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.

Machine learning forecasting for COVID-19 pandemic-associated effects on paediatric respiratory infections.

OBJECTIVE: The COVID-19 pandemic and subsequent government restrictions have had a major impact on healthcare services and disease transmission, particularly those associated with acute respiratory infection. This study examined non-identifiable routine electronic patient record data from a specialist children's hospital in England, UK, examining the effect of pandemic mitigation measures on seasonal respiratory infection rates compared with forecasts based on open-source, transferable machine learning models. METHODS: We performed a retrospective longitudinal study of respiratory disorder diagnoses between January 2010 and February 2022. All diagnoses were extracted from routine healthcare activity data and diagnosis rates were calculated for several diagnosis groups. To study changes in diagnoses, seasonal forecast models were fit to prerestriction period data and extrapolated. RESULTS: Based on 144 704 diagnoses from 31 002 patients, all but two diagnosis groups saw a marked reduction in diagnosis rates during restrictions. We observed 91%, 89%, 72% and 63% reductions in peak diagnoses of 'respiratory syncytial virus', 'influenza', 'acute nasopharyngitis' and 'acute bronchiolitis', respectively. The machine learning predictive model calculated that total diagnoses were reduced by up to 73% (z-score: -26) versus expected during restrictions and increased by up to 27% (z-score: 8) postrestrictions. CONCLUSIONS: We demonstrate the association between COVID-19 related restrictions and significant reductions in paediatric seasonal respiratory infections. Moreover, while many infection rates have returned to expected levels postrestrictions, others remain supressed or followed atypical winter trends. This study further demonstrates the applicability and efficacy of routine electronic record data and cross-domain time-series forecasting to model, monitor, analyse and address clinically important issues.

Multicentre randomised controlled trial: protocol for Plasma-Lyte Usage and Assessment of Kidney Transplant Outcomes in Children (PLUTO).

INTRODUCTION: Acute electrolyte and acid-base imbalance is experienced by many children following kidney transplantation. When severe, this can lead to complications including seizures, cerebral oedema and death. Relatively large volumes of intravenous fluid are administered to children perioperatively in order to establish perfusion to the donor kidney, the majority of which are from living and deceased adult donors. Hypotonic intravenous fluid is commonly used in the post-transplant period due to clinicians' concerns about the sodium, chloride and potassium content of isotonic alternatives when administered in large volumes.Plasma-Lyte 148 is an isotonic, balanced intravenous fluid that contains sodium, chloride, potassium and magnesium with concentrations equivalent to those of plasma. There is a physiological basis to expect that Plasma-Lyte 148 will reduce the incidence of clinically significant electrolyte and acid-base abnormalities in children following kidney transplantation compared with current practice.The aim of the Plasma-Lyte Usage and Assessment of Kidney Transplant Outcomes in Children (PLUTO) trial was to determine whether the incidence of clinically significantly abnormal plasma electrolyte levels in paediatric kidney transplant recipients will be different with the use of Plasma-Lyte 148 compared with intravenous fluid currently administered. METHODS AND ANALYSIS: PLUTO is a pragmatic, open-label, randomised controlled trial comparing Plasma-Lyte 148 to current care in paediatric kidney transplant recipients, conducted in nine UK paediatric kidney transplant centres.A total of 144 children receiving kidney transplants will be randomised to receive either Plasma-Lyte 148 (the intervention) intraoperatively and postoperatively, or current fluid. Apart from intravenous fluid composition, all participants will receive standard clinical transplant care.The primary outcome measure is acute hyponatraemia in the first 72 hours post-transplant, defined as laboratory plasma sodium concentration of <135 mmol/L. Secondary outcomes include symptoms of acute hyponatraemia, other electrolyte and acid-base imbalances and transplant kidney function.The primary outcome will be analysed using a logistic regression model adjusting for donor type (living vs deceased donor), patient weight (<20 kg vs ≥20 kg pretransplant) and transplant centre as a random effect. ETHICS AND DISSEMINATION: The trial received Health Research Authority approval on 20 January 2020. Findings will be presented to academic groups via national and international conferences and peer-reviewed journals. The patient and public involvement group will play an important part in disseminating the study findings to the public domain. TRIAL REGISTRATION NUMBERS: 2019-003025-22 and 16586164.

Associations between exhaust and non-exhaust particulate matter and stroke incidence by stroke subtype in South London.

BACKGROUND: Airborne particulate matter (PM) consists of particles from diverse sources, including vehicle exhausts. Associations between short-term PM changes and stroke incidence have been shown. Cumulative exposures over several months, or years, are less well studied; few studies examined ischaemic subtypes or PM source. AIMS: This study combines a high resolution urban air quality model with a population-based stroke register to explore associations between long-term exposure to PM and stroke incidence. METHOD: Data from the South London Stroke Register from 2005-2012 were included. Poisson regression explored association between stroke incidence and long-term (averaged across the study period) exposure to PM2.5(PM<2.5µm diameter) and PM10(PM<10µm), nitric oxide, nitrogen dioxide, nitrogen oxides and ozone, at the output area level (average population=309). Estimates were standardised for age and sex and adjusted for socio-economic deprivation. Models were stratified for ischaemic and haemorrhagic strokes and further broken down by Oxford Community Stroke Project classification and Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. RESULTS: 1800 strokes were recorded (incidence=42.6/100,000 person-years). No associations were observed between PM and overall ischaemic or haemorrhagic incidence. For an interquartile range increase in PM2.5, there was a 23% increase in incidence (Incidence rate ratio=1.23 (95%CI: 1.03-1.44)) of total anterior circulation infarcts (TACI) and 20% increase for PM2.5 from exhausts (1.20(1.01-1.41)). There were similar associations with PM10, overall (1.21(1.01-1.44)) and from exhausts (1.20(1.01-1.41)). TACI incidence was not associated with non-exhaust sources. There were no associations with other stroke subtypes or pollutants. CONCLUSION: Outdoor air pollution, particularly that arising from vehicle exhausts, may increase risk of TACI but not other stroke subtypes.

A comprehensive catalogue of somatic mutations from a human cancer genome.

All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic.

Accurate whole human genome sequencing using reversible terminator chemistry.

DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally used long (400-800 base pair) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intraspecies genetic variation. Here we report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost. Single molecules of DNA are attached to a flat surface, amplified in situ and used as templates for synthetic sequencing with fluorescent reversible terminator deoxyribonucleotides. Images of the surface are analysed to generate high-quality sequence. We demonstrate application of this approach to human genome sequencing on flow-sorted X chromosomes and then scale the approach to determine the genome sequence of a male Yoruba from Ibadan, Nigeria. We build an accurate consensus sequence from >30x average depth of paired 35-base reads. We characterize four million single-nucleotide polymorphisms and four hundred thousand structural variants, many of which were previously unknown. Our approach is effective for accurate, rapid and economical whole-genome re-sequencing and many other biomedical applications.