Confined placental mosaicism: Distribution of chromosomally abnormal cells over the term placenta.

OBJECTIVE: Non-invasive prenatal testing (NIPT) investigates placental DNA and may detect confined placental mosaicism (CPM). The aim of this study was to confirm CPM in the term placenta in cases with abnormal NIPT but normal follow-up cytogenetic studies of fetus and mother. Additionally we examined the distribution of abnormal cells over the placenta. METHODS: Four chorionic villus (CV) biopsies from four placental quadrants were requested in cases where CPM was assumed. Both cell lineages of the CV, cytotrophoblast (CTB) and mesenchymal core (MC), were analyzed separately with SNP array. RESULTS: The chromosome aberration was confirmed in 67 % of the placentas. Three quarters of the CTB and MC biopsies from these mosaic placentas were uniformly normal (57 %) or abnormal (20 %), and a minority showed mosaicism. Among 16 cases of CPM where first trimester CV were examined as well, 11 had chromosomally normal results during pregnancy. DISCUSSION: Cytogenetic investigations of term placental biopsies suspected to be affected with CPM did not reveal the chromosome aberration in one third of the placentas. This is caused by the patchy pattern in which chromosomally abnormal cells are distributed over the placenta with the majority of the biopsies being uniformly normal. Further CPM research, including its clinical impact, requires the analysis of more than four biopsies to get insight into the extent of the affected part. Moreover, a subset of CPM type 1 and 3 seems to be only detectable with NIPT and not with first trimester CVS.

[Waiting for death: an analysis of the waiting list of the expertise centre for euthanasia]. / Wachten op de dood: een analyse van de wachtlijst van Expertisecentrum Euthanasie.

BACKGROUND: The waiting list of the expertise center euthanasia (EE) in the Netherlands for patients requesting euthanasia on the basis of psychiatric suffering has increased to two years in a short space of time. AIM: Clarity about the causes and direct consequences of the EE waiting list and an answer to the question: what now? METHOD: We analyzed the EE waiting list based on various media reports, annual reports from the EE and scientific studies. RESULTS: The EE waiting list arose because, on the one hand, the demand for euthanasia among patients with a mental illness has increased, while on the other hand, the willingness to perform euthanasia among psychiatrists appears to be declining. The reasons for both trends seem multifactorial. The direct consequence of the waiting list is that patients with a mental illness have less access to euthanasia, which in itself can also have harmful and protective consequences. CONCLUSION: The EE waiting list is the result of an increasing number of requests and an apparent decrease in psychiatrists' willingness to perform euthanasia. In response to this situation, roughly three ways forward are conceivable: first the mental health care sector can assign itself a more active role in the field of euthanasia, second a further demedicalisation of the end of life is possible, or third a choice can be an amendment to EE's referral procedure. All of these options have potential pros and cons.

Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections.

The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide's and Fluspirilene's efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.

[Towards a proactive psychiatric ethics: a care ethics perspective]. / Naar een proactieve psychiatrische ethiek: een zorgethisch perspectief.

Background Proactive psychiatry requires proactive psychiatric ethics. Aim To describe ethical considerations with regard to proactive psychiatry. Method Discussion of care ethics aimed at proactive psychiatric care. Results In this contribution, we plea for a proactive psychiatric ethics, stimulating and supporting healthcare professionals in working from a developmental and contextual perspective. We describe care ethics, and show that it is in line with the principles of proactive psychiatry. We address three issues related to the development of proactive psychiatry: the goals of care; identifying risk factors; and the division of responsibilities in mental healthcare. Conclusion Proactive psychiatric ethics can be useful in identifying and discussing ethical issues associated with proactive psychiatry and thus contribute to improving practice. Tijdschrift voor Psychiatrie 63(2021)2, 150-153.

Melanoma cells can be eliminated by sialylated CD43 × CD3 bispecific T cell engager formats in vitro and in vivo.

Targeted cancer therapy with monoclonal antibodies has proven successful for different cancer types but is limited by the availability of suitable antibody targets. CD43s, a unique sialylated form of CD43 expressed by hematologic malignancies, is a recently identified target and antibodies interacting with CD43s may have therapeutic potential against acute myeloid leukemia (AML) and myelodysplastic syndrome. CD43s is recognized by the human antibody AT1413, that was derived from a high-risk AML patient who successfully cleared leukemia after allogeneic stem cell transplantation. Here we observed that AT1413 binds also to certain non-hematopoietic tumor cells, particularly melanoma and breast cancer. AT1413 immune precipitated CD43s from melanoma cells confirming that it recognizes the same target on melanoma as on AML. AT1413 induced antibody-dependent cellular cytotoxicity against short-term cultured patient-derived melanoma samples. However, AT1413 was unable to affect the growth of melanoma cells in vivo. To increase the efficacy of AT1413 as a therapeutic antibody, we generated two different formats of bispecific T-cell engaging antibodies (TCEs): one binding bivalently (bTCE) and the other monovalently (knob-in-hole; KiH) to both CD43s and CD3ε. In vitro, these TCEs redirected T-cell cytotoxicity against melanoma cells with differences in potencies. To investigate their effects in vivo, we grafted mice that harbor a human immune system with the melanoma cell line A375. Treatment with both AT1413 bTCE and AT1413 KiH significantly reduced tumor outgrowth in these mice. These data indicate a broad therapeutic potential of AT1413 that includes AML and CD43s-expressing solid tumors that originate from CD43-negative tissues.

[Physician-assisted death in psychiatry]. / Euthanasie in de psychiatrie.

In recent years, more patients with psychiatric disorders are receiving physician-assisted death (PAD). In the Netherlands, since more than 25 years psychiatric suffering is seen as a legitimate reason for PAD, but an additional independent assessment is required. Scarce empirical research shows that patients who receive PAD on the basis of psychiatric suffering have long-standing and complex complaints. Among these patients, depression and personality disorders are relatively common. The ethical justification of PAD for patients with psychiatric disorders has been the subject of debate for decades. Decisions about competence and the irremediability of suffering are challenging and for many authors reason enough to reject PAD based on psychiatric suffering. Others regard the exclusion of all patients with mental disorders as unjust. Empirical research and ethical consideration are needed for better founded considerations and a more widely supported practice concerning patients with a mental disorder who request PAD.

Last-Minute Recovery of a Psychiatric Patient Requesting Physician-Assisted Death.

Physician-assisted death is becoming legal in an increasing number of jurisdictions, but psychiatric patients are often explicitly excluded. However, in some countries, including the Netherlands, physician-assisted death of psychiatric patients is allowed. This Open Forum describes a patient with schizophrenia and symptoms diagnosed as refractory musical hallucinations. The patient requested assistance in dying only to recover after a mandatory second opinion, where his complaints were recognized as intrusive thoughts and treated accordingly. This case is used to reflect on how to deal with uncertainty about physician-assisted death of psychiatric patients and to argue for implementation of a due-diligence procedure, such as the one proposed in the Dutch Psychiatric Association's recent guideline concerning this issue.

[Euthanasia of Dutch psychiatric patients in 2015-2017]. / Euthanasie van Nederlandse psychiatrische patiënten in 2015-2017.

BACKGROUND: The Netherlands is one of the few countries in the world that allows euthanasia and assisted suicide (EAS) due to psychiatric suffering. METHODS In 2015-2017 the Dutch regional euthanasia review committees published 43 case summaries online. Of these, 35 were suitable for analysis regarding patient characteristics and physician involvement, and 3 cases were described in detail.
RESULTS: In total, 77% of the patients were women and 51% were aged 50-70 years. Major depression disorder and personality disorders were present in almost half of the patients. All patients were considered mentally competent. CONCLUSIONS Although the incidence of psychiatric EAS cases is rising, we found no shift in patient characteristics. The division between psychiatric and somatic suffering may prove more complicated than expected. Patients dying from suicide differ in various ways from patients dying through EAS. The fact that all patients are considered competent could mean that they are unjustly seen as being vulnerable or that the competence assessment lacks due diligence.

Multilingualism was associated with lower cognitive outcomes in children who were born very and extremely preterm.

AIM: This study determined whether cognitive outcomes differed between very preterm (VPT) and extremely preterm (EPT) children who were monolingual or multilingual when they reached the corrected ages of two and five years. METHODS: The data were collected at the Emma Children's Hospital, Amsterdam, The Netherlands, as part of our national neonatal follow-up programme and comprised 325 VPT/EPT children born between January 1, 2007 and January 1, 2012. The study used the Third Editions of the Bayley Scales of Infant and Toddler Development and the Wechsler Preschool and Primary Scale of Intelligence. RESULTS: We compared 234 monolingual children, 65 multilingual children who spoke Dutch and at least one foreign language at home and 26 multilingual children who didn't speak Dutch at home. The best performers on the cognitive scale at two years of age and the verbal subscales at five years of age were the monolingual children, followed by the children who spoke Dutch and at least one foreign language at home, then the children who only spoke foreign languages at home. CONCLUSION: In our study cohort from The Netherlands, multilingualism lowered the cognitive and verbal outcomes of VPT/EPT children at the corrected ages of two and five years.

[Is psychiatry ready to let patients review their own files? Inventory of initial experiences]. / Is de psychiatrie klaar voor de meelezende patiënt? Inventarisatie van eerste ervaringen.

BACKGROUND: Dutch patients will be granted the right to digitally access their own medical records, an option already available to the patients at the University Medical Center Utrecht since 2015. AIM: To start a conversation about the development of readily accessible online patient records. METHODS Describe the experiences of a University department of psychiatry with an online patient portal, obtained through discussions and questionnaires. RESULTS: During the next few years three legal developments will enable patients to acquire direct, remote, digital access to their medical files. Immediate online review of medical records improves accessibility and empowers the patient. Some therapists experienced a change in patient interaction. Furthermore, during documentation psychiatrists took into account that patients could review the contents at a later point. CONCLUSION: Patients' accessibility of online records will influence the patient-therapist dynamic. More research on the patient perspective and a discussion among professionals are necessary to further streamline broad implementation of online patient portals.

Very preterm born children at early school age: Healthcare therapies and educational provisions.

AIM: To explore changes in motor and cognitive outcomes in very preterm (VP; gestational age<30weeks) born children between ages five and six years, and to determine whether changes in these outcomes were associated with the use of healthcare therapies and educational provisions. STUDY DESIGN: Single-center observational cohort study. Five-year-old VP born children of a one-year-cohort of our neonatal follow-up program (N=90) were invited for re-assessments at age six. Use of healthcare therapies and educational provisions was registered at ages five and six years. Motor function (Movement Assessment Battery for Children-2 [M-ABC-2]; higher scores indicate better functioning) and IQ (Wechsler Preschool and Primary Scale for Intelligence [WPPSI-III-NL]) were assessed at both ages. RESULTS: Sixty-four VP born children were seen at ages five and at six years. In this year, 61% received healthcare therapies and/or educational provisions. M-ABC-2 scores of VP born children who received healthcare therapy and/or educational provisions were significantly higher (M=8.9 [SD=3.2]) at age six years than at age five years (M=7.5 [SD=3.3]); p<0.00). M-ABC-2 scores remained stable in the average range in VP born children without any support. IQ scores remained stable irrespective of received support. CONCLUSIONS: Improvements in motor outcomes are associated with the use of healthcare therapies and/or educational support between ages five and six years in VP born children. Future studies need to determine the efficacy of existing interventions, and to develop tailored interventions to support VP born children in the transfer period from preschool to primary education.

Frequency of submicroscopic chromosomal aberrations in pregnancies without increased risk for structural chromosomal aberrations: systematic review and meta-analysis.

OBJECTIVE: To establish, based on a systematic literature review, the frequency of pathogenic submicroscopic chromosomal aberrations in fetuses that are not at increased risk for unbalanced structural chromosomal aberrations, with the aim of determining whether high-resolution testing for submicroscopic aberrations is beneficial in a general pregnant population. METHODS: EMBASE, PubMed, Web of Science and CENTRAL databases were searched systematically on 3 June 2016 for all relevant articles on the prevalence of pathogenic submicroscopic copy number variants (CNVs) in fetuses referred for prenatal invasive testing because of advanced maternal age (AMA) or parental anxiety (ANX). Relevant full-text articles were analyzed and the prevalence of submicroscopic CNVs was calculated based on the extracted data. Meta-analysis was conducted in a pooled cohort of 10 614 fetuses based on the 10 largest studies (n > 300) of a total of 19 that were relevant. RESULTS: Pooled estimate analysis indicated that 0.84% (95% CI, 0.55-1.30%) of fetuses that had invasive testing because of AMA/ANX carried a pathogenic clinically significant submicroscopic aberration. The onset/penetrance of submicroscopic findings was studied in 10 314 fetuses reported in eight papers that presented aberrant cases with all necessary details to allow assessment of the findings. The pooled estimates resulting from meta-analysis of the data indicated that an early-onset syndromic disorder was detected in 0.37% (95% CI, 0.27-0.52%) of cases, a susceptibility CNV was found in 0.30% (95% CI, 0.14-0.67%) and late-onset diseases were reported in 0.11% (95% CI, 0.05%-0.21%). The prevalence of early-onset syndromic disorders caused by a submicroscopic aberration was calculated to be 1:270. When the risk for submicroscopic aberrations is added to the individual risk for microscopic chromosomal aberrations, all pregnant women have a risk of higher than 1 in 180 for a relevant chromosomal aberration, and pregnant women under 36 years of age have a higher risk for submicroscopic pathogenic aberrations than for Down syndrome. CONCLUSION: This systematic review shows that a significant proportion of fetuses in a general pregnant population carry a submicroscopic pathogenic CNV. Based on these figures, all women should be informed on their individual risk for all pathogenic chromosomal aberrations and not only for common trisomies. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Exploring the predictive power of interaction terms in a sophisticated risk equalization model using regression trees.

This study explores the predictive power of interaction terms between the risk adjusters in the Dutch risk equalization (RE) model of 2014. Due to the sophistication of this RE-model and the complexity of the associations in the dataset (N = ~16.7 million), there are theoretically more than a million interaction terms. We used regression tree modelling, which has been applied rarely within the field of RE, to identify interaction terms that statistically significantly explain variation in observed expenses that is not already explained by the risk adjusters in this RE-model. The interaction terms identified were used as additional risk adjusters in the RE-model. We found evidence that interaction terms can improve the prediction of expenses overall and for specific groups in the population. However, the prediction of expenses for some other selective groups may deteriorate. Thus, interactions can reduce financial incentives for risk selection for some groups but may increase them for others. Furthermore, because regression trees are not robust, additional criteria are needed to decide which interaction terms should be used in practice. These criteria could be the right incentive structure for risk selection and efficiency or the opinion of medical experts.

ATP13A2/PARK9 regulates endo-/lysosomal cargo sorting and proteostasis through a novel PI(3, 5)P2-mediated scaffolding function.

ATP13A2 (also called PARK9), is a transmembrane endo-/lysosomal-associated P5 type transport ATPase. Loss-of-function mutations in ATP13A2 result in the Kufor-Rakeb Syndrome (KRS), a form of autosomal Parkinson's disease (PD). In spite of a growing interest in ATP13A2, very little is known about its physiological role in stressed cells. Recent studies suggest that the N-terminal domain of ATP13A2 may hold key regulatory functions, but their nature remains incompletely understood. To this end, we generated a set of melanoma and neuroblastoma cell lines stably overexpressing wild-type (WT), catalytically inactive (D508N) and N-terminal mutants, or shRNA against ATP13A2. We found that under proteotoxic stress conditions, evoked by the proteasome inhibitor Bortezomib, endo-/lysosomal associated full-length ATP13A2 WT, catalytically-inactive or N-terminal fragment mutants, reduced the intracellular accumulation of ubiquitin-conjugated (Ub) proteins, independent of autophagic degradation. In contrast, ATP13A2 silencing increased the intracellular accumulation of Ub-proteins, a pattern also observed in patient-derived fibroblasts harbouring ATP13A2 loss-of function mutations. In treated cells, ATP13A2 evoked endocytic vesicle relocation and increased cargo export through nanovesicles. Expression of an ATP13A2 mutant abrogating PI(3,5)P2 binding or chemical inhibition of the PI(3,5)P2-generating enzyme PIKfyve, compromised vesicular trafficking/nanovesicles export and rescued intracellular accumulation of Ub-proteins in response to proteasomal inhibition. Hence, our study unravels a novel activity-independent scaffolding role of ATP13A2 in trafficking/export of intracellular cargo in response to proteotoxic stress.

Prenatal and postnatal findings in small-for-gestational-age fetuses without structural ultrasound anomalies at 18-24 weeks.

OBJECTIVE: To assess phenotypic and genotypic characteristics of small-for-gestational-age (SGA) fetuses without structural anomalies at 18-24 weeks' gestation. METHODS: This retrospective study included structurally normal singleton fetuses with an abdominal circumference ≤ 5th percentile on detailed ultrasound examination between 18 and 24 weeks' gestation. Cases were stratified according to the absence or presence of other abnormal ultrasound findings, such as abnormal amniotic fluid or soft markers. All patients were offered invasive prenatal testing with rapid aneuploidy detection by qualitative fluorescence polymerase chain reaction (QF-PCR) and, if normal, consecutive single nucleotide polymorphism (SNP) array was also offered. Detailed postnatal follow-up (≥ 5 months) was performed. In cases in which a syndromic phenotype became apparent within 5 months after birth and SNP array had not been performed prenatally, it was performed postnatally. RESULTS: A total of 211 pregnancies were eligible for inclusion. Of the 158 cases with isolated SGA on ultrasound, 36 opted for invasive prenatal testing. One case of trisomy 21 and one case of a submicroscopic abnormality (a susceptibility locus for neurodevelopmental disease) were detected. Postnatal follow-up showed a postnatal apparent syndromic phenotype in 10 cases. In one case this was due to trisomy 21 and the other nine (5.8%; 95% CI, 2.8-10.0%) cases had normal SNP array results. In 32/53 cases with SGA and associated ultrasound abnormalities, parents opted for invasive testing. One case of trisomy 21 and one of triploidy were found. In 11 cases a syndromic phenotype became apparent after birth. One was due to trisomy 21 and in one case a submicroscopic anomaly (a susceptibility locus) was found. The remaining syndromic cases (17.3%; 95% CI, 8.7-29.0%) had normal SNP array results. CONCLUSION: Testing for chromosomal anomalies should be offered in cases of SGA between 18 and 24 weeks' gestation. Whole chromosome anomalies occur in 1.3% (95% CI, 0.2-3.9%) of isolated SGA and 5.8% (95% CI, 1.5-14.0%) of associated SGA. In 0.6% (95% CI, 0.1-2.8%) and 1.9% (95% CI, 0.2-8.2%), respectively, SNP array detected a susceptibility locus for neurodevelopmental disease that would not be detected by karyotyping, QF-PCR or non-invasive prenatal testing. Therefore, and because the genetic causes of SGA are diverse, we suggest SNP array testing in cases of SGA. Thorough postnatal examination and follow-up of infants that presented with reduced fetal growth is important because chromosomally normal syndromic phenotypes occur frequently in SGA fetuses. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

[Psychopathology in families: an integral approach via the family outpatient clinic]. / Psychiatrische stoornissen binnen gezinnen: een integrale benadering via de familiepoli.

BACKGROUND: Psychiatric disorders run in families. To bridge the gap between child and youth psychiatry and adult psychiatry, GGZ inGeest has started screening parents of new registered children for psychopathology - and if indicated - offers parents treatment in the same department as their children. AIM: To examine the feasibility and usefulness of this procedure, to investigate how many parents agree to screening, further diagnostics and treatment, and to find out how many parents have in fact suffered from recent psychiatric problems. METHOD: Prior to the children's first appointment, the parents were asked to complete a questionnaire, the Adult Self Report (ASR), about their own problems. If these scores were (sub)clinical, parents were invited to participate in a telephonic interview. This consisted of the Composite International Diagnostic Interview (CIDI) and Conners' Adult ADHD Rating Scales (CAARS). If the results indicate psychopathology, further psychiatric assessment and, if necessary, treatment is offered. RESULTS: The first response was 55.7% and, if indicated, most of the parents agreed on further diagnostics. On the ASR 2 out of 5 mothers (42.1%) and 1 out of 5 fathers (21.8%) reported problems that could point to a psychiatric disorder. According to the ASR, within this high-risk group 37% of the mothers met the criteria for an axis I diagnosis (less than one month earlier) compared to 70.6% of the fathers. A mood disorder was the primary diagnosis for women, whereas men most often suffered from an anxiety disorder. In total, 19.1% of the parents screened were suffering from recent psychopathology and 75% of this group agreed to receive mental health care (treatment at the family outpatient clinic or referred to another clinic). CONCLUSION: Implementation of the family outpatient clinic scheme is feasible. However, further efforts are needed in order to reach a larger group of parents, particularly fathers. The family outpatient clinic is useful because parents who suffer from psychopathology do not always receive mental health care. However, a randomised control trial is needed to determine whether parallel treatment of parents and children can improve the treatment outcome for children.

Comfortable mobile offices: A literature review of the ergonomic aspects of mobile device use in transportation settings.

BACKGROUND: The use of mobile devices as an addition to or replacement of desktop computers for traditional office work results in more flexibility of workplaces. Consequently transportation time is used for office work and this asks for comfortable mobile offices. OBJECTIVE: The aim of this review is providing a framework of the relevant elements for comfortable mobile offices and defining needs for future research. METHODS: This literature review draws on 68 papers, theses, reviews and critiques. RESULTS: The framework is based on existing literature on traditional office ergonomics and comfort literature for different transportation modes like trains, buses, airplanes and cars. CONCLUSIONS: The main differences with traditional offices are the type of devices, dynamic versus static situation, the sole use of mobile devices and therefore the need for a good arm support to avoid an uncomfortable neck flexion, limited space, and the presence of strangers which influence the privacy perception. Important topics for future research are: the effect on the employee and the environment of the ability and demand of working anywhere, and the requirements for the physical aspects of mobile offices.

Is there one measure-of-fit that fits all? A taxonomy and review of measures-of-fit for risk-equalization models.

This study provides a taxonomy of measures-of-fit that have been used for evaluating risk-equalization models since 2000 and discusses important properties of these measures, including variations in analytic method. It is important to consider the properties of measures-of-fit and variations in analytic method, because they influence the outcomes of evaluations that eventually serve as a basis for policymaking. Analysis of 81 eligible studies resulted in the identification of 71 unique measures that were divided into 3 categories based on treatment of the prediction error: measured based on squared errors, untransformed errors, and absolute errors. We conclude that no single measure-of-fit is best across situations. The choice of a measure depends on preferences about the treatment of the prediction error and the analytic method. If the objective is measuring financial incentives for risk selection, the only adequate evaluation method is to assess the predictive performance for non-random groups.

Improving the prediction model used in risk equalization: cost and diagnostic information from multiple prior years.

Currently-used risk-equalization models do not adequately compensate insurers for predictable differences in individuals' health care expenses. Consequently, insurers face incentives for risk rating and risk selection, both of which jeopardize affordability of coverage, accessibility to health care, and quality of care. This study explores to what extent the predictive performance of the prediction model used in risk equalization can be improved by using additional administrative information on costs and diagnoses from three prior years. We analyze data from 13.8 million individuals in the Netherlands in the period 2006-2009. First, we show that there is potential for improving models' predictive performance at both the population and subgroup level by extending them with risk adjusters based on cost and/or diagnostic information from multiple prior years. Second, we show that even these extended models do not adequately compensate insurers. By using these extended models incentives for risk rating and risk selection can be reduced substantially but not removed completely. The extent to which risk-equalization models can be improved in practice may differ across countries, depending on the availability of data, the method chosen to calculate risk-adjusted payments, the value judgment by the regulator about risk factors for which the model should and should not compensate insurers, and the trade-off between risk selection and efficiency.