Does seasonal variation affect the neuroimmune system? A retrospective [11C]PBR28 PET study in healthy individuals.

INTRODUCTION: The neuroimmune system performs a wide range of functions in the brain and the central nervous system. The microglial translocator protein (TSPO) has an established role as a cell marker in identification of the neuroimmune system. Previously, human studies have shown TSPO differences in neuropsychiatric disorders. Seasonal variability has also been demonstrated in multiple systems of healthy individuals. Therefore, in this study, we attempt to understand whether seasonal changes affect brain TSPO levels using [11C]PBR28 positron emission tomography (PET) imaging. METHODS: 46 healthy subjects (mean age ± SD = 32.5 ± 10); sex (M/F) = 32/14)) underwent PET imaging with [11C]PBR28 in a retrospectively conducted analysis. All PET scans were performed on the HRRT scanner. Volume of distribution (VT) values were generated for cortical and subcortical regions and the cerebellum. Spring/summer months were defined as March to August while fall/winter months were defined as September to February and were compared through 2-tailed t-tests (SciPy library v.1.10.1 and Pinguoin library on Python v.3.8.8). Average daylight hours and temperature in New Haven, CT were obtained online (www.wunderground.com) and compared to VT with Spearman's correlations. RESULTS: There were no significant differences observed between the TSPO levels of spring/summer and fall/winter months in the brain (t = 0.52, p = 0.61). Additional analysis on all individual brain regions also indicated non-significance. Likewise, no significant correlations were found between TSPO levels in the whole brain and brain regions against daylight hours (ρ= 0.05, p = 0.74), temperature (ρ = 0.04, p = 0.81), or month (ρ = 0.08, p = 0.60). Controlling TSPO gene polymorphisms and other variables had no significant effect on the outcome. CONCLUSION: To the best of our knowledge, this is the first human study to investigate seasonal changes in TSPO expression. Our results can be interpreted as the lack of seasonal variability in the neuroimmune system, but important limitations include high interindividual variability, test-retest variability, specificity of the tracer, and a limited sample size. Limitations notwithstanding, our results conclude that TSPO levels in the brain are not impacted by light and temperature changes in different seasons.

Substance use and spine density: a systematic review and meta-analysis of preclinical studies.

The elucidation of synaptic density changes provides valuable insights into the underlying brain mechanisms of substance use. In preclinical studies, synaptic density markers, like spine density, are altered by substances of abuse (e.g., alcohol, amphetamine, cannabis, cocaine, opioids, nicotine). These changes could be linked to phenomena including behavioral sensitization and drug self-administration in rodents. However, studies have produced heterogeneous results for spine density across substances and brain regions. Identifying patterns will inform translational studies given tools that now exist to measure in vivo synaptic density in humans. We performed a meta-analysis of preclinical studies to identify consistent findings across studies. PubMed, ScienceDirect, Scopus, and EBSCO were searched between September 2022 and September 2023, based on a protocol (PROSPERO: CRD42022354006). We screened 6083 publications and included 70 for meta-analysis. The meta-analysis revealed drug-specific patterns in spine density changes. Hippocampal spine density increased after amphetamine. Amphetamine, cocaine, and nicotine increased spine density in the nucleus accumbens. Alcohol and amphetamine increased, and cannabis reduced, spine density in the prefrontal cortex. There was no convergence of findings for morphine's effects. The effects of cocaine on the prefrontal cortex presented contrasting results compared to human studies, warranting further investigation. Publication bias was small for alcohol or morphine and substantial for the other substances. Heterogeneity was moderate-to-high across all substances. Nonetheless, these findings inform current translational efforts examining spine density in humans with substance use disorders.

Alternative processes to produce chitin, chitosan, and their oligomers.

Sustainable recovery of chitin and its derivatives from shellfish waste will be achieved when the industrial production of these polymers is achieved with a high control of their molecular structure, low costs, and acceptable levels of pollution. Therefore, the conventional chemical method for obtaining these biopolymers needs to be replaced or optimized. The goal of the present review is to ascertain what alternative methods are viable for the industrial-scale production of chitin, chitosan, and their oligomers. Therefore, a detailed review of recent literature was undertaken, focusing on the advantages and disadvantages of each method. The analysis of the existing data allows suggesting that combining conventional, biological, and alternative methods is the most efficient strategy to achieve sustainable production, preventing negative impacts and allowing for the recovery of high added-value compounds from shellfish waste. In conclusion, a new process for obtaining chitinous materials is suggested, with the potential of reducing the consumption of reagents, energy, and water by at least 1/10, 1/4, and 1/3 part with respect to the conventional process, respectively.

Speeding genomic island discovery through systematic design of reference database composition.

BACKGROUND: Genomic islands (GIs) are mobile genetic elements that integrate site-specifically into bacterial chromosomes, bearing genes that affect phenotypes such as pathogenicity and metabolism. GIs typically occur sporadically among related bacterial strains, enabling comparative genomic approaches to GI identification. For a candidate GI in a query genome, the number of reference genomes with a precise deletion of the GI serves as a support value for the GI. Our comparative software for GI identification was slowed by our original use of large reference genome databases (DBs). Here we explore smaller species-focused DBs. RESULTS: With increasing DB size, recovery of our reliable prophage GI calls reached a plateau, while recovery of less reliable GI calls (FPs) increased rapidly as DB sizes exceeded ~500 genomes; i.e., overlarge DBs can increase FP rates. Paradoxically, relative to prophages, FPs were both more frequently supported only by genomes outside the species and more frequently supported only by genomes inside the species; this may be due to their generally lower support values. Setting a DB size limit for our SMAll Ranked Tailored (SMART) DB design speeded runtime ~65-fold. Strictly intra-species DBs would tend to lower yields of prophages for small species (with few genomes available); simulations with large species showed that this could be partially overcome by reaching outside the species to closely related taxa, without an FP burden. Employing such taxonomic outreach in DB design generated redundancy in the DB set; as few as 2984 DBs were needed to cover all 47894 prokaryotic species. CONCLUSIONS: Runtime decreased dramatically with SMART DB design, with only minor losses of prophages. We also describe potential utility in other comparative genomics projects.

Breastfeeding moderates the association of maternal pre-pregnancy nutritional status with offspring body composition at 30 years.

Maternal pre-pregnancy body mass index is positively associated with offspring obesity, even at adulthood, whereas breastfeeding decreases the risk of obesity. The present study was aimed at assessing whether breastfeeding moderates the association of maternal pre-pregnancy body mass index with offspring body composition at adulthood, using data from 3439 subjects enrolled in a southern Brazilian birth cohort. At 30 years of age, maternal pre-pregnancy body mass index was positively associated with offspring prevalence of obesity, abdominal obesity, as well as body mass index and fat and lean mass index. Breastfeeding moderated the association of maternal pre-pregnancy obesity with offspring adiposity at 30 years of age. For those breastfed<6 months, body mass index was 4.13 kg/m2 (95% confidence interval: 2.98; 5.28) higher among offspring of obese mothers, in relation to offspring of normal weight mothers, whereas among those breastfed≥6 months the magnitude of the difference was small [2.95 kg/m2 (95% confidence interval: 1.17; 4.73)], p-value for interaction = 0.03. Concerning obesity, among those who had been breastfed < 6 months, the prevalence of obesity was 2.56 (95% confidence interval: 1.98; 3.31) times higher among offspring of obese mothers. On the other hand, among those who were breastfed ≥ 6 months, the prevalence of obesity was 1.82 (95% confidence interval: 1.09; 3.04) times higher among offspring of obese mothers. Therefore, among overweight mothers breastfeeding for more than 6 months should be supported, as it may mitigate the consequences of maternal overweight on offspring body composition.

Validation of the structured interview section of the penn computerized adaptive test for neurocognitive and clinical psychopathology assessment (CAT GOASSESS).

Large-scale studies and burdened clinical settings require precise, efficient measures that assess multiple domains of psychopathology. Computerized adaptive tests (CATs) can reduce administration time without compromising data quality. We examined feasibility and validity of an adaptive psychopathology measure, GOASSESS, in a clinical community-based sample (N = 315; ages 18-35) comprising three groups: healthy controls, psychosis, mood/anxiety disorders. Assessment duration was compared between the Full and CAT GOASSESS. External validity was tested by comparing how the CAT and Full versions related to demographic variables, study group, and socioeconomic status. The relationships between scale scores and criteria were statistically compared within a mixed-model framework to account for dependency between relationships. Convergent validity was assessed by comparing scores of the CAT and the Full GOASSESS using Pearson correlations. The CAT GOASSESS reduced interview duration by more than 90 % across study groups and preserved relationships to external criteria and demographic variables as the Full GOASSESS. All CAT GOASSESS scales could replace those of the Full instrument. Overall, the CAT GOASSESS showed acceptable psychometric properties and demonstrated feasibility by markedly reducing assessment time compared to the Full GOASSESS. The adaptive version could be used in large-scale studies or clinical settings for intake screening.

Effectiveness of hand hygiene campaigns and interventions across the League of Arab States: a region-wide scoping review.

Hand hygiene is a standard public health practice for limiting the spread of infectious diseases, yet they are still not routine global health behaviours. This review aimed to examine the effectiveness of various hand hygiene interventions conducted across the League of Arab States, identify gaps in the existing literature, and propose areas for future research and intervention development. A scoping review was conducted across 16 databases for relevant publications published up to and including October 2023. Forty studies met the inclusion criteria; of these, 34 were hospital-based and six community-based. Of the reviewed studies, 24 provided adequate details that would enable replication of their intervention. Eighteen of the studies used some variation of the World Health Organization's Five Moments for intervention content or assessment. More than half (N = 25) reported healthcare worker or student hand hygiene behaviours as an outcome and 15 studies also included some form of patient-centred outcomes. Six studies specified the use of theory or framework for their evaluation design or intervention content, and four studies mentioned use of local government guidelines or recommendations. Future research should focus on bridging the literature gaps by emphasizing community-based studies and integrating cultural nuances into intervention designs. Additionally, applying theoretical frameworks to hand hygiene studies could enhance understanding and effectiveness, ensuring sustainable improvements in hygiene practices across diverse settings in the League of Arab States.

Parent Support for Physical Activity and Motor Skills During Early Childhood: A Mixed-Methods Application of the Multi-process Action Control Framework.

BACKGROUND: Promoting physical activity (PA) and fundamental movement skills (FMS) in early childhood is necessary to address the high rates of inactivity in children. Parent support is a determinant of PA in children, however, parental intentions to support are not always translated into behavior resulting in an intention-behavior gap. PURPOSE: Positioned within the multi-process action control (M-PAC) framework, this study used an explanatory concurrent mixed-methods design to explore parents' intentions and support of PA and FMS during early childhood. METHODS: Parents (N=124) of children aged 3-4 years completed an online survey consisting of items assessing reflective (e.g., attitudes), regulatory (e.g., planning), and reflexive (e.g., habit) processes of M-PAC and intentions and support for child PA and FMS. A subset of parents (n=20) completed a semi-structured online interview guided by the M-PAC framework. RESULTS: Significantly more parents intended to support PA (71%) compared with FMS (44%; p<0.001) and successfully translated intentions into action for PA (57%) compared with FMS (27%; p<0.001). Discriminant function analysis showed parent behavior profiles for PA and FMS support were associated with a combination of reflective, regulatory, and reflexive processes, however, these differed based on support behavior. Qualitative findings highlighted parents' differential views on PA and FMS support and contextualized the psychological processes associated with each. CONCLUSIONS: Parent PA support interventions during early childhood should include strategies for supporting FMS. Interventions should prioritize fostering a combination of reflective, regulatory, and reflexive behaviors to translate intentions to support PA and FMS into behavior among parents of young children.

Promoting physical activity (PA) and fundamental movement skills (FMS) in early childhood is necessary to address physical inactivity in young children. Parent support is a known predictor of PA in children, however, parents who intend to support PA do not always follow through with these intentions. This is referred to as the intention­behavior gap. Applying the theoretical tenets of the multi-process action control framework, this study surveyed 124 parents of children aged 3­4 years on reflective (e.g., attitudes), regulatory (e.g., planning), and reflexive (e.g., habit) processes, intentions, and behaviors related to parent PA and FMS support. Follow-up interviews were completed with 20 parents to gain a deeper understanding of parent PA and FMS support behaviors. Survey findings showed that parents' intentions and support behaviors for their child's PA and FMS were associated with a combination of reflective, regulatory, and reflexive processes. Interview findings highlighted more favorable parent perspectives toward PA support compared with FMS and further explained the psychological processes associated with each. Future parent PA support interventions during early childhood should include FMS support strategies and foster a combination of reflective, regulatory, and reflexive behaviors to bridge the gap between intentions and support behaviors among parents of young children.

Race and gender disparities in preventive health activity engagement of older adults in the southeastern United States.

A cross-sectional study was conducted to determine preventive-health-activity engagement in community-dwelling older adults participating in student-led health screenings in east Alabama. From 2017-2019, health professions students conducted health screenings at 23 community and independent living sites to assess medical and social needs of adults. Clients' responses to questions regarding vaccinations (flu/pneumonia/shingles), cancer screenings (colon/sex-specific), and other (dental/vision) screenings were aggregated to create a preventive health behavior (prevmed) score. Chi-square, t-tests, and regression analyses were conducted. Data from 464 adults ages 50-99 (72.9±10.1) years old were analyzed. The sample was 71.3% female, 63.1% Black/African American (BA), and 33.4% rural. Linear regression indicated BA race (p=0.001), currently unmarried (p=0.030), no primary care provider (p<0.001) or insurance (p=0.010), age <65 years (p=0.042) and assessment at a residential site (p=0.037) predicted lower prevmed scores. Social factors predict preventive health activity engagement in community-dwelling adults in east Alabama, indicating several opportunities to improve health outcomes.

Lower dorsal putamen D2/3 receptor availability and amphetamine-induced dopamine release are related to poorer cognitive function in recently abstinent people who smoke and healthy controls.

INTRODUCTION: In the dopamine system, the mesolimbic pathway, including the dorsal striatum, underlies the reinforcing properties of tobacco smoking, and the mesocortical pathway, including the dorsolateral prefrontal cortex (dlPFC), is critical for cognitive functioning. Dysregulated dopamine signaling has been linked to drug-seeking behaviors and cognitbie deficits. The dorsal striatum and dlPFC are structurally and functionally connected and are the key regions for cognitive functioning. We recently showed that people who smoke have lower dlPFC dopamine (D2/3R) receptor availability than people who do not, which is related to poorer cognitive function. The goal of this study was to examine the same brain-behavior relationship in the dorsal striatum. METHODS: Twenty-nine (18 males) recently abstinent people who smoke and twenty-nine sex-matched healthy controls participated in two same-day [11C]-(+)-PHNO positron emission tomography scans before and after amphetamine administration to provoke dopamine release. D2/3R availability (binding potential; BPND) and amphetamine-induced dopamine release (%ΔBPND) were calculated. Cognition (verbal learning and memory) was assessed with the CogState computerized battery. RESULTS: There were no group differences in baseline BPND. People who smoke have a smaller magnitude %ΔBPND in dorsal putamen than healthy controls (p=0.022). People who smoke perform worse on immediate (p=0.035) and delayed (p=0.011) recall than healthy controls. In all people, lower dorsal putamen BPND was associated with worse immediate (p=0.006) and delayed recall (p=0.049), and lower %ΔBPND was related to worse delayed recall (p=0.022). CONCLUSION: Lower dorsal putamen D2/3R availability and function are associated with disruptions in cognitive function that may underlie difficulty with resisting smoking. IMPLICATIONS: This study directly relates dopamine imaging outcomes in the dorsal striatum to cognitive function in recently abstinent people who smoke cigarettes and healthy controls. The current work included a well-characterized subject sample in terms of demographics, smoking characteristics, and a validated neurocognitive test of verbal learning and memory. The findings of this study extend previous literature relating dopamine imaging outcomes to cognition in recently abstinent people who smoke and people who do not smoke, expanding our understanding of brain-behavior relationships.

A Bifactor Evaluation of Self-Report and Clinician-Administered Measures of PTSD in Veterans.

The PTSD Checklist for DSM-5 (PCL-5) and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) are two of the most widely used and well-validated PTSD measures providing total and subscale scores that correspond with DSM-5 PTSD symptoms. However, there is little information about the utility of subscale scores above and beyond the total score for either measure. The current study compared the proposed DSM-5 four-factor model to a bifactor model across both measures using a sample of veterans (N = 1,240) presenting to a Veterans Affairs (VA) PTSD specialty clinic. The correlated factors and bifactor models for both measures evidenced marginal-to-acceptable fit and were retained for further evaluation. Bifactor specific indices suggested that both measures exhibited a strong general factor but weak lower-order factors. Structural regressions revealed that most of the lower-order factors provided little utility in predicting relevant outcomes. Although additional research is needed to make definitive statements about the utility of PCL-5 and CAPS-5 subscales, study findings point to numerous weaknesses. As such, caution should be exercised when using or interpreting subscale scores in future research.

High-Fat, High-Calorie Breast Milk in Women with Overweight or Obesity and Its Association with Maternal Serum Insulin Concentration and Triglycerides Levels.

The childhood obesity epidemic continues to be a challenge. Maternal obesity and excessive infant weight gain are strong predictors of childhood obesity, which itself is a major risk factor for adult obesity. The primary source of nutrition during early life is breast milk, and its composition is impacted by maternal habitus and diet. We thus studied the relationship between maternal BMI, serum lipids and insulin, and breast milk fat and calorie content from foremilk to hindmilk. Women who were exclusively breastfeeding at 7-8 weeks postpartum were BMI classified as Normal (18.5-24.9, n = 9) and women with Overweight/Obese (OW/OB ≥ 25, n = 13). Maternal blood and continuous breast milk samples obtained from foremilk to hindmilk were analyzed, and infant milk intake was assessed. Women with OW/OB had significantly higher milk fat and calorie content in the first foremilk and last hindmilk sample as compared to Normal BMI women. Amongst all women, maternal serum triglycerides, insulin, and HOMA were significantly correlated with foremilk triglyceride concentration, suggesting that maternal serum triglyceride and insulin action contribute to human milk fat content. As the milk fat content of OW/OB women has caloric implications for infant growth and childhood obesity, these results suggest the potential for modulating milk fat content by a reduction in maternal serum lipids or insulin.

The B7:CD28 family and friends: Unraveling coinhibitory interactions.

Immune responses must be tightly regulated to ensure both optimal protective immunity and tolerance. Costimulatory pathways within the B7:CD28 family provide essential signals for optimal T cell activation and clonal expansion. They provide crucial inhibitory signals that maintain immune homeostasis, control resolution of inflammation, regulate host defense, and promote tolerance to prevent autoimmunity. Tumors and chronic pathogens can exploit these pathways to evade eradication by the immune system. Advances in understanding B7:CD28 pathways have ushered in a new era of immunotherapy with effective drugs to treat cancer, autoimmune diseases, infectious diseases, and transplant rejection. Here, we discuss current understanding of the mechanisms underlying the coinhibitory functions of CTLA-4, PD-1, PD-L1:B7-1 and PD-L2:RGMb interactions and less studied B7 family members, including HHLA2, VISTA, BTNL2, and BTN3A1, as well as their overlapping and unique roles in regulating immune responses, and the therapeutic potential of these insights.

Imaging a putative marker of brain cortisol regulation in alcohol use disorder.

Background: Stress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [18F]AS2471907 to measure 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls. Methods: We imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11ß-HSD1 inhibitor radiotracer [18F]AS2471907 as a bolus injection and were imaged for 150-180 min on the High-Resolution Research Tomograph. 11ß-HSD1 availability was quantified by [18F]AS2471907 volume of distribution (VT; mL/cm3). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate. Results: Individuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [18F]AS2471907 VT was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (p < 0.05). In AUD, vmPFC [18F]AS2471907 VT was associated with drinks per week (r = 0.81, p = 0.01) and quantity per drinking episode (r = 0.75, p = 0.02). Conclusions: This is the first in vivo examination of 11ß-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11ß-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11ß-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.

The impacts of migraine on functioning: Results from two qualitative studies of people living with migraine.

OBJECTIVE: To describe the impact of migraine on functioning based on comprehensive data collection, analysis, and reporting of patients' experiences. BACKGROUND: Qualitative research conducted to understand patients' perspectives on living with migraine has often focused on narrow topics or specific groups of patients or has been selectively reported. METHODS: Qualitative interviews with 71 participants were conducted during two concept elicitation studies as part of the Migraine Clinical Outcome Assessment System (MiCOAS) project, an FDA grant-funded program designed to develop a core set of patient-centered outcome measures for migraine clinical trials. Participants self-reported being diagnosed with migraine by a healthcare professional and participated in semi-structured qualitative interviews about their experiences with the symptoms and impacts of migraine. Interview transcripts were coded to identify and define concepts, which were then grouped into broad domains based on conceptual similarities. RESULTS: A total of 66 concepts were identified: 12 for physical functioning, 16 for cognitive functioning, 10 for social role functioning, 19 for emotional and psychological functioning, and 9 related to migraine management. Participants described a complex and varied relationship between migraine attack symptoms and impacts on functioning. Impacts from migraine were further influenced by numerous contextual factors, such as people's individual social environments and the level of day-to-day demand for functioning they face. CONCLUSION: Findings showed that migraine impacted individual functioning in multiple ways and the nature of these impacts was dependent on social-contextual factors. The results are being used in the development of core measures designed to improve our understanding of the burden of migraine and the efficacy of migraine therapies. The results also offer new insights and raise new questions about migraine experience that can be used to guide future research.

Evaluation of implementation facilitation integrated into a national mentoring programme to improve access to evidence-based psychotherapy for post-traumatic stress disorder within the veterans health administration: a quality improvement report.

Despite the resources dedicated to specialised mental healthcare for patients with post-traumatic stress disorder (PTSD) within the US Veterans Health Administration, evidence-based psychotherapies (EBPs) for PTSD have been underutilised, as evidenced by low EBP reach to patients. A research-operation collaboration evaluated whether implementation facilitation delivered by regional PTSD mentors as part of a national mentoring programme improved EBP reach compared with less-intensive quality improvement interventions. We used a non-equivalent comparison-group design that included all PTSD clinics with low EBP reach at baseline (n=51). Clinics were grouped into one of four quality improvement conditions according to self-selection by regional PTSD mentors: facilitation (n=6), learning collaborative (n=15), mentoring as usual in the regions that had facilitation-target clinics (n=15) and mentoring as usual in other regions (n=15). The primary outcome was EBP reach among therapy patients with PTSD at preintervention baseline and postintervention sustainment periods. We used the ratio of odds ratios (ROR) between the two time periods to evaluate the effectiveness of facilitation compared with the other conditions, adjusting for patient-level and clinic-level confounders. 26 126 veterans with PTSD received psychotherapy in one of 51 low-reach PTSD clinics during preintervention baseline and postintervention sustainment periods. The odds of a patient receiving an EBP increased over time across conditions. The adjusted ORs of a patient receiving an EBP from baseline to sustainment were 1.35-1.69 times larger in clinics that received facilitation compared with the three comparison conditions (adjusted RORs of comparison condition versus facilitation ranged from 0.59 (95% CI 0.47 to 0.75) to 0.74 (95% CI 0.58 to 0.94)). Implementation facilitation can be integrated into a national programme for quality improvement for PTSD specialty care and may be particularly useful when less-intensive approaches are not sufficiently effective.

The role of neurosteroids in posttraumatic stress disorder and alcohol use disorder: A review of 10 years of clinical literature and treatment implications.

Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.

Age-Related Differences in Motor Skill Transfer with Brief Memory Reactivation.

Motor memories can be strengthened through online practice and offline consolidation. Offline consolidation involves the stabilization of memory traces in post-practice periods. Following initial consolidation of a motor memory, subsequent practice of the motor skill can lead to reactivation and reconsolidation of the memory trace. The length of motor memory reactivation may influence motor learning outcomes; for example, brief, as opposed to long, practice of a previously learned motor skill appears to optimize intermanual transfer in healthy young adults. However, the influence of aging on reactivation-based motor learning has been scarcely explored. Here, the effects of brief and long motor memory reactivation schedules on the retention and intermanual transfer of a visuomotor tracing task are explored in healthy older adults. Forty older adults practiced a virtual star-tracing task either three ("brief reactivation") or ten ("long reactivation") times per session over a two-week period. Comparison with a previously reported group of younger adults revealed significant age-related differences in the effect of the motor memory reactivation schedule on the intermanual transfer of the motor task. In older adults, unlike younger adults, no significant between-group differences were found by practice condition in the speed, accuracy, or skill of intermanual task transfer. That is, motor task transfer in healthy younger, but not older, adults appears to benefit from brief memory reactivation. These results support the use of age-specific motor training approaches and may inform motor practice scheduling, with possible implications for physical rehabilitation, sport, and music.

PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients.

PURPOSE: Programmed cell death protein 1 (PD-1) expression on CD8+TIM-3-LAG-3- tumor-infiltrating cells predicts positive response to PD-1 blockade in metastatic clear-cell renal cell carcinoma (mccRCC). Because inhibition of PD-1 signaling in regulatory T cells (Treg) augments their immunosuppressive function, we hypothesized that PD-1 expression on tumor-infiltrating Tregs would predict resistance to PD-1 inhibitors. EXPERIMENTAL DESIGN: PD-1+ Tregs were phenotyped using multiparametric immunofluorescence in ccRCC tissues from the CheckMate-025 trial (nivolumab: n = 91; everolimus: n = 90). Expression of CD8, PD-1, TIM-3, and LAG-3 was previously determined (Ficial and colleagues, 2021). Clinical endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). RESULTS: In the nivolumab (but not everolimus) arm, high percentage of PD-1+ Tregs was associated with shorter PFS (3.19 vs. 5.78 months; P = 0.021), shorter OS (18.1 vs. 27.7 months; P = 0.013) and marginally lower ORR (12.5% vs. 31.3%; P = 0.059). An integrated biomarker (PD-1 Treg/CD8 ratio) was developed by calculating the ratio between percentage of PD-1+Tregs (marker of resistance) and percentage of CD8+PD-1+TIM-3-LAG-3- cells (marker of response). In the nivolumab (but not everolimus) arm, patients with high PD-1 Treg/CD8 ratio experienced shorter PFS (3.48 vs. 9.23 months; P < 0.001), shorter OS (18.14 vs. 38.21 months; P < 0.001), and lower ORR (15.69% vs. 40.00%; P = 0.009). Compared with the individual biomarkers, the PD-1 Treg/CD8 ratio showed improved ability to predict outcomes to nivolumab versus everolimus. CONCLUSIONS: PD-1 expression on Tregs is associated with resistance to PD-1 blockade in mccRCC, suggesting that targeting Tregs may synergize with PD-1 inhibition. A model that integrates PD-1 expression on Tregs and CD8+TIM-3-LAG-3- cells has higher predictive value.