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Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.
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Epilepsia , Transtornos do Neurodesenvolvimento , Ubiquitina-Proteína Ligases , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Deficiências do Desenvolvimento/genética , Metilação de DNA/genética , Epigênese Genética , Epilepsia/genética , Histonas/metabolismo , Histonas/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: Pulmonary arterial hypertension (PAH) is high blood pressure in the lungs that originates from structural changes in small resistance arteries. A defining feature of PAH is the inappropriate remodeling of pulmonary arteries (PA) leading to right ventricle failure and death. Although treatment of PAH has improved, the long-term prognosis for patients remains poor, and more effective targets are needed. METHODS: Gene expression was analyzed by microarray, RNA sequencing, quantitative polymerase chain reaction, Western blotting, and immunostaining of lung and isolated PA in multiple mouse and rat models of pulmonary hypertension (PH) and human PAH. PH was assessed by digital ultrasound, hemodynamic measurements, and morphometry. RESULTS: Microarray analysis of the transcriptome of hypertensive rat PA identified a novel candidate, PBK (PDZ-binding kinase), that was upregulated in multiple models and species including humans. PBK is a serine/threonine kinase with important roles in cell proliferation that is minimally expressed in normal tissues but significantly increased in highly proliferative tissues. PBK was robustly upregulated in the medial layer of PA, where it overlaps with markers of smooth muscle cells. Gain-of-function approaches show that active forms of PBK increase PA smooth muscle cell proliferation, whereas silencing PBK, dominant negative PBK, and pharmacological inhibitors of PBK all reduce proliferation. Pharmacological inhibitors of PBK were effective in PH reversal strategies in both mouse and rat models, providing translational significance. In a complementary genetic approach, PBK was knocked out in rats using CRISPR/Cas9 editing, and loss of PBK prevented the development of PH. We found that PBK bound to PRC1 (protein regulator of cytokinesis 1) in PA smooth muscle cells and that multiple genes involved in cytokinesis were upregulated in experimental models of PH and human PAH. Active PBK increased PRC1 phosphorylation and supported cytokinesis in PA smooth muscle cells, whereas silencing or dominant negative PBK reduced cytokinesis and the number of cells in the G2/M phase of the cell cycle. CONCLUSIONS: PBK is a newly described target for PAH that is upregulated in proliferating PA smooth muscle cells, where it contributes to proliferation through changes in cytokinesis and cell cycle dynamics to promote medial thickening, fibrosis, increased PA resistance, elevated right ventricular systolic pressure, right ventricular remodeling, and PH.
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Hipertensão Arterial Pulmonar , Artéria Pulmonar , Remodelação Vascular , Animais , Humanos , Ratos , Camundongos , Masculino , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Modelos Animais de Doenças , Ratos Sprague-Dawley , Proliferação de Células , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Quinases de Proteína Quinase Ativadas por MitógenoRESUMO
N-methyl-D-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. The M3 transmembrane helices of the NMDAR couple directly to the agonist-binding domains and form a helical bundle crossing in the closed receptors that occludes the pore. The M3 functions as a transduction element whose conformational change couples ligand binding to opening of an ion conducting pore. In this study, we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix. These de novo variants were identified in children with neurological and neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia and attention deficit hyperactivity disorder. All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype. This supports the idea that a key structural feature of the M3 gate exists to stabilize the closed state so that agonist binding can drive channel opening. Given that most M3 variants enhance channel gating, we assessed the potency of FDA-approved NMDAR channel blockers on these variant receptors. These data provide new insight into the structure-function relationship of the NMDAR gate, and suggest that variants within the M3 transmembrane helix produce a gain-of-function.
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Epilepsia , Receptores de N-Metil-D-Aspartato , Criança , Humanos , Epilepsia/genética , Mutação de Sentido Incorreto , Fenótipo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de SinaisRESUMO
Genomic medicine has been transformed by next-generation sequencing (NGS), inclusive of exome sequencing (ES) and genome sequencing (GS). Currently, ES is offered widely in clinical settings, with a less prevalent alternative model consisting of hybrid programs that incorporate research ES along with clinical patient workflows. We were among the earliest to implement a hybrid ES clinic, have provided diagnoses to 45% of probands, and have identified several novel candidate genes. Our program is enabled by a cost-effective investment by the health system and is unique in encompassing all the processes that have been variably included in other hybrid/clinical programs. These include careful patient selection, utilization of a phenotype-agnostic bioinformatics pipeline followed by manual curation of variants and phenotype integration by clinicians, close collaborations between the clinicians and the bioinformatician, pursuit of interesting variants, communication of results to patients in categories that are predicated upon the certainty of a diagnosis, and tracking changes in results over time and the underlying mechanisms for such changes. Due to its effectiveness, scalability to GS and its resource efficiency, specific elements of our paradigm can be incorporated into existing clinical settings, or the entire hybrid model can be implemented within health systems that have genomic medicine programs, to provide NGS in a scientifically rigorous, yet pragmatic setting.
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Biologia Computacional , Exoma , Humanos , Exoma/genética , Fenótipo , Sequenciamento do Exoma , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Ultra rare disorders are being diagnosed at an unprecedented rate, due to genomic sequencing. These diagnoses are often a new gene association, for which little is known, and few share the diagnosis. For these diagnoses, we use the term emerging-ultrarare disorder (E-URD), defined as <100 diagnosed individuals. We contacted 20 parents of children diagnosed with an E-URD through the Duke University Research Sequencing Clinic. Seventeen completed semi-structured interviews exploring parental perspectives (7/17 had children in publications describing the phenotype; 4/17 had children in the first publication establishing a new disorder). Data were analyzed using a directed content approach informed by an empowerment framework. Parents reported a range of responses, including benefits of a diagnosis and challenges of facing the unknown, some described feeling lost and confused, while others expressed empowerment. Empowerment characteristics were hope for the future, positive emotions, engagement, and confidence/self-efficacy to connect with similar others, partner with healthcare providers, and seek new knowledge. We identified a subset of parents who proactively engaged researchers, supported research and publications, and created patient advocacy and support organizations to connect with and bolster similarly diagnosed families. Other parents reported challenges of low social support, low tolerance for uncertainty, limited knowledge about their child's disorder, as well as difficulty partnering with HCPs and connecting to an E-URD community. An overarching classification was developed to describe parental actions taken after an E-URD diagnosis: adjusting, managing, and pioneering. These classifications may help genetic counselors identify and facilitate positive steps with parents of a child with an E-URD.
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OBJECTIVE: This study aims to evaluate the effect of a performance-focused swimming programme on motor function in previously untrained adolescents with cerebral palsy and high support needs (CPHSN) and to determine whether the motor decline typical of adolescents with CPHSN occurred in these swimmers. METHODS: A Multiple-Baseline, Single-Case Experimental Design (MB-SCED) study comprising five phases and a 30-month follow-up was conducted. Participants were two males and one female, all aged 15 years, untrained and with CPHSN. The intervention was a 46-month swimming training programme, focused exclusively on improving performance. Outcomes were swim performance (velocity); training load (rating of perceived exertion min/week; swim distance/week) and Gross Motor Function Measure-66-Item Set (GMFM-66). MB-SCED data were analysed using interrupted time-series simulation analysis. Motor function over 46 months was modelled (generalised additive model) using GMFM-66 scores and compared with a model of predicted motor decline. RESULTS: Improvements in GMFM-66 scores in response to training were significant (p<0.001), and two periods of training withdrawal each resulted in significant motor decline (p≤0.001). Participant motor function remained above baseline levels for the study duration, and, importantly, participants did not experience the motor decline typical of other adolescents with CPHSN. Weekly training volumes were also commensurate with WHO recommended physical activity levels. CONCLUSIONS: Results suggest that adolescents with CPHSN who meet physical activity guidelines through participation in competitive swimming may prevent motor decline. However, this population is clinically complex, and in order to permit safe, effective participation in competitive sport, priority should be placed on the development of programmes delivered by skilled multiprofessional teams. TRIAL REGISTRATION NUMBER: ACTRN12616000326493.
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Paralisia Cerebral , Natação , Humanos , Paralisia Cerebral/reabilitação , Paralisia Cerebral/fisiopatologia , Paralisia Cerebral/terapia , Adolescente , Masculino , Natação/fisiologia , Feminino , Seguimentos , Desempenho Atlético/fisiologia , Destreza Motora/fisiologia , ParatletasRESUMO
The Hospital at Home model, called Hospital-in-Home (HIH) in the Department of Veterans Affairs, delivers coordinated, high-value care aligned with older adult and caregiver preferences. Documenting implementation barriers and corresponding strategies to overcome them can address challenges to widespread adoption. To evaluate HIH implementation barriers and identify strategies to address them, we conducted interviews with 8 HIH staff at 4 hospitals between 2010 and 2013. We utilized qualitative directed content analysis guided by the Consolidated Framework for Implementation Research (CFIR) and mapped identified barriers to possible strategies using the CFIR-Expert Recommendations for Implementing Change (ERIC) Matching Tool. We identified 11 barriers spanning 5 CFIR domains. Three implementation strategies - identifying and preparing champions, conducting educational meetings, and capturing and sharing local knowledge - achieved high expert endorsement for each barrier. A mix of strategies targeting resources, organizational readiness and fit, and leadership engagement should be considered to support the sustainability and spread of HIH.
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United States Department of Veterans Affairs , Humanos , Estados Unidos , United States Department of Veterans Affairs/organização & administração , Pesquisa Qualitativa , Masculino , Feminino , Serviços Hospitalares de Assistência Domiciliar/organização & administração , Pessoa de Meia-Idade , Idoso , Entrevistas como Assunto/métodos , Adulto , Serviços de Assistência Domiciliar/normas , Serviços de Assistência Domiciliar/tendênciasRESUMO
CONTEXT: In 2018, the Health Impact Project (the Project) developed and tested a new health in all policies (HiAP) tool called "legislative health notes" to provide state and local legislators with peer-reviewed evidence, public health data, and local data that illustrate potential positive and negative health and equity effects of proposed bills. OBJECTIVES: The Project sought to refine the health note methodology while piloting the tool in the Colorado and Indiana General Assemblies, and with the Council of the District of Columbia, and worked with affiliates to introduce them in North Carolina, Ohio, and California. DESIGN AND PARTICIPANTS: External partners solicited feedback on health notes via semistructured interviews and surveys from legislators, legislative staff, and expert reviewers who were familiar with health notes in each of these jurisdictions. RESULTS: Respondents shared that health notes were nonpartisan, were easy for nonexperts to understand, and would be more effective if delivered earlier in the legislative process. CONCLUSION: In response to informant feedback, practitioners can explore adding high-level summaries, increasing focus on health equity implications and the potential to work with legislators during the policy formulation phase. Data from this pilot suggest that legislative health notes are a promising nonpartisan and standardized tool to better understand the health and equity implications of proposed legislation.
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Política de Saúde , Formulação de Políticas , Humanos , Colorado , District of Columbia , North CarolinaAssuntos
Nitrilas , Mielofibrose Primária , Pirazóis , Pirimidinas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método Duplo-Cego , Nitrilas/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVES: We identify factors associated with sustainment of an intervention (STAR-VA) to address distress behaviors in dementia (DBD), guided by the Organizational Memory Knowledge Reservoir (KR) framework, compared across 2 types of outcomes: (1) site performance improvement on a clinical outcome, the magnitude of change in levels of DBD, and (2) self-rated adherence to STAR-VA core components, a process outcome. DESIGN: We used a cross-sectional sequential explanatory mixed methods design guided by the Organizational Memory Framework. SETTING AND PARTICIPANTS: We selected 20 of 79 sites that completed STAR-VA training and consultation based on rankings on 2 outcomes-change in an indicator of DBD and reported adherence to STAR-VA core components. We recruited key informants most knowledgeable about STAR-VA resulting in a sample of 43% behavioral coordinators, 36% nurse champions, and 21% nurse leaders. METHODS: We collected data with key informants at each Community Living Center (CLC) from December 2018 to June 2019. We analyzed data using within-case and cross-case matrixes created from the coded transcripts for each a priori KR domain. We then assessed if there were any similarities or differences for CLCs in comparable DBD performance and STAR-VA adherence categories. RESULTS: We found 4 KRs that differentiated sustainment factors based on CLC implementation process and clinical outcomes-3 KRs related to DBD performance (people, relationships, and routines) and 2 related to STAR-VA adherence (relationships and culture). CONCLUSIONS AND IMPLICATIONS: This evaluation found several knowledge retention mechanisms that differ in high and low performance/adherence sites. Our findings highlight knowledge retention/sustainment strategies based on site functioning to support sustainment strategies in the CLC. Understanding sustainment factors as they relate to clinical and process outcomes is innovative and can be used to support CLCs struggling with sustainment. More research is needed to inform tailored sustainment efforts based on site functioning in the nursing home setting.
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Veteranos , Estados Unidos , Humanos , Estudos Transversais , United States Department of Veterans Affairs , Casas de Saúde , Instituições de Cuidados Especializados de EnfermagemRESUMO
OBJECTIVE: To investigate whether the sex disparities in type 2 diabetes-associated cardiovascular disease (CVD) risks may be related to early-onset hypertension that could benefit from intensive blood pressure (BP) control. RESEARCH DESIGN AND METHODS: We analyzed intensive versus standard BP control in relation to incident CVD events in women and men with type 2 diabetes, based on their age of hypertension diagnosis. RESULTS: Among 3,792 adults with type 2 diabetes (49% women), multivariable-adjusted CVD risk was increased per decade earlier age at hypertension diagnosis (hazard ratio 1.11 [1.03-1.21], P = 0.006). Excess risk associated with early-diagnosed hypertension was attenuated in the presence of intensive versus standard antihypertensive therapy in women (P = 0.036) but not men (P = 0.76). CONCLUSIONS: Women with type 2 diabetes and early-onset hypertension may represent a higher-risk subpopulation that not only contributes to the excess in diabetes-related CVD risk for women but may benefit from intensive BP control.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipertensão , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Feminino , Hipertensão/epidemiologia , Hipertensão/complicações , Masculino , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Pessoa de Meia-Idade , Adulto , Fatores de Risco , Anti-Hipertensivos/uso terapêutico , Idoso , Fatores Sexuais , Idade de Início , Pressão Sanguínea/fisiologiaRESUMO
BACKGROUND: The iPRISM webtool is an interactive tool designed to aid the process of applying the Practical, Robust Implementation and Sustainability Model (PRISM) for the assessment of and fit with context. A learning community (LC) is a multidisciplinary group of partners addressing a complex problem. Our LC coproduced the Physical TheraPy frEqueNcy Clinical decIsion support tooL (PT-PENCIL) to guide the use of physical therapist services in acute care hospitals. OBJECTIVE: To describe our LC's activities to co-produce the PT-PENCIL, use of the iPRISM webtool to assess its preimplementation context and fit, and develop a multicomponent implementation strategy for the PT-PENCIL. DESIGN: A descriptive research design. SETTING: Three tertiary care hospitals. PARTICIPANTS: Thirteen LC partners: six clinical physical therapists, three rehabilitation managers, three researchers, and a bioinformaticist. INTERVENTIONS: Not applicable. OUTCOME MEASURES: Using the iPRISM webtool, expected fit of the PT-PENCIL was rated 1 (not aligned) to 6 (well aligned) for each PRISM domain and expected reach, effectiveness, adoption, implementation, and maintenance were rated 1 (not likely at all) to 6 (very likely). Discrete implementation strategies were identified from the Expert Recommendations for Implementing Change. RESULTS: The process spanned 18 meetings over 8 months. Ten LC partners completed the iPRISM webtool. PRISM domains with the lowest expected alignment were the "implementation and sustainability infrastructure" (mean = 4.7 out of 6; range = 3-6) and the "external environment" (mean = 4.9 of 6; range = 4-6). Adoption was the outcome with the lowest expected likelihood (mean = 4.5 out of 6; range = 1-6). Six discrete implementation strategies were identified and combined into a multicomponent strategy. CONCLUSIONS: Within a LC, we used existing implementation science resources to co-produce a novel clinical decision support tool for acute care physical therapists and develop a strategy for its implementation. Our methodology can be replicated for similar projects given the public availability of each resource used.
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OBJECTIVE: To evaluate nationwide implementation of a Guidebook designed to standardize safety practices across VA-delivered and VA-purchased care (i.e., Community Care) and identify lessons learned and strategies to improve them. DATA SOURCES AND STUDY SETTING: Qualitative data collected from key informants at 18 geographically diverse VA facilities across 17 Veterans Integrated Services Networks (VISNs). STUDY DESIGN: We conducted semi-structured interviews from 2019 to 2022 with VISN Patient Safety Officers (PSOs) and VA facility patient safety and quality managers (PSMs and QMs) and VA Facility Community Care (CC) staff to assess lessons learned by examining organizational contextual factors affecting Guidebook implementation based on the Consolidated Framework for Implementation Research (CFIR). DATA COLLECTION/EXTRACTION METHODS: Interviews were conducted virtually with 45 facility staff and 10 VISN PSOs. Using directed content analysis, we identified CFIR factors affecting implementation. These factors were mapped to the Expert Recommendations for Implementing Change (ERIC) strategy compilation to identify lessons learned that could be useful to our operational partners in improving implementation processes. We met frequently with our partners to discuss findings and plan next steps. PRINCIPAL FINDINGS: Six CFIR constructs were identified as both facilitators and barriers to Guidebook implementation: (1) planning for implementation; (2) engaging key knowledge holders; (3) available resources; (4) networks and communications; (5) culture; and (6) external policies. The two CFIR constructs that were only barriers included: (1) cosmopolitanism and (2) executing implementation. CONCLUSIONS: Our findings suggest several important lessons: (1) engage all collaborators involved in implementation; (2) ensure end-users have opportunities to provide feedback; (3) describe collaborators' purpose and roles/responsibilities clearly at the start; (4) communicate information widely and repeatedly; and (5) identify how multiple high priorities can be synergistic. This evaluation will help our partners and key VA leadership to determine next steps and future strategies for improving Guidebook implementation through collaboration with VA staff.
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BACKGROUND: Sustaining evidence-based practices (EBPs) is crucial to ensuring care quality and addressing health disparities. Approaches to identifying factors related to sustainability are critically needed. One such approach is Matrixed Multiple Case Study (MMCS), which identifies factors and their combinations that influence implementation. We applied MMCS to identify factors related to the sustainability of the evidence-based Collaborative Chronic Care Model (CCM) at nine Department of Veterans Affairs (VA) outpatient mental health clinics, 3-4 years after implementation support had concluded. METHODS: We conducted a directed content analysis of 30 provider interviews, using 6 CCM elements and 4 Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) domains as codes. Based on CCM code summaries, we designated each site as high/medium/low sustainability. We used i-PARIHS code summaries to identify relevant factors for each site, the extent of their presence, and the type of influence they had on sustainability (enabling/neutral/hindering/unclear). We organized these data into a sortable matrix and assessed sustainability-related cross-site trends. RESULTS: CCM sustainability status was distributed among the sites, with three sites each being high, medium, and low. Twenty-five factors were identified from the i-PARIHS code summaries, of which 3 exhibited strong trends by sustainability status (relevant i-PARIHS domain in square brackets): "Collaborativeness/Teamwork [Recipients]," "Staff/Leadership turnover [Recipients]," and "Having a consistent/strong internal facilitator [Facilitation]" during and after active implementation. At most high-sustainability sites only, (i) "Having a knowledgeable/helpful external facilitator [Facilitation]" was variably present and enabled sustainability when present, while (ii) "Clarity about what CCM comprises [Innovation]," "Interdisciplinary coordination [Recipients]," and "Adequate clinic space for CCM team members [Context]" were somewhat or less present with mixed influences on sustainability. CONCLUSIONS: MMCS revealed that CCM sustainability in VA outpatient mental health clinics may be related most strongly to provider collaboration, knowledge retention during staff/leadership transitions, and availability of skilled internal facilitators. These findings have informed a subsequent CCM implementation trial that prospectively examines whether enhancing the above-mentioned factors within implementation facilitation improves sustainability. MMCS is a systematic approach to multi-site examination that can be used to investigate sustainability-related factors applicable to other EBPs and across multiple contexts.
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Serviços de Saúde Mental , Saúde Mental , Humanos , Pacientes Ambulatoriais , Assistência de Longa Duração , Qualidade da Assistência à SaúdeRESUMO
Importance: Clinical outcomes after acute coronary syndromes (ACS) or percutaneous coronary interventions (PCIs) in people living with HIV have not been characterized in sufficient detail, and extant data have not been synthesized adequately. Objective: To better characterize clinical outcomes and postdischarge treatment of patients living with HIV after ACS or PCIs compared with patients in an HIV-negative control group. Data Sources: Ovid MEDLINE, Embase, and Web of Science were searched for all available longitudinal studies of patients living with HIV after ACS or PCIs from inception until August 2023. Study Selection: Included studies met the following criteria: patients living with HIV and HIV-negative comparator group included, patients presenting with ACS or undergoing PCI included, and longitudinal follow-up data collected after the initial event. Data Extraction and Synthesis: Data extraction was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Clinical outcome data were pooled using a random-effects model meta-analysis. Main Outcome and Measures: The following clinical outcomes were studied: all-cause mortality, major adverse cardiovascular events, cardiovascular death, recurrent ACS, stroke, new heart failure, total lesion revascularization, and total vessel revascularization. The maximally adjusted relative risk (RR) of clinical outcomes on follow-up comparing patients living with HIV with patients in control groups was taken as the main outcome measure. Results: A total of 15 studies including 9499 patients living with HIV (pooled proportion [range], 76.4% [64.3%-100%] male; pooled mean [range] age, 56.2 [47.0-63.0] years) and 1â¯531â¯117 patients without HIV in a control group (pooled proportion [range], 61.7% [59.7%-100%] male; pooled mean [range] age, 67.7 [42.0-69.4] years) were included; both populations were predominantly male, but patients living with HIV were younger by approximately 11 years. Patients living with HIV were also significantly more likely to be current smokers (pooled proportion [range], 59.1% [24.0%-75.0%] smokers vs 42.8% [26.0%-64.1%] smokers) and engage in illicit drug use (pooled proportion [range], 31.2% [2.0%-33.7%] drug use vs 6.8% [0%-11.5%] drug use) and had higher triglyceride (pooled mean [range], 233 [167-268] vs 171 [148-220] mg/dL) and lower high-density lipoprotein-cholesterol (pooled mean [range], 40 [26-43] vs 46 [29-46] mg/dL) levels. Populations with and without HIV were followed up for a pooled mean (range) of 16.2 (3.0-60.8) months and 11.9 (3.0-60.8) months, respectively. On postdischarge follow-up, patients living with HIV had lower prevalence of statin (pooled proportion [range], 53.3% [45.8%-96.1%] vs 59.9% [58.4%-99.0%]) and ß-blocker (pooled proportion [range], 54.0% [51.3%-90.0%] vs 60.6% [59.6%-93.6%]) prescriptions compared with those in the control group, but these differences were not statistically significant. There was a significantly increased risk among patients living with HIV vs those without HIV for all-cause mortality (RR, 1.64; 95% CI, 1.32-2.04), major adverse cardiovascular events (RR, 1.11; 95% CI, 1.01-1.22), recurrent ACS (RR, 1.83; 95% CI, 1.12-2.97), and admissions for new heart failure (RR, 3.39; 95% CI, 1.73-6.62). Conclusions and Relevance: These findings suggest the need for attention toward secondary prevention strategies to address poor outcomes of cardiovascular disease among patients living with HIV.
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Síndrome Coronariana Aguda , Infecções por HIV , Intervenção Coronária Percutânea , Humanos , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Síndrome Coronariana Aguda/cirurgia , Síndrome Coronariana Aguda/epidemiologia , Intervenção Coronária Percutânea/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Feminino , Resultado do Tratamento , Revascularização Miocárdica/estatística & dados numéricos , AdultoRESUMO
Background: Sustaining healthcare interventions once they have been implemented is a pivotal public health endeavor. Achieving sustainability requires context-sensitive adaptations to evidence-based practices (EBPs) or the implementation strategies used to ensure their adoption. For replicability of adaptations beyond the specific setting in question, the underlying logic needs to be clearly described, and adaptations themselves need to be plainly documented. The goal of this project was to describe the process by which implementation facilitation was adapted to improve the uptake of clinical care practices that are consistent with the collaborative chronic care model (CCM). Method: Quantitative and qualitative data from a prior implementation trial found that CCM-consistent care practices were not fully sustained within outpatient general mental health teams that had received 1 year of implementation facilitation to support uptake. We undertook a multistep consensus process to identify adaptations to implementation facilitation based on these results, with the goal of enhancing the sustainability of CCM-based care in a subsequent trial. The logic for these adaptations, and the resulting adaptations themselves, were documented using two adaptation-oriented implementation frameworks (the iterative decision-making for evaluation of adaptations [IDEA] and the framework for reporting adaptations and modifications to evidence-based implementation strategies [FRAME-IS], respectively). Results: Three adaptations emerged from this process and were documented using the FRAME-IS: (a) increasing the scope of implementation facilitation within the medical center, (b) having the internal facilitator take a greater role in the implementation process, and (c) shortening the implementation timeframe from 12 to 8 months, while increasing the intensity of facilitation support during that time. Conclusions: EBP sustainability may require careful adaptation of EBPs or the implementation strategies used to get them into routine practice. Recently developed frameworks such as the IDEA and FRAME-IS may be used to guide decision-making and document resulting adaptations themselves. An ongoing funded study is investigating the utility of the resulting adaptations for improving healthcare.
Evidence-based treatments may not be sustained after they have been implemented in healthcare settings. To address this, treatments and implementation strategies may need to be adapted to fit the local context or the patient population. Maximizing the usefulness of such adaptations requires documenting the decision-making process. Understanding how an implementation strategy has been adapted for a given study or setting is crucial to ensuring that adaptations don't compromise fidelity to the implementation strategy while enabling its replicability in similar settings. This article uses two adaptation frameworks to describe the process by which implementation facilitation, a common implementation strategy, was adapted to help establish and sustain effective mental health clinical teams in VA medical centers. It is our hope that our description of this process may help healthcare researchers, administrators, and policymakers to describe and document adaptations to implementation strategies in their own settings.
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Hyperpolarization activated Cyclic Nucleotide (HCN) gated channels are crucial for various neurophysiological functions, including learning and sensory functions, and their dysfunction are responsible for brain disorders, such as epilepsy. To date, HCN2 variants have only been associated with mild epilepsy and recently, one monoallelic missense variant has been linked to developmental and epileptic encephalopathy. Here, we expand the phenotypic spectrum of HCN2- related disorders by describing twenty-one additional individuals from fifteen unrelated families carrying HCN2 variants. Seventeen individuals had developmental delay/intellectual disability (DD/ID), two had borderline DD/ID, and one had borderline DD. Ten individuals had epilepsy with DD/ID, with median age of onset of 10 months, and one had epilepsy with normal development. Molecular diagnosis identified thirteen different pathogenic HCN2 variants, including eleven missense variants affecting highly conserved amino acids, one frameshift variant, and one in-frame deletion. Seven variants were monoallelic of which five occurred de novo, one was not maternally inherited, one was inherited from a father with mild learning disabilities, and one was of unknown inheritance. The remaining six variants were biallelic, with four homozygous and two compound heterozygous variants. Functional studies using two-electrode voltage-clamp recordings in Xenopus laevis oocytes were performed on three monoallelic variants, p.(Arg324His), p.(Ala363Val), and p.(Met374Leu), and three biallelic variants, p.(Leu377His), p.(Pro493Leu) and p.(Gly587Asp). The p.(Arg324His) variant induced a strong increase of HCN2 conductance, while p.(Ala363Val) and p.(Met374Leu) displayed dominant negative effects, leading to a partial loss of HCN2 channel function. By confocal imaging, we found that the p.(Leu377His), p.(Pro493Leu) and p.(Gly587Asp) pathogenic variants impaired membrane trafficking, resulting in a complete loss of HCN2 elicited currents in Xenopus oocytes. Structural 3D-analysis in depolarized and hyperpolarized states of HCN2 channels, revealed that the pathogenic variants p.(His205Gln), p.(Ser409Leu), p.(Arg324Cys), p.(Asn369Ser) and p.(Gly460Asp) modify molecular interactions altering HCN2 function. Taken together, our data broadens the clinical spectrum associated with HCN2 variants, and disclose that HCN2 is involved in developmental encephalopathy with or without epilepsy.