The Association between Functional Dyspepsia and Metabolic Syndrome-The State of the Art.

Functional dyspepsia is a common functional disorder of the gastrointestinal tract that is responsible for many primary care visits. No organic changes have been found to explain its symptoms. We hypothesize that modern lifestyles and environmental factors, especially psychological stress, play a crucial role in the high prevalence of functional dyspepsia and metabolic syndrome. While gastrointestinal tract diseases are rarely linked to metabolic disorders, chronic stress, obesity-related metabolic syndrome, chronic inflammation, intestinal dysbiosis, and functional dyspepsia have significant pathophysiological associations. Functional dyspepsia, often associated with anxiety and chronic psychological stress, can activate the neuroendocrine stress axis and immune system, leading to unhealthy habits that contribute to obesity. Additionally, intestinal dysbiosis, which is commonly present in functional dyspepsia, can exacerbate systemic inflammation and obesity, further promoting metabolic syndrome-related disorders. It is worth noting that the reverse is also true: obesity-related metabolic syndrome can worsen functional dyspepsia and its associated symptoms by triggering systemic inflammation and intestinal dysbiosis, as well as negative emotions (depression) through the brain-gut axis. To understand the pathophysiology and deliver an effective treatment strategy for these two difficult-to-cure disorders, which are challenging for both caregivers and patients, a psychosocial paradigm is essential.

Influence of Age, Gender, Frailty, and Body Mass Index on Serum IL-17A Levels in Mature Type 2 Diabetic Patients.

BACKGROUND The cytokine IL-17A is emerging as a marker of chronic inflammation in cardio-metabolic conditions. This study aimed to identify relevant factors that in older primary care patients with type 2 diabetes (T2D) could influence serum IL-17A concentrations. The results have a potential to improve risk stratification and therapy options for these patients. MATERIAL AND METHODS The study was conducted during a period of 4 months, in 2020, in the south-eastern region of Croatia. Patients from primary health care, diagnosed with T2D (N=170, M: F 75: 95, ≥50 years old), were recruited at their visits. Those with malignant diseases, on chemotherapy or biological therapy, with amputated legs, or at hemodialysis, were excluded. The multinomial regression models were used to determine independent associations of the groups of variables, indicating sociodemographic and clinical characteristics of these patients, with increasing values (quartiles) of serum IL-17A. RESULTS The regression models indicated the frailty index and sex bias are the key modifying factors in associations of other variables with IL-17A serum values. CONCLUSIONS Sex bias and the existence of different frailty phenotypes could be the essential determining factors of the serum IL-17A levels in community-dwelling patients with T2D age 50 years and older. The results support the concept of T2D as a complex disorder.

Immunomodulatory Effects of SGLT2 Inhibitors-Targeting Inflammation and Oxidative Stress in Aging.

Given that the increase in the aging population has grown into one of the largest public health issues, inflammation and oxidative stress, which are closely associated with the aging process, became a focus of recent research. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, a group of drugs initially developed as oral antidiabetics, have shown many beneficial effects over time, including improvement in renal function and cardioprotective effects. It has been shown that SGLT2 inhibitors, as a drug class, have an immunomodulatory and antioxidative effect, affecting endothelial function as well as metabolic parameters. Therefore, it is not surprising that various studies have investigated the potential mechanisms of action of SGLT2 inhibitors in age-related diseases. The proposed mechanisms by which SGLT2 inhibitors can achieve their anti-inflammatory effects include influence on AMPK/SIRT1/PGC-1α signaling, various cytokines, and the NLRP3 inflammasome. The antioxidative effect is related to their action on mitochondria and their influence on the signaling pathways of transforming growth factor ß and nuclear erythroid 2-related factor 2/antioxidant response element. Also, SGLT2 inhibitors achieve their anti-inflammatory and antioxidative effects by affecting metabolic parameters, such as uric acid reduction, stimulation of ketogenesis, reduction of body weight, lipolysis, and epicardial fat tissue. Finally, SGLT2 inhibitors display anti-atherosclerotic effects that modulate inflammatory reactions, potentially resulting in improvement in endothelial function. This narrative review offers a complete and comprehensive overview of the possible pathophysiologic mechanisms of the SGLT2 inhibitors involved in the aging process and development of age-related disease. However, in order to use SGLT2 inhibitor drugs as an anti-aging therapy, further basic and clinical research is needed to elucidate the potential effects and complex mechanisms they have on inflammation processes.

A Critical Appraisal of the Diagnostic and Prognostic Utility of the Anti-Inflammatory Marker IL-37 in a Clinical Setting: A Case Study of Patients with Diabetes Type 2.

BACKGROUND: The role of the cytokine interleukin-37 (IL-37) has been recognized in reversing inflammation-mediated metabolic costs. The aim was to evaluate the clinical utility of this cytokine as a diagnostic and prognostic marker in patients with type 2 diabetes (T2D). METHODS: We included 170 older (median: 66 years) individuals with T2D (females: 95) and classified as primary care attenders to assess the association of factors that describe patients with plasma IL-37 levels (expressed as quartiles) using multinomial regression models. We determined the diagnostic ability of IL-37 cut-offs to identify diabetes-related complications or patient subgroups by using Receiver Operating Characteristic analysis (c-statistics). RESULTS: Frailty status was shown to have a suppressive effect on IL-37 circulating levels and a major modifying effect on associations of metabolic and inflammatory factors with IL-37, including the effects of treatments. Situations in which IL-37 reached a clinically significant discriminating ability included the model of IL-37 and C-Reactive Protein in differentiating among diabetic patients with low-normal/high BMI ((<25/≥25 kg/m2), and the model of IL-37 and Thyroid Stimulating Hormone in discriminating between women with/without metabolic syndrome. CONCLUSIONS: The study has revealed limitations in using classical approaches in determining the diagnostic and prognostic utility of the cytokine IL-37 in patients with T2D and lain a foundation for new methodology approaches.

Cross-Talk between the Cytokine IL-37 and Thyroid Hormones in Modulating Chronic Inflammation Associated with Target Organ Damage in Age-Related Metabolic and Vascular Conditions.

Chronic inflammation is considered to be the main mechanism contributing to the development of age-related metabolic and vascular conditions. The phases of chronic inflammation that mediate the progression of target organ damage in these conditions are poorly known, however. In particular, there is a paucity of data on the link between chronic inflammation and metabolic disorders. Based on some of our own results and recent developments in our understanding of age-related inflammation as a whole-body response, we discuss the hypothesis that cross-talk between the cytokine IL-37 and thyroid hormones could be the key regulatory mechanism that justifies the metabolic effects of chronic tissue-related inflammation. The cytokine IL-37 is emerging as a strong natural suppressor of the chronic innate immune response. The effect of this cytokine has been identified in reversing metabolic costs of chronic inflammation. Thyroid hormones are known to regulate energy metabolism. There is a close link between thyroid function and inflammation in elderly individuals. Nonlinear associations between IL-37 and thyroid hormones, considered within the wider clinical context, can improve our understanding of the phases of chronic inflammation that are associated with target organ damage in age-related metabolic and vascular conditions.

Clustering Inflammatory Markers with Sociodemographic and Clinical Characteristics of Patients with Diabetes Type 2 Can Support Family Physicians' Clinical Reasoning by Reducing Patients' Complexity.

Diabetes mellitus type 2 (DM2) is a complex disease associated with chronic inflammation, end-organ damage, and multiple comorbidities. Initiatives are emerging for a more personalized approach in managing DM2 patients. We hypothesized that by clustering inflammatory markers with variables indicating the sociodemographic and clinical contexts of patients with DM2, we could gain insights into the hidden phenotypes and the underlying pathophysiological backgrounds thereof. We applied the k-means algorithm and a total of 30 variables in a group of 174 primary care (PC) patients with DM2 aged 50 years and above and of both genders. We included some emerging markers of inflammation, specifically, neutrophil-to-lymphocyte ratio (NLR) and the cytokines IL-17A and IL-37. Multiple regression models were used to assess associations of inflammatory markers with other variables. Overall, we observed that the cytokines were more variable than the marker NLR. The set of inflammatory markers was needed to indicate the capacity of patients in the clusters for inflammatory cell recruitment from the circulation to the tissues, and subsequently for the progression of end-organ damage and vascular complications. The hypothalamus-pituitary-thyroid hormonal axis, in addition to the cytokine IL-37, may have a suppressive, inflammation-regulatory role. These results can help PC physicians with their clinical reasoning by reducing the complexity of diabetic patients.

Clusters of Physical Frailty and Cognitive Impairment and Their Associated Comorbidities in Older Primary Care Patients.

(1) Objectives: We aimed to identify clusters of physical frailty and cognitive impairment in a population of older primary care patients and correlate these clusters with their associated comorbidities. (2) Methods: We used a latent class analysis (LCA) as the clustering technique to separate different stages of mild cognitive impairment (MCI) and physical frailty into clusters; the differences were assessed by using a multinomial logistic regression model. (3) Results: Four clusters (latent classes) were identified: (1) highly functional (the mean and SD of the "frailty" test 0.58 ± 0.72 and the Mini-Mental State Examination (MMSE) test 27.42 ± 1.5), (2) cognitive impairment (0.97 ± 0.78 and 21.94 ± 1.95), (3) cognitive frailty (3.48 ± 1.12 and 19.14 ± 2.30), and (4) physical frailty (3.61 ± 0.77 and 24.89 ± 1.81). (4) Discussion: The comorbidity patterns distinguishing the clusters depend on the degree of development of cardiometabolic disorders in combination with advancing age. The physical frailty phenotype is likely to exist separately from the cognitive frailty phenotype and includes common musculoskeletal diseases.

Low Psychological Resilience in Older Individuals: An Association with Increased Inflammation, Oxidative Stress and the Presence of Chronic Medical Conditions.

The term resilience, which has been present in science for almost half a century, stands for the capacity of some system needed to overcome an amount of disturbance from the environment in order to avoid a change to another stable state. In medicine, the concept of resilience means the ability to deal with daily stress and disturbance to our homeostasis with the intention of protecting it from disturbance. With aging, the organism becomes more sensitive to environmental impacts and more susceptible to changes. Mental disturbances and a decline in psychological resilience in older people are potentiated with many social and environmental factors along with a subjective perception of decreasing health. Distinct from findings in younger age groups, mental and physical medical conditions in older people are closely associated with each other, sharing common mechanisms and potentiating each other's development. Increased inflammation and oxidative stress have been recognized as the main driving mechanisms in the development of aging diseases. This paper aims to reveal, through a translational approach, physiological and molecular mechanisms of emotional distress and low psychological resilience in older individuals as driving mechanisms for the accelerated development of chronic aging diseases, and to systematize the available information sources on strategies for mitigation of low resilience in order to prevent chronic diseases.

AI and Big Data in Healthcare: Towards a More Comprehensive Research Framework for Multimorbidity.

Multimorbidity refers to the coexistence of two or more chronic diseases in one person. Therefore, patients with multimorbidity have multiple and special care needs. However, in practice it is difficult to meet these needs because the organizational processes of current healthcare systems tend to be tailored to a single disease. To improve clinical decision making and patient care in multimorbidity, a radical change in the problem-solving approach to medical research and treatment is needed. In addition to the traditional reductionist approach, we propose interactive research supported by artificial intelligence (AI) and advanced big data analytics. Such research approach, when applied to data routinely collected in healthcare settings, provides an integrated platform for research tasks related to multimorbidity. This may include, for example, prediction, correlation, and classification problems based on multiple interaction factors. However, to realize the idea of this paradigm shift in multimorbidity research, the optimization, standardization, and most importantly, the integration of electronic health data into a common national and international research infrastructure is needed. Ultimately, there is a need for the integration and implementation of efficient AI approaches, particularly deep learning, into clinical routine directly within the workflows of the medical professionals.

Cluster Analysis of the Associations among Physical Frailty, Cognitive Impairment and Mental Disorders.

BACKGROUND Physical frailty, cognitive impairment, and symptoms of anxiety and depression frequently co-occur in later life, but, to date, each has been assessed separately. The present study assessed their patterns in primary care patients aged ≥60 years. MATERIAL AND METHODS This cross-sectional study evaluated 263 primary care patients aged ≥60 years in eastern Croatia in 2018. Physical frailty, cognitive impairment, anxiety and depression, were assessed using the Fried phenotypic model, the Mini-Mental State Examination (MMSE), the Geriatric Anxiety Scale (GAS), and the Geriatric Depression Scale (GDS), respectively. Patterns were identified by latent class analysis (LCA), Subjects were assorted by age, level of education, and domains of psychological and cognitive tests to determine clusters. RESULTS Subjects were assorted into four clusters: one cluster of relatively healthy individuals (61.22%), and three pathological clusters, consisting of subjects with mild cognitive impairment (23.95%), cognitive frailty (7.98%), and physical frailty (6.85%). A multivariate, multinomial logistic regression model found that the main determinants of the pathological clusters were increasing age and lower mnestic functions. Lower performance on mnestic tasks was found to significantly determine inclusion in the three pathological clusters. The non-mnestic function, attention, was specifically associated with cognitive impairment, whereas psychological symptoms of anxiety and dysphoria were associated with physical frailty. CONCLUSIONS Clustering of physical and cognitive performances, based on combinations of their grades of severity, may be superior to modelling of their respective entities, including the continuity and non-linearity of age-related accumulation of pathologic conditions.

Prescribing Analgesics to Older People: A Challenge for GPs.

BACKGROUND: Due to population aging, there is an increase in the prevalence of chronic diseases, and in particular musculoskeletal diseases. These trends are associated with an increased demand for prescription analgesics and an increased risk of polypharmacy and adverse medication reactions, which constitutes a challenge, especially for general practitioners (GPs), as the providers who are most responsible for the prescription policy. OBJECTIVES: To identify patterns of analgesics prescription for older people in the study area and explore associations between a long-term analgesic prescription and comorbidity patterns, as well as the prescription of psychotropic and other common medications in a continuous use. METHODS: A retrospective study was conducted in 2015 in eastern Croatia. Patients were GP attenders ≥40 years old (N = 675), who were recruited during their appointments (consecutive patients). They were divided into two groups: those who have been continuously prescribed analgesics (N = 432) and those who have not (N = 243). Data from electronic health records were used to provide information about diagnoses of musculoskeletal and other chronic diseases, as well as prescription rates for analgesics and other medications. Exploratory methods and logistic regression models were used to analyse the data. RESULTS: Analgesics have been continuously prescribed to 64% of the patients, mostly to those in the older age groups (50-79 years) and females, and they were indicated mainly for dorsalgia symptoms and arthrosis. Non-opioid analgesics were most common, with an increasing tendency to prescribe opioid analgesics to older patient groups aged 60-79 years. The study results indicate that there is a high rate of simultaneous prescription of analgesics and psychotropic medications, despite the intention of GPs to avoid prescribing psychotropic medications to patients who use any option with opioid analgesics. In general, receiving prescription analgesics does not exceed the prescription for chronic diseases over the rates that can be found in patients who do not receive prescription analgesics. CONCLUSION: Based on the analysis of comorbidities and parallel prescribing, the results of this study can improve GPs' prescription and treatment strategies for musculoskeletal diseases and chronic pain conditions.