. Between 15 March and 30 June 2018, we randomly assigned, after stratifying by province and cluster size, 50 intervention and 71 control clusters. Masking of participants and interviewers was not possible. Primary outcomes were length-for-age Z-score among children under 5 years of age, caregiver-reported diarrhea in last 7 days among children under 5 years of age, and an index of community WASH institutions. The primary analysis was on an intention-to-treat basis, using a binary variable indicating whether the participant was in an intervention or control cluster. Three thousand two hundred eighty-three households were interviewed between November 2022 and April 2023, median 3.6 years post-intervention. The intervention had no effect on diarrhea (adjusted mean difference −0.01 [95% −0.05 to 0.03]). Diarrhea prevalence was high overall, at 38% in the treatment group and 42% in the control group. The intervention had no effect on length-for-age Z-scores in children (adjusted mean difference −0.01 [95% CI −0.15 to 0.12]). In the control group, the mean length-for-age Z-score was −2.18 (1.60 SD). Villages in the intervention group had a 0.40 higher score on the WASH institutions index (95% CI 0.16–0.65). The percentage of villages in the intervention group with an active water, sanitation, and hygiene (or just water) committee was 21 pp higher than the control group. Households in the intervention group were 24 pp (95% CI 12–36) more likely to report using an improved water source, 18 pp (95% CI 10–25) more likely to report using an improved sanitation facility, and reported more positive perceptions of water governance (adjusted difference 0.19 SD [95% CI 0.04–0.34]). The trial had several limitations, including incomplete (86%) adherence in the implementation group, the absence of baseline measures, and the reliance on self-reported outcomes for some measures.

Conclusions

The DRC’s national rural WASH program increased access to improved water and sanitation infrastructure, and created new WASH institutions, all of which persisted for at least 3.6 years. However, these effects were not sufficient to reduce diarrhea or growth faltering.

Trial registration

The Pan African Clinical Trials Registry PACTR202102616421588 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=14670).The American Economics Association RCT registry AEARCTR-0004648 (https://www.socialscienceregistry.org/trials/4648).

by Mary Ellen Gilder, Makoto Saito, Warat Haohankhunnatham, Clare L. Ling, Gornpan Gornsawun, Germana Bancone, Cindy S. Chu, Peter R. Christensen, Mallika Imwong, Prakaykaew Charunwatthana, Nay Win Tun, Aung Myat Min, Verena I. Carrara, Stephane Proux, Nicholas J. White, François Nosten, Rose McGready

Background

Malaria in pregnancy detected by microscopy is associated with maternal anaemia, reduced fetal growth, and preterm birth, but the effects of lower density (i.e., submicroscopic) malaria infections are poorly characterised. This analysis was undertaken to investigate associations between submicroscopic malaria at the first antenatal care (ANC) visit and these adverse pregnancy events on the Thailand–Myanmar border.

Methods

Blood samples taken from refugee and migrant pregnant women presenting for their first ANC visit were analysed retrospectively for malaria using ultrasensitive PCR (uPCR, limit of detection 22 parasites/mL). The relationships between submicroscopic malaria and subsequent microscopically detectable malaria, anaemia, birth weight, and preterm birth were evaluated using inverse probability weighting for stratified random sampling.

Results

First ANC visit samples from 4,352 asymptomatic women (median gestational age 16.5 weeks) attending between October 1st 2012 and December 31st 2015 were analysed. The weighted proportion of women with submicroscopic malaria infection was 4.6% (95% CI 3.9–5.6), comprising 59.8% (49.5–69.4) Plasmodium vivax, 6.5% (4.0–10.5) Plasmodium falciparum, 1.8% (0.9–3.6) mixed, and 31.9% (22.2–43.5) infections which could not be speciated. Submicroscopic parasitaemia at first ANC visit was associated with subsequent microscopically detected malaria (adjusted hazard ratio [HR] 12.9, 95% CI 8.8–18.8, p < 0.001) and lower birth weight (adjusted predicted mean difference −275 g, 95% CI −510 to −40, p = 0.022). There was no association with preterm birth. Submicroscopic P. falciparum mono-infection (adjusted HR 2.8, 95% CI 1.2–6.6, p = 0.023) and coinfection with P. falciparum and P. vivax (adjusted HR 10.3, 95% CI 2.6–40.4, p = 0.001) was associated with increased risk of maternal anaemia, but submicroscopic P. vivax mono-infection was not. That uPCR was conducted for only a part of the cohort due to cost constraints is a limitation.

Conclusions

In low transmission settings, uPCR identifies substantially more malaria infections at antenatal screening than conventional diagnostic methods. On the Thailand–Myanmar border, submicroscopic malaria at first antenatal consultation was associated with higher risks of microscopically diagnosed malaria later in pregnancy, anaemia, and reduced birth weight.

by Meng Zhu, Xia Zhu, Yuting Han, Zhimin Ma, Chen Ji, Tianpei Wang, Caiwang Yan, Ci Song, Canqing Yu, Dianjianyi Sun, Yue Jiang, Jiaping Chen, Ling Yang, Yiping Chen, Huaidong Du, Robin Walters, Iona Y Millwood, Juncheng Dai, Hongxia Ma, Zhengdong Zhang, Zhengming Chen, Zhibin Hu, Jun Lv, Guangfu Jin, Liming Li, Hongbing Shen, on behalf of the China Kadoorie Biobank Collaborative Group

Background

Polygenic risk scores (PRSs) have been extensively developed for cancer risk prediction in European populations, but their effectiveness in the Chinese population remains uncertain.

Methods and findings

We constructed 80 PRSs for the 13 most common cancers using seven schemes and evaluated these PRSs in 100,219 participants from the China Kadoorie Biobank (CKB). The optimal PRSs with the highest discriminatory ability were used to define genetic risk, and their site-specific and cross-cancer associations were assessed. We modeled 10-year absolute risk trajectories for each cancer across risk strata defined by PRSs and modifiable risk scores and quantified the explained relative risk (ERR) of PRSs with modifiable risk factors for different cancers. More than 60% (50/80) of the PRSs demonstrated significant associations with the corresponding cancer outcomes. Optimal PRSs for nine common cancers were identified, with each standard deviation increase significantly associated with corresponding cancer risk (hazard ratios (HRs) ranging from 1.20 to 1.76). Compared with participants at low genetic risk and reduced modifiable risk scores, those with high genetic risk and elevated modifiable risk scores had the highest risk of incident cancer, with HRs ranging from 1.97 (95% confidence interval (CI): 1.11–3.48 for cervical cancer, P = 0.020) to 8.26 (95% CI: 1.92–35.46 for prostate cancer, P = 0.005). We observed nine significant cross-cancer associations for PRSs and found the integration of PRSs significantly increased the prediction accuracy for most cancers. The PRSs contributed 2.6%–20.3%, while modifiable risk factors explained 2.3%–16.7% of the ERR in the Chinese population.

Conclusions

The integration of existing evidence has facilitated the development of PRSs associated with nine common cancer risks in the Chinese population, potentially improving clinical risk assessment.

by Cameron Razieh, Bethan Powell, Rosemary Drummond, Isobel L. Ward, Jasper Morgan, Myer Glickman, Chris White, Francesco Zaccardi, Jonathan Hope, Veena Raleigh, Ashley Akbari, Nazrul Islam, Thomas Yates, Lisa Murphy, Bilal A. Mateen, Kamlesh Khunti, Vahe Nafilyan

Background

Electronic health records (EHRs) are increasingly used to investigate health inequalities across ethnic groups. While there are some studies showing that the recording of ethnicity in EHR is imperfect, there is no robust evidence on the accuracy between the ethnicity information recorded in various real-world sources and census data.

Methods and findings

We linked primary and secondary care NHS England data sources with Census 2021 data and compared individual-level agreement of ethnicity recording in General Practice Extraction Service (GPES) Data for Pandemic Planning and Research (GDPPR), Hospital Episode Statistics (HES), Ethnic Category Information Asset (ECIA), and Talking Therapies for anxiety and depression (TT) with ethnicity reported in the census. Census ethnicity is self-reported and, therefore, regarded as the most reliable population-level source of ethnicity recording. We further assessed the impact of multiple approaches to assigning a person an ethnic category. The number of people that could be linked to census from ECIA, GDPPR, HES, and TT were 47.4m, 43.5m, 47.8m, and 6.3m, respectively. Across all 4 data sources, the White British category had the highest level of agreement with census (≥96%), followed by the Bangladeshi category (≥93%). Levels of agreement for Pakistani, Indian, and Chinese categories were ≥87%, ≥83%, and ≥80% across all sources. Agreement was lower for Mixed (≤75%) and Other (≤71%) categories across all data sources. The categories with the lowest agreement were Gypsy or Irish Traveller (≤6%), Other Black (≤19%), and Any Other Ethnic Group (≤25%) categories.

Conclusions

Certain ethnic categories across all data sources have high discordance with census ethnic categories. These differences may lead to biased estimates of differences in health outcomes between ethnic groups, a critical data point used when making health policy and planning decisions.

by Donovan Guttieres, Charlot Diepvens, Rebecca F. Grais, Jackline Kiarie, Nico Vandaele, Catherine Decouttere

In June 2024, Gavi, the Vaccine Alliance, launched a preventive vaccination program against Ebola virus disease (EVD). This marks a historic shift in the management of EVD, allowing at-risk countries across sub-Saharan Africa to request support in implementing preventive vaccination campaigns. This perspective piece shares considerations that can inform how countries approach preventive EVD vaccination and potential unintended consequences. It also provides insights into strategies for vaccines against other epidemic-prone pathogens. Donovan Guttieres and colleagues discuss the role of preventative vaccination in the fight against Ebola virus disease, as well as the various considerations that are required to ensure its success.

by James G. Beeson, Daniel Herbert Opi

In areas with low malaria transmission intensity, most infections during pregnancy are not detected by standard diagnostic tests. New data shows that these missed asymptomatic infections have substantial negative impacts for both the mother and the developing fetus.

by Brian Critelli, Amier Hassan, Ila Lahooti, Lydia Noh, Jun Sung Park, Kathleen Tong, Ali Lahooti, Nathan Matzko, Jan Niklas Adams, Lukas Liss, Justin Quion, David Restrepo, Melica Nikahd, Stacey Culp, Adam Lacy-Hulbert, Cate Speake, James Buxbaum, Jason Bischof, Cemal Yazici, Anna Evans-Phillips, Sophie Terp, Alexandra Weissman, Darwin Conwell, Philip Hart, Mitchell Ramsey, Somashekar Krishna, Samuel Han, Erica Park, Raj Shah, Venkata Akshintala, John A. Windsor, Nikhil K. Mull, Georgios Papachristou, Leo Anthony Celi, Peter Lee

Background

An accurate prognostic tool is essential to aid clinical decision-making (e.g., patient triage) and to advance personalized medicine. However, such a prognostic tool is lacking for acute pancreatitis (AP). Increasingly machine learning (ML) techniques are being used to develop high-performing prognostic models in AP. However, methodologic and reporting quality has received little attention. High-quality reporting and study methodology are critical for model validity, reproducibility, and clinical implementation. In collaboration with content experts in ML methodology, we performed a systematic review critically appraising the quality of methodology and reporting of recently published ML AP prognostic models.

Methods/findings

Using a validated search strategy, we identified ML AP studies from the databases MEDLINE and EMBASE published between January 2021 and December 2023. We also searched pre-print servers medRxiv, bioRxiv, and arXiv for pre-prints registered between January 2021 and December 2023. Eligibility criteria included all retrospective or prospective studies that developed or validated new or existing ML models in patients with AP that predicted an outcome following an episode of AP. Meta-analysis was considered if there was homogeneity in the study design and in the type of outcome predicted. For risk of bias (ROB) assessment, we used the Prediction Model Risk of Bias Assessment Tool. Quality of reporting was assessed using the Transparent Reporting of a Multivariable Prediction Model of Individual Prognosis or Diagnosis—Artificial Intelligence (TRIPOD+AI) statement that defines standards for 27 items that should be reported in publications using ML prognostic models. The search strategy identified 6,480 publications of which 30 met the eligibility criteria. Studies originated from China (22), the United States (4), and other (4). All 30 studies developed a new ML model and none sought to validate an existing ML model, producing a total of 39 new ML models. AP severity (23/39) or mortality (6/39) were the most common outcomes predicted. The mean area under the curve for all models and endpoints was 0.91 (SD 0.08). The ROB was high for at least one domain in all 39 models, particularly for the analysis domain (37/39 models). Steps were not taken to minimize over-optimistic model performance in 27/39 models. Due to heterogeneity in the study design and in how the outcomes were defined and determined, meta-analysis was not performed. Studies reported on only 15/27 items from TRIPOD+AI standards, with only 7/30 justifying sample size and 13/30 assessing data quality. Other reporting deficiencies included omissions regarding human–AI interaction (28/30), handling low-quality or incomplete data in practice (27/30), sharing analytical codes (25/30), study protocols (25/30), and reporting source data (19/30).

Conclusions

There are significant deficiencies in the methodology and reporting of recently published ML based prognostic models in AP patients. These undermine the validity, reproducibility, and implementation of these prognostic models despite their promise of superior predictive accuracy.

Registration

Research Registry (reviewregistry1727)

by Yen T. N. He, Ha N. H. Pham, Tri C. Nguyen, Trung Q. Bui, Nhu T. Vuong, Diem T. N. Nguyen, Thanh V. Le, Wentao Li, Cam H. Le, Tuong M. Ho, Ben W. Mol, Vinh Q. Dang, Lan N. Vuong

Background

Pregnant women with twins and a short cervical length (CL) are at greater risk of preterm birth (PTB). The comparative efficacy of cervical cerclage and cervical pessary with or without additional progesterone to prevent PTB is unknown. We aimed to assess, in women with twin pregnancies and a short CL, the effectiveness of cerclage versus pessary and the additional treatment with 400 mg vaginal progesterone versus no progesterone in preventing PTB.

Methods and findings

This multicenter, two-by-two factorial randomised trial was conducted in 2 hospitals in Ho Chi Minh City, Vietnam. Asymptomatic women with twin pregnancies and a CL ≤28 mm at 16 to 22 gestational weeks were recruited. Between March 2019 and July 2023, we randomised 219 participants (64.4% of the planned sample size) to cerclage plus progesterone (n = 55), Arabin pessary plus progesterone (n = 56), cerclage alone (n = 54) or Arabin pessary alone (n = 54). Primary outcome was any PTB <34 weeks. Following the second interim analysis, the study was terminated due to significantly lower rates of perinatal deaths and deliveries <28 weeks in the cerclage group. The primary outcome occurred in 20 (19.8%) participants receiving cerclage versus 20 (19%) participants receiving pessary (relative risk [RR] 1.04; 95% confidence interval [CI], 0.60 to 1.8). Delivery <28 weeks occurred in 1% versus 8.6% (RR 0.12; 95% CI, 0.01 to 0.52) and perinatal death occurred in 1% versus 5.8% (RR 0.17; 95% CI, 0.05 to 0.62) in the cerclage group and the pessary group, respectively. However, PTB <24 weeks, <32 weeks, and other neonatal outcomes were not significantly different between the 2 groups. For maternal side effects, vaginal discharge was significantly less frequent in the cerclage group. In participants allocated to progesterone, PTB <34 weeks occurred in 19 (18.4%) versus 21 (20.4%) participants who did not have progesterone (RR 0.90; 95% CI, 0.52 to 1.6).

Conclusions

In this prematurely halted study on pregnant women with twins and a CL ≤28 mm, cerclage and cervical pessary were comparably effective on PTB <34 weeks prevention. However, compared to pessary, cerclage was associated with significantly lower rates of PTB <28 weeks and perinatal mortality.ClinicalTrials.gov Registration: NCT03863613 (https://clinicaltrials.gov/study/NCT03863613)

by Kelly J. Fleetwood, Bruce Guthrie, Caroline A. Jackson, Paul A. T. Kelly, Stewart W. Mercer, Daniel R. Morales, John D. Norrie, Daniel J. Smith, Cathie Sudlow, Regina Prigge

Background

Depression is associated with a range of adverse physical health outcomes. We aimed to quantify the association between depression and the subsequent rate of accrual of long-term physical health conditions in middle and older age.

Methods and findings

We included 172,556 participants from the UK Biobank (UKB) cohort study, aged 40–71 years old at baseline assessment (2006–2010), who had linked primary care data available. Using self-report, primary care, hospital admission, cancer registry, and death records, we ascertained 69 long-term physical health conditions at both UKB baseline assessment and during a mean follow-up of 6.9 years. We used quasi-Poisson models to estimate associations between history of depression at baseline and subsequent rate of physical condition accrual. Within our cohort, 30,770 (17.8%) had a history of depression. Compared to those without depression, participants with depression had more physical conditions at baseline (mean 2.9 [SD 2.3] versus 2.1 [SD 1.9]) and accrued additional physical conditions at a faster rate (mean 0.20 versus 0.16 additional conditions/year during follow-up). After adjustment for age and sex, participants with depression accrued physical morbidities at a faster rate than those without depression (RR 1.32, 95% confidence interval [CI] [1.31, 1.34]). After adjustment for all sociodemographic characteristics, the rate of condition accrual remained higher in those with versus without depression (RR 1.30, 95% CI [1.28, 1.32]). This association attenuated but remained statistically significant after additional adjustment for baseline condition count and social/lifestyle factors (RR 1.10, 95% CI [1.09, 1.12]). The main limitation of this study is healthy volunteer selection bias, which may limit generalisability of findings to the wider population.

Conclusions

Middle-aged and older adults with a history of depression have more long-term physical health conditions at baseline and accrue additional physical conditions at a faster rate than those without a history of depression. Our findings highlight the importance of integrated approaches to managing both mental and physical health outcomes.

by Ally Memedovich, Brian Steele, Taylor Orr, Shanzeh Chaudhry, Mina Tadrous, Aaron S. Kesselheim, Aidan Hollis, Reed F. Beall

Background

The high cost of prescription drugs in the United States is maintained by brand-name manufacturers’ competition-free period made possible in part through patent protection, which generic competitors must challenge to enter the market early. Understanding the predictors of these challenges can inform policy development to encourage timely generic competition. Identifying categories of drugs systematically overlooked by challengers, such as those with low market size, highlights gaps where unchecked patent quality and high prices persist, and can help design policy interventions to help promote timely patient access to generic drugs including enhanced patent scrutiny or incentives for challenges. Our objective was to characterize and assess the extent to which market size and other drug characteristics can predict patent challenges for brand-name drugs.

Methods and findings

This cross-sectional study included new patented small-molecule drugs approved by the FDA from 2007 to 2018. Market size, patent, and patent challenge data came from IQVIA MIDAS pharmaceutical quarterly sales data, the FDA’s Orange Book database, and the FDA’s Paragraph IV list. Predictive models were constructed using random forest and elastic net classification. The primary outcome was the occurrence of a patent challenge within the first year of eligibility. Of the 210 new small-molecule drugs included in the sample, 55% experienced initiation of patent challenge within the first year of eligibility. Market value was the most important predictor variable, with larger markets being more likely to be associated with patent challenges. Drugs in the anti-infective therapeutic class or those with fast-track approval were less likely to be challenged. The limitations of this work arise from the exclusion of variables that were not readily available publicly, will be the target of future research, or were deemed beyond the scope of this project.

Conclusions

Generic competition does not occur with the same timeliness across all drug markets, which can leave granted patents of questionable merit in place and sustain high brand-name drug prices. Predictive models may help direct limited resources for post-grant patent validity review and adjust policy when generic competition is lacking.

by Rebecca F. Grais, Kathleen M. Neuzil, Helen Rees, Cristiana M. Toscano

This Perspective article from Rebecca Grais and colleagues places a recently published study in PLOS Medicine in the context of the evolving landscape of vaccines and pregnancy.

by Rosine Ingabire, Julien Nyombayire, Amelia Mazzei, Jean-Baptiste Mazarati, Jozef Noben, Michael Katwere, Rachel Parker, Sabin Nsanzimana, Kristin M. Wall, Tyronza Sharkey, Felix Sayinzoga, Amanda Tichacek, Niina Hammoud, Ellen Martinson, Ben Magod, Susan Allen, Etienne Karita

Background

Rwandan individuals bordering the Democratic Republic of the Congo (DRC) are at-risk of Ebola virus disease. A 2019 to 2021 vaccination campaign called UMURINZI offered a Janssen Vaccines & Prevention B.V. 2-dose heterologous Ebola vaccine regimen (Ad26.ZEBOV, MVA-BN-Filo) to Rwandan individuals aged ≥2 years and not pregnant. In this region with high rates of pregnancy, preventing pregnancy until their second dose of the Ebola vaccine is essential to ensure full protection. This analysis describes contraceptive use, pregnancy incidence, serious adverse events (SAE), and the effect of pregnancy and SAE on receipt of the second dose among women in the UMURINZI vaccination campaign.

Methods and findings

During the vaccination campaign, women who were fertile and sexually active were counseled as part of the campaign by trained UMURINZI nursing staff about preventing pregnancy until dose two (56 days post-dose one) and offered contraception. Women were followed up to their second dose appointment. Contraception, pregnancy incidence, and SAE were recorded. Of the 47,585 fertile and sexually active women, the mean age was 28·0 years (standard deviation 9·9 years), 54·7% (n = 26,051) were from Rubavu and 45·3% (n = 21,534) were from Rusizi, and 71·9% (n = 34,158) had not crossed the DRC border in the last year. Sixty-six percent (66·6%, n = 31,675) were not using modern contraception at baseline and 19·1% (n = 9,082) were using hormonal implants, 10·9% (n = 5,204) injectables, 2·9% (n = 1,393) oral contraceptive pills (OCPs), and 0·5% (n = 231) intrauterine devices. After contraceptive counseling, 8·0% (n = 2,549) of non-users initiated a method of contraception and 3·6% (n = 50) of OCP users switched to a more effective method. Of the 969 incident pregnancies detected after dose one, 18·8% (n = 182) resulted in an obstetric SAE, primarily due to spontaneous abortion which occurred in 16·0% (n = 155) of all incident pregnancies. Other obstetric SAE included 14 blighted ova, 9 stillbirths, 1 termination due to hydrops fetalis, 1 cleft palate, and 2 threatened abortions resulting in normal deliveries. Six pregnant women had a non-obstetric SAE (0·6%), including 1 postpartum death from COVID-19 and 5 hospitalizations. Among the 74,002 women without an incident pregnancy detected after dose one, 0·01% (n = 4) had an SAE; 2 were fatalities due to hypertension and diabetes in one case and seizures in the other, and the other 2 were hospitalizations. No SAE were determined to be related to the vaccine by the program physicians. Among the 74,002 women without an incident pregnancy detected after dose one, 94·6% (n = 69,986) received dose two; in contrast, among the 969 women with an incident pregnancy detected after dose one, 34·5% (n = 334) received dose two after pregnancy completion.

Conclusions

Many fertile and sexually active women who sought vaccination during UMURINZI were not using contraception prior to vaccination, and contraceptive method uptake after family planning counseling and method provision was low. Most women who became pregnant after the first vaccination dose did not receive the second dose, thus potentially reducing protection against Ebola. Family planning messaging for this context should be developed and pilot-tested. The estimated risk of spontaneous abortion was similar to previous estimates from Rwanda and other African countries.