A Randomized Controlled Study on Clinical Adherence to Evidence-Based Guidelines in the Management of Simulated Patients With Barrett's Esophagus and the Clinical Utility of a Tissue Systems Pathology Test: Results From Q-TAB.

INTRODUCTION: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma. Physicians infrequently adhere to guidelines for managing BE, leading to either reduced detection of dysplasia or inappropriate re-evaluation. METHODS: We conducted a three-arm randomized controlled trial with 2 intervention arms to determine the impact of a tissue systems pathology (TSP-9) test on the adherence to evidence-based guidelines for simulated patients with BE. Intervention 1 received TSP-9 results, and intervention 2 had the option to order TSP-9 results. We collected data from 259 practicing gastroenterologists and gastrointestinal surgeons who evaluated and made management decisions for 3 types of simulated patients with BE: nondysplastic BE, indefinite for dysplasia, and low-grade dysplasia. RESULTS: Intervention 1 was significantly more likely to correctly assess risk of progression to high-grade dysplasia/esophageal adenocarcinoma and offer treatment in accordance with US society guidelines compared with the control group (+6.9%, 95% confidence interval +1.4% to +12.3%). There was no significant difference in ordering guideline-recommended endoscopic eradication therapy. However, for cases requiring annual endoscopic surveillance, we found significant improvement in adherence for intervention 1, with a difference-in-difference of +18.5% ( P = 0.019). Intervention 2 ordered the TSP-9 test in 21.9% of their cases. Those who ordered the test performed similarly to intervention 1; those who did not, performed similarly to the control group. DISCUSSION: The TSP-9 test optimized adherence to clinical guidelines for surveillance and treatment of both patients with BE at high and low risk of disease progression. Use of the TSP-9 test can enable physicians to make risk-aligned management decisions, leading to improved patient health outcomes.

Clinical utility of a novel test for assessing cardiovascular disease risk in type 2 diabetes: a randomized controlled trial.

BACKGROUND: The risk for and treatment of cardiovascular disease (CVD) in type 2 diabetes (T2DM) is often incorrect and delayed. We wished to determine if a novel test improved physicians' ability to risk stratify, diagnose, and treat patients with T2DM. METHODS: In a 2-phase randomized controlled trial comparing the clinical workup, diagnosis, and management of online, simulated patients with T2DM in a nationwide sample of cardiologists and primary care physicians, participants were randomly assigned to control or one of two intervention groups. Intervention participants had access to standard of care diagnostic tools plus a novel diagnostic CVD risk stratification test. RESULTS: In control, there was no change in CV risk stratification of simulated patients between baseline and round 2 (37.1 to 38.3%, p = 0.778). Pre-post analysis showed significant improvements in risk stratification in both Intervention 1 (38.7 to 65.3%) and Intervention 2 (41.9 to 65.8%) (p < 0.01) compared to controls. Both intervention groups significantly increased prescribing SGLT2 inhibitors/GLP1 receptor agonists versus control, + 18.9% for Intervention 1 (p = 0.020) and 1 + 9.4% for Intervention 2 (p = 0.014). Non-pharmacologic treatment improved significantly compared to control (+ 30.0% in Intervention 1 (p < 0.001) and + 22.8% in Intervention 2 (p = 0.001). Finally, monitoring HgbA1C, blood pressure, and follow-up visit frequency improved by + 20.3% (p = 0.004) in Intervention 1 and + 29.8% (p < 0.001) in Intervention 2 compared with control. CONCLUSION: Use of the novel test significantly improved CV risk stratification among T2DM patients. Statistically significant increases treatments were demonstrated, specifically SGLT2 inhibitors and GLP1 receptor antagonists and recommendations of evidence-based non-pharmacologic treatments. Trial registration ClinicalTrials.gov, NCT05237271.

Clinical Variation in the Treatment Practices for Patients With Type 2 Diabetes: A Cross-Sectional Patient Simulation Study Among Primary Care Physicians and Cardiologists.

Background Cardiovascular disease risk stratification is necessary and critically important in patients with type 2 diabetes. Despite its known benefits to guide treatment and prevention, we hypothesized that providers do not routinely incorporate this into their diagnostic and treatment decisions. Methods and Results The QuiCER DM (QURE CVD Evaluation of Risk in Diabetes Mellitus) study enrolled 161 primary care physicians and 80 cardiologists. Between March 2022 and June 2022, we measured the care variation in risk determination among these providers caring for simulated patients with type 2 diabetes. We found a wide variation in the overall assessment of cardiovascular disease in patients with type 2 diabetes. Participants performed half of the necessary care items with quality-of-care scores, ranging between 13% and 84%, averaging 49.4±12.6%. Participants did not assess cardiovascular risk in 18.3% of cases and incorrectly stratified risk in 42.8% of cases. Only 38.9% of participants arrived at the correct cardiovascular risk stratification. Those who correctly identified a cardiovascular risk score were significantly more likely to order nonpharmacologic treatments, advising on their patients' nutrition (38.8% versus 29.9%, P=0.013) and the correct glycated hemoglobin target (37.7% versus 15.6%, P<0.001). Pharmacologic treatments, however, did not vary between those who correctly specified risk and those who did not. Conclusions Physician participants struggled to determine the correct cardiovascular disease risk and specify the appropriate pharmacologic interventions in simulated patients with type 2 diabetes. Additionally, there was a wide variation in the quality of care regardless of risk level, indicating opportunities to improve risk stratification.

Randomized prospective trial to detect and distinguish between medication nonadherence, drug-drug interactions, and disease progression in chronic cardiometabolic disease.

BACKGROUND: Disentangling nonadherence (NA), drug-drug interactions (DDIs), and disease progression from each other is an important clinical challenge for providers caring for patients with cardiometabolic diseases. NAs and DDIs are both ubiquitous and often overlooked. We studied a novel chronic disease management (CDM) test to detect medication adherence and the presence and severity of DDIs. MATERIALS AND METHODS: We conducted a prospective, randomized controlled trial of 236 primary care physicians using computer-based, simulated patients, measuring clinical care with and without access to the CDM test. The primary outcomes were whether use of the CDM test increased the accuracy of diagnoses and ordering better treatments and how effective the intervention materials were in getting participants to order the CDM test. RESULTS: Physicians given the CDM test results showed a + 13.2% improvement in their diagnosis and treatment quality-of-care scores (p < 0.001) in the NA patient cases and a + 13.6% improvement in the DDI cases (p < 0.001). The difference-in-difference calculations between the intervention and control groups were + 10.4% for NA and + 10.8% for DDI (p < 0.01 for both). After controlling for physician and practice co-factors, intervention, compared to control, was 50.4x more likely to recognize medication NA and 3.3x more likely to correctly treat it. Intervention was 26.9x more likely to identify the DDI and 15.7x more likely to stop/switch the interacting medication compared to control. We found no significant improvements for the disease progression patient cases. CONCLUSION: Distinguishing between nonadherence, drug-drug interactions, and disease progression is greatly improved using a reliable test, like the CDM test; improved diagnostic accuracy and treatment has the potential to improve patient quality of life, medication safety, clinical outcomes, and efficiency of health delivery. TRIAL REGISTRATION: clinicaltrials.gov (NCT05192590).

Clinical Variation in the Treatment Practices for Medication Nonadherence, Drug-Drug Interactions, and Recognition of Disease Progression in Patients with Chronic Cardiometabolic Diseases: A Cross-Sectional Patient Simulation Study among Primary Care Physicians.

Background: Medication nonadherence in patients with chronic diseases is common, costly, and often underdiagnosed. In the United States, approximately 40-50% of patients with cardiometabolic conditions are not adherent to long-term medications. Drug-drug interactions (DDI) are also underrecognized and may lead to medication nonadherence in this patient population. Treatment complexity associated with cardiometabolic conditions contributes to increased risk for adverse drug events and DDIs. Methods: We recruited a nationally representative sample of 246 board-certified family and internal medicine physicians to evaluate how they assessed, identified, and treated medication nonadherence, DDIs, and worsening disease. Participating physicians were asked to care for three online simulated patients, each with at least one chronic cardiometabolic disease, including atrial fibrillation, heart failure, diabetes mellitus, or hypertension, and who were taking prescription medications for their disease. Physicians' scores were based on evidence-based care recommendation criteria, including overall care quality and treatment for medication nonadherence and DDIs. Results: Overall, quality-of-care scores across all cases ranged from 13% to 87% with an average of 50.8% ± 12.1%. The average overall diagnostic plus treatment score was 21.9% ± 13.6%. Participants identified nonadherence in just 3.6% of cases, DDIs in 8.9% of cases, and disease progression in 30.3% of cases. Conclusions: Based on these study results, primary care physicians were unable to adequately diagnose and treat patients with chronic cardiometabolic diseases who either suffered from medication nonadherence, DDIs, or progression of the disease. Improved standardization and technique in identifying these diagnoses is needed in primary care. Trial Registration. This trial is registered with clinicaltrials.gov, NCT05192590.

Clinical variation in surveillance and management of Barrett's esophagus: A cross-sectional study of gastroenterologists and gastrointestinal surgeons.

Appropriate surveillance and treatment of Barrett's esophagus (BE) is vital to prevent disease progression and decrease esophageal adenocarcinoma (EAC)-related mortality. We sought to determine the variation in BE care and identify improvement opportunities. 275 physicians (113 general gastroenterologists, 128 interventional gastroenterologists, 34 gastrointestinal surgeons) cared for 3 simulated patients, one each from 3 BE clinical scenarios: non-dysplastic BE (NDBE), BE indefinite for dysplasia (IND), and BE with low grade dysplasia (LGD), and care scores were measured against societal guidelines. Overall quality-of-care scores ranged from 17% to 85% with mean of 47.9% ± 11.8% for NDBE, 50.8% ± 11.7% for IND, and 52.7% ± 12.2% for LGD. Participants appropriately determined risk of progression 20.3% of the time: 14.4% for NDBE cases, 19.9% for LGD cases, and 26.8% for IND cases (P = .001). Treatment and follow-up care scores averaged 12.9% ± 17.5% overall. For the LGD cases, guideline-recommended twice-daily PPI treatment was ordered only 24.7% of the time. Guideline-based follow-up endoscopic surveillance was done in only 27.7% of NDBE cases and 32.7% of IND cases. For the LGD cases, 45.4% ordered endoscopic eradication therapy while 25.1% chose annual endoscopic surveillance. Finally, participants provided counseling on lifestyle modifications in just 20% of cases. Overall care of patients diagnosed with BE varied widely and showed room for improvement. Specific opportunities for improvement were adherence to guideline recommended surveillance intervals, patient counseling, and treatment selection for LGD. Physicians would potentially benefit from additional BE education, endoscopic advances, and better methods for risk stratification.

Rutin ameliorates metabolic acidosis and fibrosis in alloxan induced diabetic nephropathy and cardiomyopathy in experimental rats.

Diabetic nephropathy and cardiomyopathy are two major causes of mortality among patients with diabetes mellitus (DM). Since current diabetic medications are associated with various side effects, the naturally occurring plant-derived compounds are in demand. Bioflavonoids originating from vegetables and medicinal plants have beneficial effects on diabetes by improving glycemic control, lipid metabolism, and anti-oxidant status. The present study is focused on the effect of rutin against alloxan induced diabetic nephropathy and cardiomyopathy. Male albino Wistar rats were divided into four groups, each of six rats. Group I control rats received 0.9% saline as a single dose intraperitoneally. Group II rats were induced diabetes with a single dose of alloxan monohydrate (150 mg/kg body weight in 0.9% saline) intraperitoneally. Group III rats received 0.28 M of NH4Cl in drinking water for 3 days for the experimental induction of metabolic acidosis. Group IV rats were injected with a single dose of alloxan monohydrate (150 mg/kg bodyweight) and administered rutin hydrate (100 mg/kg) for a period of 4 weeks by oral gavage. Administration of rutin prevented urinary ketone body formation and decreased serum creatinine and urea levels in alloxan induced diabetic rats. Rutin supplementation reduced the levels of serum triglycerides and cholesterol in diabetic rats. Gene expression profiling of metabolic acidosis related genes (AQP2, AQP3 and V2R) and also histopathological results demonstrated the protective effect of rutin against diabetic ketoacidodis and fibrosis. The results of the present study revealed rutin administration prevents the progression of diabetic nephropathy and cardiomyopathy through amelioration of fibrosis and metabolic acidosis.

Cholera surveillance and estimation of burden of cholera.

Cholera continues to be poorly controlled in multiple epidemic and endemic areas across the globe, with estimated annual incidence of 1.3-4.0 million cases, resulting in 21,000 to 143,000 deaths worldwide in 2015. The usual approach for patient diagnosis and cholera surveillance is clinical examination of cases of acute watery diarrhea (AWD), confirmed by positive culture or polymerase chain reaction tests. Rapid diagnostic tests (RDTs) are used in regions with limited laboratory capacities but have been found to demonstrate large variations in performance, ranging in sensitivity from 58% to 100% and in specificity from 60% to 100%. Most countries rely on hospital-based surveillance of diarrheal disease to compute the cholera burden. The World Health Organization (WHO) recommends that countries assess public health events involving cholera against the International Health Regulations 2005 criteria and determine need for official notification using the standard case definition. Cholera is an often under-recognized and under reported problem because of differences in case definitions, reluctance by authorities to acknowledge and report cholera, inadequacies in hospital surveillance systems, lack of effective diagnostic tests and commonalities in clinical presentation of cholera with other AWD etiologies. The resulting gap in burden data impairs economic analysis of disease impact and identification of areas for targeted control interventions. There is an urgent need to strengthen surveillance data by supplementing reported numbers with estimates from literature reviews and data from modelling studies, developing better-performing RDTs, enhancing monitoring and evaluation processes of in-country surveillance systems, and encouraging countries to report cholera cases by "rewarding" better reporting with technical support and improved access to vaccines. It is imperative that immediate steps are taken towards strengthening surveillance and reporting systems globally, especially in cholera-prone and resource-limited areas, where it will enable countries to articulate their demand for resources more accurately.

Combination of ramipril and rutin alleviate alloxan induced diabetic nephropathy targeting multiple stress pathways in vivo.

Diabetic nephropathy (DN) is considered as one of the major microvascular complications of diabetes mellitus (DM) which leads to end stage renal disease (ESRD). Even though existing therapeutic options are effective in decreasing albuminuria, drugs targeting the preservation of GFR and prevention of ESRD may provide better strategy for the treatment. Since metabolic disorders are multifactorial, poly-herbal medications, and drug-herbal combination are in demand. Therefore, the present work is focused on the combinatorial renoprotective effect of rutin and ramipril on alloxan induced DN in experimental rats. Male Wistar rats were divided into five groups, group I-control, group II-diabetic rats, group III-diabetic rats treated with ramipril, group IV-diabetic rats treated with rutin, group V-diabetic rats treated with ramipril and rutin for a period of six weeks. Results revealed administration of alloxan induced hyperglycemia and alteration in antioxidant profile. However, combination of a bioflavonoid with an Angiotensin converting enzyme (ACE) inhibitor administration restored the antioxidant status in experimental DN rats. Over-expression of ACE, TGF-ß1 and decreased podocin expression in diabetic rats was significantly reversed in rats administered with both ramipril and rutin. In addition to attentuating oxidative stress and fibrosis, combinatorial therapy significantly down-regulated endoplasmic reticulum stress markers GRP78 and CHOP. Notably, combination of both ramipril and rutin in low doses reduced the side effects than the administration of monotherapy alone. Histopathological results revealed that combinatorial therapy was associated with a reduction in tubulointerstitial injury. The current study contributes the understanding of the multifactorial nature of DN and implies combinatorial treatment of ACE inhibitor with an antioxidant will be a promising therapeutic strategy for DN by their mechanism of action targeting various pathophysiological changes and stress pathways.

Association of paraoxonase-1 gene polymorphisms with insulin resistance in South Indian population.

BACKGROUND AND AIM: Insulin resistance plays a crucial role in the pathogenesis of type 2 diabetes and cardiovascular diseases. Recently, paraoxonase-1(PON1) is reported to have an ability to reduce insulin resistance by promoting glucose transporter-4 (GLUT-4) expression in vitro. Single nucleotide polymorphism (SNP) in PON1 is associated with variability in enzyme activity and concentration. Based on this we aimed to investigate the association of PON1 (Q192R and L55M) polymorphisms with the risk of developing insulin resistance in adult South Indian population. METHODS: Two hundred and eighty seven (287) Type 2 diabetes patients and 293 healthy controls were enrolled in this study. All the study subjects were genotyped for PON1 (Q192R and L55M) missense polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) method. Fasting serum insulin level was measured by ELISA. RESULTS: The distribution of QR/RR and LM/MM genotypes were significantly higher in type 2 diabetes patients compared with healthy controls. Moreover, the R and M alleles were significantly associated with type 2 diabetes with an Odds Ratio of 1.68 (P < 0.005) and 2.24 (P < 0.005) respectively. SNP 192 Q > R genotypes were found to be significantly associated with higher BMI, cholesterol, triglycerides, LDL, fasting serum insulin and HOMA-IR. Further, the mutant allele or genotypes of PON1 L55M were associated with higher BMI, triglycerides, VLDL, fasting serum insulin and HOMA-IR among adult type 2 diabetes patients. CONCLUSION: PON1 (Q192R and L55M) polymorphisms may play a crucial role in pathogenesis and susceptibility of insulin resistance thus leads to the development of type 2 diabetes in South Indian population.

Oral administration of oxalate-enriched spinach extract as an improved methodology for the induction of dietary hyperoxaluric nephrocalcinosis in experimental rats.

Experimental induction of hyperoxaluria by ethylene glycol (EG) administration is disapproved as it causes metabolic acidosis while the oral administration of chemically synthesized potassium oxalate (KOx) diet does not mimic our natural system. Since existing models comprise limitations, this study is aimed to develop an improved model for the induction of dietary hyperoxaluria, and nephrocalcinosis in experimental rats by administration of naturally available oxalate rich diet. Male albino Wistar rats were divided into five groups. Group I, control; group II rats received 0.75% EG, group III rats fed with 5% KOx diet and group IV and V rats were administered with spinach extract of 250 and 500 mg soluble oxalate/day respectively, for 28 d. Urine and serum biochemistry were analyzed. After the experimental period, rats were sacrificed, liver and kidney tissue homogenates were used for antioxidant and lipid peroxidation assay. Relative change in expression of kidney injury molecule-1 (KIM-1) and crystal modulators genes in kidney tissues were evaluated. Tissue damage was assessed by histology studies of liver and kidney. Experimental group rats developed hyperoxaluria and crystalluria. Urine parameters, serum biochemistry, antioxidant profile, lipid peroxidation levels and gene expression analysis of experimental group II and III rats reflected acute kidney damage compared to group V rats. Histopathology results showed moderate hyperplasia in liver and severe interstitial inflammation in kidneys of group II and III than group V rats. Ingestion of naturally available oxalate enriched spinach extract successfully induced dietary hyperoxaluria and nephrocalcinosis in rats with minimal kidney damage.

Antioxidant activity of phenolic compounds from extracts of Eucalyptus globulus and Melaleuca styphelioides and their protective role on D-glucose-induced hyperglycemic stress and oxalate stress in NRK-49Fcells.

Phytochemicals serve as potential therapeutic agents for the prevention and treatment of diseases. In this study, we elucidate the renoprotective activity of compounds isolated from Eucalyptus globulus and Melaleuca styphelioides extracts in glucose- and oxalate-challenged NRK-49F cell model. The antioxidant potential of isolated compounds was evaluated based on their effect on antioxidant enzyme activities and lipid peroxidation levels. The results demonstrated that exposure of NRK-49F cells to glucose and oxalate stress augmented cell damage and attenuated antioxidant enzyme activities. The phytochemicals 2,2,8-trimethyl-6-formyl-chrom-3-ene-7-O-ß-D-glucopyranoside, Cornusiin B and tellimagrandin I treatment restored antioxidant enzyme activity, significantly lowered lipid peroxidation levels and effectively protected cells from glucose and oxalate stress equivalent to the known antioxidant, N-acetyl cysteine. Pterocarinin A significantly reversed cellular damage owing to glucose stress. In conclusion, the compounds isolated from E. globulus and M. styphelioides showed potential cytoprotective and anti-oxidative property against glucose- and oxalate-induced oxidative stress in NRK-49F cells.

Molecular analysis of oxalate-induced endoplasmic reticulum stress mediated apoptosis in the pathogenesis of kidney stone disease.

Oxalate, a non-essential end product of metabolism, causes hyperoxaluria and eventually calcium oxalate (CaOx) stone disease. Kidney cells exposed to oxalate stress results in generation of reactive oxygen species (ROS) and progression of stone formation. Perturbations in endoplasmic reticulum (ER) result in accumulation of misfolded proteins and Ca2+ ions homeostasis imbalance and serve as a common pathway for various diseases, including kidney disorders. ER stress induces up-regulation of pro-survival protein glucose-regulated protein 78 (GRP78) and pro-apoptotic signaling protein C/EBP homologous protein (CHOP). Since the association of oxalate toxicity and ER stress on renal cell damage is uncertain, the present study is an attempt to elucidate the interaction of GRP78 with oxalate by computational analysis and study the role of ER stress in oxalate-mediated apoptosis in vitro and in vivo. Molecular docking results showed that GRP78-oxalate/CaOx interaction takes place. Oxalate stress significantly up-regulated expression of ER stress markers GRP78 and CHOP both in vitro and in vivo. Exposure of oxalate increased ROS generation and altered antioxidant enzyme activities. N-Acetyl cysteine treatment significantly ameliorated oxalate-mediated oxidative stress and moderately attenuated ER stress marker expression. The result indicates oxalate toxicity initiated oxidative stress-induced ER stress and also activating ER stress mediated apoptosis directly. In addition, the up-regulation of transforming growth factor ß-1 revealed oxalate may induce kidney fibrosis through ER stress-mediated mechanisms. The present study provide insights into the pathogenic role of oxidative and ER stress by oxalate exposure in the formation of calcium oxalate stone.

Expression of heterologous oxalate decarboxylase in HEK293 cells confers protection against oxalate induced oxidative stress as a therapeutic approach for calcium oxalate stone disease.

Oxalates stimulate alterations in renal epithelial cells and thereby induce calcium oxalate (CaOx) stone formation. Bacillus subtilis YvrK gene encodes for oxalate decarboxylase (OxdC) which degrades oxalate to formate and CO2. The present work is aimed to clone the oxdC gene in a mammalian expression vector pcDNA and transfect into Human Embryonic Kidney 293 (HEK293) cells and evaluate the oxdC expression, cell survival rate and oxalate degrading efficiency. The results indicate cell survival rate of HEK293/pcDNAOXDC cells pre-incubated with oxalate was enhanced by 28%. HEK293/pcDNAOXDC cells expressing OxdC treated with oxalate, significantly restored antioxidant activity, mitochondrial membrane potential and intracellular reactive oxygen species (ROS) generation compared with HEK293/pcDNA. Apoptotic marker caspase 3 downregulation illustrates HEK293/pcDNAOXDC cells were able to survive under oxalate-mediated oxidative stress. The findings suggest HEK293 cells expressing oxdC capable of degrading oxalate protect cells from oxidative damage and thus serve as a therapeutic option for prevention of CaOx stone disease. [Formula: see text].