Increased Mortality in Patients Undergoing Inpatient Endoscopy During the Early COVID-19 Pandemic.

BACKGROUND AND AIMS: The Coronavirus disease 2019 (COVID-19) pandemic led to the restructuring of most healthcare systems, but the impact on patients undergoing inpatient endoscopic procedures is unknown. We sought to identify factors associated with 30-day mortality among patients undergoing inpatient endoscopy before and during the first wave of the pandemic within an academic tertiary care center. METHODS: We studied patients who underwent inpatient endoscopic procedures from March 1-May 31 in 2020 (COVID-19 era), the peak of the pandemic's first wave across the care center studied, and in March 1-May 31, 2018 and 2019 (control). Patient demographics and hospitalization/procedure data were compared between groups. Cox regression analyses were conducted to identify factors associated with 30-day mortality. RESULTS: Inpatient endoscopy volume decreased in 2020 with a higher proportion of urgent procedures, increased proportion of patients receiving blood transfusions, and a 10.1% mortality rate. In 2020, male gender, further distance from hospital, need for intensive care unit (ICU) admission, and procedures conducted outside the endoscopy suite were associated with increased risk of 30-day mortality. CONCLUSIONS: Patients undergoing endoscopy during the pandemic had higher proportions of ICU admission, more urgent indications, and higher rates of 30-day mortality. Greater proportions of urgent endoscopy cases may be due to hospital restructuring or patient reluctance to seek hospital care during a pandemic. Demographic and procedural characteristics associated with higher mortality risk may be potential areas to improve outcomes during future pandemic hospital restructuring efforts.

Socioeconomic disparities in surveillance and follow-up of patients with thoracic aortic aneurysm.

BACKGROUND: Thoracic aortic aneurysm (TAA) is a significant risk factor for aortic dissection and rupture. Guidelines recommend referral of patients to a cardiovascular specialist for periodic surveillance imaging with surgical intervention determined primarily by aneurysm size. We investigated the association between socioeconomic status (SES) and surveillance practices in patients with ascending aortic aneurysms. METHODS: We retrospectively reviewed records of 465 consecutive patients diagnosed between 2013 and 2016 with ascending aortic aneurysm ≥4 cm on computed tomography scans. Primary outcomes were clinical follow-up with a cardiovascular specialist and aortic surveillance imaging within 2 years following index scan. We stratified patients into quartiles using the area deprivation index (ADI), a validated percentile measure of 17 variables characterizing SES at the census block group level. Competing risks analysis was used to determine interquartile differences in risk of death before follow up with a cardiovascular specialist. RESULTS: Lower SES was associated with significantly lower rates of surveillance imaging and referral to a cardiovascular specialist. On competing risks regression, the ADI quartile with lowest SES had lower hazard of follow-up with a cardiologist or cardiac surgeon before death (hazard ratio: 0.46 [0.34, 0.62], p < .001). Though there were no differences in aneurysm size at time of surgical repair, patients in the lowest socioeconomic quartile were more frequently symptomatic at surgery than other quartiles (92% vs. 23%-38%, p < .001). CONCLUSION: Patients with lower SES receive less timely follow-up imaging and specialist referral for TAAs, resulting in surgical intervention only when alarming symptoms are already present.

Progression of aortic stenosis in patients with bicuspid aortic valve.

BACKGROUND: Bicuspid aortic valve is the most common congenital heart defect and predisposes patients to developing aortic stenosis more frequently and at a younger age than the general population. However, the influence of bicuspid aortic valve on the rate of progression of aortic stenosis remains unclear. METHODS: In 236 patients (177 tricuspid aortic valve and 59 bicuspid aortic valve) matched by initial severity of mild or moderate aortic stenosis, we retrospectively analyzed baseline echocardiogram at diagnosis with latest available follow-up echocardiogram. Baseline comorbidities, annualized progression rate of hemodynamic parameters, and hazard of aortic valve replacement were compared between valve phenotypes. RESULTS: Median echocardiographic follow-up was 2.6 (interquartile range [IQR] 1.6-4.2) years. Patients with tricuspid aortic stenosis were significantly older with more frequent comorbid hypertension and congestive heart failure. Median annualized progression rate of mean gradient was 2.3 (IQR 0.6-5.0) mmHg/year versus 1.5 (IQR 0.5-4.1) mmHg/year (p = .5), and that of peak velocity was 0.14 (IQR 0-0.31) m/s/year versus 0.10 (IQR 0.04-0.26) m/s/year (p = .7) for tricuspid versus bicuspid aortic valve, respectively. On multivariate analyses, bicuspid aortic valve was not significantly associated with more rapid progression of aortic stenosis. In a stepwise Cox proportional hazards model adjusted for baseline mean gradient, bicuspid aortic valve was associated with increased hazard of aortic valve replacement (hazard ratio: 1.7, 95% confidence interval [1.0-3.0], p = .049). CONCLUSION: Bicuspid aortic valve may not significantly predispose patients to more rapid progression of mild or moderate aortic stenosis. Guidelines for echocardiographic surveillance of aortic stenosis need not be influenced by valve phenotype.

Antibody-induced NKG2D blockade in a rat model of intraportal islet transplantation leads to a deleterious reaction.

Intraportal islet transplantation is plagued by an acute destruction of transplanted islets. Amongst the first responders, NK cells and macrophages harbour an activating receptor, NKG2D, recognizing ligands expressed by stressed cells. We aimed to determine whether islet NKG2D ligand expression increases with culture time, and to analyse the impact of antibody-induced NKG2D blockade in islet transplantation. NKG2D-ligand expression was analysed in rat and human islets. Syngeneic marginal mass intraportal islet transplantations were performed in rats: control group, recipients transplanted with NKG2D-recombinant-treated islets (recombinant group), and recipients treated with a mouse anti-rat anti-NKG2D antibody and transplanted with recombinant-treated islets (antibody-recombinant group). Islets demonstrated increased gene expression of NKG2D ligands with culture time. Blockade of NKG2D on NK cells decreased in vitro cytotoxicity against islets. Recipients from the control and recombinant groups showed similar metabolic results; conversely, treatment with the antibody resulted in lower diabetes reversal. The antibody depleted circulating and liver NK cells in recipients, who displayed increased macrophage infiltration of recipient origin around the transplanted islets. In vitro blockade of NKG2D ligands had no impact on early graft function. Systemic treatment of recipients with an anti-NKG2D antibody was deleterious to the islet graft, possibly through an antibody-dependent cell-mediated cytotoxicity reaction.

Voluntary Chronic Heavy Alcohol Consumption in Male Rhesus Macaques Suppresses Cancellous Bone Formation and Increases Bone Marrow Adiposity.

BACKGROUND: Chronic heavy alcohol consumption is an established risk factor for bone fracture, but comorbidities associated with alcohol intake may contribute to increased fracture rates in alcohol abusers. To address the specific effects of alcohol on bone, we used a nonhuman primate model and evaluated voluntary alcohol consumption on: (i) global markers of bone turnover in blood and (ii) cancellous bone mass, density, microarchitecture, turnover, and microdamage in lumbar vertebra. METHODS: Following a 4-month induction period, 6-year-old male rhesus macaques (Macaca mulatta, n = 13) voluntarily self-administered water or ethanol (EtOH; 4% w/v) for 22 h/d, 7 d/wk, for a total of 12 months. Control animals (n = 9) consumed an isocaloric maltose-dextrin solution. Tetracycline hydrochloride was administered orally 17 and 3 days prior to sacrifice to label mineralizing bone surfaces. Global skeletal response to EtOH was evaluated by measuring plasma osteocalcin and carboxyterminal collagen cross-links (CTX). Local response was evaluated in lumbar vertebra using dual-energy X-ray absorptiometry, microcomputed tomography, static and dynamic histomorphometry, and histological assessment of microdamage. RESULTS: Monkeys in the EtOH group consumed an average of 2.8 ± 0.2 (mean ± SE) g/kg/d of EtOH (30 ± 2% of total calories), resulting in an average blood EtOH concentration of 88.3 ± 8.8 mg/dl 7 hours after the session onset. Plasma CTX and osteocalcin tended to be lower in EtOH-consuming monkeys compared to controls. Significant differences in bone mineral density in lumbar vertebrae 1 to 4 were not detected with treatment. However, cancellous bone volume fraction (in cores biopsied from the central region of the third vertebral body) was lower in EtOH-consuming monkeys compared to controls. Furthermore, EtOH-consuming monkeys had lower osteoblast perimeter and mineralizing perimeter, no significant difference in osteoclast perimeter, and higher bone marrow adiposity than controls. No significant differences between groups were detected in microcrack density (2nd lumbar vertebra). CONCLUSIONS: Voluntary chronic heavy EtOH consumption reduces cancellous bone formation in lumbar vertebra by decreasing osteoblast-lined bone perimeter, a response associated with an increase in bone marrow adiposity.

Effects of remote ischaemic preconditioning on intraportal islet transplantation in a rat model.

Remote ischaemic preconditioning (RIPC), which is the intermittent interruption of blood flow to a site distant from the target organ, is known to improve solid organ resistance to ischaemia-reperfusion injury. This procedure could be of interest in islet transplantation to mitigate hypoxia-related loss of islet mass after isolation and transplantation. Islets isolated from control or RIPC donors were analyzed for yield, metabolic activity, gene expression and high mobility group box-1 (HMGB1) content. Syngeneic marginal mass transplantation was performed in four streptozotocin-induced diabetic groups: control, RIPC in donor only, RIPC in recipient only, and RIPC in donor and recipient. Islets isolated from RIPC donors had an increased yield of 20% after 24 h of culture compared to control donors (P = 0.007), linked to less cell death (P = 0.08), decreased expression of hypoxia-related genes (Hif1a P = 0.04; IRP94 P = 0.008), and increased intra-cellular (P = 0.04) and nuclear HMGB1. The use of RIPC in recipients only did not allow for reversal of diabetes, with increased serum HMGB1 at day 1; the three other groups demonstrated significantly better outcomes. Performing RIPC in the donors increases islet yield and resistance to hypoxia. Validation is needed, but this strategy could help to decrease the number of donors per islet recipient.

Variability in surveillance practice for patients with diagnosis of bicuspid aortic valve syndrome.

In patients with bicuspid aortic valves, guidelines call for regular follow-up to monitor disease progression and guide intervention. We aimed to evaluate how closely these recommendations are followed at a tertiary care center. Among 48,504 patients who received echocardiograms (2013-2018) at a tertiary care center, 245 patients were identified to have bicuspid aortic valve. Bivariate analyses compared characteristics between patients who did and did not receive follow-up by a cardiovascular specialist. During a median follow-up of 3.5 ± 2.2 years (mean age 55.2 ± 15.6 years, 30.2% female), 72.7% of patients had at least one visit with a cardiovascular specialist after diagnosis of bicuspid aortic valve. These patients had a higher proportion of surveillance by echocardiogram (78.7% vs. 34.3%, p < .0001), CT or MRI (41.0% vs. 3.0%, p < .0001), and were more likely to undergo surgery. Patients with moderate-severe valvular or aortic pathology were not more likely to be followed by a specialist or receive follow-up echocardiograms. Follow-up care for patients with bicuspid aortic valve was highly variable, and surveillance imaging was sparse despite guidelines. There is an urgent need for mechanisms to monitor this population with increased risk of progressive valvulopathy and aortopathy.

Changing the default option in electronic medical records reduced postoperative opioid prescriptions after cardiac surgery.

Objective: Overprescribing of opioids has contributed to the opioid epidemic. Electronic medical records systems can auto-populate a default number of opioid pills that are prescribed at time of discharge. The aim of this study was to examine the association between lowered default pill counts with changed prescribing practices after cardiac surgery. Methods: On May 18, 2017, the default number of pills prescribers see in electronic medical records in the Yale New Haven Health System was lowered from 30 to 12. Patients undergoing coronary artery grafts, valve surgeries, and thoracic aortic aneurysm surgeries were included in this study. Data were gathered and stratified into 2 groups: 1 year before and 1 year following the default change. The amount of opioid prescribed was compared between the 2 groups. Results: A total of 1741 patient charts were reviewed, 832 before the change and 909 after the change. Significant changes were seen in prescribing practices, where the average amount of opioid prescribed was about 25% lower after the change. This amounted to about 15 fewer pills of 5 mg morphine for each patient. A linear regression model adjusting for other factors determined a prescribing difference of 75.2 morphine milligram equivalents per prescription (P < .01). In addition, a significant decrease in opioids prescribed was found for each type of procedure. Conclusions: Lowering the default opioid pill count in electronic medical record systems is a simple intervention that may modify prescribing behavior to promote judicious prescribing of opioids after cardiac surgery.

Survival of Patients With Mild Secondary Mitral Regurgitation With and Without Mild Tricuspid Regurgitation.

BACKGROUND: Mild secondary mitral regurgitation (SMR) is considered clinically benign when left-ventricular ejection fraction (LVEF) is preserved, but evidence on survival associated with mild SMR in normal LVEF is limited. METHODS: We conducted a retrospective cohort study of patients who underwent echocardiography in a health care network between 2013 and 2018. We compared the survival of 4 groups: no valvular abnormalities (group 1), trace SMR with trace or mild tricuspid regurgitation (TR) (group 2), mild SMR with trace or no TR (group 3), and mild SMR with mild TR (group 4). A Cox proportional hazard model evaluated hazard of death in groups 2 to 4 compared with group 1, adjusting for demographics, comorbidities, and LVEF. The same comparisons were repeated in a subgroup of patients with preserved LVEF. RESULTS: Among the 16,372 patients of mean age 61 (51 to 71) years and 48% women, there were 8132 (49.7%) group 1 patients, 1902 (11.6%) group 2 patients, 3017 (18.4%) group 3 patients, and 3321 (20.3%) group 4 patients. Compared with group 1, group 4 had significantly increased adjusted hazard of death (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.12-1.31; P < 0.001), whereas groups 2 and 3 did not show a significantly different hazard of death. In those with preserved LVEF, the hazard was also significantly higher in group 4, compared with group 1 (HR, 1.14; 95% CI, 1.03-1.26; P = 0.013). CONCLUSIONS: Mild SMR with mild TR, irrespective of LVEF, was associated with worse survival compared with patients without any valvular abnormalities. Patients with mild SMR may require closer monitoring, even with normal LVEF.

Regenerative Medicine and Diabetes: Targeting the Extracellular Matrix Beyond the Stem Cell Approach and Encapsulation Technology.

According to the Juvenile Diabetes Research Foundation (JDRF), almost 1. 25 million people in the United States (US) have type 1 diabetes, which makes them dependent on insulin injections. Nationwide, type 2 diabetes rates have nearly doubled in the past 20 years resulting in more than 29 million American adults with diabetes and another 86 million in a pre-diabetic state. The International Diabetes Ferderation (IDF) has estimated that there will be almost 650 million adult diabetic patients worldwide at the end of the next 20 years (excluding patients over the age of 80). At this time, pancreas transplantation is the only available cure for selected patients, but it is offered only to a small percentage of them due to organ shortage and the risks linked to immunosuppressive regimes. Currently, exogenous insulin therapy is still considered to be the gold standard when managing diabetes, though stem cell biology is recognized as one of the most promising strategies for restoring endocrine pancreatic function. However, many issues remain to be solved, and there are currently no recognized treatments for diabetes based on stem cells. In addition to stem cell resesarch, several ß-cell substitutive therapies have been explored in the recent era, including the use of acellular extracellular matrix scaffolding as a template for cellular seeding, thus providing an empty template to be repopulated with ß-cells. Although this bioengineering approach still has to overcome important hurdles in regards to clinical application (including the origin of insulin producing cells as well as immune-related limitations), it could theoretically provide an inexhaustible source of bio-engineered pancreases.

Polyethylene particles inserted over calvarium induce cancellous bone loss in femur in female mice.

Focal bone resorption (osteolysis) induced by wear particles contributes to long-term orthopedic joint failure. However, the impact of focal osteolysis on remote skeletal sites has received less attention. The goal of this study was to determine the effects of polyethylene particles placed over calvaria on representative axial and appendicular skeletal sites in female mice. Because recent work has identified housing temperature as an important biological variable in mice, response to particle treatment was measured in animals housed at room (22 °C) and thermoneutral (32 °C) temperature. Osteolysis was evident in skeletal tissue adjacent to particle insertion. In addition, cancellous bone loss was observed in distal femur metaphysis. The bone loss was associated with lower osteoblast-lined perimeter and lower mineralizing perimeter in distal femur, lower osteocalcin gene expression in tibia, and lower serum osteocalcin, suggesting the response was due, at least in part, to reduced bone formation. Mild cold stress induced by sub-thermoneutral housing resulted in cancellous bone loss in distal femur and lumbar vertebra but did not influence skeletal response to particles. In summary, the results indicate that focal inflammation induced by polyethylene particles has the potential to result in systemic bone loss. This is significant because bone loss is a risk factor for fracture.