PLoS Medicine[JOURNAL]
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200 papers
Prognostic value of cervical length for spontaneous preterm birth in asymptomatic women with singleton pregnancy: An individual participant data meta-analysis.
Hughes K, Nguyen D, Aberoumand M … +37 more , Ford H, Clarke E, Banos Lopez N, Dziadosz M, Fischer R, Souza RT, Cecatti JG, Orzechowski K, Olson-Chen C, Peixoto AB, Phupong V, Rosenbloom J, Son M, Souka A, Du L, Esplin MS, Granese R, Gupta S, Kazemier B, Kindinger L, Kuusela P, Van der Ven J, Weitzner O, Minis E, Llobet AF, Frey H, Bagga R, Mishra S, Patberg E, Bennett P, Hall M, Shennan A, Brennecke S, Thangaratinam S, Seidler AL, Mol BW, Wang R
PLoS Med · 2026 Jun · PMID 42228679 · Full text
BACKGROUND: Spontaneous preterm birth (SPTB) is the leading cause of perinatal and early childhood mortality worldwide. Studies have generally suggested that mid-trimester transvaginal sonographic cervical length <25 mm...
BACKGROUND: Spontaneous preterm birth (SPTB) is the leading cause of perinatal and early childhood mortality worldwide. Studies have generally suggested that mid-trimester transvaginal sonographic cervical length <25 mm is an important predictor of SPTB. Aggregate data meta-analyses are limited by data availability and reporting in the primary literature. The purpose of this individual participant data meta-analysis (IPDMA) was to quantify the prognostic value of mid-trimester cervical length for SPTB in asymptomatic women with singleton pregnancy, and to assess other factors which may modify this association. METHODS AND FINDINGS: The project was prospectively registered with PROSPERO (CRD42020146987). We searched Medline, Embase, CINAHL, LILACS, Database of Abstracts of Reviews of Effects (DARE), Cochrane database, JBI Database of Systematic Reviews, ClinicalTrials.gov, and Google Scholar. We included cohort studies and non-treatment arms of randomized controlled trials which assessed an association between mid-trimester transvaginal sonographic cervical length and SPTB in asymptomatic women with singleton pregnancy. The search was performed on 30/9/2020, with an update performed on 4/11/2025. The primary outcome was STPB <37 weeks. Two reviewers screened all studies for inclusion and performed risk of bias assessments using QUIPS. We performed a two-stage IPDMA in a logistic regression model using cervical length as a continuous variable (the primary analysis) with restricted cubic splines to explore non-linear associations. IPD of 27 eligible studies were obtained and included (n = 91,404). Mean cervical length was 40 mm (standard deviation [SD] 9 mm) at about 20 weeks' gestation. SPTB <37 weeks occurred in 4,442 (5.2%) participants. An L-shape non-linear association between cervical length and SPTB was observed. A longer cervical length was associated with steeply lower odds of SPTB until it reached 40 mm, beyond which the odds of SPTB became stable. This means that compared to a woman with a cervical length of 40 mm, those with a cervical length of 20 and 30 mm were associated 6.22 and 2.10 higher odds of SPTB (95% confidence intervals [4.76, 8.13] and [1.85, 2.38]), respectively. Limitations included suboptimal data retrieval rate (51% of all eligible participants) and a lack of comprehensive co-predictors of SPTB across all datasets. CONCLUSION: We found a non-linear association between cervical length and SPTB. We found a non-linear association between cervical length and SPTB. Shorter cervix is associated with progressively higher risk of SPTB when length is less than 40 mm, but probability of term birth is high when cervical length is over 40 mm.
Plasma proteomic signatures of early retinal neurodegeneration in diabetes: A multi-cohort study.
Li H, Zhu Z, Yang S … +8 more , Cheng W, Tan S, Xin Z, Zhang L, Zhu Z, Chen S, Huang W, Wang W
PLoS Med · 2026 Jun · PMID 42228639 · Full text
BACKGROUND: Retinal neurodegeneration is an early and independent feature of diabetic retinal disease and has been proposed as a window into the systemic neural consequences of diabetes, yet accessible molecular biomarke...
BACKGROUND: Retinal neurodegeneration is an early and independent feature of diabetic retinal disease and has been proposed as a window into the systemic neural consequences of diabetes, yet accessible molecular biomarkers and individualized prediction tools remain scarce. We aimed to identify circulating plasma protein signatures of diabetic retinal neurodegeneration (DRN) and to translate them into a clinically usable risk prediction system. METHODS AND FINDINGS: In this multi-cohort prospective observational study, we integrated high-throughput plasma proteomics with longitudinal optical coherence tomography (OCT) in two independent populations. The discovery cohort comprised 1,492 participants had baseline plasma proteomics and OCT, and 1,218 were followed with repeated OCT over 6 years in Guangzhou Diabetic Eye Study (GDES). DRN was quantified by the annualized OCT-derived retinal nerve fiber layer thinning rate. In multivariable analyses adjusted for age, sex, smoking, systolic blood pressure, HbA1c, and diabetes duration, we identified 71 plasma proteins associated with development and progression of DRN. These proteins mapped onto pathways governing inflammatory immune recruitment, extracellular matrix remodeling, and microvascular homeostasis, providing a plausible biological basis for DRN. We developed a proteomics-based DRN model (Pro-DRN) using eight machine learning (ML) algorithms, including XGBoost and LightGBM. In the independent test set, Pro-DRN achieved a C-index of 0.860, rising to 0.908 when integrated with clinical variables. Compared with six conventional models, Pro-DRN improved discrimination (ΔC-index 0.137 to 0.159; all P < 0.001), reclassification (IDI 0.212 to 0.245; NRI 0.226 to 0.452; all P < 0.05). In the Hippisley model, the C-index increased from 0.739 (95% CI [0.670, 0.808]) to 0.898 (95% CI [0.858, 0.937]), with IDI 0.245 (95% CI [0.177, 0.318]), NRI 0.452 (95% CI [0.222, 0.673]) (both P < 0.001), and higher net benefit. The proteins most consistently driving model performance included ACTA2, COL6A3, and HSPG2. For clinical translation, we deployed the locked model as an interactive, web-based risk-assessment tool to support early DRN screening and longitudinal monitoring. Cross-ethnic external validation in UK Biobank (n = 502; recruited 2006-2010) reproduced core protein signals and consistent effect directions, confirming robustness across populations. Principal methodological limitation lies in single time point proteomic assessment. CONCLUSION: In this multi-cohort study, we present a proteomics- and ML-based precision prediction system for DRN. Pro-DRN substantially enhanced early risk stratification beyond conventional clinical factors and may support targeted screening and timely neuroprotective interventions, advancing molecularly guided strategies for diabetic eye disease prevention.
Prenatal exposure to asthma medications and risk of neurodevelopmental disorders and educational difficulties: A systematic review and meta-analysis.
Shakhshir LA, Karain A, Pell JP … +3 more , Hastie CE, Nelson SM, Fleming M
PLoS Med · 2026 Jun · PMID 42224295 · Full text
BACKGROUND: Since asthma exacerbations during pregnancy risk maternal and fetal health, continued medication is important. However, some studies have reported adverse neurodevelopmental outcomes following prenatal exposu...
BACKGROUND: Since asthma exacerbations during pregnancy risk maternal and fetal health, continued medication is important. However, some studies have reported adverse neurodevelopmental outcomes following prenatal exposure to asthma medication. Therefore, this systematic review aimed to collate the existing evidence on the associations between prenatal exposure to asthma medication and neurodevelopmental and educational outcomes. METHODS AND FINDINGS: A systematic review was conducted in accordance with PRISMA guidelines and the PECO framework. PubMed, Medline and Embase databases were searched for studies investigating prenatal exposure to one or more asthma medication and neurodevelopmental or educational outcomes published, in English, between January 2003 and September 2024, and updated in November 2025. Studies of asthma medication used for other indications were excluded. Study quality was assessed using the Newcastle-Ottawa scale. Random-effects meta-analyses were conducted where appropriate and heterogeneity was evaluated using Cochran's Q and I2 tests. Of 16,824 studies identified by the initial search, seven were eligible for inclusion. All investigated beta-2-adrenergic agonists (B2AA), with one including B2AA as mono- and polytherapy-and one study also investigated inhaled corticosteroids (ICS) exposure. Two reported associations with autism spectrum disorder (ASD) and one with attention-deficit hyperactivity disorder (ADHD). An updated search identified one additional eligible study, which examined both ADHD and ASD, as well as other neurodevelopmental disorders. The included eight studies (n = 3,867,170 participants) comprised cohort (n = 5) and case-control (n = 3) designs and reported inconsistent results. Meta-analysis of three studies (n = 1,380,871) indicated significant associations with ASD for exposure to B2AA both preconception (aOR 1.34, 95% CI [1.19,1.52]) and during pregnancy (aOR 1.29, 95% CI [1.16,1.42]). Heterogeneity was low, with no evidence of significant publication bias. Limitations of the included studies comprised residual confounding and exposure misclassification. Additionally, studies included in the meta-analysis were few in number and did not adequately distinguish between medication effects and underlying maternal asthma. CONCLUSION: Meta-analysis suggested an association between prenatal exposure to B2AA and ASD. An association with ADHD, reported in a single study, requires corroboration. To date, based on our search strategy, no association has been reported with communication skills, motor skills, problem-solving and personal-social skills, or cerebral palsy.
The NIH 2025 Public Access Policy: Immediate access, unequal costs.
Ryus CR, Raymond King C, Melnick ER
PLoS Med · 2026 Jun · PMID 42224272 · Full text
The NIH 2025 Public Access Policy eliminates embargo periods for federally funded research, expanding who can read science. Yet without addressing article processing charges and market concentration, the policy risks cre...
The NIH 2025 Public Access Policy eliminates embargo periods for federally funded research, expanding who can read science. Yet without addressing article processing charges and market concentration, the policy risks creating new barriers to who can afford to perform and publish their science.
Availability, appeal, and addictiveness by design: Tobacco and nicotine industry deliberate targeting of youth.
Maddox R, Freeman B, Pisinger C … +1 more , Banks E
PLoS Med · 2026 May · PMID 42213812 · Full text
Contemporary tobacco and nicotine products, particularly e-cigarettes, are deliberately designed, marketed, and distributed to maximize youth appeal, uptake, dependence, and use. Youth uptake is a predictable outcome of...
Contemporary tobacco and nicotine products, particularly e-cigarettes, are deliberately designed, marketed, and distributed to maximize youth appeal, uptake, dependence, and use. Youth uptake is a predictable outcome of systems designed to maximize product availability, appeal, and addictiveness.
Characterization of the VHH-Fc construct rimteravimab in healthy adults and patients hospitalized for mild-to-moderate COVID-19: Two Phase 1 randomized clinical trials.
Jansen E, Bockstal V, Herschke F … +7 more , Olsson Gisleskog P, Rinaldi M, Boerboom A, Hadi S, Gaibu N, Moutschen M, Tersago D
PLoS Med · 2026 May · PMID 42213671 · Full text
BACKGROUND: Variable Heavy domain of Heavy chains (VHH) are innovative tools to target unique epitopes, yet few have been developed as heavy chain-only antibodies for clinical use. Rimteravimab (referred to here as XVR01...
BACKGROUND: Variable Heavy domain of Heavy chains (VHH) are innovative tools to target unique epitopes, yet few have been developed as heavy chain-only antibodies for clinical use. Rimteravimab (referred to here as XVR011) is a humanized antibody developed for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19), consisting of two identical VHHs targeting the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike, with a human immunoglobulin (Ig) G1 fragment constant of antibody (Fc), silenced for Fc effector functions. We conducted two Phase 1 studies in healthy volunteers or hospitalized COVID-19 patients to evaluate its safety, tolerability, pharmacokinetics and immunogenicity. METHODS AND FINDINGS: A randomized, double-blinded, single-center, placebo-controlled, single ascending dose study was performed in healthy volunteers (Phase 1a, EXEVIR0102, EudraCT 2021-003707-17), in parallel to an open-label, multi-center, single ascending dose study in patients hospitalized for mild to moderate COVID-19 (Phase 1b, EXEVIR0101, EudraCT 2020-005299-36, NCT04884295). Participants received a single intravenous infusion of 250, 500 or 1,000 mg of XVR011. The primary objective for both trials was the safety and tolerability of XVR011. Pharmacokinetics were evaluated as a secondary objective in Phase 1a and as an exploratory objective in Phase 1b. Efficacy (evaluated as respiratory parameters and COVID-19 clinical status) and antiviral activity in patients were evaluated as a secondary objective in Phase 1b. Immunogenicity was evaluated as an exploratory objective. Part 2 of the EXEVIR0101 study (initially a phase 1b/2 study) was not conducted due to the loss of XVR011 potency against SARS-CoV-2 Omicron BA.2. Demographics, safety, efficacy, and immunogenicity were analyzed using descriptive statistics, while pharmacokinetics were analyzed with noncompartmental pharmacokinetics (PK) modeling. In the Phase 1a study, there were no infusion-related reactions, serious treatment-emergent adverse events (TEAEs) or TEAEs grade ≥3. 22/30 volunteers (73.3%) reported 53 TEAEs (49 Grade 1, 4 Grade 2) with none being related to XVR011. The most common TEAE was headache (n = 8, 26.7%) in various treatment groups. In the Phase 1b study, 27 hospitalized patients were enrolled, and followed up to 30 days. Seven patients (25.9%) reported a total of 15 TEAEs, the majority (80%) being mild to moderate (Grade 1-2). There were no treatment-related serious TEAEs. All TEAEs resolved by the end of the study. Peak exposure (maximal concentration, Cmax) and systemic exposure (area under the curve, AUC0-t, and AUC0-inf) for XVR011 increased dose-proportionally. Geomean half-life ranged from 15.4 to 17.0 days in Phase 1a, while individual half-life ranged from 11.4 to 15.6 days in Phase 1b. SARS-CoV-2 viral load, as detected in nasopharyngeal samples by reverse transcription and quantitative polymerase chain reaction (RT-qPCR), decreased similarly in all cohorts compared to baseline. No treatment-induced anti-drug antibodies (ADA) were detected in Phase 1a. In Phase 1b, higher XVR011 concentrations increased the likelihood of ADA formation, without impacting pharmacokinetics and pharmacodynamics. No obvious dose-response in COVID-19 clinical status or respiratory parameters was observed. Technological limitations included study size, absence of placebo for the Phase 1b, absence of repeated dosing, evolving SARS-CoV-2 variants and standard-of-care. CONCLUSIONS: XVR011 displayed a favourable safety, tolerability, pharmacokinetics, and immunogenicity profile, both in healthy volunteers and in patients hospitalized for mild to moderate COVID-19. These data pave the way for the design and clinical development of VHH-Fc constructs.
Sequential chemo-immunotherapy followed by standard versus reduced thoracic radiotherapy for older and/or frail stage III non-small-cell lung cancer: A randomized open-label cohort trial.
Qi WX, Li S, Wang M … +12 more , Li H, Xu F, Yao L, Yu B, Chen L, Cai G, Xu C, Sun X, Bao Z, Chen J, Xiang Y, Zhao S
PLoS Med · 2026 May · PMID 42201929 · Full text
BACKGROUND: The appropriateness of concurrent chemoradiotherapy (cCRT) for older or clinically vulnerable stage III unresectable non-small-cell lung cancer (NSCLC) patients remains contentious. Furthermore, the survival...
BACKGROUND: The appropriateness of concurrent chemoradiotherapy (cCRT) for older or clinically vulnerable stage III unresectable non-small-cell lung cancer (NSCLC) patients remains contentious. Furthermore, the survival implications of de-escalating thoracic radiotherapy (RT) intensity in this population have not been conclusively elucidated. METHODS AND FINDINGS: We conducted a phase II randomized, open-label, two-cohort (non-comparative) trial at a tertiary hospital in China (NCT05557552). Between September 30, 2022 and April 30, 2024, we enrolled 56 older and/or frail patients with stage III NSCLC who were ineligible for cCRT. The primary endpoint was the 1-year progression-free survival (PFS) rate estimated using the Kaplan-Meier method. Secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. In the intention-to-treat (ITT) set, which included all 56 randomized patients who received at least one dose of study treatment, the 1-year PFS was 84.3% (95% confidence interval [CI] [70.3%, 98.3%]) in the standard RT group and 70.7% (95% CI [54.3%, 87.1%]) in the reduced RT group. In the per-protocol set (53 patients), the 1-year PFS was 82.9% (95% CI [68.9%, 98.8%]) in the standard RT group and 73.4% (95% CI [58.3%, 92.4%]), with a median follow-up of 24 months. Among 56 patients in the safety analysis set, 71.4% of patients experienced grade 3/4 adverse events (AEs) in the standard RT group and 53.6% in the reduced RT group. One patient (3.6%) in the reduced RT and three patients (10.7%) in the standardized RT experienced grade 5 AEs. The main limitations are the non-comparative design, small sample size, and lack of power to establish non-inferiority or superiority. CONCLUSION: The current study suggested that reduced RT combined with sequential chemo-immunotherapy might be feasible for older/frail patients intolerant to cCRT, showing numerically similar survival outcomes. These exploratory findings warrant confirmation in larger, adequately powered randomized trials. TRIAL REGISTRATION: The trial had been registered on ClinicalTrials.gov on Sep 30, 2022. ClinicalTrials.gov NCT05557552.
Requiring code sharing to strengthen transparency and trust in research.
Lumbard H, Cadwallader L, Soper D … +1 more , PLOS Medicine Staff Editors
PLoS Med · 2026 May · PMID 42189815 · Full text
PLOS Medicine has always championed open science and data transparency. Now, recognizing that code is as essential a research artifact as the data it analyzes, we are strengthening our code sharing policy to further ensu...
PLOS Medicine has always championed open science and data transparency. Now, recognizing that code is as essential a research artifact as the data it analyzes, we are strengthening our code sharing policy to further ensure reproducibility and trust in the scientific record.
Differences in tuberculosis prevalence by sex in low- and middle-income countries over 1993-2025: A systematic review and meta-analysis.
Swartwood NA, Singh N, Mortazavi SA … +6 more , Can MH, Cui H, Ryuk DK, MacPherson P, Horton KC, Menzies NA
PLoS Med · 2026 May · PMID 42172294 · Full text
BACKGROUND: Global and national initiatives to combat tuberculosis (TB) have expanded over recent years. Despite this, the TB burden remains high in some population groups, with men recognized as having elevated TB risks...
BACKGROUND: Global and national initiatives to combat tuberculosis (TB) have expanded over recent years. Despite this, the TB burden remains high in some population groups, with men recognized as having elevated TB risks. Summary measures of sex differences in TB prevalence were last estimated in 2016. Since then, many additional prevalence surveys have been conducted, including in the highest TB burden countries. We conducted a systematic review of sex-stratified TB prevalence survey data published over 1993-2025, to provide updated estimates of male-to-female (M:F) TB prevalence ratios and determine whether sex-related disparities in TB burden have closed over time. METHODS AND FINDINGS: We identified surveys reporting community-representative, sex-stratified estimates of pulmonary TB prevalence in low- and middle-income countries (LMICs), including surveys from an earlier review (covering January 1993-March 2016) and a new systematic review (covering 1st December 2015-13th October 2025). This review was prospectively registered with PROSPERO (CRD42024503853) and included searches of PubMed, Embase, Global Health, the Cochrane Library, Africa Index Medicus, LILACS, and SciELO. We extracted data on bacteriologically confirmed and smear-positive TB prevalence among adults (aged ≥ 15 years), stratified by sex. Risk of bias was evaluated using eight criteria specific to prevalence surveys. We fit multi-level Bayesian regression models with study- and country-level random effects to estimate the M:F ratio of TB prevalence (male prevalence divided by female prevalence), overall and for key subgroups. In meta-regression analyses, we estimated how prevalence ratios varied over time and according to known TB risk factors and TB case definitions. We identified 10,124 publications and extracted data from 100 eligible studies representing 102 unique prevalence surveys and 4,658,310 participants (45.6% male) in 33 LMICs. TB prevalence was higher in men than women in 90/102 of the included surveys, with a pooled M:F prevalence ratio of 2.02 (95% credible interval (CrI): 1.71, 2.34) for bacteriologically confirmed TB and 2.38 (95% CrI: 1.91, 2.90) for smear-positive TB. Time trend analyses showed a 2.0% (95% CrI: -0.2, 4.5%) average annual change in the M:F ratio of bacteriologically confirmed TB over the study period. The M:F prevalence ratio was estimated to be higher for countries with greater excess HIV prevalence among men, and countries with greater gender equity (as measured by the United Nation's Gender Development Index). The estimated M:F prevalence ratio was also higher for surveys that did not restrict testing to individuals reporting TB symptoms. Study limitations include heterogeneity in survey methods and definitions, as well as limited data from the Americas, Eastern Mediterranean, and Europe WHO world regions and post-COVID-19 period. CONCLUSIONS: Men in LMICs consistently experience TB at a higher prevalence than women. Time trend estimates are uncertain, but consistent with widening sex differences in TB prevalence over the last three decades, despite efforts to address the risk factors underlying this excess TB burden.
U = U for all: Advancing equity in HIV prevention.
Torres TS, Luz PM
PLoS Med · 2026 May · PMID 42166695 · Full text
Suppression of HIV with antiretrovirals eliminates HIV transmission risk, summarized as Undetectable = Untransmittable (U = U). However, U = U literacy remains unevenly understood and shared, and stigmas persist. Equitab...
Suppression of HIV with antiretrovirals eliminates HIV transmission risk, summarized as Undetectable = Untransmittable (U = U). However, U = U literacy remains unevenly understood and shared, and stigmas persist. Equitable and accurate awareness of U = U requires culturally tailored interventions, improved provider education, and supportive policy environments beyond biomedical evidence alone.
Novel symptoms associated with eclampsia could improve detection and save lives.
Beardmore-Gray A, Shennan A
PLoS Med · 2026 May · PMID 42166530 · Full text
Eclampsia is a life-threatening complication of pre-eclampsia, yet remains difficult to predict. In this Perspective, Alice Beardmore-Gray and Andrew Shennan highlight a recent study that identifies 10 novel prodromal sy...
Eclampsia is a life-threatening complication of pre-eclampsia, yet remains difficult to predict. In this Perspective, Alice Beardmore-Gray and Andrew Shennan highlight a recent study that identifies 10 novel prodromal symptoms of eclampsia, with potential to better predict which women are at risk and therefore reduce delays in intervention.
Semaglutide-associated risk of nonarteritic anterior ischemic optic neuropathy in patients with type 2 diabetes: A systematic review and meta-analysis of observational studies.
Chrzanowski J, Walicka M, Burzyński J … +3 more , Zaraś M, Michalak A, Fendler W
PLoS Med · 2026 May · PMID 42166479 · Full text
BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, is widely used for the management of type 2 diabetes (T2DM). Recent case reports have raised concerns about a potential association between semaglutide...
BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, is widely used for the management of type 2 diabetes (T2DM). Recent case reports have raised concerns about a potential association between semaglutide use and the development of nonarteritic anterior ischemic optic neuropathy (NAION), a rare but vision-threatening condition. We aimed to evaluate whether semaglutide use is associated with an increased risk of NAION in patients with T2DM. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of observational studies comparing patients with T2DM aged ≥12 years treated with semaglutide to those receiving other glucose-lowering therapies. We searched PubMed, Scopus, and Web of Science databases from January 2023 to November 2025. Two reviewers independently extracted data on study design, population characteristics, and outcomes. Risk of bias was assessed using the Newcastle-Ottawa Scale, and ROBINS-I v.2. Certainty of the evidence was graded according to the GRADE framework. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using fixed-effects models; sensitivity analyses included crude and subgroup HRs, and overlapping study replacement. Leave-one-out analysis was conducted to assess small-study effects and publication bias. Results were contextualized within other meta-analyses, systematic reviews, consensus statements, and regulatory communications on the topic. Five eligible observational studies met the inclusion criteria, and 7 additional studies were included in the sensitivity analysis. Semaglutide use was associated with a significantly increased hazard of NAION compared with nonsemaglutide glucose-lowering regimens (HR 2.17, 95% CI [1.73, 2.74]; p < 0.001), regimens excluding other GLP-1 receptor agonists (HR 2.13, 95% CI [1.60, 2.83]; p < 0.001), and sodium-glucose co-transporter 2 inhibitor (SGLT2i) users (HR 1.96, 95% CI [1.28, 2.99]; p = 0.002). Despite the increased relative risk, the absolute risk remained low at 0.014% (95% CI [0.005%, 0.023%]; p = 0.002), corresponding to approximately 1 additional case of NAION per 7,000 semaglutide-treated patients annually. The results were consistent with meta-analyses of observational studies and corroborated decisions presented in regulatory communications. Due to exclusive focus on retrospective, registry-based observational studies, the evidence synthesis was limited and could be biased by study-level outcome misclassification and confounding. CONCLUSIONS: Our findings suggest a possible association between semaglutide use and an increased risk of NAION in patients with T2DM. Although the absolute risk is low, clinicians should be aware of this potential adverse event, particularly in individuals at increased baseline risk for optic neuropathies. While these findings support current recommendations to discontinue semaglutide in patients diagnosed with NAION, the certainty of the available evidence is low, underscoring the need for further high-quality studies to clarify this association.
Associations between hematologic dynamics during pregnancy and obstetric complications: A retrospective observational study.
Tozzo V, Petherbridge R, James K … +13 more , Hsu S, Pant D, Michalopoulos C, Foy BH, Thaweethai T, Mow C, Maya J, Camero CB, Shook L, Gray KJ, Mauney L, Higgins JM, Powe CE
PLoS Med · 2026 May · PMID 42160455 · Full text
BACKGROUND: Pregnancy alters hematologic state as measured by complete blood count (CBC), but the longitudinal changes in CBC indices that define healthy pregnancies are not well established. In a large cohort based at a...
BACKGROUND: Pregnancy alters hematologic state as measured by complete blood count (CBC), but the longitudinal changes in CBC indices that define healthy pregnancies are not well established. In a large cohort based at an academic health system in the United States, we aimed to define reference intervals and typical longitudinal changes in CBC indices during pregnancy. We then tested for associations between extreme CBC values for gestational age or extreme longitudinal changes in CBC indices and obstetric complications. METHODS AND FINDINGS: We studied nine CBC indices in individuals with singleton pregnancies who delivered after 30 weeks' gestation and presented for prenatal care prior to 20 weeks. The electronic health record (EHR)-based Maternal Health Cohort (Massachusetts General Hospital; 1998-2016) formed our discovery cohort of 45,992 pregnancies, 18% of which had relevant complications. We developed a validation cohort of 48,868, 27% with complications from EHR data in the Mass General Brigham healthcare system from 2016 to 2024. In pregnancies without complications in the discovery cohort, we derived gestational-age-specific reference intervals (2.5th-97.5th percentile) and established typical intra-pregnancy longitudinal changes. In the validation cohort, we then tested CBC values outside of the 26-29 weeks' gestation reference interval and CBC rare changes (uncommon changes in magnitude and direction) between 7-14 and 26-29 weeks' gestation for association with a composite outcome (hypertensive disorders of pregnancy, small for gestational age birthweight, preterm birth) and its individual components using generalized estimating equations. Derived reference intervals differed from those in the literature for mean red cell volume, mean red cell hemoglobin, red cell count, and mean red cell hemoglobin concentration; reference intervals for other indices were similar to those previously published. In validation, hematocrit, hemoglobin, and red cell count values above their gestational-age specific reference intervals were associated with increased risk of the composite obstetric outcome: odds ratios (ORs) of 1.4 (95% CI [1.2, 1.5] p < 0.0001) for hematocrit; 1.6 (95% CI [1.4, 1.8] p < 0.0001) for hemoglobin; and 1.6 (95% CI [1.4, 1.7] p < 0.0001) for red cell count. Uncommon increases in hemoglobin (>0.67 g/dL) or red cell count (>0.07 106/mm3) between 7-14 weeks' and 26-29 weeks' gestation were associated with increased risk for preterm birth, OR for hemoglobin 1.9 (95% CI [1.5, 2.5] p < 0.0001) and red cell count 2.1 (95% CI [1.7, 2.6] p < 0.0001). Limitations include the retrospective nature of the study and the exclusion of pregnancies without prenatal care prior to 20 weeks' and pregnancies delivered before 29 weeks' gestation. CONCLUSIONS: Elevated red blood cell-related measurements and unusually large intra-pregnancy increases in those measures are associated with subsequent obstetric complications.
Prescribed hormonal contraceptive use trends in the Estonian Biobank: A longitudinal observational study.
Džigurski J, Möls M, Läll K … +6 more , Currant H, Eltermaa M, Estonian Biobank Research Team, Mägi R, Milani L, Laisk T
PLoS Med · 2026 May · PMID 42160370 · Full text
BACKGROUND: Hormonal contraceptives (HCs) are widely used and have well-documented population-level statistics. Previous studies with short follow-ups have focussed on individual HC use and side effects. However, the sam...
BACKGROUND: Hormonal contraceptives (HCs) are widely used and have well-documented population-level statistics. Previous studies with short follow-ups have focussed on individual HC use and side effects. However, the same aspects over longer periods, HC formulation switching, and the impact of genetic factors on HC side effects remain understudied due to the limited availability of suitable datasets. We investigated whether the Estonian Biobank (EstBB) is suitable for studying genetic risk for HC side effects. METHODS AND FINDINGS: This is a longitudinal descriptive study combining prescribed HC purchase data collected from 2004 to 2022 with genetic and health data from 73,071 female EstBB HC users aged 15-55 at the time of purchase. HC usage was defined by the Anatomical Therapeutic Chemical (ATC) codes G02B, G03A, and G03HB01. Methods included calculating age-stratified annual user prevalence, inferring usage periods from purchases, assessing formulation switching, identifying the International Classification of Diseases, Tenth Revision (ICD-10)-based side effect-related diagnoses and thromboembolism risk factors, and assessing carrier status for Factor V Leiden (FVL, rs6025) and prothrombin G20210A (PTM, rs1799963) genetic variants as proof-of-concept. Over 19 years, 20 HC formulations with five administration routes (oral pills, transdermal patches, vaginal rings, subdermal implants, intrauterine devices) were used. In the EstBB, combined HCs were the most commonly used among users aged 15-29, while progestin-only HC use increased with age and over time, comparable to the Estonian population. Overall, 64.2% (n = 46,920) of users switched formulations at least once, with 17.7% (n = 12,929) being rapid switchers. Side effect-related diagnoses were observed in 23.1% (n = 2,982) of rapid switchers, with excessive/irregular menstrual bleeding being the most common. Genetic analysis revealed that 5.3% (n = 3,886) of users carried at least one variant previously associated with increased thrombosis risk (3.5% (n = 2,556) carried FVL only, 1.8% (n = 1,276) PTM only, and 0.07% (n = 54) both). Carriers of thrombosis-associated variants had a significantly higher percentage of thrombosis (6.5%) than non-carriers (4.2%; OR = 1.61, 95% CI [1.40, 1.84], p < 0.001). The study is limited by the use of administrative medication purchase records, which may not reflect actual HC use. Additionally, diagnoses identified near the HC usage period may not represent true side effects. CONCLUSIONS: This study provides insights into real-world HC usage with longitudinal, individual-level detail that is not available in population-level statistics. We show that EstBB has a robust dataset for studying the impact of genetic factors on HC side effects and disease risk. The identified HC user profiles offer a framework for genetic analyses of HC rapid switching and discontinuation. Our approach can be replicated in other biobanks to validate findings across populations.
Brain morphology in Anorexia Nervosa and its subtypes: A multi-cohort study of individual participant data.
Bernardoni F, Arold D, Schoppik L … +33 more , Bahnsen K, Ge R, Moreau C, Bang L, D'Agata F, Abbate-Daga G, Tamnes CK, Campbell I, O'Daly O, Schmidt U, Frank G, Horndasch S, Hess A, Dörfler A, Friederich HC, Simon J, Favaro A, Lavagnino L, Wierenga CE, Bischoff-Grethe A, Miles AE, Kaplan A, Voineskos A, Smeets PAM, van Elburg AA, Danner U, Thomopoulos SI, Berner L, Jahanshad N, Frangou S, King JA, Thompson P, Ehrlich S
PLoS Med · 2026 May · PMID 42160333 · Full text
BACKGROUND: In a recent coordinated meta-analysis of neuroimaging data, we reported gray matter (GM) alterations in acutely underweight patients with anorexia nervosa (AN). Here, we extend these findings by examining ind...
BACKGROUND: In a recent coordinated meta-analysis of neuroimaging data, we reported gray matter (GM) alterations in acutely underweight patients with anorexia nervosa (AN). Here, we extend these findings by examining individual variation in brain structure within AN, individual-level differentiation between AN and healthy controls (HC), and differences between AN subtypes, with potential relevance for understanding clinical heterogeneity. METHODS AND FINDINGS: We analyzed individual-level data from 11 international sites in the ENIGMA Eating Disorders Working Group, including 570 female participants with AN and 739 HC. We examined cortical thickness, cortical surface area and subcortical volumes in AN versus HC using three complementary approaches: (i) group-level differences in a mega-analysis correcting for age effects, (ii) frequencies of extreme deviations (infra-/supranormal; z < -1.96/z > 1.96) based on normative reference models by the CentileBrain Initiative, and (iii) individual-level classification performance using machine learning. The same analytic framework was applied to compare AN restricting versus binge-eating/purging subtype, additionally correcting for BMI effects. Mega-analyses reinforced previous meta-analytic findings of pronounced and widespread GM deficits in AN compared to HC. Normative modelling revealed that the frequency of infranormal z-scores (23/68 cortical thickness, 13/14 subcortical volume metrics) and supranormal z-scores (35/68 cortical thickness, 17/68 cortical surface area metrics) was significantly higher in AN than expected based on reference data. Individuals with AN could be reliably differentiated from HC using machine-learning classifiers (ROC-AUC = 0.75-0.81). In contrast, neither group-level differences nor frequency of extreme z-scores differed between AN subtypes, and individuals with different subtypes could not be reliably differentiated from each other. Importantly, the observational design cannot distinguish neurobiological differences related to AN from the effects of starvation or low BMI in the AN versus HC analyses. The lack of differences between subtypes does not exclude brain structural differences between AN subtypes that might be detectable with other modalities or analytic approaches. CONCLUSION: Using a mega-analytic approach, we confirm widespread GM deficits in AN, show that these alterations are (in some patients) extreme, and demonstrate that they enable robust classification with superior performance compared to most MRI-based psychiatric classification studies. The absence of differences between AN subtypes may reflect shared neurobiology, though other imaging modalities may reveal distinctions beyond brain structure.
Spatial transcriptomic-metabolic features of tumor foci and tumor capsule in microvascular invasion with hepatocellular carcinoma: A spatial multi-omics study.
Luo ZH, Wang N, Zhao J … +10 more , Long F, Wu S, Zhong W, Chen WM, Wang B, Wang K, Yuan Y, Zhou J, Yuan C, Wang F
PLoS Med · 2026 May · PMID 42139279 · Full text
BACKGROUND: Microvascular invasion (MVI) is closely related to the recurrence and metastasis of hepatocellular carcinoma (HCC), but the underlying cellular mechanism remains largely elusive. This study aims to elucidate...
BACKGROUND: Microvascular invasion (MVI) is closely related to the recurrence and metastasis of hepatocellular carcinoma (HCC), but the underlying cellular mechanism remains largely elusive. This study aims to elucidate the regional cellular discrepancy between MVI-positive (MVI+) and MVI-negative (MVI-) HCC by integrating Spatial transcriptomics (ST) and spatial metabolomics (SM). METHODS AND FINDINGS: ST and SM were performed on six tissue samples from four patients (including 2 MVI+, 2 MVI-, and 2 paratumor tissues), with the integration of 79 public single-cell RNA sequencing datasets of HCC. Patient identity was used as a covariate in the linear equation for regional differentially expressed gene analysis with the ST data. Clinical validation was conducted through multiplex immunofluorescence staining in 79 patients, together with external validation in the cancer genome atlas (TCGA)-liver hepatocellular carcinoma (LIHC) cohort (n = 299) and an independent microarray dataset (n = 62). For cell-type-specific metabolic profiling, spatial transcriptomic-metabolic registration was performed. The functional roles of key metabolites were further validated in vitro using inflammatory cancer-associated fibroblasts (iCAFs) derived from hepatic stellate cells (HSCs) and primary CAFs through co-culture models and various functional assays assessing cell proliferation, migration, and invasion. In the tumor lesion, a malignant STMN1+HMGN2+GPC3+ cell subtype enriched in MVI+ HCC was identified, which exhibited enhanced proliferative activity and was associated with poor prognosis. This finding was further confirmed in a local cohort of 79 patients, where multiplex immunofluorescence staining for the three genes (STMN1, HMGN2, and GPC3) showed significantly higher expression in the MVI+ group than in the MVI- group (p = 0.046). Integrated SM analysis further revealed that this cell population underwent metabolic reprogramming characterized by suppressed glycerolipid metabolism. In the tumor capsule, iCAFs-related genes were downregulated in MVI+ cases, and iCAFs were located distally from the tumor boundary. Spatial metabolite mapping showed a strong correlation between taurine and iCAFs, and functional assays demonstrated that taurine promotes HCC proliferation and migration by suppressing iCAF activity. One limitation of this study is the small sample size of spatial omics data, which hinders a more complete molecular functional analysis of the STMN1+HMGN2+GPC3+ cell subtype and iCAFs in MVI+ HCC. Larger-scale ST cohorts are required to further validate and expand the findings of this study. CONCLUSIONS: This integrative spatial atlas proposes a hypothesis that there exists a highly proliferative and metabolically reprogrammed malignant cell subtype in the tumor lesion of MVI+ HCC, and that taurine in the tumor capsule modulates iCAF activity to influence tumor progression. The exploratory results provide mechanistic insights into MVI-related HCC progression and offer potential avenues for targeted therapeutic intervention of MVI+ HCC.
Antibody fine specificity correlates with protection from malaria for the RTS,S vaccine in young African children: A post hoc analysis of a phase IIb randomised controlled trial.
Hysa A, Opi DH, Waterhouse J … +11 more , Chishimba S, Horton JL, Kingston N, Netter HJ, Wetzel D, Piontek M, Feng G, Sacarlal J, Dobaño C, Kurtovic L, Beeson JG
PLoS Med · 2026 May · PMID 42133737 · Full text
BACKGROUND: The RTS,S/AS01 malaria vaccine was recently approved for implementation in children, but only provides modest and short-lived efficacy against malaria. RTS,S targets a portion of the Plasmodium falciparum (Pf...
BACKGROUND: The RTS,S/AS01 malaria vaccine was recently approved for implementation in children, but only provides modest and short-lived efficacy against malaria. RTS,S targets a portion of the Plasmodium falciparum (Pf) circumsporozoite protein (CSP), comprising the central NANP-repeat region and C-terminal domain. Mechanisms of immunity and correlates of protection for the RTS,S vaccine are not well defined, hindering progress towards generating highly effective CSP-based vaccines. METHODS AND FINDINGS: We investigated epitope specificity and cross-reactivity of vaccine-induced antibodies to six peptides representing CSP epitopes in the N-terminal and central NANP-repeat region. We evaluated antibody reactivity in preclinical mouse vaccine studies, among CSP-specific monoclonal antibodies (mAbs), and in a large RTS,S phase IIb clinical trial in young children 1-4 years old (n = 735). The preclinical mouse vaccine studies and CSP-specific mAbs were used to initially evaluate IgG responses to the six peptides. Mice immunised with the central NANP-repeat region had IgG with cross-reactivity to an epitope in the N-terminal region. Additionally, we demonstrated that a single CSP-specific mAb could display cross-reactivity to several CSP epitopes. Through post hoc quantification and analysis of antibody responses in the RTS,S phase IIb clinical trial, we found that a subset of children generated IgG with specificity for a short NANP-repeat epitope (NANP2; amino acid sequence: NANPNANP) and cross-reactivity to an N-terminal epitope (J1; amino acid sequence: KQPADGNPDPNANPN). Notably, children with high IgG responses to NANP2 and J1 had a significantly reduced risk of clinical malaria, compared to children with low responses (IgG to NANP2 (aHR: 0.838 (95% CI [0.716, 0.981]; p = 0.028)) and J1 (aHR: 0.718 (95% CI [0.611, 0.844]; p < 0.001)), and these responses were also associated with higher antibody Fc-mediated functional activities. We have evaluated NANP2 and J1 as immunological correlates of protection in one phase IIb cohort, additional studies in other RTS,S and R21 cohorts will be important to further confirm our findings. CONCLUSIONS: These findings reveal promising new correlates of protection for RTS,S and new insights to inform the development of next-generation malaria vaccines.
First-trimester nonsteroidal anti-inflammatory drugs exposure and risk of major congenital malformations: A retrospective register-based cohort study.
Hasidim AA, Ben Shitrit I, Idan D … +5 more , Michael T, Levy A, Pariente G, Lunenfeld E, Daniel S
PLoS Med · 2026 May · PMID 42133587 · Full text
BACKGROUND: Pain and fever are common in early pregnancy, yet their management poses a major clinical dilemma. Although not confirmed, recent studies have raised safety concerns regarding acetaminophen. Evidence on the u...
BACKGROUND: Pain and fever are common in early pregnancy, yet their management poses a major clinical dilemma. Although not confirmed, recent studies have raised safety concerns regarding acetaminophen. Evidence on the use of nonsteroidal anti-inflammatory drugs (NSAID) in the first trimester remains inconclusive. This uncertainty has left clinicians with limited evidence to guide treatment decisions. This study evaluated the association between first-trimester NSAID exposure and the risk of major congenital malformations (MCMs) in a large, population-based cohort of pregnancies. METHODS AND FINDINGS: We conducted a population-based retrospective cohort study within the Southern Israeli Pregnancy Registry (siPREG) project, including all singleton pregnancies of women aged 15-45 years resulting in live births, stillbirths, or elective terminations for fetal malformations at a Soroka University Medical Center between 1998 and 2018. Pregnancies exposed to established teratogens, multiple gestations, and those with documented genetic or chromosomal anomalies were excluded. First-trimester NSAID exposure was defined by pharmacy dispensations (overall and by specific agents). MCMs were identified from linked clinical, hospitalization, and termination records through the first postnatal year. Propensity scores were estimated using covariates selected via a directed acyclic graph, including maternal age, ethnicity, diabetes, medical indication for NSAID use, exposure to other antipyretics, obesity, smoking, folic-acid use, gravidity, perinatal care, and year of pregnancy. Generalized full matching was used to balance covariates. Adjusted risk ratios were derived using weighted Poisson regression with G-computation, and two-way cluster-robust standard errors, jointly clustering by maternal identifier and matching subclass. Sensitivity analyses included a dose-response assessment across defined-daily-dose (DDD) categories and a tipping-point analysis evaluating the impact of potential misclassification from unrecorded over-the-counter NSAID use. A total of 264,858 singleton pregnancies were included in the final cohort; 20,202 (7.6%) were exposed to NSAID, most commonly ibuprofen (5.1%), diclofenac (1.6%), and naproxen (1.2%). NSAID exposure, in total and as individual agents, was not associated with MCMs overall (8.2% versus 7.0%; matched-adjusted-Relative Risk (aRR) = 0.99 (95% CI [0.90,1.10])) or with organ-system-specific MCMs, including cardiovascular (matched-aRR = 1.05 (95% CI [0.92,1.20]), musculoskeletal (matched-aRR = 1.03 (95% CI [0.77,1.39])), central nervous system (matched-aRR = 0.77 (95% CI [0.53,1.11])), cleft palate (matched-aRR = 0.95 (95% CI [0.47-1.91])), gastrointestinal (matched-aRR = 1.03 (95% CI [0.64-1.63])), and genitourinary (matched-aRR = 0.99 (95% CI [0.72,1.35])) malformations. Dose-response analyses showed no significant association with MCMs across cumulative NSAID exposure: short-term (1-7 DDD, matched-aRR = 1.06 (95% CI [0.97,1.15]), medium-term (8-21 DDD, matched-aRR = 1.10 (95% CI [0.99,1.22]), and long-term (>21 DDD, matched-aRR = 1.24 (95% CI [0.94,1.63])). The main limitation was the potential for minor exposure misclassification due to over-the-counter availability of ibuprofen, although sensitivity analyses simulating such misclassification suggested minimal impact on the risk estimates. CONCLUSION: In this large, population-based cohort, we found no evidence supporting an association between first-trimester exposure to NSAID and MCMs, providing reassuring evidence regarding their fetal safety in early pregnancy.
Contribution of nosocomial transmission to Klebsiella pneumoniae neonatal sepsis in Africa and South Asia: An observational study of infection clusters inferred from pathogen genomics and temporal data.
Odih EE, Abdulahi JA, Amulele AV … +59 more , Bates M, Heinz E, Hu W, Jain K, Magobo R, Olwagen CP, Tembo JM, Sonda T, Strysko J, Tigoi CC, Bittinger K, Cornick J, Foster-Nyarko E, Gumbi W, Jones SM, Musyani CL, McGann CM, Moustafa AM, Musicha P, Mwansa JCL, Ndumba ML, Stanton TD, Omuoyo DO, Pearse O, Phillips LT, Planet PJ, Rodrigues CMC, Secka F, Sands K, Theiller E, Zuza AM, Basu S, Chan GJ, Iregbu KC, Mazarati JB, Alemayehu SS, Walsh TR, Zahra R, Dramowski A, Fwoloshi S, Labi AK, Madrid L, Obeng-Nkrumah N, Ojok D, Wadugu BD, Whitelaw AC, Bhargava A, Jindal A, Agarwal RK, Aiken AM, Berkley JA, Coffin SE, Feasey NA, Govender NP, Hamer DH, Madhi SA, Sankar MJ, Wyres KL, Holt KE
PLoS Med · 2026 May · PMID 42127138 · Full text
BACKGROUND: Klebsiella pneumoniae is the leading cause of sepsis among neonates in low- and middle-income countries (LMICs) in Africa and Asia, contributing substantially to the overall burden of antimicrobial-resistant...
BACKGROUND: Klebsiella pneumoniae is the leading cause of sepsis among neonates in low- and middle-income countries (LMICs) in Africa and Asia, contributing substantially to the overall burden of antimicrobial-resistant infections and mortality among neonates globally. Pathogen sequencing has been used to investigate case clusters and confirm nosocomial transmission in a small number of neonatal units. Here we utilise pathogen sequence data to estimate the fraction of K. pneumoniae neonatal sepsis attributable to nosocomial transmission in African and South Asian countries. METHODS AND FINDINGS: We estimated the proportion of invasive K. pneumoniae disease involved in nosocomial transmission clusters in a given neonatal unit, using single-linkage clustering based on pairwise temporal and genetic distances estimated from bacterial whole-genome sequences aggregated from 10 contributing studies. Analysing 1,523 K. pneumoniae isolates from 27 units in 13 countries in Africa and South Asia between 2013 and 2023, we inferred 156 nosocomial transmission clusters, ranging from 2 to 188 neonates each (83 of the clusters comprised ≥3 cases). Overall, we estimated that 1,035 neonatal infections (68.0%) were part of nosocomial transmission clusters. Excluding the first infection in each cluster as a potential index case, we estimate at least 879 (57.7%) infections were acquired via nosocomial transmission. Sensitivity analyses showed that results were robust to the choice of genetic distance estimation methods and thresholds used to define clusters, and cluster estimates were stable over temporal distance thresholds ranging from 2 to 8 weeks. Isolates were mostly extended-spectrum beta-lactamase (ESBL) producers (90.9%) and included 172 multi-locus sequence types (STs). Fourteen STs, including several globally recognised multidrug-resistant lineages, were associated with transmission clusters at multiple units, and these were collectively responsible for two-thirds of all infections. Carriage of carbapenemase genes (adjusted odds ratio, aOR = 2.08 [95% confidence interval, CI: 1.04, 4.14]; p = 0.04) and ESBL genes (aOR = 2.48 [95% CI: 1.26, 4.90]; p = 0.006) were significantly positively associated with transmission in a logistic regression model with site as a covariate. Limitations of this study include the lack of sufficient clinical data to allow high-resolution investigation of transmission dynamics and lack of facility-level data to investigate contributors to the observed differences in transmission burden across sites. CONCLUSIONS: Nosocomial transmission contributes to a substantial proportion of K. pneumoniae sepsis in neonatal care units in Africa and South Asia. Reducing transmission within these settings through improved infection prevention and control and other measures could substantially reduce the neonatal sepsis burden. A high burden of transmission clusters is associated with the same drug-resistant lineages that are recognised as high-risk clones associated with hospital outbreaks in high-income countries, indicating global connectivity of the antimicrobial-resistant pathogen population.
On the evolution of the company we keep: Implications for infectious disease modeling.
Mossong J
PLoS Med · 2026 May · PMID 42127039 · Full text
Whom we meet shapes how infections spread. Where earlier focus of mathematical epidemiology was on incorporating age, more recent work has begun to reveal the importance of socioeconomic aspects for understanding and man...
Whom we meet shapes how infections spread. Where earlier focus of mathematical epidemiology was on incorporating age, more recent work has begun to reveal the importance of socioeconomic aspects for understanding and managing future epidemics.
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