Reducing the Risk of Delayed Colorectal Cancer Diagnoses Through an Ambulatory Safety Net Collaborative.

BACKGROUND: An estimated 12 million adults in the United States experience delayed diagnoses and other diagnostic errors annually. Ambulatory safety nets (ASNs) are an intervention to reduce delayed diagnoses by identifying patients with abnormal results overdue for follow-up using registries, workflow redesign, and patient navigation. The authors sought to co-design a collaborative and implement colorectal cancer (CRC) ASNs across various health care settings. METHODS: A working group was convened to co-design implementation guidance, measures, and the collaborative model. Collaborative sites were recruited through a medical professional liability insurance program and chose to begin with developing an ASN for positive at-home CRC screening or overdue surveillance colonoscopy. The 18-month Breakthrough Series Collaborative ran from January 2022 to July 2023, with sites continuing to collect data while sustaining their ASNs. Data were collected from sites monthly on patients in the ASN, including the proportion that was successfully contacted, scheduled, and completed a follow-up colonoscopy. RESULTS: Six sites participated; four had an operational ASN at the end of the Breakthrough Series, with the remaining sites launching three months later. From October 2022 through February 2024, the Collaborative ASNs collectively identified 5,165 patients from the registry as needing outreach. Among patients needing outreach, 3,555 (68.8%) were successfully contacted, 2,060 (39.9%) were scheduled for a colonoscopy, and 1,504 (29.1%) completed their colonoscopy. CONCLUSION: The Collaborative successfully identified patients with previously abnormal CRC screening and facilitated completion of follow-up testing. The CRC ASN Implementation Guide offers a comprehensive road map for health care leaders interested in implementing CRC ASNs.

Pregnancy-induced oxidative stress and inflammation are not associated with impaired maternal neuronal activity or memory function.

Pregnancy is associated with neural and behavioral plasticity, systemic inflammation, and oxidative stress. Yet, the impact of inflammation and oxidative stress on maternal neural and behavioral plasticity during pregnancy are unclear. We hypothesized that healthy pregnancy transiently reduces learning and memory, and these deficits are associated with pregnancy-induced elevations in inflammation and oxidative stress. Cognitive performance was tested using novel object recognition (recollective memory), Morris water maze (spatial memory), and open field (anxiety-like) behavior tasks in female Sprague-Dawley rats of varying reproductive states [non-pregnant (nulliparous), pregnant (near term), and 1-2 months post-pregnancy (primiparous); n = 7-8/group]. Plasma and CA1 proinflammatory cytokines were measured using a MILLIPLEX® magnetic bead assay. Plasma oxidative stress was measured via advanced oxidation protein products (AOPP) assay. CA1 markers of oxidative stress, neuronal activity, and apoptosis were quantified via western blotting. Our results demonstrate CA1 oxidative stress-associated markers were elevated in pregnant compared to nulliparous rats (p ≤ 0.017) but were equivalent levels in pregnant and primiparous rats. In contrast, reproductive state did not impact CA1 inflammatory cytokines, neuronal activity, or apoptosis. Likewise, there was no effect of reproductive state on recollective or spatial memory. Even so, spatial learning was impaired (p ≤ 0.007) while anxiety-like behavior (p ≤ 0.034) was reduced in primiparous rats. Overall, our data suggest maternal hippocampal CA1 is protected from systemic inflammation but vulnerable to peripartum oxidative stress. Peripartum oxidative stress elevations, such as in pregnancy complications, may contribute to peripartum neural and behavioral plasticity.

Oxidative stress induces release of mitochondrial DNA into the extracellular space in human placental villous trophoblast BeWo cells.

Circulating cell-free mitochondrial DNA (ccf-mtDNA) is an indicator of cell death, inflammation, and oxidative stress. ccf-mtDNA differs in pregnancies with placental dysfunction from healthy pregnancies and the direction of this difference depends on gestational age and method of mtDNA quantification. Reactive oxygen species (ROS) trigger release of mtDNA from non-placental cells; yet it is unknown whether trophoblast cells release mtDNA in response to oxidative stress, a common feature of pregnancies with placental pathology. We hypothesized that oxidative stress would induce cell death and release of mtDNA from trophoblast cells. BeWo cells were treated with antimycin A (10-320 mM) or rotenone (0.2-50 mM) to induce oxidative stress. A multiplex real-time quantitative PCR (qPCR) assay was used to quantify mtDNA and nuclear DNA in membrane bound, non-membrane bound, and vesicular-bound forms in cell culture supernatants and cell lysates. Treatment with antimycin A increased ROS (p<0.0001), induced cell necrosis (p=0.0004) but not apoptosis (p=0.6471) and was positively associated with release of membrane-bound and non-membrane bound mtDNA (p<0.0001). Antimycin A increased mtDNA content in exosome-like extracellular vesicles (vesicular-bound form; p=0.0019) and reduced autophagy marker expression (LC3A/B, p=0.0002; p62, p<0.001). Rotenone treatment did not influence mtDNA release or cell death (p>0.05). Oxidative stress induces release of mtDNA into the extracellular space and causes non-apoptotic cell death and a reduction in autophagy markers in BeWo cells, an established in vitro model of human trophoblast cells. Intersection between autophagy and necrosis may mediate the release of mtDNA from the placenta in pregnancies exposed to oxidative stress.

Experiencing violence and other predictors of within-person same-day use of multiple substances in youth: a longitudinal study in emergency settings.

Background: Although experiencing violence is a risk factor for substance use among youth, its association with same-day use of multiple substances (a form of polysubstance use) and mitigating factors is less well understood.Objectives: To identify whether prosocial factors modified the effect of experiencing violence on the frequency of same-day use, and examine gender-specific risk/protective factors for same-day use.Methods: We analyzed longitudinal data from a cohort of youth who use drugs aged 14-24 (n = 599; 58% male) presenting to an urban emergency department between 2009-2011 and assessed biannually for two years. Using Poisson-generalized linear models with person-level fixed effects, we estimated within-person associations between self-reported experiencing violence and same-day use and analyzed gender and peer/parent support as effect modifiers. We adjusted for negative peer influence, parental drug and alcohol use, family conflict, anxiety and depression, and age.Results: Overall, positive parental support corresponded to lower rates of same-day use (rate ratio [RR]:0.93, 95% CI:0.87-0.99) and experiencing violence was associated with higher rates of same-day use (RR:1.25, 95% CI:1.10-1.41). Violence exposure was a risk factor among males (RR:1.42, 95% CI:1.21-1.66), while negative peer influences and parental substance use were risk factors among females (RR:1.63, 95% CI:1.36-1.97 and RR:1.58, 95% CI:1.35-1.83, respectively). Positive peer support reduced the association between violence exposure and same-day use among males (RR:0.69, 95% CI:0.57-0.84, p < .05).Conclusions: Tailored interventions may address gender differences in coping with experiencing violence - including interventions that promote parental support among males and reduce influence from parental substance use among females.

Sex-dependent effects of chronic intermittent hypoxia: implication for obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) affects 10-26% of adults in the United States with known sex differences in prevalence and severity. OSA is characterized by elevated inflammation, oxidative stress (OS), and cognitive dysfunction. However, there is a paucity of data regarding the role of sex in the OSA phenotype. Prior findings suggest women exhibit different OSA phenotypes than men, which could result in under-reported OSA prevalence in women. To examine the relationship between OSA and sex, we used chronic intermittent hypoxia (CIH) to model OSA in rats. We hypothesized that CIH would produce sex-dependent phenotypes of inflammation, OS, and cognitive dysfunction, and these sex differences would be dependent on mitochondrial oxidative stress (mtOS). METHODS: Adult male and female Sprague Dawley rats were exposed to CIH or normoxia for 14 days to examine the impact of sex on CIH-associated circulating inflammation (IL-1ß, IL-6, IL-10, TNF-α), circulating steroid hormones, circulating OS, and behavior (recollective and spatial memory; gross and fine motor function; anxiety-like behaviors; and compulsive behaviors). Rats were implanted with osmotic minipumps containing either a mitochondria-targeting antioxidant (MitoTEMPOL) or saline vehicle 1 week prior to CIH initiation to examine how inhibiting mtOS would affect the CIH phenotype. RESULTS: Sex-specific differences in CIH-induced inflammation, OS, motor function, and compulsive behavior were observed. In female rats, CIH increased inflammation (plasma IL-6 and IL-6/IL-10 ratio) and impaired fine motor function. Conversely, CIH elevated circulating OS and compulsivity in males. These sex-dependent effects of CIH were blocked by inhibiting mtOS. Interestingly, CIH impaired recollective memory in both sexes but these effects were not mediated by mtOS. No effects of CIH were observed on spatial memory, gross motor function, or anxiety-like behavior, regardless of sex. CONCLUSIONS: Our results indicate that the impact of CIH is dependent on sex, such as an inflammatory response and OS response in females and males, respectively, that are mediated by mtOS. Interestingly, there was no effect of sex or mtOS in CIH-induced impairment of recollective memory. These results indicate that mtOS is involved in the sex differences observed in CIH, but a different mechanism underlies CIH-induced memory impairments.

Sleep apnea is a common sleeping condition in adults with a wide range of symptoms that include inflammation, oxidative stress, memory problems, anxiety, and compulsivity. Men are diagnosed with sleep apnea more often than women. Although there is limited information on how sleep apnea affects men and women differently, previous studies suggest that women may exhibit different sleep apnea symptoms than men. To examine the impact of male and female sex on common sleep apnea symptoms, we exposed adult male and female rats to a model of sleep apnea called chronic intermittent hypoxia (CIH). We found that many effects of CIH were different in males and females. CIH females had increased inflammation and motor problems, whereas CIH males had increased oxidative stress and compulsivity. To investigate the reason for these CIH sex differences, we blocked mitochondrial oxidative stress. Blocking mitochondrial oxidative stress decreased CIH associated sex differences. However, blocking mitochondrial oxidative stress had no impact on CIH-induced memory impairment that was observed in male and female rats. Our findings support previous reports that suggest that women exhibit different sleep apnea symptoms than men. Further, we extend these findings by showing that mitochondrial oxidative stress is involved in these sex differences. Clinically, patients diagnosed with sleep apnea are typically treated with continuous positive airway pressure (CPAP) machines, which have high rates of non-compliance (15­40%). Therefore, understanding why sleep apnea is causing these symptoms will be important in developing therapeutics.

Chronic intermittent hypoxia-induced hypertension: the impact of sex hormones.

Obstructive sleep apnea, a common form of sleep-disordered breathing, is characterized by intermittent cessations of breathing that reduce blood oxygen levels and contribute to the development of hypertension. Hypertension is a major complication of obstructive sleep apnea that elevates the risk of end-organ damage. Premenopausal women have a lower prevalence of obstructive sleep apnea and cardiovascular disease than men and postmenopausal women, suggesting that sex hormones play a role in the pathophysiology of sleep apnea-related hypertension. The lack of protection in men and postmenopausal women implicates estrogen and progesterone as protective agents but testosterone as a permissive agent in sleep apnea-induced hypertension. A better understanding of how sex hormones contribute to the pathophysiology of sleep apnea-induced hypertension is important for future research and possible hormone-based interventions. The effect of sex on the pathophysiology of sleep apnea and associated intermittent hypoxia-induced hypertension is of important consideration in the screening, diagnosis, and treatment of the disease and its cardiovascular complications. This review summarizes our current understanding of the impact of sex hormones on blood pressure regulation in sleep apnea with a focus on sex differences.

Sex-dependent effects of chronic intermittent hypoxia: Implication for obstructive sleep apnea.

Background Obstructive sleep apnea (OSA) affects 10-26% of adults in the United States with known sex differences in prevalence and severity. OSA is characterized by elevated inflammation, oxidative stress (OS), and cognitive dysfunction. However, there is a paucity of data regarding the role of sex in the OSA phenotype. Prior findings suggest women exhibit different OSA phenotypes than men, which could result in under-reported OSA prevalence in women. To examine the relationship between OSA and sex, we used chronic intermittent hypoxia (CIH) to model OSA in rats. We hypothesized that CIH would produce sex-dependent phenotypes of inflammation, OS, and cognitive dysfunction, and these sex differences would be dependent on mitochondrial oxidative stress (mtOS). Methods Adult male and female Sprague Dawley rats were exposed to CIH or normoxia for 14 days to examine the impact of sex on CIH-associated circulating inflammation (IL-1ß, IL-4, IL-6, IL-10, TNF-α), circulating OS, and behavior (recollective and spatial memory; gross and fine motor function; anxiety-like behaviors; and compulsive behaviors). A subset of rats was implanted with osmotic minipumps containing either a mitochondria-targeting antioxidant (MitoTEMPOL) or saline vehicle 1 week prior to CIH initiation to examine how inhibiting mtOS would affect the CIH phenotype. Results Sex-specific differences in CIH-induced inflammation, OS, motor function, and compulsive behavior were observed. In female rats, CIH increased inflammation (plasma IL-6 and IL-6/IL-10 ratio) and impaired fine motor function. Conversely, CIH elevated circulating OS and compulsivity in males. These sex-dependent effects of CIH were blocked by inhibiting mtOS. Interestingly, CIH impaired recollective memory in both sexes but these effects were not mediated by mtOS. No effects of CIH were observed on spatial memory, gross motor function, or anxiety-like behavior, regardless of sex. Conclusions Our results indicate that the impact of CIH is dependent on sex, such as an inflammatory response and OS response in females and males, respectively, that are mediated by mtOS. Interestingly, there was no effect of sex or mtOS in CIH-induced impairment of recollective memory. These results indicate that mtOS is involved in the sex differences observed in CIH, but a different mechanism underlies CIH-induced memory impairments.

Pregnancy-associated oxidative stress and inflammation are not associated with impaired maternal neuronal activity or memory function.

Pregnancy is associated with neural and behavioral plasticity, systemic inflammation, and oxidative stress. Yet, the impact of systemic inflammation and oxidative stress on maternal neural and behavioral plasticity during pregnancy are unclear. We hypothesized that the maternal hippocampal CA1, a brain region associated with cognition, would be protected from pregnancy-associated systemic elevations in inflammation and oxidative stress, mediating stable peripartum cognitive performance. Cognitive performance was tested using novel object recognition (recollective memory), Morris water maze (spatial memory), and open field (anxiety-like) behavior tasks in female Sprague-Dawley rats of varying reproductive states [non-pregnant (nulliparous), pregnant (near term), and two months post-pregnancy (primiparous); n = 7-8/group]. Plasma and CA1 proinflammatory cytokines were measured using a MILLIPLEX® magnetic bead assay. Plasma oxidative stress was measured via advanced oxidation protein products (AOPP) assay. CA1 markers of oxidative stress, neuronal activity, and apoptosis were quantified via western blotting. Our results demonstrate CA1 oxidative stress-associated markers were elevated in pregnant compared to nulliparous rats ( p ≤ 0.017) but were equivalent levels in pregnant and primiparous rats. In contrast, reproductive state did not impact CA1 inflammatory cytokines, neuronal activity, or apoptosis. Likewise, there was no effect of reproductive state on recollective or spatial memory. Even so, spatial learning was impaired ( p ≤ 0.007) while anxiety-like behavior ( p ≤ 0.034) was reduced in primiparous rats. Overall, our data suggest maternal hippocampal CA1 is protected from systemic inflammation but vulnerable to peripartum oxidative stress. Thus, peripartum oxidative stress elevations, such as in pregnancy complications, may contribute to peripartum neural and behavioral plasticity.

Oxidative stress induces release of mitochondrial DNA into the extracellular space in human placental villous trophoblast BeWo cells.

Circulating cell-free mitochondrial DNA (ccf-mtDNA) is an indicator of cell death, inflammation, and oxidative stress. ccf-mtDNA differs in pregnancies with placental dysfunction from healthy pregnancies and the direction of this difference depends on gestational age and method of mtDNA quantification. Reactive oxygen species (ROS) trigger release of mtDNA from non-placental cells; yet it is unknown whether trophoblast cells release mtDNA in response to oxidative stress, a common feature of pregnancies with placental pathology. We hypothesized that oxidative stress would induce cell death and release of mtDNA from trophoblast cells. BeWo cells were treated with antimycin A (10-320 µM) or rotenone (0.2-50 µM) to induce oxidative stress. A multiplex real-time quantitative PCR (qPCR) assay was used to quantify mtDNA and nuclear DNA in membrane bound, non-membrane bound, and vesicular-bound forms in cell culture supernatants and cell lysates. Treatment with antimycin A increased ROS (p<0.0001), induced cell necrosis (p=0.0004) but not apoptosis (p=0.6471) and was positively associated with release of membrane-bound and non-membrane bound mtDNA (p<0.0001). Antimycin A increased mtDNA content in exosome-like extracellular vesicles (vesicular-bound form; p=0.0019) and reduced autophagy marker expression (LC3A/B, p=0.0002; p62, p<0.001). Rotenone treatment did not influence mtDNA release or cell death (p>0.05). Oxidative stress induces release of mtDNA into the extracellular space and causes non-apoptotic cell death and a reduction in autophagy markers in BeWo cells, an established in vitro model of human trophoblast cells. Intersection between autophagy and necrosis may mediate the release of mtDNA from the placenta in pregnancies exposed to oxidative stress. NEW & NOTEWORTHY: This is the first study to test whether trophoblast cells release mitochondrial DNA in response to oxidative stress and to identify mechanisms of release and biological forms of mtDNA from this cellular type. This research identifies potential cellular mechanisms that can be used in future investigations to establish the source and biomarker potential of circulating mitochondrial DNA in preclinical experimental models and humans.

Sex and age differences in social and cognitive function in offspring exposed to late gestational hypoxia.

BACKGROUND: Gestational sleep apnea is a hypoxic sleep disorder that affects 8-26% of pregnancies and increases the risk for central nervous system dysfunction in offspring. Specifically, there are sex differences in the sensitivity of the fetal hippocampus to hypoxic insults, and hippocampal impairments are associated with social dysfunction, repetitive behaviors, anxiety, and cognitive impairment. Yet, it is unclear whether gestational sleep apnea impacts these hippocampal-associated functions and if sex and age modify these effects. To examine the relationship between gestational sleep apnea and hippocampal-associated behaviors, we used chronic intermittent hypoxia (CIH) to model late gestational sleep apnea in pregnant rats. We hypothesized that late gestational CIH would produce sex- and age-specific social, anxiety-like, repetitive, and cognitive impairments in offspring. METHODS: Timed pregnant Long-Evans rats were exposed to CIH or room air normoxia from GD 15-19. Behavioral testing of offspring occurred during either puberty or young adulthood. To examine gestational hypoxia-induced behavioral phenotypes, we quantified hippocampal-associated behaviors (social function, repetitive behaviors, anxiety-like behaviors, and spatial memory and learning), hippocampal neuronal activity (glutamatergic NMDA receptors, dopamine transporter, monoamine oxidase-A, early growth response protein 1, and doublecortin), and circulating hormones in offspring. RESULTS: Late gestational CIH induced sex- and age-specific differences in social, repetitive, and memory functions in offspring. In female pubertal offspring, CIH impaired social function, increased repetitive behaviors, and elevated circulating corticosterone levels but did not impact memory. In contrast, CIH transiently induced spatial memory dysfunction in pubertal male offspring but did not impact social or repetitive functions. Long-term effects of gestational CIH on social behaviors were only observed in female offspring, wherein CIH induced social disengagement and suppression of circulating corticosterone levels in young adulthood. No effects of gestational CIH were observed in anxiety-like behaviors, hippocampal neuronal activity, or circulating testosterone and estradiol levels, regardless of sex or age of offspring. CONCLUSIONS: Our results indicate that hypoxia-associated pregnancy complications during late gestation can increase the risk for behavioral and physiological outcomes in offspring, such as social dysfunction, repetitive behaviors, and cognitive impairment, that are dependent on sex and age.

Sleep apnea during late pregnancy is a common pregnancy complication that can impact the brain development of children born to mothers with sleep apnea. Children with impaired brain development may present with decreased social skills, memory issues, anxiety, and compulsivity. It is unclear if there is a cause and effect relationship between sleep apnea during late pregnancy and behavioral changes in offspring. Additionally, it is unknown whether male or female sex or age of the offspring affects these relationships. In this study, we exposed pregnant rats to a model of sleep apnea called chronic intermittent hypoxia (CIH) within late gestation and examined the behavior of the offspring and brain activity during puberty and young adulthood. We found that CIH during late pregnancy had long-term effects in the offspring that were different in males and females. Notably, female offspring displayed social impairments in response to late gestation CIH, whereas male offspring displayed cognitive dysfunction.

Novel Correlation between TGF-ß1/-ß3 and Hormone Receptors in the Human Corneal Stroma.

This study investigated the interplay between transforming growth factor beta (TGF-ß1/T1 and TGF-ß3/T3), and sex hormone receptors using our 3D in vitro cornea stroma model. Primary human corneal fibroblasts (HCFs) from healthy donors were plated in transwells at 106 cells/well and cultured for four weeks. HCFs were supplemented with stable vitamin C (VitC) and stimulated with T1 or T3. 3D construct proteins were analyzed for the androgen receptor (AR), progesterone receptor (PR), estrogen receptor alpha (ERα) and beta (ERß), luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), gonadotropin-releasing hormone receptor (GnRHR), KiSS1-derived peptide receptor (KiSS1R/GPR54), and follicle-stimulating hormone subunit beta (FSH-B). In female constructs, T1 significantly upregulated AR, PR, ERα, FSHR, GnRHR, and KiSS1R. In male constructs, T1 significantly downregulated FSHR and FSH-B and significantly upregulated ERα, ERß, and GnRHR. T3 caused significant upregulation in expressions PR, ERα, ERß, LHR, FSHR, and GNRHR in female constructs, and significant downregulation of AR, ERα, and FSHR in male constructs. Semi-quantitative Western blot findings present the interplay between sex hormone receptors and TGF-ß isoforms in the corneal stroma, which is influenced by sex as a biological variable (SABV). Additional studies are warranted to fully delineate their interactions and signaling mechanisms.

Nonpartner Violence Perpetration Among Emerging Adults: Associations With Polysubstance Use and Trait Mindfulness.

Objective: Violence is a leading cause of death among individuals ages 18-25, with alcohol misuse consistently linked with violence perpetration. However, the association between polysubstance use and violence perpetration is less clear, despite the frequency of use of alcohol with other drugs. Additionally, protective factors such as mindfulness that may reduce violence perpetration among emerging adults have been understudied. This cross-sectional study examined the association between substance use, trait mindfulness, and violence perpetration outside of romantic relationships, utilizing a compensatory model of resilience. Methods: Data were drawn from a sample of 665 emerging adults ages 18-25, recruited from an urban Emergency Department (68% men). Participants self-administered a computer survey that assessed non-partner violence perpetration (NPV), alcohol use, marijuana use, prescription drug misuse, and trait mindfulness. Fifteen percent reported non-partner violence perpetration over the past six months. Results: Multivariate logistic regression tested associations between violence perpetration, substance use, trait mindfulness, and demographic characteristics. Results showed that alcohol use alone (OR= 3.04), prescription opioid use alone (OR = 3.58), alcohol and marijuana use (OR = 3.75), and use of all three substances (OR= 7.78) were positively associated with violence perpetration. Post-hoc contrasts demonstrated the polysubstance use significantly increased risk over single substance use. Trait mindfulness (OR= 0.97) was negatively associated with violence perpetration after controlling for substance use. Conclusions: Findings suggest that polysubstance use may increase risk for violence. Interventions that address polysubstance use, potentially including mindfulness, could reduce non-partner violence perpetration among emerging adults and requires further study.

OUTdoor Swimming as a nature-based Intervention for DEpression (OUTSIDE): study protocol for a feasibility randomised control trial comparing an outdoor swimming intervention to usual care for adults experiencing mild to moderate symptoms of depression.

BACKGROUND: Depression is common and the prevalence increasing worldwide; at least 1 in 10 people will experience depression in their lifetime. It is associated with economic costs at the individual, healthcare and societal level. Recommended treatments include medication and psychological therapies. However, given the long waiting times, and sometimes poor concordance and engagement with these treatments, a greater range of approaches are needed. Evidence for the potential of outdoor swimming as an intervention to support recovery from depression is emerging, but randomised controlled trials (RCTs) evaluating clinical and cost-effectiveness are lacking. This study seeks to investigate the feasibility of conducting a definitive superiority RCT, comparing an 8-session outdoor swimming course offered in addition to usual care compared to usual care only, in adults who are experiencing mild to moderate symptoms of depression. Feasibility questions will examine recruitment and retention rates, acceptability of randomisation and measures, and identify the primary outcome measure that will inform the sample size calculation for a definitive full-scale RCT. This study will also explore potential facilitators and barriers of participation through evaluation questionnaires, focus-group discussions and interviews. METHODS/DESIGN: To address these aims and objectives, a feasibility superiority RCT with 1:1 allocation will be undertaken. We will recruit 88 participants with mild to moderate symptoms of depression through social prescribing organisations and social media in three sites in England. Participants will be randomised to either (1) intervention (8-session outdoor swimming course) plus usual care or (2) usual care only. Both groups will be followed up for a further 8 weeks. DISCUSSION: If findings from this feasibility RCT are favourable, a fully powered RCT will be conducted to investigate the clinical- and cost-effectiveness of the intervention. Findings from the definitive trial will provide evidence about outdoor swimming for depression for policymakers and has the potential to lead to greater choice of interventions for adults experiencing symptoms of depression. TRIAL REGISTRATION: Current controlled trial registration number is ISRCTN 90851983 registered on 19 May 2022.

Effect of acute heat exposure on the pressor response to a voluntary hypoxic apnea.

The pressor response induced by a voluntary hypoxic apnea is mediated largely by increased sympathetic outflow. The neural control of blood pressure is altered in recovery from acute heat exposure, but its effect on the pressor response to a voluntary hypoxic apnea has never been explored. Therefore, we tested the hypothesis that prior heat exposure would attenuate the pressor response induced by a voluntary hypoxic apnea. Eleven healthy adults (five women) were exposed to whole body passive heating (water-perfused suit) sufficient to increase body core temperature by 1.2°C. Voluntary hypoxic apneas were performed at baseline and in recovery when body core temperature returned to ≤ 0.3°C of baseline. Participants breathed gas mixtures of varying [Formula: see text] (21%, 16%, and 12%; randomized) for 1 min followed by a 15-s end-expiratory apnea. The change in arterial oxygen saturation during each apnea did not differ from baseline to recovery (P = 0.6 for interaction), whereas the pressor response induced by a voluntary hypoxia apnea was reduced ([Formula: see text] 21%, baseline 17 ± 7 mmHg vs. recovery 14 ± 7 mmHg; [Formula: see text] 16%, baseline 24 ± 8 mmHg vs. recovery 18 ± 7 mmHg; [Formula: see text] 12%, baseline 28 ± 11 mmHg vs. recovery 24 ± 11 mmHg; P = 0.01 for main effect of time). These data suggest that prior heat exposure induces a cross-stressor effect such that the pressor response to a voluntary hypoxic apnea is attenuated.NEW & NOTEWORTHY The pressor response induced by a voluntary hypoxic apnea is mediated by increased sympathetic outflow. The neural control of blood pressure is altered in recovery from acute heat exposure, but its effect on the pressor response to a voluntary hypoxic apnea has never been explored. Our data suggest that prior heat exposure induces a cross-stressor effect such that the pressor response to a voluntary hypoxic apnea is attenuated.

Sex and age differences in social and cognitive function in offspring exposed to late gestational hypoxia.

Background: Gestational sleep apnea affects 8-26% of pregnancies and can increase the risk for autism spectrum disorder (ASD) in offspring. ASD is a neurodevelopmental disorder associated with social dysfunction, repetitive behaviors, anxiety, and cognitive impairment. To examine the relationship between gestational sleep apnea and ASD-associated behaviors, we used a chronic intermittent hypoxia (CIH) protocol between gestational days (GD) 15-19 in pregnant rats to model late gestational sleep apnea. We hypothesized that late gestational CIH would produce sex- and age-specific social, mood, and cognitive impairments in offspring. Methods: Timed pregnant Long-Evans rats were exposed to CIH or room air normoxia from GD 15-19. Behavioral testing of offspring occurred during either puberty or young adulthood. To examine ASD-associated phenotypes, we quantified ASD-associated behaviors (social function, repetitive behaviors, anxiety-like behaviors, and spatial memory and learning), hippocampal activity (glutamatergic NMDA receptors, dopamine transporter, monoamine oxidase-A, EGR-1, and doublecortin), and circulating hormones in offspring. Results: Late gestational CIH induced sex- and age-specific differences in social, repetitive and memory functions in offspring. These effects were mostly transient and present during puberty. In female pubertal offspring, CIH impaired social function, increased repetitive behaviors, and increased circulating corticosterone levels, but did not impact memory. In contrast, CIH transiently induced spatial memory dysfunction in pubertal male offspring but did not impact social or repetitive functions. Long-term effects of gestational CIH were only observed in female offspring, wherein CIH induced social disengagement and suppression of circulating corticosterone levels in young adulthood. No effects of gestational CIH were observed on anxiety-like behaviors, hippocampal activity, circulating testosterone levels, or circulating estradiol levels, regardless of sex or age of offspring. Conclusions: Our results indicate that hypoxia-associated pregnancy complications during late gestation can increase the risk for ASD-associated behavioral and physiological outcomes, such as pubertal social dysfunction, corticosterone dysregulation, and memory impairments.

Firearms Availability Among High-School Age Youth With Recent Depression or Suicidality.

BACKGROUND AND OBJECTIVES: Limiting firearm access is essential to decreasing teen suicide. Previous efforts have focused on household firearms; however, less is known about firearm access and possession among teens at increased suicide risk. Our objective was to estimate prevalence of firearm possession and access among high school-aged teens with recent depression and/or lifetime history of suicidality (DLHS). METHODS: We conducted a probability-based, cross-sectional Web survey of 1914 parent-teen dyads between June 24, 2020, and July 22, 2020, with data weighted to generate a nationally representative sample of US teenagers (aged 14-18). Logistic regression analyses examined the difference between teens with and without DLHS for: (1) personal firearm possession, (2) perceived firearm access, and (3) method of firearm attainment. RESULTS: Among high school-aged teens, 22.6% (95% confidence interval [CI], 19.4-25.8) reported DLHS, 11.5% (95% CI, 8.7-14.3) reported personal firearm possession, and 44.2% (95% CI, 40.2-48.2) endorsed firearm access. Teens experiencing DLHS had increased perceived access (adjusted odds ratio, 1.56; 95% CI, 1.07-2.28) compared with non-DLHS peers. There was no association between DLHS and personal firearm possession (adjusted odds ratio, 0.97; 95% CI, 0.47-2.00). Among teens reporting firearm possession, those with DLHS were more likely to have acquired it by buying/trading for it (odds ratio, 5.66; 95% CI, 1.17-27.37) and less likely receiving it as a gift (odds ratio, 0.06; 95% CI, 0.01-0.36). CONCLUSIONS: High school-aged teens experiencing DLHS have higher perceived firearm access compared with lower-risk peers. Providers should speak directly to high school-aged teens at increased suicide risk about firearm access, in addition to counseling parents.

Adaptive interventions for alcohol misuse and violent behaviors among adolescents and emerging adults in the emergency department: A sequential multiple assignment randomized controlled trial protocol.

Alcohol use and violent behaviors among youth are associated with morbidity and mortality. An emergency department (ED) visit provides an opportunity to initiate prevention efforts. Despite promising findings from our single session SafERteens brief intervention (BI), impact is limited by modest effect sizes, with data lacking on optimal boosters to enhance effects. This paper describes the protocol for a sequential, multiple assignment, randomized trial (SMART). Adolescents and emerging adults (ages 14-20) in the ED screening positive for alcohol use and violent behaviors (physical aggression) were randomly assigned to: 1) SafERteens BI + Text Messaging (TM), or 2) SafERteens BI + remote Health Coach (HC). Participants completed weekly surveys over 8 weeks after the ED visit to tailor intervention content and measure mechanisms of change. At one-month, intervention response/non-response is determined (e.g., binge drinking or violent behaviors). Responders are re-randomized to continued intervention condition (e.g., maintenance) or minimized condition (e.g., stepped down). Non-responders are re-randomized to continued condition (e.g., maintenance), or intensified condition (e.g., stepped up). Outcomes were measured at 4 and 8 months, including primary outcomes of alcohol consumption and violence, with secondary outcomes of alcohol consequences and violence consequences. Although the original goal was to enroll 700 participants, COVID-19 impacts on research diminished recruitment in this trial (enrolled n = 400). Nonetheless, the proposed SMART is highly innovative by blending real-time assessment methodologies with adaptive intervention delivery among teens with comorbid alcohol misuse and violent behaviors. Findings will inform the content and timing booster interventions to alter risk behavior trajectories. Trial Registration:ClinicalTrials.govNCT03344666. University of Michigan # HUM00109156.

Challenges, Successes, and the Future of Firearm Injury Prevention.

Policy Points Firearm injury is a leading cause of death in the United States, with fatality rates increasing 34.9% over the past decade (2010-2020). Firearm injury is preventable through multifaceted evidence-based approaches. Reviewing past challenges and successes in the field of firearm injury prevention can highlight the future directions needed in the field. Adequate funding, rigorous and comprehensive data availability and access, larger pools of diverse and scientifically trained researchers and practitioners, robust evidence-based programming and policy implementation, and a reduction in stigma, polarization, and politicization of the science are all needed to move the field forward.