Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration

Type 2 diabetes (T2D) is a disease characterized by impaired insulin secretion. The Wnt signaling transcription factor Tcf7l2 is to date the T2D-associated gene with the largest effect on disease susceptibility. However, the mechanisms by which TCF7L2 variants affect insulin release from \u3b2-cells are not yet fully understood. By taking advantage of a tcf7l2 zebrafish mutant line, we first show that these animals are characterized by hyperglycemia and impaired islet development. Moreover, we demonstrate that the zebrafish tcf7l2 gene is highly expressed in the exocrine pancreas, suggesting potential bystander effects on \u3b2-cell growth, differentiation and regeneration. Finally, we describe a peculiar vascular phenotype in tcf7l2 mutant larvae, characterized by significant reduction in the average number and diameter of pancreatic islet capillaries. Overall, the zebrafish Tcf7l2 mutant, characterized by hyperglycemia, pancreatic and vascular defects, and reduced regeneration proves to be a suitable model to study the mechanism of action and the pleiotropic effects of Tcf7l2, the most relevant T2D GWAS hit in human populations

Reproducibility of CT-based radiomic features against image resampling and perturbations for tumour and healthy kidney in renal cancer patients.

Computed Tomography (CT) is widely used in oncology for morphological evaluation and diagnosis, commonly through visual assessments, often exploiting semi-automatic tools as well. Well-established automatic methods for quantitative imaging offer the opportunity to enrich the radiologist interpretation with a large number of radiomic features, which need to be highly reproducible to be used reliably in clinical practice. This study investigates feature reproducibility against noise, varying resolutions and segmentations (achieved by perturbing the regions of interest), in a CT dataset with heterogeneous voxel size of 98 renal cell carcinomas (RCCs) and 93 contralateral normal kidneys (CK). In particular, first order (FO) and second order texture features based on both 2D and 3D grey level co-occurrence matrices (GLCMs) were considered. Moreover, this study carries out a comparative analysis of three of the most commonly used interpolation methods, which need to be selected before any resampling procedure. Results showed that the Lanczos interpolation is the most effective at preserving original information in resampling, where the median slice resolution coupled with the native slice spacing allows the best reproducibility, with 94.6% and 87.7% of features, in RCC and CK, respectively. GLCMs show their maximum reproducibility when used at short distances

Awake Fiberoptic Intubation Protocols in the Operating Room for Anticipated Difficult Airway: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Awake fiberoptic intubation is one of the recommended strategies for surgical patients with anticipated difficult airway, especially when concurrent difficult ventilation is expected. We performed the first systematic review of randomized controlled trials assessing different protocols for awake fiberoptic intubation in anticipated difficult airway, including studies investigating elective awake fiberoptic intubation for scheduled surgery; randomized controlled trials comparing different methods for performing awake fiberoptic intubation; and adult patients with anticipated difficult airway. We excluded studies in the nonoperating theater settings, randomized controlled trials comparing awake fiberoptic intubation with other techniques, and studies based on simulation. Primary outcomes were success rate and death; secondary outcomes were major adverse events. Thirty-seven randomized controlled trials evaluating 2045 patients and 4 areas were identified: premedication, local anesthesia, sedation, and ancillary techniques to facilitate awake fiberoptic intubation. Quality of evidence was moderate-low and based on small-sampled randomized controlled trials. Overall, 12 of 2045 intubation failures (0.59%) and 7 of 2045 severe adverse events (0.34%) occurred, with no permanent consequences or death. All evaluated methods to achieve local anesthesia performed similarly well. No differences were observed in success rate with different sedatives. Dexmedetomidine resulted in fewer desaturation episodes compared to propofol and opioids with or without midazolam (relative risk, 0.51 [95% CI, 0.28-0.95]; P = .03); occurrence of desaturation was similar with remifentanil versus propofol, while incidence of apnoea was lower with sevoflurane versus propofol (relative risk, 0.43 [95% CI, 0.22-0.81]; P = .01). A high degree of efficacy and safety was observed with minimal differences among different protocols; dexmedetomidine might offer a better safety profile compared to other sedatives

Large cryptic genomic rearrangements with apparently normal karyotypes detected by array-CGH.

Background: Conventional karyotyping (550 bands resolution) is able to identify chromosomal aberrations >5-10 Mb, which represent a known cause of intellectual disability/developmental delay (ID/DD) and/or multiple congenital anomalies (MCA). Array-Comparative Genomic Hybridization (array-CGH) has increased the diagnostic yield of 15-20%. Results: In a cohort of 700 ID/DD cases with or without MCA, including 15 prenatal diagnoses, we identified a subgroup of seven patients with a normal karyotype and a large complex rearrangement detected by array-CGH (at least 6, and up to 18 Mb). FISH analysis could be performed on six cases and showed that rearrangements were translocation derivatives, indistinguishable from a normal karyotype as they involved a similar band pattern and size. Five were inherited from a parent with a balanced translocation, whereas two were apparently de novo. Genes spanning the rearrangements could be associated with some phenotypic features in three cases (case 3: DOCK8; case 4: GATA3, AKR1C4; case 6: AS/PWS deletion, CHRNA7), and in two, likely disease genes were present (case 5: NR2F2, TP63, IGF1R; case 7: CDON). Three of our cases were prenatal diagnoses with an apparently normal karyotype. Conclusions: Large complex rearrangements of up to 18 Mb, involving chromosomal regions with similar size and band appearance may be overlooked by conventional karyotyping. Array-CGH allows a precise chromosomal diagnosis and recurrence risk definition, further confirming this analysis as a first tier approach to clarify molecular bases of ID/DD and/or MCA. In prenatal tests, array-CGH is confirmed as an important tool to avoid false negative results due to karyotype intrinsic limit of detection

Comparative Safety of Originator and Biosimilar Epoetin Alfa Drugs: An Observational Prospective Multicenter Study

Background: Erythropoiesis-stimulating agents (ESAs) are biological molecules approved for the treatment of anemia associated with chronic renal failure. Biosimilars were licensed for use in Europe in 2007. Aim: This study aimed to compare the safety profile of biosimilars with respect to the reference product in a nephrology setting. Methods: A prospective study was conducted in four Italian regions between 1 October 2013 and 30 June 2015. The study population included patients aged 65 18 years undergoing hemodialysis and treated with epoetins as per the clinical practice of the participating centers. The two comparison cohorts included patients treated with either an originator or a biosimilar epoetin alfa. Each patient was followed up until occurrence of any safety outcome of interest (grouped into three major categories), switch to a different ESA product, transplant or peritoneal dialysis, death, or end of the study period, whichever came first. Results: Overall, 867 subjects were included in the study (originator: N = 423; biosimilar: N = 444). Biosimilar users were older than originator users (median age of 76 vs 64 years, respectively), more frequently affected by arrhythmia (29.3 vs 22.5%), and less frequently candidates for transplantation (3.8 vs 18.2%). Cox-regression analysis showed no increase in risk of safety outcomes in biosimilar users, even after adjusting for confounding factors: 1.0 (95% confidence interval [CI] 0.7\u20131.3) for any outcomes; 1.1 (95% CI 0.7\u20131.8) for problems related to dialysis device; 0.9 (95% CI 0.6\u20131.5) for cardio- and cerebro-vascular conditions; 0.9 (95% CI 0.6\u20131.5) for infections. Conclusion: This study confirms the comparable safety profiles of originator and biosimilar epoetin alfa drugs when used in patients receiving dialysis

The spectrum of intermediate SCN8A-related epilepsy

Objective: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies. Methods: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.Peer reviewe

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Cathepsin K Null Mice Show Reduced Adiposity during the Rapid Accumulation of Fat Stores

Growing evidences indicate that proteases are implicated in adipogenesis and in the onset of obesity. We previously reported that the cysteine protease cathepsin K (ctsk) is overexpressed in the white adipose tissue (WAT) of obese individuals. We herein characterized the WAT and the metabolic phenotype of ctsk deficient animals (ctsk−/−). When the growth rate of ctsk−/− was compared to that of the wild type animals (WT), we could establish a time window (5–8 weeks of age) within which ctsk−/−display significantly lower body weight and WAT size as compared to WT. Such a difference was not observable in older mice. Upon treatment with high fat diet (HFD) for 12 weeks ctsk−/− gained significantly less weight than WT and showed reduced brown adipose tissue, liver mass and a lower percentage of body fat. Plasma triglycerides, cholesterol and leptin were significantly lower in HFD-fed-ctsk−/− as compared to HFD-fed WT animals. Adipocyte lipolysis rates were increased in both young and HFD-fed-ctsk−/−, as compared to WT. Carnitine palmitoyl transferase-1 activity, was higher in mitochondria isolated from the WAT of HFD treated ctsk−/− as compared to WT. Together, these data indicate that ctsk ablation in mice results in reduced body fat content under conditions requiring a rapid accumulation of fat stores. This observation could be partly explained by an increased release and/or utilization of FFA and by an augmented ratio of lipolysis/lipogenesis. These results also demonstrate that under a HFD, ctsk deficiency confers a partial resistance to the development of dyslipidemia

Simulating the Impact on the Local Economy of Alternative Management Scenarios for Natural Areas

This working paper estimates the impact on the local economy of the High Garda Natural Park of alternative management scenarios for the West Garda Regional Forest. The local economy is specialized in tourist services and strongly linked to the tourist presence and their level of expenditure. We wish to investigate the effects of the participative management strategy, which takes into account users preferences and the non-participative strategy, using the SAM multiplier analysis. The local SAM has been constructed considering three sectors: agriculture, tourism and a third aggregate sector including all the other activities. The resident population has been divided into two categories: residents employed in the tourist sector and the remaining resident population. The SAM analysis shows that the accounting representation of the local economy is meaningful and that the participative program, if chosen by the central regional management, would be the most desirable program also at the local level