Impact of hospitalization for vaso-occlusive crisis on health-related quality of life in children with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is characterized by vaso-occlusive crises (VOCs) that impair the health-related quality of life (HRQoL). The aim of this study is to evaluate the impact of hospitalization for VOCs on HRQoL in children with SCD over time. METHODS: In this longitudinal cohort study, children aged 8-18 years diagnosed with SCD at the Amsterdam UMC were included between 2012 and 2021. HRQoL was annually measured as part of standard care using the Pediatric Quality of Life Inventory. The impact of hospitalization for VOC on HRQoL was evaluated using linear mixed models 3, 6, 9, and 12 months after hospitalization. The effect of frequency of hospitalization for VOC on HRQoL was evaluated over the last 12 months. RESULTS: In total, 94 children with SCD were included with a median age of 11.8 years (interquartile range [IQR]: 9-14). Thirty-seven patients (39%) had been hospitalized for a VOC. Hospitalization for VOC led to a decrease of 3.2-4.8 points in total HRQoL compared to patients without hospitalization, most pronounced 3 months after hospitalization. Recurrent admission for VOC in the last 12 months was associated with a decrease of 2.3 points in total HRQoL (p = .04). The most affected subscale was physical functioning. CONCLUSION: The adverse effects of hospitalization for VOC in children with SCD persist up to 12 months after hospitalization. After hospitalization for VOC, extra attention and support for its negative impact on HRQoL are recommended. This study also underlines the importance of systematically measuring HRQoL, allowing clinicians to intervene accordingly.

Mortality and Causes of Death From Sickle Cell Disease in The Netherlands, 1985-2017.

In the Netherlands, between 1985 and 2007 secular changes in the health care of patients with sickle cell disease (SCD) have taken place, such as penicillin prophylaxis, vaccination programs and stroke prevention. We investigated the number and causes of death in a cohort of 298 SCD patients, established in 2007, before introduction of neonatal screening, to determine preventable deaths. All patients were diagnosed with SCD before the age of 18 (median age at diagnosis 5.1 y). Their vital status was determined up to January 2017. After a total follow-up period of 4565 patient years and a median time of follow-up of 15 years for all patients, 230 patients (77%) were still alive, 45 patients (15%) were lost to follow-up and a total of 23 patients (8%) had died. Estimated survival to 18 years was 92% with a global mortality rate of 0.48 deaths/100 patient years. Leading causes of death were infection (35%) followed by neurologic complications (22%) and death in the course of a painful episode (13%). Nine of the 20 known causes of death were preventable. These results strongly suggest the benefit of comprehensive care measures for patients with SCD in the Netherlands to further prevent morbidity and mortality.

A heterozygous mutation in the third transmembrane domain causes a dominant-negative effect on signalling capability of the MC4R.

BACKGROUND: Heterozygous MC4R mutation is the most frequent cause of monogenic obesity. For most MC4R mutations a gene dosage effect seems to be the underlying mechanism. However, a dominant negative effect of a heterozygous MC4R mutation was recently identified, pointing to an additional mechanism of MC4R inactivation. METHODS: The complete loss-of-function mutation (Ser136Phe), identified in a cohort of obese Austrian patients, was characterized for cell surface expression, signal transduction and ligand binding properties. Co-transfection studies tested for a dominant negative effect. Dimerization was investigated by a sandwich ELISA and by fluorescence resonance energy transfer (FRET) approach. Potential intramolecular interactions of Ser136 were studied by homologous receptor modelling based on the crystal structure of the beta2-adrenergic receptor. RESULTS: The Ser136Phe mutation showed a dominant negative effect. The sandwich ELISA and FRET approach demonstrated dimerization of mutant and wild type receptor. Receptor modelling revealed an essential function of Ser136 at transmembrane helix 3 (TMH3) for establishing H-bonds between TMH2, TMH3, and TMH7. The mutation Ser136Phe most likely disrupts this network and leads to an incompetent helix-helix arrangement in the mutated receptor. CONCLUSION: Identification of dominant negative MC4R mutations is important to fully understand receptor function and to determine receptor regions that are involved in MC4R dimer activation.