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Menopause-Associated Lipid Metabolic Disorders and Foods Beneficial for Postmenopausal Women.
Ko, SH, Kim, HS
Nutrients. 2020;12(1)
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Menopause is the absence of menstruation due to the loss of ovarian activity with ageing. During this transition period, changes in hormones, primarily the decline in the oestrogen estradiol, give rise to altered lipid metabolism. An unfavourable lipid profile presents a risk for metabolic disorders, such as cardiovascular diseases and type 2 diabetes. Post-menopausal changes also lead to shifts in body fat and fat distribution, resulting in an increased tendency for central fat accumulation and obesity. Obesity is associated with insulin resistance. This susceptibility for weight accumulation is possibly also driven by the age-associated decline in skeletal muscle, which reduces metabolic energy expenditure. This review summarizes the physiology of menopause and postmenopause and the consequential impact on lipid metabolism. In addition, there is a discussion of dietary recommendations, nutritional and plant-derived compounds that could support the management of menopause associated changes in lipid levels, metabolic risk factors and obesity. The recommendations discussed include traditional healthy diets and low-calorie diets, with attention drawn to adequate protein intake. Furthermore, the role of probiotics, nutritional and plant-sourced constituents are considered, including Vitamin D, Omega-3 fatty acids, antioxidants like Vitamin A, β-carotene, Vitamin C and E, genistein, resveratrol, flavonoids, indoles and capsaicin. The authors advocate sourcing these compounds from a varied whole-foods diet, which would minimize nutrient interactions and absorption issues that can occur with supplementation. This review may be of interest to those supporting the nutritional needs of menopausal and post-menopausal women, that are experiencing or are at risk of experiencing metabolic disorders.
Abstract
Menopause is clinically diagnosed as a condition when a woman has not menstruated for one year. During the menopausal transition period, there is an emergence of various lipid metabolic disorders due to hormonal changes, such as decreased levels of estrogens and increased levels of circulating androgens; these may lead to the development of metabolic syndromes including cardiovascular diseases and type 2 diabetes. Dysregulation of lipid metabolism affects the body fat mass, fat-free mass, fatty acid metabolism, and various aspects of energy metabolism, such as basal metabolic ratio, adiposity, and obesity. Moreover, menopause is also associated with alterations in the levels of various lipids circulating in the blood, such as lipoproteins, apolipoproteins, low-density lipoproteins (LDLs), high-density lipoproteins (HDL) and triacylglycerol (TG). Alterations in lipid metabolism and excessive adipose tissue play a key role in the synthesis of excess fatty acids, adipocytokines, proinflammatory cytokines, and reactive oxygen species, which cause lipid peroxidation and result in the development of insulin resistance, abdominal adiposity, and dyslipidemia. This review discusses dietary recommendations and beneficial compounds, such as vitamin D, omega-3 fatty acids, antioxidants, phytochemicals-and their food sources-to aid the management of abnormal lipid metabolism in postmenopausal women.
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Diet to Reduce the Metabolic Syndrome Associated with Menopause. The Logic for Olive Oil.
Hidalgo-Mora, JJ, Cortés-Sierra, L, García-Pérez, MÁ, Tarín, JJ, Cano, A
Nutrients. 2020;12(10)
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Metabolic syndrome (MetS) is a group of risk factors that increase the risk of type 2 diabetes and cardiovascular disease. The rates of MetS are increasing worldwide. Obesity, particularly central obesity is a major determinant of insulin resistance. It is believed that insulin resistance is the driver for MetS. This is a particular concern for women as central obesity is more likely to occur during the menopause, due in part to the hormonal changes. Physical activity and nutrition have been recommended as the first line of defence against MetS with the Mediterranean diet (MD) being one of the healthiest options. Olive oil (OO) is a main component of the MD and contains certain fats and polyphenols which impact inflammation, oxidative stress and support the gut microbiome. This review provides an overview of these benefits most relevant to menopause-associated MetS. A healthy lifestyle, with nutrition as a vital component, needs to be implemented as a primary measure. The healthy diet needs to be easy to follow and effective, two conditions successfully met by the MD. OO may prove especially helpful for women, particularly during this life stage. The clinical evidence, however, is limited by the observational nature of most studies.
Abstract
The rates of metabolic syndrome are increasing in parallel with the increasing prevalence of obesity, primarily due to its concomitant insulin resistance. This is particularly concerning for women, as the years around menopause are accompanied by an increase in visceral obesity, a strong determinant of insulin resistance. A fall in estrogens and increase in the androgen/estrogen ratio is attributed a determining role in this process, which has been confirmed in other physiological models, such as polycystic ovary syndrome. A healthy lifestyle, with special emphasis on nutrition, has been recommended as a first-line strategy in consensuses and guidelines. A consistent body of evidence has accumulated suggesting that the Mediterranean diet, with olive oil as a vital component, has both health benefits and acceptable adherence. Herein, we provide an updated overview of current knowledge on the benefits of olive oil most relevant to menopause-associated metabolic syndrome, including an analysis of the components with the greatest health impact, their effect on basic mechanisms of disease, and the state of the art regarding their action on the main features of metabolic syndrome.
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Effects of Soy Foods in Postmenopausal Women: A Focus on Osteosarcopenia and Obesity.
Tang, S, Du, Y, Oh, C, No, J
Journal of obesity & metabolic syndrome. 2020;29(3):180-187
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The body composition of postmenopausal women changes rapidly due to hormonal changes, including the loss of bone (osteoporosis) and muscle (sarcopenia), usually in the presence of increased adiposity and fat redistribution towards central-type obesity. The aim of this study was to summarise the efficacy of soy foods and their impact on body composition. Research shows that soy products: - may improve the body composition of menopausal and premenopausal women. - delay the physical disabilities of menopausal women with osteosarcopenia and obesity. - may improve muscle mass and bone strength to prevent the development of osteosarcopenia in post-menopausal women. Authors conclude that further research is required since some studies have questioned the mechanism of the protective effect of soybean ingredients on certain metabolic diseases.
Abstract
Chronic diseases in postmenopausal women are caused by rapid changes in hormones and are accompanied by rapid changes in body composition (muscle, bone, and fat). In an aging society, the health of postmenopausal women is a social issue, and people's interest in ingesting high-quality protein is increasing in order to maintain a healthy body composition. This review aims to summarize the efficacy of soy foods and their impact on body composition. The soy protein and isoflavones contained in soy foods can improve muscle and bone density quality and reduce body weight. It is considered a breakthrough in preventing osteosarcopenia and obesity that may occur after menopause.
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Association of Major Food Sources of Fructose-Containing Sugars With Incident Metabolic Syndrome: A Systematic Review and Meta-analysis.
Semnani-Azad, Z, Khan, TA, Blanco Mejia, S, de Souza, RJ, Leiter, LA, Kendall, CWC, Hanley, AJ, Sievenpiper, JL
JAMA network open. 2020;3(7):e209993
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Fructose is a type of sugar that has been implicated as a contributor to the development of metabolic syndrome (MetS), which is a condition where large waist circumference, high blood pressure and elevated blood lipid levels may all coexist. However, it remains unclear as to the role of fructose containing foods in the development of MetS. This systematic review and meta-analysis of 13 prospective cohort studies aimed to determine the association of several fructose containing foods and drinks with MetS. The results showed that sugary drinks containing fructose increased the risk of MetS, whereas no associations were found with mixed fruit juice, 100% fruit juice, honey, ice cream or confectionary. Interestingly fruit and yoghurt containing fructose decreased the risk of developing MetS. It was concluded that fructose containing food and drinks are not all equal in their biological effects. Sugary drinks increased the risk of developing MetS but yoghurt and fruit had a protective effect against development. Reasons for this could be due to a generally unhealthier lifestyle in those who consume sugary drinks or may be due to the increased protective effects associated with the vitamins and minerals in fruit and yoghurt. This study could be used by healthcare professionals to recommend a diet eliminating sugary drinks and containing regular fruit and yoghurt intake.
Abstract
Importance: Sugar-sweetened beverages (SSBs) are associated with increased risk of metabolic syndrome (MetS). However, the role of other important food sources of fructose-containing sugars in the development of MetS remains unclear. Objective: To examine the association of major food sources of fructose-containing sugars with incident MetS. Data Sources: MEDLINE, Embase, and Cochrane Library were searched from database inception to March 24, 2020, in addition to manual searches of reference lists from included studies using the following search terms: sugar-sweetened beverages, fruit drink, yogurt, metabolic syndrome, and prospective study. Study Selection: Inclusion criteria included prospective cohort studies of 1 year or longer that investigated the association of important food sources of fructose-containing sugars with incident MetS in participants free of MetS at the start of the study. Data Extraction and Synthesis: Study quality was assessed using the Newcastle-Ottawa Scale. Extreme quantile risk estimates for each food source with MetS incidence were pooled using a random-effects meta-analysis. Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). Dose-response analyses were performed using a 1-stage linear mixed-effects model. The certainty of the evidence was assessed using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Results were reported according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Main Outcomes and Measures: Pooled risk ratio (RR) of incident MetS (pairwise and dose response). Results: Thirteen prospective cohort studies (49 591 participants [median age, 51 years; range, 6-90 years]; 14 205 with MetS) that assessed 8 fructose-containing foods and MetS were included. An adverse linear dose-response association for SSBs (RR for 355 mL/d, 1.14; 95% CI, 1.05-1.23) and an L-shaped protective dose-response association for yogurt (RR for 85 g/d, 0.66; 95% CI, 0.58-0.76) and fruit (RR for 80 g/d, 0.82; 95% CI, 0.78-0.86) was found. Fruit juices (mixed and 100%) had a U-shaped dose-response association with protection at moderate doses (mixed fruit juice: RR for 125 mL/d, 0.58; 95% CI, 0.42-0.79; 100% fruit juice: RR for 125 mL/d, 0.77; 95% CI, 0.61-0.97). Honey, ice cream, and confectionary had no association with MetS incidence. The certainty of the evidence was moderate for SSBs, yogurt, fruit, mixed fruit juice, and 100% fruit juice and very low for all other food sources. Conclusions and Relevance: The findings of this meta-analysis suggest that the adverse association of SSBs with MetS does not extend to other food sources of fructose-containing sugars, with a protective association for yogurt and fruit throughout the dose range and for 100% fruit juice and mixed fruit juices at moderate doses. Therefore, current policies and guidelines on the need to limit sources of free sugars may need to be reexamined.
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Sociodemographic and lifestyle-related risk factors for identifying vulnerable groups for type 2 diabetes: a narrative review with emphasis on data from Europe.
Kyrou, I, Tsigos, C, Mavrogianni, C, Cardon, G, Van Stappen, V, Latomme, J, Kivelä, J, Wikström, K, Tsochev, K, Nanasi, A, et al
BMC endocrine disorders. 2020;20(Suppl 1):134
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Type 2 diabetes mellitus (T2DM) results from progressive loss of insulin secretion, which is typically combined with various degrees of insulin resistance. The aim of this study is to provide a comprehensive overview of key sociodemographic and lifestyle-related risk factors for identifying vulnerable groups for T2DM with emphasis on data from Europe. This study is a narrative review which includes 101 publications. Literature shows that prevention of T2DM should be a collaborative effort which mobilizes multiple partners/ stakeholders at a national and international (e.g. European) level. In addition, a holistic approach is becoming increasingly essential in order to put into effect multidimensional public health programs and integrated interventions for effective T2DM prevention which will take into account both traditional and socioeconomic/socioecological factors. Authors conclude that a multidimensional approach for the prevention of T2DM may have a broader impact against the current diabesity epidemic within and across countries in Europe.
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) comprises the vast majority of all diabetes cases in adults, with alarmingly increasing prevalence over the past few decades worldwide. A particularly heavy healthcare burden of diabetes is noted in Europe, where 8.8% of the population aged 20-79 years is estimated to have diabetes according to the International Diabetes Federation. Multiple risk factors are implicated in the pathogenesis of T2DM with complex underlying interplay and intricate gene-environment interactions. Thus, intense research has been focused on studying the role of T2DM risk factors and on identifying vulnerable groups for T2DM in the general population which can then be targeted for prevention interventions. METHODS For this narrative review, we conducted a comprehensive search of the existing literature on T2DM risk factors, focusing on studies in adult cohorts from European countries which were published in English after January 2000. RESULTS Multiple lifestyle-related and sociodemographic factors were identified as related to high T2DM risk, including age, ethnicity, family history, low socioeconomic status, obesity, metabolic syndrome and each of its components, as well as certain unhealthy lifestyle behaviors. As Europe has an increasingly aging population, multiple migrant and ethnic minority groups and significant socioeconomic diversity both within and across different countries, this review focuses not only on modifiable T2DM risk factors, but also on the impact of pertinent demographic and socioeconomic factors. CONCLUSION In addition to other T2DM risk factors, low socioeconomic status can significantly increase the risk for prediabetes and T2DM, but is often overlooked. In multinational and multicultural regions such as Europe, a holistic approach, which will take into account both traditional and socioeconomic/socioecological factors, is becoming increasingly crucial in order to implement multidimensional public health programs and integrated community-based interventions for effective T2DM prevention.
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Intellectual disability and nutrition-related health.
Kolset, SO
EMBO molecular medicine. 2020;12(10):e12899
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Certain inborn errors of metabolism have been linked to several conditions with intellectual disability (ID). Treating these preventable or treatable forms of ID require the support of experts in nutrition and medicine. However, nutritional measures and diet must be adjusted to the different syndromes and their inherent implications, which requires knowledge of ID in general, and of specific diagnosis groups in particular. In addition, challenging behaviour, lower cognitive functions, and capacity in daily-life activities translate into nutritional problems such as shopping, cooking and eating patterns, including snacking, that require systematic professional support. This study shows that the development of adapted mobile phone programs and apps will be of great value in interventions, educational studies and for persons with ID to help them manage their daily chores and their diet, particularly those with moderate and light ID. Addressing the multifaceted challenges of nutrition and health in persons with ID requires more research and increased priority from funding agencies, along with increased visibility and knowledge of the various forms of ID in general.
Abstract
Intellectual disability (ID) is a condition that affects approximately 1% of the population (Maulik et al, 2011). The numbers may differ across nations, owing to different systems and diagnosis entries or lack of such, but usually range between 0.6 and 3% (Stromme & Valvatne, 1998). Persons with ID are a heterogeneous group with different diagnoses and different levels of intellectual ability. These range from profound (IQ < 20) and serious ID (IQ 20-34) to moderate (IQ 35-49) and light ID (IQ 50-69); this roughly translates into the intellectual capacity of children between 3-12 years of age. More than 75% of persons with ID have the mild form and their intellectual capacity and potential may be underestimated in some cases if IQ is the only diagnostic criteria. However, the range in itself is an important factor to take into account when addressing nutrition and health issues. It is further important to recognize that ID is also a feature of several rare disorders, and many disorders not yet identified, adding to the complexity of this group.
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Dissecting the interaction between COVID-19 and diabetes mellitus.
Chee, YJ, Tan, SK, Yeoh, E
Journal of diabetes investigation. 2020;11(5):1104-1114
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Several countries have reported higher death rates and more severe cases of covid-19 amongst individuals with chronic diseases such as type 2 diabetes. This review of 100 papers aimed to investigate the interconnecting factors which may contribute to poorer prognosis in individuals with covid-19 and type 2 diabetes. Although the evidence suggests that patients with type 2 diabetes have poorer outcomes after contracting covid-19, they are not more susceptible to infection. The paper reported that mechanisms which may increase severity in type 2 diabetics are abnormal immune function, increased susceptibility to inflammation, the increased adherence of the virus to target cells and reduced ability to fight infection. It is important to manage blood sugars when suffering from covid-19. The paper reviewed the use of several medications such as metformin, dipeptidyl peptidase-4 inhibitors (DPP4), glucagon-like peptide-1 agonists and insulin in the context of individuals suffering from covid-19, with insulin being the treatment of choice in the acutely ill patient. Current treatments of covid-19 were also reviewed such as chloroquine and hydroxychloroquine, Lopinavir-ritonavir, IL-6 receptor agonists, type 1 interferon and remdesivir. It was concluded that clinicians should be aware of the risks in patients with type 2 diabetes and covid-19. However as new data is made available, the chronic and long-term implications will become clearer. This study could be used by health care professionals to ensure that patients with type 2 diabetes do everything they can to avoid covid-19 infection and that if contracted these patients are closely monitored for severe disease.
Abstract
Coronavirus disease 2019 (COVID-19) is a global pandemic that is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus-2. Data from several countries have shown higher morbidity and mortality among individuals with chronic metabolic diseases, such as diabetes mellitus. In this review, we explore the contributing factors for poorer prognosis in these individuals. As a significant proportion of patients with COVID-19 also have diabetes mellitus, this adds another layer of complexity to their management. We explore potential interactions between antidiabetic medications and renin-angiotensin-aldosterone system inhibitors with COVID-19. Suggested recommendations for the use of antidiabetic medications for COVID-19 patients with diabetes mellitus are provided. We also review pertinent clinical considerations in the management of diabetic ketoacidosis in COVID-19 patients. In addition, we aim to increase clinicians' awareness of the metabolic effects of promising drug therapies for COVID-19. Finally, we highlight the importance of timely vaccinations for patients with diabetes mellitus.
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Enhancing immunity in viral infections, with special emphasis on COVID-19: A review.
Jayawardena, R, Sooriyaarachchi, P, Chourdakis, M, Jeewandara, C, Ranasinghe, P
Diabetes & metabolic syndrome. 2020;14(4):367-382
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A healthy immune system is one of the most important weapons in relation to the current pandemic of COVID-19 where no effective preventive and curative medicine is available. The main aim of this study was to evaluate the evidence on enhancing immunity in viral infections. This review focuses on influenza-like viral infections; however, other studies on viral infections have also been included. It included 43 articles of which 13 were on vitamins, 8 on minerals, 18 on nutraceuticals and 4 on probiotics. Results indicate that: - vitamin supplementation, especially vitamin D may be beneficial in people who are either deficient or insufficient. - adverse effects of vitamin E supplementation on the immune response have been reported. - there are several beneficial nutraceuticals, however their efficacy and safety depend on their ingredients, as well as various other factors including, methods of extraction. - in addition to basic hygienic practices, proper dietary and lifestyle behaviours are essential for prevention and treatment of respiratory viral diseases. Authors conclude that achieving recommended amounts of calories and micronutrient will be a challenge and elective micronutrient supplementations may be beneficial especially for vulnerable populations such as the elderly.
Abstract
BACKGROUND AND AIMS Balanced nutrition which can help in maintaining immunity is essential for prevention and management of viral infections. While data regarding nutrition in coronavirus infection (COVID-19) are not available, in this review, we aimed to evaluate evidence from previous clinical trials that studied nutrition-based interventions for viral diseases (with special emphasis on respiratory infections), and summarise our observations. METHODS A systematic search strategy was employed using keywords to search the literature in 3 key medical databases: PubMed®, Web of Science® and SciVerse Scopus®. Studies were considered eligible if they were controlled trials in humans, measuring immunological parameters, on viral and respiratory infections. Clinical trials on vitamins, minerals, nutraceuticals and probiotics were included. RESULTS A total of 640 records were identified initially and 22 studies were included from other sources. After excluding duplicates and articles that did not meet the inclusion criteria, 43 studies were obtained (vitamins: 13; minerals: 8; nutraceuticals: 18 and probiotics: 4). Among vitamins, A and D showed a potential benefit, especially in deficient populations. Among trace elements, selenium and zinc have also shown favourable immune-modulatory effects in viral respiratory infections. Several nutraceuticals and probiotics may also have some role in enhancing immune functions. Micronutrients may be beneficial in nutritionally depleted elderly population. CONCLUSIONS We summaries possible benefits of some vitamins, trace elements, nutraceuticals and probiotics in viral infections. Nutrition principles based on these data could be useful in possible prevention and management of COVID-19.
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How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS.
Nacul, L, O'Boyle, S, Palla, L, Nacul, FE, Mudie, K, Kingdon, CC, Cliff, JM, Clark, TG, Dockrell, HM, Lacerda, EM
Frontiers in neurology. 2020;11:826
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A good understanding of the disease course is vital not only for the design of preventative and intervention studies, but also to assess the timing and type of intervention that minimizes disease risk or optimizes prognosis. The aim of this review was to explore the long-term course of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and how presentation and pathophysiological abnormalities may vary with time. Literature shows that it is unknown how the initial host response to a stressor or insult compares in individuals who do or do not develop typical symptoms of ME/CFS. However, the return to good health, following exposure to mild or moderate levels of insult, seems to be impeded in ME/CFS when symptoms persist for longer than 3–6 months. Authors sought to provide a simple framework, similar to those of other chronic diseases, in an effort to extend the temporal perception of ME/CFS and better incorporate the less defined pre-illness stages of the disease. In fact, they conclude that by applying this framework to ME/CFS research efforts could better elucidate the pathophysiological mechanisms of the disease and identify potential therapeutic targets at distinct stages.
Abstract
We propose a framework for understanding and interpreting the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) that considers wider determinants of health and long-term temporal variation in pathophysiological features and disease phenotype throughout the natural history of the disease. As in other chronic diseases, ME/CFS evolves through different stages, from asymptomatic predisposition, progressing to a prodromal stage, and then to symptomatic disease. Disease incidence depends on genetic makeup and environment factors, the exposure to singular or repeated insults, and the nature of the host response. In people who develop ME/CFS, normal homeostatic processes in response to adverse insults may be replaced by aberrant responses leading to dysfunctional states. Thus, the predominantly neuro-immune manifestations, underlined by a hyper-metabolic state, that characterize early disease, may be followed by various processes leading to multi-systemic abnormalities and related symptoms. This abnormal state and the effects of a range of mediators such as products of oxidative and nitrosamine stress, may lead to progressive cell and metabolic dysfunction culminating in a hypometabolic state with low energy production. These processes do not seem to happen uniformly; although a spiraling of progressive inter-related and self-sustaining abnormalities may ensue, reversion to states of milder abnormalities is possible if the host is able to restate responses to improve homeostatic equilibrium. With time variation in disease presentation, no single ME/CFS case description, set of diagnostic criteria, or molecular feature is currently representative of all patients at different disease stages. While acknowledging its limitations due to the incomplete research evidence, we suggest the proposed framework may support future research design and health care interventions for people with ME/CFS.
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Potential causal factors of CFS/ME: a concise and systematic scoping review of factors researched.
Muller, AE, Tveito, K, Bakken, IJ, Flottorp, SA, Mjaaland, S, Larun, L
Journal of translational medicine. 2020;18(1):484
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Chronic fatigue syndrome /myalgic encephalomyelitis (CFS/ME) is complex and probably triggered by several interconnected factors and the identification of these is essential to develop better treatments and preventative measures. This systematic scoping review of 1161 studies aimed to discuss potential causal factors of CFS/ME. The results showed that there were several main causal factors that were investigated in the literature and no single factor dominated the research; immunological, psychological/psychosocial/socioeconomic, infectious, and neuroendocrinal/hormonal/metabolic. Studies varied in their design and methods. Interestingly research in this area was at its highest before 1995 and from 2015-2019, studies have markedly decreased. It was concluded that large variations in methods and design of studies of causal factor studies, is problematic. More large, well designed studies are required especially as research has declined recently and considering post covid-19 fatigue. This study could be used by healthcare professionals to understand where there are gaps in the research to design more robust studies in the future.
Abstract
BACKGROUND Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is understood as a complex condition, likely triggered and sustained by an interplay of biological, psychological, and social factors. Little oversight exists of the field of causal research. This systematic scoping review explores potential causal factors of CFS/ME as researched by primary studies. METHODS We searched eight databases for primary studies that examined potential causal factors of CFS/ME. Based on title/abstract review, two researchers independently sorted each study's factors into nine main categories and 71 subordinate categories, using a system developed with input given during a 2018 ME conference, specialists and representatives from a ME patient advocacy group, and using BMJ Best Practice's description of CFS/ME etiology. We also extracted data related to study design, size, diagnostic criteria and comparison groups. RESULTS We included 1161 primary studies published between January 1979 and June 2019. Based on title/abstract analysis, no single causal factor dominated in these studies, and studies reported a mean of 2.73 factors. The four most common factors were: immunological (297 studies), psychological (243), infections (198), and neuroendocrinal (198). The most frequent study designs were case-control studies (894 studies) comparing CFS/ME patients with healthy participants. More than half of the studies (that reported study size in the title/abstract) included 100 or fewer participants. CONCLUSION The field of causal hypotheses of CFS/ME is diverse, and we found that the studies examined all the main categories of possible factors that we had defined a priori. Most studies were not designed to adequately explore causality, rather to establish hypotheses. We need larger studies with stronger study designs to gain better knowledge of causal factors of CFS/ME.