Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance.

In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.

Clonal haematopoiesis and risk of chronic liver disease.

Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.

The origins and drivers of insulin resistance.

Obesity-induced insulin resistance is the major determinant of metabolic syndrome, which precedes the development of type 2 diabetes mellitus and is thus the driving force behind the emerging diabetes epidemic. The precise causes of insulin resistance are varied, and the relative importance of each is a matter of ongoing research. Here, we offer a Perspective on the heterogeneous etiology of insulin resistance, focusing in particular on the role of inflammation, lipid metabolism, and the gastrointestinal microbiota.

Multi-ancestry polygenic risk scores for venous thromboembolism.

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium genome-wide association studies meta-analyses of European- (71 771 cases and 1 059 740 controls) and African-ancestry samples (7482 cases and 129 975 controls). We used LDpred2 and PRS-CSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6781 cases and 103 016 controls) and African-ancestry sample (1385 cases and 12 569 controls). Multi-ancestry PRSs with weights tuned in European-ancestry samples slightly outperformed ancestry-specific PRSs in European-ancestry test samples (e.g. the area under the receiver operating curve [AUC] was 0.609 for PRS-CSx_combinedEUR and 0.608 for PRS-CSxEUR [P = 0.00029]). Multi-ancestry PRSs with weights tuned in African-ancestry samples also outperformed ancestry-specific PRSs in African-ancestry test samples (PRS-CSxAFR: AUC = 0.58, PRS-CSx_combined AFR: AUC = 0.59), although this difference was not statistically significant (P = 0.34). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS might be used to improve performance across diverse populations to identify individuals at highest risk for VTE.

NANOG is required to establish the competence for germ-layer differentiation in the basal tetrapod axolotl.

Pluripotency defines the unlimited potential of individual cells of vertebrate embryos, from which all adult somatic cells and germ cells are derived. Understanding how the programming of pluripotency evolved has been obscured in part by a lack of data from lower vertebrates; in model systems such as frogs and zebrafish, the function of the pluripotency genes NANOG and POU5F1 have diverged. Here, we investigated how the axolotl ortholog of NANOG programs pluripotency during development. Axolotl NANOG is absolutely required for gastrulation and germ-layer commitment. We show that in axolotl primitive ectoderm (animal caps; ACs) NANOG and NODAL activity, as well as the epigenetic modifying enzyme DPY30, are required for the mass deposition of H3K4me3 in pluripotent chromatin. We also demonstrate that all 3 protein activities are required for ACs to establish the competency to differentiate toward mesoderm. Our results suggest the ancient function of NANOG may be establishing the competence for lineage differentiation in early cells. These observations provide insights into embryonic development in the tetrapod ancestor from which terrestrial vertebrates evolved.

The Regulation of Nucleic Acid Vaccine Responses by the Microbiome.

Nucleic acid vaccines, including both RNA and DNA platforms, are key technologies that have considerable promise in combating both infectious disease and cancer. However, little is known about the extrinsic factors that regulate nucleic acid vaccine responses and which may determine their effectiveness. The microbiome is recognized as a significant regulator of immune development and response, whose role in regulating some traditional vaccine platforms has recently been discovered. Using germ-free and specific pathogen-free mouse models in combination with different protein, DNA, and mRNA vaccine regimens, we demonstrate that the microbiome is a significant regulator of nucleic acid vaccine immunogenicity. Although the presence of the microbiome enhances CD8+ T cell responses to mRNA lipid nanoparticle immunization, the microbiome suppresses Ig and CD4+ T cell responses to DNA-prime, DNA-protein-boost immunization, indicating contrasting roles for the microbiome in the regulation of these different nucleic acid vaccine platforms. In the case of mRNA lipid nanoparticle vaccination, germ-free mice display reduced dendritic cell/macrophage activation that may underlie the deficient vaccine response. Our study identifies the microbiome as a relevant determinant of nucleic acid vaccine response with implications for continued therapeutic development and deployment of these vaccines.

Race, rituximab, and relapse in TTP.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.

Effects of a comprehensive brain computed tomography deep learning model on radiologist detection accuracy.

OBJECTIVES: Non-contrast computed tomography of the brain (NCCTB) is commonly used to detect intracranial pathology but is subject to interpretation errors. Machine learning can augment clinical decision-making and improve NCCTB scan interpretation. This retrospective detection accuracy study assessed the performance of radiologists assisted by a deep learning model and compared the standalone performance of the model with that of unassisted radiologists. METHODS: A deep learning model was trained on 212,484 NCCTB scans drawn from a private radiology group in Australia. Scans from inpatient, outpatient, and emergency settings were included. Scan inclusion criteria were age ≥ 18 years and series slice thickness ≤ 1.5 mm. Thirty-two radiologists reviewed 2848 scans with and without the assistance of the deep learning system and rated their confidence in the presence of each finding using a 7-point scale. Differences in AUC and Matthews correlation coefficient (MCC) were calculated using a ground-truth gold standard. RESULTS: The model demonstrated an average area under the receiver operating characteristic curve (AUC) of 0.93 across 144 NCCTB findings and significantly improved radiologist interpretation performance. Assisted and unassisted radiologists demonstrated an average AUC of 0.79 and 0.73 across 22 grouped parent findings and 0.72 and 0.68 across 189 child findings, respectively. When assisted by the model, radiologist AUC was significantly improved for 91 findings (158 findings were non-inferior), and reading time was significantly reduced. CONCLUSIONS: The assistance of a comprehensive deep learning model significantly improved radiologist detection accuracy across a wide range of clinical findings and demonstrated the potential to improve NCCTB interpretation. CLINICAL RELEVANCE STATEMENT: This study evaluated a comprehensive CT brain deep learning model, which performed strongly, improved the performance of radiologists, and reduced interpretation time. The model may reduce errors, improve efficiency, facilitate triage, and better enable the delivery of timely patient care. KEY POINTS: • This study demonstrated that the use of a comprehensive deep learning system assisted radiologists in the detection of a wide range of abnormalities on non-contrast brain computed tomography scans. • The deep learning model demonstrated an average area under the receiver operating characteristic curve of 0.93 across 144 findings and significantly improved radiologist interpretation performance. • The assistance of the comprehensive deep learning model significantly reduced the time required for radiologists to interpret computed tomography scans of the brain.

The efficacy of the TEACH e-Learning course at improving early childhood educators' physical activity and sedentary behaviour self-efficacy, knowledge, intentions, and perceived behavioural control: a randomized controlled trial.

BACKGROUND: Early childhood educators play a critical role in promoting physical activity and reducing sedentary time in childcare centres. However, early childhood educators receive limited specialised pre- and in-service learning opportunities relating to these behaviours and may lack the capacity to effectively engage children in healthy movement behaviours. This study aimed to examine the efficacy of an e-Learning course on increasing early childhood educators' physical activity and sedentary behaviour-related capacities. METHODS: A two-group parallel randomized controlled trial was conducted with early childhood educators in Canada (Mage = 41.78, 97% female). Participants randomized to the intervention group were asked to complete a physical activity and sedentary behaviour e-Learning course within a 4-week period. Participants randomized to the waitlist control condition were assigned to a waitlist to receive the intervention after the testing period. Participants reported on their self-efficacy, knowledge, intentions, and perceived behavioural control relating to physical activity and sedentary behaviours at baseline, post-intervention, and 3 months follow-up. Linear mixed effects models were estimated to determine difference in changes in outcomes from baseline to post-intervention, and follow-up. RESULTS: A total of 209 early childhood educators participated in the study (intervention n = 98; control n = 111). The TEACH e-Learning course was found to be efficacious at improving all of the examined outcomes, with standardized effect sizes ranging from d = 0.58 to d = 0.65 for self-efficacy outcomes, d = 0.66 to d = 1.20 for knowledge outcomes, d = 0.50 to d = 0.65 for intention outcomes, and d = 0.33 to d = 0.69 for perceived behavioural control outcomes post-intervention. The intervention effects were sustained at follow-up for all outcomes apart from perceived behavioural control to limit screen time. Additionally, the magnitude of the effect for knowledge outcomes decreased at follow-up, with standardized effect sizes ranging from d = 0.49 to d = 0.67. CONCLUSIONS: The e-Learning course was highly successful at improving early childhood educators' capacity pertaining to physical activity and sedentary behaviours. Providing training content through e-Learning may be an efficacious approach to providing continual professional learning opportunities relating to physical activity and sedentary time to early childhood educators on a large scale.

Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels.

BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.

Heteroallene Insertions into Tin(II) Alkoxide Bonds.

A series of iso-carbamate complexes have been synthesized by the reaction of [SnII(OiPr)2] or [SnII(OtBu)2] with either aryl or alkyl isocyanates, ONC-R (R = 2,4,6-trimethylphenyl (Mes), 2,6-diisopropylphenyl (Dipp), isopropyl (iPr), cyclohexyl (Cy) and tert-butyl (tBu)). In the case of aryl isocyanates, mono-insertion occurs to form structurally characterized complexes [Sn{κ2-N,O-R-NC(OiPr)O}(µ-OiPr)]2 (1: R = Mes, 2: R = Dipp) and [Sn{κ2-N,O-R-NC(OtBu)O}(µ-OtBu)]2 (3: R = Mes, 4: R = Dipp). The complicated solution-state chemistry of these species has been explored using 1H DOSY experiments. In contrast, reactions of tin(II) alkoxides with alkyl isocyanates result in the formation of bis-insertion products [Sn{κ2-N,O-R-NC(OiPr)O}2] (5: R = iPr, and 6: R = Cy) and [Sn{κ2-N,O-R-NC(OtBu)O}2] (7: R = iPr, 8: R = Cy), of which complexes 6-8 have also been structurally characterized. 1H NMR studies show that the reaction of tBu-NCO with either [Sn(OiPr)2] or [Sn(OtBu)2] results in a reversible mono-insertion. Variable-temperature 2D 1H-1H exchange spectroscopy (VT-2D-EXSY) was used to determine the rate of exchange between free tBu-NCO and the coordinated tBu-iso-carbamate ligand for the {OiPr} alkoxide complex, as well as the activation energy (Ea = 92.2 ± 0.8 kJ mol-1), enthalpy (ΔH‡ = 89.4 ± 0.8 kJ mol-1), and entropy (ΔS‡ = 12.6 ± 2.9 J mol-1 K-1) for the process [Sn(OiPr)2] + tBu-NCO ↔ [Sn{κ2-N,O-tBu-NC(OiPr)O}(OiPr)]. Attempts to form Sn(II) alkyl carbonates by the insertion of CO2 into either [Sn(OiPr)2] or [Sn(OtBu)2] proved unsuccessful. However, 119Sn{1H} NMR spectroscopy of the reaction of excess CO2 with [Sn(OiPr)2] reveals the presence of a new Sn(II) species, i.e., [(iPrO)Sn(O2COiPr)], VT-2D-EXSY (1H) of which confirms the reversible alkyl carbonate formation (Ea = 70.3 ± 13.0 kJ mol-1; ΔH‡ = 68.0 ± 1.3 kJ mol-1 and ΔS‡ = -8.07 ± 2.8 J mol-1 K-1).

Extraordinary levels of per- and polyfluoroalkyl substances (PFAS) in vertebrate animals at a New Mexico desert oasis: Multiple pathways for wildlife and human exposure.

Per- and polyfluoroalkyl substances (PFAS) in the environment pose persistent and complex threats to human and wildlife health. Around the world, PFAS point sources such as military bases expose thousands of populations of wildlife and game species, with potentially far-reaching implications for population and ecosystem health. But few studies shed light on the extent to which PFAS permeate food webs, particularly ecologically and taxonomically diverse communities of primary and secondary consumers. Here we conducted >2000 assays to measure tissue-concentrations of 17 PFAS in 23 species of mammals and migratory birds at Holloman Air Force Base (AFB), New Mexico, USA, where wastewater catchment lakes form biodiverse oases. PFAS concentrations were among the highest reported in animal tissues, and high levels have persisted for at least three decades. Twenty of 23 species sampled at Holloman AFB were heavily contaminated, representing middle trophic levels and wetland to desert microhabitats, implicating pathways for PFAS uptake: ingestion of surface water, sediments, and soil; foraging on aquatic invertebrates and plants; and preying upon birds or mammals. The hazardous long carbon-chain form, perfluorooctanosulfonic acid (PFOS), was most abundant, with liver concentrations averaging >10,000 ng/g wet weight (ww) in birds and mammals, respectively, and reaching as high 97,000 ng/g ww in a 1994 specimen. Perfluorohexanesulfonic acid (PFHxS) averaged thousands of ng/g ww in the livers of aquatic birds and littoral-zone house mice, but one order of magnitude lower in the livers of upland desert rodent species. Piscivores and upland desert songbirds were relatively uncontaminated. At control sites, PFAS levels were strikingly lower on average and different in composition. In sum, legacy PFAS at this desert oasis have permeated local aquatic and terrestrial food webs across decades, severely contaminating populations of resident and migrant animals, and exposing people via game meat consumption and outdoor recreation.

Power to the people? A co-produced critical review of service user involvement in mental health professions education.

Meaningful service user involvement in health professions education requires integrating knowledge held by "lay" people affected by health challenges into professional theories and practices. Involving service users redefines whose knowledge "counts" and implies a shift in power. Such a shift is especially significant in the mental health field, where power imbalances between health professionals and service users are magnified. However, reviews of the literature on service user involvement in mental health professional education do little to explore how power manifests in this work. Meanwhile critical and Mad studies scholars have highlighted that without real shifts in power, inclusion practices can lead to harmful consequences. We conducted a critical review to explore how power is addressed in the literature that describes service user involvement in mental health professions education. Our team used a co-produced approach and critical theories to identify how power implicitly and explicitly operates in this work to unearth the inequities and power structures that service user involvement may inadvertently perpetuate. We demonstrate that power permeates service user involvement in mental health professional education but is rarely made visible. We also argue that by missing the opportunity to locate power, the literature contributes to a series of epistemic injustices that reveal the contours of legitimate knowledge in mental health professions education and its neoliberal underpinnings. Ultimately, we call for a critical turn that foregrounds power relations to unlock the social justice-oriented transformative potential of service user involvement in mental health professions education and health professions education more broadly.

Development of a Uniform Apheresis Case Report Form for Standardized Collection of Apheresis Data.

Apheresis is performed worldwide for an increasing number of indications. The development of common data elements (CDE) for apheresis related areas may facilitate conduct of new research, enhance quality initiatives including benchmarking, and improve patient care. This report describes the systematic development of the Uniform Apheresis Case Report Form (UACRF) as part of the Apheresis in the United States (ApheresUS) program. A consensus panel of 17 diverse experts in apheresis, related specialties, and electronic case report form (eCRF), and database development was assembled. The panel met via online conferencing from November 17, 2020 to December 1, 2021. A draft document was posted online for public comment from October 11, 2021 to November 10, 2021. Feedback was collected using an online survey tool. The consensus panel revised the UACRF. This version was converted to an eCRF with additional changes made to improve usability in this format. The final version of the UACRF was created on August 24, 2023. The UACRF contains 16 modules: procedure and subject eligibility, patient demographics, general procedure information, laboratory parameters, vascular access, common procedure elements, eight procedure specific modules (mononuclear cell collection and seven therapeutic modalities), outcomes, and site information. A total of 137 data elements were created, including 57 with one or more subelements. The UACRF is the first systematic attempt to develop CDE for therapeutic apheresis and white blood cell collections. Further validation of the UACRF is necessary to confirm the tool's ability to collect the relevant data elements and determine the usability of the form.

Contrasting drivers of diversity in hosts and parasites across the tropical Andes.

Geographic turnover in community composition is created and maintained by eco-evolutionary forces that limit the ranges of species. One such force may be antagonistic interactions among hosts and parasites, but its general importance is unknown. Understanding the processes that underpin turnover requires distinguishing the contributions of key abiotic and biotic drivers over a range of spatial and temporal scales. Here, we address these challenges using flexible, nonlinear models to identify the factors that underlie richness (alpha diversity) and turnover (beta diversity) patterns of interacting host and parasite communities in a global biodiversity hot spot. We sampled 18 communities in the Peruvian Andes, encompassing ∼1,350 bird species and ∼400 hemosporidian parasite lineages, and spanning broad ranges of elevation, climate, primary productivity, and species richness. Turnover in both parasite and host communities was most strongly predicted by variation in precipitation, but secondary predictors differed between parasites and hosts, and between contemporary and phylogenetic timescales. Host communities shaped parasite diversity patterns, but there was little evidence for reciprocal effects. The results for parasite communities contradicted the prevailing view that biotic interactions filter communities at local scales while environmental filtering and dispersal barriers shape regional communities. Rather, subtle differences in precipitation had strong, fine-scale effects on parasite turnover while host-community effects only manifested at broad scales. We used these models to map bird and parasite turnover onto the ecological gradients of the Andean landscape, illustrating beta-diversity hot spots and their mechanistic underpinnings.

The impact of knitted linked seams on comfort and friction perception.

Friction from knitted clothing can cause discomfort and skin issues, underscoring the importance of tactile comfort for wearers. Seamless knitted garments are assumed to be comfortable to wear, yet there is little understanding of their tactile comfort in comparison to linked seams - the most common form of knitted garment. This novel study examines the influence of a garments knitted structural architecture on clothing comfort and wearability by investigating skin friction and tactile perception across ten body regions in both male and female participants, using two commonly utilised materials and seam designs: cotton and merino wool with plain and linked seams. The impact of seam design and regional factors on skin friction and tactile perception was analysed, revealing varying levels across tested body regions. Removing seams exposed a greater surface area to skin contact, leading to higher perceived friction levels. As such, structural elements in knitted garments enhance wearer comfort.

Seamless knitwear manufacturing offers a more environmentally conscious option compared to traditional cut-and-sew processes. This study investigated the impact of knitted garment material and structure on wearer comfort by analysing skin friction and tactile perception across ten upper body regions. Removing seams increased garment-to-skin contact leading to wearer discomfort.

Predictors of homework engagement in group CBT for social anxiety: client beliefs about homework, its consequences, group cohesion, and working alliance.

OBJECTIVE: Group cognitive behaviour therapy (CBT) for social anxiety disorder (SAD) is effective, but little data exist on generic relational components of the therapeutic process, such as group cohesion and therapy alliance, and central CBT-specific components such as homework engagement, beliefs, and perceived consequences. The aim of this study was to investigate the relationships between homework, group cohesion, and working alliance during group CBT for social anxiety disorder. METHOD: Participants (N = 105) with SAD engaged in 12 sessions of group CBT. Measures of homework, working alliance, and group cohesion were completed at multiple points throughout treatment. Random-intercept cross-lagged panel models were used to evaluate the prospective relationships between measures. RESULTS: Prospective relationships between the homework outcomes did not vary throughout the treatment period, with the only significant relationships seen between the random intercepts ("trait" levels). Homework beliefs were a significant negative predictor of future group cohesion, but only in mid- to late-treatment. Homework consequences and working alliance were significantly and positively predictive of each other throughout therapy. CONCLUSION: Early homework engagement is associated with higher engagement throughout therapy. Working alliance and homework engagement are important to bolster early in group CBT.Trial registration: Australian New Zealand Clinical Trials Registry identifier: ACTRN12616000579493..

The relationships among working alliance, group cohesion and homework engagement in group cognitive behaviour therapy for social anxiety disorder.

OBJECTIVE: Few studies have investigated the role of generic relational factors, such as group cohesion and working alliance, in group cognitive behaviour therapy (CBT) for social anxiety disorder (SAD). The aim of this study was to examine the temporal associations among working alliance, group cohesion, and an index of a CBT-specific factor, homework engagement, as correlates of fear of negative evaluation and symptoms of social anxiety in group CBT for SAD. METHOD: There were 105 participants with a diagnosis of social anxiety disorder who were randomly assigned to 12 sessions of group imagery-enhanced or standard CBT. Participants completed measures at various time points during the 12-session interventions, and the relationship among variables was examined through random-intercept cross-lagged panel models. RESULTS: Group cohesion was significantly associated with social anxiety symptoms at the end of treatment, however there was no significant relationship with working alliance. Greater homework engagement predicted lower social interaction anxiety, but only during mid-treatment. CONCLUSION: The results highlight the importance of supporting group cohesion and maximising homework engagement during core components of social anxiety treatment such as behavioural experiments.

A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling.

Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10-42) associated with increased thrombin-induced platelet aggregation (ß = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.