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Bridging Mental Health and Education (BRIDGE) is an evidence-based model for embedding teacher consultation and coaching activities into school-based mental health clinicians' regular workflow. Here we describe the process of adapting BRIDGE in partnership with a large urban school district and a local managed care organization during a large-scale implementation effort. We also report the feasibility and perceived effectiveness of the adapted training and consultation model as reported by clinicians in one school year. Over 93% of trained clinicians (n = 75) initiated coaching sessions with assigned teachers. Eighty-five percent of coaching sessions were completed as scheduled (n = 505 of 592). After the completion of coaching visits, clinicians attended bi-weekly virtual group sessions for two months. Ninety percent of virtual group sessions were completed as scheduled. Clinicians indicated high levels of satisfaction and high likelihood of using BRIDGE in future. Additionally, clinicians' self-reported knowledge of BRIDGE practices and their comfort with training others in these evidence-based classroom practices improved from pre- to post- training and coaching. Expert coaches indicated that clinicians' knowledge of BRIDGE strategies, commitment to BRIDGE consultation, and likelihood of continuing to use BRIDGE strategies were high. These findings suggest that the adapted BRIDGE model is feasible and was perceived to be effective. We share lessons learned related to community-partnered, school intervention adaptation and implementation.

Public schools are a major provider of mental health services for children in the US. Mental and behavioral health services range from universal programming to individualized clinical supports to address student needs. These services in schools are delivered by various professionals including non-teaching and teaching school personnel, school-employed clinicians, and/or contracted community mental health partners. Provision of mental health services requires complex coordination of providers across disciplines, although few professionals have training in multidisciplinary collaboration strategies. Attention to team processes, such as delineating team members' roles, improving communication, and identifying collaboration strategies, may impact the effectiveness of evidence-based mental health service provision in real world settings. One intervention, Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS), has been used in healthcare with positive outcomes and has been adapted to educational settings. The current paper describes the community-partnered subsequent adaptation of TeamSTEPPS for schools. Needs assessment interviews identified challenges, successes, and goals for student mental health. Overarching themes extracted from interviews include limited resources at multiple levels (e.g., financial support, time, and personnel), communication challenges, and poor role clarity. A community advisory board provided guidance during the adaptation and implementation planning process. Adaptations to the intervention included tailoring the intervention to the school context and the development of flexible training plans. In addition, individualized implementation plans were developed with each school partner to mitigate foreseeable barriers to rolling-out TeamSTEPPS. Our team is currently piloting the adapted TeamSTEPPS intervention and implementation strategies in partnership with three school districts.

Brain aging process is influenced by various lifestyle, environmental and genetic factors, as well as by age-related and often coexisting pathologies. Magnetic resonance imaging and artificial intelligence methods have been instrumental in understanding neuroanatomical changes that occur during aging. Large, diverse population studies enable identifying comprehensive and representative brain change patterns resulting from distinct but overlapping pathological and biological factors, revealing intersections and heterogeneity in affected brain regions and clinical phenotypes. Herein, we leverage a state-of-the-art deep-representation learning method, Surreal-GAN, and present methodological advances and extensive experimental results elucidating brain aging heterogeneity in a cohort of 49,482 individuals from 11 studies. Five dominant patterns of brain atrophy were identified and quantified for each individual by respective measures, R-indices. Their associations with biomedical, lifestyle and genetic factors provide insights into the etiology of observed variances, suggesting their potential as brain endophenotypes for genetic and lifestyle risks. Furthermore, baseline R-indices predict disease progression and mortality, capturing early changes as supplementary prognostic markers. These R-indices establish a dimensional approach to measuring aging trajectories and related brain changes. They hold promise for precise diagnostics, especially at preclinical stages, facilitating personalized patient management and targeted clinical trial recruitment based on specific brain endophenotypic expression and prognosis.

Given the developmental benefits associated with higher sense of purpose, past work has aimed to understand how experiences of adversity relate to sense of purpose. With a specific focus on experiences of adversity that may impact individuals from marginalized groups, past work has found that discrimination is related to lower sense of purpose in life, but that these effects are weaker for Black adults relative to White adults. The current research aims to extend past work by examining how and for whom discrimination is related to sense of purpose in life. Moreover, the current work also aimed to understand the extent to which sense of purpose spans across generations and whether there are generational differences in the relationship between discrimination and sense of purpose. Using data from the St. Louis Personality and Aging Network study, 822 parents (G1 participants) and 654 children (G2 participants) completed measures for sense of purpose, major experiences of discrimination, and personality traits. Results found mixed evidence for a relationship between discrimination and sense of purpose, with little evidence for consistent moderators. In addition, while the current work found no evidence of intergenerational associations for sense of purpose, results showed that discrimination was positively associated across generations, suggesting a potential for an intergenerational cycle of marginalization.

Introduction: Pit viper envenomation may cause coagulopathy. The coagulopathy has been treated with crotalidae polyvalent immune fragment antigen-binding (Fab) ovine antivenom for the last few decades in the United States and usually corrects the acute coagulopathy within hours. Days after receiving Fab, coagulopathy may recur in approximately half of the patients. Another divalent antivenom, crotalidae immune F(ab’)2 (equine)–F(ab’)2–was approved by the US Food and Drug Administration for the treatment of pit viper envenomation. F(ab’)2 is composed of two linked antigen-binding fragments of immunoglobulin G. Several studies have demonstrated that F(ab’)2 is less likely to be associated with recurrence. There is no reported case of F(ab’)2-associated late coagulopathy in very young patients. We report the first case of recurrence associated with F(ab’)2 use in a preschool-age child.Case Report: A preschool-age male developed leg swelling and hypofibrinogenemia after rattlesnake envenomation. F(ab’)2 was administered to stabilize the leg edema and to correct the hypofibrinogenemia. The patient improved clinically and was discharged on hospital day five. Seven days after the rattlesnake envenomation, he returned to the emergency department as instructed. Laboratory data revealed recurrent hypofibrinogenemia.Conclusion: There are two antivenoms available in the US to treat crotalid envenomation, Fab and F(ab’)2. F(ab’)2 is less likely to be associated with recurrent coagulopathy in comparison to Fab. We report the first case of recurrence associated with F(ab’)2 in a preschool-age child. It is important that the emergency physician be aware of potential F(ab’)2-associated recurrent coagulopathy. Adult and pediatric patients may need to follow up to be evaluated for hypofibrinogenemia and/or thrombocytopenia after receiving F(ab’)2.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by abscesses, nodules, dissecting/draining tunnels, and extensive fibrosis. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, and immunostaining to provide an unprecedented view of the pathogenesis of chronic HS, characterizing the main cellular players and defining their interactions. We found a striking layering of the chronic HS infiltrate and identified the contribution of 2 fibroblast subtypes (SFRP4+ and CXCL13+) in orchestrating this compartmentalized immune response. We further demonstrated the central role of the Hippo pathway in promoting extensive fibrosis in HS and provided preclinical evidence that the profibrotic fibroblast response in HS can be modulated through inhibition of this pathway. These data provide insights into key aspects of HS pathogenesis with broad therapeutic implications.

Genetic variants and epigenetic features both contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10-8), the intergenic region between VRTN and SYNDIG1L (Score = - 37.67, P = 2.25 × 10-9), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10-8), PVRL2 (Score = 125.86, P = 1.64 × 10-9), TOMM40 (Score = - 18.58, P = 4.61 × 10-8), and APOE (Score = 75.12, P = 7.26 × 10-26). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P

BackgroundThe ALLEGRO phase 2a and 2b/3 studies demonstrated that ritlecitinib, an oral JAK3/TEC family kinase inhibitor, is efficacious at doses of ≥ 30 mg in patients aged ≥ 12 years with alopecia areata (AA).ObjectiveThe objective of this study was to evaluate the safety of ritlecitinib in an integrated analysis of four studies in AA.MethodsTwo cohorts were analyzed: a placebo-controlled and an all-exposure cohort. Proportions and study size-adjusted incidence rates (IRs) of adverse events (AEs) of interest and laboratory abnormalities are reported.ResultsIn the placebo-controlled cohort (n = 881; median exposure: 169 days), the proportion of ritlecitinib-treated patients with AEs was 70.2-75.4% across doses versus 69.5% in the placebo group; serious AEs occurred in 0-3.2% versus 1.9% for the placebo. A total of 19 patients permanently discontinued due to AEs (5 while receiving the placebo). In the all-exposure cohort (n = 1294), median ritlecitinib exposure was 624 days [2091.7 total patient-years (PY)]. AEs were reported in 1094 patients (84.5%) and serious AEs in 57 (4.4%); 78 (6.0%) permanently discontinued due to AEs. The most common AEs were headache (17.7%; 11.9/100 PY), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (15.5%; 9.8/100 PY), and nasopharyngitis (12.4%; 8.2/100 PY). There were two deaths (breast cancer and acute respiratory failure/cardiorespiratory arrest). Proportions (IRs) were < 0.1% (0.05/100 PY) for opportunistic infections, 1.5% (0.9/100 PY) for herpes zoster, 0.5% (0.3/100 PY) for malignancies (excluding nonmelanoma skin cancer), and 0.2% (0.1/100 PY) for major adverse cardiovascular events.ConclusionsRitlecitinib is well tolerated with an acceptable safety profile up to 24 months in patients aged ≥ 12 years with AA (video abstract and graphical plain language summary available).Trial registriesClinicalTrials.gov: NCT02974868 (date of registration: 11/29/2016), NCT04517864 (08/18/2020), NCT03732807 (11/07/2018), and NCT04006457 (07/05/2019).

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

Abstract Background The effect of milk on the risk of ischemic heart disease (IHD) and acute myocardial infarction (MI) is unclear. We aimed to examine the association between non-fermented and fermented milk consumption on these endpoints and investigate the relationship between milk intake and cardiometabolic-related proteins in plasma. Methods Our study is based on two Swedish prospective cohort studies that included 59,998 women and 40,777 men without IHD or cancer at baseline who provided repeated measures of diet and lifestyle factors and plasma proteomics data in two subcohorts. Through registry linkage, 17,896 cases with IHD were documented during up to 33 years of follow-up, including 10,714 with MI. We used time-updated multivariable Cox regression analysis to examine non-fermented or fermented milk intake with time to IHD or MI. Using high-throughput multiplex immunoassays, 276 cardiometabolic plasma proteins were measured in two subcohorts. We applied multivariable-adjusted regression models using a discovery-replication design to examine protein associations with increasing consumption of non-fermented or fermented milk. Results The results for non-fermented milk differed by sex (p-value for interaction = 0.01). In women, we found a pattern of successively greater risk of IHD and MI at non-fermented milk intake levels higher than 1.5 glasses/day. Compared with an intake of 0.5 glass/day (100 mL/day), non-fermented milk intake of 2 glasses/day in women conferred a multivariable-adjusted hazard ratio (HR) of 1.05 (95% CI 1.01–1.08) for IHD, an intake of 3 glasses/day an HR of 1.12 (95% CI 1.06–1.19), and an intake of 4 glasses/day an HR of 1.21 (95% CI 1.10–1.32). Findings were similar for whole, medium-fat, and low-fat milk. We did not detect higher risks of IHD with increasing milk intakes in men. Fermented milk intake was unrelated to the risk of IHD or MI in either sex. Increasing non-fermented milk intake in women was robustly associated with a higher concentration of plasma ACE2 and a lower concentration of FGF21. Conclusions We show a positive association between high amounts of non-fermented milk intake and IHD in women but not men. We suggest metabolic pathways related to ACE2 and FGF21 potentially underlie the association. Graphical abstract Our analysis of two large cohort studies involving 100,775 participants and 17,896 clinically confirmed IHD events supports a dose–response positive association between non-fermented milk intake higher than 300 mL/day with higher rates of IHD (and acute MI specifically) in women, but not in men. The higher risk of IHD with high milk intake in women was evident, irrespective of the fat content of the milk. Fermented milk intake was unrelated to the risk of IHD in both women and men. Non-fermented milk intake was associated in different directions with circulating levels of ACE2 and FGF21 in women—two essential cardiometabolic proteins, also related to IHD in women in our study.

Abstract Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The ‘Thr’ PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, ‘Thr’ PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

Abstract Background Sex as a biological variable is not a common consideration in molecular mechanistic or preclinical studies of retinal diseases. Understanding the sexual dimorphism of adult RPE and retina under physiological conditions is an important first step in improving our understanding of sex-based physio-pathological mechanisms. Methods Isobaric tags for relative and absolute quantitation (iTRAQ) were used for quantitative proteomics of male and female mouse retina and RPE (10 mice of each sex for each tissue type). Differentially expressed proteins were subjected to Gene Ontology (GO) analysis and Ingenuity Pathway Analysis (IPA). Results Differential expression analysis identified 21 differentially expressed proteins in the retina and 58 differentially expressed proteins in the RPE. Ingenuity pathway analysis identified the top canonical pathways differentially activated in the retina to be calcium transport I, nucleotide excision repair, molecular transport and cell death and survival. In the RPE, the top canonical pathways were calcium signaling, dilated cardiomyopathy signaling, actin cytoskeletal signaling and cellular assembly and organization. Conclusions These results provide insights into sex differences in the retina and RPE proteome of mice and begin to shed clues into the sexual dimorphism seen in retinal diseases.

Abstract Background Given that the majority of suicide decedents visit primary care in the year preceding death, primary care has been identified as a key setting in which to engage patients at risk for suicide in mental health services. The objective of this research was to identify barriers and facilitators to engagement in mental health services among primary care patients at risk for suicide to inform the development of strategies to increase engagement. Methods Seventy-four semi-structured qualitative interviews were conducted with primary care patients (n = 20), primary care (n = 18) and behavioral health (n = 12) clinicians, mental health intake coordinators (n = 4), and health system and clinic leaders (n = 20). Patients who had been referred for mental health services from primary care and reported an elevated score (≥ 1) on item 9 on the Patient Health Questionnaire at the time of referral were eligible to participate. Eligible clinicians and leaders were employed in a primary care or behavioral health setting in a single large health system with an integrated mental health program. Interviews typically lasted 30–60 min, were completed over video conference or phone, and were coded by members of the research team using a rapid qualitative analysis procedure. Results Participants were primarily female (64.9%), white (70.3%) and non-Hispanic/Latine (91.9%). The most identified barriers to mental health care engagement were waitlists, capacity limits, insurance, patient characteristics, communication, collaboration, and/or difficulties surrounding travel. The most commonly cited facilitators of engagement included telehealth, integrated care models, reminders, case management support, psychoeducation, motivational enhancement, and scheduling flexibility. Concrete suggestions for improving engagement in mental health services included increasing communication between providers, streamlining referral and intake processes, providing reminders and follow ups, and advocacy for increased reimbursement for suicide risk assessment. Conclusions Results underscore the myriad barriers patients at risk for suicide encounter when attempting to engage in mental health care in a primary care setting. Facilitators of engagement and suggestions for improving connections to care were also identified, which can inform the design of implementation strategies to improve engagement in mental health services among primary care patients at risk for suicide. Trial registration ClinicalTrials.gov Identifier: NCT05021224 (Registered August 19, 2021).

Abstract Alzheimer’s disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the “diffuse-AD” (R1) dimension shows widespread brain atrophy, and the “MTL-AD” (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were “druggable genes” for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction—driven by genes different from APOE—which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .

Abstract Introduction Patients with alopecia areata (AA) may have received several therapies for management of AA during their lives. In the ALLEGRO phase 2b/3 (NCT03732807) study, the oral JAK3/TEC family kinase inhibitor ritlecitinib demonstrated efficacy and an acceptable safety profile in patients aged ≥ 12 years with AA and ≥ 50% scalp hair loss. This post hoc analysis investigated associations between prior use of AA therapies and Severity of Alopecia Tool (SALT) responses in patients receiving ritlecitinib for AA. Methods Patients receiving ritlecitinib 30 mg or 50 mg once daily with or without an initial 4-week 200-mg daily loading dose were grouped by previous exposure to AA treatments, including topicals, intralesional corticosteroids (ILCS), topical immunotherapy, and systemic immunosuppressants or any prior AA treatment. Multivariable logistic regression analyses evaluated the association between response based on a SALT score of ≤ 20 and any prior treatment for AA at weeks 24 and 48. Results Of 522 patients, 360 (69.0%) had previous exposure to any AA treatment. At Week 24, SALT ≤ 20 response was positively associated with prior use of ILCS (odds ratio [OR], 2.12; 95% confidence interval [CI], 1.23–3.65; P 0.05). Previous exposure to any AA therapy was not associated with SALT ≤ 20 response at weeks 24 or 48 (all P > 0.05). Conclusions Prior AA treatment history had no effect on longer-term treatment response to ritlecitinib. Trial Registration Number NCT03732807. Graphical Abstract

During remote learning due to the COVID-19 pandemic, we developed and implemented a place-based, 5E mini-unit for New York City high school and community college Earth science students, most of whom identify as belonging to non-dominant groups. As well as supporting standard science skills such as graphing and interpreting data, we leveraged active learning and culturally responsive pedagogies such as reasoning by analogy, storytelling, virtual field trips, and sketching. These strategies were aimed at developing science content and skills, science identities, and science interest. The mini-unit was taught over 6 to 7.5 hours. Pre- and post-surveys for 107 students from three schools showed significant gains in learning (38% increase; p= <0.0001). Science identity measurements increased slightly although they stayed relatively low. Science interest measurements were higher with small increases. Teacher influence and science classroom experiences ranked as the most important influencers of science interest. For 33 community college students, no correlation was found between content learning, science identity, and science interest. In this group, females and White students had higher scores for all three measures. Between pre- and post-survey, science identity increased, particularly for Black students, while science interest decreased for all but White students. For all students, overall increases between pre- and post-survey suggest the pedagogical approaches used during remote synchronous learning were successful at helping students grow as scientists.