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Heide A Stirnadel-Farrant,1 George Mu,2 Selin Cooper-Blenkinsopp,1 Rosemary O Schroyer,3 Kevin S Thorneloe,4 Ewen M Harrison,5 Susan MS Andrews6 1Department of WorldWide Epidemiology, GlaxoSmithKline, London, UK; 2Department of Data, Methods, and Analytics, GlaxoSmithKline, Collegeville, PA, USA; 3Department of Biostatistics, GlaxoSmithKline, Collegeville, PA, USA; 4Department of Translational Medicine, GlaxoSmithKline, Collegeville, PA, USA; 5Department of Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, UK; 6Department of Global Clinical Operations Development R&D, GlaxoSmithKline, Research Triangle Park, NC, USACorrespondence: Susan MS Andrews, Global Clinical Operations Development R&D GlaxoSmithKline Five Moore Drive, Research Triangle Park, NC, 27709-3398, USA, Tel +1-(919) 649-3944, Email susan.m.andrews@gsk.comPurpose: A variety of definitions for delayed graft function (DGF) have been proposed, but none has consistently been shown to be superior for predicting long-term graft outcomes for kidney donation after circulatory death (DCD) transplantation. In this study, real-world clinical outcome data following DCD transplantation were explored to determine the value of various DGF definitions for predicting graft survival.Patients and Methods: Data from 4 centers registered in the UK-based National Health Service Blood and Transplant registry (2010 to mid-2015) were used to assess 4 definitions of DGF in this retrospective chart review study.Results: Depending on the definition used, the frequency of DGF ranged from 119/362 (32.9%) when DGF was determined with available registry data and based on a requirement for dialysis within 7 days post-transplantation, to 224/315 (71.1%) when based on failure to achieve a 10% fall in serum creatinine (SCr) versus baseline per 24 hours averaged over the first 72 hours. Patients without clinical DGF as determined by a physician upon chart review, or when defined as < 30% reduction in baseline SCr within 7 days post-transplantation with or without dialysis, had significantly better graft survival probability 1 year (hazard ratio 2.08 and 4.48, respectively) and 5 years post-transplant, whereas serum creatinine level over the first 72 hours post-transplant was not predictive of graft survival at 1 year. Patients with clinical DGF upon physician chart review also had higher SCr, lower estimated glomerular filtration rate levels, and were dialyzed more (2.3 days) versus patients without (0.2 days).Conclusion: Delayed graft function, determined clinically or using a functional definition, is associated with poorer renal function and remains a useful predictor of graft survival at 1 year after DCD kidney transplantation.Keywords: delayed graft function, DGF, donation after circulatory death, DCD, serum creatinine, SCr

Purpose: This pilot study aimed to determine the parent/caregiver's role in nutrition/eating habits, physical activity behaviors, and food access among children diagnosed with spina bifida (SB)., Methods: Parents/caregivers of children with SB were asked to participate at a single, outpatient SB clinic. Demographic, biomedical data, parent/caregiver nutrition knowledge, family nutrition and physical activity (FNPA), and food security survey scores were compared. Descriptive, regression, and correlational statistics were conducted for analysis via SPSS 29., Results: Of the 117 parents/caregivers surveyed, completed data suggested most were overweight/obese (average body mass index [BMI] of 30.63 kg/m2±8.40; n = 99) with an average nutrition knowledge score of 71% (17.83±3.33). As FNPA scores decreased, the patient/child's maximum BMI z scores increased (β= -0.043; confidence interval -0.079, -0.007; p = 0.020), suggesting the less active and/or less healthy eating habits, the higher body mass was noted for the child. Forty four percent of children (n = 99) were in the overweight/obese weight range based on maximum BMI z score., Conclusion: These findings suggest there is a need for parental/caregiver nutrition education to assist children with SB with meal and activity planning to achieve optimal health.

Background: Methods for accurate quantification of lung fluid in heart failure (HF) are needed. Dynamic contrast-enhanced (DCE)-MRI may be an appropriate modality., Purpose: DCE-MRI evaluation of fraction of fluid volume in the interstitial lung space (v e ) and vascular permeability (K trans )., Study Type: Prospective, single-center method validation., Population: Seventeen evaluable healthy volunteers (HVs), 12 participants with HF, and 3 with acute decompensated HF (ADHF)., Field Strength/sequence: T 1 mapping (spoiled gradient echo variable flip angle acquisition) followed by dynamic series (three-dimensional spoiled gradient-recalled echo acquisitions [constant echo time, repetition time, and flip angle at 1.5 T])., Assessment: Three whole-chest scans were acquired: baseline (Session 1), 1-week later (Session 2), following exercise (Session 3). Extended Tofts model quantified v e and K trans (voxel-wise basis); total lung median measures were extracted and fitted via repeat measure analysis of variance (ANOVA) model. Patient tolerability of the scanning protocol was assessed., Statistical Tests: This was constructed as an experimental medicine study., Primary Endpoints: K trans and v e at baseline (HV vs. HF), change in K trans and v e following exercise, and following lung congestion resolution (ADHF). K trans and v e were fitted separately using ANOVA. Secondary endpoint: repeatability, that is, within-participant variability in v e and K trans between sessions (coefficient of variation estimated via mixed effects model)., Results: There was no significant difference in mean K trans between HF and HV (P ≤ 0.17): 0.2216 minutes -1 and 0.2353 minutes -1 (Session 1), 0.2044 minutes -1 and 0.2567 minutes -1 (Session 2), 0.1841 minutes -1 and 0.2108 minutes -1 (Session 3), respectively. v e was greater in the HF group (all scans, P ≤ 0.02). Results were repeatable between Sessions 1 and 2; mean values for HF and HV were 0.4946 and 0.3346 (Session 1), 0.4353 and 0.3205 (Session 2), respectively. There was minimal difference in K trans or v e between scans for participants with ADHF (small population precluded significance testing). Scanning was well tolerated., Data Conclusion: While no differences were detected in K trans , v e was greater in chronic HF patients vs. HV, augmented beyond plasma and intracellular volume. DCE-MRI is a valuable diagnostic and physiologic tool to evaluate changes in fluid volume in the interstitial lung space associated with symptomatic HF., Level of Evidence: 2 TECHNICAL EFFICACY STAGE: 2., (© 2022 GlaxoSmithKline. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Introduction and Objective: Pulmonary capillary endothelial transient receptor potential vanilloid 4 (TRPV4) channel plays a critical role in mediating the development of cardiogenic pulmonary edema. GSK2798745 is a first-in-class, highly potent, selective, orally active TRPV4 channel blocker being evaluated in a first-time-in-humans study (NCT02119260)., Methods: GSK2798745 was administered in a randomized, placebo-controlled study design to healthy volunteers in three separate cohorts as single escalating doses, with and without food, and as once-daily repeat doses for up to 14 days, respectively. Two cohorts of subjects with mild to moderate heart failure were also administered GSK2798745 once daily for up to 7 days. Safety, tolerability, and systemic exposure data were collected., Results: No significant safety issues or serious adverse events were observed with GSK2798745 in healthy volunteers and patients with heart failure. GSK2798745 systemic exposure data demonstrated linear pharmacokinetics up to 12.5 mg, less than twofold accumulation with once-daily dosing, and a systemic half-life of ~ 13 h. There was a slight increase in GSK2798745 exposure [14% increase in area under the plasma concentration-time curve (AUC) and 9% increase in maximum observed plasma concentration (C max )] after administration with a high-fat meal., Conclusions: GSK2798745 was well-tolerated in healthy volunteers and patients with stable heart failure. The safety and exposure data obtained in this study allow further evaluation of the drug in long-term clinical studies in heart failure as well as other indications.

Objective: Assess the long-term efficacy and safety of prescription omega-3-acid ethyl esters (P-OM3) coadministered with simvastatin in an extension of the Combination of Prescription Omega-3 Plus Simvastatin (COMBOS) trial., Methods: COMBOS included hypertriglyceridemic patients (triglyceride [TG] >or=200 mg/dL and <500 mg/dL or >or=2.26 mmol/L and <5.64 mmol/L) with low density lipoprotein cholesterol (LDL-C) level no greater than 10% above the National Cholesterol Education Program, Adult Treatment Panel III treatment goal. After an 8-week lead-in phase with simvastatin 40 mg/day (which continued throughout the trial), subjects were randomized to 8 weeks of P-OM3 4 g/day or placebo. Completers were eligible to participate in a 24-month extension study. Those who received placebo + simvastatin in COMBOS switched to open-label P-OM3 + simvastatin ('Switchers'); those who received P-OM3 + simvastatin during COMBOS continued the same regimen (open-label) in the extension phase ('Non-switchers'). The primary endpoint was the difference between Non-switchers and Switchers in median percent change in non-high-density lipoprotein-cholesterol (non-HDL-C) from COMBOS end of treatment to Month 4 of the extension phase., Results: At Month 4 from COMBOS end of treatment, non-HDL-C was reduced by a median of 9.4% in Switchers and increased by 0.9% in Non-switchers (p < 0.001). For the total population (combined Non-switcher + Switcher population), the median percent change from COMBOS baseline to Months 4, 12, and 24 was -8.3%, -7.3%, and -8.9%, respectively (all p < 0.001). This extension study revealed no unexpected safety findings. A limitation of this study was a gap between completion of COMBOS and enrollment in the extension phase for some patients; however, a post-hoc non-HDL-C sensitivity analysis performed at the 4-month primary endpoint revealed no influence of gap on study results., Conclusions: In this 24-month extension study, P-OM3 was generally well tolerated, and produced sustained reductions in non-HDL-C levels in simvastatin-treated patients with TG levels between 200 and 500 mg/dL (2.26 mmol/L and 5.64 mmol/L)., Clinical Trial Registry Number: NCT00903409.

Purpose: The use of centralized systems to adjudicate clinical events is common in large clinical trials, in spite of relatively little published literature concerning the rationale and justification. The purpose of this manuscript is to review the reasons for central adjudication and to discuss whether trials could be simplified by limiting or streamlining the adjudication process., Methods: We reviewed the literature concerning central adjudication and documented the experience of adjudication in several clinical trials. Since definitions for nonfatal events are generally heterogeneous and subjective, one reason for a central process of adjudication is to assist in assuring systematic application of the definition used in the trial. In open-label trials, assuring that the adjudication is done blinded to treatment assignment may provide protection against differential misclassification. Regulatory authorities, including the FDA, derive confidence in the validity of results when central adjudication is performed. The clinical community has become accustomed to a certain amount of adjudication and may criticize trials that lack adjudication., Limitations: It is difficult to document the value of adjudication in trials that have reported adjudicated and nonadjudicated event rates and related treatment effects. Making rationale decisions about when and how to adjudicate is hampered by the lack of published study of when and how central adjudication is helpful to improve the quality and validity of trials and at what cost., Conclusions: Adjudication has not been shown to improve the ability to determine treatment effects. Thus, adjudication may be overly complex and overused in many large simple trials. The appropriate role of central adjudication - which trials, which outcomes, what methods - deserves scrutiny and further study.