Insulin demand regulates β cell number via the unfolded protein response

Although stem cell populations mediate regeneration of rapid turnover tissues, such as skin, blood, and gut, a stem cell reservoir has not been identified for some slower turnover tissues, such as the pancreatic islet. Despite lacking identifiable stem cells, murine pancreatic β cell number expands in response to an increase in insulin demand. Lineage tracing shows that new β cells are generated from proliferation of mature, differentiated β cells; however, the mechanism by which these mature cells sense systemic insulin demand and initiate a proliferative response remains unknown. Here, we identified the β cell unfolded protein response (UPR), which senses insulin production, as a regulator of β cell proliferation. Using genetic and physiologic models, we determined that among the population of β cells, those with an active UPR are more likely to proliferate. Moreover, subthreshold endoplasmic reticulum stress (ER stress) drove insulin demand–induced β cell proliferation, through activation of ATF6. We also confirmed that the UPR regulates proliferation of human β cells, suggesting that therapeutic UPR modulation has potential to expand β cell mass in people at risk for diabetes. Together, this work defines a stem cell–independent model of tissue homeostasis, in which differentiated secretory cells use the UPR sensor to adapt organ size to meet demand.     

Deferred consent in a minimal-risk study involving critically ill subarachnoid hemorrhage patients

INTRODUCTION:

Alterations from first-party and surrogate decision-maker consent can enhance the feasibility of research involving critically ill patients.

OBJECTIVE:

To describe the use of a deferred-consent model to enable participation of critically ill patients in a minimal-risk biomarker study.

METHODS:

A prospective observational study was conducted in which serum biomarker samples were collected three times daily over the first 14 days following aneurysmal subarachnoid hemorrhage. Sample collection was initiated on intensive care unit admission and consent was obtained when research personnel could approach the patient or the patient’s surrogate decision maker.

RESULTS:

Twenty-seven patients were eligible for the study, of whom only five were capable of providing informed consent. Full consent was obtained for 21 (78%) patients through self- (n=4) and surrogate (n=17) consent. Partial consent or refusal (only permitting the collection of blood samples as a part of routine care or use of data) occurred in three patients. Among the 22 consents sought from surrogates, three (11%) refused participation. The refusals included the sickest patients in the cohort. Once consent was provided, no patient or surrogate withdrew consent before study completion.

DISCUSSION:

Use of a deferred consent model enabled participation of critically ill patients in a minimal-risk biomarker study with no withdrawals.

CONCLUSIONS:

Further research and enhanced awareness of the potential utility of hybrid models, including deferred consent in addition to patient or surrogate consent, in the conduct of low-risk and minimally interventional time-sensitive studies of critically ill patients are required.     

Angiographic identification of extrahepatic perfusion after hepatic arterial pump placement: implications for surgical prevention

Background

Hepatic arterial infusion (HAI) chemotherapy is an effective treatment for patients with liver malignancy. Extrahepatic perfusion (EHP) after HAI pump placement requires correction prior to starting chemotherapy. The aim of this study was to define the origin of arterial branches causing EHP in order to determine if alterations in surgical technique during pump placement might prevent EHP.

Methods

A prospectively maintained, single-centre HAI database was reviewed for all patients (2008–2011) with EHP. The origin of arterial branches causing EHP was classified anatomically and patient outcomes were analysed.

Results

Of the 327 patients with pumps implanted, 24 evidenced EHP. The arterial branch responsible for EHP perfused the duodenum, pancreas and/or stomach. The branch responsible for EHP arose from the proper hepatic artery (PHA), 1^st, 2^nd, or 3^rd order hepatic artery branches in 7, 10, 5 and 2 patients, respectively. The majority of branches beyond the PHA causing EHP (13/17) originated from the right hepatic artery. In 18 patients, aberrant branches were successfully treated with embolization.

Conclusion

These findings provide the anatomic basis for prevention of up to one-third of the cases of EHP intra-operatively, decreasing the number of patients who will require additional procedures for correction of EHP post-operatively.     

Laboratory Biosafety: Benchmarking public health pain management practices during school immunizations

BackgroundPain and fear during immunizations can affect children and their future behaviour toward immunization. These negative experiences can be amplified when children receive vaccines as part of school-based immunization programs, where parental or tutor supports are missing. In 2015, HELPinKIDS&ADULTS, a Canadian network of experts, published a clinical practice guideline (CPG) on the management of pain and fear during immunization. This guideline has been endorsed by international, national and provincial organizations. However, the level of integration and implementation of the CPG into local and community immunization programs such as school-based immunization clinics is unclear.MethodsAn investigation whether public health units in Ontario integrated and implemented the pain and fear interventions recommended by the CPG into school-based immunization policies and practices was concluded.ResultsThe study shows that the majority of public health units do have pain and fear policies and procedures in place, but interventions are not integrated in a consistent and formal manner, leading to suboptimal uptake of interventions during immunizations at school.ConclusionFor pain interventions to be applied with sufficient fidelity and in enough individuals to have a meaningful effect, organizational leaders need to create directives and procedures that support implementation in a systematic and accountable manner.