Explore the vast range of titles available.

Background Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression. We aimed to evaluate PGx variation in genes supported by clinical guidelines that inform dosing of thiopurines and characterize differences in the distribution of actionable PGx variation among diverse ancestral groups. Methods Pharmacogenetic variation in TPMT and NUDT15 was captured by genome-wide genotyping of 1083 pediatric IBD patients from a diverse Canadian cohort. Genetic ancestry was inferred using principal component analysis. The proportion of PGx variation and associated metabolizer status phenotypes was compared across 5 genetic ancestral groups within the cohort (Admixed American, African, East Asian, European, and South Asian) and to prior global estimates from corresponding populations. Results Collectively, 11% of the cohort was categorized as intermediate or poor metabolizers of thiopurines, which would warrant a significant dose reduction or selection of alternate therapy. Clinically actionable variation in TPMT was more prevalent in participants of European and Admixed American/Latino ancestry (8.7% and 7.5%, respectively), whereas variation in NUDT15 was more prevalent in participants of East Asian and Admixed American/Latino ancestry (16% and 15% respectively). Conclusions These findings demonstrate the considerable interpopulation variability in PGx variation underlying thiopurine metabolism, which should be factored into testing diverse patient populations. Lay Summary In a large, pediatric inflammatory bowel disease cohort comprised of 5 genetic ancestry groups, we evaluated the distribution of loss-of-function pharmacogenetic variants in TPMT and NUDT15 and predicted phenotypes (impact on thiopurine metabolism).

Background/Objectives: Medication discontinuation attributable to adverse drug reactions (ADRs) and/or inefficacy remains a concern of psychotropic medications among children and adolescents. Pharmacogenetic (PGx) testing has been proposed to individualize treatment, although its utility remains uncertain. We retrospectively evaluated whether PGx testing of two key metabolism genes (i.e., CYP2C19 and CYP2D6) explains reported episodes of ADRs and treatment inefficacy experienced by children and adolescents with diverse mental health conditions. Methods: PGx testing of CYP2C19 and CYP2D6 was conducted for 100 participants before, during, or after the use of psychotropic medication(s) that have clinical practice guidelines supporting PGx-guided dosing. The theoretical impact on medication dosing was reviewed in the context of clinical guidelines. We then evaluated whether the PGx-inferred metabolizer phenotype was consistent with reported ADR and/or treatment inefficacy. Results: If PGx testing had been performed before the start of treatment, 43% (35/82) of participants would have been recommended dose adjustments or alternative therapy of at least one medication. PGx test results corroborated 8% (6/76) of ADR events and 3% (2/61) of inefficacies. However, no single participant had all prior reported ADRs or inefficacies explained by the results of CYP2C19 nor CYP2D6 testing. Conclusions: Reactive testing of CYP2C19 and CYP2D6 provided limited insight into isolated incidents of psychotropic medication intolerance in this population. No individual’s PGx test results explained all episodes of ADR or suboptimal response. Variation in drug metabolism genes alone does not provide an explanation for multiple episodes of inefficacy or adverse reaction. In the setting of child and adolescent psychiatry, PGx testing is best suited for preemptive use to complement clinical decision making.

Commercial pharmacogenetic testing panels capture a fraction of the genetic variation underlying medication metabolism and predisposition to adverse reactions. In this study we compared variation in six pharmacogenes detected by whole genome sequencing (WGS) to a targeted commercial panel in a cohort of 308 individuals with family history of pediatric heart disease. In 1% of the cohort, WGS identified rare variants that altered the interpretation of metabolizer status and would thus prevent potential errors in gene-based dosing.

Objective Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. Methods The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene–disease relationships (GDR) using the ClinGen gene–disease clinical validity framework to evaluate 31 genes implicated in LGMD. Results The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, and COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as definitive, 4 (11%) as moderate, and 1 (3%) as limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. Interpretation The expert‐reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case‐level data that help clarify disputed or novel LGMD associations.

In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer ( N  = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N  = 34), lapatinib (L; N  = 36), or both (TL; N  = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30–65%) and TL (52%, 95% CI 38–65%), and a lower pCR rate with L (25%, 95% CI 13–43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment ( N  = 110), after one cycle of HER2-targeted therapy alone ( N  = 89), and at time of surgery ( N  = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents. HER2+ breast cancer patients can often develop resistance to trastuzumab and therefore potential combination therapies need to be explored. Here, the authors report the results of a multi-center randomized phase II clinical trial evaluating the pathological and molecular responses associated with trastuzumab and/or lapatinib in combination with chemotherapy in HER2+ breast cancer patients.

Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene-disease relationships (GDR) using the ClinGen gene-disease clinical validity framework to evaluate 31 genes implicated in LGMD. The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes ( ) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as Definitive, 4 (11%) as Moderate and 1 (3%) as Limited. Two genes, and , though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. The expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations.

Regarding your story City Day-care Noise Issue To Be Mediated (North Shore News, June 27): When complaining about daytime noise levels, I generally hate loud motorcycles, \"pimped rides,\" construction, the wind-tunnel sounding buses and people who lay on their horns. Lawn mowers while I'm trying to have a nap also annoy the hell out of me. However, this is not happening at 11 p.m., so I don't uselessly file outrageous complaints. We have noise bylaws, and if you wanted to get to the root of the matter, which seems to be daytime noise levels, perhaps your complaints should try to amend our noise bylaws. I'm sorry, but I don't want my children to ever think that's acceptable or OK. No one's life is in danger here, I'm quite sure everyone in these meetings is getting enough to eat in the day, that they all have a comfortable bed to sleep in every night, and can afford a new pair of shoes when needed.

Editor Post: In a recent editorial you took issue with my statement that \"sugar could be cheapened to the consumer in the United States * * * by increasing the differential on Cuban sugar,\" and, more recently in discusing \"Philippine Sugar,\" you said: The Cuban producer is at the mercy of the trust exactly as the American consumer is, and the reciprocity reduction or 20 per cent, designed to benefit the Cuban producer and the American consumer, went into the pockets of the trust.\"

Editor Post: In his recent speech on the tariff Representative Keifer, of Ohio, lectured one of his fellow members, whose alleged errors proceeded, according to his critic, \"from an assumed overinformation,\" or \"overlearning, or from only a little learning on the subject.\"