A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen.

T and B cells are the two known lineages of adaptive immune cells. Here, we describe a previously unknown lymphocyte that is a dual expresser (DE) of TCR and BCR and key lineage markers of both B and T cells. In type 1 diabetes (T1D), DEs are predominated by one clonotype that encodes a potent CD4 T cell autoantigen in its antigen binding site. Molecular dynamics simulations revealed that this peptide has an optimal binding register for diabetogenic HLA-DQ8. In concordance, a synthetic version of the peptide forms stable DQ8 complexes and potently stimulates autoreactive CD4 T cells from T1D patients, but not healthy controls. Moreover, mAbs bearing this clonotype are autoreactive against CD4 T cells and inhibit insulin tetramer binding to CD4 T cells. Thus, compartmentalization of adaptive immune cells into T and B cells is not absolute, and violators of this paradigm are likely key drivers of autoimmune diseases.

Plasminogen activator urokinase interacts with the fusion protein and antagonizes the growth of Peste des petits ruminants virus.

Peste des petits ruminants is an acute and highly contagious disease caused by the Peste des petits ruminants virus (PPRV). Host proteins play a crucial role in viral replication. However, the effect of fusion (F) protein-interacting partners on PPRV infection is poorly understood. In this study, we found that the expression of goat plasminogen activator urokinase (PLAU) gradually decreased in a time- and dose-dependent manner in PPRV-infected goat alveolar macrophages (GAMs). Goat PLAU was subsequently identified using co-immunoprecipitation and confocal microscopy as an F protein binding partner. The overexpression of goat PLAU inhibited PPRV growth and replication, whereas silencing goat PLAU promoted viral growth and replication. Additionally, we confirmed that goat PLAU interacted with a virus-induced signaling adapter (VISA) to antagonize F-mediated VISA degradation, increasing the production of type I interferon. We also found that goat PLAU reduced the inhibition of PPRV replication in VISA-knockdown GAMs. Our results show that the host protein PLAU inhibits the growth and replication of PPRV by VISA-triggering RIG-I-like receptors and provides insight into the host protein that antagonizes PPRV immunosuppression.IMPORTANCEThe role of host proteins that interact with Peste des petits ruminants virus (PPRV) fusion (F) protein in PPRV replication is poorly understood. This study confirmed that goat plasminogen activator urokinase (PLAU) interacts with the PPRV F protein. We further discovered that goat PLAU inhibited PPRV replication by enhancing virus-induced signaling adapter (VISA) expression and reducing the ability of the F protein to degrade VISA. These findings offer insights into host resistance to viral invasion and suggest new strategies and directions for developing PPR vaccines.

Fluorescence-Detected Two-Dimensional Electronic Spectroscopy of a Single Molecule.

Single-molecule fluorescence spectroscopy is a powerful method that avoids ensemble averaging, but its temporal resolution is limited by the fluorescence lifetime to nanoseconds at most. At the ensemble level, two-dimensional spectroscopy provides insight into ultrafast femtosecond processes, such as energy transfer and line broadening, even beyond the Fourier limit, by correlating pump and probe spectra. Here, we combine these two techniques and demonstrate coherent 2D spectroscopy of individual dibenzoterrylene (DBT) molecules at room temperature. We excite the molecule in a confocal microscope with a phase-modulated train of femtosecond pulses and detect the emitted fluorescence with single-photon counting detectors. Using a phase-sensitive detection scheme, we were able to measure the nonlinear 2D spectra of most of the DBT molecules that we studied. Our method is applicable to a wide range of single emitters and opens new avenues for understanding energy transfer in single quantum objects on ultrafast time scales.

Hydrogen sulphide alleviates root growth inhibition induced by phosphate starvation.

Phosphorus (P) has crucial roles in plant growth and development. Hydrogen sulphide (H2S) has multiple functions in plants, particularly having the ability to promote tolerance to a variety of adversity stresses. However, it is unclear whether H2S has a function when plants suffer Pi-deficiency stress. DES1, encoding L-cysteine desulfhydrase1, is a crucial source of H2S in Arabidopsis thaliana by catalysing the substrate L-cysteine. Under phosphate starvation, the des1 mutant had a significantly shorter primary root length than the wild-type Col-0, and exogenous application of H2S donor NaHS could compensate for the root growth-sensitive phenotype. In contrast, the transgenic lines DES1ox overexpressing DES1 exhibited less sensitivity to phosphate starvation in terms of longer roots compared to the Col-0. These results demonstrate that H2S is involved in the regulation of Arabidopsis root growth under phosphate starvation. Moreover, using quantitative real-time polymerase chain reaction experiments to analyse the changes in genes induced by phosphate starvation in des1 mutant and Col-0, we screened to find that the expression of the Sulfoquinovosyl diacylglycerol 1 (SQD1) gene was significantly downregulated in the des1 mutant. Consistently, exogenous H2S significantly promoted SQD1 expression levels in roots of Col-0. Taken together, we demonstrate that DES1-mediated H2S participates in alleviating root growth inhibition by promoting the expression of SQD1 under Pi starvation.

Comparative long-term efficacy and safety of two paclitaxel-coated balloons with different coating strategies for the treatment of drug-eluting coronary stent restenosis.

BACKGROUND: We previously showed non-inferiority of a low-dose paclitaxel-coated balloon (PCB) with citrate excipient (Agent PCB) as compared to normal-dose iopromide excipient (SeQuent Please PCB) in terms of angiographic and clinical endpoints at 12 months. The long-term clinical efficacy and safety of Agent PCB is not defined. METHODS: 262 patients (323 DES-ISR lesions) were enrolled in this study and treated with either Agent PCB (125 patients, 151 lesions) in the ISAR-DESIRE 3a trial or with SeQuent Please PCB (137 patients, 172 lesions) in the setting of the randomized ISAR-DESIRE 3 trial with similar in- and exclusion criteria serving as historical control arm. The follow-up period was extended to 7 years. The efficacy and safety endpoints of this analysis were target-lesion revascularization (TLR), death, myocardial infarction (MI) and target lesion thrombosis (TLT) at 7 years. RESULTS: At 7 years, 206 patients (78.6%) were alive. The risks of TLR (hazard ratio [HR]: 1.29, 95% confidence interval [CI]: 0.87-1.90; p = 0.205), death (HR: 1.38, 95% CI: 0.82-2.35; p = 0.227), MI (HR: 1.10, 95% CI: 0.39-3.15; p = 0.852) and TLT (HR: 2.18, 95% CI: 0.20-24.10; p = 0.523) were comparable between Agent PCB and SeQuent PCB. Multivariate analysis showed comparable risks of TLR, death and MI between both PCB devices. CONCLUSIONS: In patients treated for DES-ISR by angioplasty with Agent PCB and SeQuent Please PCB, there was no statistically significant difference in TLR at 7 years. Randomized trials with standardized lesion preparation and long-term follow-up are warranted to further evaluate comparative efficacy of both devices. (ClinicalTrials. gov Identifier: NCT02367495).

Double kiss mini-crush technique to treat complex recurrent renal artery in-stent restenosis.

The double-kiss mini-crush (DKMC) technique has been successfully deployed in the past for the treatment of complex coronary lesions even for left main lesions. Our case report consists of a proof-of-principle that the DKMC technique can be successfully translated as well to the field of complex renal artery lesions. Insightful thinking out-of-the "coronary" box in concert with skillful off-label application of coronary stenting procedures may open the gate for unprecedented opportunities for the treatment of difficult-to-tackle in-stent restenosis in the renal circulation.

Kinin B1 receptor and TLR4 interaction in inflammatory response.

OBJECTIVE: We aimed to broaden our understanding of a potential interaction between B1R and TLR4, considering earlier studies suggesting that lipopolysaccharide (LPS) may trigger B1R stimulation. METHODS: We assessed the impact of DBK and LPS on the membrane potential of thoracic aortas from C57BL/6, B1R, or TLR4 knockout mice. Additionally, we examined the staining patterns of these receptors in the thoracic aortas of C57BL/6 and in endothelial cells (HBMEC). RESULTS: DBK does not affect the resting membrane potential of aortic rings in C57BL/6 mice, but it hyperpolarizes preparations in B1KO and TLR4KO mice. The hyperpolarization mechanism in B1KO mice involves B2R, and the TLR4KO response is independent of cytoplasmic calcium influx but relies on potassium channels. Conversely, LPS hyperpolarizes thoracic aorta rings in both C57BL/6 and B1KO mice, with the response unaffected by a B1R antagonist. Interestingly, the absence of B1R alters the LPS response to potassium channels. These activities are independent of nitric oxide synthase (NOS). While exposure to DBK and LPS does not alter B1R and TLR4 mRNA expression, treatment with these agonists increases B1R staining in endothelial cells of thoracic aortic rings and modifies the staining pattern of B1R and TLR4 in endothelial cells. Proximity ligation assay suggests a interaction between the receptors. CONCLUSION: Our findings provide additional support for a putative connection between B1R and TLR4 signaling. Given the involvement of these receptors and their agonists in inflammation, it suggests that drugs and therapies targeting their effects could be promising therapeutic avenues worth exploring.

Invariant VD and DJ Motifs Define a Novel Class of Human Antibodies and TCRs Prototyped by antigen receptors of Dual-Expresser Lymphocytes.

INTRODUCTION: Dual-expressing lymphocytes (DEs) are unique immune cells that express both B cell receptors (BCRs, surface antibody) and T cell receptors (TCRs). In type 1 diabetes, DE antibodies are predominated by one antibody (x-mAb), an IgM monoclonal antibody with a germline-encoded CDR3 that recognizes self-reactive TCRs. We explored if x-mAb and its interacting TCRs have distinct structural features. METHODS: Using bioinformatics, we compared x-mAb and its most common interacting TCRαß to billions of antigen receptor sequences to determine if they were unique or randomly generated. RESULTS: X-mAb represents a unique class of human antibodies with a conserved CDR3 sequence (CARx1-4DTAMVYYFYDW), consisting of a fixed DJH motif (DTAMVYYFDYW) paired with various VH genes. A public TCRß clonotype (CASSPGTEAFF) associated with x-mAb on DEs features two invariant segments, VßD (CASSPGT) and DJß (PGTEAFF), key to two large families of public TCRß clonotypes-CASSPGT-Jßx and CASSPGT-Jßx-formed by recombining the VßD motif with Jß genes and the DJß motif with Vß genes. B cells also use CASSPGT as a VHD motif for public IGH clonotypes (CASSPGT-Jßx). DISCUSSION: DEs, unlike conventional T and B cells, use invariant motifs to create public antibodies and TCRs, a trait previously seen only in cartilaginous fish.

Impact of 12-Month Angioscopic Thrombi and Yellow Plaque After Drug-Eluting Stent Implantation.

BACKGROUND: Coronary angioscopy (CAS) has 2 unique abilities: direct visualization of thrombi and plaque color. However, in the recent drug-eluting stent (DES) era, serial CAS findings after DES implantation have not been fully elucidated. We investigated the impact of CAS findings after implantation of a polymer-free biolimus A9-coated stent (PF-BCS) or durable polymer everolimus-eluting stent (DP-EES).Methods and Results: We investigated serial CAS and optical coherence tomography (OCT) findings at 1 and 12 months in 99 patients who underwent PF-BCS or DP-EES implantation. We evaluated factors correlated with angioscopic thrombi and yellow plaque, and the clinical impact of both thrombi and yellow plaque at 12 months (BTY). The BTY group included 17 (22%) patients. The incidence and grade of thrombi and yellow plaque decreased from 1 to 12 months. Although no patients had newly appearing thrombi at 12 months, 2 DP-EES patients had newly appearing yellow plaque at 12 months. Multivariable analysis revealed HbA1c, minimum stent area, and adequate strut coverage were significant factors correlated with 12-month angioscopic thrombi, and DP-EESs were significantly correlated with 12-month yellow plaque. However, BTY was not correlated with clinical events. CONCLUSIONS: The management of diabetes, stent area, and adequate stent coverage are important for intrastent thrombogenicity and polymer-free stents are useful for stabilizing plaque vulnerability.

Applications of Functional Polymeric Eutectogels.

Over the past two decades, deep eutectic solvents (DESs) have captured significant attention as an emergent class of solvents that have unique properties and applications in differing fields of chemistry. One area where DES systems find utility is the design of polymeric gels, often referred to as "eutectogels," which can be prepared either using a DES to replace a traditional solvent, or where monomers form part of the DES themselves. Due to the extensive network of intramolecular interactions (e.g., hydrogen bonding) and ionic species that exist in DES systems, polymeric eutectogels often possess appealing material properties-high adhesive strength, tuneable viscosity, rapid polymerization kinetics, good conductivity, as well as high strength and flexibility. In addition, non-covalent crosslinking approaches are possible due to the inherent interactions that exist in these materials. This review considers several key applications of polymeric eutectogels, including organic electronics, wearable sensor technologies, 3D printing resins, adhesives, and a range of various biomedical applications. The design, synthesis, and properties of these eutectogels are discussed, in addition to the advantages of this synthetic approach in comparison to traditional gel design. Perspectives on the future directions of this field are also highlighted.

Combination of FLNC and JUP variants causing arrhythmogenic cardiomyopathy in an Iranian family with different clinical features.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) characterized by progressive myocardial loss and replacement with fibro-fatty tissue is a major cause of sudden cardiac death (SCD). In particular, ACM with predominantly left ventricular involvement, known as arrhythmogenic left ventricular cardiomyopathy (ALVC), has a poor prognosis. METHODS: The proband underwent whole-exome sequencing (WES) to determine the etiology of ALVC. Family members were then analyzed using PCR and Sanger sequencing. Clinical evaluations including 12-lead ECG, transthoracic echocardiography, and cardiac MRI were performed for all available first-degree relatives. RESULTS: WES identified two variants in the FLNC (c.G3694A) and JUP (c.G1372A) genes, the combination of which results in ALVC and SCD. CONCLUSION: The present study comprehensively investigates the involvement of two discovered variants of FLNC and JUP in the pathogenesis of ALVC. More study is necessary to elucidate the genetic factors involved in the etiology of ALVC.

Targeting dihydroceramide desaturase 1 (Des1): Syntheses of ceramide analogues with a rigid scaffold, inhibitory assays, and AlphaFold2-assisted structural insights reveal cyclopropenone PR280 as a potent inhibitor.

Dihydroceramide desaturase 1 (Des1) catalyzes the formation of a CC double bond in dihydroceramide to furnish ceramide. Inhibition of Des1 is related to cell cycle arrest and programmed cell death. The lack of the Des1 crystalline structure, as well as that of a close homologue, hampers the detailed understanding of its inhibition mechanism and difficults the design of new inhibitors, thus making Des1 a strategic target. Based on previous structure-activity studies, different ceramides containing rigid scaffolds were designed. The synthesis and evaluation of these compounds as Des1 inhibitors allowed the identification of PR280 as a better Des 1 inhibitor in vitro (IC50 = 700 nM) than GT11 and XM462, the current reference inhibitors. This cyclopropenone ceramide was obtained in a 6-step synthesis with a 24 % overall yield. The highly confident 3D structure of Des1, recently predicted by AlphaFold2, served as the basis for conducting docking studies of known Des1 inhibitors and the ceramide derivatives synthesized by us in this study. For this purpose, a complete holoprotein structure was previously constructed. This study has allowed a better knowledge of key ligand-enzyme interactions for Des1 inhibitory activity. Furthermore, it sheds some light on the inhibition mechanism of GT11.

Epidemiology of peste des petits ruminants in selected districts of Borena zone, Ethiopia.

BACKGROUND: Peste des petits ruminant (PPR) is a contagious disease caused by the peste des petits ruminants virus (PPRV). The disease poses a significant economic threat to small ruminant production in Ethiopia, particularly to the striving pastoral production system. A cross-sectional study was conducted to estimate the seroprevalence and associated risk factors of PPR in the small ruminants of the Borena Zone. A total of 384 serum samples were collected randomly from sheep and goats and examined for the presence of PPRV antibodies using competition enzyme-linked immune sorbent assay (c-ELISA). Additionally, a retrospective analysis of five years of outbreak data was performed to provide insight into the spatial and temporal distribution of the disease. RESULTS: The seroprevalence of PPRV antibodies in nonvaccinated, vaccinated, and unknown vaccination status of small ruminants in this study was found to be 32.1%, 68.8%, and 45.5%, respectively. Multivariable logistic analysis revealed a statistically significant association between PPRV seropositivity and several factors, including age, animal origin, flock size, and veterinary services status. A retrospective analysis revealed 53 PPR outbreaks in the Borena Zone from 2018 to 2022, exacerbated by low vaccination coverage relative to the at-risk animal population. CONCLUSION: The study revealed significant gaps in current vaccination efforts, with herd immunity levels falling below the FAO-WOAH recommended threshold of 80%. Despite Ethiopia's ambitious goal to eradicate PPR by 2027, the frequent outbreaks and insufficient herd immunity highlight the inadequacy of the existing strategies. To effectively move toward eradication, Ethiopia must align its approach with the global PPR eradication framework, which emphasizes a comprehensive strategy that includes diagnostics, surveillance, prevention, and the establishment of a robust veterinary regulatory system, rather than relying solely on vaccination. Overcoming logistical challenges, improving vaccination coverage, and optimizing the timing of vaccination campaigns, especially in hard-to-reach areas, will be crucial for reducing outbreaks and making progress toward eradication.

Effects of ghrelin on food caching behaviour and body composition in black-capped chickadees (Poecile atricapillus).

Several metabolic hormones signal an organism's energy balance to the brain and modulate feeding behaviours accordingly. These metabolic signals may also regulate other behaviour related to energy balance, such as food caching or hoarding. Ghrelin is one such hormone, but it appears to exert different effects on appetite and fat levels in birds and mammals. Ghrelin treatment inhibits food intake and decreases fat stores in some bird species, but these effects may differ between acylated and unacylated (des-acyl) forms of ghrelin. The effect of ghrelin on food caching in birds has been examined in only one study, that found both leptin and unacylated ghrelin reduced food caching and mass gain in coal tits (Periparus ater). We expanded on this to test how both forms of ghrelin affect food caching and body composition in black-capped chickadees (Poecile atricapillus). We injected each bird with acylated ghrelin, unacylated ghrelin, and a saline control and then measured food caching every 20 min for two hours post-injection. We also measured body mass fat levels the day before, and after treatment using quantitative magnetic resonance (QMR). Contrary to prior work, we found no effects of either form of ghrelin on food caching, or body or fat mass. Future work is required to determine if the difference between our results and those of the prior study stems from species differences in response to ghrelin and/or in the motivation to cache food, or ghrelin effects being modulated by energy reserves.

Preferences of Young Adults With Psychosis for Cannabis-Focused Harm Reduction Interventions: A Cross-Sectional Study: Préférences des jeunes adultes souffrant de psychose pour les interventions de réduction des méfaits axées sur le cannabis : une étude transversale.

OBJECTIVES: Cannabis use is common in people with early-phase psychosis (EP) and is associated with worse treatment outcomes. Few targeted interventions for cannabis use behaviour in this population exist, most focusing on abstinence, none focusing on harm reduction. Many people with EP will not seek treatment for their cannabis use with current therapeutic options. Understanding preferences for cannabis-focused harm reduction interventions may be key to improving outcomes. This study aimed to determine preferences of young adults with EP who use cannabis for cannabis-focused harm reduction interventions. METHODS: Eighty-nine young adults across Canada with EP interested in reducing cannabis-related harms were recruited. An online questionnaire combining conventional survey methodology and two unique discrete choice experiments (DCEs) was administered. One DCE focused on attributes of core harm reduction interventions (DCE 1) and the second on attributes of boosters (DCE 2). We analysed these using mixed ranked-ordered logistic regression models. Preference questions using conventional survey methodology were analysed using summary statistics. RESULTS: Preferred characteristics for cannabis-focused harm reduction interventions (DCE 1) were: shorter sessions (60 min vs. 10 min, odds ratio (OR): 0.72; P < 0.001); less frequent sessions (daily vs. monthly, OR: 0.68; P < 0.001); shorter interventions (3 months vs. 1 month, OR: 0.80; P < 0.01); technology-based interventions (vs. in-person, OR: 1.17; P < 0.05). Preferences for post-intervention boosters (DCE 2) included opting into boosters (vs. opting out, OR: 3.53; P < 0.001) and having shorter boosters (3 months vs. 1 month, OR: 0.79; P < 0.01). Nearly half of the participants preferred to reduce cannabis use as a principal intervention goal (vs. using in less harmful ways or avoiding risky situations). CONCLUSIONS: Further research is required to see if technology-based harm reduction interventions for cannabis featuring these preferences translate into greater engagement and improved outcomes in EP patients.

Changes in Media Reporting Quality and Suicides Following National Media Engagement on Responsible Reporting of Suicide in Canada: Changements de la Qualité des reportages dans les médias sur les suicides suite à l'engagement des médias nationaux à la déclaration responsable du suicide au Canada.

OBJECTIVE: Responsible media reporting is an accepted strategy for preventing suicide. In 2015, suicide prevention experts launched a media engagement initiative aimed at improving suicide-related reporting in Canada; its impact on media reporting quality and suicide deaths is unknown. METHOD: This pre-post observational study examined changes in reporting characteristics in a random sample of suicide-related articles from major publications in the Greater Toronto Area (GTA) media market. Articles (n = 900) included 450 from the 6-year periods prior to and after the initiative began. We also examined changes in suicide counts in the GTA between these epochs. We used chi-square tests to analyse changes in reporting characteristics and time-series analyses to identify changes in suicide counts. Secondary outcomes focused on guidelines developed by media professionals in Canada and how they may have influenced media reporting quality as well as on the overarching narrative of media articles during the most recent years of available data. RESULTS: Across-the-board improvement was observed in suicide-related reporting with substantial reductions in many elements of putatively harmful content and substantial increases in all aspects of putatively protective content. However, overarching article narratives remained potentially harmful with 55.2% of articles telling the story of someone's death and 20.8% presenting an other negative message. Only 3.6% of articles told a story of survival. After controlling for potential confounders, a nonsignificant numeric decrease in suicide counts was identified after initiative implementation (ω = -5.41, SE = 3.43, t = 1.58, p = 0.12). CONCLUSIONS: We found evidence that a strategy to engage media in Canada changed the content of reporting, but there was only a nonsignificant trend towards fewer suicides. A more fundamental change in media narratives to focus on survival rather than death appears warranted.

The Intergenerational Transfer of Mental Disorders: A Population-Based Multigenerational Linkage Study: Le transfert intergénérationnel des troubles mentaux : une étude sur les liens multigénérationnels basée sur la population.

OBJECTIVES: The aetiology of mental disorders involves genetic and environmental factors, both reflected in family health history. We examined the intergenerational transmission of multiple mental disorders from parents and grandparents using population-based, objectively measured family histories. METHODS: This population-based retrospective cohort study used administrative healthcare databases in Manitoba, Canada and included adults living in Manitoba from 1977 to 2020 with linkages to at least one parent and one grandparent. Index date was when individuals turned 18 or 1 April 1977, whichever occurred later. Mental disorder diagnoses (mood and anxiety, substance use and psychotic disorders) were identified in individuals, parents and grandparents from hospitalization and outpatient records. Cox proportional hazards regression models included sociodemographic characteristics, individual's comorbidity and mental disorder history in a grandparent, mother and father. RESULTS: Of 109,359 individuals with no mental disorder prior to index date, 47.1% were female, 36.3% had a mental disorder during follow-up, and 90.9% had a parent or grandparent with a history of a mental disorder prior to the index date. Both paternal and maternal history of a mental disorder increased the risk of the disorder in individuals. Psychotic disorders had the strongest association with parental history and were mostly influenced by paternal (hazards ratio [HR] 3.73, 95% confidence interval [CI] 2.99 to 4.64) compared to maternal history (HR 2.23, 95% CI, 1.89 to 2.64). Grandparent history was independently associated with the risk of all mental disorders but had the strongest influence on substance use disorders (HR 1.42, 95% CI, 1.34 to 1.50). CONCLUSIONS: Parental history of mental disorders was associated with an increased risk of all mental disorders. Grandparent history of mental disorders was associated with a small risk increase of the disorders above and beyond parental history influence. This three-generation study further highlights the need for family-based interventional programs in families affected by mental disorders. PLAIN LANGUAGE SUMMARY TITLE: The Intergenerational Transfer of Mental Illnesses.

ObjectivesBoth genetics and environmental factors, such as poverty, maltreatment and parental education, have a role in the development of mental illnesses. Some genetic and environmental risk factors for mental illnesses are shared within families. We conducted a large study to test the extent to which mental illnesses are passed down through generations.MethodsThis study used healthcare data from Manitoba, Canada captured during the delivery of healthcare services for administrative purposes. These data included all adults from 1977 to 2020 who had at least one parent and one grandparent with linked data. Mental illnesses were diagnosed in individuals, parents and grandparents by doctors during hospitalizations or physician visits. The illnesses included mood and anxiety, substance use, and psychotic illnesses. We estimated the likelihood of developing a mental illness when parents and/or grandparents had a mental illness as well.ResultsThe study included 109,359 individuals; a third developed a mental illness during the study period. The majority had a history of a mental illness in a parent or grandparent. We found that a history of mental illness in a mother and father increased the chance of developing the illness. Psychotic illnesses had the strongest relation with parental history. In particular, having a father with a psychotic illness increased the chance of developing the illness by four times. The likelihood of developing a mental illness was higher if a grandparent had a mental illness, above and beyond parental history influence, particularly for substance use disorders.ConclusionsHaving a parent or grandparent with a mental illness increases an individual's chance of developing a mental illness. Family-based intervention programs are needed to support families affected by mental illnesses in coping with their heavy burden.

Adjunctive Brexpiprazole for Patient Life Engagement in Major Depressive Disorder: A Canadian, Phase 4, Open-Label, Interventional Study: Brexpiprazole d'appoint pour l'engagement dans la vie des patients souffrant de trouble dépressif majeur: une étude interventionnelle canadienne ouverte de phase 4.

OBJECTIVES: To characterize the effects of adjunctive brexpiprazole on patient life engagement and depressive symptoms in patients with major depressive disorder (MDD) using patient-reported outcomes. METHODS: An 8-week, Phase 4, open-label, interventional study was conducted at 15 Canadian trial sites between April 2021 and May 2022. Adult outpatients with MDD (at least moderately severe) and inadequate response to 1-2 antidepressants continued their current antidepressant and received oral adjunctive brexpiprazole 0.5-2 mg/day. Co-primary endpoints were change from baseline to Week 8 in Inventory of Depressive Symptomatology Self-Report (IDS-SR) 10-item Life Engagement subscale score, and IDS-SR 30-item total score. Safety was assessed by standard variables. RESULTS: Of 122 enrolled patients, 120 (98.4%) were treated (mean [SD] dose: 1.2 [0.4] mg/day) and analyzed, and 111 (91.0%) completed the study. Statistically significant least squares mean improvements to Week 8 were observed on IDS-SR10 Life Engagement subscale score (baseline mean [SD]: 16.1 [4.7]; change [95% confidence interval]: -8.11 [-9.34, -6.88]; p < 0.001) and IDS-SR total score (baseline mean [SD]: 41.3 [9.8]; change [95% confidence interval]: -17.38 [-20.08, -14.68]; p < 0.001). Improvements were observed from Week 2, onwards. Treatment-emergent adverse events with incidence ≥5% were fatigue (n = 13, 10.8%), headache (n = 13, 10.8%), insomnia (n = 12, 10.0%), nausea (n = 9, 7.5%), tremor (n = 8, 6.7%), and weight increase (n = 7, 5.8%). Six patients (5.0%) discontinued due to adverse events. Mean (SD) change in body weight from baseline to last visit was +1.9 (3.4) kg. CONCLUSIONS: Using an exploratory patient-reported outcome measure, patients with MDD and inadequate response to antidepressants who received open-label adjunctive brexpiprazole showed early and clinically meaningful improvement in patient life engagement, which should be further assessed in a prospective randomized controlled trial. Patient-rated depressive symptoms (on the validated 30-item IDS-SR) also improved. Adjunctive brexpiprazole was well tolerated, and no new safety signals were observed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04830215.

Treatment outcomes and the role of the DES scheme in the appropriate treatment selection for high-grade dural arteriovenous fistulas.

OBJECTIVE: Endovascular and microsurgical treatment are viable options for the majority of Borden type III dural arteriovenous fistulas (dAVFs). The aim of this study was to examine treatment outcomes in a comparative analysis of endovascular and surgical treatment modalities for Borden type III fistulas and explore clinical implications of the DES scheme in selecting ideal candidates for surgical therapy. METHODS: Patients diagnosed with dAVFs with leptomeningeal venous drainage admitted to the Departments of Neurosurgery or Neuroradiology of the University Hospital Zurich between January 2014 and October 2021 were included in this study. Comprehensive patient data including demographics, clinical presentation, and dAVF characteristics, including established classifications, were collected. Treatment outcomes were assessed based on postinterventional angiography findings. In addition, treatment-related complications were assessed based on the Clavien-Dindo classification. RESULTS: Among all Borden type III dAVFs, 15 were initially treated endovascularly (60% complete occlusion rate) and 10 with microsurgical disconnection (90% complete occlusion rate) (p = 0.18). Subgroup analysis of dAVFs meeting the criteria for directness and exclusivity based on the DES scheme showed a 100% complete occlusion rate after microsurgical disconnection, whereas embolization achieved a complete occlusion rate of 60% (p = 0.06). There was no significant difference in the rate or severity of treatment-related complications between treatment modalities. CONCLUSIONS: This study suggests that microsurgical disconnection is a viable primary treatment modality for Borden type III dAVFs, particularly for dAVFs that meet the criteria of directness and exclusivity according to the DES scheme. The DES scheme demonstrates its relevance in selecting the most appropriate treatment strategy for affected patients.

A Comprehensive Analysis of Non-Desmosomal Rare Genetic Variants in Arrhythmogenic Cardiomyopathy: Integrating in Padua Cohort Literature-Derived Data.

Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disease at risk of sudden death. Genetic testing impacts greatly in ACM diagnosis, but gene-disease associations have yet to be determined for the increasing number of genes included in clinical panels. Genetic variants evaluation was undertaken for the most relevant non-desmosomal disease genes. We retrospectively studied 320 unrelated Italian ACM patients, including 243 cases with predominant right-ventricular (ARVC) and 77 cases with predominant left-ventricular (ALVC) involvement, who did not carry pathogenic/likely pathogenic (P/LP) variants in desmosome-coding genes. The aim was to assess rare genetic variants in transmembrane protein 43 (TMEM43), desmin (DES), phospholamban (PLN), filamin c (FLNC), cadherin 2 (CDH2), and tight junction protein 1 (TJP1), based on current adjudication guidelines and reappraisal on reported literature data. Thirty-five rare genetic variants, including 23 (64%) P/LP, were identified in 39 patients (16/243 ARVC; 23/77 ALVC): 22 FLNC, 9 DES, 2 TMEM43, and 2 CDH2. No P/LP variants were found in PLN and TJP1 genes. Gene-based burden analysis, including P/LP variants reported in literature, showed significant enrichment for TMEM43 (3.79-fold), DES (10.31-fold), PLN (117.8-fold) and FLNC (107-fold). A non-desmosomal rare genetic variant is found in a minority of ARVC patients but in about one third of ALVC patients; as such, clinical decision-making should be driven by genes with robust evidence. More than two thirds of non-desmosomal P/LP variants occur in FLNC.