Tyrosine kinase 2 modulates splenic B cells through type I IFN and TLR7 signaling.

Tyrosine kinase 2 (TYK2) is involved in type I interferon (IFN-I) signaling through IFN receptor 1 (IFNAR1). This signaling pathway is crucial in the early antiviral response and remains incompletely understood on B cells. Therefore, to understand the role of TYK2 in B cells, we studied these cells under homeostatic conditions and following in vitro activation using Tyk2-deficient (Tyk2-/-) mice. Splenic B cell subpopulations were altered in Tyk2-/- compared to wild type (WT) mice. Marginal zone (MZ) cells were decreased and aged B cells (ABC) were increased, whereas follicular (FO) cells remained unchanged. Likewise, there was an imbalance in transitional B cells in juvenile Tyk2-/- mice. RNA sequencing analysis of adult MZ and FO cells isolated from Tyk2-/- and WT mice in homeostasis revealed altered expression of IFN-I and Toll-like receptor 7 (TLR7) signaling pathway genes. Flow cytometry assays corroborated a lower expression of TLR7 in MZ B cells from Tyk2-/- mice. Splenic B cell cultures showed reduced proliferation and differentiation responses after activation with TLR7 ligands in Tyk2-/- compared to WT mice, with a similar response to lipopolysaccharide (LPS) or anti-CD40 + IL-4. IgM, IgG, IL-10 and IL-6 secretion was also decreased in Tyk2-/- B cell cultures. This reduced response of the TLR7 pathway in Tyk2-/- mice was partially restored by IFNα addition. In conclusion, there is a crosstalk between TYK2 and TLR7 mediated by an IFN-I feedback loop, which contributes to the establishment of MZ B cells and to B cell proliferation and differentiation.

A Program of Life-Style Modification Improved the Body Weight and Micronutrient Status in Obese Patients after Bariatric Surgery.

INTRODUCTION: Bariatric surgery is an efficient approach to rapidly reduce morbid obesity and associated comorbidities. However, approximately one-fourth of patients experience weight and comorbidity recurrence, and both obesity and bariatric surgery can lead to micronutrient deficiencies. Implementing a structured program of lifestyle modification (PLM) might enhance weight loss and improve micronutrient status. METHODOLOGY: A total of 121 severely obese patients underwent Roux-en-Y gastric bypass (RYGB). Among them, 71 adhered to a PLM involving dietary changes (low- and very-low-calorie Mediterranean diets) and physical exercises (aerobic and resistance training) both before and after surgery, while 50 patients followed a conventional protocol. Anthropometric measurements and serological parameter quantifications were conducted throughout the procedures. RESULTS: The obese study population, primarily female (76.9%), with an average age of 47.11 ± 9.68, and a body mass index (BMI) of 44.68 ± 5.08 kg/m2, underwent either RYGB with a PLM or a conventional procedure. Before surgery, the PLM group exhibited significant reductions in body weight (6.3%) and phosphoremia compared to the conventional protocol (0.78%). Post-RYGB, the PLM group demonstrated shortened in-hospital stays and further BMI reductions (-16.12 kg/m2) that persisted for up to 2 years. Furthermore, the PLM group experienced increased plasma vitamin D levels (14.79 ng/mL vs. 1.2 ng/mL) for up to 2 years, as well as elevated folic acid (1.52 vs. -0.29 ng/mL) and phosphorus (0.48 vs. 0.06 mg/dL) levels at 1 month and 1 year after intervention, respectively. Notably, these effects were independent of weight loss. CONCLUSIONS: Initiating a structured PLM from the early stages of patients' preparation for RYGB could enhance and extend the benefits of weight loss and positively impact micronutrient (vitamin D, phosphorus, and folic acid) status in obese patients.

CYP2D6 Genotype and Pharmacovigilance Impact on Autism Spectrum Disorder: A Naturalistic Study with Extreme Phenotype Analysis.

The long-term use of psychopharmacology medications in autism spectrum disorder (ASD) hitherto remains controversial due to a lack of evidence about safety and tolerability. In this regard, genotyping the metabolizing enzyme cytochrome P450 (CYP) 2D6, especially its extreme phenotypes, could help to prevent drug-related adverse reactions or adverse events (AEs). There are several medications warranting CYP2D6 screening that are consumed by people with ASD, such as risperidone and aripiprazole to name a few. A naturalistic observational study was carried out in participants with ASD to analyze the influence of the CYP2D6 phenotype in drug tolerability using a local pharmacovigilance system created for this study. In this case, AEs were identified from participants' electronic health records (EHRs) and paper registries. Other variables were collected: socio-demographic information, comorbidities, and psychopharmacology prescriptions (polypharmacy defined as ≥4 simultaneous prescriptions) and doses. The genetic analysis included allelic discrimination (CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, and *41) and copy number variations. All of these were used to determine theoretical phenotypes of the metabolic profiles: poor (PM); intermediate (IM); normal (NM); and ultra-rapid (UM). Sex differences were analyzed. A total of 71 participants (30 ± 10 years old, 82% male, 45% CYP2D6 NM phenotype (32 participants)) with a median of 3 (IQR 2-4) comorbidities per person, mainly urinary incontinence (32%) and constipation (22%), were included. CYP2D6 UM showed the highest rate of polypharmacy, whilst, IM participants had the highest rates of neurological and psychiatric AEs, even worse if a CYP2D6 inhibitor drug was prescribed simultaneously. CYP2D6 pharmacogenomics and the monitoring of new antipsychotic prescriptions may make a difference in medication safety in adults with ASD. Particularly in those with psychopharmacology polymedication, it can help with AE avoidance and understanding.

The challenge of detecting adverse events in adults with autism spectrum disorder who have intellectual disability.

Adults with autism spectrum disorder (ASD) and associated intellectual disability (ID) take a high number of different psychotropic drugs simultaneously. Nowadays, little is known about this multidrug pattern efficacy and safety. The present study has endeavored to fill this gap creating a local pharmacovigilance system. A 36-month, retrospective and prospective, observational, and multicenter pharmacovigilance study was carried out in adults with ASD and ID (n = 83). Information regarding ongoing medications (polypharmacy: taking simultaneously >4 drugs; safety profile: adverse events' number, adverse drug reactions' number, and affected system; and observed-to-expected [O/E] ratio using the summary of product characteristics), and current diagnoses were recorded. A median of four ongoing medications per participant was registered, half of the sample was under polypharmacy regimen. Regarding all ongoing medications, 50% were antipsychotic drugs, and 47% of participants had >1 antipsychotic prescribed. In contrast, only 64 adverse events were identified from electronic health records, mostly due to risperidone. Half of them were related either to nervous or metabolic systems, and almost a third were not previously described in the corresponding drug summary of products characteristics. Extrapyramidalism, gynecomastia, hypercholesterolemia, and urinary retention were some AEs that occurred more frequently than expected (O/E ratio > 6 times) according to our data. The highest O/E ratio scores (>120 times) were for hypercholesterolemia and rhabdomyolysis caused by valproic acid. According to the number of adverse events and adverse drug reactions reported in electronic health records locally and nationally by clinicians, we need to increase awareness about medications safety. LAY SUMMARY: A 36-month study in adults with autism, ID, and polypharmacy (>4 drugs) was done to investigate drug safety on everyone. A median of four medications per person was registered, half were antipsychotic drugs, and 47% of participants had >1 antipsychotic medication simultaneously. Only 64 adverse events were identified from electronic health records, mostly due to risperidone. Half of them were related to nervous or metabolic systems and a third were not previously described in the drug information sheet.

Multimorbidity and psychotropic polypharmacy among participants with autism spectrum disorder with intellectual disability.

Nowadays, adults with autism spectrum disorder (ASD) experience several comorbidities whose treatment implies a wide range of psychotropic prescriptions. This study aimed to evaluate medication-related safety, drug-drug interactions, and psychotropics prescription trends. We conducted an observational and multicentric pharmacovigilance study in subjects with ASD and Intellectual disability (ID, n = 83). Clinical information (diagnoses, ongoing medications, comorbidities [multimorbidity ≥ 4 chronic health conditions]) and psychotropic prescriptions (polypharmacy ≥ 4 chronic drugs, daily drug doses, co-prescription) were registered. Ethical approval for this study was obtained. Participants (30±10 years old, 86% men, BMI 27±6 kg/m2) displayed 37% multimorbidity (mean of 3, IQR 2-4), and 57% polypharmacy (13% out of dose recommended range). Most drugs prescribed were psychotropic risperidone which is related to nervous system comorbidities (18% epilepsy, 16% insomnia, and 14% psychotic agitations). Risperidone and quetiapine were co-prescribed in 60% of the cases without any monitoring adverse event routine. The rates of multimorbidity and polypharmacy, among our young adults with ASD and ID, are concerning. Data suggest the need to develop a pharmacovigilance monitoring system to evaluate prescription accuracy, long-term safety of ongoing medications, and the fixed doses in this autistic population with associated ID.