Search

The climate effect from aviation's non‑CO2 emissions such as contrail cirrus, water vapor and nitrogen oxide induced ozone and methane changes depend on emission location and time. Among other approaches, the resulting climate effect can be reduced by lowering cruise flight levels. However, aircraft typically aim to fly at optimum altitudes and perform step climbs with increasing flight length to enhance fuel efficiency and reduce operating cost, what also limits climate effects from CO2 emissions. To account for this and to reduce the overall climate effect of flights, the higher fuel consumption at lower flight altitudes can be compensated by also reducing flight speeds. Therefore, this study analyzes the mitigation potential of flying lower and slower with regard to the overall climate effect along flight trajectories. Specifically, actually flown point profiles are combined with related meteorological parameters to evaluate the effect from reduced cruise altitudes and speeds with an updated set of prototype algorithmic climate change functions. Different case studies show varying effects for individual days during different seasons, and significant mitigation potentials due to flying lower and slower can be observed (up to 9 % on a summer day and 16 % on a winter day). A sensitivity study to explore uncertainties with regard to the quantification of contrail effects is performed as well as an investigation on possible economic consequences in terms of changes in direct operating cost and eco-efficient solutions.

Individuals with rare kidney diseases account for 5–10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure.

IntroductionDuring the COVID-19 pandemic, evidence emerged that immunosuppressed children were less affected by COVID-19 infections compared with immunosuppressed adults. The aim of our study was to investigate how COVID-19 infections affected paediatric kidney transplant recipients (pKTR) in the UK.MethodsQuestionnaires regarding COVID-19 infection data and care of pKTR during the COVID-19 pandemic were sent to all 13 UK paediatric nephrology centres examining asymptomatic and symptomatic pKTR with positive COVID-19 PCR testing from 1 April 2020 to 1 December 2021.Results63 pKTR who were 3.1 (range 0.1–15) years post-transplantation had COVID-19 infection with positive SARS-CoV-2 PCR RNA. Classical COVID-19 symptoms were present in half of the patients; with atypical presentations including diarrhoea (13%) and lethargy (13%) also noted, while a third of patients were asymptomatic. Eighteen patients (28%) were hospitalised including five asymptomatic patients admitted for other reasons. No patients needed ventilation or intensive care admission, and one patient received supplemental oxygen. There was evidence of acute kidney injury (AKI) in 71% of patients, but no patients needed kidney replacement therapy with haemofiltration or dialysis.ConclusionWe report 10.4% of the UK paediatric renal transplantation population had documented COVID-19 infections with positive SARS-CoV-2 PCR RNA with 28% of those affected requiring hospitalisation. The increased incidence of AKI, particularly after the first wave of the COVID-19 pandemic, was possibly due to increased testing. There was low morbidity and mortality compared with the adult population.

Antibiotics are our primary approach to treating complex infections, yet we have a poor understanding of how these drugs affect microbial communities. To better understand antimicrobial effects on host-associated microbial communities we treated cultured sputum microbiomes from people with cystic fibrosis (pwCF, n?=?24) with 11 different antibiotics, supported by theoretical and mathematical modeling-based predictions in a mucus-plugged bronchiole microcosm. Treatment outcomes we identified in vitro that were predicted in silico were: 1) community death, 2) community resistance, 3) pathogen killing, and 4) fermenter killing. However, two outcomes that were not predicted when antibiotics were applied were 5) community profile shifts with little change in total bacterial load (TBL), and 6) increases in TBL. The latter outcome was observed in 17.8% of samples with a TBL increase of greater than 20% and 6.8% of samples with an increase greater than 40%, demonstrating significant increases in community carrying capacity in the presence of an antibiotic. An iteration of the mathematical model showed that TBL increase was due to antibiotic-mediated release of pH-dependent inhibition of pathogens by anaerobe fermentation. These dynamics were verified in vitro when killing of fermenters resulted in a higher community carrying capacity compared to a no antibiotic control. Metagenomic sequencing of sputum samples during antibiotic therapy revealed similar dynamics in clinical samples. This study shows that the complex microbial ecology dictates the outcomes of antibiotic therapy against a polymicrobial infection.

Background: Childhood steroid-sensitive nephrotic syndrome is a frequently relapsing disease with significant short- and long-term complications, leading to high healthcare costs and reduced quality of life for patients. The majority of relapses are triggered by upper respiratory tract infections (URTIs) and evidence shows that daily low-dose prednisolone at the time of infection may reduce the risk of relapse. Objective: The aim of this study was to assess the cost effectiveness of a 6-day course of low-dose prednisolone at the start of a URTI when compared with placebo. Methods: A state-transition Markov model was developed to conduct a cost-utility analysis with the outcome measured in quality-adjusted life-years (QALYs). Resource use and outcome data were derived from the PREDNOS2 trial. The analysis was performed from a UK National Health Service perspective and the results were extrapolated to adulthood. Model parameter and structural uncertainty were assessed using sensitivity analyses. Results: The base-case results showed that administering low-dose prednisolone at the time of a URTI generated more QALYs and a lower mean cost at 1 year compared with placebo. In the long-term, low-dose prednisolone was associated with a cost saving (£176) and increased effectiveness (0.01 QALYs) compared with placebo and thus remained the dominant treatment option. These findings were robust to all sensitivity analyses. Conclusion: A 6-day course of low-dose prednisolone at the time of a URTI in children with steroid-sensitive nephrotic syndrome has the potential to reduce healthcare costs and improve quality of life compared with placebo.

Modern public transit systems are often run with automated fare collection (AFC) systems in combination with smart cards. These systems passively collect massive amounts of detailed spatio-temporal trip data, thus opening up new possibilities for public transit planning and management as well as providing new insights for urban planners. We use smart card trip data from Taipei, Taiwan, to perform an in-depth analysis of spatio-temporal station-to-station metro trip patterns for a whole week divided into several time slices. Based on simple linear regression and line graphs, days of the week and times of the day with similar temporal passenger flow patterns are identified. We visualize magnitudes of passenger flow based on actual geography. By comparing flows for January to March 2019 and for January to March 2020, we look at changes in metro trips under the impact of the coronavirus pandemic (COVID-19) that caused a state of emergency around the globe in 2020. Our results show that metro usage under the impact of COVID-19 has not declined uniformly, but instead is both spatially and temporally highly heterogeneous.

IMPORTANCE: In children with corticosteroid-sensitive nephrotic syndrome, many relapses are triggered by upper respiratory tract infections. Four small studies found that administration of daily low-dose prednisolone for 5 to 7 days at the time of an upper respiratory tract infection reduced the risk of relapse, but the generalizability of their findings is limited by location of the studies and selection of study population. OBJECTIVE: To investigate the use of daily low-dose prednisolone for the treatment of upper respiratory tract infection–related relapses. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled randomized clinical trial (Prednisolone in Nephrotic Syndrome [PREDNOS] 2) evaluated 365 children with relapsing steroid-sensitive nephrotic syndrome with and without background immunosuppressive treatment at 122 pediatric departments in the UK from February 1, 2013, to January 31, 2020. Data from the modified intention-to-treat population were analyzed from July 1, 2020, to December 31, 2020. INTERVENTIONS: At the start of an upper respiratory tract infection, children received 6 days of prednisolone, 15 mg/m2 daily, or matching placebo preparation. Those already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 daily or their alternate-day dose, whichever was greater. MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence of first upper respiratory tract infection–related relapse. Secondary outcomes included overall rate of relapse, changes in background immunosuppressive treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, and quality of life. RESULTS: The modified intention-to-treat analysis population comprised 271 children (mean [SD] age, 7.6 [3.5] years; 174 [64.2%] male), with 134 in the prednisolone arm and 137 in the placebo arm. The number of patients experiencing an upper respiratory tract infection–related relapse was 56 of 131 (42.7%) in the prednisolone arm and 58 of 131 (44.3%) in the placebo arm (adjusted risk difference, −0.02; 95% CI, −0.14 to 0.10; P = .70). No evidence was found that the treatment effect differed according to background immunosuppressive treatment. No significant differences were found in secondary outcomes between the treatment arms. A post hoc subgroup analysis assessing the primary outcome in 54 children of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40-1.10) vs 208 children of other ethnicity (risk ratio, 1.11; 95% CI, 0.81-1.54) found no difference in efficacy of intervention in those of South Asian ethnicity (test for interaction P = .09). CONCLUSIONS AND RELEVANCE: The results of PREDNOS 2 suggest that administering 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of nephrotic syndrome in children in the UK. Further work is needed to investigate interethnic differences in treatment response. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN10900733; EudraCT 2012-003476-39

Antibiotics are our primary approach to treating complex infections, yet we have a poor understanding of how these drugs affect microbial communities. To better understand antimicrobial effects on host-associated microbial communities we treated cultured sputum microbiomes from people with cystic fibrosis (pwCF, n= 24) with 11 different antibiotics, supported by theoretical and mathematical modeling-based predictions in a mucus-plugged bronchiole microcosm. Treatment outcomes we identified in vitro that were predicted in silico were: 1) community death, 2) community resistance, 3) pathogen killing, and 4) fermenter killing. However, two outcomes that were not predicted when antibiotics were applied were 5) community profile shifts with little change in total bacterial load (TBL), and 6) increases in TBL. The latter outcome was observed in 17.8% of samples with a TBL increase of greater than 20% and 6.8% of samples with an increase greater than 40%, demonstrating significant increases in community carrying capacity in the presence of an antibiotic. An iteration of the mathematical model showed that TBL increase was due to antibiotic-mediated release of pH-dependent inhibition of pathogens by anaerobe fermentation. These dynamics were verified in vitro when killing of fermenters resulted in a higher community carrying capacity compared to a no antibiotic control. Metagenomic sequencing of sputum samples during antibiotic therapy revealed similar dynamics in clinical samples. This study shows that the complex microbial ecology dictates the outcomes of antibiotic therapy against a polymicrobial infection.

•Lower ATLG doses significantly accelerate posttransplant immune reconstitution.•The day of transplant can be scheduled according to a target serum level of ATLG following first order kinetics independent from dosing.

CRADLE was a 36‐month multicenter study in pediatric (≥1 to <18 years) kidney transplant recipients randomized at 4 to 6 weeks posttransplant to receive everolimus + reduced‐exposure tacrolimus (EVR + rTAC; n = 52) with corticosteroid withdrawal at 6‐month posttransplant or continue mycophenolate mofetil + standard‐exposure TAC (MMF + sTAC; n = 54) with corticosteroids. The incidence of composite efficacy failure (biopsy‐proven acute rejection [BPAR], graft loss, or death) at month 36 was 9.8% vs 9.6% (difference: 0.2%; 80% confidence interval: −7.3 to 7.7) for EVR + rTAC and MMF + sTAC, respectively, which was driven by BPARs. Graft loss was low (2.1% vs 3.8%) with no deaths. Mean estimated glomerular filtration rate at month 36 was comparable between groups (68.1 vs 67.3 mL/min/1.73 m2). Mean changes (z‐score) in height (0.72 vs 0.39; P= .158) and weight (0.61 vs 0.82; P= .453) from randomization to month 36 were comparable, whereas growth in prepubertal patients on EVR + rTAC was better (P= .050) vs MMF + sTAC. The overall incidence of adverse events (AEs) and serious AEs was comparable between groups. Rejection was the leading AE for study drug discontinuation in the EVR + rTAC group. In conclusion, though AE‐related study drug discontinuation was higher, an EVR + rTAC regimen represents an alternative treatment option that enables withdrawal of steroids as well as reduction of CNIs for pediatric kidney transplant recipients. ClinicalTrials.gov: NCT01544491. This multicenter randomized controlled trial in children with kidney transplants reports that early conversion from standard‐dose tacrolimus, mycophenolate mofetil, and steroids to reduced‐dose tacrolimus, everolimus, and steroid withdrawal leads to comparable efficacy for both rejection and renal function and to improved growth in prepubertal children. See Chambers's editorial on page 11.

The inconsistency in outcomes reported and lack of patient-reported outcomes across trials in children with chronic kidney disease (CKD) limits shared decision making. As part of the Standardized Outcomes in Nephrology (SONG)-Kids initiative, we aimed to generate a consensus-based prioritized list of critically important outcomes to be reported in all trials in children with CKD.

Trials in children with chronic kidney disease do not consistently report outcomes that are critically important to patients and caregivers. This can diminish the relevance and reliability of evidence for decision making, limiting the implementation of results into practice and policy. As part of the Standardized Outcomes in Nephrology—Children and Adolescents (SONG-Kids) initiative, we convened 2 consensus workshops in San Diego, California (7 patients, 24 caregivers, 43 health professionals) and Melbourne, Australia (7 patients, 23 caregivers, 49 health professionals). This report summarizes the discussions on the identification and implementation of the SONG-Kids core outcomes set. Four themes were identified; survival and life participation are common high priority goals, capturing the whole child and family, ensuring broad relevance across the patient journey, and requiring feasible and valid measures. Stakeholders supported the inclusion of mortality, infection, life participation, and kidney function as the core outcomes domains for children with chronic kidney disease.

Microwave-assisted synthesis of polyglycerolsebacate (PGS) - polycaprolactone (PCL) with nanoclay composite films were fabricated in this study. PGS produced via microwave irradiation technique was blended withorgano-modified montmorillonite (O-MMT) and PCL, and cast using thermally induced phase separation technique (TIPS) to produce nanocomposite films. The fabricated films underwent different qualitative characterization to identify its morphology, porosity,wettabilityandmechanical strength. FTIR results showed changes in the band peaks signifying the interaction between PCL, O-MMT and PGS. SEM images of the films displayed filamentous and non-uniform pores present on the films, which became more visible upon the addition of O-MMT and PGS.Also, the films showed improved tensile strength and elongation upon addition of PGS, but on an optimum O-MMT amount. Furthermore, the pore size of films increased upon addition of PGS, which confirmed the effect of its hydrophilic in nature. Thiswas correlated to the enhanced wettability of the films produced and the formation of asymmetric surface structure.

Targeting AML by chimeric antigen receptor T cells (CAR-T) has been challenging due to promiscuous expression of AML-associated antigens on healthy hematopoietic stem and progenitor cells as well as a high degree of inter- and intratumoral heterogeneity. Consequently, we did not yet see the dramatic clinical successes as in B-phenotypic malignancies treated with CD19 or BCMA directed CAR-T.

In a 12‐month, multicenter, open‐label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co‐primary efficacy end point (biopsy‐proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P= .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co‐primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m2with EVR/rTAC and 72.5 mL/min/1.73 m2for sTAC/MMF (difference 3.8 mL/min/1.73m2; P= .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P= .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P= .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function. This multicenter randomized controlled trial in pediatric renal transplant recipients finds that early conversion from standard‐dose tacrolimus, mycophenolate mofetil, and steroids to everolimus, reduced‐dose tacrolimus, and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P= .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m2with EVR/rTAC and 72.5 mL/min/1.73 m2for sTAC/MMF (difference 3.8 mL/min/1.73m2; P= .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P= .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P= .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

A 4-year-old boy presented with nonimmune hemolysis, thrombocytopenia, and acute kidney injury. Investigations for an underlying cause failed to identify a definitive cause and a putative diagnosis of complement-mediated atypical hemolytic uremic syndrome (aHUS) was made. The patient was started initially on plasma exchange and subsequently eculizumab therapy, after which his kidney function rapidly improved. While on eculizumab therapy, despite adequate complement blockade, he presented 2 more times with hemolytic anemia and thrombocytopenia, but without renal involvement. Genetic analysis did not uncover a mutation in any known aHUS gene (CFH, CFI, CFB, C3, CD46, THBD, INF2, and DGKE) and anti–factor H antibodies were undetectable. Whole-exome sequencing was undertaken to identify a cause for the eculizumab resistance. This revealed a pathogenic variant in G6PD(glucose-6-phosphate dehydrogenase), which was confirmed by functional analysis demonstrating decreased erythrocyte G6PD activity. Eculizumab therapy was withdrawn. Complement-mediated aHUS is a diagnosis of exclusion and this case highlights the diagnostic difficulty that remains without an immediately available biomarker for confirmation. This case of G6PD deficiency presented with a phenotype clinically indistinguishable from complement-mediated aHUS. We recommend that G6PD deficiency be included in the differential diagnosis of patients presenting with aHUS and suggest measuring erythrocyte G6PD concentrations in these patients.

Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9–30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2,and WT1but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3,and DGKEassociated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.

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.

The colon salvages energy from starch, especially when the capacity of the small intestine to digest it is limited. The aim of this study was to determine the site and relative extent of starch digestion and fermentation in infants.

The colon salvages energy from starch, especially when the capacity of the small intestine to digest it is limited. The aim of this study was to determine the site and relative extent of starch digestion and fermentation in infants. Thirteen infants (10 male and 3 female infants), median age 11.8 months (range, 7.6–22.7 months), were fed a starchy breakfast containing 13C-labeled wheat flour after an overnight fast. Duplicate breath samples were obtained before breakfast and every 30 minutes for 12 hours. Breath 13CO2enrichment was measured using isotope ratio mass spectrometry, and results were expressed as percentage dose recovered (PDR) for each 30 minutes. The PDR data were analyzed and mathematically modeled assuming either a constant estimate of CO2production rate or adjusted for physical activity. Mean ± SD cumulative 13C PDR (cPDR) at 12 hours was 21.3% ± 8.4% for unadjusted data and 26.5% ± 11.6% for adjusted data. A composite model of two curves fit significantly better than a single curve. Modeling allowed estimation of cPDRs of small intestine (17.5% ± 6.5% and 22.7% ± 9.3% for unadjusted and adjusted data, respectively) and colon (4.6% ± 2.9% and 6.3% ± 5.4%). Modeling of 13CO2enrichment curves after ingestion of 13C-enriched wheat flour is an attractive means to estimate the contribution of the upper and lower gut to starch digestion and fermentation.

Microbes associated with fungus-growing ants represent a poorly explored source of natural products. In this study, we used mass spectrometry-based dereplication techniques for identifying a set of secondary metabolites produced during the microbial interaction between Streptomycessp. (CB0028) and Escovopsissp. (CBAcro424). Both microorganisms were isolated from the nest of the fungus-growing ant Acromyrmex echinatior. Through MALDI imaging and MS/MS molecular networking, we annotated the siderophores: desferrioxamine B (1), ferrioxamine B (2), ferrioxamine E (3) and the N-formylated peptide SCO-2138/SLI-2138 (4). MALDI imaging experiments suggest that siderophores occurred during the microbial interactions in the fungus-growing ants – microbes symbioses. This is the first report on the production of compounds 1-4by bacteria associated with fungus-growing ants.