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.

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.

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.

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.

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.

The Role of Next-Generation Probiotics in Obesity and Obesity-Associated Disorders: Current Knowledge and Future Perspectives.

Obesity and obesity-associated disorders pose a major public health issue worldwide. Apart from conventional weight loss drugs, next-generation probiotics (NGPs) seem to be very promising as potential preventive and therapeutic agents against obesity. Candidate NGPs such as Akkermansia muciniphila, Faecalibacterium prausnitzii, Anaerobutyricum hallii, Bacteroides uniformis, Bacteroides coprocola, Parabacteroides distasonis, Parabacteroides goldsteinii, Hafnia alvei, Odoribacter laneus and Christensenella minuta have shown promise in preclinical models of obesity and obesity-associated disorders. Proposed mechanisms include the modulation of gut flora and amelioration of intestinal dysbiosis, improvement of intestinal barrier function, reduction in chronic low-grade inflammation and modulation of gut peptide secretion. Akkermansia muciniphila and Hafnia alvei have already been administered in overweight/obese patients with encouraging results. However, safety issues and strict regulations should be constantly implemented and updated. In this review, we aim to explore (1) current knowledge regarding NGPs; (2) their utility in obesity and obesity-associated disorders; (3) their safety profile; and (4) their therapeutic potential in individuals with overweight/obesity. More large-scale, multicentric and longitudinal studies are mandatory to explore their preventive and therapeutic potential against obesity and its related disorders.

Therapeutic Potential of GLP-2 Analogs in Gastrointestinal Disorders: Current Knowledge, Nutritional Aspects, and Future Perspectives.

PURPOSE OF REVIEW: Although Glucagon-like peptide (GLP)-1 receptor agonists have been used for almost two decades in the treatment of diabetes mellitus type 2 and, lately, in obesity, recent years have seen an increasing interest in the pharmacological agonism of other proglucagon-derived peptides, including GLP-2. Herein, we aimed to review the available evidence on the effects of GLP-2 agonism from animal and clinical studies. Furthermore, we summarize the current clinical applications of GLP-2 agonists among patients with intestinal failure associated with short bowel syndrome (SBS-IF) as well as potential future expansion of their indications to other intestinal disorders. RECENT FINDINGS: Evidence from preclinical studies has highlighted the cellular trophic and functional beneficial actions of GLP-2 on small intestinal and colonic mucosa. Subsequently, pharmacologic agonism of GLP-2 has gathered interest for the treatment of patients with conditions pertaining to the loss of intestinal anatomical and/or functional integrity to a degree requiring parenteral support, collectively referred to as intestinal failure. GLP-2 analogs positively influence nutrient absorption in animal models and humans, although continued therapy is likely needed for sustained effects. The degradation-resistant GLP-2-analog teduglutide has received approval for the treatment of SBS-IF, in which it may decisively reduce patient dependency on parenteral support and improve quality of life. Another two longer-acting analogs, glepaglutide and apraglutide, are currently undergoing phase III clinical trials. The use of GLP-2 analogs is effective in the management of SBS-IF and may show promise in the treatment of other severe gastrointestinal disorders associated with loss of effective intestinal resorptive surface area.

Circulating Chemerin and Its Kinetics May Be a Useful Diagnostic and Prognostic Biomarker in Critically Ill Patients with Sepsis: A Prospective Study.

Chemerin, a novel adipokine, is a potent chemoattractant molecule with antimicrobial properties, implicated in immune responses. Our aim was to investigate circulating chemerin and its kinetics, early in sepsis in critically ill patients and its association with severity and prognosis. Serum chemerin was determined in a cohort of 102 critically ill patients with sepsis during the first 48 h from sepsis onset and one week later, and in 102 age- and gender-matched healthy controls. Patients were followed for 28 days and their outcomes were recorded. Circulating chemerin was significantly higher in septic patients at onset compared to controls (342.3 ± 108.1 vs. 200.8 ± 40.1 µg/L, p < 0.001). Chemerin decreased significantly from sepsis onset to one week later (342.3 ± 108.1 vs. 308.2 ± 108.5 µg/L, p < 0.001), but remained higher than in controls. Chemerin was higher in patients presenting with septic shock than those with sepsis (sepsis onset: 403.2 ± 89.9 vs. 299.7 ± 99.5 µg/L, p < 0.001; one week after: 374.9 ± 95.3 vs. 261.6 ± 91.9 µg/L, p < 0.001), and in nonsurvivors than survivors (sepsis onset: 427.2 ± 96.7 vs. 306.9 ± 92.1 µg/L, p < 0.001; one week after: 414.1 ± 94.5 vs. 264.2 ± 79.9 µg/L, p < 0.001). Moreover, patients with septic shock and nonsurvivors, presented a significantly lower absolute and relative decrease in chemerin one week after sepsis onset compared to baseline (p < 0.001). Based on ROC curve analyses, the diagnostic performance of chemerin (AUC 0.78, 95% CI 0.69-0.87) was similar to C-reactive protein (CRP) (AUC 0.78, 95% CI 0.68-0.87) in discriminating sepsis severity. However, increased chemerin at sepsis onset and one week later was an independent predictor of 28-day mortality (sepsis onset: HR 3.58, 95% CI 1.48-8.65, p = 0.005; one week after: HR 10.01, 95% CI 4.32-23.20, p < 0.001). Finally, serum chemerin exhibited significant correlations with the severity scores, white blood cells, lactate, CRP and procalcitonin, as well as with biomarkers of glucose homeostasis, but not with cytokines and soluble urokinase-type plasminogen activator receptor (suPAR). Circulating chemerin is increased early in sepsis and its kinetics may have diagnostic and prognostic value in critically ill patients. Further studies are needed to shed light on the role of chemerin in sepsis.

Could inhaled corticosteroids be the game changers in the prevention of severe COVID-19? A review of current evidence.

As the Coronavirus 2019 disease (COVID-19) pandemic is going through its second year, the world is counting more than 4.9 million lives lost. Many repurposed immunomodulatory drugs have been tried and failed to treat COVID-19. The only successful treatments that improve survival are systemic corticosteroids and tocilizumab, by targeting the systemic inflammatory cascade. An intriguing observation that patients with chronic respiratory disease seem to be less prone to COVID-19 gave ground to the hypothesis that inhaled corticosteroids (ICS) may protect them from SARS-CoV-2 infection. In this review, we summarize current evidence regarding the therapeutic role of inhaled and systemic corticosteroids in COVID-19, and we present experimental data on the potential actions of ICS against SARS-CoV-2 infection. We also discuss safety issues as well as therapeutic considerations and clinical implications of the use of ICS in COVID-19. Four randomized controlled trials (RCT) with more than 3000 participants suggest that ICS may lead to earlier clinical improvement and lower rate of hospitalization in patients with mild COVID-19, while 9 ongoing RCTs are anticipated to provide more evidence for the use of ICS in COVID-19. Recent evidence has shown promise that ICS could provide tangible benefits to patients suffering from COVID-19.

Circulating Omentin-1 as a Biomarker at the Intersection of Postmenopausal Breast Cancer Occurrence and Cardiometabolic Risk: An Observational Cross-Sectional Study.

Aberrant circulating omentin-1, which is an anti-inflammatory and pro-apoptotic adipokine, has been reported in various solid tumors. Therefore, we investigated whether or not circulating omentin-1 could be associated with postmenopausal BC (PBC) and could be used as a potential diagnostic and clinical tool taking into consideration clinicopathologic features, tumor markers, as well as anthropometric, metabolic, and inflammatory parameters. Serum omentin-1, tumor markers (CA15-3 and CEA); metabolic (insulin, glucose, HOMA index, and serum lipids), anthropometric (BMI, waist circumference, and fat mass), and inflammatory (TNF-α, IL-6, hsCRP) parameters; classic adipokines (leptin and adiponectin); the Mediterranean diet (MedDiet) score; and cardiovascular (CVD) risk were determined in 103 postmenopausal women with pathologically confirmed incident invasive BC, 103 controls matched on age, 51 patients with benign breast lesions (BBL), and 50 obese postmenopausal women of similar age. The mean serum omentin-1 was significantly lower in cases than in controls and patients with BBL (p < 0.001). In the patients, omentin-1 was inversely associated with tumor, metabolic and inflammatory biomarkers, cancer stage, and the number of infiltrated lymph nodes (p < 0.05). In all study participants, omentin-1 was negatively correlated with CVD risk and positively correlated with MedDiet score. Lower circulating omentin-1 was independently associated with PBC occurrence above and beyond known risk factors. According to the ROC curve analysis, the overall diagnostic performance of omentin-1 (0.84, 95% CI 0.79-0.89) is similar to CA15-3. Circulating omentin-1 may be a biomarker at the intersection of PBC and cardiometabolic risk in postmenopausal women, and could be modulated by the adoption of a MedDiet. Further mechanistic and large multicentric prospective and longitudinal studies are required to elucidate the ontological role of omentin-1 in BC and CVD risks, as well as its diagnostic and prognostic ability and its therapeutic potential.

Mycobiome and Cancer: What Is the Evidence?

BACKGROUND: To date, most researchhas focused on the bacterial composition of the human microbiota. In this review, we synopsize recent data on the human mycobiome and cancer, highlighting specific cancer types based on current available evidence, presenting interesting perspectives and limitations of studies and laboratory methodologies. RECENT FINDINGS: Head and neck cancer carcinoma (HNCC), colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDA) have been associated with dissimilarities in the composition of mycobiota between cancer cases and non-cancer participants. Overall, fungal dysbiosis with decreased fungal richness and diversity was common in cancer patients; however, a specific mycobiotic signature in HNSCC or CRC has not emerged. Different strains of Candida albicans have been identified among cases with HNCC, whilst Lichtheimia corymbifera, a member of the Mucoraceae family, has been shown to predominate among patients with oral tongue cancer. Virulence factors of Candida spp. include the formation of biofilm and filamentation, and the secretion of toxins and metabolites. CRC patients present a dysregulated ratio of Basidiomycota/Ascomycota. Abundance of Malassezia has been linked to the occurrence and progression of CRC and PDA, particularly in animal models of PDA. Interestingly, Schizophyllum, a component of the oral mycobiome, may exhibit anti-cancer potential. CONCLUSION: The human mycobiome, per se, along with its interactions with the human bacteriome and the host, may be implicated in the promotion and progression of carcinogenesis. Fungi may be used as diagnostic and prognostic/predictive tools or treatment targets for cancer in the coming years. More large-scale, prospective, multicentric and longitudinal studies with an integrative multi-omics methodology are required to examine the precise contribution of the mycobiome in the etiopathogenesis of cancer, and to delineate whether changes that occur in the mycobiome are causal or consequent of cancer.

Anti-viral treatment for SARS-CoV-2 infection: A race against time amidst the ongoing pandemic.

Remdesivir (GS-5734), a drug initially developed to treat hepatitis C and Ebola virus disease, was the first approved treatment for severe coronavirus disease 2019 (COVID-19). However, apart from remdesivir, there is a paucity of other specific anti-viral agents against SARS-CoV-2 infection. In 2017, researchers had documented the anti-coronavirus potential of remdesivir in animal models. At the same time, trials performed during two Ebola outbreaks in Africa showed that the drug was safe. Although vaccines against SARS-CoV-2 infection have emerged at an enormously high speed, equivalent results from efforts towards the development of anti-viral drugs, which could have played a truly life-saving role in the current stage of the pandemic, have been stagnating. In this review, we will focus on the current treatment options for COVID-19 which mainly consist of repurposed agents or treatments conferring passive immunity (convalescent plasma or monoclonal antibodies). Additionally, potential specific anti-viral therapies under development will be reviewed, such as the decoy miniprotein CTC-445.2d, protease inhibitors, mainly against the Main protein Mpro, nucleoside analogs, such as molnupiravir and compounds blocking the replication transcription complex proteins, such as zotatifin and plitidepsin. These anti-viral agents seem to be very promising but still require meticulous clinical trial testing in order to establish their efficacy and safety. The continuous emergence of viral variants may pose a real challenge to the scientific community towards that end. In this context, the advent of nanobodies together with the potential administration of a combination of anti-viral drugs could serve as useful tools in the armamentarium against COVID-19.

Vitamin D and Obesity: Current Evidence and Controversies.

PURPOSE OF REVIEW: Evidence from observational studies suggests that obesity is associated with low vitamin D. As both obesity and hypovitaminosis D present an alarmingly increased prevalence worldwide, there is an intense research interest to clarify all aspects of this association. This review summarizes current evidence from meta-analyses investigating vitamin D status in obesity, including the effects of weight loss and bariatric surgery on vitamin D status and the outcomes of vitamin D supplementation on body weight. We also discuss potential pathophysiologic mechanisms and important controversies. RECENT FINDINGS: Data from meta-analyses consistently support an inverse association of vitamin D levels with body weight. However, the impact of weight loss on improving vitamin D status is small, while studies on the supplementation with vitamin D after bariatric surgery have shown conflicting results regarding vitamin D status. Moreover, interventional studies do not support a beneficial effect of vitamin D supplementation on body weight. These findings warrant a cautious interpretation due to important methodological limitations and confounding factors, such as high heterogeneity of studies, variable methods of determination of vitamin D and definition of deficiency/insufficiency, use of various adiposity measures and definitions of obesity, and inadequate adjustment for confounding variables influencing vitamin D levels. The underlying pathogenetic mechanisms associating low vitamin D in obesity include volumetric dilution, sequestration into adipose tissue, limited sunlight exposure, and decreased vitamin D synthesis in the adipose tissue and liver. Experimental studies have demonstrated that low vitamin D may be implicated in adipose tissue differentiation and growth leading to obesity either by regulation of gene expression or through modulation of parathyroid hormone, calcium, and leptin. Obesity is associated with low vitamin D status but weight loss has little effect on improving this; vitamin D supplementation is also not associated with weight loss. Evidence regarding vitamin D status after bariatric surgery is contradicting. The link between vitamin D and obesity remains controversial due to important limitations and confounding of studies. More research is needed to clarify the complex interplay between vitamin D and adiposity.

Understanding the Co-Epidemic of Obesity and COVID-19: Current Evidence, Comparison with Previous Epidemics, Mechanisms, and Preventive and Therapeutic Perspectives.

PURPOSE OF REVIEW: A growing body of evidence suggests that obesity and increased visceral adiposity are strongly and independently linked to adverse outcomes and death due to COVID-19. This review summarizes current epidemiologic data, highlights pathogenetic mechanisms on the association between excess body weight and COVID-19, compares data from previous pandemics, discusses why COVID-19 challenges the "obesity paradox," and presents implications in prevention and treatment as well as future perspectives. RECENT FINDINGS: Data from meta-analyses based on recent observational studies have indicated that obesity increases the risks of infection from SARS-CoV-2, severe infection and hospitalization, admission to the ICU and need of invasive mechanical ventilation (IMV), and the risk of mortality, particularly in severe obesity. The risks of IMV and mortality associated with obesity are accentuated in younger individuals (age ≤ 50 years old). The meta-inflammation in obesity intersects with and exacerbates underlying pathogenetic mechanisms in COVID-19 through the following mechanisms and factors: (i) impaired innate and adaptive immune responses; (ii) chronic inflammation and oxidative stress; (iii) endothelial dysfunction, hypercoagulability, and aberrant activation of the complement; (iv) overactivation of the renin-angiotensin-aldosterone system; (v) overexpression of the angiotensin-converting enzyme 2 receptor in the adipose tissue; (vi) associated cardiometabolic comorbidities; (vii) vitamin D deficiency; (viii) gut dysbiosis; and (ix) mechanical and psychological issues. Mechanistic and large epidemiologic studies using big data sources with omics data exploring genetic determinants of risk and disease severity as well as large randomized controlled trials (RCTs) are necessary to shed light on the pathways connecting chronic subclinical inflammation/meta-inflammation with adverse COVID-19 outcomes and establish the ideal preventive and therapeutic approaches for patients with obesity.

Adherence to the Mediterranean diet is an independent predictor of circulating vitamin D levels in normal weight and non-smoker adults: an observational cross-sectional study.

We explored the association between circulating 25OHD and adherence to the Mediterranean Diet (MedDiet) in 402 Greek (21-65 years, 188 men and 214 women), normal weight, non-smoker, healthy volunteers in the Athens metropolitan area during summer and autumn, taking into account skin phototype, anthropometric, and lifestyle variables. Circulating 25OHD, parathormone, creatinine, calcium, and phosphate were determined. A vitamin D status of ≤25, ≤50, and ≤75 nmol/L was observed in 4.5, 37.3, and 74.1% of the subjects, respectively. The independent predictors of 25OHD deficiency were autumn, darker skin phototype, BMI, or waist circumference (WC), sunscreen use, less physical outdoor activity, and less adherence to the MedDiet. Higher intake of fish and olive oil was a positive independent predictor of elevated circulating 25OHD levels. In conclusion, higher adherence to the MedDiet, fish and olive oil consumption, were positively associated with circulating 25OHD independently from BMI or WC, skin phototype, season, and physical activity.

Diabetes Mellitus and SARS-CoV-2 Infection: Pathophysiologic Mechanisms and Implications in Management.

INTRODUCTION: Currently, diabetes mellitus (DM), as well as coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are major public health issues worldwide. BACKGROUND: It has been suggested that patients with DM are more vulnerable to SARS-CoV-2 infection and suffer from more severe forms of the disease. METHODS: A literature search was performed using PubMed, Scopus, and Google search engines. RESULTS: Angiotensin-converting enzyme-2 (ACE2) is the major receptor of SARS-CoV-2 in the human host. The differential expression of ACE2 in the lungs of patients with DM makes them more susceptible to COVID-19. Additionally, acute or chronic hyperglycemia renders individuals in an immune-suppressive state, with impaired innate and adaptive immunity function, also contributing to the severity of COVID-19 infection among patients with DM. Other factors contributing to a more severe course of COVID-19 include the coexistence of obesity in T2DM, the endothelial inflammation induced by the SARS-CoV-2 infection, which aggravates the endothelial dysfunction observed in both T1DM and T2DM, and the hypercoagulability presented in COVID-19 infection that increases the thrombotic tendency in DM. CONCLUSION: This review summarizes the pathophysiologic mechanisms underlying the coexistence of both pandemics as well as the current recommendations and future perspectives regarding the optimal treatment of inpatients and outpatients with DM in the era of SARS-CoV-2 infection. Notably, the currently recommended drugs for the treatment of severe COVID-19, dexamethasone and remdesivir, may cause hyperglycemia, an adverse effect that physicians should bear in mind when caring for patients with DM and COVID-19.

Understanding the Role of the Gut Microbiome and Microbial Metabolites in Non-Alcoholic Fatty Liver Disease: Current Evidence and Perspectives.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD begins as a relatively benign hepatic steatosis which can evolve to non-alcoholic steatohepatitis (NASH); the risk of cirrhosis and hepatocellular carcinoma (HCC) increases when fibrosis is present. NAFLD represents a complex process implicating numerous factors-genetic, metabolic, and dietary-intertwined in a multi-hit etiopathogenetic model. Recent data have highlighted the role of gut dysbiosis, which may render the bowel more permeable, leading to increased free fatty acid absorption, bacterial migration, and a parallel release of toxic bacterial products, lipopolysaccharide (LPS), and proinflammatory cytokines that initiate and sustain inflammation. Although gut dysbiosis is present in each disease stage, there is currently no single microbial signature to distinguish or predict which patients will evolve from NAFLD to NASH and HCC. Using 16S rRNA sequencing, the majority of patients with NAFLD/NASH exhibit increased numbers of Bacteroidetes and differences in the presence of Firmicutes, resulting in a decreased F/B ratio in most studies. They also present an increased proportion of species belonging to Clostridium, Anaerobacter, Streptococcus, Escherichia, and Lactobacillus, whereas Oscillibacter, Flavonifaractor, Odoribacter, and Alistipes spp. are less prominent. In comparison to healthy controls, patients with NASH show a higher abundance of Proteobacteria, Enterobacteriaceae, and Escherichia spp., while Faecalibacterium prausnitzii and Akkermansia muciniphila are diminished. Children with NAFLD/NASH have a decreased proportion of Oscillospira spp. accompanied by an elevated proportion of Dorea, Blautia, Prevotella copri, and Ruminococcus spp. Gut microbiota composition may vary between population groups and different stages of NAFLD, making any conclusive or causative claims about gut microbiota profiles in NAFLD patients challenging. Moreover, various metabolites may be involved in the pathogenesis of NAFLD, such as short-chain fatty acids, lipopolysaccharide, bile acids, choline and trimethylamine-N-oxide, and ammonia. In this review, we summarize the role of the gut microbiome and metabolites in NAFLD pathogenesis, and we discuss potential preventive and therapeutic interventions related to the gut microbiome, such as the administration of probiotics, prebiotics, synbiotics, antibiotics, and bacteriophages, as well as the contribution of bariatric surgery and fecal microbiota transplantation in the therapeutic armamentarium against NAFLD. Larger and longer-term prospective studies, including well-defined cohorts as well as a multi-omics approach, are required to better identify the associations between the gut microbiome, microbial metabolites, and NAFLD occurrence and progression.

Is There an Obesity Paradox in Critical Illness? Epidemiologic and Metabolic Considerations.

PURPOSE OF REVIEW: Obesity represents a global epidemic with serious implications in public health due to its increasing prevalence and its known association with a high morbidity and mortality burden. However, a growing number of data support a survival benefit of obesity in critical illness. This review summarizes current evidence regarding the obesity paradox in critical illness, discusses methodological issues and metabolic implications, and presents potential pathophysiologic mechanisms. RECENT FINDINGS: Data from meta-analyses and recent studies corroborate the obesity-related survival benefit in critically ill patients as well as in selected populations such as patients with sepsis and acute respiratory distress syndrome, but not trauma. However, this finding warrants a cautious interpretation due to certain methodological limitations of these studies, such as the retrospective design, possible selection bias, the use of BMI as an obesity index, and inadequate adjustment for confounding variables. Main pathophysiologic mechanisms related to obesity that could explain this phenomenon include higher energy reserves, inflammatory preconditioning, anti-inflammatory immune profile, endotoxin neutralization, adrenal steroid synthesis, renin-angiotensin system activation, cardioprotective metabolic effects, and prevention of muscle wasting. The survival benefit of obesity in critical illness is supported from large meta-analyses and recent studies. Due to important methodological limitations, more prospective studies are needed to further elucidate this finding, while future research should focus on the pathophysiologic role of adipose tissue in critical illness.

Deciphering the Association Between Psoriasis and Obesity: Current Evidence and Treatment Considerations.

PURPOSE OF REVIEW: Obesity and psoriasis represent chronic inflammatory states that are interconnected in a vicious cycle, sharing also a degree of synergy. In this review, we aim to decipher the various lines of evidence supporting the bidirectional association between psoriasis and obesity highlighting their pathophysiologic connections as well as we attempt to strategize a therapeutic holistic approach for obese psoriatic patients. RECENT FINDINGS: Recent meta-analyses have shown that (1) genetically higher BMI increased the odds of psoriasis occurrence; (2) obesity is associated with higher incidence and prevalence of psoriasis as well as psoriasis severity; (3) obesity is associated with lower efficacy to anti-TNF agents and may predict biologic treatment discontinuation; and (4) weight loss through diet and physical exercise may improve pre-existing psoriasis and prevent from de novo psoriasis. Methotrexate, acitretin, and cyclosporine could worsen hypertension, liver steatosis, and dyslipidemia. Since infliximab and ustekinumab are weight adjusted, they may be ideal drugs to treat obese psoriatic patients. IL-17 inhibitors are very effective independently from body weight; however, they tend to present better clearance rates in normal weight patients. There is a paucity on weight data regarding the efficacious IL-23 inhibitors. Apremilast may induce weight loss as an adverse effect presenting also some beneficial metabolic actions. Finally, simvastatin and some antidiabetic drugs could decrease psoriasis severity. More mechanistic, observational studies and well-conducted RCTs are necessary to decipher the enigmatic link between psoriasis and obesity, and to provide evidence-based specific guidelines for the screening and management of obese psoriatic patients.