Major Comorbidity In Patients Research Articles

Contemporary Concepts of the Role of Pro-inflammatory Cytokines in COVID-19-Induced Pneumonia in the Context of Metabolic Disorders (Review)

Objective — to analyse and summarise literary sources regarding contemporary concepts of the significance of pro-inflammatory cytokines in pneumonia caused by COVID-19 amidst metabolic disorders. Materials and methods. An analytical and bibliosemantic approach was utilised in the study. Google Scholar and PubMed databases were employed for the search using keywords such as «pro-inflammatory cytokines», «COVID-19», «pneumonia», «insulin resistance», «type 2 diabetes mellitus» and «metabolic disorders». Results and discussion. Diabetes mellitus and hyperglycemia are among the major comorbidities in patients with COVID-19, leading to unfavorable outcomes. Diabetes is a chronic condition affecting millions worldwide. By 2030, it is projected to become a leading cause of non-communicable mortality. Hyperglycemia in COVID-19, irrespective of insulin resistance or a history of diabetes, heralds an unfavorable prognosis. Patients with type 2 diabetes mellitus exhibit elevated inflammation levels associa­ted with obesity, insulin resistance and comorbidities such as hypertension, obesity, cardiovascular diseases and dyslipidemia. Chronic inflammation with enhanced inflammatory response to infection and viral load escalation leads to a potent systemic immune response — the «cytokine storm», closely associated with increased severity of COVID-19. There is increasing evidence that COVID-19-induced respiratory failure may be attributed to defective immune response characterised by rapid proliferation and hyperactivation of T cells, macrophages, natural killer cells and hyperproduction of chemical mediators, including pro-inflammatory cytokines, leading to increased vascular permeability and multiorgan failure. Conclusions. In our view, COVID-19 induces polyorgan distress, creating an imbalance between cellular and cytokine immune systems, resulting in hyperinflammatory cytokine storm affecting systemic homeostasis. The presence of COVID-19 in patients with diabetes mellitus, who already have immune dysregulation, exacerbates their overall condition.

Factors Affecting Mortality and Distribution of Co-morbidities in Chronic Obstructive Pulmonary Disease

Objectives: Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. This study aims to identify the rules associated with major comorbidities in patients with COPD and analyze how they affect death, thereby suggesting patient management measures that are efficient and can improve the quality of medical care.Methods: For this purpose, among the Korea Disease Control and Prevention Agency’s discharge injury in-depth survey data of more than 3 million cases from 2006 to 2021, adult patients aged 19 years or older with a principal diagnosis of chronic obstructive pulmonary disease were targeted. <i>χ</i><sup>2</sup>-test and independent sample t-test were performed to analyze the distribution of deaths by demographic characteristics, and ARM (Association Rule Mining) was analyzed for association rules for comorbidities. Logistic regression analysis was performed on factors influencing death.Results: As a result of the analysis, the mortality rate was high in patients over 75 years of age, patients admitted to the emergency room, and patients discharged from medical institutions with more than 1,000 beds. The prevalence of comorbidities was high for E11 (Type 2 diabetes mellitus) and I10 (essential hypertension). As a result of analyzing the impact on death based on major association rules, other sepsis (A41) and essential hypertension (I10), other sepsis (A41) and pneumonia, organism unspecified (J18), sequelae of tuberculosis (B90) and J96 (respiratory Failure, NEC), sequelae of tuberculosis (B90), and I27 (other pulmonary heart diseases) were found to have a high probability of death.Conclusions: Based on the major association rules affecting death, we propose to apply them to a clinical decision support system for efficient patient management and personalized treatment.

Resolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease

While cardiovascular disease (CVD) is one of the major co-morbidities in patients with rheumatoid arthritis (RA), the mechanism(s) that contribute to CVD in patients with RA remain to be fully elucidated. Herein, we observe that plasma concentrations of 13-series resolvin (RvT)4 negatively correlate with vascular lipid load in mouse inflammatory arthritis. Administration of RvT4 to male arthritic mice fed an atherogenic diet significantly reduces atherosclerosis. Assessment of the mechanisms elicited by this mediator demonstrates that RvT4 activates cholesterol efflux in lipid laden macrophages via a Scavenger Receptor class B type 1 (SR-BI)-Neutral Cholesterol Ester Hydrolase-dependent pathway. This leads to the reprogramming of lipid laden macrophages yielding tissue protection. Pharmacological inhibition or knockdown of macrophage SR-BI reverses the vasculo-protective activities of RvT4 in vitro and in male mice in vivo. Together these findings elucidate a RvT4-SR-BI centered mechanism that orchestrates macrophage responses to limit atherosclerosis during inflammatory arthritis.

Intraarticular Delivery of AAV5-Mir-125a-5p Regulates Key Molecular Mediators of Hemophilic Arthropathy

Background: Hemophilic arthropathy (HA) is a major comorbidity in patients with hemophilia characterized by chronic inflammation of the joints, stiffness and loss of function. The expression of microRNAs are known to be altered in various joint diseases such as rheumatoid arthritis and osteoarthritis which share clinical attributes with HA. One such microRNA is miR-125a-5p, known to be involved in regulating inflammatory mediators in the arthritic joints. The current study was designed to investigate the role of miR125a-5p in HA and examine the phenotypic effect of its targeted reconstitution in the joints. Methods: We utilized a chronic arthropathy model in hemophilia A mice to study the impact of miR125a-5p in disease progression. First, we performed a targeted screen of miR125a-5p and its target genes (STAT1 and TRAF6) using digital PCR (dPCR). Further, to validate if reconstitution of miR125a-5p aids in modulating the molecular mediators of HA, we performed the Adeno-associated virus vector (AAV) serotype 5 targeted delivery of miR125a (AAV5-miR125a) either alone (2.13x10 11vgs/joint) or in combination with capsid-modified AAV8-human Factor 8 (F8)(AAV8-F8) gene therapy at a low dose (1x10 11vgs/animal) intravenously in F8 tm1kaz/Jmice. Briefly, the animals were administered with vectors (alone or in combination), and seven days post vector administration, the animals were subjected to multiple bleeding episodes in the right knee (Day 0, 14, and 30) to mimic chronic hemarthrosis. On day 45, blood samples were collected from experimental animals for FVIII specific clotting assay, and joint tissues were isolated to perform further molecular and histochemical analysis. Results: Our dPCR analysis revealed a significant reduction (2-fold) of miR125a-5p (3518 copies/µl vs 7242 copies/µl, p≤0.0001) in injured joints compared to control joints. Absolute quantification of target genes, namely STAT1 and TRAF6 showed significantly higher expression in injured joints (7.6 to 10.6 fold, respectively) when compared to control joints. Further immunohistochemical examination of joint sections from the experimental mice confirmed the elevated expression of these immunological mediators (STAT1, TRAF6). Upon administration of AAV vectors containing miR125a and/or F8, we observed a significantly increased expression of miR125a-5p (~12 fold) in only miR125a vector-administered animals while the combination vector treated group had, ~44-fold higher levels of miR125a-5p. The coagulant assay revealed an increased FVIII activity (~17%) in only F8 vector-treated animals and approximately 20% FVIII levels in mice that received both miR125a and F8 vectors at low doses. Surprisingly, the animals that received only F8 vectors also showed significantly upregulated miR125a-5p expression (~20 fold) signifying the role of miR125a-5p in HA pathology. In line with the above findings, immunohistochemical analysis of joint tissues revealed decreased expression of immunological markers STAT1, TRAF6 (direct targets of miR125a-5p), and the chondro-degenerative matrix metalloproteinases 3, 9, 13 in vector-treated groups when compared to injured joints with no treatment. Hematoxylin and Eosin (H&E) staining of joint tissues from experimental animals was performed which revealed that animals that received both miR125a and F8 vectors showed decreased synovial hyperplasia, villi formation, cartilage erosion, and reduced hemosiderin deposition signifying moderate phenotype rescue. Conclusions: Our data confirms that miR125a-5p is a major molecular target that regulates inflammatory response in chronic HA. Targeted delivery of miR125a in tandem with F8 gene augmentation had an impact on several molecular mediators like STAT1, TRAF6, MMP3,9, and 13. The reconstitution of miR125a and a higher dose of F8 vectors might be beneficial to reverse chronic HA.

Prognostic value of liver fibrotic markers in patients with heart failure

Abstract Background One of the major comorbidities in patients with heart failure (HF) is hepatic dysfunction, which may occur with prolonged hepatic hypoperfusion and congestion due to HF. Although several liver fibrotic markers are associated with prognosis in patients with HF, the optimal markers for outcome prediction remain unclear. Purpose The aim of this study was to simultaneously investigate the prognostic value of liver fibrotic markers and the associations between these markers and clinical parameters in HF patients without organic liver disease. Methods We prospectively examined 211 consecutive patients with chronic HF (116 male, mean age 66 ± 14 years, LVEF 48 ± 17%) between April 2018 and August 2021, excluding those with organic liver disease, using liver magnetic resonance imaging and ultrasound. We measured seven representative liver fibrotic markers, including hyaluronic acid, type III procollagen N-terminal peptide (P-III-P), type IV collagen 7s domain, mac-2 binding protein glycosylation isomer (M2BPGi), platelet ratio index (APRI), fibrosis 4 index (FIB-4), and FibroIndex. The primary outcome of interest was the composite of all-cause death and hospitalisation for HF. Results During a median follow-up period of 747 (interquartile range 465-1042) days, the primary outcome occurred in 45 patients (21%), including 15 (7%) all-cause deaths and 30 (14%) hospitalisations for HF. Patients with higher hyaluronic acid and P-III-P levels showed a significantly higher incidence of the primary outcome than those without (P <0.001 and P = 0.005, respectively). Multivariable Cox regression analysis showed that hyaluronic acid and P-III-P levels were independently associated with the risk of the primary outcome (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.18-2.87 and HR 2.89, 95% CI 1.32-6.34, respectively) even after adjustment for the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, whereas other five liver fibrotic markers were not associated with the primary outcome. Discriminative value of the MAGGIC score for the primary outcome was significantly increased by adding hyaluronic acid and P-III-P levels (Harrel’s c-statistics; from 0.717 to 0.752 and 0.745, respectively) with significant net reclassification improvement (38% and 52%, respectively). Hyaluronic acid was predominantly correlated with age, haemoglobin, serum albumin, troponin T, N-terminal pro-brain natriuretic peptide (NT-proBNP), and pulmonary artery compliance (Figure). P-III-P levels were correlated with haemoglobin, estimated glomerular filtration rate, alkaline phosphatase, and NT-proBNP levels (Figure). Conclusion Among the representative liver fibrotic markers, hyaluronic acid and P-III-P might be optimal for outcome prediction in HF patients without organic liver disease. Hyaluronic acid and P-III-P levels were predominantly associated with several key prognostic indicators of HF simultaneously.

Association of Chronic Renal Insufficiency with Inhospital Outcomes in Primary Heart Failure Hospitalizations (Insights from the National Inpatient Sample 2004 to 2018)

Chronic kidney disease (CKD) is a major co-morbidity in patients with heart failure (HF). There are limited contemporary data characterizing the clinical profile, inhospital outcomes, and resource use in patients hospitalized for HF with co-morbid CKD. We utilized a nationally representative population to address the knowledge gap. We examined the National Inpatient Sample 2004 to 2018 database to study the co-morbid profile, in-hospital mortality, clinical resource utilization, healthcare cost, and length of stay (LOS) in primary adult HF hospitalizations stratified by presence versus absence of a diagnosis codes of CKD. There were a total of 16,050,301 adult hospitalizations with a primary HF diagnosis from January 1, 2004, to December 31, 2018. Of these, 428,175 (33.81%) had CKD; 1,110,778 (6.92%) had end-stage kidney disease (ESKD); and 9,511,348 (59.25%) had no diagnosis of CKD. Patients with hospitalizations for HF with ESKD were younger (mean age 65.4 years) compared with those without ESKD. In multivariable analysis, those with CKD had higher odds of inhospital mortality (2.82% vs 3.57%, adjusted odds ratio [aOR] 1.30, confidence interval [CI] 1.28 to 1.26, p<0.001), cardiogenic shock (1.01% vs 1.79% aOR 2.00, CI 1.95 to 2.05, p<0.001), and the need for mechanical circulatory support (0.4% vs 0.5%, aOR 1.51, 1.44 to 1.57, p<0.001) compared with those without CKD. In multivariable analysis, those with ESKD had higher odds of inhospital mortality (2.82% vs 3.84%, aOR 2.07, CI 2.01 to 2.12, p<0.001), need for invasive mechanical ventilation use (2.04% vs 3.94%, aOR 1.79, CI 1.75 to 1.84, p<0.001), cardiac arrest (0.72% vs 1.54%, aOR 2.09, CI 2.00 to 2.17, p<0.001), longer LOS (Adjusted mean difference 1.48, 1.44 to 1.53, p<0.001) and higher inflation-adjusted cost (Adjusted mean difference 3,411.63, CI 3,238.35 to 3,584.91, p<0.001) compared with those without CKD. CKD and ESKD affected about 40.7% of all primary HF hospitalizations from 2004 to 2018. The inhospital mortality, clinical complications, LOS, and inflation-adjusted cost were higher in hospitalized patients with ESKD compared with patients with and without CKD. In addition, compared with those without CKD, hospitalized patients with CKD had higher inhospital mortality, clinical complications, LOS, and inflation-adjusted cost compared with patients with no diagnosis of CKD.

Is Omicron really mild? – Comparative analysis of comorbidities and disease outcomes associated with SARS-CoV-2 Omicron (B.1.1.529) and Delta (B.1.617.2) variants

PurposeMultiple variants of SARS-CoV-2 from Alpha to Omicron have an estimated 6.1 million deaths globally till date. These variants have been found to vary in transmissibility and severity. The present study deals with comparison of morbidity and mortality with SARS-CoV-2 Omicron (B.1.1.529) and Delta (B.1.617.2) variants. Materials and methodAn observational retrospective cohort study was conducted on a cohort of laboratory confirmed patients of SARS-CoV-2 diagnosed by qRT-PCR of nasopharyngeal swabs in periods; April-2021 and January-2022; that were sequenced and variants were recorded. Patients were invited for a telephonic interview after voluntary and informed consent was obtained from each participant wherein, the demographics, co-morbidities, oxygen requirement and mortality outcomes of the patients were enquired about. ResultsA total of 200 patients, with 100 from each period were included in the study. Major comorbidities in patients included hypertension, diabetes mellitus and pulmonary disease. Patients who succumbed to the Delta variant (26%) were higher as compared to the Omicron variant (10%); with the elderly (68 ​± ​9.7 ​years) having significant mortality during the Omicron variant. The mortality was increased in patients with comorbidities as with hypertension (53.8%, 70%), diabetes mellitus (26.9%, 40%), chronic pulmonary disease (30.8%, 20%), and smoking (15.4%, 40%) in the patients infected with both Delta and Omicron variants, respectively. ConclusionThe study concluded that the newer strains of SARS-CoV-2 have potential of high transmissibility and milder disease for the population by large, however, for patients with comorbidities have a higher proportion of adverse outcomes, irrespective of the variant.

Profiles of cognitive impairment in chronic heart failure-A cluster analytic approach.

Cognitive impairment is a major comorbidity in patients with chronic heart failure (HF) with a wide range of phenotypes. In this study, we aimed to identify and compare different clusters of cognitive deficits. The prospective cohort study "Cognition.Matters-HF" recruited 147 chronic HF patients (aged 64.5 ± 10.8 years; 16.2% female) of any etiology. All patients underwent extensive neuropsychological testing. We performed a hierarchical cluster analysis of the cognitive domains, such as intensity of attention, visual/verbal memory, and executive function. Generated clusters were compared exploratively with respect to the results of cardiological, neurological, and neuroradiological examinations without correction for multiple testing. Dendrogram and the scree plot suggested three distinct cognitive profiles: In the first cluster, 42 patients (28.6%) performed without any deficits in all domains. Exclusively, the intensity of attention deficits was seen in the second cluster, including 55 patients (37.4%). A third cluster with 50 patients (34.0%) was characterized by deficits in all cognitive domains. Age (p = 0.163) and typical clinical markers of chronic HF, such as ejection fraction (p = 0.222), 6-min walking test distance (p = 0.138), NT-proBNP (p = 0.364), and New York Heart Association class (p = 0.868) did not differ between clusters. However, we observed that women (p = 0.012) and patients with previous cardiac valve surgery (p = 0.005) prevailed in the "global deficits" cluster and the "no deficits" group had a lower prevalence of underlying arterial hypertension (p = 0.029). Total brain volume (p = 0.017) was smaller in the global deficit cluster, and serum levels of glial fibrillary acidic protein were increased (p = 0.048). Apart from cognitively healthy and globally impaired HF patients, we identified a group with deficits only in the intensity of attention. Women and patients with previous cardiac valve surgery are at risk for global cognitive impairment when suffering HF and could benefit from special multimodal treatment addressing the psychosocial condition.

Obesity and Wound Healing: Focus on Mesenchymal Stem Cells.

Chronic wounds represent nowadays a major challenge for both clinicians and researchers in the regenerative setting. Obesity represents one of the major comorbidities in patients affected by chronic ulcers and therefore diverse studies aimed at assessing possible links between these two morbid conditions are currently ongoing. In particular, adipose tissue has recently been described as having metabolic and endocrine functions rather than serving as a mere fat storage deposit. In this setting, adipose-derived stem cells, a peculiar subset of mesenchymal stromal/stem cells (MSCs) located in adipose tissue, have been demonstrated to possess regenerative and immunological functions with a key role in regulating both adipocyte function and skin regeneration. The aim of the present review is to give an overview of the most recent findings on wound healing, with a special focus on adipose tissue biology and obesity.

Progression of knowledge in diabetes mellitus and covid-19

The Coronavirus Disease 19 (COVID-19) is a pandemic infectious disease caused by the novel corona virus Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2). Diabetes mellitus (DM) and hyperglycemia are among the major comorbidities in patients with COVID-19 which might modulate immune and inflammatory responses leading to poor outcomes. Several reports show that patients with DM and COVID-19 are at an increased risk for developing severe complications including acute respiratory distress syndrome, multi-organ failure, and death. Furthermore, compromised innate immunity, pro-inflammatory cytokine milieu, reduced expression of ACE-2 and use of renin-angiotensin-aldosterone system antagonists in diabetic patients may also contribute to poor prognosis in COVID-19. However, the mechanisms underlying the relationship between COVID-19 and DM remain to be elucidated. The severity and mortality was significantly higher in diabetic patients which may predispose patients with COVID-19 to poor outcomes. Most of these conclusions are preliminary, and further investigation of the optimal management in diabetic patients is necessary. Thus, it is imperative that diabetic patients should take all necessary precautions and ensure good glycemic control amid with COVID-19 pandemic.

Left Atrial Strain to Predict Stroke in Patients With Acute Heart Failure and Sinus Rhythm.

BackgroundStroke is a major comorbidity in patients with heart failure (HF), especially in those with decreased left atrial (LA) function, and thus, identifying patients highly at risk of stroke can prevent its occurrence. We evaluated the predictive value of global longitudinal strain of LA (LAGLS) in patients with acute HF and sinus rhythm.Methods and ResultsIn this retrospective study, 2461 patients (53.3% men, 69.7±14.4 years old) with sinus rhythm and LAGLS among 4312 consecutive patients with acute HF from 3 tertiary hospitals were included. HF phenotypes were defined as HF with reduced ejection fraction (EF) (left ventricular EF ≤40%), HF with midrange EF (40% <left ventricular EF <50%), and HF with preserved ejection fraction (left ventricular EF ≥50%). Primary outcome was new‐onset stroke. The mean left ventricular EF was 39.4%±15.6%. Moreover, 1388 (57.5%), 342 (14.2%), and 682 (28.3%) were classified with HF with reduced EF, HF with midrange EF, and HF with preserved EF, retrospectively. LAGLS was 17.2%±10.4%. During the follow‐up duration (mean: 30.3±25.4 months), 100 patients experienced stroke. Patients with stroke had higher LA diameter (P=0.031) and lower LAGLS (P=0.010) than those without stroke. In the univariate analysis, age, diabetes mellitus, LA diameter, LA volume index, and LAGLS were significant risk factors for stroke. In the multivariate analysis, each 1% decrease in LAGLS was associated with a 3.8% increased risk for stroke (hazard ratio [HR], 1.038; 95% CI, 1.013–1.065; P=0.003). When applying a LAGLS cutoff point of 14.5%, patients with LAGLS <14.5% had approximately twice the risk for stroke after adjusting other significant variables (HR, 1.940; 95% CI, 1.269–2.965; P=0.002).ConclusionsIn patients with acute HF and sinus rhythm, decreased LAGLS (<14.5%) was associated with an increased risk for stroke, with an annual incidence of 2.38%.

The Effect of Sacubitril/Valsartan in a Dialysis Patient with Severe Heart Failure

Heart failure (HF) is a major comorbidity in patients with end-stage renal disease (ESRD). The pathogenesis of HF in patients on renal replacement therapy represents the confluence of several traditional and nontraditional vascular risk factors, unique to the milieu of chronic kidney disease and the dialysis modality [1]. The purpose of this report is to describe the efficacy and safety of sacubitril/valsartan for an ESRD patient on hemodialysis therapy conmbined with heart failure with reduced ejection fraction (HFrEF). A 35-year-old woman was undergoing hemodialysis due to ESRD and suffering from heart failure with reduced ejection fraction. Because of worsening heart failure and hypertension, she was prescribed with sacubitril/valsartan at a dose of 50 mg twice a day, spironolactone at a dose of 20 mg three times a day and metoprolol at a dose of 23.75 mg once daily. There was a symptomatic improvement with the heart failure and reduction in NT-proBNP level, accompanied by a decrease of blood pressure after using sacubitric/valsartan. In conclusion, it is safe and effective to take sacubitril/valsartan in this hemodialysis patient with severe heart failure.

COVID-19 with Cardiovascular Disease: Can It Help Predict Prognosis?

Two recent articles both found that cardiovascular disease was the major comorbidity in patients with COVID-19. Inflammation of the cardiovascular system and hypoxemia in patients with COVID-19 are the important causes of cardiovascular system dysfunction. Through detailed analyses of the cardiovascular system, clinicians may identify specific patterns of cardiovascular abnormalities. If such a model can been established, the prognosis of COVID-19 patients with cardiovascular disease may be predicted.

Iron Administration Affects Cardiac Calcium Channel Expression in Mice: The Role of Cardiac Calcium Channel Expression in The Heart of Iron Overload Mice Model

BACKGROUND: Iron-overload cardiomyopathy (IOC) is a major comorbidity in patients with chronic repetitive blood transfusion due to myocardial iron uptake that facilitated by calcium channels. As cardiac compensatory mechanism to IOC, we hypothesized the cardiac calcium channels expression would be increased and involved in cardiomyopathy progressivity. This study was aimed to investigate the gene expression of calcium channels in the heart of the iron overload mice model.METHODS: Mice were divided into three groups according to iron administration doses 0, 0.1, and 0.3 mg/day. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were measured for the representation of cardiovascular outcomes. The heart tissues were harvested. Further mRNA levels of L-type calcium channels (LTCCs) and T-type calcium channels (TTCCs) were examined using semi-quantitative PCR. The expressions of cardiac calcium channels and blood pressure among the three groups were compared.RESULTS: The expressions of TTCCs in the two iron-injected groups were higher than the control group (p=0.018). The expressions of LTCCs were not different (p=0.413) among groups. SBP, DBP, and MAP of the iron-injected group were lower than the control group (p=0.025, p=0.011, and p=0.008, respectively).CONCLUSION: Iron administration affects the expression of TTCCs but not the LTCCs, accompanied by decreasing of systolic and diastolic blood pressure.KEYWORDS: cardiomyopathy, iron overload, L-type calcium channel, T-type calcium channel.

Factors leading to high morbidity and mortality of COVID-19 in patients with type 2 diabetes.

Coronavirus disease 2019 (COVID‐19) is a recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a novel coronavirus. Diabetes (mostly type 2 diabetes mellitus, T2DM) and hyperglycemia are among the major comorbidities in patients with COVID‐19 leading to poor outcomes. Reports show that patients with diabetes and COVID‐19 are at an increased risk for developing severe complications including acute respiratory distress syndrome, multi‐organ failure, and death. Here we explore potential mechanistic links that could explain the observed higher morbidity and mortality in this patient population. Patients with T2DM have an underlying increased level of inflammation associated with obesity and insulin resistance in addition to other comorbidities including hypertension, obesity, cardiovascular disease, dyslipidemia, and being older. We review evidence that T2DM with hyperglycemia are among factors that lead to elevated expression of angiotensin‐converting enzyme 2 (ACE2) in lungs and other tissues; ACE2 is the cellular “receptor” and port of viral entry. The preexisting chronic inflammation with augmented inflammatory response to the infection and the increasing viral load leads to extreme systemic immune response (“cytokine storm”) that is strongly associated with increased severity of COVID‐19. Based on the available evidence, it is recommended by a panel of experts that safe but stringent control of blood glucose, blood pressure, and lipids be carried out in patients with T2DM, measures that could potentially serve to decrease the severity of COVID‐19 should these patients contract the viral infection. Once the infection occurs, then attention should be directed to proper glycemic control with use of insulin and frequent monitoring of blood glucose levels.

Characteristics of Acute Gout Flare in Patients Initiated on Intravenous Bumetanide for Acute Heart Failure Exacerbation.

BackgroundHeart failure is a clinical syndrome with significant morbidity, mortality, and financial burden. These factors are magnified in patients with associated comorbidities. Therefore, addressing such conditions is critical in decreasing healthcare costs and improving patient outcomes.Gout is a major comorbidity in patients with heart failure. Acute gout flares that occur in the context of acute heart failure exacerbations (AHFE) form an independent risk factor for increased readmissions or death. In this study, we characterized the frequency and outcomes of acute gout flares in patients treated with intravenous (IV) bumetanide for AHFE.MethodsThis single-center retrospective cohort study included 130 adult patients admitted in a tertiary-care hospital between August 2016 and June 2018. Chart review identified patients who were hospitalized for AHFE with International Classification of Diseases, Tenth Revision (ICD-10) diagnosis code I50, received IV bumetanide, and developed an acute gout flare. Data were analyzed using the chi-square test for categorical variables and the two-sample t-test for continuous variables.ResultsThe annualized frequency of acute gout while receiving IV bumetanide for AHFE was 7.17%. Chronic gout patients who were on colchicine and/or allopurinol while hospitalized were less likely to develop acute gout while receiving IV bumetanide for AHFE compared with those taking neither medication (p-value =0.002). There was no significant difference in length of stay or 30-day readmissions between those who developed acute gout and those who did not.ConclusionsAcute gout flares occur with a notable frequency in patients hospitalized for AHFE who are administered IV bumetanide. It is important to continue patients’ outpatient gout regimens in an effort to mitigate acute gout flares during this time.

NIMG-37. PREDICTING SEIZURE IN GLIOMA PATIENTS USING A RANDOM FOREST CLASSIFIER TRAINED ON SEX-SPECIFIC AND MIXED COHORTS

Abstract PURPOSE Brain tumor related epilepsy (BTE) is a major co-morbidity in patients with glioma. It is difficult to determine whether the use of anti-epileptic drugs is necessary. We attempted to build a machine-learning model to predict the probability of seizure presentation (SP) with glioma. METHODS We trained a random forest classifier using the following variables: volumetric data of pre-treatment MR images (T1Gd and T2-FLAIR sequences), patient demographics (age; sex), and measurements of tumor proliferation (log(ρ)), invasiveness (log(D)) and their relative ratio (log(ρ/D)). Our cohort consisted of 221 patients total. Using an 80-20 ratio, we used 176 patients (76 SP, 100 nSP) for training and the remaining 45 patients (19 SP, 26 nSP) were used for testing. We also trained on male-only and female-only cohorts to evaluate any sex differences in prediction. For training, 108 males (53 SP, 55 nSP) were used and 28 for testing (14 SP, 14 nSP). We used 72 females (21 SP, 49 nSP) for training and 15 (7 SP, 8 nSP) for testing. We corrected for class imbalance in the female cohort before training. Using 10-fold cross-validation and a separate testing set, we measured performance by ROC curve (AUC), accuracy, sensitivity, and specificity of predictions (average of folds in cross validation). RESULTS The female model achieved the highest AUC (0.853) followed by the mixed model (0.726) and the male model (0.651). In the validation set, the accuracy/sensitivity/specificity of the three cohorts were as follows: mixed (0.726/0.696/0.750), female (0.853/0.830/0.875), and male (0.651/0.577/0.722). The performance of the testing set, in terms of accuracy/sensitivity/specificity were: mixed (0.733/0.74/0.73), female (0.8/0.57/1), and male (0.714/0.64/0.79). CONCLUSION We found a negative correlation between seizure probability and size and invasiveness of tumors. Our model shows promising performance on testing set data. Further cohort studies and training is warranted.

Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α

Fibrosis and stricture are major comorbidities in patients with eosinophilic esophagitis (EoE). Lysyl oxidase (LOX), a collagen cross-linking enzyme, has not been investigated in the context of EoE. We investigated regulation of epithelial LOX expression as a novel biomarker and functional effector of fibrostenotic disease conditions associated with EoE. LOX expression was analyzed by using RNA-sequencing, PCR assays, and immunostaining in patients with EoE; cytokine-stimulated esophageal 3-dimensional organoids; and fibroblast-epithelial cell coculture, the latter coupled with fluorescence-activated cell sorting. Gene ontology and pathway analyses linked TNF-α and LOX expression in patients with EoE, which was validated in independent sets of patients with fibrostenotic conditions. TNF-α-mediated epithelial LOX upregulation was recapitulated in 3-dimensional organoids and coculture experiments. We find that fibroblast-derived TNF-α stimulates epithelial LOX expression through activation of nuclear factor κB and TGF-β-mediated signaling. In patients receiver operating characteristic analyses suggested that LOX upregulation indicates disease complications and fibrostenotic conditions in patients with EoE. There is a novel positive feedback mechanism in epithelial LOX induction through fibroblast-derived TNF-α secretion. Esophageal epithelial LOX might have a role in the development of fibrosis with substantial translational implications.

Outcomes and Predictors of Readmissions with GI Bleeding in Patients with Left Ventricular Assist Devices.

Gastrointestinal (GI) bleeding is a major comorbidity in patients with left ventricular assist devices (LVADs). The study aim was to estimate the rate of hospital readmissions for GI bleeding in patients with LVADs using a nationally representative database. Additionally, we evaluated the etiologies, costs, endoscopy utilization, mortality, and predictors of GI bleeding readmissions in these patients. We analyzed data from the National Readmissions Database (NRD) from 2010 through 2014. We compared hospitalized adult patients with congestive heart failure (CHF) who underwent LVAD implantation (cases) with CHF patients without LVAD or heart transplant (controls). Three age- and sex-matched controls were randomly selected per single case. A multivariate Cox regression model was used to compare the hazards of 60-day all-cause and GI bleeding readmission between the groups, controlling for significant confounders. A total of 3293 hospitalized patients with CHF who had LVAD placement (cases) and 9879 who did not have LVADs (controls) were included in the study. At 60 days, patients with LVAD had a significantly higher readmission rate with GI bleeding (8.7% vs 2.3%, adjusted hazard ratio [aHR] 4.45, 95% confidence interval 3.71-5.33, P < 0.0001). The all-cause readmission rate also was higher (43.3% vs 35.7%, aHR 1.23, 95% confidence interval 1.12-1.34, P < 0.0001). The most common etiologies of bleeding in patients with LVADs were gastroduodenal and small intestinal arteriovenous malformations (28.6%). During bleeding readmissions, patients with LVAD were more likely to undergo endoscopy (72.1% vs 33.5%, P < 0.0001) and receive packed red blood cell transfusions (62% vs 36.6%, P< 0.0001) compared with controls. GI bleeding readmissions were more costly ($40,936 vs $35,313, P< 0.0001), and longer (12 vs 10.9 days, P< 0.0001) in patients with LVADs compared with controls. Independent risk factors for 60-day GI bleeding readmission were increasing age (aHR 1.04, P< 0.0001) and GI bleeding during index admission (aHR 2.68, P< 0.0001). In those without bleeding during index admission, increasing age and chronic anemia were associated with 60-day GI bleeding readmission. Mortality during bleeding readmission was similarly low in patients with LVADs compared with CHF controls (0.2% vs 0.3%, P = 0.14). After LVAD implantation, there is a fivefold increased risk of readmission with GI bleeding within 60 days. Gastroduodenal and small intestinal arteriovenous malformations are the most common culprit lesions. These findings suggest that small bowel enteroscopy should be considered as the initial test of choice in patients with suspected upper gastroduodenal bleeding. Readmissions with bleeding in patients with LVADs increase morbidity and cost of care but not mortality. Older patients and those with a history of bleeding during LVAD implantation are at higher risk of bleeding readmission and may benefit from close monitoring and cautious anticoagulation to prevent rebleeding.

Advanced iron-overload cardiomyopathy in a genetic murine model is rescued by resveratrol therapy.

Iron-overload cardiomyopathy is prevalent on a worldwide basis and is a major comorbidity in patients with genetic hemochromatosis and secondary iron overload. Therapies are limited in part due to lack of a valid preclinical model, which recapitulates advanced iron-overload cardiomyopathy. Male hemojuvelin (HJV) knockout (HJVKO) mice, which lack HJV, a bone morphogenetic co-receptor protein required for hepcidin expression and systemic iron homeostasis, were fed a high-iron diet starting at 4 weeks of age for a duration of 1 year. Aged HJVKO mice in response to iron overload showed increased myocardial iron deposition and mortality coupled with oxidative stress and myocardial fibrosis culminating in advanced iron-overload cardiomyopathy. In a parallel group, iron-overloaded HJVKO mice received resveratrol (240 mg/day) at 9 months of age until 1 year of age. Echocardiography and invasive pressure–volume (PV) loop analyses revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. In addition, myocardial sarcoplasmic reticulum Ca2+ ATPase (SERCa2a) levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCa2a levels and suppressed up-regulation of the sodium–calcium exchanger (NCX1). Further, iron-mediated oxidative stress and myocardial fibrosis were suppressed by resveratrol treatment with concomitant activation of the p-Akt and p-AMP-activated protein kinase (AMPK) signaling pathways. A combination of ageing and high-iron diet in male HJVKO mice results in a valid preclinical model that recapitulates iron-overload cardiomyopathy in humans. Resveratrol therapy resulted in normalization of cardiac function demonstrating that resveratrol represents a feasible therapeutic intervention to reduce the burden of iron-overload cardiomyopathy.