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Natriuretic peptides (NPs) are polypeptide hormones involved in the homeostasis of the cardiovascular system. They are produced by cardiomyocytes and regulate circulating blood volume and sodium concentration. Clinically, measurements of brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are recommended by international guidelines as evidence is accumulating on their usefulness. They have a high negative predictive value, and in the setting of low NPs, a diagnosis of heart failure (HF) can be safely excluded in both emergency (BNP < 100 pg/mL, NT-proBNP < 300 pg/mL) and outpatient settings (BNP < 35 pg/mL and NT-proBNP < 125 pg/mL). Moreover, the 2023 consensus from the European Society of Cardiology suggests threshold values for inclusion diagnosis. These values are also associated with increased risks of major cardiovascular events, cardiovascular mortality, and all-cause mortality whether measured in inpatient or outpatient settings. Among patients without known HF, but at high risk of developing it (e.g., in the setting of diabetes mellitus, hypertension, or atherosclerotic cardiovascular disease), NPs may be useful in stratifying cardiovascular risk, optimizing therapy, and reducing the risk of developing overt HF. In the diabetes setting, risk stratification with the use of these peptides can guide the physician to a more informed and appropriate therapeutic choice as recommended by guidelines. Notably, NP levels should be carefully interpreted in light of certain conditions that may affect their reliability, such as chronic kidney disease and obesity, as well as demographic variables, including age and sex. In conclusion, NPs are useful in the diagnosis and prognosis of HF, but they also offer advantages in the primary prevention setting.

Context: Patients with diabetes are at increased risk of dying from liver-related events, but little is known on whether this increased risk has changed in recent years., Objective: The aim of the present study is to describe time trends in cause-specific liver-related mortality in people with and without diabetes from the general Italian population., Methods: Data were retrieved from the health care utilization databases of Lombardy, a region of Italy that accounts for about 16% (almost 10 million) of its population. Annual cause-specific mortality rates and proportionate mortality were computed among individuals with and without diabetes from 2010 to 2019. Liver-related deaths were categorized as viral, alcohol related, and nonviral nonalcohol related (NVNA)., Results: Liver diseases were responsible for 2% and 1% of deaths in people with and without diabetes (2019). Among patients with diabetes, the crude mortality rate for liver diseases decreased from 1.13 to 0.64 deaths per 1000 person-years from 2010 to 2019. The largest proportion of liver-related deaths was attributable to NVNA diseases and it increased from 63% in 2010 to 68% in 2019, with a corresponding relative reduction of viral causes (from 27% to 23%). The standardized mortality ratio for patients with diabetes was 3.35 (95% CI 2.96-3.76) for NVNA, 1.66 (95% CI 1.33-2.01) for viral hepatitis, and 1.61 (95% CI 1.13-2.17) for alcoholic liver disease and it remained relatively stable over time. Excess mortality risk in patients with diabetes for liver-related mortality was higher than for cardiovascular mortality and cancer., Conclusion: While liver-related mortality rates decreased significantly among patients with diabetes, NVNA causes made up the majority of cases. Excess mortality for liver-related causes in patients with diabetes compared with controls remained constant in the studied period., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

A recent Delphi consensus proposed a new definition for metabolic dysfunction associated steatotic liver disease (MASLD) and introduced a disease entity called MetALD, a condition in which steatotic liver disease (SLD), metabolic dysfunction and moderate alcohol intake coexist. Given the limited available data on the prognostic implications of these disease entities, we performed a systematic review and meta-analysis of available cohort studies to evaluate the association of MASLD and MetALD with hard clinical outcomes. We included 5 studies for a total of 9 824 047 participants. Compared with participants without SLD, increased rates of all-cause mortality and incident cardiovascular disease were present for both MASLD and MetALD. Moreover, MetALD was also associated with significantly higher risks of cancer-related mortality (n = 2 studies, random-effects HR 2.10, 95% CI 1.35-3.28) and cardiovascular mortality (n = 3 studies, random-effects HR 1.17, 95% CI 1.12-1.22). Although preliminary, available evidence indicates a more unfavourable prognosis for patients with MetALD compared with those with MASLD., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Clinical trials have shown that in type 2 diabetes mellitus (T2D) resting office heart rate (HR) values > 70 beats/minute are associated with an increased cardiovascular risk, a worse prognosis and an unfavorable outcome. The present study was aimed at investigating whether the above mentioned treshold HR values reflect a sympathetic overdrive of marked degree., Methods: In 58 T2D patients (age range: 39-57 years) without signs of autonomic neuropathy and in 52 age-matched healthy controls, we assessed muscle sympathetic nerve activity (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC), subdividing the study population in different subgroups according to their clinic and 24-h HR values., Results: In T2D progressively greater clinic and 24-h HR values were accompanied by progressive increases in MSNA and NE. HR cutoff values indicated by clinical trials as associated with an increased cardiovascular risk (> 70 beats/minute) were accompanied by MSNA values significantly higher than those detected in patients with lower HR, this being the case also for NE. In T2D both MSNA and NE were significantly related to clinic (r = 0.93, P < 0.0001 and r = 0.87, P < 0.0001, respectively) and 24-h (r = 0.92, P < 0.0001 and r = 0.84, P < 0.0001, respectively) HR. The MSNA and NE behaviour observed in T2D was not detected in healthy controls., Conclusions: In T2D clinic HR values allow to detect patients with a greater sympathetic overactivity. Considering the adverse clinical impact of the sympathetic overdrive on prognosis, our data emphasize the need of future studies investigating the potential usefulness of lifestyle and pharmacological interventions exerting sympathomodulatory effects., (© 2024. The Author(s).)

Despite the availability of new classes of glucose-lowering drugs that improve glycaemic levels and minimise long-term complications, at least 20-25% of people with type 2 diabetes require insulin therapy. Moreover, a substantial proportion of these individuals do not achieve adequate metabolic control following insulin initiation. This is due to several factors: therapeutic inertia, fear of hypoglycaemia and/or weight gain, poor communication, complexity of insulin titration, and the number of injections needed, with the associated reduced adherence to insulin therapy. Once-weekly insulins provide a unique opportunity to simplify basal insulin therapy and to allow good glycaemic control with a low risk of hypoglycaemia. Several approaches to developing a stable and effective once-weekly insulin have been proposed, but, to date, insulin icodec and basal insulin Fc (insulin efsitora alfa) are the only two formulations for which clinical studies have been reported. The results of Phase I and II studies emphasise both efficacy (in term of glucose levels) and potential risks and adverse events. Phase III studies involving insulin icodec are reassuring regarding the risk of hypoglycaemia compared with daily basal insulin analogues. Despite some concerns raised in ongoing clinical trials, the available data suggest that weekly insulins may also be an option for individuals with type 1 diabetes, especially when adherence is suboptimal. For the first time there is an opportunity to make an important breakthrough in basal insulin therapy, particularly in people with type 2 diabetes, and to improve not only the quality of life of people with diabetes, but also the practice of diabetologists., (© 2024. The Author(s).)

Type 2 diabetes represents a growing challenge for global public health. Its prevalence is increasing worldwide, and, like obesity, it affects progressively younger populations compared to the past, with potentially greater impact on chronic complications. Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge. Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity. In this context, the aim of the present document is to summarize, in the form of a narrative literature review, the currently available data on the main mechanisms of action of GIP/GLP-1 co-agonists and the clinical effects of tirzepatide evaluated in various clinical trials., (© 2024. The Author(s).)

Objective: The purpose of this study was to determine the effectiveness of a new AI-based tool called NAIF (NAFLD-AI-Fibrosis) in identifying individuals from the general population with advanced liver fibrosis (stage F3/F4). We compared NAIF's performance to two existing risk score calculators, aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 (Fib4)., Methods: To set up the algorithm for diagnosing severe liver fibrosis (defined as Fibroscan® values E ≥ 9.7 KPa), we used 19 blood biochemistry parameters and two demographic parameters in a group of 5,962 individuals from the NHANES population (2017-2020 pre-pandemic, public database). We then assessed the algorithm's performance by comparing its accuracy, precision, sensitivity, specificity, and F1 score values to those of APRI and Fib4 scoring systems., Results: In a kept-out sub dataset of the NHANES population, NAIF achieved a predictive precision of 72 %, a sensitivity of 61 %, and a specificity of 77 % in correctly identifying adults (aged 18-79 years) with severe liver fibrosis. Additionally, NAIF performed well when tested with two external datasets of Italian patients with a Fibroscan® score E ≥ 9.7 kPa, and with an external dataset of patients with diagnosis of severe liver fibrosis through biopsy., Conclusions: The results of our study suggest that NAIF, using routinely available parameters, outperforms in sensitivity existing scoring methods (Fib4 and APRI) in diagnosing severe liver fibrosis, even when tested with external validation datasets. NAIF uses routinely available parameters, making it a promising tool for identifying individuals with advanced liver fibrosis from the general population. Word count abstract: 236., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: To evaluate the impact of adherence to glucagon like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose transporter two inhibitors (SGLT2-I) on clinical outcomes and costs in patients with type 2 diabetes mellitus (T2DM)., Materials and Methods: The 121,115 residents of the Lombardy Region (Italy) aged ≥40 years newly treated with metformin during 2007-2015 were followed to identify those who started therapy with GLP1-RA or SGLT2-I. Adherence to drug therapy over the first year was defined as the proportion of days covered >80%. Within each drug class, for each adherent patient, one non-adherent patient was matched for age, sex, duration, adherence to metformin treatment and propensity score. The primary clinical outcome was a composite of insulin initiation, hospitalisation for micro- and macrovascular complications and all-cause mortality after the first year of drug treatment. Costs were evaluated based on reimbursements from the national healthcare system., Results: After matching, 1182 pairs of adherent and non-adherent GLP1-RA users and 1126 pairs of adherent and non-adherent SGLT2-I users were included. In both groups, adherent patients experienced a significantly lower incidence of the primary outcome (HR: 0.85, 95% CI 0.72-0.98 for GLP1-RA and HR: 0.69, 95% CI 0.55-0.87 for SGLT2-I). A significant reduction in hospitalizations was found for adherent patients in the GLP1-RA group but not for the SGLT2-I group. Results were consistent when analyses were stratified by age and sex. While higher drug-related costs in the adherent group were counterbalanced by decreased hospitalisation costs in SGLT2-I treated patients, this was not the case for GLP1-RA., Conclusions: Higher adherence to drug treatment with GLP1-RA and SGLT2-I during the first year of the drug intake is associated with a lower incidence of adverse clinical outcomes in a real-world setting., (© 2024 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

In the present narrative review, we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD). We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes. We then discuss how randomized-controlled trials are performed following guidance from regulatory agencies, including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency. Difficulties and hurdles related to limitations of liver biopsy, a large number of screening failures in recruiting patients, as well as unpredictable response rates in the placebo group are evaluated. Finally, we recapitulate the strategies employed for potential drug treatments of this orphan condition. The first is to repurpose drugs that originally targeted T2DM and/or obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide), multi-agonists (tirzepatide and retatrutide), and sodium-glucose transporter 2 inhibitors. The second is to develop drugs specifically targeting NAFLD/MASLD. Among those, we focused on resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, as they are currently in Phase 3 of their clinical trial development. While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past, it is likely that approval of the first treatments is near. As occurs in many chronic conditions, combination therapy might lead to better outcomes. In the case of non-alcoholic steatohepatitis, we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease, while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Context: Despite being one of the major drivers of diabetes incidence, the degree of insulin resistance in patients with type 2 diabetes (T2D) is not usually evaluated in clinical practice or in large epidemiologic studies., Objective: To identify a model of insulin sensitivity using widely available clinical and laboratory parameters in patients with T2D and evaluate its association with all-cause and cardiovascular mortality., Methods: One hundred forty patients with T2D underwent a euglycemic hyperinsulinemic clamp to measure total body glucose disposal rate (mg kg-1 minute-1). We used demographic, clinical, and common laboratory parameters to estimate insulin sensitivity (IS) via stepwise linear regression on 85 patients (training cohort) and validated it in the remaining 55 (validation cohort). The identified equation was then applied to 3553 patients with T2D from the 1999-2010 cycles of the National Health and Nutrition Examination Survey (NHANES) to evaluate its association with all-cause and cardiovascular mortality up to December 2015., Results: The best model included triglycerides, gamma glutamyl transpeptidase, albumin excretion rate, and body mass index. The identified IS score correlated well with the clamp-derived glucose disposal rate in both the training (r = 0.77, P < .001) and the validation (r = 0.74, P < .001) cohorts. In the NHANES cohort, after a median follow-up of 8.3 years, 1054 patients died, 265 of cardiovascular causes. In a multivariable Cox proportional hazard model adjusted for age, sex, race-ethnicity, education, cigarette smoke, total cholesterol, chronic kidney disease, blood pressure, prevalent cardiovascular disease, and alcohol consumption, a higher estimated IS was associated with a lower risk of both all-cause and cardiovascular mortality., Conclusion: We propose a new model of IS in patients with T2D based on readily available clinical and laboratory data. Its potential applications are in both diagnosis as well as prognostication., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aim: Liver fibrosis is the strongest predictor of liver-related mortality in many chronic liver diseases. NT-ProBNP is independently associated with cardiovascular mortality in general population settings. Here, we evaluate the relative contribution of non-invasively identified liver fibrosis and NT-ProBNP on all-cause and cardiovascular mortality in patients with metabolic (dysfunction)-associated steatotic liver disease (MASLD)., Methods and Results: Serum NT-ProBNP levels were measured in 4229 patients with MASLD from the general population without a known history of heart failure that participated in the 1999-2004 cycles of the National Health and Nutrition Examination Survey. Presence of liver fibrosis was estimated using the Fibrosis-4 index (FIB-4). We applied Cox proportional hazard models adjusted for cardiovascular risk factors to evaluate the association between NT-ProBNP and FIB-4 levels and all-cause and cardiovascular mortality through December 2019. Mortality was lower for participants with normal levels of both biomarkers, intermediate if a single biomarker was elevated and highest when both were above the chosen threshold. In the multivariable-adjusted models, both elevated FIB-4 (≥2.67) and elevated NT-ProBNP levels (≥125 pg/ml) were independently associated with higher risks of all-cause mortality (HR 2.2, 95 % CI 1.5-3.2 and HR 1.6, 95 % CI 1.4-2.0, respectively) and cardiovascular mortality (HR 2.1, 95 % CI 1.2-3.7 and HR 2.1, 95 % CI 1.5-2.9, respectively). The associations remained consistent in subgroup analyses based on sex, obesity and age., Conclusions: Both FIB-4 and NT-ProBNP are independently associated with higher mortality in patients with MASLD. Their combined use might prove useful to risk-stratify patients in clinical practice., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Background and Aims: Several studies reported an association between liver stiffness measurement (LSM) obtained through vibration-controlled transient elastography (VCTE) and all-cause mortality in patients with nonalcoholic fatty liver disease (NAFLD). The objective of this systematic review and meta-analysis was to summarize available evidence on the nature and magnitude of this association., Methods: We systematically searched PubMed-MEDLINE and Scopus up to April 2023 for observational cohort studies in which LSM was measured with VCTE in patients with NAFLD or in general population settings, with a follow-up ≥1 year and with available data on all-cause mortality. Measures of association from individual studies were meta-analysed using random effects models. Of the 517 titles initially scrutinized, we included seven studies with data on 18 771 participants (47.1% male) and a mean follow-up of 3.6 years. We included effect estimates obtained in the models with the highest degree of adjustment for potential confounders available in each study., Results: When analysed as a categorical variable based on specific LSM cut-offs, liver fibrosis was associated with an increased risk of all-cause death (HR 2.10, 95% CI 1.56-2.83; test for overall effect z = 4.919, p < 0.001). Results were consistent when LSM was considered as a continuous variable (HR for 1 kPa increase: 1.03, 95% CI 1.01-1.05; test for overall effect z = 3.341, p = 0.001). There was borderline significant heterogeneity among the studies (I 2  = 50.2% and I 2  = 66.7% in the two analyses, respectively). No significant publication bias was detected by funnel plot analysis and Egger's and Begg's tests., Conclusion: The present meta-analysis indicates that LSM, as a proxy of liver fibrosis, is independently and directly associated with a higher mortality risk in patients with NAFLD., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Objective: The aim of the present study is to explore the epidemiologic impact of the definition of steatotic liver disease (SLD) proposed by a multi-society (American Association for the Study of the Liver-the European Association for the Study of Liver Diseases-Asociación Latinoamericana para el Estudio del Hígado) Delphi consensus statement., Methods: This is a cross-sectional study of US adults participating in the 2017-2020 cycles of the National Health and Nutrition Examination Survey who were evaluated by vibration-controlled transient elastography. Hepatic steatosis and fibrosis were diagnosed by the median value of controlled attenuation parameter and liver stiffness measurement using cut-offs of 274 dB/m and 8.0 kPa, respectively. Recently proposed criteria for metabolic dysfunction-associated steatotic liver disease (MASLD), MetALD (MASLD + significant alcohol consumption), MASLD-Viral hepatitis and cryptogenic SLD were applied., Results: SLD was present in 42.1% (95% CI: 40.3-43.9) of the 3173 included participants. Among patients with SLD, 99.4% met the metabolic dysfunction definition. Moreover, 89.4%, 7.7%, 2.4%, 0.4% and 0.1% were defined as MASLD, MetALD, MASLD-Viral, alcoholic liver disease (ALD) (significant alcohol consumption without metabolic dysfunction) and cryptogenic, respectively. No patients without metabolic dysfunction had significant liver fibrosis, which was present in 15.2%, 9.5% and 19.5% of patients with MASLD, MetALD and MASLD-viral, respectively. Approximately, 90% of the overall adult US population could be diagnosed with metabolic dysfunction according to the consensus criteria. A high degree of concordance was found between MASLD and the previously proposed metabolic dysfunction-associated fatty liver disease definition., Conclusions: Metabolic dysfunction is present in almost all patients with SLD in the United States. The new change in diagnostic criteria did not significantly impact disease prevalence., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Eating breakfast daily improves cognitive function, may contribute to learning and academic performance in children and can decrease the risk of childhood obesity. The aim of this study was to analyse how breakfast consumption changed in the period from 2008/9 to 2019 in Italy among children aged 8-9 years old participating in the OKkio alla SALUTE surveys and to explore the associations with some socio-demographic and lifestyle factors. Information about children's daily breakfast consumption (adequate, inadequate, and no breakfast) and the socio-demographic characteristics of the children and their mothers was collected through four questionnaires addressed to parents, children, teachers and head teachers. Data were analysed for the 272,781 children from 21 Italian regions from 2008/9 to 2019. The prevalence of adequate breakfast decreased from 60.7% in 2008/9 to 55.7% in 2019 and no breakfast from 10.9 to 8.7%; conversely, inadequate breakfast increased from 28.4 to 35.6%. Logistic regression models showed that the occurrence of inadequate or no breakfast consumption was significantly higher among girls, children living in the southern regions and children with less educated mothers. These findings highlight the need for effective interventions to increase daily breakfast consumption and its adequacy among children.

Background: While existing research has explored changes in health behaviours among adults and adolescents due to the COVID-19 outbreak, the impact of quarantine on young children's well-being is still less clear. Moreover, most of the published studies were carried out on small and non-representative samples. The aim of the EpaS-ISS study was to describe the impact of the COVID-19 pandemic on the habits and behaviours of a representative sample of school children aged mainly 8-9 years and their families living in Italy, exploring the changes in children's well-being during the COVID-19 pandemic compared to the immediately preceding time period., Methods: Data were collected using a web questionnaire. The target population was parents of children attending third-grade primary schools and living in Italy. A cluster sample design was adopted. A Well-Being Score (WBS) was calculated by summing the scores from 10 items concerning the children's well-being. Associations between WBS and socio-demographic variables and other variables were analysed., Results: A total of 4863 families participated. The children's WBS decreased during COVID-19 (median value from 31 to 25; p = 0.000). The most statistically significant variables related to a worsening children's WBS were: time of school closure, female gender, living in a house with only a small and unliveable outdoor area, high parents' educational level and worsening financial situation., Conclusions: According to parents ' perception, changes in daily routine during COVID-19 negatively affected children's well-being. This study has identified some personal and contextual variables associated with the worsening of children's WBS, which should be considered in case of similar events., (© 2023. Società Italiana di Pediatria.)

Unhealthy diets, physical inactivity and high body mass index (BMI) are preventable risk factors for non-communicable diseases throughout a person's lifespan. The higher prevalence of these risk factors in children from lower socio-economic groups has been generally observed. The aim of this study is to explore the effect of parents' socio-economic conditions on children's consumption of fruit, vegetables and sugar-sweetened drinks, and inactivity, sedentary behaviour, overweight and obesity. This study used data from the sixth cross-sectional survey of the surveillance "OKkio alla Salute" (Italian COSI), involving 2467 schools and 53,275 children in 2019. All the information was collected through four questionnaires addressed to parents, children, teachers and head teachers. The weights and heights of the children were measured with standard techniques and equipment to classify overweight/obesity according to the WOF-IOTF cut-offs. The results showed a high percentage of children who do not adhere to health recommendations and a high prevalence of overweight and obesity. In particular, "less healthy" behaviours and higher BMI were more frequent in children from families with a lower socio-economic status and those residing in Southern Italy. These findings highlight the need for effective interventions that address the differences in these health-related behaviours.

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD) affects ~70% of patients with type 2 diabetes (T2D), with ~20% showing signs of advanced liver fibrosis. Patients with T2D are at an increased risk of developing cirrhosis, liver failure, and hepatocellular carcinoma and their liver-related mortality is doubled compared with non-diabetic individuals. Nonetheless, the condition is frequently overlooked and disease awareness is limited both among patients and among physicians. Given recent epidemiological evidence, clinical practice guidelines recommend screening for NAFLD/MASLD and advanced liver fibrosis in patients with T2D. While many drugs are currently being tested for the treatment of NAFLD/MASLD, none of them have yet received formal approval from regulatory agencies. However, several classes of antidiabetic drugs (namely pioglitazone, sodium-glucose transporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and multi-agonists) have shown favorable effects in terms of liver enzymes, liver fat content and, in some occasions, on histologic features such as inflammation and fibrosis. Therefore, diabetologists have the opportunity to actively treat NAFLD/MASLD, with a concrete possibility of changing the natural history of the disease. In the present narrative review, we summarize evidence and clinical recommendations for NAFLD/MAFLD screening in the setting of T2D, as well as on the effect of currently available glucose-lowering drugs on hepatic endpoints.

Introduction: Serum neurofilament light chain (sNfL) levels are biomarkers of neuro-axonal injury in multiple neurological diseases. Little is known on their potential role as prognostic markers in people without known neurological conditions., Objective: The aim of this study is to evaluate the association between sNfL levels and all-cause mortality in a general population setting., Methods: sNfL levels were measured in 2071 people aged 25-75 years from the general US population that participated in the 2013-2014 cycles of the National Health and Nutrition Examination Survey (NHANES). Cognitive function was evaluated in a subset of participants aged 60-75 years using the Consortium to Establish a Registry for Alzheimer's Disease-Word Learning test, the Animal Fluency test and the Digit Symbol Substitution test. We applied Cox proportional hazard models adjusted for several potential confounders to evaluate the association between sNfL and all-cause mortality through December 2019 by linking NHANES data with data from the National Death Index., Results: In a cross-sectional analysis, higher sNfL levels were associated with worse performance in all three cognitive function tests. Over a median follow-up of 6.1 years, 85 participants died. In a multivariable model adjusted for age, sex, race-ethnicity, diabetes, chronic kidney disease, harmful alcohol consumption, cigarette smoke and prevalent cardiovascular disease, higher sNfL levels were significantly and positively associated with all-cause mortality (HR per unit increase in log-transformed sNfL: 2.46, 95% CI 1.77-3.43, p < 0.001). Results were robust when analyses were stratified according to age, sex, body mass index and kidney function., Conclusion: We found a positive association between sNfL levels and mortality in the general US population. Further studies are needed to understand the biological mechanisms underlying this association., (© 2023. The Author(s).)

Competing Interests: Conflict of interest None declared.

The aim of the EPaS-ISS study was to describe the changes in food consumption and eating behaviours of children (mainly aged 8-9 years) and their families between the pre-COVID-19 period (before February/March 2020) and the COVID-19 period (from February/March 2020 to April 2022). A web questionnaire completed by parents was used to collect data. The sociodemographic characteristics of the children and their parents were also explored through the web questionnaire. Seventeen regions out of nineteen and the two autonomous provinces (PA) of Italy participated in the study. The survey was completed for 4863 children (47.9% females). The study showed that only small changes in children's food consumption happened between the pre-COVID-19 period and the COVID-19 period; in particular, about 25% of parents reported an increase in savoury snacks and sweet food. A decrease in fruit and vegetable (about 8%) and fish (14%) consumption was also found. However, the changes seem to have mainly affected children from most disadvantaged families. The results also indicate positive changes during the COVID-19 pandemic in some families' eating behaviours, such as eating more home-cooked meals (42%) and family meals (39%), as well as cooking more with children (42%).

Sex hormones impact body composition. Data on the specific impact of each hormone on different body depots in men and women are scarce. The aim of this study is to evaluate the association between testosterone, estradiol and body fat distribution in the general population. This is a population-based cross-sectional study based on data from the 2013-2016 cycles of the National Health and Nutrition Examination Survey. Dual energy X-ray absorptiometry (DXA) and liquid chromatography tandem mass spectrometry were performed on participants aged 18-59 years to evaluate body composition and sex hormone levels, respectively. Weighted multivariable linear regression analyses were performed to evaluate the association between these parameters after adjustment for potential confounders. A total of 6655 participants (3309 males and 3346 females) was included in the analysis. Men with lower testosterone levels were older, had a higher body mass index (BMI) and had a generally unfavorable metabolic profile, while no specific trends were found in women. Among men, testosterone was positively associated with lean body mass and was negatively associated with fat mass and the android/gynoid (A/G) ratio, while an opposite trend was found for estradiol. Among women, testosterone did not impact body composition, while estradiol levels were positively associated with lean mass and were negatively associated with fat mass. Our results support the notion that the impact of different sex hormones on specific fat depots varies substantially between men and women.

Aims: Evidence on the role of 25-Hydroxyvitamin D (25(OH)D) in the occurrence and progression of nonalcoholic fatty liver disease (NAFLD) is conflicting and population-based data are scarce. Here, we assess the association between 25(OH)D levels, NAFLD and liver fibrosis in the general population., Materials and Methods: This is an analysis of data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey. We included adult participants with available data on vibration-controlled transient elastography (VCTE) and without viral hepatitis and significant alcohol consumption. Steatosis and fibrosis were diagnosed by the median values of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. 25(OH)D was measured by high performance liquid chromatography-tandem mass spectrometry., Results: A total of 3970 participants (1928 men and 2042 women) were included in the study. The prevalence of NAFLD (CAP ≥ 274 dB/m) and significant liver fibrosis (LSM ≥ 8 kPa) were 41.7% (95% CI 39.4-44.0) and 8.4% (95% CI 7.0-9.9), respectively, while 21.1% (95% CI 17.3-25.4) of participants had low 25(OH)D levels (<50 nmol/L). A multivariable logistic regression model adjusted for age, sex, race-ethnicity, body mass index, waist circumference, calendar period, diabetes, chronic kidney disease, and vitamin D supplementation showed that compared with participants with low 25(OH)D, those with optimal levels (≥75 nmol/L) had lower odds of both NAFLD (OR 0.73, 95% CI 0.55-0.98 p = 0.038) and significant liver fibrosis (OR 0.65, 95% CI 0.44-0.96, p = 0.033)., Conclusions: An inverse relationship was found between 25(OH)D and NAFLD and fibrosis, suggesting a possible role of vitamin D in NAFLD occurrence and progression., (© 2023 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Breakfast is often considered the most important meal of the day and can benefit adolescent health in several ways. The aims of the present study were (1) to identify adolescents' socio-demographic (sex, family affluence and family structure) determinants of daily breakfast consumption (DBC) and (2) to describe trends in DBC among adolescents across 23 countries. Cross-sectional surveys of nationally representative samples of adolescents (aged 11, 13, and 15 years) ( n = 589,737) participating in the Health Behaviour in School-aged Children (HBSC) survey from 2002 to 2018 were used. Multilevel logistic regression analyses modeled DBC over time, adjusted for family affluence, family structure and year of survey. Four countries showed an increased trend in DBC (the Netherlands, Macedonia, Slovenia, and England). A significant decrease in DBC was observed in 15 countries (Belgium-Fr, France, Germany, Croatia, Portugal, Spain, Hungary, Poland, Russian Federation, Ukraine, Denmark, Finland, Latvia, Lithuania and Sweden). In 4 countries no significant change was observed (Czech Republic, Scotland, Ireland and Norway). In most of the countries ( n = 19), DBC was higher among the adolescents from high-affluence homes. In all the countries analysed, the adolescents living in two-parent households report higher DBC use than those in single-parent households. More than half of the countries showed a decrease in DBC. There is a need to implement key interventions by developing different strategies (education, incorporating educational curriculum and counselling programmes) to increase DBC. Comparing DBC patterns across HBSC countries is important for understanding regional and global trends, monitoring strategies, and developing health promotion programmes.

Aim: Identifying patients with fibrotic nonalcoholic steatohepatitis (NASH) is crucial in order to refer them to specialist care as fibrotic NASH represents one of the major inclusion criteria for clinical trials. The aim of this study is to report the prevalence of fibrotic NASH in the general US population across the spectrum of glucose tolerance and evaluate the performance of the recently proposed Fibrotic NASH Index (FNI)., Methods: This is a cross-sectional study of US adults participating in the 2017-2020 cycles of the National Health and Nutrition Examination Survey. Participants with available data to calculate FNI (which is based on AST, HbA1c and HDL-cholesterol) and with a reliable vibration controlled transient elastography examination were included. We excluded participants with chronic viral hepatitis, significant alcohol consumption or other forms of liver disease. Probable fibrotic NASH was defined as a Fibroscan-AST (FAST) score ≥ 0.35., Results: We included a total of 6268 participants. The overall prevalence of probable fibrotic NASH was 5.9 % (95 % CI 5.2-6.7) and it increased progressively from participants with normal glucose tolerance (3.7 %, 95 % CI 2-9-4.7) to those with diabetes (14.7 %, 95 % CI 12.1-17.8). The performance of FNI for probable fibrotic NASH was satisfactory in the overall population (area under the receiver operating characteristic curve (AUROC): 0.93, 95 % CI 0.92-0.94) and it maintained a good accuracy also in participants with diabetes (n = 1113, AUROC 0.89, 95 % CI 0.86-0.92). In all groups it outperformed Fibrosis-4., Conclusions: FNI is an easy and reliable test to screen for NASH and its performance is maintained in patients with diabetes, a condition that was shown to negatively influence the performance of several non-invasive scores., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: To evaluate the protective effect of oral antidiabetic drugs in a large cohort of elderly patients with type 2 diabetes differing for age, clinical status, and life expectancy, including patients with multiple comorbidities and short survival., Methods: A nested case-control study was carried out by including the cohort of 188,983 patients from Lombardy (Italy), aged ≥ 65 years, who received ≥ 3 consecutive prescriptions of antidiabetic agents (mostly metformin and other older conventional agents) during 2012. Cases were the 49,201 patients who died for any cause during follow-up (up to 2018). A control was randomly selected for each case. Adherence to drug therapy was measured by considering the proportion of days of the follow-up covered by the drug prescriptions. Conditional logistic regression was used to model the risk of outcome associated with adherence to antidiabetic drugs. The analysis was stratified according to four categories of the clinical status (good, intermediate, poor, and very poor) differing for life expectancy., Results: There was a steep increase in comorbidities and a marked reduction of the 6-year survival from the very good to the very poor (or frail) clinical category. Progressive increase in adherence to treatment was associated with a progressive decrease in the risk of all-cause mortality in all clinical categories and at all ages (65-74, 75-84 and ≥ 85 years) except for the frail patient subgroup aged ≥ 85 years. The mortality reduction from lowest to highest adherence level showed a tendency to be lower in frail patients compared to the other categories. Similar although less consistent results were obtained for cardiovascular mortality., Conclusions: In elderly diabetic patients, increased adherence to antidiabetic drugs is associated with a reduction in the risk of mortality regardless of the patients' clinical status and age, with the exception of very old patients (age ≥ 85 years) in the very poor or frail clinical category. However, in the frail patient category the benefit of treatment appears to be less than in patients in good clinical conditions., (© 2023. The Author(s).)

Data are limited on the epidemiology of fibrotic non-alcoholic steatohepatitis (NASH). We applied the recently proposed Fibrotic NASH Index (FNI) to estimate trends in the prevalence of probable fibrotic NASH in the general United States population using data from the 1999-2016 cycles of the National Health and Nutrition Examination Survey. A total of 40 273 participants aged 20 years and older were included in the analysis. The prevalence of probable fibrotic NASH (FNI ≥0.33) in the overall population was 8.4% (95% CI 8.0-8.8), with higher values found in males and in Hispanic participants. It increased from 6.9% (95% CI 6.3-7.6) in 1999-2004 to 9.2% (95% CI 8.4-10.0) in 2011-2016. This positive trend was evident in both sexes and in participants with obesity and diabetes. Finally, it increased progressively with increasing age, body mass index and worse glucose tolerance. NASH prevalence is increasing in the general US population, synchronous with increasing rates of obesity and type 2 diabetes., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The progress of digital transformation in clinical practice opens the door to transforming the current clinical line for liver disease diagnosis from a late-stage diagnosis approach to an early-stage based one. Early diagnosis of liver fibrosis can prevent the progression of the disease and decrease liver-related morbidity and mortality. We developed here a machine learning (ML) algorithm containing standard parameters that can identify liver fibrosis in the general US population., Materials and Methods: Starting from a public database (National Health and Nutrition Examination Survey, NHANES), representative of the American population with 7265 eligible subjects (control population n = 6828, with Fibroscan values E < 9.7 KPa; target population n = 437 with Fibroscan values E ≥ 9.7 KPa), we set up an SVM algorithm able to discriminate for individuals with liver fibrosis among the general US population. The algorithm set up involved the removal of missing data and a sampling optimization step to managing the data imbalance (only ∼ 5 % of the dataset is the target population)., Results: For the feature selection, we performed an unbiased analysis, starting from 33 clinical, anthropometric, and biochemical parameters regardless of their previous application as biomarkers of liver diseases. Through PCA analysis, we identified the 26 more significant features and then used them to set up a sampling method on an SVM algorithm. The best sampling technique to manage the data imbalance was found to be oversampling through the SMOTE-NC. For final model validation, we utilized a subset of 300 individuals (150 with liver fibrosis and 150 controls), subtracted from the main dataset prior to sampling. Performances were evaluated on multiple independent runs., Conclusions: We provide proof of concept of an ML clinical decision support tool for liver fibrosis diagnosis in the general US population. Though the presented ML model represents at this stage only a prototype, in the future, it might be implemented and potentially applied to program broad screenings for liver fibrosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Context: Serum neurofilament light chain (sNfL) levels are biomarkers of neuroaxonal injury in multiple neurological diseases., Objective: Given the paucity of data on the distribution of sNfL levels in the general population, in the present study we identified predictors of sNfL levels in a community setting and investigated the association between diabetes and sNfL., Methods: sNfL levels were measured in 2070 people aged 20 to 75 years from the general US population (275 with and 1795 without diabetes) that participated in the 2013-2014 cycle of the National Health and Nutrition Examination Survey. We evaluated the association between diabetes and sNfL levels after adjustment for age, sex, race-ethnicity, alcohol use, and kidney function using a multivariable linear regression model. Cognitive function was evaluated in a subset of participants aged 60 to 75 years using the Consortium to Establish a Registry for Alzheimer's Disease-Word Learning test, the Animal Fluency test, and the Digit Symbol Substitution test., Results: The weighted prevalence of diabetes was 10.4% (95% CI, 9.0-11.9). In each age stratum, patients with diabetes exhibited higher sNfL levels compared with nondiabetic participants. Age, proportion of males, prevalence of diabetes, and homeostatic model of insulin resistance increased progressively across quartiles of sNfL levels in the overall population, whereas estimated glomerular filtration rate (eGFR) showed an opposite trend. In the multivariable model, age, sex, eGFR, alcohol use and diabetes were significantly associated with sNfL levels. Moreover, higher sNfL levels were associated with worse performance in all 3 cognitive function tests., Conclusion: Diabetes is associated with higher sNfL. Further large-scale and prospective studies are needed to replicate our results and evaluate the ability of sNfL to predict the incidence of neuropathy and dementia in this patient population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Even though hyperglycemia is a well-known cardiovascular risk factor, the absolute risk of cardiovascular events varies to a great extent within each glycemic category. The aim of this study is to evaluate whether N-terminal pro-B natriuretic peptide (NT-ProBNP) could help identify subjects at higher cardiovascular risk, independently of blood glucose levels., Methods: Serum NT-ProBNP levels were measured in 5502 people aged 45-79 years without heart failure from the general population (3380 with normoglycemia, 1125 with pre-diabetes and 997 with diabetes) that participated in the 1999-2004 cycles of the National Health and Nutrition Examination Survey. We applied Cox and Fine Gray models adjusted for cardiovascular risk factors to evaluate the association between NT-ProBNP levels and all-cause and cardiovascular mortality through December 2015., Results: After a median follow-up of 13 years, 1509 participants died, 330 of cardiovascular causes. In the multivariable-adjusted models, compared with participants with NT-ProBNP &lt; 100 pg/ml, those with levels 100-300 pg/ml and ≥ 300 pg/ml had a higher incidence of both all-cause mortality (HR 1.61, 95% CI 1.12-2.32, p = 0.012 and HR 2.96, 95% CI 1.75-5.00, p &lt; 0.001, respectively) and cardiovascular mortality (HR 1.57, 95% CI 1.17-2.10, p = 0.011 and HR 2.08, 95% CI 1.47-2.93, p &lt; 0.001, respectively). The association was consistent in subgroup analyses based on glycemic status, obesity, age and sex., Conclusions: Elevated NT-ProBNP is independently associated with all-cause and cardiovascular mortality in the general population and could help identify patients at the highest risk. Further studies are needed to evaluate whether intensification of treatment based on biomarker data might lead to improvements in cardiovascular risk reduction., (© 2022. The Author(s).)

Background and Aims: Glycated albumin (GA) reflects short-term glycemic control, but few data are available on its association with hard clinical outcomes. The purpose of this study is to evaluate the association between GA levels and all-cause and cardiovascular mortality in people with and without a previous diagnosis of diabetes., Methods and Results: Serum GA levels were measured in 12147 people from the general population (1319 with and 10828 without diabetes) that participated in the 1999-2004 cycles of the National Health and Nutrition Examination Survey (NHANES). We evaluated the association between GA and all-cause and cardiovascular mortality through December 2015 by linking NHANES data with data from the National Death Index. Associations were compared with those observed for hemoglobin A1c (HbA1c). After a median follow-up of 13 years, 2785 participants (619 with and 2166 without diabetes) died, 651 of cardiovascular causes. Multivariable-adjusted Cox proportional hazard models showed that higher baseline GA levels were significantly associated with a higher incidence of both outcomes in participants with (all-cause: HR 1.03, 95% CI 1.01-1.04; cardiovascular: HR 1.04, 95% CI 1.02-1.07) and without diabetes (all-cause: HR 1.05, 95% CI 1.03-1.08; cardiovascular: HR: 1.08, 95% CI 1.02-1.14); on the other hand, we found a trend for increased mortality with increasing HbA1c levels in patients with known diabetes, but not in participants without., Conclusions: For a novel measure of hyperglycemia to be considered useful, its association with hard, long term clinical outcomes is of great importance. We showed that GA is associated with mortality in the general population independently of a previous diagnosis of diabetes., Competing Interests: Conflict of interest All authors declare no conflicts of interest related to this study., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: The aim of this study is to evaluate trends in heart failure (HF) prevalence, impact of accompanying risk factors and use of effective therapeutic regimens during the last two decades in the general adult US population., Methods: We analyzed data obtained from the 1999-2018 cycles of the National Health and Nutrition Examination Survey (NHANES). Among a total of 34,403 participants 40 years or older who attended the mobile examination center visit, 1690 reported a diagnosis of HF. Trends in participant features across calendar periods were assessed by linear regression for continuous variables and logistic regression for binary variables., Results: Prevalence of self-reported HF did not change significantly from 1999 to 2002 to 2015-2018 (~3.5%), while obesity and diabetes showed a progressive increase in prevalence, affecting ~65% and ~ 45% of patients with HF in the most recent calendar period, respectively. In parallel, use of glucose lowering drugs (especially metformin and insulin) as well as statins increased from 1999 to 2010, with significant improvement of the lipid control. A modest improvement in blood pressure control was achieved in association with a significant increase in the use of angiotensin receptor blockers and beta-blockers., Conclusions: In the last 20 years, the prevalence of HF in US adults remained stable, while both obesity and diabetes increased, with the two conditions affecting half of patients with HF. Improvements in the control of dyslipidemia and, to a lesser extent, blood pressure, was detected; nonetheless, a significant gap remains in guideline-directed use of HF and diabetes medications., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The recent increase in electronic and social media use among young people has highlighted the importance of focusing on problematic social media use (PSMU) and the concurrent phenomenon of cyber aggression, as well as the role of social support. As part of the 2018 Health Behavior in School-aged Children study in Italy, this study aims to explore the role of family, peer, and teacher support in the association between cyberbullying and PSMU., Methods: Data were collected from 4183 school classes in Italy for a total of 58,976 adolescents aged 11, 13, and 15 years. The prevalence of cyber aggression (both cybervictimization and perpetration) and PSMU was estimated across subgroups of different age, gender, and geographical residence. A set of multivariable logistic regressions was then used to investigate the association between cyberbullying and PSMU, considering the effect of social support., Results: Cybervictimization was more frequent among girls than in boys. PSMU was higher in 11-year-old boys and 13-year-old girls; 8.3% and 12.7%, respectively. Social support was highest in 11-year-olds, for both sexes, and then decreased with increasing age. The risk of cyberbullying, both suffered and perpetrated, was higher in girls and in the presence of PSMU. Social support showed to be highly protective against PSMU and cyberbullying in all ages and both genders., Conclusion: Although cyber aggression is less represented in Italy than in other European countries, it is likely to increase. PSMU appears to be an important contributor to the risk of cyber aggression; however, social support has been shown to be capable of reducing the risk of both phenomena. Public health policies fostering familiar and school support can help protect adolescents' mental health, reducing the risk of problematic media use and cyberbullying.