Sotorasib is a first-in-class KRASG12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. A comprehensive nonclinical safety assessment package, including secondary/safety pharmacology and toxicology studies, was conducted to support the marketing application for sotorasib. Sotorasib was negative in a battery of genotoxicity assays and negative in an in vitro phototoxicity assay. Based on in vitro assays, sotorasib had no off-target effects against various receptors, enzymes (including numerous kinases), ion channels, or transporters. Consistent with the tumor-specific target distribution (ie, KRASG12C), there were no primary pharmacology-related on-target effects identified. The kidney was identified as a target organ in the rat but not the dog. Renal toxicity in the rat was characterized by tubular degeneration and necrosis restricted to a specific region suggesting that the toxicity was attributed to the local formation of a putative toxic reactive metabolite. In the 3-month dog study, adaptive changes of hepatocellular hypertrophy due to drug metabolizing enzyme induction were observed in the liver that was associated with secondary effects in the pituitary and thyroid gland. Sotorasib was not teratogenic and had no direct effect on embryo-fetal development in the rat or rabbit. Human, dog, and rat circulating metabolites, M24, M10, and M18, raised no clinically relevant safety concerns based on the general toxicology studies, primary/secondary pharmacology screening, an in vitro human ether-à-go-go-related gene assay, or mutagenicity assessment. Overall, the results of the nonclinical safety program support a high benefit/risk ratio of sotorasib for the treatment of patients with KRAS p.G12C-mutated tumors.

Examine associations between oral psychostimulant pharmacotherapy adherence, work productivity, and related indirect costs among US adults with ADHD.

Medication adherence (Medication Adherence Reasons Scale [MAR-Scale]), work productivity and activity impairment (Work Productivity and Activity Impairment-General Health questionnaire), and ADHD symptom level (Adult ADHD Self-Report Scale version 1.1 Symptom Checklist) were assessed in this noninterventional online survey of adults who self-reported having an ADHD diagnosis and were currently receiving oral psychostimulant treatment for ≥3 months.

Of 602 respondents, 395 had low/medium adherence (LMA MAR-Scale total score ≥1) and 207 had high adherence (HA MAR-Scale total score 0). After adjusting for covariates, the LMA group had significantly greater levels of absenteeism, absenteeism-related indirect costs, and total indirect costs (all

 < .01) than the HA group.

In adults with ADHD using oral psychostimulants, lower medication adherence was associated with greater absenteeism and indirect costs.

In adults with ADHD using oral psychostimulants, lower medication adherence was associated with greater absenteeism and indirect costs.

To evaluate the literature on a potential dexamethasone-direct oral anticoagulant (DOAC) drug interaction and provide management considerations with COVID hypercoagulability.

A search of EMBASE, PubMed, and Google Scholar (January 1990 to May 2021), limited to the English language, using applicable search terms resulted in 137 articles, with 21 relevant articles included. Regulatory agency and clinical guidance documents were also reviewed.

Included articles describe in vitro or in vivo animal or human data for dexamethasone induction of cytochrome P450 (CYP) 3A4 or P-glycoprotein (P-gp).

Dexamethasone has the potential to interact with the DOACs via CYP3A4 and/or P-gp induction. Only apixaban and rivaroxaban have CYP3A4 metabolism. Dexamethasone can increase CYP3A4 activity by up to 70% and reduce the area under the concentration-time curve (AUC) of CYP3A4 substrates by >40%, which is consistent with criteria for a weak CYP inducer. In rodents, dexamethasone P-gp induction is associated with AUC reductions of 20% to 50%. buy Y-27632 Human data are lacking.

Severe COVID-19 infection is associated with hypercoagulability. Although heparins are the preferred anticoagulants for hospitalized COVID-19 patients, DOACs are being utilized. Dexamethasone is recommended for hospitalized COVID-19 patients requiring supplemental oxygen. The concurrent use of dexamethasone and apixaban or rivaroxaban in such patients carries the potential for reduced anticoagulant effect during a state of heightened thrombotic risk.

Concurrent use of dexamethasone and apixaban or rivaroxaban in hospitalized COVID-19 patients with laboratory evidence of COVID coagulopathy should be avoided until higher-quality data are available.

Concurrent use of dexamethasone and apixaban or rivaroxaban in hospitalized COVID-19 patients with laboratory evidence of COVID coagulopathy should be avoided until higher-quality data are available.

Over the past decade, there has been a growth in the use of ankle replacements. Data from national joint registries have shown between-country differences in the utilization of ankle replacement. The reasons for these differences are, however, not well understood. Our aims were to describe and compare the annual incidence of primary ankle replacement between countries and, to examine potential reasons for variation over time.

We used aggregate data and summary statistics on ankle replacements for the period 1993 to 2019 from national joint replacement registries in Australia, Finland, New Zealand, Norway, Sweden and the United Kingdom. From the annual recorded counts of procedures, demographic data were extracted on age, sex distribution, and indication(s) for primary ankle replacement. Registry-level summary results were also obtained on data completeness, counts of hospitals/units, and health care providers performing ankle replacements annually and data collection processes (mandatory vs voluntary). Aning comparisons for this less common site for joint replacement surgery.

Level III, retrospective study.

Level III, retrospective study.

Comparison between bovine-derived demineralized bone matrix (DMBM) and iliac crest graft over long term for secondary alveolar bone grafting (SABG) in patients with unilateral cleft lip and palate (UCLP) in terms of radiological and clinical outcomes.

Prospective, randomized, parallel groups, double-blind, controlled trial.

Unit of Oral and Maxillofacial Surgery, Oral Health Science Centre, Postgraduate Institute of Medical Education & Research, Chandigarh.

Twenty patients with UCLP.

Patients were allocated into group I (Iliac crest bone graft) and group II (DMBM) for SABG. Outcomes were assessed at 2 weeks, 6 months, and then after mean follow-up period of 63 months.

Volumetric analysis of the grafted bone in the alveolar cleft site was done through cone beam computed tomography using Cavalieri principle and modified assessment tool. Clinical assessment was performed in terms of pain, swelling, duration of hospital stay, cost of surgery, alar base symmetry, and donor site morbidity associated with iliac crest harvesting.