Inhibition of FOXP3 by stapled alpha-helical peptides dampens regulatory T cell function.

Despite continuing advances in the development of novel cellular-, antibody-, and chemotherapeutic-based strategies to enhance immune reactivity, the presence of regulatory T cells (Treg cells) remains a complicating factor for their clinical efficacy. To overcome dosing limitations and off-target effects from antibody-based Treg cell deletional strategies or small molecule drugging, we investigated the ability of hydrocarbon stapled alpha-helical (SAH) peptides to target FOXP3, the master transcription factor regulator of Treg cell development, maintenance, and suppressive function. Using the crystal structure of the FOXP3 homodimer as a guide, we developed SAHs in the likeness of a portion of the native FOXP3 antiparallel coiled-coil homodimerization domain (SAH-FOXP3) to block this key FOXP3 protein-protein interaction (PPI) through molecular mimicry. We describe the design, synthesis, and biochemical evaluation of single- and double-stapled SAHs covering the entire coiled-coil expanse. We show that lead SAH-FOXP3s bind FOXP3, are cell permeable and nontoxic to T cells, induce dose-dependent transcript and protein level alterations of FOXP3 target genes, impede Treg cell function, and lead to Treg cell gene expression changes in vivo consistent with FOXP3 dysfunction. These results demonstrate a proof of concept for rationally designed FOXP3-directed peptide therapeutics that could be used as approaches to amplify endogenous immune responsiveness.

Relationship between Insurance Type and Delays in Tympanostomy Tube Placement.

OBJECTIVE: To investigate the role of insurance carriers and changes in insurance on rates of cancelation and rescheduling of tympanostomy tube surgery. METHODS: Retrospective cohort study between January 1, 2013 and December 31, 2018 at a single tertiary care academic pediatric otolaryngology practice of pediatric patients (≤18 years) who underwent tympanostomy tube placement for any indication. Patients had to have insurance providers recorded both at clinic visit and at the time of surgery. Rates of cancelation and postponement of tympanostomy tube placement were assessed. Logistic regression was performed to determine factors associated with cancelation or postponement of surgery. RESULTS: Of the 5080 patients, 2961 patients had Medicaid and 2012 patients had private insurance at the time of surgery. A total of 197 (3.96%) patients switched insurance between clinic appointment and date of surgery. Time to surgery was nearly 2 weeks more for those who had a change in insurance vs. those who did not (33 vs. 20 days, P < .001). Those who switched insurance were nearly twice as likely to have to reschedule surgery than those who did not (OR 1.95, CI 1.42-2.67). Patients who had Medicaid as the primary payer also had increased odds of needing to reschedule and postpone surgery (OR 1.39, 95% CI 1.17-1.63). CONCLUSION: Difference in insurance carrier and loss/change of insurance appear to be associated with delays in tympanostomy tube placement. Standardization of re-enrollment schedules across insurance providers or a single payer model may be useful in addressing these delays in care.

Telehealth Practice Among Health Centers During the COVID-19 Pandemic - United States, July 11-17, 2020.

Early in the coronavirus disease 2019 (COVID-19) pandemic, in-person ambulatory health care visits declined by 60% across the United States, while telehealth* visits increased, accounting for up to 30% of total care provided in some locations (1,2). In March 2020, the Centers for Medicare & Medicaid Services (CMS) released updated regulations and guidance changing telehealth provisions during the COVID-19 Public Health Emergency, including the elimination of geographic barriers and enhanced reimbursement for telehealth services† (3-6). The Health Resources and Services Administration (HRSA) administers a voluntary weekly Health Center COVID-19 Survey§ to track health centers' COVID-19 testing capacity and the impact of COVID-19 on operations, patients, and staff. CDC and HRSA analyzed data from the weekly COVID-19 survey completed by 1,009 HRSA-funded health centers (health centers¶) for the week of July 11-17, 2020, to describe telehealth service use in the United States by U.S. Census region,** urbanicity,†† staffing capacity, change in visit volume, and personal protective equipment (PPE) supply. Among the 1,009 health center respondents, 963 (95.4%) reported providing telehealth services. Health centers in urban areas were more likely to provide >30% of health care visits virtually (i.e., via telehealth) than were health centers in rural areas. Telehealth is a promising approach to promoting access to care and can facilitate public health mitigation strategies and help prevent transmission of SARS-CoV-2 and other respiratory illnesses, while supporting continuity of care. Although CMS's change of its telehealth provisions enabled health centers to expand telehealth by aligning guidance and leveraging federal resources, sustaining expanded use of telehealth services might require additional policies and resources.