NAFLD in the 21st Century: Current Knowledge Regarding Its Pathogenesis, Diagnosis and Therapeutics.

Non-alcoholic fatty liver disease (NAFLD) is a major public health issue worldwide. It is the most common liver disease in Western countries, andits global prevalence is estimated to be up to 35%. However, its diagnosis may be elusive, because liver biopsy is relatively rarely performed and usually only in advanced stages of the disease. Therefore, several non-invasive scores may be applied to more easily diagnose and monitor NAFLD. In this review, we discuss the various biomarkers and imaging scores that could be useful in diagnosing and managing NAFLD. Despite the fact that general measures, such as abstinence from alcohol and modulation of other cardiovascular disease risk factors, should be applied, the mainstay of prevention and management is weight loss. Bariatric surgery may be suggested as a means to confront NAFLD. In addition, pharmacological treatment with GLP-1 analogues or the GIP agonist tirzepatide may be advisable. In this review, we focus on the utility of GLP-1 analogues and GIP agonists in lowering body weight, their pharmaceutical potential, and their safety profile, as already evidenced inanimal and human studies. We also elaborate on other options, such as the use of vitamin E, probiotics, especially next-generation probiotics, and prebiotics in this context. Finally, we explore future perspectives regarding the administration of GLP-1 analogues, GIP agonists, and probiotics/prebiotics as a means to prevent and combat NAFLD. The newest drugs pegozafermin and resmetiron, which seem to be very promising, arealso discussed.

Alterations of the Adipo-Myokine Irisin in Sepsis and Septic Shock: Diagnostic and Prognostic Implications.

Irisin, a novel adipo-myokine with metabolic regulatory functions, exerts anti-inflammatory, antioxidant, and anti-apoptotic actions that may confer protection against sepsis-induced organ injury in experimental studies. Until now, only one human study has explored circulating irisin at sepsis onset. We aimed to examine serum irisin and its kinetics in critically ill patients with sepsis and septic shock with regard to sepsis severity and outcome. We enrolled 102 critically ill patients with sepsis or septic shock within 48 h of diagnosis and 102 age- and gender-matched healthy controls. Irisin was determined in serum upon enrollment in all participants and one week later in patients using an immunoenzymatic method. The outcome of sepsis was recorded 28 days after enrollment. At enrollment, circulating irisin was significantly lower in patients than controls (22.3 ± 6.8 µg/L vs. 28.1 ± 6.7 µg/L, p < 0.001), and increased significantly one week later (22.3 ± 6.8 µg/L vs. 26.6 ± 9.5 µg/L, p < 0.001). Irisin was significantly lower in patients who presented with septic shock than those with sepsis, and in non-survivors than survivors both at enrollment and one week later. However, kinetics of irisin did not differ between the groups (p > 0.05). Patients with higher circulating irisin during the first week of sepsis had a better outcome (p < 0.001). Lower irisin was independently associated with 28-day mortality (sepsis onset: HR 0.44, 95% C.I. 0.26-0.77, p = 0.004 and one week after: HR 0.37, 95% C.I. 0.23-0.58, p < 0.001). Irisin was negatively correlated with severity scores, metabolic, and inflammatory biomarkers. Circulating irisin decreases early in sepsis and is an independent predictor of 28-day mortality. Irisin may be a promising diagnostic and prognostic sepsis biomarker; nevertheless, larger studies are needed to explore its role in sepsis.

Sepsis-Associated Acute Kidney Injury: Where Are We Now?

Worldwide, sepsis is a well-recognized cause of death. Acute kidney injury (AKI) may be related to sepsis in up to 70% of AKI cases. Sepsis-associated AKI (SA-AKI) is defined as the presence of AKI according to the Kidney Disease: Improving Global Outcomes criteria in the context of sepsis. SA-AKI is categorized into early, which presents during the first 48 h of sepsis, and late, presenting between 48 h and 7 days of sepsis. SA-AKI is associated with a worse prognosis among patients with sepsis. However, there are different SA-AKI phenotypes as well as different pathophysiological pathways of SA-AKI. The aim of this review is to provide an updated synopsis of the pathogenetic mechanisms underlying the development of SA-AKI as well as to analyze its different phenotypes and prognosis. In addition, potential novel diagnostic and prognostic biomarkers as well as therapeutic approaches are discussed. A plethora of mechanisms are implicated in the pathogenesis of SA-AKI, including inflammation and metabolic reprogramming during sepsis; various types of cell death such as apoptosis, necroptosis, pyroptosis and ferroptosis; autophagy and efferocytosis; and hemodynamic changes (macrovascular and microvascular dysfunction). Apart from urine output and serum creatinine levels, which have been incorporated in the definition of AKI, several serum and urinary diagnostic and prognostic biomarkers have also been developed, comprising, among others, interleukins 6, 8 and 18, osteoprotegerin, galectin-3, presepsin, cystatin C, NGAL, proenkephalin A, CCL-14, TIMP-2 and L-FABP as well as biomarkers stemming from multi-omics technologies and machine learning algorithms. Interestingly, the presence of long non-coding RNAs (lncRNAs) as well as microRNAs (miRNAs), such as PlncRNA-1, miR-22-3p, miR-526b, LncRNA NKILA, miR-140-5p and miR-214, which are implicated in the pathogenesis of SA-AKI, may also serve as potential therapeutic targets. The combination of omics technologies represents an innovative holistic approach toward providing a more integrated view of the molecular and physiological events underlying SA-AKI as well as for deciphering unique and specific phenotypes. Although more evidence is still necessary, it is expected that the incorporation of integrative omics may be useful not only for the early diagnosis and risk prognosis of SA-AKI, but also for the development of potential therapeutic targets that could revolutionize the management of SA-AKI in a personalized manner.

Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Where Do We Stand?

Lipoprotein(a) [Lp(a)] consists of a low-density lipoprotein-like molecule and an apolipoprotein(a) [apo(a)] particle. Lp(a) has been suggested to be an independent risk factor of atherosclerotic cardiovascular disease (ASCVD). Lp(a) plasma levels are considered to be 70-90% genetically determined through the codominant expression of the LPA gene. Therefore, Lp(a) levels are almost stable during an individual's lifetime. This lifelong stability, together with the difficulties in measuring Lp(a) levels in a standardized manner, may account for the scarcity of available drugs targeting Lp(a). In this review, we synopsize the latest data regarding the structure, metabolism, and factors affecting circulating levels of Lp(a), as well as the laboratory determination measurement of Lp(a), its role in the pathogenesis of ASCVD and thrombosis, and the potential use of various therapeutic agents targeting Lp(a). In particular, we discuss novel agents, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) that are currently being developed and target Lp(a). The promising role of muvalaplin, an oral inhibitor of Lp(a) formation, is then further analyzed.

The Interplay Between Dietary Choline and Cardiometabolic Disorders: A Review of Current Evidence.

PURPOSE OF REVIEW: Choline is an essential nutrient for human health and cellular homeostasis as it is necessary for the synthesis of lipid cell membranes, lipoproteins, and the synthesis of the neurotransmitter acetylcholine. The aim of this review is to analyze the beneficial effects of choline and its significance in cellular metabolism and various inflammatory pathways, such as the inflammasome. We will discuss the significance of dietary choline in cardiometabolic disorders, such as non-alcoholic fatty liver disease (NAFLD), cardiovascular disease (CVD), and chronic kidney disease (CKD) as well as in cognitive function and associated neuropsychiatric disorders. RECENT FINDINGS: Choline deficiency has been related to the development of NAFLD and cognitive disability in the offspring as well as in adulthood. In sharp contrast, excess dietary intake of choline mediated via the increased production of trimethylamine by the gut microbiota and increased trimethylamine-N-oxide (TMAO) levels has been related to atherosclerosis in most studies. In this context, CVD and CKD through the accumulation of TMAO, p-Cresyl-sulfate (pCS), and indoxyl-sulfate (IS) in serum may be the result of the interplay between excess dietary choline, the increased production of TMAO by the gut microbiota, and the resulting activation of inflammatory responses and fibrosis. A balanced diet, with no excess nor any deficiency in dietary choline, is of outmost importance regarding the prevention of cardiometabolic disorders as well as cognitive function. Large-scale studies with the use of next-generation probiotics, especially Akkermansia muciniphila and Faecalibacterium prausnitzii, should further examine their therapeutic potential in this context.

ApoB100 and Atherosclerosis: What's New in the 21st Century?

ApoB is the main protein of triglyceride-rich lipoproteins and is further divided into ApoB48 in the intestine and ApoB100 in the liver. Very low-density lipoprotein (VLDL) is produced by the liver, contains ApoB100, and is metabolized into its remnants, intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL). ApoB100 has been suggested to play a crucial role in the formation of the atherogenic plaque. Apart from being a biomarker of atherosclerosis, ApoB100 seems to be implicated in the inflammatory process of atherosclerosis per se. In this review, we will focus on the structure, the metabolism, and the function of ApoB100, as well as its role as a predictor biomarker of cardiovascular risk. Moreover, we will elaborate upon the molecular mechanisms regarding the pathophysiology of atherosclerosis, and we will discuss the disorders associated with the APOB gene mutations, and the potential role of various drugs as therapeutic targets.

The Role of Endocrine Disruptors Bisphenols and Phthalates in Obesity: Current Evidence, Perspectives and Controversies.

Excess body weight constitutes one of the major health challenges for societies and healthcare systems worldwide. Besides the type of diet, calorie intake and the lack of physical exercise, recent data have highlighted a possible association between endocrine-disrupting chemicals (EDCs), such as bisphenol A, phthalates and their analogs, and obesity. EDCs represent a heterogeneous group of chemicals that may influence the hormonal regulation of body mass and adipose tissue morphology. Based on the available data from mechanistic, animal and epidemiological studies including meta-analyses, the weight of evidence points towards the contribution of EDCs to the development of obesity, associated disorders and obesity-related adipose tissue dysfunction by (1) impacting adipogenesis; (2) modulating epigenetic pathways during development, enhancing susceptibility to obesity; (3) influencing neuroendocrine signals responsible for appetite and satiety; (4) promoting a proinflammatory milieu in adipose tissue and inducing a state of chronic subclinical inflammation; (5) dysregulating gut microbiome and immune homeostasis; and (6) inducing dysfunction in thermogenic adipose tissue. Critical periods of exposure to obesogenic EDCs are the prenatal, neonatal, pubertal and reproductive periods. Interestingly, EDCs even at low doses may promote epigenetic transgenerational inheritance of adult obesity in subsequent generations. The aim of this review is to summarize the available evidence on the role of obesogenic EDCs, specifically BPA and phthalate plasticizers, in the development of obesity, taking into account in vitro, animal and epidemiologic studies; discuss mechanisms linking EDCs to obesity; analyze the effects of EDCs on obesity in critical chronic periods of exposure; and present interesting perspectives, challenges and preventive measures in this research area.

The Physiological Effects of Weight-Cycling: A Review of Current Evidence.

PURPOSE OF REVIEW: There is a common perception among the public that yo-yo dieting, defined as repeated cycles of weight loss followed by weight regain, results in accumulation of fat in the body and lower metabolic rate, thus hindering subsequent attempts to lose weight. We evaluated the effects of weight-cycling on body weight and body mass index (BMI), body composition including fat mass (FM) and lean body mass (LBM), and resting metabolic rate (RMR), by systematically reviewing existing scientific literature. RECENT FINDINGS: Twenty-three cross-sectional and cohort studies (including subjects with a history of weight-cycling compared to those without such history) and interventional studies (evaluating physiological effects during one or more cycles of weight loss and regain) were identified, conducted in generally healthy adults across various age groups, races, and both genders, who had normal weight, overweight, or obesity. Eighteen studies investigated the association between weight-cycling and body weight or BMI, and thirteen of them found no significant association. Fifteen out of twenty studies also found no increase in FM, and none of eighteen studies found a decrease in LBM. Twelve out of fourteen studies reported no adverse changes in RMR either. The overwhelming majority of evidence suggests that weight-cycling (yo-yo effect) is not associated with any adverse effects in body weight, body composition, and metabolic rate. Accordingly, healthy individuals who struggle with overweight or obesity should not be discouraged from repeated attempts to lose the excess weight.

Obesity and Leukemia: Biological Mechanisms, Perspectives, and Challenges.

PURPOSE OF REVIEW: To examine the epidemiological data on obesity and leukemia; evaluate the effect of obesity on leukemia outcomes in childhood acute lymphoblastic leukemia (ALL) survivors; assess the potential mechanisms through which obesity may increase the risk of leukemia; and provide the effects of obesity management on leukemia. Preventive (diet, physical exercise, obesity pharmacotherapy, bariatric surgery) measures, repurposing drugs, candidate therapeutic agents targeting oncogenic pathways of obesity and insulin resistance in leukemia as well as challenges of the COVID-19 pandemic are also discussed. RECENT FINDINGS: Obesity has been implicated in the development of 13 cancers, such as breast, endometrial, colon, renal, esophageal cancers, and multiple myeloma. Leukemia is estimated to account for approximately 2.5% and 3.1% of all new cancer incidence and mortality, respectively, while it represents the most frequent cancer in children younger than 5 years. Current evidence indicates that obesity may have an impact on the risk of leukemia. Increased birthweight may be associated with the development of childhood leukemia. Obesity is also associated with worse outcomes and increased mortality in leukemic patients. However, there are several limitations and challenges in meta-analyses and epidemiological studies. In addition, weight gain may occur in a substantial number of childhood ALL survivors while the majority of studies have documented an increased risk of relapse and mortality among patients with childhood ALL and obesity. The main pathophysiological pathways linking obesity to leukemia include bone marrow adipose tissue; hormones such as insulin and the insulin-like growth factor system as well as sex hormones; pro-inflammatory cytokines, such as IL-6 and TNF-α; adipocytokines, such as adiponectin, leptin, resistin, and visfatin; dyslipidemia and lipid signaling; chronic low-grade inflammation and oxidative stress; and other emerging mechanisms. Obesity represents a risk factor for leukemia, being among the only known risk factors that could be prevented or modified through weight loss, healthy diet, and physical exercise. Pharmacological interventions, repurposing drugs used for cardiometabolic comorbidities, and bariatric surgery may be recommended for leukemia and obesity-related cancer prevention.

Update on the Obesity Epidemic: After the Sudden Rise, Is the Upward Trajectory Beginning to Flatten?

PURPOSE OF REVIEW: To provide an update on current obesity prevalence trends and summarize the available evidence suggesting a possible plateau or stabilization in obesity rates after the previous sudden global rise. RECENT FINDINGS: The escalating global obesity epidemic represents one of the most serious public health challenges. There have been some indications that in high-income populations, the rate of obesity increase in adults has been stabilized after the decade 2000-2010, suggesting a possible plateau. Current evidence also suggests that obesity rates have been stabilized in children and adolescents of most economically advanced countries since 2000, which is possibly related to healthier dietary habits and increased levels of physical activity. On the other hand, there is a steady uninterrupted rise in low-income nations, and the universal trend is obesity escalation rather than slowdown, mainly driven by sharp increases in the obesity prevalence of low-income populations. Furthermore, an increasing number of high- and middle-income countries are currently experiencing an epidemic of severe obesity. In high-income populations, severe obesity is expected to double its prevalence from 10 to 20% between 2020 and 2035, posing an enormous threat for healthcare systems. Even if transiently stabilized, the obesity prevalence remains globally at unacceptably high levels, and there is no guarantee that the current stability (if any) will be maintained for long. In this review, we explore the underlying drivers of the global obesity epidemic; we provide possible explanations for the reported slowdown of the obesity rates in some countries; and we overall take a critical perspective on the obesity plateau hypothesis, emphasizing the urgent need for immediate effective actions at population and regional level in order to halt the alarming obesity escalation and its serious health risks.

The Effects of Bariatric Surgery on Pharmacokinetics of Drugs: a Review of Current Evidence.

PURPOSE OF REVIEW: Obesity constitutes a major public health concern and has been recognized as an epidemic. To date, bariatric surgery remains the most effective way for substantial long-lasting weight loss in severe obesity. The purpose of this review is to summarize how the pharmacokinetics of drugs are affected by the most common types of bariatric surgery, i.e., Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). RECENT FINDINGS: Limited data are available regarding the changes in pharmacokinetics of drugs after bariatric surgery. The lack of existing guidelines may lead patients to experience drug toxicity or therapeutic undertreatment. Pharmacokinetic parameters that need to be taken into consideration postoperatively include gastric motility, gastric volume, pH, surface area, bile secretions, carrier proteins, and first-pass metabolism. For drugs with a narrow therapeutic index, other factors need to be monitored closely, including plasma drug levels, patients' clinical outcomes, and laboratory markers. Patients should be followed up frequently and treated in accordance with their response to the drug therapy. Bariatric surgery may affect the pharmacokinetics of various drugs, due to the resultant anatomical changes and the substantial weight loss. Therefore, there is a need to identify those potential changes and adjust patients' medication doses in order to achieve higher efficacy and avoid toxicity.

Revisiting Resting Metabolic Rate: What is the Relation to Weight Fluctuations?

PURPOSE OF REVIEW: Despite the great progress in obesity-tackling strategies, a negative energy equilibrium between energy expenditure and energy intake remains the cornerstone in obesity management. The present review article aims to shed light on the complicated interrelations of resting metabolic rate to weight fluctuations. RECENT FINDINGS: Energy expenditure depends on body composition and is highly affected by weight changes, exerting a significant role in subsequent weight regain and underlining the metabolic resistance that people with obesity face when dealing with weight maintenance. The main tissue involved in energy expenditure is fat-free mass, as opposed to fat mass, which exerts a substantially lower impact. Although people with obesity display higher energy expenditures than their lean counterparts, these decrease substantially in the setting of weight loss. Metabolic adaptation is the difference between measured and predicted RMR after weight loss, either via lifestyle modification or after obesity surgery. Plausible explanations for this include differences in body composition, with loss of fat-free mass playing a significant role. This becomes especially apparent in the setting of rapid and massive weight loss, as in the case of bariatric surgery. A better understanding of energy expenditure pathophysiology may aid in further enhancing weight loss and promoting weight maintenance in people with obesity.

Real-world data show high efficacy of IL23 inhibitors guselkumab and risankizumab in psoriatic arthritis and difficult-to-treat areas.

BACKGROUND: Psoriasis and psoriatic arthritis are chronic inflammatory skin and joint diseases requiring effective therapies. Although clinical studies have shown the efficacy of IL-23 inhibitors, real-world data are limited. METHODS: We conducted a single-center retrospective Greek study enrolling patients with psoriatic arthritis and moderate-to-severe plaque psoriasis being treated at our multidisciplinary psoriasis outpatient clinic. Our aim was to investigate the efficacy and safety of IL-23 inhibitors guselkumab and risankizumab. Additionally, we sought to determine the clinical characteristics affecting treatment response. Primary endpoints were the evaluation of absolute Psoriasis Area and Severity Index (aPASI) and Disease Activity Index for Psoriatic Arthritis (DAPSA) at week 24. RESULTS: Fifty-nine patients (55.9% male, 69.5% early onset) with a mean age of 51.7 years were included. Twenty-four patients (40.7%) had a concomitant psoriatic arthritis. Obesity was the main comorbidity (49.2%) with a mean body mass index (BMI) of 31.3 kg/m2 . Additional comorbidities were hypertension (44.1%), dyslipidemia (32.2%), and diabetes (18.6%). Only eight patients (13.6%) were naïve to previous systemic treatments, whereas 40 patients (67.8%) were bio-experienced. A statistically significant improvement of aPASI and DAPSA was demonstrated after 4, 16, and 24 weeks of treatment (P < 0.05). IL23 blockers were also efficacious in difficult-to-treat areas. Clinical outcome was affected from previous treatment with biologics. Treatment response was the same between guselkumab and risankizumab (P > 0.05). CONCLUSION: This real-world study confirms the efficacy and safety of guselkumab and risankizumab in psoriatic arthritis and psoriasis reported from clinical trials.

Gut Microbiota and Its Role in the Brain-Gut-Kidney Axis in Hypertension.

PURPOSE OF REVIEW: The role of the gut microbiota in modulating blood pressure is increasingly being recognized, currently. The purpose of this review is to summarize recent findings about the mechanisms involved in hypertension with regard to the phenomenon of "gut dysbiosis." RECENT FINDINGS: Gut dysbiosis, i.e., the imbalance between the gut microbiota and the host, is characterized by a disruption of the tight junction proteins, such as occludins, claudins, and JAMs (junctional adhesion molecules), resulting in increased gut permeability or the so called "leaky gut." Due to the influence of genetic as well as environmental factors, various metabolites produced by the gut microbiota, such as indole and p-cresol, are increased. Thereby, uremic toxins, such as indoxyl sulfates and p-cresol sulfates, accumulate in the blood and the urine, causing damage in the podocytes and the tubular cells. In addition, immunological mechanisms are implicated as well. In particular, a switch from M2 macrophages to M1 macrophages, which produce pro-inflammatory cytokines, occurs. Moreover, a higher level of Th17 cells, releasing large amounts of interleukin-17 (IL-17), has been reported, when a diet rich in salt is consumed. Therefore, apart from the aggravation of uremic toxins, which may account for direct harmful effects on the kidney, there is inflammation not only in the gut, but in the kidneys as well. This crosstalk between the gut and the kidney is suggested to play a crucial role in hypertension. Notably, the brain is also implicated, with an increasing sympathetic output. The brain-gut-kidney axis seems to be deeply involved in the development of hypertension and chronic kidney disease (CKD). The notion that, by modulating the gut microbiota, we could regulate blood pressure is strongly supported by the current evidence. A healthy diet, low in animal protein and fat, and low in salt, together with the utilization of probiotics, prebiotics, synbiotics, or postbiotics, may contribute to our fight against hypertension.

Cardiometabolic effects of SGLT2 inhibitors on polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy affecting many women of reproductive age. Although its physiology is poorly understood, hyperandrogenemia and insulin resistance play a pivotal role in this complex syndrome, predisposing patients to a variety of cardiovascular and metabolic modalities. Current therapeutic options, including lifestyle modifications and medications, often do not satisfactorily improve clinical outcomes. SGLT2 inhibitors (SGLT-2i) are a novel option which can potentially improve many hormonal and metabolic parameters for patients with PCOS, though the net cardiovascular effects remain under investigation in this population of patients with PCOS. Overall, the use of SGLT-2i may be associated with beneficial somatometric, metabolic and hormonal outcomes of PCOS. To date, all available studies have recorded body mass index, waist and hip circumference, and fat mass reductions, improved insulin and androgen levels, and reduced blood pressure. The aim of the present review is to summarise PCOS-related manifestations and mechanisms leading to cardiovascular disease, to explore the cardiometabolic impact of SGLT2i on PCOS, and to critically analyse the cardiometabolic and hormonal outcomes of the recent studies on the use of SGLT2i in women with PCOS.

Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges.

Long COVID (LC) encompasses a constellation of long-term symptoms experienced by at least 10% of people after the initial SARS-CoV-2 infection, and so far it has affected about 65 million people. The etiology of LC remains unclear; however, many pathophysiological pathways may be involved, including viral persistence; a chronic, low-grade inflammatory response; immune dysregulation and a defective immune response; the reactivation of latent viruses; autoimmunity; persistent endothelial dysfunction and coagulopathy; gut dysbiosis; hormonal and metabolic dysregulation; mitochondrial dysfunction; and autonomic nervous system dysfunction. There are no specific tests for the diagnosis of LC, and clinical features including laboratory findings and biomarkers may not specifically relate to LC. Therefore, it is of paramount importance to develop and validate biomarkers that can be employed for the prediction, diagnosis and prognosis of LC and its therapeutic response, although this effort may be hampered by challenges pertaining to the non-specific nature of the majority of clinical manifestations in the LC spectrum, small sample sizes of relevant studies and other methodological issues. Promising candidate biomarkers that are found in some patients are markers of systemic inflammation, including acute phase proteins, cytokines and chemokines; biomarkers reflecting SARS-CoV-2 persistence, the reactivation of herpesviruses and immune dysregulation; biomarkers of endotheliopathy, coagulation and fibrinolysis; microbiota alterations; diverse proteins and metabolites; hormonal and metabolic biomarkers; and cerebrospinal fluid biomarkers. At present, there are only two reviews summarizing relevant biomarkers; however, they do not cover the entire umbrella of current biomarkers, their link to etiopathogenetic mechanisms or the diagnostic work-up in a comprehensive manner. Herein, we aim to appraise and synopsize the available evidence on the typical laboratory manifestations and candidate biomarkers of LC, their classification based on pathogenetic mechanisms and the main LC symptomatology in the frame of the epidemiological and clinical aspects of the syndrome and furthermore assess limitations and challenges as well as potential implications in candidate therapeutic interventions.

Obesity and Peripheral Artery Disease: Current Evidence and Controversies.

PURPOSE OF REVIEW: Obesity is a significant public health problem and a major risk factor for the development and progression of atherosclerosis and its cardiovascular manifestations. Lower extremity peripheral artery disease (PAD) affects 3%-10% of the Western population and, if left untreated, can lead to devastating outcomes with both an increased risk of morbidity and mortality. Interestingly, the association between obesity and PAD remains debatable. Whereas it is well known that PAD and obesity frequently overlap in the same patients, many studies have demonstrated a negative association between obesity and PAD and a protective effect of obesity on disease development and progression, a phenomenon described as the "obesity paradox." Possible mechanisms for this paradox may include genetic background, as assessed by mendelian randomization studies, adipose tissue dysfunction, and body fat distribution rather than adiposity, while other factors, such as sex, ethnicity, sarcopenia in the elderly population, or aggressive treatment of co-existing metabolic conditions in individuals with obesity compared to those with normal weight, could have some impact as well. RECENT RINDINGS: Few reviews and meta-analyses examining systematically the relationship between obesity and PAD exist. The impact of PAD development due to the presence of obesity remains largely controversial. However, the most current evidence, backed by a recent meta-analysis, suggests a potential protective role of a higher body mass index on PAD-related complications and mortality. In this review, we discuss the association between obesity and PAD development, progression, and management, and the potential pathophysiologic mechanisms linking the two diseases.

Diagnostic and Prognostic Value of Serum Omentin-1 in Sepsis: A Prospective Study in Critically Ill Patients.

Background and Objectives: Omentin-1, also known as intelectin-1, is a novel adipokine with anti-inflammatory activities implicated in inflammatory diseases and sepsis. We aimed to explore serum omentin-1 and its kinetics in critically ill patients early in sepsis and its association with severity and prognosis. Materials and Methods: Serum omentin-1 was determined in 102 critically ill patients with sepsis during the first 48 h from sepsis onset and 1 week later, and in 102 age- and gender-matched healthy controls. The outcome of sepsis at 28 days after enrollment was recorded. Results: Serum omentin-1 at enrollment was significantly higher in patients compared to controls (763.3 ± 249.3 vs. 451.7 ± 122.3 µg/L, p < 0.001) and it further increased 1 week after (950.6 ± 215.5 vs. 763.3 ± 249.3 µg/L, p < 0.001). Patients with septic shock (n = 42) had higher omentin-1 compared to those with sepsis (n = 60) at enrollment (877.9 ± 241.2 vs. 683.1 ± 223.7 µg/L, p < 0.001) and 1 week after (1020.4 ± 224.7 vs. 901.7 ± 196.3 µg/L, p = 0.007). Furthermore, nonsurvivors (n = 30) had higher omentin-1 at sepsis onset (952.1 ± 248.2 vs. 684.6 ± 204.7 µg/L, p < 0.001) and 1 week after (1051.8 ± 242 vs. 908.4 ± 189.8 µg/L, p < 0.01). Patients with sepsis and survivors presented higher kinetics than those with septic shock and nonsurvivors (Δ(omentin-1)% 39.8 ± 35.9% vs. 20.2 ± 23.3%, p = 0.01, and 39.4 ± 34.3% vs. 13.3 ± 18.1%, p < 0.001, respectively). Higher omentin-1 at sepsis onset and 1 week after was an independent predictor of 28-day mortality (HR 2.26, 95% C.I. 1.21-4.19, p = 0.01 and HR: 2.15, 95% C.I. 1.43-3.22, p < 0.001, respectively). Finally, omentin-1 was significantly correlated with the severity scores, the white blood cells, coagulation biomarkers, and CRP, but not procalcitonin and other inflammatory biomarkers. Conclusions: Serum omentin-1 is increased in sepsis, while higher levels and lower kinetics during the first week of sepsis are associated with the severity and 28-day mortality of sepsis. Omentin-1 may be a promising biomarker of sepsis. However, more studies are needed to explore its role in sepsis.