Cholesterol Metabolite 27-Hydroxycholesterol Enhances the Secretion of Cancer Promoting Extracellular Vesicles by a Mitochondrial ROS-Induced Impairment of Lysosomal Function.

Extracellular vesicles (EVs) serve as crucial mediators of cell-to-cell communication in normal physiology as well as in diseased states, and have been largely studied in regard to their role in cancer progression. However, the mechanisms by which their biogenesis and secretion are regulated by metabolic or endocrine factors remain unknown. Here, we delineate a mechanism by which EV secretion is regulated by a cholesterol metabolite, 27-Hydroxycholesterol (27HC), where treatment of myeloid immune cells (RAW 264.7 and J774A.1) with 27HC impairs lysosomal homeostasis, leading to shunting of multivesicular bodies (MVBs) away from lysosomal degradation, towards secretion as EVs. This impairment of lysosomal function is caused by mitochondrial dysfunction and subsequent increase in reactive oxygen species (ROS). Interestingly, cotreatment with a mitochondria-targeted antioxidant rescued the lysosomal impairment and attenuated the 27HC-mediated increase in EV secretion. Overall, our findings establish how a cholesterol metabolite regulates EV secretion and paves the way for the development of strategies to regulate cancer progression by controlling EV secretion.

High throughput screening identifies dasatinib as synergistic with trametinib in low grade serous ovarian carcinoma.

BACKGROUND: Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies. METHODS: We performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches. Validation comprised dose-response analysis across 9 LGSOC models and 5 high grade serous comparator lines. RESULTS: 16 hits of 1610 screened compounds were prioritised for validation based on >50% reduction in nuclei counts in over half of screened cell lines at 1000 nM concentration. 11 compounds passed validation, and the four agents of greatest interest (dasatinib, tyrosine kinase inhibitor; disulfiram, aldehyde dehydrogenase inhibitor; carfilzomib, proteasome inhibitor; romidepsin, histone deacetylase inhibitor) underwent synergy profiling with the recently approved MEK inhibitor trametinib. Disulfiram demonstrated excellent selectivity for LGSOC versus high grade serous ovarian carcinoma comparator lines (P = 0.003 for IC50 comparison), while the tyrosine kinase inhibitor dasatinib demonstrated favourable synergy with trametinib across multiple LGSOC models (maximum zero interaction potency synergy score 46.9). The novel, highly selective Src family kinase (SFK) inhibitor NXP900 demonstrated a similar trametinib synergy profile to dasatinib, suggesting that SFK inhibition is the likely driver of synergy. CONCLUSION: Dasatinib and other SFK inhibitors represent novel candidate treatments for LGSOC and demonstrate synergy with trametinib. Disulfiram represents an additional treatment strategy worthy of investigation.

Stimulating thyrotropin receptor antibodies in early pregnancy.

OBJECTIVES: Thyrotropin-receptor antibodies (TRAb) are used to diagnose Graves' hyperthyroidism in pregnant women. Bioassays provide a measure of thyrotropin-receptor stimulatory antibodies (TSI) specifically. The objective was to measure TSI in pregnant women for establishment of a pregnancy-specific cut-off and comparison with immunoassay measurements of TRAb. METHODS: The retrospective Danish study was performed within the North Denmark Region Pregnancy Cohort (2011-2015) that includes stored biobank samples from early pregnancy (median week 10) with immunoassay measurements of thyroid function parameters and TRAb. TSI were measured in the same samples using the Turbo TSI bioassay (Quidel/Ortho-Clinical Diagnostics) with a recommended cut-off of 0.0241 IU/L in non-pregnant adults. A pregnancy-specific TSI cut-off (95-percentile) was established using Regression on Order Statistics. RESULTS: The established TSI cut-off was 0.0418 IU/L (95 % CI: 0.0417-0.0419). Among women with early pregnancy hyperthyroidism (n=438), 43 women (9.8 %) were TSI positive using the established cut-off, and these women had lower TSH (median 0.008 mIU/L) compared to women with TSI levels below 0.0241 (median TSH 0.040 mIU/L) or in the range from 0.0241 to 0.0418 (median TSH 0.033 mIU/L). Among the 438 women with early pregnancy hyperthyroidism, 22 women were positive for TSI and TRAb, 388 were negative for both, and 28 women were positive for either TSI or TRAb. CONCLUSIONS: This is the first study on TSI measurements in a large cohort of early pregnant women. A pregnancy-specific cut-off for TSI was established and agreement in the classification with immunoassay measurements of TRAb was seen in 94 % of cases.

Assessment of Left Lung Remodeling With Magnetic Resonance Imaging in a Murine Model Following Exposure to Douglas Fir Smoke.

Wildland firefighters (WLFFs) experience lung function decline due to occupational exposure to fire smoke. WLFFs typically do not wear respiratory personal protective equipment, and if they do, it is a simple bandana, which is not effective at filtering smoke. To pinpoint the biological underpinnings of abnormal respiratory function following 3-7 years of WLFF service, we exposed mice to Douglas fir smoke (DFS) over 8 weeks. Following exposure, we assessed changes in lung structure through Magnetic Resonance Imaging (MRI) and histological analysis, which was supported by immunohistochemistry staining. With MRI, we found that the signal decay time, T2*, from ultrashort echo time (UTE) images was significantly shorter in mice exposed to DFS compared to air controls. In addition, the variation in T2* was more heterogeneously distributed throughout the left lung in DFS-exposed mice, compared to air controls. As confirmed by histological analysis, shorter T2* was caused by larger parenchyma airspace sizes and not fibrotic remodeling. Destruction of the alveolar spaces was likely due to inflammation, as measured by an influx of CD68+ macrophages and destruction due to enhanced neutrophil elastase. In addition, measurements of airspace dimensions from histology were more heterogeneously distributed throughout the lung, corroborating the enhanced relative dispersion of T2*. Findings from this study suggest that the decline in lung function observed in WLFFs may be due to emphysema-like changes in the lung, which can be quantified with MRI.

Self-reported pain severity and use of cannabis and opioids in persons with HIV in an urban primary care setting in Northern California: A cross-sectional study.

Persons with HIV (PWH) experience high levels of pain. We examined the relationship of pain severity with use of cannabis and prescription opioids among PWH. This cross-sectional study evaluated associations between self-reported pain (moderate/severe vs mild/none) and cannabis and prescription opioid use in a primary care sample of PWH enrolled in an alcohol use treatment study at Kaiser Permanente, San Francisco. Prevalence ratios (PR) for moderate/severe pain associated with cannabis, opioid use, or both in the prior 30 days were obtained from Poisson regression models. Adjusted models included race/ethnicity, education, employment, HIV ribonucleic acid levels, depression, and anxiety. Overall, 614 PWH completed baseline questionnaires from May 2013 to May 2015, among whom 182/614 (29.6%) reported moderate/severe pain. The prevalence of moderate/severe pain varied by substances: 19.1% moderate/severe pain among study participants who reported neither cannabis or opioids, 30.2% for cannabis alone, 41.2% for opioids alone, and 60.9% for those reporting both substances. In adjusted models, compared with PWH who reported neither substance (reference), prevalence of moderate/severe pain was higher for those using cannabis alone (PR 1.54; 95% CI 1.13-2.09), opioids alone (PR 1.96; 95% CI 1.31-2.94), and those reporting both (PR 2.66; 95% CI 1.91-3.70). PWH who reported opioid and/or cannabis use were more likely to report moderate/severe pain compared with PWH who did not report use of these substances. To improve patient care, it is vital to assess patients' approaches to pain management including substance use and target appropriate interventions to reduce pain in PWH.

Preliminary report of Mycoplasma Wenoynii and Candidatus Mycoplasma haemobos infection in Korean native cattle.

BACKGROUND: Hemotropic mycoplasmas or hemoplasmas are bacteria that attach to the erythrocyte surface and cause bovine hemoplasmosis. Two species, Mycoplasma wenyonii and Candidatus Mycoplasma haemobos, have been identified and shown to be distributed worldwide. However, there is currently no information available on hemoplasmas in cattle in the Republic of Korea. The aim of this study was to investigate the presence of hemoplasmas in Korean native cattle and to evaluate the association between hemoplasma infection and anemia. METHODS: One farm was selected, at which blood samples were collected from 104 Korean native cattle [grazing cattle (n = 89) and housed cattle (n = 15)]. Hemoplasmas were detected via polymerase chain reaction analysis and complete blood counts were also performed. RESULTS: The overall prevalence of hemoplasmas was 34% (35/104); 20.2% (21/104) for M. wenyonii, 3.8% (4/104) for C. M. haemobos, and 9.6% (10/104) for co-infection. Candidatus Mycoplasma haemobos was detected only in grazing cattle. Of red blood cell (RBC) parameters, C. M. haemobos-infected cattle had lower RBC and hematocrit, and higher mean cell volume than hemoplasma-negative cattle, although none of these differences were statistically significant. This is the first study to report the occurrence of M. wenyonii and C. M. haemobos. Mycoplasma wenyonii is more prevalent than C. M. haemobos in Korean native cattle. The results did not show an association between hemoplasma infection and anemia. CONCLUSIONS: Considering the infection rate of hemoplasmas shown in this study, further studies, such as on the pathogenicity and clinical significance of hemoplasmas are necessary.

Salivary Therapeutic Drug Monitoring of Antimicrobial Therapy: Feasible or Futile?

Personalised drug dosing through therapeutic drug monitoring (TDM) is important to maximise efficacy and to minimise toxicity. Hurdles preventing broad implementation of TDM in routine care include the need of sophisticated equipment and highly trained staff, high costs and lack of timely results. Salivary TDM is a non-invasive, patient-friendly alternative to blood sampling, which has the potential to overcome barriers with traditional TDM. A mobile UV spectrophotometer may provide a simple solution for analysing drug concentrations in saliva samples. Salivary TDM utilising point-of-care tests can support personalised dosing in various settings including low-resource as well as remote settings. In this opinion paper, we describe how hurdles of implementing traditional TDM may be mitigated by salivary TDM with new strategies for patient-friendly point-of-care testing.

Bayesian Vancomycin Model Selection for Therapeutic Drug Monitoring in Neonates.

BACKGROUND AND OBJECTIVE: Pharmacokinetic models can inform drug dosing of vancomycin in neonates to optimize therapy. However, the model selected needs to describe the intended population to provide appropriate dose recommendations. Our study aims to identify the population pharmacokinetic (PopPK) model(s) with the best performance to predict vancomycin exposure in neonates in our hospital. METHODS: Relevant published PopPK models for vancomycin in neonates were selected based on demographics and vancomycin dosing strategy. The predictive performance of the models was evaluated in Tucuxi using a local cohort of 69 neonates. Mean absolute error (MAE), relative bias (rBias) and relative root mean square error (rRMSE) were used to quantify the accuracy and precision of the predictive performance of each model for three different approaches: a priori, a posteriori, and Bayesian forecasting for the next course of therapy based on the previous course predictions. A PopPK model was considered clinically acceptable if rBias was between ± 20 and 95% confidence intervals included zero. RESULTS: A total of 25 PopPK models were identified and nine were considered suitable for further evaluation. The model of De Cock et al. 2014 was the only clinically acceptable model based on a priori [MAE 0.35 mg/L, rBias 0.8 % (95% confidence interval (CI) - 7.5, 9.1%), and rRMSE 8.9%], a posteriori [MAE 0.037 mg/L, rBias - 0.23% (95% CI - 1.3, 0.88%), and rRMSE 6.02%] and Bayesian forecasting for the next courses [MAE 0.89 mg/L, rBias 5.45% (95% CI - 8.2, 19.1%), and rRMSE 38.3%) approaches. CONCLUSIONS: The De Cock model was selected based on a comprehensive approach of model selection to individualize vancomycin dosing in our neonates.

A 12-year experience in the management of blunt thoracic aortic injury in Otautahi Christchurch.

BACKGROUND: Blunt thoracic aortic injury (BTAI) is associated with a high mortality and is the second most common cause of death from trauma. The approach to major trauma, imaging technology and advancement in endovascular therapy have revolutionised the management of BTAI. Endovascular therapy has now become the gold standard technique replacing surgery with its high mortality and morbidity in unstable patients. We aim to assess the outcomes following management of BTAI. METHOD: This is a retrospective study of all patients with BTAI between 1 January 2010 and 1 January 2022. Data were obtained from electronic health records. The grading of BTAI severity was done based on the Society of Vascular Surgery (SVS) Criteria. RESULTS: Fifty patients were included in the study analysis. The most common cause of BTAI was due to high-speed motor vehicle accidents (MVA) (36 patients, 72%). Grade 1 and grade 3 BTAI injuries were mostly encountered in 40% and 30% of the study cohort, respectively. Twenty-three patients (46%) underwent thoracic endovascular aortic repair (TEVAR). There was no secondary aortic re-intervention, conversion to open surgery or aortic-related deaths at 30 days or at most recent follow-up. CONCLUSION: Management of BTAI in our centre compares well with currently published studies. Long-term studies are warranted to guide clinicians in areas of controversy in BTAI management.

Exercising healthy behaviors: A latent class analysis of positive coping during the COVID-19 pandemic and associations with alcohol-related and mental health outcomes.

OBJECTIVE: To identify latent classes of positive coping behaviors during the COVID-19 pandemic and examine associations with alcohol-related and mental health outcomes across participants with and without a history of alcohol use disorder (AUD). METHODS: Baseline data from 463 participants who were enrolled in the NIAAA COVID-19 Pandemic Impact on Alcohol (C19-PIA) Study were analyzed. Latent class analysis (LCA) was applied to five positive coping behaviors during COVID-19: taking media breaks, taking care of their body, engaging in healthy behaviors, making time to relax, and connecting with others. Latent class differences and the moderating role of history of AUD on six alcohol-related and mental health outcomes were examined using multiple regression models. RESULTS: LCA revealed two latent classes: 83.4% High Positive Coping and 16.6% Low Positive Coping. Low Positive Coping was associated with higher levels of perceived stress, anxiety symptoms, and loneliness. A history of AUD was consistently associated with higher levels of alcohol-related and mental health outcomes. Significant interactions between Coping Latent Classes and history of AUD indicated that the associations of Low Positive Coping with problematic alcohol use, depressive symptoms, and drinking to cope motives were either stronger or only significant among individuals with a history of AUD. CONCLUSIONS: Individuals with a history of AUD may be particularly vulnerable to depressive symptoms and alcohol-related outcomes, especially when they do not utilize positive coping strategies. The promotion of positive coping strategies is a promising avenue to address alcohol-related and mental health problems during a public health crisis and warrants future research.

Dose Monitoring of Lamotrigine Monotherapy in Pregnancy: Are Pregnant Women with Epilepsy Currently Optimally Managed? A Systematic Review.

BACKGROUND: Lamotrigine monotherapy is the first-line treatment for epilepsy in pregnant women. However, altered pharmacokinetics during pregnancy can lead to suboptimal drug levels and increased seizure risk. This systematic review aimed to evaluate current therapeutic drug monitoring (TDM) strategies for lamotrigine monotherapy in pregnant women with epilepsy and provide guidance for monitoring and dose adjustments. METHODS: A systematic search was performed using the Ovid-MEDLINE, Ovid-EMBASE, and Ovid-Cochrane Central Register of Controlled Trials databases. Studies were included if data on lamotrigine dosing, concentration, TDM strategies, efficacy, or safety were available. RESULTS: Eleven studies were analyzed, revealing heterogeneity in outcomes with selective reporting of TDM strategies; however, clear similarities were observed. Blood samples were collected every 1-3 months during pregnancy to maintain prepregnancy baseline drug levels. Lamotrigine's apparent and relative clearance increased across trimesters, particularly in the second and third trimesters, coinciding with a period of increased seizure frequency and required dose adjustments. Details on dose adjustments were limited. Some studies have proposed using the threshold of the ratio to the target concentration to predict increased seizure risk. No distinct association was observed between adverse newborn outcomes and lamotrigine dose or serum concentration. Few maternal adverse effects have been reported after delivery, confirming the necessity of empirical postpartum tapering. CONCLUSIONS: Further studies are required to establish evidence-based standardized protocols encompassing all aspects of TDM. Early interventions, such as empirical dose increases during pregnancy and postpartum tapering, and routine monitoring from preconception to the postpartum period may enhance seizure control, reducing the risk of breakthrough seizures for the mother and unborn child.

Are dietitian recommendations followed? A descriptive study of paediatric hospitalised and ambulatory patients.

BACKGROUND: The primary objective of this cross-sectional retrospective study was to describe the implementation of dietitian prescribed nutrition recommendations in malnourished paediatric patients in the hospital and ambulatory settings. We also aimed to investigate other characteristics that could be associated with differences in implementation. METHODS: Data were collected from 186 hospitalised and 565 ambulatory patients between February 2020 and January 2021. Data included age, hospital or ambulatory specialty departments, primary diagnosis, malnutrition status, hospital length of stay (LOS), and medical nutrition therapy recommendations. Implementation by the medical team in the hospital setting and adherence by the family in the outpatient setting were categorised as "Full", "Partial" or "None". "Partial" and "None" were combined for analysis. RESULTS: Dietitian prescribed recommendations were implemented in 79.6% of hospitalised patients. In the ambulatory population, 46.4% of patients were adherent with nutrition recommendations. Within the hospital, there was a significant difference in implementation of nutrition recommendations based on age (p = 0.047), hospital department (p = 0.002) and LOS (p = 0.04), whereas, in the ambulatory population, there were no significant differences in the rate of adherence among any of the studied characteristics. CONCLUSIONS: Dietitian recommendations are frequently implemented in the hospital, whereas adherence to such recommendations is poor in the outpatient population. Interventions to improve adherence to nutrition recommendations in the ambulatory setting are needed.

Therapeutic drug monitoring of liposomal amphotericin B in children. Are we there yet? A systematic review.

INTRODUCTION: Therapeutic drug monitoring (TDM) is a tool that supports personalized dosing, but its role for liposomal amphotericin B (L-amb) is unclear. This systematic review assessed the evidence for L-amb TDM in children. OBJECTIVES: To evaluate the concentration-efficacy relationship, concentration-toxicity relationship and pharmacokinetic/pharmacodynamic (PK/PD) variability of L-amb in children. METHODS: We systematically reviewed PubMed and Embase databases following PRISMA guidelines. Eligible studies included L-amb PK/PD studies in children aged 0-18 years. Review articles, case series of 600 mg·h/L for nephrotoxicity. L-amb doses of 2.5-10 mg/kg/day were reported to achieve Cmax/MIC > 25 using an MIC of 1 mg/L. CONCLUSIONS: While significant PK variability was observed in children, evidence to support routine L-amb TDM was limited. Further studies on efficacy and toxicity benefits are required before routine TDM of L-amb can be recommended.

Factor structure of psychosis screening questionnaire in Ugandan adults.

BACKGROUND: Psychotic disorders are common and contribute significantly to morbidity and mortality of people with psychiatric diseases. Therefore, early screening and detection may facilitate early intervention and reduce adverse outcomes. Screening tools that lay persons can administer are particularly beneficial in low resource settings. However, there is limited research evaluating the validity of psychosis screening instruments in Uganda. We aimed to assess the construct validity and psychometric properties of the Psychosis Screening Questionnaire (PSQ) in Uganda in a population with no history of a psychotic disorder. METHODS: The sample consisted of 2101 Ugandan adults participating as controls in a larger multi-country case-control study on psychiatric genetics who were recruited between February 2018 and March 2020. Participants were individuals seeking outpatient general medical care, caretakers of individuals seeking care, and staff or students recruited from five medical facilities that were age 18 years or older and able to provide consent. Individuals were excluded who had acute levels of alcohol or substance use, including being under inpatient hospitalization or acute medical care for one of these conditions. We used confirmatory factor analysis (CFA) and item response theory (IRT) to evaluate the factor structure and item properties of the PSQ. RESULTS: The overall prevalence screening positive for psychotic symptoms was 13.9% 95% CI (12.4,15.4). "Strange experiences" were the most endorsed symptoms 6.6% 95% CI (5.6,7.8). A unidimensional model seemed to be a good model or well-fitting based on fit indices including the root mean square error of approximation (RMSEA of 0.00), comparative fit index (CFI of 1.000), and Tucker-Lewis Index (TLI of 1.000). The most discriminating items along the latent construct of psychosis were items assessing thought disturbance followed by items assessing paranoia, with a parameter (discrimination) value of 2.53 and 2.40, respectively. CONCLUSION: The PSQ works well in Uganda as an initial screening tool for moderate to high-level of psychotic symptoms.

Orofacial Myofunctional Therapy for Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis.

OBJECTIVE: Orofacial myofunctional therapy (OMT) is an alternative form of treatment of obstructive sleep apnea (OSA), that incorporates various exercises to optimize tongue placement and increase oropharyngeal tone. The objective of this systematic review and meta-analysis is to determine the efficacy of OMT in OSA patients. DATA SOURCES: PubMed/Medline, EMBASE, Cochrane, Web of Science. REVIEW METHODS: Using PRISMA guidelines, a directed search strategy was performed for randomized control trials (RCTs) published prior to March 24, 2023, featuring 10+ patients with OSA undergoing mono-therapeutic OMT. The primary outcome of interest was apnea-hypopnea index (AHI). Secondary outcomes included subjective sleepiness, sleep-related quality-of-life, and snoring frequency. RESULTS: Of the 1244 abstracts that were identified, 7 RCTs involving 310 patients met inclusion criteria. Adult OMT patients had a statistically significant improvement in AHI (MD -10.2; 95% CI, -15.6, -4.8, p < 0.05), subjective sleepiness (Epworth Sleepiness Scale; MD -5.66; 95% CI, -6.82, -4.5, p < 0.05), sleep-related quality-of-life (Pittsburgh Sleep Quality Index; MD -3.00; 95% CI, -4.52, -1.49, p < 0.05), and minimum oxygen saturation (MD 2.71; 95% CI, 0.23, 5.18, p < 0.05) when compared with sham OMT or no therapy. Within the single RCT featuring pediatric OMT patients, patients had poor compliance (<50%) and did not show any improvements in AHI, minimum oxygen saturation, or snoring frequency. CONCLUSION: OMT may provide a reasonable alternative for OSA patients who cannot tolerate CPAP or other more established treatment options. OMT benefits appear limited in children due to poor compliance. More studies are required to evaluate compliance and the long-term effects of OMT on OSA outcomes. LEVEL OF EVIDENCE: 1 Laryngoscope, 134:480-495, 2024.

Pubertal luteinizing hormone levels in children with chronic kidney disease and association with change in glomerular filtration rate.

BACKGROUND: Children with chronic kidney disease (CKD) are at risk for abnormalities in pubertal development. We aimed to describe the timing of pubertal onset by luteinizing hormone (LH) levels and the association between hormonal onset of puberty with changes in GFR. METHODS: Data from the Chronic Kidney Disease in Children (CKiD) study were collected prospectively. GFR was estimated at annual visits and measured by iohexol clearance every other year. LH was measured from stored repository serum samples in a nested sample of 124 participants. Hormonal onset of puberty was defined as LH level greater than or equal to 0.3 IU/L. A mixed effects model with random intercepts and slopes was used to compare the slope of decline of GFR before and after hormonal onset of puberty. The model was adjusted for age, glomerular disease diagnosis, baseline proteinuria on the log scale, and BMI. RESULTS: Median age at hormonal onset of puberty was 9.9 years (IQR 8.1, 11.9) in girls and 10.2 years (IQR 9.2, 11.0) in boys. The mixed effects model showed faster decline in both estimated GFR and measured GFR in boys after hormonal onset of puberty (p < 0.001), and a similar but attenuated accelerated estimated GFR decline was observed for girls with no difference for measured GFR. CONCLUSIONS: LH levels in the post-pubertal range were observed prior to clinical manifestations of puberty in children with CKD. Hormonal onset of puberty was associated with faster decline in GFR, particularly among boys with CKD.

Regulation of stress-induced sleep fragmentation by preoptic glutamatergic neurons.

Sleep disturbances are detrimental to our behavioral and emotional well-being. Stressful events disrupt sleep, in particular by inducing brief awakenings (microarousals, MAs), resulting in sleep fragmentation. The preoptic area of the hypothalamus (POA) is crucial for sleep control. However, how POA neurons contribute to the regulation of MAs and thereby impact sleep quality is unknown. Using fiber photometry in mice, we examine the activity of genetically defined POA subpopulations during sleep. We find that POA glutamatergic neurons are rhythmically activated in synchrony with an infraslow rhythm in the spindle band of the electroencephalogram during non-rapid eye movement sleep (NREMs) and are transiently activated during MAs. Optogenetic stimulation of these neurons promotes MAs and wakefulness. Exposure to acute social defeat stress fragments NREMs and significantly increases the number of transients in the calcium activity of POA glutamatergic neurons during NREMs. By reducing MAs, optogenetic inhibition during spontaneous sleep and after stress consolidates NREMs. Monosynaptically restricted rabies tracing reveals that POA glutamatergic neurons are innervated by brain regions regulating stress and sleep. In particular, presynaptic glutamatergic neurons in the lateral hypothalamus become activated after stress, and stimulating their projections to the POA promotes MAs and wakefulness. Our findings uncover a novel circuit mechanism by which POA excitatory neurons regulate sleep quality after stress.

Psychosis screening questionnaire: Exploring its factor structure among South African adults.

Background: Early detection of psychosis improves treatment outcomes, but there is limited research evaluating the validity of psychosis screening instruments, particularly in low-resourced countries. Aim: This study aims to assess the construct validity and psychometric properties of the psychosis screening questionnaire (PSQ) in South Africa. Setting: This study was conducted at several health centres in the Western and Eastern Cape provinces in South Africa. Methods: The sample consisted of 2591 South African adults participating as controls in a multi-country case-control study of psychiatric genetics. Using confirmatory factor analysis and item response theory, we evaluated the psychometric properties of the PSQ. Results: Approximately 11% of the participants endorsed at least one psychotic experience on the PSQ, and almost half of them (49%) occurred within the last 12 months. A unidimensional model demonstrated good fit (root mean square error of approximation [RMSEA] = 0.023, comparative fit index [CFI] = 0.977 and Tucker-Lewis Index [TLI] = 0.954). The mania item had the weakest association with a single latent factor (standardised factor loading = 0.14). Model fit improved after removing the mania item (RMSEA = 0.025, CFI = 0.991 and TLI = 0.972). With item response theory analysis, the PSQ provided more information at higher latent trait levels. Conclusion: Consistent with prior literature, the PSQ demonstrated a unidimensional factor structure among South Africans. In our study, the PSQ in screening for psychosis performed better without the mania item, but future criterion validity studies are warranted. Contribution: This study highlights that PSQ can be used to screen for early psychosis.