Impact of citrulline substitution on clinical outcome after liver transplantation in carbamoyl phosphate synthetase 1 and ornithine transcarbamylase deficiency.

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.

Detection of cytokines in nasal lavage samples of patients with cystic fibrosis: comparison of two different cytokine detection assays.

BACKGROUND: Cystic fibrosis (CF) is a genetic multisystem disorder. Inflammatory processes, which presumably begin early in infancy, play a crucial role in the progression of the disease. The detection of inflammatory biomarkers, especially in the airways, has therefore gained increasing attention. Due to improved treatment options, patients with CF produce less sputum. Nasal lavage samples therefore represent a promising alternative to induced sputum or bronchoalveolar lavage specimens. However, methodology of cytokine measurements is not standardised and comparisons of results are therefore often difficult. The aim of this study was to identify suitable detection methods of cytokines in nasal lavage samples by comparison of two different assays. METHODS: Nasal lavage samples were obtained from the same patient at the same time by trained respiratory physiotherapists using a disposable syringe and 10 ml of 0.9% sodium chloride per nostril during outpatient visits. The cytokines IL-17 A, IL-2, IL-6 and IL-10 were measured using two different assays (BD™ and Milliplex®), which have already been applied in sputum and nasal lavage samples, despite different lower detection limits. RESULTS: 22 participants were included in the study. In 95.5% of measurements, values were below the limit of detection with respect to the BD™ assay. Only IL-6 could be detected in approximately half of the patients. Individual cytokine levels were considerably higher when measured with Milliplex®, which is also reflected in a statistically significant manner (p = < 0.01). CONCLUSION: The right choice of analysis method is crucial for measuring inflammatory markers in nasal lavage samples. Compared to the literature, Milliplex® showed higher detection rates and similar concentrations to other studies. TRIAL REGISTRATION: Ethics approval was obtained from the ethics committee at Medical University of Innsbruck (EK Nr: 1055/2022).

Common variable immunodeficiency with granulomatous-lymphocytic interstitial lung disease treated with monoclonal antibodies against COVID-19: A case report.

Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency. We present a 22-year-old Caucasian woman with CVID and granulomatous lymphocytic interstitial lung disease who contracted COVID-19 and was successfully treated with sotrovimab and molnupiravir. This treatment may have contributed to the relatively mild disease course of COVID-19 in our patient.

The influence of liver transplantation on the interplay between gut microbiome and bile acid homeostasis in children with biliary atresia.

BACKGROUND: Biliary atresia (BA) causes neonatal cholestasis and rapidly progresses into cirrhosis if left untreated. Kasai portoenterostomy may delay cirrhosis. BA remains among the most common indications for liver transplantation (LT) during childhood. Liver function and gut microbiome are interconnected. Disturbed liver function and enterohepatic signaling influence microbial diversity. We, herein, investigate the impact of LT and reestablishment of bile flow on gut microbiome-bile acid homeostasis in children with BA before (pre, n = 10), 3 months (post3m, n = 12), 12 months (post12m, n = 9), and more than 24 months (post24 + m, n = 12) after LT. METHODS: We analyzed the intestinal microbiome of BA patients before and after LT by 16S-rRNA-sequencing and bioinformatics analyses, and serum primary and secondary bile acid levels. RESULTS: The gut microbiome in BA patients exhibits a markedly reduced alpha diversity in pre (p = 0.015) and post3m group (p = 0.044), and approximated healthy control groups at later timepoints post12m (p = 1.0) and post24 + m (p = 0.74). Beta diversity analysis showed overall community structure similarities of pre and post3m (p = 0.675), but both differed from the post24 + m (p < 0.001). Longitudinal analysis of the composition of the gut microbiome revealed the Klebsiella genus to show increased abundance in the post24 + m group compared with an age-matched control (p = 0.029). Secondary bile acid production increased 2+ years after LT (p = 0.03). Multivariable associations of microbial communities and clinical metadata reveal several significant associations of microbial genera with tacrolimus and mycophenolate mofetil-based immunosuppressive regimens. CONCLUSIONS: In children with BA, the gut microbiome shows strongly reduced diversity before and shortly after LT, and approximates healthy controls at later timepoints. Changes in diversity correlate with altered secondary bile acid synthesis at 2+ years and with the selection of different immunosuppressants.

Workload and job satisfaction among Austrian pediatricians: gender and generational aspects.

BACKGROUND: The aim of this study was to evaluate different factors that may contribute to workload and job satisfaction among Austrian pediatricians. METHODS: We conducted an online survey with 16 questions and performed statistical analyses. RESULTS: Of 375 participating pediatricians, 61% were female, 39% male, 61% clinicians, 21% panel doctors and 12% private doctors. Overall, job satisfaction was moderate (6 ± 2.4 on a positive scale of 0-10). Higher working hours (p = 0.014) and higher patient numbers (p = 0.000) were significantly associated with lower job satisfaction. Lowest satisfaction was described for administrative or other nonmedical work. Lack of time for patient consultation was also correlated with poor satisfaction. Pediatricians older than 65 years reported the highest job satisfaction whereas pediatricians between 55 and 65 years and younger than 36 years showed the lowest scores. Although male pediatricians worked significantly more often more than 40 h per week than females (75% vs. 53%, p = 0.000), female pediatricians were less satisfied about the proportion of administrative (p = 0.015) and other nonmedical work (p = 0.014). CONCLUSION: New working models considering less workload, particularly less nonmedical work and intensified collaboration between pediatric clinicians and practitioners are needed to allow more available time per patient, to increase job satisfaction and thus to raise attractivity for pediatric primary care.

Immunological Memory and Affinity Maturation After Vaccination in Patients With Propionic Acidemia.

Earlier studies have recommended routine childhood immunization in patients with propionic acidemia (PA); however, the literature presents insufficient data on the response to vaccines, notably specific IgG concentrations and avidity maturation, after measles, mumps, rubella (MMR), and diphtheria/tetanus (DiphtTe) vaccinations in this population. In patients with PA, cellular and humoral changes of the immune system (e.g. a decreased CD4+ T cell count, with a reversal of CD4/CD8 T cell ratio, a deficient gamma-globulin fraction, and in one case a decreased lymphocyte blastogenesis) have been reported. Former reports also detected pancytopenias accompanying febrile infections in PA patients. In the current study, we analyzed vaccine-specific IgG concentrations and avidity maturation after MMR and DiphtTe vaccinations in 10 patients with PA. Compared to gender and age matched controls, all 10 had protective IgG concentrations for at least one tested antigen, and in 6 out of 10 patients high relative avidity indices for measles and rubella were detected. In summary, the present study revealed a sufficient immune response and outcome, indicating an acceptable humoral memory in patients with PA after booster vaccinations.

Nitisinone treatment during two pregnancies and breastfeeding in a woman with tyrosinemia type 1 - a case report.

OBJECTIVES: Tyrosinaemia type 1, an inherited disorder of tyrosine metabolism, is usually treated with a tyrosine-defined diet and since 2000 with nitisinone. So far, data about effects of nitisone during pregnancy and breastfeeding are rare. This is the first report of two pregnancies in a patient with tyrosinaemia type 1 while under treatment with nitisinone. CASE PRESENTATION: We here present a 20-year-old female patient with tyrisonemia type 1 receiving treatment with nitisinone and a tyrosine-defined diet since she was diagnosed with tyrosinaemia type 1 at the age of 18 months. During two pregnancies blood concentrations of tyrosine, succinylacetone and nitisinone were measured regularly. Neither infant has tyrosinaemia type 1 and both showed an initial increase in concentrations of tyrosine, succinylacetone and nitisinone. All three metabolites dropped within two weeks after birth. Both were exclusively breastfed for about two weeks. Both children show age-appropriate physical and mental development. CONCLUSIONS: Nitisinone therapy during pregnancy and the short breastfeeding period did not result in adverse events in our patient or her children. Regular assessments of tyrosine, succinylacetone and nitisinone should be made during pregnancy and the breastfeeding period in both the mother and the infant. For better understanding, in principle, all cases of pregnancy and breastfeeding with tyrosinemia type 1 should be assessed and followed to further evaluate the implications of tyrosinaemia type 1 and its treatment during pregnancy. Additionally, even though experience with breastfeeding is limited, medication with nitisinone is safe and there is no reason to consider breastfeeding unsafe or to not recommend it.

High Prevalence of Undocumented SARS-CoV-2 Infections in the Pediatric Population of the Tyrolean District of Schwaz.

Complementing the adult seroprevalence data collected at the time of the rapid SARS-CoV-2 mass vaccination in the district of Schwaz in 2021, we set out to establish the seroprevalence of SARS-CoV-2 among the pediatric population of the district. A total of 369 children, mean age 9.9 (SD 3.4), participated in the study, answering a structured questionnaire on the history of SARS-CoV-2 infection, household contacts, symptoms and history of vaccination. We determined binding and neutralizing antibody levels using plasma samples provided. We estimated the overall prevalence of SARS-CoV-2 infection in the general pediatric population at the time of the study using the census data from Statistik Austria and daily reports of officially confirmed cases. Excluding study participants who reported a history of PCR-confirmed infection, the age-standardized seroprevalence of previously unknown SARS-CoV-2 infection among the general pediatric population of the district was 27% (95% CI: 26.1-27.8). Adding this to the officially documented cases, the true overall prevalence was 32.8% (95% CI: 31.9-33.6) in contrast to the officially documented 8.0% (95% CI: 7.5-8.5) by June 2021. This translated into a proportion of 75.7% (95% CI: 74.4-77.0) of cases being officially undocumented, suggesting a high extent of silent SARS-CoV-2 infections in the pediatric population and possibly silent transmission.

Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier.

The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1, MDH2, GOT2, SLC25A12) sharing a neurological/epileptic phenotype, as well as citrin deficiency (SLC25A13) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1-individuals with a neurological phenotype treated with KD, 11 experienced benefits-mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1-defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving.

Long-term experience with triheptanoin in 12 Austrian patients with long-chain fatty acid oxidation disorders.

BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of rare inborn errors of metabolism with autosomal recessive inheritance that may cause life-threatening events. Treatment with triheptanoin, a synthetic seven-carbon fatty acid triglyceride compound with an anaplerotic effect, seems beneficial, but clinical experience is limited. We report our long-term experience in an Austrian cohort of LC-FAOD patients. METHODS: We retrospectively assessed clinical outcome and total hospitalization days per year before and after start with triheptanoin by reviewing medical records of 12 Austrian LC-FAOD patients RESULTS: For 12 Austrian LC-FAOD patients at three metabolic centers, triheptanoin was started shortly after birth in 3/12, and between 7.34 and 353.3 (median 44.5; mean 81.1) months of age in 9/12 patients. For 11 pediatric patients, mean duration of triheptanoin intake was 5.3 (median 3.9, range 1.2-15.7) years, 10/11 pediatric patients have an ongoing intake of triheptanoin. One patient quit therapy due to reported side effects. Total hospitalization days per year compared to before triheptanoin treatment decreased by 82.3% from 27.1 (range 11-65) days per year to 4.8 (range 0-13) days per year, and hospitalization days in the one year pre- compared to the one year post-triheptanoin decreased by 69.8% from 27.1 (range 4-75) days to 8.2 (range 0-25) days. All patients are in good clinical condition, show normal psychomotor development and no impairment in daily life activities. CONCLUSION: In this retrospective observational study in an Austrian LC-FAOD cohort, triheptanoin data show improvement in disease course. Triheptanoin appears to be a safe and beneficial treatment option in LC-FAOD. For further clarification, additional prospective randomized controlled trials are needed.