A pragmatic, open-label, randomized controlled trial of Plasma-Lyte-148 versus standard intravenous fluids in children receiving kidney transplants (PLUTO).

Acute electrolyte and acid-base imbalance is experienced by many children following kidney transplant. This is partly because doctors give very large volumes of artificial fluids to keep the new kidney working. When severe, fluid imbalance can lead to seizures, cerebral edema and death. In this pragmatic, open-label, randomized controlled trial, we randomly assigned (1:1) pediatric kidney transplant recipients to Plasma-Lyte-148 or standard of care perioperative intravenous fluids (predominantly 0.45% sodium chloride and 0.9% sodium chloride solutions). We then compared clinically significant electrolyte and acid-base abnormalities in the first 72 hours post-transplant. The primary outcome, acute hyponatremia, was experienced by 53% of 68 participants in the Plasma-Lyte-148 group and 58% of 69 participants in the standard fluids group (odds ratio 0·77 (0·34 - 1·75)). Five of 16 secondary outcomes differed with Plasma-Lyte-148: hypernatremia was significantly more frequent (odds ratio 3·5 (1·1 - 10·8)), significantly fewer changes to fluid prescriptions were made (rate ratio 0·52 (0·40-0·67)), and significantly fewer participants experienced hyperchloremia (odds ratio 0·17 (0·07 - 0·40)), acidosis (odds ratio 0·09 (0·04 - 0·22)) and hypomagnesemia (odds ratio 0·21 (0·08 - 0·50)). No other secondary outcomes differed between groups. Serious adverse events were reported in 9% of participants randomized to Plasma-Lyte-148 and 7% of participants randomized to standard fluids. Thus, perioperative Plasma-Lyte-148 did not change the proportion of children who experienced acute hyponatremia compared to standard fluids. However fewer fluid prescription changes were made with Plasma-Lyte-148, while hyperchloremia and acidosis were less common.

Making your way as an academic paediatric trainee in the UK.

A career path in academic paediatric medicine is an extremely rewarding one, and while not traditionally considered an academic specialty, it offers a wealth of exciting research opportunities. Developing academic paediatrics is becoming increasingly important, as recently reviewed in the Royal College of Paediatrics and Child Health (RCPCH) Turning the Tide report, and developing future leaders in academic paediatrics is a key goal of the academic training pathways. Strategies are being implemented to ensure that the enthusiasm of academic trainees is maintained, and their development into future leaders is secured.

Should We Work Smarter or Harder for Our Health? A Comparison of Intensity and Domain-Based Time-Use Compositions and Their Associations With Cognitive and Cardiometabolic Health.

BACKGROUND: Each day is made up of a composition of "time-use behaviors." These can be classified by their intensity (eg, light or moderate-vigorous physical activity [PA]) or domain (eg, chores, socializing). Intensity-based time-use behaviors are linked with cognitive function and cardiometabolic health in older adults, but it is unknown whether these relationships differ depending on the domain (or type/context) of behavior. METHODS: This study included 397 older adults (65.5 ±â€…3.0 years, 69% female, 16.0 ±â€…3.0 years education) from Adelaide and Newcastle, Australia. Time-use behaviors were recorded using the Multimedia Activity Recall for Children and Adults, cognitive function was measured using the Addenbrooke's Cognitive Examination III and Cambridge Neuropsychological Test Automated Battery, and systolic and diastolic blood pressure, total cholesterol, and waist-hip ratio were also recorded. Two 24-hour time-use compositions were derived from each participant's Multimedia Activity Recall for Children and Adults, including a 4-part intensity composition (sleep, sedentary behavior, light, and moderate-vigorous PA) and an 8-part domain composition (Sleep, Self-Care, Chores, Screen Time, Quiet Time, Household Administration, Sport/Exercise, and Social). RESULTS: Linear regressions found significant associations between the domain composition and both Addenbrooke's Cognitive Examination III (p = .010) and waist-hip ratio (p = .009), and between the intensity composition and waist-hip ratio (p = .025). Isotemporal substitution modeling demonstrated that the domains of sedentary behaviors and PA impacted their associations with Addenbrooke's Cognitive Examination III, while any PA appeared beneficial for waist-hip ratio. CONCLUSIONS: Findings suggest the domain of behavior should be considered when aiming to support cognitive function, whereas, for cardiometabolic health, it appears sufficient to promote any type of PA.

The role of genetics in drug dosing.

Renal transplantation is the optimal form of renal replacement therapy (RRT) for the majority of patients. Both short- and long-term graft rejection are well recognized complications following transplantation, and optimal immunosuppression is often difficult to achieve. Pharmacodynamics (PD) and pharmacokinetics (PK) are hard to predict in all patients, and best practice involves the use of standard dosing based on weight and therapeutic drug monitoring (TDM). Pharmacogenetics (PG) is the use of genetic screening to predict metabolic responses to different immunosuppressive drugs and enables more accurate predictions of PD and PK to be made. This has the potential to improve graft outcome by reducing both short- and long-term graft rejection.

Kidney Transplantation in Small Children: Association Between Body Weight and Outcome-A Report From the ESPN/ERA-EDTA Registry.

BACKGROUND: Many centers accept a minimum body weight of 10 kg as threshold for kidney transplantation (Tx) in children. As solid evidence for clinical outcomes in multinational studies is lacking, we evaluated practices and outcomes in European children weighing below 10 kg at Tx. METHODS: Data were obtained from the European Society of Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry on all children who started kidney replacement therapy at <2.5 y of age and received a Tx between 2000 and 2016. Weight at Tx was categorized (<10 versus ≥10 kg) and Cox regression analysis was used to evaluate its association with graft survival. RESULTS: One hundred of the 601 children received a Tx below a weight of 10 kg during the study period. Primary renal disease groups were equal, but Tx <10 kg patients had lower pre-Tx weight gain per year (0.2 versus 2.1 kg; P < 0.001) and had a higher preemptive Tx rate (23% versus 7%; P < 0.001). No differences were found for posttransplant estimated glomerular filtration rates trajectories (P = 0.23). The graft failure risk was higher in Tx <10 kg patients at 1 y (graft survival: 90% versus 95%; hazard ratio, 3.84; 95% confidence interval, 1.24-11.84), but not at 5 y (hazard ratio, 1.71; 95% confidence interval, 0.68-4.30). CONCLUSIONS: Despite a lower 1-y graft survival rate, graft function, and survival at 5 y were identical in Tx <10 kg patients when compared with Tx ≥10 kg patients. Our results suggest that early transplantation should be offered to a carefully selected group of patients weighing <10 kg.

Student Pharmacists during the Pandemic: Development of a COVID-19 Knowledge, Attitudes, and Practices (COVKAP) Survey.

BACKGROUND: The COVID-19 pandemic has caused innumerable changes to all aspects of human life and behavior, including academic life. This study describes the development of a COVID-19 Knowledge, Attitudes, and Practices (COVKAP) Survey among U.S. student pharmacists. The survey was administered at Doctor of Pharmacy programs in three states-Tennessee, Ohio, and Pennsylvania. METHODS: The COVKAP survey-an online cross-sectional survey-was distributed to U.S. student pharmacists enrolled in three different colleges of pharmacy in three states during the fall semester of 2020. The survey was developed using literature review and Dillman's recommendations for survey design. The COVKAP survey consisted of 23 closed and Likert-scale questions, and three open-ended questions. The research team conducted descriptive and inductive thematic analyses on the quantitative and qualitative data, respectively using SPSS (v27) and Dedoose® software. RESULTS: A total of 421 responses were received. Respondents were predominantly female (72%) and White (79%). The average age of respondents was 23.4 years. The qualitative analysis revealed three themes: (1) Wellbeing and mental health struggles; (2) Being part of the decision-making process; (3) Necessity of adequate protection measures. CONCLUSIONS: Preliminary study findings indicate that student pharmacists' concerns and the challenges that they face in their academic pursuits are largely similar across the three states in this study and inform about the importance of recognizing and mitigating the impact of widespread disruption in education. This disruption provides an opportunity for pharmacy academia to examine practices and methods that can be improved upon to help students become successful practitioners.

Fabrication, Testing, and Simulation of All-Solid-State Three-Dimensional Li-Ion Batteries.

Demonstration of three-dimensional all-solid-state Li-ion batteries (3D SSLIBs) has been a long-standing goal for numerous researchers in the battery community interested in developing high power and high areal energy density storage solutions for a variety of applications. Ideally, the 3D geometry maximizes the volume of active material per unit area, while keeping its thickness small to allow for fast Li diffusion. In this paper, we describe experimental testing and simulation of 3D SSLIBs fabricated using materials and thin-film deposition methods compatible with semiconductor device processing. These 3D SSLIBs consist of Si microcolumns onto which the battery layers are sequentially deposited using physical vapor deposition. The power performance of the 3D SSLIBs lags significantly behind that of similarly prepared planar SSLIBs. Analysis of the experimental results using finite element modeling indicates that the origin of the poor power performance is the structural inhomogeneity of the 3D SSLIB, coupled with low electrolyte ionic conductivity and diffusion rate in the cathode, which lead to highly nonuniform internal current density distribution and poor cathode utilization.

Current progress in pharmacogenetics and individualized immunosuppressive drug dosing in organ transplantation.

The immunosuppressive drugs used in organ transplantation typically have a narrow therapeutic index, with wide variation in the blood concentration achieved from a given dose observed between individuals. This issue has been addressed through the use of therapeutic drug monitoring (TDM), but it may take 5 to 7 days to reach target blood concentrations using this approach. This timeline is not conducive to achieving sufficiently high concentrations in all patients to prevent graft rejection without exposing the patient to excessive toxicity over the critical 2- to 3-day period following transplantation. SNPs in drug-metabolizing enzymes and transporter proteins have been associated with the pharmacokinetic and pharmacodynamic characteristics of immunosuppressive drugs. Data suggest that genetic prediction of the optimal initial drug dose leads to earlier attainment of target blood concentrations compared with using the standard initial dose. The pharmacogenetic strategy that is closest to translation into clinical practice is the use of the cytochrome P450 (CYP)3A5 genotype to predict the optimal initial dose for tacrolimus. Genetic prediction of the optimal dose may be particularly useful for drugs with a long half-life, such as sirolimus, which require several days to achieve a steady state following the implementation of a change in drug dosing, resulting in a long response-time for TDM. The influence of genetic factors on intracellular drug concentrations and the consequences for efficacy and toxicity are an emerging area of research. The SNPs described in this process could be added to existing molecular tissue typing methodology at minimal extra financial expense.

Transgenic expression of aflatoxin aldehyde reductase (AKR7A1) modulates aflatoxin B1 metabolism but not hepatic carcinogenesis in the rat.

In both experimental animals and humans, aflatoxin B(1) (AFB(1)) is a potent hepatic toxin and carcinogen against which a variety of antioxidants and experimental or therapeutic drugs (e.g., oltipraz, related dithiolethiones, and various triterpenoids) protect from both acute toxicity and carcinogenesis. These agents induce several hepatic glutathione S-transferases (GST) as well as aldo-keto reductases (AKR) which are thought to contribute to protection. Studies were undertaken in transgenic rats to examine the role of one inducible enzyme, AKR7A1, for protection against acute and chronic actions of AFB(1) by enhancing detoxication of a reactive metabolite, AFB(1) dialdehyde, by reduction to alcohols. The AFB(1) dialdehyde forms adducts with protein amino groups by a Schiff base mechanism and these adducts have been theorized to be at least one cause of the acute toxicity of AFB(1) and to enhance carcinogenesis. A liver-specific AKR7A1 transgenic rat was constructed in the Sprague-Dawley strain and two lines, AKR7A1(Tg2) and AKR7A1(Tg5), were found to overexpress AKR7A1 by 18- and 8-fold, respectively. Rates of formation of AFB(1) alcohols, both in hepatic cytosols and as urinary excretion products, increased in the transgenic lines with AKR7A1(Tg2) being the highest. Neither line offered protection against acute AFB(1)-induced bile duct proliferation, a functional assessment of acute hepatotoxicity by AFB(1), nor did they protect against the formation of GST-P positive putative preneoplastic foci as a result of chronic exposure to AFB(1). These results imply that the prevention of protein adducts mediated by AKR are not critical to protection against AFB(1) tumorigenicity.

Venepuncture technique training vs practice: a survey of foundation year 1 doctors.

This survey investigated potential disparity between foundation year 1 doctors' formal undergraduate venepuncture training and their actual clinical practice. Is there still a high prevalence of needle and syringe use?