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New Findings What is the central question of this study? Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular risk in patients with both diabetic and non‐diabetic kidney disease: can SGLT2 inhibition improve renal pressure natriuresis (PN), an important mechanism for long‐term blood pressure control, which is impaired in type 1 diabetes mellitus (T1DM)? What is the main finding and its importance? The SGLT2 inhibitor dapagliflozin did not enhance the acute in vivo PN response in either healthy or T1DM Sprague–Dawley rats. The data suggest that the mechanism underpinning the clinical benefits of SGLT2 inhibitors on health is unlikely to be due to an enhanced natriuretic response to increased blood pressure. Type 1 diabetes mellitus (T1DM) leads to serious complications including premature cardiovascular and kidney disease. Hypertension contributes importantly to these adverse outcomes. The renal pressure natriuresis (PN) response, a key regulator of blood pressure (BP), is impaired in rats with T1DM as tubular sodium reabsorption fails to down‐regulate with increasing BP. We hypothesised that sodium–glucose cotransporter 2 (SGLT2) inhibitors, which reduce cardiovascular risk in kidney disease, would augment the PN response in T1DM rats. Non‐diabetic or T1DM (35–50 mg/kg streptozotocin i.p.) adult male Sprague–Dawley rats were anaesthetised (thiopental 50 mg/kg i.p.) and randomised to receive either dapagliflozin (1 mg/kg i.v.) or vehicle. Baseline sodium excretion was measured and then BP was increased by sequential arterial ligations to induce the PN response. In non‐diabetic animals, the natriuretic and diuretic responses to increasing BP were not augmented by dapagliflozin. Dapagliflozin induced glycosuria, but this was not influenced by BP. In T1DM rats the PN response was impaired. Dapagliflozin again increased urinary glucose excretion but did not enhance PN. Inhibition of SGLT2 does not enhance the PN response in rats, either with or without T1DM. SGLT2 makes only a minor contribution to tubular sodium reabsorption and does not contribute to the impaired PN response in T1DM.

P2X7 receptors mediate immune and endothelial cell responses to extracellular ATP. Acute pharmacological blockade increases renal blood flow and filtration rate, suggesting that receptor activation promotes tonic vasoconstriction. P2X7 expression is increased in kidney disease and blockade/knockout is renoprotective. We generated a P2X7 knockout rat on F344 background, hypothesising enhanced renal blood flow and protection from angiotensin-II-induced renal injury. CRISPR/Cas9 introduced an early stop codon into exon 2 of P2rx7 , abolishing P2X7 protein in kidney and reducing P2rx7 mRNA abundance by ~ 60% in bone-marrow derived macrophages. The M1 polarisation response to lipopolysaccharide was unaffected but P2X7 receptor knockout suppressed ATP-induced IL-1β release. In male knockout rats, acetylcholine-induced dilation of the renal artery ex vivo was diminished but not the response to nitroprusside. Renal function in male and female knockout rats was not different from wild-type. Finally, in male rats infused with angiotensin-II for 6 weeks, P2X7 knockout did not reduce albuminuria, tubular injury, renal macrophage accrual, and renal perivascular fibrosis. Contrary to our hypothesis, global P2X7 knockout had no impact on in vivo renal hemodynamics. Our study does not indicate a major role for P2X7 receptor activation in renal vascular injury.

Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic nephropathy, is characterized by phenotypic variability that exceeds genic effects. Dysregulated metabolism and immune cell function are key disease modifiers. The tryptophan metabolites, kynurenines, produced through indoleamine 2,3-dioxygenase 1 (IDO1), are known immunomodulators. Here, we study the role of tryptophan metabolism in PKD using an orthologous disease model (C57BL/6J Pkd1 RC/RC ). We found elevated kynurenine and IDO1 levels in Pkd1 RC/RC kidneys versus wild type. Further, IDO1 levels were increased in ADPKD cell lines. Genetic Ido1 loss in Pkd1 RC/RC animals resulted in reduced PKD severity, as measured by cystic index and percentage kidney weight normalized to body weight. Consistent with an immunomodulatory role of kynurenines, Pkd1 RC/RC ; Ido1 –/– mice presented with significant changes in the cystic immune microenvironment (CME) versus controls. Kidney macrophage numbers decreased and CD8 + T cell numbers increased, both known PKD modulators. Also, pharmacological IDO1 inhibition in Pkd1 RC/RC mice and kidney-specific Pkd2 -knockout mice with rapidly progressive PKD resulted in less severe PKD versus controls, with changes in the CME similar to those in the genetic model. Our data suggest that tryptophan metabolism is dysregulated in ADPKD and that its inhibition results in changes to the CME and slows disease progression, making IDO1 a therapeutic target for ADPKD.

Background Helicobacter pylori infection causes gastritis, peptic ulcers, and gastric cancer. The infection is typically acquired in childhood and persists throughout life. The major impediment to successful therapy is antibiotic resistance. This systematic review and meta-analysis aimed to comprehensively assess the global prevalence of antibiotic resistance in pediatric H. pylori infection. Methods We performed a systematic search of publication databases that assessed H. pylori resistance rates to clarithromycin, metronidazole, levofloxacin, amoxicillin, and tetracycline in children. The WHO region classification was used to group pooled primary and secondary resistance estimates along with 95% confidence interval (CI). H. pylori antibiotic resistance rates were retrieved and combined with odds ratios (95% CI) to investigate the global prevalence and temporal trends. Subgroup analysis of the prevalence of antibiotic resistance was conducted by country, age groups, and susceptibility testing methods. Results Among 1417 records obtained initially, 152 studies were selected for eligibility assessment after applying exclusion criteria in multiple steps. Ultimately, 63 studies involving 15,953 individuals were included comprising data from 28 countries in 5 WHO regions. The primary resistance rates were metronidazole 35.3% (5482/15,529, 95% CI: 28.7–42.6), clarithromycin 32.6% (5071/15,555, 95% CI: 27.7–37.9), tetracycline 2.1% (148/7033, 95% CI: 1.3–3.6), levofloxacin 13.2% (1091/8271, 95% CI: 9.3–18.4), and amoxicillin 4.8% (495/10305, 95% CI: 2.5–8.8). Raising antibiotic resistance was detected in most WHO regions. Conclusions The escalating trend of H. pylori antibiotic resistance in children warrants urgent attention globally. National and regional surveillance networks are required for antibiotic stewardship in children infected with H. pylori . Graphical Abstract

Innate and adaptive immune cells modulate the severity of autosomal dominant polycystic kidney disease (ADPKD), a common kidney disease with inadequate treatment options. ADPKD has parallels with cancer, in which immune checkpoint inhibitors have been shown to reactivate CD8 + T cells and slow tumor growth. We have previously shown that in PKD, CD8 + T cell loss worsens disease. This study used orthologous early-onset and adult-onset ADPKD models ( Pkd1 p.R3277C) to evaluate the role of immune checkpoints in PKD. Flow cytometry of kidney cells showed increased levels of programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte associated protein 4 (CTLA-4) on T cells and programmed cell death ligand 1 (PD-L1)/CD80 on macrophages and epithelial cells in Pkd1 RC/RC mice versus WT, paralleling disease severity. PD-L1/CD80 was also upregulated in ADPKD human cells and patient kidney tissue versus controls. Genetic PD-L1 loss or treatment with an anti–PD-1 antibody did not impact PKD severity in early-onset or adult-onset ADPKD models. However, treatment with anti–PD-1 plus anti–CTLA-4, blocking 2 immune checkpoints, improved PKD outcomes in adult-onset ADPKD mice; neither monotherapy altered PKD severity. Combination therapy resulted in increased kidney CD8 + T cell numbers/activation and decreased kidney regulatory T cell numbers correlative with PKD severity. Together, our data suggest that immune checkpoint activation is an important feature of and potential novel therapeutic target in ADPKD.

Tuberous Sclerosis Complex (TSC) is a genetic condition which leads to a loss of inhibition of cellular growth. Facial angiofibromas (FAs) are hamartomatous growths associated with TSC that appear as multiple small, erythematous papules on the skin of the face and may resemble more severe forms of acne vulgaris. FAs have been reported in up to 74.5% of pediatric TSC patients, rising to up to 88% in adults >30 years old. They have not been closely studied, potentially overshadowed by other, systemic features of TSC. To investigate the impact of FAs, a common clinical feature for patients with TSC, we performed a non-interventional study in the form of a survey, completed by people living with TSC and FAs, or their caregiver as a proxy, if necessary. Patients were recruited via patient organizations in the UK and Germany. Data was received from 108 families in the UK (44 patients, 64 caregivers) and 127 families in Germany (50 patients, 64 caregivers). Exclusion criteria were those outside of 6-89 years, those without FAs, or those enrolled in a clinical trial. Where caregivers reported on behalf of an individual unable to consent, they were required to be adults (>18 years). Patient experience in the design of the survey was considered from practical and logistical perspectives with survey questions assessing multiple aspects relating to FAs including age of onset, perceived severity, treatments, perceived efficacy of treatments and perceived psychosocial impacts of the FAs. The psychosocial impacts of FAs for the individuals as well as for caregivers were explored in terms of social, occupational and leisure activities. Results of the survey demonstrated that for those with TSC-related moderate or severe FAs, there is an impact on quality of life and psychosocial impacts in the form of anxiety and depression. This finding was also noted by caregivers of TSC individuals in these categories. The treatment most frequently received to improve FAs, topical rapamycin/sirolimus, was found to be successful in the majority of those who received it.

We describe a three‐year‐old girl with an unusual c‐terminal binding protein 1 ( CTBP1 ) gene variant. She presented with features of hypotonia, ataxia, developmental delay and tooth enamel defect syndrome (HADDTS), following numerous chest infections, poor weight gain and delayed motor development during the early years. After many years of genetic testing where no diagnosis was found, whole genome sequencing (WGS) identified a missense variant in the CTBP1 gene (NM_001012614.1): c.991C > T p.(Arg331Trp). We present some of the brain MRI (cerebellar atrophy) and muscle biopsy features (central nuclei/cores) characteristic of this condition. The underlying mechanisms have not yet been elucidated. Although the clinical features make this condition recognisable, we are aware that in the small community of patients with this condition, the time to diagnosis may be exceptionally long. WGS has allowed us to accelerate this process. We are hopeful that earlier identification will bring better care for the affected children and allow the genetic implications to be discussed with their families.

ObjectiveAromatic L-amino acid decarboxylase deficiency (AADCd) is a rare neurometabolic disorder resulting from variants in the dopa decarboxylase (DDC) gene. Diagnosis of AADCd is often delayed because of variable clinical presentation. Patients are frequently misdiagnosed with more common conditions, such as cerebral palsy (CP) owing to a lack of AADCd awareness. REVEAL-CP is a prospective, multicentre, multinational, interventional, non-registrational study designed to investigate the prevalence of AADCd in patients presenting with symptoms of CP and to characterise genotypes associated with high 3-O-methyldopa (3-OMD) levels in dried blood spot samples. Following the study, UK paediatric neurologist investigators completed a survey on learning opportunities to improve the early identification of patients with AADCd who may be eligible for treatment.MethodsThe REVEAL-CP study screened patient records. After exclusion of patients with genetic and/or CSF neurotransmitter analysis, 49 UK patients were identified as being suitable for 3-OMD testing. Following the study, UK investigators completed a survey developed in collaboration with PharmaGenesis London, a third-party agency, including questions requiring yes/no, Likert scale (strongly agree; somewhat agree; neither agree nor disagree; somewhat disagree; strongly disagree; don’t know) and/or qualitative responses. Consensus was reached if the majority of investigator respondents somewhat or strongly agreed to individual questions.ResultsSix investigators completed the survey and reached consensus on the following recommendations to improve AADCd patient identification in the UK: adoption of a more centralised record system between NHS trusts, particularly between community and secondary paediatric practices; implementing genetic testing as the primary diagnostic tool for patients with CP-like symptoms of unknown aetiology; increasing awareness among clinicians of the differential diagnosis of neurotransmitter disorders in patients with CP-like symptoms; and earlier use of 3-OMD testing in the diagnostic workup of patients presenting with unexplained movement disorders or CP-like symptoms, alongside testing for serum prolactin and urinary organic acids including vanillactate, through the establishment of a nationally accredited 3-OMD service.ConclusionsA greater number of patients with CP-like symptoms of unknown aetiology could be screened for AADCd, taking into consideration the investigators’ suggestions. For rare diseases like AADCd, the provision of additional resources will be key for targeted patient screening. Given the recent EMA and MHRA marketing authorisation approvals for the first licensed gene therapy for AADCd, these improved efforts for early diagnosis could prove critical to the timely and effective management of patients with AADCd.ReferencesRizzi S, et al. Behav Neurol 2022;2022:2210555.Opladen T, et al. Mol Genet Metab Rep 2016;9:61–6.Burlina A, et al. Mol Genet Metab 2021;133:56–62.Chien YH, et al. Mol Genet Metab 2016;118:259–63.

ObjectiveIn a recent review of life expectancy for those with severe impairment with cerebral palsy (CP), Rosenthal’s conclusions stated, ‘tracheostomies deserve further debate and data acquisition’.1 We sourced clinical information using healthcare coding data (used for funding within the National Health Service) from one regional hospital.MethodsThe authors collaborated with business intelligence data analysts to identify two deceased CP datasets with and without a history of tracheostomy. ICD10 codes were used for CP and tracheostomy in addition to OPCS4 (procedural codes). Medical records of deceased patients with CP were reviewed. The data collected included: demographic data, age at death, cause of death, aetiology, age of tracheostomy and comorbidity data of tube feeding, non-invasive ventilation, epilepsy, movement disorder, severe learning difficulties and unassisted ambulation. Patients born after a single point in time were used to ensure comparable medical care. Patients with tracheostomy were cross-checked with an in-department record; no records had been omitted, and missing data were presented in the analysis.ResultsIn those with CP and tracheostomy (CPTrache) (n=6), the median age of death was 14.6 (range: 6.1 – 37.3) and a median age of tracheostomy insertion of 7.9 (range: 0.0 – 29.0). Those with CP who had not undergone tracheostomy insertion (CPNoTrache) had a median age of death of 12.5 (range 0.5 – 36.6). Compared to the CPNoTrache group, the CPTrache group had a higher prevalence of grade 5 GMFCS (CPTrache vs CPNoTrache; 100% vs 52%), tube-feeding (100% vs 76%), Non-invasive ventilation (67% vs 12%), and severe learning difficulties (100% vs 82%) compared to the CPNoTrache group.ConclusionsWe prove that coding data can support clinical research on rare and complex conditions. We have demonstrated that this method does not omit patients with a history of tracheostomy. We provide the first observational data on the outcomes of individuals with CP with tracheostomy and the differing prevalence of comorbidities compared to the CP population without tracheostomy. Although there is no significant difference in survival age, the patients with CP who have undergone tracheostomy insertion appear to have higher rates of comorbidities. This study would benefit from a greater cohort size via analysis of national Hospital Episode Statistics and data and the use of additional codes to assess for comorbidities, e.g., epilepsy, in place of an author review of medical notes.ReferenceRosenthal M. Life expectancy and its adjustment in cerebral palsy with severe impairment: Are we doing this right? Developmental Medicine and Child Neurology 2022;64(6):709–14.

BackgroundIdiopathic intracranial hypertension (IIH) is a potentially disabling condition. There is a lack of evidence and national guidance on how to diagnose and treat paediatric IIH, leading to variation in clinical practice. We conducted a national Delphi consensus via the Children’s Headache Network to propose a best-practice diagnostic and therapeutic pathway.MethodsThe Delphi process was selected as the most appropriate methodology for examining current opinion among experts in the UK. 104 questions were considered by 66 healthcare professionals, addressing important aspects of IIH care: assessment, diagnosis, treatment, follow-up and surveillance. General paediatricians, paediatric neurologists, ophthalmologists, opticians, neuroradiologists and neurosurgeons with a clinical interest or experience in IIH, were invited to take part.ResultsThe Delphi process consisted of three rounds comprising 104 questions (round 1, 67; round 2, 24; round 3 (ophthalmological), 13) and was completed between March 2019 and August 2021. There were 54 and 65 responders in the first and second rounds, respectively. The Delphi was endorsed by the Royal College of Ophthalmologists, which engaged 59 ophthalmologists for round 3.ConclusionsThis UK-based Delphi consensus process reached agreement for the management of paediatric IIH and has been endorsed by the Children’s Headache Network and more broadly, the British Paediatric Neurology Association. It provides a basis for a pragmatic clinical approach. The recommendations will help to improve clinical care while minimising under and over diagnosis.