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.

Efficacy and safety of autologous whole blood clot in diabetic foot ulcers: a randomised controlled trial.

OBJECTIVE: Diabetic foot ulcers (DFUs) present a significant global health challenge, resulting in high morbidity and economic costs. Current available treatments often fail to achieve satisfactory healing rates, highlighting the need for novel therapies. This study evaluated the safety and efficacy of a novel autologous whole blood clot (AWBC)-a blood-based, biodegradable provisional matrix-in conjunction with standard of care (SoC) when compared to SoC alone in the treatment of hard-to-heal DFUs. METHOD: A multicentre, prospective, blinded assessor, randomised controlled trial was conducted at 16 sites across the US, South Africa and Turkey. A cohort of patients with hard-to-heal DFUs was enrolled and randomised to either the AWBC group or the control group. The primary endpoint was complete wound closure at 12 weeks, while secondary endpoints included time to heal and percentage area reduction (PAR) at four and eight weeks. Data were analysed using both intention-to-treat (ITT) and per-protocol (PP) populations. RESULTS: The cohort included 119 patients. AWBC treatment resulted in a significantly higher healing rate compared to the control in both ITT (41% versus 15%, respectively; p=0.002) and PP populations (51% versus 18%, respectively; p=0.0075). AWBC treatment also resulted in a shorter mean time to heal and higher durability of wound closure. Safety analysis showed a similar incidence of adverse events (AEs) between groups, with no device-related AEs. CONCLUSION: The AWBC system, by modulating the wound microenvironment and providing a functional extracellular matrix, offered a promising new approach to treating hard-to-heal DFUs, demonstrating superior healing outcomes compared to SoC alone in this study.

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.

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.

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.

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.

Liver retinol transporter and receptor for serum retinol-binding protein (RBP4).

Vitamin A (retinol) is absorbed in the small intestine, stored in liver, and secreted into circulation bound to serum retinol-binding protein (RBP4). Circulating retinol may be taken up by extrahepatic tissues or recycled back to liver multiple times before it is finally metabolized or degraded. Liver exhibits high affinity binding sites for RBP4, but specific receptors have not been identified. The only known high affinity receptor for RBP4, Stra6, is not expressed in the liver. Here we report discovery of RBP4 receptor-2 (RBPR2), a novel retinol transporter expressed primarily in liver and intestine and induced in adipose tissue of obese mice. RBPR2 is structurally related to Stra6 and highly conserved in vertebrates, including humans. Expression of RBPR2 in cultured cells confers high affinity RBP4 binding and retinol transport, and RBPR2 knockdown reduces RBP4 binding/retinol transport. RBPR2 expression is suppressed by retinol and retinoic acid and correlates inversely with liver retinol stores in vivo. We conclude that RBPR2 is a novel retinol transporter that potentially regulates retinol homeostasis in liver and other tissues. In addition, expression of RBPR2 in liver and fat suggests a possible role in mediating established metabolic actions of RBP4 in those tissues.

Mitochondrial function/dysfunction in white adipose tissue.

The role of mitochondria in white adipocytes has long been neglected due in part to their lower abundance in these cells. However, accumulating evidence suggests that mitochondria are vital for maintaining metabolic homeostasis in white adipocytes because of their involvement in adipogenesis, fatty acid synthesis and esterification, branched-chain amino acid catabolism and lipolysis. It is therefore not surprising that white adipose tissue function can be perturbed by altering mitochondrial components or oxidative capacity. Moreover, studies in humans and animals with significantly altered fat mass, such as in obesity or lipoatrophy, indicate that impaired mitochondrial function in adipocytes may be linked directly to the development of metabolic diseases such as diabetes and insulin resistance. However, recent studies that specifically targeted mitochondrial function in adipocytes indicated dissociation between impaired mitochondrial oxidative capacity and systemic insulin sensitivity.

Impairment of autophagy in endothelial cells prevents shear-stress-induced increases in nitric oxide bioavailability.

Autophagy is a lysosomal catabolic process by which cells degrade or recycle their contents to maintain cellular homeostasis, adapt to stress, and respond to disease. Impairment of autophagy in endothelial cells studied under static conditions results in oxidant stress and impaired nitric oxide (NO) bioavailability. We tested the hypothesis that vascular autophagy is also important for induction of NO production caused by exposure of endothelial cells to shear stress (i.e., 3 h × ≈20 dyn/cm(2)). Atg3 is a requisite autophagy pathway mediator. Control cells treated with non-targeting control siRNA showed increased autophagy, reactive oxygen species (ROS) production, endothelial NO synthase (eNOS) phosphorylation, and NO production upon exposure to shear stress (p < 0.05 for all). In contrast, cells with >85% knockdown of Atg3 protein expression (via Atg3 siRNA) exhibited a profound impairment of eNOS phosphorylation, and were incapable of increasing NO in response to shear stress. Moreover, ROS accumulation and inflammatory cytokine production (MCP-1 and IL-8) were exaggerated (all p < 0.05) in response to shear stress. These findings reveal that autophagy not only plays a critical role in maintaining NO bioavailability, but may also be a key regulator of oxidant-antioxidant balance and inflammatory-anti-inflammatory balance that ultimately regulate endothelial cell responses to shear stress.

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.

Incidence, Recognition, and Follow-up of Laboratory Evidence of Acute Kidney Injury in Primary Care Practices: Analysis of 93,259 Creatinine Results.

BACKGROUND: Community acquired acute kidney injury (CA-acute kidney injury) is under-recognized in the outpatient setting and is associated with adverse outcomes. METHODS: We analyzed the incidence of CA-acute kidney injury in an academic primary care practice and community health center and assessed recognition/followup as determined by repeat creatinine measurement (loop-closed). We reviewed 93,259 specimens for 36,593 unique patients from 1/1/2018 through 12/31/2021. RESULTS: There were 220 unique patients with CA-acute kidney injury defined as a >75% increase in creatinine from baseline; incidence: 150/100,000 (0.15% per year). 137 patients (62.3%) had repeat serum creatinine performed within 30 days. Chart reviews of the 83 (37.72%) patients with open loops found there was no follow-up creatinine ordered in 69/83 (83.1%) patients. Mean baseline creatinine was higher and eGFR was lower in the loop-closed group (0.92±0.4mg/dl; 84.45±27.49mls/min) versus (0.63±0.34mg/dl; 105.19±26.67mls/min) in the loop-open group (p<.0001). Preexisting chronic kidney disease was more prevalent in loop-closed patients (35/137; 25.6%) compared to those with open-loops (3/83; 3.6%). Patients with baseline chronic kidney disease were more likely to have the loop-closed. Progression to new chronic kidney disease was common among CA-acute kidney injury patients, occurring in 23.94% of loop-open and 17.50% of loop-closed patients. New baseline eGFR was lower in all groups. CONCLUSIONS: Clinicians frequently overlooked a clinically significant change in eGFR, especially when the baseline creatinine and incident creatinine levels were in the "normal" range.

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.

Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass.

Intra-abdominal fat is associated with insulin resistance and cardiovascular risk. Levels of serum retinol-binding protein (RBP4), secreted by fat and liver cells, are increased in obesity and type 2 diabetes (T2D). Here we report that, in 196 subjects, RBP4 is preferentially expressed in visceral (Vis) versus subcutaneous (SC) fat. Vis fat RBP4 mRNA was increased approximately 60-fold and 12-fold in Vis and SC obese subjects respectively versus lean subjects, and approximately 2-fold with impaired glucose tolerance/T2D subjects versus normoglycemic subjects. In obese subjects, serum RBP4 was increased 2- to 3-fold, and serum transthyretin, which stabilizes RBP4 in the circulation, was increased 35%. Serum RBP4 correlated positively with adipose RBP4 mRNA and intra-abdominal fat mass and inversely with insulin sensitivity, independently of age, gender, and body mass index. RBP4 mRNA correlated inversely with GLUT4 mRNA in Vis fat and positively with adipocyte size in both depots. RBP4 levels are therefore linked to Vis adiposity, and Vis fat may be a major source of RBP4 in insulin-resistant states.

Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: results from the Hypertrophy, Insulin, Glucose, and Electrolytes (HINGE) trial.

BACKGROUND: Patients undergoing aortic valve replacement for critical aortic stenosis often have significant left ventricular hypertrophy. Left ventricular hypertrophy has been identified as an independent predictor of poor outcome after aortic valve replacement as a result of a combination of maladaptive myocardial changes and inadequate myocardial protection at the time of surgery. Glucose-insulin-potassium (GIK) is a potentially useful adjunct to myocardial protection. This study was designed to evaluate the effects of GIK infusion in patients undergoing aortic valve replacement surgery. METHODS AND RESULTS: Patients undergoing aortic valve replacement for aortic stenosis with evidence of left ventricular hypertrophy were randomly assigned to GIK or placebo. The trial was double-blind and conducted at a single center. The primary outcome was the incidence of low cardiac output syndrome. Left ventricular biopsies were analyzed to assess changes in 5' adenosine monophosphate-activated protein kinase (AMPK), Akt phosphorylation, and protein O-linked ß-N-acetylglucosamination (O-GlcNAcylation). Over a 4-year period, 217 patients were randomized (107 control, 110 GIK). GIK treatment was associated with a significant reduction in the incidence of low cardiac output state (odds ratio, 0.22; 95% confidence interval, 0.10 to 0.47; P=0.0001) and a significant reduction in inotrope use 6 to 12 hours postoperatively (odds ratio, 0.30; 95% confidence interval, 0.15 to 0.60; P=0.0007). These changes were associated with a substantial increase in AMPK and Akt phosphorylation and a significant increase in the O-GlcNAcylation of selected protein bands. CONCLUSIONS: Perioperative treatment with GIK was associated with a significant reduction in the incidence of low cardiac output state and the need for inotropic support. This benefit was associated with increased signaling protein phosphorylation and O-GlcNAcylation. Multicenter studies and late follow-up will determine whether routine use of GIK improves patient prognosis.

The combination of the novel glycolysis inhibitor 3-BrOP and rapamycin is effective against neuroblastoma.

Children with high-risk and recurrent neuroblastoma have poor survival rates, and novel therapies are needed. Many cancer cells have been found to preferentially employ the glycolytic pathway for energy generation, even in the presence of oxygen. 3-BrOP is a novel inhibitor of glycolysis, and has demonstrated efficacy against a wide range of tumor types. To determine whether human neuroblastoma cells are susceptible to glycolysis inhibition, we evaluated the role of 3-BrOP in neuroblastoma model systems. Neuroblastoma tumor cell lines demonstrated high rates of lactate accumulation and low rates of oxygen consumption, suggesting a potential susceptibility to inhibitors of glycolysis. In all ten human tested neuroblastoma tumor cell lines, 3-BrOP induced cell death via apoptosis in a dose and time dependent manner. Furthermore, 3-BrOP-induced depletion of ATP levels correlated with decreased neuroblastoma cell viability. In a mouse neuroblastoma xenograft model, glycolysis inhibition with 3-BrOP demonstrated significantly reduced final tumor weight. In neuroblastoma tumor cells, treatment with 3-BrOP induced mTOR activation, and the combination of 3-BrOP and mTOR inhibition with rapamycin demonstrated synergistic efficacy. Based on these results, neuroblastoma tumor cells are sensitive to treatment with inhibitors of glycolysis, and the demonstrated synergy with rapamycin suggests that the combination of glycolysis and mTOR inhibitors represents a novel therapeutic approach for neuroblastoma that warrants further investigation.

Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.

In obesity and type 2 diabetes, expression of the GLUT4 glucose transporter is decreased selectively in adipocytes. Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4(-/-)) mice show insulin resistance secondarily in muscle and liver. Here we show, using DNA arrays, that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4(-/-) mice. We show that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity and type 2 diabetes. RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance. Conversely, genetic deletion of Rbp4 enhances insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalizes serum RBP4 levels and improves insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impairs insulin signalling in muscle. Thus, RBP4 is an adipocyte-derived 'signal' that may contribute to the pathogenesis of type 2 diabetes. Lowering RBP4 could be a new strategy for treating type 2 diabetes.

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.