High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control

To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR’s mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.Trial Registration: Clinicaltrials.gov NCT01073020.

Circulating miRNA in Patients Undergoing Total Pancreatectomy and Islet Autotransplantation

Circulating microRNAs (miRNAs) can be biomarkers for diagnosis and progression of several pathophysiological conditions. In a cohort undergoing total pancreatectomy with islet autotransplantation (TPIAT) from the multicenter Prospective Observational Study of TPIAT (POST), we investigated associations between a panel of circulating miRNAs (hsa-miR-375, hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-216a-5p, hsa-miR-320d, hsa-miR-200c, hsa-miR-125b, hsa-miR-7-5p, hsa-miR-221-3p, hsa-miR-122-5p) and patient, disease and islet-isolation characteristics. Plasma samples ( n = 139) were collected before TPIAT and miRNA levels were measured by RTPCR. Disease duration, prior surgery, and pre-surgical diabetes were not associated with circulating miRNAs. Levels of hsa-miR-29b-3p ( P = 0.03), hsa-miR-148a-3p ( P = 0.04) and hsa-miR-221-3p ( P = 0.01) were lower in those with genetic risk factors. Levels of hsa-miR-148a-3p ( P = 0.04) and hsa-miR-7-5p ( P = 0.04) were elevated in toxic/metabolic disease. Participants with exocrine insufficiency had lower hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-320d, hsa-miR-221-3p ( P < 0.01) and hsa-miR-375, hsa-miR-200c-3p, and hsa-miR-125b-5p ( P < 0.05). Four miRNAs were associated with fasting C-peptide before TPIAT (hsa-miR-29b-3p, r = 0.18; hsa-miR-148a-3p, r = 0.21; hsa-miR-320d, r = 0.19; and hsa-miR-221-3p, r = 0.21; all P < 0.05), while hsa-miR-29b-3p was inversely associated with post-isolation islet equivalents/kg and islet number/kg ( r = −0.20, P = 0.02). Also, hsa-miR-200c ( r = 0.18, P = 0.03) and hsa-miR-221-3p ( r = 0.19, P = 0.03) were associated with islet graft tissue volume. Further investigation is needed to determine the predictive potential of these miRNAs for assessing islet autotransplant outcomes.

Nature of dispensing errors in selected hospitals providing free healthcare: A multi-center study in Sri Lanka

Background Dispensing errors may result in patient harm. Dispensing errors are preventable if we knew its nature, but only very little information is available on these errors that occur in limited resourced settings where healthcare is provided free of charge. Therefore, the purpose of this study was to determine the types and prevalence of dispensing errors in selected hospitals in Sri Lanka. Methods A prospective, cross sectional and multi-centered study (in one tertiary care and two secondary care hospitals) was conducted among 420 patients attending medical, surgical, diabetes and pediatric clinics of study hospitals, proportioned according to population size, and selected through a systematic random sampling. A prescription audit was conducted. Dispensing errors were categorized as content, labelling, documentation, concomitant, and other errors based on definitions developed in-house. The total number of dispensing errors identified was used as the denominator for calculating percentages. Results A total of 420 prescriptions (1849 medicines) were analyzed (Hospital-01, 248 prescriptions with 1010 medicines; Hospital-02, 84 prescriptions with 400 medicines; Hospital-03, 88 prescriptions with 439 medicines), where 16,689 dispensing errors were detected. However, most frequent were labelling errors (63.1%). There were 4.9% content errors, 21% concomitant errors, 10.6% documentation errors, and 0.4% of other errors. No omissions or deteriorated medicines were detected. Conclusions Dispensing errors happen in Sri Lankan hospitals that operate with limited resources and provide free healthcare to citizens. However, most were labeling errors with little chance of immediate harm. Content errors were minimal. More emphasis on error-proofing the dispensing process could improve medication safety in these hospitals.

Advantages of Porous TiNi Materials for Dental Implants in Diabetes Mellitus Patients

Structural changes in osseous tissue under surgically modeled diabetes mellitus in rabbits are studied experimentally with the focus on macro- and microelemental composition. The effect of growth factors on regeneration of mucosa is analyzed in Brattlebororats with inherited diabetes insipidus. Larger animals, dogs, were used to study the morphology of osseointegration with various implant materials under experimental surgical diabetes mellitus. The advantages of porous implants over other materials are shown.

Isolation of Human Islets for Autologous Islet Transplantation in Children and Adolescents with Chronic Pancreatitis

Chronic pancreatitis is an inflammatory disease of the pancreas that causes permanent changes in the function and structure of the pancreas. It is most commonly a complication of cystic fibrosis or due to a genetic predisposition. Chronic pancreatitis generally presents symptomatically as recurrent abdominal pain, which becomes persistent over time. The pain eventually becomes disabling. Once specific medical treatments and endoscopic interventions are no longer efficacious, total pancreatectomy is the alternative of choice for helping the patient achieve pain control. While daily administrations of digestive enzymes cannot be avoided, insulin-dependent diabetes can be prevented by transplanting the isolated pancreatic islets back to the patient. The greater the number of islets infused, the greater the chance to prevent or at least control the effects of surgical diabetes. We present here a technical approach for the isolation and preservation of the islets proven to be efficient to obtain high numbers of islets, favoring the successful treatment of young patients.