Mitochondrial chaperon TNF-receptor- associated protein 1 as a novel apoptotic regulator conferring susceptibility to Pneumocystis jirovecii pneumonia.

Molecular chaperons stabilize protein folding and play a vital role in maintaining tissue homeostasis. To this intent, mitochondrial molecular chaperons may be involved in the regulation of oxidative phosphorylation and apoptosis during stress events such as infections. However, specific human infectious diseases relatable to defects in molecular chaperons have yet to be identified. To this end, we performed whole exome sequencing and functional immune assessment in a previously healthy Asian female, who experienced severe respiratory failure due to Pneumocystis jiroveci pneumonia and non-HIV-related CD4 lymphocytopenia. This revealed that a chaperon, the mitochondrial paralog of HSP90, TRAP1, may have been involved in the patient's susceptibility to an opportunistic infection. Two rare heterozygous variants in TRAP1, E93Q, and A64T were detected. The patient's peripheral blood mononuclear cells displayed diminished TRAP1 expression, but had increased active, cleaved caspase-3, caspase-7, and elevated IL-1ß production. Transfection of A64T and E93Q variants in cell lines yielded decreased TRAP1 compared to transfected wildtype TRAP1 and re-capitulated the immunotypic phenotype of enhanced caspase-3 and caspase-7 activity. When infected with live P. jiroveci, the E93Q or A64T TRAP1 mutant expressing cells also exhibited reduced viability. Patient cells and cell lines transfected with the TRAP1 E93Q/A64T mutants had impaired respiration, glycolysis, and increased ROS production. Of note, co-expression of E93Q/A64T double mutants caused more functional aberration than either mutant singly. Taken together, our study uncovered a previously unrecognized role of TRAP1 in CD4+ lymphocytopenia, conferring susceptibility to opportunistic infections.

NIR-induced photothermal-responsive shape memory polyurethane for versatile smart material applications.

Stimuli responsiveness has been an attractive feature of smart material design, allowing the chemical and physical properties of the materials to change in response to small environmental variations. The versatile shape memory polyurethane (SMPU) has been advanced into thermally-responsive SMPU, enabling its use in neurovascular stents, smart fibers for compression garments, and thermal-responsive components for aircraft and aerospace structures. While thermally-induced SMPU materials exhibit excellent shape recovery and fixity, they encounter limitations such as long response times, energy-intensive heating processes, and potential damage to heat-sensitive components, hindering their wide application. Thus, SMPU has further advanced into a photothermal-responsive material by incorporating photothermal agents into the polymer matrix, offering faster response times, compatibility with heat-sensitive materials, and enhanced mechanical properties, expanding the versatility and applicability of shape memory technology. This review focuses on the classes of NIR-induced photothermal agent used in SMPU systems, their synthesis methods, and photothermal-responsive mechanism under NIR-light, which offers a dual responsiveness to the host SMPU. The advantages and limitations of NIR-induced photothermal SMPU are reviewed, and challenges in their development are discussed.

Effects of Dietary Nitrate Supplementation on High-Intensity Cycling Sprint Performance in Recreationally Active Adults: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis investigated the influence of dietary nitrate supplementation on performance metrics during cycling sprint exercise according to the PRISMA guidelines. Searches were conducted on MEDLINE, PubMed, ScienceDirect, Scopus, and SPORTDiscus databases up to September 2023. Inclusion criteria were healthy recreationally active men and women who consumed nitrate-rich and nitrate-deficient beetroot juice to assess performance outcomes of mean power, peak power, time-to-peak power, and minimum power during 30-s cycling sprints. Risk of bias was assessed using the Cochrane Risk of Bias 2 and TESTEX tools and funnel plots. A random effects model was performed on six studies and showed that dietary nitrate had significant effects on time-to-peak power (SMD: -0.66, 95% CI: -1.127 to -0.192, p = 0.006) but not on mean power, peak power, or minimum power. Subgroup analysis revealed that an acute low nitrate dose improved time-to-peak power (SMD: -0.977, 95% CI: -1.524 to -0.430, p < 0.001) but not after a multiday moderate nitrate dose (SMD: -0.177, 95% CI: -0.619 to -0.264, p = 0.431). These data suggest that acute nitrate supplementation can benefit time-to-peak power during 30-s cycling sprints, but due to the limited availability of data and heterogeneity in methodology, these results should be interpreted with caution. There was insufficient data on women to analyze sex-based differences. Future studies are required to provide insight on how supplementation regimen and population impact the effects of dietary nitrate for enhancing cycling sprint performance.

Clinical Characteristics and Mortality Risks Among Patients With Culture-Proven Coccidioidomycosis Who Are Critically Ill: A Multicenter Study in an Endemic Region.

Background: Coccidioidomycosis is an endemic mycosis in the southwestern United States. While most infections are mild, severe cases can be devastating. We aimed to describe the clinical characteristics and mortality risks of patients in the intensive care unit (ICU) with culture-proven coccidioidomycosis. Methods: We performed a retrospective chart review of patients in the ICU with positive Coccidioides spp culture in a large health care system in Arizona between 1 October 2017 and 1 July 2022. All data were entered into REDCap. Results: An overall 145 patients were identified and included. The median age was 51 years, with the majority male (69%) and non-Hispanic White (39%). Most patients (n = 104, 72%) had pulmonary coccidioidomycosis, and 41 had extrapulmonary disease (17 meningitis, 13 fungemia, 10 musculoskeletal disease, and 4 pericardial or aortic involvement). Seventy patients (48%) died during hospitalization, and most (91%) received antifungal therapy during hospitalization. In the multivariate logistic regression model, age ≥60 years (odds ratio [OR], 7.0; 95% CI, 2.6-18.8), cirrhosis (OR, 13.1; 95% CI, 1.6-108.8), and mechanical ventilation or vasopressor support (OR, 15.4; 95% CI, 3.9-59.6) were independently associated with increased all-cause mortality, but pre-ICU antifungal use had a statistically insignificant mortality risk association (OR, 0.5; 95% CI, .2-1.2). Conclusions: In our study of patients in the ICU with coccidioidomycosis and multiple comorbidities, the mortality rate was high. Older age, cirrhosis, and mechanical ventilation or vasopressor support were significantly associated with high mortality. Future studies are recommended to evaluate those risk factors and the efficacy of rapid diagnosis and early therapy in patients at high risk.

Acute inorganic nitrate ingestion does not impact oral microbial composition, cognitive function, or high-intensity exercise performance in female team-sport athletes.

The purpose of this study was to investigate the effects of acute nitrate (NO3-)-rich beetroot juice ingestion on explosive and high-intensity exercise performance, oral microbiota composition, and cognitive flexibility (i.e., function), before and after maximal intermittent running exercise. Fifteen women team-sport athletes were assigned in a randomized, double-blind, crossover design to consume concentrated NO3--depleted beetroot juice (PL; 0.1 mmol NO3-) and NO3--rich beetroot juice (BR; 12.0 mmol NO3-) 2.5 h prior to performing a battery of exercise performance tasks and cognitive testing before and after the Yo-Yo intermittent recovery level 1 (YYIR1) running test. Resting plasma [NO3-] and plasma nitrite ([NO2-]) were elevated following BR (P < 0.001). BR did not impact global composition or relative abundance of taxa in the oral microbiome (P > 0.05) or cognitive flexibility before or after exercise (P > 0.05). There was no significant difference in performance during 20-m (PRE, PL: 4.38 ± 0.27 vs. BR: 4.38 ± 0.32 s; POST, PL: 4.45 ± 0.29 vs. BR: 4.43 ± 0.35 s) and 10-m sprints (PRE, PL 2.78 ± 0.15 vs. BR 2.79 ± 0.18 s; POST, PL: 2.82 ± 0.16 vs. BR: 2.81 ± 0.19 s), isokinetic handgrip dynamometry, medicine ball throw, horizontal countermovement jump, or YYIR1 (PL: 355 ± 163 m vs. BR: 368 ± 184 m) between BR and PL (P > 0.05). These findings indicate that acute dietary NO3- may not influence the oral microbiome, explosive and high-intensity exercise performance, or cognitive function in women team-sport athletes.

Dyadic relationships between informal caregivers and older adults with chronic heart failure: A systematic review and meta-synthesis.

AIM: To synthesise the qualitative evidence on dyadic relationships between informal caregivers (ICs) and older adults with chronic heart failure (HF). METHODS AND RESULTS: A systematic review and meta-synthesis were conducted. Eight databases were searched for English peer-reviewed studies and grey literature published from inception to 27 February 2024. Qualitative and mixed-method studies involving older adults ≥ 55 years old with chronic HF and discussing patient-caregiver relationships in community settings were included. Data were synthesised using Sandelowski and Barroso's 2-step framework. A meta-summary was developed using thematic analysis, and findings were synthesised using the Theory of Dyadic Illness Management. Twenty-four studies from 2008 to 2024 were included (n = 580 participants). The meta-summary consisted of four themes and nine subthemes: (1) Characteristics of dyad relationships, (2) How both parts of the dyad care for each other, (3) Chronic HF and dyad relationships, (4) Knowledge of managing chronic HF. These were reorganised into the meta-synthesis: dyadic appraisal, dyadic management behaviours, dyadic health, contextual factors affecting dyadic relationships and management behaviours, and illness management as a dyadic phenomenon. CONCLUSION: Investigating relationship dynamics and their impact on dyads and chronic HF self-care is vital. Where possible, healthcare providers should prioritise dyadic care when caregivers are involved and deliver individualised care to improve patient and caregiver outcomes. Assessing and optimising dyadic relations, addressing individual perceptions and needs as part of clinical care, and before implementing self-care interventions in research may help ensure that self-care is appropriately tailored and would not be hindered by relationship conflicts.

The impact of media reporting of suicides on subsequent suicides in Asia: A systematic review.

Introduction: This systematic review is aimed at (1) evaluating the association between media portrayals of suicides and subsequent copycat suicides or attempts among the general public in Asia, (2) understanding the factors associated with copycat suicides and (3) determining the positive impacts of the media reporting of suicides (e.g. increased help-seeking, coping). Method: A systematic review and narrative synthesis of English and Chinese articles from 8 electronic databases (i.e. PsycINFO, MEDLINE, Embase, CINAHL, Web of Science, Ariti, China National Knowledge Infrastructure and OpenGrey) from January 2000 to May 2023 was conducted. Observational studies were included, and the data were analysed through narrative synthesis. The protocol was registered with PROSPERO (CRD42021281535). Results: Among the 32 studies included (n=29 for evidence synthesis) in the review, there is good-quality evidence to show that copycat suicides and suicide attempts increase after media reports of a suicide, regardless of country, celebrity status, study design, type of media, mode of suicide or follow-up period. Females, younger age groups and those sharing similar characteristics as the deceased in publicised suicides (age, gender) were more susceptible to negative impact. Reporting of the mode of death of the deceased increased suicides by the same method among the public. Conclusion: Media portrayals of suicide appear to have a negative impact on copycat suicides at the population level in Asia. Thus, in addition to tighter media control, healthcare systems, professional medical bodies and community outreach services should work collaboratively to promote early help-seeking in those with psychological distress.

Evaluating a maladaptive personality-informed model of social support and post-traumatic stress disorder.

BACKGROUND: Social support is a robust predictor of post-traumatic stress disorder (PTSD). Although the inverse relationship between perceived social support and PTSD (social causation model) is supported, less is understood about the antecedents of the social causation model. Further, there is limited research in non-Western psychiatric populations that experience elevated rates of trauma and PTSD (e.g., mood disorders). The present study evaluated whether cumulative traumatic life events influenced current PTSD symptoms through maladaptive personality traits and perceptions of social support among Asian patients with mood disorders. METHODS: A total of 200 Asian patients (77.5 % Chinese) with mood disorders were assessed for maladaptive personality traits, perceptions of social support, cumulative traumatic life events, PTSD, and depressive symptoms. Structural equation modelling was conducted to evaluate the extended social causation model. RESULTS: The extended social causation model demonstrated acceptable fit to the data (Comparative Fit Index [CFI] = 0.90; absolute Root Mean Square Error of Approximation [RMSEA] = 0.08). There were significant indirect effects of cumulative traumatic life events on current PTSD symptoms (ß = 0.29, p < .001; 85 % variance explained) and depressive symptoms (ß = 0.28, p < .001; 69 % variance explained). LIMITATIONS: Results may not be generalizable beyond the Singapore population due to the socio-cultural and environmental context. CONCLUSIONS: The present findings provide conceptual support for a maladaptive personality-informed model of social support and PTSD, which could better inform trauma-focused interventions in preventing and treating the debilitating effects of PTSD in psychiatric populations.

The protective role of resilience and social support against burnout during the COVID-19 pandemic.

Background: The COVID-19 pandemic brought on a range of stressors in homes and workplaces. With no sign of ending after one year, burnout was a concern. Resilience has been known to shield against the effects of stress. While often thought of as an individual trait, previous studies have shown social support to improve resilience. The study aimed to examine the extent of burnout in the Singapore population and whether social support and resilience cushioned the impact of COVID-19 related stressors a year into the pandemic. Methods: Participants were 858 Singapore residents who participated in a larger study between October 2021 and September 2022. The Copenhagen Burnout Inventory provided Work-and Personal-related burnout scores. Multivariable linear regression was used to identify demographic variables associated with burnout. Path analysis revealed the associations between COVID-19 stressors, social support, resilience and burnout. Results: 22 and 19% of the sample reported work and personal burnout respectively, with younger adults being more burnt out than older adults. Higher stress was associated with higher burnout and higher social support was associated with lower burnout. Path analysis revealed that the relationship between social support and burnout was partially accounted for by increased resilience. Conclusion: Managing altered work arrangements, career expectations, and increased responsibilities at home may contribute to greater levels of burnout in the younger adults. Increased employer support and targeted interventions could mitigate the impact of these stressors. The study also highlighted the importance of maintaining social connections even while physically distancing.

Mesenchymal Stem Cell Exosomes Enhance Posterolateral Spinal Fusion in a Rat Model.

Spinal fusion, a common surgery performed for degenerative lumbar conditions, often uses recombinant human bone morphogenetic protein 2 (rhBMP-2) that is associated with adverse effects. Mesenchymal stromal/stem cells (MSCs) and their extracellular vesicles (EVs), particularly exosomes, have demonstrated efficacy in bone and cartilage repair. However, the efficacy of MSC exosomes in spinal fusion remains to be ascertained. This study investigates the fusion efficacy of MSC exosomes delivered via an absorbable collagen sponge packed in a poly Ɛ-caprolactone tricalcium phosphate (PCL-TCP) scaffold in a rat posterolateral spinal fusion model. Herein, it is shown that a single implantation of exosome-supplemented collagen sponge packed in PCL-TCP scaffold enhanced spinal fusion and improved mechanical stability by inducing bone formation and bridging between the transverse processes, as evidenced by significant improvements in fusion score and rate, bone structural parameters, histology, stiffness, and range of motion. This study demonstrates for the first time that MSC exosomes promote bone formation to enhance spinal fusion and mechanical stability in a rat model, supporting its translational potential for application in spinal fusion.

Targeting the DNA damage response in hematological malignancies.

Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g., Poly ADP-Ribose Polymerase (PARP) inhibitors for BRCA deficient ovarian cancers. Though lagging behind that of solid cancers, DDR inhibitors (DDRi) are being clinically developed for haematological cancers. Furthermore, a high proliferative index characterize many such cancers, suggesting a rationale for combinatorial strategies targeting DDR and replicative stress. In this review, we summarize pre-clinical and clinical data on DDR inhibition in haematological malignancies and highlight distinct haematological cancer subtypes with activity of DDR agents as single agents or in combination with chemotherapeutics and targeted agents. We aim to provide a framework to guide the design of future clinical trials involving haematological cancers for this important class of drugs.

How do professionals and non-professionals respond to non-suicidal self-injury? Lived experiences of psychiatric outpatients in Singapore.

BACKGROUND: For young people who engage in non-suicidal self-injury (NSSI), receiving negative responses to their NSSI can pose a barrier to future help-seeking. This qualitative study aimed to explore helpful and unhelpful ways in which professionals and non-professionals respond to NSSI, from the perspectives of individuals with lived experiences of NSSI. METHODS: Semi-structured interviews were conducted with 20 outpatients (6 males, 14 females) aged 17 to 29 years from a tertiary psychiatric hospital in Singapore, who had reported engaging in NSSI behavior in an earlier study. The interviews were audio recorded and transcribed verbatim. Thematic analysis was used to identify themes and subthemes in the data. RESULTS: Professionals' responses were organized into three main themes: 'prescribing solutions without understanding needs', 'disapproval or judgment', and 'helpful responses'. Non-professionals' responses were organized into four main themes: 'emotionally charged responses', 'avoidance and inaction', 'poor understanding of reasons for NSSI', and 'providing tangible support and acknowledging NSSI'. Participants also described how unhelpful responses negatively impacted their willingness to seek help. CONCLUSIONS: Our findings provide a better understanding of responses to NSSI that are considered helpful and unhelpful, and can be used to improve existing guidelines on responding to NSSI.

Pathological personality explains individual differences in global emotion dysregulation within the pathway between child maltreatment and severe depressive symptoms.

OBJECTIVE: Global emotion dysregulation mediates the relationship between child maltreatment and severe depressive symptoms; however, there is a lack of research on maladaptive personality traits and their contribution to individual differences in global emotion dysregulation within this conceptual model. The present study tested a preliminary serial mediation model where maladaptive personality traits and global emotion dysregulation mediate the relationship between child maltreatment and severe depressive symptoms. METHOD: A total of 200 patients with mood disorders (Mage = 36.5 years; 54% females) were assessed for maladaptive personality traits (Personality Inventory for Diagnostic and Statistical Manual of Mental Disorders [5th ed.] Brief Form), global emotion dysregulation (Difficulties in Emotion Regulation Scale-Short), childhood trauma (Childhood Trauma Questionnaire), and depressive symptoms (Patient Health Questionnaire-9). RESULTS: Ordinary least squares regression and partial least squares-structural equation modeling revealed a consistent and significant indirect effect of child maltreatment on severe depressive symptoms through negative affectivity, detachment, psychoticism, and global emotion dysregulation. Among child maltreatment types, only emotional abuse had a significant indirect effect on severe depressive symptoms through maladaptive personality traits and global emotion dysregulation, b = 0.50, SE = 0.09, 95% confidence intervals [0.326, 0.694] after controlling for age, gender, and remaining types of child maltreatment. CONCLUSIONS: Findings support the view that maladaptive personality traits shed important insights on individual differences in global emotion dysregulation, and this information could aid clinical formulation and treatment of childhood adversity-related psychopathology. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Treatment delays for mental disorders in Singapore: results from the Singapore Mental Health Study 2016.

PURPOSE: Although the trajectory of mental disorders can be improved with timely treatment, many people defer treatment-seeking. This study aimed to examine the prevalence and correlates of treatment delays for mental disorders in Singapore, as well as perceived effectiveness of treatment received. METHODS: A total of 6126 respondents, aged 18 and above, participated in the Singapore Mental Health Study 2016-a cross-sectional, nationwide study conducted in Singapore from 2016 to 2018. Lifetime treatment contact for mood, anxiety, and alcohol use disorders (AUD) was assessed using the World Mental Health-Composite International Diagnostic Interview (Version 3.0). Multivariable logistic regression was conducted to examine correlates of delayed treatment. RESULTS: A total of 137 participants had made lifetime treatment contact for a mental disorder. The proportion of respondents who received delayed treatment (i.e., at least one year after onset of disorder) was 60.8% for any disorder, 59.5% for mood disorders, 56.3% for anxiety disorders, and 92.7% for AUD. The median delay was 5 years for mood disorders, one year for anxiety disorders, and 4 years for AUD. Treatment delay was significantly associated with older age, higher educational qualification, lifetime AUD, and earlier age of onset of disorder. 58.4% of respondents with lifetime treatment contact had received treatment that they considered effective. CONCLUSION: The high prevalence and long durations of treatment delay underscore the need to encourage help-seeking for mental disorders, especially since treatment is generally perceived to be helpful. Our findings also highlight several population groups more susceptible to receiving delayed treatment.

A head-to-head comparison of the measurement properties of EQ-5D-3L and EQ-5D-5L in Chinese family caregivers of cancer patients.

BACKGROUND: Although both EQ-5D-3L(3L) and EQ-5D-5L(5L) have demonstrated good measurement properties in several patient populations, there is currently limited evidence comparing the measurement properties of 3L and 5L in family caregivers (FCs) of cancer patients. PURPOSE: This study aimed to compare the measurement properties of 3L and 5L in a sample of family caregivers of cancer patients. METHODS: A consecutive sample of FCs of cancer patients recruited from three tertiary hospitals were invited to complete the two versions of the EQ-5D in two rounds of interviews. We compared i) the ceiling effect using the McNemar's test, ii) test-retest reliability using intraclass correlation coefficient (ICC) and Cohen's Kappa, iii) convergent validity using Spearman's rank correlation coefficient, iv) known-group validity using F-statistic, v) and discriminant capacity using ordinal logistic regression. RESULTS: A total of 416 FCs completed the baseline questionnaire and 120 caregivers completed the follow-up questionnaire. Ceiling effects were smaller in 5L (12.5%) than in 3L (20.7%). The convergent validity (r = 0.344-0.771), known-groups validity (Fratio5L/3L = 2.06-4.09), discriminant capacity (ES = 0.341-0.396), and test-retest reliability (ICC = 0.725) of the 5L were slightly better than those of the 3L in China. CONCLUSION: The current study found both 3L and 5L to be suitable for use by FCs of cancer patients. However, 5L showed superior measurement properties compared to 3L and therefore could be the preferred instrument when EQ-5D data of cancer patients FCs is required.

Heterogeneity of cortical pTDP-43 inclusion morphologies in amyotrophic lateral sclerosis.

BACKGROUND: Despite the presence of significant cortical pTDP-43 inclusions of heterogeneous morphologies in patients diagnosed with amyotrophic lateral sclerosis (ALS), pathological subclassification is routinely performed in the minority of patients with concomitant frontotemporal dementia (FTD). OBJECTIVE: In order to improve current understanding of the presence and relevance of pathological pTDP-43 subtypes in ALS, the present study examined the pattern of cortical pTDP-43 aggregates in 61 ALS cases without FTD. RESULTS: Based on the presence, morphology and composition of pTDP-43 pathology, three distinct ALS-TDP subtypes were delineated: (1) A predominant pattern of pTDP-43 granulofilamentous neuronal inclusions (GFNIs) and grains that were immuno-negative for p62 was identified in 18% of cases designated ALS-TDP type E; (2) neuronal cytoplasmic inclusions (NCIs) that were immuno-positive for both pTDP-43 and p62 were observed in 67% of cases assigned ALS-TDP type B; and (3) scarce cortical pTDP-43 and p62 aggregates were identified in 15% of cases coined ALS-TDP type SC (scarce cortical). Quantitative analyses revealed a significantly greater burden of pTDP-43 GFNI and grains in ALS-TDP type E. Principal component analysis demonstrated significant relationships between GFNIs, grains and ALS-TDP subtypes to support the distinction of subtypes E and B. No significant difference in age at death or disease duration was found between ALS-TDP subgroups to suggest that these subtypes represent earlier or later stages of the same disease process. Instead, a significantly higher ALS-TDP stage, indicating greater topographical spread of pTDP-43, was identified in ALS-TDP type E. Alzheimer's disease neuropathological change (ABC score ≥ intermediate) and Lewy body disease (Braak stage ≥ IV) was more prevalent in the ALS-TDP type SC cohort, which also demonstrated a significantly lower overall cognitive score. CONCLUSION: In summary, the present study demonstrates that ALS-TDP does not represent a single homogenous neuropathology. We propose the subclassification of ALS-TDP into three distinct subtypes using standard immuno-stains for pTDP-43 and p62 in the motor cortex, which is routinely sampled and evaluated for diagnostic neuropathological characterisation of ALS. We propose that future studies specify both clinicopathological group and pTDP-43 subtype to advance current understanding of the pathogenesis of clinical phenotypes in pTDP-43 proteinopathies, which will have significant relevance to the development of targeted therapies for this heterogeneous disorder.

Sleep disturbance as transdiagnostic mediator between adverse childhood experiences and psychopathology in children and adolescents: A structural equation modeling meta-analysis.

Background: Increasing research efforts have focused on understanding why some individuals develop severe psychopathology after exposure to adverse childhood experiences (ACEs). Sleep disturbances (insomnia, nightmares, and sleep disorders) are prevalent sequelae of ACEs and associated with psychopathology; however, there is no meta-analytic evidence on whether sleep disturbance functions as a transdiagnostic mediator in the relationship between ACEs and psychopathology (internalizing/externalizing disorders and psychosis) in children and adolescents. Methods: Systematic searches in three databases (PubMed; PsycINFO; Web of Science) identified 98 articles (N = 402,718; age range 1-17 years) and the present study used a novel two-stage meta-analytic structural equation model to investigate whether ACEs predict psychopathology through sleep disturbance. Subgroup analyses determined potential biases due to study design (cross-sectional vs. longitudinal) and geographical differences (Western vs. non-Western countries). Sensitivity analyses evaluated the influence of early childhood (<5 years old) and overlapping symptoms (i.e., nightmares and trauma symptoms) on model stability. Results: The pooled correlations among ACEs, sleep disturbance, and psychopathology were significant; the effect sizes ranged from moderate to high (r = 0.21 to r = 0.29). The indirect effect from ACEs via sleep disturbance to psychopathology was significant (ß = 0.05, 95% CI [0.04, 0.06]). The direct effect of ACEs on psychopathology was significant (ß = 0.18, 95% CI 0.13-0.24). Subgroup analyses revealed larger effects for cross-sectional studies than longitudinal studies (Δ χ2 (3) = 9.71, p = 0.021). Sensitivity analyses revealed stable and consistent results. Conclusions: The present meta-analytic results indicate that sleep disturbance is a transdiagnostic mediator in the relationship between ACEs and psychopathology among children and adolescents. Further research is required to determine the synergistic effects between sleep disturbance and other risk mechanisms, and elucidate the complex pathways that lead to disorder in the aftermath of childhood adversities.

Microphysiological Modeling of Gingival Tissues and Host-Material Interactions Using Gingiva-on-Chip.

Gingiva plays a crucial barrier role at the interface of teeth, tooth-supporting structures, microbiome, and external agents. To mimic this complex microenvironment, an in vitro microphysiological platform and biofabricated full-thickness gingival equivalents (gingiva-on-chip) within a vertically stacked microfluidic device is developed. This design allowed long-term and air-liquid interface culture, and host-material interactions under flow conditions. Compared to static cultures, dynamic cultures on-chip enabled the biofabrication of gingival equivalents with stable mucosal matrix, improved epithelial morphogenesis, and barrier features. Additionally, a diseased state with disrupted barrier function representative of gingival/oral mucosal ulcers is modeled. The apical flow feature is utilized to emulate the mechanical action of mouth rinse and integrate the assessment of host-material interactions and transmucosal permeation of oral-care formulations in both healthy and diseased states. Although the gingiva-on-chip cultures have thicker and more mature epithelium, the flow of oral-care formulations induced increased tissue disruption and cytotoxic features compared to static conditions. The realistic emulation of mouth rinsing action facilitated a more physiological assessment of mucosal irritation potential. Overall, this microphysiological system enables biofabrication of human gingiva equivalents in intact and ulcerated states, providing a miniaturized and integrated platform for downstream host-material and host-microbiome applications in gingival and oral mucosa research.

Survival in sporadic ALS is associated with lower p62 burden in the spinal cord.

The autophagy marker p62 appears as a consistent component of pathological aggregates in amyotrophic lateral sclerosis (ALS) and its modulation to facilitate protein degradation has been proposed as a potential therapeutic target. Importantly, recent studies have implicated diffuse phosphorylated TDP-43 inclusions that are immuno-negative for p62 in more rapid disease, highlighting the need for better understanding of p62 involvement in ALS pathogenesis. The present study set out to assess p62 pathology in the motor neurons of 31 patients with sporadic ALS that had either a short (<2 years) or longer (4-7 years) disease duration to determine its association with pTDP-43 pathology, motor neuron loss, and survival in sporadic disease. Our results identified significantly more cytoplasmic p62 aggregates in the spinal cord of patients with a shorter survival. Disease duration demonstrated a negative association with p62 burden and density of remaining motor neurons in the spinal cord, suggesting that survival in sporadic ALS is associated with the successful clearance of lower motor neurons with p62 aggregates. These findings implicate the autophagy pathway in ALS survival and provide support for further study of p62 as a potential prognostic biomarker in ALS.