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AimsLate onset sepsis is a major cause of morbidity and mortality within the field of neonatology, with coagulase- negative staphylococci being the most commonly reported pathogens. Due to staphylococcal resistance patterns vancomycin is an essential therapeutic agent. Its efficacy correlates directly with duration of bacterial exposure at therapeutic levels. Some studies have suggested that continuous infusion achieves quicker and more sustained therapeutic levels than traditional intermittent dosing. Continuous dosing was introduced in our neonatal units in September 2015. This piece of work audits adherence to local prescribing and monitoring guidance whilst assessing the effectiveness of the new continuous regimes.MethodAll infants commenced on continuous vancomycin over a six month period were included. Cases were identified via pharmacy records and data collected retrospectively and prospectively. Key areas were: loading and initial continuous doses, therapeutic drug monitoring (TDM), time spent in therapeutic range and the associated effects of gestation and baseline creatinine. Adverse effects were also considered. Data was analysed using Excel and Prism.Results45 treatment episodes were eligible for analysis. Corrected gestation ranged from 24+5 to 41+6. Mean weight was 1450 g and mean duration of therapy 6.5 days. Loading, initial continuous dosing and TDM were generally carried out in line with local guidelines. Regarding the first level measured after commencement of the continuous regime; 9% of levels with continuous infusion were subtherapeutic. A previous audit of intermittent vancomycin dosing showed that 50% of first levels were subtherapeutic. Statistically there was a weak correlation between creatinine level prior to commencement of continuous vancomycin and the first level. Of all 298 levels measured 56% were therapeutic, 19% were supratherapeutic and 25% subtherapeutic. Time spent in therapeutic range was comparable across the range of gestational groups.ConclusionContinuous vancomycin dosing showed promising results in this population. Adherence to local guidelines in terms of prescribing and monitoring was good. The time taken to reach therapeutic range was shorter than previously achieved with intermittent dosing. Maintaining levels with this therapeutic range was also seen to be favourable. More detailed analysis of our results suggests that our dosing guidance is adjusted correctly to take into account important variables in vancomycin pharmacokinetics such as corrected gestational age and renal function. No adverse effects specific to vancomycin were noted during the course of this work.

In urea cycle disorders (UCDs) ammonia scavenger drugs, usually sodium‐based, have been the mainstay of treatment. Increasingly, glycerol phenylbutyrate (GPB, Ravicti®) is being used but scant real‐world data exist regarding clinical outcomes. A retrospective study of UCD patients initiated on or switched to GPB was performed at a UK centre. Data on population characteristics, treatment aspects, laboratory measurements, and clinical outcomes were collected before and after patients started GPB with a sub‐group analysis undertaken for patients with ≥12 months of data before and after starting GPB. UCDs included arginosuccinate synthetase deficiency ( n  = 8), arginosuccinate lyase deficiency ( n  = 6), ornithine carbamoyltransferase deficiency ( n  = 3), and carbamoyl phosphate synthetase 1 deficiency ( n  = 3). In the sub‐group analysis ( n  = 11), GPB resulted in lower plasma ammonia (31 vs. 41 μmol/L, p  = 0.037), glutamine (670 vs. 838 μmol/L, p  = 0.002), annualised hyperammonaemic episodes (0.2 vs. 1.9, p  = 0.020), hospitalisations (0.5 vs. 2.2, p  = 0.010), and hyperammonaemic episodes resulting in hospitalisation (0.2 vs. 1.6, p  = 0.035) reflecting changes seen in the whole group. Overall, patients exposed to sodium and propylene glycol levels above UK daily limits reduced by 78% and 83% respectively. Mean levels of branched chain amino acids, haemoglobin, and white cell count were unchanged. Two adverse drug reactions (pancytopenia, fatigue/appetite loss) resolved without GPB discontinuation. Patients/families preferred GPB for its lower volume, greater palatability and easier administration. GPB appeared to improve biochemical measures and clinical outcomes. The causes are multi‐factorial and are likely to include prolonged action of GPB and its good tolerability, even at higher doses, facilitating tighter control of ammonia.

Background Newborn screening has enabled the early diagnosis of Glutaric aciduria type 1, with the possibility of improving neurological outcomes in affected children. Achieving those outcomes requires parents to effectively manage their child’s condition by adherence to a strict dietary regime and responding to situations that may trigger decompensation. The specific information and support needs of this group of parents are unknown. Methods A focus group with five parents was conducted to gain insights into the information that parents needed and the ways in which they accessed and used information to manage their child’s condition. A topic guide was used to direct the discussion which was recorded and fully transcribed. All participants gave informed consent. Data were analysed using thematic analysis, a structured approach that contributes to transparency and validity of results while allowing the integration of predetermined and emerging themes. To ensure rigour, two researchers were involved in initial coding of data and key analytic decisions. Results Two main themes were identified. ‘ Understanding the condition’ explored parent’s needs to understand the scientific complexity of the condition and to be aware of the worst case scenario associated with loss of metabolic control. ‘ Managing the condition’ explained how parents co-ordinated and controlled the involvement of other carers and parents’ need to be active partners in medical management to feel in control of the situation. Conclusions The study highlights the importance of addressing parents’ initial and ongoing informational needs so they can fulfil their role and protect their child from metabolic harm.

Long‐term management of urea cycle disorders (UCDs) often involves unlicensed oral sodium benzoate (NaBz) which has a high volume and unpleasant taste. A more palatable treatment is licenced and available (glycerol phenylbutyrate [GPB], Ravicti) but guidance on how to transition patients from NaBz is lacking. A retrospective analysis of clinical and biochemical data was performed for eight children who transitioned from treatment with a single ammonia scavenger, NaBz, to GPB at a single metabolic centre; UCDs included arginosuccinic aciduria (ASA) (n = 5), citrullinaemia type 1 (n = 2) and carbamoyl phosphate synthetase I deficiency (CPS1) (n = 1). Patients transitioned either by gradual transition over 1–2 weeks (n = 3) or direct replacement of NaBz with GPB (n = 5). Median initial dose of GPB was 8.5 mL/m2/day based on published product information; doses were revisited subsequently in clinic and titrated individually (range 4.5–11 mL/m2/day). Pre‐transition and post‐transition mean ammonia levels were 37 μmol/L (SD 28 μmol/L) and 29 μmol/L (SD 22 μmol/L), respectively (p = 0.09), and mean glutamine levels were 664 μmol/L (SD 225 μmol/L) and 598 μmol/L (SD 185 μmol/L), respectively (p = 0.24). There were no reductions in levels of branched chain amino acids. No related adverse drug reactions were reported. Patients preferred GPB because of its lower volume and greater palatability. Direct replacement of NaBz with GPB maintained metabolic control and was simple for the health service and patients to manage. A more cautious approach with additional monitoring would be warranted in brittle patients and patients whose ammonia levels are difficult to control.

Background PPCS deficiency disorder (PPCS DD) is an ultra-rare, autosomal recessive form of dilated cardiomyopathy (DCM) caused by pathogenic variants in PPCS, which encodes the enzyme catalyzing the second step in the coenzyme A (CoA) biosynthesis pathway. To date, only six patients worldwide have been identified. Methods Whole-exome sequencing was performed to identify pathogenic PPCS variants in affected individuals. Protein stability was assessed by Western blotting. CoA levels were quantified using a microplate-based assay in patient-derived fibroblasts, cardiac progenitor cells, and cardiomyocytes. Functional evaluation of cardiac cells and engineered heart patches was conducted to investigate contractile performance and arrhythmogenicity. Pantethine was tested as a potential therapeutic agent both in vitro and through long-term clinical follow-up in patients. Results Causative PPCS variants are identified in six individuals with DCM and variable associated features, including neuromuscular and neurological symptoms. Identified variants lead to reduced PPCS protein stability and decreased cellular CoA levels. Cardiac cells exhibit impaired contractility and arrhythmias, which are partially rescued by pantethine treatment. Clinically, patients receiving pantethine show sustained improvement over time. Conclusions Our study expands the genetic and clinical spectrum of PPCS deficiency disorder, identifying six new cases with diverse phenotypes. Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells. Pantethine treatment shows promise in partially rescuing DCM phenotypes, both in vitro and in patients. However, complete reversal may require early intervention. These findings underscore the importance of timely diagnosis and treatment in PPCS DD. Future research should focus on optimizing pantethine supplementation and exploring additional therapies to enhance CoA levels and cardiac function in affected individuals. Zhang, Dorn, Gnutti et al. identify pathogenic PPCS variants in people with PPCS deficiency disorder. Cardiac cells exhibit impaired contractility and arrhythmias, which is partially rescued by pantethine treatment. Plain language summary PPCS deficiency disorder is an extremely rare inherited disease that causes heart muscle weakness (dilated cardiomyopathy) and other symptoms. It results from changes in a gene involved in making coenzyme A (CoA), a vital molecule for cell energy. This study identified six new patients with the condition and investigated how these gene changes affect heart function. Researchers used patient cells and lab-grown heart tissues to study the disease and tested pantethine, a compound that helps increase CoA levels. They found that pantethine improved heart cell function and showed positive effects in treated patients. These results highlight the importance of early diagnosis and treatment. In the future, therapies such as pantethine could offer hope for improving heart health in affected individuals.

Argininosuccinate lyase is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide biosynthesis cycle. Inherited argininosuccinate lyase deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonaemia and nitric oxide deficiency. Patients present with developmental delay, epilepsy and movement disorders, associated with nitric oxide-mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for movement disorders-related symptoms: movement disorders such as ataxia, tremor and dystonia, hypotonia and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an ASA patient with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide 123I-ioflupane, in Asl-deficient mice treated by hASL mRNA with normalised ureagenesis. Movement disorders in ASA appears in the 2nd and 3rd decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonaemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal 123I-ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late-onset movement disorders with functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy. Movement disorders-related symptoms in ASA appear in the 2nd and 3rd decades of life, becoming more prevalent with age and shows abnormal neuroimaging features of basal ganglia in ASA patients, not recapitulated in ASA mice.