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OBJECTIVES The aim of this study was to investigate the performance of the EuroSCORE II over time and dynamics in values of predictors included in the model. METHODS A cohort study was performed using data from the Netherlands Heart Registration. All cardiothoracic surgical procedures performed between 1 January 2013 and 31 December 2019 were included for analysis. Performance of the EuroSCORE II was assessed across 3-month intervals in terms of calibration and discrimination. For subgroups of major surgical procedures, performance of the EuroSCORE II was assessed across 12-month time intervals. Changes in values of individual EuroSCORE II predictors over time were assessed graphically. RESULTS A total of 103 404 cardiothoracic surgical procedures were included. Observed mortality risk ranged between 1.9% [95% confidence interval (CI) 1.6–2.4] and 3.6% (95% CI 2.6–4.4) across 3-month intervals, while the mean predicted mortality risk ranged between 3.4% (95% CI 3.3–3.6) and 4.2% (95% CI 3.9–4.6). The corresponding observed:expected ratios ranged from 0.50 (95% CI 0.46–0.61) to 0.95 (95% CI 0.74–1.16). Discriminative performance in terms of the c-statistic ranged between 0.82 (95% CI 0.78–0.89) and 0.89 (95% CI 0.87–0.93). The EuroSCORE II consistently overestimated mortality compared to observed mortality. This finding was consistent across all major cardiothoracic surgical procedures. Distributions of values of individual predictors varied broadly across predictors over time. Most notable trends were a decrease in elective surgery from 75% to 54% and a rise in patients with no or New York Heart Association I class heart failure from 27% to 33%. CONCLUSIONS The EuroSCORE II shows good discriminative performance, but consistently overestimates mortality risks of all types of major cardiothoracic surgical procedures in the Netherlands.

Purpose: While neonatal bloodspot screening (NBS) for severe combined immunodeficiency (SCID) has been introduced more than a decade ago, implementation in NBS programs remains challenging in many countries. Even if high-quality test methods and follow-up care are available, public uptake and parental acceptance are not guaranteed. The aim of this study was to describe the parental perspective on NBS for SCID in the context of an implementation pilot. Psychosocial aspects have never been studied before for NBS for SCID and are important for societal acceptance, a major criterion when introducing new disorders in NBS programs. Methods: To evaluate the perspective of parents, interviews were conducted with parents of newborns with abnormal SCID screening results (N = 17). In addition, questionnaires about NBS for SCID were sent to 2000 parents of healthy newborns who either participated or declined participation in the SONNET-study that screened 140,593 newborns for SCID. Results: Support for NBS for SCID was expressed by the majority of parents in questionnaires from both a public health perspective and a personal perspective. Parents emphasized the emotional impact of an abnormal screening result in interviews. (Long-term) stress and anxiety can be experienced during and after referral indicating the importance of uniform follow-up protocols and adequate information provision. Conclusion: The perspective of parents has led to several recommendations for NBS programs that are considering screening for SCID or other disorders. A close partnership of NBS programs’ stakeholders, immunologists, geneticists, and pediatricians-immunologists in different countries is required for moving towards universal SCID screening for all infants.

Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3'-phospho-adenosine-5'-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. Patients and Methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. Results: We identified a novel PAPSS2 frameshift mutation, c. 1371del, p. W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c. 809G>A, p. G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p. W462Cfs*3, showed increased 5 alpha-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome.

Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic aciduria (e.g. organic acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11% presented 3-methylglutaconic aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.