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Bile salts can strongly influence energy metabolism through systemic signaling, which can be enhanced by inhibiting the hepatic bile salt transporter Na + taurocholate cotransporting polypeptide (NTCP), thereby delaying hepatic reuptake of bile salts to increase systemic bile salt levels. Bulevirtide is an NTCP inhibitor and was originally developed to prevent NTCP-mediated entry of Hepatitis B and D into hepatocytes. We previously demonstrated that NTCP inhibition lowers body weight, induces glucagon-like peptide-1 (GLP1) secretion, and lowers plasma cholesterol levels in murine obesity models. In humans, a genetic loss-of-function variant of NTCP has been associated with reduced plasma cholesterol levels. Here, we aimed to assess if Bulevirtide treatment attenuates atherosclerosis development by treating female Ldlr -/- mice with Bulevirtide or vehicle for 11 weeks. Since this did not result in the expected increase in plasma bile salt levels, we generated Oatp1a1 -/- Ldlr -/- mice, an atherosclerosis-prone model with human-like hepatic bile salt uptake characteristics. These mice showed delayed plasma clearance of bile salts and elevated bile salt levels upon Bulevirtide treatment. At the study endpoint, Bulevirtide-treated female Oatp1a1 -/- Ldlr -/- mice had reduced atherosclerotic lesion area in the aortic root that coincided with lowered plasma LDL-c levels, independent of intestinal cholesterol absorption. In conclusion, Bulevirtide, which is considered safe and is EMA-approved for the treatment of Hepatitis D, reduces atherosclerotic lesion area by reducing plasma LDL-c levels. We anticipate that its application may extend to atherosclerotic cardiovascular diseases, which warrants clinical trials., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Counseling for whole-exome sequencing (WES) could benefit from aligning parents' pre- and post-disclosure attitudes. A few studies have qualitatively compared parents' pre- and post-disclosure attitudes toward receiving WES results for their child in a diagnostic setting. This study explored these attitudes in the context of children with a developmental delay., Methods: Semi-structured interviews were conducted with parents (n = 27) of 16 children undergoing diagnostic WES in trio-analysis, both before and after receiving results., Results: Three key insights emerged. First, the distinction between hoping and expecting was relevant for shaping parents' experiences with receiving results related to the primary indication. Second, parents of young children whose development of autonomous capacities was uncertain sometimes found themselves in a situation resembling a Catch-22 when confronted with decisions about unsolicited findings (UFs): an important reason for consenting to WES was to gain a better picture of how the child might develop, but in order to make responsible choices about UFs, some ideas of their child's development is needed. Third, default opt-ins and opt-outs helped parents fathom new kinds of considerations for accepting or declining UFs in different categories, thereby aiding decision-making., Conclusion: Results from this study are relevant for counseling and policy development., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Massively parallel sequencing techniques, such as whole exome sequencing (WES) and whole genome sequencing (WGS), may reveal unsolicited findings (UFs) unrelated to the diagnostic aim. Such techniques are frequently used for diagnostic purposes in pediatric cases of developmental delay (DD). Yet policy guidelines for informed consent and return of UFs are not well equipped to address specific moral challenges that may arise in these children's situations., Discussion: In previous empirical studies conducted by our research group, we found that it is sometimes uncertain how children with a DD will develop and whether they could come to possess capacities for autonomous decision-making in the future. Parents sometimes felt this brought them into a Catch-22 like situation when confronted with choices about UFs before undergoing WES in trio-analysis (both the parents' and child's DNA are sequenced). An important reason for choosing to consent to WES was to gain more insight into how their child might develop. However, to make responsible choices about receiving or declining knowledge of UFs, some idea of their child's future development of autonomous capacities is needed. This undesirable Catch-22 situation was created by the specific policy configuration in which parents were required to make choices about UFs before being sequencing (trio-analysis). We argue that this finding is relevant for reconfiguring current policies for return of UFs for WES/WGS and propose guidelines that encompass two features. First, the informed consent process ought to be staged. Second, differing guidelines are required for withholding/disclosing a UF in cases of DD appropriate to the level of confidence there is about the child's future developmental of autonomous capacities., Conclusion: When combined with a dynamic consent procedure, these two features of our guidelines could help overcome significant moral challenges that present themselves in the situations of children undergoing genomic sequencing for clarifying a DD., (© 2023. The Author(s).)

Background & Aims: Intestine-restricted inhibitors of the apical sodium-dependent bile acid transporter (ASBT, or ileal bile acid transporter) are approved as treatment for several inheritable forms of cholestasis but are also associated with abdominal complaints and diarrhoea. Furthermore, blocking ASBT as a single therapeutic approach may be less effective in moderate to severe cholestasis. We hypothesised that interventions that lower hepatic bile salt synthesis in addition to intestinal bile salt uptake inhibition provide added therapeutic benefit in the treatment of cholestatic disorders. Here, we test combination therapies of intestinal ASBT inhibition together with obeticholic acid (OCA), cilofexor, and the non-tumorigenic fibroblast growth factor 15 (Fgf15)/fibroblast growth factor 19 (FGF19) analogue aldafermin in a mouse model of cholestasis., Methods: Wild-type male C57Bl6J/OlaHsd mice were fed a 0.05% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and received daily oral gavage with 10 mg/kg OCA, 30 mg/kg cilofexor, 10 mg/kg ASBT inhibitor (Linerixibat; ASBTi), or a combination. Alternatively, wild-type male C57Bl6J/OlaHsd mice were injected with adeno-associated virus vector serotype 8 (AAV8) to express aldafermin, to repress bile salt synthesis, or to control AAV8. During a 3-week 0.05% DDC diet, mice received daily oral gavage with 10 mg/kg ASBTi or placebo control., Results: Combination therapy of OCA, cilofexor, or aldafermin with ASBTi effectively reduced faecal bile salt excretion. Compared with ASBTi monotherapy, aldafermin + ASBTi further lowered plasma bile salt levels. Cilofexor + ASBTi and aldafermin + ASBTi treatment reduced plasma alanine transaminase and aspartate transaminase levels and fibrotic liver immunohistochemistry stainings. The reduction in inflammation and fibrogenesis in mice treated with cilofexor + ASBTi or aldafermin + ASBTi was confirmed by gene expression analysis., Conclusions: Combining pharmacological intestinal bile salt uptake inhibition with repression of bile salt synthesis may form an effective treatment strategy to reduce liver injury while dampening the ASBTi-induced colonic bile salt load., Impact and Implications: Combined treatment of intestinal ASBT inhibition with repression of bile salt synthesis by farnesoid X receptor agonism (using either obeticholic acid or cilofexor) or by expression of aldafermin ameliorates liver damage in cholestatic mice. In addition, compared with ASBT inhibitor monotherapy, combination treatments lower colonic bile salt load., Competing Interests: The authors declare no conflict of interest with regard to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

Introduction: The inflammatory milieu after acute retinal necrosis (ARN) may lead to a breakdown of the inner and outer blood-retinal barrier and consequently to a cystoid macular edema (CME) with accumulation of intra- and subretinal fluid. Up to now, there is no established therapeutic approach for CME in ARN patients.Case report: We report a case of an immunocompetent 14-year-old female with chronic ARN-related CME, which was unresponsive to valacyclovir, prednisone and intravitreal ranibizumab injections. A combination treatment of tocilizumab, an interleukin-6 receptor inhibitor, and intravitreal aflibercept was successful to control the CME.Conclusion: In selected patients with treatment-refractory CME following ARN a therapy with tocilizumab and intravitreal aflibercept might be considered.

Background & Aims: Non-absorbable inhibitors of the apical sodium-dependent bile acid transporter (ASBT; also called ileal bile acid transporter [IBAT]) are recently approved or in clinical development for multiple cholestatic liver disorders and lead to a reduction in pruritus and (markers for) liver injury. Unfortunately, non-absorbable ASBT inhibitors (ASBTi) can induce diarrhoea or may be ineffective if cholestasis is extensive and largely precludes intestinal excretion of bile acids. Systemically acting ASBTi that divert bile salts towards renal excretion may alleviate these issues., Methods: Bile duct ligation (BDL) was performed in ASBT-deficient (ASBT knockout [KO]) mice as a model for chronic systemic ASBT inhibition in obstructive cholestasis. Co-infusion of radiolabelled taurocholate and inulin was used to quantify renal bile salt excretion after BDL. In a second (wild-type) mouse model, a combination of obeticholic acid (OCA) and intestine-restricted ASBT inhibition was used to lower the bile salt pool size before BDL., Results: After BDL, ASBT KO mice had reduced plasma bilirubin and alkaline phosphatase compared with wild-type mice with BDL and showed a marked reduction in liver necrotic areas at histopathological analysis, suggesting decreased BDL-induced liver damage. Furthermore, ASBT KO mice had reduced bile salt pool size, lower plasma taurine-conjugated polyhydroxylated bile salt, and increased urinary bile salt excretion. Pretreatment with OCA + ASBTi in wild-type mice reduced the pool size and greatly improved liver injury markers and liver histology., Conclusions: A reduced bile salt pool at the onset of cholestasis effectively lowers cholestatic liver injury in mice. Systemic ASBT inhibition may be valuable as treatment for cholestatic liver disease by lowering the pool size and increasing renal bile salt output even under conditions of minimal faecal bile salt secretion., Lay Summary: Novel treatment approaches against cholestatic liver disease (resulting in reduced or blocked flow of bile) involve non-absorbable inhibitors of the bile acid transport protein ASBT, but these are not always effective and/or can cause unwanted side effects. In this study, we demonstrate that systemic inhibition/inactivation of ASBT protects mice against developing severe cholestatic liver injury after bile duct ligation, by reducing bile salt pool size and increasing renal bile salt excretion., Competing Interests: Ambys consultancy to institution of SFJVDG. The other authors report no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Background & Aims: Organic solute transporter (OST) subunits OSTα and OSTβ facilitate bile acid efflux from the enterocyte into the portal circulation. Patients with deficiency of OSTα or OSTβ display considerable variation in the level of bile acid malabsorption, chronic diarrhea, and signs of cholestasis. Herein, we generated and characterized a mouse model of OSTβ deficiency., Methods: Ostβ -/- mice were generated using CRISR/Cas9 and compared to wild-type and Ostα -/- mice. OSTβ was re-expressed in livers of Ostβ -/- mice using adeno-associated virus serotype 8 vectors. Cholestasis was induced in both models by bile duct ligation (BDL) or 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) feeding., Results: Similar to Ostα -/- mice, Ostβ -/- mice exhibited elongated small intestines with blunted villi and increased crypt depth. Increased expression levels of ileal Fgf15, and decreased Asbt expression in Ostβ -/- mice indicate the accumulation of bile acids in the enterocyte. In contrast to Ostα -/- mice, induction of cholestasis in Ostβ -/- mice by BDL or DDC diet led to lower survival rates and severe body weight loss, but an improved liver phenotype. Restoration of hepatic Ostβ expression via adeno-associated virus-mediated overexpression did not rescue the phenotype of Ostβ -/- mice., Conclusions: OSTβ is pivotal for bile acid transport in the ileum and its deficiency leads to an intestinal phenotype similar to Ostα -/- mice, but it exerts distinct effects on survival and the liver phenotype, independent of its expression in the liver. Our findings provide insights into the variable clinical presentation of patients with OSTα and OSTβ deficiencies., Lay Summary: Organic solute transporter (OST) subunits OSTα and OSTβ together facilitate the efflux of conjugated bile acids into the portal circulation. Ostα knockout mice have longer and thicker small intestines and are largely protected against experimental cholestatic liver injury. Herein, we generated and characterized Ostβ knockout mice for the first time. Ostα and Ostβ knockout mice shared a similar phenotype under normal conditions. However, in cholestasis, Ostβ knockout mice had a worsened overall phenotype which indicates a separate and specific role of OSTβ, possibly as an interacting partner of other intestinal proteins., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Authors.)

Background: About half of all children with rheumatic diseases need continuous medical care during adolescence and adulthood. A good transition into adult rheumatology is essential. Guidelines for a structured transition process have therefore been recommended by the European League Against Rheumatism (EULAR) and the Paediatric Rheumatology European Society (PReS). However, implementation of these guidelines requires resources often not available in a busy clinical practice., Aims: To assess the current practice of transitional care in Switzerland in relation to EULAR/PReS recommendations and to describe gaps and challenges in following the recommendations., Methods: All paediatric Swiss rheumatology centres and their collaborating adult centres offering a transition service to adult care were invited to participate in this survey. The responsible paediatric and adult rheumatologist of each centre was interviewed separately using a structured manual addressing the EULAR/PReS transitional care recommendations., Results: All 10 paediatric and 9 out of 10 adult rheumatologists agreed to participate. Centres varied in the number of patients in transition, from n = 0 to n = 111. The following EULAR/PReS recommendations were implemented and applied in most centres: continuity in the healthcare team, consultations focused on adolescents and young adults, joint consultations between the paediatric and adult rheumatologist, and access to the EULAR website. Only rarely did a centre have a written transition policy or evaluate their transitional care programme. The vast majority of the interviewees had no specific training in adolescent health. Most centres rated their transitional care performance as very good., Conclusion: Transition in Switzerland is not uniform and consequently the implementation of the EULAR/PReS recommendations is variable in Swiss rheumatology centres. Skills of healthcare professionals, continuity between clinical settings, size of the centres, and hospital focus on the needs of adolescents and young adults may represent key predictors of successful transitional care for patients with chronic rheumatic diseases. Future studies should examine these variables.

In a previous study we found that parents of children with developmental delay (DD) favoured acceptance of unsolicited findings (UFs) for medically actionable conditions in childhood, but that preferences diverged for UFs with no medical actionability, or only in adulthood, and regarding carrier status. Sometimes the child's future autonomy formed a reason for withholding UFs for the present, despite an unfavourable prognosis concerning the child's cognitive capabilities. This might be different for children undergoing whole exome sequencing (WES) for reasons other than DD and who are expected to exert future autonomy. This is the focus of the current study. We conducted nine qualitative, semi-structured interviews with parents of children, ages <1-15, after consenting to WES, but prior to feedback of results, and with three adolescent children. Several parents wished to receive any information that might in whatever way be relevant to the health and well-being of their child, and to a lesser extent wished the inclusion of information about non-actionable disorders and information concerning carrier status of autosomal recessive disorders. Although parents understood the rationale behind the centre's UFs disclosure policy, they also felt that they needed this information in order to be able to exert their parental responsibility and take good care of a child still dependent on them. Parents reason from their notion of parental responsibility but are also inclined to take adolescent children's preferences seriously and acknowledge the child's incipient autonomy as a ground for granting an increasing degree of self-determination on the road to adulthood.

Epigenetic markers could potentially be used for risk assessment in risk-stratified population-based cancer screening programmes. Whereas current screening programmes generally aim to detect existing cancer, epigenetic markers could be used to provide risk estimates for not-yet-existing cancers. Epigenetic risk-predictive tests may thus allow for new opportunities for risk assessment for developing cancer in the future. Since epigenetic changes are presumed to be modifiable, preventive measures, such as lifestyle modification, could be used to reduce the risk of cancer. Moreover, epigenetic markers might be used to monitor the response to risk-reducing interventions. In this article, we address ethical concerns related to personal responsibility raised by epigenetic risk-predictive tests in cancer population screening. Will individuals increasingly be held responsible for their health, that is, will they be held accountable for bad health outcomes? Will they be blamed or subject to moral sanctions? We will illustrate these ethical concerns by means of a Europe-wide research programme that develops an epigenetic risk-predictive test for female cancers. Subsequently, we investigate when we can hold someone responsible for her actions. We argue that the standard conception of personal responsibility does not provide an appropriate framework to address these concerns. A different, prospective account of responsibility meets part of our concerns, that is, concerns about inequality of opportunities, but does not meet all our concerns about personal responsibility. We argue that even if someone is responsible on grounds of a negative and/or prospective account of responsibility, there may be moral and practical reasons to abstain from moral sanctions., Competing Interests: Competing interests: UCLB (UCL's commercialisation company) has filed patents on DNA methylation and risk prediction on which Martin Widschwendter is named as an inventor., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Information of an individual's epigenome can be useful in cancer screening to enable personalised decision making on participation, treatment options and further screening strategies. However, adding this information might result in complex risk predictions on multiple diseases, unsolicited findings and information on (past) environmental exposure and behaviour. This complicates informed consent procedures and may impede autonomous decision-making. In this article we investigate and identify the specific features of epigenetic risk-stratified cancer screening that challenge the current informed consent doctrine. Subsequently we describe current and new informed consent models and the principle of respect for autonomy and argue for a specific informed consent model for epigenetic risk-stratified screening programmes. Next, we propose a framework that guides the development of Patient Decision Aids (PDAs) to support informed consent and promote autonomous choices in the specific context of epigenetic cancer screening programmes., Competing Interests: The authors declare no conflict of interest.

The incidence of cancer is continuing to rise and risk-tailored early diagnostic and/or primary prevention strategies are urgently required. The ideal risk-predictive test should: integrate the effects of both genetic and nongenetic factors and aim to capture these effects using an approach that is both biologically stable and technically reproducible; derive a score from easily accessible biological samples that acts as a surrogate for the organ in question; and enable the effectiveness of risk-reducing measures to be monitored. Substantial evidence has accumulated suggesting that the epigenome and, in particular, DNA methylation-based tests meet all of these requirements. However, the development and implementation of DNA methylation-based risk-prediction tests poses considerable challenges. In particular, the cell type specificity of DNA methylation and the extensive cellular heterogeneity of the easily accessible surrogate cells that might contain information relevant to less accessible tissues necessitates the use of novel methods in order to account for these confounding issues. Furthermore, the engagement of the scientific community with health-care professionals, policymakers and the public is required in order to identify and address the organizational, ethical, legal, social and economic challenges associated with the routine use of epigenetic testing.

Background and Objective: Advances in omics open new opportunities for cancer risk prediction and risk-based screening interventions. However, implementation of risk prediction in clinical practice may impact the ethical, legal, and regulatory aspects of current cancer screening programs. In order to support decision-making, we analyzed the ethical, legal, and regulatory issues and developed a set of Points to Consider to support management of these issues., Methods: We analyzed the legal and policy frameworks applicable to breast and cervical cancer screening programs in 7 European countries. We identified the most relevant issues to be considered, and we developed considerations for their management, based on the literature, the legal and policy frameworks, and our experience with similar issues., Results: The considerations focus on five topics: (A) health services planning, (B) information and invitation, (C) consent and data/sample collection, (D) risk calculation and communication of results, and (E) storage of data and residual samples., Conclusion: Current frameworks might not be adequate to implement a risk prediction approach using omics factors due to the different characteristics of such approaches., (The Author(s). Published by S. Karger AG, Basel.)

Parents' preferences for unsolicited findings (UFs) from diagnostic whole-exome sequencing (WES) for their children remain largely unexplored. Our aim was to gain insight into parental considerations favoring acceptance/decline of UFs pertaining to their child. We conducted 20 qualitative, semistructured interviews with parents (n=34) of children with a developmental delay, aged <1 to 17 years, after consenting to WES, but before feedback of results. Key findings from our study were that all parents favored acceptance of UFs for medically actionable conditions in childhood, but that preferences and considerations diverged for UFs with no medical actionability, or only in adulthood, and regarding carrier-status. Sometimes non-medical utility considerations (considerations of usefulness of knowing UFs, not rooted in (preventive) medical treatment or controls) were given in favor of disclosure of UFs. Sometimes the child's future autonomy formed a reason to withhold UFs at present, despite an unfavorable prognosis concerning the child's cognitive capabilities. Some parents only preferred receiving UFs if these findings were directly related to their reasons for seeking a diagnosis. These findings are essential for developing morally responsible policy and for counseling. Further research should focus on whether considerations of non-medical utility alone can justify disclosure of UFs and whether reasons for seeking a diagnosis place further constraints on what UFs may be returned/withheld. How parents can be aided in contemplating different scenarios regarding their child's future development also deserves further inquiry.

Background: In pre-hospital Emergency Medical Services (EMS) more research is needed to direct and underpin care delivery and inform policy. To target future research efforts, this study aimed to determine future research priorities with representatives of the EMS field., Methods: A four-round online Delphi survey was used to discuss different viewpoints and reach consensus on research priorities. A multidisciplinary panel of experts was recruited in the field of pre-hospital EMS and adjoining (scientific) professional organisations (n = 62). 48 research topics were presented in Delphi I, and the panel was asked to rate their importance on a 5-point scale. In Delphi II and III the panel selected their priority research topics, and arguments why and suggestions for research questions were collected and reported back. In Delphi IV appropriateness of the remaining topics and agreement within the expert panel was taken into account to make up the final list of research priorities., Results: The response on the Delphi-survey was high: 95% (n = 59; Delphi I); 97% (n = 60, Delphi II); 94% (n = 58, Delphi III); 97% (n = 60, Delphi IV). The panel reduced the number of research topics from 48 topics in Delphi I to 12 topics in Delphi III. A variety of arguments and suggestions for research questions were collected, giving insight in reasons why research on these topics in the near future is needed. Delphi IV showed an adequate level of agreement with respect to the 12 presented research topics. The following 9 topics were rated as appropriate for the national pre-hospital EMS research agenda: Non-conveyance to the hospital (ranked highest); Performance measures for quality of care; Hand over/registration/exchange of patient data; Care and task substitution; Triage; Assessment of acute neurologic signs & symptoms; Protocols and protocol adherence; Immobilisation; and Open/secure airway., Discussions: The research priorities identified in our study resemble those in other studies. However, the topic 'non-conveyance to the hospital' was determined as a priority in this study but not in other studies., Conclusions: The national pre-hospital EMS research agenda can focus future research efforts to improve the evidence base and clinical practice of pre-hospital emergency medical services. Dissemination and implementation of the research agenda deserves careful attention.

In daily practice, pharmacists are regularly confronted with moral problems in which deciding what to do is not always a straightforward decision. In this contribution we show how the use of a specific method for moral deliberation can (in retrospect or prospective) aid moral judgements. We use the case of dispensing isotretinoin to demonstrate one ethical reflection method, namely the Utrecht Method.

Background: To determine the clinical presentation, current treatment and outcome of children with nonbacterial inflammatory bone disease., Methods: Retrospective multicenter study of patients entered into the Swiss Pediatric Rheumatology Working Group registry with a diagnosis of chronic nonbacterial osteomyelitis (CNO) and synovitis acne pustulosis hyperostosis osteitis (SAPHO) syndrome. The charts were reviewed for informations about disease presentation, treatment, course and outcome., Results: Forty-one children (31 girls and 10 boys) from 6 pediatric hospitals in Switzerland diagnosed between 1995 and 2010 were included in the study. The diagnosis was multifocal CNO (n = 33), unifocal CNO (n = 4) and SAPHO syndrome (n = 4). Mean age at onset of CNO was 9.5 years (range 1.4-15.6) and mean follow-up time was 52 months (range 6-156 months). Most patients (n = 27) had a chronic persistent disease course (>6 months), 8 patients had a course with one or more relapses and 6 patients had only one episode of CNO. Forty nine percent had received at least one course of antibiotics. In 57% treatment with nonsteroidal anti-inflammatory drugs (NSAID) was sufficient to control the disease. Twelve out of 16 children with NSAID failure subsequently received corticosteroids, methotrexate, TNF α inhibitors, bisphosphonates or a combination of these drugs., Conclusions: In a multicenter cohort of 41 children 22% started with unifocal lesion with a significant diagnostic delay. A higher proportion presented with chronic persistent disease than with a recurrent form. An osteomyelitis in the pelvic region is significantly associated with other features of juvenile spondylarthritis.

Objective: To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey., Methods: International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course., Results: A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide., Conclusion: The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.

The Dutch Termination of Life on Request and Assisted Suicide Act [Wet toetsing levensbeëindiging op verzoek en hulp bij zelfdoding (Wtl)] came into force in 2002. Its aim is to increase the degree of due care exercised by physicians when terminating a patient's life and to provide a legal framework within which physicians account for their actions in such cases. On the basis of the second evaluation of the Act, published in December 2012, this article provides an overview of the most recent legal developments regarding the Dutch Euthanasia Act. Special attention is given to patients with dementia, psychiatric patients and patient who are "weary of life".

There has been a move in medicine towards patient-centred care, leading to more demands from patients for particular therapies and treatments, and for wish-fulfilling medicine: the use of medical services according to the patient's wishes to enhance their subjective functioning, appearance or health. In contrast to conventional medicine, this use of medical services is not needed from a medical point of view. Boundaries in wish-fulfilling medicine are partly set by a physician's decision to fulfil or decline a patient's wish in practice. In order to develop a better understanding of how wish-fulfilling medicine occurs in practice in The Netherlands, a qualitative study (15 semistructured interviews and 1 focus group) was undertaken. The aim was to investigate the range and kind of arguments used by general practitioners and plastic surgeons in wish-fulfilling medicine. These groups represent the public funded realm of medicine as well as privately paid for services. Moreover, GPs and plastic surgeons can both be approached directly by patients in The Netherlands. The physicians studied raised many arguments that were expected: they used patient autonomy, risks and benefits, normality and justice to limit wish-fulfilling medicine. In addition, arguments new to this debate were uncovered, which were frequently used to justify compliance with a patient's request. Such arguments seem familiar from conventional medicine, including empathy, the patient-doctor relationship and reassurance. Moreover, certain arguments that play a significant role in the literature on wish-fulfilling medicine and enhancement were not mentioned, such as concepts of disease and the enhancement-treatment dichotomy and 'suspect norms'.

We created a registry to evaluate long term outcome, efficacy and adverse events for children treated wit TNF-alpha inhibitors in Switzerland. 106 patients (68 female/38 male) were included. 61 patients were treated with Etanercept (Enbrel) and 45 with Infliximab (Remicade). Concomitant treatment at baseline included corticosteroids in 26% and Methotrexate in 75% of the patients. Subjective disease activity three months after initiation of TNF-alpha was better in 81%, worse in 4% and stable in 15% of the patients. In total 24 adverse events in 21 patients were reported. Treatment with TNF-alpha inhibitors seems to be safe and effective for children and adolescents with rheumatologic diseases.

It has been suggested that the recent rapid developments in the fields of neuroscience and psychopharmacology have increased the possibilities for pharmacological enhancement of mental functioning. Here, evidence is reviewed which shows that drugs acting on a variety of neurotransmitter systems can indeed enhance cognition, and to a lesser extent mood and pro-social behavior. Moreover, it seems possible to interfere with the (re)consolidation of traumatic memories. There are, however, a number of caveats: first, as cognition-enhancing drugs can simultaneously exert both linear and quadratic (U-shaped) effects, doses most effective in facilitating one behavior could at the same time exert null or even detrimental effects on other cognitive domains. Second, individuals with a 'low memory span' might benefit from cognition-enhancing drugs, whereas 'high span subjects' are 'overdosed'. And finally, evidence suggests that a number of trade-offs could occur. For example, increases of cognitive stability might come at the cost of a decreased capacity to flexibly alter behavior. A short overview of ethical issues raised by the use of cognition and mood enhancing drugs demonstrates the tremendous variety in views and opinions regarding the subject.

Pharmacogenomics is the study of the myriad interactions between genes and pharmacotherapy. Developments in pharmacogenomics have changed and will affect pharmaceutical research, drug development and the practice of medicine in a significant way. In this article, we make an inventory of the ethical implications that might arise as a result of possible developments in pharmacogenomics and investigate whether the present ethical framework will be able to adequately answer arising questions. We think that many of the questions related to the consequences of pharmacogenomics are answerable along the lines of present ethical thinking. We also believe, however, that many 'changes of degree' may result in a 'change of kind.' We therefore think that pharmacogenomics may potentially have such a profound influence on scientific research and the pharmaceutical industry, the practice of medicine and society at large, that this will generate its own unique dynamic, which will require new ethical research. We suggest that the notion of 'responsibility' will be a major focus of such research.