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THE EFFECTS OF BEHAVIORAL ACTIVATION THERAPY FOR ANHEDONIA IN A TRANSDIAGNOSTIC SAMPLE: A RANDOMIZED, PARALLEL-ARM TRIAL
Get PDFReduction in motivation and the capacity for experiencing pleasure, also known as anhedonia, is a common transdiagnostic symptom and a negative prognostic marker for psychopathology. In this randomized, parallel-arm clinical trial, a novel intervention called Behavioral Activation for Anhedonia (BATA) was compared to Mindfulness-Based Cognitive Therapy (MBCT) in a transdiagnostic cohort of adults with clinically significant anhedonia. Participants received 8 – 15 individual psychotherapy sessions, once per week, lasting 45 – 60 minutes of either BATA (n = 61) or MBCT (n = 55). Anhedonia severity was assessed approximately weekly using the Snaith Hamilton Pleasure Scale (SHAPS), the primary outcome measure. Additional internalizing symptoms of psychopathology were assessed up to five times using five secondary outcome measures. Results showed indicators of treatment feasibility were similar across conditions, though MBCT demonstrated a non-significant trend towards greater attrition than BATA (adjusted odd’s ratio: 2.04 [0.88, 4.73]). Treatment effects on the primary clinical endpoint did not significantly differ, with a 14-week SHAPS score estimated difference of -0.20 [-2.25, 1.84] points in BATA compared to MBCT (z = 0.19, p = 0.845). The 14-week expected improvement in SHAPS scores across the combined sample was -7.18 [-8.22, -6.15] points (z = 13.6, p < 0.001). There were no significant differences in the proportion of participants demonstrating reliable and clinically significant improvements on the SHAPS, or in the magnitude of reductions on secondary clinical endpoints. In conclusion, despite the development of BATA specifically to enhance motivation and positive affect, there was no evidence of clinical superiority over MBCT in an anhedonic adult sample.Doctor of Philosoph
Neovascular glaucoma associated with central retinal vein occlusion in a young patient with hyperlipidemia
Get PDFThis case report presents a rare instance of neovascular glaucoma secondary to central retinal vein occlusion in a previously healthy man in his early 30s who exhibited acute unilateral vision loss, ocular pain, and elevated intraocular pressure. Ophthalmic imaging, including ultra-widefield fundus photography and optical coherence tomography, revealed retinal hemorrhages, intraretinal fluid, and iris neovascularization consistent with ischemic central retinal vein occlusion and secondary neovascular glaucoma. Notably, systemic evaluation revealed severe hyperlipidemia associated with the patient’s strict nonvegetarian diet, with no other identifiable risk factors. Treatment included intravitreal antivascular endothelial growth factor injections, Ahmed glaucoma valve implantation, and panretinal photocoagulation followed by pars plana vitrectomy. The patient experienced partial visual recovery after the initiation of lipid-lowering therapy and dietary counseling. This case underscores the importance of considering modifiable metabolic factors, particularly extreme dietary patterns, in young patients presenting with central retinal vein occlusion. It supports the incorporation of systemic lipid screening and dietary assessment into the diagnostic workup of atypical retinal vascular events. Although causality cannot be established, this case advocates the need for further investigation into the systemic implications of diet-related hyperlipidemia in ocular vascular disease
Integrin beta 1 facilitates non-enveloped hepatitis E virus cell entry through the recycling endosome
Get PDFHepatitis E virus (HEV) is a major cause of acute hepatitis and mainly transmitted faecal-orally. HEV particles present in faeces are naked (nHEV), whereas those found in the blood are quasi-enveloped (eHEV) with a cell-derived lipid membrane. Despite its global health impact, the cellular life cycle of HEV remains poorly understood, particularly regarding the mechanisms of viral entry into host cells. To address this knowledge gap, we develop a high content RNA-FISH-based imaging assay that allows for the investigation of the entry pathways of both naked and quasi-enveloped HEV particles. Surprisingly, we find that integrin α3, previously implicated in nHEV cell entry, is not expressed in the cell types that are most permissive for HEV infection. Instead, we identify integrin β1 (ITGB1) pairing with different α-integrins as the key player mediating nHEV cell entry. Our results indicate that the interaction of nHEV with ITGB1 facilitates entry through Rab11-positive recycling endosomes. In contrast, eHEV particles do not interact with ITGB1 and enter cells using a classical endocytic route via Rab5a-positive early endosomes. The entry of both types of HEV particles requires endosomal acidification and proteolytic cleavage by lysosomal cathepsins, which ultimately results in delivery of the HEV genome to the cytoplasm
Novel regulators of heparan sulfate proteoglycans modulate cellular uptake of α-synuclein fibrils
Get PDFSynucleinopathies are characterized by the accumulation and propagation of α-synuclein (α-syn) aggregates throughout the brain, leading to neuronal dysfunction and death. In this study, we used an unbiased FACS-based genome-wide CRISPR/Cas9 knockout screening to identify genes that regulate the entry and accumulation of α-syn preformed fibrils (PFFs) in cells. We identified key genes and pathways specifically implicated in α-syn PFFs intracellular accumulation, including heparan sulfate proteoglycans (HSPG) biosynthesis and Golgi trafficking. All confirmed hits affected heparan sulfate (HS), a post-translational modification known to act as a receptor for proteinaceous aggregates including α-syn and tau. Intriguingly, deletion of SLC39A9 and C3orf58 genes, encoding respectively a Golgi-localized exporter of Zn2+, and the Golgi-localized putative kinase DIPK2A, specifically impaired the uptake of α-syn PFFs, by preventing the binding of PFFs to the cell surface. Mass spectrometry-based analysis of HS chains in SLC39A9-/- and C3orf58-/- cells indicated major defects in HS homeostasis. Additionally, Golgi accumulation of NDST1, a prime HSPG biosynthetic enzyme, was detected in C3orf58-/- cells. Interestingly, C3orf58-/- human iPSC-derived microglia and dopaminergic neurons exhibited a strong reduction in their ability to internalize α-syn PFFs. Altogether, our data identifies new modulators of HSPGs that regulate α-syn PFFs cell surface binding and uptake
The Role of Brain-Derived Neurotrophic Factor in the Neurobiology of Borderline Personality Disorder: A Systematic Review and Meta-Analysis
Get PDFBorderline Personality Disorder (BPD) is a severe psychiatric condition rooted in dysfunctional neuroplasticity within key fronto-limbic circuits. Brain-Derived Neurotrophic Factor (BDNF), a master regulator of neuronal growth and synaptic function, is a critical molecular candidate for understanding the pathophysiology of BPD. This systematic review and meta-analysis synthesizes the complete body of literature examining the multifaceted role of BDNF in BPD, encompassing peripheral protein levels, genetic polymorphisms, and epigenetic regulation. Our analysis reveals a field characterized by significant yet interpretable heterogeneity. Studies on circulating BDNF levels have yielded conflicting results, with reports of both decreased and increased concentrations in BPD patients. A qualitative meta-analysis demonstrates that these discrepancies are largely attributable to methodological inconsistencies, particularly the failure to control for comorbid major depressive disorder, antidepressant medication status, and the type of biological sample assayed (serum vs. plasma). Genetic association studies find no consistent link between the common BDNF Val66Met polymorphism (rs6265) and a direct risk for BPD diagnosis. However, evidence strongly indicates that this polymorphism functions as a key modulator of gene-environment interactions and BPD-related endophenotypes; the Val/Val genotype appears to confer vulnerability to trauma-induced impulsive aggression, while the Met allele is associated with deficits in amygdala habituation, a neural correlate of emotional dysregulation. The most compelling evidence emerges from epigenetic studies. A consistent body of research demonstrates that BPD is associated with hypermethylation of the BDNF gene promoter, and that the degree of this methylation is directly proportional to the severity of experienced childhood trauma. Critically, these epigenetic marks are dynamic, with successful psychotherapy correlating with a decrease in BDNF methylation.m We conclude by outlining critical directions for future research, emphasizing the need for methodological rigor and the potential of BDNF-related mechanisms as novel therapeutic targets
[APHA] Nationwide, mail-based drug checking to prevent drug-related harms in an ever-changing drug supply
No full textBackground
Street drugs change constantly, but we don't find out what's in them until it's too late, when people are either dead or arrested: There is no opportunity for recovery or prevention. Analytical chemistry can be harnessed to provide people who use drugs (and health professionals) with real-time information on the drug supply and attendant physiological harms.
Intervention
We describe the development and success of a novel, low-threshold, mail-based drug checking program serving health departments, harm reduction organizations, drug user unions, paramedics, clinics, hospitals, and researchers. Unlike law enforcement drug information systems, samples are provided anonymously and voluntarily. Samples are analyzed using untargeted gas chromatography-mass spectrometry (GCMS). Crucially, lab results are provided directly to sample donors, inverting traditional post-hoc result dissemination, allowing people to make better decisions about what they put in their bodies. Aggregate patterns are displayed in "live reports" updated daily using Python-based machine learning tools.
Results
Between March 2022 and March 2025, a total of 11,578 drug samples were collected by 166 public health programs, originating in 243 counties in 40 states. Using GCMS, 404 unique substances were identified in the unregulated drug supply. Most commonly identified substances were fentanyl (n=5,738), methamphetamine (n=2,775), xylazine (n=2,086), acetaminophen (n=2,024), cocaine (n=2,015), and heroin (1,642). Fentanyl was almost always found with other substances, averaging 4.7 (95% CI: 4.6, 4.8) substances per sample in addition to fentanyl. Carfentanil was found in n=68 samples from 9 states; nitazenes n=133 from 14 states. During Summer 2024, the drug checking community of practice was the first-in-the-nation to identify and characterize the adulterant bis(2,2,6,6-tetrametyl-4-piperidyl) sebacate (n=1,082; 14 states), demonstrating proof of concept.
Implications
Drug checking is a viable public health paradigm in the United States. While festival drug checking extends back to the 1970s, modern problems with synthetic opioids provide renewed urgency for point-of-care expansion
Prognostic significance of CD8+ T cell Spatial Biomarkers in ER+ and ER- breast cancer: A retrospective cohort study.
Get PDFBACKGROUND: Tumor infiltrating lymphocytes (TILs) are prognostic in triple-negative breast cancer, but not estrogen receptor (ER) positive cancers which comprise 70%-80% of breast cancers. This is due to the relatively low immune infiltration in ER-positive tumors. However, few studies have explored the prognostic impact of lower abundance TILs evaluated using spatial methods. The objective of this study was to explore whether the distribution of lymphocytes with respect to tumor cells predicts prognosis. METHODS AND FINDINGS: In this retrospective cohort study, we used multiplex immunofluorescent (IF)-stained images of tissue microarray cores (stained for cytokeratin [Ck], CD8, and FoxP3) obtained from 1,467 study participants to compute distance-based visual morphometry for epithelial and immune cells, including two new metrics, proximity and consistency. Proximity and consistency are defined as functions of the mean and variance of nearest neighbor distances between Ck+ tumor cells and CD8+ T cells. Prognostic significance of proximity and consistency were compared to lymphocyte counts using log-rank tests of differences in Kaplan-Meier survival curves and Cox proportional hazards models. Better recurrence-free survival (RFS) was observed for both ER+ and ER- breast cancers with high proximity and consistency of CD8+ T cells. Among ER- breast cancers, proximity had the highest RFS hazard ratio (HR 1.84, 95% CI [1.18, 2.87]; p = 0.0069) compared to count and consistency. Among ER-positive participants, RFS hazard ratios for proximity and consistency were 2.04 (95% CI [1.39, 2.98]; p = 0.0003) and 1.82 (95% CI [1.23, 2.69]; p = 0.0026), respectively. These associations were stronger than those observed for lymphocyte count (HR 1.35, 95% CI [0.92, 1.98]; p = 0.1289). Independent prognostic value of was demonstrated by controlling clinical and demographic variables such as age, tumor grade, stage, ER status, progesterone receptor status, and human epidermal growth factor receptor 2 status. These IF-derived spatial metrics were also associated with established TILs metrics and RNA expression-based measures of tumor adaptive immune response. Though these results are promising, our exploration of the tumor immune microenvironment was limited by the small number of immune markers available for our data. CONCLUSIONS: Spatial characteristics described by proximity and consistency are frequently associated with recurrence irrespective of ER status. The prognostic significance of proximity in ER+ breast cancer implies that spatial parameters may identify individuals who would benefit from immune therapy; up to 75% of breast cancers experience T cell proximity suggestive of immune susceptibility
Multi-Collaborator Engagement to Identify Research Priorities for Early Intervention in Cerebral Palsy
Get PDFBackground/Objectives: Although clinical practice guidelines and evidence-based practices for early cerebral palsy (CP) diagnosis and treatment are well established, their implementation remains inconsistent across care settings. This study sought to identify key research priorities related to early CP diagnosis and treatment and to develop an actionable framework through multi-collaborator consensus building. Methods: The 97 adult participants included 42 who have lived experience with CP. Before the conference, participants completed a survey rating the importance of research topics. During the conference, aggregated results were presented, followed by 16 focus group discussions to refine research priorities. A follow-up survey was conducted to validate the final priorities. Results: Six actionable items were identified: improving diagnosis communication, ensuring early referrals and interdisciplinary collaboration, creating inclusive education and training, scaling evidence-based therapies and researching new interventions, developing social support systems, and advocating for policy and cultural change. A research framework was developed that outlines how these priorities can be addressed through three main strategies: education and training, research expansion, and policy advocacy. Conclusions: This study highlights the critical need for comprehensive and compassionate care for families receiving a CP diagnosis. Key priorities include early detection, coordinated multidisciplinary teams, and well-trained professionals delivering evidence-based interventions. The comprehensive framework addressing these priorities lays the foundation for future patient-centered comparative clinical effectiveness research
Transformation leadership with knowledge sharing and employee career growth: the role of self-efficacy and psychological capital
Get PDFExisting research lacks a systematic exploration of the relationships among transformational leadership, knowledge sharing, and employee career growth, as well as the mechanisms of self-efficacy and psychological capital in this context, especially the integrated analysis of mediating and moderating effects. This study aims to fill this gap by constructing a structural equation model based on social exchange theory and comprehensively applying qualitative and quantitative research methods. It deeply analyzes how transformational leadership promotes employee career growth through knowledge sharing and reveals the moderating and strengthening roles of self-efficacy and psychological capital. Based on 412 valid questionnaires and 15 in—depth interview data, methods such as descriptive statistics, regression analysis, mediating effect test, and moderating effect test were used to systematically verify the internal relationships among variables, providing new theoretical perspectives and empirical support for organizational management practices. The study found that transformational leadership has a significant positive impact on employee career growth (β = 0.603, p < 0.001), and knowledge sharing plays a partial mediating role between them (mediating effect value = 0.1505); self-efficacy significantly moderates the relationship between transformational leadership and knowledge sharing (β = 0.412, p < 0.001), and the mediating effect of knowledge sharing gradually weakens as the level of self-efficacy increases (low level: 0.0994; high level: 0.0615); psychological capital strengthens the positive relationship between transformational leadership and knowledge sharing (β = 0.422, p < 0.001) and enhances the mediating effect of knowledge sharing (low level: 0.1094; high level: 0.0715). Theoretically, this study enriches transformational leadership theory, deepens the understanding of the mediating mechanism of knowledge sharing, and expands the application boundaries of self-efficacy and psychological capital in organizational behavior. Practically, it suggests that enterprise managers should pay attention to cultivating transformational leadership styles, especially by improving leadership effectiveness through the four dimensions of moral example, visionary motivation, individualized consideration, and leadership charisma
Author Correction: Fine-mapping genomic loci refines bipolar disorder risk genes
Get PDFCorrection to "Fine-mapping genomic loci refines bipolar disorder risk genes