Bolstering FDA Pathways for Reducing Death and Disease from Tobacco.

This JAMA Forum discusses the US Food and Drug Administration's efforts to implement the 2009 Family Smoking Prevention and Tobacco Control Act through approval of products that demonstrate evidence to help smokers quit and to reduce their risk of relapse.

The potential for artificial intelligence to transform healthcare: perspectives from international health leaders.

Artificial intelligence (AI) has the potential to transform care delivery by improving health outcomes, patient safety, and the affordability and accessibility of high-quality care. AI will be critical to building an infrastructure capable of caring for an increasingly aging population, utilizing an ever-increasing knowledge of disease and options for precision treatments, and combatting workforce shortages and burnout of medical professionals. However, we are not currently on track to create this future. This is in part because the health data needed to train, test, use, and surveil these tools are generally neither standardized nor accessible. There is also universal concern about the ability to monitor health AI tools for changes in performance as they are implemented in new places, used with diverse populations, and over time as health data may change. The Future of Health (FOH), an international community of senior health care leaders, collaborated with the Duke-Margolis Institute for Health Policy to conduct a literature review, expert convening, and consensus-building exercise around this topic. This commentary summarizes the four priority action areas and recommendations for health care organizations and policymakers across the globe that FOH members identified as important for fully realizing AI's potential in health care: improving data quality to power AI, building infrastructure to encourage efficient and trustworthy development and evaluations, sharing data for better AI, and providing incentives to accelerate the progress and impact of AI.

Rapid binding to protofilament edge sites facilitates tip tracking of EB1 at growing microtubule plus-ends.

EB1 is a key cellular protein that delivers regulatory molecules throughout the cell via the tip-tracking of growing microtubule plus-ends. Thus, it is important to understand the mechanism for how EB1 efficiently tracks growing microtubule plus-ends. It is widely accepted that EB1 binds with higher affinity to GTP-tubulin subunits at the growing microtubule tip, relative to GDP-tubulin along the microtubule length. However, it is unclear whether this difference in affinity alone is sufficient to explain the tip-tracking of EB1 at growing microtubule tips. Previously, we found that EB1 binds to exposed microtubule protofilament-edge sites at a ~70 fold faster rate than to closed-lattice sites, due to diffusional steric hindrance to binding. Thus, we asked whether rapid protofilament-edge binding could contribute to efficient EB1 tip tracking. A computational simulation with differential EB1 on-rates based on closed-lattice or protofilament-edge binding, and with EB1 off-rates that were dependent on the tubulin hydrolysis state, robustly recapitulated experimental EB1 tip tracking. To test this model, we used cell-free biophysical assays, as well as live-cell imaging, in combination with a Designed Ankyrin Repeat Protein (DARPin) that binds exclusively to protofilament-edge sites, and whose binding site partially overlaps with the EB1 binding site. We found that DARPin blocked EB1 protofilament-edge binding, which led to a decrease in EB1 tip tracking on dynamic microtubules. We conclude that rapid EB1 binding to microtubule protofilament-edge sites contributes to robust EB1 tip tracking at the growing microtubule plus-end.

Food Is Medicine: A Presidential Advisory From the American Heart Association.

Unhealthy diets are a major impediment to achieving a healthier population in the United States. Although there is a relatively clear sense of what constitutes a healthy diet, most of the US population does not eat healthy food at rates consistent with the recommended clinical guidelines. An abundance of barriers, including food and nutrition insecurity, how food is marketed and advertised, access to and affordability of healthy foods, and behavioral challenges such as a focus on immediate versus delayed gratification, stand in the way of healthier dietary patterns for many Americans. Food Is Medicine may be defined as the provision of healthy food resources to prevent, manage, or treat specific clinical conditions in coordination with the health care sector. Although the field has promise, relatively few studies have been conducted with designs that provide strong evidence of associations between Food Is Medicine interventions and health outcomes or health costs. Much work needs to be done to create a stronger body of evidence that convincingly demonstrates the effectiveness and cost-effectiveness of different types of Food Is Medicine interventions. An estimated 90% of the $4.3 trillion annual cost of health care in the United States is spent on medical care for chronic disease. For many of these diseases, diet is a major risk factor, so even modest improvements in diet could have a significant impact. This presidential advisory offers an overview of the state of the field of Food Is Medicine and a road map for a new research initiative that strategically approaches the outstanding questions in the field while prioritizing a human-centered design approach to achieve high rates of patient engagement and sustained behavior change. This will ideally happen in the context of broader efforts to use a health equity-centered approach to enhance the ways in which our food system and related policies support improvements in health.

Robust microtubule dynamics facilitate low-tension kinetochore detachment in metaphase.

During mitosis, sister chromatids are stretched apart at their centromeres via their attachment to oppositely oriented kinetochore microtubules. This stretching generates inwardly directed tension across the separated sister centromeres. The cell leverages this tension signal to detect and then correct potential errors in chromosome segregation, via a mechanical tension signaling pathway that detaches improperly attached kinetochores from their microtubules. However, the sequence of events leading up to these detachment events remains unknown. In this study, we used microfluidics to sustain and observe low-tension budding yeast metaphase spindles over multiple hours, allowing us to elucidate the tension history prior to a detachment event. We found that, under conditions in which kinetochore phosphorylation weakens low-tension kinetochore-microtubule connections, the mechanical forces produced via the dynamic growth and shortening of microtubules is required to efficiently facilitate detachment events. Our findings underscore the critical role of robust kinetochore microtubule dynamics in ensuring the fidelity of chromosome segregation during mitosis.

Analysis of Lipids, Fatty Acid, and Cholesterol in Membrane Microdomains.

The original concept that lipid and protein components are randomly distributed in cellular membranes has been challenged by evidence of compartmentalization of such components into discrete membrane microdomains (known as lipid rafts). The lipid microdomain hypothesis has generated significant controversy and rigorous inquiry to test the idea that such domains concentrate machinery to mediate cellular processes such as signaling, synaptic plasticity, and endocytosis. As such, a large number of studies have used biochemical, cell biological, and biophysical methodologies to define the composition of membrane microdomains in experimental contexts. Although biochemical preparation strategies are not without limitations (as discussed herein), the isolation of detergent-resistant and detergent-free membrane domains can provide important information about the segregation of lipids and proteins in membranes. In this chapter, we describe methodologies to isolate membranes from cell or tissue sources with biophysical/biochemical properties of membrane microdomains and also provide methods for subsequent classical or mass spectrometry-based lipid analytical approaches.

A Nationwide Analysis of Aneurysmal Subarachnoid Hemorrhage Mortality, Complications, and Health Economics in the USA.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating neurological condition. Endovascular coiling or surgical clipping have equivocal success rates, but relatively little is known regarding the health economics and complications of these procedures at the population level. We aimed to analyze the complication profiles and healthcare resource utilization (HRCU) associated with the treatment of aSAH in the USA. We performed a retrospective analysis utilizing the IBM MarketScan database between 2008 and 2015. Primary outcomes included economic analysis stratified by post-operative complication; determination of the effect of several factors on total cost by multivariable regression; and analysis of the incidence, timing, and associated HCRU of aSAH-related post-operative complications. Of the 2374 patients meeting inclusion criteria for economic analysis, 1783 (75.1%) patients had at least one of the ten complications. The most common complications included hydrocephalus (43.8%), transient cerebral ischemia (including vasospasm) (30.6%), ischemic stroke (29.1%), syndrome of inappropriate antidiuretic hormone (SIADH)/hyposmolarity/hyponatremia (22.1%), and seizures (14.9%). Patients who experienced complications had higher median 90-day total costs [$161,127 (Q1 to Q3, $101,411 to $257,662)] than those who did not [$97,376 (Q1 to Q3, $55,692 to $147,447)]. Length of stay was longest for those with pulmonary embolism and pneumonia (27 days) and shortest for those with SIADH/hyposmolarity/hyponatremia (16 days). Brain compression/herniation had the highest mortality rate (19.5%). In total, 14.6% of all patients experienced a readmission within 30 days. In conclusion, patients with aSAH have high post-operative complication rates and costs. Development of novel interventions to reduce complications and improve outcomes is crucial.

Reforms Needed to Modernize the US Food and Drug Administration's Oversight of Dietary Supplements, Cosmetics, and Diagnostic Tests.

This JAMA Forum discusses long-awaited reforms that could modernize the US Food and Drug Administration's regulatory processes, promote innovation, and provide US consumers greater assurance that the products they use are safe and reliable.

Kinesin-14 motors participate in a force balance at microtubule plus-ends to regulate dynamic instability.

Kinesin-14 molecular motors represent an essential class of proteins that bind microtubules and walk toward their minus-ends. Previous studies have described important roles for Kinesin-14 motors at microtubule minus-ends, but their role in regulating plus-end dynamics remains controversial. Kinesin-14 motors have been shown to bind the EB family of microtubule plus-end binding proteins, suggesting that these minus-end-directed motors could interact with growing microtubule plus-ends. In this work, we explored the role of minus-end-directed Kinesin-14 motor forces in controlling plus-end microtubule dynamics. In cells, a Kinesin-14 mutant with reduced affinity to EB proteins led to increased microtubule lengths. Cell-free biophysical microscopy assays were performed using Kinesin-14 motors and an EB family marker of growing microtubule plus-ends, Mal3, which revealed that when Kinesin-14 motors bound to Mal3 at growing microtubule plus-ends, the motors subsequently walked toward the minus-end, and Mal3 was pulled away from the growing microtubule tip. Strikingly, these interactions resulted in an approximately twofold decrease in the expected postinteraction microtubule lifetime. Furthermore, generic minus-end-directed tension forces, generated by tethering growing plus-ends to the coverslip using λ-DNA, led to an approximately sevenfold decrease in the expected postinteraction microtubule growth length. In contrast, the inhibition of Kinesin-14 minus-end-directed motility led to extended tip interactions and to an increase in the expected postinteraction microtubule lifetime, indicating that plus-ends were stabilized by nonmotile Kinesin-14 motors. Together, we find that Kinesin-14 motors participate in a force balance at microtubule plus-ends to regulate microtubule lengths in cells.

Understanding Use of Real-World Data and Real-World Evidence to Support Regulatory Decisions on Medical Product Effectiveness.

RWE has potential to provide efficient and relevant information on the effectiveness of medical products, complementing the data generated in clinical trials; however, how RWE can support regulatory decision-making is unclear, potentially limiting its use. The objective of this study was to identify and characterize instances where RWE was included in the evidence package to support the effectiveness of a medical product regulated by U.S. Food and Drug Administration. A retrospective landscape analysis was conducted to identify instances where RWE was submitted to support effectiveness through targeted review of white and gray literature and publicly available FDA reviews of medical products. Trained evaluators examined FDA reviews to determine if and how RWE contributed to regulatory decision-making regarding effectiveness. Evaluators identified 34 instances of RWE submitted between 1954 and 2020, where 26% of instances were for oncology, 18% for hematology, and 12% for neurology. Over 50% of the products were indicated for use in rare disease or pediatric populations. 82% of products where RWE was submitted received an orphan designation. RWE was included in the product label in 59% of instances. Stated reasons indicating why submitted RWE did not significantly contribute to regulatory decision-making included lack of pre-specification of study design and analysis as well as data reliability and relevancy concerns. While there is historical use of RWE to support medical product effectiveness for oncology and rare diseases, potential exists to leverage the strengths of RWE to support other therapeutic areas and capture outcomes that are most relevant to patients.

Oxidative stress pathogenically remodels the cardiac myocyte cytoskeleton via structural alterations to the microtubule lattice.

In the failing heart, the cardiac myocyte microtubule network is remodeled, which contributes to cellular contractile failure and patient death. However, the origins of this deleterious cytoskeletal reorganization are unknown. We now find that oxidative stress, a condition characteristic of heart failure, leads to cysteine oxidation of microtubules. Our electron and fluorescence microscopy experiments revealed regions of structural damage within the microtubule lattice that occurred at locations of oxidized tubulin. The incorporation of GTP-tubulin into these damaged, oxidized regions led to stabilized "hot spots" within the microtubule lattice, which suppressed the shortening of dynamic microtubules. Thus, oxidative stress may act inside of cardiac myocytes to facilitate a pathogenic shift from a sparse microtubule network into a dense, aligned network. Our results demonstrate how a disease condition characterized by oxidative stress can trigger a molecular oxidation event, which likely contributes to a toxic cellular-scale transformation of the cardiac myocyte microtubule network.

State variation in effects of state social distancing policies on COVID-19 cases.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) sickened over 20 million residents in the United States (US) by January 2021. Our objective was to describe state variation in the effect of initial social distancing policies and non-essential business (NEB) closure on infection rates early in 2020. METHODS: We used an interrupted time series study design to estimate the total effect of all state social distancing orders, including NEB closure, shelter-in-place, and stay-at-home orders, on cumulative COVID-19 cases for each state. Data included the daily number of COVID-19 cases and deaths for all 50 states and Washington, DC from the New York Times database (January 21 to May 7, 2020). We predicted cumulative daily cases and deaths using a generalized linear model with a negative binomial distribution and a log link for two models. RESULTS: Social distancing was associated with a 15.4% daily reduction (Relative Risk = 0.846; Confidence Interval [CI] = 0.832, 0.859) in COVID-19 cases. After 3 weeks, social distancing prevented nearly 33 million cases nationwide, with about half (16.5 million) of those prevented cases among residents of the Mid-Atlantic census division (New York, New Jersey, Pennsylvania). Eleven states prevented more than 10,000 cases per 100,000 residents within 3 weeks. CONCLUSIONS: The effect of social distancing on the infection rate of COVID-19 in the US varied substantially across states, and effects were largest in states with highest community spread.

Association of ACO Shared Savings Success and Serious Illness Spending.

EXECUTIVE SUMMARY: Accountable care organizations (ACOs) need confidence in their return on investment to implement changes in care delivery that prioritize seriously ill and high-cost Medicare beneficiaries. The objective of this study was to characterize spending on seriously ill beneficiaries in ACOs with Medicare Shared Savings Program (MSSP) contracts and the association of spending with ACO shared savings. The population included Medicare fee-for-service beneficiaries identified with serious illness (N = 2,109,573) using the Medicare Master Beneficiary Summary File for 100% of ACO-attributed beneficiaries linked to MSSP beneficiary files (2014-2016). Lower spending for seriously ill Medicare beneficiaries and risk-bearing contracts in ACOs were associated with achieving ACO shared savings in the MSSP. For most ACOs, the seriously ill contribute approximately half of the spending and constitute 8%-13% of the attributed population. Patient and geographic (county) factors explained $2,329 of the observed difference in per beneficiary per year spending on seriously ill beneficiaries between high- and low-spending ACOs. The remaining $12,536 may indicate variation as a result of potentially modifiable factors. Consequently, if 10% of attributed beneficiaries were seriously ill, an ACO that moved from the worst to the best quartile of per capita serious illness spending could realize a reduction of $1,200 per beneficiary per year for the ACO population overall. Though the prevalence and case mix of seriously ill populations vary across ACOs, this association suggests that care provided for seriously ill patients is an important consideration for ACOs to achieve MSSP shared savings.

Hospital-level compliance with the commission on cancer's quality of care measures and the association with patient survival.

BACKGROUND: Quality measurement has become a priority for national healthcare reform, and valid measures are necessary to discriminate hospital performance and support value-based healthcare delivery. The Commission on Cancer (CoC) is the largest cancer-specific accreditor of hospital quality in the United States and has implemented Quality of Care Measures to evaluate cancer care delivery. However, none has been formally tested as a valid metric for assessing hospital performance based on actual patient outcomes. METHODS: Eligibility and compliance with the Quality of Care Measures are reported within the National Cancer Database, which also captures data for robust patient-level risk adjustment. Hospital-level compliance was calculated for the core measures, and the association with patient survival was tested using Cox regression. RESULTS: Seven hundred sixty-eight thousand nine hundred sixty-nine unique cancer cases were included from 1323 facilities. Increasing hospital-level compliance was associated with improved survival for only two measures, including a 35% reduced risk of mortality for the gastric cancer measure G15RLN (HR 0.65, 95% CI 0.58-0.72) and a 19% reduced risk of mortality for the colon cancer measure 12RLN (HR 0.81, 95% CI 0.77-0.85). For the lung cancer measure LNoSurg, increasing compliance was paradoxically associated with an increased risk of mortality (HR 1.14, 95% CI 1.08-1.20). For the remaining measures, hospital-level compliance demonstrated no consistent association with patient survival. CONCLUSION: Hospital-level compliance with the CoC's Quality of Care Measures is not uniformly aligned with patient survival. In their current form, these measures do not reliably discriminate hospital performance and are limited as a tool for value-based healthcare delivery.

Vital Directions For Health And Health Care: Priorities For 2021.

In 2016, in anticipation of the US presidential election and forthcoming new administration, the National Academy of Medicine launched a strategic initiative to marshal expert guidance on pressing health and health care priorities. Published as Vital Directions for Health and Health Care, the products of the initiative provide trusted, nonpartisan, evidence-based analysis of critical issues in health, health care, and biomedical science. The current collection of articles published in Health Affairs builds on the initial Vital Directions series by addressing a set of issues that have a particularly compelling need for attention from the next administration: health costs and financing, early childhood and maternal health, mental health and addiction, better health and health care for older adults, and infectious disease threats. The articles also reflect the current experience with both the coronavirus disease 2019 (COVID-19) pandemic and the health inequities that have been drawn out sharply by COVID-19, as well as the implications going forward for action.