Revisiting sex as a biological variable in hypertension research.

Half of adults in the United States have hypertension as defined by clinical practice guidelines. Interestingly, women are generally more likely to be aware of their hypertension and have their blood pressure controlled with treatment compared with men, yet hypertension-related mortality is greater in women. This may reflect the fact that the female sex remains underrepresented in clinical and basic science studies investigating the effectiveness of therapies and the mechanisms controlling blood pressure. This Review provides an overview of the impact of the way hypertension research has explored sex as a biological variable (SABV). Emphasis is placed on epidemiological studies, hypertension clinical trials, the genetics of hypertension, sex differences in immunology and gut microbiota in hypertension, and the effect of sex on the central control of blood pressure. The goal is to offer historical perspective on SABV in hypertension, highlight recent studies that include SABV, and identify key gaps in SABV inclusion and questions that remain in the field. Through continued awareness campaigns and engagement/education at the level of funding agencies, individual investigators, and in the editorial peer review system, investigation of SABV in the field of hypertension research will ultimately lead to improved clinical outcomes.

A Mixed Methods Study Exploring Patient Safety Culture at Four VHA Hospitals.

BACKGROUND: Patient safety culture (PSC) fosters an environment of trust where people are encouraged to share information to promote psychological safety. To measure PSC, the Veteran's Health Administration (VHA) developed a PSC survey consisting of 20 items administered to all VHA employees. The survey comprises four scales: (1) risk identification and Just Culture, (2) error transparency and mitigation, (3) supervisor communication and trust, and (4) team cohesion and engagement. Our objective was to compare the PSC survey data to qualitative data regarding high reliability organization (HRO) implementation from four purposively selected VHA hospitals to assess how it manifests and converges. METHODS: Qualitative data focused on understanding HRO implementation efforts were collected from key informants between 2019 and 2020 at 4 of the 18 VHA HRO implementation hospitals. To explore the extent and manifestation of each of the PSC scales among the 4 sites, we combined the qualitative data with the PSC survey data from each hospital using a joint display. RESULTS: Survey responses were significantly different between the 4 hospitals for all 4 PSC scales. Of the 20 PSC survey items, 12 (60.0%) significantly differed across the 4 hospitals. For example, we saw cross-hospital differences in the following survey items: "We are given feedback about changes put into place based on event reports" and "We take the time to identify and assess risks to patient safety." Qualitative data supported manifestations for 80.0% (16/20) of PSC individual survey items among hospitals. CONCLUSION: The authors found that the qualitative data manifestations were well aligned with the VHA PSC scales, but relationships were not always consistent between data sources. Further research is necessary to elucidate these relationships.

Variations in antihypertensive medication treatment and blood pressure control among Veterans with HIV and existing hypertension.

BACKGROUND: Hypertension is a leading risk factor for cardiovascular disease among patients living with HIV (PLWH). Understanding the predictors and patterns of antihypertensive medication prescription and blood pressure (BP) control among PLWH with hypertension (HTN) is important to improve the primary prevention efforts for this high-risk population. We sought to identify important patient-level correlates for (e.g., race) and assess inter-facility variations in antihypertension medication prescriptions and BP control among Veterans living with HIV (VLWH) and HTN. METHODS: We studied VLWH with a diagnosis of HTN who received care in the Veterans Health Administration (VHA) from January 2018 to December 2019. We evaluated HTN treatment and blood pressure control across demographic variables, including race, and by medical comorbidities. Data were also compared among VHA facilities. Predictors of HTN treatment and control were assessed in two-level hierarchical multivariate logistic regression models to estimate odds ratios (ORs). The VHA facility random-effects parameters from the hierarchical models were used to calculate the median odds ratios to characterize the variation across the different VHA facilities. RESULTS: A total of 17,468 VLWH with HTN (mean age 61 years, 97% male, 54% Black, 40% White) who received care within the VHA facilities in 2018-2019 were included. 73% were prescribed antihypertension medications with higher prescription rates among Black versus White patients (75% vs. 71%) and higher prescription rates among patients with a history of cardiovascular disease, diabetes, and kidney disease (>80%), and those receiving antiretroviral therapy and with controlled HIV viral load (∼75%). Only 27% of VLWH with HTN had optimal BP control of systolic BP <130 mmHg and diastolic BP <80 mmHg, with a lower rate of control among Black versus White patients (24% v. 31%). In multivariate regression, Black patients had a higher likelihood of HTN medication prescription (OR 1.32, 95% CI: 1.22-1.42 used Table 3) but were less likely to have optimal BP control (OR 0.82; 0.76-0.88). Important correlates of antihypertensive prescription and optimal BP control included: number of outpatient visits, and histories of diabetes, coronary artery disease, and heart failure. There was about 10% variability in both antihypertensive prescription and BP control patterns between VHA facilities for patients with similar characteristics. There was increased inter-facility variation antihypertensive prescription among those with a history of heart failure and those not receiving antiretroviral therapy. CONCLUSION: In a retrospective analysis of large VHA data, we found that VLWH with HTN have suboptimal antihypertensive medication prescription and BP control. Black VLWH had higher HTN medication prescription rates but lower optimal BP control.

Optimizing Renal Transporter Immunodetection: Consequences of Freeze-Thaw during Sample Preparation.

Renal transporters (co-transporters, channels, claudins) mediate homeostasis of fluids and electrolytes and are targets of hormonal and therapeutic regulators. Assessing renal transporter abundance with antibody probes by immunoblotting is an essential tool for mechanistic studies. While journals require authors to demonstrate antibody specificity, there are no consensus guidelines for kidney sample preparation leading to lab-to-lab variability in immunoblot results. In this study, we determined the impact of sample preparation, specifically freeze-thawed (Froz) versus freshly-processed (Fresh) kidneys (female and male rats and mice) on immunoblot signal detection of fifteen renal transporters, and the impact of protease inhibitors during homogenization. In female Sprague Dawley rat kidneys homogenized with: aprotinin, Na2EDTA, PMSF, and phosphatase inhibitors, immunodetection signals were ~50% lower in Frozen versus Fresh samples for most transporters. Inclusion of additional inhibitors (Roche cOmpleteTM Protease Inhibitor, "+") only partially increased transporter immunoblot signals to near Fresh levels. In male Sprague Dawley rats, immunoblot signal density was lower in Froz+ versus Fresh+ despite additional inhibitors. In C57BL/6 male mice, immunoblot signals from proximal tubule transporters were lower in Froz vs Fresh by ~25-50% and was greater in Froz+. In contrast, female mice exhibited selective transporter signal degradation in Froz not improved with additional protease inhibitors. Thus, kidney sample preparation variables, including freeze-thaw and protease inhibition, have substantial transporter-specific effects on quantification of renal transporter abundance by immunoblot. These findings underscore the critical importance of assessing and reporting the impact of sample preparation protocols on transporter recovery to ensure robust rigor and reproducibility.

Use of the iPRISM webtool in a learning community to assess implementation context and fit of a novel clinical decision support tool for physical therapy triage in acute care hospitals.

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.

The power of Para sport: the effect of performance-focused swimming training on motor function in adolescents with cerebral palsy and high support needs (GMFCS IV) - a single-case experimental design with 30-month follow-up.

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.

Clinical Outcomes After Acute Coronary Syndromes or Revascularization Among People Living With HIV: A Systematic Review and Meta-Analysis.

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 1 531 117 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.

MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature.

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.

Quality improvement lessons learned from National Implementation of the "Patient Safety Events in Community Care: Reporting, Investigation, and Improvement Guidebook".

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.

PDZ-Binding Kinase, a Novel Regulator of Vascular Remodeling in Pulmonary Arterial Hypertension.

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.

Early-Onset Hypertension and Sex-Specific Residual Risk for Cardiovascular Disease in Type 2 Diabetes.

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.

The book is just being written: The enduring journey of parents of children with emerging- ultrarare disorders.

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.

Mono and biallelic variants in HCN2 cause severe neurodevelopmental disorders.

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.

Legislative Health Notes: Preliminary Learnings From Piloting a New Policy Analysis Tool.

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.

De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor.

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.

Adaptation for sustainability in an implementation trial of team-based collaborative care.

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.

Sustaining the collaborative chronic care model in outpatient mental health: a matrixed multiple case study.

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.