EAN guideline on palliative care of people with severe, progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Patients with severe, progressive multiple sclerosis (MS) have complex physical and psychosocial needs, typically over several years. Few treatment options are available to prevent or delay further clinical worsening in this population. The objective was to develop an evidence-based clinical practice guideline for the palliative care of patients with severe, progressive MS. METHODS: This guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Formulation of the clinical questions was performed in the Patients-Intervention-Comparator-Outcome format, involving patients, carers and healthcare professionals (HPs). No uniform definition of severe MS exists: in this guideline, constant bilateral support required to walk 20 m without resting (Expanded Disability Status Scale score > 6.0) or higher disability is referred to. When evidence was lacking for this population, recommendations were formulated using indirect evidence or good practice statements were devised. RESULTS: Ten clinical questions were formulated. They encompassed general and specialist palliative care, advance care planning, discussing with HPs the patient's wish to hasten death, symptom management, multidisciplinary rehabilitation, interventions for caregivers and interventions for HPs. A total of 34 recommendations (33 weak, 1 strong) and seven good practice statements were devised. CONCLUSIONS: The provision of home-based palliative care (either general or specialist) is recommended with weak strength for patients with severe, progressive MS. Further research on the integration of palliative care and MS care is needed. Areas that currently lack evidence of efficacy in this population include advance care planning, the management of symptoms such as fatigue and mood problems, and interventions for caregivers and HPs.

Live birth rate after intrauterine insemination is not different between women with lower quartile versus higher quartile normal range thyroid stimulating hormone levels.

STUDY QUESTION: Does lower quartile normal range thyroid stimulating hormone (TSH) compared to higher quartile normal range in women without thyroid hormone substitution affect live birth rate after a complete IUI treatment series? SUMMARY ANSWER: Lower quartile normal range TSH, in women without thyroid hormone substitution, does not affect live birth rate after a complete intrauterine insemination treatment series compared to higher quartile normal range TSH. WHAT IS KNOWN ALREADY: TSH is historically seen as the most sensitive test for thyroid function. Its distribution is right-skewed. Whether the preconceptional upper reference TSH values in subfertile women should be 2.5 or 4.5 mIU/L is under debate. Studies have shown that IUI patients treated with levothyroxine for TSH levels above 2.5 mIU/L show higher pregnancy rates. However, no adverse outcome is associated with untreated high normal TSH levels studied in first IUI cycles. Thyroid peroxidase antibodies have also impaired outcomes in some studies whereas others have shown an effect only in combination with high normal TSH levels. As a subgroup, patients with unexplained infertility showed increased levels of TSH. This article adds to the value of TSH evaluation and fertility outcome in four quartiles and in the context of a completed IUI treatment modus of a maximum of six inseminations. STUDY DESIGN SIZE DURATION: This is a retrospective cohort study in 909 women undergoing 3588 IUI cycles starting treatment between the first of January 2008 and the first of March 2012. PARTICIPANTS/MATERIALS SETTING METHODS: Women aged 22-45 years with TSH 0.3-4.5 mIU/L without thyroid hormone substitution were included at Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands, an Iodine-sufficient area. The primary endpoint was live birth. Clinical pregnancy, pregnancy loss and ongoing pregnancy were secondary endpoints. Logistic regression was used with the natural logarithm of TSH as a continuous predictor. Chi-square tests and logistic regression were used to compare groups of patients based on TSH values in four quartile TSH groups (0.3-1.21 mIU/L; 1.22-1.75 mIU/L; 1.76-2.34 mIU/L; 2.35-4.5 mIU/L) on basic characteristics and on the endpoints while adjusting for confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Analysis with the natural logarithm of TSH as a continuous variable showed no association with live birth, pregnancy chance or pregnancy loss. There were no differences in any of the outcomes across the quartile TSH level ranges after regression analysis before and after adjusting for age, BMI, use of alcohol, tobacco, use or gonadotrophins, sperm count, diminished ovarian reserve, unexplained infertility and primary or secondary subfertility.The distribution of primary and secondary subfertility and smoking characteristics were remarkably different across the four groups, with proportionally the lowest prevalence of primary subfertility and the highest rate of smoking in the lowest TSH group (0.3-1.20 mIU/L). LIMITATIONS REASONS FOR CAUTION: Unknown values of free thyroxine and thyroid peroxidase antibodies, as well as the retrospective character of the study, limit the clinical interpretability. WIDER IMPLICATIONS OF THE FINDINGS: TSH in the highest quartile range (2.35-4.5 mIU/L) in subfertile women preceding IUI is not associated with a lower live birth rate or rate of clinical and ongoing pregnancy, or with loss of pregnancies, compared to subfertile women with TSH in the lower three quartile groups after complete intrauterine insemination treatment. STUDY FUNDING/COMPETING INTERESTS: The department of Obstetrics and Gynaecology, division of Reproductive Medicine, and of Internal Medicine, division of Endocrinology provided support. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Patient and caregiver involvement in the formulation of guideline questions: findings from the European Academy of Neurology guideline on palliative care of people with severe multiple sclerosis.

BACKGROUND AND PURPOSE: Patient and public involvement in clinical practice guideline development is recommended to increase guideline trustworthiness and relevance. The aim was to engage multiple sclerosis (MS) patients and caregivers in the definition of the key questions to be answered in the European Academy of Neurology guideline on palliative care of people with severe MS. METHODS: A mixed methods approach was used: an international online survey launched by the national MS societies of eight countries, after pilot testing/debriefing on 20 MS patients and 18 caregivers, focus group meetings of Italian and German MS patients and caregivers. RESULTS: Of 1199 participants, 951 (79%) completed the whole online survey and 934 from seven countries were analysed: 751 (80%) were MS patients (74% women, mean age 46.1) and 183 (20%) were caregivers (36% spouses/partners, 72% women, mean age 47.4). Participants agreed/strongly agreed on inclusion of the nine pre-specified topics (from 89% for 'advance care planning' to 98% for 'multidisciplinary rehabilitation'), and <5% replied 'I prefer not to answer' to any topic. There were 569 free comments: 182 (32%) on the pre-specified topics, 227 (40%) on additional topics (16 guideline-pertinent) and 160 (28%) on outcomes. Five focus group meetings (three of MS patients, two of caregivers, and overall 35 participants) corroborated the survey findings. In addition, they allowed an explanation of the guideline production process and the exploration of patient-important outcomes and of taxing issues. CONCLUSIONS: Multiple sclerosis patient and caregiver involvement was resource and time intensive, but rewarding. It was the key for the formulation of the 10 guideline questions and for the identification of patient-important outcomes.

[Results of the assessment procedure for dentists with a foreign degree in the Netherlands]. / Resultaten van de toetsingsprocedure van tandartsen met een buitenlands diploma.

During the period from 1 January 2007 to 1 January 2017, 138 dentists with a foreign dental degree (obtained outside the European Economic Area or Switzerland) who wanted to practice dentistry in the Netherlands have undertaken the assessment procedure to obtain a certificate of professional competence. The procedure comprises a Dutch language proficiency and communications test, followed by tests of competence specific to the dental profession. For 68 dentists (49%), no deficiencies in knowledge or skills were identified. They could register in the BIG-register [for healthcare professionals] for the supervisory period. For 49 (36%), the deficiencies could be eliminated with specific training. In the case of 21 dentists (15%), training was not possible. The number of dentists from this group who were enrolled in the BIG-register in 2017 was determined. On the reference date, 100 dentists (73%) were enrolled. Of the 49 dentists who were permitted to participate in a specific educational programme, 48 had started such a programme: 38 had completed it by 2017, 9 are still actively involved, and 1 stopped the programme. If they complete the programme, the number of dentists who have been enrolled in the BIG-register after [successfully] finishing the assessment procedure could rise to 115 (83%).

[Assessment of physicians with a foreign diploma; results of 10 years of testing of physicians with a foreign diploma]. / Toetsing van artsen met een buitenlands diploma.

OBJECTIVE: To determine the result of the assessment procedure, initiated on 1 December 2005, for physicians with a foreign diploma who wish to practice in the Netherlands. DESIGN: Retrospective, descriptive study. METHOD: The Commission for Foreign Healthcare Graduates (CBGV) collected data on physicians with a foreign diploma who followed the procedure for requesting a declaration of professional competence and admission to the Dutch Individual Healthcare Professions (BIG) register between December 2005 - December 2015. The procedure comprises a language and communication test, followed by tests of professional competence. On the grounds of the test results, the CBGV can decide if a physician should follow a specific training course. The number of physicians who ultimately obtained BIG registration was determined. RESULTS: During the study period, 183 of the 206 physicians with a foreign diploma passed the general knowledge and skills tests. A total of 176 of the 183 physicians took the professional competence tests. In 43 (25%) of them no shortcomings in knowledge and skills were seen. They were registered in the BIG register for a period of supervision. In 129 (73%), shortfalls were made up by means of focused training programme. In 4 (2%) of them no training was possible. On the date of assessment, 137 (78%) physicians were registered. This number is expected to rise to 151 (86%). CONCLUSION: The provision of a further course of training that is focused on the elimination of identified shortcomings in physicians with a foreign diploma, increases the percentage of foreign physicians that are successfully admitted to the BIG register.

Smac/DIABLO release from mitochondria and XIAP inhibition are essential to limit clonogenicity of Type I tumor cells after TRAIL receptor stimulation.

Death receptors, such as Fas/CD95 and TRAIL receptors, engage the extrinsic pathway for caspase activation, but also couple to the intrinsic mitochondrial route. In so-called Type II cells, death receptors require the mitochondrial pathway for apoptotic execution, whereas in Type I cells they reportedly do not. For established tumor cell lines, the Type I/Type II distinction is based on short-term apoptosis assays. We report here that the mitochondrial pathway is essential for apoptotic execution of Type I tumor cells by death receptors, when long-term clonogenicity is taken into account. A blockade of the mitochondrial pathway in Type I tumor cells - by RNA interference for Bid or Bcl-2 overexpression - reduced effector caspase activity and mediated significant clonogenic resistance to TRAIL. Downstream from the mitochondria, Caspase-9 did not contribute to clonogenic death of TRAIL-treated Type I cells. Rather, the release of Smac/DIABLO and the inhibition of XIAP activity proved to be crucial for full effector caspase activity and clonogenic execution. Thus, in Type I cells the intrinsic pathway downstream from death receptors is not redundant, but limits clonogenicity by virtue of Smac/DIABLO release and XIAP inhibition. This finding is relevant for cancer therapy using death receptor agonists.

[International medical graduates in Dutch health care: the new assessment procedure]. / Artsen met een buitenlands diploma in de Nederlandse patiëntenzorg: de nieuwe assessmentprocedure.

On December 1, 2005 in the Netherlands, a new procedure was introduced to assess international medical graduates (IMGs) with a diploma acquired outside the European Economic Area (EEA). This procedure includes (a) general tests on the active and passive use of Dutch medical language, English reading proficiency, basic IT skills and knowledge of the Dutch health care system, and (b) a specific set of tests of medical competence, including knowledge of basic sciences, clinical knowledge and clinical skills. IMGs who wish to get their diploma acknowledged and be registered as a physician are required to complete this assessment. With the introduction of this procedure, the Netherlands have joined a minority of countries inside and outside Europe with setting high standards for intake procedures. It is advocated that all European countries should devise such procedures, as a European Directive (2005/36/EC) on the recognition of professional qualifications prohibits the assessment of medical graduates with a diploma that is recognised in another EEA country.

Women's opinion on the use and offer of ovarian reserve testing: a first step towards a wide ranged social discussion.

OBJECTIVE: To determine the opinion among three groups of women (sub-fertile women, fertile women and female medical students), concerning the use of ovarian reserve tests to determine the chance of an assisted reproductive techniques' (ART) induced pregnancy or a spontaneous pregnancy. DESIGN: Prospective study using questionnaires in three groups of women: patients visiting the out patient infertility clinic at the Academic Medical Centre Groningen, women who had delivered at least two children and female medical students. RESULTS: The response rate varied from 63% (female medical students) to 56% (fertile women with children) and 48% (sub-fertile women). The greater part of women of all three groups found it was up to the women themselves to decide whether or not to start fertility treatment, even though the ovarian reserve test indicated little chance of success. 71% of the sub-fertile women stated that any chance justified fertility treatment. None of the three groups of women were very enthusiastic about the use of these tests for family planning. CONCLUSIONS: Based on results of ovarian reserve tests women could decide not to partake of a - generally demanding - fertility treatment. The outcome of the study, however, does not support this: even low chances of success are found acceptable. The ability to determine the individual ovarian reserve makes this test also a suitable device for family planning. The discussion whether these new possibilities will be useful for reproductive science will greatly depend on women's attitude towards this issue.

Costs, effects, and savings of screening for cystic fibrosis gene carriers.

STUDY OBJECTIVE: Evaluating the costs, effects, and savings of several strategies for cystic fibrosis (CF) gene carrier screening. DESIGN: A general model for evaluating prenatal, preconceptional, school, and neonatal carrier screening was constructed. For prenatal and preconceptional screening, two strategies were evaluated: single entry and double entry two step couple screening. Firstly, the Dutch situation was evaluated prospectively; subsequently the results were generalised to other carrier frequencies. SETTING: Prospective simulation model. MAIN RESULTS: Of all screening strategies, neonatal carrier screening gives most carrier couples an informed choice concerning reproduction. If the parents of carrier newborns would not be tested however, prenatal screening detects most carrier couples. Prenatal and single entry preconceptional screening programmes have a favourable cost-savings balance in the Netherlands under a wide range of assumptions. For double entry preconceptional screening and neonatal screening, high enough values of uptake of screening, prenatal diagnosis, and induced abortion are necessary. School carrier screening does not have a favourable cost-savings balance. CONCLUSIONS: If a CF screening programme is judged to be useful on individual and social grounds, costs considerations are no obstacle for prenatal and single entry preconceptional screening.

Experiences and career intentions of general practice registrars from The Netherlands.

For some years prospective general practitioners (GPs) from the Netherlands have come to Britain to complete their training. Not all report enjoying their time here, and many leave this country after training. The aim of this study was to examine reasons for coming to Britain, experiences, perceptions and career intentions. The sample consisted of 14 general practice registrars working in their practice year in Southern England. Data were collected through in-depth semistructured interviews and analysed by thematic qualitative analysis. The main reasons for training in this country were easier access, a quicker route to specialization and the quality of training provided. Most had positive professional and personal experiences and saw the British system of training GPs as up to date and supportive of their educational and professional needs. They highlighted some of the positive aspects of the British system, such as the emphasis on teamwork and collaboration with other primary care professionals. They did, however, point out problems and conflicts; for instance, they saw the health care system in Britain as more bureaucratic and as providing unequal access for different groups of the population. Despite their fear of litigation, which they saw as one of the drawbacks for British general practitioners, most looked favourably on the option of staying in or returning to this country if possible. All registrars valued their stay in Britain; however, personal circumstances often dictated a return to Holland. Our findings have implications for manpower planning and recruitment for general practice in both Britain and Holland.

The nonhospital costs of care of patients with CF in The Netherlands: results of a questionnaire.

Cystic fibrosis (CF) causes a relatively high medical consumption. A large part of the treatment takes place at home. Because data regarding nonhospital care are lacking, we wished to determine the costs of care of patients with CF outside the hospital. A questionnaire was sent to 73 patients with CF from two Dutch hospitals (response rate 64%, 14 children and 33 adults). Average consumption and average costs per patient per year were calculated for children and adults for six categories: nonhospital medical care; domestic help; diet; travelling because of CF; medication; and devices and special facilities at home, work or school. The average nonhospital costs of care amounted to Pounds 4,641 per child per year (range Pounds 712-13,269) and Pounds 10,242 per adult (range Pounds 1,653-26,571). Nonhospital medical care for children and adults accounted for, respectively, 8 and 5% of these costs, domestic help for 15 and 9%, diet for 10 and 7%, travelling because of CF for 4 and 8%, medication for 63 and 67%, and devices and special facilities at home, work or school for 1 and 4%. Nonhospital costs of care of cystic fibrosis are very high and amount to 50% of the total (medical and nonmedical) lifetime costs of cystic fibrosis.

Cost of care of patients with cystic fibrosis in The Netherlands in 1990-1.

BACKGROUND: Research on the cost of care of patients with cystic fibrosis is scarce. The aim of this study was to estimate the costs using age-specific medical consumption from real patient data. METHODS: The age-specific medical consumption of patients with cystic fibrosis in The Netherlands in 1991 was estimated from a survey of medical records and a patient questionnaire. A distinction was made between costs of hospital care, hospital and non-hospital medication, and home care. Costs per year were obtained by multiplying the yearly amount of care and the costs per unit. RESULTS: On average the annual cost of a patient with cystic fibrosis in 1991 was 10,908 pounds (hospital care 42%, medication 37%, home care 20%). The cost of care of cystic fibrosis in The Netherlands, with approximately 1000 patients, is estimated at 10.9 million pounds per year, which is 0.07% of the total health care budget. The cost of care of a patient up to the age of 35 is estimated at 614,587 pounds. When year-to-year survival is taken into account and future costs are discounted to the year of birth with a yearly discount rate of 5%, the cost of care of a patient with cystic fibrosis is estimated at 164,365 pounds for 1991. This estimate will be used in a prospective evaluation of screening for cystic fibrosis carriers. CONCLUSIONS: The cost of care of patients with cystic fibrosis estimated by age-specific medical consumption of real patients is higher than that estimated by non-age-specific medical consumption and/or expert opinions.

Comparison of single-entry and double-entry two-step couple screening for cystic fibrosis carriers.

Both single-entry two-step (SETS) couple screening and double-entry two-step (DETS) couple screening have been recommended as methods to screen for cystic fibrosis gene carriers. In this paper we compare the expected results from both types of screening. In general, DETS results in a higher detection rate of couples in which both partners are carriers, but also in a higher proportion of couples with only one identified carrier who have a significant remaining risk in their offspring.

[Screening for gene carrier state of cystic fibrosis: pros and cons of various scenarios]. / Screening op gendragerschap van cystische fibrose: voor- en nadelen van verschillende scenario's.

OBJECTIVE: The discovery of the gene for cystic fibrosis (CF) and its most frequent mutations makes screening for carrier state possible in the general population. We surveyed the possible strategies for a screening offer to persons without a family history of CF. DESIGN: Theoretical evaluation. METHOD: With probability calculations and evaluation of psychosocial factors, the advantages and drawbacks of embryonal, neonatal, school, preconceptional and prenatal screening were evaluated. RESULTS: Embryonal and neonatal screening have the disadvantage that a number of preventive options are no longer open, and school screening has psychosocial disadvantages. The offer of screening should be made to persons in the reproductive age group, preferably before a pregnancy. A screening offer made to couples is preferable to an offer made to individuals. A consequence of the fact that present test sensitivity is still incomplete is that screening does not reduce the estimated risk of positive/negative couples having a child with CF to less than the risk without screening (1:3600). Couple screening gives more certainty about the risk, but it results in twice as many positive/negative couples as stepwise screening (only when one partner is positive is the second partner screened).