Fluids and Barriers of the CNS

BackgroundPleuroparenchymal fibroelastosis (PPFE) is a rare, fibrotic lung disease with poor prognosis, usually affecting adults which most commonly occurs idiopathically. Biallelic pathogenic variants in DGUOK cause mitochondrial DNA (mtDNA) depletion syndrome, predominantly affecting infants with severe hepatic and neurological symptoms. Detailed description of pulmonary manifestations with late-onset presentation have not been reported. MethodsWe describe nine patients with PPFE and DGUOK-associated mitochondriopathy. Clinical, radiological, histopathological, and genetic data were systematically collected from all patients. Functional studies, single nucleus RNA sequencing (snRNAseq), immunofluorescence staining, transmission electron microscopy and respiratory chain enzyme activity assays were conducted on patient-derived fibroblasts, muscle or lung tissues. mtDNA content quantification was performed on whole genome sequencing (WGS) data. ResultsAll patients (ages 5-36) presented with progressive dyspnea, weight loss and some with spontaneous pneumothoraces. Chest computed tomography and lung biopsies showed features of PPFE. Biallelic pathogenic DGUOK variants were identified in all patients, seven of them carry an unreported intronic variant leading to mtDNA depletion. snRNAseq of lung tissue from four pediatric patients identified Aberrant Basaloid cells and intermediate cells as their precursor localized at the fibrotic edge. Mitochondrial alterations were identified by electron microscopy. ConclusionPPFE in children and young adults is associated with DGUOK-related mitochondriopathy. For the first time, we demonstrate Aberrant Basaloid cells in pediatric fibrotic lung tissue. Since pulmonary involvement may be underrecognized or misinterpreted and the clinical presentation may not always be typical of a mitochondriopathy, we recommend genetic testing in all patients with PPFE of unknown origin.

Background Venous thromboembolism (VTE) remains a major cause of perioperative morbidity in cranial neurosurgery, yet clinical practice varies widely, and formal guidelines are inconsistent. Understanding internationally sampled neurosurgical practice is essential for informing consensus and future trials. Methods An international, 2-stage cross-sectional, internet-based survey was conducted. Practising neurosurgeons performing elective adult cranial surgery were eligible. Descriptive statistics were used to summarise practice. Responses covered patterns of pre-operative haemostasis decision making, use and timing of mechanical and/or chemical prophylaxis, use of perioperative imaging prior to anticoagulation, and frequency of clinical assessment for VTE. Associations with geographical income status, subspecialty, and years post-certification were statistically tested. Practice heterogeneity was quantified and contextual influence was summarised using mean effect sizes across stratifying variables in order to determine domains of true equipoise. Results Of 585 responses, 456 (78%) met criteria for inclusion: representing 322 units across 78 countries (71% high-income). Thirteen per cent reported no departmental VTE plan; 23% followed no guidelines and 12% used multiple. Routine pre-operative testing almost universally included haemoglobin/platelets/haematocrit, with fibrinogen more common in high-income settings. Compared with high-income country respondents, low- and middle-income respondents reported higher haemoglobin transfusion thresholds (>90 g/dL; p<0.001) and shorter antiplatelet interruption (p[&le;]0.03), and less frequent outpatient VTE assessment (p<0.001). Mechanical prophylaxis was common (TEDs 81%, IPC 62%), typically started pre- or intra-operatively. Among those completing the chemoprophylaxis section (n=310), 57% required a CT or MRI scan before LMWH which was then initiated on average 31.4 hours after surgery. 1% of respondents did not routinely use LMWH. Many clinical decisions demonstrated statistical equipoise ie. high heterogeneity with low contextual influence. Conclusion Peri-operative haemostasis and VTE prophylaxis practices in adult elective cranial neurosurgery vary substantially worldwide, with some decisions reflecting geographical or socioeconomic differences and many others reflecting true clinical equipoise rather than contextual determinants. By mapping contemporary real-world practice across diverse health-system contexts, this study provides a necessary empirical foundation for rational trial design and future guideline development.

Modelling of hemodynamics in the circle of Willis (CoW) depends on vascular segmentation, which may vary based on imaging modality. Computed tomography angiography (CTA) is commonly used in clinic but involves radiation and injection of contrast agents, whereas magnetic resonance angiography (MRA) offers a non-invasive alternative. This study aims to compare CoW morphology and modelled cerebral perfusion pressure of CTA and MRA segmentations, validating if MRA can replace CTA in modelling workflows. CTA and time-of-flight MRA (TOF-MRA) of the CoW was performed in 19 patients undergoing elective aortic arch surgery (67{+/-}7 years, 8 women). The CoW was semi-automatically segmented based on signal intensity thresholding. A TOF-MRA threshold was optimized against the CTA segmentation, using the CTA as reference standard. Computational fluid dynamics (CFD) modelling with boundary conditions based on subject-specific flow rates from 4D flow MRI simulated cerebral perfusion pressure in the segmented geometries. A baseline simulation and a unilateral brain inflow simulation, i.e., occlusion of a carotid, were carried out. Linear mixed models indicated there was no effect of choice of modality on either average arterial lumen area (CTA - TOF-MRA: -0.2{+/-}1.3 mm2; p=0.762) or baseline pressure drops (0.2{+/-}1.9 mmHg; p=0.257). In the unilateral inflow simulation, we found no difference in pressure laterality (-6.6{+/-}18.4 mmHg; p=0.185) or collateral flow rate (10{+/-}46 ml/min; p=0.421). TOF-MRA geometries can with signal intensity thresholding be matched to produce similar morphology and modelled cerebral perfusion pressure to CTA geometries. The modelled pressure drops over the collateral arteries were sensitive to the segmentation regardless of modality.

Altered iron homeostasis has long been implicated in Parkinson's Disease (PD), although the mechanisms have not been clear. Given the critical role of PD-related activating mutations in LRRK2 (leucine-rich repeat protein kinase 2) within membrane trafficking pathways we examined the impact of a homozygous mutant LRRK2G2019S on iron homeostasis within the RAW macrophage cell line with high iron capacity. Proteomics analysis revealed a dysregulation of iron-related proteins in steady state with highly elevated levels of ferritin light chain and a reduction of ferritin heavy chain. LRRK2G2019S mutant cells showed efficient ferritinophagy upon iron chelation, but upon iron overload there was a near complete block in the degradation of the ferritinophagy adaptor NCOA4. These conditions lead to an accumulation of phosphorylated Rab8 at the plasma membrane, which is selectively inhibited by LRRK type II kinase inhibitors. Iron overload then leads to increased oxidative stress and ferroptotic cell death. These data implicate LRRK2 as a key regulator of iron homeostasis and point to the need for an increased focus on the mechanisms of iron dysregulation in PD.

BackgroundPreterm birth is one of the most significant etiologies for neonatal morbidity and mortality. Preterm delivery is classified as iatrogenic preterm delivery and spontaneous preterm delivery. The role of placental pathology is studied. Materials and methodsWe have previously collected placental pathology data with maternal pregnancy and neonatal birth data, and we investigated the role of placental pathology in preterm delivery. Preterm delivery was categorized as late preterm (34-36 weeks), moderate preterm (32 to 33 weeks), and extreme preterm (less than 32 weeks). Neonatal, maternal, placental gross and histologic features, and laboratory parameters were compared across groups using chi-square tests for categorical variables and Kruskal-Wallis tests for continuous variables using various programs in R-package. ResultsTotally 3723 singleton placentas including 3307 term (88.8%) and 416 preterm placentas (11.2%) were examined with maternal pregnancy data and neonatal birth data. There were 614 placentas from patients with preeclampsia/pregnancy induced hypertension (PRE/PIH) (16.5%). Preterm delivery showed significantly lower fetal birth weight, placental weight, and fetal-placental ratio (all p<0.01). Maternal Black race was more prevalent in preterm groups (up to 50.8% in extreme preterm vs. 33.2% in term, p<0.01). Preterm delivery was statistically associated with PRE/PIH and maternal vascular malperfusion (MVM), maternal and fetal inflammatory response (MIR and FIR), and increased pre-delivery white blood count (WBC). Extreme preterm deliveries were markedly associated with intrauterine fetal death (27.5%, p<0.01) and MIR/FIR (56.7%, p<0.01). After excluding PRE/PIH patients, preterm delivery was statistically associated with MIR/FIR and increased WBC. ConclusionsDistinct clinicopathologic profiles exist across preterm subcategories, with MVM predominating in late/moderate preterm and severe pathologic features (including fetal demise and acute inflammation) in extreme preterm. These findings highlight heterogeneous etiologies of preterm delivery.

PurposeNavigational ability develops throughout childhood alongside the maturation of brain regions supporting egocentric and allocentric processing. In Autism Spectrum Disorder (ASD), atypical hippocampal development may impact flexible spatial memory; however, findings on navigational ability in autistic children remain inconsistent. This study aimed to compare both objective and perceived navigation ability in children with ASD and typically developing (TD) peers. MethodTwenty-six children with high-functioning ASD and twenty-five age- and gender-matched TD children (M_age = 12.04 years, SD = 1.64) completed a battery of navigational tasks from the Spatial Performance Assessment for Cognitive Evaluation (SPACE), including Path Integration, Egocentric Pointing, Mapping, Associative Memory, and Perspective Taking. Perceived navigation ability was assessed using the Santa Barbara Sense of Direction (SBSOD) scale. ResultsNo significant group differences were observed across any objective navigation tasks. However, children with ASD reported significantly lower perceived navigation ability compared to TD peers. ConclusionThese findings suggest a dissociation between perceived and actual navigational ability in ASD. By early adolescence, objective navigation performance appears intact, potentially reflecting sufficient maturation of underlying neural systems or the presence of compensatory mechanisms. The results underscore the importance of incorporating objective, task-based measures when assessing cognitive abilities in autistic populations.

ImportanceBlood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are entering clinical use in neurology as markers of neuroaxonal and astrocytic injury, but their utility in psychiatry is unclear. ObjectiveTo determine whether psychiatric diagnoses are associated with altered plasma NfL and GFAP levels. Design, Setting, and ParticipantsThis population-based study examined plasma NfL and GFAP among 47,495 participants from the UK Biobank (54.0% female; 93.5% White; mean [SD] age 56.8 [8.2] years) who provided blood samples and sociodemographic and clinical data between 2006 and 2010. Normative modeling was applied to assess associations between 7 lifetime psychiatric diagnostic categories and deviations from expected NfL and GFAP levels, while accounting for neurological diagnoses, cardiometabolic burden, and substance use. Data were analyzed between July 2025 and March 2026. Main Outcomes and MeasuresDeviations in plasma NfL and GFAP levels from normative predictions. ResultsRelative to the reference population, plasma NfL levels were higher among individuals with bipolar disorder (d=0.20; 95% CI, 0.03-0.37; p=0.03), recurrent depressive disorder (d=0.23; 95% CI, 0.07-0.38; p=0.009), and depressive episodes (d=0.06; 95% CI, 0.02-0.10; p=0.01), lower among individuals with anxiety disorders (d=-0.07; 95% CI, -0.12 to -0.02; p=0.008), but did not differ in schizophrenia spectrum, stress-related, or other psychiatric disorders. Plasma GFAP levels were not elevated in any psychiatric disorders. Variability in NfL levels was greater among individuals with schizophrenia spectrum disorders (variance ratio [VR]=1.30; p=0.005), depressive episodes (VR=1.06; p=0.006), and anxiety disorders (VR=1.08; p=0.005). Variability in GFAP levels was increased only in anxiety disorders (VR=1.08; p=0.01). Plasma NfL levels exceeding percentile-based normative thresholds were more common among individuals with schizophrenia spectrum disorders, bipolar disorder, recurrent depressive disorder, and depressive episodes. Neurological diagnoses, cardiometabolic burden, and substance use were associated with plasma NfL and GFAP levels. Conclusions and RelevanceThis study provides population-level evidence of plasma NfL elevation in bipolar and depressive disorders and increased variability in schizophrenia spectrum, bipolar and depressive disorders, supporting its potential as a biomarker in psychiatry and informing its ongoing neurological applications. Plasma GFAP levels, in contrast, were largely unaltered across psychiatric disorders. Key PointsO_ST_ABSQuestionC_ST_ABSAre plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels altered in psychiatric disorders? FindingsIn this cohort study including 47,495 individuals, normative modeling revealed that plasma NfL levels were elevated in bipolar and depressive disorders, whereas plasma GFAP levels were not elevated in any psychiatric disorder. Plasma NfL levels also showed higher variability in schizophrenia spectrum, bipolar, and depressive disorders. MeaningPlasma NfL shows distinct alterations in schizophrenia spectrum and affective disorders, supporting its further investigation as a biomarker in clinical psychiatry and highlighting the need to consider psychiatric comorbidity in neurological applications.

Single photon emission computed tomography (SPECT) is a highly specialized imaging modality that enables measurement of regional cerebral perfusion and, in particular, resting cerebral blood flow (rCBF). Recent technological advances have improved SPECT quantification and reliability, making it increasingly useful for studying rCBF abnormalities and perfusion network alterations in psychiatric and neurological disorders. To characterize large scale functional organization in SPECT data, data driven decomposition methods such as independent component analysis (ICA) have been used to extract covarying perfusion patterns that map onto interpretable brain networks. Blind ICA provides a data driven approach to estimate these networks without strong prior assumptions. More recently, a hybrid approach that leverages spatial priors to guide a spatially constrained ICA (sc ICA) have been used to fully automate the ICA analysis while also providing participant-specific network estimates. While this has been reliably demonstrated in fMRI with the NeuroMark template, there is currently no comparable SPECT template. A SPECT template would enable automatic estimation of functional SPECT networks with participant-specific expressions that correspond across participants and studies. The current study introduces a new replicable NeuroMark SPECT template for estimating canonical perfusion covariance patterns (networks). We first identify replicable SPECT networks using blind ICA applied to two large sample SPECT datasets. We then demonstrate the use of the resulting template by applying sc-ICA to an independent schizophrenia dataset. In sum, this work presents and shares the first NeuroMark SPECT template and demonstrating its utility in an independent cohort, providing a scalable and robust framework for network-based analyses.

Background: Gamma oscillation dysfunction has been implicated in neuropsychiatric disorders. Restoring gamma oscillations via brain stimulation represents an emerging therapeutic approach. However, the strength of its clinical effects and treatment moderators remain unclear. Method: We conducted a systematic review and meta-analysis to examine the clinical effects of gamma neuromodulation in neuropsychiatric disorders. A literature search for controlled trials using gamma stimulation was performed across five databases up until April 2025. Effect sizes were calculated using Hedge's g. Separate analyses using the random-effects model examined the clinical effects in schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder, and autism spectrum disorder. For SZ and MDD, subgroup analyses evaluated the effects of stimulation modality, stimulation frequency, treatment duration, and pulses per session. Result: Fifty-six studies met the inclusion criteria (NSZ = 943, NMDD = 916, NBD = 175, NASD = 232). In SZ, gamma stimulation was associated with improvements in positive (k = 10, g = -0.60, p < 0.001), negative (k = 12, g = -0.37, p = 0.03), depressive (k = 8, g = -0.39, p < 0.001), anxious symptoms (k = 5, g = -0.59, p < 0.001), and overall cognitive function (k = 7, g = 0.55, p < 0.001). Stimulation frequency and treatment duration moderated therapeutic effects. In MDD, reductions in depressive symptoms were observed (k = 23, g = -0.34, p = 0.007). Conclusion: Gamma neuromodulation showed moderate therapeutic benefits in SZ and MDD. Substantial heterogeneity likely reflects protocol differences, highlighting the need for well-powered future trials.

BackgroundEarly-life adversity (ELA) is a risk factor for enduring pain in youth and is associated with alterations in brain morphology and function. However, it remains unclear whether ELA-related neurobiological changes contribute to the development of enduring pain in early adolescence. MethodsUsing data from the Adolescent Brain Cognitive Development (ABCD) Study, we examined multimodal magnetic resonance imaging (MRI) markers in children assessed at baseline (ages 9-11 years) and at 2-year follow-up (ages 11-13 years). ELA exposure was defined at baseline to maximise temporal separation between early adversity and later enduring pain. Participants with enduring pain at follow-up (n = 322) were compared to matched pain-free controls (n = 644). Structural MRI, diffusion MRI (fractional anisotropy, mean diffusivity), and resting-state functional connectivity data were analysed. Linear models tested main effects of enduring pain, ELA, and their interaction on brain metrics, controlling for relevant covariates. ResultsELA exposure was associated with smaller caudate and nucleus accumbens volumes, and reduced surface area of the left rostral middle frontal gyrus. No significant effects of enduring pain or ELA-by-enduring pain interaction were observed across grey matter, white matter, or functional connectivity measures. ConclusionsELA was associated with alterations in fronto-striatal regions in late childhood, but these changes were not linked to enduring pain in early adolescence. These findings suggest that ELA-related neurobiological alterations may represent early markers of vulnerability rather than concurrent correlates of enduring pain. Longitudinal follow-up is needed to determine whether these alterations contribute to later chronic pain risk.

BackgroundNegative symptoms are core features of schizophrenia that relate strongly to functional impairment, yet interventions targeting these symptoms remain largely ineffective. Emerging theoretical work highlights how environmental factors may shape and maintain negative symptoms. Although racial disparities in schizophrenia diagnosis among Black Americans are well documented and linked to racial stress and psychosis, the impact of racial stress on negative symptoms has not been examined. This study provides an initial test of a novel theory proposing that racial stress - here measured by racial discrimination - influences negative symptom severity through exacerbation of negative cognitions about the self, particularly defeatist performance beliefs (DPB). Study DesignParticipants diagnosed with schizophrenia-spectrum disorder (SSD) (N = 208; 80 Black, 128 White) completed the Positive and Negative Syndrome Scale (PANSS), the Defeatist Beliefs Scale, and self-report measures of subjective racial and ethnic discrimination (Racial and Ethnic Minority Scale and General Ethnic Discrimination Scale). Relationships among variables were tested using linear regression and mediation analysis. Study ResultsBlack participants exhibited significantly greater total and experiential negative symptoms than White participants with no group difference in DPB. Racial discrimination explained 46% of the relationship between race and negative symptoms. Among Black participants, higher DPB were associated with greater negative symptom severity. Discrimination was positively related to both DPB and negative symptoms. DPB partially mediated the relationship between discrimination and negative symptoms. ConclusionsFindings suggest that racial stress contributes to negative symptom severity via defeatist beliefs among Black individuals, highlighting potential targets for culturally informed interventions.

Background Higher levels of sedentary behaviour, such as leisure screen time (LST), and lower levels of physical activity are associated with diseases across multiple body systems which contribute to a large global health burden. Whether these associations are causal is unclear. The primary aim of this study is to investigate the causal effects of higher LST (given greater power) and, secondarily, lower moderate-to-vigorous intensity physical activity (MVPA), on a wide range of diseases in a hypothesis-free approach. Methods A two-sample Mendelian randomisation phenome-wide association study was conducted for the main analyses. Genetic single nucleotide polymorphisms (SNPs) were first selected as exposure genetic instruments for LST (hours of television watched per day; 117 SNPs) and MVPA (higher vs. lower; 18 SNPs) based on the genome-wide significant threshold (p < 5*10-8) from the largest relevant genome-wide association study (GWAS). For disease outcomes, we used summary results from FinnGen GWAS, including 1,719 diseases defined by hospital discharge International Classification of Diseases (ICD) codes in 453,733 European participants. For the main analyses, we used the inverse-variance weighting method with a Bonferroni corrected p-value of p [&le;] 3.47*10-4. Sensitivity analyses included Steiger filtering, MR-Egger and weighted median analyses, and data from UK Biobank were used to explore replication. Findings Genetically predicted higher LST was associated with increased risk of 87 (5.1% of the 1,719) diseases. Most of these diseases were in musculoskeletal and connective tissue (n=37), genitourinary (n=12) and respiratory (n=8) systems. Genetic liability to lower MVPA was associated with six diseases: three in musculoskeletal and connective tissue and genitourinary systems (with greater risk of these diseases also identified with higher LST), and three in respiratory and genitourinary systems. Sensitivity analyses largely supported the main analyses. Results replicated in UK Biobank, where data available. Conclusions Higher levels of sedentary behaviour, and lower levels of physical activity, causally increase the risk of diseases across multiple body systems, making them promising targets for reducing multimorbidity.

Objectives: Longer lifespans lead to longer time on retirement, despite the efforts to raise the retirement age. Therefore, it is important to study how the retirement years can be spent without diseases. This study examined socioeconomic and sociodemographic differences in healthy years spent on retirement. Methods: We followed a cohort of retired Finnish municipal employees (N=4231, average follow-up 15.4 years) on national administrative registers for major chronic diseases: cancer, coronary heart disease, cerebrovascular disease, diabetes, asthma or chronic obstructive pulmonary disease, dementia, mental disorders, and alcohol-related disorders. Median healthy years on retirement and age at first occurrence of illness (ICD-10 and ATC-based) in each combination of sex, occupational class, and age of retirement were predicted using Royston-Parmar models. Prevalence rates for each diagnostic group were calculated. Results: Most healthy years on retirement were spent by women having worked in semi-professional jobs who retired at age 60-62 (median predicted healthy years 11.6, 95% CI 10.4-12.7). The least healthy years on retirement were spent by men having worked in routine non-manual jobs who retired after age 62 (median predicted healthy years 6.5, 95% CI 4.4-9.5). Diabetes was slightly more common among lower occupational class women, and dementia among manual working women having retired at age 60-62. Discussion: Healthy years on retirement are not enjoyed equally by women and men and those who retire early or later. Policies aiming to increase the retirement age should consider the effects of these gaps on retirees and the equitability of those effects.

The global ambition to end the human immunodeficiency virus (HIV) epidemic requires understanding which system-level policy levers, enacted under the framework of Universal Health Coverage (UHC), are most effective in achieving both transmission reduction and diagnostic coverage. This study addresses an important evidence gap by quantifying the within-country association between measurable UHC policy indicators and the estimated rate of new HIV infections across nine Southeast Asian countries between 2013 and 2022. Employing a Fixed-Effects panel data methodology, the analysis controls for time-invariant national heterogeneity, ensuring reliable estimates of policy impact. We found that marginal changes in total current health expenditure (CHE) as a percentage of gross domestic product (GDP) were not statistically significantly associated with changes in HIV incidence. However, increases in the UHC Infectious Disease Service Coverage Index were statistically significantly associated with concurrent reductions in HIV incidence (p < 0.001), suggesting the efficacy of targeted service implementation as the principal driver of curbing new HIV infections. In addition, the UHC Reproductive, Maternal, Newborn, and Child Health Service Coverage Index exhibited a statistically significant positive association with changes in HIV incidence (p < 0.01), which is interpreted as a vital surveillance artefact resulting from expanded detection and reporting of previously undiagnosed HIV cases. Furthermore, out-of-pocket (OOP) health expenditure as a percentage of CHE showed a counter-intuitive negative association with changes in HIV incidence (p < 0.01), suggesting this metric primarily shows ongoing indirect cost burdens on the established patient cohort, or, alternatively, presents a diagnostic access barrier that results in lower case finding. These findings suggest that policymakers should prioritise investment in targeted infectious disease service efficacy over aggregate fiscal commitment and utilise integrated sexual health platforms for strengthened HIV surveillance and case identification.

Schizophrenia (SCZ) and type 2 diabetes mellitus (T2DM) are common comorbid disorders that severely impair patient prognosis and quality of life. This study aimed to explore the association between the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and MTHFR promoter methylation in patients with comorbid SCZ and T2DM. A total of 120 participants were enrolled from Liaocheng Fourth Peoples Hospital between January 2025 and June 2025, comprising 30 subjects in each of the four groups: SCZ group, T2DM group, SCZ-T2DM comorbid (SCZ+T2DM) group, and healthy control (CTL) group. Corresponding primers were designed for genetic analysis, and methylation-specific PCR (MSP) was performed to detect the methylation level of the MTHFR promoter. Genotype distribution of the MTHFR C677T polymorphism was consistent with Hardy-Weinberg equilibrium (HWE) (p>0.05). The C677T polymorphism was significantly associated with an elevated risk of SCZ and T2DM comorbidity (p<0.05). Notably, the methylation rate of the MTHFR promoter in the SCZ+T2DM group (95.00%) was not significantly higher than that in the CTL group (90.00%) (p>0.05). In conclusion, the MTHFR gene may serve as a susceptibility gene for SCZ-T2DM comorbidity, whereas MTHFR promoter methylation is not associated with the pathogenesis of this comorbid condition. These results indicate that genetic variation in MTHFR, rather than promoter methylation, contributes critically to the comorbidity of SCZ and T2DM in the Han Chinese population. Our findings may provide novel molecular insights into their shared pathophysiology and inform future clinical strategies for patients with this complex phenotype.

PurposeAntibiotic use (ABU) is a major driver of antimicrobial resistance (AMR), but ABU patterns are poorly understood in low-income countries where the burden of AMR is great and ABU is insufficiently regulated. Here, we report ABU from ten sites ranging from rural villages to small cities in Madagascar, a country with high AMR levels, and present results from modeling to identify factors that may be associated with ABU in this setting. MethodsWe conducted surveys of 290 individuals from ten sites in the SAVA Region of northeast Madagascar to gather data on sociodemographic characteristics, agricultural and animal husbandry practices, recent antibiotic use, the antibiotics that participants recalled using in their lifetimes, and the sources of their antibiotics. Using these data, we conducted statistical analyses with a mixed-effects logistic model to determine which characteristics were associated with recent antibiotic use. ResultsNearly all respondents (N=283, 97.6%) reported ABU in their lifetimes, with amoxicillin being the most widely reported antibiotic (N=255, 90.1% of those reporting ABU). All recalled antibiotics were classified as frontline drugs except for ciprofloxacin. Most respondents who reported antibiotic use also reported obtaining antibiotics without prescriptions from local stores (N=273, 96.5%), while only 52.3% (N=148) reported obtaining antibiotics through a prescriptive route, such as from a health clinic or private doctor. Of the 127 individuals (44.9%) who reported recent ABU, men were found to be significantly less likely to have recently taken antibiotics than women. ConclusionsOur findings provide new insights into ABU in agricultural settings in low-income countries, which have historically been understudied in AMR and pharmacoepidemiologic research. Knowledge of ABU patterns supports understanding of AMR dynamics and AMR control efforts in these contexts, such as interventions on inappropriate antibiotic dispensing. Key pointsO_LIAntibiotic use (ABU) in Madagascar is largely unstudied despite its role in antimicrobial resistance (AMR), which Madagascar faces a high burden of. C_LIO_LIABU was widespread among livestock owners in northeast Madagascar, with the majority of study participants reporting ABU in their lifetimes and most people reporting ABU also having taken antibiotics in the previous three months. C_LIO_LIMost respondents reported obtaining their antibiotics from non-pharmaceutical stores, indicating high levels of unregulated ABU, though more than half also reported sourcing their antibiotics through prescriptive means (like doctors and health clinics). C_LIO_LIMen were less likely than women to have taken antibiotics in the previous three months. C_LIO_LIThese findings support the development of interventions to mitigate the burden of AMR in Madagascar and similar contexts while underscoring the need for more comprehensive research on the drivers and patterns of ABU. C_LI Plain language summaryIn this study, we provide basic information on antibiotic use (ABU) patterns in Madagascar, a country that experiences high levels of resistance but has been particularly understudied in AMR and pharmacological research. We surveyed 290 farmers with livestock from ten sites across northeast Madagascar about their ABU and found that nearly all study participants (N=283, 97.6%) have used antibiotics in their lifetimes, while a little under half of those who reported ABU also reported using antibiotics in the previous three months (N=127, 44.9%). The most used antibiotic was amoxicillin (N=255, 90.1%). Most people obtained their antibiotics from sources that do not require prescriptions, like general stores, indicating that most ABU is unregulated. Through modeling, we also found that men were less likely than women to have taken antibiotics in the previous three months (OR=0.50, CI 0.30-0.82). These findings help us better understand the dynamics of ABU in low-income countries, which have historically been understudied in AMR and pharmacological research. They also support efforts to mitigate the burden of AMR by revealing ABU dynamics that may contribute to the emergence and spread of AMR, as well as identifying targets for intervention to curb inappropriate ABU.

BackgroundCurable sexually transmitted infections (STIs), including Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis, remain highly prevalent among pregnant women in South Africa. Despite poor diagnostic performance in pregnancy, syndromic management remains standard care. Point-of-care (POC) screening enables aetiological diagnosis and same-visit treatment but is not yet included in national guidelines. We conducted a mixed-methods process evaluation to examine determinants of antenatal POC STI screening implementation in public facilities. MethodsThis evaluation was embedded within the three-arm Philani Ndiphile randomized trial (March 2021-February 2025) across four public clinics in the Eastern Cape. Screening used a near-POC, electricity-dependent nucleic acid amplification test with a 90-minute turnaround time. Reach, Adoption, Implementation, and Maintenance were assessed using the RE-AIM framework. Quantitative indicators included uptake of screening, treatment, and follow-up attendance. Qualitative data included in-depth interviews with 20 pregnant women and five focus group discussions with 21 research staff and government healthcare workers. The Consolidated Framework for Implementation Research guided qualitative analysis. Findings were integrated using narrative weaving. ResultsScreening uptake was high (99.0%), with treatment coverage of 95.2% at baseline and 93.5% at repeat screening. Same-day treatment was lower (50.7% and 69.8%) and varied substantially by facility, reflecting operational constraints including turnaround time, patient volume, infrastructure, and electricity. Attendance was higher when screening was integrated into routine ANC. Women valued screening for infant health, while providers recognised advantages over syndromic management but highlighted workforce, resource, and maintenance constraints. Socioeconomic factors, including transport costs, hunger, and work commitments, influenced retention and waiting. ConclusionsAntenatal POC STI screening was acceptable and achieved high treatment coverage in a research setting. However, same-day treatment was constrained by operational requirements of the testing platform. Scale-up will require workflow integration, strengthened health system capacity, and faster diagnostics suited to routine antenatal care. Key MessagesO_ST_ABSWhat is already known on this topicC_ST_ABSSyndromic management remains standard antenatal care in many low-resource settings despite failing to capture up to 89% of infections that remain asymptomatic. Point-of-care aetiological screening has demonstrated feasibility, acceptability, and potential clinical benefit in research settings, yet has not been widely adopted into national policy. Limited evidence exists on the health system requirements and contextual determinants influencing scale-up within routine public facilities. What this study addsThis mixed-methods process evaluation demonstrates high uptake and treatment coverage of antenatal POC STI screening in a trial setting, while identifying facility-level, structural, and socioeconomic factors shaping same-day treatment and retention. We show that implementation success varies substantially across clinics and depends on assay characteristics, workflow integration, human resources, infrastructure reliability, and follow-up capacity. How this study might affect research, practice or policyThese findings provide implementation-relevant evidence to inform national policy deliberations on integrating POC STI screening into antenatal care. Sustainable scale-up will require context-adapted delivery models, strengthened workforce and supply systems, faster diagnostics, and alignment with existing ANC workflows to ensure equitable and durable impact.

BackgroundThis study aimed to assess caregiver knowledge of Infant and Young Child Feeding (IYCF), child health, severe acute malnutrition (SAM) screening, and Community-Based Management of Acute Malnutrition (CMAM), its determinants, and associations with IYCF/ WaSH (water, sanitation, and hygiene) practices among caregivers of children 6-59 months with SAM in Ethiopian agrarian and pastoralist settings. MethodData were from the baseline survey of the R-SWITCH Ethiopia cluster-randomized controlled trial (cRCT), which screened [~]28,000 children aged 6-59 months and identified 686 SAM cases. Caregiver knowledge was evaluated using a validated 32-item questionnaire (Cronbachs for internal reliability) and analyzed via linear mixed-effects and Poisson regression models in Stata 17. ResultsCaregiver knowledge was positively associated with improved IYCF/WaSH practices among children aged 6-23 months with SAM, including higher minimum dietary diversity (MDD: IRR=1.50), minimum acceptable diet (MAD: IRR=1.63), and reduced zero vegetable/fruit intake (IRR=0.77), as well as MDD in children aged 24-59 months, improved water access (IRR=1.19), water treatment (IRR=2.02), and handwashing stations (IRR=1.41). Literate ({beta} = 4.1; 95% CI:1.5-6.6, p= 0.016), pregnant({beta} = 4.4; 95% CI:0.9-7.8, 0.018), having child weighing at a health post/ health center ({beta} = 8.9;95% CI:3.5-14.2,p [&le;] 0.001), and higher household wealth index ({beta} = 11.8;95% CI:3.6-20.1,p= 0.005) were associated with higher knowledge, while possible depression ({beta} = -0.3;95% CI: -0.5 to 0.0, p= 0.015) was associated with lower knowledge. ConclusionCaregiver knowledge determines better IYCF/WaSH practices among children aged 6-59 months with SAM. Literacy, pregnancy, having child weighing at a health post or health center, and greater household wealth were associated with caregivers knowledge, whereas possible depression was associated with lower knowledge. Integrating context-specific caregiver education and mental health support into CMAM, GMP(Growth monitoring and promotion), and primary care services could enhance feeding/WaSH practices in Ethiopia.

BackgroundInsecticides remain the cornerstone of mosquito vector control for malaria, dengue, and other mosquito-borne diseases, yet global patterns of deployment and their socioeconomic and environmental drivers are poorly characterized. Understanding where and why insecticides are used is essential for better targeting control efforts and ensuring they are effective, equitable, and efficient. MethodsWe analyzed annual country-level insecticide-use data from 122 countries (1990-2019), reported as standard spray coverage for insecticide-treated nets (ITNs), residual spraying (RS), spatial spraying (SS), and larviciding (LA). Generalized linear mixed models and hurdle models quantified associations between deployment and disease incidence, human development index (HDI), human population density, temperature, and precipitation. Models were evaluated using repeated cross-validation and applied to generate downscaled predictions of insecticide use at subnational administrative region level 2 (ADM2) globally. FindingsInsecticide deployment increased with malaria and dengue incidence, but this response was substantially stronger in higher-HDI countries, indicating that deployment depends on socioeconomic capacity as well as disease burden that leads to weaker scaling in lower-resource settings. Intervention types exhibited distinct patterns; ITN use tracked malaria burden, whereas infrastructure-intensive approaches (e.g., RS and SS) were concentrated in higher-HDI settings and increased with Aedes-borne disease incidence. Downscaled ADM2-level maps uncovered substantial within-country heterogeneity that is obscured at the national scale, highlighting regions where predicted deployment remains low relative to disease risk across sub-Saharan Africa, South Asia, and parts of Latin America. InterpretationGlobal insecticide deployment reflects not only epidemiological need but also economic and logistical capacity, creating mismatches between risk and control. High-resolution mapping can support more equitable allocation of interventions, guide insecticide resistance stewardship, and improve strategic planning as climate and urbanization reshape mosquito-borne disease risk.

Background Comprehensive sexuality education (CSE) is essential to the health and well-being of young people. In the Democratic Republic of Congo (DRC), where more than 65% of the population is under the age of 25, access to interpersonal CSE remains limited owing to sociocultural and structural barriers. This exposes young people to persistent socio-sanitary vulnerabilities. In this context, mobile health apps (MHAs) constitute a promising solution, supported by the growing use of smartphones among young Congolese. However, this group's intention to use MHAs for CSE has been the subject of little research to date. Objective The aim of this study was to identify predictors of intention to use MHAs among young Congolese, based on the extended Unified Theory of Acceptance and Use of Technology (UTAUT2). Methods A predictive correlational study was conducted in eight public secondary schools in Bukavu (DRC) with a stratified random sample of 859 students. Predictors of intention to use--performance expectancy (PE), effort expectancy (EE), social influence (SI), facilitating conditions (FC), and perceived risk (PR)--and moderators--age, gender, and past MHA experience--were measured from data collected through a self-administered UTAUT questionnaire. Descriptive and multivariate analyses were run on SPSS version 28. Results Mean age of participants was 16.3 years (SD = 1.5). Boys made up 55.1% of the sample. Overall, 51.0% of the sample owned a smartphone, of which 62.3% reported having easy access to mobile data and 16.2% were already using MHAs to learn about sexual health. Intention to use MHAs was positively influenced by PE ({beta} = 0.523, p < 0.001), EE ({beta} = 0.115, p < 0.001), and SI ({beta} = 0.113, p < 0.001). FC (p = 0.260) and PR (p = 0.631), however, had no significant influence. Age moderated all of the relationships tested (F (1, 849-854) = 9.97-20.82; p [&le;] 0.002), with more marked effects observed among younger participants 14-15 years old. The final model explained 44% of the variance, indicating good predictive power. Conclusion Intention to use digital CSE was explained primarily by PE, EE, and SI and moderated by age. To strengthen this intention, stakeholders will need to promote e-interventions that are pertinent, easy to use, socially valorized, and tailored to young people's needs and to the local context.