Cognitive functioning within psychosis is heterogeneous, and data-driven approaches may help evaluate this heterogeneity. Brain network connectivity within first-episode psychosis (FEP) may provide an additional tool for understanding cognitive heterogeneity. FEP participants and healthy controls (HC) completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and premorbid intellectual functioning was estimated using The American National Adult Reading Test (AmNART). k-means clustering of RBANS domain scores identified cognitive subgroups within FEP. Resting-state functional connectivity (FC) of the default mode (DMN), dorsal attention (DAN), executive control (ECN), and salience networks (SN) was assessed at baseline (prior to antipsychotic treatment), 6-, and 16 weeks. Voxelwise linear mixed models evaluated group-by-time interactions within each network. Two cognitive subgroups were identified within FEP (impaired and intact). All subjects had average premorbid intellectual functioning. At baseline, the cognitively impaired FEP subgroup showed reduced functional connectivity relative to healthy controls across regions within the DAN and ECN, with no significant differences observed between FEP subgroups (PFDR < .05). Over time, the impaired subgroup exhibited fluctuating FC in the DAN and ECN, while the intact subgroup showed FC changes only in the ECN (PFDR < .05). HCs also showed minor changes in the DAN and ECN. Distinct FEP cognitive subgroups show differential changes in FC. Notably, the impaired subgroup's shift from average premorbid intellectual functioning to impaired cognition suggests potential cognitive deterioration in a subset of psychosis participants. These results underscore the importance of considering both cognitive and neural heterogeneity in FEP.

Background and Hypothesis Converging evidence from animal and human studies has implicated gamma-aminobutyric acid (GABA)-ergic dysfunction in the pathophysiology of psychosis spectrum disorders. However, little is known about GABA’s role in the early illness stages. Based on prior research, we hypothesized that GABA levels would already be altered in first episode psychosis patients (FEP), and that they would be associated with patients’ cognitive function and response to treatment. Study Design We used magnetic resonance spectroscopy with a MEGA-PRESS sequence to quantify GABA in the dorsal anterior cingulate cortex (ACC) at baseline and over the course of antipsychotic treatment with risperidone. We compared GABA levels between 79 medication-naïve FEP and 113 healthy controls (HC) longitudinally over a period of 16 weeks and examined their relationships to cognition and treatment response. Study Results We found significantly lower GABA levels in FEP compared to HC at all 3 time points (baseline, 6 weeks, 16 weeks), but did not observe a significant main effect of time or an interaction of group by time. We found no significant correlations between GABA and cognitive scores. Baseline GABA levels of patients considered treatment nonresponders significantly differed from HC, whereas responders did not. Conclusions Our findings suggest that GABA dysfunction in the ACC may be an important feature of the core pathophysiology of psychosis. This dysfunction does not appear to be attenuated by conventional antipsychotic treatment, though baseline levels may be indicative of clinical prognosis in FEP.

Early access to health care is essential to avert morbidity and mortality. A telemedicine and medication delivery service (TMDS) is an innovative solution to address this need; however, pathways to scalability are unclear. We sought to evaluate a scalable pediatric TMDS. A TMDS in Haiti was configured for scalability by triaging severe cases to hospital-level care, nonsevere cases with higher clinical uncertainty to in-person examinations at households, and nonsevere cases with low clinical uncertainty to medication delivery alone. This design was evaluated in a prospective cohort study conducted among pediatric patients 10 years old or younger. Clinical and operational metrics were compared with a formative reference study in which all nonsevere patients received an in-person examination. The primary outcomes were rates of clinical improvement/recovery and in-person care seeking at 10 days. In total, 1,043 cases were enrolled in the scalable TMDS mode, and 19% (190) of nonsevere cases received an in-person examination; 382 cases were enrolled in the reference study, and 94% (338) of nonsevere cases received an in-person examination. At 10 days, rates of improvement were similar for the scalable and reference modes. Rates of participants who sought follow-up care were 15% in the scalable mode and 24% in the reference mode. In the context of a 5-fold reduction of in-person examinations, participants in the scalable mode had noninferior rates of improvement at 10 days. These findings highlight an innovative and now scalable solution to improve early access to health care without compromising safety.

BackgroundThe ADAPT guidance proposes a process model for adapting evidence-informed interventions to novel contexts. Herein, we leveraged this guidance to adapt a paediatric nighttime telemedicine and medication delivery service from Haiti, a setting with low malaria prevalence, to Ghana, where malaria is a leading cause of paediatric mortality.MethodsCore components of the intervention were defined and conserved. Discretionary components were identified and considered for adaptation. The service was defined by a workflow involving a call from a guardian of a sick child, a telemedicine assessment, referral of severe cases, and medication delivery/in-person assessments for non-severe cases. Key adaptations related to partner organisation (private to public/government), clinician type (nurse to emergency medical technician), user fees (sliding scale to none), and point-of-care testing (none to malaria rapid diagnostic testing). The adapted model was implemented in Jamestown and Usshertown, Ghana, on 16 November 2022 as part of a 12-month study to evaluate implementation outcomes and the role of the telemedicine assessment. Empiric thresholds for safety and feasibility were set a priori and served as benchmarks for this study and points of iteration for future studies.ResultsIn the first year of implementation, 517 cases were enrolled; 492 were included in the analysis, 96% of which were reached at 10-day follow-up. Safety and feasibility thresholds were met. 98% of febrile cases received rapid diagnostic testing for malaria; 4% tested positive. At 10 days, 97% of cases were improving/well, and no severe adverse events were reported. The median lengths of the telemedicine assessment, time to delivery, and in-person assessments were 9, 49, and 43 min, respectively. 99% of participants expressed interest in using the service again. There was fair congruence between paired telemedicine and in-person assessments for vital sign assessments and mild/moderate triage decisions.ConclusionsA nighttime paediatric telemedicine and medication delivery service adapted and implemented per the ADAPT Guidance met a priori-defined safety and feasibility metrics in the malaria-endemic country of Ghana. The role of telemedicine in assessing vital signs and informing mild versus moderate triage decisions may be limited.Trial RegistrationThis study was registered on on 8/17/2022 (NCT05506683).

INTRODUCTION:Deaths related to drug overdose and suicide in the USA have increased 500% and 35%, respectively, over the last two decades. The human and economic costs to society associated with these 'deaths of despair' are immense. Great efforts and substantial investments have been made in treatment and prevention, yet these efforts have not abated these increasing trajectories of deaths over time. The COVID-19 pandemic has exacerbated and highlighted these problems. Notably, some geographical areas (eg, Appalachia, farmland) and some communities (eg, low-income persons, 'essential workers', minoritised populations) have been disproportionately affected. Risk factors have been identified for substance use and suicide deaths: forms of adversity, neglect, opportunity indexes and trauma. Yet, the biological, psychological and social mechanisms driving risk are not uniform. Notably, most people exposed to risk factors do not become symptomatic and could broadly be considered resilient. Achieving a better understanding of biological, psychological and social mechanisms underlying both pathology and resilience will be crucial for improving approaches for prevention and treatment and creating precision medicine approaches for more efficient and effective treatment. METHODS AND ANALYSIS:The State of Ohio Adversity and Resilience (SOAR) study is a prospective, longitudinal, multimodal, integrated familial study designed to identify biological, psychological and social risk and resilience factors and processes leading to mental health disorders, substance use disorders, substance overdose, suicide and associated psychological/medical comorbidities which reduce life expectancy and quality of life. It includes two nested longitudinal samples: (1) WD Survey: an address-based random population epidemiological sample of 15 000 individuals (unique households) representative of the state of Ohio assessed for psychosocial, psychiatric, behavioural health and substance use factors and (2) Brain Health Study: a family-based, multimodal, deep-phenotyping study conducted in 1200 families (up to 3600 persons aged 12-72 years) including MRI, electroencephalography, blood biomarkers and psychiatric diagnostic interviews, as well as neuropsychological, psychosocial functioning and family/community history, dynamics and support assessments. SOAR is designed to discover, develop and deploy advanced predictive analytics and interventions to transform mental health prevention, diagnosis, treatment and recovery. ETHICS AND DISSEMINATION:All participants will provide written informed consent (or parental permission and assent for minors). The study was approved by The Ohio State University Institutional Review Board (study numbers 2023H0316 (Brain Health) and 2023H0350 (Wellness Survey). The Brain Health study was also approved by institutional review boards at each partnering institution involved in conducting participant assessments. Findings will be disseminated to academic peers, clinicians and healthcare consumers, policymakers and the general public, using local and international academic channels (academic journals, evidence briefs and conferences) and outreach (workshops and seminars).

The developmental trajectory of emotion recognition (ER) skills is thought to vary by nonverbal modality, with vocal ER becoming mature later than facial ER. To investigate potential neural mechanisms contributing to this dissociation at a behavioural level, the current study examined whether youth's neural functional connectivity during vocal and facial ER tasks showed differential developmental change across time. Youth ages 8-19 ( n = 41) completed facial and vocal ER tasks while undergoing functional magnetic resonance imaging, at two timepoints (1 year apart; n = 36 for behavioural data, n = 28 for neural data). Partial least squares analyses revealed that functional connectivity during ER is both distinguishable by modality (with different patterns of connectivity for facial vs. vocal ER) and across time-with changes in connectivity being particularly pronounced for vocal ER. ER accuracy was greater for faces than voices, and positively associated with age; although task performance did not change appreciably across a 1-year period, changes in latent functional connectivity patterns across time predicted participants' ER accuracy at Time 2. Taken together, these results suggest that vocal and facial ER are supported by distinguishable neural correlates that may undergo different developmental trajectories. Our findings are also preliminary evidence that changes in network integration may support the development of ER skills in childhood and adolescence.

ABSTRACTA complex microbial community in the gut may prevent the colonization of enteric pathogens such as Salmonella. Some individual or a combination of species in the gut may confer colonization resistance against Salmonella. To gain a better understanding of the colonization resistance against Salmonella enterica, we isolated a library of 1,300 bacterial strains from feral chicken gut microbiota which represented a total of 51 species. Using a co-culture assay, we screened the representative species from this library and identified 30 species that inhibited Salmonella enterica subspecies enterica serovar Typhimurium in vitro. To improve the Salmonella inhibition capacity, from a pool of fast-growing species, we formulated 66 bacterial blends, each of which composed of 10 species. Bacterial blends were more efficient in inhibiting Salmonella as compared to individual species. The blend that showed maximum inhibition (Mix10) also inhibited other serotypes of Salmonella frequently found in poultry. The in vivo effect of Mix10 was examined in a gnotobiotic and conventional chicken model. The Mix10 consortium significantly reduced Salmonella load at day 2 post-infection in gnotobiotic chicken model and decreased intestinal tissue damage and inflammation in both models. Cell-free supernatant of Mix10 did not show Salmonella inhibition, indicating that Mix10 inhibits Salmonella through either nutritional competition, competitive exclusion, or through reinforcement of host immunity. Out of 10 species, 3 species in Mix10 did not colonize, while 3 species constituted more than 70% of the community. Two of these species were previously uncultured bacteria. Our approach could be used as a high-throughput screening system to identify additional bacterial sub-communities that confer colonization resistance against enteric pathogens and its effect on the host.IMPORTANCESalmonella colonization in chicken and human infections originating from Salmonella-contaminated poultry is a significant problem. Poultry has been identified as the most common food linked to enteric pathogen outbreaks in the United States. Since multi-drug-resistant Salmonella often colonize chicken and cause human infections, methods to control Salmonella colonization in poultry are needed. The method we describe here could form the basis of developing gut microbiota-derived bacterial blends as a microbial ecosystem therapeutic against Salmonella.

Cholera is a diarrhoeal disease caused by Vibrio cholerae. It remains a major public health challenge in the endemic region around the Bay of Bengal. Over decadal time scales, one lineage typically dominates the others and spreads in global pandemic waves. However, it remains unclear to what extent diverse lineages co-circulate during a single outbreak season. Defining the pool of diversity during finer time scales is important because the selective pressures that impact V. cholerae - namely antibiotics and phages - are dynamic on these time scales. To study the nationwide diversity of V. cholerae, we long-read sequenced 273 V. cholerae genomes from seven hospitals over one year (2018) in Bangladesh. Four major V. cholerae lineages were identified: known lineages BD-1, BD-2a, and BD-2b, and a novel lineage that we call BD-3. In 2022, BD-1 caused a large cholera outbreak in Dhaka, apparently outcompeting BD-2 lineages. We show that, in 2018, BD-1 was already dominant in the five northern regions, including Dhaka, consistent with an origin from India in the north. By contrast, we observed a higher diversity of lineages in the two southern regions near the coast. The four lineages differed in pangenome content, including integrative and conjugative elements (ICEs) and genes involved in resistance to bacteriophages and antibiotics. Notably, BD-2a lacked an ICE and is predicted to be more sensitive to phages and antibiotics, but nevertheless persisted throughout the year-long sampling period. Genes associated with antibiotic resistance in V. cholerae from Bangladesh in 2006 were entirely absent from all lineages in 2018-19, suggesting shifting costs and benefits of encoding these genes. Together, our results highlight the dynamic nature of the V. cholerae pangenome and the geographic structure of its lineage diversity.

Previous research has identified regions of the brain that are sensitive to emotional intensity in faces, with some evidence for developmental differences in this pattern of response. However, comparable understanding of how the brain tracks linear variations in emotional prosody is limited—especially in youth samples. The current study used novel stimuli (morphing emotional prosody from neutral to anger/happiness in linear increments) to investigate whether neural response to vocal emotion was parametrically modulated by emotional intensity and whether there were age-related changes in this effect. Participants aged 8–21 years (n = 56, 52

Despite an increasingly detailed picture of the molecular mechanisms of bacteriophage (phage)-bacterial interactions, we lack an understanding of how these interactions evolve and impact disease within patients. In this work, we report a year-long, nationwide study of diarrheal disease patients in Bangladesh. Among cholera patients, we quantified Vibrio cholerae (prey) and its virulent phages (predators) using metagenomics and quantitative polymerase chain reaction while accounting for antibiotic exposure using quantitative mass spectrometry. Virulent phage (ICP1) and antibiotics suppressed V. cholerae to varying degrees and were inversely associated with severe dehydration depending on resistance mechanisms. In the absence of antiphage defenses, predation was "effective," with a high predator:prey ratio that correlated with increased genetic diversity among the prey. In the presence of antiphage defenses, predation was "ineffective," with a lower predator:prey ratio that correlated with increased genetic diversity among the predators. Phage-bacteria coevolution within patients should therefore be considered in the deployment of phage-based therapies and diagnostics.

ABSTRACT Cholera rapid diagnostic tests (RDTs) are vulnerable to virulent bacteriophage predation. We hypothesized that an enhanced cholera RDT that detects the common virulent bacteriophage ICP1 might serve as a proxy for pathogen detection. We previously developed a monoclonal antibody (mAb) to the ICP1 major capsid protein. Our objective was to design and assemble a first-of-its-kind RDT that detects both a bacterial pathogen ( Vibrio cholerae ) and associated virulent bacteriophage (ICP1). Candidate mAbs were expanded to increase design options and evaluated by immunological assays (ELISA; western blot). A subset of mAbs were selected for gold conjugation and printing on the RDT. The detection limit of the prototype RDTs was determined in diarrheal stools with the addition of ICP1. Three mAb candidates were developed and evaluated for the capsid decoration protein (ORF123) and tail fiber protein (ORF93), and the prior mAb for the major capsid protein (ORF122). A single mAb sandwich RDT prototype for ORF122 was able to detect ICP1; RDTs with mAbs to ORF123 and ORF93 failed to detect ICP1 in single- or dual-sandwich configurations. Biologically relevant concentrations for ICP1 were detected only after boiling the stool with ICP1; analysis by electron microscopy (EM) suggested increased epitope availability after boiling. In this study, we demonstrate a proof of concept for a functional RDT that can detect both the primary pathogen and a common virulent bacteriophage as a proxy for pathogen detection. Further optimization is required before scaled production and implementation. IMPORTANCE This paper represents an important step forward to address the vulnerability of cholera RDTs to the effects of phage predation on the target Vibrio cholerae . The assembly and evaluation of an RDT that detects both the primary pathogen and a phage as a proxy for the primary pathogen is an innovative solution. When optimized and evaluated in clinical studies, this tool may become critical in the cholera response tool kit as well as represent a diagnostic proof-of-concept for other infectious agents.

Senecavirus A (SVA) is a non-enveloped, positive sense, single-stranded RNA virus that causes vesicular diseases in pigs. Interferon-induced transmembrane 3 (IFITM3) is an interferon-stimulated gene (ISG) that exhibits broad antiviral activity. We investigated the role of IFITM3 in SVA replication. Both viral protein expression and supernatant virus titer were significantly increased when endogenous IFITM3 was knocked down by approximately 80% in human non-smallcell lung carcinoma cell line (NCI-H1299) compared to silencing RNA control. Interestingly, overexpression of exogenous IFITM3 in NCI-H1299 cells also significantly enhanced viral protein expression and virus titer compared to vector control, which was positively correlated with induction of autophagy mediated by IFITM3 overexpression. Overall, our results indicate an antiviral role of endogenous IFITM3 against SVA. The exact molecular mechanisms by which endogenous IFITM3 limits SVA replication remain to be determined in future studies.

Transgender/non-binary (TNB) adolescents are at increased risk for mental health concerns, and caregiver awareness is important to facilitate access to care. Yet, limited research has examined caregiver awareness of TNB mental health. Thus, we examined (1) the prevalence of internalizing symptoms (depression, generalized anxiety, separation anxiety, social anxiety) among TNB adolescents and (2) associations between adolescent and caregiver reports of adolescent mental health symptoms. TNB adolescents (N = 75) aged 12–18 and a caregiver were recruited from a multidisciplinary gender clinic in Ohio. Adolescents self-reported their mental health symptoms via the CDI and SCARED. Caregivers reported their perceptions of the adolescent’s mental health symptoms via the CASI-5. Descriptive statistics assessed participant characteristics, adolescent self-reported mental health symptoms, and caregiver proxy reports of adolescent mental health symptoms. Pearson’s correlations and scatterplots were used to compare adolescent and caregiver reports and McNemar tests assessed if the differences were statistically significant. Most TNB adolescents reported elevated symptoms of depression (59 Conclusions: Though adolescent and caregiver reports were low to moderately correlated, youth reports were consistently higher, suggesting the importance of interventions to increase caregiver understanding of TNB adolescent mental health.

OBJECTIVE The purpose of this case study was to describe the transmission of porcine reproductive and respiratory syndrome virus (PRRSV) under field and experimental conditions via the consumption of PRRSV-positive swine feed. ANIMALS 1 domestic swine breeding herd and 20 laboratory-maintained experimental domestic pigs. CLINICAL PRESENTATION, PROGRESSION, AND PROCEDURES A 2,500-sow PRRSV-naïve biosecure breeding herd became infected during the autumn months. It experienced a feed outage involving a specific bin on October 23 (day 0), with the bin refilled on October 24 (day 1). From October 28 to 30 (days 5 to 7), signs of anorexia and hyperemia were observed in 30 gestating sows after consuming feed from this bin. On November 1 (day 9), blood samples from 10 affected sows were PRRSV positive by reverse transcriptase PCR. In contrast, sows in the same room that had consumed feed from other bins were clinically normal and PRRSV negative. To investigate whether the feed delivery introduced PRRSV to the herd, on November 2 (day 10) 4 samples of feed material from the interior walls of the index bin were collected and tested by reverse transcriptase PCR. TREATMENT AND OUTCOME All 4 samples were positive for PRRSV RNA with cycle threshold values ranging from 26 to 29. Nucleic acid sequencing indicated that the open reading frame 5 region of the PRRSV in feed samples was 100% homologous to PRRSV from index cases. To assess viability of the virus, PRRSV-naïve pigs were allowed to consume the index feed bin samples and became infected with PRRSV based on viral RNA in oral fluid samples, clinical signs, and postmortem lesions. CLINICAL RELEVANCE These results suggest that feed was a likely source of PRRSV introduction to the herd. This is the first report of PRRSV transmission through feed.

Depression is associated with alterations in prosody when speaking (e.g., less variation in pitch, slowed speech rate), but less is known about its impact on emotional prosody. This is particularly important to investigate in parent–child contexts, as parental expression of emotion may contribute to the intergenerational transmission of depression risk. The current study asked mothers of preschool-aged children (with and without a history of major depressive disorder during their child’s lifetime) to produce child-relevant sentences in neutral, angry, and happy tones of voice. We examined whether groups’ portrayals were acoustically or perceptually different, in speech analyses and listener ratings. Mothers with a history of depression expressed happiness with less range in pitch and a slower speech rate (slower, more monotonous voice) than mothers with no history of depression. Across groups, happy exemplars with less range in pitch were rated as less emotionally intense, recognizable, and authentically happy by listeners; slower speech rate was associated with opposite perceptual ratings. However, listeners’ ratings did not differ by depression group as a whole. Results suggest that a history of depression may influence maternal vocal expression of happiness, but that its impact on listeners’ perceptions may depend on mothers’ idiosyncratic use of acoustic cues.

Maternal depression is a predictor of the emergence of depression in the offspring. Attention bias (AB) to negative emotional stimuli in children may serve as a risk factor for children of depressed parents. The present study aimed to examine the effect of maternal major depressive disorder (MDD) history on AB to emotional faces in children at age four, before the age of onset for full-blown psychiatric symptoms. The study also compared AB patterns between mothers and their offspring. Fifty-eight mothers and their four-year-old children participated in this study, of which 27 high-risk (HR) children had mothers with MDD during their children's lifetime. Attention to emotional faces was measured in both children and their mothers using an eye-tracking visual search task. HR children exhibited faster detection and longer dwell time toward the sad than happy target faces. The low-risk (LR) children also displayed a sad bias but to a lesser degree. Children across both groups showed AB towards angry target faces, likely reflecting a normative AB pattern. Our findings indicate that AB to sad faces may serve as an early marker of depression risk. However, we provided limited support for the mother-child association of AB. Future research is needed to examine the longitudinal intergenerational transmission of AB related to depression and possible mechanisms underlying the emergence of AB in offspring of depressed parents.

Background:Informally trained health care providers, such as village doctors in Bangladesh, are crucial in providing health care services to the rural poor in low- and middle-income countries. Despite being one of the primary vendors of antibiotics in rural Bangladesh, village doctors often have limited knowledge about appropriate antibiotic use, leading to varied and potentially inappropriate dispensing and treatment practices. In this study, we aimed to identify, map, and survey village doctors in the Sitakunda subdistrict of Bangladesh to understand their distribution, practice characteristics, clinical behaviours, access to technologies, and use of these technologies for clinical decision-making. Methods:Using a 'snowball' sampling method, we identified and mapped 411 village doctors, with 371 agreeing to complete a structured survey. Results:The median distance between a residential household and the closest village doctor practice was 0.37 km, and over half of the practices (51.2%) were within 100 m of the major highway. Village doctors were predominately male (98.7%), with a median age of 39. After completing village doctor training, 39.4% had completed an internship, with a median of 15 years of practice experience. Village doctors reported seeing a median of 84 patients per week, including a median of five paediatric diarrhoea cases per week. They stocked a range of antibiotics, with ciprofloxacin and metronidazole being the most prescribed for diarrhoea. Most had access to phones with an internet connection and used online resources for clinical decision-making and guidance. Conclusions:The findings provide insights into the characteristics and practices of village doctors and point to the potential for internet and phone-based interventions to improve patient care and reduce inappropriate antibiotic use in this health care provider group.