Abstract Background Multicenter longitudinal objective data for survival into adulthood of patients who have undergone Fontan procedures are lacking. Objectives This study sought to describe ...transplant-free survival and explore relationships between laboratory measures of ventricular performance and functional status over time. Methods Exercise testing, echocardiography, B-type natriuretic peptide, functional health assessment, and medical history abstraction were repeated 9.4 ± 0.4 years after the Fontan Cross-Sectional Study (Fontan 1) and compared with previous values. Cox regression analysis explored risk factors for interim death or cardiac transplantation. Results From the original cohort of 546 subjects, 466 were contacted again, and 373 (80%) were enrolled at 21.2 ± 3.5 years of age. Among subjects with paired testing, the percent predicted maximum oxygen uptake decreased (69 ± 14% vs. 61 ± 16%; p < 0.001; n = 95), ejection fraction decreased (58 ± 11% vs. 55 ± 10%; p < 0.001; n = 259), and B-type natriuretic peptide increased (median interquartile range 13 7 to 25 pg/mol vs. 18 9 to 36 pg/mol; p < 0.001; n = 340). At latest follow-up, a lower Pediatric Quality of Life Inventory physical summary score was associated with poorer exercise performance (R2 adjusted = 0.20; p < 0.001; n = 274). Cumulative complications since the Fontan procedure included additional cardiac surgery (32%), catheter intervention (62%), arrhythmia treatment (32%), thrombosis (12%), and protein-losing enteropathy (8%). Since Fontan 1, 54 subjects (10%) have received a heart transplant (n = 23) or died without transplantation (n = 31). The interval risk of death or/cardiac transplantation was associated with poorer ventricular performance and functional health status assessed at Fontan 1, but it was not associated with ventricular morphology, the subject’s age, or the type of Fontan connection. Conclusions Interim transplant-free survival over 12 years in this Fontan cohort was 90% and was independent of ventricular morphology. Exercise performance decreased and was associated with worse functional health status. Future interventions might focus on preserving exercise capacity. (Relationship Between Functional Health Status and Ventricular Performance After Fontan—Pediatric Heart Network; NCT00132782 )
Excessive shedding of apoptotic enterocytes into the intestinal lumen is observed in inflammatory bowel disease and is correlated with disease relapse. Based on their cytolytic capacity and ...surveillance behavior, we investigated whether intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs) are actively involved in the shedding of enterocytes into the lumen.
Intravital microscopy was performed on GFP γδ T cell reporter mice treated with intraperitoneal lipopolysaccharide (10 mg/kg) for 90 minutes to induce tumor necrosis factor–mediated apoptosis. Cell shedding in various knockout or transgenic mice in the presence or absence of blocking antibody was quantified by immunostaining for ZO-1 funnels and cleaved caspase-3 (CC3). Granzyme A and granzyme B release from ex vivo–stimulated γδ IELs was quantified by enzyme-linked immunosorbent assay. Immunostaining for γδ T cell receptor and CC3 was performed on duodenal and ileal biopsies from controls and patients with Crohn’s disease.
Intravital microscopy of lipopolysaccharide-treated mice revealed that γδ IELs make extended contact with shedding enterocytes. These prolonged interactions require CD103 engagement by E-cadherin, and CD103 knockout or blockade significantly reduced lipopolysaccharide-induced shedding. Furthermore, we found that granzymes A and B, but not perforin, are required for cell shedding. These extracellular granzymes are released by γδ IELs both constitutively and after CD103/E-cadherin ligation. Moreover, we found that the frequency of γδ IEL localization to CC3-positive enterocytes is increased in Crohn’s disease biopsies compared with healthy controls.
Our results uncover a previously unrecognized role for γδ IELs in facilitating tumor necrosis factor–mediated shedding of apoptotic enterocytes via CD103-mediated extracellular granzyme release.
Sentinel tissue-resident T cells facilitate the extrusion of epithelial cells undergoing programmed cell death in response to proinflammatory signals via integrin-mediated extracellular serine protease release.
Improvements in cardiovascular disease (CVD) rates among young adults in the past 2 decades have been offset by increasing racial/ethnic and gender disparities, persistence of unhealthy lifestyle ...habits, overweight and obesity, and other CVD risk factors. To enhance the promotion of cardiovascular health among young adults 18 to 39 years old, the medical and broader public health community must understand the biological, interpersonal, and behavioral features of this life stage. Therefore, the National Heart, Lung, and Blood Institute, with support from the Office of Behavioral and Social Science Research, convened a 2-day workshop in Bethesda, Maryland, in September 2017 to identify research challenges and opportunities related to the cardiovascular health of young adults. The current generation of young adults live in an environment undergoing substantial economic, social, and technological transformations, differentiating them from prior research cohorts of young adults. Although the accumulation of clinical and behavioral risk factors for CVD begins early in life, and research suggests early risk is an important determinant of future events, few trials have studied prevention and treatment of CVD in participants <40 years old. Building an evidence base for CVD prevention in this population will require the engagement of young adults, who are often disconnected from the healthcare system and may not prioritize long-term health. These changes demand a repositioning of existing evidence-based treatments to accommodate new sociotechnical contexts. In this article, the authors review the recent literature and current research opportunities to advance the cardiovascular health of today's young adults.
The insulin-like growth factor (IGF) axis is fundamental for mammalian growth and development. However, no comprehensive reference data on gene expression across tissues and pre- and postnatal ...developmental stages are available for any given species. Here we provide systematic promoter- and splice variant specific information on expression of IGF system components in embryonic (Day 48), fetal (Day 153), term (Day 277, placenta) and juvenile (Day 365-396) tissues of domestic cow, a major agricultural species and biomedical model. Analysis of spatiotemporal changes in expression of IGF1, IGF2, IGF1R, IGF2R, IGFBP1-8 and IR genes, as well as lncRNAs H19 and AIRN, by qPCR, indicated an overall increase in expression from embryo to fetal stage, and decrease in expression from fetal to juvenile stage. The stronger decrease in expression of lncRNAs (average -16-fold) and ligands (average -12.1-fold) compared to receptors (average -5.7-fold) and binding proteins (average -4.3-fold) is consistent with known functions of IGF peptides and supports important roles of lncRNAs in prenatal development. Pronounced overall reduction in postnatal expression of IGF system components in lung (-12.9-fold) and kidney (-13.2-fold) are signatures of major changes in organ function while more similar hepatic expression levels (-2.2-fold) are evidence of the endocrine rather than autocrine/paracrine role of IGFs in postnatal growth regulation. Despite its rapid growth, placenta displayed a more stable expression pattern than other organs during prenatal development. Quantitative analyses of contributions of promoters P0-P4 to global IGF2 transcript in fetal tissues revealed that P4 accounted for the bulk of transcript in all tissues but skeletal muscle. Demonstration of IGF2 expression in fetal muscle and postnatal liver from a promoter orthologous to mouse and human promoter P0 provides further evidence for an evolutionary and developmental shift from placenta-specific P0-expression in rodents and suggests that some aspects of bovine IGF expression may be closer to human than mouse.
Despite an increase in enrollments across public and private higher education sectors, Black/African American and Hispanic students in graduate and professional programs are disproportionately ...affected by educational debt. Using nationally-representative data from NPSAS:2000 and NPSAS:2016, findings show that, in general, Black/African American and Hispanic graduate students borrowed more than students of other races and experienced the largest percentage increase in borrowing from 2000 to 2016. While debt is typically higher for all graduate students in private versus public institutions, the highest debt was incurred by Black/African Americans in private for-profit programs. Implications are discussed, including the need to provide opportunities for enrollment without creating disproportionately higher debt for students of color.
Background
Recent evidence suggests that glucagon‐like peptide 1 receptor agonists, commonly used to treat diabetes and obesity (Norgaard, 2022), are neuroprotective (Cheng, 2022), which may result ...in an improvement in cognitive function (Norgaard, 2022). The aim of this review is to determine the potential effectiveness of glucagon‐like peptide 1 receptor agonist therapy at improving cognitive function in a human population in literature published thus far.
Method
Searches for applicable studies were conducted on PubMed, Cochrane library, Google scholar, CINAHL and Clinical Trials.gov. Studies which compare the efficacy of the glucagon‐like peptide 1 receptor agonist to placebo were included. The main outcome is the change in cognitive function assessed via cognitive testing. Data was expressed as mean difference/hazard ratio and corresponding 95% confidence interval. Quality assessment was conducted with the Cochrane risk of bias tool for randomized trials (RoB 2). Heterogeneity was assessed with the chi‐squared test and I2 statistic. The study was registered on PROSPERO (ID: CRD42022366254).
Result
A total of n = 11,424 studies were identified for this review. After the removal of duplicates and the application of eligibility criteria, five studies (comprising n = 8,950 individuals) were included. Risk of bias across the included studies was low. Only one study reported an improvement in cognitive function associated with glucagon‐like peptide 1 receptor agonists. The results of the meta‐analysis inclusive of the five studies are inconclusive.
Conclusion
Overall, four of the five included studies were hampered by short drug duration times and small population sizes, which may have impacted the final result and conclusion. There is an urgent need for therapies to improve cognitive function, due to the rapid rise in cognitive decline worldwide. Glucagon‐like peptide 1 receptor agonists may fill this need, although further research is warranted.
Cheng. (2022). The Role of Glucagon‐Like Peptide‐1 Receptor Agonists (GLP‐1 RA) in Diabetes‐Related Neurodegenerative Diseases. Drug Des Devel Ther, 16: 665‐684.
Norgaard. (2022). Treatment with glucagon‐like peptide‐1 receptor agonists and incidence of dementia: Data from pooled double‐blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement (N.Y), 8(1):e12268.
Adaptive optics is a relatively new field, yet it is spreading rapidly and allows new questions to be asked about how the visual system is organized. The editors of this feature issue have posed a ...series of question to scientists involved in using adaptive optics in vision science. The questions are focused on three main areas. In the first we investigate the use of adaptive optics for psychophysical measurements of visual system function and for improving the optics of the eye. In the second, we look at the applications and impact of adaptive optics on retinal imaging and its promise for basic and applied research. In the third, we explore how adaptive optics is being used to improve our understanding of the neurophysiology of the visual system.
Survivorship Care Plans (SCPs) may facilitate long-term care for cancer survivors, but their effectiveness has not been established in hematopoietic cell transplantation recipients. We evaluated the ...impact of individualized SCPs on patient-reported outcomes among transplant survivors. Adult (≥18 years at transplant) survivors who were 1-5 years post transplantation, proficient in English, and without relapse or secondary cancers were eligible for this multicenter randomized trial. SCPs were developed based on risk-factors and treatment exposures using patient data routinely submitted by transplant centers to the Center for International Blood and Marrow Transplant Research and published guidelines for long-term follow up of transplant survivors. Phone surveys assessing patient-reported outcomes were conducted at baseline and at 6 months. The primary end point was confidence in survivorship information, and secondary end points included cancer and treatment distress, knowledge of transplant exposures, health care utilization, and health-related quality of life. Of 495 patients enrolled, 458 completed a baseline survey and were randomized (care plan=231, standard care=227); 200 (87%) and 199 (88%) completed the 6-month assessments, respectively. Patients' characteristics were similar in the two arms. Participants on the care plan arm reported significantly lower distress scores at 6 months and an increase in the Mental Component Summary quality of life score assessed by the Short Form 12 (SF-12) instrument. No effect was observed on the end point of confidence in survivorship information or other secondary outcomes. Provision of individualized SCPs generated using registry data was associated with reduced distress and improved mental domain of quality of life among 1-5 year hematopoietic cell transplantation survivors. Trial registered at
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