Emerging evidence for glucagon-like peptide-1 agonists in slowing chronic kidney disease progression.

PURPOSE OF REVIEW: Diabetic kidney disease continues to increase, and several novel therapeutic agents have been shown to slow the progression of chronic kidney disease in those with diabetes. This review summarizes more recent data on the role of glucagon-like peptide-1 (GLP-1) receptor agonists and kidney outcomes. RECENT FINDINGS: Posthoc analysis of cardiovascular outcome trials, as well as several retrospective studies, demonstrate benefits of GLP-1 receptor agonist therapy for chronic kidney disease progression in diabetics. Although limited randomized clinical trials evidence assessing the effects of GLP-1 receptor agonists on kidney outcomes in diabetic chronic kidney disease patients have been published, FLOW-CKD trial was halted based on interim data for efficacy, and results are awaited. SUMMARY: GLP-1 receptor agonism is a promising therapy for slowing the progression of diabetic chronic kidney disease. Recent studies support kidney benefits GLP-1 receptor agonists over insulin and dipeptidyl peptidase-4-inhibitors, and the FLOW-CKD trial would inform the potential benefits for reducing the need for dialysis and kidney-disease related mortality in those with kidney disease.

Chronic Interstitial Nephritis in Agricultural Communities: Observational and Mechanistic Evidence Supporting the Role of Nephrotoxic Agrochemicals.

Chronic interstitial nephritis in agricultural communities (CINAC) is an epidemic of kidney disease affecting specific tropical and subtropical regions worldwide and is characterized by progressive CKD in the absence of traditional risk factors, such as hypertension and diabetes. CINAC prevalence is higher among young, male agricultural workers, but it also affects women, children, and nonagricultural workers in affected areas. Biopsies from patients with CINAC across regions commonly demonstrate tubular injury with lysosomal aggregates, tubulointerstitial inflammation, and fibrosis and variable glomerular changes. Each endemic area holds environmental risk factors and patient/genetic milieus, resulting in uncertainty about the cause(s) of the disease. Currently, there is no specific treatment available for CINAC. We highlight survey findings of Houston-based migrant workers with CINAC and draw similarities between kidney injury phenotype of patients with CINAC and mice treated chronically with paraquat, an herbicide used worldwide. We propose potential pathways and mechanisms for kidney injury in patients with CINAC, which may offer clues for potential therapies.

Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia.

PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.

Simulation-based workshop for emergency preparedness in otolaryngology.

Objectives: This study aimed to evaluate the outcomes of a hands-on simulation-based course with emphasis on procedural techniques, clinical reasoning, and communication skills developed to improve junior Otolaryngology - Head and Neck Surgery (OHNS) residents' preparedness in managing otolaryngologic emergencies. Methods: Junior OHNS residents and faculty from residency programs in California, Nevada, and Arizona participated in this workshop in 2020 and 2021. The stations featured airway management techniques, ultrasound-guided needle aspiration, nasoseptal hematoma evacuation, and facial fracture repair using various models and cadavers. Participants completed a pre-workshop survey, post-workshop survey, and 2-month follow-up survey that assessed resident anxiety and confidence in three OHNS emergency situations across knowledge, manual skills, and teamwork using a 5-point Likert scale. Results: Pre-workshop surveys reported the least anxiety and most confidence in teamwork, but the most anxiety and least confidence in technical skills and knowledge related to foreign body retrieval and airway management. Immediately post-workshop participants reported significant reductions in anxiety and increases in confidence, largest in the manual skills domain, in foreign body retrieval (anxiety: -0.99, confidence: +0.95, p < .01) and airway management stations (anxiety: -0.68, confidence: +1.07, p < .01). Data collected for the epistaxis station showed decreasing confidence and increasing anxiety following the workshop. Conclusion: Our findings demonstrate the effectiveness of a workshop in preparing junior residents in potentially lifesaving otolaryngologic techniques that residents will encounter. Optimizing use of simulation centered training can inform the future of residency education, improving confidence and decreasing anxiety in residents responsible for the safety of patients. Level of Evidence: III.

Treatment of Severe COVID-19 Infection With Remdesivir in Peritoneal Dialysis.

End-stage kidney disease (ESKD) has been shown to be correlated with an increased risk of COVID-19 infection and mortality. Remdesivir is an effective non-EUA U.S. Food and Drug Administration (FDA)-approved antiviral agent for the treatment of COVID-19 in hospitalized adult and pediatric patients, though a lack of data has prevented its use in patients with severe kidney disease including dialysis patients. Some observational studies report the use of remdesivir in hemodialysis patients, but there are no reports of patients treated with remdesivir on peritoneal dialysis. Dialysis modalities may affect drug pharmacokinetics, and safety and efficiency of remdesivir in peritoneal dialysis is unknown. We report the first case, to our knowledge, of using remdesivir in a patient treated with peritoneal dialysis with no significant adverse events. This case illustrates the potential for remdesivir to be considered in peritoneal dialysis patients with severe COVID infection. Proper risk analysis and careful monitoring should be done, given the unpredictable clearance of the drug.

Evaluation of an Academic Detailing Program to Improve Blood Pressure Measurement and Hypertension Treatment in Urban Community Health Centers.

INTRODUCTION: Hypertension is estimated at a prevalence of 30 to 50% in the United States. Only 54% of patients with hypertension have their condition adequately controlled. This study aimed to use academic detailing (AD) to improve practice team knowledge and confidence in blood pressure (BP) management, specifically in low-income, underresourced patient populations. METHODS: AD was developed for five practices that care for high percentages of Medicaid-eligible patients. A needs assessment was administered to each site's practice champion to determine high-yield AD sessions for their team. Presession and postsession evaluations were completed by practice team members. RESULTS: Fifty providers and eight staff member participants completed evaluations over nine sessions for two AD topics at four practice sites. Statistical significance was found for several items within sessions including accurately choosing cuff sizes and identifying barriers to home BP monitoring. DISCUSSION: AD is a potentially financially efficient model to improve knowledge and confidence in hypertension care at the practice level. Tailoring session content to specific needs of a practice site, along with an identified practice champion, facilitated implementation of the program. This replicable model is one way to deliver evidence-based information to those who serve Medicaid-eligible patients.

A Multifaceted Hit-Finding Approach Reveals Novel LC3 Family Ligands.

Autophagy-related proteins (Atgs) drive the lysosome-mediated degradation pathway, autophagy, to enable the clearance of dysfunctional cellular components and maintain homeostasis. In humans, this process is driven by the mammalian Atg8 (mAtg8) family of proteins comprising the LC3 and GABARAP subfamilies. The mAtg8 proteins play essential roles in the formation and maturation of autophagosomes and the capture of specific cargo through binding to the conserved LC3-interacting region (LIR) sequence within target proteins. Modulation of interactions of mAtg8 with its target proteins via small-molecule ligands would enable further interrogation of their function. Here we describe unbiased fragment and DNA-encoded library (DEL) screening approaches for discovering LC3 small-molecule ligands. Both strategies resulted in compounds that bind to LC3, with the fragment hits favoring a conserved hydrophobic pocket in mATG8 proteins, as detailed by LC3A-fragment complex crystal structures. Our findings demonstrate that the malleable LIR-binding surface can be readily targeted by fragments; however, rational design of additional interactions to drive increased affinity proved challenging. DEL libraries, which combine small, fragment-like building blocks into larger scaffolds, yielded higher-affinity binders and revealed an unexpected potential for reversible, covalent ligands. Moreover, DEL hits identified possible vectors for synthesizing fluorescent probes or bivalent molecules for engineering autophagic degradation of specific targets.

Postoperative Gabapentin's Effect on Opioid Consumption and Pain Control Following Sinonasal Surgery.

OBJECTIVE: This study investigates the impact of postoperative gabapentin on opioid consumption and pain control following endoscopic sinus surgery (ESS) and/or septoplasty. METHODS: Patients who underwent ESS and/or septoplasty at a single institution from 2021 to 2022 were enrolled. All patients received postoperative hydrocodone-acetaminophen for pain control. Half of the patients were also prescribed gabapentin for the first postoperative day in addition to hydrocodone-acetaminophen. Subjects completed the Revised American Pain Society Patient Outcome Questionnaire 24 h and 7 days after surgery. We conducted a multivariable regression analysis to assess opioid consumption and improvement in pain scores in the first week between gabapentin and non-gabapentin groups. RESULTS: A total of 102 subjects, 51 in each arm, were enrolled. The mean age was 52 years and 53% of participants were female. Controlling for important baseline demographic, clinical, and surgically related variables, the addition of postoperative gabapentin was associated with a 44% (9.5 mg from 21.6 mg) reduction in opioids consumed in the first postoperative week (B = -9.54, 95% C.I. = [-17.84, -1.24], p = 0.025). In addition, patients in both arms exhibited similar improvement in pain severity and sleep interference in the first 7 days (B = -1.59, 95% C.I. = [-5.03, 1.84], p = 0.36). CONCLUSION: To the best of our knowledge, this is the first study to investigate the impact of postoperative gabapentin on opioid consumption and pain control following ESS and/or septoplasty. Our analysis demonstrated that postoperative gabapentin effectively reduced opioid use during the first postoperative week without compromising pain control. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1065-1072, 2023.

Forming Cardi-OH: A Statewide Collaborative to Improve Cardiovascular Health in Ohio.

Background Cardiovascular risk factor control is challenging, especially in disadvantaged populations. However, few statewide efforts exist to tackle this challenge. Therefore, our objective is to describe the formation of a unique statewide cardiovascular health collaborative so others may learn from this approach. Methodology With funding from the Ohio Department of Medicaid's Ohio Medicaid Technical Assistance and Policy Program, we used a collective impact model to link the seven medical schools in Ohio, primary care clinics across the state, the Ohio Department of Medicaid, and Ohio's Medicaid Managed Care Plans in a statewide health improvement collaborative for expanding primary care capacity to improve cardiovascular health in Ohio. Results Initial dissemination activities for primary care teams included a virtual case-based learning series focused on hypertension and social determinants of health, website resources, a monthly newsletter with clinical tips, webinars, and in-person conferences. The collaborative is aligned with a separately funded hypertension quality improvement project for paired implementation. Conclusions The collective impact model is a useful framework for developing a statewide collaborative focused on the dissemination and implementation of evidence-based best practices for cardiovascular health improvement and disparity reduction. Statewide collaboratives bringing payers, clinicians, and academic partners together have the potential to substantially impact cardiovascular health.