Augmenter of liver regeneration enhances the success rate of fetal pancreas transplantation in rodents

Background. Treatment of fetal pancreas (FP) isografts with insulin- like growth factor-I greatly improves the rate of conversion to euglycemia in diabetic rats. Complete knowledge of other factors that may facilitate the engraftment and function of FP in vivo is still embryonic. Augmenter of liver regeneration (ALR) is a newly described polypeptide growth factor found in weanling rat livers. ALR has trophic effects on regenerating liver. We studied the effects of in situ administration of this agent on FP isografts in rats. Methods. Streptozotocin-diabetic Lewis rats (blood glucose >300 mg/dl) received 16 FP isografts transplanted intramuscularly. ALR was delivered from day 1 through day 14, in doses of 40 or 400 ng/kg/d. Animals were followed for 3 months with serial weights and blood glucose monitoring. These animals were compared with those treated with vehicle alone. Results. Of the group treated with ALR at 40 ng/kg/day for 14 days, 89% (eight of nine) were euglycemic (P=0.0003). Of the group treated with ALR at 400 ng/kg/day for 14 days, 88% (seven of eight) were euglycemic (P=0.0007). Of the group treated with vehicle alone, none of the six were euglycemic. Euglycemia is defined here as glucose<200 mg/dl for 3 days. Pathology of the intramuscular transplant site showed patches of islet tissue embedded in fat. These patches demonstrated insulin immunoreactivity. Conclusions. Diabetes was reversed in a significantly greater proportion of FP + ALR-treated recipients than those animals treated with vehicle alone. Local delivery of growth factors my be used as an adjunct to FP transplantation to improve the rate of success. This in situ model may be useful to further evaluate other soluble factors

Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery

Background: Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI. Methods: This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments. Results: A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P=0.02; odds ratio, 0.58 (95% CI, 0.37-0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment. Conclusions: The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897)

Development of Gene Expression Markers of Acute Heat-Light Stress in Reef-Building Corals of the Genus Porites

Coral reefs are declining worldwide due to increased incidence of climate-induced coral bleaching, which will have widespread biodiversity and economic impacts. A simple method to measure the sub-bleaching level of heat-light stress experienced by corals would greatly inform reef management practices by making it possible to assess the distribution of bleaching risks among individual reef sites. Gene expression analysis based on quantitative PCR (qPCR) can be used as a diagnostic tool to determine coral condition in situ. We evaluated the expression of 13 candidate genes during heat-light stress in a common Caribbean coral Porites astreoides, and observed strong and consistent changes in gene expression in two independent experiments. Furthermore, we found that the apparent return to baseline expression levels during a recovery phase was rapid, despite visible signs of colony bleaching. We show that the response to acute heat-light stress in P. astreoides can be monitored by measuring the difference in expression of only two genes: Hsp16 and actin. We demonstrate that this assay discriminates between corals sampled from two field sites experiencing different temperatures. We also show that the assay is applicable to an Indo-Pacific congener, P. lobata, and therefore could potentially be used to diagnose acute heat-light stress on coral reefs worldwide

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Hematopoietic Stem Cell Transplantation as Treatment for Type 1 Diabetes

Type 1 diabetes mellitus is an autoimmune disease associated with B cell derived antibodies and T cell proliferative responses to a variety of islet cell peptides. Near normalization of blood sugar levels as monitored by glycosylated hemoglobin (HgbAlC) diminishes diabetic secondary complications. Insulin, while prolonging life, is not a cure and intensive insulin therapy to control blood sugar is not always practical, especially in lower economic classes or developing countries. Even in developed countries, serious sequela and mortality still occur. 1-5 In America, diabetes remains the most common cause of blindness and renal failure, and the sixth leading cause of death. Hematopoietic stem cell transplantation in early onset diabetes, and in established diabetes when combined with either pancreas or islet cell transplantation, offers hope of curing diabetes by reintroduction of islet cell tolerance

Teprasiran, A Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study

Acute kidney injury (AKI) affects up to 30% of cardiac surgery patients, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA (siRNA) that temporarily inhibits p53-mediated cell death, which underlies AKI. This prospective, multicenter, double-blind, randomized, controlled Phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran vs. placebo (1:1), in reducing the incidence, severity, and duration of AKI following cardiac surgery in high-risk patients. The primary endpoint was proportion of patients who developed AKI determined by serum creatinine (sCr) by post-operative day 5. Other endpoints included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite endpoint of major adverse kidney events at day 90 (MAKE90), including death, renal replacement therapy (RRT) and ≥25% reduction of estimated glomerular filtration rate (eGFR) was assessed. Both sCr and serum cystatin-C (sCys) were used for eGFR assessments. A total of 360 patients were randomized in 41 centers. 341 dosed patients were 73±7.5 years old (mean±SD), 72% were male, and median Euroscore-II (European System for Cardiac Operative Risk Evaluation) was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran vs. 50% for placebo-treated patients, a 12.8% absolute risk reduction (ARR), p=0.02; OR=0.58 (95% CI 0.37 to 0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran vs. 6.7% of placebo-treated patients had Grade 3 AKI; 7% teprasiran vs. 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the MAKE90 composite in the overall population. No safety issues were identified with teprasiran treatment. The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced following teprasiran administration. A Phase 3 study with a MAKE90 primary outcome which has recently completed enrollment was designed based on these findings (NCT03510897). URL: https://clinicaltrials.gov/ Unique Identifier: NCT02610283

Autologous Hematopoietic Stem Cell Transplantation for Type 1 Diabetes

In this review, we present (1) the scientific basis for the use of high-dose immunosuppression followed by autologous peripheral blood hematopoietic stem cell transplantation for newly diagnosed type 1 diabetes (T1D); (2) an update of the clinical and laboratory outcome of 20 patients transplanted at the University Hospital of the Ribeirao Preto Medical School, University of Sao Paulo, Brazil, and followed up to January/2008, including 4 relapses among 19 patients without previous ketoacidosis; (3) a commentary on criticisms to our article that appeared in four articles from the scientific literature; and (4) a discussion of the prospectives for cellular therapy for T1D.CNPqFAPESP FINEPCAPESFAEPAFUNDHER