CBP Regulates Recruitment and Release of Promoter-Proximal RNA Polymerase II.

Transcription activation involves RNA polymerase II (Pol II) recruitment and release from the promoter into productive elongation, but how specific chromatin regulators control these steps is unclear. Here, we identify a novel activity of the histone acetyltransferase p300/CREB-binding protein (CBP) in regulating promoter-proximal paused Pol II. We find that Drosophila CBP inhibition results in "dribbling" of Pol II from the pause site to positions further downstream but impedes transcription through the +1 nucleosome genome-wide. Promoters strongly occupied by CBP and GAGA factor have high levels of paused Pol II, a unique chromatin signature, and are highly expressed regardless of cell type. Interestingly, CBP activity is rate limiting for Pol II recruitment to these highly paused promoters through an interaction with TFIIB but for transit into elongation by histone acetylation at other genes. Thus, CBP directly stimulates both Pol II recruitment and the ability to traverse the first nucleosome, thereby promoting transcription of most genes.

Association of Medicare Advantage Enrollment With Financial Burden of Care : A Retrospective Cohort Study.

BACKGROUND: Compared with traditional Medicare (TM), Medicare Advantage (MA) plans typically offer supplemental benefits and lower copayments for in-network services and must include an out-of-pocket spending limit. OBJECTIVE: To examine whether the financial burden of care decreased for persons switching from TM to MA (TM-to-MA switchers) relative to those remaining in TM (TM stayers). DESIGN: Retrospective longitudinal cohort study comparing changes in financial outcomes between TM-to-MA switchers and TM stayers. SETTING: Population-based. PARTICIPANTS: 7054 TM stayers and 1544 TM-to-MA switchers from the Medical Expenditure Panel Survey, 2014 to 2021. MEASUREMENTS: Individual health care costs (out-of-pocket spending and cost sharing), financial burden (high and catastrophic), and subjective financial hardship (difficulty paying medical bills, paying medical bills over time, and inability to pay medical bills). RESULTS: Compared with TM stayers, TM-to-MA switchers had small differences in out-of-pocket spending ($168 [95% CI, -$133 to $469]) and proportions of total health expenses paid out of pocket (cost sharing) (0.2 percentage point [CI, -1.3 to 1.7 percentage points]), families with out-of-pocket spending greater than 20% of their income (high financial burden) (0.3 percentage point [CI, -2.5 to 3.0 percentage points]), families reporting out-of-pocket spending greater than 40% of their income (catastrophic financial burden) (0.7 percentage point [CI, -0.1 to 1.6 percentage points]), families reporting paying medical bills over time (-0.2 percentage point [CI, -1.7 to 1.4 percentage points]), families having problems paying medical bills (-0.4 percentage point [CI, -2.7 to 1.8 percentage points]), and families reporting being unable to pay medical bills (0.4 percentage point [CI, -1.3 to 2.0 percentage points]). LIMITATION: Inability to account for all medical care and cost needs and variations across MA plans, small baseline differences in out-of-pocket spending, and potential residual confounding. CONCLUSION: Differences in financial outcomes between beneficiaries who switched from TM to MA and those who stayed with TM were small. Differences in financial burden ranged across outcomes and did not have a consistent pattern. PRIMARY FUNDING SOURCE: The National Research Foundation of Korea.

Health Care Spending, Use, and Financial Hardship Among Traditional Medicare and Medicare Advantage Enrollees With Mental Health Symptoms.

OBJECTIVE: We examined the differences in health care spending and utilization, and financial hardship between Traditional Medicare (TM) and Medicare Advantage (MA) enrollees with mental health symptoms. DESIGN: Cross-sectional study. PARTICIPANTS: We identified Medicare beneficiaries with mental health symptoms using the Patient Health Questionnaire-2 and the Kessler-6 Psychological Distress Scale in the 2015-2021 Medical Expenditure Panel Survey. MEASUREMENTS: Outcomes included health care spending and utilization (both general and mental health services), and financial hardship. The primary independent variable was MA enrollment. RESULTS: MA enrollees with mental health symptoms were 2.3 percentage points (95% CI: -3.4, -1.2; relative difference: 16.1%) less likely to have specialty mental health visits than TM enrollees with mental health symptoms. There were no significant differences in total health care spending, but annual out-of-pocket spending was $292 (95% CI: 152-432; 18.2%) higher among MA enrollees with mental health symptoms than TM enrollees with mental health symptoms. Additionally, MA enrollees with mental health symptoms were 5.0 (95% CI: 2.9-7.2; 22.3%) and 2.5 percentage points (95% CI: 0.8-4.2; 20.9%) more likely to have difficulty paying medical bills over time and to experience high financial burden than TM enrollees with mental health symptoms. CONCLUSION: Our findings suggest that MA enrollees with mental health symptoms were more likely to experience limited access to mental health services and high financial hardship compared to TM enrollees with mental health symptoms. There is a need to develop policies aimed at improving access to mental health services while reducing financial burden for MA enrollees.

Social Risk and Dialysis Facility Performance in the First Year of the ESRD Treatment Choices Model.

Importance: The End-Stage Renal Disease Treatment Choices (ETC) model randomly selected 30% of US dialysis facilities to receive financial incentives based on their use of home dialysis, kidney transplant waitlisting, or transplant receipt. Facilities that disproportionately serve populations with high social risk have a lower use of home dialysis and kidney transplant raising concerns that these sites may fare poorly in the payment model. Objective: To examine first-year ETC model performance scores and financial penalties across dialysis facilities, stratified by their incident patients' social risk. Design, Setting, and Participants: A cross-sectional study of 2191 US dialysis facilities that participated in the ETC model from January 1 through December 31, 2021. Exposure: Composition of incident patient population, characterized by the proportion of patients who were non-Hispanic Black, Hispanic, living in a highly disadvantaged neighborhood, uninsured, or covered by Medicaid at dialysis initiation. A facility-level composite social risk score assessed whether each facility was in the highest quintile of having 0, 1, or at least 2 of these characteristics. Main Outcomes and Measures: Use of home dialysis, waitlisting, or transplant; model performance score; and financial penalization. Results: Using data from 125 984 incident patients (median age, 65 years [IQR, 54-74]; 41.8% female; 28.6% Black; 11.7% Hispanic), 1071 dialysis facilities (48.9%) had no social risk features, and 491 (22.4%) had 2 or more. In the first year of the ETC model, compared with those with no social risk features, dialysis facilities with 2 or more had lower mean performance scores (3.4 vs 3.6, P = .002) and lower use of home dialysis (14.1% vs 16.0%, P < .001). These facilities had higher receipt of financial penalties (18.5% vs 11.5%, P < .001), more frequently had the highest payment cut of 5% (2.4% vs 0.7%; P = .003), and were less likely to achieve the highest bonus of 4% (0% vs 2.7%; P < .001). Compared with all other facilities, those in the highest quintile of treating uninsured patients or those covered by Medicaid experienced more financial penalties (17.4% vs 12.9%, P = .01) as did those in the highest quintile in the proportion of patients who were Black (18.5% vs 12.6%, P = .001). Conclusions: In the first year of the Centers for Medicare & Medicaid Services' ETC model, dialysis facilities serving higher proportions of patients with social risk features had lower performance scores and experienced markedly higher receipt of financial penalties.

The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2.

The kinase mTOR has emerged as an important regulator of the differentiation of helper T cells. Here we demonstrate that differentiation into the T(H)1 and T(H)17 subsets of helper T cells was selectively regulated by signaling from mTOR complex 1 (mTORC1) that was dependent on the small GTPase Rheb. Rheb-deficient T cells failed to generate T(H)1 and T(H)17 responses in vitro and in vivo and did not induce classical experimental autoimmune encephalomyelitis (EAE). However, they retained their ability to become T(H)2 cells. Alternatively, when mTORC2 signaling was deleted from T cells, they failed to generate T(H)2 cells in vitro and in vivo but preserved their ability to become T(H)1 and T(H)17 cells. Our data identify mechanisms by which two distinct signaling pathways downstream of mTOR regulate helper cell fate in different ways. These findings define a previously unknown paradigm that links T cell differentiation with selective metabolic signaling pathways.

Medicare Advantage Enrollment Among Beneficiaries With End-Stage Renal Disease in the First Year of the 21st Century Cures Act.

Importance: Before 2021, most Medicare beneficiaries with end-stage renal disease (ESRD) were unable to enroll in private Medicare Advantage (MA) plans. The 21st Century Cures Act permitted these beneficiaries to enroll in MA plans effective January 2021. Objective: To examine changes in MA enrollment among Medicare beneficiaries with ESRD after enactment of the 21st Century Cures Act overall and by race or ethnicity and dual-eligible status. Design, Setting, and Participants: This cross-sectional time-trend study used data from Medicare beneficiaries with ESRD (both kidney transplant recipients and those undergoing dialysis) between January 2019 and December 2021. Data were analyzed between June and October 2022. Exposures: 21st Century Cures Act. Main Outcomes and Measures: Primary outcomes were the proportion of Medicare beneficiaries with prevalent ESRD who switched from traditional Medicare to MA between 2020 and 2021 and those with incident ESRD who newly enrolled in MA in 2021. Individuals who stayed in traditional Medicare were enrolled in 2020 and 2021 and those who switched to MA were enrolled in traditional Medicare in 2020 and MA in 2021. Results: Among 575 797 beneficiaries with ESRD in 2020 or 2021 (mean [SD] age, 64.7 [14.2] years, 42.2% female, 34.0% Black, and 7.7% Hispanic or Latino), the proportion of beneficiaries enrolled in MA increased from 24.8% (December 2020) to 37.4% (December 2021), a relative change of 50.8%. The largest relative increases in MA enrollment were among Black (72.8% relative increase), Hispanic (44.8%), and dual-eligible beneficiaries with ESRD (73.6%). Among 359 617 beneficiaries with TM and prevalent ESRD in 2020, 17.6% switched to MA in 2021. Compared with individuals who stayed in traditional Medicare, those who switched to MA had modestly more chronic conditions (6.3 vs 6.1; difference, 0.12 conditions [95% CI, 0.10-0.16]) and similar nondrug spending in 2020 (difference, $509 [95% CI, -$58 to $1075]) but were more likely to be Black (difference, 19.5 percentage points [95% CI, 19.1-19.9]) and have dual Medicare-Medicaid eligibility (difference, 20.8 percentage points [95% CI, 20.4-21.2]). Among beneficiaries who were newly eligible for Medicare ESRD benefits in 2021, 35.2% enrolled in MA. Conclusions and Relevance: Results suggest that increases in MA enrollment among Medicare beneficiaries with ESRD were substantial the first year after the 21st Century Cures Act, particularly among Black, Hispanic, and dual-eligible individuals. Policy makers and MA plans may need to assess network adequacy, disenrollment, and equity of care for beneficiaries who enrolled in MA.

Legislative and Regulatory Options for Improving Medicare Advantage.

The Medicare Advantage program was created to expand beneficiary choice and to reduce spending through capitated payment to private insurers. However, many stakeholders now argue that Medicare Advantage is failing to deliver on its promise to reduce spending. Three problematic design features in Medicare Advantage payment policy have received particular scrutiny: (1) how baseline payments to insurers are determined, (2) how variation in patient risk affects insurer payment, and (3) how payments to insurers are adjusted for quality performance. The authors analyze the statute underlying these three design features and explore legislative and regulatory strategies for improving Medicare Advantage. They conclude that regulatory approaches for improving risk adjustment and for recouping overpayments from risk-score gaming have the highest potential impact and are the most feasible improvement measures to implement.

Medicare Advantage Chart Reviews Are Associated With Billions in Additional Payments for Some Plans.

BACKGROUND: In the Medicare Advantage (MA) program, private plans receive capitated payments that are adjusted based on their enrollees' number and type of clinical conditions. Plans have the ability to review charts to identify additional conditions that are not present in claims data, thereby increasing risk-adjusted payments. Recently the Government Accountability Office released a report raising concerns about the use of these chart reviews as a potential tool for upcoding. OBJECTIVES: To measure the extent to which plans receive additional payments for chart reviews, and the variation in chart reviews across plans. RESEARCH DESIGN: In this cross-sectional study we use 2015 MA Encounter data to calculate how many additional diagnoses codes were added for each enrollee using chart reviews. We then calculate how these additional diagnosis codes translate to additional reimbursements across plans. SUBJECTS: A total of 14,021,692 beneficiaries enrolled in 510 MA contracts in 2015. MEASURES: Individual and contract level hierarchical condition category codes, total plan reimbursement. RESULTS: Chart reviews were associated with a $2.3 billion increase in payments to plans, a 3.7% increase in Medicare spending to MA plans. Just 10% of plans accounted for 42% of the $2.3 billion in additional spending attributed to chart review. Among these plans, the relative increase in risk score from chart review was 17.2%. For-profit plans engaged in chart reviews substantially more frequently than nonprofit plans. CONCLUSIONS: Given the substantial and highly variable increase in payments attributable to chart review, further investigation of the validity of this practice and its implications for Medicare spending is needed.

Understanding the Relationship Between Nursing Home Experience With Human Immunodeficiency Virus and Patient Outcomes.

BACKGROUND: As the population with human immunodeficiency virus (HIV) continues to age, the need for nursing home (NH) care is increasing. OBJECTIVES: To assess whether NH's experience in treating HIV is related to outcomes. RESEARCH DESIGN: We used claims and assessment data to identify individuals with and without HIV who were admitted to NHs in 9 high HIV prevalent states. We classified NHs into HIV experience categories and estimate the effects of NH HIV experience on patient's outcomes. We applied an instrumental variable using distances between each individual's residence and NHs with different HIV experience. SUBJECTS: In all, 5,929,376 admissions for those without HIV and 53,476 admissions for residents with HIV. MEASURES: Our primary outcomes were 30-day hospital readmissions, likelihood of becoming a long stay resident, and 180-day mortality posthospital discharge. RESULTS: Residents with HIV tended to have poorer outcomes than residents without HIV, regardless of the NH they were admitted to. Residents with HIV admitted to high HIV experience NHs were more likely to be readmitted to the hospital than those admitted to NHs with lower HIV experience (19.6% in 0% HIV NHs, 18.7% in 05% HIV NHs and 22.9% in 5%-50% HIV NHs). CONCLUSIONS: Residents with HIV experience worse outcomes in NHs than residents without HIV. Increased HIV experience was not related to improved outcomes.

Comparing Receipt of Prescribed Post-acute Home Health Care Between Medicare Advantage and Traditional Medicare Beneficiaries: an Observational Study.

BACKGROUND: Medicare Advantage (MA) covers more than 1/3rd of all Medicare beneficiaries. MA plans are required to provide the same benefits as Traditional Medicare (TM), but can impose utilization management tools to control costs. OBJECTIVE: To assess differences between TM and MA enrollees in the probability of receiving prescribed post-acute home health (HH) care and to describe MA plan characteristics associated with HH receipt. DESIGN: Retrospective cross-sectional analysis of claims data, HH patient assessment data, and MA plan data from 2011 to 2017. PARTICIPANTS: Medicare beneficiaries aged 66 and older with an incident hospitalization for joint replacement, pneumonia, chronic obstructive pulmonary disease, stroke, urinary tract infection, septicemia, acute renal failure, or congestive heart failure. MAIN MEASURES: Receipt of prescribed HH as indicated by a HH discharge code and corresponding HH patient assessment within 14 days of hospital discharge. KEY RESULTS: There were 2,723,245 beneficiaries prescribed HH at discharge (68% TM, 32% MA). About 75% of TM enrollees and 62% of MA enrollees received prescribed post-acute HH. In adjusted analyses, MA enrollees had an -11.7 percentage point (pp) (95% confidence interval (CI): -16.8, -6.5) lower probability of receiving HH compared with TM enrollees. In adjusted analyses, HMO enrollees in plans with cost sharing (- 8.4 pp; 95% CI: - 14.3, - 2.5), referrals (- 3.7 pp; 95% CI: - 6.1, - 1.2), and pre-authorization (- 5.1 pp; 95% CI: - 8.3, - 2.0) were less likely to receive prescribed HH. In adjusted analyses, PPO enrollees in plans with cost sharing were -7.0 pp (95% CI: - 12.7, - 1.4) less likely to receive HH, but there was no difference for those with referrals (1.1 pp; 95% CI, - 1.5, 3.7) or pre-authorization (1.6 pp; 95% CI: - 0.6, - 3.9). CONCLUSIONS: Among Medicare beneficiaries, MA enrollees were less likely to receive prescribed post-acute HH compared with TM. As enrollment in MA continues to grow, it is important to examine how differences in utilization relate to outcomes.

The Relationship Between Medicare Advantage Star Ratings and Enrollee Experience.

BACKGROUND: Medicare Advantage plans, private managed care plans that enrolled 34% of Medicare beneficiaries in 2019, received $6 billion in annual bonus payments on the basis of their performance on a 5-star rating system. Little is known, however, as to the extent these ratings adequately capture enrollee experience. OBJECTIVES: To measure the effect of exposure to higher rated Medicare Advantage contracts on enrollee experience. DESIGN: An instrumental variables analysis using MA contract consolidation as an exogenous shock to the quality of plan enrollees are exposed to. PARTICIPANTS: A total of 345,897 MA enrollees enrolled in non-consolidated contracts and 21,405 enrollees who were consolidated. MAIN MEASURES: The primary exposure was enrollee star rating, instrumented using contract consolidation. The primary outcomes were enrollee self-reported experience measures. KEY RESULTS: There were no significant effects on increased star ratings on 23 of 27 outcomes. A one-star increase in contract star rating leads to a 5.4 percentage point increase in reporting that pain does not interfere with daily activities (95%CI 2.4, 8.4), and a 4.4 percentage reduction in the likelihood that a physician would talk to the enrollee about physical activity (95%CI: -7.8, -1.1, all p<0.05). A one-star increase in contract star rating led to an 8.4 percentage point reduction in achieving the top score on the received needed information index (95%CI: -16.4, -0.4), and a 1.8 percentage point reduction in responding with the lowest score for the overall rating of care (95%CI: -3.5, -0.1). CONCLUSIONS: Exposure to a higher rated MA contract did not appreciably increase enrollee experience. Policymakers should consider reassessing how these ratings and associated bonus payments are currently calculated.

Association of Race and Ethnicity and Medicare Program Type With Ambulatory Care Access and Quality Measures.

Importance: There are racial inequities in health care access and quality in the United States. It is unknown whether such differences for racial and ethnic minority beneficiaries differ between Medicare Advantage and traditional Medicare or whether access and quality are better for minority beneficiaries in 1 of the 2 programs. Objective: To compare differences in rates of enrollment, ambulatory care access, and ambulatory care quality by race and ethnicity in Medicare Advantage vs traditional Medicare. Design, Setting, and Participants: Exploratory observational cohort study of a nationally representative sample of 45 833 person-years (26 887 persons) in the Medicare Current Beneficiary Survey from 2015 to 2018, comparing differences in program enrollment and measures of access and quality by race and ethnicity. Exposures: Minority race and ethnicity (Black, Hispanic, Native American, or Asian/Pacific Islander) vs White or multiracial; Medicare Advantage vs traditional Medicare enrollment. Main Outcomes and Measures: Six patient-reported measures of ambulatory care access (whether a beneficiary had a usual source of care in the past year, had a primary care clinician usual source of care, or had a specialist visit) and quality (influenza vaccination, pneumonia vaccination, and colon cancer screening). Results: The final sample included 6023 persons (mean age, 68.9 [SD, 12.6] years; 57.3% women) from minority groups and 20 864 persons (mean age, 71.9 [SD, 10.8] years; 54.9% women) from White or multiracial groups, who accounted for 9816 and 36 017 person-years, respectively. Comparing Medicare Advantage vs traditional Medicare among minority beneficiaries, those in Medicare Advantage had significantly better rates of access to a primary care clinician usual source of care (79.1% vs 72.5%; adjusted marginal difference, 4.0%; 95% CI, 1.0%-6.9%), influenza vaccinations (67.3% vs 63.0%; adjusted marginal difference, 5.2%; 95% CI, 1.9%-8.5%), pneumonia vaccinations (70.7% vs 64.6%; adjusted marginal difference, 6.1%; 95% CI, 2.7%-9.4%), and colon cancer screenings (69.4% vs 61.1%; adjusted marginal difference, 7.1%; 95% CI, 3.8%-10.3%). Comparing minority vs White or multiracial beneficiaries across both programs, minority beneficiaries had significantly lower rates of access to a primary care clinician usual source of care (adjusted marginal difference, 4.7%; 95% CI, 2.5%-6.8%), specialist visits (adjusted marginal difference, 10.8%; 95% CI, 8.3%-13.3%), influenza vaccinations (adjusted marginal difference, 4.3%; 95% CI, 1.2%-7.4%), and pneumonia vaccinations (adjusted marginal difference, 6.4%; 95% CI, 3.9%-9.0%). The interaction of race and ethnicity with insurance type was not statistically significant for any of the 6 outcome measures. Conclusions and Relevance: In this exploratory study of Medicare beneficiaries in 2015-2018, enrollment in Medicare Advantage vs traditional Medicare was significantly associated with better outcomes for access and quality among minority beneficiaries; however, minority beneficiaries were significantly more likely to experience worse outcomes for most access and quality measures than White or multiracial beneficiaries in both programs.

Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP.

p300 and CBP are highly related histone acetyltransferase (HAT) enzymes that regulate gene expression, and their dysregulation has been linked to cancer and other diseases. p300/CBP is composed of a number of domains including a HAT domain, which is inhibited by the small molecule A-485, and an acetyl-lysine binding bromodomain, which was recently found to be selectively antagonized by the small molecule I-CBP112. Here we show that the combination of I-CBP112 and A-485 can synergize to inhibit prostate cancer cell proliferation. We find that the combination confers a dramatic reduction in p300 chromatin occupancy compared to the individual effects of blocking either domain alone. Accompanying this loss of p300 on chromatin, combination treatment leads to the reduction of specific mRNAs including androgen-dependent and pro-oncogenic prostate genes such as KLK3 (PSA) and c-Myc. Consistent with p300 directly affecting gene expression, mRNAs that are significantly reduced by combination treatment also exhibit a strong reduction in p300 chromatin occupancy at their gene promoters. The relatively few mRNAs that are up-regulated upon combination treatment show no correlation with p300 occupancy. These studies provide support for the pharmacologic advantage of concurrent targeting of two domains within one key epigenetic modification enzyme.

Optimal kinetic exposures for classic and candidate antitrypanosomals.

OBJECTIVES: Efficacy is determined not only by size, but also by shape, of drug exposure. Here the critical importance of the temporal pattern of drug concentrations (pharmacokinetic profile) is examined for antitrypanosomals in vitro. METHODS: An in vitro hollow-fibre cartridge system was used to study contrasting drug profiles with four clinically used agents and two experimental candidates against the deadly parasite Trypanosoma brucei. Artificial kinetics were employed intentionally to favour either high peak concentration or sustained duration of drug. RESULTS: Changing the shape of drug exposure significantly impacted drug efficacy. Suramin, melarsoprol and pentamidine were concentration-driven and therefore more efficacious when applied as short-lived high peaks. In contrast, difluoromethylornithine (DFMO) was time-driven, and therefore maximally effective as a constant infusion. Kinetic preference was robust over a wide range of drug exposures. Promising clinical candidates SCYX-7158 (acoziborole) and fexinidazole (parent and sulfone) were concentration-driven, suggesting optimal clinical regimens would involve relatively high but intermittent dosing. CONCLUSIONS: Antitrypanosomals have an intrinsic pharmacokinetic driver for optimal efficacy, with important implications for clinical management and future candidate development.

A Retrospective Study of Administrative Data to Identify High-Need Medicare Beneficiaries at Risk of Dying and Being Hospitalized.

BACKGROUND: Developing a definition of what constitutes high need among Medicare beneficiaries using administrative data is an important prerequisite to evaluating value-based payment reforms. While various definitions of high need exist, their predictive validity for different patient outcomes in the following year has not been systematically assessed for both fee-for-service (FFS) and Medicare Advantage (MA) beneficiaries. OBJECTIVE: To develop a definition of high need using administrative data in 2014 and to examine its predictive validity for patient outcomes in 2015 as compared to alternative definitions for both FFS and MA beneficiaries. DESIGN: Retrospective cohort study of national Medicare claims and post-acute assessment data. PARTICIPANTS: All Medicare beneficiaries in 2014 who survived until the end of the year (n = 54,717,039). MAIN MEASURES: Two or more complex conditions, 6 or more chronic conditions, acute or post-acute health services utilization, indicators of frailty, complete dependency in mobility or in any activities of daily living in post-acute care assessments, hospitalization, mortality, days in community, Medicare expenditures. KEY RESULTS: Based on our definition of high-need patients, 13.17% of FFS and 8.85% of MA beneficiaries were identified as high need in 2014. High-need FFS patients had mortality rates 7.1 times higher (16.23% vs. 2.27%) and hospitalization rates 3.4 times higher (40.69 vs. 12.03) in 2015 compared to other beneficiaries. Competing high-need definitions all had good specificity (≥ 0.88). Having 3 or more Hierarchical Chronic Conditions yielded a good positive predictive value for hospitalization, at 0.50, but only identified 19.71% of FFS beneficiaries hospitalized and 28.46% of FFS decedents that year as high need, as opposed to 33.92% and 51.98% for the new definition. Results were similar for MA beneficiaries. CONCLUSIONS: The proposed high-need definition has better sensitivity and yields a sample of almost 5 million FFS and 1.5 million MA beneficiaries, facilitating outcome performance comparisons across health systems.

Safeguarding Research Using Federal Health Insurance Data.

This Viewpoint discusses the importance of researcher access to federal health care data following a CMS decision to limit the use of physical data and proposes solutions to maintain access and security.

Molecular impact of covalent modifications on nonribosomal peptide synthetase carrier protein communication.

Nonribosomal peptide synthesis involves the interplay between covalent protein modifications, conformational fluctuations, catalysis, and transient protein-protein interactions. Delineating the mechanisms involved in orchestrating these various processes will deepen our understanding of domain-domain communication in nonribosomal peptide synthetases (NRPSs) and lay the groundwork for the rational reengineering of NRPSs by swapping domains handling different substrates to generate novel natural products. Although many structural and biochemical studies of NRPSs exist, few studies have focused on the energetics and dynamics governing the interactions in these systems. Here, we present detailed binding studies of an adenylation domain and its partner carrier protein in apo-, holo-, and substrate-loaded forms. Results from fluorescence anisotropy, isothermal titration calorimetry, and NMR titrations indicated that covalent modifications to a carrier protein modulate domain communication, suggesting that chemical modifications to carrier proteins during NRPS synthesis may impart directionality to sequential NRPS domain interactions. Comparison of the structure and dynamics of an apo-aryl carrier protein with those of its modified forms revealed structural fluctuations induced by post-translational modifications and mediated by modulations of protein dynamics. The results provide a comprehensive molecular description of a carrier protein throughout its life cycle and demonstrate how a network of dynamic residues can propagate the molecular impact of chemical modifications throughout a protein and influence its affinity toward partner domains.

Pharmacological activation of myosin II paralogs to correct cell mechanics defects.

Current approaches to cancer treatment focus on targeting signal transduction pathways. Here, we develop an alternative system for targeting cell mechanics for the discovery of novel therapeutics. We designed a live-cell, high-throughput chemical screen to identify mechanical modulators. We characterized 4-hydroxyacetophenone (4-HAP), which enhances the cortical localization of the mechanoenzyme myosin II, independent of myosin heavy-chain phosphorylation, thus increasing cellular cortical tension. To shift cell mechanics, 4-HAP requires myosin II, including its full power stroke, specifically activating human myosin IIB (MYH10) and human myosin IIC (MYH14), but not human myosin IIA (MYH9). We further demonstrated that invasive pancreatic cancer cells are more deformable than normal pancreatic ductal epithelial cells, a mechanical profile that was partially corrected with 4-HAP, which also decreased the invasion and migration of these cancer cells. Overall, 4-HAP modifies nonmuscle myosin II-based cell mechanics across phylogeny and disease states and provides proof of concept that cell mechanics offer a rich drug target space, allowing for possible corrective modulation of tumor cell behavior.