Failure Of People Research Articles

Large Deletion in the Factor VIII Gene Is a Predictor of Immune Tolerance Induction Failure in People with Severe and Moderately-Severe Hemophilia a and High-Responding Inhibitors

Introduction Immune tolerance induction (ITI) is a therapeutic approach to eradicate inhibitors against factor VIII (FVIII) in people with inherited hemophilia A (PwHA). The success of ITI is highly variable, ranging from 60% to 80% across studies. Beyond inhibitor titers, other predictors of ITI outcome are unknown. Deleterious variants in FVIII gene ( F8) are well established risk factors for alloantibodies development in PwHA, although few studies have investigated the role of F8 variants on ITI outcome.Therefore we aimed to comprehensively analyze the association of F8 pathogenic variants on ITI outcome in severe PwHA with high-responding inhibitors. Methods We included severe (FVIII < 1 international units [IU]/dL) and moderately-severe (FVIII 1-2 IU/dL) unrelated PwHA and high-responding inhibitors who completed ITI from a large, admixed population of two well-characterized cohorts - the HEMFIL and the Brazilian Immune Tolerance (BrazIT) studies. We collected socio-demographic, clinical and laboratory data. ITI outcomes were defined according to previous definitions as failure, partial and total successes. Inversions of intron 1 and 22 (Inv22) were detected by polymerase chain reaction (PCR), and high-throughput sequencing approaches were used to unveil the additional F8 variants. The association between F8 pathogenic variants and ITI outcome was adjusted for inhibitor levels. To investigate whether F8 variants associated with inhibitor development were also related to ITI outcome, variants were categorized as “high-risk”, “intermediate-risk”, and “low-risk” categories. These categories for inhibitor development were then compared with the outcomes of ITI (total and partial successes and failure) using data from this study. Results We included158 PwHA, median age 6.6 years at ITI start, 90.5% were severe (Table 1). Inv22 was the most prevalent variant (55.1%) (Table 1). In comparison with Inv22-1, the risk of ITI failure was about 9 times higher (adjusted odds ratio [adjOR] 9.29; 95% confidence interval [95% CI] 1.95-53.70) among carriers of large deletions (Table 2). Conversely, Inv22-2 was associated with favorable ITI outcome in a univariate analysis (OR 0.15; 0.01-0.84), and after adjustment (adjOR 0.32; 95% CI 0.02-1.96) (Table 2). F8 deleterious variants sorted as high-risk and intermediate-risk according to a previously published classification on inhibitor development were associated with failure and successful outcomes, respectively. Conclusion Our study showed that F8 large deletions are independent predictors of ITI failure, and Inv22-2 is likely to be a predictor of successful ITI. We found a correspondence between variants classified as high-risk and intermediate-risk to inhibitor development with ITI failure and success, respectively. We suggest that F8 genotyping should be considered before indication of ITI, as ITI outcome can vary according to individual variant burden.

Abstract 14262: Cancer - A Driver of Heart Failure in People With Diabetes

Introduction: Despite the risk of heart failure (HF) in the survivorship phase of some cancers, the risk is not high enough to justify HF screening. However, people with diabetes mellitus (DM) have an increased risk of both HF and cancer. Examining this at-risk population may allow for better understanding of the effect cancer has on the development of HF. Hypothesis: Among people with DM, HF is more common in those with than without prior cancer. Methods: Data from the Australian National Diabetes Services Scheme (NDSS; 1,114,356 DM, types 1 and 2) from 2010 to 2019, was linked with public hospital data, the National Death Index and national Pharmaceutical Benefits Scheme (PBS) database. People with cancer were identified by the prescription of chemotherapy agents on the PBS dataset or a hospital admission with cancer. Incident HF was detected via first hospitalisation with HF as the primary diagnosis or death due to HF. The model was adjusted for age and sex. Results: Of the total cohort (1,114,356 people with DM), 48,014 experienced HF during 6,663,046 person-years of follow up from 2010-2019. Specifically, of 175,656 people with DM and cancer, 8,464 experienced HF during 644,620 person-years of follow up. The HF incidence rate ratio (IRR) of people with DM and cancer was 1.63 (95%CI: 1.59-1.67), compared to people with DM but no cancer. Cancer admission alone had an IRR of 1.97 (1.90-2.05), with an IRR of 1.50 (1.46-1.54) in DM treated with chemotherapy with or without admission. Conclusion: Cancer diagnosis is associated with an increased incidence of HF among people with DM. The higher IRR of people with cancer admission alone supports the association of cancer with HF irrespective of chemotherapy. Further studies controlling for confounders of cardiovascular risk and refinements by age are required to justify grounds for HF screening.

Evolution of technology in sports: Impact on performance, management, and fan experience

Like other aspects of life, sport, and exercise science have been significantly impacted by technological breakthroughs. Modern sports and the different subfields of exercise research are impossible to envision without technology. The usage of technologies is always clouded with ambivalence and irritation. Ironically, it is people's failure to completely comprehend the scale and depth of technology's influence and also doubt as to what function certain technical improvements play in sports that have contributed most to its pervasiveness. Sports technology has, in fact, significantly altered the field of exercise and sport research. It's important to note that technology has significantly altered how we perceive the athletic body. The impact of technology on sports performance is thus examined in this essay, taking into account technological ideas, the pursuit of increased performance, various sports technology kinds, and the benefits and drawbacks of sports technology in contemporary sports. It is advised that individuals who manage, handle, and utilize sports be prepared to make informed decisions about the kind and application of sports technologies that would support the correct performance.

Empagliflozin Improves Circulating Vascular Regenerative Cell Content in People Not Living With Diabetes But With Cardiovascular Risk Factors.

SGLT2 inhibitors have been reported to reduce cardiovascular events and heart failure in people with and without diabetes. These medications have been shown to counter regenerative cell exhaustion in the context of prevalent diabetes. This study sought to determine if empagliflozin attenuates regenerative cell exhaustion in people without diabetes. Peripheral blood mononuclear cells were collected at the baseline and 6-month visits from individuals randomized to receive empagliflozin (10 mg/day) or placebo who were participating in the EMPA-HEART 2 CardioLink-7 trial. Precursor cell phenotypes were characterized by flow cytometry for cell-surface markers combined with high aldehyde dehydrogenase activity to identify precursor cell subsets with progenitor (ALDHhi) versus mature effector (ALDHlow) cell attributes. Samples from individuals assigned to empagliflozin (n = 25) and placebo (n = 21) were analyzed. At baseline, overall frequencies of primitive progenitor cells (ALDHhiSSClow), monocyte (ALDHhiSSCmid), and granulocyte (ALDHhiSSChi) precursor cells in both groups were similar. At 6 months, participants randomized to empagliflozin demonstrated increased ALDHhiSSClowCD133+CD34+ pro-angiogenic cells (P=0.048), elevated ALDHhiSSCmidCD163+ regenerative monocyte precursors (P=0.012) and decreased ALDHhiSSCmidCD86+CD163- pro-inflammatory monocyte (P=0.011) polarization compared to placebo. Empagliflozin promoted the recovery of multiple circulating pro-vascular cell subsets in people without diabetes suggesting that the cardiovascular benefits of SGLT2 inhibitors may be attributed in part to the attenuation of vascular regenerative cell exhaustion that is independent of diabetes status.

Management of Type 2 Diabetes Mellitus and Kidney Failure in People with HIV-Infection in Africa: Current Status and a Call to Action.

There is an increasing global burden of diabetes mellitus (DM) and chronic kidney disease (CKD), coupled with a high burden of people with HIV (PWH). Due to an increased lifespan on ART, PWH are now at risk of developing non-communicable diseases, including DM. Africa has the greatest burden of HIV infection and will experience the greatest increase in prevalence of DM over the next two decades. In addition, there is a rising number of people with CKD and progression to kidney failure. Therefore, there is an urgent need for the early identification and management of all 3 diseases to prevent disease progression and complications. This is particularly important in Africa for people with CKD where there is restricted or no access to dialysis and/or transplantation. This review focuses on the epidemiology and pathophysiology of the interaction between HIV infection and DM and the impact that these diseases have on the development and progression of CKD. Finally, it also aims to review the data on the management, which stems from the growing burden of all three diseases.

Achieving the third 95 in sub-Saharan Africa: application of machine learning approaches to predict viral failure.

Viral failure in people with HIV (PWH) may be influenced by multiple sociobehavioral, clinical, and context-specific factors, and supervised learning approaches may identify novel predictors. We compared the performance of two supervised learning algorithms to predict viral failure in four African countries. Cohort study. The African Cohort Study is an ongoing, longitudinal cohort enrolling PWH at 12 sites in Uganda, Kenya, Tanzania, and Nigeria. Participants underwent physical examination, medical history-taking, medical record extraction, sociobehavioral interviews, and laboratory testing. In cross-sectional analyses of enrollment data, viral failure was defined as a viral load at least 1000 copies/ml among participants on antiretroviral therapy (ART) for at least 6 months. We compared the performance of lasso-type regularized regression and random forests by calculating area under the curve (AUC) and used each to identify factors associated with viral failure; 94 explanatory variables were considered. Between January 2013 and December 2020, 2941 PWH were enrolled, 1602 had been on antiretroviral therapy (ART) for at least 6 months, and 1571 participants with complete case data were included. At enrollment, 190 (12.0%) had viral failure. The lasso regression model was slightly superior to the random forest in its ability to identify PWH with viral failure (AUC: 0.82 vs. 0.75). Both models identified CD4 + count, ART regimen, age, self-reported ART adherence and duration on ART as important factors associated with viral failure. These findings corroborate existing literature primarily based on hypothesis-testing statistical approaches and help to generate questions for future investigations that may impact viral failure.

Treatment success of rescue regimens after dual therapy failure in people living with HIV in a real-life setting

Few data on the management of two-drug regimen (2DR) failure in people living with human immunodeficiency virus (PLWH) are available. Retrospective study on treatment-experienced PLWH on a 2DR, who underwent virological failure [(VF) two consecutive viral loads (VLs) ≥50 copies/mL, a single VL ≥1000 copies/mL, or an antiretroviral therapy (ART) switch after a single VL ≥50 copies/mL with previous blips] or discontinuation for toxicity (baseline). We included integrase strand transfer inhibitor (INSTI)-based [one INSTI plus one nucleoside reverse transcriptase inhibitor (NRTI) (n=78) or one non-NRTI (n=20)] or boosted protease inhibitor (PI/b)-based [one PI/b plus one NRTI (n=116) or one INSTI (n=12)] 2DRs. Probabilities of treatment success (TS), VF, and discontinuation for any other cause of rescue regimens were estimated by Kaplan-Meier curves. A stepwise Cox model was performed to assess predictors of TS. Overall, 226 PLWH were evaluated: at baseline, 144 individuals discontinued 2DR for toxicity and 82 had VF [median viremia 81 (63-212) copies/mL]; 171 switched therapy (49.7% to a triple-regimen, 40.9% to a different 2DR), while 55 (exclusively among those with VF) maintained their failing regimens. The probabilities of 12- and 24-month TS were 75.6% and 64.7%, respectively. Higher TS probabilities were observed in individuals who switched ART at 2DR failure (p=0.003) and in PLWH who discontinued 2DR for toxicity (p=0.008). A therapy switch was the only predictor of TS (p=0.002). Overall probability of success of rescue regimens introduced after 2DR failure is good; an immediate ART switch is associated with higher efficacy, so this approach should be encouraged.

Associations between cognitive impairment and chronic heart failure in people over the age of 65: data from the Russian multicenter study EUCALYPTUS

Associations between cognitive impairment and chronic heart failure in people over the age of 65: data from the Russian multicenter study EUCALYPTUS

Cardiac autopsy findings in patients with COVID-19

Coronavirus disease 2019 (COVID-19) infection was first discovered in December 2019 and was soon declared a worldwide pandemic. With the decrease in the severity of the deadly disease, there is a false sense of relief globally. However, there has been an increasing trend in the cases of cardiovascular and other complications of COVID-19 which has raised concern about the sequelae of this infection. The number of cases of sudden cardiac death and myocardial infection, post-COVID-19 has seen a major leap, especially in healthy people of both genders. Systemic comorbidities and immunocompromised states have a direct effect on the prognosis of patients. The SARS-CoV-2 infection not just affects the respiratory system but multi-organ involvement is seen due to this deadly virus. The heart is a vital organ that has acute- acute and long-term consequences, what is known as long-COVID, which lead to increased morbidity and mortality. There are increased cases of multiple cardiovascular problems such as blood clots, cardiovascular accidents, myocarditis, myocardial infarction, and heart failure in people after recovering from SARS-CoV-2 infection. The histopathological findings in the heart due to COVID-19 infection can be interstitial edema with the presence or absence of myocarditis, lymphocytic endotheliitis, microvascular microthrombi, thrombosis, interstitial fibrosis with no endothelins, or rarely myocarditis. While the tissue diagnosis during acute illness is less likely feasible, autopsy findings can be helpful to understand better pathophysiology of the disease and thus help in the better management of the patient. This review was performed to analyze the postmortem findings of the heart in patients infected with the SARS-COV-2 virus, to understand the effect of COVID-19 and its complications on the heart. The pathological changes in the cardiovascular system need to be explained and correlated with the clinical findings and prognosis of the patients. We also want to hypothesize that these findings, especially myocarditis lead to sudden death in the young, which gets undetected on routine investigations.

Effects of Oleanolic Acid on Myocardial Injury in Diabetic Mice by Regulating Phosphatidylinositol 3 Kinase/Protein Kinase B/Glucose Transporter Type 4 Signalling Pathway

One of the leading causes of diabetes-related deaths is myocardial damage, which may be the cause of heart failure in people with type 2 diabetes mellitus. The objective of the research was to look at the impact of coronary failure with kind a pair of type 2 diabetes mellitus. This project aimed to explore the protective impact of oleanolic acid on myocardial damage in type 2 diabetes mellitus and to investigate the connected mechanism. Specific pathogen free grade db/db male mice were elected as model, while the Db/m mice were opted for control. Different doses of drug intervention were performed and the general condition, cardiac function, blood glucose, blood lipids, degree of myocardial injury, and degree of oxidative stress were examined by morphological examination of myocardial tissues, biochemical examination, and gene and protein amount detection. The results showed that lactate dehydrogenase, creatine kinase isoenzyme, total cholesterol, triglycerides and malondialdehyde levels in serum of Db/db mice were increased, while phosphatidylinositol 3 kinase, protein kinase B, glucose transporter 4 expression and superoxide dismutase level in myocardial tissue were decreased. After using oleanolic acid, the serum concentrations of lactate dehydrogenase, creatine kinase isoenzyme, total cholesterol, triglycerides and malondialdehyde were declined in Db/db mice, while phosphatidylinositol 3 kinase, protein kinase B, glucose transporter 4 expression and superoxide dismutase level were rised. The results recommend that oleanolic acid has protective impact on cardiac muscle injury in Db/db mice and conjointly the mechanism could also be correlated with promoting the activation of phosphatidylinositol 3 kinase/protein kinase B/glucose transporter 4 signal transduction.

Adherence monitoring methods to measure virological failure in people living with HIV on long-term antiretroviral therapy in Uganda.

Appointment keeping and self-report within 7-day or and 30-days recall periods are non-objective measures of antiretroviral treatment (ART) adherence. We assessed incidence of virological failure (VF), predictive performance and associations of these adherence measures with VF among adults on long-term ART. Data for persons initiated on ART between April 2004 and April 2005, enrolled in a long-term ART cohort at 10-years on ART (baseline) and followed until December 2021 was analyzed. VF was defined as two consecutives viral loads ≥1000 copies/ml at least within 3-months after enhanced adherence counselling. We estimated VF incidence using Kaplan-Meier and Cox-proportional hazards regression for associations between each adherence measure (analyzed as time-dependent annual values) and VF. The predictive performance of appointment keeping and self-reporting for identifying VF was assessed using receiver operating characteristic curves and reported as area under the curve (AUC). We included 900 of 1,000 participants without VF at baseline: median age was 47 years (Interquartile range: 41-51), 60% were women and 88% were virally suppressed. ART adherence was ≥95% for all three adherence measures. Twenty-one VF cases were observed with an incidence rate of 4.37 per 1000 person-years and incidence risk of 2.4% (95% CI: 1.6%-3.7%) over the 5-years of follow-up. Only 30-day self-report measure was associated with lower risk of VF, adjusted hazard ratio (aHR) = 0.14, 95% CI:0.05-0.37). Baseline CD4 count ≥200cells/ml was associated with lower VF for all adherence measures. The 30-day self-report measure demonstrated the highest predictive performance for VF (AUC = 0.751) compared to appointment keeping (AUC = 0.674), and 7-day self-report (AUC = 0.687). The incidence of virological failure in this study cohort was low. Whilst 30- day self-report was predictive, appointment keeping and 7-day self-reported adherence measures had low predictive performance in identifying VF. Viral load monitoring remains the gold standard for adherence monitoring and confirming HIV treatment response.

Risk of Heart Failure between Different Metabolic States of Health and Weight: A Meta-Analysis of Cohort Studies.

We conducted a systematic review of cohort studies comparing the risk of heart failure in people with differing metabolic health and obesity statuses. We searched three electronic databases (PubMed, Web of Science, Scopus), where the studies of the relationships of metabolic health and obesity statuses with heart failure were included. Fixed-effects or random-effects models were used to estimate the summary relative risks [RRs]. Ten cohort studies were selected. Compared with individuals with normal metabolic health and body mass, the pooled RRs (95% confidence intervals) for heart failure were 1.23 (1.17, 1.29) for metabolic healthy overweight individuals, 1.52 (1.40, 1.64) for metabolic healthy individuals with obesity, 1.56 (1.30, 1.87) for metabolically unhealthy normal-weight individuals, 1.75 (1.55, 1.98) for metabolically unhealthy overweight individuals, and 2.28 (1.96, 2.66) for metabolic unhealthy individuals with obesity. A sensitivity analysis suggested that no single study had a substantial effect on the results. The Egger's and Begg's tests showed no evidence of publication bias. People with overweight or obesity were at a higher risk of heart failure, even if metabolically healthy. In addition, compared with metabolically healthy normal-weight individuals; metabolically unhealthy normal-weight individuals, and those with overweight or and obesity, were at higher risk of heart failure.

Abstract 10573: Left Ventricular Structure, Function, and Clinical Outcomes in Methamphetamine-Associated Heart Failure

Introduction: Methamphetamine use and overdose deaths are increasing. People who use methamphetamine are at risk for methamphetamine-associated heart failure (meth-HF). Cardiac fibrosis has been reported in nonischemic cardiomyopathies, but the role of cardiac fibrosis and other factors underlying the pathophysiology and reversibility of meth-HF remain unknown. Methods: Participants with meth-HF were recruited into a prospective cohort at a safety net hospital in San Francisco. Data collection included medical history, clinical outcomes, longitudinal echocardiograms (TTEs), markers of inflammation and fibrosis, and cardiac magnetic resonance imaging (CMR). Outcomes included mortality, changes in LVEF, and hospital readmission. Results: Forty-six participants enrolled: median age 51 years, 83% male, 41% Black, 20% Asian, 33% unstably housed, 76% actively using methamphetamine. Baseline TTEs demonstrated LV dilation (median LVIDd 5.7cm, LVIDs 4.7cm) and severely reduced LV systolic function (LVEF<30% in 62%). After median 9 months follow-up, 13% were deceased. Compared to survivors, baseline LV dimensions were larger (mean LVIDd 6.7 vs 5.5cm, p<0.05; LVIDs 6.1 vs 4.5cm, p<0.05) and LVEF was lower (mean 19% vs 29%, p<0.05) among those who died. At baseline, smaller LV size, higher LVEF, and guideline-directed medical therapy (GDMT) were more common in those with LVEF improvement >10% (Fig). CMRs were often abnormal with late gadolinium enhancement and elevated extracellular volume, but there was no clear association with LV recovery. Conclusions: Despite their young age, the meth-HF population has a high mortality rate and severely reduced LVEF with LV dilation. Smaller LV size, higher LVEF, and GDMT were more common in those with LVEF improvement. These findings suggest that early identification and treatment of heart failure in people who use methamphetamine, along with drug cessation, may be associated with reversibility and improved outcomes.

Exosomal miR-625-3p secreted by cancer-associated fibroblasts in colorectal cancer promotes EMT and chemotherapeutic resistance by blocking the CELF2/WWOX pathway

Migration, invasion, epithelial-mesenchymal transformation (EMT), and chemotherapeutic resistance are the leading causes of therapeutic failure in people with colorectal cancer (CRC). The migration of exosomal miRNA between cancer cells and the tumor microenvironment is directly associated with malignant behavior in cancer-associated fibroblasts (CAFs). In the context of earlier research, the purpose of the current study was to assess the role and potential mechanism of miR-625-3p released by CAFs in CRC cells. Exosomes were extracted and purified from CAFs conditioned medium by ultracentrifugation. Western blot, immunohistochemistry, CCK-8, transwell assay, H&E staining, Tunnel, real-time PCR, double luciferase assay, RNA-binding protein immunoprecipitation (RIP), and immunofluorescence double staining experiments were used to investigate the effects of CAFs-Exo and miR-625-3p on CRC cell invasion, migration, proliferation, EMT, chemotherapeutic resistance, and molecular mechanisms. The current results indicated that CAFs-Exo was directly internalized by CRC cells, and exosomal miR-625-3p derived from CAFs might promote migration, invasion, EMT and chemotherapeutic resistance in CRC cells by inhibiting the CELF2/WWOX pathway, providing a potential candidate for CRC prediction and treatment.

Sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: Are clinical trial benefits for heart failure reflected in real-world clinical practice? A systematic review and meta-analysis of observational studies.

To determine the absolute risk reduction (ARR) of heart failure events in people treated with sodium-glucose co-transporter-2 (SGLT2) inhibitors. We searched PubMed, EMBASE, CINAHL and ISI Web of Science for observational studies published to 9 May 2022 that explored the association between SGLT2 inhibitors and any indication for heart failure (including new diagnosis or hospitalization for heart failure) in type 2 diabetes. Identified studies were independently screened by two reviewers and assessed for bias using the Newcastle-Ottawa scale. Eligible studies with comparable outcome data were pooled for meta-analysis using random-effects models, reporting hazard ratios (HRs) with 95% confidence intervals (CIs). The ARR per 100 person-years was determined overall, and in subgroups with and without baseline cardiovascular disease (CVD). From 43 eligible studies, with a total of 4 818 242 participants from 17 countries, 21 were included for meta-analysis. SGLT2 inhibitors were associated with a reduced risk of hospitalization for heart failure (HR 0.65, 95% CI 0.59-0.72) overall and both in those with CVD (HR 0.78, 95% CI 0.68-0.89) and without CVD (HR 0.53, 95% CI 0.39-0.71). Risk reduction for hospitalization for heart failure in people with a history of CVD (ARR 1.17, 95% CI 0.78-1.55) was significantly greater than for those without CVD (ARR 0.39, 95% CI 0.32-0.47). The number-needed-to-treat to prevent one event of hospitalization for heart failure was 86 (95% CI 65-128) person-years of treatment for the CVD group and 256 (95% CI 215-316) person-years for those without CVD. Real-world SGLT2 inhibitor use supports randomized trial data for the size effect of reduced hospitalization for heart failure in type 2 diabetes, although with a much lower ARR in people without CVD.

Hepatocyte Transplantation Rebalances Cytokines for Hepatic Regeneration in Rats with Ataxia Telangiectasia Mutated Pathway-Related Acute Liver Failure

Inadequate DNA damage response related to ataxia telangiectasia mutated gene restricts hepatic regeneration in acute liver failure. Resolving mechanistic gaps in liver damage and repair requires additional animal models that are unconstrained by ultrarapid and unpredictable mortalities or substantial divergences from human pathology. This study used Fischer 344 rats primed with the antitubercular drug, rifampicin, plus phenobarbitone, and monocrotaline, a DNA adduct-forming alkaloid. Rifampicin and monocrotaline can cause liver failure in people. This regimen resulted in hepatic oxidative stress, necrosis, DNA double-strand breaks, liver test abnormalities, altered serum cytokine expression, and mortality. Healthy donor hepatocytes were transplanted ectopically in the peritoneal cavity to study whether they could supply metabolic support and rebalance inflammatory or protective cytokines affecting liver regeneration events. Hepatocyte transplantation increased candidate cytokine levels (granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-γ, IL-10, and IL-12), leading to Atm, Stat3, and Akt signaling in hepatocytes and nonparenchymal cells, lowering of inflammation, and improvements in intermediary metabolism, DNA repair, and hepatocyte proliferation. Such control of DNA damage and inflammation, along with stimulation of hepatic growth, offers paradigms for cell signaling to restore hepatic homeostasis and regeneration in acute liver failure. Further studies of molecular pathways of high pathobiological impact will advance the knowledge of liver regeneration.

Epicardial adipose tissue volume and density is associated with cardiac dysfunction in asymptomatic people with type 2 diabetes

Abstract Background Type 2 diabetes (T2D) is associated with several perturbations of cardiac structure and function, which are precursors to the development of heart failure. Excess accumulation of epicardial adipose tissue (EAT) may contribute to cardiac dysfunction in individuals with T2D. Lipid-laden adipocytes have a lower computed tomography (CT) attenuation and can be readily identified using cardiac CT. Using a multimodality cardiac imaging approach, we aimed to assess the association of total and low attenuation EAT volume with early markers of cardiac dysfunction in people with T2D. Methods Prospective case-control study, in which participants with and without T2D and no known cardiovascular disease, underwent comprehensive cardiovascular phenotyping including multiparametric cardiac magnetic resonance imaging (MRI), echocardiography and non-contrast cardiac CT. EAT volume was measured from CT scans using a deep learning method and volumes indexed to body surface area. Total EAT was defined according to CT adipose tissue attenuation range of −30 to −190 Hounsfield Units (HU) and low attenuation EAT as −90 to −190 HU. Left ventricular (LV) volumes, function and strain measurements were derived from cardiac MRI images and diastolic function also assessed using echocardiography. Markers of early cardiac dysfunction in those with T2D were assessed for associations with EAT in T2D participants using multivariable linear regression analyses. Results Two hundred and fifty-four participants were included: demographic, anthropometric and imaging variables are displayed in Table 1. Subjects with T2D had increased LV concentric remodelling (higher LV mass/volume ratio), diastolic dysfunction (lower circumferential peak early diastolic strain rate (PEDSR) and average E/e') and reduced systolic function (global longitudinal strain, GLS) compared with controls. Total and low attenuation indexed EAT volumes were 1.6-fold and 2-fold higher, respectively, in participants with T2D compared to controls (Figure 1). After adjustment for age, gender, ethnicity, insulin resistance, systolic blood pressure and waist/hip ratio, total and low attenuation indexed EAT volume were independently associated with LV mass/volume ratio (total indexed EAT volume: β=0.002, p=0.02, low attenuation indexed EAT volume: β=0.004, p=0.01) and LV GLS (total indexed EAT volume: β=−0.02, p<0.01, low attenuation indexed EAT volume: β=−0.04, p=0.02) in subjects with T2D, but not indices of diastolic dysfunction. Conclusion Total and low attenuation EAT volumes are higher in individuals with T2D, and excess EAT accumulation is independently associated with early markers of cardiac dysfunction. Further studies into the underlying mechanisms of this interaction may facilitate the development of interventions targeted at EAT, which could mitigate against the development of heart failure in people with T2D. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): United Kingdom National Institute for Health Research

The Relationship Between the Blood-Brain-Barrier and the Central Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors.

Diabetes and obesity are growing problems worldwide and are associated with a range of acute and chronic complications, including acute myocardial infarction (AMI) and stroke. Novel anti-diabetic medications designed to treat T2DM, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is), exert beneficial effects on metabolism and the cardiovascular system. However, the underlying mechanisms are poorly understood. GLP-1RAs induce anorexic effects by inhibiting the central regulation of food intake to reduce body weight. Central/peripheral administration of GLP-1RAs inhibits food intake, accompanied by an increase in c-Fos expression in neurons within the paraventricular nucleus (PVN), amygdala, the nucleus of the solitary tract (NTS), area postrema (AP), lateral parabrachial nucleus (LPB) and arcuate nucleus (ARC), induced by the activation of GLP-1 receptors in the central nervous system (CNS). Therefore, GLP-1RAs need to pass through the blood-brain barrier to exert their pharmacological effects. In addition, studies revealed that SGLT-2is could reduce the risk of chronic heart failure in people with type 2 diabetes. SGLT-2 is extensively expressed throughout the CNS, and c-Fos expression was also observed within 2 hours of administration of SGLT-2is in mice. Recent clinical studies reported that SGLT-2is improved hypertension and atrial fibrillation by modulating the “overstimulated” renin-angiotensin-aldosterone system (RAAS) and suppressing the sympathetic nervous system (SNS) by directly/indirectly acting on the rostral ventrolateral medulla. Despite extensive research into the central mechanism of GLP-1RAs and SGLT-2is, the penetration of the blood-brain barrier (BBB) remains controversial. This review discusses the interaction between GLP-1RAs and SGLT-2is and the BBB to induce pharmacological effects via the CNS.

A Prospective Study to Evaluate the Effects of Sodium-Glucose Cotransporter 2 Inhibitors in Type 2 Diabetic Patients with Chronic Kidney Disease

Introduction: Recent studies suggest that sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective at slowing the progression of kidney disease and lowering the risk of kidney failure in people with kidney disease and type 2 diabetes. There is no such study from India. The present study was performed to evaluate the effects of SGLT2i in Indian patients with diabetes and chronic kidney disease (CKD). Materials and Methods: This prospective study included 86 patients with diabetes and chronic kidney disease and with an estimated creatinine clearance of >30 mL/minute. Forty-one patients received SGLT2i and 45 patients did not receive SGLT2i. Patients were followed up for at least 12 months. Body mass index (BMI), blood pressure, HbA1c, urine protein to creatinine ratio (UPCR), doubling of serum creatinine and rate of decline of the estimated creatinine clearance were compared between the two groups. Results: The two groups were comparable at baseline in terms of age, sex, blood pressure, BMI, HbA1c, and degree of renal impairment. Over 12 months the UPCR decreased by 0.03 in SGLT2i group and increased by 1.1 in non SGLT2i group (P < 0.05). Doubling of serum creatinine occurred in 4.8% of patients in the SGLT2i group as compared to 18% in the control group (P < 0.05). The rate of decline of the estimated creatinine clearance in the SGLT2i group was 4.9 ml/min/year as compared to 9.4 ml/min/year in the non SGLT2i group (P < 0.05). At 12 months the BMI in the SGLT2i group decreased by 1.49 as compared to 0.12 in the non SGLT2i group (P < 0.05). The blood pressure and HbA1c control were similar in both groups during the study period suggesting that the observed effect was due to SGLT2 inhibition itself and not due to blood pressure or blood glucose control. Conclusion: Our study showed that treatment with SGLT2i had significant renoprotective effects, as shown by a reduction in urinary protein excretion, less percentage of patients developing doubling of serum creatinine, and a slower rate of decline in creatinine clearance.

Antipsychotics and mood stabilizers on risk for hepatic failure in people with schizophrenia and bipolar disorder

IntroductionPatients with severe mental disease have a considerably shorter lifespan than the general population. The majority of psychiatric drugs are metabolized by the liver. Cytochromes play a central role, interactions between drugs are expected. Neuroleptics are frequently associated with weight gain, steatosis development, elevation of liver enzymes and rare acute cytolytic hepatitis, particularly with clozapine and olanzapine. Mood stabilizers, like Valproate classically gives mitochondrial steatosis with potentially important damages, and also possible acute liver failure.ObjectivesThis case presents a 56-year-old patient, previously diagnosed of schizoaffective disorder, with chronic psychotic symptoms that showed high drug resistance. She had been treated in the past with most common antipsychotic drugs with no clinical response. While being in treatment with valproate and olanzapine, she was started on clozapine while olanzapine removed. Two weeks later she developed Acute Pharmacologic Hepatitis with mild liver failure.MethodsPhysical examination was normal. Mental exam revealed presence of delusion. Blood tests showed: hyperbilirubinemia and mil coagulopathy. Clozapine dose was reduced and valproate was suspended.ResultsThe patient showed a substantial improvement of hepatic damage. Delusions are active after 12 weeks of treatment with clozapine.ConclusionsPsychiatric disorders and liver illnesses are entangled in multiple ways. Screening for liver diseases is essential in order to prevent liver complications in patients receiving psychotropic medications. Further investigation of combinations of agents such as mood stabilizers and atypical antipsychotics may yield valuable insights into the potential of combination therapies to enhance clinical outcomes in patients with Severe Mental Disease.DisclosureNo significant relationships.