Single-Cell Profiling Unveils the Inflammatory Heterogeneity within Cutaneous Lesions of Bullous Pemphigoid.

Bullous pemphigoid (BP) is a subepidermal blistering skin disease with a complex pathogenesis involving various immune cells. However, the transcriptional features of these cells remain poorly defined. In this study, we constructed a comprehensive and single-cell resolution atlas of various immune cells within BP skin lesions through integrative single-cell analysis, flow cytometry, and multiplex immunohistochemistry. We observed prominent expansion and transcriptional changes in mast cells, macrophages, basophils, and neutrophils within BP lesions. Mast cells within the lesions adopted an active state and exhibited an elevated capacity for producing proinflammatory mediators. We observed an imbalance of macrophages/dendritic cells within BP lesions. Two macrophage subpopulations (NLRP3+ and C1q+) with distinct transcriptional profiles were identified and upregulated effector programs. T-peripheral helper-like T helper 2 cells were expanded in skin lesions and peripheral blood of patients with BP and were capable of promoting B-cell responses. In addition, we observed clonally expanded granzyme B-positive CD8+ T cells within BP lesions. Chemokine receptor mapping revealed the potential roles of macrophages and mast cells in recruiting pathogenic immune cells and underlying mechanisms within BP lesions. Thus, this study reveals key immune pathogenic features of BP lesions, thereby providing valuable insights for potential therapeutic interventions in this disease.

Integrative single-cell analysis reveals distinct adaptive immune signatures in the cutaneous lesions of pemphigus.

Pemphigus, an autoimmune bullous disease affecting the skin and mucosal membranes, is primarily driven by anti-desmoglein (Dsg) autoantibodies. However, the underlying immune mechanisms of this disease remain largely elusive. Here, we compile an unbiased atlas of immune cells in pemphigus cutaneous lesions at single-cell resolution. We reveal clonally expanded antibody-secreting cells (ASCs) that exhibit variable hypermutation and accumulation of IgG4 class-switching in their immunoglobulin genes. Importantly, pathogenic Dsg-specific ASCs are localized within pemphigus lesions and can evolve from both Dsg-autoreactive and non-binding precursors. We observe an altered distribution of CD4+ T cell subsets within pemphigus lesions, including an imbalance of Th17/Th2 cells. Significantly, we identify a distinct subpopulation of Th17 cells expressing CXCL13 and IL-21 within pemphigus lesions, implying its pivotal role in B cell recruitment and local production of autoantibodies. Furthermore, we characterize multiple clonally expanded CD8+ subpopulations, including effector GMZB+ and GMZK+ subsets with augmented cytotoxic activities, within pemphigus lesions. Chemokine-receptor mapping uncovers cell-type-specific signaling programs involved in the recruitment of T/B cells within pemphigus lesions. Our findings significantly contribute to advancing the understanding of the heterogeneous immune microenvironment and the pathogenesis of pemphigus cutaneous lesions, thereby providing valuable insights for potential therapeutic interventions in this disease.

Adrenoceptors in the Eye - Physiological and Pathophysiological Relevance.

The autonomic nervous system plays a crucial role in the innervation of the eye. Consequently, it comes as no surprise that catecholamines and their corresponding receptors have been extensively studied and characterized in numerous ocular structures, including the cornea, conjunctiva, lacrimal gland, trabecular meshwork, uvea, and retina. These investigations have unveiled substantial clinical implications, particularly in the context of treating glaucoma, a progressive neurodegenerative disorder responsible for irreversible vision loss on a global scale. The primary therapeutic approaches for glaucoma frequently involve the modulation of α1-, α2-, and ß-adrenoceptors, making them pivotal targets. In this chapter, we offer a comprehensive overview of the expression, distribution, and functional roles of adrenoceptors within various components of the eye and its associated structures. Additionally, we delve into the pivotal role of adrenoceptors in the pathophysiology of glaucoma. Furthermore, we provide a concise historical perspective on adrenoceptor research, examine the distinct contributions of individual adrenoceptor subtypes to the treatment of various ocular conditions, and propose potential future avenues of exploration in this field.

Effects of aircraft noise cessation on blood pressure, cardio- and cerebrovascular endothelial function, oxidative stress, and inflammation in an experimental animal model.

Large epidemiological studies have shown that traffic noise promotes the development of cardiometabolic diseases. It remains to be established how long these adverse effects of noise may persist in response to a noise-off period. We investigated the effects of acute aircraft noise exposure (mean sound level of 72 dB(A) applied for 4d) on oxidative stress and inflammation mediating vascular dysfunction and increased blood pressure in male C57BL/6 J mice. 1, 2 or 4d of noise cessation after a 4d continuous noise exposure period completely normalized noise-induced endothelial dysfunction of the aorta (measured by acetylcholine-dependent relaxation) already after a 1d noise pause. Vascular oxidative stress and the increased blood pressure were partially corrected, while markers of inflammation (VCAM-1, IL-6 and leukocyte oxidative burst) showed a normalization within 4d of noise cessation. In contrast, endothelial dysfunction, oxidative stress, and inflammation of the cerebral microvessels of noise-exposed mice did not improve at all. These data demonstrate that the recovery from noise-induced damage is more complex than expected demonstrating a complete restoration of large conductance vessel function but persistent endothelial dysfunction of the microcirculation. These findings also imply that longer noise pauses are required to completely reverse noise-induced vascular dysfunction including the resistance vessels.

Real-World Evidence Analysis of a Hybrid Closed-Loop System.

BACKGROUND: We analyzed real-world evidence to assess the performance of the mylife CamAPS FX hybrid closed-loop system. METHODS: Users from 15 countries across different age groups who used the system between May 9, 2022, and December 3, 2022, and who had ≥30 days of continuous glucose monitor data, and ≥30% of closed-loop usage were included in the current analysis (N = 1805). RESULTS: Time in range (3.9-10 mmol/L) was 72.6 ± 11.5% (mean ± SD) for all users and increased by age from 66.9 ± 11.7% for users ≤6 years old to 81.8 ± 8.7% for users ≥65 years. Time spent in hypoglycemia (<3.9 mmol/L) was 2.3% [1.3, 3.6] (median [interquartile range]). Mean glucose and glucose management indicator were 8.4 ± 1.1 mmol/L and 6.9%, respectively. Time using closed-loop was high at 94.7% [90.0, 96.9]. CONCLUSIONS: Glycemic outcomes from the present real-world evidence are comparable to results obtained from previous randomized controlled studies and confirm the efficacy of this hybrid closed-loop system in real-world settings.

Protective Effect of Nicorandil on Contrast-Induced Acute Kidney Injury After Emergency Percutaneous Coronary Intervention.

Objective: To investigate the protective effect of nicorandil on contrast-induced acute kidney injury (CIAKI) in patients with acute ST-segment elevation myocardial infarction (STEMI) after emergency percutaneous coronary intervention (PCI). Methods: This is a single-center, retrospective control study. A total of 156 patients with STEMI were divided into the nicorandil group (n = 55) and the control group (n = 101). The incidence of CIAKI, defined as an increase of >25% or absolute values > 44.2 µmol/L in serum creatinine (Scr) from baseline within 72 h of exposure to a contrast agent after exclusion of other causes, was the primary endpoint. The secondary endpoints were: (1) changes of Scr, estimated glomerular filtration rate (eGFR), uric acid, and ß2-microglobulin at 24/48/72 h and 5 to 7 days after PCI; (2) the peak value difference of creatine kinase isoenzymes (CK-MB) after PCI; (3) adverse events within 6 months after PCI. Results: The overall incidence of CIAKI was 21.8%; the incidence of CIAKI in the nicorandil group was significantly lower (12.7% [7/55]) than in the control group (26.7% [27/101]) (P = .043). Compared with the control group, Scr, uric acid, and ß2-microglobulin levels were lower, and the level of eGFR was higher in nicorandil group (P all < .05). The peak value of CK-MB in the nicorandil group was lower than that in the control group (105.30 [56.61, 232.04] vs 178.00 [77.08, 271.91]U/L, P = .042). There was no significant difference in adverse events between the 2 groups within 6 months after PCI. Moreover, multivariate logistic regression analysis showed that hypertension and diabetes were independent risk factors for CIAKI, while nicorandil treatment was a protective factor. Conclusion: Our data suggest that intravenous nicorandil after emergency PCI has a protective effect on the occurrence of CIAKI in STEMI patients.

Increase in hypoglycaemia and hyperglycaemia in people with diabetes admitted to hospital during COVID-19 pandemic.

BACKGROUND: We used detailed information on patients with diabetes admitted to hospital to determine differences in clinical outcomes before and during the COVID-19 pandemic in the UK. METHODS: The study used electronic patient record data from Imperial College Healthcare NHS Trust. Hospital admission data for patients coded for diabetes was analysed over three time periods: pre-pandemic (31st January 2019-31st January 2020), Wave 1 (1st February 2020-30th June 2020), and Wave 2 (1st September 2020-30th April 2021). We compared clinical outcomes including glycaemia and length of stay. RESULTS: We analysed data obtained from 12,878, 4008 and 7189 hospital admissions during the three pre-specified time periods. The incidence of Level 1 and Level 2 hypoglycaemia was significantly higher during Waves 1 and 2 compared to the pre-pandemic period (25 % and 25.1 % vs. 22.9 % for Level 1 and 11.7 % and 11.5 % vs. 10.3 % for Level 2). The incidence of hyperglycaemia was also significantly higher during the two waves. The median hospital length of stay increased significantly (4.1[1.6, 9.8] and 4.0[1.4, 9.4] vs. 3.5[1.2, 9.2] days). CONCLUSIONS: During the COVID-19 pandemic in the UK, hospital in-patients with diabetes had a greater number of hypoglycaemic/hyperglycaemic episodes and an increased length of stay when compared to the pre-pandemic period. This highlights the necessity for a focus on improved diabetes care during further significant disruptions to healthcare systems and ensuring minimisation of the impact on in-patient diabetes services. SUMMARY: Diabetes is associated with poorer outcomes from COVID-19. However the glycaemic control of inpatients before and during the COVID-19 pandemic is unknown. We found the incidence of hypoglycaemia and hyperglycaemia was significantly higher during the pandemic highlighting the necessity for a focus on improved diabetes care during further pandemics.

Mitigation of aircraft noise-induced vascular dysfunction and oxidative stress by exercise, fasting, and pharmacological α1AMPK activation: molecular proof of a protective key role of endothelial α1AMPK against environmental noise exposure.

AIMS: Environmental stressors such as traffic noise represent a global threat, accounting for 1.6 million healthy life years lost annually in Western Europe. Therefore, the noise-associated health side effects must be effectively prevented or mitigated. Non-pharmacological interventions such as physical activity or a balanced healthy diet are effective due to the activation of the adenosine monophosphate-activated protein kinase (α1AMPK). Here, we investigated for the first time in a murine model of aircraft noise-induced vascular dysfunction the potential protective role of α1AMPK activated via exercise, intermittent fasting, and pharmacological treatment. METHODS AND RESULTS: Wild-type (B6.Cg-Tg(Cdh5-cre)7Mlia/J) mice were exposed to aircraft noise [maximum sound pressure level of 85 dB(A), average sound pressure level of 72 dB(A)] for the last 4 days. The α1AMPK was stimulated by different protocols, including 5-aminoimidazole-4-carboxamide riboside application, voluntary exercise, and intermittent fasting. Four days of aircraft noise exposure produced significant endothelial dysfunction in wild-type mice aorta, mesenteric arteries, and retinal arterioles. This was associated with increased vascular oxidative stress and asymmetric dimethylarginine formation. The α1AMPK activation with all three approaches prevented endothelial dysfunction and vascular oxidative stress development, which was supported by RNA sequencing data. Endothelium-specific α1AMPK knockout markedly aggravated noise-induced vascular damage and caused a loss of mitigation effects by exercise or intermittent fasting. CONCLUSION: Our results demonstrate that endothelial-specific α1AMPK activation by pharmacological stimulation, exercise, and intermittent fasting effectively mitigates noise-induced cardiovascular damage. Future population-based studies need to clinically prove the concept of exercise/fasting-mediated mitigation of transportation noise-associated disease.

Traffic noise, e.g. from aircraft, significantly contributes to an increased risk of cardiovascular or metabolic diseases in the general population by brain-dependent stress reactions leading to higher levels of circulating stress hormones and vasoconstrictors, all of which cause hypertension, oxidative stress, and inflammation. With the present experimental studies, we provide for the first time molecular mechanisms responsible for successful noise mitigation: Physical exercise, intermittent fasting, and pharmacological activation of the adenosine monophosphate-activated protein kinase (AMPK), a metabolic master regulator protein, prevent cardiovascular damage caused by noise exposure, such as hypertension, endothelial dysfunction, and reactive oxygen species formation (e.g. free radicals) and inflammation.These beneficial mitigation manoeuvers are secondary to an activation of the endothelial AMPK, thereby mimicking the antidiabetic drug metformin.

A UK nationwide study of adults admitted to hospital with diabetic ketoacidosis or hyperosmolar hyperglycaemic state and COVID-19.

AIMS: To investigate characteristics of people hospitalized with coronavirus-disease-2019 (COVID-19) and diabetic ketoacidosis (DKA) or hyperosmolar hyperglycaemic state (HHS), and to identify risk factors for mortality and intensive care admission. MATERIALS AND METHODS: Retrospective cohort study with anonymized data from the Association of British Clinical Diabetologists nationwide audit of hospital admissions with COVID-19 and diabetes, from start of pandemic to November 2021. The primary outcome was inpatient mortality. DKA and HHS were adjudicated against national criteria. Age-adjusted odds ratios were calculated using logistic regression. RESULTS: In total, 85 confirmed DKA cases, and 20 HHS, occurred among 4073 people (211 type 1 diabetes, 3748 type 2 diabetes, 114 unknown type) hospitalized with COVID-19. Mean (SD) age was 60 (18.2) years in DKA and 74 (11.8) years in HHS (p < .001). A higher proportion of patients with HHS than with DKA were of non-White ethnicity (71.4% vs 39.0% p = .038). Mortality in DKA was 36.8% (n = 57) and 3.8% (n = 26) in type 2 and type 1 diabetes respectively. Among people with type 2 diabetes and DKA, mortality was lower in insulin users compared with non-users [21.4% vs. 52.2%; age-adjusted odds ratio 0.13 (95% CI 0.03-0.60)]. Crude mortality was lower in DKA than HHS (25.9% vs. 65.0%, p = .001) and in statin users versus non-users (36.4% vs. 100%; p = .035) but these were not statistically significant after age adjustment. CONCLUSIONS: Hospitalization with COVID-19 and adjudicated DKA is four times more common than HHS but both associate with substantial mortality. There is a strong association of previous insulin therapy with survival in type 2 diabetes-associated DKA.

Sulodexide Prevents Hyperglycemia-Induced Endothelial Dysfunction and Oxidative Stress in Porcine Retinal Arterioles.

Diabetes mellitus may cause severe damage to retinal blood vessels. The central aim of this study was to test the hypothesis that sulodexide, a mixture of glycosaminoglycans, has a protective effect against hyperglycemia-induced endothelial dysfunction in the retina. Functional studies were performed in isolated porcine retinal arterioles. Vessels were cannulated and incubated with highly concentrated glucose solution (HG, 25 mM D-glucose) +/- sulodexide (50/5/0.5 µg/mL) or normally concentrated glucose solution (NG, 5.5 mM D-glucose) +/- sulodexide for two hours. Endothelium-dependent and endothelium-independent vasodilatation were measured by videomicroscopy. Reactive oxygen species (ROS) were quantified by dihydroethidium (DHE) fluorescence. Using high-pressure liquid chromatography (HPLC), the intrinsic antioxidant properties of sulodexide were investigated. Quantitative PCR was used to determine mRNA expression of regulatory, inflammatory, and redox genes in retinal arterioles, some of which were subsequently quantified at the protein level by immunofluorescence microscopy. Incubation of retinal arterioles with HG caused significant impairment of endothelium-dependent vasodilation, whereas endothelium-independent responses were not affected. In the HG group, ROS formation was markedly increased in the vascular wall. Strikingly, sulodexide had a protective effect against hyperglycemia-induced ROS formation in the vascular wall and had a concentration-dependent protective effect against endothelial dysfunction. Although sulodexide itself had only negligible antioxidant properties, it prevented hyperglycemia-induced overexpression of the pro-oxidant redox enzymes, NOX4 and NOX5. The data of the present study provide evidence that sulodexide has a protective effect against hyperglycemia-induced oxidative stress and endothelial dysfunction in porcine retinal arterioles, possibly by modulation of redox enzyme expression.

Effectiveness and safety of electrical stimulation for treating pressure ulcers: A systematic review and meta-analysis.

AIM: This study aims to synthesize qualitative evidence on the effectiveness and safety of electrical stimulation for treating pressure ulcers. BACKGROUND: Electrical stimulation is often used clinically to treat pressure ulcers, but its effectiveness and safety and some potential problems are not clear. DESIGN: This is a qualitative systematic review. DATA SOURCES: The data sources are four English databases (PubMed, EMBASE, The Cochrane Library and Web of Science) and four Chinese databases (CNKI, SinoMed, VIP and WANFANG). METHODS: Two reviewers independently examined the records according to the eligibility criteria and extracted the data of each included study. We used the Review Manager 5.3 software to perform data analysis. RESULTS: Seventeen randomized controlled trials including 740 patients were included in this study. Meta-analysis of eight randomized controlled trials demonstrated that electrical stimulation significantly reduced the ulcer surface in contrast with standard wound care alone or pulsed sham electrical stimulation. Nine studies showed that electrical stimulation increased the risk of pressure ulcers being completely healed than the controlled group. Three studies reported that adverse reactions were rare. CONCLUSIONS: This study demonstrated that electrical stimulation was a relatively effective and safe adjunctive therapy for pressure ulcers treatment.

Co-exposure to urban particulate matter and aircraft noise adversely impacts the cerebro-pulmonary-cardiovascular axis in mice.

Worldwide, up to 8.8 million excess deaths/year have been attributed to air pollution, mainly due to the exposure to fine particulate matter (PM). Traffic-related noise is an additional contributor to global mortality and morbidity. Both health risk factors substantially contribute to cardiovascular, metabolic and neuropsychiatric sequelae. Studies on the combined exposure are rare and urgently needed because of frequent co-occurrence of both risk factors in urban and industrial settings. To study the synergistic effects of PM and noise, we used an exposure system equipped with aerosol generator and loud-speakers, where C57BL/6 mice were acutely exposed for 3d to either ambient PM (NIST particles) and/or noise (aircraft landing and take-off events). The combination of both stressors caused endothelial dysfunction, increased blood pressure, oxidative stress and inflammation. An additive impairment of endothelial function was observed in isolated aortic rings and even more pronounced in cerebral and retinal arterioles. The increase in oxidative stress and inflammation markers together with RNA sequencing data indicate that noise particularly affects the brain and PM the lungs. The combination of both stressors has additive adverse effects on the cardiovascular system that are based on PM-induced systemic inflammation and noise-triggered stress hormone signaling. We demonstrate an additive upregulation of ACE-2 in the lung, suggesting that there may be an increased vulnerability to COVID-19 infection. The data warrant further mechanistic studies to characterize the propagation of primary target tissue damage (lung, brain) to remote organs such as aorta and heart by combined noise and PM exposure.

Associations of microvascular complications with all-cause death in patients with diabetes and COVID-19: The CORONADO, ABCD COVID-19 UK national audit and AMERICADO study groups.

AIM: To provide a detailled analysis of the microvascular burden in patients with diabetes hopitalized for COVD-19. MATERIALS AND METHODS: We analysed data from the French CORONADO initiative and the UK Association of British Clinical Diabetologists (ABCD) COVID-19 audit, two nationwide multicentre studies, and the AMERICADO, a multicentre study conducted in New York area. We assessed the association between risk of all-cause death during hospital stay and the following microvascular complications in patients with diabetes hospitalized for COVID-19: diabetic retinopathy and/or diabetic kidney disease and/or history of diabetic foot ulcer. RESULTS: Among 2951 CORONADO, 3387 ABCD COVID-19 audit and 9327 AMERICADO participants, microvascular diabetic complications status was ascertained for 1314 (44.5%), 1809 (53.4%) and 7367 (79.0%) patients, respectively: 1010, 1059 and 1800, respectively, had ≥1 severe microvascular complication(s) and 304, 750 and 5567, respectively, were free of any complications. The patients with isolated diabetic kidney disease had an increased risk of all-cause death during hospital stay: odds ratio [OR] 2.53 (95% confidence interval [CI] 1.66-3.83), OR 1.24 (95% CI 1.00-1.56) and OR 1.66 (95% CI 1.40-1.95) in the CORONADO, the ABCD COVID-19 national audit and the AMERICADO studies, respectively. After adjustment for age, sex, hypertension and cardiovascular disease (CVD), compared to those without microvascular complications, patients with microvascular complications had an increased risk of all-cause death during hospital stay in the CORONADO, the ABCD COVID-19 diabetes national audit and the AMERICADO studies: adjusted OR (adj OR) 2.57 (95% CI 1.69-3.92), adj OR 1.22 (95% CI 1.00-1.52) and adj OR 1.33 (95% CI 1.15-1.53), respectively. In meta-analysis of the three studies, compared to patients free of complications, those with microvascular complications had an unadjusted OR for all-cause death during hospital stay of 2.05 (95% CI 1.42-2.97), which decreased to 1.62 (95% CI 1.19-2.119) after adjustment for age and sex, and to 1.50 (1.12-2.02) after hypertension and CVD were further added to the model. CONCLUSION: Microvascular burden is associated with an increased risk of death in patients hospitalized for COVID-19.

Safety of User-Initiated Intensification of Insulin Delivery Using Cambridge Hybrid Closed-Loop Algorithm.

OBJECTIVE: Many hybrid closed-loop (HCL) systems struggle to manage unusually high glucose levels as experienced with intercurrent illness or pre-menstrually. Manual correction boluses may be needed, increasing hypoglycemia risk with overcorrection. The Cambridge HCL system includes a user-initiated algorithm intensification mode ("Boost"), activation of which increases automated insulin delivery by approximately 35%, while remaining glucose-responsive. In this analysis, we assessed the safety of "Boost" mode. METHODS: We retrospectively analyzed data from closed-loop studies involving young children (1-7 years, n = 24), children and adolescents (10-17 years, n = 19), adults (≥24 years, n = 13), and older adults (≥60 years, n = 20) with type 1 diabetes. Outcomes were calculated per participant for days with ≥30 minutes of "Boost" use versus days with no "Boost" use. Participants with <10 "Boost" days were excluded. The main outcome was time spent in hypoglycemia <70 and <54 mg/dL. RESULTS: Eight weeks of data for 76 participants were analyzed. There was no difference in time spent <70 and <54 mg/dL between "Boost" days and "non-Boost" days; mean difference: -0.10% (95% confidence interval [CI] -0.28 to 0.07; P = .249) time <70 mg/dL, and 0.03 (-0.04 to 0.09; P = .416) time < 54 mg/dL. Time in significant hyperglycemia >300 mg/dL was 1.39 percentage points (1.01 to 1.77; P < .001) higher on "Boost" days, with higher mean glucose and lower time in target range (P < .001). CONCLUSIONS: Use of an algorithm intensification mode in HCL therapy is safe across all age groups with type 1 diabetes. The higher time in hyperglycemia observed on "Boost" days suggests that users are more likely to use algorithm intensification on days with extreme hyperglycemic excursions.

The association between macrovascular complications and intensive care admission, invasive mechanical ventilation, and mortality in people with diabetes hospitalized for coronavirus disease-2019 (COVID-19).

BACKGROUND: It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. METHODS: We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020-October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. RESULTS: Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83-2.45 with an I2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29-1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31-0.75], I2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40-0.68], I2 37%) were significantly lower for people with previous macrovascular disease. CONCLUSIONS: This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup.

Association Between SGLT2 Inhibitor Treatment and Diabetic Ketoacidosis and Mortality in People With Type 2 Diabetes Admitted to Hospital With COVID-19.

OBJECTIVE: To determine the association between prescription of SGLT2 inhibitors (SGLT2is) and diabetic ketoacidosis (DKA) incidence or mortality in people with type 2 diabetes (T2D) hospitalized with COVID-19. RESEARCH DESIGN AND METHODS: This was a retrospective cohort study based on secondary analysis of data from a large nationwide audit from a network of 40 centers in the U.K. with data collection up to December 2020. The study was originally designed to describe risk factors associated with adverse outcomes among people with diabetes who were admitted to hospital with COVID-19. The primary outcome for this analysis was DKA on or during hospital admission. The secondary outcome was mortality. Crude, age-sex adjusted, and multivariable logistic regression models were used to generate odds ratios (ORs) and 95% CIs for people prescribed SGLT2i compared with those not prescribed SGLT2i. RESULTS: The original national audit included 3,067 people with T2D who were admitted to hospital with COVID-19, of whom 230 (7.5%) were prescribed SGLT2is prior to hospital admission. The mean age of the overall cohort was 72 years, 62.3% were men, and 34.9% were prescribed insulin. Overall, 2.8% of the total population had DKA and 35.6% of people in the study died. The adjusted odds of DKA were not significantly different between those prescribed SGLT2is and those not (OR 0.56; 95% CI 0.16-1.97). The adjusted odds of mortality associated with SGLT2is were similar in the total study population (OR 1.13; 95% CI 0.78-1.63), in the subgroup prescribed insulin (OR 1.02; 95% CI 0.59-1.77), and in the subgroup that developed DKA (OR 0.21; 95% CI 0.01-8.76). CONCLUSIONS: We demonstrate a low risk of DKA and high mortality rate in people with T2D admitted to hospital with COVID-19 and limited power, but no evidence, of increased risk of DKA or in-hospital mortality associated with prescription of SGLT2is.

Association of statin and/or renin-angiotensin-aldosterone system modulating therapy with mortality in adults with diabetes admitted to hospital with COVID-19: A retrospective multicentre European study.

BACKGROUND & AIMS: To assess the impact of pre-admission renin-angiotensin-aldosterone system inhibitor (RAASi) and statin use on mortality following COVID-19 hospitalization in adults with pre-existing diabetes. METHODS: Retrospective cohort study of adults with diabetes admitted to ninety-nine participating hospitals in the United Kingdom, France and Spain during the first wave of the COVID-19 pandemic. Logistic regression models adjusted for demographic factors and comorbidity were used to describe associations with mortality in hospital or within 28 days of admission and individual or combined RAASi and statin therapy prescription followed by a country level meta-analysis. RESULTS: Complete data were available for 3474 (42.6%) individuals. Prescribing patterns varied by country: 25-50% neither RAASi nor statin therapy, 14-36% both RAASi and statin therapy, 9-24% RAASi therapy alone, 12-36% statin alone. Overall, 20-37% of patients died within 28 days. Meta-analysis found no evidence of an association between mortality and prescription of RAASi therapy (OR 1.09, CI 0.78-1.52 (I2 22.2%)), statin (OR 0.97, CI 0.59-1.61 (I2 72.9%)) or both (OR 1.14, CI 0.67-1.92 (I2 78.3%)) compared to those prescribed neither drug class. CONCLUSIONS: This large multicentre, multinational study found no evidence of an association between mortality from COVID-19 infection in people with diabetes and use of either RAASi, statin or combination therapy. This provides reassurance that clinicians should not change their RAASi and statin therapy prescribing practice in people with diabetes during the COVID-19 pandemic.

Ketogenic diet for epilepsy: an overview of systematic review and meta-analysis.

Ketogenic diet therapy (KDT) is an established nonpharmacologic treatment in various types of epilepsy. We aim to evaluate the quality of the systematic reviews and meta-analyses (SRMAs) of KDT for epilepsy and summarize the evidence on their effects. We conducted an overview on MEDLINE, EMBASE, Cochrane Database of Systematic Review, and Web of Science from database inception to 3 September 2020. Two investigators independently performed study selection to include SRMAs, extracted data and assessed the quality of SRMAs with the AMSTAR-2 and PRISMA statement. Twenty-four SRMAs were selected which encompassed a total of 255 original studies. Four reviews assessed the effects of KDT on infant patients; thirteen reviews reported on children and adolescent patients; eight reviews focused on adults or all patients; four assessed cognitive and behavior outcomes; three assessed quality of life; two assessed growth and development outcomes; seventeen reported on adverse effects; seven reported on retention; ten reported on attrition and reasons; and four reported on death outcomes. Overall, positive effects of KDT for epilepsy on seizure frequency reduction, as well as cognition and behavior were observed. In contrast, the effects of KDT on quality of life, growth and development were more controversial. The present overview indicates that KDT is safe. The most prevalent adverse events were GI, weight loss, and metabolic disorders, while the most common reasons for discontinuance were the lack of observed efficacy and dietary intolerance.

Chronic social defeat stress causes retinal vascular dysfunction.

PURPOSE: The roles of vascular dysfunction and chronic stress have been extensively discussed in the pathophysiology of glaucoma. Our aim was to test whether chronic stress causes retinal vascular dysfunction and therewith induces retinal ganglion cells (RGCs) loss. METHODS: Twelve mice underwent chronic social defeat (CSD) stress, while 12 mice received control treatment only. Intraocular pressure (IOP) was measured with a rebound tonometer. Blood plasma corticosterone concentration and adrenal gland weight were used to assess stress levels. Brn-3a staining in retinas and PPD staining in optic nerve cross sections were conducted to assess the survival of RGCs and axons respectively. The ET-1 and α-SMA levels were determined in retina. Retinal vascular autoregulation, functional response to various vasoactive agents and vascular mechanics were measured using video microscopy. RESULTS: No significant difference in IOP levels was observed during and after CSD between CSD mice and controls. CSD stress caused hypercortisolemia 2 days post-CSD. However, increased corticosterone levels went back to normal 8 months after CSD. CSD-exposed mice developed adrenal hyperplasia 3 days post-CSD, which was normalized by 8 months. RGC and axon survival were similar between CSD mice and controls. However, CSD stress caused irreversible, impaired autoregulation and vascular dysfunction of retinal arterioles in CSD mice. In addition, impaired maximal dilator capacity of retinal arterioles was observed 8 months post-CSD rather than 3 days post-CSD. Remarkably, ET-1 levels were increased 3 days post-CSD while α-SMA levels were decreased 8 months post-CSD. CONCLUSIONS: We found that CSD stress does not cause IOP elevation, nor loss of RGCs and their axons. However, it strikingly causes irreversible impaired autoregulation and endothelial function in murine retinal arterioles. In addition, CSD changed vascular mechanics on a long-term basis. Increased ET-1 levels and loss of pericytes in retina vessels may involve in this process.