Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common but poorly understood form of heart failure, characterized by impaired diastolic function. It is highly heterogeneous with multiple comorbidities, including obesity and diabetes, making human studies difficult. METHODS: Metabolomic analyses in a mouse model of HFpEF showed that levels of indole-3-propionic acid (IPA), a metabolite produced by gut bacteria from tryptophan, were reduced in the plasma and heart tissue of HFpEF mice as compared with controls. We then examined the role of IPA in mouse models of HFpEF as well as 2 human HFpEF cohorts. RESULTS: The protective role and therapeutic effects of IPA were confirmed in mouse models of HFpEF using IPA dietary supplementation. IPA attenuated diastolic dysfunction, metabolic remodeling, oxidative stress, inflammation, gut microbiota dysbiosis, and intestinal epithelial barrier damage. In the heart, IPA suppressed the expression of NNMT (nicotinamide N-methyl transferase), restored nicotinamide, NAD+/NADH, and SIRT3 (sirtuin 3) levels. IPA mediates the protective effects on diastolic dysfunction, at least in part, by promoting the expression of SIRT3. SIRT3 regulation was mediated by IPA binding to the aryl hydrocarbon receptor, as Sirt3 knockdown diminished the effects of IPA on diastolic dysfunction in vivo. The role of the nicotinamide adenine dinucleotide circuit in HFpEF was further confirmed by nicotinamide supplementation, Nnmt knockdown, and Nnmt overexpression in vivo. IPA levels were significantly reduced in patients with HFpEF in 2 independent human cohorts, consistent with a protective function in humans, as well as mice. CONCLUSIONS: Our findings reveal that IPA protects against diastolic dysfunction in HFpEF by enhancing the nicotinamide adenine dinucleotide salvage pathway, suggesting the possibility of therapeutic management by either altering the gut microbiome composition or supplementing the diet with IPA.

Feasibility and Acceptability of a Videoconferencing CBT Intervention for Anxiety in People with Parkinson's Disease.

OBJECTIVES: In people with Parkinson's disease (PwPD), non-motor symptoms such as anxiety are common and have negative impacts on their quality of life. There are currently few interventions that address anxiety in PwPD, and access to diagnosis and treatment is often limited for those living in rural areas. The aim of this study was to evaluate the feasibility and acceptability of a telehealth videoconferencing CBT intervention for anxiety in PwPD. METHODS: A pre- and post-test feasibility study (N = 10) was conducted and evaluated utilizing the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, and Maintenance). RESULTS: Lack of access to the internet and videoconferencing technology were identified as barriers to participation. Physical health issues also impacted recruitment and retention. Non-completers were significantly older and less likely to have a carer involved in the intervention. Clinician adoption of the intervention was low while participant acceptability of videoconferencing technology varied and required carer support. CONCLUSIONS: Providing access to technology and support to overcome technological issues, as well as telehealth training for clinicians, are recommended in future studies to improve recruitment, retention, and implementation. CLINICAL IMPLICATIONS: Identification of barriers and facilitators provides future studies with the knowledge to tailorize their program to better suit PwPD.

A physiotherapy group exercise and self-management approach to improve physical activity in people with mild-moderate Parkinson's disease: a randomized controlled trial.

BACKGROUND: Physical activity levels are low in people with Parkinson's disease (PD) and have proved difficult to increase with exercise programs alone. Intervention approaches that address both the capacity to engage in physical activity and self-management strategies to change and maintain exercise behaviours are needed to address this intractable issue. METHODS: This will be an assessor-blinded, randomized controlled trial performed in Brisbane, Australia. Ninety-two people with mild-moderate PD will be randomly allocated to two groups: usual care, and a physiotherapy-led group exercise program combined with self-management strategies. In the intervention group, twelve, 80-min sessions will be conducted over 4 weeks in groups of up to 4 participants. The intervention will consist of circuit training including treadmill walking to target aerobic fitness, and activities targeting strength, balance, and gait performance. In addition, each session will also incorporate strategies focusing on self-management and behaviour change, augmented by the provision of a fitness activity tracker. Outcome measures will be collected at baseline (T1), immediately post intervention (T2) and at 6 months follow-up (T3). The primary outcome measure is free-living physical activity (average daily step count over 7 days) at pre (T1) and post (T2) intervention measured using an activPAL™ device. Secondary outcome measures captured at all time points include time spent walking, sedentary and in moderate intensity exercise over 7 days; spatiotemporal gait performance (step length, gait speed, endurance); health-related quality of life; and outcome expectations and self-efficacy for exercise. DISCUSSION: Sustainability of gains in physical activity following exercise interventions is a challenge for most populations. Our incorporation of a chronic disease self-management approach into the exercise program including fitness tracking extends previous trials and has potential to significantly improve free-living physical activity in people with PD. TRIAL REGISTRATION: This study has been prospectively registered in Australian and New Zealand Clinical Trial Registry (ACTRN12617001057370), registered on 19/07/2017. Available from www.anzctr.org.au/ACTRN12617001057370.aspx .

ChatGPT-4 Can Help Hand Surgeons Communicate Better With Patients.

The American Society for Surgery of the Hand and British Society for Surgery of the Hand produce patient-focused information above the sixth-grade readability recommended by the American Medical Association. To promote health equity, patient-focused content should be aimed at an appropriate level of health literacy. Artificial intelligence-driven large language models may be able to assist hand surgery societies in improving the readability of the information provided to patients. The readability was calculated for all the articles written in English on the American Society for Surgery of the Hand and British Society for Surgery of the Hand websites, in terms of seven of the commonest readability formulas. Chat Generative Pre-Trained Transformer version 4 (ChatGPT-4) was then asked to rewrite each article at a sixth-grade readability level. The readability for each response was calculated and compared with the unedited articles. Chat Generative Pre-Trained Transformer version 4 was able to improve the readability across all chosen readability formulas and was successful in achieving a mean sixth-grade readability level in terms of the Flesch Kincaid Grade Level and Simple Measure of Gobbledygook calculations. It increased the mean Flesch Reading Ease score, with higher scores representing more readable material. This study demonstrated that ChatGPT-4 can be used to improve the readability of patient-focused material in hand surgery. However, ChatGPT-4 is interested primarily in sounding natural, and not in seeking truth, and hence, each response must be evaluated by the surgeon to ensure that information accuracy is not being sacrificed for the sake of readability by this powerful tool.

A biologging database of mobulid rays from the Gulf of California, Mexico.

We initiated a tagging program in 2004 to determine the large-scale and long-term movement patterns of three species of Mobulid Ray (Mobula mobular, M. munkiana, M. thurstoni). Between 2004 and 2014 we deployed 48 pop-up archival (PAT) tags that recorded temperature, pressure, and light level. Pressure and light level records were then used to calculate animal depth and geolocation. Transmitted and when available recovered raw data files from successful deployments (n = 45) were auto-ingested from the manufacturer into the United States Animal Telemetry Network's (ATN) Data Assembly Center (DAC). Through the ATN DAC, all necessary metadata were compiled, dataset was prepped for release, and derived geolocation trajectories (n = 43) were visualized within their public facing data portal. These data and the full metadata records are available for download from the ATN portal as well as permanently archived under the DataONE Research Workspace member node.

Hippocampal resting-state connectivity is associated with posterior-cortical cognitive impairment in Parkinson's disease.

AIM: Frontal and posterior-cortical cognitive subtypes in Parkinson's disease (PD) present with executive/attention and memory/visuospatial deficits, respectively. As the posterior-cortical subtype is predicted to progress rapidly toward dementia, the present study aimed to explore biological markers of this group using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: K-means cluster analysis delineated subtypes (cognitively intact, frontal, posterior-cortical, and globally impaired) among 85 people with PD. A subset of PD participants (N = 42) and 20 healthy controls (HCs) underwent rs-fMRI. Connectivity of bilateral hippocampi with regions of interest was compared between posterior-cortical, cognitively intact, and HC participants using seed-based analysis, controlling for age. Exploratory correlations were performed between areas of interest from the group analysis and a series of cognitive tests. RESULTS: The posterior-cortical subtype (N = 19) showed weaker connectivity between the left hippocampus and right anterior temporal fusiform cortex compared to the cognitively intact (N = 11) group, p-false discovery rate (FDR) = .01, and weaker connectivity between bilateral hippocampi and most fusiform regions compared to HCs (N = 20). No differences were found between HCs and cognitively intact PD. Exploratory analyses revealed strongest associations between connectivity of the right anterior temporal fusiform cortex and left hippocampus with category fluency (p-FDR = .01). CONCLUSION: Results suggest that weakened connectivity between the hippocampus and fusiform region is a unique characteristic of posterior-cortical cognitive deficits in PD. Further exploration of hippocampal and fusiform functional integrity as a marker of cognitive decline in PD is warranted.

Agricultural and urban practices are correlated to changes in the resistome of riverine systems.

The objective of this study was to comprehensively characterise the resistome, the collective set of antimicrobial resistance genes in a given environment, of two rivers, from their source to discharge into the sea, as these flow through areas of different land use. Our findings reveal significant differences in the riverine resistome composition in areas of different land uses, with increased abundance and diversity of AMR in downstream agricultural and urban locations, with the resistome in urban areas more similar to the resistome in wastewater. The changes in resistome were accompanied by changes in microbial communities, with a reduction in microbial diversity in downstream agricultural and urban affected areas, driven mostly by increased relative abundance in the phyla, Bacteroidetes and Proteobacteria. These results provide insight into how pollution associated with agricultural and urban activities affects microbial communities and influences AMR in aquatic water bodies. These results add valuable insights to form effective strategies for mitigating and preserving aquatic ecosystems. Overall, our study highlights the critical role of the environment in the development and dissemination of AMR and underscores the importance of adopting a One Health approach to address this global public health threat.

Echocardiographic predictors of cardiovascular outcome in heart failure with preserved ejection fraction.

AIMS: The optimal echocardiographic predictors of cardiovascular outcome in heart failure (HF) with preserved ejection fraction (HFpEF) are unknown. We aimed to identify independent echocardiographic predictors of cardiovascular outcome in patients with HFpEF. METHODS AND RESULTS: Systematic literature search of three electronic databases was conducted from date of inception until November 2022. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for echocardiographic variables from multivariate prediction models for the composite primary endpoint of cardiovascular death and HF hospitalization were pooled using a random effects meta-analysis. Specific subgroup analyses were conducted for studies that enrolled patients with acute versus chronic HF, and for those studies that included E/e', pulmonary artery systolic pressure (PASP), renal function, natriuretic peptides and diuretic use in multivariate models. Forty-six studies totalling 20 056 patients with HFpEF were included. Three echocardiographic parameters emerged as independent predictors in all subgroup analyses: decreased left ventricular (LV) global longitudinal strain (HR 1.24, 95% CI 1.10-1.39 per 5% decrease), decreased left atrial (LA) reservoir strain (HR 1.30, 95% CI 1.13-1.1.50 per 5% decrease) and lower tricuspid annular plane systolic excursion (TAPSE) to PASP ratio (HR 1.17, 95% CI 1.07-1.25 per 0.1 unit decrease). Other independent echocardiographic predictors of the primary endpoint were a higher E/e', moderate to severe tricuspid regurgitation, LV mass index and LA ejection fraction, although these variables were less robust. CONCLUSIONS: Impaired LV global longitudinal strain, lower LA reservoir strain and lower TAPSE/PASP ratio predict cardiovascular death and HF hospitalization in HFpEF and are independent of filling pressures, clinical characteristics and natriuretic peptides. These echocardiographic parameters reflect key functional changes in HFpEF, and should be incorporated in future prospective risk prediction models.

Cardiac Substrate Utilization and Relationship to Invasive Exercise Hemodynamic Parameters in HFpEF.

The authors conducted transcardiac blood sampling in healthy subjects and subjects with heart failure with preserved ejection fraction (HFpEF) to compare cardiac metabolite and lipid substrate use. We demonstrate that fatty acids are less used by HFpEF hearts and that lipid extraction is influenced by hemodynamic factors including pulmonary pressures and cardiac index. The release of many products of protein catabolism is apparent in HFpEF compared to healthy myocardium. In subgroup analyses, differences in energy substrate use between female and male hearts were identified.

Rapid benefits in older age from transition to whole food diet regardless of protein source or fat to carbohydrate ratio: Arandomised control trial.

Plant-based diets reduces the risk of chronic conditions. The interaction between protein source and other macronutrients-fat (F) and carbohydrate (C)-has yet to be investigated. The aim was to assess the main and interactive effects of protein-source (plant vs. animal) and F:C (high or low) and the transition from an Australian diet to a whole food diet on various health markers in older individuals. This single-blinded, parallel, randomised experimental trial used a 2 × 2 factorial design to compare pro-vegetarian (70:30 plant to animal) versus omnivorous (50:50 plant to animal) diets at 14% protein and varying fat-to-carbohydrate ratios (high fat ~40% vs. low fat ~30%) over 4 weeks. Study foods were provided, alcohol consumption was discouraged, and dietary intake was determined through food records. Analysis included both RCT and observational data. Changes in appetite, palatability of diets, and dietary intake were assessed. Body composition, muscle strength, function, gut microbiome, and cardiometabolic health parameters were measured. Data from 113 (of the 128 randomised) individuals aged 65-75 years were analysed. Pro-vegetarian diets reduced diastolic blood pressure, total cholesterol and glucose levels. Moreover, the overall sample exhibited increased short-chain fatty acids and FGF21 levels, as well as improvements in body composition, function, and cardio-metabolic parameters irrespective of dietary treatment. Transitioning to a diet rich in fruit, vegetables, fibre, and moderate protein was associated with improved health markers in older age, with added benefits from pro-vegetarian diets. Further research on long-term effects is needed.

Quantitative source apportionment of faecal indicator bacteria from anthropogenic and zoogenic sources of faecal contamination.

Recreational bathing waters are complex systems with diverse inputs from multiple anthropogenic and zoogenic sources of faecal contamination. Faecal contamination is a substantial threat to water quality and public health. Here we present a comprehensive strategy to estimate the contribution of faecal indicator bacteria (FIB) from different biological sources on two at-risk beaches in Dublin, Ireland. The daily FIB loading rate was determined for three sources of contamination: a sewage-impacted urban stream, dog and wild bird fouling. This comparative analysis determined that the stream contributed the highest daily levels of FIB, followed by dog fouling. Dog fouling may be a significant source of FIB, contributing approximately 20 % of E. coli under certain conditions, whereas wild bird fouling contributed a negligible proportion of FIB (<3 %). This study demonstrates that source-specific quantitative microbial source apportionment (QMSA) strategies are vital to identify primary public health risks and target interventions to mitigate faecal contamination.

Preventing sheep carotid artery spasm for vascular graft surgery and computed tomography angiography.

The development of small-diameter vascular grafts requires testing in large animal models before advancing to clinical trials. Vascular graft interposition implantation in sheep carotid arteries (CAs) is the most widely used model, but ovine CAs are prone to severe spasm following surgical manipulation, potentially impairing graft performance assessment. There is a paucity in the literature on reducing sheep CA spasm using effective vasodilator therapeutic protocols. In this study, four healthy Merino cross White Suffolk wethers (1-2 years, 52.1 ± 0.8 kg) underwent CT angiography and CA graft surgery. CT angiography using iodinated contrast agent was performed with innominate artery access via the CA or ascending aortic arch access via the femoral artery. Sheep were randomly allocated to then underwent right CA sham surgery or left CA vascular graft implantation. A variety of vasodilators, including papaverine, sodium nitroprusside, verapamil and their combination, were tested for preventing or treating CA spasms intraoperatively. Blood flow was reassessed immediately after CA surgery using CT angiography. The results showed that innominate artery access via the CA for CT angiography in sheep induced pre-surgical CA spasm with reduced arterial flow. Conversely, ascending aortic arch access via the femoral artery for CT angiography did not cause CA spasm and maintained arterial flow. During CA graft surgery, surgical trauma induced CA spasm, which was prevented by localised intraarterial administration of vasodilators papaverine hydrochloride and verapamil prior to significant surgical manipulation.

Profiling people with Parkinson's disease at risk of cognitive decline: Insights from PPMI and ICICLE-PD data.

Introduction: A subset of people with Parkinson's disease (PD) develop dementia faster than others. We aimed to profile PD cognitive subtypes at risk of dementia based on their rate of cognitive decline. Method: Latent class mixed models stratified subtypes in Parkinson's Progression Markers Initiative (PPMI) (N = 770) and ICICLE-PD (N = 212) datasets based on their decline in the Montreal Cognitive Assessment over at least 4 years. Baseline demographic and cognitive data at diagnosis were compared between subtypes to determine their clinical profile. Results: Four subtypes were identified: two with stable cognition, one with steady decline, and one with rapid decline. Performance on Judgement of Line Orientation, but not category fluency, was associated with a steady decline in the PPMI dataset, and deficits in category fluency, but not visuospatial function, were associated with a steady decline in the ICICLE-PD dataset. Discussion: People with PD susceptible to cognitive decline demonstrate unique clinical profiles at diagnosis, although this differed between cohorts. Highlights: Four cognitive subtypes were revealed in two Parkinson's disease samples.Unique profiles of cognitive impairment were related to cognitive decline.Judgement of Line Orientation/category fluency predictive of steady decline.Global deficits related to rapid cognitive decline and increased dementia risk.

The Efficacy of Risk Factor Modification Compared to NAD+ Repletion in Diastolic Heart Failure.

Heart failure (HF) with left ventricular diastolic dysfunction is a growing global concern. This study evaluated myocardial oxidized nicotinamide adenine dinucleotide (NAD+) levels in human systolic and diastolic HF and in a murine model of HF with preserved ejection fraction, exploring NAD+ repletion as therapy. We quantified myocardial NAD+ and nicotinamide phosphoribosyltransferase levels, assessing restoration with nicotinamide riboside (NR). Findings show significant NAD+ and nicotinamide phosphoribosyltransferase depletion in human diastolic HF myocardium, but NR successfully restored NAD+ levels. In murine HF with preserved ejection fraction, NR as preventive and therapeutic intervention improved metabolic and antioxidant profiles. This study underscores NAD+ repletion's potential in diastolic HF management.

Cardio-Oncology Recommendations for Pediatric Oncology Patients: An Australian and New Zealand Delphi Consensus.

Cardio-oncology is a new multidisciplinary area of expertise that seeks to pre-emptively and proactively address cardiac complications that emerge during and following cancer therapy. Modern therapies including molecular targeted therapy and immunotherapy have broadened the agents that can cause cardiac sequelae, often with complications arising within days to weeks of therapy. Several international guidelines have been developed for the acute monitoring of cardio-oncology side effects. However, none are specific to pediatrics. We have addressed this gap in the literature by undertaking a rigorous Delphi consensus approach across 11 domains of cardio-oncology care using an Australian and New Zealand expert group. The expert group consisted of pediatric and adult cardiologists and pediatric oncologists. This Delphi consensus provides an approach to perform risk and baseline assessment, screening, and follow-up, specific to the cancer therapeutic. This review is a useful tool for clinicians involved in the cardio-oncology care of pediatric oncology patients.