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Background and aims To compare biventricular and biatrial myocardial strain indices assessed by two-dimensional speckle tracking echocardiography (2D-STE) in women with gestational diabetes mellitus (GDM) and those with uncomplicated pregnancy at the third trimester of pregnancy and in post-partum. Methods and results 30 consecutive GDM women and 30 age-, ethnicity- and gestational week-matched controls without any comorbidity were examined in this prospective case-control study. All women underwent obstetric visit, blood tests and transthoracic echocardiography (TTE) implemented with 2D-STE analysis of all cardiac chambers at 36-38 weeks’ gestation. TTE and 2D-STE were repeated at 6–10 weeks after delivery. At 36-38 weeks’ gestation, GDM women, compared to controls, had significantly higher body mass index (BMI), blood pressure values and inflammatory markers. TTE showed increased left ventricular (LV) mass and impaired LV diastolic function in GDM women, whereas there was no significant difference between the groups in ejection fraction. 2D-STE revealed that biventricular global longitudinal strain (GLS) and biatrial reservoir strain indices were significantly lower in GDM women than controls. Third trimester BMI was inversely correlated with LV-GLS (r=–0.86) and was independently associated with reduced LV-GLS (less negative than –20%) in GDM women in post-partum (OR 1.81, 95%CI 1.14-2.89). A BMI value ≥30 Kg/m2 had 100% sensitivity and 99.5% specificity for identifying GDM women with impaired LV-GLS in post-partum (AUC=0.97). Conclusion Women with GDM, compared to women with uncomplicated pregnancy, have significantly lower biventricular and biatrial myocardial deformation indices. These abnormalities may be persistent in post-partum in GDM women with obesity.

Microvascular disease (MVD) is associated with amputation linked to peripheral artery disease (PAD) in the general population. No study evaluated the impact of diabetic microvascular complications on the outcomes of vascular diabetic foot ulcers (DFU). The aim of the study was to investigate whether retinopathy, nephropathy, and polyneuropathy can predict the outcomes of DFU in type 2 diabetic patients with PAD.Three hundred and thirty-one consecutive patients with vascular DFU were enrolled and followed up for 44.1 ± 23.9 months.The prevalence of retinopathy was significantly higher in subjects with ulcer persistence (45.2%; p 0.01), minor amputation (48.9%; p 0.001), and major amputation (57.9%; p 0.001) than in healed patients (23.3%), and in non-survivors than in survivors (64.9 versus 20.5%; p 0.001). The prevalence of nephropathy was significantly greater in subjects with ulcer persistence (83.9%; p 0.01), minor amputation (86.7%; p 0.001), and major amputation (94.7%; p 0.001) than in those with healed DFU (64.4%), and in non-survivors than in survivors (88.3 versus 65.7%; p 0.001). The prevalence of polyneuropathy was significantly higher in non-survivors than in survivors (76.6 versus 61.0%; p = 0.012). Multivariate analysis showed that absence of retinopathy (OR: 0.451; 95% CI: 0.250-0.815; p 0.001) and nephropathy (OR: 0.450; 95% CI: 0.212-0.951; p = 0.036) were independently associated with healing. Moreover, retinopathy was a predictor both of minor amputation (OR: 2.291; 95% CI: 1.061-4.949; p = 0.034) and mortality (OR: 5.274; 95% CI: 2.524-11.020; p 0.001). Polyneuropathy never entered the regression model.Diabetic microvascular complications, in particular retinopathy, may predict the outcomes of vascular DFU. Longitudinal studies should confirm this finding.

Olfactory and gustatory dysfunction are recognized as common symptoms in patients with COVID-19, with a prevalence ranging, respectively, between 41–61% and 38.2–49%. This review focused on relating the variations in dietary habits with the reduction/loss of smell and/or taste in patients who contracted the COVID-19 infection. Primarily, we reviewed the main pathological mechanisms involved in COVID 19-induced anosmia/dysosmia and ageusia/dysgeusia. Then, we explored and summarized the behavioural changes in food intake and body weight during the COVID-19 pandemic in relation to sensory impairment and the underlying mechanisms. Most studies on this topic argue that the altered chemosensory perception (taste and smell) mainly induces reduced appetite, leading to a faster fullness sensation during the consumption of a meal and, therefore, to a decrease in body weight. On the other hand, a reduced perception of the food’s sensory properties may trigger compensatory responses that lead some individuals to increase food intake with a different effect on body weight. Regarding body weight, most studies evaluated malnutrition in patients hospitalized for COVID-19; more studies are warranted to investigate nutritional status specifically in non-hospitalized patients with olfactory and gustatory dysfunctions caused by COVID-19 infection.

Background: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation. Aims: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients. Methods: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3–3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period. Results: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6–68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites ( n = 3–66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated. Conclusions: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD. Trial registration: ClinicalTrials.gov Identifier: NCT04648423

Purpose Aims of the present study were to investigate a wide array of psychological symptoms through validated psychometric tests, before and after 5 weeks of deep Transcranial Magnetic Stimulation (dTMS) in individuals with obesity, and to identify possible relationships with neuroendocrine parameters. Methods Forty-five patients with obesity (33 F, 12 M; age 48.8 ± 9.9 years; body wt 97.6 ± 14.2 Kg; BMI 36.2 ± 4.2) were randomized into two groups: 26 received high frequency (HF) dTMS and 19 Sham stimulation for 5 weeks. At baseline and after the 5-week treatment, all patients underwent the following psychometric evaluations: Food Cravings Questionnaire-Trait (FCQ-T) and its subscales, Barratt Impulsiveness Scale-11 (BIS-11), State and Trait Anxiety Inventory (STAI-y1 and STAI-y2), and Beck Depression Inventory (BDI). Hormonal and neuroendocrine markers were assessed at the first and last dTMS session. Results By adjusting for baseline variables and treatment arms, a significant decrease in body wt and BMI was found in HF group, both with univariate (p = 0.019) and multivariate analyses (p = 0.012). Impulsivity significantly decreased in HF group, both with univariate (p = 0.031) and multivariate analyses (p = 0.011). A positive association between the impulsivity score change and the leptin level variation (p = 0.031) was found. Conclusion The decrease of impulsivity together with the BMI reduction in individuals with obesity, treated with real stimulation, suggests that impulsivity may be a risk factor for obesity. Treatment with dTMS revealed to be effective in reducing both BMI and impulsivity by enhancing inhibitory capacity of Pre-Frontal Cortex (PFC), and modulating neuroendocrine system, especially leptin.

Prader-Willi Syndrome (PWS) is the most common syndromic type of human obesity. Multiple endocrine abnormalities due to hypothalamic dysfunction as well as cognitive and behavioral disorders occur in PWS. Hypothalamic dysfunction, dysregulated mesocorticolimbic reward system, and impaired prefrontal cortex (PFC) function are implicated in the pathophysiology of hyperphagia and obesity in PWS. All available therapeutic tools have not fully targeted at counteract the mechanisms underlying obesity in PWS. Previously, we demonstrated the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) in inducing weight loss in obesity by modulating the brain dopaminergic system and enhancing the inhibitory activity of the PFC on eating behaviour (Ferrulli et al, DOM 2019) . In this case-report, for the first time, we tested the efficacy and safety of rTMS in a 23-year-old patient with PWS, in whom repeated interventions aimed at inducing weight loss have failed. A 5-week high frequency (18 Hz) rTMS treatment, associated with diet, resulted in a 3.5% weight loss (127.4 vs. 123 Kg, BMI: 50.4 vs. 48.6 Kg/m2, WHR: 1.14 vs. 1.12) . Concerning the metabolic parameters, an improvement in lipid profile has been shown (CHO/HDL/LDL/TG: 212/40/142/152 vs. 190/40/124/131 mg/dL) . While no significant changes emerged in the psychometric assessment of food craving, impulsiveness, quality of life, self-esteem, interestingly, a robust improvement in the Mini-Mental State Examination score (corrected for age and schooling) has been found [from 22 (severe impairment) to 27 (moderate impairment) ]. The improvement in the cognitive status assessed through the Montreal Cognitive Assessment was weaker (17/30 to 19/30) . In view of the urgent need of novel effective interventions for obesity in PWS, these findings support a potential role of rTMS in reducing food drive and behaviors impacting hyperphagia and obesity in PWS, with a possible impact also on cognitive functions. Disclosure A.Ferrulli: None. D.Cannavaro: None. C.Macrì: None. S.Massarini: None. L.Luzi: Advisory Panel; Eli Lilly and Company, Speaker’s Bureau; Eli Lilly and Company, Novo Nordisk. Funding IRCCS Multimedica - Ricerca Corrente

Introduction Obesity is a condition that generally limits work capacity and predisposes to a number of comorbidities and related diseases, the last being COVID-19 and its complications and sequelae. Physical exercise, together with diet, is a milestone in its management and rehabilitation, although there is still a debate on intensity and duration of training. Anaerobic threshold (AT) is a broad term often used either as ventilatory threshold or as lactate threshold, respectively, detected by respiratory ventilation and/or respiratory gases (VCO2 and VO2), and by blood lactic acid. Aims and methodology This review outlines the role of AT and of the different variations of growth hormone and catecholamine, in subjects with obesity vs normal weight individuals below and beyond AT, during a progressive increase in exercise training. We present a re-evaluation of the effects of physical activity on body mass and metabolism of individuals with obesity in light of potential benefits and pitfalls during COVID-19 pandemic. Comparison of a training program at moderate-intensity exercise ( AT) exercise at the end of the aerobic session will be discussed. Results Based on our data and considerations, a tailored strategy for individuals with obesity concerning the most appropriate intensity of training in the context of rehabilitation is proposed, with special regard to potential benefits of work program above AT. Conclusion Adding bouts of exercise above AT may improve lactic acid and H+ disposal and improve growth hormone. Long-term aerobic exercise may improve leptin reduction. In this way, the propensity of subjects with obesity to encounter a serious prognosis of COVID-19 may be counteracted and the systemic and cardiorespiratory sequelae that may ensue after COVID-19, can be overcome. Individuals with serious comorbidities associated with obesity should avoid excessive exercise intensity.

Purpose Repetitive Transcranial Magnetic Stimulation (rTMS) has been demonstrated to be effective in body weight control in individuals with obesity. Most clinical trials on rTMS provided a reassuring safety profile. In the present work, we present an extensive analysis on both severe and mild Adverse Events (AEs) in obese individuals treated with rTMS. Methods We examined the intensity, duration, correlation with the treatment, up to 1 year after the end of rTMS treatment. Results Descriptive analysis included a total of 63 subjects undergoing a 5-week deep rTMS experimental treatment for obesity (age 48.3 ± 10.4 years; BMI 36.3 ± 4.4 kg/m2): 31 patients were treated with high-frequency rTMS (HF), 13 with low-frequency rTMS (LF), and 19 were sham treated (Sham). Thirty-two subjects (50.8%) reported a total of 52 AEs, including mainly moderate (51.9%) events. The most frequently reported side effects were headaches of moderate intensity (40.4%) and local pain/discomfort (19.2%) and resulted significantly more frequent in HF group compared to other groups (p, Highlights A safety analysis in obese individuals treated with TMS did not reveal any unexpected safety concern up to 1 year after the end of the treatment. Only headache and local pain/discomfort have been significantly more frequent in the high-frequency TMS-treated group compared with low-frequency and sham-treated groups. TMS exhibits a good safety profile in the obese population potentially more susceptible to side effects of brain stimulation.

Purpose Scarce information on the prevalence and characteristics of olfactory disfunction (OD) in type 2 diabetic (T2D) patients are available. The aims of this study were (1) to assess the olfactory function in T2D patients and to compare it with a control group of individuals without T2D, and (2) to evaluate the differences in OD within T2D patients according to the presence of diabetic complications. Methods A group of 39 T2D patients and a control group of 39 healthy individuals were enrolled. Each subject underwent an evaluation of the olfactory performance using the Sniffing Olfactory Screening Test (SOST) and completed a questionnaire assessing the subjective perception of olfaction. According to the presence of diabetic complications, the group of T2D patients was divided into two subgroups. Non-parametric tests and regression analysis were used for statistical analysis. Results No differences in the subjective perception of olfaction were demonstrated among T2D patients (with and without complications) and controls. A significant difference for the SOST score was demonstrated among the different groups. In particular, OD was more frequent in T2D patients than in controls. In addition, OD was far more frequent in T2D patients with complications. Regression analysis did not demonstrate any significant association between OD and clinical/demographic characteristics of T2D patients. Conclusion T2D patients were more frequently affected by OD. The subgroup analysis suggested a possible relationship between OD and diabetic complications since patients with T2D diabetic complications demonstrated lower olfactory abilities than controls subjects and T2D patients without diabetic complications.

Background and aims: Deep repetitive Transcranial Magnetic Stimulation (deep rTMS) over the bilateral insula and prefrontal cortex (PFC) can promote weight-loss in obesity, preventing cardiometabolic complications as Type 2 Diabetes (T2D). To investigate the changes in the functional brain integration after dTMS, we conducted a resting-state functional connectivity (rsFC) study in obesity.Methods and results: This preliminary study was designed as a randomized, double-blind, sham controlled study: 9 participants were treated with high-frequency stimulation (realTMS group), 8 were sham-treated (shamTMS group). Out of the 17 enrolled patients, 6 were affected by T2D. Resting-state fMRI scans were acquired at baseline (T0) and after the 5-week intervention (T1). Body weight was measured at three time points [T0, T1, 1-month follow-up visit (FU1)]. A mixed-model analysis showed a significant group-by-time interaction for body weight (p Z .04), with a significant decrease (p < .001) in the realTMS group. The rsFC data revealed a significant increase of degree centrality for the realTMS group in the medial orbitofrontal cortex (mOFC) and a significant decrease in the occipital pole.Conclusion: An increase of whole-brain functional connections of the mOFC, together with the decrease of whole-brain functional connections with the occipital pole, may reflect a brain mechanism behind weight-loss through a diminished reactivity to bottom-up visual-sensory processes in favor of increased reliance on top-down decision-making processes. Trial registration number: ClinicalTrials.gov NCT03009695.(c) 2021 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.

The world population is facing a health challenge never seen since the Spanish influenza of one hundred years ago. During the last months, the scientific community has been debating on the potential harmful effect of angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin II receptor type 1 receptor blockers (AT1-receptor blockers, ARBs) during the COVID-19 pandemic. That is because the S spike protein of SARS-CoV viruses utilizes the angiotensin-converting enzyme 2 (ACE2) as a receptor to enter alveolar epithelial cells. Obesity, often associated to type 2 Diabetes, was shown to worsen the prognosis of SARS-CoV-2 infection. Herein we discuss the complex interaction between the renin-angiotensin-aldosterone system (RAAS), its receptors, and the interaction with the Kallikrein-Kinin-system (KKS) and the potential activation of the coagulation cascade. Alteration of the equilibrium between the RAAS system and the KKS cascade may explain the frequent thromboembolic complications of COVID-19 mainly seen in obese and diabetic-obese patients. In contrast, angiotensin (1-7) contributes to maintaining a correct balance between RAAS and KKS system. Our conclusion is that the higher mortality rate in patients with obesity is linked to the alteration of RAS and RAS-KKS interaction consequent to SARS-CoV-2-cell entrance. At present, no data support the necessity of modifying ACEi or ARBs treatment in hypertensive patients.

Obesity is now recognized as a chronic or non-communicable disease; it plays a relevant pathophysiological role in the development of complications, arising as a result of complex interaction of genetic, nutritional, and metabolic factors. The physiology of weight regulation, the pathophysiology that leads to unwanted weight gain, and the maintenance of obesity have been extensively studied in recent years. The most widely used criterion for classifying obesity is the body mass index (BMI). However, according to the body fat composition and distribution, five phenotypes of obesity can be identified: (1) metabolically unhealthy obesity (MUO); (2) metabolically healthy obesity (MHO); (3) metabolically obese normal weight (MONW) phenotype; (4) normal weight obese (NWO) syndrome; (5) sarcopenic obesity. In this chapter, an extensive and detailed description of different obesity phenotypes has been offered. Furthermore, this chapter displays the diagnostic criteria of obesity according to the latest guidelines and a classification of obesity, based on primary and secondary causes (endocrine, genetic, iatrogenic, and psychological).

Overweight and obesity are often associated with impaired thyroid function. Conversely, thyroid dysfunctions are associated with changes in body weight and basal metabolic rate.

In obesity, metabolic and voluntary factors regulate appetite, and a dysregulation of the reward pathway was demonstrated in all addiction disorders. Deep transcranial magnetic stimulation (dTMS) is already used to modulate cerebral dopamine activation in neuro-psychiatric diseases. We presently assess the acute effect of high frequency (HF) and low frequency (LF) dTMS on the modulation of the main neuropeptides and neurotransmitters involved in the reward pathway in obese subjects. This study was designed as a double-blind, sham-controlled, randomized clinical trial. Thirty-three obese patients (9 males, 24 females, age 48.1 ± 10.6, BMI 36.4 ± 4.7) were enrolled in the study. All patients were studied during a single dTMS session and blood aliquots were drawn before and after a single dTMS session. Metabolic and neuro-endocrine parameters were evaluated before and after: (1) 18 Hz dTMS (HF, 13 patients); (2) 1 Hz dTMS (LF, 10 patients); (3) Sham treatment (Sham, 10 patients). No statistically significant variations in metabolic parameters, systolic and diastolic blood pressure, and heart rate were shown acutely. HF showed a significant increase of β-endorphin compared to other groups (p = 0.048); a significant increase of ghrelin in LF (p = 0.041) was also demonstrated. A single session of HF dTMS treatment determines in obese subjects an acute increase of β-endorphin level, indicating an activation of the reward pathway. The present findings constitute proof of principle for a potential application of this methodology in obesity treatment.

The association between obesity and psychological distress has been widely demonstrated. Systematic reviews have highlighted the bidirectional nature of this relationship. Strategies aimed at improving dopamine function may be beneficial in the treatment of both obesity and the associated psychological symptoms. Deep Transcranial Magnetic Stimulation (dTMS) has been demonstrated capable of inducing satiety and body weight loss in obesity, through modulation of dopaminergic system. Aim of this study was to evaluate possible beneficial effects of a 5-week dTMS treatment on psychological conditions in obesity. A total of 33 obese patients (9 males, 24 females, age 48.1±10.6 years, BMI 36.9±4.7 Kg/m2) were randomized and completed the study: 13 obese subjects underwent a 5-week treatment with high-frequency (HF) dTMS (18 Hz), 10 were treated with low-frequency (LF) dTMS (1 Hz), and 10 were Sham-treated. Depressive symptoms [Zung Self-Rating Depression Scale (SDS), Beck Depression Inventory (BDI)], state [State-Trait Anxiety Inventory (STAI-1)] and trait anxiety (STAI-2), impulsiveness [Barratt Impulsiveness Scale (BIS)] were evaluated at baseline and at the end of 15 dTMS sessions. After 5 weeks, a significant weight loss was found in HF vs. LF and vs. sham (p=0.001). In the same group, a significant decrease in both Zung SDS (37.3±4.2 vs. 26.7±5.4, p=0.049 vs. baseline; p=0.036 vs. Sham) and BDI scores (4.8±4.1 vs. 2.6±2.5, p=0.019 vs. baseline) was found. In HF, state (37.1±7.9 vs. 32.4, p=0.024) and trait anxiety (35.6±10.5 vs. 30.1±7.8, p=0.016), and impulsiveness (55.6±9.3 vs. 51.6±8.4, p=0.021) scores significantly decreased compared to baseline. Weight loss over 5 weeks of dTMS treatment was associated with psychological benefit; the improvement of psychological conditions in obese subjects has been hypothesized to be due to a direct effect of HF dTMS, as well as a weight loss secondary result. The reduction of impulsivity could concur to a greater control of food craving in HF. Disclosure A. Ferrulli: None. C. Macrì: None. V. Dangelo: None. L. Luzi: Consultant; Self; McKinsey & Company. Research Support; Self; Allergan, Gelesis, SunStar Inc. Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Menarini Group, Novartis AG, Novo Nordisk Inc., Sunstar Foundation. Funding Italian Ministry of Health

There are reported gender differences in brain connectivity associated with obesity. In the elderlies, the neural endophenotypes of obesity are yet to be elucidated. We aim at exploring the brain metabolic and connectivity correlates to different BMI levels in elderly individuals, taking into account gender as variable of interest. We evaluated the association between BMI, brain metabolism and connectivity, in elderly females and males, by retrospectively collecting a large cohort of healthy elderly subjects (N=222; age=74.03±5.88 [61.2-85.9] years; M/F=115/107; BMI=27.00±4.02 [19.21-38.79] kg/m2). Subjects underwent positron emission tomography with [18F]FDG. We found that, in females, high BMI was associated with increased brain metabolism in the orbitofrontal cortex (R=0.44; p

AIM To test the hypothesis that deep transcranial magnetic stimulation (dTMS) reduces food craving and causes weight loss via neuromodulation. MATERIALS AND METHODS This pilot study was designed as a randomized, double-blind, sham-controlled study. A total of 33 obese people (nine men, 24 women, mean age 48.1 ± 10.6 years, body mass index [BMI] 36.9 ± 4.7 kg/m2 ) were randomized and completed the study: 13 participants underwent a 5-week treatment with high-frequency (HF) dTMS (18 Hz; HF group), 10 were treated with low-frequency (LF) dTMS (1 Hz; LF group), and 10 were sham-treated (sham group). Food craving, and metabolic and neuro-endocrine variables were evaluated at baseline, after the 5-week treatment, and at follow-up visits (1 month, 6 months, 1 year after the end of treatment). RESULTS The mixed-model analysis for repeated measures showed a significant interaction of time and groups for body weight (P = 0.001) and BMI (P = 0.001), with a significant body weight (-7.83 ± 2.28 kg; P = 0.0009) and BMI (-2.83 ± 0.83, P = 0.0009) decrease in the HF versus the sham group. A decreasing trend in food craving in the HF versus the LF and sham groups (P = 0.073) was observed. A significant improvement of metabolic and physical activity variables was found (P

Growing evidence highlights the crucial role of gut microbiota in affecting different aspects of obesity. Potential mechanisms for microbial control over eating behavior include microbiota influence on reward and satiety pathways, neurotransmitters release, and hypothalamic-pituitary-adrenal (HPA) axis modulation. A methodology proved to be effective in modulating orexigenic/anorexigenic pathways and food-reward system in obesity is the dTMS. Considering its assets, we hypothesized a potential role of dTMS in inducing weight loss in obesity also via microbiota composition modulation. Twenty-two obese subjects (5 M, 17 F; 44.6±2.5 years; BMI 37.5±1.1 kg/m2) were allocated into 3 groups receiving 15 sessions (3 per week for 5 weeks) of high frequency (18 Hz, HF), low frequency (1 Hz, LF) dTMS, or sham stimulation. Fecal samples were collected at baseline and after 5 weeks of treatment. Total bacterial DNA was extracted from fecal samples using the QIAamp DNA Stool Mini Kit (Qiagen, Italy) and analyzed by a metagenomics approach (Ion Personal Genome Machine). After 5 weeks, a weight loss in HF (-3.4±1.0%; p In conclusion, the weight loss, induced by HF dTMS, improves sympathetic activity and gut microbiota composition in obese subjects, mainly promoting bacterial species with anti-inflammatory properties, that are typical of healthy subjects intestinal flora. Disclosure A. Ferrulli: None. M. Toscano: None. M. Adamo: None. I. Terruzzi: None. L. Drago: None. L. Luzi: Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company. Research Support; Self; Gelesis. Consultant; Self; McKinsey & Company. Speaker's Bureau; Self; Menarini Group, Merck Sharp & Dohme Corp.. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sunstar Foundation. Speaker's Bureau; Self; Smith & Nephew.

Several studies reported a significant association with obesity and cognitive deficits in aging, especially for executive, attention and memory domains. The neural effects of obesity and the correlated cognitive dysfunction have yet to be elucidated. We retrospectively collected a large cohort of healthy elderlies (N=222; age=74.03±5.88y; M/F=112/105; BMI range=19.21-38.79), from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. All subjects underwent in vivo positron emission tomography with 18F-Fluorodeoxyglucose (FDG), thus we were able to evaluate the correlation between BMI, synaptic function and metabolic connectivity in the whole brain and within the resting-state neural networks, crucially considering the effect of gender. We found a significant positive correlation between BMI levels and brain metabolism in female group only (R=.435; P Disclosure A. Sala: None. M. Malpetti: None. A. Ferrulli: None. L. Gianolli: None. L. Luzi: Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company. Research Support; Self; Gelesis. Consultant; Self; McKinsey & Company. Speaker's Bureau; Self; Menarini Group, Merck Sharp & Dohme Corp.. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sunstar Foundation. Speaker's Bureau; Self; Smith & Nephew. D. Perani: None.

There is growing evidence for the role of the insular cortex in various types of cravings, including food craving. Here, we used resting-state functional brain connectivity (FBC) to explore system-level dysfunctions in the brain of obese (OB) individuals and their correlations with the leptin levels. We first used hierarchical clustering to identify the brain regions whose altered functioning was consistently reported by neuroimaging studies on food perception in OB subjects. We found that a cluster centred in left anterior insula and overlying frontal operculum (AI/fO) was specifically associated with hyper-responsivity in OB. This cluster was then used as a seed for a seed-based FBC analysis in 10 OB and 11 normal weight controls matched for sex, age and education. The analysis implied the calculation of the functional correlations of each brain voxel with the seed along the resting state fMRI time series. OB patients, compared to the control group, showed hyper-connectivity between the left AI/fO and key regions of the reward system, such as the left medial orbitofrontal cortex (OFC), in addition to the bilateral parahippocampal gyri and the posterior cingulate gyrus; conversely, they exhibited hypo-connectivity between the seed and the left dorsolateral prefrontal cortex, a key region involved in inhibitory control (all Ps < .corrected for multiple comparisons). Finally, we found a substantial trend for a negative correlation between AI/fO-OFC hyper-connectivity and plasma levels of leptin (ρ = - .612, p = .06). Our results provide evidence for an imbalance between reward and inhibitory control systems in OB patients, which might be worsened by an altered response to food intake regulatory hormones (e.g., anorexigenic leptin), thus driving the overeating behavior. Moreover, our results suggest that the left AI could be a suitable target for drugs or neuro-modulatory treatment to recalibrate the FBC of a network involved in food intake, reward and cognitive control. Disclosure F. Devoto: None. A. Ferrulli: None. L. Zapparoli: None. R. Bonandrini: None. L. Sconfienza: None. G. Banfi: None. L. Luzi: Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company. Research Support; Self; Gelesis. Consultant; Self; McKinsey & Company. Speaker's Bureau; Self; Menarini Group, Merck Sharp & Dohme Corp.. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sunstar Foundation. Speaker's Bureau; Self; Smith & Nephew. E. Paulesu: None.

The dysregulation of food intake in chronic obesity has been explained by different theories. To assess their explanatory power, we meta-analyzed 22 brain-activation imaging studies. We found that obese individuals exhibit hyper-responsivity of the brain regions involved in taste and reward for food-related stimuli. Consistent with a Reward Surfeit Hypothesis, obese individuals exhibit a ventral striatum hyper-responsivity in response to pure tastes, particularly when fasting. Furthermore, we found that obese subjects display more frequent ventral striatal activation for visual food cues when satiated: this continued processing within the reward system, together with the aforementioned evidence, is compatible with the Incentive Sensitization Theory. On the other hand, we did not find univocal evidence in favor of a Reward Deficit Hypothesis nor for a systematic deficit of inhibitory cognitive control. We conclude that the available brain activation data on the dysregulated food intake and food-related behavior in chronic obesity can be best framed within an Incentive Sensitization Theory. Implications of these findings for a brain-based therapy of obesity are briefly discussed.

Deep transcranial magnetic stimulation (dTMS) is a neurostimulation technique for deep brain structures that has recently been successfully applied in the clinic for the treatment of addiction. In contrast to the conventional magnetic stimulation, which uses planar coils [Figure-of-Eight (FoE)] to target specific superficial regions of the brain, dTMS requires the design of complex 3-D coils in order to induce deeply penetrating fields. Recent clinical studies have focused on the use of H4 coils, which utilizes a left–right symmetric structure for bilateral stimulation of the prefrontal cortex, and demonstrated efficacy for therapy such as smoking cessation. The mechanism of activity, however, remains poorly understood, in part because the affected regions of the brain are not known in detail. To this purpose, computational techniques applied to highly detailed inhomogeneous tissue phantoms provide a powerful tool for testing coil efficacy. In this work, we quantified both electric field ${\mathbf E}$ distribution and its penetration depth in the prefrontal cortex, induced by a specific Hesed-coil, H4, designed for the addiction treatment and by the traditional FoE coil for comparison. Results show that H4 coil preferentially targets the insula and cingulate cortex. Moreover, it can induce in the deepest tissues E amplitude ranging between 20% and 40% of the cortical peak, and it can penetrate the cortex up to 4 cm with a E > 50% of the cortical peak, thus noticeably increasing the penetration depth of the traditional TMS systems.

Aldosterone regulates electrolyte and fluid homeostasis through binding to the mineralocorticoid receptors (MRs). Previous work provides evidence for a role of aldosterone in alcohol use disorders (AUDs). We tested the hypothesis that high functional activity of the mineralocorticoid endocrine pathway contributes to vulnerability for AUDs. In Study 1, we investigated the relationship between plasma aldosterone levels, ethanol self-administration and the expression of CYP11B2 and MR (NR3C2) genes in the prefrontal cortex area (PFC) and central nucleus of the amygdala (CeA) in monkeys. Aldosterone significantly increased after 6- and 12-month ethanol self-administration. NR3C2 expression in the CeA was negatively correlated to average ethanol intake during the 12 months. In Study 2, we measured Nr3c2 mRNA levels in the PFC and CeA of dependent and nondependent rats and the correlates with ethanol drinking during acute withdrawal. Low Nr3c2 expression levels in the CeA were significantly associated with increased anxiety-like behavior and compulsive-like drinking in dependent rats. In Study 3, the relationship between plasma aldosterone levels, alcohol drinking and craving was investigated in alcohol-dependent patients. Non-abstinent patients had significantly higher aldosterone levels than abstinent patients. Aldosterone levels positively correlated with the number of drinks consumed, craving and anxiety scores. These findings support a relationship between ethanol drinking and the aldosterone/MR pathway in three different species. Funding Agencies|European Foundation for Alcohol Research (ERAB) [EA0619]; ERAB exchange award [EXA0802]; National Institutes of Health (NIH) [ZIA-AA000218]; Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Research Program of the National Institute on Drug Abuse (NIDA); National Institute of Mental Health [MH101076]; Swedish Research Council; Pearson Center for Alcoholism and Addiction Research; NIAAA [AA023867, AA010760, AA08459, AA109431]

SummaryBackground Alcohol abuse represents the most common cause of liver disease in the Western countries. Pre-clinical and clinical studies showed that alcohol consumption affects amount and composition of gut microbiota. Moreover, gut flora plays an important role in the pathogenesis of alcoholic liver injury. Aim To review the relationship between alcohol administration and changes on gut microbiota, its involvement in the pathogenesis of alcoholic liver disease, and how gut microbiota modulation could be a target for the treatment of alcoholic liver disease. Methods Articles were identified using the PubMed database with the search terms ‘Alcohol’, ‘Gut Microbiota’, ‘Alcoholic liver disease’, ‘Probiotic’, ‘Prebiotic’, ‘Symbiotic’ and ‘Antibiotic’. English-language articles were screened for relevance. Full review of publications for the relevant studies was conducted, including additional publications that were identified from individual article reference lists. Results Alcohol abuse induces changes in the composition of gut microbiota, although the exact mechanism for this alteration is not well known. The translocation of bacterial products into the portal blood appears to play a key role in alcohol-induced liver damage. Several studies show that the modulation of gut microbiota seem to be a promising strategy to reduce alcohol-induced liver injury. Conclusions Further studies are needed to better understand the relationship between alcohol administration and changes in gut microbiota, and its involvement in alcoholic liver disease. Moreover larger studies are needed to confirm the preliminary results on the therapeutic effects of gut microbiota modulation.

Symptoms of alcohol withdrawal syndrome (AWS) may develop within 6-24 h after the abrupt discontinuation or decrease of alcohol consumption. Symptoms can vary from autonomic hyperactivity and agitation to delirium tremens. The gold-standard treatment for AWS is with benzodiazepines (BZDs). Among the BZDs, different agents (i.e., long-acting or short-acting) and different regimens (front-loading, fixed-dose or symptom-triggered) may be chosen on the basis of patient characteristics. Severe withdrawal could require ICU admission and the use of barbiturates or propofol. Other drugs, such as α2-agonists (clonidine and dexmetedomidine) and β-blockers can be used as adjunctive treatments to control neuroautonomic hyperactivity. Furthermore, neuroleptic agents can help control hallucinations. Finally, other medications for the treatment for AWS have been investigated with promising results. These include carbamazepine, valproate, sodium oxybate, baclofen, gabapentin and topiramate. The usefulness of these agents are discussed.

Alcohol Use Disorders (AUD) is a leading cause of mortality and morbidity worldwide. At present disulfiram, naltrexone and acamprosate are approved for the treatment of AUD in U.S. and Europe. Nalmefene is approved in Europe and sodium oxybate is approved in Italy and Austria only. Baclofen received a 'temporary recommendation for use' in France.The safety of the above mentioned medications on liver, digestive system, kidney function, nervous system, pregnancy and lactation and their possible side effects are described and discussed.Mechanism of action and metabolism of these drugs as well as patients' clinical characteristics can affect the safety of treatment. All approved medications are valid tools for the treatment of AUD in patients without advanced liver disease. For some drugs, attention should be paid to patients with renal failure and medications may be used with caution, adjusting the dosage according to kidney function. In patients with AUD and advanced liver disease, at present only baclofen has been formally tested in randomized controlled trials showing its safety in this population.

Cocoa helps maintain endothelium-dependent vasodilation; consumption of hazelnuts has been associated with reduced cardiovascular disease risk. This study assesses the effects of hazelnuts and cocoa on vascular reactivity and metabolic profile. Sixty-one healthy volunteers, examined in a randomised, controlled, two-week intervention, received one of six breakfast integrations containing either hazelnuts, cocoa, both or none. Consumption of unpeeled hazelnuts improved HDL-cholesterol (+7.3%, p = .01 vs. baseline, p = .02 vs. control). Brachial artery peak systolic velocities (PSV) at rest increased with hazelnut integrations by 43.4% (p = .04 vs. control) and hazelnut-cocoa integrations by 26.4% (p = .01 vs. control). PSV after 3-min cuff occlusion increased by 60.7% (p = .002 vs. control) with a peeled hazelnut snack and by 64.7% with a hazelnut-cocoa integration (p = .04 vs. control). The combination hazelnut-cocoa may act in a synergic and protective way on cardiovascular system.

Excessive alcohol consumption represents one of the main causes of non-ischemic dilated cardiomyopathy. Alcoholic cardiomyopathy is characterized by dilation and impaired contraction of one or both myocardial ventricles. It represents the final effect of alcohol-induced toxicity to the heart. Several pathophysiological mechanisms have been proposed at the basis of alcohol-induced damage, most of which are still object of research. Unfortunately, symptoms of alcoholic cardiomyopathy are not specific and common to other forms of heart failure and appear when dilatation and systolic dysfunction are consolidated. Thus, early diagnosis is mandatory to prevent the development and progression to heart failure. Although physicians are aware of this disease, several pitfalls in the diagnosis, natural history, prognosis and treatment are still present. The aim of this narrative review is to describe clinical characteristics of alcoholic cardiomyopathy, highlighting the areas of uncertainty.

Previous studies in humans with type 1 diabetes mellitus (T1D) and in nonobese diabetic mice have investigated the beneficial immunomodulatory potential of aerobic physical activity. Performing high volume of aerobic exercise may favorably regulate autoimmunity in diabetes. We tested whether increased physical activity is a self-sufficient positive factor in T1D subjects. During a 3-month observational period, active (six males; 40.5 ± 6.1 years; BMI: 24.5 ± 2.1) and sedentary (four males, three females; 35.9 ± 8.9 years; BMI: 25.7 ± 3.8) T1D individuals on insulin pump therapy were studied for metabolic, inflammatory, and autoimmune parameters. At baseline and at the end of a 3-month period, glycosylated hemoglobin (HbA1c), autoantibodies (anti-GAD, anti-ZnT8, anti-IA2, and ICA) and proinflammatory cytokines (IL-6 and TNF-α) were evaluated. During the third month of the period, physically active T1D patients showed a significant reduction in the average glucose levels (-9%, p = 0.025, by CGM) compared to the first month values, and even their hyperglycemic episodes (>180 mg/dl) diminished significantly (-24.2%, p = 0.032 vs. first month). Moreover, active T1D subjects exhibited an improved body composition with respect to sedentary controls. No significant changes were detected as to the autoimmune and inflammatory profiles. This study confirms the beneficial role of physical exercise associated with insulin pump therapy in order to improve metabolic control in individuals with T1D. These preliminary positive observations need to be challenged in a prolonged interventional follow-up.

Repetitive Transcranial Magnetic Stimulation (rTMS) of the dorsolateral prefrontal cortex may affect neuro-adaptations associated with alcohol use disorder (AUD), potentially influencing craving and alcohol intake. We investigated alcohol intake and dopamine transporter (DAT) availability by Single Photon Emission Computed Tomography (SPECT) in the striatum of AUD patients before and after deep rTMS. Fourteen patients underwent baseline clinical and SPECT assessment. Eleven out of fourteen patients were randomized into two groups for the REAL (n.5) or SHAM (n.6) treatment. Clinical and SPECT evaluations were then carried out after four weeks of rTMS sessions (T1). At baseline, AUD patients showed higher striatal DAT availability than healthy control subjects (HC). Patients receiving the REAL stimulation revealed a reduction in DAT availability at T1, whereas the SHAM-treated group did not. In addition, patients receiving the REAL stimulation had a decrease in alcohol intake. The results of this longitudinal pilot study may suggest a modulatory effect of deep rTMS on dopaminergic terminals and a potential clinical efficacy in reducing alcohol intake in AUD patients. Further investigations are required to confirm these preliminary data.

Benzodiazepines (BDZs) are the gold standard in the treatment of alcohol withdrawal syndrome (AWS). Sodium oxybate (SMO) has been tested as a treatment for AWS with encouraging results. The aim of this phase IV, multicenter, randomized, double-blind, double-dummy study was to evaluate the efficacy of SMO in comparison with oxazepam in the treatment of uncomplicated AWS.Alcohol-dependent outpatients (n = 126) affected by uncomplicated AWS according to the Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar) scale were enrolled in the study and randomized in two groups: 61 patients received SMO and 65 patients received oxazepam for 10 days. The primary endpoint was the reduction of symptoms of AWS measured by the change in the total CIWA-Ar score from baseline (day 1) to the end of the study (day 10). This study is registered with ClinicalTrials.gov, number: NCT02090504 RESULTS: A significant decrease of the mean total CIWA-Ar score from baseline to the end of the study was found in both the SMO (p0.0001) and the oxazepam group (p0.0001), with no significant differences between the two treatments (p = 0.21). Treatment with SMO and oxazepam resulted in a marked decrease in the severity of the mean CIWA subscales, i.e. sweating, tremor, and anxiety, with no significant differences between the two treatments. Both drugs were well tolerated and no severe side effects were reported.SMO is as effective as oxazepam, one of the gold standard BDZs, in the treatment of uncomplicated AWS. Due to its tolerability and absence of significant side effects, SMO may be considered a valid alternative choice in the treatment of AWS.

Persistent hiccup is a worrying symptom both for patients, because of reduced quality of life, and for physicians, because of frustration for unsuccessful treatments.To test baclofen administration for the treatment of persistent hiccup.We report a series of seven patients affected by persistent hiccup successfully treated with baclofen.Hiccup stopped in all patients after a single administration of the drug.Baclofen is a GABA(B) receptor agonist. It is conceivable that the reduction of dopamine release by GABA(B) receptor stimulation is able to interrupt hiccup's reflex arc.

Objective Metadoxine is approved in Europe for alcohol intoxication and is also indicated for alcoholic liver disease (ALD). This study aims to investigate the use of metadoxine as a potential pharmacotherapy for alcohol dependence (AD). Methods This is a retrospective study of 94 outpatients with AD, who received metadoxine for alcohol intoxication and were assessed for alcohol consumption, craving [Visual Analog Scale (VAS)] and liver-related and alcohol-related biomarkers [aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl-transpeptidase, mean corpuscular volume]. Results Range of metadoxine dose was 500-2000 mg/day, with a mean dose of 1277(s.d.290) mg/day, and for a period of 2-42 days, with a mean period of 8.9(s.d.7.0) days. Follow-up data were available for 52 patients (55.3%); 35(67.3%) patients were completely abstinent. There was a significant decrease in drinks per week, even after substituting baseline drinking as follow-up data for dropouts (p Discussion Despite important limitations, this study represents a further preliminary observation suggesting metadoxine as a novel alcohol pharmacotherapy, including in alcohol-dependent patients with ALD.

Aims: Subjects with chronic alcohol abuse can present several metabolic and nutritional alterations. The hypothalamic-pituitary-adrenal (HPA) axis may play a role in these nutritional and metabolic disorders. The goal of this study was to investigate if there is any relationship between HP-hormones and metabolic and nutritional parameters in alcoholic subjects. Methods: Sixteen alcoholics were considered before and after 3 months of total alcohol abstinence. HP-related hormones were determined. Nutritional and metabolic parameters were assessed by dual-energy X-ray absorptiometry (DXA) and indirect calorimetry. Results: At baseline, a significant negative correlation was found between fat mass (FM) and cortisol ( r = −0.54, P = 0.03). During abstinence, a significant increase of both body mass index (BMI) ( P < 0.0001) and FM ( P < 0.0001) was found at 12 weeks compared to baseline. A significant decrease of both plasma cortisol ( P = 0.044) and aldosterone ( P = 0.023) was found at 12 weeks compared to baseline. At 12 weeks, the significant correlation between cortisol and FM disappeared. Conclusions: A higher HPA-axis activation—reflected by higher cortisol levels—was associated with a lower FM in alcoholics. Conversely, during total abstinence a reduced HPA-axis activity can play a role in the parallel nutritional recovery. The present results suggest a role of the HPA axis throughout cortisol both in the etiology of the alcohol-related nutritional alterations and in their recovery after a period of total alcohol abstinence.

Background: A relationship between some hypothalamic–pituitary–related hormones and craving for alcohol has been suggested, leading to hypothesize a role of some hormones in the neurobiology of alcohol dependence. Investigating this association in alcohol-dependent (AD) patients was the aim of this preliminary and exploratory study. Methods: Cortisol, adrenocorticotropic hormone, prolactin, thyroid-stimulating hormone (TSH), free T3, free T4, growth hormone, follicle-stimulating hormone, luteinizing hormone as well as administering the Obsessive-Compulsive Drinking Scale (OCDS) and Penn Alcohol Craving Scale (PACS) were assessed at baseline and after 12 weeks in 25 current AD patients. Patients were treated with baclofen (10 mg t.i.d.) for these 12 weeks. Sixteen patients remained totally abstinent for 12 weeks. Results: At baseline, a significant inverse correlation was found between TSH and PACS (r = −0.46; p = 0.022) and OCDS scores (r = −0.53; p = 0.007). A significant direct correlation was found between free T3 and OCDS score (r = 0.44; p = 0.026). In the 16 abstinent patients, craving scores were significantly decreased at 12 weeks (p