Interruption of the intratumor CD8+ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy.

PD-1 blockade unleashes potent antitumor activity in CD8+ T cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen the response to immunotherapy. Tumor-Treg inhibition is a promising strategy to improve the efficacy of checkpoint blockade immunotherapy; however, our understanding of the mechanisms supporting tumor-Tregs during PD-1 immunotherapy is incomplete. Here, we show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients. Mechanistically, Treg accumulation is not caused by Treg-intrinsic inhibition of PD-1 signaling but depends on an indirect effect of activated CD8+ T cells. CD8+ T cells produce IL-2 and colocalize with Tregs in mouse and human melanomas. IL-2 upregulates the anti-apoptotic protein ICOS on tumor-Tregs, promoting their accumulation. Inhibition of ICOS signaling before PD-1 immunotherapy improves control over immunogenic melanoma. Thus, interrupting the intratumor CD8+ T cell:Treg crosstalk represents a strategy to enhance the therapeutic efficacy of PD-1 immunotherapy.

Distal colonocytes targeted by C. rodentium recruit T-cell help for barrier defence.

Interleukin 22 (IL-22) has a non-redundant role in immune defence of the intestinal barrier1-3. T cells, but not innate lymphoid cells, have an indispensable role in sustaining the IL-22 signalling that is required for the protection of colonic crypts against invasion during infection by the enteropathogen Citrobacter rodentium4 (Cr). However, the intestinal epithelial cell (IEC) subsets targeted by T cell-derived IL-22, and how T cell-derived IL-22 sustains activation in IECs, remain undefined. Here we identify a subset of absorptive IECs in the mid-distal colon that are specifically targeted by Cr and are differentially responsive to IL-22 signalling. Major histocompatibility complex class II (MHCII) expression by these colonocytes was required to elicit sustained IL-22 signalling from Cr-specific T cells, which was required to restrain Cr invasion. Our findings explain the basis for the regionalization of the host response to Cr and demonstrate that epithelial cells must elicit MHCII-dependent help from IL-22-producing T cells to orchestrate immune protection in the intestine.

Breast Cancer Polygenic Risk Score Validation and Effects of Variable Imputation.

Breast cancer (BC) is a complex disease affecting one in eight women in the USA. Advances in population genomics have led to the development of polygenic risk scores (PRSs) with the potential to augment current risk models, but replication is often limited. We evaluated 2 robust PRSs with 313 and 3820 SNPs and the effects of multiple genotype imputation replications in BC cases and control populations. Biological samples from BC cases and cancer-free controls were drawn from three European ancestry cohorts. Genotyping on the Illumina Global Screening Array was followed by stringent quality control measures and 20 genotype imputation replications. A total of 468 unrelated cases and 4337 controls were scored, revealing significant differences in mean PRS percentiles between cases and controls (p < 0.001) for both SNP sets (313-SNP PRS: 52.81 and 48.07; 3820-SNP PRS: 55.45 and 49.81), with receiver operating characteristic curve analysis showing area under the curve values of 0.596 and 0.603 for the 313-SNP and 3820-SNP PRS, respectively. PRS fluctuations (from ~2-3% up to 9%) emerged across imputation iterations. Our study robustly reaffirms the predictive capacity of PRSs for BC by replicating their performance in an independent BC population and showcases the need to average imputed scores for reliable outcomes.

Spectral analysis and kinetic modeling of radioluminescence in air and nitrogen.

In this article we present a quantitative analysis of the second positive system of molecular nitrogen and the first negative system of the molecular nitrogen cation excited in the presence of ionizing radiation. Optical emission spectra of atmospheric air and nitrogen surrounding 210Po sources were measured from 250 to 400 nm. Multi-Boltzmann and non-Boltzmann vibrational distribution spectral models were used to determine the vibrational temperature and vibrational distribution function of the emitting N2(C3Πu) and N2+(B2Σ+u) states. A zero-dimensional kinetic model, based on the electron energy distribution function (EEDF) and steady-state excitation and de-excitation of N2(X1Σ+g), N2+(B2Σ+u), N2+(X2Σ+g), N4+, O2+, and N2(C3Πu, v), was developed for the prediction of the relative spectral intensity of both the N2+(B2Σ+u → X2Σ+g) emission band and the vibrational bands of N2(C3Πu → B3Πg) for comparison with the experimental data.

Diagnosis and Treatment of Perioperative Allergic Complications: A Practical Review.

Background: Reported drug allergies are commonly encountered by surgeons and can lead to uncertainty in selecting an appropriate agent due to concerns of associated risks with related and cross-reactive drugs. This uncertainty can ultimately lead to increased infection rates. Methods: A literature review was conducted in PubMed using a combination of the terms "allergy," "allergic reaction," "anaphylaxis," and "surgery," "surgical," or "operating room" for articles published within the last 10 years. Publications identified with these search terms were then filtered for review articles, sorted by "best match," and a maximum of 100 articles were manually reviewed for each combination of search terms. Results: Search results yielded 46,484 articles, 676 of which were ultimately included for manual review, based on selection criteria. Specifically, articles selected for inclusion focused on surgical allergic reactions that were either related to mechanism of action, causative agent for the allergic reaction, timing of allergic reaction, or recommendations for appropriate management. Conclusions: Allergic reactions can be a common occurrence in the operative room. Knowledge of likely causative agents, timing of a reaction to various agents, and appropriate management in the immediate and delayed setting can improve outcomes and safety for plastic surgery patients.

The Future of Municipal Wastewater Reuse Concentrate Management: Drivers, Challenges, and Opportunities.

Water reuse is rapidly becoming an integral feature of resilient water systems, where municipal wastewater undergoes advanced treatment, typically involving a sequence of ultrafiltration (UF), reverse osmosis (RO), and an advanced oxidation process (AOP). When RO is used, a concentrated waste stream is produced that is elevated in not only total dissolved solids but also metals, nutrients, and micropollutants that have passed through conventional wastewater treatment. Management of this RO concentrate─dubbed municipal wastewater reuse concentrate (MWRC)─will be critical to address, especially as water reuse practices become more widespread. Building on existing brine management practices, this review explores MWRC management options by identifying infrastructural needs and opportunities for multi-beneficial disposal. To safeguard environmental systems from the potential hazards of MWRC, disposal, monitoring, and regulatory techniques are discussed to promote the safety and affordability of implementing MWRC management. Furthermore, opportunities for resource recovery and valorization are differentiated, while economic techniques to revamp cost-benefit analysis for MWRC management are examined. The goal of this critical review is to create a common foundation for researchers, practitioners, and regulators by providing an interdisciplinary set of tools and frameworks to address the impending challenges and emerging opportunities of MWRC management.

Examining strength at home couples to prevent intimate partner violence on a military installation: A randomized controlled trial.

OBJECTIVES: In this study, the effectiveness of a couples-based group intervention to prevent intimate partner violence (IPV), Strength at Home Couples (SAH-C), was examined on a military installation relative to a comparison intervention, Supportive Prevention (SP). It was expected that greater reductions in use of physical, psychological, and sexual IPV behaviors, as well as reduced suicidality, would be found among service members and their partners in SAH-C relative to SP. METHOD: Participants included 138 couples randomized to SAH-C and SP through a clinical controlled trial embedded in a hybrid effectiveness implementation study which took place on a military installation. The Revised Conflict Tactics Scales and Multidimensional Measure of Emotional Abuse were used to measure IPV, and 13 Military Suicide Research Consortium common data elements were used to assess suicidality. RESULTS: Service members randomized to SAH-C evidenced greater reductions based on effect sizes across the assessment time points for all IPV variables, including use of overall physical IPV, severe physical IPV, sexual IPV, psychological IPV, and coercive control IPV relative to those randomized to SP. Partners of service members demonstrated a similar general pattern for reductions in use of IPV, but findings were not as robust as for service members. Both service members and partners demonstrated greater reductions in suicidality based on effect sizes when randomized to SAH-C relative to SP. CONCLUSIONS: Findings extend prior work demonstrating the promising effects of SAH-C delivered in the military context and highlight the possible benefits of SAH-C in preventing self-harm thoughts and behaviors. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Predictors of veteran attendance in an intimate partner violence intervention.

This study examined session attendance data from 2,754 veterans who participated in a national implementation of a trauma-informed intimate partner violence intervention, Strength at Home, across the Veterans Affairs Healthcare System. Potential correlates of attendance were demographic characteristics, posttraumatic stress disorder (PTSD) symptom severity, alcohol use, court involvement, current military involvement, and intervention modality (in-person vs. virtual). Given the trauma-informed nature of the intervention, it was expected that trauma-relevant risk factors, specifically PTSD symptom severity and racial minority status, would be less strongly associated with attendance than barriers related to other demographic variables and higher alcohol use, intervention modality, and court involvement. Results indicated that age, education level, employment status, retirement status, PTSD symptom severity, alcohol use, and court involvement were associated with session attendance in the expected direction at the bivariate level. Only education level, employment status, retirement status, alcohol use, and court involvement emerged as unique predictors of attendance such that more educated, employed, retired, and court-mandated veterans with less alcohol use attended more sessions. These findings suggest the importance of a trauma-informed, coordinated community response to intimate partner violence intervention and integration of motivational components surrounding problematic alcohol use to enhance compliance and mitigate barriers to attendance. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Regulatory T cells in skin mediate immune privilege of the hair follicle stem cell niche.

Immune tolerance is maintained in lymphoid organs (LOs). Despite the presence of complex immune cell networks in non-LOs, it is unknown whether self-tolerance is maintained in these tissues. We developed a technique to restrict genetic recombination to regulatory T cells (Tregs) only in skin. Selective depletion of skin Tregs resulted in T cell-mediated inflammation of hair follicles (HFs). Suppression did not rely on CTLA-4, but instead on high-affinity interleukin-2 (IL-2) receptor expression by skin Tregs, functioning exclusively in a cell-extrinsic manner. In a novel model of HF stem cell (HFSC)-driven autoimmunity, we reveal that skin Tregs immunologically protect the HFSC niche. Finally, we used spatial transcriptomics to identify aberrant IL-2 signaling at stromal-HF interfaces in a rare form of human alopecia characterized by HFSC destruction and alopecia areata. Collectively, these results reveal the fundamental biology of Tregs in skin uncoupled from the systemic pool and elucidate a mechanism of self-tolerance.

Financial Literacy in Plastic Surgery Training: Importance and Current Status.

BACKGROUND: Medical training is known to impose financial burden on trainees, which has been shown to contribute to burnout, even possibly compromising patient care. Financial literacy allows for management of financial situations affecting professional and personal life. The authors aimed to evaluate the financial status and knowledge among plastic surgery residents. METHODS: A survey regarding finances and financial literacy of plastic surgery residents was sent to all the current accredited U.S. residency programs. The same survey was distributed internally. A descriptive analysis was performed, and multiple Fisher exact tests and a t test evaluated comparisons. RESULTS: Eighty-six residents were included. Most trainees had a student loan (59.3%), with 22.1% having loans more than $300,000. A majority had at least one personal loan debt other than educational (51.1%). Residents with more debt were significantly less likely to pay off their balances monthly. A total of 17.4% of trainees had no plan for how to invest their retirement savings, whereas 55.8% reported not knowing how much they need to save to retire. One in five trainees did not feel prepared to manage personal finances/retirement planning after graduation, a majority had no formal personal finance education in their curriculum, and 89.5% agreed that financial literacy education would be beneficial. Our institutional data largely mirrored national data. CONCLUSIONS: Many residents are lacking in financial knowledge, despite most having significant debt. Additional financial literacy education is needed in plastic surgery training. Curricula development at an institutional or national society level are possible paths toward a coordinated response to this need.

Updates on Diversity Among Cardiology-Related Fellowships.

Within the United States (US) medical system, diversity in healthcare is a growing concern although studies have shown improved patient outcomes when healthcare teams are diverse. We were interested in cardiology-related fellowships from internal medicine and surgical specialties to understand how females, osteopaths (DOs), and non-US graduates were represented compared to males, allopathic medical doctors (MD), and US-graduated peers. We obtained data about accredited cardiology fellowship programs from the Fellowship and Residency Electronic Interactive Database Access System (FRIEDA™) for 2022-2023 and determined statistical significance for male/female, DO/MD, and US/non-US graduate status by reviewing program sites. Statistical analysis utilized SAS Studio 3.8, version 9.4 (SAS Institute, Inc., Cary, NC) and Wilson score for confidence intervals. Cardiology-related fellowships from internal medicine and surgery backgrounds showed generalized marked disparities (p<0.001) with only a couple of exceptions. For Interventional Cardiology, non-US graduates were well represented (p=0.3775), and for Heart Failure & Transplant Cardiology, females were represented equally (p=0.0863). For all other specialties and values, females, DOs, and non-US graduates were underrepresented. Despite conversations about diversity, underrepresentation persists. We encourage further steps to address barriers preventing underrepresented groups from advancing to their full potential in leadership and careers. Increasing diversity promotes competence, empathy, communication, and inclusive patient care.

Kruppel-like factor 2+ CD4 T cells avert microbiota-induced intestinal inflammation.

Intestinal colonization by antigenically foreign microbes necessitates expanded peripheral immune tolerance. Here we show commensal microbiota prime expansion of CD4 T cells unified by the Kruppel-like factor 2 (KLF2) transcriptional regulator and an essential role for KLF2+ CD4 cells in averting microbiota-driven intestinal inflammation. CD4 cells with commensal specificity in secondary lymphoid organs and intestinal tissues are enriched for KLF2 expression, and distinct from FOXP3+ regulatory T cells or other differentiation lineages. Mice with conditional KLF2 deficiency in T cells develop spontaneous rectal prolapse and intestinal inflammation, phenotypes overturned by eliminating microbiota or reconstituting with donor KLF2+ cells. Activated KLF2+ cells selectively produce IL-10, and eliminating IL-10 overrides their suppressive function in vitro and protection against intestinal inflammation in vivo. Together with reduced KLF2+ CD4 cell accumulation in Crohn's disease, a necessity for the KLF2+ subpopulation of T regulatory type 1 (Tr1) cells in sustaining commensal tolerance is demonstrated.

Genome-Wide DNA Methylation Profiles in Whole-Blood and Buccal Samples-Cross-Sectional, Longitudinal, and across Platforms.

The field of DNA methylation research is rapidly evolving, focusing on disease and phenotype changes over time using methylation measurements from diverse tissue sources and multiple array platforms. Consequently, identifying the extent of longitudinal, inter-tissue, and inter-platform variation in DNA methylation is crucial for future advancement. DNA methylation was measured in 375 individuals, with 197 of those having 2 blood sample measurements ~10 years apart. Whole-blood samples were measured on Illumina Infinium 450K and EPIC methylation arrays, and buccal samples from a subset of 58 participants were measured on EPIC array. The data were analyzed with the aims to examine the correlation between methylation levels in longitudinal blood samples in 197 individuals, examine the correlation between methylation levels in the blood and buccal samples in 58 individuals, and examine the correlation between blood methylation profiles assessed on the EPIC and 450K arrays in 83 individuals. We identified 136,833, 7674, and 96,891 CpGs significantly and strongly correlated (>0.50) longitudinally, across blood and buccal samples as well as array platforms, respectively. A total of 3674 of these CpGs were shared across all three sets. Analysis of these shared CpGs identified previously found associations with aging, ancestry, and 7016 mQTLs as well.

IL-2-induced Stat3 Signaling is Critical for Effector Treg Cell Programming.

Maintenance of immune homeostasis to the intestinal mictrobiota is dependent on a population of effector regulatory T (eTreg) cells that develop from microbiota-reactive induced (i)Treg cells. A cardinal feature of eTreg cells is their production of IL-10, which plays a non-redundant role in immune tolerance of commensal microbes. Here, we identify an unexpected role for IL-2-induced Stat3 signaling to program iTreg cells for eTreg cell differentiation and Il10 transcriptional competency. IL-2 proved to be both necessary and sufficient for eTreg cell development - contingent on Stat3 output of the IL-2 receptor coordinate with IL-2 signaling during early Treg cell commitment. Induction of iTreg cell programming in absence of IL-2-induced Stat3 signaling resulted in impaired eTreg cell differentiation and a failure to produce IL-10. An IL-2 mutein with reduced affinity for the IL-2Rγ (γ c ) chain was found to have blunted IL-2R Stat3 output, resulting in a deficiency of Il10 transcriptional programming that could not be fully rescued by Stat3 signaling subsequent to an initial window of iTreg cell differentiation. These findings expose a heretofore unappreciated role of IL-2 signaling that acts early to program subsequent production of IL-10 by developing eTreg cells, with broad implications for IL-2-based therapeutic interventions in immune-mediated diseases.

Trauma-informed parenting intervention for veterans: A preliminary uncontrolled trial of Strength at Home-Parents.

Trauma exposure and posttraumatic stress disorder (PTSD) are highly prevalent in military and veteran populations and are associated with parenting difficulties. Unfortunately, there is a lack of accessible, trauma-informed, and evidence-based parenting support interventions within the Department of Veterans Affairs (VA). Strength at Home-Parents (SAHP) is a trauma-informed psychotherapy group that aims to improve parenting behaviors and overall parent-child and family functioning among U.S. military veterans with PTSD symptoms. SAHP was developed to maximize ease of use by VA providers and accessibility for parents. Here we report data from an uncontrolled trial of SAHP delivered using synchronous video technology in a sample of veterans using VA care (N = 53) who met the criteria for PTSD and parent-child functioning difficulties. Enrollment and retention rates met study goals and suggest feasibility and acceptability of study methods. Significant pre- to postintervention improvements were observed in measures of dysfunctional discipline, parenting stress, general family functioning, child psychosocial functioning, and parental PTSD and depression symptoms. Coupled with high satisfaction ratings, findings support further study of the intervention, including in an efficacy trial. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

More Than Results: The Clinical and Research Relationship in the Evolving Detection and Surveillance of SARS-CoV-2.

INTRODUCTION: During the coronavirus disease 2019 (COVID-19) pandemic, real-time reverse transcription polymerase chain reaction (RT-PCR) became an essential tool for laboratories to provide high-sensitivity qualitative diagnostic testing for patients and real-time data to public health officials. Here we explore the predictive value of quantitative data from RT-PCR cycle threshold (Ct) values in epidemiological measures, symptom presentation, and variant transition. METHODS: To examine the association with hospitalizations and deaths, data from 74,479 patients referred to the Avera Institute for Human Genetics (AIHG) for COVID-19 testing in 2020 were matched by calendar week to epidemiological data reported by the South Dakota Department of Health. We explored the association between symptom data, patient age, and Ct values for 101 patients. We also explored changes in Ct values during variant transition detected by genomic surveillance sequencing of the AIHG testing population during 2021. RESULTS: Measures from AIHG diagnostic testing strongly explain variance in the South Dakota state positivity percentage (R2 = 0.758), a two-week delay in hospitalizations (R2 = 0.856), and a four-week delay in deaths (R2 = 0.854). Based on factor analysis of patient symptoms, three groups could be distinguished which had different presentations of age, Ct value, and time from collection. Additionally, conflicting Ct value results among SARSCoV- 2 variants during variant transition may reflect the community transmission dynamics. CONCLUSIONS: Measures of Ct value in RT-PCR diagnostic assays combined with routine screening have valuable applications in monitoring the dynamics of SARS-CoV-2 within communities.

Diversity Differences Among Cardiovascular Fellowships Across Five Geographic Regions in the United States.

Introduction Diversity and inclusion in cardiovascular fellowships are necessary for addressing the healthcare needs of diverse patient populations. However, regional disparities in the diversity of these programs persist, diminishing efforts to create a representative workforce. We observe the regional differences in the diversity of cardiovascular fellowship programs, focusing on gender, doctorate designation, and graduation within the United States (US) or other. We hypothesized that males, medical doctors (MD), and US graduates would be in majority across all regions. Methods Data for cardiovascular fellowships from the Fellowship and Residency Electronic Database Access (FREIDA) system for the matriculation year 2022-2023 was obtained to assess the representation of male vs female gender, MD vs osteopathic doctor (DO) designation, and US vs non-US graduate. We then compared these backgrounds to five defined regions (Midwest, Northeast, Southeast, Southwest, and West) in the United States to define representation for backgrounds across geographic areas. Statistical significance was determined by p<0.05 with the use of SAS Studio 3.8, version 9.4 (Cary, NC: SAS Institute, Inc.), and Wilson score for confidence intervals. Results We found significant disparities across all background factors for all regions. This includes that females, DOs, and non-US graduates were underrepresented among Midwest, Northeast, Southeast, Southwest, and West regions, and the p-value was <0.001 for all variations. Specifically for Midwest, the female frequency was 155 (23.81%; CI: 21, 27; p<0.001), DO frequency was 101 (15.51%; CI: 13, 19; p<0.001), and non-US graduate frequency was 206 (31.84%; CI: 28, 36; p<0.001). For Northeast, the female frequency was 231 (29.62; CI: 27, 33; p<0.001), DO frequency was 72 (9.22; CI: 7, 11; p<0.001), and non-US graduate frequency was 239 (30.68; CI 28, 34; p<0.001). For Southeast, the female frequency was 178 (25.99; CI: 23, 29; p<0.001), DO frequency was 67 (9.78; CI: 8, 12; p<0.001), and non-US graduate frequency 279 (41.46; CI: 38, 45; p<0.001). For Southwest, the female frequency was 74 (26.71; CI: 22, 32; p<0.001), DO frequency was 21 (7.58; CI 5, 11; p<0.001), and non-US graduate frequency was 110 (39.71; CI: 34,46; p<0.001). For West, the female frequency was 107 (31.75; CI 27, 37; p<0.001), DO frequency was 15 (4.45; CI: 3, 7; p<0.001), and non-US graduate frequency was 54 (16.07; CI: 13, 20; p<0.001). Conclusion We emphasize the regional disparities for females, DOs, and non-US graduates within cardiovascular fellowships in the past matriculation year. Understanding that we have not reached diversity goals allows for further reflection and implementation of targeted interventions and initiatives aimed at promoting equal opportunities for applicants. This is true for all regions of the United States. By addressing these disparities, fellowship programs can more effectively mirror the diverse patient populations they serve and foster a healthcare environment that is inclusive and accommodating. This, in turn, contributes to the overall enhancement of healthcare outcomes.