Sex-Specific Skeletal Muscle Gene Expression Responses to Exercise Reveal Novel Direct Mediators of Insulin Sensitivity Change.

BACKGROUND: Understanding the causal pathways, systems, and mechanisms through which exercise impacts human health is complex. This study explores molecular signaling related to whole-body insulin sensitivity (Si) by examining changes in skeletal muscle gene expression. The analysis considers differences by biological sex, exercise amount, and exercise intensity to identify potential molecular targets for developing pharmacologic agents that replicate the health benefits of exercise. METHODS: The study involved 53 participants from the STRRIDE I and II trials who completed eight months of aerobic training. Skeletal muscle gene expression was measured using Affymetrix and Illumina technologies, while pre- and post-training Si was assessed via an intravenous glucose tolerance test. A novel gene discovery protocol, integrating three literature-derived and data-driven modeling strategies, was employed to identify causal pathways and direct causal factors based on differentially expressed transcripts associated with exercise intensity and amount. RESULTS: In women, the transcription factor targets identified were primarily influenced by exercise amount and were generally inhibitory. In contrast, in men, these targets were driven by exercise intensity and were generally activating. Transcription factors such as ATF1, CEBPA, BACH2, and STAT1 were commonly activating in both sexes. Specific transcriptional targets related to exercise-induced Si improvements included TACR3 and TMC7 for intensity-driven effects, and GRIN3B and EIF3B for amount-driven effects. Two key signaling pathways mediating aerobic exercise-induced Si improvements were identified: one centered on estrogen signaling and the other on phorbol ester (PKC) signaling, both converging on the epidermal growth factor receptor (EGFR) and other relevant targets. CONCLUSIONS: The signaling pathways mediating Si improvements from aerobic exercise differed by sex and were further distinguished by exercise intensity and amount. Transcriptional adaptations in skeletal muscle related to Si improvements appear to be causally linked to estrogen and PKC signaling, with EGFR and other identified targets emerging as potential skeletal muscle-specific drug targets to mimic the beneficial effects of exercise on Si.

Implementing falls prevention patient education in hospitals - older people's views on barriers and enablers.

BACKGROUND: World falls guidelines recommend that hospitalised older patients receive individualised falls prevention education, yet no studies have sought older people's feedback on how best to deliver falls prevention education in hospitals. The objective of the study was to explore the perspectives of older people and their caregivers about barriers and enablers to implementation of a tailored hospital falls education program. METHODS: A qualitative descriptive design was used. Three focus groups and 16 semi-structured interviews were conducted. A purposive sample of older people who had previous hospital admissions and caregivers of older people were selected to review a co-designed patient falls education program (the revised Safe Recovery program). They provided feedback on how to implement the program in hospital settings. Data were thematically analysed taking an deductive-inductive approach. RESULTS: Participants were 37 older people [female n = 24 (64.9%), age range 64 to 89 years] and nine caregivers (female n = 8). The first theme was that the Safe Recovery Program resources were of high quality, enabling strong patient engagement and increased knowledge and awareness about falls prevention in hospitals. The second theme identified practical strategies to enable program delivery in hospital wards. The key enablers identified were: timing of delivery around wellness and the patient's mobility; tailoring messages for each older patient; key staff members being assigned to lead program delivery. Participants recommended that staff assist older patients to set appropriate behavioural goals in relation to preventing falls in hospitals. They also recommended that staff raise older patients' confidence and motivation to take action to reduce the risk of falls. Providing resources in other languages and alternative shorter versions was recommended to enable broad dissemination. CONCLUSIONS: Older people and their caregivers advised that implementing falls education in hospitals can be enabled by using high quality resources, delivering falls education in a timely manner and personalising the education and support to individual needs.

Liver-specific deletion of de novo DNA methyltransferases protects against glucose intolerance in high-fat diet-fed male mice.

Alterations to gene transcription and DNA methylation are a feature of many liver diseases including fatty liver disease and liver cancer. However, it is unclear whether the DNA methylation changes are a cause or a consequence of the transcriptional changes. It is even possible that the methylation changes are not required for the transcriptional changes. If DNA methylation is just a minor player in, or a consequence of liver transcriptional change, then future studies in this area should focus on other systems such as histone tail modifications. To interrogate the importance of de novo DNA methylation, we generated mice that are homozygous mutants for both Dnmt3a and Dnmt3b in post-natal liver. These mice are viable and fertile with normal sized livers. Males, but not females, showed increased adipose depots, yet paradoxically, improved glucose tolerance on both control diet and high-fat diets (HFD). Comparison of the transcriptome and methylome with RNA sequencing and whole-genome bisulfite sequencing in adult hepatocytes revealed that widespread loss of methylation in CpG-rich regions in the mutant did not induce loss of homeostatic transcriptional regulation. Similarly, extensive transcriptional changes induced by HFD did not require de novo DNA methylation. The improved metabolic phenotype of the Dnmt3a/3b mutant mice may be mediated through the dysregulation of a subset of glucose and fat metabolism genes which increase both glucose uptake and lipid export by the liver. However, further work is needed to confirm this.

Cessation of Smoking Trial in the Emergency Department (COSTED): a multicentre randomised controlled trial.

BACKGROUND: Supporting people to quit smoking is one of the most powerful interventions to improve health. The Emergency Department (ED) represents a potentially valuable opportunity to deliver a smoking cessation intervention if it is sufficiently resourced. The objective of this trial was to determine whether an opportunistic ED-based smoking cessation intervention can help people to quit smoking. METHODS: In this multicentre, parallel-group, randomised controlled superiority trial conducted between January and August 2022, adults who smoked daily and attended one of six UK EDs were randomised to intervention (brief advice, e-cigarette starter kit and referral to stop smoking services) or control (written information on stop smoking services). The primary outcome was biochemically validated abstinence at 6 months. RESULTS: An intention-to-treat analysis included 972 of 1443 people screened for inclusion (484 in the intervention group, 488 in the control group). Of 975 participants randomised, 3 were subsequently excluded, 17 withdrew and 287 were lost to follow-up. The 6-month biochemically-verified abstinence rate was 7.2% in the intervention group and 4.1% in the control group (relative risk 1.76; 95% CI 1.03 to 3.01; p=0.038). Self-reported 7-day abstinence at 6 months was 23.3% in the intervention group and 12.9% in the control group (relative risk 1.80; 95% CI 1.36 to 2.38; p<0.001). No serious adverse events related to taking part in the trial were reported. CONCLUSIONS: An opportunistic smoking cessation intervention comprising brief advice, an e-cigarette starter kit and referral to stop smoking services is effective for sustained smoking abstinence with few reported adverse events. TRIAL REGISTRATION NUMBER: NCT04854616.

Methodological Issues with Head and Neck Cancer Prognostic Risk Prediction Models.

OBJECTIVE: Prognostic risk prediction models estimate the probability of developing head and neck cancer (HNC), providing valuable information for managing the disease. While different prognostic HNC risk prediction models have been developed worldwide, a comprehensive evaluation of their methods is lacking. We conducted a scoping review with a critical assessment aiming to identify the methodological strengths and limitations of HNC risk prediction models. METHOD: We searched Medline, Embase, Scopus, Web of Science, and CAB Abstracts databases and included full-text-available peer-reviewed published papers on developing or validating a prognostic HNC risk prediction model. Study quality was appraised using the PROBAST tool. RESULTS: Nine papers were included. Although all had a high risk of bias, mainly in the analysis domain, only two studies had high concerns about clinical applicability. CONCLUSION: Currently published studies provide insufficient information on methods, making it difficult to judge the models' quality and applicability. Future investigations should follow the guidelines in reporting the prediction modelling studies.

Comparative Outcomes of a Transthyretin Amyloid Cardiomyopathy Cohort Versus Patients With Heart Failure With Preserved Ejection Fraction Enrolled in the TOPCAT Trial.

Background Transthyretin cardiac amyloidosis (ATTR-CM), found in 6% to 15% of cohorts with heart failure with preserved ejection fraction, has long been considered a rare disease with poor prognosis. New treatments have made it one of the few directly treatable causes of heart failure. This study sought to determine whether patients with ATTR-CM, particularly those treated with tafamidis, have comparable survival to an unselected cohort with heart failure with preserved ejection fraction. Methods and Results We compared the clinical characteristics and outcomes between a single-center cohort of patients with ATTR-CM (n=114) and patients with heart failure with preserved ejection fraction enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial (n=1761, excluding Russia and Georgia). The primary outcome was a composite of all-cause death, heart failure hospitalization, myocardial infarction, and stroke. Subgroup analysis of patients with ATTR-CM treated with tafamidis was also performed. Patients with ATTR-CM had higher rates of the primary composite outcome compared with patients enrolled in the TOPCAT trial (hazard ratio [HR], 1.44 [95% CI, 1.09-1.91]; P=0.01), with similar rates of all-cause death (HR, 1.43 [95% CI, 0.99-2.06]; P=0.06) but higher rates of heart failure hospitalizations (HR, 1.62 [95% CI, 1.15-2.28]; P<0.01). Compared with patients enrolled in TOPCAT, patients with ATTR-CM treated with tafamidis had similar rates of the primary composite outcome (HR, 1.30 [95% CI, 0.86-1.96]; P=0.21) and all-cause death (HR, 1.10 [95% CI, 0.57-2.14]; P=0.78) but higher rates of heart failure hospitalizations (HR, 1.96 [95% CI, 1.27-3.02]; P<0.01). Conclusions Patients with ATTR-CM treated with tafamidis have similar rates of all-cause death compared with patients with heart failure with preserved ejection fraction, with higher rates of heart failure hospitalizations.

The Relationship of Food Insecurity to Nutritional Risk in Independent Living Older Adults.

Understanding the factors that augment optimal health during aging is critical as the US older adult population is increasing. Most research about food insecurity, nutritional risk, and perceived health among older adults are in urban areas or congregate living facilities. Thus, the purpose of this project was to study the relationships among these factors, plus activities of daily living, in community-dwelling older adults in a medium-sized city. Using a qualitative-quantitative study design, a cross-sectional survey was completed by 167 low-income senior apartment residents. Food insecurity in this group was higher than the national and state rate, yet nutrition assistance programs were underutilized and participants under 75 years were more food insecure than their older counterparts. Food insecure residents were at greater nutritional risk, had poorer self-reported health status, were more likely to be depressed, and had a less independent function, including limitations on the ability to shop for and prepare food. The study area is desirable to retirees due to lower cost of living; however, access to services, such as grocery stores, public transportation, and health care providers is limited. This research indicates the need for increased outreach, nutrition assistance, and support services to ensure healthy aging in these regions.

Clinical portfolios as a tool to develop competence in radiography education.

INTRODUCTION: Clinical portfolios are used in healthcare programmes to prepare students for their professional careers by promoting reflective practice and critical thinking. There is a paucity of research related to students' and educators' perceptions of the effectiveness of clinical portfolios in radiography education. METHODS: A cross-sectional, questionnaire-based study was conducted to explore radiography students' and educators' opinions on the contribution of portfolios to students' personal and professional development. Optimal portfolio content and administration was investigated. Questionnaires were distributed to a stratified sample of second-, third- and fourth-year undergraduate radiography students and recent graduates from a 4-year BSc Radiography program in Ireland. A second questionnaire was sent to academic staff involved in clinical education. Participation was on a voluntary basis and data anonymous. RESULTS: Sixty participants provided the student perspective and seven provided the educator perspective. All educators and most radiography students (58-83%) agreed that the portfolio contributed effectively to personal and professional development. Tutor feedback and competency assessments were ranked the most valuable elements of the portfolio by both students and educators. The remainder content ranked from most to least beneficial were; image appraisal assignments, self-reflection, training needs analysis and modality objective lists. Final-year students and new graduates valued self-reflections more than novice students. Online portfolio administration was preferred over paper administration (5:3) due to greater efficiency, accessibility, and interactivity. CONCLUSION: The clinical portfolio was perceived to be an effective tool for developing competence in radiography education. Study findings may be used to optimise radiography clinical portfolio design and administration. IMPLICATIONS FOR PRACTICE: This study is the first to highlight elements of a clinical portfolio deemed most effective in competence development from the perspective of radiography students and educators.

Characterizing individual trainee learning curves in surgical training: Challenges and opportunities.

The surgical learning curve is an observable and measurable phenomenon. In the era of competency-based approaches to surgical training, monitoring the trajectory of individual trainee competence attainment could represent a meaningful method of formative and summative assessment. While technology can assist this approach, a number of significant barriers to the implementation of such assessment methods remain, including: accurate data collection, standard setting, and reliable assessment. Translating individual learning curve data into quantifiable case minimum targets in training poses further difficulties, and may not be possible for all procedures, particularly those that are less frequently performed and assessed. In spite of these challenges, significant benefits could be realized through an individualized approach to competency assessment using trainee learning curve data. Tracking competence acquisition against criterion-referenced standards could allow for targeted training and remediation, conforming with modern theories of adult education and empowering trainees to take control of their own learning. Learning curve data could also be used to assess the effects of educational interventions such as simulation-based training on subsequent competence acquisition rates. Ultimately, the individual learning curves of trainees could be used to inform personalised decisions regarding entrustment, credentialing, and certification, allowing training programmes to move beyond minimum operative experience targets as a crude proxy measure of competence.

A Case Report of a Vertical Zone III Sacral Fracture Due to Acute Lower Extremity Hyperabduction While Windsurfing.

Typically associated with motor vehicle accidents and falls, sacral fractures result from sudden compression of the iliac wings, placing bidirectional traction forces on the anterior and/or posterior aspects of the sacrum. Here we describe a vertical Zone III sacral fracture caused by sudden, forceful hyperabduction of the lower extremities. To the authors' knowledge this is the first report of a Zone III sacral fracture caused by this mechanism which occurred when the patient encountered a large wave while windsurfing. Imaging revealed a longitudinal fracture to the anterior sacrum, with a concomitant Zone II fracture and pubic symphysis diastasis. The patient was treated using anterior fixation plating and posterior percutaneous pinning. The purpose of this study is to increase provider awareness of an often underdiagnosed fracture, alert water sports enthusiasts of the risks associated with windsurfing, describe signs and symptoms of this often overlooked fracture, and discuss treatment modalities based on radiographic and clinical assessments of fracture stability.

National epidemiologic trends (2008-2018) in the United States for the incidence and expenditures associated with incisional hernia in relation to abdominal surgery.

PURPOSE: It is unknown whether the trend of rising incisional hernia (IH) repair (IHR) incidence and costs until 2011 currently persists. We aimed to evaluate how the IHR procedure incidence, cost and patient risk-profile have changed over the last decade relative to all abdominal surgeries (AS). METHODS: Repeated cross-sectional analysis of 38,512,737 patients undergoing inpatient 4AS including IHR within the 2008-2018 National Inpatient Sample. Yearly incidence (procedures/1,000,000 people [PMP]), hospital costs, surgical and patient characteristics were compared between IHR and AS using generalized linear and multinomial regression. RESULTS: Between 2008-2018, 3.1% of AS were IHR (1,200,568/38,512,737). There was a steeper decrease in the incidence of AS (356.5 PMP/year) compared to IHR procedures (12.0 PMP/year) which resulted in the IHR burden relative to AS (2008-2018: 12,576.3 to 9,113.4 PMP; trend difference P < 0.01). National costs averaged $47.9 and 1.7 billion/year for AS and IHR, respectively. From 2008-2018, procedure costs increased significantly for AS (68.2%) and IHR (74.6%; trends P < 0.01). Open IHR downtrended (42.2%), whereas laparoscopic (511.1%) and robotic (19,301%) uptrended significantly (trends P < 0.01). For both AS and IHR, the proportion of older (65-85y), Black and Hispanic, publicly-insured, and low-income patients, with higher comorbidity burden, undergoing elective procedures at small- and medium-sized hospitals uptrended significantly (all P < 0.01). CONCLUSION: IH persists as a healthcare burden as demonstrated by the increased proportion of IHR relative to all AS, disproportionate presence of high-risk patients that undergo these procedures, and increased costs. Targeted efforts for IH prevention have the potential of decreasing $17 M/year in costs for every 1% reduction.

Patients undergoing colorectal surgery at a Veterans Affairs Hospital do not experience racial disparity in length of stay either before or after implementing an enhanced recovery pathway.

BACKGROUND: Enhanced Recovery Pathways (ERP) have been shown to reduce racial disparities following surgery. The objective of this study is to determine whether ERP implementation mitigates racial disparities at a Veterans Affairs Hospital. METHODS: A retrospective cohort study was conducted using data obtained from the Veterans Affairs Surgical Quality Improvement Program. All patients undergoing elective colorectal surgery following ERP implementation were included. Current procedural terminology (CPT) codes were used to identify patients who underwent similar procedures prior to ERP implementation. RESULTS: Our study included 417 patients (314 pre-ERP vs. 103 ERP), 97.1% of which were male, with an average age of 62.32 (interquartile range (IQR): 25-90). ERP patients overall had a significantly shorter post-operative length of stay (pLOS) vs. pre-ERP patients (median 4 days (IQR: 3-6.5) vs. 6 days (IQR: 4-9) days (p < 0.001)). Within the pre-ERP group, median pLOS for both races was 6 days (IQR: 4-6; p < 0.976) and both groups experienced a decrease in median pLOS (4 vs. 6 days; p < 0.009 and p < 0.001) following ERP implementation. CONCLUSIONS: Racial disparities did not exist in patients undergoing elective surgery at a single VA Medical Center. Implementation of an ERP significantly reduced pLOS for black and white patients.

Clinical management of amyloid cardiomyopathy.

Clinical heart failure, restrictive cardiomyopathy, and arrhythmias are hallmark features of amyloid cardiomyopathy. In contrast to the advancements in targeted therapies, there is a general lack of evidence-based practice guidelines for clinical management of amyloid cardiomyopathy. In this review, we review the role of routine medical therapy in amyloid cardiomyopathy, from heart failure management to orthostatic hypotension, atrial arrhythmias, thromboembolic complications, and prevention of sudden death. We conclude by discussing approaches to patients with end-stage disease.

Characterizing hernia centers in the United States: what defines a hernia center?

PURPOSE: A universal definition for what constitutes a hernia center does not exist. The purpose of this study was to characterize hernia centers in the United States by analyzing hernia centers and their non-hernia center counterparts. METHODS: A web-based search was conducted to identify defining features of hernia centers including faculty demographics and composition, research output, research funding, clinical trials, and website content. Hernia centers and non-hernia centers were compared. RESULTS: Most hernia centers (n = 36) are in urban areas (89%) and distributed evenly across regions of the United States. Hernia centers are associated with University program types (p = 0.001) while non-hernia centers are associated with University-Affiliate (p = 0.001) and Community (p = 0.02) program types. Hernia centers are associated with Abdominal Core Health Quality Collaborative participation (p = 0.01) and Center of Excellence by the Surgical Review Corporation certification (p = 0.005). Hernia centers are associated with presence of active clinical trials (p < 0.001) and number of clinical trials (p < 0.001). Hernia centers are associated with industry-sponsored trials (p < 0.001) but are not associated with NIH-sponsored trials. Fifty percent of hernia centers have PRS faculty. The vast majority of hernia center websites describe hernias treated (92%) and repair techniques (89%). The majority of hernia center mission statements emphasize an individualized care plan (61%) and multidisciplinary care (57%). Only 39% of websites and 17% of mission statements mention research. CONCLUSION: In the United States, hernia centers are clinically oriented, multidisciplinary surgical teams at predominantly urban, University programs that may use this title to attract patient referrals and industry sponsorship of clinical trials.

Prevalence and Outcomes of p.Val142Ile TTR Amyloidosis Cardiomyopathy: A Systematic Review.

BACKGROUND: The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly develop a cardiomyopathy (variant transthyretin amyloidosis cardiomyopathy) phenotype. Yet, there are conflicting data on the prevalence and outcomes of p.Val142Ile variant carriers. METHODS: We performed a systematic review of the prevalence and outcomes of p.Val142Ile variant transthyretin amyloidosis cardiomyopathy among subjects of African descent. We found 62 relevant articles after searching the MEDLINE databases from 1980 to 2020 that reported data for ≈150 000 subjects. RESULTS: The reported worldwide prevalence of the p.Val142Ile variant is 0.3% to 1.6% in the general population. Among people of African descent, the reported prevalence from all studies ranges from 1.1% to 9.8%, but for studies with >1000 subjects, it is 3% to 3.5%. The prevalence of the p.Val142Ile variant in a region is dependent on the reported percentage of subjects who are of African descent in that region. p.Val142Ile variant transthyretin amyloidosis cardiomyopathy typically presents in the seventh to eighth decade of life and the majority of cases reported were male, with 25% to 38% diagnosed with atrial fibrillation. It was associated with a longitudinally worse quality of life and a lower adjusted survival compared with other types of transthyretin amyloidosis cardiomyopathy. CONCLUSIONS: The p.Val142Ile variant is the most common variant of the transthyretin gene with most carriers being of African descent. The true penetrance is unknown but the p.Val142Ile variant is associated with increased rates of incident heart failure and portends a lower overall survival. Increased awareness could lead to earlier diagnosis and improved heart failure outcomes among those of African descent, which is of increasing importance given the advent of novel therapeutics for this disease.

Acute ingestion of a high-fructose drink impairs vascular autonomic modulation and reflex control of blood pressure in first-degree relatives of diabetic patients.

First-degree relatives of diabetes patients, despite being euglycemic, presented impaired BRS and exacerbation of sympathetic modulation after ingestion of a high fructose drink when challenged to orthostatic stress. This finding alerts the importance of early autonomic dysfunction even in clinically healthy people, especially in face of a stressful situation.

Progress Towards Using Linked Population-Based Data For Geohealth Research: Comparisons Of Aotearoa New Zealand And The United Kingdom.

Globally, geospatial concepts are becoming increasingly important in epidemiological and public health research. Individual level linked population-based data afford researchers with opportunities to undertake complex analyses unrivalled by other sources. However, there are significant challenges associated with using such data for impactful geohealth research. Issues range from extracting, linking and anonymising data, to the translation of findings into policy whilst working to often conflicting agendas of government and academia. Innovative organisational partnerships are therefore central to effective data use. To extend and develop existing collaborations between the institutions, in June 2019, authors from the Leeds Institute for Data Analytics and the Alan Turing Institute, London, visited the Geohealth Laboratory based at the University of Canterbury, New Zealand. This paper provides an overview of insight shared during a two-day workshop considering aspects of linked population-based data for impactful geohealth research. Specifically, we discuss both the collaborative partnership between New Zealand's Ministry of Health (MoH) and the University of Canterbury's GeoHealth Lab and novel infrastructure, and commercial partnerships enabled through the Leeds Institute for Data Analytics and the Alan Turing Institute in the UK. We consider the New Zealand Integrated Data Infrastructure as a case study approach to population-based linked health data and compare similar approaches taken by the UK towards integrated data infrastructures, including the ESRC Big Data Network centres, the UK Biobank, and longitudinal cohorts. We reflect on and compare the geohealth landscapes in New Zealand and the UK to set out recommendations and considerations for this rapidly evolving discipline.

Successful radiofrequency perforation and balloon decompression of cor triatriatum sinister using novel technique, a case series.

Cor triatriatum sinister (CTS) is a rare congenital cardiac anomaly representing <0.1% of all congenital cardiac malformations. It is characterized by the presence of a left atrial (LA) membrane that leads to left ventricular inflow obstruction. Uncorrected, obstructed CTS may have significant sequelae such as pulmonary hypertension or arrhythmias. Transcatheter balloon decompression has been described as a successful alternative to surgical resection of the obstructing membrane. Our review of the literature revealed no reported cases utilizing radiofrequency (RF) energy to perforate the CTS membrane prior to balloon decompression. This manuscript describes two patients with CTS who were treated successfully with a transcatheter technique using RF energy to perforate the obstructing membrane prior to balloon angioplasty and decompression of the LA.