Safety, Virology, Pharmacokinetics, and Clinical Experience of High-Dose Intravenous Sotrovimab for the Treatment of Mild to Moderate COVID-19: An Open-Label Clinical Trial.

Background: Five hundred milligrams of intravenous (IV) sotrovimab has been shown to be well tolerated and efficacious against pre-Omicron strains in treating patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk for disease progression. Methods: This was an open-label, single-arm substudy of phase 3 COMET-TAIL (NCT04913675) assessing the safety and tolerability of a 2000 mg IV dose of sotrovimab. Symptomatic patients (aged ≥18 years) with COVID-19 at high risk for progression were enrolled from June 30 through July 11, 2022, when Omicron BA.5, BA.2.12.1, and BA.4 were the predominant circulating variants in the United States. The primary end point was the occurrence of adverse events (AEs), serious AEs (SAEs), AEs of special interest, and COVID-19 disease-related events (DREs) through day 8. Safety, pharmacokinetics, viral load, and hospitalization >24 hours for acute management of illness or death through day 29 were assessed. Results: All participants (n = 81) were Hispanic, 58% were female, and 51% were aged ≥55 years. Through day 8, no AEs, including infusion-related reactions or hypersensitivity, were reported; 2 participants reported DREs (mild cough, n = 2). One SAE (acute myocardial infarction), which was considered unrelated to sotrovimab or COVID-19 by the investigator, occurred on day 27 and was the only hospitalization reported. Maximum serum concentration (geometric mean) was 745.9 µg/mL. Viral load decreased from baseline through day 29; only 2 (3%) participants had a persistently high viral load (≥4.1 log10 copies/mL) at day 8. Conclusions: Two thousand milligrams of IV sotrovimab was well tolerated, with no safety signals observed. Trial registration: ClinicalTrials.gov Identifier: NCT04913675.

Design Principles in mHealth Interventions for Sustainable Health Behavior Changes: Protocol for a Systematic Review.

BACKGROUND: In recent years, mHealth has increasingly been used to deliver behavioral interventions for disease prevention and self-management. Computing power in mHealth tools can provide unique functions beyond conventional interventions in provisioning personalized behavior change recommendations and delivering them in real time, supported by dialogue systems. However, design principles to incorporate these features in mHealth interventions have not been systematically evaluated. OBJECTIVE: The goal of this review is to identify best practices for the design of mHealth interventions targeting diet, physical activity, and sedentary behavior. We aim to identify and summarize the design characteristics of current mHealth tools with a focus on the following features: (1) personalization, (2) real-time functions, and (3) deliverable resources. METHODS: We will conduct a systematic search of electronic databases, including MEDLINE, CINAHL, Embase, PsycINFO, and Web of Science for studies published since 2010. First, we will use keywords that combine mHealth, interventions, chronic disease prevention, and self-management. Second, we will use keywords that cover diet, physical activity, and sedentary behavior. Literature found in the first and second steps will be combined. Finally, we will use keywords for personalization and real-time functions to limit the results to interventions that have reported these design features. We expect to perform narrative syntheses for each of the 3 target design features. Study quality will be evaluated using the Risk of Bias 2 assessment tool. RESULTS: We have conducted a preliminary search of existing systematic reviews and review protocols on mHealth-supported behavior change interventions. We have identified several reviews that aimed to evaluate the efficacy of mHealth behavior change interventions in a range of populations, evaluate methodologies for assessing mHealth behavior change randomized trials, and assess the diversity of behavior change techniques and theories in mHealth interventions. However, syntheses on the unique features of mHealth intervention design are absent in the literature. CONCLUSIONS: Our findings will provide a basis for developing best practices for designing mHealth tools for sustainable behavior change. TRIAL REGISTRATION: PROSPERO CRD42021261078; https://tinyurl.com/m454r65t. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/39093.

Procedure-specific acute pain trajectory after elective total hip arthroplasty: systematic review and data synthesis.

BACKGROUND: For most procedures, there is insufficient evidence to guide clinicians in the optimal timing of advanced analgesic methods, which should be based on the expected time course of acute postoperative pain severity and aimed at time points where basic analgesia has proven insufficient. METHODS: We conducted a systematic search of the literature of analgesic trials for total hip arthroplasty (THA), extracting and pooling pain scores across studies, weighted for study size. Patients were grouped according to basic anaesthetic method used (general, spinal), and adjuvant analgesic interventions such as nerve blocks, local infiltration analgesia, and multimodal analgesia. Special consideration was given to high-risk populations such as chronic pain or opioid-dependent patients. RESULTS: We identified and analysed 71 trials with 5973 patients and constructed pain trajectories from the available pain scores. In most patients undergoing THA under general anaesthesia on a basic analgesic regimen, postoperative acute pain recedes to a mild level (<4/10) by 4 h after surgery. We note substantial variability in pain intensity even in patients subjected to similar analgesic regimens. Chronic pain or opioid-dependent patients were most often actively excluded from studies, and never analysed separately. CONCLUSIONS: We have demonstrated that it is feasible to construct procedure-specific pain curves to guide clinicians on the timing of advanced analgesic measures. Acute intense postoperative pain after THA should have resolved by 4-6 h after surgery in most patients. However, there is a substantial gap in knowledge on the management of patients with chronic pain and opioid-dependent patients.

Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer.

Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to α-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α upregulates GPT2 gene expression through an AKT-independent, PDK1-RSK2-ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with PIK3CA mutations, but not with WT PIK3CA. Together, these data establish oncogenic PIK3CA mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring PIK3CA mutations.