Simona Panunzi

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.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).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).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.).

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.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.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.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.Catholic University of Rome.

<h2>Summary</h2><h3>Background</h3> 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. <h3>Methods</h3> 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 [HbA_1c] >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 (HbA_1c <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. <h3>Findings</h3> 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 HbA_1c 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 <i>vs</i> medical therapy 2·7 [95% CI 1·3–5·6]; OR for RYGB <i>vs</i> medical therapy 0·7 [0·3–1·9]). <h3>Interpretation</h3> 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. <h3>Funding</h3> Fondazione Policlinico Universitario Agostino Gemelli IRCCS.

Study objective To study intraoperative and postoperative complications of laparoscopic myomectomy and patients’ characteristics influencing this risk. Design Prospective study, with a review of the patient records by the first author (Canadian Task Force classification II-2). Setting Four Italian referral centers. Patients The incidence and type of complications occurring in 2050 laparoscopic myomectomies undertaken from January 1998 through December 2004 were recorded. Interventions The surgical technique, as well as the expertise of the operators, was the same for the 4 centers. Injection of vasoconstrictive agents was used in 37%. The serosa was always incised in a vertical fashion; mechanical enucleation of the myoma was completed whenever possible; suture was performed in 1 or 2 layers with deep and large stitches swaged to 1 or 0 polyglactin sutures that were tied intracorporeally or extracorporeally. Measurements and main results Single or multiple myomectomies (n = 2050) for symptomatic myomas measuring at least 4 cm in diameter were performed. Most patients (48%) had more than 1 myoma, with a maximum of 15 per patient (myomas removed for patients: 2.26 ± 1.8, mean ± SD). Myoma size ranged from 1 to 20 cm (mean 6.40 ± 2.6 SD). Myomas smaller than 4 cm were removed during myomectomy for larger ones. Total complication rate was 11.1% (225/2050 cases). Minor complications accounted for 9.1% (187/2050 cases) and major complications for 2.02% (38/2050 cases). The most serious events were hemorrhages (14 cases, 0.68%) requiring blood transfusions in 3 cases (0.14%); 10 postoperative hematomas (0.48%, one in the broad ligament and 9 in the myomectomy scar); 1 bowel injury (0.04%); 1 postoperative acute kidney failure (0.04%); and 2 unexpected sarcomas (0.09%). Failure to complete planned surgery occurred in 7 cases (0.34%). Two patients were readmitted for surgery (0.09%): 1 had a laparoscopic hysterectomy because of a severe blood loss, and the other had drainage of a hematoma in the broad ligament. After a follow-up period of 41.70 ± 23.03 months (mean ± SD), 386 (22.9%) patients conceived, with a pregnancy rate in patients wishing pregnancy of 69.8%; among them, 1 (0.26%) recorded spontaneous uterine rupture at 33 weeks gestation. Odds ratio computed to estimate the risk of complications in relation to the patient characteristics showed that the probability of complications significantly rises with an increase in the number (more than 3 myomas OR: 4.46, p <.001) and with the intramural (OR: 1.48, p <.05) or the intraligamentous location of myomas (OR: 2.36, p <.01) whereas the myoma size seems to influence particularly the risk of major complications (OR: 6.88, p <.001). Conclusions This is one of the largest series reported of laparoscopic myomectomy and the first focused on complications. The complication rate appears to be better than acceptable in comparison with complication rates reported after laparotomic myomectomies. Laparoscopic myomectomy, when performed by an experienced surgeon, can be considered a safe technique with an extremely low failure rate and good results in terms of pregnancy outcome.

In Brief 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/m2 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. This meta-analysis study compares diabetes outcome after bariatric surgery in subjects with body mass index of 35 kg/m2 or more or body mass index of less than 35 kg/m2 to determine which predictors of diabetes remission are best in the 2 groups. Differences in type 2 diabetes mellitus remission after different bariatric surgery procedures were also studied.

Eligibility criteria for bariatric surgery in diabetes include BMI ≥35 kg/m(2) and poorly controlled glycemia. However, BMI does not predict diabetes remission, and thus, predictors need to be identified.Seven hundred twenty-seven patients were included in a database merged from the Swedish Obese Subjects (SOS) study and two randomized controlled studies, with 415 surgical and 312 medical patients in total. Bariatric operations were divided into gastric only (GO) and gastric plus diversion (GD).Sixty-four percent of patients in the surgical arm and 15.0% in the medical arm experienced diabetes remission (P < 0.001). GO yielded 60% remission, and GD yielded 76% remission. The best predictors of diabetes remission were lower baseline glycemia and shorter diabetes duration. However, when operation type was considered, GD predicted a higher likelihood of remission and greater weight loss. Patients in remission (responders) lost more weight (25% vs. 17%) and waist circumference (18% vs. 13%) and experienced better insulin sensitivity than nonresponders.Surgery is more effective than medical treatment in achieving diabetes remission and tighter glycemic control. Shorter diabetes duration, lower fasting glycemia before surgery, and GD versus GO procedures independently predict higher rates of remission, whereas baseline HbA1c and waist circumference predict improved glycemic control. The results show the advantage of an early operation together with better controlled glycemia on diabetes remission independently of BMI.

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.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.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.Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH.Fondazione Policlinico Universitario A Gemelli, Policlinico Universitario Umberto I and S Camillo Hospital, Rome, Italy.

The surgical option could represent a valid alternative to medical therapy in some diabetic patients. However, no data are available on long-term effects of metabolic surgery on diabetic complications. We aimed to determine whether patients with newly diagnosed type 2 diabetes who underwent bilio-pancreatic diversion (BPD) had less micro- and macrovascular complications than those who received conventional therapy.This was an unblinded, case-controlled trial with 10-years' follow-up, conducted from July 1998 through October 2009 at the Day Hospital of Metabolic Diseases, Catholic University, Rome, Italy. A consecutive sample of 110 obese patients (BMI >35 kg/m(2)) with newly diagnosed type 2 diabetes was enrolled. The study was completed by 50 subjects. The main outcome measure was long-term effects (10 years) of BPD versus those associated with conventional therapy on microvascular outcome, micro- and macroalbuminuria, and glomerular filtration rate (GFR). Secondary measures included macrovascular outcomes, type 2 diabetes remission, glycated hemoglobin, and hyperlipidemia.Ten-year GFR variation was -45.7 ± 18.8% in the medical arm and 13.6 ± 24.5% in the surgical arm (P < 0.001). Ten-year hypercreatininemia prevalence was 39.3% in control subjects and 9% in BPD subjects (P = 0.001). After 10 years, all BPD subjects recovered from microalbuminuria, whereas microalbuminuria appeared or progressed to macroalbuminuria in control subjects. Three myocardial infarctions, determined by electrocardiogram, and one stroke occurred in control subjects. After the 10-year follow-up, coronary heart disease (CHD) probability was 0.22 ± 0.10 and 0.05 ± 0.04 in the medical and surgical groups, respectively (P < 0.001). Remission from type 2 diabetes was observed in all patients within 1 year of surgery. Surgical and medical subjects had lost 34.60 ± 10.25 and 0.38 ± 6.10% of initial weight at the 10-year follow-up (P < 0.001).Renal and cardiovascular complications were dramatically reduced in the surgical arm, indicating long-term benefits of BPD on diabetic complications, at least in the case of morbid obesity with decompensated type 2 diabetes.

Roux-en-Y gastric bypass (RYGB) induces type 2 diabetes remission (DR) in 60% of patients at 1 year, yet long-term relapse occurs in half of these patients. Scoring methods to predict DR outcomes 1 year after surgery that include only baseline parameters cannot accurately predict 5-year DR (5y-DR). We aimed to develop a new score to better predict 5y-DR.We retrospectively included 175 RYGB patients with type 2 diabetes with 5-year follow-up. Using machine learning algorithms, we developed a scoring method, 5-year Advanced-Diabetes Remission (5y-Ad-DiaRem), predicting longer-term DR postsurgery by integrating medical history, bioclinical data, and antidiabetic treatments. The scoring method was based on odds ratios and variables significantly different between groups. This score was further validated in three independent RYGB cohorts from three European countries.Compared with 5y-DR patients, patients who had relapsed after 5 years exhibited more severe type 2 diabetes at baseline, lost significantly less weight during the 1st year after RYGB, and regained more weight afterward. The 5y-Ad-DiaRem includes baseline (diabetes duration, number of antidiabetic treatments, and HbA1c) and 1-year follow-up parameters (glycemia, number of antidiabetic treatments, remission status, 1st-year weight loss). The 5y-Ad-DiaRem was accurate (area under the receiver operating characteristic curve [AUROC], 90%; accuracy, 85%) at predicting 5y-DR, performed better than the Diabetes Remission score (DiaRem) and the Advanced-DiaRem (AUROC, 81% and 84%; accuracy, 79% and 78%, respectively), and correctly reclassified 13 of 39 patients misclassified with the DiaRem. The 5y-Ad-DiaRem robustness was confirmed in the independent cohorts.The 5y-Ad-DiaRem accurately predicts 5y-DR and appears relevant to identify patients at risk for relapse. Using this score could help personalize patient care after the 1st year post-RYGB to maximize weight loss, limit weight regains, and prevent relapse.

Mingrone, Geltrude; Panunzi, Simona; De Gaetano, Andrea; Guidone, Caterina; Iaconelli, Amerigo; Leccesi, Laura; Nanni, Giuseppe; Pomp, Alfons; Castagneto, Marco; Ghirlanda, Giovanni; Rubino, Francesco Author Information

ContextWe compared the incidence of hypoglycemia after Roux-en-Y gastric bypass (RYGB) vs sleeve gastrectomy (SG).

Abstract 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% (β = 1.28%, P = 0.01). Conversely, a 1% reduction of HOMA‐IR index reduced NAS by 0.3% (β = 0.31%, P &lt; 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.

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 .

Polycystic ovary syndrome (PCOS) and menopausal subjects are characterized by an increased cardiovascular and type 2 diabetes mellitus risk, at least partially related to insulin disturbances. The evaluation of insulin resistance in these patients could be useful as primary prevention. The aim of the study was to verify the validity of several indexes of insulin sensitivity in PCOS and menopausal subjects by comparing the data obtained by these indexes to those of euglycemic-hyperinsulinemic clamp studies.One hundred PCOS and 110 menopausal subjects were analyzed; all subjects underwent an oral glucose tolerance test (75 g) and euglycemic-hyperinsulinemic clamp study. Seven PCOS patients and 13 menopausal subjects had impaired glucose tolerance or type 2 diabetes mellitus and were excluded from the study. After analysis of correlation coefficients between the evaluated indexes and the clamp studies, the sensitivity and specificity of different cut-off values for each parameter were analyzed by receiver operating characteristic (ROC) curves.The best correlation coefficients with clamp studies were obtained with the Avignon insulin sensitivity index (SiM) (R(s) = 0.7812) in PCOS patients and the Matsuda and De Fronzo index (R(s) = 0.6178) in menopausal patients. The best predictive index of insulin resistance in PCOS was a Avignon insulin sensitivity basal index (SibB) value of 62 or less (78% sensitivity, 95% specificity) and an insulin area under the curve (AUC) of 7,000 microIU/ml or more (>/=50,225 pmol/liter) x 120 min (83% sensitivity, 90% specificity). In the menopausal population, the best predictive performance was obtained by an insulin AUC of 10,000 microIU/ml or more (>/=71,750 pmol/liter) x 240 min (70% sensitivity, 88% specificity).The presence of high correlation coefficients does not necessarily mean that the indexes of insulin resistance have an optimal predictive performance; this is probably due to the presence of many borderline values. The simple evaluation of insulin AUC seems to effectively replace the euglycemic-hyperinsulinemic clamp in routine clinical practice, allowing results superimposable to those obtained by minimal model analysis.

Context: The wide family of the phytoestrogens has become an alternative to the classical hormonal therapy in menopause; nevertheless, some findings are still conflicting. Objective: To examine the effect of genistein administration on metabolic parameters and vascular reactivity considering the basal endocrine status of the patients. Design and Setting: A randomized placebo controlled study was conducted at a university hospital. Participants: Fifty postmenopausal women participated. Interventions: Thirty subjects (group A) were randomized to receive 54 mg/d genistein while 20 subjects (group B) were treated with the placebo for 24 wk. In group A, we distinguish two subgroups: 14 normoinsulinemic and 12 hyperinsulinemic patients. Main Outcome Measures: Anthropometric measures, hormonal and lipid assays, oral glucose tolerance test with glycemic, insulin, and C-peptide evaluation, indexes of insulin sensitivity and endothelial function, and euglycemic-hyperinsulinemic clamps were performed. Results: The insulin basal values significantly decreased in group A, whereas the homeostasis model index of insulin sensitivity and the fasting glucose levels significantly improved compared with placebo group. The genistein administration decreased fasting glucose and area under the curve glucose levels in the normoinsulinemic patients after treatment. In the hyperinsulinemic patients, a significant reduction in fasting insulin, fasting C-peptide, and area under the curve insulin levels as well as an increase in fractional hepatic insulin extraction was shown. In these patients, high-density lipoprotein cholesterol levels were significantly improved. The endothelium-dependent and -independent dilatation improved in the treated group. Normoinsulinemic patients showed both a significantly enhanced flow-mediated and nitrate-mediated dilatation, whereas no significant changes were found in the hyperinsulinemic group. Conclusions: The glycoinsulinemic metabolism and the endothelial function were significantly influenced by genistein. In particular, normoinsulinemic patients showed an improvement in glycemic and vascular reactivity indexes. Conversely, an improvement in the insulin sensitivity indexes was noted in hyperinsulinemic patients.

The lifetime risk of developing symptomatic knee osteoarthritis is 60% in subjects with obesity. It is unclear which is the best weight loss interventions leading to a meaningful improvement of osteoarthritis symptoms and clinical conditions in subjects with obesity. Our network meta-analysis compares different weight loss interventions on the improvement of osteoarthritis symptoms and clinical conditions in subjects affected by obesity. PubMed, Embase, and Cochrane databases were systematically searched for eligible studies until November 2020. Thirty eligible studies comprising 4651 adults (74.6% women) were included. The most effective interventions reducing pain were bariatric surgery, low-calorie diet and exercise, and intensive weight loss and exercise (-62.7 [95% CrI: -74.6, -50.6]; -34.4 [95% CrI: -48.1, -19.5]; -27.1 [95% CrI: -40.4, -13.6] respectively). For every 1% weight loss Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain, function, and stiffness scores decreased by about 2% points. In conclusion, our meta-analysis shows that a substantial weight loss is necessary to reduce significantly knee pain and joint stiffness and to improve physical function: 25% weight reduction from baseline is necessary to obtain a 50% reduction of each subscale of the WOMAC score. However, performing physical exercise is essential to preserve the lean body mass and to avoid sarcopenia. Our results apply to a large spectrum of body mass index (BMI), from overweight to severe obesity.

Due to the increasing importance of identifying insulin resistance, a need exists to have a reliable mathematical model representing the glucose/insulin control system. Such a model should be simple enough to allow precise estimation of insulin sensitivity on a single patient, yet exhibit stable dynamics and reproduce accepted physiological behavior.A new, discrete Single Delay Model (SDM) of the glucose/insulin system is proposed, applicable to Intra-Venous Glucose Tolerance Tests (IVGTTs) as well as to multiple injection and infusion schemes, which is fitted to both glucose and insulin observations simultaneously. The SDM is stable around baseline equilibrium values and has positive bounded solutions at all times. Applying a similar definition as for the Minimal Model (MM) SI index, insulin sensitivity is directly represented by the free parameter KxgI of the SDM. In order to assess the reliability of Insulin Sensitivity determinations, both SDM and MM have been fitted to 40 IVGTTs from healthy volunteers. Precision of all parameter estimates is better with the SDM: 40 out of 40 subjects showed identifiable (CV < 52%) KxgI from the SDM, 20 out of 40 having identifiable SI from the MM. KxgI correlates well with the inverse of the HOMA-IR index, while SI correlates only when excluding five subjects with extreme SI values. With the exception of these five subjects, the SDM and MM derived indices correlate very well (r = 0.93).The SDM is theoretically sound and practically robust, and can routinely be considered for the determination of insulin sensitivity from the IVGTT. Free software for estimating the SDM parameters is available.

A family of delay-differential models of the glucose-insulin system is introduced, whose members represent adequately the Intra-Venous Glucose Tolerance Test and allied experimental procedures of diabetological interest. All the models in the family admit positive bounded unique solutions for any positive initial condition and are persistent. The models agree with the physics underlying the experiments, and they all present a unique positive equilibrium point. <br>&nbsp;&nbsp Local stability is investigated in a pair of interesting member models: one, a discrete-delays differential system; the other, a distributed-delay system reducing to an ordinary differential system evolving on a suitably defined extended state space. In both cases conditions are given on the physical parameters in order to ensure the local asymptotic stability of the equilibrium point. These conditions are always satisfied, given the actual parameter estimates obtained experimentally. A study of the global stability properties is performed, but while from simulations it could be conjectured that the models considered are globally asymptotically stable, sufficient stability criteria, formally derived, are not actually satisfied for physiological parameters values. Given the practical importance of the models studied, further analytical work may be of interest to conclusively characterize their behavior.

Some individuals with normal glucose tolerance (NGT) exhibit a 1-h excursion of plasma glucose during oral glucose tolerance testing as high as that of individuals with impaired glucose tolerance (IGT). The aim of this study was to characterize their metabolic phenotype.A total of 1,205 healthy volunteers (aged 29-61 years) underwent assessment of 1) oral glucose tolerance and 2) insulin sensitivity (standardized euglycemic-hyperinsulinemic clamp), as part of the Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study.One-hour plasma glucose correlated better than 2-h plasma glucose with total insulin secretion (r = 0.43), beta-cell glucose sensitivity (r = -0.46), and beta-cell rate sensitivity (r = -0.18). Receiver operating characteristic analysis identified 8.95 mmol/l as the best cutoff value for prediction of IGT from 1-h plasma glucose (sensitivity 77% and specificity 80%). Participants with NGT with 1-h plasma glucose >8.95 mmol/l had larger waist circumference, higher BMI, lower insulin sensitivity, higher fasting glucose, and higher insulin secretion than their counterparts with 1-h plasma glucose <or=8.95 mmol/l (P < 0.001 for all comparisons). Moreover, they exhibited lower beta-cell glucose sensitivity (P < 0.001), beta-cell rate sensitivity (P < 0.001), and potentiation factor (P = 0.026). When compared with conventionally defined IGT, they were not different in waist circumference and BMI, hepatic insulin extraction, beta-cell glucose sensitivity, beta-cell rate sensitivity, and potentiation factor but did have greater insulin sensitivity along with reduced basal (P = 0.001) and total insulin secretion (P = 0.002).Higher values of 1-h plasma glucose may identify an intermediate condition between NGT and IGT characterized by greater insulin resistance, reduced beta-cell glucose sensitivity, and reduced beta-cell rate sensitivity.

To evaluate the results in terms of dosimetric parameters and acute toxicity of two clinical studies (MARA-1 and MARA-2) on accelerated IMRT-based postoperative radiotherapy. These results are compared with historical control group (CG) of patients treated with "standard" 3D postoperative radiotherapy.Prescribed dose to the breast was 50.4Gy in the CG, 40Gy in MARA-1 (low risk of local recurrence), and 50Gy in MARA-2 (medium-high risk of recurrence). The tumor bed total dose was 60.4Gy (sequential 10Gy electron boost), 44Gy (concomitant 4Gy boost), and 60Gy (concomitant 10Gy boost) in CG, MARA-1 and MARA-2 studies, respectively. Overall treatment time was of 32 fractions for CG (6.4weeks); 16 fractions for MARA-1 study (3.2weeks) and 25 fractions for MARA-2 study (5weeks).Three hundred and thirty two patients were included in the analysis. Dosimetric analysis showed D(max) and V(107%) reduction (p<0.001) and D(min) improvement (p<0.001) in the PTV in patients treated with IMRT. Grade 2 acute skin toxicity was 33.6%, 13.1%, and 45.1% in the CG, MARA-1, and MARA-2, respectively (p<0.001), and grade 3 acute skin toxicity was 3.1%, 1.0%, and 2.0%, respectively. Similarly, larger PTV and use of chemotherapy with anthracyclines and taxanes were associated with a greater acute toxicity. With a median follow-up of 31 months, no patients showed local or nodal relapse.A simplified step and shoot IMRT technique allowed better PTV coverage and reduced overall treatment time (CG, 6.6weeks; MARA-1, 3.2weeks; MARA-2, 5weeks) with acceptable short-term toxicity.

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.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.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.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.

The aim of this article is to show the good performance obtained by the state observer applied to a delay differential equations (DDE) model of the glucose-insulin system recently used in the artificial pancreas (AP) framework. Validation is carried out by real clinical measurements available from 20 healthy subjects who underwent an intravenous glucose tolerance test (IVGTT). The results show that the observer behavior is robust with respect to the initial conditions, which have been set according to a pair of very critical cases of under- and overestimation. Also, the robustness of the observer with respect to some model parameters, such as the delay in the pancreatic insulin production, is discussed.

Objective: To evaluate the safety and efficacy of the administration of low doses of glucocorticoids in patients with cystic fibrosis (CF) by using autologous erythrocytes loaded with dexamethasone 21-phosphate. Study design: Nine consecutive CF patients (patients nos. 1–9) received autologous erythrocytes loaded with increasing amounts of dexamethasone 21-phosphate to obtain a slow delivery of dexamethasone in circulation. The appearance of possible adverse effects, the reproducibility of the procedure, and the dexamethasone pharmacokinetics were evaluated. Subsequently, patient no. 9 and eight additional patients (patient nos. 10–17) received dexamethasone 21-phosphate-loaded erythrocytes at 1-month intervals to evaluate the efficacy of continuous release in circulation of low doses of dexamethasone. Results: Erythrocytes from CF patients can be processed to be loaded with increasing dexamethasone 21-P concentrations. Once reinfused in respective donors, a slow and prolonged delivery of dexamethasone in the blood stream was measured up to 28 days. Repeated administrations of drug-loaded erythrocytes at 4-week intervals for 15 months showed that very low doses of glucocorticoids provide significant improvement in FEV1 values and significant reduction of infective relapses due to Pseudomonas aeruginosa without adverse effects. Conclusions: The administration of very low doses of glucocorticoids using autologous erythrocytes is possible, with benefits for patients and without side effects. This method is likely to be extended to other chronic diseases.

Polymorphisms in the interleukin 1beta gene (IL-1B-31T/C and IL-1B-511C/T single nucleotide changes) and in the interleukin 1 receptor anatagonist gene (IL-1RN2 variable number of tandem repeats) have been studied with respect to gastric cancer susceptibility. Available data support an aetiologic role of these genetic variants in the presence of concomitant Helicobacter pylori infection. Their contribution without H. pylori infection is still an open field of investigation.IL-1B and IL-1RN polymorphisms were investigated in 138 H. pylori-negative Italian patients with sporadic gastric cancer and 100 H. pylori-negative controls. Unconditional regression with odd ratios (OR) and 95% confidence intervals (CI), haplotype and linkage disequilibrium analyses were used to investigate the association of the polymorphisms with disease.In all gastric cancer cases, carriers of the homozygous IL-1B-511T/T genotype showed a significant risk for the development of the disease (OR 3.2 with 95% CI 1.27-8.05). In cases with intestinal-type gastric cancer, however, both IL-1B-511T and IL-1RN2 alleles were associated with disease. In this subgroup, the odds ratio for carriers of both IL-1B-511T and IL-1RN2 was 6.49 (95% CI 2.07-20.4). Haplotype analysis supported the aetiologic contribution of these alleles in gastric cancer of the intestinal histotype.In conclusion, IL-1B-511T and IL-1RN2 may contribute to intestinal gastric cancer risk in the absence of concomitant H. pylori infection. In this setting, future epidemiologic studies should consider dietary habits and exposure to carcinogens interacting with pro-inflammatory host genotypes.

Summary Background A potential approach to the treatment of morbid obesity is reduction of gastric emptying to achieve satiety. Botulinum toxin A (Btx‐A) is a long‐acting inhibitor of acetylcholine‐mediated peristalsis, which is mainly responsible for gastric motility. Aim To investigate whether botulinum toxin A, injected in the antrum of obese patients, delays gastric emptying. Methods In a double_blind study, 18 healthy obese subjects (body mass index &gt;30) were randomized into three groups (BTX133, BTX200 and Saline); they received Btx‐A133U, Btx‐A200U, or saline under endoscopic control. Gastric emptying was tested by scintigraphy before and 10 days after treatment. Body weight variations and appetite sensation were recorded after 5 weeks. Results Fourteen patients completed the study. The botulinum toxin A‐treated groups showed weight reduction, which was not statistically significant. The effects on gastric emptying were variable. Most of the botulinum toxin A treated patients reported a reduced appetite. Conclusion This pilot clinical trial suggests potential activity of botulinum toxin A for the manipulation of appetite.

The problem of tracking a desired plasma glucose evolution is considered, for cases of basal hyperglycemia. A time-delay model is used to describe the glucose–insulin regulatory system, aiming to detail the endogenous pancreatic insulin release, which is not negligible in Type 2 diabetic patients. Insulin is assumed to be administered by means of intra-venous infusions. Only measurements of glycemia are considered: to this aim a nonlinear observer for time-delay systems is used to estimate the plasma insulin concentration. In the spirit of the separation theorem, a nonlinear control law is proposed, based on the exact input/output feedback linearization, which makes use of the observer estimates instead of the full state measurements. The local convergence of the tracking error to zero is theoretically proved. Simulations are performed in a virtual environment, taking into account the standard technology concerning blood glucose sensors and insulin delivery devices. Numerical results show the robustness of the proposed approach with respect to the uncertainties of the model parameters, as well as to the glucose measurement errors and insulin pump malfunctioning.

Background Abnormally low plasma levels of coenzyme Q10 (CoQ10) have been found in patients with cancer of the breast, lung, or pancreas. Objective A prospective study of patients with melanoma was conducted to assess the usefulness of CoQ10 plasma levels in predicting the risk of metastasis and the duration of the metastasis-free interval. Methods Between January 1997 and August 2004, plasma CoQ10 levels were measured with high-performance liquid chromatography in 117 consecutive melanoma patients without clinical or instrumental evidence of metastasis according to American Joint Committee on Cancer criteria and in 125 matched volunteers without clinically suspect pigmented lesions. Patients taking CoQ10 or cholesterol-lowering medications and those with a diagnosis of diabetes mellitus were excluded from the study. Multiple statistical methods were used to evaluate differences between patients and control subjects and between patients who did (32.5%) and did not (67.5%) develop metastases during follow-up. Results CoQ10 levels were significantly lower in patients than in control subjects (t test: P < .0001) and in patients who developed metastases than in the metastasis-free subgroup (t test: P < .0001). Logistic regression analysis indicated that plasma CoQ10 levels were a significant predictor of metastasis (P = .0013). The odds ratio for metastatic disease in patients with CoQ10 levels that were less than 0.6 mg/L (the low-end value of the range measured in a normal population) was 7.9, and the metastasis-free interval was almost double in patients with CoQ10 levels 0.6 mg/L or higher (Kaplan-Meier analysis: P < .001). Limitations A study with a larger sample, which is currently being recruited, and a longer follow-up will doubtlessly increase the statistical power and enable survival statistics to be obtained. Conclusions Analysis of our findings suggests that baseline plasma CoQ10 levels are a powerful and independent prognostic factor that can be used to estimate the risk for melanoma progression. Abnormally low plasma levels of coenzyme Q10 (CoQ10) have been found in patients with cancer of the breast, lung, or pancreas. A prospective study of patients with melanoma was conducted to assess the usefulness of CoQ10 plasma levels in predicting the risk of metastasis and the duration of the metastasis-free interval. Between January 1997 and August 2004, plasma CoQ10 levels were measured with high-performance liquid chromatography in 117 consecutive melanoma patients without clinical or instrumental evidence of metastasis according to American Joint Committee on Cancer criteria and in 125 matched volunteers without clinically suspect pigmented lesions. Patients taking CoQ10 or cholesterol-lowering medications and those with a diagnosis of diabetes mellitus were excluded from the study. Multiple statistical methods were used to evaluate differences between patients and control subjects and between patients who did (32.5%) and did not (67.5%) develop metastases during follow-up. CoQ10 levels were significantly lower in patients than in control subjects (t test: P < .0001) and in patients who developed metastases than in the metastasis-free subgroup (t test: P < .0001). Logistic regression analysis indicated that plasma CoQ10 levels were a significant predictor of metastasis (P = .0013). The odds ratio for metastatic disease in patients with CoQ10 levels that were less than 0.6 mg/L (the low-end value of the range measured in a normal population) was 7.9, and the metastasis-free interval was almost double in patients with CoQ10 levels 0.6 mg/L or higher (Kaplan-Meier analysis: P < .001). A study with a larger sample, which is currently being recruited, and a longer follow-up will doubtlessly increase the statistical power and enable survival statistics to be obtained. Analysis of our findings suggests that baseline plasma CoQ10 levels are a powerful and independent prognostic factor that can be used to estimate the risk for melanoma progression.

Quality assurance procedures (QA) may reduce the risk of errors in radiotherapy. The aim of this study was to assess a QA program based on independent check (IC) procedures in patients undergoing 3D, intensity modulated (IMRT) and extracranial stereotactic (ESRT) radiotherapy.IC for set-up (IC1) and for radiotherapy treatments (IC2) was tested on 622 patients over a year. Fifteen events/parameters and 17 parameters were verified by IC1 and IC2, respectively. A third evaluation check (IC3) was performed before treatment. Potential errors were classified based on their magnitude. Incidents involving only incorrect or incomplete documentation were segregated. Treatments were classified based on a complexity index (COMIX).With IC1, 75 documentation incidents and 31 potential errors were checked, and with IC2 111 documentation incidents and 6 potential errors were checked. During the study period 10 errors undetected by standard procedures (IC1, IC2) were detected by chance or by IC3. The incidence of errors and serious errors undetected by standard procedures was 1.6% and 0.6%, respectively. There was no higher incidence of errors undetected in patients undergoing IMRT or ESRT, while there was a higher incidence of errors undetected in more complex treatments (p < 0.001).Systematic QA procedures can reduce the risk of errors. The risk of errors undetected by standard procedures is not correlated with the treatment technological level (3D versus IMRT/ESRT).

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: and for the irradiated volume; and for the ipsilateral lung; and for the heart. Stratification was made according to breast size and supraclavicular (SCV) nodal irradiation. As respect to irradiated volume, a significant reduction of (mean values: versus ) and (mean % values: versus ), and an increase of (mean % values: versus ) 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 (mean values: versus ) and (mean values versus ) 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. PACS numbers: 87.53.Kn; 87.55.de

The impact of allogeneic perioperative blood transfusions (APTs) on the prognosis of gastric cancer patients undergoing curative-intent gastrectomy is still a highly debated topic. Two meta-analyses were published in 2015, and new studies report conflicting results. A literature review was conducted using PubMed, Scopus, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews, updated to March 1, 2016. Thirty-eight non-randomized studies reporting data on overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS) and postoperative complications (PCs) were included. An inverse variance random-effects meta-analysis was conducted. APTs showed an association with worse OS, DFS, DSS and an increased number of PCs. The hazard ratio (HR) for OS was 1.49, with a 95% confidence interval (95% CI) of 1.32–1.69 (p < .00001; Q-test p = .001, I-squared = 56%). After outlier exclusion, the HR for OS was 1.34 (95% CI = 1.23–1.45, p < .00001; Q-test p = .64, I-squared = 0%). The HR for DFS was 1.48 (95% CI = 1.18–1.86, p = .0007; Q-test p = .31, I-squared = 16%), and the HR for DSS was 1.66 (95% CI = 1.5–2.19, p = .0004; Q-test p = .96, I-squared = 0%). The odds ratio for PCs was 3.33 (95% CI = 2.10–5.29, p < .00001; Q-test p = .14, I-squared = 42%). This meta-analysis showed a significant association between transfusions and OS, DFS, DSS and PCs. The quality of the evidence was low. Aggregation, selection and selective reporting bias were detected. The biases shifted the results towards significance. Further studies using accurate adjustment methods are needed. Until such additional studies are performed, caution in administering transfusions and optimization of cancer patient blood management are warranted.

Abstract We investigated in a case‐control study a possible role of thymidylate synthase gene ( TS ) polymorphisms for gastric cancer susceptibility. Lymphocyte genomic DNA from 134 Italian gastric cancer patients and 139 controls was used for genotyping two polymorphisms in the TS 5′‐untranslated region (5′‐UTR); a double (2R) or triple (3R) 28‐bp repeat and a G/C polymorphism within the triple repeats allele (3G allele). Samples were also genotyped at a 6‐bp deletion/insertion (del6 or ins6) polymorphism at position 1494 in the TS 3′‐untranslated region (3′‐UTR). Unconditional regression with odd ratios (OR) and 95% confidence intervals (CI), haplotype and linkage disequilibrium analyses were used to investigate the association of the polymorphisms with the disease. The global allelic distribution was in Hardy‐Weinberg equilibrium. Genotypes with the 3G allele (2R/3G, 3C/3G, 3G/3G) were significantly more frequent in patients than controls and were associated with gastric cancer risk (OR = 2.06; 95% CI = 1.26–3.35). A significant risk was also observed for carriers of the del6 allele in the 3′‐UTR. Odds ratios for combined 3G‐del6/ins6 and 3G‐del6/del6 genotypes were 2.59 (95% CI = 1.36–4.94) and 2.81 (95% CI = 1.22–6.64), respectively. The 3G‐del6 haplotype showed a significant association with the disease ( p = 0.01). Polymorphisms in the TS gene may contribute to gastric cancer susceptibility and this finding deserve further investigation in the context of novel strategies for gastric cancer prevention. In vitro , 3G genotypes have been related to high TS mRNA expression, which may underlie one of the possible etiologic mechanisms. © 2004 Wiley‐Liss, Inc.

Context: Hyperhomocysteinemia as well as alterations of glycemic and lipidic metabolism are recognized as risk factors for cardiovascular diseases. Objective: The aim of this study was to examine the effect of l-folic acid supplementation on homocysteine (Hcy) and related thiols, such as cysteine (Cys) and Cys-glycine (Cys-Glyc) pathways and their relationship to glucose, insulin, and lipidic metabolism in normoinsulinemic postmenopausal women. Design: This study was a randomized placebo, not double-blind, trial. Setting: The study was performed in an academic research center. Patients or Other Participants: Twenty healthy postmenopausal women were selected. No patient was taking drugs known to affect lipid or glucose metabolism. Intervention(s): Patients underwent two hospitalizations before and after 8 wk of l-acid folic (7.5 mg/d) or placebo administration. The glycemic metabolism was studied by an oral glucose tolerance test and a hyperinsulinemic euglycemic clamp. Hcy metabolism was studied by a standardized oral methionine-loading test. Main Outcome Measure(s): Hcy, Cys, and Cys-Glyc, basally and after a methionine loading test, were measured. Basal insulin, glucose, and peptide C levels as well as area under the curve for insulin, area under the curve for peptide, hepatic insulin extraction, and metabolic index were assayed. The total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol levels and the cholesterol/HDL and LDL/HDL ratios were also measured. Results: The total basal Hcy concentration and the plasma postmethionine loading Hcy values were significantly decreased (P &amp;lt; 0.01) in l-folic acid-treated patients, whereas postmethionine loading Cys-Glyc levels were markedly increased (P &amp;lt; 0.02). Furthermore, l-folic acid intake induced a significant improvement in carbohydrate metabolism through an increase in fractional hepatic insulin extraction (P &amp;lt; 0.05) and peripheral insulin sensitivity (P &amp;lt; 0.02) in normoinsulinemic women. HDL levels considerably increased, inducing an improvement in other atherosclerotic indexes, such as cholesterol/HDL and LDL/HDL ratios (P &amp;lt; 0.03). Conclusions: These results show that folic acid supplementation lowers plasma Hcy levels and improves insulin and lipid metabolism, reducing the risk of cardiovascular disease.

Objective. Calprotectin is a granulocyte cytosolic protein that is considered to be a promising marker of subclinical inflammation. High faecal calprotectin concentrations (FCCs) have been found in several intestinal diseases, but no data are currently available on patients with coeliac disease. The purpose of this pilot study was to evaluate FCCs in untreated coeliac patients and to correlate them with clinical score and histological characteristics. Material and methods. Twenty-eight consecutive coeliac patients were recruited. Thirty healthy adult volunteers participated as the control group. FCCs were determined by ELISA. Clinical assessment was carried out in all patients. The histological severity of lesions and the infiltration of neutrophil polymorphs in the intestinal mucosa were also evaluated. Mean FCCs in patients and the control group were compared by means of the t-test for independent samples. In coeliac patients, differences in FCCs in subgroups identified by clinical score, lesion severity and neutrophil infiltration were evaluated by the Kruskal-Wallis non-parametric test. Results. FCCs in untreated coeliac patients were not significantly different from those in controls (p=0.163). Among coeliac patients, FCCs were not significantly different in relation to the level of clinical score, lesion severity or neutrophil infiltration (p=0.92, p=0.96 and p=0.74, respectively). Conclusions. This study shows, for the first time, that FCCs in untreated coeliac patients do not differ significantly from those in controls.

The Minimal Model, (MM), used to assess insulin sensitivity (IS) from Intra-Venous Glucose-Tolerance Test (IVGTT) data, suffers from frequent lack of identifiability (parameter estimates with Coefficients of Variation (CV) less than 52%). The recently proposed Single Delay Model (SDM) is evaluated as a practical alternative. The SDM was applied to 74 IVGTTs from lean (19), overweight (22), obese (22) and morbidly obese (11) subjects. Estimates from the SDM (KxgI) were compared with the corresponding MM (SI), 1/HOMA-IR index and Euglycemic-Hyperinsulinemic Clamp (M-EHC over 7 subjects) estimates. KxgI was identifiable in 73 out of 74 subjects (CV = 69% in the 74th subject) and ranged from 1.25 × 10-5 to 4.36 × 10-4min-1pM-1; SI CV was >52% in 36 subjects (up to 2.36 × 109%) and presented 18 extreme values (≤ 1.5 × 10-12 or ≥ 3.99). KxgI correlated well with 1/HOMA-IR (r = 0.56, P < 0.001), whereas the correlations KxgI-SI and 1/HOMA-IR-SI were high (r = 0.864 and 0.52 respectively) and significant (P < 0.001 in both cases) only in the non-extreme SI sub-sample (56 subjects). Correlations KxgI vs. M-EHC and SI vs. M-EHC were positive (r = 0.92, P = 0.004 and r = 0.83, P = 0.02 respectively). KxgI decreased for higher BMI's (P < 0.001), SI significantly so only over the non-extreme-SI sub-sample. The Acute Insulin Response Index was also computed and the expected inverse (hyperbolic) relationship with the KxgI observed. Precise estimation of insulin sensitivity over a wide range of BMI, stability of all other model parameters, closer adherence to accepted physiology make the SDM a useful alternative tool for the evaluation of insulin sensitivity from the IVGTT.

Diabetes mellitus has become a prevalent disease in the world. Diagnostic protocol for the onset of diabetes mellitus is the initial step in the treatments. The intravenous glucose tolerance test (IVGTT) has been considered as the most accurate method to determine the insulin sensitivity and glucose effectiveness. It is well known that there exists a time delay in insulin secretion stimulated by the elevated glucose concentration level. However, the range of the length of the delay in the existing IVGTT models are not fully discussed and thus in many cases the time delay may be assigned to a value out of its reasonable range. In addition, several attempts had been made to determine when the unique equilibrium point is globally asymptotically stable. However, all these conditions are delay-independent. In this paper, we discuss the range of the time delay and provide easy-to-check delay-dependent conditions for the global asymptotic stability of the equilibrium point for a recent IVGTT model through Liapunov function approach. Estimates of the upper bound of the delay for global stability are given in corollaries. In addition, the numerical simulation in this paper is fully incorporated with functional initial conditions, which is natural and more appropriate in delay differential equation systems.

Closed-loop devices delivering medical treatments in an automatic fashion clearly require a thorough preliminary phase according to which the proposed control law is tested and validated as realistically as possible, before arranging in vivo experiments in a clinical setting. The present note develops a virtual environment aiming to validate a recently proposed model-based glucose control law on a solid simulation framework. From a theoretical viewpoint, the artificial pancreas has been designed by suitably exploiting a minimal set of delay differential equations modeling the glucose–insulin regulatory system; on the other hand, the validation platform makes use of a different, multi-compartmental model to build up a population of virtual patients. Simulations are carried out by properly addressing the available technological limits and the unavoidable uncertainties in real-time continuous glucose sensors as well as possible malfunctioning on the insulin delivery devices. The results show the robustness of the proposed control law that turns out to be efficient and extremely safe on a heterogenous population of virtual patients.

In order to provide a method for precise identification of insulin sensitivity from clinical Oral Glucose Tolerance Test (OGTT) observations, a relatively simple mathematical model (Simple Interdependent glucose/insulin MOdel SIMO) for the OGTT, which coherently incorporates commonly accepted physiological assumptions (incretin effect and saturating glucose-driven insulin secretion) has been developed. OGTT data from 78 patients in five different glucose tolerance groups were analyzed: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), IFG+IGT, and Type 2 Diabetes Mellitus (T2DM). A comparison with the 2011 Salinari (COntinuos GI tract MOdel, COMO) and the 2002 Dalla Man (Dalla Man MOdel, DMMO) models was made with particular attention to insulin sensitivity indices ISCOMO, ISDMMO and kxgi (the insulin sensitivity index for SIMO). ANOVA on kxgi values across groups resulted significant overall (P<0.001), and post-hoc comparisons highlighted the presence of three different groups: NGT (8.62×10−5±9.36×10−5 min−1pM−1), IFG (5.30×10−5±5.18×10−5) and combined IGT, IFG+IGT and T2DM (2.09×10−5±1.95×10−5, 2.38×10−5±2.28×10−5 and 2.38×10−5±2.09×10−5 respectively). No significance was obtained when comparing ISCOMO or ISDMMO across groups. Moreover, kxgi presented the lowest sample average coefficient of variation over the five groups (25.43%), with average CVs for ISCOMO and ISDMMO of 70.32% and 57.75% respectively; kxgi also presented the strongest correlations with all considered empirical measures of insulin sensitivity. While COMO and DMMO appear over-parameterized for fitting single-subject clinical OGTT data, SIMO provides a robust, precise, physiologically plausible estimate of insulin sensitivity, with which habitual empirical insulin sensitivity indices correlate well. The kxgi index, reflecting insulin secretion dependency on glycemia, also significantly differentiates clinically diverse subject groups. The SIMO model may therefore be of value for the quantification of glucose homeostasis from clinical OGTT data.

Several models of Gastric Emptying (GE) have been employed in the past to represent the rate of delivery of stomach contents to the duodenum and jejunum. These models have all used a deterministic form (algebraic equations or ordinary differential equations), considering GE as a continuous, smooth process in time. However, GE is known to occur as a sequence of spurts, irregular both in size and in timing. Hence, we formulate a simple stochastic process model, able to represent the irregular decrements of gastric contents after a meal. The model is calibrated on existing literature data and provides consistent predictions of the observed variability in the emptying trajectories. This approach may be useful in metabolic modeling, since it describes well and explains the apparently heterogeneous GE experimental results in situations where common gastric mechanics across subjects would be expected.

Abstract 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 ( R a ) and disappearance ( R d ) and endogenous glucose production (EGP) were calculated by infusing [6,6- 2 H 2 ]glucose with or without oral [U- 13 C 6 ]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 &lt; 0.001 from paired t test). Insulin secretion was higher during oral administration than during IGIVI (p&lt; 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.

In this paper we deal with the problem of tracking a desired plasma glucose concentration by means of intra-venous insulin administration, for Type 2 diabetic patients exhibiting basal hyperglycemia.A nonlinear time-delay model is used to describe the glucose-insulin regulatory system, according to which a model-based approach is exploited to design a semiglobal sampled-data dynamic output feedback controller.It is shown that emulation, by Euler approximation, of a proposed continuous-time control law yields stabilization in the sampleand-hold sense to the closed-loop system.The glucose regulator makes use of only sampled glucose measurements.Theoretical results are validated through a virtual environment broadly accepted as a substitute to animal trials for the preclinical testing of control strategies in plasma glucose regulation.Numerical results are encouraging and pave the way to further clinical verifications.

The present study investigates whether epigenetic differences emerge in the heart of patients undergoing cardiac surgery for an aortic valvular replacement (AVR) or coronary artery bypass graft (CABG). An algorithm is also established to determine how the pathophysiological condition might influence the human biological cardiac age.Blood samples and cardiac auricles were collected from patients who underwent cardiac procedures: 94 AVR and 289 CABG. The CpGs from three independent blood-derived biological clocks were selected to design a new blood- and the first cardiac-specific clocks. Specifically, 31 CpGs from six age-related genes, ELOVL2, EDARADD, ITGA2B, ASPA, PDE4C, and FHL2, were used to construct the tissue-tailored clocks. The best-fitting variables were combined to define new cardiac- and blood-tailored clocks validated through neural network analysis and elastic regression. In addition, telomere length (TL) was measured by qPCR. These new methods revealed a similarity between chronological and biological age in the blood and heart; the average TL was significantly higher in the heart than in the blood. In addition, the cardiac clock discriminated well between AVR and CABG and was sensitive to cardiovascular risk factors such as obesity and smoking. Moreover, the cardiac-specific clock identified an AVR patient's subgroup whose accelerated bioage correlated with the altered ventricular parameters, including left ventricular diastolic and systolic volume.This study reports on applying a method to evaluate the cardiac biological age revealing epigenetic features that separate subgroups of AVR and CABG.

When a subject is at rest and meals have not been eaten for a relatively long time (e.g. during the night), presumably near-constant, zero-order glucose production occurs in the liver. Glucose elimination from the bloodstream may be proportional to glycemia, with an apparently first-order, linear elimination rate. Besides glycemia itself, unobserved factors (insulinemia, other hormones) may exert second and higher order effects. Random events (sleep pattern variations, hormonal cycles) may also affect glycemia. The time-course of transcutaneously, continuously measured glycemia (CGM) thus reflects the superposition of different orders of control, together with random system error. The problem may be formalized as a fractional random walk, or fractional Brownian motion. In the present work, the order of this fractional stochastic process is estimated on night-time CGM data from one subject.

A novel supervised neural network-based algorithm is designed to reliably distinguish in electrocardiographic (ECG) records between normal and ischemic beats of the same patient. The basic idea behind this paper is to consider an ECG digital recording of two consecutive R-wave segments (RRR interval) as a noisy sample of an underlying function to be approximated by a fixed number of Radial Basis Functions (RBF). The linear expansion coefficients of the RRR interval represent the input signal of a feed-forward neural network which classifies a single beat as normal or ischemic. The system has been evaluated using several patient records taken from the European ST-T database. Experimental results show that the proposed beat classifier is very reliable, and that it may be a useful practical tool for the automatic detection of ischemic episodes.

This note investigates the problem of plasma glucose regulation by means of subcutaneous insulin administration. A discrete delay differential equation model of the glucose-insulin regulatory system has been considered, which properly takes into account also the pancreatic insulin release, in such a way to allow insulin therapies for both Type I and Type II diabetes (in this latter case the endogenous insulin delivery is not negligible). The method of exact input/output feedback linearization and stabilization is used, in order to ensure the local convergence of the tracking error to zero. Simulations are performed in a virtual environment, and numerical results show the effectiveness of the proposed approach.

As only 1% of clinically eligible subjects choose to undergo surgical treatment for obesity, other options should be investigated. This study aimed to assess the effects of intensive lifestyle modification (ILM) with or without 3-mg liraglutide daily vs. sleeve gastrectomy (SG) on BMI after 1 year. In this study performed at an Italian university hospital, non-diabetic patients eligible for bariatric surgery were recruited from a weight-loss clinic and had the option to choose from three possible weight-loss programmes up to an allocation of 25 subjects in each arm matched by BMI and age. ILM consisted in 813 kcal of a very low-calorie diet (VLCD) for 1 month, followed by a diet of 12 kcal/kg body weight of high protein and high fat for 11 months plus 30 min of brisk walking daily and at least 3 h of aerobic exercise weekly. SG patients followed a VLCD for 1 month and a free diet thereafter. Patients were evaluated at baseline and at 1, 3, 6, 9 and 12 months. A total of 75 patients were enrolled; retention was 100% in the SG and 85% in the two medical arms. SG reduced BMI by 32% (P < 0.001 vs. medical arm), while ILM + liraglutide and ILM led to BMI reductions of 24% and 14%, respectively (P < 0.001). More women allocated themselves to the ILM + liraglutide group. Weight loss was 43 kg with SG, 26 kg with ILM + liraglutide and 15 kg with ILM alone. Lean body mass reductions were −11.6 kg with SG, −6.3 kg with ILM and −8.3 kg with ILM + liraglutide. Prevalence of prediabetes was significantly lower with ILM + liraglutide, and insulin resistance was reduced by about 70% by both ILM + liraglutide and SG vs. 39% by ILM alone. Cardiometabolic risk factors were greatly reduced in all three groups. At least in the short-term, liraglutide 3.0 mg once daily associated with drastic calorie-intake restriction and intensive physical activity promoted a 24% weight loss, which was almost two times greater than ILM alone and only about 25% less than with SG, while preserving lean body mass. Although this study was non-randomised, it was designed to explore the efficacy of medical treatments for obesity in everyday clinical practice.

&lt;i&gt;Background/Aims:&lt;/i&gt; Small intestinal bacterial overgrowth (SIBO) is defined by any condition in which the proximal part of the small bowel harbors for a long time &gt;10&lt;sup&gt;5&lt;/sup&gt; bacteria/ml of the intestinal juice. No data are currently available about direct or indirect parameters indicating the presence of leukocytes in the gut wall and mucosal neutrophil turnover in patients with SIBO. In our pilot study we evaluate fecal calprotectin concentrations (FCC) in patients with SIBO in order to identify a possible presence of subclinical intestinal inflammation. &lt;i&gt;Methods:&lt;/i&gt; 40 consecutive patients with SIBO resulting positive to hydrogen glucose breath test, and 40 adult healthy volunteers were included in the study. FCC were determined by ELISA. Mean FCC were compared by means of the t-test for independent samples. &lt;i&gt;Results:&lt;/i&gt; FCC in patients with SIBO were not significantly different compared to controls (p = 0.907). &lt;i&gt;Conclusion:&lt;/i&gt; Our study shows for the first time that FCC in patients with SIBO do not significantly differ from controls, suggesting that in SIBO there are no intestinal subclinical inflammatory changes involving principally the neutrophils.

The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes growth and progression in prostate cancer (PCa); however, little is known about its possible impact in PCa metabolism. The aim of this work has been the assessment of the metabolic reprogramming associated with MALAT1 silencing in human PCa cells and in an ex vivo model of organotypic slice cultures (OSCs). Cultured cells and OSCs derived from primary tumors were transfected with MALAT1 specific gapmers. Cell growth and survival, gene profiling, and evaluation of targeted metabolites and metabolic enzymes were assessed. Computational analysis was made considering expression changes occurring in metabolic markers following MALAT1 targeting in cultured OSCs. MALAT1 silencing reduced expression of some metabolic enzymes, including malic enzyme 3, pyruvate dehydrogenase kinases 1 and 3, and choline kinase A. Consequently, PCa metabolism switched toward a glycolytic phenotype characterized by increased lactate production paralleled by growth arrest and cell death. Conversely, the function of mitochondrial succinate dehydrogenase and the expression of oxidative phosphorylation enzymes were markedly reduced. A similar effect was observed in OSCs. Based on this, a predictive algorithm was developed aimed to predict tumor recurrence in a subset of patients. MALAT1 targeting by gapmer delivery restored normal metabolic energy pathway in PCa cells and OSCs.

Searchable abstracts of presentations at key conferences in obesity ISSN 2632-9808 (online)

The thyroid is one of the largest endocrine glands in humans. The thyroid produces two major hormones: thyroxine (T4) and triiodothyronine (T3). The secretion and production of thyroid hormones are controlled via two feedbacks: one positive, where the thyrotropin-releasing hormone (TRH) stimulates the thyroid-stimulating hormone (TSH) that stimulates the production of T3 and T4 hormones; one negative, where high circulating levels of T3 and T4 in turn inhibit the production of both TRH and TSH. T3 and T4 also depend on iodine intake. The present work proposes a comprehensive mathematical model of the thyroid and TSH control system through which both the effect of the hormones and of iodine can be assessed. The proposed model is composed of 22 compartments, which describe the dynamics of iodine, T3, T4, TSH, TRH and Thyroglobulin (Tg) in blood and in the extra-cellular space. The effect of Sodium Iodide Symporter (NIS, a membrane protein mediating iodide transport) and of Thyroperoxidase (TPO, an enzyme involved in the thyroid hormone synthesis) on thyroid metabolism is also described and a gastrointestinal sub-model is incorporated in order to describe the oral administration of iodine, levothyroxine (L-T4) and levothyronine (L-T3). TSH oscillations are described using a series of impulses generated by a biological oscillator. The model has been validated on several independent data sets retrieved from the literature, where euthyroid volunteers underwent different clinical experiments with the oral administration of L-T4 (in 400, 450, 600μg dosages) or L-T3 (75μg) and with intravenous injections of TRH.

The paper investigates the problem of tracking a desired plasma glucose evolution by means of intra-venous insulin administration.A modelbased approach is followed.A recent model of the glucose/insulin regulatory system which consists of discrete-delay nonlinear differential equations is used.A disturbance is added to the insulin kinetics in order to model uncertainties concerning both the insulin delivery rate and the mechanism actuating the insulin pump.A feedback control law which yields input-to-state stability of the closed loop error system with respect to the disturbance is provided.Such control law depends on the glucose and insulin measurements at the present and at a delayed time.In silico simulations validate the theoretical results.

Given the high cost and side effects of radioprotective agents such as amifostine, attention has been focused on potentially equally effective but less expensive and toxic natural substances. We evaluated the potential radioprotective effects of wine in preventing skin toxicity in patients with breast cancer.Before treatment, the medical history and habits of patients were assessed and the information recorded in their clinical folders. Patients were divided into three groups based on the dose/fractionation scheme used: control group, 60.4 Gy (standard technique); Modulated Accelerated Radiotherapy in Adjuvant treatment of breast cancer (MARA)-1 protocol group, 44 Gy (concomitant boost to tumoral bed); and MARA-2 protocol group, 60 Gy (concomitant boost to tumoral bed). The impact of the following variables on acute skin toxicity was evaluated by chart review: radiotherapy protocol, planning target volume (PTV), comorbidity (e.g., hypertension and diabetes), hemoglobin level before therapy, adjuvant hormone therapy, adjuvant chemotherapy, cigarette smoking, and drinking habits.The study population consisted of 348 patients. More severe skin toxicity was significantly associated with the radiotherapy protocol (p < 0.001) and median PTV (p = 0.005). In addition, the incidence of acute toxicity of Grade 2 or greater was higher in patients without alcohol intake (38.4% vs. 22.3%, p = 0.021). The daily amount of alcohol intake also influenced the incidence of skin toxicity, with an incidence of 38.4% in patients with no wine intake, 31.8% in patients drinking half a glass per day, 13.6% in patients drinking one glass per day, and 35.0% in patients drinking two glasses per day. Multivariate analysis showed that wine intake, PTV, and radiotherapy protocol were all significantly correlated with acute toxicity.Our results indicate that wine may have a radioprotective effect; however, prospective studies are needed to confirm this beneficial effect of wine and its components.

The Burn Specific Health Scale-Brief questionnaire is a widely validated tool for estimating the health related quality of life and for assessing the best multidisciplinary management of burn patients. The aim of this study was to translate the BSHS-B into French and to investigate its reliability and validity.According to the procedure proposed by the Scientific Advisory Committee of the Medical Outcomes Trust, the Burn Specific Health Scale-Brief (BSHS-B) was translated from the English version into French. In order to test the reliability of the French version of the BSHS-B, 53 burn patients French speakers completed the BSHS-B and SF-36 questionnaires from two to four years after burn. Ten of them have been re-tested at 6 months after the first evaluation. To evaluate clinical utility of the BSHS-F, internal consistency, construct validity (using SF-36) and stability in time were assessed using Cronbach's alpha statistic, Spearman rank test, and intra-class correlation coefficient respectively.The French version of the BSHS-B Cronbach's alpha coefficient was 0.93 and was >0.80 for all the sub-domains. French version of the BSHS-B and the SF-36 were positively correlated, all the associations were statistically significant (p<0.01). Intra-class correlation coefficients for test-retest ranged between 0.95 and 0.99 for the sub-domains. The intra-class correlation coefficient (ICC) for the total score was 0.98.The French version of the BSHS-B shows a robust rate of internal consistency, construct validity and stability in time, supporting its application in routine clinical practice as well as in international studies.

Obstructive sleep apnea (OSA) has a high prevalence in patients with obesity. Only patients with clinical symptoms of OSA are admitted to polysomnography; however, many patients with OSA are asymptomatic. We aimed to create and validate a population-based risk score that predicts the severity of OSA in patients with obesity.We here report the cross-sectional analysis at baseline of an ongoing study investigating the long-term effect of bariatric surgery on OSA. One-hundred sixty-one patients of the Obesity Center of the Catholic University Hospital in Rome, Italy were included in the study. The patients underwent overnight cardiorespiratory monitoring, blood chemistry analyses, hepatic ultrasound, and anthropometric measurements. The patients were divided into 2 groups according OSA severity assessed by the apnea-hypopnea index (AHI): AHI < 15 = no or mild and AHI ≥ 15 moderate to severe OSA. A statistical prediction model was created and validated. C statistics was used to evaluate the discrimination performance of the model.The prevalence of OSA was 96.3% with 74.5% of the subjects having moderate/severe OSA. Sex, body mass index, diabetes, and age were included in the final prediction model that had excellent discrimination ability (C statistics equals to 83%). An OSA risk chart score for clinical use was created.Patients with severe obesity are at a very high risk for moderate or severe OSA in particular if they are men, older, more obese, and/or with type 2 diabetes. The OSA risk chart can be useful for general practitioners and patients as well as for bariatric surgeons to select patients with high risk of moderate to severe OSA for further polysomnography.

The Euglycemic Hyperinsulinemic Clamp (EHC) is the most widely used experimental procedure for the determination of insulin sensitivity, and in its usual form the patient is followed under insulinization for two hours. In the present study, sixteen subjects with BMI between 18.5 and 63.6 kg/m(2) were studied by long-duration (five hours) EHC.From the results of this series and from similar reports in the literature it is clear that, in obese subjects, glucose uptake rates continue to increase if the clamp procedure is prolonged beyond the customary 2 hours. A mathematical model of the EHC, incorporating delays, was fitted to the recorded data, and the insulin resistance behaviour of obese subjects was assessed analytically. Obese subjects had significantly less effective suppression of hepatic glucose output and higher pancreatic insulin secretion than lean subjects. Tissue insulin resistance appeared to be higher in the obese group, but this difference did not reach statistical significance.The use of a mathematical model allows a greater amount of information to be recovered from clamp data, making it easier to understand the components of insulin resistance in obese vs. normal subjects.

The secretion of insulin by the pancreas has been the object of much attention over the past several decades. Insulin is known to be secreted by pancreatic β-cells in response to hyperglycemia: its blood concentrations however exhibit both high-frequency (period approx. 10 minutes) and low-frequency oscillations (period approx. 1.5 hours). Furthermore, characteristic insulin secretory response to challenge maneuvers have been described, such as frequency entrainment upon sinusoidal glycemic stimulation; substantial insulin peaks following minimal glucose administration; progressively strengthened insulin secretion response after repeated administration of the same amount of glucose; insulin and glucose characteristic curves after Intra-Venous administration of glucose boli in healthy and pre-diabetic subjects as well as in Type 2 Diabetes Mellitus. Previous modeling of β-cell physiology has been mainly directed to the intracellular chain of events giving rise to single-cell or cell-cluster hormone release oscillations, but the large size, long period and complex morphology of the diverse responses to whole-body glucose stimuli has not yet been coherently explained. Starting with the seminal work of Grodsky it was hypothesized that the population of pancreatic β-cells, possibly functionally aggregated in islets of Langerhans, could be viewed as a set of independent, similar, but not identical controllers (firing units) with distributed functional parameters. The present work shows how a single model based on a population of independent islet controllers can reproduce very closely a diverse array of actually observed experimental results, with the same set of working parameters. The model’s success in reproducing a diverse array of experiments implies that, in order to understand the macroscopic behaviour of the endocrine pancreas in regulating glycemia, there is no need to hypothesize intrapancreatic pacemakers, influences between different islets of Langerhans, glycolitic-induced oscillations or β-cell sensitivity to the rate of change of glycemia.

In 1978, Thomas J. Sorensen defended a thesis in chemical engineering at the University of California, Berkeley, where he proposed an extensive model of glucose-insulin control, model which was thereafter widely employed for virtual patient simulation. The original model, and even more so its subsequent implementations by other Authors, presented however a few imprecisions in reporting the correct model equations and parameter values. The goal of the present work is to revise the original Sorensen’s model, to clearly summarize its defining equations, to supplement it with a missing gastrio-intestinal glucose absorption and to make an implementation of the revised model available on-line to the scientific community.

A closed-loop therapy for diabetic patients is proposed, by suitably exploiting a discrete Delay Differential Equation (DDE) model of the glucose-insulin system. To this aim, plasma glucose concentration is regulated by means of subcutaneous insulin administration, in order to track a desired glucose profile. The method of exact input/output feedback linearization and stabilization is used, in order to ensure the local convergence of the tracking error to zero. The use of a state observer for delay systems makes it so that the control law requires only glucose measurements, which are easily achievable according to the present technology. Even if exogenous insulin administration is standardly used for Type I diabetic patients (who do not have a pancreatic insulin release), the use of a DDE model allows to extend the proposed treatment also to Type II diabetes. Performed simulations show the effectiveness of the proposed approach.

Exogenous insulin administration is the basic way to face the widespread disease of Diabetes Mellitus. To this aim, closed-loop approaches, though theoretically realizable according to the control theory results and to the recent technology concerning continuous glucose measurements and affordable insulin infusion pumps, require a careful and thorough testing ground on a virtual environment before arranging an in-vivo clinical setting of experiments. In this work, a model-based control law for the plasma glycemia, recently published by the same authors, is evaluated by closing the loop on a virtual patient, whose model equations are different from the ones used to synthesize the control law. That means: a minimal model of the glucose-insulin system to design the insulin therapy, and a different, more detailed, comprehensive model to test in silico the control scheme. Uncertainties on the blood glucose measurements, as well as malfunctioning on the insulin delivery devices are considered, according to the standard technology, in order to obtain an effective benchmark for the closed-loop control and to show in fact the robustness of the proposed approach.

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.

Surgical site infection (SSI) rate is reported to range around 16%. Preoperative skin disinfection is keystone for SSI reduction. Chlorhexidine-alcohol has been reported to be more effective than Povidone-iodine (PVI). However, in many countries established habits and the inferior costs of PVI restrain the employment of chlorhexidine disinfection kits (ChloraPrep®) for the preparation of the surgical field.The costs of surgical field preparation in clean-contaminated surgery utilizing PVI (Betadine) and chlorhexidine alcohol and the evaluation of surgeon compliance and satisfaction, were studied by a observational study on 50 surgical operations in which surgical field was prepared with PVI checking established guidelines, and on 50 surgical operations in which chlorhexidine-alcohol (ChloraPrep) was employed. The use of auxiliary material was tabulated as well as the timing of the phases of disinfection and the surgeon's opinions.The use of auxiliary material (gloves, gauzes, paper towels, surgical instruments, small swabs for umbilical cleaning) is associated with the type of disinfectant, with major use of auxiliary materials recorded in PVI disinfection. PVI disinfection does not follow stringent guidelines, in particular waiting for the disinfectant to dry. PVI guidelines are more demanding than those relative to ChloraPrep. The time necessary for the preparation of the field is significantly longer for PVI. Auxiliary material and guideline compliance must be taken into account when calculating costs; the former are direct costs (even though marginal) and the latter can determine major infective risk.Chlorhexidine in kits is easier and faster to use than PVI, requires less auxiliary material and has been shown previously to reduce SSI in clean contaminated surgery.

In this paper we deal with the problem of tracking a desired plasma glucose evolution by means of intra-venous insulin administration, for Type 2 diabetic patients exhibiting basal hyperglycemia. A nonlinear time-delay model is used to describe the glucose-insulin regulatory system, and a modelbased approach is exploited in order to design a global sampleddata control law for such system. Sontag's universal formula is designed to obtain a steepest descent feedback induced by a suitable control Lyapunov-Krasovskii functional. Such a feedback is a stabilizer in the sample-and-hold sense. Furthermore, the input-to-state stability redesign method is used in order to attenuate the effects of bounded actuation disturbances and observation errors, which can appear for uncertainties in the instruments. The proposed control law depends on sampled glucose and insulin measurements. Theoretical results are validated through simulations.

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.

The aim of this study was to compare intensity-modulated radiation therapy (IMRT) with 3D conformal technique (3D-CRT), with respect to target coverage and irradiation of organs at risk for high dose postoperative radiotherapy (PORT) of the prostate fossa. 3D-CRT and IMRT treatment plans were compared with respect to dose to the rectum and bladder. The dosimetric comparison was carried out in 15 patients considering 2 different scenarios: (1) exclusive prostate fossa irradiation, and (2) pelvic node irradiation followed by a boost on the prostate fossa. In scenario (1), a 3D-CRT plan (box technique) and an IMRT plan were calculated and compared for each patient. In scenario (2), 3 treatment plans were calculated and compared for each patient: (a) 3D-CRT box technique for both pelvic (prophylactic nodal irradiation) and prostate fossa irradiation (3D-CRT only); (b) 3D-CRT box technique for pelvic irradiation followed by an IMRT boost to the prostatic fossa (hybrid 3D-CRT and IMRT); and (c) IMRT for both pelvic and prostate fossa irradiation (IMRT only). For exclusive prostate fossa irradiation, IMRT significantly reduced the dose to the rectum (lower Dmean, V50%, V75%, V90%, V100%, EUD, and NTCP) and the bladder (lower Dmean, V50%, V90%, EUD and NTCP). When prophylactic irradiation of the pelvis was also considered, plan C (IMRT only) performed better than plan B (hybrid 3D-CRT and IMRT) as respect to both rectum and bladder irradiation (reduction of Dmean, V50%, V75%, V90%, equivalent uniform dose [EUD], and normal tissue complication probability [NTCP]). Plan (b) (hybrid 3D-CRT and IMRT) performed better than plan (a) (3D-CRT only) with respect to dose to the rectum (lower Dmean, V75%, V90%, V100%, EUD, and NTCP) and the bladder (Dmean, EUD, and NTCP). Postoperative IMRT in prostate cancer significantly reduces rectum and bladder irradiation compared with 3D-CRT.

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.

Objective: In this article we provide evidence of a significant spontaneous humoral response in cancer patients. Methods: A panel of tumor-associated antigens, previously identified through serological screening of phage-displayed cDNA libraries from solid human tumors, breast carcinoma cell lines and human testis by employing breast cancer patient sera, was used in this study to survey sera from 182 patients with known disease histories and clinical stages. Results: This analysis reveals a statistically significant association between tumor disease and presence in peripheral blood of IgG antibodies against four autoantigens. One of these antigens (D7-1) is particularly interesting in that the antibody response against it grows with cancer progression from stages I through IV, with an incidence of 13.2, 13.5, 18.2 and 27%, respectively. The significance of this stage-dependent increase in the incidence is confirmed by the Mantel–Haenszel Chi-squared test (P = 0.001). Conclusions: Our data confirm association between breast cancer diagnosis of patients and presence in their peripheral blood of antibodies against several autoantigens identified by phage display.

Closed-loop glucose control schemes, usually based on intravenous/subcutaneous insulin administration, need to cope with the problem of exogenous glucose intake (e.g. a meal), a disturbance hard to anticipate in timing, in amount and in the rate of effective absorption of the nutrient. In this note, an intravenous feedback control law is considered, based on the use of a Delay Differential Equation (DDE) model of the glucose-insulin system, with the external meal treated as a completely unknown disturbance. It is shown that the closed-loop system satisfies the local Input-to-State Stability (ISS) property with respect to the unknown disturbance. The equivalence between asymptotic stability and local input-to-state stability for retarded nonlinear systems is proven. Simulations show the efficacy of the control algorithm with respect to a standard plasma glucose appearance rate profile following a meal, taken from the literature.

Pregnant women living in industrially contaminated sites (ICSs) are exposed to environmental contaminants through different pathways, and thus children’s health may be affected by pollutants. We created the Neonatal Environment and Health Outcomes (NEHO) longitudinal birth cohort in three ICSs in the Mediterranean area of southern Italy, collecting comprehensive information on personal data and lifestyles by questionnaire. Through multiple correspondence analysis, we identified possible clusters of enrolled women, and a neural network classifier analysis (NNCA) was performed to identify variables capable of predicting the attrition rate of the study. NEHO recruited 845 mother–child pairs over two years. The mothers’ mean age was 31.1 ± 5.2 SD years. We found significant differences in socioeconomic status (SES) among the three evaluated ICS, and an overall 11.1% prevalence of mothers who actively smoked during pregnancy. Active smoking during pregnancy was strongly associated with the lowest socioeconomic level (p &lt; 0.0001). By means of the NNCA, we found that smoking during pregnancy and the lowest education level characterized the cluster with the highest attrition rate (p &lt; 0.001). Our results demonstrate that reason for public health concern still exists regarding smoking during pregnancy and that SES influences both lifestyles, producing negative pregnancy outcomes and a higher survey attrition rate.

The paper investigates the problem of tracking a desired plasma glucose evolution by means of intra-venous insulin administration. A model-based approach is followed, according to a recent model of the glucose/insulin regulatory system which consists of a discrete-delay nonlinear differential equation model. A disturbance is added to the insulin kinetics in order to model uncertainties concerning both the insulin delivery rate and the mechanism actuating the insulin pump. A feedback control law which yields input-to-state stability of the closed loop error system with respect to such a disturbance is provided, which depends on the glucose and insulin measurements at the present and at a delayed time. In silico simulations validate the theoretical results.

The paper investigates the problem of tracking a desired plasma glucose evolution by means of intra-venous insulin administration. A model-based approach is followed. Only measurements of glycemia are considered. A nonlinear observer for delay differential systems is used for the estimation of insulinemia. In the spirit of the separation theorem, a nonlinear control law is proposed, based on the feedback linearization, which makes use of the observer estimations instead of the full state measurements. The local convergence of the tracking error to zero is theoretically proved. In silico simulations, which also take into account input saturation, show the very good performance of the proposed control technique.

A partial differential Progressive Tubular Reabsorption (PTR) model, describing renal tubular glucose reabsorption and urinary glucose excretion following a glucose load perturbation, is proposed and fitted to experimental data from five subjects. For each subject the Glomerular Filtration Rate was estimated and both blood and urine glucose were sampled following an Intra-Venous glucose bolus. The PTR model was compared with a model representing the conventional Renal Threshold Hypothesis (RTH). A delay bladder compartment was introduced in both formulations. For the RTH model, the average threshold for glycosuria varied between 9.90±4.50 mmol/L and 10.63±3.64 mmol/L (mean ± Standard Deviation) under different hypotheses; the corresponding average maximal transport rates varied between 0.48±0.45 mmol/min (86.29±81.22 mg/min) and 0.50±0.42 mmol/min (90.62±76.15 mg/min). For the PTR Model, the average maximal transports rates varied between 0.61±0.52 mmol/min (109.57±93.77 mg/min) and 0.83±0.95 mmol/min (150.13±171.85 mg/min). The time spent by glucose inside the tubules before entering the bladder compartment varied between 1.66±0.73 min and 2.45±1.01 min. The PTR model proved much better than RTH at fitting observations, by correctly reproducing the delay of variations of glycosuria with respect to the driving glycemia, and by predicting non-zero urinary glucose elimination at low glycemias. This model is useful when studying both transients and steady-state glucose elimination as well as in assessing drug-related changes in renal glucose excretion.

Clostridium difficile infection (CDI) accounts for the majority of nosocomial cases of diarrhea, and with recent upsurge of multidrug-resistant strains, morbidity and mortality have increased. Data on clinical impact of CDI come mostly from Anglo-Saxon countries, while in Italy only two studies address the issue and no economic data exist on costs of CDI in the in hospital setting. A retrospective cross-sectional study with pharmacoeconomic analysis was performed on the CDI series of the Policlinico Gemelli of Rome, a major 1400 bed Hospital.The clinical charts of 133 patients in a 26 month period were reviewed. All costs of the involved resources were calculated and statistical analysis was carried out with means and standard deviations, and categorical variables as number and percentages.The results show the significant sanitary costs of CDI in an Italian hospital setting. The cost analysis of the various elements (exams, imaging studies, therapies, etc.) shows that none independently influences the high cost burden of CDI, but that it is the simple length of hospital stay that represents the most important factor.Prevention of CDI is the most cost-effective approach. The major break-through in cost reduction of CDI would be a therapeutical intervention or procedure that shortens hospital length of stay.

Dicarboxylic acids with an even number of carbon atoms have been proposed as an alternate energy substrate for enteral or parenteral nutrition in the acutely ill patient, due to their water solubility and their yielding TCA cycle intermediates upon beta-oxidation. In the present work, a nonlinear compartmental model of the kinetics of dodecanedioic acid is developed, and its parameters are estimated from time concentration experimental observations obtained from six healthy volunteers undergoing a per os administration of 3 g of the substance. Although the model is linear in the transfer of the free substance from plasma to the tissues, the exchange between gut and plasma compartments is represented as a saturable function. Albumin binding is then incorporated to obtain the final model in terms of the measured total concentrations. Estimates of the model's structural parameters were computed for each experimental subject, and the usual single-subject approximate confidence regions for the parameters were derived by inversion of the Hessian at the optimum. To verify the applicability of this approximation, the nonlinearity of the expectation surface at the optimum was measured by computing the normal (intrinsic) component of curvature. Because the model curvature was excessive in all subjects, the usual approximation could not be trusted to provide acceptable approximations to the parameter confidence regions. A suitable Monte Carlo simulation yielded empirical joint parameter distributions from which the approximate parameter variances could finally be obtained.

In this work we consider the local sampled-data stabilization of human plasma glycemia. It is proved theoretically that the implementation by sampling and holding, for suitable small sampling period, of a state feedback which is shown in the literature to yield local stabilization when applied in a continuous time basis, yields local practical stabilization, with arbitrarily small final target ball. The model of the system is given by a nonlinear retarded functional differential equation and the above state feedback is provided by standard tools of differential geometry for time-delay systems. The proposed theoretical result proves an important property for the digital implementation of the controller, which has been shown in past literature to perform very well when checked in closed-loop with well known computer simulators of diabetic patients approved by the Food and Drug Administration as a substitute of animal trials.

A composite model, describing the glucose/insulin dynamics following daily food administration and insulin injections in Type 1 Diabetes Mellitus patients is presented. Three daily meals have been simulated, food intake representing four different types of foodstuffs, along with three rapid-acting insulin injections and one long-acting insulin injection. Three different scenarios (depending on whether food intake and/or administration times were fixed or random) were hypothesized: simulations show a very realistic time-course for both glucose and insulin dynamics over long (20 days) and short (one day) time periods.

Mathematical models of the cardiovascular system and of cerebral autoregulation (CAR) have been employed for several years in order to describe the time course of pressures and flows changes subsequent to postural changes. The assessment of the degree of efficiency of cerebral auto regulation has indeed importance in the prognosis of such conditions as cerebro-vascular accidents or Alzheimer. In the quest for a simple but realistic mathematical description of cardiovascular control, which may be fitted onto non-invasive experimental observations after postural changes, the present work proposes a first version of an empirical Stochastic Delay Differential Equations (SDDEs) model. The model consists of a total of four SDDEs and two ancillary algebraic equations, incorporates four distinct delayed controls from the brain onto different components of the circulation, and is able to accurately capture the time course of mean arterial pressure and cerebral blood flow velocity signals, reproducing observed auto-correlated error around the expected drift.

Exogenous insulin administration is the standard way to regulate hyperglycemia in diabetic patients and, in the recent decades, the challenging task to design an artificial pancreas has been addressed with the aim to synthesize a closedloop control law by means of sampled glucose measurements.Model-based control law allow to explicitly exploit the glucoseinsulin mathematical model, but need to cope with different sources of uncertainties and disturbances affecting the system.The present note investigates the framework of the H∞ control as a tool to attenuate the effect of a meal, modeled as an unknown disturbance.To this end an LMI-based feedback control law is synthesized, by properly exploiting a Delay Differential Equation model of the glucose-insulin system, that makes use of only glucose measurements, to avoid the use of insulin measurements, known to be slower and more cumbersome to obtain, more expensive and also less accurate than glucose measurements.It is shown by simulations that, besides to regulate plasma glycemia onto a desired level starting from a hyperglycemic state, the control law efficiently constrains the post-prandial increase of glycemia on a very tight control, preventing dangerous oscillations.

A realistic representation of the long-term physiologic adaptation to developing insulin resistance would facilitate the effective design of clinical trials evaluating diabetes prevention or disease modification therapies. In the present work, a realistic, robust description of the evolution of the compensation of the glucose-insulin system in healthy and diabetic individuals, with particular attention to the physiological compensation to worsening insulin resistance is formulated, its physiological assumptions are presented, and its performance over the span of a lifetime is simulated. Model-based simulations of the long-term evolution of the disease and of its response to therapeutic interventions are consistent with the transient benefits observed with conventional therapies, and with promising effects of radical improvement of insulin sensitivity (as by metabolic surgery) or of β-cell protection. The mechanistic Diabetes Progression Model provides a credible tool by which long-term implications of anti-diabetic interventions can be evaluated.

A glucose control problem is considered, with the aim to regulate a basal hyperglycemic state down to a safe euglycemic level. A discrete Delay Differential Equation (DDE) model of the glucose-insulin system is considered, that properly takes into account also the pancreatic insulin release, not negligible in Type 2 diabetic patients. Insulin is supposed to be administered subcutaneously. A geometric approach is considered, according to which the feedback linearization with delay cancelation theory is applied. In order to use only glucose measurements to synthesize the control law an observer for nonlinear delay systems is exploited, and the local convergence of the tracking error to zero is theoretically proven. Simulations are performed in a virtual environment, that properly takes into account input saturation: numerical results show the effectiveness of the proposed approach as well as that of the observer.

The Euglycemic Hyperinsulinemic Clamp (EHC) is considered the gold standard experiment for the determination of insulin sensitivity. It consists of a nontrivial perturbation experiment, during which large amounts of insulin are administered intra-venously to the subject, and exogenous glucose is administered, according to given protocols, in order to keep glycemia constant. This note proposes a closed-loop glucose control methodology for the EHC. A Delay Differential Equation (DDE) model of the EHC is considered to synthesize the control law. The use of an observer for nonlinear DDE systems allows the use of only glucose measurements in order to design the feedback (instead of insulin measurements, which are less accurate, more expensive and more cumbersome to obtain). The main result consists in the proof of convergence of the observer estimate error in case of a piecewise-constant control, which is what occurs in practice by intermittent manual regulation of the glucose infusion pump. Numerical results show the effectiveness of the proposed methodology.

Published compact and extended models of the glucose-insulin physiologic control system are compared, in order to understand why a specific functional form of the compact model proved to be necessary for a satisfactory representation of acute perturbation experiments such as the Intra Venous Glucose Tolerance Test (IVGTT). A spectrum of IVGTT's of virtual subjects ranging from normal to IFG to IGT to frank T2DM were simulated using an extended model incorporating the population-of-controllers paradigm originally hypothesized by Grodsky, and proven to be able to capture a wide array of experimental results from heterogeneous perturbation procedures. The simulated IVGTT's were then fitted with the Single-Delay Model (SDM), a compact model with only six free parameters, previously shown to be very effective in delivering precise estimates of insulin sensitivity and secretion during an IVGTT. Comparison of the generating, extended-model parameter values with the obtained compact model estimates shows that the functional form of the nonlinear insulin-secretion term, empirically found to be necessary for the compact model to satisfactorily fit clinical observations, captures the pancreatic reserve level of the simulated virtual patients. This result supports the validity of the compact model as a meaningful analysis tool for the clinical assessment of insulin sensitivity.

Risk perception (RP) evaluation during pregnancy and its relationship with lifestyles are considered useful tools for understanding communities living in high-risk areas and preventing dangerous exposure. It is well known that exposure to pollutants and less-healthy lifestyles may result in increased disease occurrence during life. Our work investigated environmental RP through ad hoc questionnaires administered to 611 mothers within the NEHO birth cohort, recruited in three heavily contaminated areas of Southern Italy. Four different RP indices, an exploratory factorial analysis (EFA), and a latent class analysis were evaluated from questionnaires. The highest values of risk perception index were observed in the Milazzo site (0.64 ± 0.16) and the lowest in the Crotone site (0.5 ± 0.18). EFA revealed four latent factors, including different items describing environmental pollution, and subjects were classified into four latent classes with different RP indices. Significant RP profiles were different among the sites (p &lt; 0.001). Our results did not demonstrate any association between RP and lifestyles during pregnancy. Improving healthy lifestyle behaviours, particularly in polluted areas, would generate co-benefits by preventing further risk factors. As remediation interventions can take a long time, it needs to improve healthy lifestyles in residents until remediation is completed.

A closed-loop control scheme is here investigated, for the Euglycemic Hyperinsulinemic Clamp (EHC), the gold standard experiment to estimate the individual insulin sensitivity. During the EHC large amounts of insulin are administered intra-venously to the subject, and plasma glycemia is maintained at a normal, baseline level by means of an exogenous glucose infusion, according to established protocols. Based on a Delay Differential Equation (DDE) model of the glucose-insulin system, a closed-loop control has been recently proposed by the same authors showing that, in way of principle, it is possible to design an observer-based control law for the exogenous glucose profile, by solely exploiting real-time plasma glucose measurements. This note further investigates the closed-loop control scheme in order to validate it in spite of the many sources of uncertainties and malfunctioning that inevitably arise. The main feature is to close the feedback onto a different, large-scale multi-compartmental model (standing for a Virtual Patient, VP), instead of the small-scale, DDE model adopted to design the control law. The chosen large-scale model for the VP has been recently accepted by the Food and Drug Administration as a substitute to animal trials for the preclinical testing of control strategies in artificial pancreas. A benchmark based on a population of heterogeneous virtual patients has been implemented and the very good results show the robustness of the proposed methodology.

Transoral gastroplasty (TOGA) is a safe and less invasive procedure than traditional bariatric surgery. We studied the effects of TOGA on the risk of progression from prediabetes to overt type 2 diabetes mellitus (T2DM) or on regression from diabetes or prediabetes to a lower risk category. Prospective, observational study (October 2008 to October 2010) performed at Catholic University, Rome, Italy. Fifty consecutive subjects 18–60 years old, 35 ≥ body mass index < 55 kg/m2, were enrolled. Glucose tolerance, insulin sensitivity, and secretion were studied at baseline and 1 week and 1, 6, and 12 months after TOGA. Plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and ghrelin levels were measured. Forty-three patients (86%) completed the 1-year postoperative follow-up. Patients lost 16.90% of baseline weight (P level × factor time <0.001). Body mass index decreased from 42.24 ± 3.43 to 34.65 ± 4.58 kg/m2 (P < .001). Twenty-three patients (53.5%) were diagnosed as normal glucose tolerance (NGT) before treatment, 2 (4.6%) were impaired fasting glucose (IFG), 12 (27.9%) were impaired glucose tolerance (IGT), 1 (2.3%) had both IFG and IGT, and 5 (11.6%) had T2DM. At 1-year posttreatment, the percentages changed to 86.0% NGT, 2.3% IFG, 11.6% IGT, 0% IFG plus IGT, and 0% T2DM, respectively. Peripheral insulin resistance and homeostasis model of assessment-insulin resistance improved significantly. Fasting glucose-dependent insulinotropic peptide and ghrelin decreased from 316.9 ± 143.1 to 156.2 ± 68.2 pg/mL (P < .001) and from 630.6 ± 52.1 to 456.7 ± 73.1 pg/mL (P < .001), respectively, whereas GLP-1 increased from 16.2 ± 4.9 to 23.7 ± 9.5 pg/mL (P < .001). TOGA induced glucose disposal improvement with regression of diabetes to NGT or IGT and regression of IGT and IFG to NGT in half of the cases. Regressors showed a much larger increase of GLP-1 levels than progressors.

This paper investigates the problem of plasma glucose regulation by means of intra-venous insulin administration. A model-based approach is followed, according to a discrete-time framework, since the available standard technology provides sampled glucose measurements and piece-wise constant insulin delivery devices. The digital control scheme is designed on the basis of an approximated sampled model, whose continuous-time original version is available in the recent literature, and has been shown to very well resemble real data on healthy subjects as well as on diabetic patients (both type 1 and type 2 Diabetes Mellitus). In silico simulations show the high performance of the proposed digital control law.

Type-2 Diabetes Mellitus (T2DM) is a metabolic syndrome characterized by low insulin sensitivity, so that higher amounts of insulin are required in order to keep glycemia in a safe range (approximately, 60 ~ 110 mg/dl or, equivalently, 3.33 ~ 6.11 mM). Although insulin resistance and T2DM are often treated without exogenous insulin administration, the possibility to early treat pre-diabetic states or T2DM patients with insulin administration could be envisaged if the clinical need exists (e.g. surgical stress, infection). The present work introduces a possible new therapeutic insulin administration dosing approach for T2DM patients. The IVGTT glycemia and insulinemia profiles of a diseased patient are collected and, successively, its metabolic parameters are obtained by fitting a compact delay model to those data. Then a controller is designed exploiting the previous model as a tool. Finally, the tuned controller is applied to the patient as an artificial pancreas supplying external insulin administration. The results are shown on a virtual patient, whose behavior is described by a comprehensive, validated extensive model.

The dynamics of pedestrian crowds during exceptional tragic events are very complex depending on a series of human behaviors resulting from combinations of basic interaction principles and self-organization. The Alert–Panic–Control (APC) model is one of the mathematical models in the literature for representing such complicated processes, mainly focusing on psychologists’ points of view (i.e., emotion contagion). This work proposes a Hybrid APC (HAPC) model including new processes, such as the effect of resonance, the victims caused by people in state of panic, new interactions between populations based on imitation and emotional contagion phenomena and the ability to simulate multiple disaster situations. Results from simulated scenarios showed that in the first 5 min 54.45% of population move towards a state of alert, 13.82% enter the control state and 31.73% pass to the state of panic, highlighting that individuals respond to a terrible incident very quickly, right away after it occurs.

Abstract 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 &lt; 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.

An Agent-Based Model (ABM) of glioblastoma in-filtration into surrounding healthy brain tissue is presented. The model incorporates variable cell movement rates and replication rates depending on internal energy levels, thus representing the history of residency of the cells in the energy-poor core or energy-rich edge regions of the original tumor spheroid. The model is able to reproduce the fragmented infiltration front of glioblastoma and is quantitatively consistent with reported data of glioblastoma growth and spread. While basic, the model can be easily expanded to include different cell sub-populations, study the interaction of tumor and immune system and explore different treatment scenarios with a view to personalized therapy.

A simple model of a neuronal circuit based on a stochastic discrete-time difference equation is described. The model assumes loosely connected clusters of densely connected neurons within each cluster, and a circuit topology is produced by connecting the clusters in sequence. The action of the glia is simulated by two parameters referring to its trophic action in restoring neuronal energy levels after firing and to its scavenging action at the synaptic level affecting the probability that an impulse is transmitted. It is shown that only glial trophic support within a limited range allows ordinate cyclic functioning of the circuit. It is also shown that changes in local action at the synapse determine changes in the frequency of the cycling. This kind of model paves the way to a quantitative description of changes in neurodegenerative diseases, so as to potentially predict the evolution of quality of life in these conditions.

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.

Two important statistical parameter estimation pitfalls, examples of which can be found in the literature, are here reviewed and discussed. The first concerns the lack of model qualitative behaviour analysis before proceeding to the actual parameter estimation phase: this may give rise in the worst cases to aberrant model behaviour and to meaningless parameter estimates. The second concerns the use of interpolated noisy observations taken to represent the real input or driving variable into a model: this gives rise to the artifactual reproduction of meaningful features of the output variables, based on data errors and hence inherently non-reproducible. This is particularly dangerous when using noisy observations instead of model predictions in coupled systems. Examples of these pitfalls are drawn from existing glucose-insulin modelling literature and recommendations are made.

To achieve accurate and affordable predictions of glucose and insulin plasma concentrations is of paramount importance, especially in the field of the artificial pancreas, where real-time measurements could be properly exploited in model-based glucose control algorithms. This note focuses on a recently developed research line that makes use of a state observer to estimate insulin in real-time from glucose measurements, since it is known that insulin measurements are slower and more cumbersome to obtain, more expensive and also less accurate. Based on these predictions, glucose control algorithms can be designed and can be exploited for both intravenous and subcutaneous insulin infusions. The safety, robustness, and efficacy of the observer-based control algorithms have been validated on a population of rather heterogenous virtual patients, modeled by a different, comprehensive model of the glucose–insulin system, recently accepted by the Food and Drug Administration as a substitute of animal trials.

In recent years, there has been a rise in Major Incidents with big impact on the citizens health and the society.Without the possibility of conducting live experiments when it comes to physical and/or toxic trauma, only an accurate in silico reconstruction allows us to identify organizational solutions with the best possible chance of success, in correlation with the limitations on available resources (e.g.medical team, first responders, treatments, transports, and hospitals availability) and with the variability of the characteristic of event (e.g.type of incident, severity of the event and type of lesions).Utilizing modelling and simulation techniques, a simplified mathematical model of physiological evolution for patients involved in physical and toxic trauma incident scenarios has been developed and implemented.The model formalizes the dynamics, operating standards and practices of medical response and the main emergency service in the chain of emergency management during a Major Incident.

Plasma glucose regulation is commonly attained in Type 1 Diabetes Mellitus (T1DM) patients, as well as in advanced Type 2 Diabetes Mellitus (T2DM), by means of Sub-Cutaneous (SC) insulin administration. In order to study this extremely common and relevant clinical problem from a theoretical point of view, a Delay Differential Equation (DDE) model of the glucose-insulin system has been considered. The model extends a previous DDE model, already used for glucose control, by endowing it with a SC Insulin compartment and by introducing modifications regarding insulin-independent glucose uptake and Hepatic Glucose Output (HGO). Pancreatic insulin release (non-negligible in T2DM) is considered, in order for the control method to address both T1DM and T2DM. The method of exact input/output feedback linearization and stabilization is used, to ensure the local convergence of the tracking error to zero. Numerical simulations show the effectiveness of the proposed approach.

Roux-en-Y gastric bypass (RYGB) is the most performed bariatric operation. Reactive hypoglycaemia is a frequent late complication occurring in about 72% of RYGB patients, which can present with various intensities up to the serious form of neuroglycopaenia. However, it seems to occur also after sleeve gastrectomy (SG) although much more rarely.A single centre, open, 1-year randomised trial to compare the incidence of hypoglycaemia after RYGB or SG. A secondary objective is the assessment of the comparative ability of the two surgical procedures in determining the improvement or normalisation of insulin sensitivity, given the established relevance of insulin resistance in the cardiometabolic syndrome of obesity.The study will be published and presented to international meetings and, due to the safety issue, it will represent a relevant information for national healthcare systems. The protocol was approved by the Catholic University Ethical Committee (A1534/CE/2012). Clinicaltrials.gov Registration n. NCT01581801.

Botulinum toxin blocks acetylcholine release from nerve endings and acts as a long term, reversible inhibitor of muscle contraction as well as of salivary, sweat gland, adrenal and prostatic secretions. The aim of the present study is to investigate whether gastric submucosal injection of botulinum toxin type A reduces stimulated gastric production of HCl.Sixty-four rats were randomized in two groups and laparotomized. One group was treated with botulinum toxin-A 10 U by multiple submucosal gastric injections, while the second group was injected with saline. Two weeks later, acid secretion was stimulated by pyloric ligation and acid output was measured. Body weight, food and water intake were also recorded daily.HCl production after pyloric ligation was found to be significantly lower in botulinum toxin-treated rats (657 +/- 90.25 micromol HCl vs. 1247 +/- 152. P = 0.0017). Botulinum toxin-treated rats also showed significantly lower food intake and weight gain.Botulinum toxin type A reduces stimulated gastric acidity. This is likely due either to inhibition of the cholinergic stimulation of gastric parietal cells, or to an action on the myenteric nervous plexuses. Reduction of growth and food intake may reflect both impaired digestion and decreased gastric motility.