[How to provide meaningful primary care to patients with an addiction?] / Wat is zinvolle eerstelijnszorg aan verslaafde patiënten?

Offering meaningful care to patients with an addiction is not always easy. This also holds true for general physicians. In this article we provide a legal and practical framework for general physicians on how to provide meaningful care for this group of patients. Various interventions are described. In case meaningful care does not seem to be an option, then the general physician has to draw his conclusions.

Identifying the sectors involved in the European public health emergency preparedness and response: a systematic review.

OBJECTIVES: A systematic review was conducted with the aims of identifying sectors mentioned in the public health emergency preparedness and response (PHEPR) literature and mapping the involvement of those sectors in the seven PHEPR cycle domains. SETTING: A detailed search strategy was conducted in Embase and Scopus, covering the period between 1 January 2005 and 1 January 2020. METHODS: Published articles focusing on preparedness for and/or response to public health emergencies of multiple origins on the European continent were included. The frequency with which predetermined sectors were mentioned when describing collaboration during the preparedness and response cycle was determined. RESULTS: The results show that description of the involvement of sectors in PHEPR in general and collaboration during PHEPR is predominantly confined to a limited number of sectors, namely 'Governmental institutions', 'Human health industry', 'Experts' and 'Civil Society'. Description is also limited to only three domains of the PHEPR cycle, namely 'Risk and crisis management', 'Pre-event preparations and governance' and 'Surveillance'. CONCLUSIONS: Optimal preparedness and response require predefined collaboration with a broader scope of partners than currently seems to be the case based on this literature review. We recommend considering these outcomes when planning multisectoral collaboration during preparedness and response, as well as the need to further operationalise the term 'multisectoral collaboration' during PHEPRs. PROSPERO REGISTRATION NUMBER: PROSPERO with registration number 176 331.

Cognitive and neurological outcome of patients in the Dutch pyridoxine-dependent epilepsy (PDE-ALDH7A1) cohort, a cross-sectional study.

BACKGROUND: Pyridoxine monotherapy in PDE-ALDH7A1 often results in adequate seizure control, but neurodevelopmental outcome varies. Detailed long-term neurological outcome is unknown. Here we present the cognitive and neurological features of the Dutch PDE-ALDH7A1 cohort. METHODS: Neurological outcome was assessed in 24 patients (age 1-26 years); classified as normal, complex minor neurological dysfunction (complex MND) or abnormal. Intelligence quotient (IQ) was derived from standardized IQ tests with five severity levels of intellectual disability (ID). MRI's and treatments were assessed. RESULTS: Ten patients (42%) showed unremarkable neurological examination, 11 (46%) complex MND, and 3 (12%) cerebral palsy (CP). Minor coordination problems were identified in 17 (71%), fine motor disability in 11 (46%), posture/muscle tone deviancies in 11 (46%) and abnormal reflexes in 8 (33%). Six patients (25%) had an IQ > 85, 7 (29%) borderline, 7 (29%) mild, 3 (13%) moderate, and 1 severe ID. Cerebral ventriculomegaly on MRI was progressive in 11. Three patients showed normal neurologic exam, IQ, and MRI. Eleven patients were treated with pyridoxine only and 13 by additional lysine reduction therapy (LRT). LRT started at age <3 years demonstrated beneficial effect on IQ results in 3 patients. DISCUSSION: Complex MND and CP occurred more frequently in PDE-ALDH7A1 (46% and 12%) than in general population (7% and 0.2%, Peters et al., 2011, Schaefer et al., 2008). Twenty-five percent had a normal IQ. Although LRT shows potential to improve outcomes, data are heterogeneous in small patient numbers. More research with longer follow-up via the International PDE Registry (www.pdeonline.org) is needed.

Effect of BH4 on blood phenylalanine and tyrosine variations in patients with phenylketonuria.

BACKGROUND: In patients with phenylketonuria, stability of blood phenylalanine and tyrosine concentrations might influence brain chemistry and therefore patient outcome. This study prospectively investigated the effects of tetrahydrobiopterin (BH4), as a chaperone of phenylalanine hydroxylase on diurnal and day-to-day variations of blood phenylalanine and tyrosine concentrations. METHODS: Blood phenylalanine and tyrosine were measured in dried blood spots (DBS) four times daily for 2 days (fasting, before lunch, before dinner, evening) and once daily (fasting) for 6 days in a randomized cross-over design with a period with BH4 and a period without BH4. The sequence was randomized. Eleven proven BH4 responsive PKU patients participated, 5 of them used protein substitutes during BH4 treatment. Natural protein intake and protein substitute dosing was adjusted during the period without BH4 in order to keep DBS phenylalanine levels within target range. Patients filled out a 3-day food diary during both study periods. Variations of DBS phenylalanine and Tyr were expressed in standard deviations (SD) and coefficient of variation (CV). RESULTS: BH4 treatment did not significantly influence day-to-day phenylalanine and tyrosine variations nor diurnal phenylalanine variations, but decreased diurnal tyrosine variations (median SD 17.6 µmol/l, median CV 21.3%, p = 0.01) compared to diet only (median SD 34.2 µmol/l, median CV 43.2%). Consequently, during BH4 treatment diurnal phenylalanine/tyrosine ratio variation was smaller, while fasting tyrosine levels tended to be higher. CONCLUSION: BH4 did not impact phenylalanine variation but decreased diurnal tyrosine and phenylalanine/tyrosine ratio variations, possibly explained by less use of protein substitute and increased tyrosine synthesis.

High protein prescription in methylmalonic and propionic acidemia patients and its negative association with long-term outcome.

BACKGROUND AND OBJECTIVE: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are inborn errors of metabolism. While survival of MMA and PA patients has improved in recent decades, long-term outcome is still unsatisfactory. A protein restricted diet is the mainstay for treatment. Additional amino acid mixtures (AAM) can be prescribed if natural protein is insufficient. It is unknown if dietary treatment can have an impact on outcome. DESIGN: We performed a nationwide retrospective cohort study and evaluated both longitudinal dietary treatment and clinical course of Dutch MMA and PA patients. Protein prescription was compared to the recommended daily allowances (RDA); the safe level of protein intake as provided by the World Health Organization. The association of longitudinal dietary treatment with long-term outcome was evaluated. RESULTS: The cohort included 76 patients with a median retrospective follow-up period of 15 years (min-max: 0-48 years) and a total of 1063 patient years on a protein restricted diet. Natural protein prescription exceeded the RDA in 37% (470/1287) of all prescriptions and due to AAM prescription, the total protein prescription exceeded RDA in 84% (1070/1277). Higher protein prescriptions were associated with adverse outcomes in severely affected patients. In PA early onset patients a higher natural protein prescription was associated with more frequent AMD. In MMA vitamin B12 unresponsive patients, both a higher total protein prescription and AAM protein prescription were associated with more mitochondrial complications. A higher AAM protein prescription was associated with an increased frequency of cognitive impairment in the entire. CONCLUSION: Protein intake in excess of recommendations is frequent and is associated with poor outcome.

Early diagnosis of ataxia telangiectasia in the neonatal phase: a parents' perspective.

Ataxia telangiectasia (A-T) is a severe neurodegenerative disorder with variable immunodeficiency. Together with the Dutch A-T community, we investigated the opinion of A-T parents on an early A-T diagnosis in the asymptomatic phase of the disease. During an annual national meeting for A-T patients and families, the topic of an early A-T diagnosis was discussed in relation to the recent introduction of neonatal screening for severe combined immunodeficiency (SCID) in the Netherlands. Based on the discussion, individual arguments were identified and processed into a questionnaire, which was sent out to 64 A-T parents (32 families). Arguments included were insecurity to diagnosis, possible medical advantages, appropriate genetic counseling and family planning, loss of "golden" year(s), and early cancer screening for parents. The response rate was 55% (n = 35 parents). Twenty-six (74%) parents felt that the advantages of an early diagnosis outweighed the disadvantages, five parents thought that the disadvantages would outweigh the advantages (14%), and four parents did not indicate a preference.Conclusion: The majority of parents of a child with A-T would have preferred an early diagnosis during the asymptomatic phase of the disease, because the uncertainty during the diagnostic process had had a major impact on their lives. In addition, the knowledge of being carriers of an ATM gene mutation influenced decisions about family planning. Parents who opposed against an early diagnosis emphasized the joy of having a seemingly healthy child until diagnosis.What is Known:• Ataxia telangiectasia (A-T) is a devastating DNA repair disorder with a huge impact on quality of life of patients and their parents.• Patients with A-T may incidentally be identified at birth as the consequence of neonatal screening for severe combined immunodeficiency (SCID).What is New:• The majority of Dutch parents of A-T patients (74%) would have preferred an early diagnosis of their child in the asymptomatic phase of the disease.• Major arguments for an early A-T diagnosis were (1) the experienced insecurity in diagnostic trajectories and its impact on families and (2) the knowledge of being ATM mutation carriers when deciding about family planning. An argument against an early diagnosis is losing the joy of having a seemingly healthy child until diagnosis.

MANAGEMENT OF ENDOCRINE DISEASE: Approach to the management of children and adolescents with Gender Dysphoria.

Over the past 20 years, the care for transgender adolescents has developed throughout many countries following the "Dutch Approach" initiated in the 90's in pioneer countries as the Netherlands, United States and Canada, with increasing numbers of children and adolescents seeking care in transgender clinics. This medical approach has considerable positive impacts on the psychological outcomes of these adolescents and several studies have been recently published underlining the relative safety of such treatments. This paper reviews the current standards of care for transgender children and adolescents with particular emphasis on disparities among countries and short to medium-term outcomes. Finally it highlights ethical considerations regarding categorization of gender dysphoria, timing of treatment initiation, infertility, and how to deal with the long-term consequences.

The aetiology of community-acquired pneumonia and implications for patient management.

PURPOSE: Understanding which pathogens are associated with clinical manifestation of community-acquired pneumonia (CAP) is important to optimise treatment. We performed a study on the aetiology of CAP and assessed possible implications for patient management in the Netherlands. METHODS: Patients with CAP attending the emergency department of a general hospital were invited to participate in the study. We used an extensive combination of microbiological techniques to determine recent infection with respiratory pathogens. Furthermore, we collected data on clinical parameters and potential risk factors. RESULTS: From November 2007 through January 2010, 339 patients were included. Single bacterial infection was found in 39% of these patients, single viral infection in 12%, and mixed bacterial-viral infection in 11%. Streptococcus pneumoniae was the most frequently identified pathogen (22%; n=74). Infection with atypical bacteria was detected in 69 (20%) of the patients. CONCLUSION: Initial empirical antibiotics should be effective against S. pneumoniae, the most common pathogen identified in CAP patients. The large proportion of patients with infection with atypical bacteria points to the need for improved diagnostic algorithms including atypical bacteria, especially since these atypical bacteria are not covered by the first-choice antibiotic treatment according to the recently revised Dutch guidelines on the management of CAP.

The 48-hour tetrahydrobiopterin loading test in patients with phenylketonuria: evaluation of protocol and influence of baseline phenylalanine concentration.

BACKGROUND: The 24- and 48-hour tetrahydrobiopterin (BH4) loading test (BLT) performed at a minimum baseline phenylalanine concentration of 400 µmol/l is commonly used to test phenylketonuria patients for BH4 responsiveness. This study aimed to analyze differences between the 24- and 48-hour BLT and the necessity of the 400 µmol/l minimum baseline phenylalanine concentration. METHODS: Data on 186 phenylketonuria patients were collected. Patients were supplemented with phenylalanine if phenylalanine was <400 µmol/l. BH4 20mg/kg was administered at T = 0 and T = 24. Blood samples were taken at T=0, 8, 16, 24 and 48 h. Responsiveness was defined as ≥ 30% reduction in phenylalanine concentration at ≥ 1 time point. RESULTS: Eighty-six (46.2%) patients were responsive. Among responders 84% showed a ≥ 30% response at T = 48. Fifty-three percent had their maximal decrease at T = 48. Fourteen patients had ≥ 30% phenylalanine decrease not before T = 48. A ≥ 30% decrease was also seen in patients with phenylalanine concentrations <400 µmol/l. CONCLUSION: In the 48-hour BLT, T = 48 seems more informative than T = 24. Sampling at T = 32, and T = 40 may have additional value. BH4 responsiveness can also be predicted with baseline blood phenylalanine <400 µmol/l, when the BLT is positive. Therefore, if these results are confirmed by data on long-term BH4 responsiveness, we advise to first perform a BLT without phenylalanine loading and re-test at higher phenylalanine concentrations when no response is seen. Most likely, the 48-hour BLT is a good indicator for BH4 responsiveness, but comparison with long term responsiveness is necessary.

Depressive behaviour in children diagnosed with a mitochondrial disorder.

A higher incidence of depression has been described in adults with primary oxidative phosphorylation disease. We evaluated the psychological characteristics of eighteen non-retarded pediatric patients diagnosed with a disorder of the oxidative phosphorylation. We found significantly higher rate of withdrawn, depressive behaviour compared to population norm scores, to children with other types of inborn errors of metabolism and also in comparison to patients with Sotos syndrome. The occurrence of depressive behaviour showed no correlation with the degree of mitochondrial dysfunction. These findings support the hypothesis that mood disorders could be associated to abnormal cerebral energy metabolism.

Reproductive decision-making in the context of mitochondrial DNA disorders: views and experiences of professionals.

Although a scientific and ethical debate about the possible reproductive options for carriers of mitochondrial DNA (mtDNA) mutations is developing, not much information regarding the views and experiences of professionals exists. This paper explores the attitudes and experiences of professionals involved on a daily basis with their patients' reproductive decision-making in the context of mtDNA disease. Qualitative international multicenter design using in-depth semi-structured interviews with 20 professionals has been utilized. We identified four main themes emerging from the interviews. Firstly, we illustrate the discussion among professionals as to what extent mitochondrial genetics differs from other areas in genetics, both technically and ethically. Secondly, we show the discomfort and doubts of professionals when an mtDNA mutation is involved, because of the uncertainty remaining after testing. Thirdly, we discuss how professionals struggle with the tension between, on the one hand, the ideal of reproductive autonomy and, on the other hand, the reality of their professional responsibility and complex clinical decision-making. Fourthly, we delineate the strategies used by professionals in order to make attempts to control uncertainty. This paper illustrates the impact on professionals of reproductive decision-making in the context of mtDNA disease. It shows their feelings of discomfort when interpreting and explaining uncertain or ambiguous data and may be perceived as an example of how professionals deal with the inherent limitations in genetic knowledge representing the state of the art. Insight into the experiences of professionals may contribute to a further improvement of reproductive genetic counseling in the context of mtDNA disorders.

Major depression in adolescent children consecutively diagnosed with mitochondrial disorder.

A higher incidence of major depression has been described in adults with a primary oxidative phosphorylation disease. Intriguingly however, not all patients carrying the same mutation develop symptoms of major depression, pointing out the significance of the interplay of genetic and non-genetic factors in the etiology. In a series of paediatric patients evaluated for mitochondrial dysfunction, out of 35 children with a biochemically and genetically confirmed mitochondrial disorder, we identified five cases presenting with major depression prior to the diagnosis. The patients were diagnosed respectively with mutations in MTTK, MTND1, POLG1, PDHA1 and the common 4977 bp mtDNA deletion. Besides cerebral lactic acidemia protein and glucose concentrations, immunoglobins, anti-gangliosides and neurotransmitters were normal. No significant difference could be confirmed in the disease progression or the quality of life, compared to the other, genetically confirmed mitochondrial patients. In three out of our five patients a significant stress life event was confirmed. We propose the abnormal central nervous system energy metabolism as the underlying cause of the mood disorder in our paediatric patients. Exploring the genetic etiology in children with mitochondrial dysfunction and depression is essential both for safe medication and adequate counselling.

Normal biochemical analysis of the oxidative phosphorylation (OXPHOS) system in a child with POLG mutations: a cautionary note.

We report a 5-year-old child carrying polymerase gamma (POLG1) mutations, but strikingly normal oxidative phosphorylation analysis in muscle, fibroblasts and liver. Mutations in POLG1 have so far been described in children with severe combined oxidative phosphorylation (OXPHOS) deficiencies and with the classical Alpers-Huttenlocher syndrome. The patient presented with a delayed psychomotor development and ataxia during the first two years of life. From the third year of life he developed epilepsy and regression in development, together with symptoms of visual impairment and sensorineuronal deafness. Cerebrospinal fluid showed elevated lactic acid and protein concentrations. An elder brother had died due to combined OXPHOS deficiencies. Despite the clinical similarity with the elder brother, except for liver involvement, the OXPHOS system analysis in a frozen muscle biopsy was normal. For this reason a fresh muscle biopsy was performed, which has the advantage of the possibility of measuring the substrate oxidation rates and ATP production, part of the mitochondrial energy-generating system (MEGS). During the same session, biopsies of liver and fibroblasts were taken. These three tissues showed normal measurements of the MEGS capacity. Based on the phenotype of Alpers-Huttenlocher syndrome in the elder brother, we decided to screen the POLG1 gene. Mutation analysis showed compound heterozygosity with two known mutations, A467T and G848S. The normal MEGS capacity in this patient expands the already existing complexity and heterogeneity of the childhood POLG1 patients and, on the basis of the high frequency of POLG1 mutations in childhood, warrants a liberal strategy with respect to mutation analysis.

[Ethics of medical scientific research: informed consent and the therapeutic misconception]. / Ethiek van medisch-wetenschappelijk onderzoek: informed consent en de therapeutische misconceptie.

--Ethical approval of research involving human beings is based on two pillars: supervision of the scientific merit of the research and the risks and burdens for participants by an institutional review board (IRB) or the Dutch Central Committee on Research Involving Human Subjects (CCMO), and obtaining informed consent from the participant or his or her legal guardian. --Discussions on the ethical acceptability of a study generally focus on the first pillar, assessment by an IRB. The second pillar, obtaining informed consent, is often neglected. --Some ethical concepts play a role in obtaining informed consent, especially the concept of the 'therapeutic misconception', i.e. that participating in a study is the same as receiving individualised treatment from a physician. --Of importantance in this matter is the fundamental difference between the research relationship (between investigator and participant) and treatment relationship (between physician and patient). --Understanding the concept of therapeutic misconception is essential to explaining why it is often difficult to obtain valid informed consent from patients for medical research.

[Hopeless and unbearable suffering and deliberate ending of life of newborn infants]. / Uitzichtloos en ondraaglijk lijden en actieve levensbeëindiging bij pasgeborenen.

Deliberate ending of life of newborns is an extreme measure that is usually based on hopeless and existing unbearable suffering. There are currently developments that may lead to clarification and refinement of the standards and rules surrounding deliberate ending of life of newborns. This pertains to the phase immediately following the decision to refrain from curative treatment. An important aspect here is that parents and doctors will have to reach agreement on the extent to which the suffering of the newborn can be classified as unbearable. Furthermore, in the case of deliberate ending of life of newborns, consideration must be given not only to current suffering but also the severe suffering that will develop in the near future. The points ofspecial importance that the medical profession had developed in relation to the assessment of future unbearable suffering may provide assistance here and should be implemented.

Mitochondrial disease criteria: diagnostic applications in children.

BACKGROUND: Based on a previous prospective clinical and biochemical study, a consensus mitochondrial disease scoring system was established to facilitate the diagnosis in patients with a suspected mitochondrial disorder. OBJECTIVE: To evaluate the specificity of the diagnostic system, we applied the mitochondrial disease score in 61 children with a multisystem disease and a suspected oxidative phosphorylation disorder who underwent a muscle biopsy and were consecutively diagnosed with a genetic mutation. METHODS: We evaluated data of 44 children diagnosed with a disorder in oxidative phosphorylation, carrying a mutation in the mitochondrial or nuclear DNA. We compared them with 17 children who, based on the clinical and metabolic features, also had a muscle biopsy but were finally diagnosed with a nonmitochondrial multisystem disorder by further genetic analysis. RESULTS: All children with a genetically established diagnosis of a primary oxidative phosphorylation disorder had a mitochondrial disease score above 6 (probable mitochondrial disorder), and 73% of the children had a score above 8 (definite mitochondrial disorder) at evaluation of the muscle biopsy. In the nonmitochondrial multisystem disorder group, the score was significantly lower, and no patients reached a score comparable with a definite respiratory chain disorder. CONCLUSIONS: The mitochondrial disease criteria system has a high specificity to distinguish between mitochondrial and other multisystem disorders. The method could also be applied in children with a suspected mitochondrial disorder, prior to performing a muscle biopsy.

Skeletal muscle ultrasonography in children with a dysfunction in the oxidative phosphorylation system.

OBJECTIVE: The aim of this prospective study was to investigate the diagnostic value of quantitative skeletal muscle ultrasonography in children suspected of having a mitochondrial disorder. METHODS: Muscle thickness and quantitatively determined echo intensity of four muscles were established in 53 children with symptoms indicative of a mitochondrial disorder. RESULTS: A sensitivity of 25 to 46 % was found, depending on the chosen cut-off point (abnormal or borderline abnormal), with a specificity of 85 to 100 %. Except for one, all abnormal ultrasound scans were found in children over five years of age. Within the group of patients with a mitochondrial disorder, a significant correlation was found between muscle echo intensity and age (r = 0.38; p = 0.047). CONCLUSIONS: We conclude that skeletal muscle ultrasound can be of additional value in the diagnosis of children with suspected mitochondrial disorders, especially in children over five years of age. With its low sensitivity, it is not suitable for screening purposes. However, since all abnormal ultrasound scans were found in children with a mitochondrial disorder, and no significant correlation with the MDC score was found, muscle ultrasound can be used complementary to this scoring system to facilitate the decision-making in pursuing further invasive diagnostics.

[A multidisciplinary approach is necessary in the neonatal withdrawal syndrome]. / Multidisciplinaire benadering nodig bij neonataal abstinentiesyndroom.

Two baby boys, born of mothers that were abusing drugs, were restless and hypertonic, typical symptoms of the neonatal withdrawal syndrome. The symptoms disappeared during treatment with phenobarbital and methadone. The children were then placed in a foster home. Symptoms of the neonatal withdrawal syndrome are excitation of the central nervous system, the gastrointestinal tract and the respiratory tract. For both legal and medical reasons it is essential to test the urine of the neonate for drugs. The Finnegan score is a useful tool to decide whether medical treatment is indicated. Medical treatment consists of the administration of phenobarbital and or methadone. The Child Protection Agency of the Ministry of Justice is notified of the child's birth. If parents that are abusing drugs have been shown not to be able to look after their children, they are limited in their right to parenthood.

[Optimal breastfeeding to prevent hyperbilirubinaemia in healthy, term newborns]. / Optimale borstvoeding ter preventie van hyperbilirubinemie bij gezonde, voldragen pasgeborenen.

In a newborn infant, frequent bowel movements diminish the enterohepatic circulation of bilirubin, thereby increasing bilirubin excretion. In breastfed newborn infants, the frequency of latching on and administration of supplementary feeds are associated with serum bilirubin concentrations. Frequent breast feeding (at least 8 times a day) and fewer supplementary feeds will result in increased breast milk intake, less weight loss, and lower bilirubin concentrations. In the case of a breastfed infant presenting with neonatal hyperbilirubinaemia, the advice should be to breastfeed more frequently and to withhold supplementary feedings. An icteric newborn infant should be seen and weighed daily. If the infant has lost more than 10% of its birth weight, drinks poorly, or fails to gain weight despite latching onto the breast frequently, it should be referred to the paediatrician for further diagnosis and treatment. To ensure optimal production of breast milk during the first days after birth, early latching on is recommended, preferably within one hour after birth.

Assessment of effluent turbidity in mesophilic and thermophilic activated sludge reactors - origin of effluent colloidal material.

Two lab-scale plug flow activated sludge reactors were run in parallel for 4 months at 30 and 55 degrees C. Research focussed on: (1) COD (chemical oxygen demand) removal, (2) effluent turbidity at both temperatures, (3) the origin of effluent colloidal material and (4) the possible role of protozoa on turbidity levels. Total COD removal percentages over the whole experimental period were 66+/-7% at 30 degrees C and 53+/-11% at 55 degrees C. Differences in total COD removal between both systems were due to less removal of soluble and colloidal COD at 55 degrees C compared to the reference system. Thermophilic effluent turbidity was caused by a combination of influent colloidal particles that were not effectively retained in the sludge flocs, and erosion of the thermophilic activated sludge itself, as shown by denaturing gradient gel electrophoresis (DGGE) profiles. DGGE analysis of PCR-amplified 16S rDNA fragments from mesophilic and thermophilic sludge differed, indicating that different microbial communities were present in the two reactor systems. The effects of protozoal grazing on the effluent turbidity of both reactors was negligible and thus could not account for the large turbidity differences observed.