SLCO1B1 *15 allele is associated with methotrexate-induced nausea in pediatric patients with inflammatory bowel disease.

Low-dose methotrexate (MTX) is an immunosuppressant used to treat inflammatory bowel disease (IBD). SLCO1B1 genetic variation has been associated with delayed MTX clearance and increased toxicity. The purpose of this study was to evaluate the association between SLCO1B1 genetic variation and MTX-induced nausea in children with IBD. We performed a single center retrospective chart analysis of 278 patients who were prescribed MTX for IBD. Two hundred two patients had banked DNA and were genotyped for three SLCO1B1 single nucleotide polymorphisms (SNPs; rs4149056, rs2306283, and rs11045819). Diplotypes were determined by combining the SNPs into *1, *4, *5, *14, *15, and *37 alleles. Incidence of nausea was abstracted from clinician notes. Prescriptions and demographics were extracted from the medical record. The cohort was 69.8% boys, 89.1% White, and 87.6% had a diagnosis of Crohn's disease with a mean age of 16.0 (± 3.8) years. MTX-induced nausea was noted in 34% of the cohort. MTX-induced nausea was associated with the number of reduced-function *15 alleles (p = 0.034) and occurred 2.26 times more often in patients with at least one *15 allele who did not initiate MTX treatment with concomitant ondansetron (p = 0.034). MTX-induced nausea was significantly independently associated with SLCO1B1 diplotype (p = 0.006) after controlling for MTX dose group and concomitant ondansetron. Our data demonstrate that the SLCO1B1 *15 allele is associated with MTX-induced nausea in pediatric patients with IBD. Additionally, *15 allele carriers could benefit from a dose reduction of MTX to reduce exposure and treatment initiation with concomitant ondansetron to reduce nausea.

A Programmatic Response, Including Bamlanivimab or Casirivimab-imdevimab Administration, Reduces Hospitalization and Death in COVID-19 Positive Abdominal Transplant Recipients.

BACKGROUND: (COVID-19) has resulted in significant morbidity and mortality in solid organ transplant recipients. In December 2020, at the peak of the Los Angeles outbreak, our center rapidly implemented a protocol to improve outpatient management and provide bamlanivimab or casirivimab-imdevimab [COVID monoclonal antibody (mAb) therapies] to all eligible COVID-19 positive liver and kidney transplant recipients. METHODS: A retrospective review of all abdominal organ transplant recipients who were COVID-19 polymerase chain reaction positive between February 2020 and February 2021 from our center was performed. Patient demographics, COVID-19 treatments, hospitalizations, and survival were reviewed. Patients were considered eligible for COVID mAb therapy if they met outpatient criteria at the time of diagnosis. RESULTS: In the study period, 121 patients in the kidney transplant recipients group (KG) and 105 patients in the liver or combined liver/kidney transplant recipients group (LG) were COVID-19 polymerase chain reaction positive. Hospitalization rates were similar for the KG (45%) versus LG (35%) (P = 0.20), but mortality was higher for the KG (22%) when compared to LG (10%) (P = 0.02). Our programmatic response, including outpatient COVID mAb therapies, reduced hospitalizations (P = 0.01) and deaths (P = 0.01). Ninety-four KG and 87 LG patients were identified as potentially eligible for COVID mAb therapy, and 17 KG and 17 LG patients were treated. COVID mAb therapies reduced hospitalization from 32% to 15% (P = 0.045) and eliminated mortality (13% versus 0%, P = 0.04). CONCLUSIONS: An aggressive approach including outpatient COVID mAb therapy in the COVID positive abdominal organ transplant recipients significantly decreased hospitalization and death. Early outpatient intervention for COVID-19 disease in transplant patients should be considered where possible.

Brief ampakine treatments slow the progression of Huntington's disease phenotypes in R6/2 mice.

Daily, systemic injections of a positive AMPA-type glutamate receptor modulator (ampakine) have been shown to reduce synaptic plasticity defects in rodent models of aging and early-stage Huntington's disease (HD). Here we report that long-term ampakine treatment markedly slows the progression of striatal neuropathology and locomotor dysfunction in the R6/2 HD mouse model. Remarkably, these effects were produced by an ampakine, CX929, with a short half-life. Injected once daily for 4-7 weeks, the compound increased protein levels of brain-derived neurotrophic factor (BDNF) in the neocortex and striatum of R6/2 but not wild-type mice. Moreover, ampakine treatments prevented the decrease in total striatal area, blocked the loss of striatal DARPP-32 immunoreactivity and reduced by 36% the size of intra-nuclear huntingtin aggregates in R6/2 striatum. The CX929 treatments also markedly improved motor performance of R6/2 mice on several measures (rotarod, vertical pole descent) but did not influence body weight or lifespan. These findings describe a minimally invasive, pharmacologically plausible strategy for treatment of HD and, potentially, other neuropathological diseases.