👤 Thomas P Meehan

Genetic factors are thought to play an important role in antipsychotic-induced weight gain (AIWG). This study conducted a meta-analysis of current research of the pharmacogenetic associations of adult AIWG. The analysis included papers providing comparisons of weight gain across at least two allele combinations for at least one single nucleotide polymorphism (SNP). Inclusion criteria were, patients 18 years of age or older and had received a diagnosis of severe mental illness, for which antipsychotic medication was prescribed. The association with AIWG needed to be replicated across at least two papers reporting separate sample sets. Two hundred twenty-three papers were assessed for eligibility. Of the 223 papers, 148 were excluded, leaving 75 studies to be included. Six SNPs in six different genes were identified as having significant associations ( The study identified six SNPs that predispose adult individuals to AIWG, with Show less

Immune effector cell-associated neurotoxicity syndrome (ICANS) can be a severe, life-threatening toxicity following CAR T-cell therapy. While currently evaluated by the immune effector cell-associated encephalopathy (ICE) score, not all patients have changes in their ICE score and not all signs and symptoms of neurotoxicity are captured. We conducted a prospective, single center cohort pilot study to evaluate a novel, rapid neurocognitive assessment tool (CART-NS) in detecting early, subtle neurotoxicity prior to the onset of ICANS and any deterioration in the ICE score. CART-NS includes 8 abbreviated forms of neurocognitive tests and 2 symptom questionnaires. Following baseline measurements, CART-NS was administered at 8-hour intervals during the first 30 days after CAR T-cell infusion. Performance on all measures was significantly lower when patients developed Grade 1 or 2 ICANS (P < .05). Performance on Oral Symbol Digit, Stroop, and the Paced Visual Serial Addition Test was lower between Day 0 and +3 in patients who developed ICANS and persisted even after clinical resolution. Early changes in the Stroop test (AUC = 0.857, 95% CI 0.628-1.000) were most predictive of ICANS onset when measured during the first 36 hour following CAR T-cell infusion. Significant elevations in CRP, G-CSF, GM-CSF, IFNγ, IL-10, IL-15, IL-27, and MIG/CXCL-9 were associated with ICANS development. Brief neurocognitive testing can be feasibly applied for the early detection of ICANS after CAR T-cell therapy, predict which patients may go on to develop ICANS in the first 30 days, and overcome limitations of the ICE assessment tool. Show less

Bardet-Biedl syndrome (BBS) is a rare oligogenic disorder exhibiting both clinical and genetic heterogeneity. Although the BBS phenotype is variable both between and within families, the syndrome is characterized by the hallmarks of developmental and learning difficulties, post-axial polydactylia, obesity, hypogenitalism, renal abnormalities, retinal dystrophy, and several less frequently observed features. Eleven genes mutated in BBS patients have been identified, and more are expected to exist, since about 20-30% of all families cannot be explained by the known loci. To investigate the etiopathogenesis of BBS, we created a mouse null for one of the murine homologues, Bbs4, to assess the contribution of one gene to the pleiotropic murine Bbs phenotype. Bbs4 null mice, although initially runted compared to their littermates, ultimately become obese in a gender-dependent manner, females earlier and with more severity than males. Blood chemistry tests indicated abnormal lipid profiles, signs of liver dysfunction, and elevated insulin and leptin levels reminiscent of metabolic syndrome. As in patients with BBS, we found age-dependent retinal dystrophy. Behavioral assessment revealed that mutant mice displayed more anxiety-related responses and reduced social dominance. We noted the rare occurrence of birth defects, including neural tube defects and hydrometrocolpos, in the null mice. Evaluations of these null mice have uncovered phenotypic features with age-dependent penetrance and variable expressivity, partially recapitulating the human BBS phenotype. Show less