Mild traumatic brain injury gives rise to chronic depression-like behavior and associated alterations in glutamatergic protein expression.

Mild traumatic brain injury (mTBI) is known to result in chronic somatic, cognitive, and emotional symptoms. Depression is commonly reported among individuals suffering from persistent concussion symptoms; however, the underlying mechanisms are not understood. The glutamatergic system has recently been linked with mTBI and depression due to reports of similar changes in expression of glutamatergic proteins. Using a closed-head controlled cortical impact (cCCI) model in adult male rats (n = 8/group), this study investigated the emergence of self-care deficits and changes in social interaction behaviors at four, eight and twelve weeks post-injury. Western blotting was used to assess associated changes in expression of glutamate transporters and N-methyl-D-aspartate (NMDA) receptor subunits at twelve weeks. Splash test results revealed deficits in self-care behaviors beginning at eight weeks, which continued through twelve weeks in the injury group. Injured animals also exhibited decreased preference for social novelty at four weeks and loss of desire for social interaction as a whole by twelve weeks. GluN1 was increased in injured animals compared to shams in the frontal cortex and amygdala, while decreased GLT-1 was observed in the hippocampus. Linear regression was performed to evaluate relationships between behavioral and molecular variables; the results suggested that injury affects these relationships in a region-dependent manner. Together, these results suggest that the development of chronic depression-like behavior was associated with changes in glutamatergic protein expression. Deeper investigations into how injury influences glutamatergic synaptic protein expression are needed, as this has the potential to affect circuit-level neurotransmission that drives depression-like behavior following mTBI.

Regulation of Age-Related Lipid Metabolism in Ovarian Cancer.

Although a lot of effort has been dedicated to ovarian cancer (OC) research, the mortality rate is still among the highest in female gynecologic malignancies. The effects of the aged tumor microenvironment are still being undermined despite age being the highest risk factor in ovarian cancer development and progression. In this study, we have conducted RNA sequencing and lipidomics analysis of gonadal adipose tissues from young and aged rat xenografts before and after ovarian cancer formation. We have found significantly higher tumor formation rates and volumes in aged OC xenograft rat models compared to their young counterparts (p<0.05), suggesting the aged adipose microenvironment (AME) is more susceptible to OC outgrowth. We have revealed significant shifts in the gene expression enrichment from groups of young vs. aged rats before tumor formation, groups of young vs. aged rats when the tumor formed, and groups of aged rats before and after tumor formation. We also observed shifts in the lipid components of the gonadal adipose tissues between young and aged rat xenografts when tumors were generated. Additionally, we found that the aged AME was associated with age-related changes in the immune cell composition, especially inflammation-related cells. The top hits showing the most differences between aged and young adipose tissues were eight genes including S100a8, S100a9, Il1rl1, Lcn2, C3, Hba-a1, Fcna, and Pnpla3, 22 lipids including multiple isoforms of free fatty acids (FFA) and triglyceride (TG), as well as four immune cells including neutrophil, myeloid dendritic cell, T cell CD4+ (non-regulatory), and mast cell activation. The functional correlation among S100a8, S100a9, neutrophil, and FFA (18:3) was also determined. Furthermore, FFA (18:3), which was shown to be downregulated in aged xenograft rats, was capable of inhibiting OC cell proliferation. In conclusion, our study suggested that aging promoted OC proliferation through changes in genes/pathways, lipid metabolism, and immune cells. Targeting the aging adipose microenvironment, particularly lipid metabolism reprogramming, holds promise as a therapeutic strategy for OC, which warrants further investigation. Significance: Aging microenvironment of OC may be regulated by S100a8 and S100a9 secreted by adipocytes, preadipocytes, or neutrophils through affecting the lipid metabolism, such as FFA (18:3).

Associations of Gestational Exposure to Air Pollution and Polycyclic Aromatic Hydrocarbons with Placental Inflammation.

Restricted fetal growth (RFG) is a leading contributor to perinatal mortality and has been associated with gestational exposure to air pollution, such as fine particulate matter (PM2.5), nitrogen dioxide (NO2), and polycyclic aromatic hydrocarbons (PAHs). This study examines the association between trimester-specific and weekly means of air pollution throughout gestation and placental inflammatory markers at delivery. In a prospective cohort study of 263 pregnant women in Rochester, NY, we measured interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in placental tissue and estimated gestational exposure to PM2.5 and NO2 using a high-resolution spatial-temporal model. Exposure to PAHs was estimated using urinary 1-hydroxypyrene (1-OHP) concentrations collected once per trimester. Using distributed lag models with a penalized spline function, each interquartile range (2.6 µg/m3) increase in PM2.5 concentration during gestational weeks 6-11 was associated with decreased placental IL-6 levels (-22.2%, 95% CI: -39.0%, -0.64%). Using multiple linear regression models, each interquartile range increase of 1-OHP was associated with an increase in TNF-α in the first trimester (58.5%, 95% CI: 20.7%, 74.2%), third trimester (22.9%, 95% CI: 0.04%, 49.5%), and entire pregnancy (29.6%, 95%CI: 3.9%,60.6%). Our results suggest gestational exposure to air pollution may alter the inflammatory environment of the placenta at delivery.

Evaluation of a peer-led research best practices training for community health workers and promotoras.

Introduction: Community health workers and promotoras (CHW/Ps) increasingly support research conducted in communities but receive variable or no training. We developed a culturally and linguistically tailored research best practices course for CHW/Ps that can be taken independently or in facilitated groups. The purpose of this study was to evaluate the facilitated training. Methods: CHW/Ps were recruited from communities and partners affiliated with study sites in Michigan, Florida, and California. They participated in virtual or in-person training facilitated by a peer in English or Spanish and then completed a survey about their abilities (i.e., knowledge and skills for participating in research-related work) and perceptions of the training. Linear regression analyses were used to examine differences in training experience across several factors. Results: A total of 394 CHW/Ps, mean age 41.6 ± 13.8 years, completed the training and survey (n = 275 English; 119 Spanish). Most CHW/Ps were female (80%), and 50% identified as Hispanic, Latino, or Spanish. Over 95% of CHW/Ps rated their abilities as improved after training; 98% agreed the course was relevant to their work and felt the training was useful. Small differences were observed between training sites. Discussion: Most CHW/Ps rated the training positively and noted improved knowledge and skills for engaging in research-related work. Despite slight site differences, the training was well received, and CHW/Ps appreciated having a facilitator with experience working in community-based settings. This course offers a standard and scalable approach to training the CHW/P workforce. Future studies can examine its uptake and effect on research quality.

Did we personalize? Assessing personalization by an online reinforcement learning algorithm using resampling.

There is a growing interest in using reinforcement learning (RL) to personalize sequences of treatments in digital health to support users in adopting healthier behaviors. Such sequential decision-making problems involve decisions about when to treat and how to treat based on the user's context (e.g., prior activity level, location, etc.). Online RL is a promising datadriven approach for this problem as it learns based on each user's historical responses and uses that knowledge to personalize these decisions. However, to decide whether the RL algorithm should be included in an "optimized" intervention for real-world deployment, we must assess the data evidence indicating that the RL algorithm is actually personalizing the treatments to its users. Due to the stochasticity in the RL algorithm, one may get a false impression that it is learning in certain states and using this learning to provide specific treatments. We use a working definition of personalization and introduce a resampling-based methodology for investigating whether the personalization exhibited by the RL algorithm is an artifact of the RL algorithm stochasticity. We illustrate our methodology with a case study by analyzing the data from a physical activity clinical trial called HeartSteps, which included the use of an online RL algorithm. We demonstrate how our approach enhances data-driven truth-in-advertising of algorithm personalization both across all users as well as within specific users in the study.

Exposure to Low-Level Air Pollution and Hyperglycemia Markers during Pregnancy: A Repeated Measure Analysis.

Epidemiologic evidence has emerged showing an association between exposure to air pollution and increased risks of gestational diabetes mellitus (GDM). This study examines the effect of low-level air pollution exposure on a subclinical biomarker of hyperglycemia (i.e., HbA1c) in pregnant people without diabetes before conception. We measured HbA1c in 577 samples repeatedly collected from 224 pregnant people in Rochester, NY, and estimated residential concentrations of PM2.5 and NO2 using high-resolution spatiotemporal models. We observed a U-shaped trajectory of HbA1c during pregnancy with average HbA1c levels of 5.13 (±0.52), 4.97 (±0.54), and 5.43 (±0.40)% in early-, mid-, and late pregnancy, respectively. After adjustment for the U-shaped trajectory and classic GDM risk factors, each interquartile range increase in 10 week NO2 concentration (8.0 ppb) was associated with 0.09% (95% CI: 0.02 to 0.16%) and 0.18% (95% CI: 0.08 to 0.28%) increases in HbA1c over the entire pregnancy and in late pregnancy, respectively. These associations remained robust among participants without GDM. Using separate distributed lag models, we identified a period between 8th and 14th gestational weeks as critical windows responsible for increased levels of HbA1c measured at 14th, 22nd, and 30th gestational weeks. Our results suggest that low-level air pollution contributes to hyperglycemia in medically low-risk pregnant people.

A mobile health intervention for emerging adults with regular cannabis use: A micro-randomized pilot trial design protocol.

BACKGROUND: Emerging adult (EA) cannabis use is associated with increased risk for health consequences. Just-in-time adaptive interventions (JITAIs) provide potential for preventing the escalation and consequences of cannabis use. Powered by mobile devices, JITAIs use decision rules that take the person's state and context as input, and output a recommended intervention (e.g., alternative activities, coping strategies). The mHealth literature on JITAIs is nascent, with additional research needed to identify what intervention content to deliver when and to whom. METHODS: Herein we describe the protocol for a pilot study testing the feasibility and acceptability of a micro-randomized trial for optimizing MiWaves mobile intervention app for EAs (ages 18-25; target N = 120) with regular cannabis use (≥3 times per week). Micro-randomizations will be determined by a reinforcement learning algorithm that continually learns and improves the decision rules as participants experience the intervention. MiWaves will prompt participants to complete an in-app twice-daily survey over 30 days and participants will be micro-randomized twice daily to either: no message or a message [1 of 6 types varying in length (short, long) and interaction type (acknowledge message, acknowledge message + click additional resources, acknowledge message + fill in the blank/select an option)]. Participants recruited via social media will download the MiWaves app, and complete screening, baseline, weekly, post-intervention, and 2-month follow-up assessments. Primary outcomes include feasibility and acceptability, with additional exploratory behavioral outcomes. CONCLUSION: This study represents a critical first step in developing an effective mHealth intervention for reducing cannabis use and associated harms in EAs.

Epigenome-wide differential methylation and differential variability as predictors of high-grade cervical intraepithelial neoplasia (cin2+).

CpG site methylation patterns have potential to improve differentiation of high-grade screening-detected cervical abnormalities. We assessed CpG differential methylation (DM) and differential variability (DV) in high-grade (CIN2+) vs. low-grade (≤CIN1) lesions. In ≤CIN1 (n=117) and CIN2+ (n=31) samples, cervical sample DNA underwent testing with Illumina HumanMethylation arrays. We assessed DM and DV of CpG methylation M values among nine cervical cancer-associated genes. We fit CpG-specific linear models and estimated empirical Bayes standard errors and false discovery rates (FDR). An exploratory epigenome-wide association study (EWAS) aimed to detect novel DM and DV CpGs (FDR<0.05) and Gene Ontology (GO) term enrichment. Compared to ≤CIN1, CIN2+ exhibited greater methylation at CCNA1 Cluster 1 (M value difference 0.24; 95% CI 0.04, 0.43) and RARB Cluster 2 (0.16; 95% CI 0.05, 0.28), and lower methylation at CDH1 Cluster 1 (-0.15; 95% CI -0.26, -0.04). CIN2+ exhibited lower variability at CDH1 Cluster 2 (variation difference -0.24; 95% CI -0.41, -0.05) and FHIT Cluster 1 (-0.30; 95% CI -0.50, -0.09). EWAS detected 3,534 DM and 270 DV CpGs. Forty-four GO terms were enriched with DM CpGs related to transcriptional, structural, developmental, and neuronal processes. Methylation patterns may help triage screening-detected cervical abnormalities and inform US screening algorithms.

Effect-Invariant Mechanisms for Policy Generalization.

Policy learning is an important component of many real-world learning systems. A major challenge in policy learning is how to adapt efficiently to unseen environments or tasks. Recently, it has been suggested to exploit invariant conditional distributions to learn models that generalize better to unseen environments. However, assuming invariance of entire conditional distributions (which we call full invariance) may be too strong of an assumption in practice. In this paper, we introduce a relaxation of full invariance called effect-invariance (e-invariance for short) and prove that it is sufficient, under suitable assumptions, for zero-shot policy generalization. We also discuss an extension that exploits e-invariance when we have a small sample from the test environment, enabling few-shot policy generalization. Our work does not assume an underlying causal graph or that the data are generated by a structural causal model; instead, we develop testing procedures to test e-invariance directly from data. We present empirical results using simulated data and a mobile health intervention dataset to demonstrate the effectiveness of our approach.

Spatial Intracranial Pressure Fields Driven by Blast Overpressure in Rats.

Free-field blast exposure imparts a complex, dynamic response within brain tissue that can trigger a cascade of lasting neurological deficits. Full body mechanical and physiological factors are known to influence the body's adaptation to this seemingly instantaneous insult, making it difficult to accurately pinpoint the brain injury mechanisms. This study examined the intracranial pressure (ICP) profile characteristics in a rat model as a function of blast overpressure magnitude and brain location. Metrics such as peak rate of change of pressure, peak pressure, rise time, and ICP frequency response were found to vary spatially throughout the brain, independent of blast magnitude, emphasizing unique spatial pressure fields as a primary biomechanical component to blast injury. This work discusses the ICP characteristics and considerations for finite element models, in vitro models, and translational in vivo models to improve understanding of biomechanics during primary blast exposure.

Outcomes and patient perspectives of a novel virtual spinal referral pathway in a non-specialist centre.

INTRODUCTION: In Irish orthopaedic centres without dedicated spinal services, the care of patients is facilitated through tertiary referral centres in Dublin, Cork & Galway. The outpatient waiting list for elective spinal opinion remains lengthy and challenging. Previous practice in University Hospital Waterford (UHW) necessitated an assessment with a local non-spinal orthopaedic specialist following a GP referral, incurring up to a 2-year wait prior to subspecialist spinal referral. These patients subsequently incurred a further wait for an appointment at the tertiary referral centre. A novel virtual spine clinic in collaboration with the Mater Misericordiae University Hospital (MMUH) was developed to fast-track this process. AIMS AND METHODS: A retrospective study was performed to audit efficiency by assessing time to initial consultation and time to virtual consultation, treatment outcomes, and patient satisfaction using an adapted patient-satisfaction questionnaire (PSQ-18) and a semi-structured interview. This study reflected the unique nature of patient experience in this pathway. RESULTS: The median time from referral to being seen in an in-person rapid access physiotherapist combined orthopaedic clinic was 185 days. The median time from initial consultation to virtual consultation was 36 days. The median time interval from virtual consultation to intervention was 110 days. Twenty percent of patients underwent surgery, 14% were further seen in the MMUH outpatients, 7% managed with the trial of physiotherapy, 7% required no follow-up, and 50% planned for radiologically guided spinal injections. DISCUSSION AND CONCLUSION: This novel pathway is efficient for orthopaedic units without a dedicated spinal service. This can easily be replicated across other orthopaedic centres with minimal cost implications.

Text Messages to Promote Physical Activity in Patients With Cardiovascular Disease: A Micro-Randomized Trial of a Just-In-Time Adaptive Intervention.

BACKGROUND: Text messages may enhance physical activity levels in patients with cardiovascular disease, including those enrolled in cardiac rehabilitation. However, the independent and long-term effects of text messages remain uncertain. METHODS: The VALENTINE study (Virtual Application-supported Environment to Increase Exercise) was a micro-randomized trial that delivered text messages through a smartwatch (Apple Watch or Fitbit Versa) to participants initiating cardiac rehabilitation. Participants were randomized 4× per day over 6-months to receive no text message or a message encouraging low-level physical activity. Text messages were tailored on contextual factors (eg, weather). Our primary outcome was step count 60 minutes following a text message, and we used a centered and weighted least squares mean method to estimate causal effects. Given potential measurement differences between devices determined a priori, data were assessed separately for Apple Watch and Fitbit Versa users over 3 time periods corresponding to the initiation (0-30 days), maintenance (31-120 days), and completion (121-182 days) of cardiac rehabilitation. RESULTS: One hundred eight participants were included with 70 552 randomizations over 6 months; mean age was 59.5 (SD, 10.7) years with 36 (32.4%) female and 68 (63.0%) Apple Watch participants. For Apple Watch participants, text messages led to a trend in increased step count by 10% in the 60-minutes following a message during days 1 to 30 (95% CI, -1% to +20%), with no effect from days 31 to 120 (+1% [95% CI, -4% to +5%]), and a significant 6% increase during days 121 to 182 (95% CI, +0% to +11%). For Fitbit users, text messages significantly increased step count by 17% (95% CI, +7% to +28%) in the 60-minutes following a message in the first 30 days of the study with no effect subsequently. CONCLUSIONS: In patients undergoing cardiac rehabilitation, contextually tailored text messages may increase physical activity, but this effect varies over time and by device. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04587882.

Resilience partially mediates the association between perceived social isolation and life satisfaction in people with systemic sclerosis.

Objectives: Systemic sclerosis (SSc) negatively affects quality of life, yet the factors influencing life satisfaction, a key aspect of well-being, remain unclear in this population. Social isolation is common in SSc, potentially linked to decreased life satisfaction, but the underlying mechanisms are unexplored. Resilience, a modifiable psychological resource, may act as a mediator in this relationship among people with SSc. This study aimed to examine the relationship between perceived social isolation and life satisfaction and to investigate whether resilience mediates this relationship. Methods: The Patient-Reported Outcomes Measurement Information System Social Isolation Short Form, the Connor-Davidson Resilience Scale, and the Satisfaction with Life Scale were used to assess perceived social isolation, resilience, and life satisfaction. Linear regressions were conducted using the PROCESS macro for SPSS. Results: Among 163 individuals with SSc who provided complete data at baseline (mean age = 54.7 ± 11.9 years), 47% had diffuse cutaneous SSc, and 57% had an early disease duration. Perceived social isolation was negatively associated with life satisfaction. Resilience partially mediated the association between perceived social isolation and life satisfaction in people with SSc. Conclusions: Findings revealed a significant association between perceived social isolation and life satisfaction and the mediating role of resilience in this association among people with SSc. Results suggest resilience may act as a protective mediator, counteracting the negative influence of perceived social isolation on life satisfaction. Findings support the promotion of social connection and resilience to enhance life satisfaction in people with SSc. Clinical Trials Registration #: NCT04908943.

Persisting neurobehavioral consequences of daily or intermittent paternal cannabis administration in F1 and F2 Rats.

Repeated paternal preconception exposure to Δ9-tetrahydrocannabinol (Δ9-THC) alone or together with the other constituents in a cannabis extract has been shown in our earlier studies in rats to cause significant neurobehavioral impairment in their offspring. In the current study, we compared the effects of daily cannabis extract (CE) exposure to cannabis on two consecutive days per week, modeling weekend cannabis use in human. The CE contained Δ9-THC as well as cannabidiol and cannabinol. We also extended the investigation of the study to cross-generational effects of grand-paternal cannabis exposure on the F2 generation and included testing the effects of paternal cannabis exposure on responding for opiate self-administration in F1 and F2 generation offspring. We replicated the findings of neurobehavioral impairment in F1 offspring of male rats exposed to cannabis extract containing 4 mg/kg/day of Δ9-THC daily for four weeks prior to mating with drug naïve females. The 4-week cannabis extract exposure caused a significant decrease in weight gain in the male rats exposed daily. In contrast, their offspring showed significantly greater body weights and anogenital distances (AGD) in the third to fourth weeks after birth. The behavioral effects seen in the F1 generation were increased habituation of locomotor activity in the figure-8 maze in female offspring and increased lever pressing for the opiate drug remifentanil in male offspring. The F2 generation showed significantly impaired negative geotaxis and an elimination of the typical sex-difference in locomotor activity, with effects not seen in the F1 generation. This study shows that daily paternal cannabis exposure for four weeks prior to mating causes significant neurobehavioral impairment in the F1 and F2 offspring. Intermittent exposure on two consecutive days per week for four weeks caused comparable neurobehavioral impairment. In sum, there should be concern about paternal as well as maternal exposure to cannabis concerning neurobehavioral development of their offspring.

Tobacco exposures are associated with health care utilization (HCU) and health care costs in pregnant persons and their newborn babies.

INTRODUCTION: Identifying health care utilization and costs associated with active and passive smoking during pregnancy could help improve health management strategies. METHODS: Data are from the Newborn Epigenetics STudy (NEST), a birth cohort enrolled from 2005-2011 in Durham and adjacent counties in North Carolina, United States. Participants included those for whom prenatal serum samples were assayed and for whom administrative data were obtainable (N=1,045). Zero-inflated Poisson (ZIP) regression models were used to assess associations between cotinine, adjusted for covariates (e.g., race and ethnicity, age at delivery, cohabitation status, education), and health care utilization outcomes. Generalized linear regression models were used to estimate average total charges. Simulation models were conducted to determine the economic benefits of reducing SHS and smoking during pregnancy. RESULTS: Increasing levels of cotinine were positively associated with parent's number of ED visits (coefficient(b)=0.0012, standard error (SE)=0.0002; P<.001), the number of ICU hours (b=0.0079, SE=0.0025; P=.002)), time spent in the ICU (b=0.0238, SE=0.0020, P<.001), and the number of OP visits (b=0.0003, SE=0.0001; P<.001). For infants, higher cotinine levels were associated with higher number of ED (b=0.0012, SE=0.0004; P=.005), ICU (b=0.0050, SE=0.001; P<.001), and OP (b=0.0006, SE=0.0002; P<.001) visits and longer time spent in the ED (b=0.0025, SE=0.0003; P<.001), ICU (b=0.0005, SE=0.0001; P<.001), and IP (b=0.0020, SE=0.0002; P<.001). Simulation results showed that a 5% reduction in smoking would correspond to a potential median cost savings of $150,533 from ED visits of parents and infants. CONCLUSION: Our findings highlight the importance of smoke exposure cessation during pregnancy to reduce health care utilization and costs for both parents and infants. IMPLICATIONS: This study reinforces the importance of reducing smoking and secondhand smoke exposure during pregnancy. Focusing on expanding cessation services to this group could help reduce morbidities observed within this population. Furthermore, there is the potential for health care costs savings to health care systems, especially to those with high delivery numbers. These cost savings are represented by potential reductions in ED, OP, and ICU hours and visits.

Peer-Led Symptom Management Intervention to Enhance Resilience in People With Systemic Sclerosis: Mediation Analysis From a Randomized Clinical Trial.

OBJECTIVE: Facilitated self-management interventions have the potential to enhance resilience and well-being. We examined whether resilience is a mediator of improving physical and psychological symptoms for people with systemic sclerosis (SSc) who participated in a 12-week online peer-led symptom management intervention. METHODS: We conducted a secondary data analysis from a randomized control trial comparing a peer health-coached intervention to a waitlist control. Participants completed the Connor-Davidson Resilience Scale, the Functional Assessment of Chronic Illness Therapy-Fatigue scale, and the Patient Reported Outcomes Measurement Information System measures of pain interference and depressive symptoms at the baseline and at weeks 6 and 12. Linear mixed effect regression models were used to assess the effect of intervention on changes in resilience. Causal mediation analyses were conducted to examine whether changes in resilience at week 12 mediated intervention effects on changes in fatigue, pain interference, and depressive symptoms at week 12. RESULTS: One hundred and seventy-three eligible participants were enrolled. Participants in the intervention group reported improvements in resilience (P < 0.001). These changes in resilience mediated the intervention effects on fatigue with indirect effect of -1.41 (95% confidence interval [CI] -2.41 to -0.41), pain interference of -0.86 (95% CI -1.65 to -0.08), and depressive symptoms of -1.99 (95% CI -3.16 to -0.81). CONCLUSION: For participants in the intervention who had positive improvements in their physical and psychological symptoms, increased resilience was a mechanism for these improvements. These findings support the importance of addressing resilience to improve symptoms in similar SSc interventions.

Lack of detectable sex differences in the mitochondrial function of Caenorhabditis elegans.

BACKGROUND: Sex differences in mitochondrial function have been reported in multiple tissue and cell types. Additionally, sex-variable responses to stressors including environmental pollutants and drugs that cause mitochondrial toxicity have been observed. The mechanisms that establish these differences are thought to include hormonal modulation, epigenetic regulation, double dosing of X-linked genes, and the maternal inheritance of mtDNA. Understanding the drivers of sex differences in mitochondrial function and being able to model them in vitro is important for identifying toxic compounds with sex-variable effects. Additionally, understanding how sex differences in mitochondrial function compare across species may permit insight into the drivers of these differences, which is important for basic biology research. This study explored whether Caenorhabditis elegans, a model organism commonly used to study stress biology and toxicology, exhibits sex differences in mitochondrial function and toxicant susceptibility. To assess sex differences in mitochondrial function, we utilized four male enriched populations (N2 wild-type male enriched, fog-2(q71), him-5(e1490), and him-8(e1498)). We performed whole worm respirometry and determined whole worm ATP levels and mtDNA copy number. To probe whether sex differences manifest only after stress and inform the growing use of C. elegans as a mitochondrial health and toxicologic model, we also assessed susceptibility to a classic mitochondrial toxicant, rotenone. RESULTS: We detected few to no large differences in mitochondrial function between C. elegans sexes. Though we saw no sex differences in vulnerability to rotenone, we did observe sex differences in the uptake of this lipophilic compound, which may be of interest to those utilizing C. elegans as a model organism for toxicologic studies. Additionally, we observed altered non-mitochondrial respiration in two him strains, which may be of interest to other researchers utilizing these strains. CONCLUSIONS: Basal mitochondrial parameters in male and hermaphrodite C. elegans are similar, at least at the whole-organism level, as is toxicity associated with a mitochondrial Complex I inhibitor, rotenone. Our data highlights the limitation of using C. elegans as a model to study sex-variable mitochondrial function and toxicological responses.

Impact of a resilience-building energy management intervention for people with systemic sclerosis: a mixed methods study.

Objectives: People with SSc often experience fatigue, which significantly affects daily life functioning and quality of life. We aimed to explore participants' experiences of a peer health-coached resilience-building energy management to enhance well-being (RENEW) intervention on symptoms and well-being and to use mixed methods to compare how SSc duration influenced the experiences of participants who had clinically significant fatigue improvement vs those who did not. Methods: Semi-structured interviews were conducted with 21 participants from the parent clinical trial randomized to the RENEW intervention. Data were analysed using the rigorous and accelerated data reduction technique combined with thematic content analysis. A mixed methods approach used a joint display to identify themes related to the impact of SSc duration on fatigue improvement status. Participants were categorized into short/improvement, short/limited improvement, long/improvement, and long/limited improvement. Results: Our team generated four themes: participant and peer health-coach relationship, physical and psychological well-being improvement, need for a tailored approach and easy program access through technology. Mixed methods analysis revealed that, regardless of SSc duration, participants with improved fatigue reported increasing self-awareness of SSc-related symptoms and learning coping strategies to manage fatigue. Participants in the short/improvement group reported preferences for slower pacing of the program and pairing with a coach with similar symptom severity. Participants in the long/limited improvement group sought SSc-specific symptom management information. Conclusion: Incorporating peer health coaches and technology is beneficial for self-management interventions for people with SSc. Future tailoring of RENEW based on SSc duration and symptom severity is needed. Clinical trial registration number: clinicatrials.gov, NCT04908943.

Maternal Childhood Adversity and Infant Epigenetic Aging: Moderation by Restless Sleep During Pregnancy.

Maternal exposure to childhood adversity is associated with detrimental health outcomes throughout the lifespan and may have implications for offspring. Evidence links maternal adverse childhood experiences (ACEs) to detrimental birth outcomes, yet the impact on the infant's epigenome is unclear. Moreover, maternal sleep habits during pregnancy may influence this association. Here, we explore whether restless sleep during pregnancy moderates the association between exposure to maternal childhood adversity and infant epigenetic age acceleration in 332 mother-infant dyads (56% female; 39% Black; 25% Hispanic). During the 2nd trimester, mothers self-reported childhood adversity and past-week restless sleep; DNA methylation from umbilical vein endothelial cells was used to estimate five epigenetic clocks. Multivariable linear regression was used to test study hypotheses. Despite no evidence of main effects, there was evidence of an interaction between maternal ACEs and restless sleep in predicting infant epigenetic age acceleration using the EPIC Gestational Age clock. Only infants whose mothers reported exposure to both ACEs and restless sleep demonstrated accelerated epigenetic aging. Results provide preliminary evidence that maternal childhood adversity and sleep may influence the infant epigenome.

Influence of substance use on male reproductive health and offspring outcomes.

The prevalence of substance use globally is rising and is highest among men of reproductive age. In Africa, and South and Central America, cannabis use disorder is most prevalent and in Eastern and South-Eastern Europe, Central America, Canada and the USA, opioid use disorder predominates. Substance use might be contributing to the ongoing global decline in male fertility, and emerging evidence has linked paternal substance use with short-term and long-term adverse effects on offspring development and outcomes. This trend is concerning given that substance use is increasing, including during the COVID-19 pandemic. Preclinical studies have shown that male preconception substance use can influence offspring brain development and neurobehaviour through epigenetic mechanisms. Additionally, human studies investigating paternal health behaviours during the prenatal period suggest that paternal tobacco, opioid, cannabis and alcohol use is associated with reduced offspring mental health, in particular hyperactivity and attention-deficit hyperactivity disorder. The potential effects of paternal substance use are areas in which to focus public health efforts and health-care provider counselling of couples or individuals interested in conceiving.