Patient experiences of a lifestyle program for metabolic syndrome offered in family medicine clinics: a mixed methods study.

BACKGROUND: Patient perspectives on new programs to manage metabolic syndrome (MetS) are critical to evaluate for possible implementation in the primary healthcare system. Participants' perspectives were sought for the Canadian Health Advanced by Nutrition and Graded Exercise (CHANGE) study, which enrolled 293 participants, and demonstrated 19% reversal of MetS after 1 year. The main purpose of this study was to examine participants' perceptions of their experiences with the CHANGE program, enablers and barriers to change. METHODS: A convergent parallel mixed methods design combined patients' perspectives collected by questionnaires (n = 164), with insights from focus groups (n = 41) from three sites across Canada. Qualitative data were thematically analyzed using interpretative description. Insights were organized within a socio-ecologic framework. RESULTS: Key aspects identified by participants included intra-individual factors (personal agency, increased time availability), inter-individual factors (trust, social aspects) and organizational factors (increased mental health support, tailored programs). CONCLUSION: Results revealed participants' overall support for the CHANGE program, especially the importance of an extended program under the guidance of a family physician along with a skilled and supportive team. Team delivery of a lifestyle program in primary care or family medicine clinics is a complex intervention and use of a mixed methods design was helpful for exploring patient experiences and key issues on enablers and barriers to health behavior change.

Effects of Emergent Literacy Interventions for Preschoolers With Autism Spectrum Disorder.

Combining data from a series of three planned, consecutive independent randomized controlled trials (RCTs), the present study investigates two literacy interventions for preschool children with autism spectrum disorder (ASD). For the first cohort, children were randomized to interactive book reading treatment (IBR)or a business-as-usual (BAU) control condition; in Cohort 2, children were randomized to phonological awareness treatment (PA)or BAU; in Cohort 3, children were randomized to IBR or PA. Both treatments were implemented weekly in the classroom from November to May. Combined across cohorts, data from n =47 IBR, n =42 PA, and n =44 BAU students from 57 classrooms in 8 districts were available for analysis. Model results showed that IBR had significantly greater pretest-posttest gains than the sample mean on expressive vocabulary and listening comprehension (d*=0.29 and 0.30), whereas PA had significantly greater phonological awareness gains (d*=0.39).

Analysis of plasma metabolomes from 11 309 subjects in five population-based cohorts.

Plasma metabolomics holds potential for precision medicine, but limited information is available to compare the performance of such methods across multiple cohorts. We compared plasma metabolite profiles after an overnight fast in 11,309 participants of five population-based Swedish cohorts (50-80 years, 52% women). Metabolite profiles were uniformly generated at a core laboratory (Metabolon Inc.) with untargeted liquid chromatography mass spectrometry and a comprehensive reference library. Analysis of a second sample obtained one year later was conducted in a subset. Of 1629 detected metabolites, 1074 (66%) were detected in all cohorts while only 10% were unique to one cohort, most of which were xenobiotics or uncharacterized. The major classes were lipids (28%), xenobiotics (22%), amino acids (14%), and uncharacterized (19%). The most abundant plasma metabolome components were the major dietary fatty acids and amino acids, glucose, lactate and creatinine. Most metabolites displayed a log-normal distribution. Temporal variability was generally similar to clinical chemistry analytes but more pronounced for xenobiotics. Extensive metabolite-metabolite correlations were observed but mainly restricted to within each class. Metabolites were broadly associated with clinical factors, particularly body mass index, sex and renal function. Collectively, our findings inform the conduct and interpretation of metabolite association and precision medicine studies.

Statin treatment after surgical aortic valve replacement for aortic stenosis is associated with better long-term outcome.

OBJECTIVES: The aim of this study was to evaluate the association between statin use after surgical aortic valve replacement for aortic stenosis and long-term risk for major adverse cardiovascular events (MACEs) in a large population-based, nationwide cohort. METHODS: All patients who underwent isolated surgical aortic valve replacement due to aortic stenosis in Sweden 2006-2020 and survived 6 months after discharge were included. Individual patient data from 5 nationwide registries were merged. Primary outcome is MACE (defined as all-cause mortality, myocardial infarction or stroke). Multivariable Cox regression model adjusted for age, sex, comorbidities, valve type, operation year and secondary prevention medications is used to evaluate the association between time-updated dispense of statins and long-term outcome in the entire study population and in subgroups based on age, sex and comorbidities. RESULTS: A total of 11 894 patients were included. Statins were dispensed to 49.8% (5918/11894) of patients at baseline, and 51.0% (874/1713) after 10 years. At baseline, 3.6% of patients were dispensed low dose, 69.4% medium dose and 27.0% high-dose statins. After adjustments, ongoing statin treatment was associated with a reduced risk for MACE [adjusted hazard ratio 0.77 (95% confidence interval 0.71-0.83). P < 0.001], mainly driven by a reduction in all-cause mortality [adjusted hazard ratio, 0.70 (0.64-0.76)], P < 0.001. The results were consistent in all subgroups. CONCLUSIONS: The results suggest that statin therapy might be beneficial for patients undergoing surgical aortic valve replacement for aortic stenosis. Randomized controlled trials are warranted to establish causality between statin treatment and improved outcome.

Unilateral caudate inactivation increases motor impulsivity in rhesus monkeys.

Impulsivity, the tendency to react quickly and without consideration of consequences, is correlated with asymmetry in the volume of the caudate nucleus in human patients. In this study, we sought to determine whether the induction of functional asymmetry in the caudate nucleus of monkeys would produce phenomenologically comparable behavior. We found that unilateral suppression of the ventral caudate nucleus increases impulsive behavior in rhesus monkeys. Impulsivity was modeled by the subjects' inability to maintain hold of a touch-sensitive bar until presentation of an imperative signal. Two methods were used to suppress activity in the caudate region. First, muscimol was locally infused. Second, a viral construct expressing the hM4Di DREADD (designer receptor exclusively activated by designer drug) was injected at the same site. Clozapine N-oxide and deschloroclozapine activate the DREADD to suppress neuronal activity. Both methods of suppression, pharmacological and chemogenetic, increased the rate of early bar releases, a behavior we interpret to indicate impulsivity. Thus, we demonstrate a causal relationship between caudate asymmetry and impulsivity.

Engaging Young Black Males in Sexual and Reproductive Health Care: A Review of the Literature.

Young Black males (YBM) ages 18 to 24 years are more at risk of contracting sexually transmitted infections (STIs) and have a substantially greater need for sexual reproductive health (SRH) services than other groups. Despite this significant need, the extant literature does not provide a comprehensive picture of how YBM seek preventive care services (e.g., STI testing). Therefore, the purpose of this review is to address YBM's SRH access and use of STI/HIV testing and screening in this population, with a specific emphasis on young heterosexual Black males, by identifying barriers and facilitators of engaging with SRH care. An electronic search was performed using Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo, PubMed, and Scopus online databases. Keywords were adapted to each database and included variations of "Black males," "sexual reproductive healthcare services," "youth (18-24 years old)," and "healthcare access and utilization." Studies from the review reported that barriers to engaging in SRH care included lack of health insurance, ideas of masculinity that conflict with SRH care, stigma related to accessing services, and lack of knowledge regarding available services and care options. The top facilitators for utilizing SRH care were engagement on behalf of health clinics, confidence gained from social support, access to quality health care in one's community, and trust in the health care system and providers. This review contributes to the current state of the science and is important to the improvement of high-quality services for this population, including respect, choice in care, confidentially, and compassion.

The impact of immunization on the association between poverty and child survival: evidence from Kassena-Nankana District of northern Ghana.

BACKGROUND: Research conducted in Africa has consistently demonstrated that parental poverty and low educational attainment adversely affect child survival. Research conducted elsewhere has demonstrated that low-cost vaccines against preventable diseases reduce childhood mortality. Therefore, the extension of vaccination to impoverished populations is widely assumed to diminish equity effects. Recent evidence that childhood mortality is increasing in many countries where vaccination programmes are active challenges this assumption. DATA AND METHODS: This paper marshals data from accurate and complete immunization records and survival histories for 18,368 children younger than five years in a rural northern Ghanaian population that is generally impoverished, but where family wealth and parental educational differentials exist nonetheless. Time-conditional Weibull hazard models are estimated to test the hypothesis that childhood immunization offsets the detrimental effects of poverty and low educational attainment. CONCLUSIONS: Findings show that the adverse effects of poverty disappear and that the effects of educational attainment are reduced in survival models that control for immunization status. This finding lends empirical support to policies that promote immunization as a strategic component of poverty-reduction programmes.

Methods for isolation and transcriptional profiling of individual cells from the human heart.

BACKGROUND: Global transcriptional profiling of individual cells represents a powerful approach to systematically survey contributions from cell-specific molecular phenotypes to human disease states but requires tissue-specific protocols. Here we sought to comprehensively evaluate protocols for single cell isolation and transcriptional profiling from heart tissue, focusing particularly on frozen tissue which is necessary for study of human hearts at scale. METHODS AND RESULTS: Using flow cytometry and high-content screening, we found that enzymatic dissociation of fresh murine heart tissue resulted in a sufficient yield of intact cells while for frozen murine or human heart resulted in low-quality cell suspensions across a range of protocols. These findings were consistent across enzymatic digestion protocols and whether samples were snap-frozen or treated with RNA-stabilizing agents before freezing. In contrast, we show that isolation of cardiac nuclei from frozen hearts results in a high yield of intact nuclei, and leverage expression arrays to show that nuclear transcriptomes reliably represent the cytoplasmic and whole-cell transcriptomes of the major cardiac cell types. Furthermore, coupling of nuclear isolation to PCM1-gated flow cytometry facilitated specific cardiomyocyte depletion, expanding resolution of the cardiac transcriptome beyond bulk tissue transcriptomes which were most strongly correlated with PCM1+ transcriptomes (r = 0.8). We applied these methods to generate a transcriptional catalogue of human cardiac cells by droplet-based RNA-sequencing of 8,460 nuclei from which cellular identities were inferred. Reproducibility of identified clusters was confirmed in an independent biopsy (4,760 additional PCM1- nuclei) from the same human heart. CONCLUSION: Our results confirm the validity of single-nucleus but not single-cell isolation for transcriptional profiling of individual cells from frozen heart tissue, and establishes PCM1-gating as an efficient tool for cardiomyocyte depletion. In addition, our results provide a perspective of cell types inferred from single-nucleus transcriptomes that are present in an adult human heart.

Susceptibility to Ventricular Arrhythmias Resulting from Mutations in FKBP1B, PXDNL, and SCN9A Evaluated in hiPSC Cardiomyocytes.

BACKGROUND: We report an inherited cardiac arrhythmia syndrome consisting of Brugada and Early Repolarization Syndrome associated with variants in SCN9A, PXDNL, and FKBP1B. The proband inherited the 3 mutations and exhibited palpitations and arrhythmia-mediated syncope, whereas the parents and sister, who carried one or two of the mutations, were asymptomatic. METHODS AND RESULTS: We assessed the functional impact of these mutations in induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) derived from the proband and an unaffected family member. Current and voltage clamp recordings, as well as confocal microscopy analysis of Ca2+ transients, were evaluated in hiPSC-CMs from the proband and compared these results with hiPSC-CMs from undiseased controls. Genetic analysis using next-generation DNA sequencing revealed heterozygous mutations in SCN9A, PXDNL, and FKBP1B in the proband. The proband displayed right bundle branch block and exhibited episodes of syncope. The father carried a mutation in FKBP1B, whereas the mother and sister carried the SCN9A mutation. None of the 3 family members screened developed cardiac events. Action potential recordings from control hiPSC-CM showed spontaneous activity and a low upstroke velocity. In contrast, the hiPSC-CM from the proband showed irregular spontaneous activity. Confocal microscopy of the hiPSC-CM of the proband revealed low fluorescence intensity Ca2+ transients that were episodic in nature. Patch-clamp measurements in hiPSC-CM showed no difference in I Na but reduced I Ca in the proband compared with control. Coexpression of PXDNL-R391Q with SCN5A-WT displayed lower I Na density compared to PXDNL-WT. In addition, coexpression of PXDNL-R391Q with KCND3-WT displayed significantly higher I to density compared to PXDNL-WT. CONCLUSION: SCN9A, PXDNL, and FKBP1B variants appeared to alter spontaneous activity in hiPSC-CM. Only the proband carrying all 3 mutations displayed the ERS/BrS phenotype, whereas one nor two mutations alone did not produce the clinical phenotype. Our results suggest a polygenic cause of the BrS/ERS arrhythmic phenotype due to mutations in these three gene variants caused a very significant loss of function of I Na and I Ca and gain of function of I to.

Whole-genome sequencing based on formalin-fixed paraffin-embedded endomyocardial biopsies for genetic studies on outcomes after heart transplantation.

BACKGROUND: Whole-genome sequencing (WGS) of heart transplant recipient- and donor-derived cardiac biopsies may facilitate organ matching, graft failure prediction, and immunotolerance research. The objective of this study was to determine the feasibility of WGS based on formalin-fixed paraffin-embedded endomyocardial biopsies. METHODS AND RESULTS: The study included serial donor- and recipient samples from patients who had undergone heart transplantation at Skane University Hospital, Lund, Sweden, between 1988 and 2009. DNA extraction and WGS were conducted. Additional WGS sequencing quality metrics and coverage were obtained with the Genome Analysis Toolkit (GATK). 455 endomyocardial samples from 37 heart transplant recipients were acquired from routine rejection monitoring and stored as formalin-fixed paraffin-embedded samples. They were analyzed after 3-26 years of storage. DNA was extracted from 114 samples and WGS was run on 85 samples. DNA extraction yielded 313 ng (IQR 96-601) for all samples. A coverage of 11.3x (IQR 9.0-15.9) was recorded for all WGS samples. Three samples stored for > 25 years yielded a coverage of > 25x. Data were generated for 1.7 billion reads per sample (IQR 1.4-2.7). A Transition/Transversion (TiTv) ratio of 2.09 ± 0.05 was calculated for all WGS samples. No associations were found among storage time, DNA yield, or sequencing quality metrics. CONCLUSIONS: The present study demonstrated the feasibility of whole-genome sequencing based on endomyocardial biopsies. This process could enable large-scale retrospective genomic studies using stored histopathological samples.

Accelerating Biomarker Discovery Through Electronic Health Records, Automated Biobanking, and Proteomics.

BACKGROUND: Circulating biomarkers can facilitate diagnosis and risk stratification for complex conditions such as heart failure (HF). Newer molecular platforms can accelerate biomarker discovery, but they require significant resources for data and sample acquisition. OBJECTIVES: The purpose of this study was to test a pragmatic biomarker discovery strategy integrating automated clinical biobanking with proteomics. METHODS: Using the electronic health record, the authors identified patients with and without HF, retrieved their discarded plasma samples, and screened these specimens using a DNA aptamer-based proteomic platform (1,129 proteins). Candidate biomarkers were validated in 3 different prospective cohorts. RESULTS: In an automated manner, plasma samples from 1,315 patients (31% with HF) were collected. Proteomic analysis of a 96-patient subset identified 9 candidate biomarkers (p < 4.42 × 10-5). Two proteins, angiopoietin-2 and thrombospondin-2, were associated with HF in 3 separate validation cohorts. In an emergency department-based registry of 852 dyspneic patients, the 2 biomarkers improved discrimination of acute HF compared with a clinical score (p < 0.0001) or clinical score plus B-type natriuretic peptide (p = 0.02). In a community-based cohort (n = 768), both biomarkers predicted incident HF independent of traditional risk factors and N-terminal pro-B-type natriuretic peptide (hazard ratio per SD increment: 1.35 [95% confidence interval: 1.14 to 1.61; p = 0.0007] for angiopoietin-2, and 1.37 [95% confidence interval: 1.06 to 1.79; p = 0.02] for thrombospondin-2). Among 30 advanced HF patients, concentrations of both biomarkers declined (80% to 84%) following cardiac transplant (p < 0.001 for both). CONCLUSIONS: A novel strategy integrating electronic health records, discarded clinical specimens, and proteomics identified 2 biomarkers that robustly predict HF across diverse clinical settings. This approach could accelerate biomarker discovery for many diseases.

Profiling of the plasma proteome across different stages of human heart failure.

Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood. The systematic characterization of circulating proteins across different stages of HF may provide pathophysiological insights and identify therapeutic targets. Here we report application of aptamer-based proteomics to identify proteins associated with prospective HF incidence in a population-based cohort, implicating modulation of immunological, complement, coagulation, natriuretic and matrix remodeling pathways up to two decades prior to overt disease onset. We observe further divergence of these proteins from the general population in advanced HF, and regression after heart transplantation. By leveraging coronary sinus samples and transcriptomic tools, we describe likely cardiac and specific cellular origins for several of the proteins, including Nt-proBNP, thrombospondin-2, interleukin-18 receptor, gelsolin, and activated C5. Our findings provide a broad perspective on both cardiac and systemic factors associated with HF development.

Development of a patient experience questionnaire to improve lifestyle services in primary care.

AimWe developed a self-report tool to assess patients' experiences with lifestyle services in team-based primary care and pilot tested the questionnaire as part of a lifestyle intervention study to reverse metabolic syndrome. BACKGROUND: Older client satisfaction questionnaires have been generally inadequate for quality improvement purposes, as they have been focused mainly on interpersonal skills of providers and/or in the context of one disease. New approaches to assessing the patient experience of lifestyle programs in primary care are needed and could inform quality improvement efforts over time. METHODS: The first phase in developing the questionnaire involved a group-administered questionnaire distributed to 38 healthcare providers in five groups to prioritize variables to include in the survey. Concepts were taken from a previous review of available questionnaires assessing primary care services. The draft questionnaire was reviewed by 11 participants from a lifestyle program using think-aloud cognitive interviewing techniques. The modified self-administered questionnaire (paper and online versions) was then pilot tested with 164 recipients of a nutrition and physical activity intervention program.FindingsProviders ranked the top variables to include in the questionnaire as: 'trust,' 'general communication,' 'first-contact accessibility,' 'whole-person care,' and 'respectfulness.' After cognitive interviewing and revisions, 21 multiple choice and two open-ended questions were used for pilot testing. Pilot testing identified additional minor wording changes that were needed for clarity, a decreased number of questions for redundant concepts, and decreased options for ceiling effects, resulting in 20 multiple choice and one open-ended question. CONCLUSIONS: The modified self-administered patient experience questionnaire to assess lifestyle services in primary care has undergone rigorous development. Further validation is needed. The assessment of patient experience of lifestyle programs can be used to supplement other data to assess the overall effectiveness of such programs.

Bridging the gap between evidence-based innovation and national health-sector reform in Ghana.

Although experimental trials often identify optimal strategies for improving community health, transferring operational innovation from well-funded research programs to resource-constrained settings often languishes. Because research initiatives are based in institutions equipped with unique resources and staff capabilities, results are often dismissed by decisionmakers as irrelevant to large-scale operations and national health policy. This article describes an initiative undertaken in Nkwanta District, Ghana, focusing on this problem. The Nkwanta District initiative is a critical link between the experimental study conducted in Navrongo, Ghana, and a national effort to scale up the innovations developed in that study. A 2002 Nkwanta district-level survey provides the basis for assessing the likelihood that the Navrongo model is replicable elsewhere in Ghana. The effect of community-based health planning and services exposure on family planning and safe-motherhood indicators supports the hypothesis that Navrongo effects are transferable to impoverished rural settings elsewhere, confirming the need for strategies to bridge the gap between Navrongo evidence-based innovation and national health-sector reform.