Galactokinase 1 is the source of elevated galactose-1-phosphate and cerebrosides are modestly reduced in a mouse model of classic galactosemia.

Classic galactosemia (CG) arises from loss-of-function mutations in the Galt gene, which codes for the enzyme galactose-1-phosphate uridylyltransferase (GALT), a central component in galactose metabolism. The neonatal fatality associated with CG can be prevented by galactose dietary restriction, but for decades it has been known that limiting galactose intake is not a cure and patients often have lasting complications. Even on a low-galactose diet, GALT's substrate galactose-1-phosphate (Gal1P) is elevated and one hypothesis is that elevated Gal1P is a driver of pathology. Here we show that Gal1P levels were elevated above wildtype (WT) in Galt mutant mice, while mice doubly mutant for Galt and the gene encoding galactokinase 1 (Galk1) had normal Gal1P levels. This indicates that GALK1 is necessary for the elevated Gal1P in CG. Another hypothesis to explain the pathology is that an inability to metabolize galactose leads to diminished or disrupted galactosylation of proteins or lipids. Our studies reveal that levels of a subset of cerebrosides-galactosylceramide 24:1, sulfatide 24:1, and glucosylceramide 24:1-were modestly decreased compared to WT. In contrast, gangliosides were unaltered. The observed reduction in these 24:1 cerebrosides may be relevant to the clinical pathology of CG, since the cerebroside galactosylceramide is an important structural component of myelin, the 24:1 species is the most abundant in myelin, and irregularities in white matter, of which myelin is a constituent, have been observed in patients with CG. Therefore, impaired cerebroside production may be a contributing factor to the brain damage that is a common clinical feature of the human disease.

Exploring the Impact of In Basket Metrics on the Adoption of a New Electronic Health Record System Among Specialists in a Tertiary Hospital in Alberta: Descriptive Study.

BACKGROUND: Health care organizations implement electronic health record (EHR) systems with the expectation of improved patient care and enhanced provider performance. However, while these technologies hold the potential to create improved care and system efficiencies, they can also lead to unintended negative consequences, such as patient safety issues, communication problems, and provider burnout. OBJECTIVE: This study aims to document metrics related to the In Basket communication hub (time in In Basket per day, time in In Basket per appointment, In Basket messages received per day, and turnaround time) of the EHR system implemented by Alberta Health Services, the province-wide health delivery system called Connect Care (Epic Systems). The objective was to identify how a newly implemented EHR system was used, the timing of its use, and the duration of use specifically related to In Basket activities. METHODS: A descriptive study was conducted. Due to the diversity of specialties, the providers were grouped into medical and surgical based on previous similar studies. The participants were further subgrouped based on their self-reported clinical full-time equivalent (FTE ) measure. This resulted in 3 subgroups for analysis: medical FTE <0.5, medical FTE >0.5, and surgical (all of whom reported FTE >0.5). The analysis was limited to outpatient clinical interactions and explicitly excluded inpatient activities. RESULTS: A total of 72 participants from 19 different specialties enrolled in this study. The providers had, on average, 8.31 appointments per day during the reporting periods. The providers received, on average, 21.93 messages per day, and they spent 7.61 minutes on average in the time in In Basket per day metric and 1.84 minutes on average in the time in In Basket per appointment metric. The time for the providers to mark messages as done (turnaround time) was on average 11.45 days during the reporting period. Although the surgical group had, on average, approximately twice as many appointments per scheduled day, they spent considerably less connected time (based on almost all time metrics) than the medical group. However, the surgical group took much longer than the medical group to mark messages as done (turnaround time). CONCLUSIONS: We observed a range of patterns with no consistent direction. There does not seem to be evidence of a "learning curve," which would have shown a consistent reduction in time spent on the system over time due to familiarity and experience. While this study does not show how the included metrics could be used as predictors of providers' satisfaction or feelings of burnout, the use trends could be used to start discussions about future Canadian studies needed in this area.

Control-IQ Technology Use in Individuals With High Insulin Requirements: Results From the Multicenter Higher-IQ Trial.

BACKGROUND: Control-IQ technology version 1.5 allows for a wider range of weight and total daily insulin (TDI) entry, in addition to other changes to enhance performance for users with high basal rates. This study evaluated the safety and performance of the updated Control-IQ system for users with basal rates >3 units/h and high TDI in a multicenter, single arm, prospective study. METHODS: Adults with type 1 diabetes (T1D) using continuous subcutaneous insulin infusion (CSII) and at least one basal rate over 3 units/h (N = 34, mean age = 39.9 years, 41.2% female, diabetes duration = 21.8 years) used the t:slim X2 insulin pump with Control-IQ technology version 1.5 for 13 weeks. Primary outcome was safety events (severe hypoglycemia and diabetic ketoacidosis (DKA)). Central laboratory hemoglobin A1c (HbA1c) was measured at system initiation and 13 weeks. Participants continued using glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose transport protein 2 (SGLT-2) inhibitors, or other medications for glycemic control and/or weight loss if on a stable dose. RESULTS: All 34 participants completed the study. Fifteen participants used a basal rate >3 units/h for all 24 hours of the day. Nine participants used >300 units TDI on at least one day during the study. There were no severe hypoglycemia or DKA events. Time in range 70-180 mg/dL was 64.8% over the 13 weeks, with 1.0% time <70 mg/dL. Hemoglobin A1c decreased from 7.69% at baseline to 6.87% at 13 weeks (-0.82%, P < .001). CONCLUSIONS: Control-IQ technology version 1.5, with wider range of weight and TDI input and enhancements for users with high insulin requirements, was safe in individuals with T1D in this study.

A Novel INS Mutation in the C-Peptide Region Causing Hyperproinsulinemic Maturity Onset Diabetes of Youth Type 10.

Monogenetic diabetes mellitus (DM) describes a collection of single-gene diseases marked by hyperglycemia presenting in childhood or adulthood and the absence of immunological markers of type 1 DM. Mutations in the human insulin gene INS give rise to two separate clinical syndromes: permanent neonatal DM, type 4 (PNDM4), and maturity-onset diabetes of youth, type 10 (MODY10); the former presents shortly after birth and the latter presents in childhood and adulthood. We describe a 40-year-old man in a kindred with high prevalence of DM who presented with severe hyperglycemia but not ketoacidosis or hypertriglyceridemia. Twelve years after initial presentation, the patient had elevated proinsulin and normal plasma C-peptide when nearly euglycemic on treatment with insulin glargine. A novel INS mutation, Gln65Arg, within the C-peptide region was identified. The INS (p.Gln65Arg) mutation may cause MODY10 by disrupting proinsulin maturation.

A randomized trial of iPad distraction to reduce children's pain and distress during intravenous cannulation in the paediatric emergency department.

OBJECTIVES: We compared the addition of iPad distraction to standard care, versus standard care alone, to manage the pain and distress of intravenous (IV) cannulation. METHODS: Eighty-five children aged 6 to 11 years requiring IV cannulation (without child life services present) were recruited for a randomized controlled trial from a paediatric emergency department. Primary outcomes were self-reported pain (Faces Pain Scale-Revised [FPS-R]) and distress (Observational Scale of Behavioral Distress-Revised [OSBD-R]), analyzed with two-sample t-tests, Mann-Whitney U-tests, and regression analysis. RESULTS: Forty-two children received iPad distraction and 43 standard care; forty (95%) and 35 (81%) received topical anesthesia, respectively (P=0.09). There was no significant difference in procedural pain using an iPad (median [interquartile range]: 2.0 [0.0, 6.0]) in addition to standard care (2.0 [2.0, 6.0]) (P=0.35). There was no significant change from baseline behavioural distress using an iPad (mean ± SD: 0.53 ± 1.19) in addition to standard care (0.43 ± 1.56) (P=0.44). Less total behavioural distress was associated with having prior emergency department visits (odds ratio [95% confidence interval]: -1.90 [-3.37, -0.43]) or being discharged home (-1.78 [-3.04, -0.52]); prior hospitalization was associated with greater distress (1.29 [0.09, 2.49]). Significantly more parents wished to have the same approach in the future in the iPad arm (41 of 41, 100%) compared to standard care (36 of 42, 86%) (P=0.03). CONCLUSIONS: iPad distraction during IV cannulation in school-aged children was not associated with less pain or distress than standard care alone. The effects of iPad distraction may have been blunted by topical anesthetic cream usage. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT02326623.

What are the care needs of families experiencing cardiac arrest?: A survivor and family led scoping review.

AIM: The sudden and unexpected cardiac arrest of a family member can be a grief-filled and life-altering event. Every year many hundreds of thousands of families experience the cardiac arrest of a family member. However, care of the family during the cardiac arrest and afteris poorly understood and incompletely described. This review has been performed with persons with lived experience of cardiac arrest to describe, "What are the needs of families experiencing cardiac arrest?" from the moment of collapse until the outcome is known. METHODS: This review was guided by specific methodological framework and reporting items (PRISMA-ScR) as well as best practices in patient and public involvement in research and reporting (GRIPP2). A search strategy was developed for eight online databases and a grey literature review. Two reviewers independently assessed all articles for inclusion and extracted relevant study information. RESULTS: We included 47 articles examining the experience and care needs of families experiencing cardiac arrest of a family member. Forty one articles were analysed as six represented duplicate data. Ten family care need themes were identified across five domains. The domains and themes transcended cardiac arrest setting, aetiology, family-member age and family composition. The five domains were i) focus on the family member in cardiac arrest, ii) collaboration of the resuscitation team and family, iii) consideration of family context, iv) family post-resuscitation needs, and v) dedicated policies and procedures. We propose a conceptual model of family centred cardiac arrest. CONCLUSION: Our review provides a comprehensive mapping and description of the experience of families and their care needs during the cardiac arrest of a family-member. Furthermore, our review was conducted with co-investigators and collaborators with lived experience of cardiac arrest (survivors and family members of survivors and non-survivors alike). The conceptual framework of family centred cardiac arrest care presented may aid resuscitation scientists and providers in adopting greater family centeredness to their work.

A randomized trial of robot-based distraction to reduce children's distress and pain during intravenous insertion in the emergency department.

OBJECTIVES: Our objectives were to evaluate the effectiveness of humanoid robot-based distraction on reducing distress and pain in children undergoing intravenous insertion. METHODS: A two-arm, open-label randomized controlled trial was conducted April 2017-May 2018, in a pediatric emergency department (ED). A sample of 86 children aged 6-11 years who required intravenous insertion were recruited. Exclusion criteria included hearing/visual impairments, neurocognitive delay, sensory impairment to pain, previous enrollment, and ED clinical staff discretion. Outcome measures included the Observed Scale of Behavioral Distress-Revised (OSBD-R) (distress) and the Faces Pain Scale-Revised (FPS-R) (pain). RESULTS: Of the 86 children recruited (median age 9 years, IQR 7,10); 55% (47/86) were male, 9% (7/82) were premature, 82% (67/82) had a previous ED visit, 31% (25/82) had a previous hospitalization and 78% (64/82) had previous intravenous insertion. Ninety-six percent (78/81) received topical anesthetic prior to intravenous insertion. Total OSBD-R distress score was 1.49 ± 2.36 (standard care) versus 0.78 ± 1.32 (robot) (p < 0.05). FPS-R pain score was 4 (IQR 2,6) (standard care) versus 2 (IQR 0,4) (robot) (p = 0.13). Parental anxiety immediately after the procedure was 36.7 (11.1) (standard care) versus 31.3 (8.5) (robot) (p = 0.04). Parents were more satisfied with pain management in the robotic distraction group (95% vs 72% very satisfied) (p = 0.002). CONCLUSIONS: Humanoid robot-based distraction therapy is associated with a modest positive impact on child distress for pediatric intravenous insertion, but not pain. It can be considered a potential tool in the ED toolkit for procedural pain-associated distress reduction. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02997631.

RéSUMé: OBJECTIFS: Nos objectifs étaient d'évaluer l'efficacité de la distraction robotique humanoïde pour réduire la détresse et la douleur chez les enfants subissant une insertion intraveineuse. MéTHODES: Un essai contrôlé randomisé ouvert à deux bras a été mené d'avril 2017 à mai 2018, dans un service d'urgence pédiatrique. Un échantillon de 86 enfants âgés de 6 à 11 ans ayant besoin d'une insertion intraveineuse a été recruté. Les critères d'exclusion comprenaient des déficiences auditives / visuelles, un retard neurocognitif, une déficience sensorielle de la douleur, une inscription antérieure et la discrétion du personnel clinique des urgences. Les mesures des résultats comprenaient l'échelle d'hétéro-évaluation comportementale (OSBD-R: Observational Scale of Behavioral Distress ­ Revised) (détresse) et l'échelle de visages (FPS-R: Faces Pain Scale-Revised) (douleur). RéSULTATS: Sur les 86 enfants recrutés (âge médian 9 ans, IQR 7,10) ; 55 % (47/86) étaient de sexe masculin, 9 % (7/82) étaient prématurés, 82 % (67/82) avaient une visite antérieure aux urgences, 31 % (25/82) avaient déjà été hospitalisés et 78 % (64/82) avaient déjà été insérés par voie intraveineuse. Quatre-vingt-seize pour cent (78/81) ont reçu une anesthésie topique avant l'insertion intraveineuse. Le score total de détresse OSBD-R était de 1,49 ± 2,36 (soins standard) contre 0,78 ± 1,32 (robot) (p < 0,05). Le score de douleur FPS-R était de 4 (IQR 2,6) (soins standard) contre 2 (IQR 0, 4) (robot) (p=0,13). L'anxiété parentale immédiatement après l'intervention était de 36,7 (11,1) (soins standard) contre 31,3 (8,5) (robot) (p=0,04). Les parents étaient plus satisfaits de la gestion de la douleur dans le groupe de distraction robotique (95 % vs 72 % très satisfaits) (p = 0,002). CONCLUSIONS: La thérapie de distraction à base de robot humanoïde est associée à un impact positif modeste sur la détresse de l'enfant pour l'insertion intraveineuse pédiatrique, mais pas la douleur. Il peut être considéré comme un outil potentiel dans la boîte à outils des Services d'Urgences pour la réduction de la détresse associée à la douleur procédurale.

Characterizing Pain in Children with Acute Gastroenteritis Who Present for Emergency Care.

OBJECTIVE: To characterize the pain experienced by children with acute gastroenteritis (AGE) in the 24 hours before emergency department (ED) presentation. Secondary objectives included characterizing ED pain, discharge recommendations, overall analgesic use, and factors that influenced analgesic use and pain severity. STUDY DESIGN: A prospective cohort was recruited from 2 pediatric EDs (December 2014 to September 2017). Eligibility criteria included <18 years of age, AGE (≥3 episodes of diarrhea or vomiting in the previous 24 hours), and symptom duration <7 days at presentation. RESULTS: We recruited 2136 patients, median age 20.8 months (IQR 10.4, 47.4) and 45.8% (979/2136) female. In the 24 hours before enrollment, most caregivers reported moderate (28.6% [610/2136, 95% CI 26.7-30.5]) or severe (46.2% [986/2136, CI 44.0-48.3]) pain for their child. In the ED, they reported moderate (31.1% [664/2136, 95% CI 29.1-33.1]) or severe ([26.7% [571/2136, 95% CI 24.9-28.7]) pain; analgesia was provided to 21.2% (452/2131). The most common analgesics used in the ED were acetaminophen and ibuprofen. At discharge, these were also most commonly recommended. Factors associated with greater analgesia use in the ED were high pain scores during the index visit, having a primary care physician, earlier presentation to emergency care, fewer diarrheal episodes, presence of fever, and hospitalization at index visit. CONCLUSIONS: Most caregivers of children presenting to the ED with AGE reported moderate or severe pain, both before and during their visit. Future research should focus on the development of effective, safe, and timely pain management plans.

Patient Portal Implementation and Uptake: Qualitative Comparative Case Study.

BACKGROUND: Giving patients access to their health information is a provincial and national goal, and it is critical to the delivery of patient-centered care. With this shift, patient portals have become more prevalent. In Alberta, the Alberta Health Services piloted a portal (MyChart). There was a need to identify factors that promoted the use of this portal. Furthermore, it was imperative to understand why there was variability in uptake within the various clinics that participated in the pilot. OBJECTIVE: This study aims to identify potential factors that could improve the uptake of MyChart from the perspectives of both users and nonusers at pilot sites. We focused on factors that promoted the use of MyChart along with related benefits and barriers to its use, with the intention that this information could be incorporated into the plan for its province-wide implementation. METHODS: A qualitative comparative case study was conducted to determine the feasibility, acceptability, and initial perceptions of users and to identify ways to increase uptake. Semistructured interviews were conducted with 56 participants (27 patients, 21 providers, 4 nonmedical staff, and 4 clinic managers) from 5 clinics. Patients were asked about the impact of MyChart on their health and health care. Providers were asked about the impact on the patient-provider relationship and workflow. Managers were asked about barriers to implementation. The interviews were recorded, transcribed verbatim, and entered into NVivo. A thematic analysis was used to analyze the data. RESULTS: Results from a comparison of factors related to uptake of MyChart in 5 clinics (2 clinics with high uptake, 1 with moderate uptake, 1 with low uptake, and 1 with no uptake) are reported. Some theoretical constructs in our study, such as intention to use, perceived value, similarity (novelty) of the technology, and patient health needs, were similar to findings published by other research teams. We also identified some new factors associated with uptake, including satisfaction or dissatisfaction with the current status quo, performance expectancy, facilitating conditions, behavioral intentions, and use behavior. All these factors had an impact on the level of uptake in each setting and created different opportunities for end users. CONCLUSIONS: There is limited research on factors that influence the uptake of patient portals. We identified some factors that were consistent with those reported by others but also several new factors that were associated with the update of MyChart, a new patient portal, in the clinics we studied. On the basis of our results, we posit that a shared understanding of the technology among patients, clinicians, and managers, along with dissatisfaction with nonportal-based communications, is foundational and must be addressed for patient portals to support improvements in care.

Effects of a Web-Based Patient Portal on Patient Satisfaction and Missed Appointment Rates: Survey Study.

BACKGROUND: Although electronic medical record (EMR)-tethered patient portals are common in other countries, they are still emerging in Canada. OBJECTIVE: We aimed to report user satisfaction and the effects of a patient portal on medical appointment attendance in a Canadian cohort of patients within our publicly funded health care system. METHODS: Two surveys were deployed, via email, at 2 weeks and 6 months following the first recorded patient portal access. Database audits of visit attendance were used to supplement and cross reference survey data. RESULTS: Between January 2016 and July 2018, 4296 patients accessed the patient portal. During the study, 28% (957/3421) consented patient portal users responded to one or more semistructured electronic surveys. Of respondents, 93% (891/957) reported that the patient portal was easy to use, 51% (492/975) reported it saved time when scheduling an appointment, and 40% (382/957) reported that they had to repeat themselves less during appointments. Respondents reported patient portal-related changes in health system use, with 48% (462/957) reporting avoiding a clinic visit and 2.7% (26/957) avoiding an emergency department visit. Across 19,968 visits in clinics where the patient portal was introduced, missed appointments were recorded in 9.5% (858/9021) of non-patient portal user visits, compared with 4.5% (493/9021) for patient portal users, representing a 53% relative reduction in no-show rates. CONCLUSIONS: Early experience with an EMR-tethered patient portal showed strong reports of positive patient experience, a self-reported decrease in health system use, and a measured decrease in missed appointment rates. Implications on the expanded use of patient portals requires more quantitative and qualitative study in Canada.

Digital Technology Distraction for Acute Pain in Children: A Meta-analysis.

CONTEXT: Digital distraction is being integrated into pediatric pain care, but its efficacy is currently unknown. OBJECTIVE: To determine the effect of digital technology distraction on pain and distress in children experiencing acutely painful conditions or procedures. DATA SOURCES: Medline, Embase, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Institute of Electrical and Electronics Engineers Xplore, Ei Compendex, Web of Science, and gray literature sources. STUDY SELECTION: Quantitative studies of digital technology distraction for acutely painful conditions or procedures in children. DATA EXTRACTION: Performed by 1 reviewer with verification. Outcomes were child pain and distress. RESULTS: There were 106 studies (n = 7820) that reported on digital technology distractors (eg, virtual reality and video games) used during common procedures (eg, venipuncture, dental, and burn treatments). No studies reported on painful conditions. For painful procedures, digital distraction resulted in a modest but clinically important reduction in self-reported pain (standardized mean difference [SMD] -0.48; 95% confidence interval [CI] -0.66 to -0.29; 46 randomized controlled trials [RCTs]; n = 3200), observer-reported pain (SMD -0.68; 95% CI -0.91 to -0.45; 17 RCTs; n = 1199), behavioral pain (SMD -0.57; 95% CI -0.94 to -0.19; 19 RCTs; n = 1173), self-reported distress (SMD -0.49; 95% CI -0.70 to -0.27; 19 RCTs; n = 1818), observer-reported distress (SMD -0.47; 95% CI -0.77 to -0.17; 10 RCTs; n = 826), and behavioral distress (SMD -0.35; 95% CI -0.59 to -0.12; 17 RCTs; n = 1264) compared with usual care. LIMITATIONS: Few studies directly compared different distractors or provided subgroup data to inform applicability. CONCLUSIONS: Digital distraction provides modest pain and distress reduction for children undergoing painful procedures; its superiority over nondigital distractors is not established. Context, preferences, and availability should inform the choice of distractor.

Autophagy Ablation in Adipocytes Induces Insulin Resistance and Reveals Roles for Lipid Peroxide and Nrf2 Signaling in Adipose-Liver Crosstalk.

Autophagy is a homeostatic cellular process involved in the degradation of long-lived or damaged cellular components. The role of autophagy in adipogenesis is well recognized, but its role in mature adipocyte function is largely unknown. We show that the autophagy proteins Atg3 and Atg16L1 are required for proper mitochondrial function in mature adipocytes. In contrast to previous studies, we found that post-developmental ablation of autophagy causes peripheral insulin resistance independently of diet or adiposity. Finally, lack of adipocyte autophagy reveals cross talk between fat and liver, mediated by lipid peroxide-induced Nrf2 signaling. Our data reveal a role for autophagy in preventing lipid peroxide formation and its transfer in insulin-sensitive peripheral tissues.

Emergency Physician Use of the Alberta Netcare Portal, a Province-Wide Interoperable Electronic Health Record: Multi-Method Observational Study.

BACKGROUND: The adoption and use of an electronic health record (EHR) can facilitate real-time access to key health information and support improved outcomes. Many Canadian provinces use interoperable EHRs (iEHRs) to facilitate health information exchange, but the clinical use and utility of iEHRs has not been well described. OBJECTIVE: The aim of this study was to describe the use of a provincial iEHR known as the Alberta Netcare Portal (ANP) in 4 urban Alberta emergency departments. The secondary objectives were to characterize the time spent using the respective electronic tools and identify the aspects that were perceived as most useful by emergency department physicians. METHODS: In this study, we have included 4 emergency departments, 2 using paper-based ordering (University of Alberta Hospital [UAH] and Grey Nuns Community Hospital [GNCH]) and 2 using a commercial vendor clinical information system (Peter Lougheed Centre [PLC] and Foothills Medical Centre [FMC]). Structured clinical observations of ANP use and system audit logs analysis were compared at the 4 sites from October 2014 to March 2016. RESULTS: Observers followed 142 physicians for a total of 566 hours over 376 occasions. The median percentage of observed time spent using ANP was 8.5% at UAH (interquartile range, IQR, 3.7%-13.3%), 4.4% at GNCH (IQR 2.4%-4.4%), 4.6% at FMC (IQR 2.4%-7.6%), and 5.1% at PLC (IQR 3.0%-7.7%). By combining administrative and access audit data, the median number of ANP screens (ie, results and reports displayed on a screen) accessed per patient visit were 20 at UAH (IQR 6-67), 9 at GNCH (IQR 4-29), 7 at FMC (IQR 2-18), and 5 at PLC (IQR 2-14). When compared with the structured clinical observations, the statistical analysis of screen access data showed that ANP was used more at UAH than the other sites. CONCLUSIONS: This study shows that the iEHR is well utilized at the 4 sites studied, and the usage patterns implied clinical value. Use of the ANP was highest in a paper-based academic center and lower in the centers using a commercial emergency department clinical information system. More study about the clinical impacts of using iEHRs in the Canadian context including longer term impacts on quality of practice and safety are required.

Towards a 'smart' cost-benefit tool: using machine learning to predict the costs of criminal justice policy interventions.

BACKGROUND: The Manning Cost-Benefit Tool (MCBT) was developed to assist criminal justice policymakers, policing organisations and crime prevention practitioners to assess the benefits of different interventions for reducing crime and to select those strategies that represent the greatest economic return on investment. DISCUSSION: A challenge with the MCBT and other cost-benefit tools is that users need to input, manually, a considerable amount of point-in-time data, a process that is time consuming, relies on subjective expert opinion, and introduces the potential for data-input error. In this paper, we present and discuss a conceptual model for a 'smart' MCBT that utilises machine learning techniques. SUMMARY: We argue that the Smart MCBT outlined in this paper will overcome the shortcomings of existing cost-benefit tools. It does this by reintegrating individual cost-benefit analysis (CBA) projects using a database system that securely stores and de-identifies project data, and redeploys it using a range of machine learning and data science techniques. In addition, the question of what works is respecified by the Smart MCBT tool as a data science pipeline, which serves to enhance CBA and reconfigure the policy making process in the paradigm of open data and data analytics.

Endothelial Cell Autophagy Maintains Shear Stress-Induced Nitric Oxide Generation via Glycolysis-Dependent Purinergic Signaling to Endothelial Nitric Oxide Synthase.

OBJECTIVE: Impaired endothelial cell (EC) autophagy compromises shear stress-induced nitric oxide (NO) generation. We determined the responsible mechanism. APPROACH AND RESULTS: On autophagy compromise in bovine aortic ECs exposed to shear stress, a decrease in glucose uptake and EC glycolysis attenuated ATP production. We hypothesized that decreased glycolysis-dependent purinergic signaling via P2Y1 (P2Y purinoceptor 1) receptors, secondary to impaired autophagy in ECs, prevents shear-induced phosphorylation of eNOS (endothelial nitric oxide synthase) at its positive regulatory site S1117 (p-eNOSS1177) and NO generation. Maneuvers that restore glucose transport and glycolysis (eg, overexpression of GLUT1 [glucose transporter 1]) or purinergic signaling (eg, addition of exogenous ADP) rescue shear-induced p-eNOSS1177 and NO production in ECs with impaired autophagy. Conversely, inhibiting glucose transport via GLUT1 small interfering RNA, blocking purinergic signaling via ectonucleotidase-mediated ATP/ADP degradation (eg, apyrase), or inhibiting P2Y1 receptors using pharmacological (eg, MRS2179 [2'-deoxy-N6-methyladenosine 3',5'-bisphosphate tetrasodium salt]) or genetic (eg, P2Y1-receptor small interfering RNA) procedures inhibit shear-induced p-eNOSS1177 and NO generation in ECs with intact autophagy. Supporting a central role for PKCδT505 (protein kinase C delta T505) in relaying the autophagy-dependent purinergic-mediated signal to eNOS, we find that (1) shear stress-induced activating phosphorylation of PKCδT505 is negated by inhibiting autophagy, (2) shear-induced p-eNOSS1177 and NO generation are restored in autophagy-impaired ECs via pharmacological (eg, bryostatin) or genetic (eg, constitutively active PKCδ) activation of PKCδT505, and (3) pharmacological (eg, rottlerin) and genetic (eg, PKCδ small interfering RNA) PKCδ inhibition prevents shear-induced p-eNOSS1177 and NO generation in ECs with intact autophagy. Key nodes of dysregulation in this pathway on autophagy compromise were revealed in human arterial ECs. CONCLUSIONS: Targeted reactivation of purinergic signaling and PKCδ has strategic potential to restore compromised NO generation in pathologies associated with suppressed EC autophagy.

The Inhibitory G Protein α-Subunit, Gαz, Promotes Type 1 Diabetes-Like Pathophysiology in NOD Mice.

The α-subunit of the heterotrimeric Gz protein, Gαz, promotes ß-cell death and inhibits ß-cell replication when pancreatic islets are challenged by stressors. Thus, we hypothesized that loss of Gαz protein would preserve functional ß-cell mass in the nonobese diabetic (NOD) model, protecting from overt diabetes. We saw that protection from diabetes was robust and durable up to 35 weeks of age in Gαz knockout mice. By 17 weeks of age, Gαz-null NOD mice had significantly higher diabetes-free survival than wild-type littermates. Islets from these mice had reduced markers of proinflammatory immune cell infiltration on both the histological and transcript levels and secreted more insulin in response to glucose. Further analyses of pancreas sections revealed significantly fewer terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive ß-cells in Gαz-null islets despite similar immune infiltration in control mice. Islets from Gαz-null mice also exhibited a higher percentage of Ki-67-positive ß-cells, a measure of proliferation, even in the presence of immune infiltration. Finally, ß-cell-specific Gαz-null mice phenocopy whole-body Gαz-null mice in their protection from developing hyperglycemia after streptozotocin administration, supporting a ß-cell-centric role for Gαz in diabetes pathophysiology. We propose that Gαz plays a key role in ß-cell signaling that becomes dysfunctional in the type 1 diabetes setting, accelerating the death of ß-cells, which promotes further accumulation of immune cells in the pancreatic islets, and inhibiting a restorative proliferative response.

High stakes and high emotions: providing safe care in Canadian emergency departments.

BACKGROUND: The high-paced, unpredictable environment of the emergency department (ED) contributes to errors in patient safety. The ED setting becomes even more challenging when dealing with critically ill patients, particularly with children, where variations in size, weight, and form present practical difficulties in many aspects of care. In this commentary, we will explore the impact of the health care providers' emotional reactions while caring for critically ill patients, and how this can be interpreted and addressed as a patient safety issue. DISCUSSION: ED health care providers encounter high-stakes, high-stress clinical scenarios, such as pediatric cardiac arrest or resuscitation. This health care providers' stress, and at times, distress, and its potential contribution to medical error, is underrepresented in the current medical literature. Most patient safety research is limited to error reporting systems, especially medication-related ones, an approach that ignores the effects of health care provider stress as a source of error, and limits our ability to learn from the event. Ways to mitigate this stress and avoid this type of patient safety concern might include simulation training for rare, high-acuity events, use of pre-determined clinical order sets, and post-event debriefing. CONCLUSION: While there are physiologic and anatomic differences that contribute to patient safety, we believe that they are insufficient to explain the need to address critical life-threatening event-related patient safety issues for both adults and, especially, children. Many factors make patient safety during critical medical events distinct from general patient safety issues, but it is, perhaps, this heightened high-stress, emotional climate that is the most distinct and important part of all. We believe that consideration of this concept is essential when discussing safety improvement in critical medical events.

Hepatocytes Are the Principal Source of Circulating RBP4 in Mice.

RBP4 is produced mainly by hepatocytes. In type 2 diabetes and obesity, circulating RBP4 is increased and may act systemically to cause insulin resistance and glucose intolerance. Observations that adipocyte RBP4 mRNA increases in parallel with circulating RBP4 in these conditions, whereas liver RBP4 mRNA does not, led to a widely held hypothesis that elevated circulating RBP4 is a direct result of increased production by adipocytes. To test this, we generated mice with hepatocyte-specific deletion of RBP4 (liver RBP4 knockout or LRKO mice). Adipose tissue RBP4 expression and secretion remained intact in LRKO mice and increased as expected in the setting of diet-induced insulin resistance. However, circulating RBP4 was undetectable in LRKO mice. We conclude that adipocyte RBP4 is not a significant source of circulating RBP4, even in the setting of insulin resistance. Adipocyte RBP4, therefore, may have a more important autocrine or paracrine function that is confined within the adipose tissue compartment.