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Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study.
Holman, N, Knighton, P, Kar, P, O'Keefe, J, Curley, M, Weaver, A, Barron, E, Bakhai, C, Khunti, K, Wareham, NJ, et al
The lancet. Diabetes & endocrinology. 2020;8(10):823-833
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Plain language summary
Diabetes, cardiovascular disease, and hypertension are the most common chronic conditions predisposing people to severe COVID-19 disease. The aim of this population-based cohort study, using data from 98% of general practices in England, was to investigate the associations between various risk factors, including poor blood sugar control, and COVID-19-related deaths in people with type 1 and type 2 diabetes. Between Feb 16 and May 11, 2020, 1604 people with type 1 diabetes and 36 291 people with type 2 diabetes died from all causes, of which almost 30% had COVID-19 listed on the death certificate, either a primary underlying or secondary cause of death. Male gender, age and being of Black or Asian ethnicity were associated with an increased mortality from COVID-19. Poor blood sugar control, as determined by HbA1C, prior to infection was strongly associated with COVID-19-related death, independent of other risk factors. Obesity (BMI of 30 or over) as well as being underweight were also significantly associated with COVID-19 mortality. The authors discuss that people with diabetes are at increased risk of many serious infections and that high blood glucose levels are known to impair immunity and may amplify the hyperimmune response associated with severe COVID-19.
Abstract
BACKGROUND Diabetes has been associated with increased COVID-19-related mortality, but the association between modifiable risk factors, including hyperglycaemia and obesity, and COVID-19-related mortality among people with diabetes is unclear. We assessed associations between risk factors and COVID-19-related mortality in people with type 1 and type 2 diabetes. METHODS We did a population-based cohort study of people with diagnosed diabetes who were registered with a general practice in England. National population data on people with type 1 and type 2 diabetes collated by the National Diabetes Audit were linked to mortality records collated by the Office for National Statistics from Jan 2, 2017, to May 11, 2020. We identified the weekly number of deaths in people with type 1 and type 2 diabetes during the first 19 weeks of 2020 and calculated the percentage change from the mean number of deaths for the corresponding weeks in 2017, 2018, and 2019. The associations between risk factors (including sex, age, ethnicity, socioeconomic deprivation, HbA1c, renal impairment [from estimated glomerular filtration rate (eGFR)], BMI, tobacco smoking status, and cardiovascular comorbidities) and COVID-19-related mortality (defined as International Classification of Diseases, version 10, code U07.1 or U07.2 as a primary or secondary cause of death) between Feb 16 and May 11, 2020, were investigated by use of Cox proportional hazards models. FINDINGS Weekly death registrations in the first 19 weeks of 2020 exceeded the corresponding 3-year weekly averages for 2017-19 by 672 (50·9%) in people with type 1 diabetes and 16 071 (64·3%) in people with type 2 diabetes. Between Feb 16 and May 11, 2020, among 264 390 people with type 1 diabetes and 2 874 020 people with type 2 diabetes, 1604 people with type 1 diabetes and 36 291 people with type 2 diabetes died from all causes. Of these total deaths, 464 in people with type 1 diabetes and 10 525 in people with type 2 diabetes were defined as COVID-19 related, of which 289 (62·3%) and 5833 (55·4%), respectively, occurred in people with a history of cardiovascular disease or with renal impairment (eGFR <60 mL/min per 1·73 m2). Male sex, older age, renal impairment, non-white ethnicity, socioeconomic deprivation, and previous stroke and heart failure were associated with increased COVID-19-related mortality in both type 1 and type 2 diabetes. Compared with people with an HbA1c of 48-53 mmol/mol (6·5-7·0%), people with an HbA1c of 86 mmol/mol (10·0%) or higher had increased COVID-19-related mortality (hazard ratio [HR] 2·23 [95% CI 1·50-3·30, p<0·0001] in type 1 diabetes and 1·61 [1·47-1·77, p<0·0001] in type 2 diabetes). In addition, in people with type 2 diabetes, COVID-19-related mortality was significantly higher in those with an HbA1c of 59 mmol/mol (7·6%) or higher than in those with an HbA1c of 48-53 mmol/mol (HR 1·22 [95% CI 1·15-1·30, p<0·0001] for 59-74 mmol/mol [7·6-8·9%] and 1·36 [1·24-1·50, p<0·0001] for 75-85 mmol/mol [9·0-9·9%]). The association between BMI and COVID-19-related mortality was U-shaped: in type 1 diabetes, compared with a BMI of 25·0-29·9 kg/m2, a BMI of less than 20·0 kg/m2 had an HR of 2·45 (95% CI 1·60-3·75, p<0·0001) and a BMI of 40·0 kg/m2 or higher had an HR of 2·33 (1·53-3·56, p<0·0001); the corresponding HRs for type 2 diabetes were 2·33 (2·11-2·56, p<0·0001) and 1·60 (1·47-1·75, p<0·0001). INTERPRETATION Deaths in people with type 1 and type 2 diabetes rose sharply during the initial COVID-19 pandemic in England. Increased COVID-19-related mortality was associated not only with cardiovascular and renal complications of diabetes but, independently, also with glycaemic control and BMI. FUNDING None.
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The circulating metabolome of human starvation.
Steinhauser, ML, Olenchock, BA, O'Keefe, J, Lun, M, Pierce, KA, Lee, H, Pantano, L, Klibanski, A, Shulman, GI, Clish, CB, et al
JCI insight. 2018;(16)
Abstract
The human adaptive starvation response allows for survival during long-term caloric deprivation. Whether the physiology of starvation is adaptive or maladaptive is context dependent: activation of pathways by caloric restriction may promote longevity, yet in the context of caloric excess, the same pathways may contribute to obesity. Here, we performed plasma metabolite profiling of longitudinally collected samples during a 10-day, 0-calorie fast in humans. We identify classical milestones in adaptive starvation, including the early consumption of gluconeogenic amino acids and the subsequent surge in plasma nonesterified fatty acids that marks the shift from carbohydrate to lipid metabolism, and demonstrate findings, including (a) the preferential release of unsaturated fatty acids and an associated shift in plasma lipid species with high degrees of unsaturation and (b) evidence that acute, starvation-mediated hypoleptinemia may be a driver of the transition from glucose to lipid metabolism in humans.
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Lifestyle modification in the prevention and treatment of atrial fibrillation.
Menezes, AR, Lavie, CJ, De Schutter, A, Milani, RV, O'Keefe, J, DiNicolantonio, JJ, Morin, DP, Abi-Samra, FM
Progress in cardiovascular diseases. 2015;(2):117-25
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Abstract
Atrial fibrillation (AF) is the most common arrhythmia worldwide and has a significant impact on morbidity and mortality. Additionally, the incidence and prevalence of AF is expected to increase in the United States and worldwide over the next few decades. While the pathophysiology concerning the development of AF is not completely understood, multiple modifiable, as well as non-modifiable risk factors, for AF development have been discovered. The goal of this paper is to provide an overview of the modifiable risk factors that contribute to the development and recurrence of AF, in addition to discussing potential lifestyle changes that may aid in the prevention and treatment of AF.
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Atrial fibrillation in the 21st century: a current understanding of risk factors and primary prevention strategies.
Menezes, AR, Lavie, CJ, DiNicolantonio, JJ, O'Keefe, J, Morin, DP, Khatib, S, Milani, RV
Mayo Clinic proceedings. 2013;(4):394-409
Abstract
Atrial fibrillation (AF) is the most common arrhythmia worldwide, and it has a significant effect on morbidity and mortality. It is a significant risk factor for stroke and peripheral embolization, and it has an effect on cardiac function. Despite widespread interest and extensive research on this topic, our understanding of the etiology and pathogenesis of this disease process is still incomplete. As a result, there are no set primary preventive strategies in place apart from general cardiology risk factor prevention goals. It seems intuitive that a better understanding of the risk factors for AF would better prepare medical professionals to initially prevent or subsequently treat these patients. In this article, we discuss widely established risk factors for AF and explore newer risk factors currently being investigated that may have implications in the primary prevention of AF. For this review, we conducted a search of PubMed and used the following search terms (or a combination of terms): atrial fibrillation, metabolic syndrome, obesity, dyslipidemia, hypertension, type 2 diabetes mellitus, omega-3 fatty acids, vitamin D, exercise toxicity, alcohol abuse, and treatment. We also used additional articles that were identified from the bibliographies of the retrieved articles to examine the published evidence for the risk factors of AF.
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Erectile dysfunction and cardiovascular disease.
Menezes, A, Artham, S, Lavie, CJ, Milani, RV, O'Keefe, J
Postgraduate medicine. 2011;(3):7-16
Abstract
Cardiovascular disease (CVD) and erectile dysfunction (ED) are 2 closely intertwined disease processes. Over the past 2 decades, there have been many studies that have linked both conditions and established ED as a risk factor for CVD. In the United States and worldwide, a large population of adult men has ED and/or CVD. Worldwide, approximately 140 million men have ED, and the number is expected to double in the next 15 years. Because ED and CVD share many of the same risk factors, the relationship between CVD and ED is a very valid concern. Our goal is to examine the association and pathophysiological relationship between ED and CVD. We will also review common risk factors, current treatments, and management of the 2 conditions. Finally, we will discuss the risks of sexual activity in patients who have CVD.
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Societal interactions in ovarian cancer metastasis: a quorum-sensing hypothesis.
Hickson, J, Diane Yamada, S, Berger, J, Alverdy, J, O'Keefe, J, Bassler, B, Rinker-Schaeffer, C
Clinical & experimental metastasis. 2009;(1):67-76
Abstract
The biochemical and biological mechanisms metastatic cancer cells use to function as communities and thwart internal and external growth control mechanisms remain undefined. In this work, we present the hypothesis that cancer cells may use a Quorum-Sensing mechanism to regulate multicellular functions and control steps in metastatic colonization. Quorum sensing is a bacterial cell-cell communication process used to track increasing cell-population density and, in response to changes in cell number, coordinate gene expression and behavior on a community-wide scale. Important parallels between the behavior of societies of bacterial cells and societies of malignant cancer cells exist in the bacterial literature. Of relevance to metastasis is the finding that pathogenic bacteria use quorum sensing to determine when their population numbers are high enough to collectively form biofilms in or on host organisms. Biofilms are complex, heterogeneous communities of bacterial cells encased within an extracellular matrix attached to a solid surface. Biofilms exacerbate disease and are refractory to a battery of therapies. We suggest that the quorum-sensing-controlled bacterial biofilm formation process closely parallels the steps in metastatic colonization. Cells migrate toward/on target surfaces (organ-specific homing), show cell-cell and cell-matrix interactions (tumor cell-stromal cell crosstalk), remain subclinical until they can mount an effective attack (dormancy), form complex structures with channels for nutrient flow (vascularized lesions), and contain resistant cells which can cause disease recurrence (persistors). Using ovarian cancer as an example, we present data supporting the connection between metastatic colonization and quorum sensing and discuss the implications for understanding and controlling metastasis formation.