Assessing value of contrast-enhanced ultrasound vs. conventional transthoracic ultrasound in improving diagnostic yield of percutaneous needle biopsy of peripheral lung lesions.

OBJECTIVE: The aim of the present study was to systematically assess the value of contrast-enhanced ultrasound (CEUS) vs. conventional transthoracic ultrasound (TUS) in improving diagnostic accuracy of percutaneous needle biopsy (PTNB) for subpleural lung lesions. PATIENTS AND METHODS: 232 patients with subpleural lesions were 1:1 randomly assigned to a group were CEUS was performed (n=116, mean age=65.5±5.6, M=69) or not (n=116, mean age=66.0±5.3, M=70). For CEUS study was used an injection of 4.8 mL of SonoVue (Bracco, Italy). For PTNB was employed a Menghini-modified technique with a semi-automatic 18-gauge needle. RESULTS: The mean diameter of subpleural lesions was 2.85±0.7 cm in the CEUS+ group and 2.95±0.6cm in the CEUS- group. Only 3 lesions, 1 in the CEUS+ group and 2 in the CEUS- group measured >5 cm. CEUS showed no superiority in terms of diagnostic accuracy compared to conventional TUS (p=0.34). Similar results were obtained in the sub-analysis of lesions sized between 1-2 cm (p=1.00) and 2-5 cm (p=0.08). As the lesion size increased, the detection rate of necrosis in lesions increased by CEUS (from 8% to 31%). CEUS showed no superiority in terms of diagnostic accuracy in the sub-analysis of necrotic lesions at CECT (p=0.38). AUC values for both the groups assessed an excellent diagnostic yield for TUS-PTNB (≥0.80). CONCLUSIONS: CEUS study does not improve the diagnostic accuracy of TUS-guided PTNB for peripheral lung lesions <5 cm of diameter. Further studies evaluating CEUS guidance for larger (>5 cm) and necrotic lesions are needed prior that its potential can be clarified.

EAN guideline on palliative care of people with severe, progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Patients with severe, progressive multiple sclerosis (MS) have complex physical and psychosocial needs, typically over several years. Few treatment options are available to prevent or delay further clinical worsening in this population. The objective was to develop an evidence-based clinical practice guideline for the palliative care of patients with severe, progressive MS. METHODS: This guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Formulation of the clinical questions was performed in the Patients-Intervention-Comparator-Outcome format, involving patients, carers and healthcare professionals (HPs). No uniform definition of severe MS exists: in this guideline, constant bilateral support required to walk 20 m without resting (Expanded Disability Status Scale score > 6.0) or higher disability is referred to. When evidence was lacking for this population, recommendations were formulated using indirect evidence or good practice statements were devised. RESULTS: Ten clinical questions were formulated. They encompassed general and specialist palliative care, advance care planning, discussing with HPs the patient's wish to hasten death, symptom management, multidisciplinary rehabilitation, interventions for caregivers and interventions for HPs. A total of 34 recommendations (33 weak, 1 strong) and seven good practice statements were devised. CONCLUSIONS: The provision of home-based palliative care (either general or specialist) is recommended with weak strength for patients with severe, progressive MS. Further research on the integration of palliative care and MS care is needed. Areas that currently lack evidence of efficacy in this population include advance care planning, the management of symptoms such as fatigue and mood problems, and interventions for caregivers and HPs.

Serum vitamin D deficiency in subjects with severe acquired brain injury and relationship with functional severity.

BACKGROUND: Vitamin D may be important for the development and function of the nervous system. Low serum vitamin D levels have been detected in several neurological diseases. OBJECTIVE: To ascertain the relationship between 25(OH)D serum level and disability in subjects with severe acquired brain injury (sABI). DESIGN: Prospective cross-sectional study Methods: Consecutive subjects with sABI admitted to neuro-rehabilitation were enrolled. A sample of subjects from the neurological ward was considered the control group. Vitamin D serum levels and blood parameters were measured at admission. Disability Rating Scale (DRS), Glasgow Outcome Scale (GOS), and Level of Cognitive Functioning (LCF) were used in assessing disability. RESULTS: A total of 104 subjects (34 F, 70 M; mean age 53.9 ± 15.2 years) were enrolled: 54 (19 F, 35 M) with sABI and 50 (15 F, 35 M) subjects as control group. Deficient mean serum levels of vitamin D (19.2 ± 9.4 ng/mL) were detected in the subjects with sABI and a significant inverse correlation between vitamin D serum levels and DRS score was detected (p = 0.04). CONCLUSION: Subjects with sABI showed vitamin D deficiency that might correlate to disability severity. The reason is unclear and might represent a secondary phenomenon resulting from the inflammatory process.

Pseudobulbar affect as a negative prognostic indicator in amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate whether the presence of pseudobulbar affect (PBA) in an early stage of the disease influences survival in a population-based incident cohort of amyotrophic lateral sclerosis (ALS). METHODS: Incident ALS cases, diagnosed according to El Escorial criteria, were enrolled from a prospective population-based registry in Puglia, Southern Italy. The Center for Neurologic Study-Lability Scale (CNS-LS), a self-administered questionnaire, was used to evaluate PBA. Total scores range from 7 to 35. A score ≥13 was used to identify PBA. Cox proportional hazard models were used for survival analysis. The modified C-statistic for censored survival data was used for models' discrimination. RECursive Partitioning and AMalgamation (RECPAM) analysis was used to identify subgroups of patients with different patterns of risk, depending on baseline characteristics. RESULTS: We enrolled 94 sporadic ALS, median age of 64 years (range: 26-80). At the censoring date, 65 of 94 (69.2%), 39 of 60 (65.0%), and 26 of 34 (76.5%) patients reached the outcome (tracheotomy/death), in the whole, non-PBA and in the PBA groups, respectively. Kaplan-Meier survival curves for the two subgroups were not significantly different (log-rank test: 1.3, P = .25). The discrimination ability of a multivariable model with demographic and clinical variables of interest was not improved by adding PBA. In the RECPAM analysis, ALSFRSr and the total score of CNS-LS scale (

Salmonella, Escherichia coli and Enterobacteriaceae in the peanut supply chain: From farm to table.

Due to recent foodborne outbreaks, peanuts have been considered a potential risk for Salmonella transmission. For this reason, the aim of this study was to determine the prevalence and contamination load of Salmonella, Escherichia coli and Enterobacteriaceae throughout the peanut supply chain in Brazil. Samples of peanuts and peanut-containing processed products from post-harvest (n=129), secondary processing (n=185) and retail market (n=100) were analyzed. The results showed high Enterobacteriaceae counts in the post-harvest samples. At the end of the secondary processing, 16% of the samples remained contaminated by this group of microorganisms. Six peanut samples from primary production and one sample of peanut butter were tested positive for E. coli while Salmonella was detected in nine samples (2.2%): six from post-harvest, two from the initial stage of the secondary processing and one from retail. The Salmonella counts ranged between 0.004 and 0.092MPN/g and five serotypes were identified (Muenster, Miami, Javiana, Oranienburg, Glostrup). The results demonstrated a high prevalence of Enterobacteriaceae and low prevalence of E. coli throughout the peanut supply chain. Furthermore, it was verified that peanuts may become contaminated by Salmonella during different stages of the supply chain, especially at post-harvest.

Pharmacogenetics of oral antidiabetes drugs: evidence for diverse signals at the IRS1 locus.

To investigate the role of IRS1 locus on failure to oral antidiabetes drugs (OADs) we genotyped single-nucleotide polymorphisms (SNPs), rs2943641, rs7578326 (tagging all SNPs genome-wide associated with type 2 diabetes (T2D) and related traits at this locus) and rs1801278 (that is, the loss-of-function IRS1 G972R amino acid substitution) in 2662 patients with T2D. Although no association with OAD failure was observed for rs2943641 and rs7578326 SNPs (odds ratio (OR): 1.04, 95% confidence interval (CI): 0.93-1.16 and OR: 0.97, 95% CI: 0.87-1.09 respectively), a significant association was observed for rs1801278 (OR: 1.34, 95% CI: 1.08-1.66). When meta-analyzed with previous published data, an allelic OR of 1.41 (1.15-1.72; P=0.001) was obtained, so that homozygous R972R individuals have >80% higher risk of failing to OADs as compared with their G972G counterparts. In all, though further studies are needed for confirming this finding, our present data point to IRS1 rs1801278 as a potential biomarker for pursuing the goal of stratified medicine in the field of antihyperglycemic treatment in T2D.

Brain structural and functional signatures of impulsive-compulsive behaviours in Parkinson's disease.

This study assessed brain structural and functional alterations in patients with Parkinson's disease and impulsive-compulsive behaviours (PD-ICB) compared with controls and PD no-ICB cases. Eighty-five PD patients (35 PD-ICB) and 50 controls were recruited. All subjects underwent three-dimensional T1-weighted, diffusion tensor (DT), and resting state functional magnetic resonance imaging (RS fMRI). We assessed cortical thickness with surface-based morphometry, subcortical volumes using FIRST, DT MRI metrics using region of interest and tractography approaches, and RS fMRI using a model free approach. Compared with controls, both PD groups showed a pattern of brain structural alterations in the basal ganglia (more evident in PD no-ICB patients), sensorimotor and associative systems. Compared with PD no-ICB, PD-ICB cases showed left precentral and superior frontal cortical thinning, and motor and extramotor white matter tract damage. Compared with controls, all patients had an increased functional connectivity within the visual network. Additionally, PD no-ICB showed increased functional connectivity of bilateral precentral and postcentral gyri within the sensorimotor network compared with controls and PD-ICB. Severity and duration of PD-ICB modulated the functional connectivity between sensorimotor, visual and cognitive networks. Relative to PD no-ICB, PD-ICB patients were characterised by a more severe involvement of frontal, meso-limbic and motor circuits. These data suggest ICB in PD as the result of a disconnection between sensorimotor, associative and cognitive networks with increasing motor impairment, psychiatric symptoms, and ICB duration. These findings may have important implications in understanding the neural substrates underlying ICB in PD.

Randomised clinical trial: sofosbuvir and ledipasvir in patients with transfusion-dependent thalassaemia and HCV genotype 1 or 4 infection.

BACKGROUND: Patients with thalassaemia major depend on blood transfusions. In Italy, up to 80% of thalassaemia patients bear HCV antibodies due to HCV contaminated transfusions before 1990. Thalassaemia patients with HCV infection have high risk of developing HCC. Treatment based on Pegylated-IFN (Peg-IFN) and Ribavirin (RBV) was limited by relevant side effects. AIM: To evaluate the impact of Sofosbuvir/Ledipasvir (SOF/LDV) fixed dose combination for 12 weeks without RBV, in patients with thalassaemia major and HCV Genotype 1 or 4 (GT1/4). METHODS: Open label, historically-controlled, nationwide multicentre study in thalassaemia patients including naïve with cirrhosis and prior treatment failure without cirrhosis. SOF/LDV single pill was administered for 12 weeks to 100 patients of whom 16% had cirrhosis. The control group included 96 patients with comparable baseline characteristics treated with Peg-IFN/RBV. The primary end point was sustained virologic response at follow-up week 12 or 24 after IFN-free or Peg-IFN/RBV, respectively. RESULTS: In the study group, sustained virological response (SVR) was reported in 98% of patients (95% CI 95.3%-100%). Cirrhotic as well as prior treatment failure achieved 100% SVR. In the control group, SVR was 47.9% (95% CI 37.9%-57.9%). Adverse events including fatigue, headache, nausea, decrease in haemoglobin or increase in ferritin levels were rare and significantly less common in the study than in the historical control group. CONCLUSIONS: In conclusion, SOF/LDV for 12 weeks provides simple, highly effective and safe Peg-IFN/RBV-free treatment for HCV GT1/4 thalassaemia patients. EUDRACT number 2015-002401-1.

Clinical worthlessness of genetic prediction of common forms of diabetes mellitus and related chronic complications: A position statement of the Italian Society of Diabetology.

AIM: We are currently facing several attempts aimed at marketing genetic data for predicting multifactorial diseases, among which diabetes mellitus is one of the more prevalent. The present document primarily aims at providing to practicing physicians a summary of available data regarding the role of genetic information in predicting diabetes and its chronic complications. DATA SYNTHESIS: Firstly, general information about characteristics and performance of risk prediction tools will be presented in order to help clinicians to get acquainted with basic methodological information related to the subject at issue. Then, as far as type 1 diabetes is concerned, available data indicate that genetic information and counseling may be useful only in families with many affected individuals. However, since no disease prevention is possible, the utility of predicting this form of diabetes is at question. In the case of type 2 diabetes, available data really question the utility of adding genetic information on top of well performing, easy available and inexpensive non-genetic markers. Finally, the possibility of using the few available genetic data on diabetic complications for improving our ability to predict them will also be presented and discussed. For cardiovascular complication, the addition of genetic information to models based on clinical features does not translate in a substantial improvement in risk discrimination. For all other diabetic complications genetic information are currently very poor and cannot, therefore, be used for improving risk stratification. CONCLUSIONS: In all, nowadays the use of genetic testing for predicting diabetes and its chronic complications is definitively of little value in clinical practice.

MECHANISMS IN ENDOCRINOLOGY: Endogenous subclinical hypercortisolism and bone: a clinical review.

In recent years, the condition of subclinical hypercortisolism (SH) has become a topic of growing interest. This is due to the fact that SH prevalence is not negligible (0.8-2% in the general population) and that, although asymptomatic, this subtle cortisol excess is not harmless, being associated with an increased risk of complications, in particular of osteoporosis and fragility fractures. As specific symptoms of hypercortisolism are absent in SH, the SH diagnosis relies only on biochemical tests and it is a challenge for physicians. As a consequence, even the indications for the evaluation of bone involvement in SH patients are debatable and guidelines are not available. Finally, the relative importance of bone density, bone quality and glucocorticoid sensitivity in SH is a recent field of research. On the other hand, SH prevalence seems to be increased in osteoporotic patients, in whom a vertebral fracture may be the presenting symptom of an otherwise asymptomatic cortisol excess. Therefore, the issue of who and how to screen for SH among the osteoporotic patients is widely debated. The present review will summarize the available data regarding the bone turnover, bone mineral density, bone quality and risk of fracture in patients with endogenous SH. In addition, the role of the individual glucocorticoid sensitivity in SH-related bone damage and the problem of diagnosing and managing the bone consequences of SH will be reviewed. Finally, the issue of suspecting and screening for SH patients with apparent primary osteoporosis will be addressed.

Microbiological contamination in peanut confectionery processing plants.

AIMS: In order to investigate Enterobacteriaceae, coliforms, Escherichia coli and Salmonella contamination, a survey was conducted at three peanut confectionery processing companies (A, B and C) in Brazil. METHODS AND RESULTS: Samples of different peanut confectionery products (n = 59), peanut raw material (n = 30), manufacturing environment (n = 116) and workers' hand surfaces (n = 12) were analysed. Salmonella and E. coli were not detected in any final product or raw material analysed. Enterobacteriaceae was isolated from 15% of final products. Coliforms were detected in only one sample. Referring to the raw material, six samples showed contamination by Enterobacteriaceae and three samples by coliforms. For the process environment, 19% and 11% of samples presented Enterobacteriaceae and coliforms. Escherichia coli was detected in 5% of samples, and one of these samples tested positive for Salmonella; this strain was serotyping as S. Heidelberg. All food handlers surveyed in Company C showed Enterobacteriaceae and coliforms on their hands. Escherichia coli was isolated from one food worker's hand. CONCLUSION: The results showed that the manufacturing environment, including food handlers were considered the main sources for possible contamination of peanut confectionery products. SIGNIFICANCE AND IMPACT OF THE STUDY: This has been the first study to investigate the occurrence of Salmonella and other Enterobacteriaceae throughout peanut confectionery processing lines. The results might be used to assist risk assessment studies and to establish more effective control measures.

Time to generalization and prediction of survival in patients with amyotrophic lateral sclerosis: a retrospective observational study.

BACKGROUND AND PURPOSE: A strong association between time to generalization (TTG), considered as the time of spreading of the clinical signs from spinal or bulbar localization to both, and survival was recently identified in patients with amyotrophic lateral sclerosis (ALS). Thus, TTG may be used as an early to intermediate end-point in survival studies. The aim of the present study was to test TTG as a predictor of survival in ALS. METHODS: This was an observational retrospective study of ALS patients from a tertiary referral centre over a 5-year follow-up period. RESULTS: In 212 ALS patients, TTG was associated with time to death/tracheostomy [R 0.62, 95% confidence interval (CI) 0.53-0.70; P < 0.001]. In a time-to-event analysis, longer TTG resulted in lower risk to reach a composite outcome (death or tracheostomy) both in univariate [hazard ratio (HR) 0.98, 95% CI 0.97-0.99] and multivariate Cox analyses (HR 0.98, 95% CI 0.96-0.99). TTG predicted death/tracheostomy at 4 years (C-statistic 0.58; 95% CI 0.53-0.63) and at 5 years (C-statistic 0.58; 95% CI 0.53-0.62). CONCLUSIONS: Based on the present results from a large clinical cohort, TTG may be used as a new early to intermediate end-point to describe the ALS natural history. TTG may be potentially useful as a new primary outcome measure for clinical trials.

Diffusion tensor magnetic resonance imaging in very early onset pediatric multiple sclerosis.

OBJECTIVES: Active myelination during childhood may influence the impact of multiple sclerosis (MS) on brain structural integrity. We studied normal-appearing white matter (NAWM) in children with MS onset before age 12 years using diffusion tensor (DT) magnetic resonance imaging (MRI). METHODS: DT MRI scans were obtained from 22 MS children with their first attack before age 12 years, and 31 healthy controls from two referral centers. Using probabilistic tractography, brain tissue integrity within interhemispheric, intrahemispheric, and projection tracts was compared between patients and site-matched controls. The impact of disease and age at MRI on tract NAWM fractional anisotropy (FA) and mean diffusivity (MD) values was evaluated using linear models. RESULTS: Compared to controls, pediatric MS patients had reduced FA and increased MD of the bilateral superior longitudinal fasciculus and corpus callosum (CC), without center-by-group interaction. CC NAWM average FA was correlated with brain T2 lesion volume. In controls, the majority of the tracts analyzed showed a significant increase of FA and decrease of MD with age. Such a linear correlation was lost in patients. CONCLUSIONS: In very young pediatric MS patients, DT MRI abnormalities affect brain WM tracts differentially, and are only partially correlated with focal WM lesions. Impaired maturation of WM tracts with age may be an additional factor contributing to these findings.

Cerebrospinal fluid neurofilament light chain levels: marker of progression to generalized amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: To evaluate whether cerebrospinal fluid (CSF) neurofilament light chain (NFL) levels could predict the time to generalization (TTG) in amyotrophic lateral sclerosis (ALS). METHODS: Cerebrospinal fluid NFL levels of 37 cases of sporadic ALS were measured and the time of symptom spreading from spinal or bulbar localization to both (TTG) was evaluated in all patients. RESULTS: Kaplan-Meier analysis showed a short TTG in patients with high NFL levels (log-rank test chi-squared = 19.4, P < 0.0001). In a multivariate regression model patients with NFL levels above the median had an eight-fold higher risk of generalization (adjusted hazard ratio 7.9, 95% confidence interval 2.9-21.4, P < 0.0001) compared with those with NFL levels below the median. CONCLUSIONS: This study shows that in sporadic ALS NFL, a marker of neurodegeneration, is correlated with TTG, a clinical intermediate parameter of survivorship.

Forceps minor damage and co-occurrence of depression and fatigue in multiple sclerosis.

OBJECTIVE: Using diffusion tensor magnetic resonance imaging (DT MRI), we analyzed the architectural integrity of the brain white matter (WM) from a large cohort of MS patients to identify the structural substrates of the concomitant presence of depression and fatigue. METHODS: Brain dual-echo, 3D T1-weighted and DT MRI scans were acquired from 147 MS patients and 90 gender- and age-matched healthy controls (HCs). Patients were stratified by the presence of depression (92 depressed (D), 55 not depressed (nD)) and fatigue (81 fatigued (F), 66 not fatigued (nF)). Sixty-five patients had co-occurrence of depression and fatigue (DF). Whole-brain voxel-wise comparisons of WM DT MRI abnormalities were performed using tract-based-spatial-statistics (TBSS). Tract-specific analyses were run in brain WM tracts using standard-space templates. RESULTS: Whole-brain voxel-wise analysis yielded no significant differences between patient subgroups. At tract-specific analysis, DF patients had reduced fractional anisotropy (FA) of the forceps minor. Reduced FA of the right anterior thalamic radiation and right uncinate fasciculus was found in F-MS vs not F-MS patients after correcting for depression. No significant differences were found between D vs not D-MS patients, after correcting for fatigue. CONCLUSIONS: This study provides evidence for partially overlapping damage to frontal and fronto-temporal pathways underlying depression and fatigue in MS.

Metabolomics signature improves the prediction of cardiovascular events in elderly subjects.

AIMS: Age is one of the most important determinants of cardiovascular health, therefore the management of cardiovascular diseases (CVD) in elderly people entails great challenge. A possible explanation of vascular senescence process is the mitochondrial damage and dysfunction. We hypothesized that metabolomic profiling would identify biomarkers predicting major cardiovascular events (MACEs) in elderly people, improving the clinical standard cardiovascular risk factors. METHODS AND RESULTS: Targeted-mass-spectrometry-based profiling of 49 metabolites was performed in a group of very old participants (n = 67, mean age = 85 ± 3 years) with a high rate of previous CVD (68%). Principal Component Analysis, Random Survival Forest analysis and Cox proportional hazards regression modeling were used to evaluate the relation between the metabolite factors and recurring MACEs. We tested discrimination ability and reclassification of clinical and metabolomic models. At follow-up (median = 3.5 years), 17 MACEs occurred (5 cardiovascular deaths, 1 nonfatal myocardial infarction, 7 nonfatal strokes and 4 peripheral artery surgeries) (incidence = 7.3% person-years). Metabolite factor 1, composed by medium- and long-chain acylcarnitines, and factor 7 (alanine) were independently associated with MACEs, after adjustment for clinical CV covariates [HR = 1.77 (95%CI = 1.11-2.81, p = 0.016) and HR = 2.18 (95%CI = 1.17-4.07, p = 0.014), respectively]. However, only factor 1 significantly increases the prediction accuracy of the Framingham Recurring-Coronary-Heart-Disease-Score, with a significant improvement in discrimination (integrated discrimination improvement = 7%, p = 0.01) and correctly reclassifying 41% of events and 37% of non-events resulting in a cNRI = 0.79 (p = 0.005). CONCLUSIONS: Aging mitochondrial dysfunction evaluated by metabolomic profiling is associated with MACEs, independently of standard predictors.

High density cholesterol level as predictor of clinical response to anti-TNF-alpha therapy in psoriatic patients.

Psoriasis is a common, chronic, inflammatory, and debilitating disease of the skin. Infliximab is a human/mouse chimeric anti-TNF-alpha antibody effective in the management of psoriasis. Availability of biomarkers for prediction of response, could optimize the therapeutic approach. The aim of this study was to identify predictors of clinical response to infliximab in psoriatic patients in the long-term treatment. Patients affected with psoriasis and suitable for treatment with infliximab were prospectively enrolled. Patients treated for a period longer than 96 weeks were included in the study and divided into high responders and low responders according to infliximab efficacy (PASI 90). A logistic regression analysis was used to explore independent association between high clinical response and possible biomarkers of prediction. A total of 112 patients were included for the analysis. Multiple regression analysis showed that high levels of HDL cholesterol and the short duration of psoriasis [OR 1.11 (CI 1.05-1.18) and OR 0.94 (CI 0.89-0.99)] predicted the most effective clinical response to infliximab. Our findings, which highlight a possible role for HDL cholesterol as clinical predictor for psoriasis treatment, are particularly noteworthy in the context of clinical strategies, but also suggest a possible role for lipid metabolism in aspects of psoriasis that deserves further investigation.

The SH2B1 obesity locus and abnormal glucose homeostasis: lack of evidence for association from a meta-analysis in individuals of European ancestry.

BACKGROUND/AIMS: The development of type 2 diabetes (T2D) is influenced both by environmental and by genetic determinants. Obesity is an important risk factor for T2D, mostly mediated by obesity-related insulin resistance. Obesity and insulin resistance are also modulated by the genetic milieu; thus, genes affecting risk of obesity and insulin resistance might also modulate risk of T2D. Recently, 32 loci have been associated with body mass index (BMI) by genome-wide studies, including one locus on chromosome 16p11 containing the SH2B1 gene. Animal studies have suggested that SH2B1 is a physiological enhancer of the insulin receptor and humans with rare deletions or mutations at SH2B1 are obese with a disproportionately high insulin resistance. Thus, the role of SH2B1 in both obesity and insulin resistance makes it a strong candidate for T2D. However, published data on the role of SH2B1 variability on the risk for T2D are conflicting, ranging from no effect at all to a robust association. METHODS: The SH2B1 tag SNP rs4788102 (SNP, single nucleotide polymorphism) was genotyped in 6978 individuals from six studies for abnormal glucose homeostasis (AGH), including impaired fasting glucose, impaired glucose tolerance or T2D, from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) consortium. Data from these studies were then meta-analyzed, in a Bayesian fashion, with those from DIAGRAM+ (n = 47,117) and four other published studies (n = 39,448). RESULTS: Variability at the SH2B1 obesity locus was not associated with AGH either in the GENIUS consortium (overall odds ratio (OR) = 0.96; 0.89-1.04) or in the meta-analysis (OR = 1.01; 0.98-1.05). CONCLUSION: Our data exclude a role for the SH2B1 obesity locus in the modulation of AGH.

Role of obesity on all-cause mortality in whites with type 2 diabetes from Italy.

Mortality rate of diabetic patients is twice as much that of non-diabetic individuals. The role of obesity on mortality risk in patients with type 2 diabetes is controversial. Aim of our study was to address the relationship between obesity and all-cause mortality in a real-life set of white patients with type 2 diabetes from central-southern Italy from the Gargano Mortality Study (GMS). In addition, we used genetic data from genome-wide association studies (GWAs)-derived single nucleotide polymorphisms (SNPs) firmly associated with body mass index (BMI), in order to investigate the intrinsic nature of reduced mortality rate we, in fact, observed in obese patients. Study subjects with type 2 diabetes (n = 764) are part of the GMS, which is aimed at unraveling predictors of incident all-cause mortality. Time-to-death analyses were performed by Cox regression. Association between genotype risk score and obesity was tested by logistic regression. Of the 32 SNPs firmly associated with BMI, we investigated those with BMI ß value ≥0.10 kg/m(2) and allele frequency ≥10 %. Genotyping was performed by KBioscience (http://www.lgcgenomics.com/). In GMS, obesity predicted a 45 % reduction in all-cause mortality. Individuals with high "obesity genetic load" (i.e., those carrying >9 risk alleles) were 60 % more likely to be obese as compared to individuals with low "obesity genetic load." Most importantly, mortality rate was not different in individuals with high and low "obesity genetic load," thus indicating no role of obesity genes on all-cause mortality and speaking against a cause-effect relationship underlying the association between obesity and reduced mortality rate.