Dysregulation of kappa opioid receptor neuromodulation of lateral habenula synaptic function following a repetitive mild traumatic brain injury.

Mild traumatic brain injury (mTBI) increases the risk of affective disorders, anxiety and substance use disorder. The lateral habenula (LHb) plays an important role in pathophysiology of psychiatric disorders. Recently, we demonstrated a causal link between mTBI-induced LHb hyperactivity due to excitation/inhibition (E/I) imbalance and motivational deficits in male mice using a repetitive closed head injury mTBI model. A major neuromodulatory system that is responsive to traumatic brain injuries, influences affective states and also modulates LHb activity is the dynorphin/kappa opioid receptor (Dyn/KOR) system. However, the effects of mTBI on KOR neuromodulation of LHb function are unknown. Here, we first used retrograde tracing in male and female Cre mouse lines and identified several major KOR-expressing and two prominent Dyn-expressing inputs projecting to the mouse LHb, highlighting the medial prefrontal cortex (mPFC) and the ventromedial nucleus of the hypothalamus (VMH) as the main LHb-projecting Dyn inputs that regulate KOR signaling to the LHb. We then functionally evaluated the effects of in vitro KOR modulation of spontaneous synaptic activity within the LHb of male and female sham and mTBI mice at 4 week post-injury. We observed sex-specific differences in spontaneous release of glutamate and GABA from presynaptic terminals onto LHb neurons with higher levels of presynaptic glutamate and GABA release in females compared to male mice. However, KOR effects on the spontaneous E/I ratios and synaptic drive ratio within the LHb did not differ between male and female sham and mTBI mice. KOR activation generally suppressed spontaneous glutamatergic transmission without altering GABAergic transmission, resulting in a significant but sex-similar reduction in net spontaneous E/I and synaptic drive ratios in LHb neurons of sham mice. Following mTBI, while responses to KOR activation at LHb glutamatergic synapses remained intact, LHb GABAergic synapses acquired an additional sensitivity to KOR-mediated inhibition where we observed a reduction in GABA release probability in response to KOR stimulation in LHb neurons of mTBI mice. Further analysis of percent change in spontaneous synaptic ratios induced by KOR activation revealed that independent of sex mTBI switches KOR-driven synaptic inhibition of LHb neurons (normally observed in sham mice) in a subset of mTBI mice toward synaptic excitation resulting in mTBI-induced divergence of KOR actions within the LHb. Overall, we uncovered the sources of major Dyn/KOR-expressing synaptic inputs projecting to the mouse LHb. We demonstrate that an engagement of intra-LHb Dyn/KOR signaling provides a global KOR-driven synaptic inhibition within the mouse LHb independent of sex. The additional engagement of KOR-mediated action on LHb GABAergic transmission by mTBI could contribute to the E/I imbalance after mTBI, with Dyn/KOR signaling serving as a disinhibitory mechanism for LHb neurons of a subset of mTBI mice.

Reduced Cost Sharing and Medication Management Services for COPD: A Randomized Clinical Trial.

Importance: High out-of-pocket costs and improper use of maintenance inhalers contribute to poor outcomes among patients with chronic obstructive pulmonary disease (COPD). There is limited evidence for how addressing these barriers could improve adherence and affect COPD exacerbations, spending, or racial disparities in these outcomes. Objective: To examine the effect of a national program to reduce beneficiary cost sharing for COPD maintenance inhalers and provide medication management services that included education on proper technique for inhaler use. Design, Setting, and Participants: This randomized clinical trial included individuals with COPD. All individuals were enrolled in Medicare Advantage. Data were collected from January 2019 to December 2021, and data were analyzed from January 2023 to May 2024. Intervention: Invitation to enroll in a program that reduced cost sharing for maintenance inhalers to $0 or $10 and provided medication management services. The random assignment of the invitation was used to estimate the effects of the invitation and program enrollment, overall and by race. Main Outcomes and Measures: Inhaler adherence measured as proportion of days covered (PDC), moderate-to-severe exacerbations, short-acting inhaler fills, total spending, and as an exploratory outcome, out-of-pocket spending. Results: Of 19 113 included patients, 55.2% were female; 9.5% were Black, 81.1% were White, and 9.4% were another or unknown race; and the median (IQR) age was 74 (69-80) years. Program enrollment was higher in the invited group (29.4%) than the control group (5.1%). The PDC for maintenance inhalers was higher in the invited group than the control group (32.0% vs 28.4%; adjusted invitation effect, 3.8 percentage points; 95% CI, 3.1-4.5); the adjusted effect of the program (the local average treatment effect) was 15.5 percentage points (95% CI, 12.8-18.1), a 55% relative increase in adherence. Mean (SD) out-of-pocket spending for prescriptions was lower in the invited group ($619.5 [$863.1]) than the control group ($675.0 [$887.3]; adjusted invitation effect, -$49.5; 95% CI, -68.9 to -30.0; adjusted program effect, -$203.0; 95% CI, -282.8 to -123.2), but there was no statistically significant difference in exacerbations, short-acting inhaler fills, or total spending. Among Black individuals, the adjusted invitation effect on maintenance inhaler PDC was 5.5 percentage points (95% CI, 3.3-7.7), and the adjusted program effect was 19.5 percentage points (95% CI, 12.4-26.7). Among White individuals, the adjusted invitation effect was 3.7 percentage points (95% CI, 2.9-4.4), and the adjusted program effect was 15.1 percentage points (95% CI, 12.1-18.1). The difference between the invitation effects by race was not statistically significant (1.8 percentage points; 95% CI, -0.5 to 4.1; P = .13). Conclusions and Relevance: Individuals in Medicare Advantage who received an invitation to enroll in a program that reduced cost sharing for maintenance inhalers and provided medication management services had higher inhaler adherence compared with the control group. The difference in the program's effect on inhaler adherence between Black and White individuals was substantial but not statistically significant. Trial Registration: ClinicalTrials.gov Identifier: NCT05497999.

Response to McEvoy et al., 2023, Cumulative Blast Exposure Estimate Model for Special Operations Forces Combat Soldiers.

This letter to the editor is intended to highlight potential inaccuracies in a recent study published by McEvoy and colleagues (2023) describing a blast exposure model for special operations service members. Explosive weights for the breaching charges described appear inaccurate and may negatively impact future research or databases, as indicated by the authors future directions. Likewise, safety implications derived from this study may be misleading unless the calculation errors for net explosive weights and blast overpressure PSI are corrected. This response offers corrected calculations based on DoD explosive safety guidelines and commentary on future directions for blast exposure documentation and risk-mitigation.

Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior.

Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI during late adolescence (at ∼8 weeks old). In this study, we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. We show that mTBI increases LHb spontaneous tonic activity in female mice similar to what we previously observed in male mice, as well as promoting LHb neuronal hyperexcitability and hyperpolarization-induced LHb bursting in both male and female mice. Interestingly, mTBI only increases LHb intrinsic excitability in male mice coincident with higher levels of the hyperpolarization-activated cation currents (HCN/Ih) and reduces levels of the M-type potassium currents while potentiating M-currents without altering intrinsic excitability in LHb neurons of female mice. Because persistent dysregulation of brain CRF systems is suggested to contribute to chronic psychiatric morbidities and that LHb neurons are highly responsive to CRF, we tested whether the LHb CRF subsystem becomes engaged following mTBI. We found that in vitro inhibition of CRF receptor type 1 (CRFR1) within the LHb reverses mTBI-induced enhancement of LHb tonic activity and hyperexcitability in both sexes, suggesting that an augmented intra-LHb CRF-CRFR1-mediated signaling contributes to the overall LHb hyperactivity following mTBI. Behaviorally, mTBI diminishes motivation for self-care grooming in female mice as in male mice. mTBI also alters defensive behaviors in the looming shadow task by shifting the innate defensive behaviors toward more passive action locking rather than escape behaviors in response to an aerial threat in both male and female mice, as well as prolonging the latency to escape responses in female mice. While this model of mTBI reduces social preference in male mice, it induces higher social novelty seeking during the novel social encounters in both male and female mice. Overall, our study provides further translational validity for the use of this pre-clinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially affect young males and females when exposed to this type of mTBI during late adolescence.

Dysregulation of Kappa Opioid Receptor Neuromodulation of Lateral Habenula Synaptic Function following a Repetitive Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) increases the risk of cognitive deficits, affective disorders, anxiety and substance use disorder in affected individuals. Substantial evidence suggests a critical role for the lateral habenula (LHb) in pathophysiology of psychiatric disorders. Recently, we demonstrated a causal link between persistent mTBI-induced LHb hyperactivity due to synaptic excitation/inhibition (E/I) imbalance and motivational deficits in self-care grooming behavior in young adult male mice using a repetitive closed head injury mTBI model. One of the major neuromodulatory systems that is responsive to traumatic brain and spinal cord injuries, influences affective states and also modulates LHb activity is the dynorphin/kappa opioid receptor (Dyn/KOR) system. However, the effects of mTBI on KOR neuromodulation of LHb function is unknown. To address this, we first used retrograde tracing to anatomically verify that the mouse LHb indeed receives Dyn/KOR expressing projections. We identified several major KOR-expressing and Dyn-expressing synaptic inputs projecting to the mouse LHb. We then functionally evaluated the effects of in vitro KOR modulation of spontaneous synaptic activity within the LHb of male and female sham and mTBI mice at 4week post-injury using the repetitive closed head injury mTBI model. Similar to what we previously reported in the LHb of male mTBI mice, mTBI presynaptically diminished spontaneous synaptic activity onto LHb neurons, while shifting synaptic E/I toward excitation in female mouse LHb. Furthermore, KOR activation in either mouse male/female LHb generally suppressed spontaneous glutamatergic transmission without altering GABAergic transmission, resulting in a significant reduction in E/I ratios and decreased excitatory synaptic drive to LHb neurons of male and female sham mice. Interestingly following mTBI, while responses to KOR activation at LHb glutamatergic synapses were observed comparable to those of sham, LHb GABAergic synapses acquired an additional sensitivity to KOR-mediated inhibition. Thus, in contrast to sham LHb, we observed a reduction in GABA release probability in response to KOR stimulation in mTBI LHb, resulting in a chronic loss of KOR-mediated net synaptic inhibition within the LHb. Overall, our findings uncovered the previously unknown sources of major Dyn/KOR-expressing synaptic inputs projecting to the mouse LHb. Further, we demonstrate that an engagement of intra-LHb Dyn/KOR signaling provides a global suppression of excitatory synaptic drive to the mouse LHb which could act as an inhibitory braking mechanism to prevent LHb hyperexcitability. The additional engagement of KOR-mediated modulatory action on LHb GABAergic transmission by mTBI could contribute to the E/I imbalance after mTBI, with Dyn/KOR signaling serving as a disinhibitory mechanism for LHb neurons in male and female mTBI mice.

Predictions and errors are distinctly represented across V1 layers.

Popular accounts of mind and brain propose that the brain continuously forms predictions about future sensory inputs and combines predictions with inputs to determine what we perceive.1,2,3,4,5,6 Under "predictive processing" schemes, such integration is supported by the hierarchical organization of the cortex, whereby feedback connections communicate predictions from higher-level deep layers to agranular (superficial and deep) lower-level layers.7,8,9,10 Predictions are compared with input to compute the "prediction error," which is transmitted up the hierarchy from superficial layers of lower cortical regions to the middle layers of higher areas, to update higher-level predictions until errors are reconciled.11,12,13,14,15 In the primary visual cortex (V1), predictions have thereby been proposed to influence representations in deep layers while error signals may be computed in superficial layers. Despite the framework's popularity, there is little evidence for these functional distinctions because, to our knowledge, unexpected sensory events have not previously been presented in human laminar paradigms to contrast against expected events. To this end, this 7T fMRI study contrasted V1 responses to expected (75% likely) and unexpected (25%) Gabor orientations. Multivariate decoding analyses revealed an interaction between expectation and layer, such that expected events could be decoded with comparable accuracy across layers, while unexpected events could only be decoded in superficial laminae. Although these results are in line with these accounts that have been popular for decades, such distinctions have not previously been demonstrated in humans. We discuss how both prediction and error processes may operate together to shape our unitary perceptual experiences.

A panel network analysis of posttraumatic stress disorder and obsessive-compulsive disorder symptoms across the perinatal period.

The perinatal period is marked by a higher risk of experiencing depressive, anxiety, and/or trauma-related symptoms, a phenomenon that affects millions of individuals each year. Obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) symptoms commonly co-occur but have rarely been examined together beyond prevalence estimates in the perinatal period. Our study aimed to explore patterns of associations among OCD and PTSD symptoms to elucidate within- and between-person effects and how these effects may change over time. Participants (N = 270) were recruited during pregnancy from an academic medical center affiliated with a midwestern university. PTSD, OCD, and depressive symptoms were assessed at pregnancy, 4, 8, and 12 weeks postpartum. A panel graphical vector autoregression model was used to estimate networks. The temporal network provided information regarding directed predictive effects between symptoms, and hyperarousal, neutralizing, and ordering were the most stable and predictive symptoms across time. The contemporaneous network, which yields undirected partial correlations between symptoms at a given moment, indicated that there were positive associations between intrusions and avoidance, hyperarousal and negative alterations in cognitions and mood, as well as between hyperarousal and dysphoria. This study identified hyperarousal and neutralizing as the PTSD and OCD symptoms with the strongest stability, predictive power, and association with other symptoms. Clinically, this indicates that screening for hyperarousal and neutralizing symptoms may identify individuals who could maximally benefit from treatment in the perinatal period. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Geographic variation of mutagenic exposures in kidney cancer genomes.

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior.

Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI injury during late adolescence (at ~8 weeks old). Here we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior, and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. We show that mTBI increases LHb spontaneous tonic activity in female mice similar to what we previously observed in male mice as well as promoting LHb neuronal hyperexcitability and hyperpolarization-induced LHb bursting in both male and female mice. Interestingly, mTBI only increases LHb intrinsic excitability in male mice coincident with higher levels of the hyperpolarization-activated cation currents (HCN/Ih) and reduces levels of the M-type potassium currents while potentiating M-currents without altering intrinsic excitability in LHb neurons of female mice. Since persistent dysregulation of brain CRF systems is suggested to contribute to chronic psychiatric morbidities and that LHb neurons are highly responsive to CRF, we then tested whether LHb CRF subsystem becomes engaged following mTBI. We found that in vitro inhibition of CRF receptor type 1 (CRFR1) within the LHb normalizes mTBI-induced enhancement of LHb tonic activity and hyperexcitability in both sexes, suggesting that an augmented intra-LHb CRF-CRFR1-mediated signaling contributes to the overall LHb hyperactivity following mTBI. Behaviorally, mTBI diminishes motivation for self-care grooming in female mice as in male mice. mTBI also alters defensive behaviors in the looming shadow task by shifting the innate defensive behaviors towards more passive action-locking rather than escape behaviors in response to an aerial threat in both male and female mice as well as prolonging the latency to escape responses in female mice. While, this model of mTBI reduces social preference in male mice, it induces higher social novelty seeking during the novel social encounters in both male and female mice. Overall, our study provides further translational validity for the use of this preclinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially affect young males and females when exposed to this type of mTBI injury during late adolescence.

From pregnancy to the postpartum: Unraveling the complexities of symptom profiles among trauma-exposed women.

BACKGROUND: Many women experience new onset or worsening of existing posttraumatic stress disorder (PTSD) symptoms during pregnancy and the early postpartum period. However, perinatal PTSD symptom profiles and their predictors are not well understood. METHODS: Participants (N = 614 community adults) completed self-report measures across three methodologically similar longitudinal studies. Mixture modeling was used to identify latent subgroups of trauma-exposed women with distinct patterns of symptoms at pregnancy, 1-month, and 3-month postpartum. RESULTS: Mixture modeling demonstrated two classes of women with relatively homogenous profiles (i.e., low vs. high symptoms) during pregnancy (n = 237). At 1-month postpartum (n = 391), results suggested a five-class solution: low symptoms, PTSD only, depression with primary appetite loss, depression, and comorbid PTSD and depression. At 3-months postpartum (n = 488), three classes were identified: low symptoms, elevated symptoms, and primary PTSD. Greater degree of exposure to interpersonal trauma and reproductive trauma, younger age, and minoritized racial/ethnic identity were associated with increased risk for elevated symptoms across the perinatal period. LIMITATIONS: Only a subset of potential predictors of PTSD symptoms were examined. Replication with a larger and more racially and ethnically diverse sample of pregnant women is needed. CONCLUSIONS: Results highlight limitations of current perinatal mental health screening practices, which could overlook women with elevations in symptoms (e.g., intrusions) that are not routinely assessed relative to others (e.g., depressed mood), and identify important risk factors for perinatal PTSD symptoms to inform screening and referral.

Veterans with chronic pain: Examining gender differences in pain type, overlap, and the impact of post-traumatic stress disorder.

BACKGROUND: Women are more likely to experience multiple overlapping pain conditions (MOPCs) relative to men. Post-traumatic stress disorder can negatively impact the severity and trajectory of chronic pain and its treatment. Specific associations between gender, post-traumatic stress disorder (PTSD), and MOPCs require further examination. METHODS: A cohort of all Veterans in 2021 who met criteria for one or more of 12 chronic pain types was created using national Veterans Health Administration administrative data. MOPCs were defined as the number of pain types for which each patient met criteria. Multivariable logistic regression models estimated gender differences in frequency for each of the 12 pain subtypes, after controlling for demographics and comorbidities. Negative binomial regression was used to estimate gender differences in the count of MOPCs and to explore moderation effects between gender and PTSD. RESULTS: The cohort included 1,936,859 Veterans with chronic pain in 2021, which included 12.5% women. Among those with chronic pain, women Veterans had higher rates of MOPCs (mean = 2.3) relative to men (mean = 1.9): aIRR = 1.31, 95% CI: 1.30-1.32. PTSD also served as an independent risk factor for MOPCs in adjusted analysis (aIRR = 1.23, 95% CI: 1.23-1.24). The interaction term between gender and PTSD was not significant (p = 0.87). Independent of PTSD, depressive disorders also served as a strong risk factor for MOPCs (aIRR = 1.37, 95% CI: 1.36-1.37). CONCLUSIONS: Individuals with MOPCs and PTSD may have complex treatment needs. They may benefit from highly coordinated trauma-sensitive care and integrated interventions that simultaneously address pain and PTSD. SIGNIFICANCE: Women were significantly more likely than men to experience MOPCs. PTSD was also significantly, independently, associated with MOPCs. Patients, particularly women, may benefit from tailored interventions that address both trauma and MOPCs.

AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula.

The scaffolding A-kinase anchoring protein 150 (AKAP150) is critically involved in kinase and phosphatase regulation of synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a key role in brain's processing of rewarding/aversive experiences, however its role in the lateral habenula (LHb, as an important brain reward circuitry) is completely unknown. Using whole cell patch clamp recordings in LHb of male wildtype and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), here we show that the genetic disruption of PKA anchoring to AKAP150 significantly reduces AMPA receptor-mediated glutamatergic transmission and prevents the induction of presynaptic endocannabinoid-mediated long-term depression in LHb neurons. Moreover, ΔPKA mutation potentiates GABAA receptor-mediated inhibitory transmission while increasing LHb intrinsic excitability through suppression of medium afterhyperpolarizations. ΔPKA mutation-induced suppression of medium afterhyperpolarizations also blunts the synaptic and neuroexcitatory actions of the stress neuromodulator, corticotropin releasing factor (CRF), in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPA and GABAA receptor synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPA receptor and potassium channel trafficking and endocannabinoid signaling within the LHb.

Infertility-related stress, quality of life, and reasons for fertility treatment discontinuation among US women: A secondary analysis of a cross-sectional study.

OBJECTIVE: Fertility treatments often cause women high levels of stress and low quality of life (QoL). Women discontinue fertility treatments for a variety of reasons, yet little is known about infertility-related stress and QoL among women who discontinue treatments. The purpose of this study was to examine infertility-related stress and QoL among women who discontinued fertility treatments compared to those who continued treatments, and reasons for treatment discontinuation. METHODS: A secondary analysis was conducted to examine infertility-related stress and QoL among 70 women who discontinued from fertility treatments compared to 166 women who received fertility treatments. Statistical analysis included descriptive statistics, chi-square test for independence, independent t-tests, and binary logistic regression analysis. Conventional content analysis was conducted on responses to an open-text question about reasons for treatment discontinuation. RESULTS: No differences in infertility-related stress and QoL were found between groups. Explanatory variables of treatment discontinuation included income [odds ratios (OR) 2.50, 95% CI 1.12-5.61], QoL dissatisfaction (OR 2.49, 95% CI 1.33-4.69), and infertility duration three years or greater (OR 2.40, 95% CI 1.30-4.42). Three themes of treatment discontinuation were identified: Covering the Cost; Waiting for a Resolution; Re-envisioning Family Identity. CONCLUSION: Infertility-related stress and QoL are similar among women who discontinued and who received fertility treatments, highlighting the need for emotional support services for women regardless of their treatment status. During the period of infertility, treatment discontinuation related to cost, waiting for a resolution, or re-envisioning family identity occurred, suggesting opportunities for specific interventions to support women's mental health needs.

Associations between forgiveness and physical and mental health in the context of long COVID.

OBJECTIVE: Forgiveness has been positively associated with health in those with functional disorders. This cross-sectional study examined the relationships among dimensions of forgiveness and physical and mental health in individuals with and without long COVID. METHODS: Adults (N = 4316) in the United States took part in an online survey study detailing long COVID presence, physical and mental health, and trait forgiveness. T-tests were performed to assess differences in types of trait forgiveness between individuals with and without long COVID. Linear regression models assessed the contribution of demographic covariates and forgiveness subscales to the physical and mental health of individuals with and without long COVID. RESULTS: Of 4316 participants, 379 (8.8%) reported current long COVID. Participants were an average age of 43.7, and most identified as female (51.9%), white (87.8%), and non-Hispanic/Latino (86.6%). Individuals with long COVID reported significantly less forgiveness of self (p < 0.001, d = 0.33), forgiveness of others (p = 0.004, d = 0.16), and forgiveness of situations (p < 0.001, d = 0.34) than those without long COVID. Among the long COVID sample, forgiveness of self and situations were positively associated with mental health (p < 0.05), but not physical health (p > 0.05). Forgiveness of others was negatively associated with both physical and mental health (p < 0.05). CONCLUSION: Forgiveness may be an important consideration in understanding health among individuals with long COVID, emphasizing the importance of developing a multifaceted understanding of the condition.

Just as Essential: The Mental Health of Educators During the COVID-19 Pandemic.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic deleteriously impacted physical and mental health. In the summer of 2020, return-to-learn plans were enacted, including virtual, hybrid, and in-person plans, impacting educators and students. We examined (1) how return-to-learn plan was related to depressive and social anxiety symptoms among educators and (2) how psychological flexibility related to symptoms. METHODS: Educators (N = 853) completed a survey via Qualtrics that assessed internalizing symptoms, psychological flexibility, and occupational characteristics. Two one-way analyses of variance (ANOVAs) examined between-group differences in return-to-learn plans across depression and social anxiety. Two hierarchical linear regressions examined the relation between psychological flexibility components and depressive and social anxiety symptoms. RESULTS: Median T-scores were well above the national normative means for General Depression (median T-score: 81) and Social Anxiety (median T-score: 67). There were no significant differences between reopening plans in general depression nor social anxiety T-scores. Psychological flexibility accounted for 33% of the variance in depressive symptoms and 24% of the variance in social anxiety symptoms. CONCLUSIONS: Results indicated high levels of psychiatric symptoms among educators during COVID-19, and psychological flexibility was associated with lower symptoms. Addressing educator mental health is of utmost importance in future research.

Interoception, Affect, and Cognition in Older Adults.

Interoception is the detection of signals that arise from within the body. Interoceptive sensitivity has been found to be associated with affect and cognition among younger adults, and examination of these relationships in older adult samples is beginning to emerge. Here, we take an exploratory approach to determine how demographic, affective, and cognitive variables relate to interoceptive sensitivity in neurologically normal older adults, aged 60-91 years old. Ninety-one participants completed a comprehensive neuropsychological battery, self-report questionnaires, and a heartbeat counting task to measure interoceptive sensitivity. Our findings revealed several relationships: 1) interoceptive sensitivity was inversely correlated with measures of positive emotionality: participants with higher interoceptive sensitivity tended to have lower levels of positive affect and trait extraversion; 2) interoceptive sensitivity was found to positively correlate with cognition: participants who performed better on the heartbeat-counting task also tended to perform better on a measure of delayed verbal memory; and 3) when examining the predictors of interoceptive sensitivity in a single hierarchical regression model, higher interoceptive sensitivity was related to: higher time estimation, lower positive affect, lower extraversion, and higher verbal memory. In total, the model accounted for 38% of the variability in interoceptive sensitivity (R2 = .38). These results suggest that, among older adults, interoceptive sensitivity is facilitative for aspects of cognition but perhaps disruptive for certain aspects of emotional experience.

A smoking cessation intervention for rural veterans tailored to individual risk factors: A multicenter randomized clinical trial.

INTRODUCTION: Rates of cigarette use remain elevated among those living in rural areas. Depressive symptoms, risky alcohol use, and weight concerns frequently accompany cigarette smoking and may adversely affect quitting. Whether treatment for tobacco use that simultaneously addresses these issues affects cessation outcomes is uncertain. METHODS: The study was a multicenter, two-group, randomized controlled trial involving mostly rural veterans who smoke (N = 358) receiving treatment at one of five Veterans Affairs Medical Centers. The study randomly assigned participants to a tailored telephone counseling intervention or referral to their state tobacco quitline. Both groups received guideline-recommended smoking cessation pharmacotherapy, selected using a shared decision-making approach. The primary outcome was self-reported seven-day point prevalence abstinence (PPA) at three and six months. The study used salivary cotinine to verify self-reported quitting at six months. RESULTS: Self-reported PPA was significantly greater in participants assigned to Tailored Counseling at three (OR = 1.66; 95 % CI: 1.07-2.58) but not six (OR = 1.35; 95 % CI: 0.85-2.15) months. Post hoc subgroup analyses examining treatment group differences based on whether participants had a positive screen for elevated depressive symptoms, risky alcohol use, and/or concerns about weight gain indicated that the cessation benefit of Tailored Counseling at three months was limited to those with ≥1 accompanying concern (OR = 2.02, 95 % CI: 1.20-3.42). Biochemical verification suggested low rates of misreporting. CONCLUSIONS: A tailored smoking cessation intervention addressing concomitant risk factors enhanced short-term abstinence but did not significantly improve long-term quitting. Extending the duration of treatment may be necessary to sustain treatment effects.

Extracellular matrix-templating fibrous hydrogels promote ovarian tissue remodeling and oocyte growth.

Synthetic matrices which mimic the extracellular composition of native tissue create a comprehensive model for studying development and disease. Here, we have engineered a composite material which retains cell-secreted ECM for the culture of ovarian follicles by embedding electrospun dextran fibers functionalized with basement membrane binder (BMB) peptide in PEG hydrogels. In the presence of ECM-sequestering fibers, encapsulated immature primordial follicles and ovarian stromal cells aggregated into large organoid-like structures with dense deposition of laminin, perlecan, and collagen I, leading to steroidogenesis and significantly greater rates of oocyte survival and growth. We determined that cell aggregation restored key cell-cell interactions critical for oocyte survival, whereas oocyte growth was dependent on cell-matrix interactions achieved in the presence of BMB. Here we have shown that sequestration and retention of cell-secreted ECM along synthetic fibers mimics fibrous ECM structure and restores the cell-cell and cell-matrix interactions critical for engineering an artificial ovary.

The effect of acceptance and commitment therapy on the psychological flexibility and inflexibility of undergraduate students: A systematic review and three-level meta-analysis.

Rising rates of mental health problems in undergraduate students is a critical public health issue. There is evidence supporting the efficacy of acceptance and commitment therapy (ACT) in decreasing psychological symptoms in undergraduates, which is thought to be facilitated through increases in psychological flexibility (PF) and decreases in psychological inflexibility (PIF). However, little is known about the effect of ACT on these processes in undergraduates. We conducted a systematic review and three-level meta-analysis examining this effect in 20 studies, which provided 56 effect sizes. A combined sample of 1,750 undergraduates yielded a small-to-medium overall effect (g = .38, SE = .09, p < .001, 95% CI: [0.20, 0.56]). This effect did not depend on control group type, intervention modality, number of sessions, the questionnaire used, whether PF or PIF was measured, or participant age. However, there was a significant mean effect only in studies with a specific clinical target, but not in those without one. Furthermore, the higher the percentage of female participants, the lower the reported effect size. Results suggested that ACT may increase PF and decrease PIF in undergraduates and highlighted various conceptual and measurement issues. Study protocol and materials were preregistered (https://osf.io/un6ce/).

Quantitative interpretation of bone marrow biopsies in MPN-What's the point in a molecular age?

The diagnosis of myeloproliferative neoplasms (MPN) requires the integration of clinical, morphological, genetic and immunophenotypic findings. Recently, there has been a transformation in our understanding of the cellular and molecular mechanisms underlying disease initiation and progression in MPN. This has been accompanied by the widespread application of high-resolution quantitative molecular techniques. By contrast, microscopic interpretation of bone marrow biopsies by haematologists/haematopathologists remains subjective and qualitative. However, advances in tissue image analysis and artificial intelligence (AI) promise to transform haematopathology. Pioneering studies in bone marrow image analysis offer to refine our understanding of the boundaries between reactive samples and MPN subtypes and better capture the morphological correlates of high-risk disease. They also demonstrate potential to improve the evaluation of current and novel therapeutics for MPN and other blood cancers. With increased therapeutic targeting of diverse molecular, cellular and extra-cellular components of the marrow, these approaches can address the unmet need for improved objective and quantitative measures of disease modification in the context of clinical trials. This review focuses on the state-of-the-art in image analysis/AI of bone marrow tissue, with an emphasis on its potential to complement and inform future clinical studies and research in MPN.