Integrated Devices: A New Regulatory Pathway to Promote Revolutionary Innovation.

Policy Points Current medical device regulatory frameworks date back half a century and are ill suited for the next generation of medical devices that involve a significant software component. Existing Food and Drug Administration efforts are insufficient because of a lack of statutory authority, whereas international examples offer lessons for improving and harmonizing domestic medical device regulatory policy. A voluntary alternative pathway built upon two-stage review with individual component review followed by holistic review for integrated devices would provide regulators with new tools to address a changing medical device marketplace.

Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library.

The ß2-adrenergic receptor (ß2AR) has been a model system for understanding regulatory mechanisms of G-protein-coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known ß-adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human ß2AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 [([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide], exhibiting a unique chemotype and low micromolar affinity for the ß2AR. Binding of 15 to the receptor cooperatively enhances orthosteric inverse agonist binding while negatively modulating binding of orthosteric agonists. Studies with a specific antibody that binds to an intracellular region of the ß2AR suggest that 15 binds in proximity to the G-protein binding site on the cytosolic surface of the ß2AR. In cell-signaling studies, 15 inhibits cAMP production through the ß2AR, but not that mediated by other Gs-coupled receptors. Compound 15 also similarly inhibits ß-arrestin recruitment to the activated ß2AR. This study presents an allosteric small-molecule ligand for the ß2AR and introduces a broadly applicable method for screening DNA-encoded small-molecule libraries against purified GPCR targets. Importantly, such an approach could facilitate the discovery of GPCR drugs with tailored allosteric effects.

Using artificial intelligence to improve administrative process in Medicaid.

Administrative burden across state-federal benefits programs is unsustainable, and artificial intelligence (AI) and associated technologies have emerged and resulted in significant interest as possible solutions. While early in development, AI has significant potential to reduce administrative waste and increase efficiency, with many government agencies and state legislators eager to adopt the new technology. Turning to existing frameworks defining what functions are considered "inherently governmental" can help determine where more autonomous implementation could be not only appropriate but also provide unique advantages. Such areas could include eligibility and redetermination of Medicaid eligibility as well as preventing improper Medicaid payments. However, while AI is promising, this technology may not be ready for fully autonomous implementation and instead could be deployed to augment human capabilities with robust safeguards until it has proven to be more reliable. In the meantime, the Centers for Medicare and Medicaid Services should release clear guidance around the use of AI by state Medicaid programs, and policymakers must work together to harness AI technologies in order to improve the efficiency and effectiveness of the Medicaid program.

Patient Flow and Reutilization of Crisis Services Within 30 Days in a Comprehensive Crisis System.

OBJECTIVE: Crisis services are undergoing an unprecedented expansion in the United States, but research is lacking on crisis system design. This study describes how individuals flow through a well-established crisis system and examines factors associated with reutilization of such services. METHODS: This cross-sectional study used Medicaid claims to construct episodes describing the flow of individuals through mobile crisis, specialized crisis facility, emergency department, and inpatient services. Claims data were merged with electronic health record (EHR) data for the subset of individuals receiving care at a crisis response center. A generalized estimating equation was used to calculate adjusted odds ratios for demographic, clinical, and operational factors associated with reutilization of services within 30 days of an episode's end point. RESULTS: Of 41,026 episodes, most (57.4%) began with mobile crisis services or a specialized crisis facility rather than the emergency department. Of the subset (N=9,202 episodes) with merged EHR data, most episodes (63.3%) were not followed by reutilization. Factors associated with increased odds of 30-day reutilization included Black race, homelessness, stimulant use, psychosis, and episodes beginning with mobile crisis services or ending with inpatient care. Decreased odds were associated with depression, trauma, and involuntary legal status. Most (59.3%) episodes beginning with an involuntary legal status ended with a voluntary status. CONCLUSIONS: Crisis systems can serve a large proportion of individuals experiencing psychiatric emergencies and divert them from more restrictive and costly levels of care. Understanding demographic, clinical, and operational factors associated with 30-day reutilization may aid in the design and implementation of crisis systems.

Bone marrow stromal cell-derived hepcidin has antimicrobial and immunomodulatory activities.

Bone marrow stromal cells (BMSCs) have immunomodulatory activities in numerous species and have been used in clinical trials. BMSCs also make antibacterial agents. Since hepcidin is known to have antimicrobial effects in fish, we wondered if it might also be used as an antimicrobial agent by mammalian BMSCs. In the present study, we show hepcidin expression in both mouse (mBMSC) and human BMSCs (hBMSC). We observed a hBMSC hepcidin-dependent degradation of ferroportin in HEK-293 reporter cells in vitro. In human and mouse bone marrows (BM) we detected hepcidin-positive BMSCs in close proximity to hematopoietic progenitors. The conditioned culture medium of hBMSCs significantly reduced bacterial proliferation that was partially blocked by a hepcidin-neutralizing antibody. Similarly, medium in which hepcidin-deficient (Hamp-/-) mouse BMSCs had been grown was significantly less effective in reducing bacterial counts than the medium of wild-type cells. In a zymosan-induced peritonitis mouse model we found that mBMSC-derived hepcidin reduced the number of invading polymorphonuclear (PMN) cells in the peritoneal cavity. Our results show that BMSC-derived hepcidin has antimicrobial properties in vitro and also reduces inflammation in vivo. We conclude that hepcidin should be added to the expanding arsenal of agents available to BMSCs to fight infections and inflammation.

Data-driven, client-centric applied behavior analysis treatment-dose optimization improves functional outcomes.

BACKGROUND: With increasing numbers of individuals diagnosed with autism spectrum disorder (ASD) and with affirmation of applied behavior analysis (ABA) as an evidence-based standard of care for ASD, there has been a proliferation of agencies offering ABA services over the last several decades. Disagreement exists among ABA providers and health plans that reimburse those providers on the optimal number of hours of ABA services that should be reimbursed. This study aims to understand whether children who receive more hours of ABA therapy achieve better outcomes and to evaluate the impact of the COVID-19-induced shift to telehealth clinical supervision on outcomes. METHODS: A retrospective cohort analysis was performed using data from the Vineland 3 Comprehensive Interview Form to assess function throughout ABA treatment. Paired sample t tests, independent sample t tests, Cohen's D, and Pearson correlations were used to determine relationships between Vineland scores and input variables including hours of service and modality of supervision (in-person vs. telehealth). RESULTS: While statistically and clinically significant improvements in function were observed, children appear to have improved outcomes independent of the number of hours of service received. There were also no significant associations between modality of supervision and Vineland standard scores. CONCLUSIONS: These findings challenge prior research that demonstrated a linear dose-response relationship. By tailoring treatment dosage to the individual client's needs, providers may be able to better maximize functional progress of the client, to preserve family time, and to utilize health plan dollars more efficiently.