Obesity in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Obesity is common in patients with coronavirus disease 2019 (COVID-19). The effects of obesity on clinical outcomes of COVID-19 warrant systematical investigation. OBJECTIVE: This study explores the effects of obesity with the risk of severe disease among patients with COVID-19. METHODS: Body mass index (BMI) and degree of visceral adipose tissue (VAT) accumulation were used as indicators for obesity status. Publication databases including preprints were searched up to August 10, 2020. Clinical outcomes of severe COVID-19 included hospitalization, a requirement for treatment in an intensive care unit (ICU), invasive mechanical ventilation (IMV), and mortality. Risks for severe COVID-19 outcomes are presented as odds ratios (OR) and 95% confidence interval (95%CI) for cohort studies with BMI-defined obesity, and standardized mean difference (SMD) and 95%CI for controlled studies with VAT-defined excessive adiposity. RESULTS: A total of 45, 650 participants from 30 studies with BMI-defined obesity and 3 controlled studies with VAT-defined adiposity were included for assessing the risk of severe COVID-19. Univariate analyses showed significantly higher ORs of severe COVID-19 with higher BMI: 1.76 (95%: 1.21, 2.56, P = 0.003) for hospitalization, 1.67 (95%CI: 1.26, 2.21, P<0.001) for ICU admission, 2.19 (95%CI: 1.56, 3.07, P<0.001) for IMV requirement, and 1.37 (95%CI: 1.06, 1.75, P = 0.014) for death, giving an overall OR for severe COVID-19 of 1.67 (95%CI: 1.43, 1.96; P<0.001). Multivariate analyses revealed increased ORs of severe COVID-19 associated with higher BMI: 2.36 (95%CI: 1.37, 4.07, P = 0.002) for hospitalization, 2.32 (95%CI: 1.38, 3.90, P = 0.001) for requiring ICU admission, 2.63 (95%CI: 1.32, 5.25, P = 0.006) for IMV support, and 1.49 (95%CI: 1.20, 1.85, P<0.001) for mortality, giving an overall OR for severe COVID-19 of 2.09 (95%CI: 1.67, 2.62; P<0.001). Compared to non-severe COVID-19 patients, severe COVID-19 cases showed significantly higher VAT accumulation with a SMD of 0.49 for hospitalization (95% CI: 0.11, 0.87; P = 0.011), 0.57 (95% CI: 0.33, 0.81; P<0.001) for requiring ICU admission and 0.37 (95% CI: 0.03, 0.71; P = 0.035) for IMV support. The overall SMD for severe COVID-19 was 0.50 (95% CI: 0.33, 0.68; P<0.001). CONCLUSIONS: Obesity increases risk for hospitalization, ICU admission, IMV requirement and death among patients with COVID-19. Further, excessive visceral adiposity appears to be associated with severe COVID-19 outcomes. These findings emphasize the need for effective actions by individuals, the public and governments to increase awareness of the risks resulting from obesity and how these are heightened in the current global pandemic.

Pancreatic Angiopathy Associated With Islet Amyloid and Type 2 Diabetes Mellitus.

OBJECTIVES: Type 2 diabetes (T2D) is histopathologically characterized by islet amyloid and is closely connected with vascular complications. Here, we explore the presence of pancreatic angiopathy (PA) associated with islet amyloid and T2D. METHODS: From a total of 172 autopsy cases who had a history of T2D diagnosis, we randomly selected 30 T2D autopsy cases with islet amyloid (DA+) in comparison with islet amyloid-free (DA-) 30 T2D cases and 60 nondiabetic (ND) controls. Amyloid deposits and PA including atherosclerosis of pancreatic interlobar arteries, arterial calcification, atheroembolism, hyaline arteriosclerosis of small arterioles, and islet capillary density were detected in all groups. RESULTS: Pancreatic angiopathy was found in 91.7% of patients with T2D and in 68.3% of ND controls (P < 0.01). Furthermore, 100% of DA+ patients and 83.3% of DA- subjects showed PA. The intraislet capillary density was significantly lower in DA+ subjects than DA- subjects (mean [standard deviation], DA+: 205 [82] count/mm; DA-: 344 [76] count/mm; ND: 291 [94] count/mm; P < 0.01). Finally, interlobar arteriosclerosis (R = 0.603, P < 0.01) was linearly correlated with the severity of islet amyloid deposits. CONCLUSIONS: Pancreatic angiopathy might be both a cause and a consequence of islet amyloid and T2D.

Global trend of diabetes mortality attributed to vascular complications, 2000-2016.

BACKGROUND: The global epidemic of diabetes mellitus continues to grow and affects developed and developing countries alike. Intensive glycemic control is thought to modify the risks for vascular complications, hence the risks for diabetes-related death. We investigated the trend of diabetic vascular complication-related deaths between 2000 and 2016 in the global diabetes landscape. METHODS: We collected 17 years of death certificates data from 108 countries in the World Health Organization mortality database between 2000 and 2016, with coding for diabetic complications. Crude and age-standardized proportions and rates were calculated. Trend analysis was done with annual average percentage change (AAPC) of rates computed by joinpoint regression. RESULTS: From 2000 through 2016, 7,108,145 deaths of diabetes were reported in the 108 countries. Among them, 26.8% (1,904,787 cases) were attributed to vascular complications in damaged organs, including the kidneys (1,355,085 cases, 71.1%), peripheral circulatory (515,293 cases, 27.1%), nerves (28,697 cases, 1.5%) and eyes (5751 cases, 0.3%). Overall, the age-standardized proportion of vascular complication-related mortality was 267.8 [95% confidence interval (95% CI), 267.5-268.1] cases per 1000 deaths and the rate was 53.6 (95% CI 53.5-53.7) cases per 100,000 person-years. Throughout the 17-year period, the overall age-standardized proportions of deaths attributable to vascular complications had increased 37.9%, while the overall age-standardized mortality rates related to vascular complications had increased 30.8% (AAPC = 1.9% [1.4-2.4%, p < 0.05]). These increases were predominantly driven by a 159.8% increase in the rate (AAPC = 2.7% [1.2-4.3%, p < 0.05]) from renal complications. Trends in the rates and AAPC of deaths varied by type of diabetes and of complications, as well as by countries, regions and domestic income. CONCLUSION: Diabetic vascular complication-related deaths had increased substantially during 2000-2016, mainly driven by the increased mortality of renal complications.

Human Amylin: From Pathology to Physiology and Pharmacology.

The histopathological hallmark of type 2 diabetes is islet amyloid implicated in the developing treatment options. The major component of human islet amyloid is 37 amino acid peptide known as amylin or islet amyloid polypeptide (IAPP). Amylin is an important hormone that is co-localized, copackaged, and co-secreted with insulin from islet ß cells. Physiologically, amylin regulates glucose homeostasis by inhibiting insulin and glucagon secretion. Furthermore, amylin modulates satiety and inhibits gastric emptying via the central nervous system. Normally, human IAPP is soluble and natively unfolded in its monomeric state. Pathologically, human IAPP has a propensity to form oligomers and aggregate. The oligomers show misfolded α-helix conformation and can further convert themselves to ß-sheet-rich fibrils as amyloid deposits. The pathological findings and physiological functions of amylin have led to the introduction of pramlintide, an amylin analog, for the treatment of diabetes. The history of amylin's discovery is a representative example of how a pathological finding can translate into physiological exploration and lead to pharmacological intervention. Understanding the importance of transitioning from pathology to physiology and pharmacology can provide novel insight into diabetes mellitus and Alzheimer's disease.

Amyloids in Site-Specific Autoimmune Reactions and Inflammatory Responses.

Amyloid deposition is a histological hallmark of common human disorders including Alzheimer's disease (AD) and type 2 diabetes. Although some reports highlight that amyloid fibrils might activate the innate immunity system via pattern recognition receptors, here, we provide multiple lines of evidence for the protection by site-specific amyloid protein analogs and fibrils against autoimmune attacks: (1) strategies targeting clearance of the AD-related brain amyloid plaque induce high risk of deadly autoimmune destructions in subjects with cognitive dysfunction; (2) administration of amyloidogenic peptides with either full length or core hexapeptide structure consistently ameliorates signs of experimental autoimmune encephalomyelitis; (3) experimental autoimmune encephalomyelitis is exacerbated following genetic deletion of amyloid precursor proteins; (4) absence of islet amyloid coexists with T-cell-mediated insulitis in autoimmune diabetes and autoimmune polyendocrine syndrome; (5) use of islet amyloid polypeptide agonists rather than antagonists improves diabetes care; and (6) common suppressive signaling pathways by regulatory T cells are activated in both local and systemic amyloidosis. These findings indicate dual modulation activity mediated by amyloid protein monomers, oligomers, and fibrils to maintain immune homeostasis. The protection from autoimmune destruction by amyloid proteins offers a novel therapeutic approach to regenerative medicine for common degenerative diseases.

Correlation of Adventitial Vasa Vasorum with Intracranial Atherosclerosis: A Postmortem Study.

BACKGROUND AND PURPOSE: Vasa vasorum (VV) have been believed to be rare or non-existent in small-caliber intracranial arteries. In a series of human cerebral artery specimens, we identified and examined the distribution of VV in association with co-existing intracranial atherosclerosis. METHODS: We obtained cerebral artery specimens from 32 consecutive autopsies of subjects aged 45 years or above. We scrutinized middle cerebral artery (MCA), vertebral artery (VA), and basilar artery (BA) for the presence of adventitial VV. We described the distribution of VV, and the characteristics of co-existing atherosclerotic lesions. RESULTS: Among 157 intracranial arteries, adventitial VV were present in 74 of the 157 specimens (47%), involving MCA (n=13, 18%), BA (n=14, 19%), and VA (n=47, 64%). Although qualitatively these 74 adventitial VV distributed similarly in arteries with or without atherosclerotic lesions (disease-free arteries n=4/8; arteries of pre-atherosclerosis n=17/42; and arteries of progressive atherosclerosis n=53/107), the presence of adventitial VV in intracranial VA was associated with a heavier plaque load (1.72±1.66 mm2 vs. 0.40±0.32 mm2, P<0.001), severer luminal stenosis (25%±21% vs. 12%±9%, P=0.002), higher rate of concentric lesions (79% vs. 36%, P=0.002), and denser intraplaque calcification (44% vs. 0%, P=0.003). Histologically, intracranial VA with VV had a larger diameter (3.40±0.79 mm vs. 2.34±0.58 mm, P<0.001), thicker arterial wall (0.31±0.13 mm vs. 0.23±0.06 mm, P=0.002), and a larger intima-media (0.19±0.09 mm vs. 0.13± 0.04 mm, P=0.003) than VA without VV. CONCLUSION: s Our study demonstrated the distribution of adventitial VV within brain vasculature and association between vertebral VV and progressive atherosclerotic lesions with a heavier plaque load and denser intraplaque calcification.

Postmortem Study Exploring Distribution and Patterns of Intracranial Artery Calcification.

Background and Purpose- Intracranial artery calcification detected by computed tomography is associated with ischemic stroke as an indicator of intracranial atherosclerosis. However, little is known about its histopathology. This study aimed to explore the intracranial calcification patterns and their associations with atherosclerotic plaques. Methods- We recruited 32 adult autopsy cases to assess the calcification patterns and distributions in the middle cerebral artery, vertebral artery, and basilar artery. The relationships of calcification patterns with plaque phenotype and luminal stenosis were evaluated. The calcification patterns on computed tomography were correlated with that on histology. Results- Visible calcifications were detected within 37 (39%) segments, including 25 segments with intimal calcification, 6 segments with internal elastic lamina calcification, 3 segments with adventitial calcification, and 3 segments with concurrent calcification. Calcification occurred more often in the vertebral artery (51%), followed by the middle cerebral artery (35%) and basilar artery (14%; P<0.01 for vertebral artery versus basilar artery). Internal elastic lamina calcification was predominantly detected in the vertebral artery (7/8, 88%). All of the 27 (100%) intimal calcifications were present in the progressive atherosclerotic lesions ( P<0.001), whereas only 3/8 (38%) internal elastic lamina calcifications and 4/6 (67%) adventitial calcifications were associated with progressive plaques. Arteries with intimal calcification had more severe luminal stenosis than those without (46% versus 21%; P<0.001). Conclusions- Our histological findings indicate that the presence of intracranial artery calcification has 3 patterns, including intimal, internal elastic lamina, and adventitial calcifications. But only intimal calcification is related with progressive atherosclerotic lesions, indicative of a proxy for intracranial atherosclerosis.

Interaction of renin-angiotensin system gene polymorphisms with hypertension in Chinese patients with type 1 diabetes and retinopathy.

BACKGROUND: The objective of this research was to investigate the interaction of RAS gene polymorphisms in Chinese patients with type 1 diabetes mellitus (T1DM) and diabetic retinopathy (DR). METHODS: Genomic DNA was extracted from peripheral blood leukocytes and genotyping for the angiotensin converting enzyme (ACE) gene I/D and angiotensinogen (AGT) gene M/T polymorphisms was performed using the polymerase chain reaction method. 311 T1DM patients were recruited for the assessment of ACE and AGT polymorphisms relating to DR. RESULTS: Compared with the diabetic non-retinopathy (DNR) patients, DR patients had lower proportion of diabetic nephropathy (p<0.001) and M allele (p=0.013). Intriguingly, the frequency D allele (p=0.035) was lower in DR patients with hypertension, as well as DD (p=0.003) and DI genotype (p=0.012) in DR patients with normal blood pressure after multiple tests with Bonferroni correction, but D allele (p=0.025) displayed higher in normotensive patients with T1DM. Logistic regression analyses indicated that no significant relationship existed about the genotype and allele polymorphisms with the progress of DR after adjusting for confounding factors. CONCLUSIONS: Interaction of hypertension and the RAS gene polymorphisms might have a role in the DR development in Chinese T1DM patients.

Risk for cancer in living kidney donors and recipients.

OBJECTIVE: Malignancy following renal transplantation remains inconsistent with the reported safety of kidney donation during the long-term follow-up. METHODS: We conducted searches of the published literature which included healthy participants, recipients, living kidney donors (LKDs), and the availability of outcome data for malignancy. Eight from 938 potentially relevant studies were analyzed by means of fixed-effects model or random-effects model, as appropriately. RESULTS: In 48,950 participants, the follow-up range was 18 months to 20 years, and the mean age of the subjects was approximately 41 years. The incidence rate with 95% confidence interval (CI) for malignancy after kidney transplantation was 0.03 (0.01-0.05) in recipients and 0.03 (0.1-0.07) in LKDs, giving a pooled incidence rate of 0.03 (95% CI 0.02-0.04). LKDs contrasted nondonors by the overall odds ratio and 95% CI for total cancer of 2.80 (2.69-2.92). CONCLUSIONS: Kidney transplantation was associated with an increased risk of cancer during a long-term follow-up. Long-term risk for cancer in LKDs and kidney recipients should be monitored.

The relationship between ACE/AGT gene polymorphisms and the risk of diabetic retinopathy in Chinese patients with type 2 diabetes.

AIMS: This study aims to investigate the association between renin-angiotensin system gene polymorphism and diabetic retinopathy (DR) in Chinese patients with type 2 diabetes. METHODS: We consecutively included 1491 patients for the assessment of ACE I/D and AGT M/T gene polymorphisms in 345 DR cases and 1146 patients without retinopathy (DNR). Albuminuria was defined by urine albumin creatinine ratio and albumin excretion rate. RESULTS: Compared with the NDR patients, the DR cases displayed a higher proportion of diabetic nephropathy (32.68% vs. 6.52%, χ2 = 150.713, p < 0.001). The DR cases and DNR individuals did not differ in the frequency of genotypes and alleles of ACE I/D and AGT M/T (all p > 0.05). Intriguingly, DR patients with obesity showed higher frequency of DD (χ2 = 4.181, p = 0.041), but no significant difference exists in the other stratified BMI and hypertension analyses (all p > 0.05). Binary logistic regression displays that the association of the ACE and AGT gene polymorphisms in DR patients is not significant after adjusting for confounding covariates in all the comparisons. CONCLUSIONS: The ACE and AGT gene polymorphisms are not associated with the progress of diabetes developing into retinopathy in Chinese patients with type 2 diabetes. However, more investigations are needed to further prove the association.

Expression and clinical significance of HOXA5, E-cadherin, and ß-catenin in cervical squamous cell carcinoma.

OBJECTIVES: HOXA5 has been identified as a biomarker in pathogenesis of several cancers, such as non-small cell lung cancer (NSCLC) and breast cancer cells. The role has not been explored in cervical squamous cell carcinoma (CSCC). METHODS: Tissues of 120 cases with CSCC and 30 controls with chronic cervicitis were constructed from our archived surgical pathology files and staining with HOXA5. Additional antibodies to E-cadherin and ß-catenin were stained for comparison. For each marker, low expression was defined as staining score 0 to 3 points, whereas high expression referred to 4 points and above. Fifty-four patients in this research with cervical cancer were followed up for prognostic assessment. RESULT: HOXA5 had high expression in chronic cervicitis and low in CSCC (P=0.004). The positivity rates of HOXA5 in patients without muscular layer invasion (MLI) and lymphatic invasion (LI) was higher than that in metastasis (113 vs. 17; 117 vs. 3). Consistently, low expression of HOXA5 was more common in poorly differentiated carcinoma, CSCC subjects without MLI and LI. Expression of E-cadherin and ß-catenin was parallel with the expression of HOXA5. Additionally, patients with higher expression of HOXA5 had much more favorable prognosis than those with lower expression among follow up of the 54 patients. CONCLUSION: In parallel with E-cadherin and ß-catenin, low expression of HOXA5 was more common in CSCC patients with poor differentiation, without MLI and LI, among those which showed poor prognosis.