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Background: This study of Malawian children with rheumatic heart disease (RHD) sought to detect demographic, clinical, and echocardiographic risk factors for mortality.

Methods: Pediatric patients with RHD were recruited from March to October, 2018 from clinic rosters and inpatient consults in Lilongwe and Blantyre, Malawi. An echocardiogram was performed upon study enrollment. Cox regression analyses were performed to assess for factors associated with mortality over nearly 2 years of follow-up.

Results: Of 118 patients, nearly two-thirds were female (64.4%) and median age was 12 (IQR 10-14). Just under half (47.0%) lived >40km from a tertiary care center. There was a high prevalence of severe mitral regurgitation (65.3%), and pericardial effusion was present in 18.6%. Nearly a quarter (23.7%) died during follow-up. In univariable Cox regression, living >40km from tertiary care, living in a remote area, moderate or severe malnutrition, taking a beta blocker, severe mitral stenosis, any severe valve disease, severe left atrial enlargement, and presence of a pericardial effusion were statistically significant risk factors for mortality (p<0.05). In the adjusted model, living >40km from tertiary care (HR 2.66, CI 1.06-6.07, p=0.037), malnutrition (mild HR 3.92, CI 1.03-14.91, p=0.045); moderate HR 7.41, CI 1.92-28.54, p=0.004; severe HR 4.91, CI 1.44-16.71, p=0.011), beta blocker use (HR 4.62, CI 1.63-13.10, p=0.004), and presence of a pericardial effusion (HR 6.96, CI 3.00-16.13, p<0.001) remained independent risk factors for mortality.

Conclusions: This study of Malawian children emphasizes the dire prognosis of RHD in under-resourced settings and provides potential area of focus for targeted intervention.

Introduction: Maternal mental health conditions, comprising maternal suicide and drug overdose, are currently the leading cause of maternal mortality in the United States. However, the relationship between suicidality and drug use behavior in the perinatal period is not well understood. We examined the association between suicidality and drug use behavior among perinatal individuals. Given the racial disparities in both drug use and suicide rates in the U.S., we also examined any differences in suicidality and drug use behavior by race.

Methods: Participants were recruited from a High-Risk Obstetric & Gynecological Clinic in the Midwestern U.S that specializes in providing obstetric care to perinatal individuals who have histories or current use of opioids and other illicit drugs. Participants (N = 66) were a sub-sample of a larger cohort enrolled in an mHealth intervention to support recovery from opioid and stimulant use disorders. We performed chi-square tests and t-tests to examine any significant associations between lifetime suicidality and drug use behavior during the perinatal period.

Results: The final analytic sample included participants who had responded to the suicidality survey questions (n=43). Nearly 40% (n=16) of our sample endorsed a lifetime history of suicidal thoughts and behaviors (SITB). Of those, 87% (n=15) reported a previous suicide attempt . SITB was significantly associated with cravings for opioids during the perinatal period (p = .01) as well as comorbidities with perinatal anxiety symptoms? ( p < .05), depression symptoms? (p < .05), and bipolar disorder (p < .05). A higher proportion of recent cannabis use was found among mothers with SITB, compared to those without SITB (p=0.04). Mothers with SITB also had a strong positive correlation between preconception and postnatal nicotine use compared to mothers without SITB (p < .01). Finally, while white mothers endorsed more lifetime overdoses (p= 0.01), Black mothers endorsed higher cravings for opioids during pregnancy (p = 0.03).

Conclusions: A history of SITB is a distinct risk factor for both illicit and recreational drug use behavior in the perinatal period, and frequently co-occurs with other perinatal mental health conditions. Further research is needed to better understand the directionality of this relationship and the complex interplay between high risk drug use behavior and suicidality.

Health behaviors such as physical activity and sleep affect mental health, but the effect of each health behavior varies substantially across individuals, limiting the usefulness of generic behavioral recommendations. We collected one year of continuous wearable and ecological momentary assessment data from 3,139 participants in the Intern Health Study (2018-2023), and examined individual-level associations between wearable-derived features and mood across the internship year. The behaviors associated with mood were highly heterogeneous between individuals: the two most prevalent drivers of mood were wake-up time (the strongest driver for 34.0% of subjects) and step count (10.6% of subjects). The correlation directionality remained largely stable despite fluctuations in strength. Interestingly, 20.3% of subjects showed no significant correlations. These findings highlight the limitations of population-level recommendations and the critical need for personalized, data-driven approaches to mental health assessment and intervention. To translate these personalized insights into actionable support, we developed MoodDriver, a large language models (LLM)-powered system that generates tailored feedback emails based on each participant's behavioral and physiological patterns. This work demonstrates the feasibility of combining digital phenotyping with large language models to advance precision digital mental health for high-risk populations.

Biological ageing begins before birth, with early-life exposures shaping late-life health. These exposures drive health inequities early, yet specific exposures and the composition of the ageing exposome remain largely undefined. This gap may persist as the field lacks agnostic investigations accounting for non-linearity, interactions and subtle signals. We aimed to identify exposures predictive of epigenetic ageing accumulated during childhood and adolescence and explore the composition of the "missing" exposome. In the FinnTwin12 cohort (847 participants measured at ages 12, 14, 17, and 22), over 500 exposures (including lifestyle, green environments, air pollutants, and demographic factors) were analysed using exposome-wide association studies and data-driven ML models (Knockoff Boosted Tree, sNPLS and Boruta). Epigenetic age (blood DNA methylation at age 22) was estimated using GrimAge and DunedinPACE. Our exposure set explains ∼28% of the variance in epigenetic age (R ² _GrimAge = 25.7%; R ² _DunedinPACE = 30.8%). Predictors of increased epigenetic age included lifestyle and socioeconomic factors ( smoking , alcohol use , youth unemployment ), alongside green space , while tree cover , vegetation index , neighbourhood age structure and aerial black carbon emerged as predictors of decreased epigenetic age. Twin modelling revealed that unexplained variance - the 'missing exposome' - consists primarily of environmental factors unshared by twin siblings, distinct from the substantial genetic component captured by our model. Our results underscore the need to expand the exposome approach and model non-linearities to reveal subtle environmental signals accumulating early in life. Because identified predictors include modifiable systemic factors, they offer opportunities to alter health trajectories and mitigate inequity early on.

Background: Mycoplasma genitalium (MG) is an emerging sexually transmitted infection (STI) associated with pelvic inflammatory disease and tubal factor infertility. Its relationship with impaired fecundity remains unclear and is rarely examined in the context of co-seropositivity with other STIs.

Methods: We conducted a secondary analysis of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial, a prospective preconception cohort of women with proven fecundity and prior pregnancy loss. MG serostatus was determined using Western blot-based IgG assays on 1146 stored serum specimens. Chlamydia trachomatis (CT) and other STIs were also measured. Associations between MG seropositivity and measures of impaired fecundity were assessed. Pregnancy loss and live birth were modeled using inverse-probability weighted quasi-Poisson and unweighted log-binomial models to calculate relative risks (RR). Fecundability-odds-ratio (FOR) was estimated using a discrete Cox proportional hazards model accounting for left truncation and right censoring. Propensity score (PS) weighted versions of these models assessed risks associated with CT co-seropositivity. Analyses were adjusted for demographic and reproductive history variables.

Results: Overall, 17.1% (n=210) of participants were MG seropositive, with 27.6% (n=58) co-seropositive with CT . Compared to STI-seronegative women, MG seropositivity was not associated with any outcome, although trends were observed for reduced fecundability (FOR _adj : 0.87, 95% CI 0.70-1.08) and live birth (RR _adj : 0.94, 95% CI 0.79-1.11). Co-seropositivity with CT was associated with lower likelihood of live birth [Relative Risk (RR) _PS-weighted : 0.82, 95% CI: 0.70-0.96]. Sensitivity analyses supported the robustness of these findings.

Conclusions: Being co-seropositive for MG and CT preconception may impair fecundity.

Objective: To compare early cerebrospinal fluid (CSF) cytokine profiles in intracerebral hemorrhage (ICH) versus subarachnoid hemorrhage (SAH), with a focus on angiography-negative SAH (anSAH).

Methods: We conducted a retrospective observational cohort study of adults with spontaneous hemorrhagic stroke (ICH or SAH). For cytokine analyses, we included patients with external ventricular drains (EVDs) and analyzed the first CSF sample obtained within 72 hours of symptom onset. Cytokines were measured using a multiplex bead-based assay and included interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor A (VEGF-A), C-C motif chemokine ligand-2 (CCL2), and granulocyte colony-stimulating factor (G-CSF). Cytokine concentrations were log-transformed due to non-normal distribution. Functional outcomes were assessed using the modified Rankin Scale (mRS) at discharge and 3 months.

Results: CSF cytokine analyses included 120 patients with available CSF samples (43 ICH and 77 SAH), while functional outcome analyses included a broader cohort of 490 patients with ICH or SAH to characterize discharge and 3-month outcomes across hemorrhage subtypes. Compared with SAH, ICH demonstrated higher early CSF log[IL-8] and log[VEGF-A] and had worse functional outcomes at discharge and 3 months. Within SAH, anSAH had higher log[IL-8] and log[VEGF-A] than aSAH, and its cytokine profile more closely aligned with that of primary ICH in hemorrhages without vascular malformations.

Discussion: Early CSF cytokine patterns suggest anSAH shares a more ICH-like inflammatory signature than aneurysmal SAH, supporting anSAH as a potentially biologically distinct SAH phenotype.

Linezolid is a critical last-resort antimicrobial for multidrug-resistant Enterococcus faecium , particularly against vancomycin-resistant lineages where therapeutic options are severely limited. While resistance has historically arisen through de novo chromosomal mutations, the global emergence of transferable resistance mechanisms threatens to render more infections untreatable. Here, we characterise a recent (2023-2024) hospital-associated outbreak of linezolid-resistant E. faecium in Queensland, Australia. Although the cohort comprised a variety of sequence types, the outbreak was primarily driven by the clonal expansion of an ST80 lineage carrying the plasmid-borne poxtA-Ef gene. Standard short-read genomic surveillance failed to resolve the genetic context of the resistance determinant. However, long-read sequencing revealed that poxtA-Ef was carried within a novel transposon, Tn 8026 , situated on a linear plasmid. Structural analysis defined Tn 8026 as a unique element flanked by IS 1678 and the novel insertion sequence IS Efa26 . Furthermore, we identified an instance of Tn 8026 integration into the chromosome, providing functional evidence of its mobility and capacity for stabilisation within the genome. Global genomic screening demonstrated that Tn 8026 significantly predates the local outbreak, identified in a historical Norwegian isolate from 2012, indicating a long-standing yet unrecognised global reservoir. Phylogenomic analysis provided strong evidence that the linear plasmid was imported from the Indian subcontinent, initiating a chain of silent dissemination in eastern Australia where the lineage circulated undetected prior to clinical recognition. Crucially, we also confirmed the presence of the linear plasmid in Enterococcus gallinarum , demonstrating its capacity to mobilise transmissible linezolid resistance across enterococcal species boundaries. These findings emphasise the need for detailed long-read-based surveillance of mobile genetic elements, with a particular focus on identifying linear plasmids that are often overlooked.

Oscillatory coupling between respiration, heart rate, and cortical function is fundamental to physiological regulation yet remains poorly characterized in humans. Diminished respiratory heart rate variability (RespHRV)-the rhythmic heart rate modulation accompanying respiration-has emerged as a transdiagnostic biomarker of mental and physical health, reduced in anxiety, depression, cardiovascular disease, and aging (Beauchaine & Thayer, 2015; Menuet & Gourine et al., 2025). However, the cortical substrates that coordinate rhythmic cardiovascular-respiratory coupling are not well understood. Our current findings highlight the involvement of the left orbitofrontal cortex (OFC) in oscillatory cardiorespiratory dynamics. In adults aged 50-70 (N = 55; mean age = 60.1 ± 6.0 years; 29 female), across both a slow-paced breathing condition and a random-paced breathing condition, greater heart rate oscillatory power during 9-week breathing training sessions predicted OFC volume increases. OFC changes were most strongly linked with upper low-frequency range power during practice (0.09-0.13 Hz; p < 0.005, cluster-corrected) but were not tightly constrained by precise breathing frequency. These effects covaried with improved attentional and executive performance, including reduced pupil responses to distractors and enhanced working-memory and associative-memory scores. Our findings identify the orbitofrontal cortex as a key site of cortical plasticity linked to rhythmic cardiovascular-respiratory engagement. By delineating how oscillatory body-brain coupling supports cognitive control-related processes, including attentional filtering and memory updating, this work bridges mechanistic neuroscience and translational intervention science, suggesting a frequency-general pathway through which simple breathing practices may enhance neurovisceral integration and cognitive resilience in aging.

Summary: Greater oscillatory heart rate power during breathing training, particularly within the upper low-frequency range (0.09-0.13 Hz), predicted increases in left orbitofrontal cortex (OFC) volume.OFC volume increases were associated with improved attentional and executive performance, including reduced pupil reactivity to distractors and enhanced working-memory and associative-memory scores.These findings suggest that rhythmic cardiovascular-respiratory coupling supports cortical plasticity and cognitive resilience, providing a frequency-general mechanism through which breathing practices enhance neurovisceral integration in aging.

Background: Elimination of Plasmodium vivax is challenging due to its dormant liver stages (hypnozoites), which can reactivate weeks or months after the primary infection, causing relapses and ongoing transmission of the parasite. Despite these challenges, P. vivax clinical case numbers have declined over the past decade in Cambodia. We used parasite genotyping to assess whether the decline in case numbers was reflected in parasite diversity and relatedness as a proxy to transmission.

Methods: Genotyping was conducted on 182 symptomatic P. vivax isolates collected in eastern Cambodia in 2014, 2015, 2019 and 2023. A panel of 93 microhaplotype markers (vivaxGEN panel) was genotyped using Illumina sequencing. Population genetic measures were applied to determine infection diversity and relatedness (identity-by-descent (IBD)) each year.

Results: The genetic results correlated well with clinical case numbers for the study years. The percentage of polyclonal infections was 5% in 2023 compared to 22-48% in earlier years (p<0.05) suggesting substantial reduction in superinfection and aligning with accelerated primaquine use in 2021. The cases in 2023 also had the highest percentage of infections with IBD >0.95 with one or more other infections (81.4% versus 8.9-10.8% in 2014-2019) indicative of inbreeding following population bottlenecking. In 2019, there was a spike in polyclonal infections (48%) and population diversity following local interruption of critical malaria control services.

Conclusions: Our findings illustrate the potential of microhaplotype genotyping to inform on P. vivax transmission to assess intervention efficacy. In eastern Cambodia, the data provides evidence to support of widespread use of radical cure for patients with P. vivax malaria.

Background: Candidemia is a rare but life-threatening bloodstream infection that remains difficult to predict using conventional risk stratification approaches, highlighting the need for improved predictive strategies. As a result, empiric antifungal therapy is often delayed even in high-risk patients.

Methods: We developed a deep learning model (PyTorch_EHR) to predict 7-day candidemia risk by using electronic health record data from two large cohorts (Houston Methodist Hospital System [HMHS] and MIMIC-IV), including adult inpatients who underwent at least one blood culture. Model performance was compared with logistic regression (LR), LightGBM, and established intensive care unit candidemia scores. We further implemented a two-step prediction framework integrating candidemia and 30-day mortality risk models to inform empiric antifungal decision-making.

Results: Among 213,404 and 107,507 patients in the HMHS and MIMIC-IV cohorts, candidemia occurred in fewer than 1% (851 [0.4%] and 634 [0.6%], respectively). PyTorch_EHR outperformed LR, LightGBM, and existing candidemia scores, particularly in terms of area under the precision-recall curve (AUPRC) in HMHS and MIMIC-IV. By integrating 30-day mortality risk, the two-step framework identified an additional 20 and 28 candidemia cases beyond the one-step model, increasing coverage to 61% (121/199) and 46% (68/147) in HMHS and MIMIC-IV, respectively. Many patients identified by the two-step framework had high mortality yet did not receive empiric antifungal therapy (61.1% HMHS; 82.6% MIMIC-IV).

Conclusion: A two-step deep-learning framework integrating candidemia and mortality risk may support early identification of high-risk patients and facilitate timely empiric antifungal therapy.Prospective studies are warranted to confirm the findings.