Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.

PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

Incidence of Medication-Related Osteonecrosis of the Jaw in Patients With Breast Cancer During a 20-Year Follow-Up: A Population-Based Multicenter Retrospective Study.

PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) is one of the most important toxicities of antiresorptive therapy, which is standard practice for patients with breast cancer and bone metastases. However, the population-based incidence of MRONJ is not well established. We therefore performed a retrospective multicenter study to assess the incidence for a whole Austrian federal state (Tyrol). MATERIALS AND METHODS: This retrospective multicenter study was conducted between 2000 and 2020 at all nine breast centers across Tyrol, Austria. Using the cancer registry, the total Tyrolean population was screened for all patients with breast cancer. All patients with breast cancer and bone metastases receiving antiresorptive therapy were finally included in the study. RESULTS: From 8,860 patients initially screened, 639 individuals were eligible and included in our study. Patients received antiresorptive therapy once per month without de-escalation of therapy. MRONJ was diagnosed in 56 (8.8%, 95% CI, 6.6 to 11.0) patients. The incidence of MRONJ was 11.6% (95% CI, 8.0 to 15.3) in individuals treated with denosumab only, 2.8% (95% CI, 0.7 to 4.8) in those treated with bisphosphonates only, and 16.3% (95% CI, 8.8 to 23.9) in the group receiving bisphosphonates followed by denosumab. Individuals developed MRONJ significantly earlier when treated with denosumab. Time to MRONJ after treatment initiation was 4.6 years for individuals treated with denosumab only, 5.1 years for individuals treated with bisphosphonates only, and 8.4 years for individuals treated with both consecutively. CONCLUSION: MRONJ incidence in breast cancer patients with bone metastases was found to be considerably higher, especially for patients receiving denosumab, when compared with available data in the literature. Additionally, patients treated with denosumab developed MRONJ significantly earlier.

Mortality of Hemato-Oncologic Patients Admitted to a Pediatric Intensive Care Unit: A Single-Center Experience.

Introduction: Mortality in children with hemato-oncologic disease admitted to a pediatric intensive care unit (PICU) is higher compared to the general population. The reasons for this fact remain unexplored. The aim of this study was to assess outcomes and trends in hemato-oncologic patients admitted to a PICU, with analytical emphasis on emergency admissions. Methods: Patients with a hemato-oncologic diagnosis admitted to a tertiary care university hospital PICU between 1 January 2009 and 31 December 2019 were retrospectively analyzed. Additionally, patient mortality 6 months after PICU admission and follow-up mortality until 31 December 2020 were recorded. Measurements and Main Results: We reviewed a total of 701 PICU admissions of 338 children with hemato-oncologic disease, of which 28.5% were emergency admissions with 200 admissions of 122 patients. Of these, 22 patients died, representing a patient mortality of 18.0% and an admission mortality of 11.0% in this group. Follow-up patient mortality was 25.4% in emergency-admitted children. Multivariable analysis revealed severe neutropenia at admission and invasive mechanical ventilation (IMV) as independent risk factors for PICU death (p = 0.029 and p = 0.002). The total number of PICU admissions of hemato-oncologic patients rose notably over time, from 44 in 2009 to 125 in 2019. Conclusion: Although a high proportion of emergency PICU admissions of hemato-oncologic patients required intensive organ support, mortality seemed to be lower than previously reported. Moreover, in this study, total PICU admissions of the respective children rose notably over time.

Changes in characteristics and outcomes of critically ill COVID-19 patients in Tyrol (Austria) over 1 year.

BACKGROUND: Widely varying mortality rates of critically ill Coronavirus disease 19 (COVID-19) patients in the world highlighted the need for local surveillance of baseline characteristics, treatment strategies and outcome. We compared two periods of the COVID-19 pandemic to identify important differences in characteristics and therapeutic measures and their influence on the outcome of critically ill COVID-19 patients. METHODS: This multicenter prospective register study included all patients with a SARS-CoV­2 infection confirmed by polymerase chain reaction, who were treated in 1 of the 12 intensive care units (ICU) from 8 hospitals in Tyrol, Austria during 2 defined periods (1 February 2020 until 17 July: first wave and 18 July 2020 until 22 February 2021: second wave) of the COVID-19 pandemic. RESULTS: Overall, 508 patients were analyzed. The majority (n = 401) presented during the second wave, where the median age was significantly higher (64 years, IQR 54-74 years vs. 72 years, IQR 62-78 years, p < 0.001). Invasive mechanical ventilation was less frequent during the second period (50.5% vs 67.3%, p = 0.003), as was the use of vasopressors (50.3% vs. 69.2%, p = 0.001) and renal replacement therapy (12.0% vs. 19.6%, p = 0.061), which resulted in shorter ICU length of stay (10 days, IQR 5-18 days vs. 18 days, IQR 5-31 days, p < 0.001). Nonetheless, ICU mortality did not change (28.9% vs. 21.5%, p = 0.159) and hospital mortality even increased (22.4% vs. 33.4%, p = 0.039) in the second period. Age, frailty and the number of comorbidities were significant predictors of hospital mortality in a multivariate logistic regression analysis of the overall cohort. CONCLUSION: Advanced treatment strategies and learning effects over time resulted in reduced rates of mechanical ventilation and vasopressor use in the second wave associated with shorter ICU length of stay. Despite these improvements, age appears to be a dominant factor for hospital mortality in critically ill COVID-19 patients.