The Role of γδ T Cells as a Line of Defense in Viral Infections after Allogeneic Stem Cell Transplantation: Opportunities and Challenges.

In the complex interplay between inflammation and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-HSCT), viral reactivations are often observed and cause substantial morbidity and mortality. As toxicity after allo-HSCT within the context of viral reactivations is mainly driven by αß T cells, we describe that by delaying αß T cell reconstitution through defined transplantation techniques, we can harvest the full potential of early reconstituting γδ T cells to control viral reactivations. We summarize evidence of how the γδ T cell repertoire is shaped by CMV and EBV reactivations after allo-HSCT, and their potential role in controlling the most important, but not all, viral reactivations. As most γδ T cells recognize their targets in an MHC-independent manner, γδ T cells not only have the potential to control viral reactivations but also to impact the underlying hematological malignancies. We also highlight the recently re-discovered ability to recognize classical HLA-molecules through a γδ T cell receptor, which also surprisingly do not associate with GVHD. Finally, we discuss the therapeutic potential of γδ T cells and their receptors within and outside the context of allo-HSCT, as well as the opportunities and challenges for developers and for payers.

[A step-by-step guide for safe off-label prescribing]. / Een stappenplan voor verantwoord off-labelgebruik.

The Dutch Medicines Act and the Medical Treatment Contracts Act (WGBO) form the legal framework for off-label prescribing. These acts are complemented with position statements and guidelines of professional organizations. However, this legal framework is not yet sufficiently embedded in daily practice. The explicit translation of the legal conditions into practical stepwise guidance can therefore provide important guidance when prescribing off-label. This article describes a step-by-step guide for responsible off-label prescribing. The step-by-step guide ensures that decisions about off-label use of drugs are made based on a deliberate and explicit consideration of the unmet medical need and alternative treatment strategies against the potential risks and benefits for the individual patient. In addition, the step-by-step guide ensures the correct provision of information to patients. In this way, the step-by-step guide enables the doctor to meet the regulatory requirements on the off-label prescription of drugs. In addition, we need better information provision on off-label use and professional consensus on information and consent obligation in order to be able to prescribe even more effectively off-label.

Comprehensive evaluation of microneedle-based intradermal adalimumab delivery vs. subcutaneous administration: results of a randomized controlled clinical trial.

AIMS: To evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single subcutaneous (s.c.) dose using a conventional needle. METHODS: In this single-centre double-blind, placebo-controlled, double-dummy clinical trial in 24 healthy adults we compared 40 mg adalimumab (0.4 mL) administered i.d. using a hollow microneedle with a s.c. dose using a conventional needle. Primary parameters were pain, acceptability and local tolerability; secondary parameters safety, pharmacokinetics and immunogenicity. We explored usability of optical coherence tomography, clinical photography, thermal imaging, and laser speckle contrast imaging to evaluate skin reaction after i.d. injections. In vitro protein analysis was performed to assess compatibility of adalimumab with the hollow microneedle device. RESULTS: While feasible and safe, injection pain of i.d. adalimumab was higher compared to s.c. adalimumab (35.4 vs. 7.9 on a 100-point visual analogue scale). Initial absorption rate and relative bioavailability were higher after i.d. adalimumab (time to maximum plasma concentration = 95 h [47-120]; Frel = 129% [6.46%]) compared to s.c. adalimumab (time to maximum plasma concentration = 120 h [96-221]). Anti-adalimumab antibodies were detected in 50% and 83% of the subjects after i.d. and s.c. adalimumab, respectively. We observed statistically significantly more erythema and skin perfusion after i.d. adalimumab, compared to s.c. adalimumab and placebo injections (P < .0001). Cytokine secretion after whole blood lipopolysaccharide challenge was comparable between administration routes. CONCLUSIONS: Intradermal injection of adalimumab using hollowing microneedles was perceived as more painful and less accepted than s.c. administration, but yields a higher relative bioavailability with similar safety and pharmacodynamic effects.

Off-label use of medicines in neonates, infants, children, and adolescents: a joint policy statement by the European Academy of Paediatrics and the European society for Developmental Perinatal and Pediatric Pharmacology.

Health-care professionals who prescribe medicines have the professional duty to choose medicines that are in the best interest of their individual patient, irrespective if that patient is an adult or a child. However, the availability of medicines with an appropriate label for pediatric use is lagging behind those for adults, and even available pediatric drugs are sometimes not suitable to administer to children. Consequently, health-care professionals often have no other option than to prescribe off-label medicines to children. An important reason for use of off-label medicines is to improve access to (innovative) treatments or to address medical needs and preferences of patients, especially when no other options are available. However, off-label use of medicines is in general not supported by the same level of evidence as medicines licensed for pediatric use. This may result in increased uncertainty on efficacy as well as the risk for toxicity and other side effects. In addition, liability may also be of concern, counterbalanced by professional guidelines.Conclusion: The purpose of this joint EAP/ESDPPP policy statement is to offer guidance for HCPs on when and how to prescribe off-label medicines to children and to provide recommendations for future European policy.

An exploratory survey on the state of training in adolescent medicine and health in 36 European countries.

The development of adolescent health and medicine as a medical discipline lags behind in Europe compared with other regions of the world. This study aims to evaluate the structure and content of adolescent medicine and health training curricula for medical students, paediatricians, and other primary care physicians in the European region. A questionnaire survey was sent by e-mail to experts in the field from 36 European countries, addressing the content of adolescent health issues. Data was obtained from all 36 countries. At the undergraduate level, seven countries reported some mandatory stand-alone teaching (sessions dealing specifically with adolescents), while seven countries reported optional stand-alone teaching. In only 7 out of 36 countries were issues critical to adolescents covered as stand-alone sessions. At the postgraduate level, 15 countries delivered stand-alone mandatory training sessions to primary, secondary, or tertiary care paediatricians, covering most of the five critical areas listed in the questionnaire. In another 13 countries, such sessions were not mandatory and were inexistent in eight of them. The coverage among school physicians was similar but was much lower among general practitioners.Conclusion: Paediatric associations and academic institutions should advocate for a better coverage of adolescent health and medicine in the training curricula of health care providers. What is known: • In most European countries, adolescent medicine is still poorly represented as a discipline. • Experts have recently published recommendations regarding what form the structure and content of a training curriculum in this field should take. What is new: • This paper gives information on the extent and content of training in adolescent medicine and health as currently offered within under- and postgraduate European training curricula, in terms of stand-alone mandatory (versus optional) sessions. • In many European countries, both medical students and residents are poorly exposed to the basic knowledge and skills pertaining to adolescent health care.

Medical care for migrant children in Europe: a practical recommendation for first and follow-up appointments.

Between 2015 and 2017, an estimated 200,000 to 400,000 children were seeking asylum each year in EU/EEA countries. As access to high-quality health care is important, we collected and compared current recommendations across Europe for a consensus recommendation on medical care for migrant (asylum-seeking and refugee) children. Existing recommendations were collected from published literature and identified through national representatives from paediatric societies of 31 EU/EEA countries through the European Academy of Paediatrics (EAP). Recommendations were systematically extracted and collected in a database. Those mentioned in at least one recommendation were evaluated for inclusion, and evidence on recommendations was specifically identified in literature searches focused on recent evidence from Europe. For eight EU/EEA countries, a national recommendation was identified. Growth and development, vision and hearing impairment, skin and dental problems, immunisations, anaemia, micronutrient deficiency, helminths, hepatitis B and C, human immunodeficiency virus, malaria, schistosomiasis, syphilis, tuberculosis, mental health disorder and sexual health were most frequently mentioned and therefore selected for inclusion in the recommendation.Conclusion: The current document includes general recommendations on ethical standards, use of interpreters and specific recommendations for prevention or early detection of communicable and non-communicable diseases. It may serve as a tool to ensure the fundamental right that migrant children in Europe receive a comprehensive, patient-centred health care.

The effect of repeated methotrexate injections on the quality of life of children with rheumatic diseases.

In clinical practice, the burden of repeated injections in children with rheumatic disease receiving disease-modifying anti-rheumatic drugs is significant. To investigate the nature and extent of impact on the quality of life after repeated injections, we conducted a literature review. Two relevant papers were identified, both about children with juvenile idiopathic arthritis (JIA) being administered methotrexate. The results suggest that the combination of needle fear, impact of methotrexate treatment, and procedural consequences, e.g., blood sampling, all contribute to the distress and the loss of quality of life of children with JIA. Remarkably, no studies examining fear of injections or injection pain in children with rheumatic diseases receiving biologicals were identified.Conclusion: Strategies to optimize administration of disease modifying anti-rheumatic drugs should be systematically investigated. What is Known: • Repeated parenteral administration of drugs is burdensome for children with rheumatic diseases. What is New: • Needle fear should be investigated systematically to optimize administration of disease-modifying anti-rheumatic drugs.

Basic training requirements for health care professionals who care for children.

The European Academy of Paediatrics (EAP) is the paediatric section of the European Union of Medical Specialists (UEMS). The UEMS is responsible for the supervision and approval of training programmes in paediatrics and in its subspecialties. This implies also that EAP has the responsibility to address the training of all professionals working with children, to ensure that their paediatric competences and skills are adequate when dealing with children. The EAP has developed syllabi for paediatricians that provide standards of practice, and criteria for the assessment of competencies in trainees and training centres across Europe. The EAP recommends that all health care professionals working with children should have an officially approved training in child health in addition to formal qualifications in their own field. Moreover, the existing paediatric workforce must maintain their knowledge and skills with relevant continuous professional development and medical education in child health. CONCLUSION: There is a need to reassess the training of all health care professionals caring for children, ensuring that it supports new models of integrated and multidisciplinary care and focuses on the needs of the child and the family. A standardised, competency-based minimum paediatric training programme/curriculum should be part in the specialty curriculums.

European Antibiotic Awareness Day 2017: training the next generation of health care professionals in antibiotic stewardship.

Antimicrobial stewardship (AMS) aims to optimise treatment, minimise the risk of adverse effects and reduce health care costs. In addition, it is recognised as a key component to stop the current spread of antimicrobial resistance in Europe. Educational programmes are particularly important for the successful implementation of AMS. Training should start during medical school, continue during clinical training and be reinforced throughout postgraduate training. National core curricula for paediatric training should include passive and active training of competencies needed for AMS and future paediatricians should be skilled in taking leadership roles in AMS initiatives. Other core members of the paediatric AMS team should also receive training focused on the unique medical needs of the paediatric patient. CONCLUSION: Ideally, all communities, hospitals and health regions in Europe should have AMS that serve all patient types, including children. We all have the responsibility to ensure that existing antibiotics remain effective. What is Known: • Antimicrobial stewardship (AMS) is a key component to stop the current spread of antimicrobial resistance • Educational programmes are particularly important for the successful implementation of AMS What is New: • All medical doctors in Europe who will be undertaking significant practice in child health should master the competencies needed to prescribe antibiotics to children rationally as described in the European Academy of Paediatrics (EAP) Curriculum for Common Trunk Training in Paediatrics • Interdisciplinary approaches of education need to be developed, as all hospitals and health regions in Europe ideally should have AMS programmes that serve all patient types, including children.

Paediatric departments need to improve residents' training in adolescent medicine and health: a position paper of the European Academy of Paediatrics.

In many European countries, paediatric junior staff has no formal training in adolescent medicine and is ill-equipped to deal with issues and health problems such as substance use, unprotected sex, eating disorders and transition to adult care. This position paper of the European Academy of Paediatrics proposes a set of competency-based training goals and objectives as well as pedagogic approaches that are expected to improve the capacity of paediatricians to meet the needs of this important segment of the paediatric population. The content has been developed from available publications and training programmes and mostly covers the generic aspects of adolescent healthcare, such as how to communicate effectively, how to review and address lifestyles, how to perform a respectful and relevant physical examination, how to address common problems of adolescents and how to support adolescents in coping with a chronic condition. CONCLUSION: The European Academy of Paediatrics urges national bodies, paediatric associations and paediatric teaching departments to adopt these training objectives and put them into practice, so that paediatricians will be better prepared in the future to meet the challenge of delivering appropriate and effective healthcare to adolescents.

European Academy of Paediatric consensus statement on successful transition from paediatric to adult care for adolescents with chronic conditions.

Around one in ten adolescents suffer from chronic conditions and disabilities, and the transition from paediatric to adult care can be particularly challenging. Unplanned transfers can complicate education, work and health and result in patients being lost to follow-up, poor treatment adherence and more frequent hospitalisation. The Adolescent Health and Medicine Working Group of the European Academy of Paediatrics has developed a consensus statement for a successful transition. CONCLUSION: This statement will help paediatricians, adult care specialists, policymakers and other stakeholders to handle chronic care transitions so that they meet the expectations and needs of adolescents and their families.

We strongly support childhood immunisation-statement from the European Academy of Paediatrics (EAP).

The eradication of smallpox and the elimination of several other infectious diseases from much of the world has provided convincing evidence that vaccines are among the most effective interventions for promoting health. The current scepticism about immunisation among members of the new US administration carries a risk of decreasing immunisation rates also in Europe. While only a small minority of the population are strongly anti-vaccine, their public activities have significantly influenced an uncertainty among the general population about both the safety of and the necessity for vaccination. Therefore, the EAP calls for greater publically available, scientifically supported information on vaccination, particularly targeted at health care providers, for the further development of electronically based immunisation information systems (IIS). We further call on all European countries to work together both in legislative and public health arenas in order to increase vaccination coverage among the paediatric population. In the interest of children and their parents, the EAP expresses its strong support for childhood immunisation and recommended vaccination schedules. We are prepared to work with governments and media and share the extensive evidence demonstrating the effectiveness and safety of vaccines.

Pharmacokinetics and pharmacodynamics of a new highly concentrated intranasal midazolam formulation for conscious sedation.

AIM: To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam. METHODS: In this four-way crossover, double-blind, double-dummy, randomized, placebo-controlled study, 16 subjects received 2.5 mg Nazolam, 5.0 mg Nazolam, 2.5 mg intravenous midazolam or placebo on different occasions. Pharmacokinetics of midazolam and α-hydroxy-midazolam were characterized and related to outcome variables for sedation (saccadic peak velocity, the Bond and Lader visual analogue scale for sedation, the simple reaction time task and the observer's assessment of alertness/sedation). Nasal tolerance was evaluated through subject reporting, and ear, nose and throat examination. RESULTS: Nazolam bioavailability was 75%. Maximal plasma concentrations of 31 ng ml-1 (CV, 42.3%) were reached after 11 min (2.5 mg Nazolam), and of 66 ng ml-1 (coefficient of variability, 31.5%) after 14 min (5.0 mg Nazolam). Nazolam displayed a significant effect on OAA/S scores. Sedation onset (based on SPV change) occurred 1 ± 0.7 min after administration of 2.5 mg intravenous midazolam, 7 ± 4.4 min after 2.5 mg Nazolam, and 4 ± 1.8 min after 5 mg Nazolam. Sedation duration was 118 ± 95.6 min for 2.5 mg intravenous midazolam, 76 ± 80.4 min for 2.5 mg Nazolam, and 145 ± 104.9 min for 5.0 mg Nazolam. Nazolam did not lead to nasal mucosa damage. CONCLUSIONS: This study demonstrates the nasal tolerance, safety and efficacy of Nazolam. When considering the preparation time needed for obtaining venous access, conscious sedation can be achieved in the same time span as needed for intravenous midazolam. Nazolam may offer important advantages in conscious sedation.

Detection of colorectal polyps in humans using an intravenously administered fluorescent peptide targeted against c-Met.

Colon cancer prevention currently relies on colonoscopy using white light to detect and remove polyps, but small and flat polyps are difficult to detect and frequently missed when using this technique. Fluorescence colonoscopy combined with a fluorescent probe specific for a polyp biomarker may improve polyp detection. Here we describe GE-137, a water-soluble probe consisting of a 26-amino acid cyclic peptide that binds the human tyrosine kinase c-Met conjugated to a fluorescent cyanine dye. Intravenous administration of GE-137 leads to its accumulation specifically in c-Met-expressing tumors in mice, and it is safe and well tolerated in humans. Fluorescence colonoscopy in patients receiving intravenous GE-137 enabled visualization of all neoplastic polyps that were visible with white light (38), as well as an additional nine polyps that were not visible with white light. This first-in-human pilot study shows that molecular imaging using an intravenous fluorescent agent specific for c-Met is feasible and safe, and that it may enable the detection of polyps missed by other techniques.

Comparison of body surface area versus weight-based growth hormone dosing for girls with Turner syndrome.

BACKGROUND/AIMS: Growth Hormone (GH) dosage in childhood is adjusted for body size, but there is no consensus whether body weight (BW) or body surface area (BSA) should be used. We aimed at comparing the biological effect and cost-effectiveness of GH treatment dosed per m2 BSA in comparison with dosing per kg BW in girls with Turner syndrome (TS). METHODS: Serum IGF-I, GH dose, and adult height gain (AHG) from girls participating in two Dutch and five Swedish studies on the efficacy of GH were analyzed, and the cumulative GH dose and costs were calculated for both dose adjustment methods. Additional medication included estrogens (if no spontaneous puberty occurred) and oxandrolone in some studies. RESULTS: At each GH dose, the serum IGF-I standard deviation score remained stable over time after an initial increase after the start of treatment. On a high dose (at 1 m2 equivalent to 0.056-0.067 mg/kg/day), AHG was at least equal on GH dosed per m2 BSA compared with dosing per kg BW. The cumulative dose and cost were significantly lower if the GH dose was adjusted for m2 BSA. CONCLUSION: Dosing GH per m2 BSA is at least as efficacious as dosing per kg BW, and is more cost-effective.

Catch-up growth after hypothyroidism is caused by delayed growth plate senescence.

Catch-up growth is defined as a linear growth rate greater than expected for age after a period of growth inhibition. We hypothesized that catch-up growth occurs because growth-inhibiting conditions conserve the limited proliferative capacity of growth plate chondrocytes, thus slowing the normal process of growth plate senescence. When the growth-inhibiting condition resolves, the growth plates are less senescent and therefore grow more rapidly than normal for age. To test this hypothesis, we administered propylthiouracil to newborn rats for 8 wk to induce hypothyroidism and then stopped the propylthiouracil to allow catch-up growth. In untreated controls, the growth plates underwent progressive, senescent changes in multiple functional and structural characteristics. We also identified genes that showed large changes in mRNA expression in growth plate and used these changes as molecular markers of senescence. In treated animals, after stopping propylthiouracil, these functional, structural, and molecular senescent changes were delayed, compared with controls. This delayed senescence included a delayed decline in longitudinal growth rate, resulting in catch-up growth. The findings demonstrate that growth inhibition due to hypothyroidism slows the developmental program of growth plate senescence, including the normal decline in the rate of longitudinal bone growth, thus accounting for catch-up growth.

Depletion of resting zone chondrocytes during growth plate senescence.

With age, the growth plate undergoes senescent changes that cause linear bone growth to slow and finally cease. Based on previous indirect evidence, we hypothesized that this senescent decline occurs because growth plate stem-like cells, located in the resting zone, have a finite proliferative capacity that is gradually depleted. Consistent with this hypothesis, we found that the proliferation rate in rabbit resting zone chondrocytes (assessed by continuous 5-bromo-2'-deoxy-uridine labeling) decreases with age, as does the number of resting zone chondrocytes per area of growth plate. Glucocorticoid excess slows growth plate senescence. To explain this effect, we hypothesized that glucocorticoid inhibits resting zone chondrocyte proliferation, thus conserving their proliferative capacity. Consistent with this hypothesis, we found that dexamethasone treatment decreased the proliferation rate of rabbit resting zone chondrocytes and slowed the numerical depletion of these cells. Estrogen is known to accelerate growth plate senescence. However, we found that estradiol cypionate treatment slowed resting zone chondrocyte proliferation. Our findings support the hypotheses that growth plate senescence is caused by qualitative and quantitative depletion of stem-like cells in the resting zone and that growth-inhibiting conditions, such as glucocorticoid excess, slow senescence by slowing resting zone chondrocyte proliferation and slowing the numerical depletion of these cells, thereby conserving the proliferative capacity of the growth plate. We speculate that estrogen might accelerate senescence by a proliferation-independent mechanism, or by increasing the loss of proliferative capacity per cell cycle.

Growth plate senescence is associated with loss of DNA methylation.

The overall body size of vertebrates is primarily determined by longitudinal bone growth at the growth plate. With age, the growth plate undergoes programmed senescence, causing longitudinal bone growth to slow and eventually cease. Indirect evidence suggests that growth plate senescence occurs because stem-like cells in the growth plate resting zone have a finite proliferative capacity that is gradually exhausted. Similar limits on replication have been observed when many types of animal cells are placed in cell culture, an effect known as the Hayflick phenomenon. However, we found that the number of population doublings of rabbit resting zone chondrocytes in culture did not depend on the age of the animal from which the cells were harvested, suggesting that the mechanisms limiting replicative capacity of growth plate chondrocytes in vivo are distinct from those in vitro. We also observed that the level of DNA methylation in resting zone chondrocytes decreased with age in vivo. This loss of methylation appeared to occur specifically with the slow proliferation of resting zone chondrocytes in vivo and was not observed with the rapid proliferation of proliferative zone chondrocytes in vivo (i.e. the level of DNA methylation did not change from the resting zone to the hypertrophic zone), with proliferation of chondrocytes in vitro, or with growth of the liver in vivo. Thus, the overall level of DNA methylation decreases during growth plate senescence. This finding is consistent with the hypothesis that the mechanism limiting replication of growth plate chondrocytes in vivo involves loss of DNA methylation and, thus, loss of DNA methylation might be a fundamental biological mechanism that limits longitudinal bone growth in mammals, thereby determining the overall adult size of the organism.