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.

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.

An Early Implementation Analysis of Syringe Services Programs in Kentucky: Barriers and Facilitators Identified by Program Operators and Local Officials.

Kentucky is one of ten states that require syringe services program (SSP) approval from local officials to operate legally. Public health leaders and local officials participated in semi-structured interviews in 2016 about the barriers and facilitators of SSP adoption and implementation (N = 22). Interviews were transcribed verbatim, and a thematic content analysis was conducted using Nvivo software. Political support, program champions who led education efforts, and access to resources and training facilitated SSP adoption. The most frequently reported barriers to adoption were often rooted in stigma and included the lack of political will to approve SSPs or lack of recognition of the need for a SSP. Requiring approval from local governing authorities could impose significant implementation delays, limits to the range of harm reduction services provided, and threaten harm reduction program sustainability. Removing barriers to the adoption and implementation of harm reduction programs is critical in order to effectively scale up harm reduction services to reduce the risks of infection and fatal overdose.

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.

Factors associated with receptive injection equipment sharing among people who inject drugs: findings from a multistate study at the start of the COVID-19 pandemic.

BACKGROUND: Receptive injection equipment sharing (i.e., injecting with syringes, cookers, rinse water previously used by another person) plays a central role in the transmission of infectious diseases (e.g., HIV, viral hepatitis) among people who inject drugs. Better understanding these behaviors in the context of COVID-19 may afford insights about potential intervention opportunities in future health crises. OBJECTIVE: This study examines factors associated with receptive injection equipment sharing among people who inject drugs in the context of COVID-19. METHODS: From August 2020 to January 2021, people who inject drugs were recruited from 22 substance use disorder treatment programs and harm reduction service providers in nine states and the District of Columbia to complete a survey that ascertained how the COVID-19 pandemic affected substance use behaviors. We used logistic regression to identify factors associated with people who inject drugs having recently engaged in receptive injection equipment sharing. RESULTS: One in four people who inject drugs in our sample reported having engaged in receptive injection equipment sharing in the past month. Factors associated with greater odds of receptive injection equipment sharing included: having a high school education or equivalent (adjusted odds ratio [aOR] = 2.14, 95% confidence interval [95% CI] 1.24, 3.69), experiencing hunger at least weekly (aOR = 1.89, 95% CI 1.01, 3.56), and number of drugs injected (aOR = 1.15, 95% CI 1.02, 1.30). Older age (aOR = 0.97, 95% CI 0.94, 1.00) and living in a non-metropolitan area (aOR = 0.43, 95% CI 0.18, 1.02) were marginally associated with decreased odds of receptive injection equipment sharing. CONCLUSIONS: Receptive injection equipment sharing was relatively common among our sample during the early months of the COVID-19 pandemic. Our findings contribute to existing literature that examines receptive injection equipment sharing by demonstrating that this behavior was associated with factors identified in similar research that occurred before COVID. Eliminating high-risk injection practices among people who inject drugs requires investments in low-threshold and evidence-based services that ensure persons have access to sterile injection equipment.

Pharmacokinetics of a single dose of Aficamten (CK-274) on cardiac contractility in a A31P MYBPC3 hypertrophic cardiomyopathy cat model.

Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiac disease in cats and lacks efficacious preclinical pharmacologic intervention, prompting investigation of novel therapies. Genetic mutations encoding sarcomeric proteins are implicated in the development of HCM and small molecule myosin inhibitors are an emerging class of therapeutics designed to target the interaction of actin and myosin to alleviate the detrimental effects of inappropriate contractile protein interactions. The purpose of this study was to characterize the pharmacodynamic effects of a single oral dose of the novel cardiac myosin inhibitor aficamten (CK-274) on cardiac function in purpose bred cats with naturally occurring A31P MYBPC3 mutation and a clinical diagnosis of HCM with left ventricular outflow tract obstruction (LVOTO). Five purpose bred cats were treated with aficamten (2 mg/kg) or vehicle and echocardiographic evaluations were performed at 0, 6, 24, and 48 h post-dosing. High dose aficamten (2 mg/kg) reduced left ventricular fractional shortening (LVFS%) by increasing the LV systolic internal dimension (LVIDs) and reduced isovolumic relaxation time (IVRT) compared with baseline without significant adverse effects. The marked reduction in systolic function and reduced IVRT coupled with an increased heart rate in treated cats, suggest a lower dose may be optimal. Further studies to determine optimal dosing of aficamten are indicated.

Myofilament glycation in diabetes reduces contractility by inhibiting tropomyosin movement, is rescued by cMyBPC domains.

Diabetes doubles the risk of developing heart failure (HF). As the prevalence of diabetes grows, so will HF unless the mechanisms connecting these diseases can be identified. Methylglyoxal (MG) is a glycolysis by-product that forms irreversible modifications on lysine and arginine, called glycation. We previously found that myofilament MG glycation causes sarcomere contractile dysfunction and is increased in patients with diabetes and HF. The aim of this study was to discover the molecular mechanisms by which MG glycation of myofilament proteins cause sarcomere dysfunction and to identify therapeutic avenues to compensate. In humans with type 2 diabetes without HF, we found increased glycation of sarcomeric actin compared to non-diabetics and it correlated with decreased calcium sensitivity. Depressed calcium sensitivity is pathogenic for HF, therefore myofilament glycation represents a promising therapeutic target to inhibit the development of HF in diabetics. To identify possible therapeutic targets, we further defined the molecular actions of myofilament glycation. Skinned myocytes exposed to 100 µM MG exhibited decreased calcium sensitivity, maximal calcium-activated force, and crossbridge kinetics. Replicating MG's functional affects using a computer simulation of sarcomere function predicted simultaneous decreases in tropomyosin's blocked-to-closed rate transition and crossbridge duty cycle were consistent with all experimental findings. Stopped-flow experiments and ATPase activity confirmed MG decreased the blocked-to-closed transition rate. Currently, no therapeutics target tropomyosin, so as proof-of-principal, we used a n-terminal peptide of myosin-binding protein C, previously shown to alter tropomyosin's position on actin. C0C2 completely rescued MG-induced calcium desensitization, suggesting a possible treatment for diabetic HF.

Risk Factors for Infection and Health Impacts of the Coronavirus Disease 2019 (COVID-19) Pandemic in People With Autoimmune Diseases.

BACKGROUND: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences. METHODS: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health. RESULTS: In total, 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95% CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95% CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95% CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income. CONCLUSIONS: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.

A Novel "Cut and Paste" Method for In Situ Replacement of cMyBP-C Reveals a New Role for cMyBP-C in the Regulation of Contractile Oscillations.

RATIONALE: cMyBP-C (cardiac myosin-binding protein-C) is a critical regulator of heart contraction, but the mechanisms by which cMyBP-C affects actin and myosin are only partly understood. A primary obstacle is that cMyBP-C localization on thick filaments may be a key factor defining its interactions, but most in vitro studies cannot duplicate the unique spatial arrangement of cMyBP-C within the sarcomere. OBJECTIVE: The goal of this study was to validate a novel hybrid genetic/protein engineering approach for rapid manipulation of cMyBP-C in sarcomeres in situ. METHODS AND RESULTS: We designed a novel cut and paste approach for removal and replacement of cMyBP-C N'-terminal domains (C0-C7) in detergent-permeabilized cardiomyocytes from gene-edited Spy-C mice. Spy-C mice express a TEVp (tobacco etch virus protease) cleavage site and a SpyTag (st) between cMyBP-C domains C7 and C8. A cut is achieved using TEVp which cleaves cMyBP-C to create a soluble N'-terminal γC0C7 (endogenous [genetically encoded] N'-terminal domains C0 to C7 of cardiac myosin binding protein-C) fragment and an insoluble C'-terminal SpyTag-C8-C10 fragment that remains associated with thick filaments. Paste of new recombinant (r)C0C7 domains is achieved by a covalent bond formed between SpyCatcher (-sc; encoded at the C'-termini of recombinant proteins) and SpyTag. Results show that loss of γC0C7 reduced myofilament Ca2+ sensitivity and increased cross-bridge cycling (ktr) at submaximal [Ca2+]. Acute loss of γC0C7 also induced auto-oscillatory contractions at submaximal [Ca2+]. Ligation of rC0C7 (exogenous [recombinant] N'-terminal domains C0 to C7 of cardiac myosin binding protein-C)-sc returned pCa50 and ktr to control values and abolished oscillations, but phosphorylated (p)-rC0C7-sc did not completely rescue these effects. CONCLUSIONS: We describe a robust new approach for acute removal and replacement of cMyBP-C in situ. The method revealed a novel role for cMyBP-C N'-terminal domains to damp sarcomere-driven contractile waves (so-called spontaneous oscillatory contractions). Because phosphorylated (p)-rC0C7-sc was less effective at damping contractile oscillations, results suggest that spontaneous oscillatory contractions may contribute to enhanced contractility in response to inotropic stimuli.

Exploring the impact of the COVID-19 pandemic on syringe services programs in rural Kentucky.

BACKGROUND: The coronavirus pandemic (COVID-19) exacerbated risks for adverse health consequences among people who inject drugs by reducing access to sterile injection equipment, HIV testing, and syringe services programs (SSPs). Several decades of research demonstrate the public health benefits of SSP implementation; however, existing evidence primarily reflects studies conducted in metropolitan areas and before the COVID-19 pandemic. OBJECTIVES: We aim to explore how the COVID-19 pandemic affected SSP operations in rural Kentucky counties. METHODS: In late 2020, we conducted eighteen in-depth, semi-structured interviews with persons (10 women, 8 men) involved in SSP implementation in rural Kentucky counties. The interview guide broadly explored the barriers and facilitators to SSP implementation in rural communities; participants were also asked to describe how COVID-19 affected SSP operations. RESULTS: Participants emphasized the need to continue providing SSP-related services throughout the pandemic. COVID-19 mitigation strategies (e.g., masking, social distancing, pre-packing sterile injection equipment) limited relationship building between staff and clients and, more broadly, the pandemic adversely affected overall program expansion, momentum building, and coalition building. However, participants offered multiple examples of innovative solutions to the myriad of obstacles the pandemic presented. CONCLUSION: The COVID-19 pandemic impacted SSP operations throughout rural Kentucky. Despite challenges, participants reported that providing SSP services remained paramount. Diverse adaptative strategies were employed to ensure continuation of essential SSP services, demonstrating the commitment and ingenuity of program staff. Given that SSPs are essential for preventing adverse injection drug use-associated health consequences, further resources should be invested in SSP operations to ensure service delivery is not negatively affected by co-occurring crises.

Law enforcement and syringe services program implementation in rural counties in Kentucky: a qualitative exploration.

BACKGROUND: Existing research in urban areas has documented a multitude of ways in which law enforcement may affect risks for bloodborne infectious disease acquisition among people who inject drugs (PWID), such as via syringe confiscation and engaging in practices that deter persons from accessing syringe services programs (SSPs). However, limited work has been conducted to explore how law enforcement may impact SSP implementation and operations in rural counties in the United States. This creates a significant gap in the HIV prevention literature given the volume of non-urban counties in the United States that are vulnerable to injection drug use-associated morbidity and mortality. OBJECTIVE: This study explores the influence of law enforcement during processes to acquire approvals for SSP implementation and subsequent program operations in rural Kentucky counties. METHODS: From August 2020 to October 2020, we conducted eighteen in-depth qualitative interviews among persons involved with SSP implementation in rural counties in Kentucky (USA). Interviews explored the factors that served as barriers and facilitators to SSP implementation and operations, including the role of law enforcement. RESULTS: Participants described scenarios in which rural law enforcement advocated for SSP implementation; however, they also reported police opposing rural SSP implementation and engaging in adverse behaviors (e.g., targeting SSP clients) that may jeopardize the public health of PWID. Participants reported that efforts to educate rural law enforcement about SSPs were particularly impactful when they discussed how SSP implementation may prevent needlestick injuries. CONCLUSIONS: The results of this study suggest that there are multiple ways in which rural SSP implementation and subsequent operations in rural Kentucky counties are affected by law enforcement. Future work is needed to explore how to expeditiously engage rural law enforcement, and communities more broadly, about SSPs, their benefits, and public health necessity.

Intersecting substance use treatment and harm reduction services: exploring the characteristics and service needs of a community-based sample of people who use drugs.

BACKGROUND: Substance use treatment and harm reduction services are essential components of comprehensive strategies for reducing the harms of drug use and overdose. However, these services have been historically siloed, and there is a need to better understand how programs that serve people who use drugs (PWUD) are integrating these services. In this study, we compared treatment and harm reduction services offered by a multistate sample of substance use service providers and assessed how well they align with characteristics and needs of clients they serve early in the COVID-19 pandemic. METHODS: We recruited a convenience sample of programs that deliver harm reduction and/or treatment services in ten US states. Program directors participated in a survey assessing the services offered at their program. We also recruited clients of these programs to participate in a survey assessing a range of sociodemographic and health characteristics, substance use behaviors, and health service utilization. We then cross-compared client characteristics and behaviors relative to services being offered through these programs. RESULTS: We collected and analyzed data from 511 clients attending 18 programs that we classified as either offering treatment with medications for opioid use disorder (MOUD) (N = 6), syringe service programs (SSP) (N = 8), or offering both MOUD and SSP (N = 4). All programs delivered a range of treatment and harm reduction services, with MOUD & SSP programs delivering the greatest breadth of services. There were discrepancies between services provided and characteristics and behaviors reported by clients: 80% of clients of programs that offered MOUD without SSP actively used drugs and 50% injected drugs; 40% of clients of programs that offered SSP without MOUD sought drug treatment services. Approximately half of clients were unemployed and unstably housed, but few programs offered direct social services. CONCLUSIONS: In many ways, existing programs are not meeting the service needs of PWUD. Investing in innovative models that empower clients and integrate a range of accessible and flexible treatment, harm reduction and social services can pave the way for a more effective and equitable service system that considers the long-term health of PWUD.

Binge-Eating Disorder and Type 2 Diabetes: A Review.

OBJECTIVE: To familiarize health care providers with diagnosis and treatment of binge-eating disorder (BED), a common comorbidity of type 2 diabetes (T2DM). METHODS: Literature review of binge eating and T2DM. Key words used in search include BED, T2DM, obesity, and treatment. RESULTS: The prevalence of BED in patients with T2DM appears to be much higher than the 2% to 3.5% prevalence seen in the general population. Studies suggest that up to 20% of patients with T2DM have an underlying eating disorder, the most common of which is binge eating. BED is probably underdiagnosed, even though there are multiple simple tools that providers can use to improve screening for the disorder. Though the relationship between BED and hemoglobin A1c control can vary, it appears that binge-eating behaviors can worsen metabolic markers, including glycemic control. Various medications used by patients with diabetes have been associated with new-onset BED, and treatment may be as simple as removing or replacing such agents. Several medications have been found to significantly reduce binge-eating frequency, and potentially, weight. Patients with BED generally benefit from psychotherapy, including cognitive behavioral therapy. CONCLUSION: BED, only recently added to the International Classification of Disease-10 diagnostic list, is very common in patients with obesity and T2DM. The diagnosis is important to establish, as treatment or referral for treatment, could potentially improve many of the comorbidities and metrics of T2DM.

COVID-19 and psychological distress in Norway: The role of trust in the healthcare system.

AIM: The study aims to examine groups at risk for psychological distress in connection with the COVID-19 outbreak, and the role of trust in the healthcare system as a possible moderator. METHODS: Data were collected from a large sample of the Norwegian population (n = 4008) through the Norwegian Citizen Panel (NCP). A linear regression was conducted to examine the effects of COVID-19 related risk factors on psychological distress, using the 10-item Hopkins Symptom Checklist (HSCL-10). Finally, we conducted a moderation analysis to examine the interaction of trust in the healthcare system and COVID-19 related risk factors. RESULTS: A linear regression showed that female gender, younger age, lower level of education, being infected with COVID-19, being medically vulnerable, working in the healthcare system, being in voluntary quarantine and having an immigrant background predicted mean HSCL-10 scores. The moderation analysis revealed that people in the medically vulnerable group, those below 61, and those in quarantine reported higher psychological distress when they also had lower trust in the healthcare system. CONCLUSIONS: Findings indicate important groups to take into consideration in mental healthcare strategies and policies. However, most participants in the current study reported psychological distress levels that were below the clinical cut-off, suggesting that the majority may have coped relatively well in the early stages of the pandemic.

Classification of major and minor blood group antigens in the Kuwaiti Arab population.

Ethnic differences in blood group frequencies might result in clinically important mismatches for transfusions. Arab people represent a large population for which no comprehensive database of red cell genotypes is available and Kuwaitis are no exception. For instance, the Rh blood group is the most elaborate blood group system that shows a high degree of polymorphism among different ethnic groups, there has been little classification of RH alleles in Arab people. Blood samples from 917 Kuwaiti Arab donors in the Kuwaiti Bone Marrow registry were tested with a single-nucleotide polymorphism DNA array. Blood group antigen prevalence were compared to known prevalence in European populations. Multiple subjects were found to be antigen negative for certain phenotypes that is considered rare by the American Rare Donor Program; (Fy(a-,b-) and Kell). In the minor blood group antigens, the FYA allele was predicted to be low in Kuwaitis, when compared to other published accounts. The frequencies of MNS blood antigens in the study population were not significantly different from those reported for European/Caucasian populations. The predicted frequency of the Diego blood group antigen was similar to that observed in a South Asian population. The weak D 1, 2, 3 phenotypes were not prevalent in the Kuwaiti Arab population; however, other RHD variants were detected. We provided information about blood group antigens in the Kuwaiti population that is important for guiding transfusion care. Several interesting findings demonstrated clinical importance, which could be useful in developing transfusion medicine policies and approaches.

Substance use disorders in refugee and migrant groups in Sweden: A nationwide cohort study of 1.2 million people.

BACKGROUND: Refugees are at higher risk of some psychiatric disorders, including post-traumatic stress disorder (PTSD) and psychosis, compared with other non-refugee migrants and the majority population. However, it is unclear whether this also applies to substance use disorders, which we investigated in a national register cohort study in Sweden. We also investigated whether risk varied by region of origin, age at migration, time in Sweden, and diagnosis of PTSD. METHODS AND FINDINGS: Using linked Swedish register data, we followed a cohort born between 1984 and 1997 from their 14th birthday or arrival in Sweden, if later, until an International Classification of Diseases, 10th revision (ICD-10), diagnosis of substance use disorder (codes F10.X-19.X), emigration, death, or end of follow-up (31 December 2016). Refugee and non-refugee migrants were restricted to those from regions with at least 1,000 refugees in the Swedish registers. We used Cox proportional hazards regression to estimate unadjusted and adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) in refugee and non-refugee migrants, compared with Swedish-born individuals, for all substance use disorders (F10.X-19.X), alcohol use disorders (F10.X), cannabis use disorders (F12.X), and polydrug use disorders (F19.X). In adjusted analyses, we controlled for age, sex, birth year, family income, family employment status, population density, and PTSD diagnosis. Our sample of 1,241,901 participants included 17,783 (1.4%) refugee and 104,250 (8.4%) non-refugee migrants. Refugees' regions of origin were represented in proportions ranging from 6.0% (Eastern Europe and Russia) to 41.4% (Middle East and North Africa); proportions of non-refugee migrants' regions of origin ranged from 11.8% (sub-Saharan Africa) to 33.7% (Middle East and North Africa). These groups were more economically disadvantaged at cohort entry (p < 0.001) than the Swedish-born population. Refugee (aHR: 0.52; 95% CI 0.46-0.60) and non-refugee (aHR: 0.46; 95% CI 0.43-0.49) migrants had similarly lower rates of all substance use disorders compared with Swedish-born individuals (crude incidence: 290.2 cases per 100,000 person-years; 95% CI 287.3-293.1). Rates of substance use disorders in migrants converged to the Swedish-born rate over time, indicated by both earlier age at migration and longer time in Sweden. We observed similar patterns for alcohol and polydrug use disorders, separately, although differences in cannabis use were less marked; findings did not differ substantially by migrants' region of origin. Finally, while a PTSD diagnosis was over 5 times more common in refugees than the Swedish-born population, it was more strongly associated with increased rates of substance use disorders in the Swedish-born population (aHR: 7.36; 95% CI 6.79-7.96) than non-refugee migrants (HR: 4.88; 95% CI 3.71-6.41; likelihood ratio test [LRT]: p = 0.01). The main limitations of our study were possible non-differential or differential under-ascertainment (by migrant status) of those only seen via primary care and that our findings may not generalize to undocumented migrants, who were not part of this study. CONCLUSIONS: Our findings suggest that lower rates of substance use disorders in migrants and refugees may reflect prevalent behaviors with respect to substance use in migrants' countries of origin, although this effect appeared to diminish over time in Sweden, with rates converging towards the substantial burden of substance use morbidity we observed in the Swedish-born population.

Genomic characterization of the RH locus detects complex and novel structural variation in multi-ethnic cohorts.

PURPOSE: Rh antigens can provoke severe alloimmune reactions, particularly in high-risk transfusion contexts, such as sickle cell disease. Rh antigens are encoded by the paralogs, RHD and RHCE, located in one of the most complex genetic loci. Our goal was to characterize RH genetic variation in multi-ethnic cohorts, with the focus on detecting RH structural variation (SV). METHODS: We customized analytical methods to estimate paralog-specific copy number from next-generation sequencing (NGS) data. We applied these methods to clinically characterized samples, including four World Health Organization (WHO) genotyping references and 1135 Asian and Native American blood donors. Subsequently, we surveyed 1715 African American samples from the Jackson Heart Study. RESULTS: Most samples in each dataset exhibited SV. SV detection enabled prediction of the immunogenic RhD and RhC antigens in concordance (>99%) with serological phenotyping. RhC antigen expression was associated with exon 2 hybrid alleles (RHCE*CE-D(2)-CE). Clinically relevant exon 4-7 hybrid alleles (RHD*D-CE(4-7)-D) and exon 9 hybrid alleles (RHCE*CE-D(9)-CE) were prevalent in African Americans. CONCLUSION: This study shows custom NGS methods can accurately detect RH SV, and that SV is important to inform prediction of relevant RH alleles. Additionally, this study provides the first large NGS survey of RH alleles in African Americans.

C0 and C1 N-terminal Ig domains of myosin binding protein C exert different effects on thin filament activation.

Mutations in genes encoding myosin, the molecular motor that powers cardiac muscle contraction, and its accessory protein, cardiac myosin binding protein C (cMyBP-C), are the two most common causes of hypertrophic cardiomyopathy (HCM). Recent studies established that the N-terminal domains (NTDs) of cMyBP-C (e.g., C0, C1, M, and C2) can bind to and activate or inhibit the thin filament (TF). However, the molecular mechanism(s) by which NTDs modulate interaction of myosin with the TF remains unknown and the contribution of each individual NTD to TF activation/inhibition is unclear. Here we used an integrated structure-function approach using cryoelectron microscopy, biochemical kinetics, and force measurements to reveal how the first two Ig-like domains of cMyPB-C (C0 and C1) interact with the TF. Results demonstrate that despite being structural homologs, C0 and C1 exhibit different patterns of binding on the surface of F-actin. Importantly, C1 but not C0 binds in a position to activate the TF by shifting tropomyosin (Tm) to the "open" structural state. We further show that C1 directly interacts with Tm and traps Tm in the open position on the surface of F-actin. Both C0 and C1 compete with myosin subfragment 1 for binding to F-actin and effectively inhibit actomyosin interactions when present at high ratios of NTDs to F-actin. Finally, we show that in contracting sarcomeres, the activating effect of C1 is apparent only once low levels of Ca(2+) have been achieved. We suggest that Ca(2+) modulates the interaction of cMyBP-C with the TF in the sarcomere.

Point mutations in the tri-helix bundle of the M-domain of cardiac myosin binding protein-C influence systolic duration and delay cardiac relaxation.

Cardiac myosin binding protein-C (cMyBP-C) is an essential regulatory protein required for proper systolic contraction and diastolic relaxation. We previously showed that N'-terminal domains of cMyBP-C stimulate contraction by binding to actin and activating the thin filament in vitro. In principle, thin filament activating effects of cMyBP-C could influence contraction and relaxation rates, or augment force amplitude in vivo. cMyBP-C binding to actin could also contribute to an internal load that slows muscle shortening velocity as previously hypothesized. However, the functional significance of cMyBP-C binding to actin has not yet been established in vivo. We previously identified an actin binding site in the regulatory M-domain of cMyBP-C and described two missense mutations that either increased (L348P) or decreased (E330K) binding affinity of recombinant cMyBP-C N'-terminal domains for actin in vitro. Here we created transgenic mice with either the L348P or E330K mutations to determine the functional significance of cMyBP-C binding to actin in vivo. Results showed that enhanced binding of cMyBP-C to actin in L348P-Tg mice prolonged the time to end-systole and slowed relaxation rates. Reduced interactions between cMyBP-C and actin in E330K-Tg mice had the opposite effect and significantly shortened the duration of ejection. Neither mouse model displayed overt systolic dysfunction, but L348P-Tg mice showed diastolic dysfunction presumably resulting from delayed relaxation. We conclude that cMyBP-C binding to actin contributes to sustained thin filament activation at the end of systole and during isovolumetric relaxation. These results provide the first functional evidence that cMyBP-C interactions with actin influence cardiac function in vivo.