Effectiveness of diabetes self-management education via a smartphone application in insulin treated type 2 diabetes patients - design of a randomised controlled trial ('TRIGGER study').

Health care providers aim to stimulate self-management in type 2 diabetes (T2DM) patients. However, they have a limited number of patient contacts to do this. With the growing number of T2DM patients, innovative and cost-effective interventions to promote self-management are needed. We aim to evaluate the effectiveness of diabetes self-management education via a smartphone app in T2DM patients on insulin therapy

Proteins in stool as biomarkers for non-invasive detection of colorectal adenomas with high risk of progression

Screening to detect colorectal cancer (CRC) in an early or premalignant state is an effective method to reduce CRC mortality rates. Current stool-based screening tests, e.g. fecal immunochemical test (FIT), have a suboptimal sensitivity for colorectal adenomas and difficulty distinguishing adenomas at high risk of progressing to cancer from those at lower risk. We aimed to identify stool protein biomarker panels that can be used for the early detection of high-risk adenomas and CRC. Proteomics data (LC–MS/MS) were collected on stool samples from adenoma (n = 71) and CRC patients (n = 81) as well as controls (n = 129). Colorectal adenoma tissue samples were characterized by low-coverage whole-genome sequencing to determine their risk of progression based on specific DNA copy number changes. Proteomics data were used for logistic regression modeling to establish protein biomarker panels. In total, 15 of the adenomas (15.8%) were defined as high risk of progressing to cancer. A protein panel, consisting of haptoglobin (Hp), LAMP1, SYNE2, and ANXA6, was identified for the detection of high-risk adenomas (sensitivity of 53% at specificity of 95%). Two panels, one consisting of Hp and LRG1 and one of Hp, LRG1, RBP4, and FN1, were identified for high-risk adenomas and CRCs detection (sensitivity of 66% and 62%, respectively, at specificity of 95%). Validation of Hp as a biomarker for high-risk adenomas and CRCs was performed using an antibody-based assay in FIT samples from a subset of individuals from the discovery series (n = 158) and an independent validation series (n = 795). Hp protein was significantly more abundant in high-risk adenoma FIT samples compared to controls in the discovery (p = 0.036) and the validation series (p = 9e-5). We conclude that Hp, LAMP1, SYNE2, LRG1, RBP4, FN1, and ANXA6 may be of value as stool biomarkers for early detection of high-risk adenomas and CRCs

Identification of key genes for carcinogenic pathways associated with colorectal adenoma-to-carcinoma progression

Colorectal adenomas form a biologically and clinically distinct intermediate stage in development of colorectal cancer (CRC) from normal colon epithelium. Only 5% of adenomas progress into adenocarcinomas, indicating that malignant transformation requires other biological alterations than those involved in adenoma formation. The present study aimed to explore which cancer-related biological processes are affected during colorectal adenoma-to-carcinoma progression and to identify key genes within these pathways that can serve as tumor markers for malignant transformation. The activity of 12 cancer-related biological processes was compared between 37 colorectal adenomas and 31 adenocarcinomas, using the pathway analysis tool Gene Set Enrichment Analysis. Expression of six gene sets was significantly increased in CRCs compared to adenomas, representing chromosomal instability, proliferation, differentiation, invasion, stroma activation, and angiogenesis. In addition, 18 key genes were identified for these processes based on their significantly increased expression levels. For AURKA and PDGFRB, increased mRNA expression levels were verified at the protein level by immunohistochemical analysis of a series of adenomas and CRCs. This study revealed cancer-related biological processes whose activities are increased during malignant transformation and identified key genes which may be used as tumor markers to improve molecular characterization of colorectal tumors

Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10−5 and c.2702T > G [p.V901G], MAF 2.51 × 10−3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05–13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10−8), viability (P = 8.9 × 10−7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10−4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10−5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia

Effectiveness of diabetes self-management education via a smartphone application in insulin treated type 2 diabetes patients - Design of a randomised controlled trial ('TRIGGER study')

Background: Health care providers aim to stimulate self-management in type 2 diabetes (T2DM) patients. However, they have a limited number of patient contacts to do this. With the growing number of T2DM patients, innovative and cost-effective interventions to promote self-management are needed. We aim to evaluate the effectiveness of diabetes self-management education via a smartphone app in T2DM patients on insulin therapy. Methods: Non-blinded two-arm multi-centre randomised controlled superiority trial with parallel-groups and equal randomisation ('TRIGGER study'). Eligible patients are 40-70 years, on insulin therapy since at least 3 months, with HbA1c > 53 mmol/mol (> 7%). In total 228 patients will be recruited. The intervention group (n = 114) will receive diabetes self-management education via a smartphone app to trigger diabetes self-management: unidirectional text messages, free of charge, evidence and psychological theory based, with regard to dietary habits, physical activity, hypoglycaemia and glucose variability. Patients choose their preferred frequency (two to six times per week), topics (two or three additionally to hypoglycaemia, which is an obligatory topic), and duration (6 or 9 months). The control group (n = 114) will receive care-as-usual. The primary study endpoint is the HbA1c level after a follow-up of 6 months. The percentage of patients who achieve an HbA1c level ≤ 53 mmol/mol (≤7%) without hypoglycaemia (plasma glucose < 3.5 mmol/L (< 63 mg/dL)) is a co-primary outcome. Secondary outcomes are body mass index, waist circumference, insulin dose, lipid profile, blood pressure, number of hypoglycaemic events, glycaemic variability, self-management (SDSCA), food habits (FFQ), physical activity (IPAQ), health status (EQ-5D-5 L, SF36), diabetes-dependent quality of life (ADDQoL), diabetes treatment satisfaction (DTSQ), satisfaction with the app, the cost-effectiveness of the intervention after 3 months, and sustainability of the intervention effect (3 months extra follow-up in intervention group to compare prolonged to discontinued use of the app). We will use the intention-to-treat principle to analyse data. Discussion: Innovative solutions are needed to improve the (cost-) effectiveness of self-management for the increasing number of T2DM patients. This trial will provide evidence on the effectiveness of a newly developed smartphone app, designed to trigger diabetes self-management. Trial registration: Dutch Trial Register NTR5515, registration date: 18 November 2015 (prospectively registered)

Effectiveness of diabetes self-management education via a smartphone application in insulin treated type 2 diabetes patients - design of a randomised controlled trial ('TRIGGER study').

Health care providers aim to stimulate self-management in type 2 diabetes (T2DM) patients. However, they have a limited number of patient contacts to do this. With the growing number of T2DM patients, innovative and cost-effective interventions to promote self-management are needed. We aim to evaluate the effectiveness of diabetes self-management education via a smartphone app in T2DM patients on insulin therapy

Can a biomarker triage test reduce colonoscopy burden in fecal immunochemical test screening?

Aim: To assess the potential of biomarker triage testing (BM-TT) in the Dutch colorectal cancer (CRC) screening program. Materials & methods: Using the Adenoma and Serrated pathway to Colorectal CAncer model, we simulated fecal immunochemical test (FIT)47-screening and various FIT plus BM-TT screening scenarios in which only individuals with both a positive FIT and BM-TT are referred to colonoscopy. Results: Adding a low polyp sensitivity BM-TT to FIT-screening reduced colonoscopy burden (89-100%) while increasing CRC mortality (27-41%) compared with FIT47-screening only. The FIT plus high polyp sensitivity BM-TT scenarios also decreased colonoscopy burden (71-89%) while hardly affecting CRC mortality (FIT47 0-4% increase, FIT15 2-7% decrease). Conclusion: Adding a BM-TT to FIT-screening considerably reduces colonoscopy burden, but could also decrease screening effectiveness. Combining FIT15 with a high polyp sensitivity BM-TT seems most promising

Peptide-mediated ‘miniprep’ isolation of extracellular vesicles is suitable for high-throughput proteomics

Extracellular vesicles (EVs) are cell-secreted membrane vesicles enclosed by a lipid bilayer derived from endosomes or from the plasma membrane. Since EVs are released into body fluids, and their cargo includes tissue-specific and disease-related molecules, they represent a rich source for disease biomarkers. However, standard ultracentrifugation methods for EV isolation are laborious, time-consuming, and require high inputs. Ghosh and co-workers recently described an isolation method utilizing Heat Shock Protein (HSP)-binding peptide Vn96 to aggregate HSP-decorated EVs, which can be performed at small ‘miniprep’ scale. Based on microscopic, immunoblot, and RNA sequencing analyses this method compared well with ultracentrifugation-mediated EV isolation, but a detailed proteomic comparison was lacking. Therefore, we compared both methods using label-free proteomics of replicate EV isolations from HT-29 cell-conditioned medium. Despite a 30-fold different scale (ultracentrifugation: 60 ml/Vn96-mediated aggregation: 2 ml) both methods yielded comparable numbers of identified proteins (3115/3085), with similar reproducibility of identification (72.5%/75.5%) and spectral count-based quantification (average CV: 31%/27%). EV fractions obtained with either method contained established EV markers and proteins linked to vesicle-related gene ontologies. Thus, Vn96 peptide-mediated aggregation is an advantageous, simple and rapid approach for EV isolation from small biological samples, enabling high-throughput analysis in a biomarker discovery setting

A fully covered self-expandable metal stent with antimigration features for benign biliary strictures: a prospective, multicenter cohort study

BACKGROUND: Self-expandable metal stents (SEMSs) are increasingly used for the treatment of benign biliary strictures (BBSs). A new fully covered SEMS (FCSEMS) with flared ends and high conformability was designed to prevent migration of the stent. OBJECTIVE: To evaluate the efficacy of a novel FCSEMS with antimigration features. DESIGN: Prospective cohort study. SETTING: Five hospitals in the Netherlands and Belgium. PATIENTS: Consecutive patients with BBS. INTERVENTION: FCSEMS placement for 3 months. MAIN OUTCOME MEASUREMENTS: Initial and long term clinical success, stent migration rate and safety. RESULTS: Thirty-eight patients (24 men; mean age, 53 ± 16 years) were included. Stent placement was technically successful in 37 patients (97%). Two patients died of an unrelated cause before stent removal, and no data on these patients were available on stricture resolution. Initial clinical success was achieved in 28 of 35 patients (80%). During follow-up after stent removal, a symptomatic recurrent stricture developed in 6 of 28 patients (21%). Overall, the long-term clinical success rate was 63% (22 of 35 patients). Stent migration occurred in 11 of 35 patients (31%), including 5 symptomatic (14%) and 6 asymptomatic (17%) migrations. In total, 11 serious adverse events occurred in 10 patients (29%), with cholangitis (n = 5) being most common. LIMITATIONS: Nonrandomized study design. CONCLUSIONS: Good initial clinical success was achieved after placement of this novel FCSEMS, but stricture recurrence was in the upper range compared with other FCSEMSs. The antimigration design could not prevent migration in a significant number of patients with a persisting stricture.status: publishe

A fully covered self-expandable metal stent with antimigration features for benign biliary strictures : a prospective, multicenter cohort study

BACKGROUND: Self-expandable metal stents (SEMSs) are increasingly used for the treatment of benign biliary strictures (BBSs). A new fully covered SEMS (FCSEMS) with flared ends and high conformability was designed to prevent migration of the stent. OBJECTIVE: To evaluate the efficacy of a novel FCSEMS with antimigration features. DESIGN: Prospective cohort study. SETTING: Five hospitals in the Netherlands and Belgium. PATIENTS: Consecutive patients with BBS. INTERVENTION: FCSEMS placement for 3 months. MAIN OUTCOME MEASUREMENTS: Initial and long term clinical success, stent migration rate and safety. RESULTS: Thirty-eight patients (24 men; mean age, 53 ± 16 years) were included. Stent placement was technically successful in 37 patients (97%). Two patients died of an unrelated cause before stent removal, and no data on these patients were available on stricture resolution. Initial clinical success was achieved in 28 of 35 patients (80%). During follow-up after stent removal, a symptomatic recurrent stricture developed in 6 of 28 patients (21%). Overall, the long-term clinical success rate was 63% (22 of 35 patients). Stent migration occurred in 11 of 35 patients (31%), including 5 symptomatic (14%) and 6 asymptomatic (17%) migrations. In total, 11 serious adverse events occurred in 10 patients (29%), with cholangitis (n = 5) being most common. LIMITATIONS: Nonrandomized study design. CONCLUSIONS: Good initial clinical success was achieved after placement of this novel FCSEMS, but stricture recurrence was in the upper range compared with other FCSEMSs. The antimigration design could not prevent migration in a significant number of patients with a persisting stricture