How to move forward in shared decision-making in pediatric palliative care.

Pediatric palliative care has grown immensely in recent years in the world. However, shared decision-making remains a complex process, especially in pediatric palliative care. In particular, a number of issues are priorities to improve the shared decision-making process and ensure high-quality pediatric palliative care for every child. Working on these priorities will improve shared decision-making and thereby enhance high-quality pediatric palliative care around the globe.

CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders.

PURPOSE: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system. METHODS: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences. RESULTS: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models. CONCLUSION: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.

Pediatric palliative care across continents: Communication and shared-decision-making.

Despite the significant growth and development of pediatric palliative care worldwide, significant challenges remain. One of those challenges is shared decision-making, by which parents, families and professionals all work together to develop a plan of care that reflects both the medical facts and the patient's family's values. Shared decision-making about palliative care and about death and dying may mean different things in different cultures and countries. It is therefore important to learn and compare practices around the world.

The resilience of Jewish communities living in the diaspora: a scoping review.

Introduction: Throughout history, Jewish communities have been exposed to collectively experienced traumatic events. Little is known about the role that the community plays in the impact of these traumatic events on Jewish diaspora people. This scoping review aims to map the concepts of the resilience of Jewish communities in the diaspora and to identify factors that influence this resilience. Methods: We followed the Joanna Briggs Institute (JBI) methodology. Database searches yielded 2,564 articles. Sixteen met all inclusion criteria. The analysis was guided by eight review questions. Results: Community resilience of the Jewish diaspora was often described in terms of coping with disaster and struggling with acculturation. A clear definition of community resilience of the Jewish diaspora was lacking. Social and religious factors, strong organizations, education, and communication increased community resilience. Barriers to the resilience of Jewish communities in the diaspora included the interaction with the hosting country and other communities, characteristics of the community itself, and psychological and cultural issues. Discussion: Key gaps in the literature included the absence of quantitative measures of community resilience and the lack of descriptions of how community resilience affects individuals' health-related quality of life. Future studies on the interaction between community resilience and health-related individual resilience are warranted.

Improvement and implementation of a national individual care plan in paediatric palliative care: a study protocol.

INTRODUCTION: Paediatric palliative care (PPC) is care for children with life-threatening or life-limiting conditions, and can involve complex high-tech care, which can last for months or years. In 2015, the National Individual Care Plan (ICP) for PPC was developed and has shown to be successful. The ICP can be seen as an instrument to facilitate coordination, quality and continuity of PPC. However, in practice, an ICP is often completed too late and for too few children. We aim to improve the coordination, quality and continuity of care for every child with a life-threatening or life-limiting condition and his/her family by further developing and implementing the ICP in the Netherlands. METHODS AND ANALYSIS: To evaluate the original ICP, ICP 1.0, interviews and questionnaires will be held among parents of children who have or have had an ICP 1.0 and healthcare professionals (HCPs) who used ICP 1.0. Based on the results, ICP 1.0 will be further developed. An implementation strategy will be written and the renewed ICP, ICP 2.0, will be nationally tested in an implementation period of approximately 7 months. During the implementation period, ICP 2.0 will be used for all children who are registered with Children's Palliative Care teams. After the implementation period, ICP 2.0 will be evaluated using interviews and questionnaires among parents of children who received ICP 2.0 and HPCs who worked with ICP 2.0. Based on these results, ICP 2.0 will be further optimised into the final version: ICP 3.0. ETHICS AND DISSEMINATION: This study received ethical approval. The ICP 3.0 will be disseminated through the Dutch Centre of Expertise in Children's Palliative Care, to ensure wide availability for the general public and HCPs within PPC. Additionally, we aim to publish study results in open-access, peer-reviewed journals and to present results at national and international scientific meetings.

Opinions on hypertension care and therapy adherence at the healthcare provider and healthcare system level: a qualitative study in the Hague, Netherlands.

OBJECTIVES: Hypertension is a common cause of cardiovascular morbidity and mortality. Although hypertension can be effectively controlled by blood pressure-lowering drugs, uncontrolled blood pressure is common despite use of these medications. One explanation is therapy non-adherence. Therapy non-adherence can be addressed at the individual level, the level of the healthcare provider and at the healthcare system level. Since the latter two levels are often overlooked, we wished to explore facilitators and barriers on each of these levels in relation to hypertension care for people with hypertension, with a specific focus on therapy adherence. DESIGN: Qualitative study using focus groups of healthcare providers. Data were analysed using the theoretical domains framework (TDF) and the behaviour change wheel. SETTING AND PARTICIPANTS: Participants were from a highly urbanised city environment (the Hague, Netherlands), and included nine primary care physicians, six practice nurses and five secondary care physicians involved in hypertension care. RESULTS: Nine domains on the TDF were found to be relevant at the healthcare provider level ('knowledge', 'physical, cognitive and interpersonal skills', 'memory, attention and decision processes', 'professional, social role and identity', 'optimism', 'beliefs about consequences', 'intention', 'emotion' and 'social influences') and two domains ('resources' and 'goals') were found to be relevant at the system level. Facilitators for these domains were good interpersonal skills, paying attention to behavioural factors such as medication use, and the belief that treatment improves health outcomes. Barriers were related to time, interdisciplinary collaboration, technical and financial issues, availability of blood pressure devices and education of people with hypertension. CONCLUSIONS: This study highlighted a need for better collaboration between primary and secondary care, for more team-based care including pharmacists and social workers, tools to improve interpersonal skills and more time for patient-healthcare provider communication.

The Use of the Bolk Model for Positive Health and Living Environment in the Development of an Integrated Health Promotion Approach: A Case Study in a Socioeconomically Deprived Neighborhood in The Netherlands.

BACKGROUND: Despite considerable efforts, health disparities between people with high and low socioeconomic status (SES) have not changed over the past decades in The Netherlands. To create a culture of health and an environment in which all people can flourish, a shift in focus is needed from disease management towards health promotion. The Bolk model for Positive Health and Living Environment was used as a tool to guide this shift. This study aimed to describe how this model was used and perceived by stakeholders in a case study on an integrated health promotion approach for residents with low SES. METHODS: An instrumental case study was undertaken in Venserpolder, a neighborhood in Amsterdam South East of approximately 8500 residents. A participatory action approach was used that allowed continuous interaction between the residents, health care professionals, researchers, and other stakeholders. The Bolk model is a tool, based on the conceptual framework of positive health, that was developed to guide health promotion practice. Its use in the case study was evaluated by means of semistructured interviews with stakeholders, using qualitative directed content analyses. RESULTS: The Bolk model was found to be a useful tool to identify and map the needs and strengths of residents with low SES. The model facilitated the development and implementation of eight health promotion pilots by transforming the needs and strengths of residents into concrete actions carried out by responsible actors in the neighborhood. Although the Bolk model seemed to be accepted by all stakeholders, the shift towards positive health thinking appeared to be more embodied by local professionals than by residents. Adjustments were proposed to enhance the applicability of the model in a multicultural setting, to increase its cultural sensitivity and to use language more familiar to residents. CONCLUSIONS: The Bolk model for positive health and living environment seems to be promising in the guidance of health promotion practices in Amsterdam South East. Further research and development are needed to improve its cultural sensitivity and to investigate its applicability in a broader range of public health settings.

ß-Ureidopropionase deficiency due to novel and rare UPB1 mutations affecting pre-mRNA splicing and protein structural integrity and catalytic activity.

ß-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyses the conversion of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid to ß-alanine and ß-aminoisobutyric acid, ammonia and CO2. To date, only a limited number of genetically confirmed patients with a complete ß-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 10 newly identified ß-ureidopropionase deficient individuals. Patients presented mainly with neurological abnormalities and markedly elevated levels of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid in urine. Analysis of UPB1, encoding ß-ureidopropionase, showed 5 novel missense variants and two novel splice-site variants. Functional expression of the UPB1 variants in mammalian cells showed that recombinant ß-ureidopropionase carrying the p.Ala120Ser, p.Thr129Met, p.Ser300Leu and p.Asn345Ile variant yielded no or significantly decreased ß-ureidopropionase activity. Analysis of the crystal structure of human ß-ureidopropionase indicated that the point mutations affect substrate binding or prevent the proper subunit association to larger oligomers and thus a fully functional ß-ureidopropionase. A minigene approach showed that the intronic variants c.[364 + 6 T > G] and c.[916 + 1_916 + 2dup] led to skipping of exon 3 and 8, respectively, in the process of UPB1 pre-mRNA splicing. The c.[899C > T] (p.Ser300Leu) variant was identified in two unrelated Swedish ß-ureidopropionase patients, indicating that ß-ureidopropionase deficiency may be more common than anticipated.

Children with atopic dermatitis show increased activity of ß-glucocerebrosidase and stratum corneum levels of glucosylcholesterol that are strongly related to the local cytokine milieu.

BACKGROUND: Atopic dermatitis (AD) is characterized by immune dysregulations and an impaired skin barrier, including abnormalities in lipid organization. In the stratum corneum (SC), ß-glucocerebrosidase (GBA) mediates transformation of glucosylceramide (GlcCER) into ceramide (CER) and cholesterol into glucosylcholesterol (GlcChol). Alteration in GBA activity might contribute to skin barrier defects in AD. OBJECTIVES: To investigate GBA activity in the SC of children with AD before and after topical corticosteroid therapy and to compare it with healthy controls; to determine SC levels of GlcCER- and CER-containing hydroxysphingosine base (GlcCER[H] and CER[H], respectively) and GlcChol; and to relate them to disease severity, skin barrier function and the local cytokine milieu. METHODS: Lipid markers and cytokines of innate, T helper 1 and T helper 2 immunity were determined in SC collected from healthy children and from clinically unaffected skin of children with AD, before and after 6 weeks of therapy with topical corticosteroids. AD severity was assessed by Scoring Atopic Dermatitis and skin barrier function by transepidermal water loss (TEWL). RESULTS: Baseline GBA activity and GlcChol levels were increased in children with AD but declined after therapy. CER[H] levels and the CER[H] to GlcCER[H] ratio were increased in AD. GBA activity and GlcChol correlated with TEWL and levels of multiple cytokines, especially interleukin-1α and interleukin-18. GlcChol was strongly associated with disease severity. CONCLUSIONS: We show increased GBA activity and levels of GlcChol in AD. Our data suggest an important role of inflammation in disturbed lipid processing. GBA activity or GlcChol might be useful biomarkers in the monitoring of therapeutic responses in AD. What is already known about this topic? Patients with atopic dermatitis (AD) have a reduced skin barrier, mainly caused by altered lipid organization. The mechanisms underlying these lipid anomalies are not fully understood but likely reflect both genetic abnormalities in AD skin and the local cutaneous inflammatory environment. What does this study add? We show increased activity of the ceramide-generating enzyme ß-glucocerebrosidase in AD. Activity of this enzyme was correlated with the local cytokine milieu and declined after local corticosteroid therapy. We show that glucosylcholesterol levels in the stratum corneum are increased in AD. The function of glucosylcholesterol and the physiological consequences of increased levels are not clear yet; however, its levels were strongly correlated with skin barrier function: high transepidermal water loss strongly correlated with high levels of glucosylcholesterol. What is the translational message? Correction of cutaneous inflammation largely restores alterations in lipid metabolism in the stratum corneum of infants with AD.

Motives for withdrawal of participation in biobanking and participants' willingness to allow linkages of their data.

Data repositories, like research biobanks, seek to optimise the number of responding participants while simultaneously attempting to increase the amount of data donated per participant. Such efforts aim to increase the repository's value for its uses in medical research to contribute to improve health care, especially when data linkage is permitted by participants. We investigated individuals' motives for participating in such projects and potential reasons for their withdrawal from participation in a population-based biobank. In addition, we analysed how these motives were related to various characteristics of the participants and their willingness to permit data linkage to their personal data for research. These questions were explored using a sample of participants in the Dutch Lifelines biobank (n = 2615). Our results indicated that motives for participation and withdrawal were premised on benefits or harm to society and to the individuals themselves. Although general values and trust both played key roles in participation, potential withdrawal and willingness to permit data linkage, they were differentially associated with motives for participation and withdrawal. These findings support and nuance previous findings by highlighting the distinctiveness and complexity of decision making regarding participation in or withdrawal from data donation. We suggest some new directions for improving recruitment, retention and safeguarding strategies in biobanking. In addition, our data provide initial evidence regarding how factors may relate with the probability that individuals will agree to data linkages, when controlling for their unique effects. Future research should further investigate how perceptions of harm and benefits may influence decision making on withdrawal of participation.

Demographic and prosocial intrapersonal characteristics of biobank participants and refusers: the findings of a survey in the Netherlands.

Research in genetics relies heavily on voluntary contributions of personal data. We aimed to acquire insights into the differences between participants and refusers of participation in a Dutch population-based biobank. Accordingly, we assessed the demographic and prosocial intrapersonal characteristics of respondents who participated (n = 2615) or refused to participate (n = 404) in the Lifelines biobank and databank. Our results indicated that health-related values critically influence participation decisions. The participation threshold for Lifelines was determined by an absence of health-related values and of trust in government. Therefore, considering these factors in communication and recruitment strategies could enhance participation in biomedical research. No indications were found of a stronger general prosociality of participants or their trust in researchers beyond the context of biobanking. This emphasizes the contextual understanding of the decision of participation in biobanking. Our findings may contribute to improving recruitment strategies by incorporating relevant values and/or highlighting prosocial benefits. Moreover, they foreground the need to address trust issues in collaborations between data repositories and commercial companies. Future research should explore how prosocial intrapersonal characteristics drive participation and withdrawal decisions and relate to contextual attributes.

Effects of psychological treatment of mental health problems in pregnant women to protect their offspring: randomised controlled trial.

BACKGROUND: Perinatal depression and anxiety are associated with unfavourable child outcomes. AIMS: To assess among women with antenatal depression or anxiety the effectiveness of prenatally initiated cognitive-behavioural therapy (CBT) on mother and child compared with care as usual (CAU). Trial registration: Netherlands Trial Register number NTR2242. METHOD: Pregnant women (n = 282) who screened positive for symptoms of depression and/or anxiety were randomised to either CBT (n = 140) or CAU (n = 142). The primary outcome was child behavioural and emotional problems at age 18 months, assessed using the Child Behavior Checklist (CBCL). Secondary outcomes were maternal symptoms during and up to 18 months after pregnancy, neonatal outcomes, mother-infant bonding and child cognitive and motor development at age 18 months. RESULTS: In total, 94 (67%) women in the CBT group and 98 (69%) in the CAU group completed the study. The mean CBCL Total Problems score was non-significantly higher in the CBT group than in the CAU group (mean difference: 1.38 (95% CI -1.82 to 4.57); t = 0.85, P = 0.399). No effects on secondary outcomes were observed except for depression and anxiety, which were higher in the CBT group than in the CAU group at mid-pregnancy. A post hoc analysis of the 98 women with anxiety disorders showed lower infant gestational age at delivery in the CBT than in the CAU group. CONCLUSIONS: Prenatally initiated CBT did not improve maternal symptoms or child outcomes among non-help-seeking women with antenatal depression or anxiety. Our findings are not in line with present recommendations for universal screening and treatment for antenatal depression or anxiety, and future work may include the relevance of baseline help-seeking.

Trust in Centralized Large-Scale Data Repository: A Qualitative Analysis.

Exponential increases in digital data and calls for participation in human research raise questions about when and why individuals voluntarily provide personal data. We conducted 36 in-depth interviews with ex-participants, participants, and nonparticipants in a biobank to identify key factors influencing trust in centralized large-scale data repository for human research. Our findings indicated that trust depends strongly on whether such data repository benefits the public, the interests of data collectors, the characteristics of the collected data, and application of informed consent for retaining control over personal data. Concerns about the aims and range of data repository appeared to influence withdrawal of participation. Our findings underscore ethical and practical issues relating to data collection and consent procedures in human research.

What If Pregnancy Is Not Seventh Heaven? The Influence of Specific Life Events during Pregnancy and Delivery on the Transition of Antenatal into Postpartum Anxiety and Depression.

INTRODUCTION: Postpartum symptoms of anxiety and depression are known to have a negative impact on mother and child, and major life events constitute a major risk factor for these symptoms. We aimed to investigate to what extent specific life events during pregnancy, delivery complications, unfavorable obstetric outcomes, and antenatal levels of anxiety or depression symptoms were independently associated with postpartum levels of anxiety and depression symptoms. METHODS: Within a prospective population-based cohort study (n = 3842) in The Netherlands, antenatal symptoms of anxiety or depression were measured at the end of the first trimester and at five months postpartum. Antenatal life events were assessed during the third trimester, and information on delivery and obstetric outcomes was obtained from midwives and gynecologists. Linear regression analyses were performed to quantify the associations. RESULTS: Antenatal levels of both anxiety and depression symptoms were associated with postpartum levels of anxiety and depression symptoms. Life events related to health and sickness of self or loved ones, to the relation with the partner or conflicts with loved ones, or to work, finance, or housing problems were significantly associated with higher postpartum levels of anxiety symptoms (p < 0.001) and depression symptoms (p < 0.001) adjusted for antenatal levels. No statistically significant results were observed for pregnancy-related events, delivery complications, or unfavorable obstetric outcomes. CONCLUSIONS: Women with increased antenatal levels of anxiety or depression symptoms are at increased risk of elevated levels of both postpartum depression and anxiety symptoms. Experiencing life events during pregnancy that were not related to the pregnancy was associated with higher levels of anxiety and depression in the postpartum period, as opposed to pregnancy-related events, delivery complications, or unfavorable obstetric outcomes. These results suggest that events during pregnancy but not related to the pregnancy and birth are a highly important predictor for postpartum mental health.

Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS.

We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5' untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.

Deficiency of perforin and hCNT1, a novel inborn error of pyrimidine metabolism, associated with a rapidly developing lethal phenotype due to multi-organ failure.

Pyrimidine nucleotides are essential for a vast number of cellular processes and dysregulation of pyrimidine metabolism has been associated with a variety of clinical abnormalities. Inborn errors of pyrimidine metabolism affecting enzymes in the pyrimidine de novo and degradation pathway have been identified but no patients have been described with a deficiency in proteins affecting the cellular import of ribonucleosides. In this manuscript, we report the elucidation of the genetic basis of the observed uridine-cytidineuria in a patient presenting with fever, hepatosplenomegaly, persistent lactate acidosis, severely disturbed liver enzymes and ultimately multi-organ failure. Sequence analysis of genes encoding proteins directly involved in the metabolism of uridine and cytidine showed two variants c.1528C > T (p.R510C) and c.1682G > A (p.R561Q) in SLC28A1, encoding concentrative nucleotide transporter 1 (hCNT1). Functional analysis showed that these variants affected the three-dimensional structure of hCNT1, altered glycosylation and decreased the half-life of the mutant proteins which resulted in impaired transport activity. Co-transfection of both variants, mimicking the trans disposition of c.1528C > T (p.R510C) and c.1682G > A (p.R561Q) in the patient, significantly impaired hCNT1 biological function. Whole genome sequencing identified two pathogenic variants c.50delT; p.(Leu17Argfs*34) and c.853_855del; p.(Lys285del) in the PRF1 gene, indicating that our patient was also suffering from Familial Hemophagocytic Lymphohistiocytosis type 2. The identification of two co-existing monogenic defects might have resulted in a blended phenotype. Thus, the clinical presentation of isolated hCNT1 deficiency remains to be established.

Dihydropyrimidine Dehydrogenase Deficiency: Homozygosity for an Extremely Rare Variant in DPYD due to Uniparental Isodisomy of Chromosome 1.

Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway and can lead to intellectual disability, motor retardation, and seizures. Genetic variations in DPYD have also emerged as predictive risk factors for severe toxicity in cancer patients treated with fluoropyrimidines. We recently observed a child born to non-consanguineous parents, who demonstrated seizures, cognitive impairment, language delay, and MRI abnormalities and was found to have marked thymine-uraciluria. No residual DPD activity could be detected in peripheral blood mononuclear cells. Molecular analysis showed that the child was homozygous for the very rare c.257C > T (p.Pro86Leu) variant in DPYD. Functional analysis of the recombinantly expressed DPD mutant showed that the DPD mutant carrying the p.Pro86Leu did not possess any residual DPD activity. Carrier testing in parents revealed that the father was heterozygous for the variant but unexpectedly the mother did not carry the variant. Microsatellite repeat testing with markers covering chromosome 1 showed that the DPD deficiency in the child is due to paternal uniparental isodisomy. Our report thus extends the genetic spectrum underlying DPYD deficiency.

Low socioeconomic status increases effects of negative life events on antenatal anxiety and depression.

PROBLEM: Low socioeconomic status and prior negative life events are documented risk factors for antenatal anxiety and depression, preterm birth and birth weight. We aimed to asses whether the adverse effects of prior negative life events increase with lower socioeconomic status and which aspects of socioeconomic status are most relevant. METHODS: We performed a population-based cohort study in the Netherlands including 5398 women in their first trimester of pregnancy. We assessed the number of negative life events prior to pregnancy, aspects of paternal and maternal socio-economic position and symptoms of anxiety and depression. Associations of the number of prior negative life events with anxiety, depression, low birth weight and gestational age were quantified. FINDINGS: The number of prior negative life events, particularly when they had occurred in the two years before pregnancy and maternal aspects of low socioeconomic status (educational level, unemployment and income) were associated with antenatal anxiety and depression. Furthermore, low socioeconomic status increased the adverse effects of prior negative life events. Obstetric outcomes showed similar trends, although mostly not statistically significant. DISCUSSION: Low socioeconomic status and prior negative life events both have an adverse effect on antenatal anxiety and depression. Furthermore, low socioeconomic status increases the adverse impact of prior negative life events on anxiety and depressive symptoms in pregnancy. CONCLUSION: Interventions for anxiety and depression during pregnancy should be targeted particularly to unemployed, less-educated or low-income women who recently experienced negative life events.

Respiratory Health in Adolescents Born Moderately-Late Preterm in a Community-Based Cohort.

OBJECTIVES: To determine the long-term effects of moderately-late preterm (MLP) birth on respiratory and allergic symptoms, lung function, and exercise capacity in adolescence. STUDY DESIGN: Outcome variables in this prospective cohort were prevalence of symptoms determined by International Study of Asthma and Allergies in Childhood questionnaires, lung function, and exercise measures. RESULTS: Response rate was 47% and did not vary importantly by background characteristics. In total, 71 children (aged 13-14 years) participated in the measurements, 37 born MLP and 34 born full term. Both groups were comparable in height, weight, and exercise activities but differed in gestational age (MLP 34 ± 1 weeks, full term 39 ± 0.9 weeks) and birth weight (MLP 2442 ± 539 g, full term 3693 ± 393 g). Adolescents born MLP reported more (dry) cough (MLP 25% vs those born full term 3%, P = .016) and hay fever (MLP 34% vs those born full term 9%, P = .015). Adolescents born MLP did not report more wheeze, dyspnea, asthma, and eczema. Most lung function measurements were within the normal range for both groups, except peak expiratory flow (MLP 86% of predicted vs those born full term 93%, P = .05) and maximum expiratory flow when 75% of the forced vital capacity has been exhaled (MLP 86% predicted vs those born full term 96% predicted, P = .06), which were at the lower limit of normal. We observed no differences between the groups in exercise parameters. CONCLUSION: Moderately late preterm birth has little effect on respiratory health in adolescence. Adolescents born MLP report few symptoms, have only slightly more lung function abnormalities than those born full term, and do not differ in the maximal exercise test and in physical activity level. TRIAL REGISTRATION: ISRCTN 80622320.

Genome sequencing reveals a novel genetic mechanism underlying dihydropyrimidine dehydrogenase deficiency: A novel missense variant c.1700G>A and a large intragenic inversion in DPYD spanning intron 8 to intron 12.

Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with a variable clinical presentation. A family with three DPD-deficient patients presented with unusual clinical phenotypes including pregnancy-induced symptoms, transient visual impairment, severe developmental delay, cortical blindness, and delayed myelination in the brain. DPYD Sanger sequencing showed heterozygosity for the c.1905+1G>A mutation and a novel missense variant c.1700G>A (p.G567E). The recombinantly expressed p.G567E DPD variant showed increased temperature lability probably caused by structural rearrangements within the DPD protein. Genome sequencing of the affected son established compound heterozygosity for the c.1700G>A and an imperfect 115,731 bp inversion with breakpoints at chr1: 98,113,121 (intron 8) and chr1: 97,997,390 (intron 12) of the DPYD associated with a 4 bp deletion (chr1: 97,997,386_97,997,389del). Whole exome and mitochondrial DNA analyses for the mother and daughter did not reveal additional mutated genes of significance. Thus, an inversion in DPYD should be considered in patients with an inconclusive genotype or unusual clinical phenotype.