Single-Cell RNA Sequencing Reveals Repair Features of Human Umbilical Cord Mesenchymal Stromal Cells.

RATIONALE: The chronic lung disease bronchopulmonary dysplasia (BPD) is the most severe complication of extreme prematurity. BPD results in impaired lung alveolar and vascular development and long-term respiratory morbidity, for which only supportive therapies exist. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) improve lung structure and function in experimental BPD. Results of clinical trials with MSCs for many disorders do not yet match the promising preclinical studies. A lack of specific criteria to define functionally distinct MSCs persists. OBJECTIVES: To determine and correlate single-cell UC-MSC transcriptomic profile with therapeutic potential. METHODS: UC-MSCs from five term donors and human neonatal dermal fibroblasts (HNDFs, control cells of mesenchymal origin) transcriptomes were investigated by single-cell RNA sequencing analysis (scRNA-seq). The lung-protective effect of UC-MSCs with a distinct transcriptome and control HNDFs was tested in vivo in hyperoxia-induced neonatal lung injury in rats. MEASUREMENTS AND MAIN RESULTS: UC-MSCs showed limited transcriptomic heterogeneity, but were different from HNDFs. Gene ontology enrichment analysis revealed distinct - progenitor-like and fibroblast-like - UC-MSC subpopulations. Only the treatment with progenitor-like UC-MSCs improved lung function and structure and attenuated pulmonary hypertension in hyperoxia-exposed rat pups. Moreover, scRNA-seq identified major histocompatibility complex class I as a molecular marker of non-therapeutic cells and associated with decreased lung retention. CONCLUSIONS: UC-MSCs with a progenitor-like transcriptome, but not with a fibroblast-like transcriptome, provide lung protection in experimental BPD. High expression of major histocompatibility complex class I is associated with reduced therapeutic benefit. scRNA-seq may be useful to identify subsets of MSCs with superior repair capacity for clinical application.

Safety and biodistribution of XC001 (encoberminogene rezmadenovec) gene therapy in rats: a potential therapy for cardiovascular diseases.

Adenovirus-mediated gene therapy holds promise for the treatment of cardiovascular diseases such as refractory angina. However, potential concerns around immunogenicity and vector dissemination from the target injected tissue require evaluation. This study was undertaken to evaluate the safety and biodistribution of XC001, a replication-deficient adenovirus serotype 5 vector expressing multiple isoforms of human vascular endothelial growth factor (VEGF), following direct administration into normal rat myocardium. Animals received the buffer formulation or increasing doses of XC001 (1 × 107, 2.5 × 108 or 2.5 × 109 viral particles). Based on in-life parameters (general health, body weights, clinical pathology, serum cardiac troponin I, plasma VEGF, and gross necropsy), there were no findings of clinical concern. On Day 8, intramyocardial administration of XC001 was associated with dose-related, left ventricular myocardial inflammation at injection sites, resolving by Day 30. XC001 DNA was not detected in blood at any time but was present at Day 8 around the site of injection and to a much lesser extent in the spleen, liver, and lungs, persisting at low levels in the heart and spleen until at least Day 91. These findings demonstrate that intramyocardial injection of XC001 is supported for use in human studies.

A preclinical systematic review and meta-analysis assessing the effect of biological sex in lipopolysaccharide-induced acute lung injury.

It is unclear what effect biological sex has on outcomes of acute lung injury (ALI). Clinical studies are confounded by their observational design. We addressed this knowledge gap with a preclinical systematic review of ALI animal studies. We searched MEDLINE and Embase for studies of intratracheal/intranasal/aerosolized lipopolysaccharide administration (the most common ALI model) that reported sex-stratified data. Screening and data extraction were conducted in duplicate. Our primary outcome was histological tissue injury and secondary outcomes included alveolar-capillary barrier alterations and inflammatory markers. We used a random-effects inverse variance meta-analysis, expressing data as standardized mean difference (SMD) with 95% confidence intervals (CIs). Risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. We identified six studies involving 132 animals across 11 independent experiments. A total of 41 outcomes were extracted, with the direction of effect suggesting greater severity in males than females in 26/41 outcomes (63%). One study reported on lung histology and found that male mice exhibited greater injury than females (SMD: 1.61, 95% CI: 0.53-2.69). Meta-analysis demonstrated significantly elevated albumin levels (SMD: 2.17, 95% CI: 0.63-3.70) and total cell counts (SMD: 0.80, 95% CI: 0.27-1.33) in bronchoalveolar lavage fluid from male mice compared with female mice. Most studies had an "unclear risk of bias." Our findings suggest sex-related differences in ALI severity. However, these conclusions are drawn from a small number of animals and studies. Further research is required to address the fundamental issue of biological sex differences in LPS-induced ALI.

Brief interventions 2.0: a new agenda for alcohol policy, practice and research.

BACKGROUND: Alcohol problems are increasing across the world and becoming more complex. Limitations to international evidence and practice mean that the screening and brief intervention paradigm forged in the 1980s is no longer fit for the purpose of informing how conversations about alcohol should take place in healthcare and other services. A new paradigm for brief interventions has been called for. BRIEF INTERVENTIONS 2.0: We must start with a re-appraisal of the roles of alcohol in society now and the damage it does to individual and population health. Industry marketing and older unresolved ideas about alcohol continue to impede honest and thoughtful conversations and perpetuate stigma, stereotypes, and outright fictions. This makes it harder to think about and talk about how alcohol affects health, well-being, and other aspects of life, and how we as a society should respond. To progress, brief interventions should not be restricted only to the self-regulation of one's own drinking. Content can be orientated to the properties of the drug itself and the overlooked problems it causes, the policy issues and the politics of a powerful globalised industry. This entails challenging and reframing stigmatising notions of alcohol problems, and incorporating wider alcohol policy measures and issues that are relevant to how people think about their own and others' drinking. We draw on recent empirical work to examine the implications of this agenda for practitioners and for changing the public conversation on alcohol. CONCLUSION: Against a backdrop of continued financial pressures on health service delivery, this analysis provokes debate and invites new thinking on alcohol. We suggest that the case for advancing brief interventions version 2.0 is both compelling and urgent.

SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics.

Rationale: Genetic studies suggest that SOX17 (SRY-related HMG-box 17) deficiency increases pulmonary arterial hypertension (PAH) risk. Objectives: On the basis of pathological roles of estrogen and HIF2α (hypoxia-inducible factor 2α) signaling in pulmonary artery endothelial cells (PAECs), we hypothesized that SOX17 is a target of estrogen signaling that promotes mitochondrial function and attenuates PAH development via HIF2α inhibition. Methods: We used metabolic (Seahorse) and promoter luciferase assays in PAECs together with the chronic hypoxia murine model to test the hypothesis. Measurements and Main Results: Sox17 expression was reduced in PAH tissues (rodent models and from patients). Chronic hypoxic pulmonary hypertension was exacerbated by mice with conditional Tie2-Sox17 (Sox17EC-/-) deletion and attenuated by transgenic Tie2-Sox17 overexpression (Sox17Tg). On the basis of untargeted proteomics, metabolism was the top pathway altered by SOX17 deficiency in PAECs. Mechanistically, we found that HIF2α concentrations were increased in the lungs of Sox17EC-/- and reduced in those from Sox17Tg mice. Increased SOX17 promoted oxidative phosphorylation and mitochondrial function in PAECs, which were partly attenuated by HIF2α overexpression. Rat lungs in males displayed higher Sox17 expression versus females, suggesting repression by estrogen signaling. Supporting 16α-hydroxyestrone (16αOHE; a pathologic estrogen metabolite)-mediated repression of SOX17 promoter activity, Sox17Tg mice attenuated 16αOHE-mediated exacerbations of chronic hypoxic pulmonary hypertension. Finally, in adjusted analyses in patients with PAH, we report novel associations between a SOX17 risk variant, rs10103692, and reduced plasma citrate concentrations (n = 1,326). Conclusions: Cumulatively, SOX17 promotes mitochondrial bioenergetics and attenuates PAH, in part, via inhibition of HIF2α. 16αOHE mediates PAH development via downregulation of SOX17, linking sexual dimorphism and SOX17 genetics in PAH.

Pulmonary and Neurologic Effects of Mesenchymal Stromal Cell Extracellular Vesicles in a Multifactorial Lung Injury Model.

Rationale: Bronchopulmonary dysplasia, a chronic respiratory condition originating from preterm birth, is associated with abnormal neurodevelopment. Currently, there is an absence of effective therapies for bronchopulmonary dysplasia and its associated brain injury. In preclinical trials, mesenchymal stromal cell therapies demonstrate promise as a therapeutic alternative for bronchopulmonary dysplasia. Objectives: To investigate whether a multifactorial neonatal mouse model of lung injury perturbs neural progenitor cell function and to assess the ability of human umbilical cord-derived mesenchymal stromal cell extracellular vesicles to mitigate pulmonary and neurologic injury. Methods: Mice at Postnatal Day 7 or 8 were injected intraperitoneally with LPS and ventilated with 40% oxygen at Postnatal Day 9 or 10 for 8 hours. Treated animals received umbilical cord-mesenchymal stromal cell-derived extracellular vesicles intratracheally preceding ventilation. Lung morphology, vascularity, and inflammation were quantified. Neural progenitor cells were isolated from the subventricular zone and hippocampus and assessed for self-renewal, in vitro differentiation ability, and transcriptional profiles. Measurements and Main Results: The multifactorial lung injury model produced alveolar and vascular rarefaction mimicking bronchopulmonary dysplasia. Neural progenitor cells from lung injury mice showed reduced neurosphere and oligodendrocyte formation, as well as inflammatory transcriptional signatures. Mice treated with mesenchymal stromal cell extracellular vesicles showed significant improvement in lung architecture, vessel formation, and inflammatory modulation. In addition, we observed significantly increased in vitro neurosphere formation and altered neural progenitor cell transcriptional signatures. Conclusions: Our multifactorial lung injury model impairs neural progenitor cell function. Observed pulmonary and neurologic alterations are mitigated by intratracheal treatment with mesenchymal stromal cell-derived extracellular vesicles.

Development of an intervention to manage benzodiazepine dependence and high-risk use in the context of escalating drug related deaths in Scotland: an application of the MRC framework.

BACKGROUND: Scotland has the highest rate of drug related deaths (DRD) in Europe. These are deaths in people who use drugs such as heroin, cocaine, benzodiazepines and gabapentinoids. It is a feature of deaths in Scotland that people use combinations of drugs which increases the chance of a DRD. Many deaths involve 'street' benzodiazepines, especially a drug called etizolam. Many of the 'street' benzodiazepines are not licensed in the UK so come from illegal sources. People who use opiates can be prescribed a safer replacement medication (e.g., methadone). While guidance on management of benzodiazepines use highlights that there is little evidence to support replacement prescribing, practice and evidence are emerging. AIM: To develop an intervention to address 'street' benzodiazepines use in people who also use opiates. METHODS: The MRC Framework for Complex Interventions was used to inform research design. Co-production of the intervention was achieved through three online workshops with clinicians, academics working in the area of substance use, and people with lived experience (PWLE). Each workshop was followed by a PWLE group meeting. Outputs from workshops were discussed and refined by the PWLE group and then further explored at the next workshop. RESULTS: After these six sessions, a finalised logic model for the intervention was successfully achieved that was acceptable to clinicians and PWLE. Key components of the intervention were: prescribing of diazepam; anxiety management, sleep, and pain; and harm reduction resources (locked box and a range of tips), personal safety conversations, as well as a virtual learning environment. CONCLUSION: A co-produced intervention was developed for next stage clinical feasibility testing.

Let's Move with Leon. A randomised controlled trial of a UK digital intervention to improve physical activity in people with a musculoskeletal condition.

OBJECTIVE: This article presents a real-world evaluation of a digital intervention, 'Let's Move with Leon', designed to improve physical activity and health-related quality of life (HRQoL) in people with a musculoskeletal condition. STUDY DESIGN: A pragmatic randomised controlled trial. METHODS: After randomisation and withdrawals were removed, 184 participants were assigned to receive the digital intervention with 185 assigned to a control group. Self-reported physical activity was the primary outcome. Health-related quality of life, the number of days completing strength-based exercises per week, the capability, opportunity, and motivation to be active, and step count were secondary outcomes. Outcomes were assessed over 4, 8 and 13 weeks. RESULTS: Significant improvements were seen for self-reported physical activity at 13 weeks, reported strength days at 8 weeks, perceptions of physical capability and automatic motivation to be active at 4 and 8 weeks. No improvements were seen in step count or HRQoL over the control group. CONCLUSION: Digital interventions such as 'Let's Move with Leon' have the potential to increase physical activity in people with a musculoskeletal condition; however, improvements are likely to be small. Small improvements in physical activity may not be enough to improve HRQoL.

Measurement of person-centred consultation skills among healthcare practitioners: a systematic review of reviews of validation studies.

BACKGROUND: Person-centred care is integral to high-quality health service provision, though concepts vary and the literature is complex. Validated instruments that measure person-centred practitioner skills, and behaviours within consultations, are needed for many reasons, including in training programmes. We aimed to provide a high-level synthesis of what was expected to be a large and diverse literature through a systematic review of existing reviews of validation studies a of instruments that measure person-centred practitioner skills and behaviours in consultations. The objectives were to undertake a critical appraisal of these reviews, and to summarise the available validated instruments and the evidence underpinning them. METHODS: A systematic search of Medline, EMBASE, PsycINFO and CINAHL was conducted in September 2020. Systematic reviews of validation studies of instruments measuring individual practitioner person-centred consultation skills or behaviours which report measurement properties were included. Review quality was assessed with the Joanna Briggs Institute Critical Appraisal Checklist for Systematic Reviews and Research Syntheses. Details of the reviews, the included validation studies, and the instruments themselves are tabulated, including psychometric data, and a narrative overview of the reviews is provided. RESULTS: Four reviews were eligible for inclusion. These used different conceptualisations of person-centredness and targeted distinct, sometimes mutually exclusive, practitioners and settings. The four reviews included 68 unique validation studies examining 42 instruments, but with very few overlaps. The critical appraisal shows there is a need for improvements in the design of reviews in this area. The instruments included within these reviews have not been subject to extensive validation study. DISCUSSION: There are many instruments available which measure person-centred skills in healthcare practitioners and this study offers a guide to what is available to researchers and research users. The most relevant and promising instruments that have already been developed, or items within them, should be further studied rigorously. Validation study of existing material is needed, not the development of new measures.

'Really putting a different slant on my use of a glass of wine': patient perspectives on integrating alcohol into Structured Medication Reviews in general practice.

Background: Alcohol is often overlooked in primary care even though it has wide-ranging impacts. The Structured Medication Review (SMR) in England is a new 'holistic' service designed to tackle problematic polypharmacy, delivered by clinical pharmacists in a general practice setting. Implementation has been protracted owing to the COVID-19 pandemic. This study explores early patient experiences of the SMR and views on the acceptability of integrating clinical attention to alcohol as another drug linked to their conditions and medicines, rather than as a standalone 'healthy living' or 'lifestyle' question. Method: Semi-structured interviews with a sample of 10 patients who drank alcohol twice or more each week, recruited to the study by five clinical pharmacists during routine SMR delivery. Results: SMRs received were remote, brief, and paid scant attention to alcohol. Interviewees were interested in the possibility of receiving integrated attention to alcohol within a SMR that was similar to the service specification. They saw alcohol inclusion as congruent with the aims of a holistic medicines review linked to their medical history. For some, considering alcohol as a drug impacting on their medications and the conditions for which they were prescribed, introduced a new frame for thinking about their own drinking. Conclusions: Including alcohol in SMRs and changing the framing of alcohol away from a brief check with little meaningful scope for discussion, toward being fully integrated within the consultation, was welcomed as a concept by participants in this study. This was not their current medication review experience.

Mortality trends in pulmonary arterial hypertension in Canada: a temporal analysis of survival per ESC/ERS guideline era.

BACKGROUND: The evolution in pulmonary arterial hypertension (PAH) management has been summarised in three iterations of the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. No study has assessed whether changes in management, as reflected in the changing guidelines, has translated to improved long-term survival in PAH. METHODS: We performed a mixed retrospective/prospective analysis of treatment-naïve, incident PAH patients (n=392) diagnosed at three major centres in Canada from 2009 to 2021. Patients were divided into two groups based on their diagnosis date and in accordance with the 2009 and 2015 ESC/ERS guideline iterations. Overall survival was assessed based on date of diagnosis and initial treatment strategy (i.e. monotherapy versus combination therapy). RESULTS: There was a shift towards more aggressive upfront management with combination therapy in Canada after the publication of the 2015 ESC/ERS guidelines (10.4% and 30.8% in patients from 2009 to 2015 and 36.0% and 57.4% in patients diagnosed after 2015 for baseline and 2-year follow-up, respectively). A key factor associated with combination therapy after 2015 was higher pulmonary vascular resistance (p=0.009). The 1-, 3- and 5-year survival rates in Canada were 89.2%, 75.6% and 56.0%, respectively. Despite changes in management, there was no improvement in long-term survival before and after publication of the 2015 ESC/ERS guidelines (p=0.53). CONCLUSIONS: There was an increase in the use of initial and sequential combination therapy in Canada after publication of the 2015 ESC/ERS guidelines, which was not associated with improved long-term survival. These data highlight the continued difficulties of managing this aggressive pulmonary disease in an era without a cure.

Mesenchymal stromal (stem) cell therapy modulates miR-193b-5p expression to attenuate sepsis-induced acute lung injury.

Although mesenchymal stromal (stem) cell (MSC) administration attenuates sepsis-induced lung injury in pre-clinical models, the mechanism(s) of action and host immune system contributions to its therapeutic effects remain elusive. We show that treatment with MSCs decreased expression of host-derived microRNA (miR)-193b-5p and increased expression of its target gene, the tight junctional protein occludin (Ocln), in lungs from septic mice. Mutating the Ocln 3' untranslated region miR-193b-5p binding sequence impaired binding to Ocln mRNA. Inhibition of miR-193b-5p in human primary pulmonary microvascular endothelial cells prevents tumour necrosis factor (TNF)-induced decrease in Ocln gene and protein expression and loss of barrier function. MSC-conditioned media mitigated TNF-induced miR-193b-5p upregulation and Ocln downregulation in vitro When administered in vivo, MSC-conditioned media recapitulated the effects of MSC administration on pulmonary miR-193b-5p and Ocln expression. MiR-193b-deficient mice were resistant to pulmonary inflammation and injury induced by lipopolysaccharide (LPS) instillation. Silencing of Ocln in miR-193b-deficient mice partially recovered the susceptibility to LPS-induced lung injury. In vivo inhibition of miR-193b-5p protected mice from endotoxin-induced lung injury. Finally, the clinical significance of these results was supported by the finding of increased miR-193b-5p expression levels in lung autopsy samples from acute respiratory distress syndrome patients who died with diffuse alveolar damage.

Understanding potential barriers and enablers to a perioperative early phase cell therapy trial.

BACKGROUND AIMS: Early-phase cell therapy clinical trials depend on patient and physician involvement, yet barriers can impede their participation. METHODS: To optimize engagement for a planned cell therapy trial to prevent perioperative cardiac complications, the authors conducted semi-structured interviews with at-risk patients and physicians who could potentially be involved in the study. The authors used the theoretical domains framework to systematically identify potential barriers and enablers. RESULTS: Forty-one interviews were conducted to reach data saturation, and four overall potential barriers to participation (themes) were identified. Theme 1 emphasizes that patients and physicians need accessible information to better understand the benefits and risks of the novel therapy and trial procedures and to address misconceptions. Theme 2 underscores the need for clarity on whether the trial's primary purpose is safety or efficacy, as this may influence patient and physician decisions. Theme 3 recognizes the resource and logistic realities for patients (e.g., convenient follow-up appointments) and physicians (e.g., personnel to assist in trial procedures, competing priorities). Theme 4 describes the importance of social influences (e.g., physicians and family, peers/colleagues) that may affect decisions to participate and the importance of patient preferences (e.g., availability of physicians to discuss the trial, including caregivers in discussions). CONCLUSIONS: Prospectively addressing these issues may help optimize feasibility prior to conducting an expensive, resource-intensive trial.

Immunophenotypic characterization and therapeutics effects of human bone marrow- and umbilical cord-derived mesenchymal stromal cells in an experimental model of sepsis.

Sepsis is a complicated multi-system disorder characterized by a dysregulated host response to infection. Despite substantial progress in the understanding of mechanisms of sepsis, translation of these advances into clinically effective therapies remains challenging. Mesenchymal Stromal Cells (MSCs) possess immunomodulatory properties that have shown therapeutic promise in preclinical models of sepsis. The therapeutic effects of MSCs may vary depending on the source and type of these cells. In this comparative study, the gene expression pattern and surface markers of bone marrow-derived MSCs (BM-MSCs) and umbilical cord-derived MSCs (UC-MSCs) as well as their therapeutic effects in a clinically relevant mouse model of polymicrobial sepsis, cecal ligation and puncture (CLP), were investigated. The results showed remarkable differences in gene expression profile, surface markers and therapeutic potency in terms of enhancing survival and pro/anti-inflammatory responses between the two MSC types. BM-MSCs improved survival concomitant with an enhanced systemic bacterial clearance and improved inflammatory profile post CLP surgery. Despite some improvement in the inflammatory profile of the septic animals, treatment with UC-MSCs did not enhance survival or bacterial clearance. Overall, the beneficial therapeutic effects of BM-MSCs over UC-MSCs may likely be attributed to their pro-inflammatory function, and to some extent anti-inflammatory features, reflected in their gene expression pattern enhancing macrophage polarization to M1/M2 phenotypes resulting in a balanced pro- and anti-inflammatory response against polymicrobial sepsis.

Endothelial cells in the pathogenesis of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease that involves pulmonary vasoconstriction, small vessel obliteration, large vessel thickening and obstruction, and development of plexiform lesions. PAH vasculopathy leads to progressive increases in pulmonary vascular resistance, right heart failure and, ultimately, premature death. Besides other cell types that are known to be involved in PAH pathogenesis (e.g. smooth muscle cells, fibroblasts and leukocytes), recent studies have demonstrated that endothelial cells (ECs) have a crucial role in the initiation and progression of PAH. The EC-specific role in PAH is multi-faceted and affects numerous pathophysiological processes, including vasoconstriction, inflammation, coagulation, metabolism and oxidative/nitrative stress, as well as cell viability, growth and differentiation. In this review, we describe how EC dysfunction and cell signalling regulate the pathogenesis of PAH. We also highlight areas of research that warrant attention in future studies, and discuss potential molecular signalling pathways in ECs that could be targeted therapeutically in the prevention and treatment of PAH.

Surrogate Humane Endpoints in Small Animal Models of Acute Lung Injury: A Modified Delphi Consensus Study of Researchers and Laboratory Animal Veterinarians.

OBJECTIVES: In many jurisdictions, ethical concerns require surrogate humane endpoints to replace death in small animal models of acute lung injury. Heterogenous selection and reporting of surrogate endpoints render interpretation and generalizability of findings between studies difficult. We aimed to establish expert-guided consensus among preclinical scientists and laboratory animal veterinarians on selection and reporting of surrogate endpoints, monitoring of these models, and the use of analgesia. DESIGN: A three-round consensus process, using modified Delphi methodology, with researchers who use small animal models of acute lung injury and laboratory animal veterinarians who provide care for these animals. Statements on the selection and reporting of surrogate endpoints, monitoring, and analgesia were generated through a systematic search of MEDLINE and Embase. Participants were asked to suggest any additional potential statements for evaluation. SETTING: A web-based survey of participants representing the two stakeholder groups (researchers, laboratory animal veterinarians). Statements were rated on level of evidence and strength of support by participants. A final face-to-face meeting was then held to discuss results. SUBJECTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-two statements were evaluated, and 29 were rated as important, with varying strength of evidence. The majority of evidence was based on rodent models of acute lung injury. Endpoints with strong support and evidence included temperature changes and body weight loss. Behavioral signs and respiratory distress also received support but were associated with lower levels of evidence. Participants strongly agreed that analgesia affects outcomes in these models and that none may be necessary following nonsurgical induction of acute lung injury. Finally, participants strongly supported transparent reporting of surrogate endpoints. A prototype composite score was also developed based on participant feedback. CONCLUSIONS: We provide a preliminary framework that researchers and animal welfare committees may adapt for their needs. We have identified knowledge gaps that future research should address.

Medical Therapy for Heart Failure Associated With Pulmonary Hypertension.

The past 2 decades have witnessed a >40% improvement in mortality for patients with heart failure and left ventricular systolic dysfunction. 1 This success has coincided with the stepwise availability of drugs that target neurohormonal activation: ß-adrenergic receptor blockers (ß-blockers), ACE (angiotensin-converting enzyme) inhibitors and ANG (angiotensin) II blockers, neprilysin inhibitors, and aldosterone antagonists. Our understanding of right heart failure (RHF) has lagged behind and many proven targeted therapies for left heart failure do not appear to provide similar benefits for RHF. Until recently, the right ventricle (RV) has often been viewed as less important than the left ventricle and in contemporary literature received the moniker "The Forgotten Ventricle". Recent advances in echocardiography and magnetic resonance imaging have enabled detailed assessments of RV anatomy and physiology in both health and disease allowing us to more accurately describe the clinical sequelae and end-organ manifestations of RHF. RV function is now recognized as one of the most important predictors of prognosis in many cardiovascular disease states. 2 Despite the significance of RV function to survival, there are no clinically approved therapies that directly nor selectively improve RV function. As well, relative to our understanding of left heart failure, the basis for RHF remains poorly understood. This article aims to condense the current knowledge on RV adaptation and failure, review current management strategies for RHF, and explore evolving therapeutic approaches.

[11C]meta-hydroxyephedrine PET evaluation in experimental pulmonary arterial hypertension: Effects of carvedilol of right ventricular sympathetic function.

BACKGROUND: Little is known about the sequelae of chronic sympathetic nervous system (SNS) activation in patients with pulmonary arterial hypertension (PAH) and right heart failure (RHF). We aimed to, (1) validate the use of [11C]-meta-hydroxyephedrine (HED) for assessing right ventricular (RV) SNS integrity, and (2) determine the effects of ß-receptor blockade on ventricular function and myocardial SNS activity in a PAH rat model. METHODS: PAH was induced in male Sprague-Dawley rats (N = 36) using the Sugen+chronic hypoxia model. At week 5 post-injection, PAH rats were randomized to carvedilol (15 mg·kg-1·day-1 oral; N = 16) or vehicle (N = 16) for 4 weeks. Myocardial SNS function was assessed with HED positron emission tomography(PET). RESULTS: With increasing PAH disease severity, immunohistochemistry confirmed selective sympathetic denervation within the RV and sparing of parasympathetic nerves. These findings were confirmed on PET with a significant negative relationship between HED volume of distribution(DV) and right ventricular systolic pressure (RVSP) in the RV (r = -0.90, p = 0.0003). Carvedilol did not reduce hemodynamic severity compared to vehicle. RV ejection fraction (EF) was lower in both PAH groups compared to control (p < 0.05), and was not further reduced by carvedilol. Carvedilol improved SNS function in the LV with significant increases in the HED DV, and decreased tracer washout in the LV (p < 0.05) but not RV. CONCLUSIONS: PAH disease severity correlated with a reduction in HED DV in the RV. This was associated with selective sympathetic denervation. Late carvedilol treatment did not lead to recovery of RV function. These results support the role of HED imaging in assessing SNS innervation in a failing right ventricle.

Exploratory Validation Study of the Individual AUDIT-C Items among Older People.

AIMS: The AUDIT-C is a brief and commonly used alcohol screening tool, with few data available on the relative validity of the three individual items in older adult populations. The aim of this study was to explore the validity of the AUDIT-C items in identifying unhealthy drinking among older people, with a view to developing a single-item screener. METHODS: A sample of 143 older adults (mean age = 71) were recruited from non-clinical settings in the UK. AUDIT-C scores were compared to an unhealthy drinking reference category of consuming more than the UK recommended weekly units of alcohol. Standard analyses were conducted for men and women, and for those prescribed medications for long term conditions. RESULTS: The AUDIT-C items performed well in identifying unhealthy drinking in this sample of older people, with generally high sensitivity, specificity and area under the ROC curve. No significant differences were found in the validity of the three items, though the combined sensitivity and specificity scores and ROC values for item 3 were consistently slightly lower than for items 1 and 2. The findings were similar for men and women, and for participants prescribed medications for long-term conditions. CONCLUSIONS: AUDIT-C items 1 and 2 performed as well as item 3 in identifying unhealthy drinking among older people in this study. Both are reasonable single-item screener candidates, especially given relative ease of administration, with further validation study needed to examine psychometrics and how alcohol screening for older people can best be implemented in clinical settings.

A scoping review of qualitative research on perceptions of one's own alcohol use.

BACKGROUND: This scoping review aims to map the extent, range and nature of qualitative research on people's 'perceptions' of their own alcohol consumption. METHODS: A systematic search of five electronic databases was conducted. A total of 915 abstracts were screened and 452 full texts examined, of which 313 papers met the inclusion criteria (including a report of qualitative data on perceptions, experiences or views of people's own drinking in peer-reviewed journals published in English). RESULTS: This study maps the available literature assembled over approximately 30 years, which was found to be extensive and diverse. Many existing studies are focused largely on people's 'experiences' of their own drinking behaviours, particularly when they were drinking in ways commonly understood as heavy, risky or problematic. Fewer studies focused on populations whose drinking was not heavy or was risky in less obvious ways, such as older adults prescribed medications for chronic health conditions. Most studies were conducted since 2010, with the rate of publications increasing since 2014. CONCLUSIONS: This review identifies gaps in the evidence regarding people's perceptions of their own drinking and opportunities for qualitative studies to make valuable contributions to alcohol research. Gaps discussed include patterns of drinking that are less obviously problematic, and in relation to consumption of alcohol in those parts of the world where overall consumption and harms from alcohol are high. Such studies could usefully be informed by existing studies in the evidence mapping.