For better or worse: Governing healthcare organisations in times of financial distress.

Due to processes of financialisation, financial parties increasingly penetrate the healthcare domain and determine under which conditions care is delivered. Their influence becomes especially visible when healthcare organisations face financial distress. By zooming-in on two of such cases, we come to know more about the considerations, motives and actions of financial parties in healthcare. In this research, we were able to examine the social dynamics between healthcare executives, banks and health insurers involved in a Dutch hospital and mental healthcare organisation on the verge of bankruptcy. Informed by interviews, document analysis and translation theory, we reconstructed the motives and strategies of executives, banks and health insurers and show how they play a crucial role in decision-making processes surrounding the survival or downfall of healthcare organisations. While parties are bound by legislation and company procedures, the outcome of financial distress can still be influenced. Much depends on how executives are perceived by financial stakeholders and how they deal with threats of destabilisation of the network. We further draw attention to the consequences of financialisation processes on the practices of healthcare organisations in financial distress.

A qualitative study on the perspectives of mothers who had been diagnosed with primary carnitine deficiency through newborn screening of their child.

BACKGROUND: Primary carnitine deficiency is an inborn error of metabolism, which can lead to life-threating complications early in life. Low carnitine levels can be detected by newborn bloodspot screening (NBS). However, NBS can also identify, mostly asymptomatic, mothers with primary carnitine deficiency. To identify mothers' needs and areas for improving screening practice, this study explored the experiences with, and opinions on primary carnitine deficiency screening in NBS among women diagnosed through NBS of their newborn. METHODS: Twelve Dutch women were interviewed, 3-11 years after diagnosis. Data were analysed using a thematic approach. RESULTS: Four main themes were derived: 1) psychological impact of primary carnitine deficiency diagnosis, 2) becoming a patient and "patient-in-waiting", 3) information issues and care provision, and 4) primary carnitine deficiency as part of the NBS panel. Mothers shared that they did not experience major psychological distress of the diagnosis. They did experience (recall) various emotions following the initial abnormal NBS result, including fear and anxiety as well as relief, and emotions regarding their own diagnosis, including uncertainty about health risks and treatment effectiveness. Some felt a patient-in-waiting. Many participants experienced a lack of information, especially shortly after receiving the abnormal NBS result. All shared the belief that screening for primary carnitine deficiency in NBS is beneficial for the newborn, and, given the information they received, also considered the knowledge beneficial for their own health. CONCLUSIONS: Psychological burden following diagnosis was experienced by women as limited, although the experienced lack of information amplified feelings of uncertainty and anxiety. Most mothers believed that benefits of knowing about primary carnitine deficiency outweighed the disadvantages. Mothers' perspectives should be incorporated in policy-making about primary carnitine deficiency in NBS.

Parents' views on accepting, declining, and expanding newborn bloodspot screening.

INTRODUCTION: The goal of newborn bloodspot screening (NBS) is the early detection of treatable disorders in newborns to offer early intervention. Worldwide, the number of conditions screened for is expanding, which might affect public acceptance. In the Netherlands, participation is high (>99%), but little is known about how parents perceive NBS. This study assessed parents' views on accepting, declining and expanding NBS. METHODS: A total of 804 of 6051 (13%) invited parents who participated in NBS in the Netherlands during the last two weeks of December 2019, and 48 of 1162 (4%) invited parents who declined participation in NBS in 2019 and 2020, completed a questionnaire. RESULTS: The most important reason for parents to participate in NBS was to prevent health complaints, whereas the most important reason to decline NBS was parents' viewpoint on life and the belief that the heel prick would be painful for the child. Compared to NBS participants, respondents who declined NBS were more actively religious, considered alternative medicine or lifestyle more important, were less inclined to vaccinate their child for infectious diseases, and reported more doubt about NBS participation (all differences p < .001). Informed choice was lower among respondents who declined NBS (44%) compared to participants in NBS (83%, p < .001), mostly due to insufficient knowledge. Of the NBS participants, 95% were positive about NBS expansion. Most NBS participants agreed to include conditions that could unintentionally reveal a diagnosis in the mother instead of the child (86%) or a condition that may not cause symptoms until later in the child's life (84%). CONCLUSION: Most participants made an informed decision to participate in NBS and are positive about screening for more conditions. Insights into parents' views on (non-)participation and expansion of NBS can help to ensure that NBS suits the population needs while safeguarding ethical principles for screening.

Expanding Neonatal Bloodspot Screening: A Multi-Stakeholder Perspective.

Neonatal bloodspot screening (NBS) aims to detect treatable disorders in newborns. The number of conditions included in the screening is expanding through technological and therapeutic developments, which can result in health gain for more newborns. NBS expansion, however, also poses healthcare, ethical and societal challenges. This qualitative study explores a multi-stakeholders' perspective on current and future expansions of NBS. Semi-structured interviews were conducted with 22 Dutch professionals, including healthcare professionals, test developers and policy makers, and 17 parents of children with normal and abnormal NBS results. Addressed themes were (1) benefits and challenges of current expansion, (2) expectations regarding future developments, and (3) NBS acceptance and consent procedures. Overall, participants had a positive attitude toward NBS expansion, as long as it is aimed at detecting treatable disorders and achieving health gain. Concerns were raised regarding an increase in results of uncertain significance, diagnosing asymptomatic mothers, screening of subgroups ("males only"), finding untreatable disorders, along with increasingly complex consent procedures. Regarding the scope of future NBS expansions, two types of stakeholder perspectives emerged. Stakeholders with a "targeted-scope" perspective saw health gain for the neonate as the exclusive NBS aim. They thought pre-test information could be limited, and parents should be protected against too much options or information. Stakeholders with a "broad-scope" perspective thought the NBS aim should be formulated broader, for example, also taking (reproductive) life planning into account. They put more emphasis on individual preferences and parental autonomy. Policy-makers should engage with both perspectives when making further decisions about NBS.

Primary Ovarian Failure in Addition to Classical Clinical Features of Coats Plus Syndrome in a Female Carrying 2 Truncating Variants of CTC1.

Coats plus syndrome is an autosomal recessive multisystemic and pleiotropic disorder affecting the eyes, brain, bone, and gastrointestinal tract, usually caused by compound heterozygous variants of the conserved telomere maintenance component 1 gene (CTC1), involved in telomere homeostasis and replication. So far, most reported patients are compound heterozygous for a truncating mutation and a missense variant. The phenotype is believed to result from telomere dysfunction, with accumulation of DNA damage, cellular senescence, and stem cell depletion. Here, we report a 23-year-old female with prenatal and postnatal growth retardation, microcephaly, osteopenia, recurrent fractures, intracranial calcification, leukodystrophy, parenchymal brain cysts, bicuspid aortic valve, and primary ovarian failure. She carries a previously reported maternally inherited pathogenic variant in exon 5 (c.724_727del, p.(Lys242Leufs*41)) and a novel, paternally inherited splice site variant (c.1617+5G>T; p.(Lys480Asnfs*17)) in intron 9. CTC1 transcript analysis showed that the latter resulted in skipping of exon 9. A trace of transcripts was normally spliced resulting in the presence of a low level of wild-type CTC1 transcripts. We speculate that ovarian failure is caused by telomere shortening or chromosome cohesion failure in oocytes and granulosa cells, with early decrease in follicular reserve. This is the first patient carrying 2 truncating CTC1 variants and the first presenting primary ovarian failure.

Informing Parents about Newborn Screening: A European Comparison Study.

Knowledge about newborn screening (NBS) is an important factor for parents to make an informed decision about participation. In Europe, countries inform parents differently about their NBS program, potentially including different knowledge aspects in their information. The aim of this study was to assess twenty-six European parental information products and to analyze their knowledge aspects through a content analysis. The analyzed aspects were compared to a list of eight knowledge aspects from scientific literature. The list includes aspects important for parents' decision-making, such as the purpose of screening. The study showed that most of the eight knowledge aspects are included in NBS information products of the majority of countries. However, there were differences between countries, for example in the amount of detail and phrasing of the information. Additional relevant knowledge aspects have also been identified and are recommended to optimize information products, such as the handling of residual bloodspot samples. This study only assessed knowledge aspects in information products meant for printing, but many countries also use other communication methods, and the impact on knowledge of the delivery of the information needs further study. Preferences of parents on alternative communication methods need to be considered and evaluated on their effectiveness.

Postnatal Brain Growth Patterns in Pontocerebellar Hypoplasia.

BACKGROUND: Pontocerebellar hypoplasia (PCH) is a rare group of disorders mainly affecting the cerebellum and pons. Supratentorial structures are variably involved. We assessed brain growth patterns in patients with the most frequent forms of PCH, namely PCH1B (OMIM#614678) and PCH2A (OMIM#277470), since in these types of PCH, pre- and postnatal neurodegeneration is established by neuropathological profiling. To assess the influence of the different pathomechanisms on postnatal growth patterns, we included CASK-associated microcephaly and PCH (MICPCH, OMIM#300749) patients in our analyses, as MICPH mimics PCH on magnetic resonance imaging (MRI) but represents a developmental disorder including abnormal neuronal migration. METHODS: A total of 66 patients were included: 9 patients with PCH1B, 18 patients with PCH2A, 6 patients with MICPCH, and 33 age- and gender-matched hospital-based controls. Segmentation of the vermis and cerebellum was performed manually, as were measurements of the thickness of the head of the caudate nucleus, the width of the anterior horn, and lateral ventricle size. RESULTS: The cerebellum was severely hypoplastic at birth in all patients, and postnatal growth was nearly absent. In patients with PCH1B/2A, we found relative sparing of the vermis compared with the cerebellar hemispheres. In addition, PCH1B and PCH2A cases demonstrated thinning of the head of the caudate nucleus, an associated increase in anterior horn width, and an increase in lateral ventricle size. None of these features were seen in the MICPCH group. CONCLUSIONS: Our findings confirm the progressive nature including caudate nucleus atrophy in PCH1B and PCH2A. In MICPCH, the relative sparing of supratentorial structures confirms its different pathomechanism.

Does artemether-lumefantrine administration affect mosquito olfactory behaviour and fitness?

BACKGROUND: Artemisinin-based combination therapy (ACT) is the recommended treatment against uncomplicated Plasmodium falciparum infections, and ACT is widely used. It has been shown that gametocytes may be present after ACT and transmission to mosquitoes is still possible. Artemether-lumefantrine (AL) is a broadly used artemisinin-based combination medicine. Here, it is tested whether AL influences behaviour and fitness of Anopheles mosquitoes, which are the main vectors of P. falciparum. RESULTS: Dual-choice olfactometer and screenhouse experiments showed that skin odour of healthy human individuals obtained before, during and after AL-administration was equally attractive to Anopheles coluzzii and Anopheles gambiae sensu stricto, apart from a small (but significant) increase in mosquito response to skin odour collected 3 weeks after AL-administration. Anopheles coluzzii females fed on parasite-free blood supplemented with AL or on control-blood had similar survival, time until oviposition and number of eggs produced. CONCLUSIONS: Based on the results, AL does not appear to influence malaria transmission through modification of vector mosquito olfactory behaviour or fitness. Extending these studies to Plasmodium-infected individuals and malaria mosquitoes with parasites are needed to further support this conclusion.

Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations.

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.

Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis.

Pontocerebellar hypoplasia (PCH) is a heterogeneous neurodegenerative disorder with a prenatal onset. Using whole-exome sequencing, we identified variants in the gene Coenzyme A (CoA) synthase (COASY) gene, an enzyme essential in CoA synthesis, in four individuals from two families with PCH, prenatal onset microcephaly, and arthrogryposis. In family 1, compound heterozygous variants were identified in COASY: c.[1549_1550delAG]; [1486-3 C>G]. In family 2, all three affected siblings were homozygous for the c.1486-3 C>G variant. In both families, the variants segregated with the phenotype. RNA analysis showed that the c.1486-3 C>G variant leads to skipping of exon 7 with partial retention of intron 7, disturbing the reading frame and resulting in a premature stop codon (p.(Ala496Ilefs*20)). No CoA synthase protein was detected in patient cells by immunoblot analysis and CoA synthase activity was virtually absent. Partial CoA synthase defects were previously described as a cause of COASY Protein-Associated Neurodegeneration (CoPAN), a type of Neurodegeneration and Brain Iron Accumulation (NBIA). Here we demonstrate that near complete loss of function variants in COASY are associated with lethal PCH and arthrogryposis.

What's new in pontocerebellar hypoplasia? An update on genes and subtypes.

BACKGROUND: Pontocerebellar hypoplasia (PCH) describes a rare, heterogeneous group of neurodegenerative disorders mainly with a prenatal onset. Patients have severe hypoplasia or atrophy of cerebellum and pons, with variable involvement of supratentorial structures, motor and cognitive impairments. Based on distinct clinical features and genetic causes, current classification comprises 11 types of PCH. MAIN TEXT: In this review we describe the clinical, neuroradiological and genetic characteristics of the different PCH subtypes, summarize the differential diagnosis and reflect on potential disease mechanisms in PCH. Seventeen PCH-related genes are now listed in the OMIM database, most of them have a function in RNA processing or translation. It is unknown why defects in these apparently ubiquitous processes result in a brain-specific phenotype. CONCLUSIONS: Many new PCH related genes and phenotypes have been described due to the appliance of next generation sequencing techniques. By including such a broad range of phenotypes, including non-degenerative and postnatal onset disorders, the current classification gives rise to confusion. Despite the discovery of new pathways involved in PCH, treatment is still symptomatic. However, correct diagnosis of PCH is important to provide suitable care and counseling regarding prognosis, and offer appropriate (prenatal) genetic testing to families.

A SEPSECS mutation in a 23-year-old woman with microcephaly and progressive cerebellar ataxia.

Mutations in the SEPSECS gene are associated with pontocerebellar hypoplasia type 2D. Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare autosomal recessive neurodegenerative disorders, mainly affecting pons and cerebellum. Patients have severe motor and cognitive impairments and often die during infancy. Here, we report a 23-year-old woman with slowly progressive cerebellar ataxia and cognitive impairment, in whom a homozygous missense mutation in the SEPSECS gene (c.1321G>A; p.Gly441Arg) was identified with whole exome sequencing. Our findings underline that defects in selenoprotein synthesis can also result in milder cerebellar atrophy presenting at a later age.

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

Mutations in the mitochondrial arginyl tRNA synthetase (RARS2) gene are associated with Pontocerebellar Hypoplasia type 6 (PCH6). Here we report two patients, compound heterozygous for RARS2 mutations, presenting with early onset epileptic encephalopathy and (progressive) atrophy of both supra- and infratentorial structures. Early pontocerebellar hypoplasia was virtually absent and respiratory chain (RC) defects could not be detected in muscle biopsies. Both patients carried a novel missense mutation c.1544A>G (p.(Asp515Gly)) in combination with either a splice site (c.297+2T>G) or a frameshift (c.452_454insC) mutation. The splice site mutation induced skipping of exon 4.These two patients expand the phenotypical spectrum associated with RARS2 mutations beyond the first report of PCH6 by Edvardson and colleagues. We propose to classify RARS2-associated phenotypes as an early onset mitochondrial encephalopathy, since this is more in agreement with both clinical presentation and underlying genetic cause.

A de novo missense mutation in the inositol 1,4,5-triphosphate receptor type 1 gene causing severe pontine and cerebellar hypoplasia: Expanding the phenotype of ITPR1-related spinocerebellar ataxia's.

We report a de novo missense mutation (c.7649T>A) in the inositol, 1,4,5 triphosphate receptor type 1 (ITPR1) gene in a patient with severe pontocerebellar hypoplasia. The mutation results in an amino acid substitution of a highly conserved isoleucine by asparagine (p. I2550N) in the transmembrane domain. Mutations and deletions of the ITPR1 gene are associated with several types of autosomal dominant spinocerebellar ataxia, varying in age of onset and severity. Patients have signs of cerebellar ataxia and at most, a mild cerebellar atrophy on MRI. In contrast, the patient we report here has profound cerebellar and pontine hypoplasia. Our finding therefore further expands the spectrum of ITPR1-related ataxias. © 2016 Wiley Periodicals, Inc.

Whole Exome Sequencing Reveals Compound Heterozygosity for Ethnically Distinct PEX7 Mutations Responsible for Rhizomelic Chondrodysplasia Punctata, Type 1.

We describe two brothers who presented at birth with bone growth abnormalities, followed by development of increasingly severe intellectual and physical disability, growth restriction, epilepsy, and cerebellar and brain stem atrophy, but normal ocular phenotypes. Case 1 died at 19 years of age due to chronic respiratory illnesses without a unifying diagnosis. The brother remains alive but severely disabled at 19 years of age. Whole exome sequencing identified compound heterozygous stop mutations in the peroxisome biogenesis factor 7 gene in both individuals. Mutations in this gene cause rhizomelic chondrodysplasia punctata, type 1 (RCDP1). One mutation, p.Arg232 (∗) , has only been documented once before in a Japanese family, which is of interest given these two boys are of European descent. The other mutation, p.Leu292 (∗) , is found in approximately 50% of RCDP1 patients. These are the first cases of RCDP1 that describe the coinheritance of the p.Arg232 (∗) and p.Leu292 (∗) mutations and demonstrate the utility of WES in cases with unclear diagnoses.

Macro-invertebrate decline in surface water polluted with imidacloprid.

Imidacloprid is one of the most widely used insecticides in the world. Its concentration in surface water exceeds the water quality norms in many parts of the Netherlands. Several studies have demonstrated harmful effects of this neonicotinoid to a wide range of non-target species. Therefore we expected that surface water pollution with imidacloprid would negatively impact aquatic ecosystems. Availability of extensive monitoring data on the abundance of aquatic macro-invertebrate species, and on imidacloprid concentrations in surface water in the Netherlands enabled us to test this hypothesis. Our regression analysis showed a significant negative relationship (P<0.001) between macro-invertebrate abundance and imidacloprid concentration for all species pooled. A significant negative relationship was also found for the orders Amphipoda, Basommatophora, Diptera, Ephemeroptera and Isopoda, and for several species separately. The order Odonata had a negative relationship very close to the significance threshold of 0.05 (P = 0.051). However, in accordance with previous research, a positive relationship was found for the order Actinedida. We used the monitoring field data to test whether the existing three water quality norms for imidacloprid in the Netherlands are protective in real conditions. Our data show that macrofauna abundance drops sharply between 13 and 67 ng l(-1). For aquatic ecosystem protection, two of the norms are not protective at all while the strictest norm of 13 ng l(-1) (MTR) seems somewhat protective. In addition to the existing experimental evidence on the negative effects of imidacloprid on invertebrate life, our study, based on data from large-scale field monitoring during multiple years, shows that serious concern about the far-reaching consequences of the abundant use of imidacloprid for aquatic ecosystems is justified.