Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial.

BACKGROUND: Observational studies suggest that bariatric-metabolic surgery might greatly improve non-alcoholic steatohepatitis (NASH). However, the efficacy of surgery on NASH has not yet been compared with the effects of lifestyle interventions and medical therapy in a randomised trial. METHODS: We did a multicentre, open-label, randomised trial at three major hospitals in Rome, Italy. We included participants aged 25-70 years with obesity (BMI 30-55 kg/m2), with or without type 2 diabetes, with histologically confirmed NASH. We randomly assigned (1:1:1) participants to lifestyle modification plus best medical care, Roux-en-Y gastric bypass, or sleeve gastrectomy. The primary endpoint of the study was histological resolution of NASH without worsening of fibrosis at 1-year follow-up. This study is registered at ClinicalTrials.gov, NCT03524365. FINDINGS: Between April 15, 2019, and June 21, 2021, we biopsy screened 431 participants; of these, 103 (24%) did not have histological NASH and 40 (9%) declined to participate. We randomly assigned 288 (67%) participants with biopsy-proven NASH to lifestyle modification plus best medical care (n=96 [33%]), Roux-en-Y gastric bypass (n=96 [33%]), or sleeve gastrectomy (n=96 [33%]). In the intention-to-treat analysis, the percentage of participants who met the primary endpoint was significantly higher in the Roux-en-Y gastric bypass group (54 [56%]) and sleeve gastrectomy group (55 [57%]) compared with lifestyle modification (15 [16%]; p<0·0001). The calculated probability of NASH resolution was 3·60 times greater (95% CI 2·19-5·92; p<0·0001) in the Roux-en-Y gastric bypass group and 3·67 times greater (2·23-6·02; p<0·0001) in the sleeve gastrectomy group compared with in the lifestyle modification group. In the per protocol analysis (236 [82%] participants who completed the trial), the primary endpoint was met in 54 (70%) of 77 participants in the Roux-en-Y gastric bypass group and 55 (70%) of 79 participants in the sleeve gastrectomy group, compared with 15 (19%) of 80 in the lifestyle modification group (p<0·0001). No deaths or life-threatening complications were reported in this study. Severe adverse events occurred in ten (6%) participants who had bariatric-metabolic surgery, but these participants did not require re-operations and severe adverse events were resolved with medical or endoscopic management. INTERPRETATION: Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH. FUNDING: Fondazione Policlinico Universitario A Gemelli, Policlinico Universitario Umberto I and S Camillo Hospital, Rome, Italy.

Accurate liquid biopsy for the diagnosis of non-alcoholic steatohepatitis and liver fibrosis.

OBJECTIVE: Clinical diagnosis and approval of new medications for non-alcoholic steatohepatitis (NASH) require invasive liver biopsies. The aim of our study was to identify non-invasive biomarkers of NASH and/or liver fibrosis. DESIGN: This multicentre study includes 250 patients (discovery cohort, n=100 subjects (Bariatric Surgery Versus Non-alcoholic Steato-hepatitis - BRAVES trial); validation cohort, n=150 (Liquid Biopsy for NASH and Liver Fibrosis - LIBRA trial)) with histologically proven non-alcoholic fatty liver (NAFL) or NASH with or without fibrosis. Proteomics was performed in monocytes and hepatic stellate cells (HSCs) with iTRAQ-nano- Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (LC-MS/MS), while flow cytometry measured perilipin-2 (PLIN2) and RAB14 in peripheral blood CD14+CD16- monocytes. Neural network classifiers were used to predict presence/absence of NASH and NASH stages. Logistic bootstrap-based regression was used to measure the accuracy of predicting liver fibrosis. RESULTS: The algorithm for NASH using PLIN2 mean florescence intensity (MFI) combined with waist circumference, triglyceride, alanine aminotransferase (ALT) and presence/absence of diabetes as covariates had an accuracy of 93% in the discovery cohort and of 92% in the validation cohort. Sensitivity and specificity were 95% and 90% in the discovery cohort and 88% and 100% in the validation cohort, respectively.The area under the receiver operating characteristic (AUROC) for NAS level prediction ranged from 83.7% (CI 75.6% to 91.8%) in the discovery cohort to 97.8% (CI 95.8% to 99.8%) in the validation cohort.The algorithm including RAB14 MFI, age, waist circumference, high-density lipoprotein cholesterol, plasma glucose and ALT levels as covariates to predict the presence of liver fibrosis yielded an AUROC of 95.9% (CI 87.9% to 100%) in the discovery cohort and 99.3% (CI 98.1% to 100%) in the validation cohort, respectively. Accuracy was 99.25%, sensitivity 100% and specificity 95.8% in the discovery cohort and 97.6%, 99% and 89.6% in the validation cohort. This novel biomarker was superior to currently used FIB4, non-alcoholic fatty liver disease fibrosis score and aspartate aminotransferase (AST)-to-platelet ratio and was comparable to ultrasound two-dimensional shear wave elastography. CONCLUSIONS: The proposed novel liquid biopsy is accurate, sensitive and specific in diagnosing the presence and severity of NASH or liver fibrosis and is more reliable than currently used biomarkers. CLINICAL TRIALS: Discovery multicentre cohort: Bariatric Surgery versus Non-Alcoholic Steatohepatitis, BRAVES, ClinicalTrials.gov identifier: NCT03524365.Validation multicentre cohort: Liquid Biopsy for NASH and Fibrosis, LIBRA, ClinicalTrials.gov identifier: NCT04677101.

Metabolic surgery versus conventional medical therapy in patients with type 2 diabetes: 10-year follow-up of an open-label, single-centre, randomised controlled trial.

BACKGROUND: No data from randomised controlled trials of metabolic surgery for diabetes are available beyond 5 years of follow-up. We aimed to assess 10-year follow-up after surgery compared with medical therapy for the treatment of type 2 diabetes. METHODS: We did a 10-year follow-up study of an open-label, single-centre (tertiary hospital in Rome, Italy), randomised controlled trial, in which patients with type 2 diabetes (baseline duration >5 years; glycated haemoglobin [HbA1c] >7·0%, and body-mass index ≥35 kg/m2) were randomly assigned (1:1:1) to medical therapy, Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion (BPD) by a computerised system. The primary endpoint of the study was diabetes remission at 2 years (HbA1c <6·5% and fasting glycaemia <5·55 mmol/L without ongoing medication for at least 1 year). In the 10-year analysis, durability of diabetes remission was analysed by intention to treat (ITT). This study is registered with ClinicalTrials.gov, NCT00888836. FINDINGS: Between April 30, 2009, and Oct 31, 2011, of 72 patients assessed for eligibility, 60 were included. The 10-year follow-up rate was 95·0% (57 of 60). Of all patients who were surgically treated, 15 (37·5%) maintained diabetes remission throughout the 10-year period. Specifically, 10-year remission rates in the ITT population were 5·5% for medical therapy (95% CI 1·0-25·7; one participant went into remission after crossover to surgery), 50·0% for BPD (29·9-70·1), and 25·0% for RYGB (11·2-46·9; p=0·0082). 20 (58·8%) of 34 participants who were observed to be in remission at 2 years had a relapse of hyperglycaemia during the follow-up period (BPD 52·6% [95% CI 31·7-72·7]; RYGB 66·7% [41·7-84·8]). All individuals with relapse, however, maintained adequate glycaemic control at 10 years (mean HbA1c 6·7% [SD 0·2]). Participants in the RYGB and BPD groups had fewer diabetes-related complications than those in the medical therapy group (relative risk 0·07 [95% CI 0·01-0·48] for both comparisons). Serious adverse events occurred more frequently among participants in the BPD group (odds ratio [OR] for BPD vs medical therapy 2·7 [95% CI 1·3-5·6]; OR for RYGB vs medical therapy 0·7 [0·3-1·9]). INTERPRETATION: Metabolic surgery is more effective than conventional medical therapy in the long-term control of type 2 diabetes. Clinicians and policy makers should ensure that metabolic surgery is appropriately considered in the management of patients with obesity and type 2 diabetes. FUNDING: Fondazione Policlinico Universitario Agostino Gemelli IRCCS.

A population approach for the estimation of methylmercury ToxicoKinetics in red mullets.

It is known that, as the vast majority of the anthropogenically emitted mercury can be found in aquatic ecosystems, where several methylating bacteria are present, fish consumption represents the most critical intake source of the most toxic form of mercury, the methylmercury (MeHg). The aim of this work is to predict MeHg levels in the fish muscles which, being the edible portion, are part of the human diet. A physiologically based toxicokinetics model was developed to evaluate the kinetics of MeHg in red mullets. Fishes were described by means of a multi-compartment model including stomach, gut, blood, muscles and an additional compartment virtually encompassing all the remaining organs. Absorption, distribution and excretion were modelled considering different MeHg routes of administration and excretion: intake by ingestion of contaminated food, intake and elimination through inhalation-exhalation and excretion through feces. The model has been firstly validated on Terapon jarbua fish (using the weighted least squares method for parameter estimation) to be subsequently readapted to predict methylmercury concentrations in the muscle of red mullets (using an approximate Bayesian computation approach). This simple multicompartmental model could be considered part, a link in the chain, of a wider more complex project aiming at tracking the fate of MeHg from polluted seawater to the human end consumer. The present study could be useful to surveillance organizations in order to carry out a more comprehensive and informed risk assessment analysis and to take appropriate preventive measures by evaluating possible new MeHg concentration thresholds to minimize public health hazards.

Pioglitazone and bariatric surgery are the most effective treatments for non-alcoholic steatohepatitis: A hierarchical network meta-analysis.

AIMS: To compare different treatments for non-alcoholic steatohepatitis (NASH) and to determine an effectiveness hierarchy. MATERIALS AND METHODS: We conducted a systematic review and Bayesian network meta-analysis including randomized controlled trials or prospective trials with at least 6 months' follow-up and histologically proven NASH in adult participants. Monte Carlo simulations were performed, each generating 10 000 data points, and results are reported as medians and 95% credibility intervals (CrIs). A meta-regression was conducted to find the effects of body mass index (BMI) decrement or reduction of homeostatic model assessment of insulin resistance (HOMA-IR) index on non-alcoholic fatty liver disease activity score (NAS) change. RESULTS: The review identified 48 eligible trials comprising 2356 adults (55.6% men). Data were pooled using a random-effects model. The most effective treatments in terms of NAS reduction per semester were pioglitazone and Roux-en-Y gastric bypass (RYGB; -1.50 [95% CrI -2.08, -1.00] for pioglitazione and -1.00 [95% CrI -1.70, -0.32] for RYGB). Pioglitazone was also the best therapy for steatosis and lobular inflammation reduction. RYGB was the best treatment for hepatocellular ballooning reduction, whereas antioxidants appeared to be best for fibrosis improvement. For each 1% decrement in BMI, NAS was reduced by 1.3% (ß = 1.28%, P = 0.01). Conversely, a 1% reduction of HOMA-IR index reduced NAS by 0.3% (ß = 0.31%, P < 0.001). Treatments that were regarded as promising, such as elafibranor, simtuzumab, selonsertib, cenicriviroc, obeticholic acid and liraglutide, did not reduce either NAS or liver fibrosis significantly. CONCLUSIONS: Pioglitazione and RYGB are the most effective therapies for NASH. Antioxidants may be effective in reducing liver fibrosis. Weight loss and improvement of hepatic insulin resistance are promising approaches in the treatment of NASH.

Insulin sensitivity depends on the route of glucose administration.

AIMS/HYPOTHESIS: The small intestine plays an important role in hepatic and whole-body insulin sensitivity, as shown by bariatric surgery. Our goal was to study whether routes and dose of glucose administration have an acute impact on insulin sensitivity. The primary endpoint of this proof-of-concept study was the difference in insulin-mediated metabolic clearance rate (MCR/I) of glucose between the oral and intravenous routes of glucose administration. Secondary endpoints were differences in insulin effect on proteolysis, ketogenesis, lipolysis and glucagon levels. METHODS: In this parallel cohort study, we administered multiple oral glucose loads to 23 participants (aged between 18 and 65 years) with morbid obesity and with normal or impaired glucose tolerance or type 2 diabetes. In a different session, we administered isoglycaemic intravenous glucose infusions (IGIVI) to match the plasma glucose levels observed during the oral challenges. Glucose rate of appearance (Ra) and disappearance (Rd) and endogenous glucose production (EGP) were calculated by infusing [6,6-2H2]glucose with or without oral [U-13C6]glucose. Plasma small polar metabolites were measured by gas chromatography and time-of-flight mass spectrometry. Lipids were measured by ultra-HPLC and quadrupole mass spectrometry. Glucagon-like peptide-1, insulin, C-peptide and glucagon were also measured. Participants, caregivers, people doing measurements or examinations, and people assessing the outcomes were unblinded to group assignment. RESULTS: Glucose MCR/I was significantly higher during IGIVI than during oral glucose administration, independently of glycaemic status (12 ± 6 for IGIVI vs 7.4 ± 3 ml min-1 kg-1 per nmol/l for oral, p< 0.001 from paired t test). Insulin secretion was higher during oral administration than during IGIVI (p< 0.001). The disposition index was significantly lower during the oral procedure: 4260 ± 1820 vs 5000 ± 2360 (ml min-1 kg-1 (nmol/l)-1 pmol/min; p = 0.005). Insulin clearance was significantly higher when glucose was infused rather than ingested (2.53 ± 0.82 vs 2.16 ± 0.49 l/min in intravenous and oral procedure, respectively, p = 0.006). The efficacy of insulin in inhibiting lipolysis and proteolysis was decreased after oral glucose loads. A heat map diagram showed a different pattern for the metabolites between the two routes of glucose administration. CONCLUSIONS/INTERPRETATION: Our study shows that insulin sensitivity depends on the route of glucose administration, the oral route leading to increased insulin secretion and compensatory insulin resistance compared with the intravenous route. The efficacy of insulin in blocking lipolysis and protein breakdown is lower after oral glucose loads vs the intravenous route. Our findings suggest that, while the glucose-mediated incretin release is followed by an increase in insulin release, the effect of the released insulin is limited by an increase in insulin resistance. TRIAL REGISTRATION: ClinicalTrials.gov NCT03223129. Graphical abstract.

Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial.

BACKGROUND: Randomised controlled trials have shown that bariatric surgery is more effective than conventional treatment for the short-term control of type-2 diabetes. However, published studies are characterised by a relatively short follow-up. We aimed to assess 5 year outcomes from our randomised trial designed to compare surgery with conventional medical treatment for the treatment of type 2 diabetes in obese patients. METHODS: We did our open-label, randomised controlled trial at one diabetes centre in Italy. Patients aged 30-60 years with a body-mass index of 35 kg/m(2) or more and a history of type 2 diabetes lasting at least 5 years were randomly assigned (1:1:1), via a computer-generated randomisation procedure, to receive either medical treatment or surgery by Roux-en-Y gastric bypass or biliopancreatic diversion. Participants were aware of treatment allocation before the operation and study investigators were aware from the point of randomisation. The primary endpoint was the rate of diabetes remission at 2 years, defined as a glycated haemaglobin A1c (HbA1c) concentration of 6·5% or less (≤47·5 mmol/mol) and a fasting glucose concentration of 5·6 mmol/L or less without active pharmacological treatment for 1 year. Here we analyse glycaemic and metabolic control, cardiovascular risk, medication use, quality of life, and long-term complications 5 years after randomisation. Analysis was by intention to treat for the primary endpoint and by per protocol for the 5 year follow-up. This study is registered with ClinicalTrials.gov, number NCT00888836. FINDINGS: Between April 27, 2009, and Oct 31, 2009, we randomly assigned 60 patients to receive either medical treatment (n=20) or surgery by gastric bypass (n=20) or biliopancreatic diversion (n=20); 53 (88%) patients completed 5 years' follow-up. Overall, 19 (50%) of the 38 surgical patients (seven [37%] of 19 in the gastric bypass group and 12 [63%] of 19 in the bilipancreatic diversion group) maintained diabetes remission at 5 years, compared with none of the 15 medically treated patients (p=0·0007). We recorded relapse of hyperglycaemia in eight (53%) of the 15 patients who achieved 2 year remission in the gastric bypass group and seven (37%) of the 19 patients who achieved 2 year remission in the biliopancreatic diversion group. Eight (42%) patients who underwent gastric bypass and 13 (68%) patients who underwent biliopancreatic diversion had an HbA1c concentration of 6·5% or less (≤47·5 mmol/mol) with or without medication, compared with four (27%) medically treated patients (p=0·0457). Surgical patients lost more weight than medically treated patients, but weight changes did not predict diabetes remission or relapse after surgery. Both surgical procedures were associated with significantly lower plasma lipids, cardiovascular risk, and medication use. Five major complications of diabetes (including one fatal myocardial infarction) arose in four (27%) patients in the medical group compared with only one complication in the gastric bypass group and no complications in the biliopancreatic diversion group. No late complications or deaths occurred in the surgery groups. Nutritional side-effects were noted mainly after biliopancreatic diversion. INTERPRETATION: Surgery is more effective than medical treatment for the long-term control of obese patients with type 2 diabetes and should be considered in the treatment algorithm of this disease. However, continued monitoring of glycaemic control is warranted because of potential relapse of hyperglycaemia. FUNDING: Catholic University of Rome.

A glycemia-structured population model.

Structured models are population models in which the individuals are characterized with respect to the value of some variable of interest, called the structure variable. In the present paper, we propose a glycemia-structured population model, based on a linear partial differential equation with variable coefficients. The model is characterized by three rate functions: a new-adult population glycemic profile, a glycemia-dependent mortality rate and a glycemia-dependent average worsening rate. First, we formally analyze some properties of the solution, the transient behavior and the equilibrium distribution. Then, we identify the key parameters and functions of the model from real-life data and we hypothesize some plausible modifications of the rate functions to obtain a more beneficial steady-state behavior. The interest of the model is that, while it summarizes the evolution of diabetes in the population in a completely different way with respect to previously published Monte Carlo aggregations of individual-based models, it does appear to offer a good approximation of observed reality and of the features expected in the clinical setting. The model can offer insights in pharmaceutical research and be used to assess possible public health intervention strategies.

Simulation of Trauma Incidents : Modelling the Evolution of Patients and Resources.

Mathematical modeling and simulation with medical applications has gained much interest in the last few years, mainly due to the widespread availability of low-cost technology and computational power. This paper presents an integrated platform for the in-silico simulation of trauma incidents, based on a suite of interacting mathematical models. The models cover the generation of a scenario for an incident, a model of physiological evolution of the affected individuals, including the possible effect of the treatment, and a model of evolution in time of the required medical resources. The problem of optimal resource allocation is also investigated. Model parameters have been identified according to the expertise of medical doctors and by reviewing some related literature. The models have been implemented and exposed as web services, while some software clients have been built for the purpose of testing. Due to its extendability, our integrated platform highlights the potential of model-based simulation in different health-related fields, such as emergency medicine and personal health systems. Modifications of the models are already being used in the context of two funded projects, aiming at evaluating the response of health systems to major incidents with and without model-based decision support.

Predictors of remission of diabetes mellitus in severely obese individuals undergoing bariatric surgery: do BMI or procedure choice matter? A meta-analysis.

OBJECTIVE: To compare diabetes remission after bariatric surgery in subjects with body mass index (BMI) of 35 kg/m2 or more or BMI of less than 35 kg/m to determine which predictors are best. BACKGROUND: BMI is currently the only selection criterion for bariatric surgery in diabetic subjects. Many studies have challenged BMI for predicting diabetes remission. METHODS: Data sources were PubMed, Cochrane Library, and EMBASE databases from January 1980 to June 2013. The selected studies were randomized controlled trials, controlled clinical trials, or cohort studies with 10 or more patients per arm. Of 1437 screened articles, 94 studies were included with 94,579 patients undergoing surgical procedures (4944 with type 2 diabetes mellitus). Weight, BMI, glycated hemoglobin A1c, fasting glucose, and insulin were abstracted by 2 independent reviewers. The effect size was the percent diabetes remission. RESULTS: Meta-analysis was performed for BMI less than 35 kg/m2 (group 1) and BMI 35 kg/m2 or more (group 2). Diabetes remission was 72% [95% confidence interval (CI), 65-80] in group 1 and 71% (95% CI, 65-77) in group 2. Diabetes resolution was 89% (95% CI, 83-94) after biliopancreatic diversion, 77% (95% CI, 72-82) after Roux-en-Y bypass, 62% (95% CI, 46-79) after gastric banding, and 60% (95% CI, 51-70) after sleeve gastrectomy. The only significant predictor of glycated hemoglobin A1c reduction was waist circumference, lower baseline waist associating with higher reduction. CONCLUSIONS: Bariatric surgery determines similar diabetes remission rates in patients with BMI of 35 kg/m2 or more or BMI of less than 35 kg/m2. Baseline BMI is unrelated to diabetes remission. The association of baseline waist circumference with glycated hemoglobin A1c reduction is likely due to selection bias. Bariatric or metabolic effects of the surgical procedures appear independent, and different indices are needed to predict them.

Bariatric surgery versus conventional medical therapy for type 2 diabetes.

BACKGROUND: Roux-en-Y gastric bypass and biliopancreatic diversion can markedly ameliorate diabetes in morbidly obese patients, often resulting in disease remission. Prospective, randomized trials comparing these procedures with medical therapy for the treatment of diabetes are needed. METHODS: In this single-center, nonblinded, randomized, controlled trial, 60 patients between the ages of 30 and 60 years with a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 35 or more, a history of at least 5 years of diabetes, and a glycated hemoglobin level of 7.0% or more were randomly assigned to receive conventional medical therapy or undergo either gastric bypass or biliopancreatic diversion. The primary end point was the rate of diabetes remission at 2 years (defined as a fasting glucose level of <100 mg per deciliter [5.6 mmol per liter] and a glycated hemoglobin level of <6.5% in the absence of pharmacologic therapy). RESULTS: At 2 years, diabetes remission had occurred in no patients in the medical-therapy group versus 75% in the gastric-bypass group and 95% in the biliopancreatic-diversion group (P<0.001 for both comparisons). Age, sex, baseline BMI, duration of diabetes, and weight changes were not significant predictors of diabetes remission at 2 years or of improvement in glycemia at 1 and 3 months. At 2 years, the average baseline glycated hemoglobin level (8.65±1.45%) had decreased in all groups, but patients in the two surgical groups had the greatest degree of improvement (average glycated hemoglobin levels, 7.69±0.57% in the medical-therapy group, 6.35±1.42% in the gastric-bypass group, and 4.95±0.49% in the biliopancreatic-diversion group). CONCLUSIONS: In severely obese patients with type 2 diabetes, bariatric surgery resulted in better glucose control than did medical therapy. Preoperative BMI and weight loss did not predict the improvement in hyperglycemia after these procedures. (Funded by Catholic University of Rome; ClinicalTrials.gov number, NCT00888836.).

Effect of indoor nitrogen dioxide on lung function in urban environment.

BACKGROUND: High levels of indoor NO2 are associated with increased asthma symptoms and decreased expiratory peak flows in children. We investigated the association of exposure to domestic indoor NO2, objectively measured in winter and spring, with respiratory symptoms and lung function in a sample of adolescents from a southern Mediterranean area. METHODS: From a large school population sample (n=2150) participating in an epidemiological survey in the urban area of the City of Palermo (southern Italy), a sub-sample of 303 adolescents was selected which furnished an enriched sample for cases of current asthma. All subjects were evaluated by a health questionnaire, skin prick tests and spirometry. One-week indoor NO2 monitoring of their homes was performed by diffusive sampling during spring and again during winter. RESULTS: We found that about 25% of subjects were exposed to indoor NO2 levels higher than the 40µg/m(3) World Health Organization limit, during both spring and winter. Moreover, subjects exposed to the highest indoor NO2 concentrations had increased frequency of current asthma (p=0.005), wheeze episodes in the last 12 months (p<0.001), chronic phlegm (p=0.013), and rhinoconjunctivitis (p=0.008). Finally, subjects with a personal history of wheeze ever had poorer respiratory function (FEF25-75%, p=0.01) when exposed to higher indoor NO2 concentrations. CONCLUSIONS: Home exposure to high indoor NO2 levels frequently occurs in adolescents living in a southern Mediterranean urban area and is significantly associated with the risks for increased frequency of both respiratory symptoms and reduced lung function.

Exposure profiles in pregnant women from a birth cohort in a highly contaminated area of southern Italy.

Protecting the health of pregnant women from environmental stressors is crucial for reducing the burden of non-communicable diseases. In industrially contaminated sites, this action is particularly challenging due to the heterogeneous pollutant mixtures in environmental matrices. The aim of this study was to evaluate distribution patterns of mercury, hexachlorobenzene and polychlorobiphenyls in the serum of 161 pregnant women recruited in the framework of the Neonatal Environment and Health Outcomes (NEHO) cohort and living both inside and outside the National Priority Contaminated Site (NPCS) of Priolo. Food macro-categories were determined, and serum levels of contaminants were used to perform k-means cluster analysis and identify the role of food in pollutant transfer from the environment. Two groups of mothers with high and low measured pollutant levels were distinguished. Concentrations in mothers in the high-exposure cluster were at least twofold for all the evaluated pollutants (p < 0.0001) and included mothers living inside and outside NPCS, with a predominance of individuals from the NPCS (p = 0.045). Fish consumption was higher in the high-exposure cluster (p = 0.019). These findings suggest a link between contamination of environmental matrices such as sediment with maternal exposure, through the intake of local food. Such consideration appears poorly investigated in the context of contaminated sites.

Modeling outcome trajectories in patients with acquired brain injury using a non-linear dynamic evolution approach.

This study describes a dynamic non-linear mathematical approach for modeling the course of disease in acquired brain injury (ABI) patients. Data from a multicentric study were used to evaluate the reliability of the Michaelis-Menten (MM) model applied to well-known clinical variables that assess the outcome of ABI patients. The sample consisted of 156 ABI patients admitted to eight neurorehabilitation subacute units and evaluated at baseline (T0), 4 months after the event (T1) and at discharge (T2). The MM model was used to characterize the trend of the first Principal Component Analysis (PCA) dimension (represented by the variables: feeding modality, RLAS, ERBI-A, Tracheostomy, CRS-r and ERBI-B) in order to predict the most plausible outcome, in terms of positive or negative Glasgow outcome score (GOS) at discharge. Exploring the evolution of the PCA dimension 1 over time, after day 86 the MM model better differentiated between the time course for individuals with a positive and negative GOS (accuracy: 85%; sensitivity: 90.6%; specificity: 62.5%). The non-linear dynamic mathematical model can be used to provide more comprehensive trajectories of the clinical evolution of ABI patients during the rehabilitation period. Our model can be used to address patients for interventions designed for a specific outcome trajectory.

A geometrical approach to the PKPD modelling of inhaled bronchodilators.

The present work introduces a new method to model the pharmacokinetics (PK) and pharmacodynamics (PD) of an inhaled dose of bronchodilator, alternative to classic compartmental representations or computational fluid dynamics. A five compartment PK model comprising alimentary tract absorption (gut), bronchial tree mucosa, bronchial muscles, plasma, and elimination/excretion pathways has been developed. Many anatomical and physiological features of the bronchial tree depend on bronchial generation or on mean distance from the larynx. Among these are diameters, resistances, and receptor density, which determine together the local response to the inhaled drug; integrating these local responses over the whole bronchial tree allows an approximation of total bronchodilator response and airflow resistance. While the PK part of the model reflects classical compartmental assumptions, the PD part adds a simplified geometrical and functional description of the bronchial tree to a typical empirical model of local effect on bronchial muscle, leading to the direct computation of the approximate forced expiratory volume in 1 s (FEV(1)). In the present work the construction of the model is detailed, with reference to literature data. Simulation of a hypothetical asthmatic subject is employed to illustrate the behaviour of the model in representing the evolution over time of the distribution and pharmacological effect of an inhaled dose of a bronchodilator. The relevance of particle size and drug formulation diffusivity on therapeutic efficacy is discussed.

A modelling approach to hepatic glucose production estimation.

Stable isotopes are currently used to measure glucose fluxes responsible for observed glucose concentrations, providing information on hepatic and peripheral insulin sensitivity. The determination of glucose turnover, along with fasting and postprandial glucose concentrations, is relevant for inferring insulin sensitivity levels. At equilibrium (e.g. during the fasting state) the rate of glucose entering the circulation equals its rate of disappearance from the circulation. If under these conditions tracer is infused at a constant rate and Specific Activity (SA) or Tracer to Tracee (TTR) ratio is computed, the Rate of Appearance (RA) equals the Rate of Disappearance (RD) and equals the ratio between infusion rate and TTR or SA. In the post-prandial situation or during perturbation studies, however, estimation of RA and RD becomes more complex because they are not necessarily equal and, furthermore, may vary over time due to gastric emptying, glucose absorption, appearance of ingested or infused glucose, variations of EGP and glucose disappearance. Up to now, the most commonly used approach to compute RA, RD and EGP has been the single-pool model by Steele. Several authors, however, report pitfalls in the use of this method, such as "paradoxical" increase in EGP immediately after meal ingestion and "negative" rates of EGP. Different attempts have been made to reduce the impact of these errors, but the same problems are still encountered. In the present work a completely different approach is proposed, where cold and labeled [6, 6-2H2] glucose observations are simultaneously fitted and where both RD and EGP are represented by simple but reasonable functions. As an example, this approach is applied to an intra-venous experiment, where cold glucose is infused at variable rates to reproduce a desired glycaemic time-course. The goal of the present work is to show that appropriate, if simple, modelling of the whole infusion procedure together with the underlying physiological system allows robust estimation of EGP with single-tracer administration, without the artefacts produced by the Steele method.

Validation of a simplified-geometry model of inhaled formoterol pharmacodynamics in asthmatic patients.

PharmacoKinetics (PK) and PharmacoDynamics (PD) mathematical models of inhaled bronchodilators represent useful tools for understanding the mechanisms of drug action and for the individuation of therapy regimens. A PK/PD model for inhaled bronchoactive compounds was previously proposed, incorporating a simplified-geometry approach: the key feature of that model is a mixed compartmental and spatially distributed representation of the kinetics, with the direct computation of representative flow rates from Ohm's law and bronchial diameter profiles. The aim of the present work is the enrichment and validation of this simplified geometry modeling approach against clinical efficacy data. The improved model is used to compute airflow response to treatment for each single virtual patient from a simulated population and it is found to produce very good fits to observed FEV1 profiles. The model provides a faithful quantitative description of the increasing degree of improvement with respect to basal conditions with continuing administration and with increasing drug dosages, as clinically expected.

The Influence of Sociodemographic Factors, Lifestyle, and Risk Perception on Dietary Patterns in Pregnant Women Living in Highly Contaminated Areas: Data from the NEHO Birth Cohort.

During pregnancy, maternal nutrition and lifestyle play a critical role in influencing fetal development and newborn health outcomes. The aim of this study is to investigate the factors influencing the adherence to dietary patterns in pregnant women living in highly contaminated areas, and whether women with higher environmental risk perception manifest different nutritional behaviors during pregnancy. Food consumption data on 816 pregnant women from the Neonatal Environment and Health Outcomes (NEHO) residential birth cohort were analyzed. Dietary patterns were computed by principal component analysis. A multinomial logistic regression was also applied to identify sociodemographic, lifestyle, and pregnancy-related determinants of adherence to dietary patterns during pregnancy. Three patterns of food consumption-explaining 24.9% of the total variance-were identified as "prudent", "high energy", and "vegetarian" patterns. Results suggest that food choices during pregnancy follow a social gradient and align with other health behaviors during pregnancy: older, better educated, and physically active women with higher risk perception are more likely to follow healthier dietary patterns. Knowledge about what is eaten can contribute to dietary choices. Interventions to improve the prenatal nutrition knowledge of pregnant women are needed, especially concerning younger mothers and those with lower educational levels.

Forward planned intensity modulated radiotherapy (IMRT) for whole breast postoperative radiotherapy. Is it useful? When?

The purpose was to compare the dosimetric results observed in 201 breast cancer patients submitted to tangential forward intensity-modulated radiation therapy (IMRT) with those observed in 131 patients treated with a standard wedged 3D technique for postoperative treatment of whole breast, according to breast size and supraclavicular node irradiation. Following dosimetric parameters were used for the comparison: D(max), D(min), D(mean), V(95%) and V(107%) for the irradiated volume; D(max), D(mean), V(80%) and V(95%) for the ipsilateral lung; D(max), D(mean), V(80%) and V(95%) for the heart. Stratification was made according to breast size and supraclavicular (SCV) nodal irradiation. As respect to irradiated volume, a significant reduction of V(107%) (mean values: 7.0 ± 6.6 versus 2.4 ± 3.7, p < 0.001) and D(max) (mean % values: 111.2 ± 2.7 versus 107.7 ± 6.3, p < 0.001), and an increase of D(min) (mean % values: 65.0 ± 17.4 versus 74.9 ± 12.9, p < 0.001) were observed with forward IMRT. The homogeneity of dose distribution to target volume significantly improved with forward IMRT in all patient groups, irrespective of breast size or supraclavicular nodal irradiation. When patients treated with supraclavicular nodal irradiation were excluded from the analysis, forward IMRT slightly reduced V(80%) (mean values: 3.7 ± 2.6 versus 3.0 ± 2.4, p = 0.03) and V(95%) (mean values 1.9 ± 1.8 versus 1.2%± 1.5; p = 0.001) of the ipsilateral lung. The dose to the heart tended to be lower with IMRT but this difference was not statistically significant. Tangential forward IMRT in postoperative treatment of whole breast improved dosimetric parameters in terms of homogeneity of dose distribution to the target in a large sample of patients, independent of breast size or supraclavicular nodal irradiation. Lung irradiation was slightly reduced in patients not undergoing to supraclavicular irradiation.

A comparison among three maximal mathematical models of the glucose-insulin system.

The most well-known and widely used mathematical representations of the physiology of a diabetic individual are the Sorensen and Hovorka models as well as the UVAPadova Simulator. While the Hovorka model and the UVAPadova Simulator only describe the glucose metabolism of a subject with type 1 diabetes, the Sorensen model was formulated to simulate the behaviour of both normal and diabetic individuals. The UVAPadova model is the most known model, accepted by the FDA, with a high level of complexity. The Hovorka model is the simplest of the three models, well documented and used primarily for the development of control algorithms. The Sorensen model is the most complete, even though some modifications were required both to the model equations (adding useful compartments for modelling subcutaneous insulin delivery) and to the parameter values. In the present work several simulated experiments, such as IVGTTs and OGTTs, were used as tools to compare the three formulations in order to establish to what extent increasing complexity translates into richer and more correct physiological behaviour. All the equations and parameters used for carrying out the simulations are provided.