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Objective: To identify the association between insulin out-of-pocket costs (OOPC) and adherence to insulin in Medicare Advantage (MA) patients., Data Sources and Study Setting: The study is based on Optum Labs Data Warehouse, a longitudinal, real-world data asset with de-identified administrative claims and electronic health record data., Study Design: Using descriptive and multivariable logistic regression analyses, we identified the likelihood of patients with diabetes having ≥60 consecutive days between an expected insulin fill date and the actual fill date (refill lapse) by OOPC, categorized by $0, >$0-$20 (reference), >$20-$35, >$35-$50, and > $50 per 30-day supply., Data Collection/extraction Methods: The study included MA enrollees with type 1 or type 2 diabetes and prescription claims for insulin between 2014 and 2018., Principal Findings: Those with average insulin OOPC per 30-day supply >$35 or $0 were more likely to have an insulin refill lapse versus OOPC of >$0 to $20, with odds ratios ranging 1.18 (95% CI 1.13-1.22) to 1.74 (95% CI 1.66-1.83) depending on OOPC group and diabetes type., Conclusions: Capping average insulin OOPC at $35 per 30-day supply may help avoid cost-related insulin non-adherence in MA patients; efforts to address non-cost barriers to medication adherence remain important., (© 2023 The Authors. Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Background: As a result of aging, skeletal muscle undergoes atrophy and a decrease in function. This age-related skeletal muscle weakness is known as "sarcopenia". Sarcopenia is part of the frailty observed in humans. In order to discover treatments for sarcopenia, it is necessary to determine appropriate preclinical models and the genes and signaling pathways that change with age in these models., Methods and Results: To understand the changes in gene expression that occur as a result of aging in skeletal muscles, we generated a multi-time-point gene expression signature throughout the lifespan of mice and rats, as these are the most commonly used species in preclinical research and intervention testing. Gastrocnemius, tibialis anterior, soleus, and diaphragm muscles from male and female C57Bl/6J mice and male Sprague Dawley rats were analyzed at ages 6, 12, 18, 21, 24, and 27 months, plus an additional 9-month group was used for rats. More age-related genes were identified in rat skeletal muscles compared with mice; this was consistent with the finding that rat muscles undergo more robust age-related decline in mass. In both species, pathways associated with innate immunity and inflammation linearly increased with age. Pathways linked with extracellular matrix remodeling were also universally downregulated. Interestingly, late downregulated pathways were exclusively found in the rat limb muscles and these were linked to metabolism and mitochondrial respiration; this was not seen in the mouse., Conclusions: This extensive, side-by-side transcriptomic profiling shows that the skeletal muscle in rats is impacted more by aging compared with mice, and the pattern of decline in the rat may be more representative of the human. The observed changes point to potential therapeutic interventions to avoid age-related decline in skeletal muscle function., (© 2023. The Author(s).)

Monoclonal antibodies can provide important pre- or post-exposure protection against infectious disease for those not yet vaccinated or in individuals that fail to mount a protective immune response after vaccination. Inmazeb (REGN-EB3), a three-antibody cocktail against Ebola virus, lessened disease and improved survival in a controlled trial. Here, we present the cryo-EM structure at 3.1 Å of the Ebola virus glycoprotein, determined without symmetry averaging, in a simultaneous complex with the antibodies in the Inmazeb cocktail. This structure allows the modeling of previously disordered portions of the glycoprotein glycan cap, maps the non-overlapping epitopes of Inmazeb, and illuminates the basis for complementary activities and residues critical for resistance to escape by these and other clinically relevant antibodies. We further provide direct evidence that Inmazeb protects against the rapid emergence of escape mutants, whereas monotherapies even against conserved epitopes do not, supporting the benefit of a cocktail versus a monotherapy approach., Competing Interests: Declaration of interests The Regeneron employees have stock and/or options in the company. C.A.K. is an officer of the company. The antibodies are patented: WO/2016/123019., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The presentation of virus-derived peptides by HLA class I molecules on the surface of an infected cell and the recognition of these HLA-peptide complexes by, and subsequent activation of, CD8 + cytotoxic T cells provides an important mechanism for immune protection against viruses. Recent advances in proteogenomics have allowed researchers to discover a growing number of unique HLA-restricted viral peptides, resulting in a rapidly expanding repertoire of targets for immunotherapeutics (i.e. bispecific antibodies, engineered T-cell receptors (TCRs), chimeric antigen receptor T-cells (CAR-Ts)) to infected tissues. However, genomic variability between viral strains, such as Hepatitis-B virus (HBV), in combination with differences in patient HLA alleles, make it difficult to develop therapeutics against these targets. To address this challenge, we developed a novel proteogenomics approach for generating patient-specific databases that enable the identification of viral peptides based on the viral transcriptomes sequenced from individual patient liver samples. We also utilized DNA sequencing of patient samples to identify HLA genotypes and assist in target selection. Liver samples from 48 HBV infected patients, primarily from Asia, were examined to reconstruct patient-specific HBV genomes, identify regions within the human chromosomes targeted by HBV integrations and obtain a comprehensive view of HBV peptide epitopes using our HLA class-I (HLA-I) immunopeptidomics discovery platform. Two previously reported HLA associated HBV-derived peptides, HLA-A02 binder FLLTRILTI (S 194-202 ) from the large surface antigen and HLA-A11 binder STLPETTVVRR (C 141-151 ) from the capsid protein were validated by our discovery platform, but both were detected at very low frequencies. In addition, we identified and validated, using heavy peptide analogues, novel strain-specific HBV-HLA associated peptides, such as GSLPQEHIVQK (P 606-616 ) and variants. Overall, our novel approach can guide the development of bispecific antibody, TCR-T, or CAR-T based therapeutics for the treatment of HBV-related HCC and inform vaccine development., Competing Interests: Regeneron authors own options and/or stock of the company. The novel proteogenomics method and unique HBV peptides detected in the study have been described in a pending provisional patent application. GA, CK, and WO are officers of Regeneron. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from Regeneron Pharmaceuticals, Inc. Regeneron Pharmaceuticals was involved in the study design, collection, analysis, interpretation of data, and the writing of this article., (Copyright © 2022 Srivastava, Copin, Choy, Zhou, Olsen, Wolf, Shah, Rye-Weller, Chen, Chan, Coppola, Lanza, Negron, Ni, Atwal, Kyratsous, Olson and Salzler.)

Monocytes are highly plastic immune cells that modulate antitumor immunity. Therefore, identifying factors that regulate tumor monocyte functions is critical for developing effective immunotherapies. Here, we determine that endogenous cancer cell-derived type I interferons (IFNs) control monocyte functional polarization. Guided by single-cell transcriptomic profiling of human and mouse tumors, we devise a strategy to distinguish and separate immunostimulatory from immunosuppressive tumor monocytes by surface CD88 and Sca-1 expression. Leveraging this approach, we show that cGAS-STING-regulated cancer cell-derived IFNs polarize immunostimulatory monocytes associated with anti-PD-1 immunotherapy response in mice. We also demonstrate that immunosuppressive monocytes convert into immunostimulatory monocytes upon cancer cell-intrinsic cGAS-STING activation. Consistently, we find that human cancer cells can produce type I IFNs that polarize monocytes, and our immunostimulatory monocyte gene signature is enriched in patient tumors that respond to anti-PD-1 immunotherapy. Our work exposes a role for cancer cell-derived IFNs in licensing monocyte functions that influence immunotherapy outcomes., Competing Interests: Declaration of interests All authors were employees of Regeneron Pharmaceuticals at the time of their contributions. E.O. is now an employee of Bristol Myers Squibb, X.Y. is now an employee of Novartis, and E.M. is now an employee of Calico., (Copyright © 2022. Published by Elsevier Inc.)

BACKGROUND: High out-of-pocket costs (OOPCs) for insulin can lead to cost-related nonadherence and poor outcomes, prompting payers to limit insulin OOPCs. However, data are scarce on whether insulin OOPCs at policy-relevant levels is associated with improved adherence and outcomes. OBJECTIVE: To identify associations between insulin OOPCs and insulin adherence, noninsulin antihyperglycemic (AHG) medication adherence, and diabetes-related emergency department (ED) visits and hospitalizations. METHODS: This retrospective cohort study was conducted using OptumLabs Data Warehouse, a longitudinal, real-world data asset with deidentified administrative claims and electronic health record data. Individuals with type 1 diabetes (T1D) or type 2 diabetes (T2D), insulin use on January 1 of a study year (index date: 2007-2018), continuous commercial health plan eligibility 12 months pre-index and post-index date, and at least 1 insulin claim during the 12-month follow-up period were included. Average insulin OOPCs per 30-day supply in the follow-up period was identified and categorized ($0, > $0-$20 [referent group], > $20-$35, > $35-$50, and > $50). The proportion of patients with a gap in insulin supply of 60 or more continuous days, AHG nonadherence per modified proportion of days covered less than 0.80, and a diabetes-related ED visit or hospitalization were identified and compared by insulin OOPC category vs more than $0 to $20 using pairwise chi-square tests and multivariable logistic regression. RESULTS: The study included 21,085 individuals with T1D and 72,512 with T2D. Patients with average OOPCs more than $50 were more likely to have a gap in insulin supply vs those with OOPCs more than $0 to $20, with an odds ratio (OR) of 1.14 (95% CI =1.05-1.24) and 1.38 (95% CI = 1.32-1.45) for T1D and T2D, respectively. Those with T2D and OOPCs more than $35 were also more likely to have a 60-day gap in insulin supply (OR 1.17; 95% CI = 1.11-1.23). Odds of having a diabetes-related hospitalization or ED visit did not increase with higher OOPCs; rather, associations tended to be inverse. Nonadherence to AHG medications in the T2D cohort was higher with insulin OOPCs more than $20 vs those more than $0-$20 ( P < 0.05 for all). CONCLUSIONS: Individuals with T2D were more likely to have a 60-day gap in insulin supply when the OOPC was more than $35 per 30-day supply and with the OOPC more than $50 in those with T1D. These findings suggest that health plans can facilitate adherence to insulin therapy and possibly to noninsulin AHG medications by protecting patients with diabetes from experiencing high insulin OOPC. A study with a longer follow-up period is warranted to fully assess ED and hospitalization outcomes. DISCLOSURES: This study was funded by the Robert Wood Johnson Foundation, Health Data for Action Research Program. The study sponsor played no role in the design or conduct of this study. The views expressed here do not necessarily reflect the views of the Foundation.

Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting., Competing Interests: Declaration of interests Regeneron authors own options and/or stock of the company. This work has been described in one or more pending provisional patent applications. G.S.A., G.H., D.M.W., L.L., N.S., A.J.M., G.D.Y., and C.A.K. are officers of Regeneron., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

An urgent global quest for effective therapies to prevent and treat coronavirus disease 2019 (COVID-19) is ongoing. We previously described REGN-COV2, a cocktail of two potent neutralizing antibodies (REGN10987 and REGN10933) that targets nonoverlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In this report, we evaluate the in vivo efficacy of this antibody cocktail in both rhesus macaques, which may model mild disease, and golden hamsters, which may model more severe disease. We demonstrate that REGN-COV-2 can greatly reduce virus load in the lower and upper airways and decrease virus-induced pathological sequelae when administered prophylactically or therapeutically in rhesus macaques. Similarly, administration in hamsters limits weight loss and decreases lung titers and evidence of pneumonia in the lungs. Our results provide evidence of the therapeutic potential of this antibody cocktail., (Copyright © 2020, American Association for the Advancement of Science.)

Antibodies targeting the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present a promising approach to combat the coronavirus disease 2019 (COVID-19) pandemic; however, concerns remain that mutations can yield antibody resistance. We investigated the development of resistance against four antibodies to the spike protein that potently neutralize SARS-CoV-2, individually as well as when combined into cocktails. These antibodies remain effective against spike variants that have arisen in the human population. However, novel spike mutants rapidly appeared after in vitro passaging in the presence of individual antibodies, resulting in loss of neutralization; such escape also occurred with combinations of antibodies binding diverse but overlapping regions of the spike protein. Escape mutants were not generated after treatment with a noncompeting antibody cocktail., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Pain disorders affect a large number of individuals throughout the world and are costly. Although randomized clinical trials assess the efficacy (i.e., how well treatments work in controlled settings) of pain pharmacotherapy, clinical trials do not assess effectiveness (i.e., how well treatments work in real-world settings). The number of observational studies that use real-world data to assess the effectiveness of medications is increasing rapidly in many disease areas. It is important for clinicians to understand how real-world data may be used to assess the effectiveness of medications. This paper aims to review the current body of literature assessing the effectiveness of pain pharmacotherapy using medical records. To do this, a literature search was conducted to identify papers published between January 2013 and September 2015 that examined the effectiveness of pain pharmacotherapy using electronic medical records. The search found only three papers meeting these criteria, which were described, reviewed, and critiqued in this paper. Electronic medical records are an underutilized source of data to assess pain outcomes in real-world settings. Although there are many methodological challenges in using these data, there is also great opportunity to impact clinical practice and explore the real-world effectiveness of pharmacotherapy used in pain management.