Implementation Of New Mexico's 'No Behavioral Health Cost Sharing' Law: A Qualitative Study.

Out-of-pocket spending is a long-standing challenge for privately insured people. New Mexico passed the first US law prohibiting private insurers from applying cost sharing to behavioral health treatment, effective January 1, 2022. We examined the perceptions of key informants, including clinicians, insurers, and state officials, about implementing the No Behavioral Health Cost Sharing law to explore how it might affect downstream outcomes such as spending and access. The law was viewed favorably and implemented without much difficulty. Clinicians noted widespread positive impacts, particularly for those needing intensive treatment. However, they worried about workforce capacity and the exclusion of people covered under self-insured employer plans, which are exempt from state regulation under the Employee Retirement Income Security Act (ERISA) of 1974. Insurers found the law to be in alignment with their organizational goals, but they expressed concern about the administrative burden caused by increased reviews of claims, and some were monitoring for unintended consequences (for example, waste and fraud) that could lead to increased premiums. Engagement strategies were needed to inform eligible members and facilitate enrollment in eligible plans. The law provides a potential model for states to improve access to behavioral health care, but impacts may be limited by factors such as workforce, awareness, and federal ERISA constraints.

Perceptions of a naloxone leave behind program among emergency medical services personnel in Michigan, USA.

Introduction: In 2020, Michigan implemented its first Naloxone Leave-Behind Program for Emergency Medical Service (EMS) field providers. Under the program, EMS field providers leave naloxone kits to individuals aged 15 or older they encounter in the field who have overdosed, who indicate they have a substance use disorder, or exhibit signs of opioid use and/or to bystanders, friends, or family that are present at the encounter. Methods: Survey of EMS field providers and administrators to assess perspectives on the Michigan NLB program. Comparisons of perspectives between field providers and administrators working in EMS agencies operating in medical control authorities (MCAs) participating in the NLB program (i.e., participating agencies) with field providers and administrators working for EMS agencies serving non-participating MCAs. Results: Most EMS field providers and administrators supported the Michigan NLB program. However, some were concerned about the unintended consequences of leaving behind naloxone, including the potential for recipients to use more drugs or be less likely to seek treatment. Perspectives of NLB program effectiveness were similar between EMS administrators and field providers. Participating administrators' top-cited barrier to implementation was convincing field providers to leave behind naloxone, while non-participating administrators were concerned with stocking naloxone kits. Conclusions: Additional engagement and training to address concerns by EMS field providers and administrators about the benefits of the NLB program are needed to expand program participation intensity. Streamlining naloxone procurement and increasing messaging about free access to naloxone for participating in the program may help increase adoption.

Lessons Learned Implementing Syringe Services Programs at Rural Health Departments in Kentucky.

Until recently, most syringe services programs (SSPs) in the United States operated in metropolitan areas. This study explores how SSP implementers at rural health departments in Kentucky secured support for SSP operations. In late 2020, we conducted in-depth, semi-structured interviews with 18 people involved with rural SSP implementation in Kentucky. Participants were asked to reflect on their experiences building support for SSP operations among rural health department staff and community members. Participants reported that attitudes and beliefs about SSP implementation among rural health department staff shifted quickly following engagement in educational activities and interaction with SSP clients. Participants explained that successful SSP implementation at rural health departments required sustained educational activities among community members and authorizing authorities. Future work should explore how rural communities may advocate for low-threshold and evidence-based policies that support the provision of harm reduction services.

Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) remains the most common cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule sarcomere inhibitors are promising novel therapeutics for the management of obstructive HCM (oHCM) patients and have shown efficacy in left ventricular outflow tract obstruction (LVOTO) relief. The objective of this study was to explore the 6-, 24-, and 48-hour (h) pharmacodynamic effects of the cardiac myosin inhibitor, CK-586, in six purpose-bred cats with naturally occurring oHCM. A blinded, randomized, five-treatment group, crossover preclinical trial was conducted to assess the pharmacodynamic effects of CK-586 in this oHCM model. Dose assessments and select echocardiographic variables were assessed five times over a 48-h period. Treatment with oral CK-586 safely ameliorated LVOTO in oHCM cats. CK-586 treatment dose-dependently eliminated obstruction (reduced LVOTOmaxPG), increased measures of systolic chamber size (LVIDs Sx), and decreased select measures of heart function (LV FS% and LV EF%) in the absence of impact on heart rate. At all tested doses, a single oral CK-586 dose resulted in improved or resolved LVOTO with well-tolerated, dose-dependent, reductions in LV systolic function. The results from this study pave the way for the potential use of CK-586 in both the veterinary and human clinical setting.

How policymakers innovate around behavioral health: adoption of the New Mexico "No Behavioral Health Cost-Sharing" law.

State policymakers have long sought to improve access to mental health and substance use disorder (MH/SUD) treatment through insurance market reforms. Examining decisions made by innovative policymakers ("policy entrepreneurs") can inform the potential scope and limits of legislative reform. Beginning in 2022, New Mexico became the first state to eliminate cost-sharing for MH/SUD treatment in private insurance plans subject to state regulation. Based on key informant interviews (n = 30), this study recounts the law's passage and intended impact. Key facilitators to the law's passage included receptive leadership, legislative champions with medical and insurance backgrounds, the use of local research evidence, advocate testimony, support from health industry figures, the severity of MH/SUD, and increased attention to MH/SUD during the COVID-19 pandemic. Findings have important implications for states considering similar laws to improve access to MH/SUD treatment.

Piloting racial bias training for hospital emergency department providers treating patients with opioid use disorder.

Racial disparities in opioid overdose have increased in recent years. Several studies have linked these disparities to health care providers' inequitable delivery of opioid use disorder (OUD) services. In response, health care policymakers and systems have designed new programs to improve equitable OUD care delivery. Racial bias training has been 1 commonly utilized program. Racial bias training educates providers about the existence of racial disparities in the treatment of people who use drugs and the role of implicit bias. Our study evaluates a pilot racial bias training delivered to 25 hospital emergency providers treating patients with OUDs in 2 hospitals in Detroit, Michigan. We conducted a 3-part survey, including a baseline assessment, post-training assessment, and a 2-month follow-up to evaluate the acceptability and feasibility of scaling the racial bias training to larger audiences. We also investigate preliminary data on changes in self-awareness of implicit bias, knowledge of training content, and equity in care delivery to patients with OUD. Using qualitative survey response data, we found that training participants were satisfied with the content and quality of the training and especially valued the small-group discussions, motivational interviewing, and historical context.

Prescription Drug Dispensing and Patient Costs After Implementation of a No Behavioral Health Cost-Sharing Law.

Importance: On January 1, 2022, New Mexico implemented a No Behavioral Cost-Sharing (NCS) law that eliminated cost-sharing for mental health and substance use disorder (MH/SUD) treatments in plans regulated by the state, potentially reducing a barrier to treatment for MH/SUDs among the commercially insured; however, the outcomes of the law are unknown. Objective: To assess the association of implementation of the NCS with out-of-pocket spending for prescription for drugs primarily used to treat MH/SUDs and monthly volume of dispensed drugs. Design, Settings, and Participants: This retrospective cohort study used a difference-in-differences research design to examine trends in outcomes for New Mexico state employees, a population affected by the NCS, compared with federal employees in New Mexico who were unaffected by NCS. Data were collected on prescription drugs for MH/SUDs dispensed per month between January 2021 and June 2022 for New Mexico patients with a New Mexico state employee health plan and New Mexico patients with a federal employee health plan. Data analysis occurred from December 2022 to January 2024. Exposure: Enrollment in a state employee health plan or federal health plan. Main Outcomes and Measures: The primary outcomes were mean patient out-of-pocket spending per dispensed MH/SUD prescription and the monthly volume of dispensed MH/SUD prescriptions per 1000 employees. A difference-in-differences estimation approach was used. Results: The implementation of the NCS law was associated with a mean (SE) $6.37 ($0.30) reduction (corresponding to an 85.6% decrease) in mean out-of-pocket spending per dispensed MH/SUD medication (95% CI, -$7.00 to -$5.75). The association of implementation of NCS with the volume of prescriptions dispensed was not statistically significant. Conclusions and Relevance: These findings suggest that the implementation of the New Mexico NCS law was successful in lowering out-of-pocket spending on prescription medications for MH/SUDs, but that there was no association of NCS with the volume of medications dispensed in the first 6 months after implementation. A key challenge is to identify policies that protect from high out-of-pocket spending while also promoting access to needed care.

Myosin-binding protein C regulates the sarcomere lattice and stabilizes the OFF states of myosin heads.

Muscle contraction is produced via the interaction of myofilaments and is regulated so that muscle performance matches demand. Myosin-binding protein C (MyBP-C) is a long and flexible protein that is tightly bound to the thick filament at its C-terminal end (MyBP-CC8C10), but may be loosely bound at its middle- and N-terminal end (MyBP-CC1C7) to myosin heads and/or the thin filament. MyBP-C is thought to control muscle contraction via the regulation of myosin motors, as mutations lead to debilitating disease. We use a combination of mechanics and small-angle X-ray diffraction to study the immediate and selective removal of the MyBP-CC1C7 domains of fast MyBP-C in permeabilized skeletal muscle. We show that cleavage leads to alterations in crossbridge kinetics and passive structural signatures of myofilaments that are indicative of a shift of myosin heads towards the ON state, highlighting the importance of MyBP-CC1C7 to myofilament force production and regulation.

Substance use disorder treatment carve outs in Medicaid managed care.

INTRODUCTION: Medicaid managed care organizations (MCO) play a major role in addressing the nation's epidemic of drug overdose and mortality by administering substance use disorder (SUD) treatment benefits for over 50 million Americans. While it is known that some Medicaid MCO plans delegate responsibility for managing SUD treatment benefits to an outside "carve out" entity, the extent and structure of such carve out arrangements are unknown. This is an important gap in knowledge, given that carve outs have been linked to reductions in rates of SUD treatment receipt in several studies. To address this gap, we examined carve out arrangements used by Medicaid MCO plans to administer SUD treatment benefits in ten states. METHODS: Data for this study was gleaned using a purposive sampling approach through content analysis of publicly available benefits information (e.g., member handbooks, provider manuals, prescription drug formularies) from 70 comprehensive Medicaid MCO plans in 10 selected states (FL, GA, IL, MD, MI, NH, OH, PA, UT, and WV) active in 2018. Each Medicaid MCO plan's documents were reviewed and coded to indicate whether a range of SUD treatment services (e.g., inpatient treatment, outpatient treatment, residential treatment) and medications were carved out, and if so, to what type of entity (e.g., behavioral health organization). RESULTS: A large majority of Medicaid MCO plans carved out at least some (28.6 %) or all (40.0 %) SUD treatment services, with nearly all plans carving out some (77.1 %) or all (14.3 %) medications, mainly due to the carving out of methadone treatment. Medicaid MCO plans most commonly carved out SUD treatment services to behavioral health organizations, while most medications were carved out to state Medicaid fee-for-service plans. CONCLUSIONS: Carve out arrangements for SUD treatment vary dramatically across states, across plans, and even within plans. Given that some studies have linked carve out arrangements to reductions in treatment access, their widespread use among Medicaid MCO plans is cause for further consideration by policymakers and other key interest groups. Moreover, reliance on such complex arrangements for administering care may create challenges for enrollees who seek to learn about and access plan benefits.

Medicaid Managed Care Prior Authorization For Buprenorphine Tied To State Partisanship And Health Plan Profit Status, 2018.

Buprenorphine is among the most effective drugs for treating opioid use disorder, yet only a quarter of Americans who need it receive it. Requiring prior authorization has been identified as an important barrier to buprenorphine access. However, the practice remains widespread in Medicaid-the largest insurer of Americans with opioid use disorder. In this study, we examined how prior authorization for buprenorphine is related to plan structure and state political environment, using data on all 266 comprehensive Medicaid managed care plans active in 2018. We found substantial variation in prior authorization use across states, with all plans requiring prior authorization in eleven states and no plans requiring it in thirteen other states. We found that for-profit plans and those located in Republican states were more likely to impose prior authorization policies. Our findings suggest that managed care plans' decisions regarding use of prior authorization may be shaped by internal pressures to control costs, as well as by differing partisan stances regarding the need to prevent criminal diversion of buprenorphine.

Post-hospitalization remote monitoring for patients with heart failure or chronic obstructive pulmonary disease in an accountable care organization.

BACKGROUND: Post-hospitalization remote patient monitoring (RPM) has potential to improve health outcomes for high-risk patients with chronic medical conditions. The purpose of this study is to determine the extent to which RPM for patients with congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD) is associated with reductions in post-hospitalization mortality, hospital readmission, and ED visits within an Accountable Care Organization (ACO). METHODS: Nonrandomized prospective study of patients in an ACO offered enrollment in RPM upon hospital discharge between February 2021 and December 2021. RPM comprised of vital sign monitoring equipment (blood pressure monitor, scale, pulse oximeter), tablet device with symptom tracking software and educational material, and nurse-provided oversight and triage. Expected enrollment was for at least 30-days of monitoring, and outcomes were followed for 6 months following enrollment. The co-primary outcomes were (a) the composite of death, hospital admission, or emergency care visit within 180 days of eligibility, and (b) time to occurrence of this composite. Secondary outcomes were each component individually, the composite of death or hospital admission, and outpatient office visits. Adjusted analyses involved doubly robust estimation to address confounding by indication. RESULTS: Of 361 patients offered remote monitoring (251 with CHF and 110 with COPD), 140 elected to enroll (106 with CHF and 34 with COPD). The median duration of RPM-enrollment was 54 days (IQR 34-85). Neither the 6-month frequency of the co-primary composite outcome (59% vs 66%, FDR p-value = 0.47) nor the time to this composite (median 29 vs 38 days, FDR p-value = 0.60) differed between the groups, but 6-month mortality was lower in the RPM group (6.4% vs 17%, FDR p-value = 0.02). After adjustment for confounders, RPM enrollment was associated with nonsignificantly decreased odds for the composite outcome (adjusted OR [aOR] 0.68, 99% CI 0.25-1.34, FDR p-value 0.30) and lower 6-month mortality (aOR 0.41, 99% CI 0.00-0.86, FDR p-value 0.20). CONCLUSIONS: RPM enrollment may be associated with improved health outcomes, including 6-month mortality, for selected patient populations.

Association between high-threshold practices and buprenorphine treatment termination.

BACKGROUND: Regular counseling and frequent drug testing are common requirements for patients with opioid use disorder in buprenorphine treatment. State policies throughout the United States often reinforce these high-threshold practices, as was the case with Michigan, USA. METHODS: We sought to explore the association between counseling requirements, drug testing practices, and buprenorphine treatment termination rates through administering a survey to buprenorphine prescribers in Michigan. RESULTS: In our sample of 377 prescribers, we found associations between high-threshold practices like drug testing at every clinical visit and requiring counseling and buprenorphine treatment termination rates. Relative to prescribers who randomly drug tested, drug tested at fixed intervals, or did not require any drug testing, prescribers who drug-tested patients at every visit were 38% more likely to terminate treatment. Prescribers who required counseling were 33% more likely to terminate treatment than those who did not require counseling. CONCLUSION: With the elimination of the USA Drug Enforcement Administration X-waiver in December 2022, state policies need to minimize high-threshold practices that reduce buprenorphine treatment continuity and undermine an effective response to the overdose crisis.

Utilization of Medications for Opioid Use Disorder Among West Virginia Medicaid Enrollees Following Medicaid Coverage of Methadone.

BACKGROUND: West Virginia entered an institution for mental disease Section 1115 waiver with the Centers for Medicare & Medicaid Services in 2018, which allowed Medicaid to cover methadone at West Virginia's nine opioid treatment programs (OTPs) for the first time. METHODS: We conducted time trend and geospatial analyses of Medicaid enrollees between 2016 and 2019 to examine medications for opioid use disorder utilization patterns following Medicaid coverage of methadone, focusing on distance to an OTP as a predictor of initiating methadone and conditional on receiving any, longer treatment duration. RESULTS: Following Medicaid coverage of methadone in 2018, patients receiving methadone comprised 9.5% of all Medicaid enrollees with an opioid use disorder (OUD) diagnosis and 10.6% in 2019 (P < 0.01). In 2018, two-thirds of methadone patients either had no prior OUD diagnosis or were not previously enrolled in Medicaid in our observation period. Patients residing within 20 miles of an OTP were more likely to receive methadone (marginal effect [ME]: -0.041, P < 0.001). Similarly, patients residing in metropolitan areas were more likely to receive treatment than those residing in nonmetropolitan areas (ME: -0.019, P < 0.05). Metropolitan patients traveled an average of 15 miles to an OTP; nonmetropolitan patients traveled more than twice as far (P < 0.001). We found no significant association between distance and treatment duration. CONCLUSIONS: West Virginia Medicaid's new methadone coverage was associated with an influx of new enrollees with OUD, many of whom had no previous OUD diagnosis or prior Medicaid enrollment. Methadone patients frequently traveled far distances for treatment, suggesting that the state needs additional OTPs and innovative methadone delivery models to improve availability.

Introduction of Medicare coverage in opioid treatment programs: Findings from the first three years.

BACKGROUND: Prior to January of 2020, there was no Medicare reimbursement for services delivered in opioid treatment programs (OTPs). OTPs are the only authorized providers of opioid use disorder (OUD) treatment with methadone, a critical tool to address the opioid overdose crisis. While prior research has examined the availability of MOUD other than methadone for Medicare beneficiaries, research has not identified organizational and local Medicare beneficiary characteristics associated with Medicare insurance acceptance among OTPs. OBJECTIVES: This study has two objectives: 1) to determine the extent to which OTPs began accepting Medicare insurance in the first three years following the new Medicare OTP benefit; and 2) to identify organizational characteristics and local Medicare beneficiary characteristics associated with OTP acceptance of Medicare. METHODS: We used data from the 2021-2023 National Directory of Drug and Alcohol Abuse Treatment Facilities to examine OTP acceptance of Medicare. We used logistic regression to identify organizational characteristics and local Medicare beneficiary characteristics associated with OTP acceptance of Medicare (n = 4630 OTPs). RESULTS: By 2022, about 78.7 % of OTPs accepted Medicare, compared to only 41.1 % of non-OTPs. The odds of Medicare acceptance were lower among for-profit OTPs, compared to non-profit OTPs, and higher among OTPs that accepted Medicaid and private insurance. Additionally, the odds of accepting Medicare were lower for OTPs located in the Northeast, Midwest, and South, compared to OTPs located in the West. Finally, the odds of accepting Medicare were higher for OTPs located in counties with higher percentages of Non-Hispanic White Medicare beneficiaries. CONCLUSIONS: We found high rates of Medicare acceptance among OTPs in the first three years of the Medicare OTP benefit, suggesting increased access to OUD treatment via OTPs for Medicare beneficiaries. While promising, results indicate potential geographic and racial/ethnic disparities in access to OTPs.

Up in smoke? Limited evidence of a smoking harm paradox in 17-year cohort study.

BACKGROUND: Socioeconomic differences in the impact of alcohol consumption on health have been consistently reported in the so-called "alcohol harm paradox" (i.e., individuals from higher socioeconomic backgrounds (SES) drink more alcohol than individuals from lower SES, but the latter accrue more alcohol-related harm). Despite the severe health risks of smoking however, there is a scarcity of studies examining a possible "smoking harm paradox" (SHP). We aim to fill this gap. METHODS: We conducted a prospective cohort study with adolescents from the Norwegian Longitudinal Health Behaviour Study (NLHB). Our study used data from ages 13 to 30 years. To analyse our data, we used the random-intercept cross-lagged panel model (RI-CLPM) with smoking and self-reported health as mutual lagged predictors and outcomes as well as parental income and education as grouping variables. Parental income and education were used as proxies for adolescent socioeconomic status (SES). Smoking was examined through frequency of smoking (every day, every week, less than once a week, not at all). General health compared to others was measured by self-report. RESULTS: Overall, we found inconclusive evidence of the smoking harm paradox, as not all effects from smoking to self-reported health were moderated by SES. Nevertheless, the findings do suggest that smoking predicted worse subjective health over time among individuals in the lower parental education group compared with those in the higher parental education group. This pattern was not found for parental income. CONCLUSIONS: While our results suggest limited evidence for a smoking harm paradox (SHP), they also suggest that the impact of adolescent smoking on later subjective health is significant for individuals with low parental education but not individuals with high parental education. This effect was not found for parental income, highlighting the potential influence of parental education over income as a determinant of subjective health outcomes in relation to smoking.

Development of a Food List to Assess the Diet of South Asians Living in the U.S.: Preliminary Results From a Formative Study.

Introduction: South Asians are an underrepresented population subgroup in the U.S., yet they have higher rates of chronic diseases. There is currently no tool that assesses the nutrition intake of South Asians in the U.S., despite their unique dietary profile that may be associated with disease outcomes. The objective of this preliminary study was to create a food list, inclusive of herbs and spices, that will be used in the development of the web-based South Asian Food Intake System for dietary assessment of South Asian adults living in the U.S. Methods: Authors used a Qualtrics survey to collect sociodemographic information (n=66), and 24-hour diet recall and Home Food Inventory interviews were conducted through Zoom (n=31). Grocery store tours and cookbook and existing food frequency questionnaire review were conducted. Results: A food list of 484 individual food items was generated. These items were sorted into 12 main food categories and condensed into 302 line items. Most respondents (68%) reported consuming South Asian meals regularly and utilizing herbs/spices during food preparation (83%). Conclusions: This pilot study describes the data collection to develop a food list for the South Asian Food Intake System, which can be utilized by educators, clinicians, and researchers to more accurately collect information about dietary intake among South Asian Americans.

Exploring trauma and wellbeing of people who use drugs after witnessing overdose: A qualitative study.

BACKGROUND: The national overdose crisis is often quantified by overdose deaths, but understanding the traumatic impact for those who witness and respond to overdoses can help elucidate mental health needs and opportunities for intervention for this population. Many who respond to overdoses are people who use drugs. This study adds to the literature on how people who use drugs qualitatively experience trauma resulting from witnessing and responding to overdose, through the lens of the Trauma-Informed Theory of Individual Health Behavior. METHODS: We conducted 60-min semi-structured, in-depth phone interviews. Participants were recruited from six states and Washington, DC in March-April 2022. Participants included 17 individuals who witnessed overdose(s) during the COVID-19 pandemic. The interview guide was shaped by theories of trauma. The codebook was developed using a priori codes from the interview guide; inductive codes were added during content analysis. Transcripts were coded using ATLAS.ti. RESULTS: A vast majority reported trauma from witnessing overdoses. Participants reported that the severity of trauma varied by contextual factors such as the closeness of the relationship to the person overdosing or whether the event was their first experience witnessing an overdose. Participants often described symptoms of trauma including rumination, guilt, and hypervigilance. Some reported normalization of witnessing overdoses due to how common overdoses were, while some acknowledged overdoses will never be "normal." The impacts of witnessing overdose on drug use behaviors varied from riskier substance use to increased motivation for treatment and safer drug use practices. CONCLUSION: Recognizing the traumatic impact of witnessed overdoses is key to effectively addressing the full range of sequelae of the overdose crisis. Trauma-informed approaches should be central for service providers when they approach this subject with clients, with awareness of how normalization can reduce help-seeking behaviors and the need for psychological aftercare. We found increased motivation for behavior change after witnessing, which presents opportunity for intervention.

Multi-Omic, Histopathologic, and Clinicopathologic Effects of Once-Weekly Oral Rapamycin in a Naturally Occurring Feline Model of Hypertrophic Cardiomyopathy: A Pilot Study.

Hypertrophic cardiomyopathy (HCM) remains the single most common cardiomyopathy in cats, with a staggering prevalence as high as 15%. To date, little to no direct therapeutical intervention for HCM exists for veterinary patients. A previous study aimed to evaluate the effects of delayed-release (DR) rapamycin dosing in a client-owned population of subclinical, non-obstructive, HCM-affected cats and reported that the drug was well tolerated and resulted in beneficial LV remodeling. However, the precise effects of rapamycin in the hypertrophied myocardium remain unknown. Using a feline research colony with naturally occurring hereditary HCM (n = 9), we embarked on the first-ever pilot study to examine the tissue-, urine-, and plasma-level proteomic and tissue-level transcriptomic effects of an intermittent low dose (0.15 mg/kg) and high dose (0.30 mg/kg) of DR oral rapamycin once weekly. Rapamycin remained safe and well tolerated in cats receiving both doses for eight weeks. Following repeated weekly dosing, transcriptomic differences between the low- and high-dose groups support dose-responsive suppressive effects on myocardial hypertrophy and stimulatory effects on autophagy. Differences in the myocardial proteome between treated and control cats suggest potential anti-coagulant/-thrombotic, cellular remodeling, and metabolic effects of the drug. The results of this study closely recapitulate what is observed in the human literature, and the use of rapamycin in the clinical setting as the first therapeutic agent with disease-modifying effects on HCM remains promising. The results of this study establish the need for future validation efforts that investigate the fine-scale relationship between rapamycin treatment and the most compelling gene expression and protein abundance differences reported here.

Myosin-binding protein C forms C-links and stabilizes OFF states of myosin.

Contraction force in muscle is produced by the interaction of myosin motors in the thick filaments and actin in the thin filaments and is fine-tuned by other proteins such as myosin-binding protein C (MyBP-C). One form of control is through the regulation of myosin heads between an ON and OFF state in passive sarcomeres, which leads to their ability or inability to interact with the thin filaments during contraction, respectively. MyBP-C is a flexible and long protein that is tightly bound to the thick filament at its C-terminal end but may be loosely bound at its middle- and N-terminal end (MyBP-CC1C7). Under considerable debate is whether the MyBP-CC1C7 domains directly regulate myosin head ON/OFF states, and/or link thin filaments ("C-links"). Here, we used a combination of mechanics and small-angle X-ray diffraction to study the immediate and selective removal of the MyBP-CC1C7 domains of fast MyBP-C in permeabilized skeletal muscle. After cleavage, the thin filaments were significantly shorter, a result consistent with direct interactions of MyBP-C with thin filaments thus confirming C-links. Ca2+ sensitivity was reduced at shorter sarcomere lengths, and crossbridge kinetics were increased across sarcomere lengths at submaximal activation levels, demonstrating a role in crossbridge kinetics. Structural signatures of the thick filaments suggest that cleavage also shifted myosin heads towards the ON state - a marker that typically indicates increased Ca2+ sensitivity but that may account for increased crossbridge kinetics at submaximal Ca2+ and/or a change in the force transmission pathway. Taken together, we conclude that MyBP-CC1C7 domains play an important role in contractile performance which helps explain why mutations in these domains often lead to debilitating diseases.