Decline in Left Ventricular Early Systolic Function with Worsening Kidney Function in Children with Chronic Kidney Disease: Insights from the 4C and HOT-KID Studies.

INTRODUCTION: Adults with childhood-onset chronic kidney disease (CKD) have an increased risk of cardiovascular disease. First-phase ejection fraction (EF1), a novel measure of early systolic function, may be a more sensitive marker of left ventricular dysfunction than other markers in children with CKD. OBJECTIVE: To examine whether EF1 is reduced in children with CKD. METHODS: Children from the 4C and HOT-KID studies were stratified according to estimated glomerular filtration rate (eGFR). The EF1 was calculated from the fraction of left ventricular (LV) volume ejected up to the time of peak aortic flow velocity. RESULTS: The EF1 was measured in children ages 10.9 ± 3.7 (mean ± SD) years, 312 with CKD and 63 healthy controls. The EF1 was lower, while overall ejection fraction was similar, in those with CKD compared with controls and decreased across stages of CKD (29.3% ± 3.7%, 23.5% ± 4.5%, 19.8% ± 4.0%, 18.5% ± 5.1%, and 16.7% ± 6.6% in controls, CKD 1, 2, 3, and ≥ 4, respectively, P < .001). The relationship of EF1 to eGFR persisted after adjustment for relevant confounders (P < .001). The effect size for association of measures of LV structure or function with eGFR (SD change per unit change in eGFR) was greater for EF1 (ß = 0.365, P < .001) than for other measures: LV mass index (ß = -0.311), relative wall thickness (ß = -0.223), E/e' (ß = -0.147), and e' (ß = 0.141) after adjustment for confounders in children with CKD. CONCLUSIONS: Children with CKD exhibit a marked and progressive decline in EF1 with falling eGFR. This suggests that EF1 is a more sensitive marker of LV dysfunction when compared to other structural or functional measures and that early LV systolic function is a key feature in the pathophysiology of cardiac dysfunction in CKD.

Behavioral responses of field-collected German cockroaches to pyrethroids and pyrethroid-formulated insecticides.

BACKGROUND: Pyrethroids are synthetic insecticides with low mammalian toxicity and broad-spectrum activity across insects. One major challenge with pyrethroids is their perceived repellency. This perception can influence decisions made by pest control operators, especially when insecticides are used to reduce insect entry into or movement within structures. One major indoor pest that has been repeatedly shown to be repelled by some pyrethroids is the German cockroach, Blattella germanica. However, most experiments evaluating pyrethroid repellency in the German cockroach have used end-point assays, which do not provide information on the movement that led to the final position. Therefore, we evaluated the kinetic behavioral response of field-collected German cockroaches to five pyrethroid-based products and their active ingredients (A.I.) in open behavioral arenas using advanced video tracking software. In addition, in an effort to compare our free-moving experiments with end-point assays, we evaluated sheltering behavior using two-choice harborage arrestment assays where German cockroaches were provided a choice between pyrethroid-treated and untreated shelters. RESULTS: All pyrethroid-formulated products and their respective A.I.'s failed to affect field-collected German cockroach movement behavior in free-moving assays, while positive controls (DEET, corn mint oil) resulted in reduced time spent by German cockroaches in treated areas. However, despite their willingness to move over pyrethroids-treated surfaces, field-collected German cockroaches displayed a reduced propensity to arrest on pyrethroids treated tents. CONCLUSION: While most pyrethroids/pyrethroid-formulated products affected German cockroach arrestment, pyrethroids and pyrethroid-formulated products failed to change German cockroach movement behavior in free-moving assays. These results indicate the pyrethroids tested act as contact irritants rather than true-spatial repellents on field-collected German cockroaches. This distinction is critical to refining pest management strategies involving pyrethroids. © 2023 Society of Chemical Industry.

Intensive compared with less intensive blood pressure control to prevent adverse cardiac remodelling in children with chronic kidney disease (HOT-KID): a parallel-group, open-label, multicentre, randomised, controlled trial.

BACKGROUND: Optimal target blood pressure to reduce adverse cardiac remodelling in children with chronic kidney disease is uncertain. We hypothesised that lower blood pressure would reduce adverse cardiac remodelling. METHODS: HOT-KID, a parallel-group, open-label, multicentre, randomised, controlled trial, was done in 14 clinical centres across England and Scotland. We included children aged 2-15 years with stage 1-4 chronic kidney disease-ie, an estimated glomerular filtration rate (eGFR) higher than 15 mL/min per 1·73 m2-and who could be followed up for 2 years. Children on antihypertensive medication were eligible as long as it could be changed to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) if they were not already receiving these therapies. Participants were randomly assigned (1:1) to standard treatment (auscultatory office systolic blood pressure target between the 50th and 75th percentiles) or intensive treatment (systolic target <40th percentile) by the chief investigator using a rapid, secure, web-based randomisation system. ACE inhibitors or ARBs were used as first-line agents, with the dose titrated every 2-4 weeks to achieve the target blood pressure levels. The primary outcome was mean annual difference in left ventricular mass index (LVMI) by echocardiography measured by a masked observer and was assessed in the intention-to-treat population, defined as all the children who underwent randomisation irrespective of the blood pressure reached. Secondary and safety outcomes were the differences between groups in mean left ventricular relative wall thickness, renal function, and adverse effects and were also assessed in the intention-to-treat population. This trial is registered with ISRCTN, ISRCTN25006406. FINDINGS: Between Oct 30, 2012, and Jan 5, 2017, 64 participants were randomly assigned to the intensive treatment group and 60 to the standard treatment group (median age of participants was 10·0 years [IQR 6·8-12·6], 69 [56%] were male and 107 [86%] were of white ethnicity). Median follow-up was 38·7 months (IQR 28·1-52·2). Blood pressure was lower in the intensive treatment group compared with standard treatment group (mean systolic pressure lower by 4 mm Hg, p=0·0012) but in both groups was close to the 50th percentile. The mean annual reduction in LVMI was similar for intensive and standard treatments (-1·9 g/m2·7 [95% CI -2·4 to -1·3] vs -1·2 g/m2·7 [-1·5 to 0·8], with a treatment effect of -0·7 g/m2·7 [95% CI -1·9 to 2·6] per year; p=0·76) and mean value in both groups at the end of follow-up within the normal range. At baseline, elevated relative wall thickness was more marked than increased LVMI and a reduction in relative wall thickness was greater for the intensive treatment group than for the standard treatment group (-0·010 [95% CI 0·015 to -0·006] vs -0·004 [-0·008 to 0·001], treatment effect -0·020 [95% CI -0·039 to -0·009] per year, p=0·0019). Six (5%) participants reached end-stage kidney disease (ie, an eGFR of <15 mL/min per 1·73 m2; three in each group) during the course of the study. The risk difference between treatment groups was 0·02 (95% CI -0·15 to 0·19, p=0·82) for overall adverse events and 0·07 (-0·05 to 0·19, p=0·25) for serious adverse events. Intensive treatment was not associated with worse renal outcomes or greater adverse effects than standard treatment. INTERPRETATION: These results suggest that cardiac remodelling in children with chronic kidney disease is related to blood pressure control and that a target office systolic blood pressure at the 50th percentile is close to the optimal target for preventing increased left ventricular mass. FUNDING: British Heart Foundation.

Advanced chronic kidney disease among UK children.

The UK Renal Registry currently collects information on UK children with kidney failure requiring long-term kidney replacement therapy (KRT), which supports disease surveillance and auditing of care and outcomes; however, data are limited on children with chronic kidney disease (CKD) not on KRT. METHODS: In March 2020, all UK Paediatric Nephrology centres submitted data on children aged <16 years with severely reduced kidney function as of December 2019, defined as an estimated glomerular filtration rate <30 mL/min/1.73 m2. RESULTS: In total, 1031 children had severe CKD, the majority of whom (80.7%) were on KRT. The overall prevalence was 81.2 (95% CI 76.3 to 86.3) per million of the age-related population. CONCLUSIONS: The prevalence of severe CKD among UK children is largely due to a high proportion of children on long-term KRT. Expanding data capture to include children with CKD before reaching failure will provide greater understanding of the CKD burden in childhood.

Culturally adapted evidence-based treatments for adults with substance use problems: A systematic review and meta-analysis.

BACKGROUND: This systematic review/meta-analysis aimed to synthesize empirical evidence from randomized controlled trials on the efficacy of culturally adapted interventions (CAIs) for substance use and related consequences for adults of color. METHODS: Six electronic databases were searched to identify eligible studies. Two reviewers independently screened studies, extracted data, and assessed risks of bias. We used robust variance estimation in meta-regression to synthesize effect size estimates and conduct moderator analyses. RESULTS: Twenty-two studies met the inclusion criteria and were included in the review. The overall effect size was 0.23 (95 % Confidence Interval [CI] = 0.12, 0.35). The subgroup effect sizes for comparing CAIs with inactive controls and with active controls were 0.31 (CI = 0.14, 0.48) and 0.14 (CI=-0.02, 0.29), respectively. The effect sizes for alcohol use, illicit drug use, unspecified substance use outcomes, and substance use related consequences were 0.25 (CI = 0.08, 0.43), 0.35 (CI =-0.30, 1.00), 0.22 (CI=-0.17, 0.62), and 0.02 (CI=-0.11, 0.16), respectively. Moderator analysis showed that CAIs' effects might not vary significantly by treatment model, dose, country, follow-up assessment timing, participant age, or gender/sex. CONCLUSIONS: Research on substance use interventions that are culturally adapted for people of color is growing, and more high-quality studies are needed to draw definitive conclusions about CAIs' treatment effects. Our study found CAIs to be a promising approach for reducing substance use and related consequences. We call for more efficacy/effectiveness and implementation research to further advance the development and testing of evidence-based CAIs that meet the unique needs and sociocultural preferences of diverse populations.

UK national study of barriers to renal transplantation in children.

AIMS: To investigate access to paediatric renal transplantation and examine potential barriers within the process. METHODS: Cross-sectional, multicentre, observational study where paediatric nephrology centres in the UK were requested to provide data on transplantation plans for all children (<18 years) with end-stage kidney disease (ESKD). RESULTS: 308 children with ESKD were included in this study from 12 out of 13 UK paediatric nephrology centres. 139 (45%) were being prepared for living donor transplantation and 82 (27%) were listed for deceased donor transplantation. The most common cited factors delaying transplantation from occurring in children were disease factors (36%), donor availability (27%) and size of the child (20%). Psychosocial factors were listed as a barrier in 19% of children. CONCLUSIONS: In this study we have documented the main barriers to renal transplantation in children. Some identified factors may be modifiable through local or national intervention, including donor availability and patient psychosocial factors.

The Efficacy of Denosumab in the Management of a Tibial Paediatric Aneurysmal Bone Cyst Compromised by Rebound Hypercalcaemia.

Surgery is the main treatment option for patients with aneurysmal bone cyst (ABC). We report our experience of using denosumab as an alternative treatment in a child with a multiply recurrent and unresectable tibial ABC. The efficacy and safety of denosumab in the paediatric population, and in the treatment of ABC, are still to be fully evaluated. We describe a 13-year-old boy with an extensive and aggressive ABC involving the proximal tibia, which had recurred following multiple previous surgeries. The patient had ongoing severe pain, was unable to weight-bear, and was at significant risk of pathological fracture. En bloc resection and embolization were not deemed viable, and a decision to use denosumab was made. He received 17 doses of subcutaneous denosumab (70 mg/m2) over a 27-month period, at increasing dose intervals. His symptoms significantly improved, and bony consolidation was observed within six months of treatment. He was able to walk without protection and fully weight-bear without any pain by 18 months. With an increase to a six-month dosing interval, the patient presented with a severe, symptomatic rebound hypercalcaemia requiring bisphosphonate therapy. This reoccurred on two further occasions. This case adds to the evidence that denosumab is effective in the treatment of ABC in paediatric patients, but there is a risk of rebound hypercalcaemia. Therefore, patient awareness and biochemical monitoring for rebound hypercalcaemia are essential.

Co-Existence of Congenital Adrenal Hyperplasia and Bartter Syndrome due to Maternal Uniparental Isodisomy of HSD3B2 and CLCNKB Mutations.

INTRODUCTION: We present a patient with co-existence of 3ß-hydroxysteroid dehydrogenase type 2 (HSD3B2) deficiency and Bartter syndrome, a unique dual combination of opposing pathologies that has not been reported previously in the literature. CASE: A female infant (46,XX) born at 34/40 weeks' gestation, weighing 2.67 kg (-1.54 standard deviation score) to non-consanguineous parents presented on day 4 of life with significant weight loss. Subsequent investigations revealed hyponatraemia, hypochloraemia, metabolic alkalosis, elevated 17-hydroxyprogesterone, ACTH, and renin. Urine steroid profile suggested HSD3B2 deficiency, which was confirmed by the identification of a homozygous HSD3B2 mutation. Due to the persistence of the hypochlo-raemic and hypokalemic alkalosis, an underlying renal tubulopathy was suspected. Sequence analysis of a targeted tubulopathy gene panel revealed a homozygous deletion in CLCNKB, consistent with Bartter syndrome type 3. The mother was found to be heterozygous for both mutations in -HSD3B2 and CLCNKB, and the father was negative for both. Single-nucleotide polymorphism microarray analysis confirmed 2 segments of homozygosity on chromosome 1 of maternal ancestry, encompassing both HSD3B2 and CLCKNB. DISCUSSION: Identification of a homozygous rare mutation in an offspring of non-consanguineous parents should raise suspicion of uniparental disomy, especially if the phenotype is unusual, potentially encompassing more than one disorder. The persistence of hypokalemic alkalosis, the biochemical fingerprint of hyperaldosteronism in a child with a form of CAH in which aldosterone production is severely impaired, challenges our current understanding of mineralocorticoid-mediated effects in the collecting duct.

Opioid use, postoperative complications, and implant survival after unicompartmental versus total knee replacement: a population-based network study.

BACKGROUND: There is uncertainty around whether to use unicompartmental knee replacement (UKR) or total knee replacement (TKR) for individuals with osteoarthritis confined to a single compartment of the knee. We aimed to emulate the design of the Total or Partial Knee Arthroplasty Trial (TOPKAT) using routinely collected data to assess whether the efficacy results reported in the trial translate into effectiveness in routine practice, and to assess comparative safety. METHODS: We did a population-based network study using data from four US and one UK health-care database, part of the Observational Health Data Sciences and Informatics network. The inclusion criteria were the same as those for TOPKAT; briefly, we identified patients aged at least 40 years with osteoarthritis who had undergone UKR or TKR and who had available data for at least one year prior to surgery. Patients were excluded if they had evidence of previous knee arthroplasty, knee fracture, knee surgery (except diagnostic), rheumatoid arthritis, infammatory arthropathies, or septic arthritis. Opioid use from 91-365 days after surgery, as a proxy for persistent pain, was assessed for all participants in all databases. Postoperative complications (ie, venous thromboembolism, infection, readmission, and mortality) were assessed over the 60 days after surgery and implant survival (as measured by revision procedures) was assessed over the 5 years after surgery. Outcomes were assessed in all databases, except for readmission, which was assessed in three of the databases, and mortality, which was assessed in two of the databases. Propensity score matched Cox proportional hazards models were fitted for each outcome. Calibrated hazard ratios (cHRs) were generated for each database to account for observed differences in control outcomes, and cHRs were then combined using meta-analysis. FINDINGS: 33 867 individuals who received UKR and 557 831 individuals who received TKR between Jan 1, 2005, and April 30, 2018, were eligible for matching. 32 379 with UKR and 250 377 with TKR were propensity score matched and informed the analyses. UKR was associated with a reduced risk of postoperative opioid use (cHR from meta-analysis 0·81, 95% CI 0·73-0·90) and a reduced risk of venous thromboembolism (0·62, 0·36-0·95), whereas no difference was seen for infection (0·85, 0·51-1·37) and readmission (0·79, 0·47-1·25). Evidence was insufficient to conclude whether there was a reduction in risk of mortality. UKR was also associated with an increased risk of revision (1·64, 1·40-1·94). INTERPRETATION: UKR was associated with a reduced risk of postoperative opioid use compared with TKR, which might indicate a reduced risk of persistent pain after surgery. UKR was associated with a lower risk of venous thromboembolism but an increased risk of revision compared with TKR. These findings can help to inform shared decision making for individuals eligible for knee replacement surgery. FUNDING: EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative (2) Joint Undertaking (EHDEN).

The long-term outcome of prenatally detected posterior urethral valves: a 10 to 23-year follow-up study.

OBJECTIVE: To document the functional outcome of patients with prenatally detected posterior urethral valves (PUV) in the second decade of life, and to evaluate the possible impact of prenatal diagnosis on the long-term outcome of this condition. PATIENTS AND METHODS: We analysed the functional outcome of 25 patients with prenatally detected PUV born between 1984 and 1996, whose mean (range) age at follow-up was 17.7 (10-23) years. The findings were compared with those in 17 patients (mean age 16.1 years) who had presented clinically to our unit during the same period. The duration of follow-up in both groups was >or=10 years. Late outcomes were also compared with published data for PUV. Outcome measures included; death, incidence of end-stage renal failure (ESRF), age at transplantation and the most the recently available plasma creatinine level in untransplanted patients. We also examined any possible association between functional outcome and early predictors, including nadir plasma creatinine level at <1 year and vesico-ureteric reflux (VUR). RESULTS: Three patients died (12%), two as neonates and one aged 3 years. Of five patients who had been shunted in utero, four died or developed early-onset renal failure. In the 23 prenatally detected patients who survived the neonatal period, four (17%) had a renal transplant at a mean (range) age of 6.5 (3.0-12.0) years. Of 19 patients with prenatally detected PUV who had not been transplanted in the first 12 years of life, only one (5%) developed new-onset ESRF at 10.0-23.4 years whilst 11 (58%) of these patients had normal creatinine values. In the untransplanted patients there was a statistically significant correlation between age and plasma creatinine level, but no correlation between late functional outcome and nadir creatinine in the first year of life, or bilateral VUR. CONCLUSIONS: Prenatal diagnosis had little impact on mortality or ESRF in the first decade of life. This appears to be largely predetermined by renal dysplasia and the severity of intrauterine obstruction. However, the functional outcome of patients with prenatally detected PUV aged 10-23 years was considerably better than published long-term data and the outcome of clinically presenting patients in our study. These findings suggest that the long-term prognosis of PUV of intermediate severity might be improved by prenatal diagnosis.

Intravenous iron treatment in paediatric chronic kidney disease patients not on erythropoietin.

Intravenous (i.v.) iron treatment reduces erythropoietin (EPO) dose in paediatric haemodialysis patients. The efficacy in paediatric nonhaemodialysis patients is less well established. i.v. iron is routinely given in our institution to these patients, including some who have not started EPO. The effect of this strategy was examined. Patients with chronic kidney disease (CKD) or peritoneal dialysis (PD) not on EPO were identified. Case notes were reviewed for haemoglobin (Hb), red cell and iron indices for 6 months before and at least 3 months after i.v. iron. Five patients were identified. Mean age was 13.3 years and mean i.v. iron (Venofer) dose = 3.1 mg/kg. Median number of doses = 7 (range 3-10). Hb increased significantly after i.v. iron from 11.4 +/- 0.7 to 12.8 +/- 1.3 g/dl (p = 0.02). Mean cell volume increased from 87.7+/-3.4 to 90.1 +/- 3.7 fl (p = 0.01), and mean cell Hb remained unchanged: 29.2 +/- 1.2 to 29.7 +/- 1.0 pg (p = 0.12). Absolute and percentage reticulocyte count remained unchanged. There was no change in iron indices: ferritin 55.1 +/- 31.3 to 97.3 +/- 46.5 ng/ml (p = 0.3), iron 18.9 +/- 6.9 to 18.1 +/- 4.2 micromol/l (p = 0.7), transferrin 1.9 +/- 1.6 to 2.0 +/- 0.1 g/l (p = 1.0), transferrin saturation 35.7 +/- 8.1 to 40.3 +/- 18.0% (p = 0.5). i.v. iron slightly improved Hb levels in five paediatric CKD and PD patients not receiving EPO. This strategy may delay the need for EPO treatment and deserves further evaluation.