Publications by authors named "Stephen L Atkin"

246 Publications

Targeting AMPK by Statins: A Potential Therapeutic Approach.

Drugs 2021 May 3. Epub 2021 May 3.

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Statins are a group of lipid-lowering drugs that inhibit cholesterol biosynthesis and have anti-inflammatory, anti-tumor, and immunomodulatory properties. Several lines of evidence indicate that statins regulate multiple proteins associated with the regulation of differing cellular pathways. The 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway plays an important role in metabolism homeostasis with effects on cellular processes including apoptosis and the inflammatory responses through several pathways. Recently, it has been shown that statins can affect the AMPK pathway in differing physiological and pathological ways, resulting in anti-cancer, cardio-protective, neuro-protective, and anti-tubercular effects; additionally, they have therapeutic effects on non-alcoholic fatty liver disease and diabetes mellitus-associated complications. Statins activate AMPK as an energy sensor that inhibits cell proliferation and induces apoptosis in cancer cells, whilst exerting its cardio-protective effects through inhibition of inflammation and fibrosis, and promotion of angiogenesis. Furthermore, statin-associated AMPK activation leads to decreased lipid accumulation and decreased amyloid beta deposition in the liver and brain, respectively, and may have therapeutic effects on the liver and neurons. In this review, we summarize the results of studies of AMPK-associated therapeutic effects of statins in different pathological conditions.
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http://dx.doi.org/10.1007/s40265-021-01510-4DOI Listing
May 2021

Amyloid-related protein changes associated with dementia differ according to severity of hypoglycemia.

BMJ Open Diabetes Res Care 2021 Apr;9(1)

Diabetes Research Center, Qatar Biomedical Research Institute, Doha, Qatar

Introduction: Hypoglycemia in type 2 diabetes (T2D) may increase risk for Alzheimer's disease (AD), but no data on changes in AD-related proteins with differing degrees of hypoglycemia exist. We hypothesized that milder prolonged hypoglycemia would cause greater AD-related protein changes versus severe transient hypoglycemia.

Research Design And Methods: Two prospective case-control induced hypoglycemia studies were compared: study 1, hypoglycemic clamp to 2.8 mmol/L (50 mg/dL) for 1 hour in 17 subjects (T2D (n=10), controls (n=7)); study 2, hypoglycemic clamp to 2.0 mmol/L (36 mg/dL) undertaken transiently and reversed in 46 subjects (T2D (n=23), controls (n=23)). Blood sampling at baseline, hypoglycemia and 24-hour post-hypoglycemia, with proteomic analysis of amyloid-related proteins performed.

Results: In control subjects, the percentage change from baseline to hypoglycemia differed between study 1 and study 2 for 5 of 11 proteins in the AD-related panel: serum amyloid A1 (SAA1) (p=0.009), pappalysin (PAPPA) (p=0.002), apolipoprotein E2 (p=0.02), apolipoprotein E3 (p=0.03) and apolipoprotein E4 (p=0.02). In controls, the percentage change from baseline to 24 hours differed between studies for two proteins: SAA1 (p=0.003) and PAPPA (p=0.004); however, after Bonferroni correction only SAA1 and PAPPA remain significant. In T2D, there were no differential protein changes between the studies.

Conclusions: The differential changes in AD-related proteins were seen only in control subjects in response to iatrogenic induction of hypoglycemic insults of differing length and severity and may reflect a protective response that was absent in subjects with T2D. Milder prolonged hypoglycemia caused greater AD-related protein changes than severe acute hypoglycemia in control subjects.

Trial Registration Numbers: NCT02205996, NCT03102801.
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http://dx.doi.org/10.1136/bmjdrc-2021-002211DOI Listing
April 2021

Plasma heat shock protein response to euglycemia in type 2 diabetes.

BMJ Open Diabetes Res Care 2021 Apr;9(1)

Diabetes Research Center, Qatar Biomedical Research Institute, Doha, Qatar

Introduction: Glucose variability is associated with mortality and macrovascular diabetes complications. The mechanisms through which glucose variability mediates tissue damage are not well understood, although cellular oxidative stress is likely involved. As heat shock proteins (HSPs) play a role in the pathogenesis of type 2 diabetes (T2D) complications and are rapidly responsive, we hypothesized that HSP-related proteins (HSPRPs) would differ in diabetes and may respond to glucose normalization.

Research Design And Methods: A prospective, parallel study in T2D (n=23) and controls (n=23) was undertaken. T2D subjects underwent insulin-induced blood glucose normalization from baseline 7.6±0.4 mmol/L (136.8±7.2 mg/dL) to 4.5±0.07 mmol/L (81±1.2 mg/dL) for 1 hour. Control subjects were maintained at 4.9±0.1 mmol/L (88.2±1.8 mg/dL). Slow Off-rate Modified Aptamer-scan plasma protein measurement determined a panel of HSPRPs.

Results: At baseline, E3-ubiquitin-protein ligase (carboxyl-terminus of Hsc70 interacting protein (CHIP) or HSPABP2) was lower (p=0.03) and ubiquitin-conjugating enzyme E2G2 higher (p=0.003) in T2D versus controls. Following glucose normalization, DnaJ homolog subfamily B member 1 (DNAJB1 or HSP40) was reduced (p=0.02) in T2D, with HSP beta-1 (HSPB1) and HSP-70-1A (HSP70-1A) (p=0.07 and p=0.09, respectively) also approaching significance relative to T2D baseline levels.

Conclusions: Key HSPRPs involved in critical protein interactions, CHIP and UBE2G2, were altered in diabetes at baseline. DNAJB1 fell in response to euglycemia, suggesting that HSPs are reacting to basal stress that could be mitigated by tight glucose control with reduction of glucose variability.
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http://dx.doi.org/10.1136/bmjdrc-2020-002057DOI Listing
April 2021

Regulation of circulating CTRP-2/CTRP-9 and GDF-8/GDF-15 by intralipids and insulin in healthy control and polycystic ovary syndrome women following chronic exercise training.

Lipids Health Dis 2021 Apr 19;20(1):34. Epub 2021 Apr 19.

Qatar Metabolic Institute, Department of Medicine and Academic Health System, Hamad Medical Corporation, Doha, Qatar.

Background: Polycystic ovary syndrome (PCOS) is associated with obesity, diabetes, and insulin resistance. The circulating C1Q/TNF-related proteins (CTRP-2, CTRP-9) and growth differentiation factors (GDF-8, GDF-15) contribute to glucose and lipid homeostasis. The effects of intralipids and insulin infusion on CTRP-2, CTRP-9, GDF-8 and GDF-15 in PCOS and control subjects before and after chronic exercise training were examined.

Methods: Ten PCOS and nine healthy subjects were studied at baseline status and after moderate-intensity chronic exercise training (1 h exercise, 3 times per week, 8 weeks). All participants were infused with 1.5 mL/min of saline or intralipids (20%) for 5 h, and during the last 2 h of saline or intralipids infusion hyperinsulinemic-euglycemic clamp (HIEC) was performed. CTRP-2, CTRP-9, GDF-8 and GDF-15 levels were measured at 0, 3 and 5 h.

Results: Intralipids dramatically increased CTRP-2 levels in PCOS (P = 0.02) and control (P = 0.004) subjects, which was not affected by insulin infusion or by exercise. Intralipids alone had no effects on CTRP-9, GDF-8, or GDF-15. Insulin increased the levels of GDF-15 in control subjects (P = 0.05) during the saline study and in PCOS subjects (P = 0.04) during the intralipid infusion. Insulin suppressed CTRP9 levels during the intralipid study in both PCOS (P = 0.04) and control (P = 0.01) subjects. Exercise significantly reduced fasting GDF-8 levels in PCOS (P = 0.03) and control (P = 0.04) subjects; however, intralipids infusion after chronic exercise training increased GDF-8 levels in both PCOS (P = 0.003) and control (P = 0.05) subjects and insulin infusion during intralipid infusion reduced the rise of GDF-8 levels.

Conclusion: This study showed that exogenous lipids modulate CTRP-2, which might have a physiological role in lipid metabolism. Since chronic exercise training reduced fasting GDF-8 levels; GDF-8 might have a role in humoral adaptation to exercise. GDF-15 and CTRP-9 levels are responsive to insulin, and thus they may play a role in insulin responses.
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http://dx.doi.org/10.1186/s12944-021-01463-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054421PMC
April 2021

Decoys as potential therapeutic tools for diabetes.

Drug Discov Today 2021 Apr 20. Epub 2021 Apr 20.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Current therapeutic approaches for diabetes are focused on improving glycemic control to prevent diabetes-related complications, but such approached are not completely successful. Decoy technologies such as decoy oligodeoxynucleotides (ODNs) and decoy peptides have emerged as therapeutic tools in diabetes. Decoy ODNs carry a DNA recognition motif for the binding of transcription factors in order to trap them and block their effects, whereas decoy peptides mimic the binding structure of the receptor protein, bind to the docking site of the target ligand, and prevent the interaction of the ligand and receptor. This review summarizes the technologies that have been developed to date and the studies that have investigated the therapeutic effects of decoy ODNs and peptides in diabetes.
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http://dx.doi.org/10.1016/j.drudis.2021.04.004DOI Listing
April 2021

Crocin Improves Oxidative Stress in Testicular Tissues of Streptozotocin-Induced Diabetic Rats.

Adv Exp Med Biol 2021 ;1308:273-281

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Crocin has been shown to have potent antioxidant properties, but its potential antioxidative effects on testicular tissue during uncontrolled diabetes is unknown. Wistar rats were randomly divided into four separate groups; normal, normal-treated, diabetic and diabetic treated (n = 6 per group). Diabetes was induced by a single intravenous injection of streptozotocin (45 mg/kg). Two treated groups of animals (diabetic and non-diabetic) received Crocin daily for 56 days (40 mg/kg/intraperitoneally). At the end of the 56th day, animals were sacrificed and blood and testicular tissue obtained. The level of nitrate, malondialdehyde, glutathione, and the activities of superoxide dismutase and catalase enzymes were determined. Crocin therapy moderated the increased oxidative stress in testicular tissue induced by diabetes with a significant reduction in nitrate and malondialdehyde, whilst reducing superoxide dismutase and catalase enzyme activities in diabetes (p < 0.001), though glutathione was unaffected. Treatment by Crocin in normal rats also modestly improved parameters of oxidative stress (p < 0.05). Crocin has a protective effect on diabetes induced oxidative stress in testicular tissue in an animal model, though it is unclear if this is a direct antioxidant effect.
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http://dx.doi.org/10.1007/978-3-030-64872-5_19DOI Listing
April 2021

Medicinal Plants and Phytochemicals Regulating Insulin Resistance and Glucose Homeostasis in Type 2 Diabetic Patients: A Clinical Review.

Adv Exp Med Biol 2021 ;1308:161-183

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Diabetes is a major health problem affecting more than four hundred million adults worldwide. The transition from normal glucose tolerance to type 2 diabetes (T2D) is preceded by increased Insulin resistance (IR), an independent predictor of the development of T2D in high risk (e.g. obese populations, pre-diabetes) individuals. Insulin deficiency resulting from increased IR results in progressive glucose homeostasis dysfunction. Data has shown that IR is affected by many different factors such as genetics, age, exercise, dietary nutrients, obesity, and body fat distribution. One of the most important factors is diet, which plays an essential role in addressing T2D and metabolic syndrome. Nutraceuticals and medicinal plants have been shown to have efficacy in preventing chronic diseases like cancer, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, diabetes mellitus and metabolic syndrome, likely through the anti-inflammatory properties found in nutraceuticals. However, the effect of these compounds, including traditional plant medicines, herbal formulations or their extracts on IR have not been systematically investigated. The objective of this review was to assess the reported effects of medicinal plants and bioactive natural compounds on IR. The findings confirm that most of the herbal bioactive compounds including resveratrol, garlic, curcumin, cinnamon, ginger, nuts, berberine, anthocyanin, soybean, flaxseed, vegetable oils, and soluble fibers have benefit in their efficacy for decreasing IR, fasting blood sugar (FBS), fasting insulin and HbA1c.
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http://dx.doi.org/10.1007/978-3-030-64872-5_13DOI Listing
April 2021

Therapeutic Effect of Curcumin in Women with Polycystic Ovary Syndrome Receiving Metformin: A Randomized Controlled Trial.

Adv Exp Med Biol 2021 ;1308:109-117

Department of Gynecology and Obstetrics, Iran University of Medical Sciences, Tehran, Iran.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, for which the insulin sensitizer metformin has been used therapeutically. It has been shown that curcumin also exhibits insulin-sensitizing properties. Given that metformin acts as an ovulation inducing agent and both curcumin and metformin can reduce insulin resistance, the aim of the current study was to evaluate the effect of metformin with and without curcumin nanomicelles in the treatment of women with polycystic ovary syndrome. This clinical trial was conducted on 100 women with PCOS, diagnosed according to the Rotterdam criteria, who were sequentially recruited and randomly divided into two groups (n = 50 each). Group 1 received 500 mg metformin three times daily and group 2 received 80 mg/day capsule of curcumin nanomicelle and 500 mg metformin three times a day for 3 months. After collecting fasting blood samples, biochemical parameters including triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, plasma glucose, alanine amino transferase (ALT) and aspartate aminotransferase (AST) were evaluated based on enzymatic methods. Hormonal parameters were assessed using immunoassay kits. Insulin resistance (HOMA-IR) and insulin-sensitivity check index (QUICKI) were also assessed. After treatment, fasting insulin, HOMA-IR, and total testosterone in group 2 were significantly lower than those in group 1 (p < 0.05). Post-treatment LDL-C levels in groups 1 and 2 were 117.9 ± 24 and 91.12 ± 19.46 mg/dL, respectively (p < 0.01). In addition, HDL-C levels were increased with curcumin (group 1: 38.1 ± 4.36 mg/dL; group 2: 44.12 ± 7.3 mg/dL, p < 0.05). Total cholesterol was decreased with curcumin level (group 1: 207.9 ± 39.84 mg/dL; group 2; 159.7 ± 48.43 mg/dL, p < 0.05), with a decrease in triglycerides levels (group 1: 141.6 ± 9.57; group 2: 97.5 ± 8.8 mg/dL, p < 0.01). This study showed that curcumin has a synergistic effect with metformin in the improvement of insulin resistance and lipid profile in patients with PCOS. Therefore, the combined use of metformin and curcumin may have therapeutic utility in patients with PCOS.
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http://dx.doi.org/10.1007/978-3-030-64872-5_9DOI Listing
April 2021

Platelet Protein-Related Abnormalities in Response to Acute Hypoglycemia in Type 2 Diabetes.

Front Endocrinol (Lausanne) 2021 30;12:651009. Epub 2021 Mar 30.

Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.

Introduction: Patients with severe COVID-19 infections have coagulation abnormalities indicative of a hypercoagulable state, with thromboembolic complications and increased mortality. Platelets are recognized as mediators of inflammation, releasing proinflammatory and prothrombotic factors, and are hyperactivated in COVID-19 infected patients. Activated platelets have also been reported in type 2 diabetes (T2D) patients, putting these patients at higher risk for thromboembolic complications of COVID-19 infection.

Methods: A case-control study of T2D (n=33) and control subjects (n=30) who underwent a hyperinsulinemic clamp to induce normoglycemia in T2D subjects: T2D: baseline glucose 7.5 ± 0.3mmol/l (135.1 ± 5.4mg/dl), reduced to 4.5 ± 0.07mmol/l (81 ± 1.2mg/dl) with 1-hour clamp; Controls: maintained at 5.1 ± 0.1mmol/l (91.9 ± 1.8mg/dl). Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was used to determine a panel of platelet proteins.

Results: Prothrombotic platelet proteins were elevated in T2D versus controls: platelet factor 4 (PF4, p<0.05); platelet glycoprotein VI (PGVI p<0.05); P-selectin (p<0.01) and plasminogen activator inhibitor I (PAI-1, p<0.01). In addition, the antithrombotic platelet-related proteins, plasmin (p<0.05) and heparin cofactor II (HCFII, p<0.05), were increased in T2D. Normalization of glucose in the T2D cohort had no effect on platelet protein levels.

Conclusion: T2D patients have platelet hyperactivation, placing them at higher risk for thromboembolic events. When infected with COVID-19, this risk may be compounded, and their propensity for a more severe COVID-19 disease course increased.

Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03102801, identifier NCT03102801.
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http://dx.doi.org/10.3389/fendo.2021.651009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043308PMC
April 2021

Association of Complement-Related Proteins in Subjects With and Without Second Trimester Gestational Diabetes.

Front Endocrinol (Lausanne) 2021 30;12:641361. Epub 2021 Mar 30.

Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar.

Introduction: Gestational Diabetes Mellitus (GDM) development is related to underlying metabolic syndrome that is associated with elevated complement C3 and C4. Elevated C3 levels have been associated with preeclampsia and the development of macrosomia.

Methods: This case-control study included 34 pregnant women with GDM and 16 non-diabetic (ND) women in their second trimester. Complement-related proteins were measured and correlated with demographic, biochemical, and pregnancy outcome data.

Results: GDM women were older with a higher BMI (p<0.001); complement C3, C4 and Factor-H were significantly elevated (p=0.001, p=0.05, p=0.01, respectively). When adjusted for age and BMI, Complement C3 (p=0.04) and Factor-H (p=0.04) remained significant. Partial correlation showed significant correlation between C4 with serum alanine aminotransferase (ALT) (p<0.05) and 2 term diastolic blood pressure (p<0.05); Factor-H and C-reactive protein (CRP; p<0.05). Pearson bivariate analysis revealed significant correlations between C3, C4, and Factor-H and CRP; p<0.05; C3 and gestational age at delivery (GA; p<0.05); C4 and ALT and second-trimester systolic blood pressure (STBP) (p=0.008 and p<0.05, respectively); Factor-H and glycated hemoglobin (HbA1c) (p<0.05). Regression analysis showed that the elevation of C3 could be accounted for by age, BMI, GA and CRP, with CRP being the most important predictor (p=0.02). C4 elevation could be accounted for by ALT, CRP and STBP. CRP predicted Factor-H elevation.

Conclusion: The increased C3, C4 and Factor-H during the second trimester of pregnancy in GDM are not independently associated with GDM; inflammation and high BMI may be responsible for their elevation. The elevation of second trimester C3 in GDM is associated with earlier delivery and further work is needed to determine if this is predictive.
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http://dx.doi.org/10.3389/fendo.2021.641361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043150PMC
March 2021

Time Till Viral Clearance of Severe Acute Respiratory Syndrome Coronavirus 2 Is Similar for Asymptomatic and Non-critically Symptomatic Individuals.

Front Med (Lausanne) 2021 26;8:616927. Epub 2021 Mar 26.

Royal College of Surgeons in Ireland, Manama, Bahrain.

Despite the modeled estimations of the burden of asymptomatic spread, the duration of viral positivity and infectiousness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains understudied. The objective of the present study was to estimate and compare the time till viral clearance of SARS-CoV-2 in asymptomatic and non-critical symptomatic individuals. We studied 184 SARS-CoV-2-positive participants, of whom 145 were asymptomatic. Our analysis uncovered that time till viral negativity is similar for subclinical [median time till viral clearance: 11 days, interquartile range (IQR): 8, 14] and overt infections (median: 11 days, IQR: 9, 14) after controlling for age and sex. This has implications in understanding the period of infectivity for SARS-CoV-2 in order to plan adequate public health measures to control the community spread.
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http://dx.doi.org/10.3389/fmed.2021.616927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032858PMC
March 2021

Potential Alteration of Statin-Related Pharmacological Features in Diabetes Mellitus.

Biomed Res Int 2021 26;2021:6698743. Epub 2021 Mar 26.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Objective: Type 2 diabetes mellitus is a chronic metabolic disease caused by insulin resistance or insulin deficiency resulting in elevated blood glucose levels. Poorly controlled diabetes is associated with the development of cardiovascular disease and dyslipidemia. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statin) are an important class of therapeutic agents used to control hyperlipidemia and prevent cardiovascular disease in diabetic and nondiabetic patients. Since the effect of diabetes on the pharmacokinetics and pharmacodynamics of drugs and toxins has been shown, the aim was to review previous studies on the efficacy of statins such as atorvastatin, simvastatin, pravastatin, pitavastatin, fluvastatin, and rosuvastatin in clinical and preclinical studies in both diabetic and nondiabetic groups.

Method: For this purpose, Web of Science, PubMed, Scopus, and Google Scholar databases were reviewed, and related English articles published until October 2020 were included in this review article.

Results: The findings revealed that diabetes affected statin effectiveness through changes in pharmacokinetic parameters such as clearance and biotransformation biomarkers at mRNA and protein levels. Plasma and serum concentrations of statins were accompanied by alteration in cellular activities including oxidative stress, Akt inhibition, and endothelial nitric oxide synthase (eNOS) and phosphorylation that were reflected in changes in the adverse drug reaction profile of the differing statins.

Conclusion: Given that dyslipidemia frequently accompanies diabetes and statin therapy is common, more clinical studies are needed regarding the effects of diabetes on the effectiveness of these drugs.
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http://dx.doi.org/10.1155/2021/6698743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018846PMC
March 2021

Comparing Levels of Metabolic Predictors of Coronary Heart Disease between Healthy Lean and Overweight Females.

Metabolites 2021 Mar 15;11(3). Epub 2021 Mar 15.

Biomedical Research Center, Qatar University, P. O. Box 2713 Doha, Qatar.

Screening for the metabolomic signature of coronary heart disease (CHD) before disease onset could help in early diagnosis and potentially disease prevention. In this study, the levels of 17 CHD metabolic biomarkers in apparently healthy overweight females were compared to lean counterparts, and their associations with conventional clinical risk factors were determined. Clinical and metabolic data from 200 apparently healthy non-obese Qatari females were collected from Qatar Biobank (discovery cohort). Logistic regression was used to assess the association between body mass index (BMI) groups and 17 CHD metabolic biomarkers, and receiver operating characteristic (ROC) analysis was used to evaluate the prognostic value of CHD metabolic biomarkers in overweight. Stepwise linear regression was performed to identify the classical risk factors associated with CHD metabolites differentiating the two BMI groups. Validation of the association of CHD metabolic biomarkers with BMI groups was performed in 107 subjects (replication cohort). Out of the tested CHD metabolic biomarkers, five were significantly different between lean and overweight females in the discovery cohort (AUC = 0.73). Among these, the association of mannose, asparagine, and linoleate with BMI groups was confirmed in the replication cohort (AUC = 0.97). Significant correlations between predictors of CHD in overweight healthy women and classical risk factors were observed, including serum levels of cholesterol, testosterone, triiodothyronine, thyroxine, creatinine, albumin, bilirubin, glucose, c-peptide, uric acid, calcium and chloride. Apparently, healthy overweight females exhibit significantly different levels of specific CHD metabolites compared to their lean counterparts, offering a prognostic potential with preventative value.
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http://dx.doi.org/10.3390/metabo11030169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999722PMC
March 2021

Glucose excursions in type 2 diabetes modulate amyloid-related proteins associated with dementia.

J Transl Med 2021 03 31;19(1):131. Epub 2021 Mar 31.

Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.

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http://dx.doi.org/10.1186/s12967-021-02797-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011191PMC
March 2021

Vitamin D deficiency effects on cardiovascular parameters in women with polycystic ovary syndrome: A retrospective, cross-sectional study.

J Steroid Biochem Mol Biol 2021 Mar 27;211:105892. Epub 2021 Mar 27.

Royal College of Surgeons Ireland in Bahrain, Bahrain. Electronic address:

Purpose: Polycystic ovary syndrome (PCOS) is associated with vitamin D deficiency (25-hydroxyvitamin D (25(OH)D), and both are associated with increased cardiovascular risk; therefore, the combination of PCOS and moderate vitamin D deficiency may exacerbate the cardiovascular and metabolic characteristics in women with PCOS. This study sought to address this question.

Methods: In this retrospective, cross-sectional study, demographic and metabolic data from women aged 18-40 years from the Qatar Biobank (QBB) (78 diagnosed with PCOS, 641 controls) was analyzed.

Results: Moderate vitamin D deficiency was seen in both normal and PCOS cohorts irrespective of body mass index (BMI) stratification into normal, overweight and obese. Significant differences in free androgen index (FAI) and high density lipoproteins (HDL) (p < 0.05) were seen in PCOS irrespective of BMI, though insulin resistance and increased C-reactive protein (CRP) (p < 0.05) were seen only in obese PCOS subjects; however, there was no correlation (Pearson coefficient) of any these parameters with vitamin D for women with or without PCOS, nor when vitamin D deficiency was compared to vitamin D insufficiency (above and below 20 ng/mL, respectively) between the normal and PCOS groups.

Conclusion: Moderate vitamin D deficiency did not associate with nor exacerbate insulin resistance, androgen levels, inflammation or cardiovascular risk indices in women with PCOS, suggesting that a prospective study on vitamin D deficiency to confirm non-causality is required.
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http://dx.doi.org/10.1016/j.jsbmb.2021.105892DOI Listing
March 2021

Identification of macrophage activation-related biomarkers in obese type 2 diabetes that may be indicative of enhanced respiratory risk in COVID-19.

Sci Rep 2021 03 19;11(1):6428. Epub 2021 Mar 19.

Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.

Hyperactivation of the immune system through obesity and diabetes may enhance infection severity complicated by Acute Respiratory Distress Syndrome (ARDS). The objective was to determine the circulatory biomarkers for macrophage activation at baseline and after serum glucose normalization in obese type 2 diabetes (OT2D) subjects. A case-controlled interventional pilot study in OT2D (n = 23) and control subjects (n = 23). OT2D subjects underwent hyperinsulinemic clamp to normalize serum glucose. Plasma macrophage-related proteins were determined using Slow Off-rate Modified Aptamer-scan plasma protein measurement at baseline (control and OT2D subjects) and after 1-h of insulin clamp (OT2D subjects only). Basal M1 macrophage activation was characterized by elevated levels of M1 macrophage-specific surface proteins, CD80 and CD38, and cytokines or chemokines (CXCL1, CXCL5, RANTES) released by activated M1 macrophages. Two potent M1 macrophage activation markers, CXCL9 and CXCL10, were decreased in OT2D. Activated M2 macrophages were characterized by elevated levels of plasma CD163, TFGβ-1, MMP7 and MMP9 in OT2D. Conventional mediators of both M1 and M2 macrophage activation markers (IFN-γ, IL-4, IL-13) were not altered. No changes were observed in plasma levels of M1/M2 macrophage activation markers in OT2D in response to acute normalization of glycemia. In the basal state, macrophage activation markers are elevated, and these reflect the expression of circulatory cytokines, chemokines, growth factors and matrix metalloproteinases in obese individuals with type 2 diabetes, that were not changed by glucose normalisation. These differences could potentially predispose diabetic individuals to increased infection severity complicated by ARDS. Clinical trial reg. no: NCT03102801; registration date April 6, 2017.
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http://dx.doi.org/10.1038/s41598-021-85760-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979696PMC
March 2021

Correction to: COVID-19 biomarkers for severity mapped to polycystic ovary syndrome.

J Transl Med 2021 Mar 15;19(1):106. Epub 2021 Mar 15.

Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.

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http://dx.doi.org/10.1186/s12967-021-02782-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959273PMC
March 2021

Vitamin D Association With Macrophage-Derived Cytokines in Polycystic Ovary Syndrome: An Enhanced Risk of COVID-19 Infection?

Front Endocrinol (Lausanne) 2021;12:638621. Epub 2021 Feb 25.

Research Department, Royal College of Surgeons of Ireland, Manama, Bahrain.

Background: Women with polycystic ovary syndrome (PCOS) often have vitamin D deficiency, a known risk factor for severe COVID-19 disease. Alveolar macrophage-derived cytokines contribute to the inflammation underlying pulmonary disease in COVID-19. We sought to determine if basal macrophage activation, as a risk factor for COVID-19 infection, was present in PCOS and, if so, was further enhanced by vitamin D deficiency.

Methods: A cross-sectional study in 99 PCOS and 68 control women who presented sequentially. Plasma levels of a macrophage-derived cytokine panel were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. Vitamin D was measured by tandem mass spectroscopy.

Results: Vitamin D was lower in PCOS women (p<0.0001) and correlated negatively with body mass index (BMI) in PCOS (r=0.28, p=0.0046). Basal macrophage activation markers CXCL5, CD163 and MMP9 were elevated, whilst protective CD200 was decreased (p<0.05); changes in these variables were related to, and fully accounted for, by BMI. PCOS and control women were then stratified according to vitamin D concentration. Vitamin D deficiency was associated with decreased CD80 and IFN-γ in PCOS and IL-12 in both groups (p<0.05). These factors, important in initiating and maintaining the immune response, were again accounted for by BMI.

Conclusion: Basal macrophage activation was higher in PCOS with macrophage changes related with increased infection risk associating with vitamin D; all changes were BMI dependent, suggesting that obese PCOS with vitamin D deficiency may be at greater risk of more severe COVID-19 infection, but that it is obesity-related rather than an independent PCOS factor.
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http://dx.doi.org/10.3389/fendo.2021.638621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947877PMC
March 2021

Metabolic consequences of obesity on the hypercoagulable state of polycystic ovary syndrome.

Sci Rep 2021 Mar 5;11(1):5320. Epub 2021 Mar 5.

Royal College of Surgeons in Ireland Bahrain, Adliya, Kingdom of Bahrain.

Polycystic ovary syndrome (PCOS) women have a hypercoagulable state; however, whether this is intrinsically due to PCOS or, alternatively, a consequence of its metabolic complications is unclear. We determined plasma coagulation pathway protein levels in PCOS (n = 146) and control (n = 97) women recruited to a PCOS biobank. Circulating levels of a panel of 18 clotting pathway proteins were determined by Slow Off-rate Modified Aptamer-scan plasma protein measurement. Cohorts were age matched, though PCOS had elevated body mass index (p < 0.001), insulin (p < 0.001) and C-reactive protein (CRP) (p < 0.0001). Eight pro-coagulation proteins were elevated in PCOS: plasminogen activator inhibitor-1 (p < 0.0001), fibrinogen (p < 0.01), fibrinogen gamma chain (p < 0.0001), fibronectin (p < 0.01), von Willebrand factor (p < 0.05), D-dimer (p < 0.0001), P-selectin (p < 0.05), and plasma kallikrein (p < 0.001). However, two anticoagulant proteins, vitamin K-dependent protein-S (p < 0.0001) and heparin cofactor-II (p < 0.001) were elevated and prothrombin was decreased (p < 0.05). CRP, as a marker of inflammation, and insulin resistance (HOMA-IR) correlated with 11 and 6 of the clotting proteins, respectively (p < 0.05). When matched for BMI < 25 (16 PCOS, 53 controls) HOMA-IR remained elevated (p < 0.05) and heparin cofactor-II was increased (p < 0.05). In a multivariate analysis accounting for inflammation, insulin resistance and BMI, there was no correlation of PCOS with any of the coagulation proteins. The hypercoagulable state in PCOS is not intrinsic to the disease as it can be fully accounted for by BMI, inflammation and insulin resistance.
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http://dx.doi.org/10.1038/s41598-021-84586-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935919PMC
March 2021

apoA2 correlates to gestational age with decreased apolipoproteins A2, C1, C3 and E in gestational diabetes.

BMJ Open Diabetes Res Care 2021 Mar;9(1)

Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar.

Introduction: Pregnant women with gestational diabetes mellitus (GDM) are at risk of adverse outcomes, including gestational hypertension, pre-eclampsia, and preterm delivery. This study was undertaken to determine if apolipoprotein (apo) levels differed between pregnant women with and without GDM and if they were associated with adverse pregnancy outcome.

Research Design And Methods: Pregnant women (46 women with GDM and 26 women without diabetes (ND)) in their second trimester were enrolled in the study. Plasma apos were measured and correlated to demographic, biochemical, and pregnancy outcome data.

Results: apoA2, apoC1, apoC3 and apoE were lower in women with GDM compared with control women (p=0.0019, p=0.0031, p=0.0002 and p=0.015, respectively). apoA1, apoB, apoD, apoH, and apoJ levels did not differ between control women and women with GDM. Pearson bivariate analysis revealed significant correlations between gestational age at delivery and apoA2 for women with GDM and control women, and between apoA2 and apoC3 concentrations and C reactive protein (CRP) as a measure of inflammation for the whole group.

Conclusions: Apoproteins apoA2, apoC1, apoC3 and apoE are decreased in women with GDM and may have a role in inflammation, as apoA2 and C3 correlated with CRP. The fact that apoA2 correlated with gestational age at delivery in both control women and women with GDM raises the hypothesis that apoA2 may be used as a biomarker of premature delivery, and this warrants further investigation.
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http://dx.doi.org/10.1136/bmjdrc-2020-001925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938976PMC
March 2021

The high prevalence of asymptomatic SARS-CoV-2 infection reveals the silent spread of COVID-19.

Int J Infect Dis 2021 Apr 26;105:656-661. Epub 2021 Feb 26.

Royal College of Surgeons in Ireland, Bahrain; Bahrain Defence Force Hospital, Bahrain. Electronic address:

Purpose: The COVID-19 pandemic has led to over 92 million cases and 1.9 million deaths worldwide since its outbreak. Public health responses have focused on identifying symptomatic individuals to halt spread. However, evidence is accruing that asymptomatic individuals are infectious and contributing to this global pandemic.

Methods: Observational data of 320 index cases and their 1289 positive contacts from the National COVID-19 Database in Bahrain were used to analyze symptoms, infectivity rate and PCR Cycle threshold (Ct) values.

Results: No significant difference (p = 1.0) in proportions of symptomatic (n = 160; 50.0%) and asymptomatic index cases (n = 160; 50.0%) were seen; however, SARS-CoV-2 positive contact cases were predominantly asymptomatic (n = 1127, 87.4%). Individuals aged 0-19 years constituted a larger proportion of positive contact cases (20.8%) than index cases (4.7%; p < 0.001). A total of 22% of the positive contacts were infected by symptomatic male index cases aged between 30-39 years. The total numbers of exposed contacts (p = 0.33), infected contacts (p = 0.81) and hence infectivity rate (p = 0.72) were not different between symptomatic and asymptomatic index cases. PCR Ct values were higher in asymptomatic compared to symptomatic index cases (p < 0.001), and higher in asymptomatic compared to symptomatic positive contacts (p < 0.001). No differences between the infectivity rates of index cases with Ct values <30 and values ≥30 were observed (p = 0.13).

Conclusion: These data reveal that the high asymptomatic incidence of SARS-CoV-2 infection in Bahrain and subsequent positive contacts from an index case were more likely to be asymptomatic, showing the high "silent" risk of transmission and need for comprehensive screening for each positive infection to help halt the ongoing pandemic.
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http://dx.doi.org/10.1016/j.ijid.2021.02.100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908846PMC
April 2021

Biomarkers of COVID-19 severity may not serve patients with polycystic ovary syndrome.

J Transl Med 2021 02 11;19(1):63. Epub 2021 Feb 11.

Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.

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http://dx.doi.org/10.1186/s12967-021-02723-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876982PMC
February 2021

The relationship of soluble neuropilin-1 to severe COVID-19 risk factors in polycystic ovary syndrome.

Metabol Open 2021 Mar 18;9:100079. Epub 2021 Jan 18.

Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.

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http://dx.doi.org/10.1016/j.metop.2021.100079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834728PMC
March 2021

Relationship between total vitamin D metabolites and complications in patients with type 2 diabetes.

Biomed Rep 2021 Jan 23;14(1):18. Epub 2020 Nov 23.

Royal College of Surgeons in Ireland, P.O. Box 15503, Manama, Bahrain.

In our previous study, it was shown that endogenous vitamin D and its metabolites are associated with diabetic microvascular complications and cardiovascular risk factors. The aim of the present study was to determine if the relationship between total vitamin D (vitamin D supplements plus endogenous vitamin D) was a better predictor of complications in type 2 diabetes (T2DM). A total of 460 patients with T2DM participated in the present cross-sectional study. Plasma levels of total vitamin D and its metabolites (1,25-dihydroxyvitamin D (1,25(OH)D), 25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D (24,25(OH)D) were measured by isotope-dilution liquid chromatography tandem mass spectrometry analysis. 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D were associated with diabetic retinopathy and coronary artery disease, but total 1,25-dihydroxyvitamin D and total 25-hydroxyvitamin D levels were not statistically associated with any complications. Total 1,25-dihydroxyvitamin D showed the same positive association as 1,25-dihydroxyvitamin D for hypertension and dyslipidemia, and total 25-hydroxyvitamin D showed the same positive association as 25-hydroxyvitamin D for dyslipidemia. Total 24,25-dihydroxyvitamin D showed the same positive association only with dyslipidemia as did 24,25-dihydroxyvitamin D. However, total 25-hydroxyvitamin D was associated with hypertension, whereas 25-hydroxyvitamin D was not. Vitamin D metabolites were associated with diabetic retinopathy, whereas total vitamin D levels were not, suggesting that endogenous vitamin D metabolites are a better measure of diabetic microvascular complications. However, both total vitamin D and vitamin D metabolites were associated with cardiovascular risk factors in patients with type 2 diabetes.
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http://dx.doi.org/10.3892/br.2020.1394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716709PMC
January 2021

Mapping of type 2 diabetes proteins to COVID-19 biomarkers: A proteomic analysis.

Metabol Open 2021 Mar 13;9:100074. Epub 2020 Dec 13.

Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.

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http://dx.doi.org/10.1016/j.metop.2020.100074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753193PMC
March 2021

COVID-19 biomarkers for severity mapped to polycystic ovary syndrome.

J Transl Med 2020 12 22;18(1):490. Epub 2020 Dec 22.

Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.

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http://dx.doi.org/10.1186/s12967-020-02669-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753500PMC
December 2020

Relationship between a single measurement at baseline of body mass index, glycated hemoglobin, and the risk of mortality and cardiovascular morbidity in type 2 diabetes mellitus.

Cardiovasc Endocrinol Metab 2020 Dec 25;9(4):177-182. Epub 2020 May 25.

Department of Research, Royal College of Surgeons in Ireland and Medical University of Bahrain, Busaiteen, Bahrain.

Objective: This study aims to evaluate the relationship between a single measurement at baseline of body mass index (BMI), glycated hemoglobin (HbA1c) and subsequent clinical outcomes in patients with type 2 diabetes mellitus (T2DM).

Method: Patients with T2DM were recruited from an outpatient diabetes clinic in a single large teaching hospital in Kingston upon Hull, UK. At baseline, demographics and HbA1c were recorded. Patients were categorized by BMI: normal weight (18.5-24.9 kg/m), overweight (25-29.9 kg/m), and obese (>30 kg/m). Multivariable Cox regression models that included demographic, risk factors, and comorbidities were separately constructed for all-cause, cardiovascular, cancer and sepsis-related mortality, using four groups of HbA1c (<6%, 6.0-6.9%, 7.0-7.9%, and >8%).

Results: In total, 6220 patients with T2DM (median age 62 years, 54% male) were followed for a median of 10.6 years. HbA1c levels >8.0% were associated with increased risk of all-cause mortality and cardiovascular death. However, this increased risk was not consistent across the weight categories and reached statistical significance only in overweight patients (BMI 25-29.9 kg/m).

Conclusions: In a large cohort of patients with T2DM elevated HbA1c levels at baseline did not consistently predict increased risk of all-cause and cardiovascular mortality across the different BMI categories.
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http://dx.doi.org/10.1097/XCE.0000000000000202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673766PMC
December 2020

The prevalence of asymptomatic and symptomatic COVID-19 in a cohort of quarantined subjects.

Int J Infect Dis 2021 Jan 3;102:285-288. Epub 2020 Nov 3.

Royal College of Surgeons, Bahrain. Electronic address:

Background: The frequency of asymptomatic SARS-CoV-2 infection with viral spread is unclear. Asymptomatic SARS-CoV-2 infection development and progression was investigated in subjects undergoing mandatory quarantine on airport arrival.

Methods: 2714 subjects were tested for SARS-CoV-2 and all were quarantined for 2 weeks. Viral retesting was undertaken on symptom development and routinely at 14 days if asymptomatic. Asymptomatic, positive patients underwent viral testing every 2 days to determine viral clearance.

Results: 188/2714 (6.9%) patients became SARS-CoV-2 positive. On arrival, 136/188 tested positive, with 44/188 (23.4%) symptomatic and 92/188 (48.9%) asymptomatic. All 92 patients remained asymptomatic and were retested every 2 days until viral clearance. 2526 quarantined subjects remained virus free at 14 days. Viral clearance did not differ between symptomatic and asymptomatic patients (12.6 ± 1.0 days and 12.1 ± 0.4 days, respectively). Of the 52/188 (27.7%) testing negative on arrival, 27/52 subsequently became positive and developed symptoms 2-13 days after arrival. 25/188 (13.3%) remained asymptomatic and tested positive at day 14, with viral testing undertaken every 2 days in these subjects; of these, 24 remained asymptomatic, with viral clearance at 9.4 ± 0.7 days - less than for those who were asymptomatic on arrival (p < 0.002).

Conclusion: Asymptomatic patients with COVID-19 were more prevalent than those exhibiting symptoms, and are an infection reservoir.
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http://dx.doi.org/10.1016/j.ijid.2020.10.091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607262PMC
January 2021

Do biomarkers of COVID-19 severity simply reflect a stress response in type 2 diabetes: Biomarker response to hypoglycemia.

Metabolism 2021 01 4;114:154417. Epub 2020 Nov 4.

Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar. Electronic address:

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http://dx.doi.org/10.1016/j.metabol.2020.154417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609242PMC
January 2021