Unexplained Residual Risk In Type 2 Diabetes: How Big Is The Problem?

PURPOSE OF REVIEW: What is new? Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes (T2D) individuals. Of the major risk factors for CVD, less than 10% of T2D people meet the American Diabetes Association/American Heart Association recommended goals of therapy. The present review examines how much of the absolute cardiovascular (CV) risk in type 2 diabetes patients can be explained by major CV intervention trials. RECENT FINDINGS: Multiple long-term cardiovascular (CV) intervention trials have examined the effect of specific target-directed therapies on the MACE endpoint. Only one prospective study, STENO-2, has employed a multifactorial intervention comparing intensified versus conventional treatment of modifiable risk factors in T2D patients, and demonstrated a 20% absolute CV risk reduction. If the absolute CV risk reduction in these trials is added to that in the only prospective multifactorial intervention trial (STENO-2), the unexplained CV risk is 44.1%. What are the clinical implications? Potential explanations for the unaccounted-for reduction in absolute CV risk in type 2 diabetes (T2D) patients are discussed. HYPOTHESIS: failure to take into account synergistic interactions between major cardiovascular risk factors is responsible for the unexplained CV risk in T2D patients. Simultaneous treatment of all major CV risk factors to recommended AHA/ADA guideline goals is required to achieve the maximum reduction in CV risk.

Learning Curve for Endoscopic Submucosal Dissection With an Untutored, Prevalence-Based Approach in the United States.

BACKGROUND & AIMS: Endoscopic submucosal dissection (ESD) is widely used in Asia to resect early-stage gastrointestinal neoplasms, but use of ESD in Western countries is limited. We collected data on the learning curve for ESD at a high-volume referral center in the United States to guide development of training programs in the Americas and Europe. METHODS: We performed a retrospective analysis of consecutive ESDs performed by a single operator at a high-volume referral center in the United States from 2009 through 2017. ESD was performed in 540 lesions: 449 mucosal (10% esophageal, 13% gastric, 5% duodenal, 62% colonic, and 10% rectal) and 91 submucosal. We estimated case volumes required to achieve accepted proficiency benchmarks (>90% for en bloc resection and >80% for histologic margin-negative (R0) resection) and resection speeds >9cm2/hr. RESULTS: Pathology analysis of mucosal lesions identified 95 carcinomas, 346 premalignant lesions, and 8 others; the rate of en bloc resection increased from 76% in block 1 (50 cases) to a plateau of 98% after block 5 (250 cases). The rate of R0 resection improved from 45% in block 1 to >80% after block 5 (250 cases) and ∼95% after block 8 (400 cases). Based on cumulative sum analysis, approximately 170, 150, and 280 ESDs are required to consistently achieve a resection speed >9cm2/hr in esophagus, stomach, and colon, respectively. CONCLUSIONS: In an analysis of ESDs performed at a large referral center in the United States, we found that an untutored, prevalence-based approach allowed operators to achieve all proficiency benchmarks after ∼250 cases. Compared with Asia, ESD requires more time to learn in the West, where the untutored, prevalence-based approach requires resection of challenging lesions, such as colon lesions and previously manipulated lesions, in early stages of training.

A novel technique of endoscopic submucosal dissection for circumferential ileocecal valve adenomas with terminal ileum involvement: the "doughnut resection" (with videos).

BACKGROUND: Ileocecal valve (ICV) lesions are difficult to resect endoscopically and patients are often referred for laparoscopic colectomy. ICV involvement has been shown to be related to technical failure and tumor recurrence after endoscopic mucosal resection (EMR) and represents a challenge for endoscopic submucosal dissection (ESD). Few publications have focused specifically on endoscopic management of ICV lesions. METHODS: We developed a novel ESD technique, the "doughnut resection," for circumferential ICV adenomas with terminal ileum involvement. Two circumferential mucosal incisions are performed, one in the ileum and the other in the cecum, followed by submucosal dissection of the disk of tissue between the two incisions around a guiding stent placed across the valve that helps guide the dissection as it crosses the valve orifice. The lesion is removed en bloc in the shape of a "doughnut" with two concentric assessable lateral margins. The underwater ESD technique and a gastroscope were used to facilitate the resection. RESULTS: Seven patients received the doughnut resection. The median patient age was 67 years. All patients had prior biopsy and three had prior endoscopic resection (1-6 times). The median specimen diameter was 4.5 cm (range 3-8). All resections were en bloc and R0. There was no perforation, delayed bleeding, or other clinically significant adverse events. After a median follow-up of 21 months (range 12-32), there was no tumor recurrence. CONCLUSION: The "doughnut resection" is a feasible, safe, and effective method to remove circumferential ICV lesions endoscopically even for patients with multiple prior tumor manipulations.

Impact of depression on in-hospital outcomes for adults with type 2 myocardial infarction: A United States population-based analysis.

BACKGROUND: Type 2 myocardial infarction (T2MI) is an ischemic myocardial injury in the context of oxygen supply/demand mismatch in the absence of a primary coronary event. However, though there is a rising prevalence of depression and its potential association with type 1 myocardial infarction (T1MI), data remains non-existent to evaluate the association with T2MI. AIM: To identify the prevalence and risk of T2MI in adults with depression and its impact on the in-hospital outcomes. METHODS: We queried the National Inpatient Sample (2019) to identify T2MI hospitalizations using Internal Classification of Diseases-10 codes in hospitalized adults (≥ 18 years). In addition, we compared sociodemographic and comorbidities in the T2MI cohort with vs without comorbid depression. Finally, we used multivariate regression analysis to study the odds of T2MI hospitalizations with vs without depression and in-hospital outcomes (all-cause mortality, cardiogenic shock, cardiac arrest, and stroke), adjusting for confounders. Statistical significance was achieved with a P value of < 0.05. RESULTS: There were 331145 adult T2MI hospitalizations after excluding T1MI (median age: 73 years, 52.8% male, 69.9% white); 41405 (12.5%) had depression, the remainder; 289740 did not have depression. Multivariate analysis revealed lower odds of T2MI in patients with depression vs without [adjusted odds ratio (aOR) = 0.88, 95% confidence interval (CI): 0.86-0.90, P = 0.001]. There was the equal prevalence of prior MI with any revascularization and a similar prevalence of peripheral vascular disease in the cohorts with depression vs without depression. There is a greater prevalence of stroke in patients with depression (10.1%) vs those without (8.6%). There was a slightly higher prevalence of hyperlipidemia in patients with depression vs without depression (56.5% vs 48.9%), as well as obesity (21.3% vs 17.9%). There was generally equal prevalence of hypertension and type 2 diabetes mellitus in both cohorts. There was no significant difference in elective and non-elective admissions frequency between cohorts. Patients with depression vs without depression also showed a lower risk of all-cause mortality (aOR = 0.75, 95%CI: 0.67-0.83, P = 0.001), cardiogenic shock (aOR = 0.65, 95%CI: 0.56-0.76, P = 0.001), cardiac arrest (aOR = 0.77, 95%CI: 0.67-0.89, P = 0.001) as well as stroke (aOR = 0.79, 95%CI: 0.70-0.89, P = 0.001). CONCLUSION: This study revealed a significantly lower risk of T2MI in patients with depression compared to patients without depression by decreasing adverse in-hospital outcomes such as all-cause mortality, cardiogenic shock, cardiac arrest, and stroke in patients with depression.

Effect of weight-maintaining ketogenic diet on glycemic control and insulin sensitivity in obese T2D subjects.

INTRODUCTION: Low carbohydrate ketogenic diets have received renewed interest for the treatment of obesity and type 2 diabetes. These diets promote weight loss, improve glycemic control, and reduce insulin resistance. However, whether the improvements in glycemic control and insulin sensitivity are secondary to the weight loss or result from a direct effect of hyperketonemia is controversial. RESEARCH DESIGN AND METHODS: 29 overweight obese subjects were randomized to one of three dietary interventions for 10 days: (1) Weight-maintaining standard diet; (2) Weight-maintaining ketogenic diet; (3) Weight-maintaining ketogenic diet plus supplementation with the ketone ester of beta-hydroxybutyrate (ß-OH-B), 8 g every 8 hours. At baseline, all subjects had oral glucose tolerance test, 2-step euglycemic insulin clamp (20 mU/m2.min and 60 mU/m2.min) with titrated glucose and indirect calorimetry. RESULTS: Body weight, fat content, and per cent body fat (DEXA) remained constant over the 10-day dietary intervention period in all three groups. Plasma ß-OH-B concentration increased twofold, while carbohydrate oxidation decreased, and lipid oxidation increased demonstrating the expected shifts in substrate metabolism with institution of the ketogenic diet. Glucose tolerance either decreased slightly or remained unchanged in the two ketogenic diet groups. Whole body (muscle), liver, and adipose tissue sensitivity to insulin remained unchanged in all 3 groups, as did the plasma lipid profile and blood pressure. CONCLUSION: In the absence of weight loss, a low carbohydrate ketogenic diet has no beneficial effect on glucose tolerance, insulin sensitivity, or other metabolic parameters.

Effect of Hyperketonemia on Myocardial Function in Patients with Heart Failure and Type 2 Diabetes.

We examined the effect of increased plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in type 2 diabetes (T2DM) patients with heart failure (HF). Three groups (I,II,III) of T2DM (12 per group) with LV ejection fraction ≤50% received incremental infusions of ß-OH-B for 3-6 hours to raise plasma ß-OH-B concentration throughout the physiologic (Groups I and II) and pharmacologic (Group III) range. Cardiac MRI was performed at baseline and after each ß-OH-B infusion to provide measures of cardiac function. On a separate day, Group II also received NaHCO3 infusion, thus serving as their own control for time, volume, and pH. Additionally, Group II underwent positron emission tomography study with 18F-fluoro-2-deoxyglucose to examine effect of hyperketonemia on MGU. Groups I, II, III achieved plasma ß-OH-B levels of 0.7±0.3, 1.6±0.2, 3.2±0.2 mmol/L, respectively. Cardiac output, LVEF, and stroke volume increased significantly during ß-OH-B infusion in Groups II (CO, 4.54 to 5.30; EF, 39.9 to 43.8; SV, 70.3 to 80.0) and III (CO, 5.93 to 7.16; EF, 41.1 to 47.5; SV, 89.0 to 108.4) and did not change with NaHCO3 infusion in Group II. The increase in LVEF was greatest in Group III (p<0.001 vs Group II). MGU and MBF were not altered by ß-OH-B. In T2DM patients with LVEF≤50%, increased plasma ß-OH-B significantly increased LV function dose-dependently. Since MGU did not change, the myocardial benefit of ß-OH-B resulted from providing an additional fuel for the heart without inhibiting MGU.

Elevated lipoprotein(a) levels: A crucial determinant of cardiovascular disease risk and target for emerging therapies.

Cardiovascular disease (CVD) remains a significant global health challenge despite advancements in prevention and treatment. Elevated Lipoprotein(a) [Lp(a)] levels have emerged as a crucial risk factor for CVD and aortic stenosis, affecting approximately 20 of the global population. Research over the last decade has established Lp(a) as an independent genetic contributor to CVD and aortic stenosis, beginning with Kare Berg's discovery in 1963. This has led to extensive exploration of its molecular structure and pathogenic roles. Despite the unknown physiological function of Lp(a), studies have shed light on its metabolism, genetics, and involvement in atherosclerosis, inflammation, and thrombosis. Epidemiological evidence highlights the link between high Lp(a) levels and increased cardiovascular morbidity and mortality. Newly emerging therapies, including pelacarsen, zerlasiran, olpasiran, muvalaplin, and lepodisiran, show promise in significantly lowering Lp(a) levels, potentially transforming the management of cardiovascular disease. However, further research is essential to assess these novel therapies' long-term efficacy and safety, heralding a new era in cardiovascular disease prevention and treatment and providing hope for at-risk patients.

Impact Of body Mass Index on Cardiopulmonary Outcomes of COVID-19 Hospitalizations Complicated by Severe Sepsis.

Background: Body Mass Index (BMI) has a significant impact on Coronavirus disease (COVID-19) patient outcomes; however, major adverse cardiac and cerebrovascular outcomes in patients with severe sepsis have been poorly understood. Our study aims to explore and provide insight into its association. Methods: This is an observational study looking at the impact of BMI on COVID-19-severe sepsis hospitalizations. The primary outcomes are adjusted odds of all-cause in-hospital mortality, respiratory failure, and major adverse cardiac and cerebrovascular events (MACCE), which include acute myocardial infarction, cardiac arrest, and acute ischemic stroke. The secondary outcome was healthcare resource utilization. Coexisting comorbidities and patient features were adjusted with multivariable regression analyses. Results: Of 51,740 patients with severe COVID-19-sepsis admissions, 11.4% were overweight, 24.8% had Class I obesity (BMI 30-34.9), 19.8% had Class II obesity (BMI 35-39.9), and 43.9% had the categorization of Class III obesity (BMI >40) cohorts with age>18 years. The odds of MACCE in patients with class II obesity and class III obesity (OR 1.09 and 1.54; 95CI 0.93-1.29 and 1.33-1.79) were significantly higher than in overweight (p < 0.001). Class I, Class II, and Class III patients with obesity revealed lower odds of respiratory failure compared to overweight (OR 0.89, 0.82, and 0.82; 95CI 0.75-1.05, 0.69-0.97, and 0.70-0.97), but failed to achieve statistical significance (p = 0.079). On multivariable regression analysis, all-cause in-hospital mortality revealed significantly higher odds in patients with Class III obesity, Class II, and Class I (OR 1.56, 1.17, and 1.06; 95CI 1.34-1.81, 0.99-1.38, and 0.91-1.24) vs. overweight patients (p < 0.001). Conclusions: Patients with Class II and Class III obesity had significantly higher odds of MACCE and in-hospital mortality in COVID-19-severe sepsis admissions.

COVID-19-associated familial acute disseminated encephalomyelitis (ADEM): A case report.

BACKGROUND: Several neurological complications are being reported in hospitalized patients with severe COVID-19 infection. This is presumed due to direct spread of infection or due to immunological response. Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory and demyelinating disorder of the central nervous system that is often preceded by infection or vaccination. Very few cases of ADEM have been reported in the literature that are associated with COVID-19 infection. CASE REPORT: Here we demonstrate familial cases of ADEM in a hospitalized father and son, who presented to the emergency department with fever and shortness of breath, later diagnosed with COVID-19, and subsequently requiring mechanical ventilation. Both patients developed neurological symptoms with upper motor neuron involvement at approximately day 30 of admission. MRI of the brain demonstrated bilateral multifocal periventricular white matter FLAIR signal hyperintensities consistent with ADEM. The patients were treated with medium dose IV methylprednisolone with variable outcomes. The 49-year-old son developed severe residual neurological deficits with encephalomalacic changes on MRI which required extensive rehabilitation; meanwhile, the 68-year-old father predominantly had pulmonary sequelae including fibrosis and the development of a pneumatocele, but he had a better neurological outcome. CONCLUSION: To our knowledge, this is the first reported case report of ADEM involving father and son in severe COVID-19 infection. Final neurological outcomes in these patients appeared to be in line with the severity of COVID-19 infection. More research is needed to better understand the management of ADEM in patients with severe COVID-19 infection.

Usefulness of Timed Up and Go (TUG) Test for Prediction of Adverse Outcomes in Patients Undergoing Thoracolumbar Spine Surgery.

BACKGROUND: Spine surgery rates have increased and the high postoperative morbidity in these patients result in increased costs. Consequently, it is essential to identify patients at risk of adverse outcomes. OBJECTIVE: To assess whether preoperative Timed Up and Go (TUG) test performance can predict high-grade postoperative complications. METHODS: A prospective cohort study of patients undergoing elective thoracolumbar spine surgery in a tertiary care hospital between 2017 and 2018. Patients were assessed preoperatively and assigned to the slow-TUG group if unable to perform or test performance time was ≥18.4 s. Primary outcome: high-grade postoperative complications. Secondary outcomes: overall complications, length of stay (LOS), discharge to healthcare facility, readmission and emergency department (ED) presentation. Patients were followed-up until 6 wk after surgery. RESULTS: One hundred three patients (mean age 62.95 ± 10.97 yr) were enrolled. Slow-TUG group were more likely to be classified as American Society of Anaesthesiology (ASA) class 3 (74.1% vs 47.4%, P = .02), non-independent (25.9% vs 5.3%, P < .01), and frail (92.3% vs 42.1%, P < .01). TUG was an independent predictor of high-grade complications (adjusted odds ratio (OR): 4.97, 95% CI: 1.18-22.47), overall complications (OR: 3.77, 95% CI: 1.33-11.81), discharge to a skilled-nursing facility (OR: 3.2, 95% CI: 1.00-10.70), readmission within 6 wk of surgery (OR: 9.14, 95% CI: 2.39-41.26) and LOS (adjusted incident rate ratio (IRR): 1.45, 95% CI: 1.16-1.80). CONCLUSION: Compared to traditional risk factors, TUG is an important predictor of adverse postoperative outcomes and may be used preoperatively to identify high-risk thoracolumbar surgery patients.