The critical role of cardiorespiratory fitness in disease prevention.

Cardiorespiratory fitness (CRF) has been increasingly recognized in recent years as an important predictor of risk for adverse outcomes in numerous chronic conditions. In fact, a growing body of epidemiological and clinical evidence demonstrates that CRF is a potentially stronger predictor of mortality than established risk factors such as smoking, hypertension, hyperlipidemia, and type 2 diabetes. Moreover, adding CRF to these traditional risk factors significantly improves the reclassification of risk for adverse outcomes. The utility of CRF now extends far beyond all-cause and cardiovascular mortality to include the prevention and treatment of numerous other chronic conditions; CRF has been demonstrated to have a mitigating influence in as many as 40 such conditions. Herein we discuss the impact of CRF in the prevention of chronic disease in both adults and children. This discussion includes recent data on interactions between CRF and aging, obesity, statin use, incidence of diabetes, and the impact of CRF and physical activity patterns in adolescents including mental health, scholastic achievement, and cardiometabolic health. Finally, we discuss how CRF, as an essential vital sign, can be implemented in clinical practice.

High prevalence of dysfunctional uterine bleeding in candidates for metabolic/bariatric surgery: increased endometrial cancer risk?

BACKGROUND: Endometrial cancer (EC) is the strongest obesity-associated malignancy and the fastest-growing cancer in young women. Early identification of EC and other endometrial pathology (malignant and nonmalignant) in women with severe obesity may improve treatment options and uterine preservation. Screening for endometrial pathology using abnormal or postmenopausal uterine bleeding (APUB) as a surrogate in women pursuing metabolic/bariatric surgery may be clinically beneficial, but data supporting this effort are limited. OBJECTIVE: To develop and institute a screening program for APUB as a surrogate for endometrial pathology in bariatric surgery candidates. SETTING: Two, academic metabolic/bariatric surgery programs in Louisiana, United States. METHODS: The Modified SAMANTA is a 10-item questionnaire that was implemented to identify patients with APUB, specifically combining tools designed to identify anovulatory/postmenopausal and heavy menstrual bleeding. Demographic (age, race), body mass index, and questionnaire data were analyzed with respect to positive screening using data from March 2021 through May 2023. RESULTS: Of 1371 eligible women presenting for surgical evaluation, 664 (48.4%) positive screens were identified and referred for gynecologic evaluation to rule out endometrial hyperplasia/cancer or other endometrial pathology. The likelihood of positive screening for APUB was associated with increasing BMI (P = .001) and Black/African American race (P = .003), as well as increasing SAMANTA score (P < .001). In contrast, risk of positive screening was negatively associated with increasing age (P < .001). CONCLUSIONS: Women presenting for metabolic/bariatric surgery have a high prevalence of APUB and, given this dysfunctional bleeding and concurrent obesity, are at greater risk for underlying EC. Potential risk factors for APUB, given their associations with screening positive, include increased body mass index, younger age, and Black/African American race. Standardized screening with appropriate gynecologic referral should be a routine part of the overall evaluation for women with severe obesity.

More People, More Active, More Often for Heart Health - Taking Action on Physical Activity.

Physical inactivity is a leading contributor to increased cardiovascular morbidity and mortality. Almost 500 million new cases of preventable noncommunicable diseases (NCDs) will occur globally between 2020 and 2030 due to physical inactivity, costing just over US$300 billion, or around US$ 27 billion annually (WHO 2022). Active adults can achieve a reduction of up to 35% in risk of death from cardiovascular disease. Physical activity also helps in moderating cardiovascular disease risk factors such as high blood pressure, unhealthy weight and type 2 diabetes. For people with cardiovascular disease, hypertension, type 2 diabetes and many cancers, physical activity is an established and evidence-based part of treatment and management. For children and young people, physical activity affords important health benefits. Physical activity can also achieve important cross-sector goals. Increased walking and cycling can reduce journeys by vehicles, air pollution, and traffic congestion and contribute to increased safety and liveability in cities.

Limitations of the 2015-2021 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database for emergency bariatric operations.

BACKGROUND: The Metabolic and Bariatric Surgery Quality Improvement Project (MBSAQIP) is the largest bariatric surgery-specific clinical data set. OBJECTIVES: In 2020, the definition of emergency cases was altered to include only revisional or conversion cases and not primary cases. The aim of this study was to examine how this change affects the utility of the data set for emergency case tracking. SETTING: MBSAQIP database. METHODS: Emergency cases were extracted from available MBSAQIP data (2015-2021). A comparison of co-morbidity profiles was done, specifically before and after the recent change to how "emergency" is defined in the data set. RESULTS: Eleven thousand and twenty-nine of the 1,048,575 total cases were coded as "emergency cases." From 2015 to 2019, 10,574 emergency cases were performed (∼2115 cases/yr), markedly decreasing in 2020 and 2021 to 455 cases (∼228 cases/yr). Before 2020, the most common procedures were the unlisted procedure of the stomach (45.14%, n = 3101), gastric band removal (25.3%, n = 2676), and reduction of internal hernia (11.8%, n = 1244). Between 2020 and 2021, this distribution changed with Roux-en-Y gastric bypass (RYGB), the most common emergency procedure (29.23%, n = 133). As expected from the change that captured only revisional cases, the average operative length was greater between 2020 and 2021 (127.6 versus 86.5 min). CONCLUSIONS: Capturable emergency cases declined in 2020, a trend related to changing the definition of emergency as part of MBSAQIP standards. This change excludes data on internal hernia reduction and does not likely reflect a real change in the prevalence of emergency bariatric cases. Because capture for emergency cases has diminished, so has any prior utility of using MBSAQIP data for studying emergency cases.

m6A RNA methylation orchestrates transcriptional dormancy during paused pluripotency.

Embryos across metazoan lineages can enter reversible states of developmental pausing, or diapause, in response to adverse environmental conditions. The molecular mechanisms that underlie this remarkable dormant state remain largely unknown. Here we show that N6-methyladenosine (m6A) RNA methylation by Mettl3 is required for developmental pausing in mouse blastocysts and embryonic stem (ES) cells. Mettl3 enforces transcriptional dormancy through two interconnected mechanisms: (1) it promotes global mRNA destabilization and (2) it suppresses global nascent transcription by destabilizing the mRNA of the transcriptional amplifier and oncogene N-Myc, which we identify as a crucial anti-pausing factor. Knockdown of N-Myc rescues pausing in Mettl3-/- ES cells, and forced demethylation and stabilization of Mycn mRNA in paused wild-type ES cells largely recapitulates the transcriptional defects of Mettl3-/- ES cells. These findings uncover Mettl3 as a key orchestrator of the crosstalk between transcriptomic and epitranscriptomic regulation during developmental pausing, with implications for dormancy in adult stem cells and cancer.

Bariatric surgery alters mitochondrial function in gut mucosa.

BACKGROUND: The obesity pandemic has worsened global disease burden, including type 2 diabetes, cardiovascular disease, and cancer. Metabolic/bariatric surgery (MBS) is the most effective and durable obesity treatment, but the mechanisms underlying its long-term weight loss efficacy remain unclear. MBS drives substrate oxidation that has been linked to improvements in metabolic function and improved glycemic control that are potentially mediated by mitochondria-a primary site of energy production. As such, augmentation of intestinal mitochondrial function may drive processes underlying the systemic metabolic benefits of MBS. Herein, we applied a highly sensitive technique to evaluate intestinal mitochondrial function ex vivo in a mouse model of MBS. METHODS: Mice were randomized to surgery, sham, or non-operative control. A simplified model of MBS, ileal interposition, was performed by interposition of a 2-cm segment of terminal ileum into the proximal bowel 5 mm from the ligament of Treitz. After a four-week recovery period, intestinal mucosa of duodenum, jejunum, ileum, and interposed ileum were assayed for determination of mitochondrial respiratory function. Citrate synthase activity was measured as a marker of mitochondrial content. RESULTS: Ileal interposition was well tolerated and associated with modest body weight loss and transient hypophagia relative to controls. Mitochondrial capacity declined in the native duodenum and jejunum of animals following ileal interposition relative to controls, although respiration remained unchanged in these segments. Similarly, ileal interposition lowered citrate synthase activity in the duodenum and jejunum following relative to controls but ileal function remained constant across all groups. CONCLUSION: Ileal interposition decreases mitochondrial volume in the proximal intestinal mucosa of mice. This change in concentration with preserved respiration suggests a global mucosal response to segment specific nutrition signals in the distal bowel. Future studies are required to understand the causes underlying these mitochondrial changes.

The Vagus Nerve Mediates Gut-Brain Response to Duodenal Nutrient Administration.

BACKGROUND: Obesity contributes significant disease burden worldwide, including diabetes, cardiovascular disease, and cancer. While bariatric surgery is the most effective and durable obesity treatment, the mechanisms underlying its effects remain unknown. Although neuro-hormonal mechanisms have been suspected to mediate at least some of the gut-brain axis changes following bariatric surgery, studies examining the intestine and its regionally specific post-gastric alterations to these signals remain unclear. MATERIALS AND METHODS: Vagus nerve recording was performed following the implantation of duodenal feeding tubes in mice. Testing conditions and measurements were made under anesthesia during baseline, nutrient or vehicle solution delivery, and post-delivery. Solutions tested included water, glucose, glucose with an inhibitor of glucose absorption (phlorizin), and a hydrolyzed protein solution. RESULTS: Vagus nerve signaling was detectable from the duodenum and exhibited stable baseline activity without responding to osmotic pressure gradients. Duodenal-delivered glucose and protein robustly increased vagus nerve signaling, but increased signaling was abolished during the co-administration of glucose and phlorizin. DISCUSSION: Gut-brain communication via the vagus nerve emanating from the duodenum is nutrient sensitive and easily measurable in mice. Examination of these signaling pathways may help elucidate how the nutrient signals from the intestine are altered when applied to obesity and bariatric surgery mouse models. Future studies will address quantifying the changes in neuroendocrine nutrient signals in health and obesity, with specific emphasis on identifying the changes associated with bariatric surgery and other gastrointestinal surgery.

m 6 A RNA methylation orchestrates transcriptional dormancy during developmental pausing.

Embryos across metazoan lineages can enter reversible states of developmental pausing, or diapause, in response to adverse environmental conditions. The molecular mechanisms that underlie this remarkable dormant state remain largely unknown. Here we show that m 6 A RNA methylation by Mettl3 is required for developmental pausing in mice by maintaining dormancy of paused embryonic stem cells and blastocysts. Mettl3 enforces transcriptional dormancy via two interconnected mechanisms: i) it promotes global mRNA destabilization and ii) suppresses global nascent transcription by specifically destabilizing the mRNA of the transcriptional amplifier and oncogene N-Myc, which we identify as a critical anti-pausing factor. Our findings reveal Mettl3 as a key orchestrator of the crosstalk between transcriptomic and epitranscriptomic regulation during pausing, with implications for dormancy in stem cells and cancer.

The role of bariatric and metabolic surgery in the development, diagnosis, and treatment of endometrial cancer.

The obesity pandemic continues to contribute to a worsening burden of disease worldwide. The link between obesity and diseases such as diabetes, cardiovascular disease, and cancer has been well established, yet most patients living with obesity remain untreated or undertreated. Metabolic and bariatric surgery is the most effective and durable treatment for obesity, is safe, and may have a protective benefit with respect to cancer incidence. In this review, an overview of the link between obesity, metabolic surgery, and cancer is discussed with emphasis on indications for endometrial cancer, the malignancy most strongly associated with obesity. Considerable evidence from retrospective and prospective cohort studies supports a decreased risk of endometrial cancer in patients with obesity who undergo bariatric surgery compared with nonsurgical controls. Survivors of endometrial cancer are at increased risk of poor health outcomes associated with obesity, and women with endometrial cancer are more likely to die of cardiovascular disease and other obesity-related illnesses than of the malignancy itself. Recent advances in anticancer drug therapies have targeted pathways that may also be therapeutically altered with metabolic surgery. Metabolic surgery has significant potential to enter the treatment paradigm for endometrial cancer, and gynecologic oncologist visits present an opportunity to identify patients who may benefit the most.

Integrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2).

Musashi 2 (MSI2) is an RNA binding protein (RBP) that regulates asymmetric cell division and cell fate decisions in normal and cancer stem cells. MSI2 appears to repress translation by binding to 3' untranslated regions (3'UTRs) of mRNA, but the identity of functional targets remains unknown. Here, we used individual nucleotide resolution cross-linking and immunoprecipitation (iCLIP) to identify direct RNA binding partners of MSI2 and integrated these data with polysome profiling to obtain insights into MSI2 function. iCLIP revealed specific MSI2 binding to thousands of mRNAs largely in 3'UTRs, but translational differences were restricted to a small fraction of these transcripts, indicating that MSI2 regulation is not triggered by simple binding. Instead, the functional targets identified here were bound at higher density and contain more 'UAG' motifs compared to targets bound nonproductively. To further distinguish direct and indirect targets, MSI2 was acutely depleted. Surprisingly, only 50 transcripts were found to undergo translational induction on acute loss. Using complementary approaches, we determined eukaryotic translation initiation factor 3A (EIF3A) to be an immediate, direct target. We propose that MSI2 downregulation of EIF3A amplifies these effects on translation. Our results also underscore the challenges in defining functional targets of RBPs since mere binding does not imply a discernible functional interaction.

The prognostic ability of cardiac output determined by inert gas rebreathing technique in pulmonary hypertension.

This investigation validated the inert gas rebreathing (IGR) technique and determined IGR prognostic ability compared to invasive cardiac output measurements in patients with pulmonary hypertension. IGR compared with thermodilution cardiac output demonstrated a moderate bias. IGR technique demonstrated long-term prognostic value comparable to invasive cardiac output in pulmonary hypertension patients.

Perm1 promotes cardiomyocyte mitochondrial biogenesis and protects against hypoxia/reoxygenation-induced damage in mice.

Normal contractile function of the heart depends on a constant and reliable production of ATP by cardiomyocytes. Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. Further, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and estrogen-related receptor (ERR)-induced regulator, muscle 1) that is enriched in skeletal and cardiac-muscle mitochondria and transcriptionally regulated by PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1) and ERR. The role of Perm1 in the heart is poorly understood and is studied here. We utilized cell culture, mouse models, and human tissue, to study its expression and transcriptional control, as well as its role in transcription of other factors. Critically, we tested Perm1's role in cardiomyocyte mitochondrial function and its ability to protect myocytes from stress-induced damage. Our studies show that Perm1 expression increases throughout mouse cardiogenesis, demonstrate that Perm1 interacts with PGC-1α and enhances activation of PGC-1 and ERR, increases mitochondrial DNA copy number, and augments oxidative capacity in cultured neonatal mouse cardiomyocytes. Moreover, we found that Perm1 reduced cellular damage produced as a result of hypoxia and reoxygenation-induced stress and mitigated cell death of cardiomyocytes. Taken together, our results show that Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction induced by ischemic injury.

Downregulation of the FTO m6A RNA demethylase promotes EMT-mediated progression of epithelial tumors and sensitivity to Wnt inhibitors.

Post-transcriptional modifications of RNA constitute an emerging regulatory layer of gene expression. The demethylase fat mass- and obesity-associated protein (FTO), an eraser of N6-methyladenosine (m6A), has been shown to play a role in cancer, but its contribution to tumor progression and the underlying mechanisms remain unclear. Here, we report widespread FTO downregulation in epithelial cancers associated with increased invasion, metastasis and worse clinical outcome. Both in vitro and in vivo, FTO silencing promotes cancer growth, cell motility and invasion. In human-derived tumor xenografts (PDXs), FTO pharmacological inhibition favors tumorigenesis. Mechanistically, we demonstrate that FTO depletion elicits an epithelial-to-mesenchymal transition (EMT) program through increased m6A and altered 3'-end processing of key mRNAs along the Wnt signaling cascade. Accordingly, FTO knockdown acts via EMT to sensitize mouse xenografts to Wnt inhibition. We thus identify FTO as a key regulator, across epithelial cancers, of Wnt-triggered EMT and tumor progression and reveal a therapeutically exploitable vulnerability of FTO-low tumors.

Canadian 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years or older: an integration of physical activity, sedentary behaviour, and sleep.

The Canadian Society for Exercise Physiology assembled a Consensus Panel representing national organizations, content experts, methodologists, stakeholders, and end-users and followed an established guideline development procedure to create the Canadian 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years or older: An Integration of Physical Activity, Sedentary Behaviour, and Sleep. These guidelines underscore the importance of movement behaviours across the whole 24-h day. The development process followed the strategy outlined in the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. A large body of evidence was used to inform the guidelines including 2 de novo systematic reviews and 4 overviews of reviews examining the relationships among movement behaviours (physical activity, sedentary behaviour, sleep, and all behaviours together) and several health outcomes. Draft guideline recommendations were discussed at a 4-day in-person Consensus Panel meeting. Feedback from stakeholders was obtained by survey (n = 877) and the draft guidelines were revised accordingly. The final guidelines provide evidence-based recommendations for a healthy day (24-h), comprising a combination of sleep, sedentary behaviours, and light-intensity and moderate-to-vigorous-intensity physical activity. Dissemination and implementation efforts with corresponding evaluation plans are in place to help ensure that guideline awareness and use are optimized. Novelty First ever 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years or older with consideration of a balanced approach to physical activity, sedentary behaviour, and sleep Finalizes the suite of 24-Hour Movement Guidelines for Canadians across the lifespan.

Resistance training and health in adults: an overview of systematic reviews.

The objective of this overview of systematic reviews was to determine the benefits and harms of resistance training (RT) on health outcomes in adults aged 18 years or older, compared with not participating in RT. Four electronic databases were searched in February 2019 for systematic reviews published in the past 10 years. Eligibility criteria were determined a priori for population (community dwelling adults), intervention (exclusively RT), comparator (no RT or different doses of RT), and health outcomes (critical: mortality, physical functioning, health-related quality of life, and adverse events; important: cardiovascular disease, type 2 diabetes mellitus, mental health, brain health, cognitive function, cancer, fall-related injuries or falls, and bone health). We selected 1 review per outcome and we used the GRADE process to assess the strength of evidence. We screened 2089 records and 375 full-text articles independently, in duplicate. Eleven systematic reviews were included, representing 364 primary studies and 382 627 unique participants. RT was associated with a reduction in all-cause mortality and cardiovascular disease incidence, and an improvement in physical functioning. Effects on health-related quality of life or cognitive function were less certain. Adverse events were not consistently monitored or reported in RT studies, but serious adverse events were not common. Systematic reviews for the remaining important health outcomes could not be identified. Overall, RT training improved health outcomes in adults and the benefits outweighed the harms. (PROSPERO registration no.: CRD42019121641.) Novelty This overview was required to inform whether there was new evidence to support changes to the recommended guidelines for resistance training.

A systematic review of compositional data analysis studies examining associations between sleep, sedentary behaviour, and physical activity with health outcomes in adults.

This systematic review determined if the composition of time spent in movement behaviours (i.e., sleep, sedentary behaviour (SED), light physical activity, and moderate-to-vigorous physical activity (MVPA)) is associated with health in adults. Five electronic databases were searched in August 2019. Studies were eligible for inclusion if they were peer-reviewed, examined community-dwelling adults, and used compositional data analysis to examine the associations between the composition of time spent in movement behaviours and health outcomes. Eight studies (7 cross-sectional, 1 prospective cohort) of >12 000 unique participants were included. Findings indicated that the 24-h movement behaviour composition was associated with all-cause mortality (1 of 1 analyses), adiposity (4 of 4 analyses), and cardiometabolic biomarkers (8 of 15 analyses). Reallocating time into MVPA from other movement behaviours was associated with favourable changes to most health outcomes and taking time out of SED and reallocating it into other movement behaviours was associated with favourable changes to all-cause mortality. The quality of evidence was very low for all health outcomes. In conclusion, these findings support the notion that the composition of movement across the entire 24-h day matters, and that recommendations for sleep, SED, and physical activity should be combined into a single public health guideline. (PROSPERO registration no.: CRD42019121641.) Novelty The 24-h movement behaviour composition is associated with a variety of health outcomes. Reallocating time into MVPA is favourably associated with health. Reallocating time out of SED is associated with favourable changes to mortality risk.

Cardiomyocyte Expression of ZO-1 Is Essential for Normal Atrioventricular Conduction but Does Not Alter Ventricular Function.

RATIONALE: ZO-1 (Zonula occludens-1), a plasma membrane-associated scaffolding protein regulates signal transduction, transcription, and cellular communication. Global deletion of ZO-1 in the mouse is lethal by embryonic day 11.5. The function of ZO-1 in cardiac myocytes (CM) is largely unknown. OBJECTIVE: To determine the function of CM ZO-1 in the intact heart, given its binding to other CM proteins that have been shown instrumental in normal cardiac conduction and function. METHODS AND RESULTS: We generated ZO-1 CM-specific knockout (KO) mice using α-Myosin Heavy Chain-nuclear Cre (ZO-1cKO) and investigated physiological and electrophysiological function by echocardiography, surface ECG and conscious telemetry, intracardiac electrograms and pacing, and optical mapping studies. ZO-1cKO mice were viable, had normal Mendelian ratios, and had a normal lifespan. Ventricular morphometry and function were not significantly different between the ZO-1cKO versus control (CTL) mice, basally in young or aged mice, or even when hearts were subjected to hemodynamic loading. Atrial mass was increased in ZO-1cKO. Electrophysiological and optical mapping studies indicated high-grade atrioventricular (A-V) block in ZO-1cKO comparing to CTL hearts. While ZO-1-associated proteins such as vinculin, connexin 43, N-cadherin, and α-catenin showed no significant change with the loss of ZO-1, Connexin-45 and Coxsackie-adenovirus (CAR) proteins were reduced in atria of ZO-1cKO. Further, with loss of ZO-1, ZO-2 protein was increased significantly in ventricular CM in a presumed compensatory manner but was still not detected in the AV nodal myocytes. Importantly, the expression of the sodium channel protein NaV1.5 was altered in AV nodal cells of the ZO-1cKO versus CTL. CONCLUSIONS: ZO-1 protein has a unique physiological role in cardiac nodal tissue. This is in alignment with its known interaction with CAR and Cx45, and a new function in regulating the expression of NaV1.5 in AV node. Uniquely, ZO-1 is dispensable for function of the working myocardium.

Raoultella ornithinolytica and Klebsiella oxytoca pyogenic liver abscess presenting as chronic cough.

Raoultella ornithinolytica is a Gram-negative rod belonging to the Enterobacteriaceae family and closely related to Klebsiella spp. It is commonly present in aquatic environments. Human infections caused by R. ornithinolytica are being increasingly recognized. It has been documented to cause various hospital-acquired infections including but not limited to gastrointestinal, skin, and genitourinary infections. The organism has been particularly associated with invasive procedures and is commonly seen in patients with malignancy, diabetes, chronic kidney disease and immunodeficiency. To our knowledge, we report the first case of pyogenic liver abscess caused by this organism. The patient presented subtly with a chronic, nonresolving cough and was managed successfully by surgical drainage and appropriate antimicrobials.