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After a revision surgery, approximately 1-2 % of patients will develop a periprosthetic joint infection (PJI). During the revision surgery, the infected prosthesis is removed, a debridement is performed and a new or temporary spacer is placed. Additionally, patients are treated with antibiotics during and after the surgery. Adequate exposure of the administered antibiotic to the pathogen is of crucial importance during the treatment of any infection. Inadequately low concentrations are associated with an increase in antibiotic resistance, antibiotic related side effects, treatment failures and prolonged infections. While high concentrations may lead to serious adverse events and potential lasting damage. Despite the importance of optimal dosing, there is a lack of knowledge with respect to the correlation between the plasma concentrations and target site concentrations of the antibiotics. Two of the commonly administered antimicrobial agents during the arthroplasty exchange are cefuroxime and flucloxacillin. Therefore, an accurate, specific, and sensitive quantification method is required in order to assess pharmacokinetics of cefuroxime and flucloxacillin in synovial tissue and bone. The aim of this study is to develop and validate a quantification method for the measurement of cefuroxime and flucloxacillin in human synovial tissue and bone using the UPC 2 -MS/MS conform Food and Drug Administration guidelines. The method was found linear for both compounds in both matrices (r 2  > 0.990) from 1 µg/g to 20 µg/g, except for cefuroxime in bone, which was validated from 1 µg/g to 15 µg/g. We developed and validated a quantification method for cefuroxime and flucloxacillin in synovial tissue and bone using a simple sample preparation and a short analysis run time of 5.0 min, which has been already successfully applied in a clinical study. To our knowledge, no methods have been described earlier for the simultaneous quantification of cefuroxime and flucloxacillin in synovial tissue and bone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Healthcare services have been seriously disrupted during the COVID-19 pandemic. The aim of this study was to examine the extent to which Dutch citizens have experienced postponed healthcare and how this affected their self-reported health. In addition, individual characteristics that were associated with experiencing postponed healthcare and with self-reported negative health effects were investigated., Methods: An online survey about postponed healthcare and its consequences was developed, and sent out to participants of the Dutch LISS (Longitudinal Internet Studies for the Social Sciences) panel ( n  = 2.043). Data were collected in August 2022. Multivariable logistic regression analyses were carried out to explore characteristics associated with postponed care and self-reported negative health outcomes., Results: Of the total population surveyed, 31% of the panel experienced postponed healthcare, either initiated by the healthcare provider (14%), on their own initiative (12%) or as a combination of both (5%). Postponed healthcare was associated with being female (OR = 1.61; 95% CI = 1.32; 1.96), presence of chronic diseases (OR = 1.55, 95% CI = 1.24; 1.95), high income (OR = 0.62, 95% CI = 0.48; 0.80) and worse self-reported health (poor vs. excellent OR = 2.88, 95% CI = 1.17; 7.11). Overall, 40% experienced temporary or permanent self-reported negative health effects due to postponed care. Negative health effects as a result of postponed care were associated with presence of chronic conditions and low income levels ( p  < 0.05). More respondents with worse self-reported health and foregone healthcare reported permanent health effects as compared to those with temporary health effects ( p  < 0.05)., Discussion: People with an impaired health status are most likely to experiencing postponed healthcare and negative health consequences as a result. Furthermore, those with negative health consequences decided to forego health by themselves more often. As part of long-term plans to maintain the accessibility of healthcare services, specific attention should be paid to reaching out to people with an impaired health status., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Visscher, Kouwenberg, Oosterhoff, Rotteveel and de Wit.)

Background: The COVID-19 pandemic had a major impact on the continuity of healthcare provision. Appointments, treatments and surgeries for non-COVID patients were often delayed, with associated health losses for patients involved., Objective: To develop a method to quantify the health impact of delayed elective care for non-COVID patients., Methods: A model was developed that estimated the backlog of surgical procedures in 2020 and 2021 using hospital registry data. Quality-adjusted life years (QALYs) were obtained from the literature to estimate the non-generated QALYs related to the backlog. In sensitivity analyses QALY values were varied by type of patient prioritization. Scenario analyses for future increased surgical capacity were performed., Results: In 2020 and 2021 an estimated total of 305,374 elective surgeries were delayed. These delays corresponded with 319,483 non-generated QALYs. In sensitivity analyses where QALYs varied by type of patient prioritization, non-generated QALYs amounted to 150,973 and 488,195 QALYs respectively. In scenario analyses for future increased surgical capacity in 2022-2026, the non-generated QALYs decreased to 311,220 (2% future capacity increase per year) and 300,710 (5% future capacity increase per year). Large differences exist in the extent to which different treatments contributed to the total health losses., Conclusions: The method sheds light on the indirect harm related to the COVID-19 pandemic. The results can be used for policy evaluations of COVID-19 responses, in preparations for future waves or other pandemics and in prioritizing the allocation of resources for capacity increases., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: School-based health-promoting interventions are increasingly seen as an effective population strategy to improve health and prevent obesity. Evidence on the long-term effectiveness of school-based interventions is scarce. This study investigates the four-year effectiveness of the school-based Healthy Primary School of the Future (HPSF) intervention on children's body mass index z-score (BMIz), and on the secondary outcomes waist circumference (WC), dietary and physical activity (PA) behaviours., Methods and Findings: This study has a quasi-experimental design with four intervention schools, i.e., two full HPSFs (focus: diet and PA), two partial HPSFs (focus: PA), and four control schools. Primary school children (aged 4-12 years) attending the eight participating schools were invited to enrol in the study between 2015 and 2019. Annual measurements consisted of children's anthropometry (weight, height and waist circumference), dietary behaviours (child- and parent-reported questionnaires) and PA levels (accelerometers). Between 2015 and 2019, 2236 children enrolled. The average exposure to the school condition was 2·66 (SD 1·33) years, and 900 participants were exposed for the full four years (40·3%). After four years of intervention, both full (estimated intervention effect (B = -0·17 (95%CI -0·27 to -0·08) p = 0·000) and partial HPSF (B = -0·16 (95%CI-0·25 to -0·06) p = 0·001) resulted in significant changes in children's BMIz compared to control schools. Likewise, WC changed in favour of both full and partial HPSFs. In full HPSFs, almost all dietary behaviours changed significantly in the short term. In the long term, only consumption of water and dairy remained significant compared to control schools. In both partial and full HPSFs, changes in PA behaviours were mostly absent., Interpretation: This school-based health-promoting intervention is effective in bringing unfavourable changes in body composition to a halt in both the short and long term. It provides policy makers with robust evidence to sustainably implement these interventions in school-based routine., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Currently, antibiotic treatment is often a standard dosing regimen in bone and joint infections (BJI). However, it remains unknown if exposure at the target-site is adequate. The aim of this review is to gain more insight in the relationship between the target site concentration of antibiotic and the minimal inhibitory concentration to target the bacteria in bone and joint infections (BJI)., Areas Covered: A literature search was performed by Erasmus MC Medical library. Bone, bone tissue and synovial concentration of antibiotics were covered in humans. In addition, we reported number of patients, dose, sampling method, analytical method and tissue and plasma concentrations. We used the epidemiological cutoff value (ECOFF) values of the targeted micro-organisms. If more than 3 publications were available on the antibiotic, we graphically presented ECOFFS values against reported antibiotic concentrations., Expert Opinion: For most antibiotics, the literature is sparse. In addition, a lot of variable and total antibiotic concentrations are published. Ciprofloxacin, cefazolin, cefuroxime, vancomycin and linezolid seem to have adequate average exposure if correlating total concentration to ECOFF, when standard dosing is used. With regard to other antibiotics, results are inconclusive. More extensive pharmacokinetic/pharmacodynamic modeling in BJI is needed.

Purpose: The aim of this study is to systematically review and critically assess the methodological quality of literature regarding prevalence, characteristics and factors influencing pain, other than phantom limb pain (PLP) in persons with lower limb amputation (LLA)., Materials and Methods: A systematic review was performed (PROSPERO CRD42019138018). Literature was searched using PubMed, EMBASE, PsycINFO, and PEDro. Studies were included if describing pain other than PLP at least three months after amputation. For residual limb pain (RLP) and back pain, a meta-regression was performed., Results: Fifty-one studies were included in which predominantly young males with a unilateral traumatic amputation using a prosthesis were investigated. Pooled prevalence of RLP was 0.51 (95% CI 0.40-0.62) with a positive association with presence of back pain ( p  = 0.044) in the univariate meta-regression. Pooled prevalence of back pain was 0.55 (95% CI 0.45-0.64), with a positive association of time since amputation ( p  < 0.001) and co-occurrence of RLP ( p  = 0.050)., Conclusions: Back pain and RLP are common after LLA. The prevalence of back pain was positively associated with the presence of RLP, and vice versa. Future studies should give more attention to other chronic pain types, to persons with a diabetic or vascular cause of amputation, and to pain-related interference.Implications for RehabilitationBoth back pain and residual limb pain occur in more than 50% of persons with lower limb amputation (LLA), and both pain types are positively associated.Clinicians should be aware that chronic pain is common after LLA and can have a significant impact on the functioning of persons with LLA.Future research on this topic should give more attention to other chronic pain types, to persons with a diabetic or vascular cause of amputation, and to pain-related interference.

This mixed methods study aimed to examine plausible body mass index (BMI) trajectories after exposure to a primary school-based lifestyle intervention to aid in estimating the long-term intervention benefits. BMI trajectories for children at control schools (mean 7.6 years of age) were modelled until 20 years of age through extrapolating trial evidence (N = 1647). A reference scenario assumed that the observed 2-year effects of the 'Healthy Primary Schools of the Future' (HPSF) and 'Physical Activity Schools' (PAS) were fully maintained over time. This was modelled by applying the observed 2-year BMI effects until 20 years of age. Expert opinions on likely trends in effect maintenance after the 2-year intervention period were elicited qualitatively and quantitatively, and were used for developing alternative scenarios. Expert elicitation revealed three scenarios: (a) a constant exposure-effect and an uncontrolled environment with effect decay scenario, (b) a household multiplier and an uncontrolled environment with effect decay scenario, and (c) a household multiplier and maintainer scenario. The relative effect of HPSF at 20 years of age was -0.21 kg/m 2 under the reference scenario, and varied from -0.04 kg/m 2 to -0.06 kg/m (a) , and -0.50 kg/m 2 . For PAS, the relative effect was -0.17 kg/m (b) under the reference scenario, and varied from -0.04 kg/m 2 , to -0.21 kg/m (c) . For PAS, the relative effect was -0.17 kg/m 2 under the reference scenario, and varied from -0.04 kg/m 2 (a, b) , to -0.21 kg/m 2 (c) . The mixed methods approach proved to be useful in modelling plausible BMI trajectories and specifying uncertainty on effect maintenance. Further observations until adulthood could reduce the uncertainty around future benefits. This trial was retrospectively registered at Clinicaltrials.gov (NCT02800616)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Background: This study estimated the lifetime cost-effectiveness and equity impacts associated with two lifestyle interventions in the Dutch primary school setting (targeting 4-12 year olds)., Methods: The Healthy Primary School of the Future (HPSF; a healthy school lunch and structured physical activity) and the Physical Activity School (PAS; structured physical activity) were compared to the regular Dutch curriculum (N = 1676). An adolescence model, calculating weight development, and the RIVM Chronic Disease Model, calculating overweight-related chronic diseases, were linked to estimate the lifetime impact on chronic diseases, quality adjusted life years (QALYs), healthcare, and productivity costs. Cost-effectiveness was expressed as the additional costs/QALY gained and we used €20,000 as threshold. Scenario analyses accounted for alternative effect maintenance scenarios and equity analyses examined cost-effectiveness in different socioeconomic status (SES) groups., Results: HPSF resulted in a lifetime costs of €773 (societal perspective) and a lifetime QALY gain of 0.039 per child versus control schools. HPSF led to lower costs and more QALYs as compared to PAS. From a societal perspective, HPSF had a cost/QALY gained of €19,734 versus control schools, 50% probability of being cost-effective, and beneficial equity impact (0.02 QALYs gained/child for low versus high SES). The cost-effectiveness threshold was surpassed when intervention effects decayed over time., Conclusions: HPSF may be a cost-effective and equitable strategy for combatting the lifetime burden of unhealthy lifestyles. The win-win situation will, however, only be realised if the intervention effect is sustained into adulthood for all SES groups., Trial Registration: Clinicaltrials.gov ( NCT02800616 ). Registered 15 June 2016 - Retrospectively registered.

Background: This study examines the social return on investment (SROI) of the "Healthy Primary School of the Future" initiative after 2 years. Methods: Healthy Primary Schools of the Future (HPSF) provide a healthy lunch and daily structured physical activity sessions, whereas Physical Activity Schools (PAS) focus on physical activity only. We evaluated the 2-years investments and effects ( N = 1,676 children) of both school environments (four schools) compared to control schools (four schools). Investments and outcomes were grouped within the healthcare, education, household & leisure, and labor & social security sector. Outcomes that could be expressed in monetary terms were used for the calculation of social return on investment. Results: HPSF and PAS created outcomes for the healthcare sector by favorable changes in health behaviors, body mass index [both significant], and medical resource use [not significant]. Outcomes for the education sector included a favorable impact on perceived social behaviors and school satisfaction, and absenteeism from school [latter not significant], and more engagement with the community was experienced. The per child investments, €859 (HPSF) and €1017 (PAS), generated a benefit of €8 (HPSF) and €49 (PAS) due to reduced school absenteeism and medical resource use. Conclusions: Within 2 years of intervention implementation, the HPSF initiative created outcomes in several sectors, but the benefits did not outweigh the investments. Follow-up assessments as well as modeling long-term outcomes are needed to assess the total value of the interventions. Until then, the SROI framework can inform strategies for obtaining stakeholder support and intervention implementation. Trial registration: The study was registered in the ClinicalTrials.gov database on 14 June 2016 (NCT02800616)., (Copyright © 2020 Oosterhoff, van Schayck, Bartelink, Bosma, Willeboordse, Winkens and Joore.)

Objectives: Schools play an important role in promoting healthy behaviours in children and can offer perspective in the ongoing obesity epidemic. The 'Healthy Primary School of the Future' (HPSF) aims to improve children's health and well-being by enhancing school health promotion. The current study aims to assess the effect of HPSF on children's body mass index (BMI) z-score after 1 and 2 years follow-up and to investigate whether HPSF has different effects within specific subgroups of children., Design: A longitudinal quasi-experimental design., Setting: Four intervention and four control schools participated; located in a low socioeconomic status region in the Netherlands., Participants: 1676 children (aged 4-12 years)., Interventions: HPSF uses a contextual systems approach and includes health-promoting changes in the school. Central to HPSF is the provision of a daily healthy lunch and structured physical activity sessions each day. Two intervention schools implemented both changes (full HPSF), two intervention schools implemented only the physical activity change (partial HPSF)., Main Outcome Measures: BMI z-score, determined by measurements of children's height and weight at baseline, after 1 and 2 years follow-up., Results: The intervention effect was significant after 1-year follow-up in the partial HPSF (standardised effect size (ES)=-0.05), not significant in the full HPSF (ES=-0.04). After 2 years follow-up, BMI z-score had significantly decreased in children of both the full HPSF (ES=-0.08) and the partial HPSF (ES=-0.07) compared with children of the control schools, whose mean BMI z-score increased from baseline to 2 years. None of the potential effect modifiers (gender, baseline study year, socioeconomic status and baseline weight status) were significant., Conclusions: HPSF was effective after 1 and 2 years follow-up in lowering children's BMI z-scores. No specific subgroups of children could be identified who benefitted more from the intervention., Trial Registration Number: NCT02800616., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Combatting disparities in health outcomes among children is a major public health concern. This study focuses on two questions: (1) To what extent does socioeconomic status (SES) contribute to disparities in health outcomes? and (2) To what extent can social inequalities in health outcomes be explained by differences in children's health behaviours?, Design: This study included 2-year follow-up data of 1259 children (4-12 years of age) who participated in the 'Healthy Primary School of the Future' project (ClinicalTrials.gov NCT02800616). SES was measured by maternal and paternal education and household income (adjusted for family size). Health outcomes were body mass index (BMI) z-score, health resource use, school absenteeism, health-related quality of life and psychosocial health, measured over 2 years of follow-up (2015-2017). Health behaviours included physical activity, and consumption of fruits, vegetables and sweetened beverages. Associations between SES and baseline health behaviours were examined, and mixed models for repeated measures were used to assess associations between SES and health outcomes over 2 years of follow-up., Results: A high socioeconomic background was significantly associated with better health outcomes (all outcomes). For example, children with a low SES had higher BMI z-scores (beta coefficient: 0.42, 95% CI 0.22 to 0.62) and higher consumption healthcare costs (ratio of mean costs: 2.21, 95% CI 1.57 to 3.10). Effects of SES changed very little after controlling for health behaviours., Discussion: Our findings strongly suggest that socioeconomic background has a pervasive impact on disparities in child health, but gives little support to the idea that social inequalities in child health can be tackled by means of lifestyle interventions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Schools can help to improve children's health. The 'Healthy Primary School of the Future' (HPSF) aims to sustainably integrate health and well-being into the school system. This study examined the effects of HPSF on children's dietary and physical activity (PA) behaviours after 1 and 2 years' follow-up. The study ( n = 1676 children) has a quasi-experimental design with four intervention schools, i.e., two full HPSF (focus: nutrition and PA) and two partial HPSF (focus: PA), and four control schools. Accelerometers and child- and parent-reported questionnaires were used at baseline, after 1 (T1) and 2 (T2) years. Mixed-model analyses showed significant favourable effects for the full HPSF versus control schools for, among others, school water consumption (effect size (ES) = 1.03 (T1), 1.14 (T2)), lunch intake of vegetables (odds ratio (OR) = 3.17 (T1), 4.39 (T2)) and dairy products (OR = 4.43 (T1), 4.52 (T2)), sedentary time (ES = -0.23 (T2)) and light PA (ES = 0.22 (T2)). Almost no significant favourable effects were found for partial HPSF compared to control schools. We conclude that the full HPSF is effective in promoting children's health behaviours at T1 and T2 compared with control schools. Focusing on both nutrition and PA components seems to be more effective in promoting healthy behaviours than focusing exclusively on PA., Competing Interests: The authors declare no conflicts of interests. None of the funding bodies had a role in the design of the study or the writing of this manuscript, nor a role in the data collection, analysis, interpretation of data, and writing of publications.

Current guidelines for economic evaluations do not provide specific recommendations for the evaluation of school-based lifestyle interventions. This study examined and discussed the key aspects in the design of economic evaluations on school-based interventions targeting weight-related behaviours among 4-12 year olds. The PubMed and CRD databases (NHS EED) were searched. Grey literature was identified from reference lists and websites of relevant organizations. Full economic evaluations on school-based interventions targeting physical activity, sedentariness, or diet were selected. Key aspects included the objective, audience, intervention, comparator, population, type of analysis, perspective, costs, outcomes, and time horizon. Information was also extracted on measuring and valuing costs and outcomes, linking and extrapolating outcomes, and the maintenance of intervention effects. The 23 included studies reported on cost-effectiveness (CEAs) (N = 12), cost-utility (CUAs) (N = 9), social cost benefit (SCBA) (N = 2), and social return on investment (SROI) (N = 1) analysis. The usual practice comparator was generally not clearly defined. The SROI analysis was the single study that included outcomes in other persons than the child. Healthcare costs (N = 14), productivity costs (N = 4), and costs to the household (N = 3), or education (N = 2) sector were examined. The outcome in trial-based CEAs consisted of a variety of weight-related measures. Seven distinctive models were used to extrapolate health and/or productivity costs. To enhance the usefulness of economic evaluations on school-based lifestyle interventions in allocating public health budgets, transparent reporting on key aspects, broadening the scope of economic evaluations, and standardizing the measurement, valuation, and extrapolation of costs and outcomes should be improved. This study was conducted in Maastricht, the Netherlands., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

A uniform approach for costing school-based lifestyle interventions is currently lacking. The objective of this study was to develop a template for costing primary school-based lifestyle interventions and apply this to the costing of the "Healthy Primary School of the Future" (HPSF) and the "Physical Activity School" (PAS), which aim to improve physical activity and dietary behaviors. Cost-effectiveness studies were reviewed to identify the cost items. Societal costs were reflected by summing up the education, household and leisure, labor and social security, and health perspectives. Cost inputs for HPSF and PAS were obtained for the first year after implementation. In a scenario analysis, the costs were explored for a hypothetical steady state. From a societal perspective, the per child costs were €2.7/$3.3 (HPSF) and €- 0.3/$- 0.4 (PAS) per day during the first year after implementation, and €1.0/$1.2 and €- 1.3/$- 1.6 in a steady state, respectively (2016 prices). The highest costs were incurred by the education perspective (first year: €8.7/$10.6 (HPSF) and €4.0/$4.9 (PAS); steady state: €6.1/$7.4 (HPSF) and €2.1/$2.6 (PAS)), whereas most of the cost offsets were received by the household and leisure perspective (first year: €- 6.0/$- 7.3 (HPSF) and €- 4.4/$- 5.4 (PAS); steady state: €- 5.0/$- 6.1 (HPSF) and €- 3.4/$- 4.1 (PAS)). The template proved helpful for costing HPSF and PAS from various stakeholder perspectives. The costs for the education sector were fully (PAS) and almost fully (HPSF) compensated by the savings within the household sector. Whether the additional costs of HPSF over PAS represent value for money will depend on their relative effectiveness.

Background: This study assesses socio-economic health inequalities (SEHI) over primary school-age (4- to 12-years old) across 13 outcomes (i.e. body-mass index [BMI], handgrip strength, cardiovascular fitness, current physical conditions, moderate to vigorous physical activity, sleep duration, daily fruit and vegetable consumption, daily breakfast, exposure to smoking, mental strengths and difficulties, self-efficacy, school absenteeism and learning disabilities), covering four health domains (i.e. physical health, health behaviour, mental health and academic health)., Methods: Multilevel mixed effect (linear and logistic) regression analyses were applied to cross-sectional data of a Dutch quasi-experimental study that included 1403 pupils from nine primary schools. Socioeconomic background (high-middle-low) was indicated by maternal education (n = 976) and parental material deprivation (n = 784)., Results: Pupils with higher educated mothers had lower BMIs, higher handgrip strength and higher cardiovascular fitness; their parents reported more daily fruit and vegetable consumption, daily breakfast and less exposure to smoking. Furthermore these pupils showed less mental difficulties and less school absenteeism compared with pupils whose mothers had a lower education level. When using parental material deprivation as socio-economic indicator, similar results were found for BMI, cardiovascular fitness, sleep duration, exposure to smoking and mental strengths and difficulties. Socio-economic differences in handgrip strength, cardiovascular fitness and sleep duration were larger in older than in younger pupils., Conclusions: Childhood SEHI are clearly found across multiple domains, and some are larger in older than in younger pupils. Interventions aiming to tackle SEHI may therefore need a comprehensive and perhaps more fundamental approach.

The National Institute for Health and Care Excellence invited Eli Lilly and Company Ltd, the company manufacturing ixekizumab (tradename Taltz ® ), to submit evidence for the clinical and cost effectiveness of ixekizumab. Ixekizumab was compared with tumour necrosis factor-α inhibitors (etanercept, infliximab, adalimumab), ustekinumab, secukinumab, best supportive care and, if non-biological treatment or phototherapy is suitable, also compared with systemic non-biological therapies and phototherapy with ultraviolet B radiation for adults with moderate-to-severe plaque psoriasis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group. This article presents a summary of the company submission, the Evidence Review Group report and the development of the National Institute for Health and Care Excellence guidance for the use of this drug in England and Wales by the Appraisal Committee. The Evidence Review Group produced a critical review of the clinical and cost effectiveness of ixekizumab based on the company submission. The company submission presented three randomised controlled trials identified in a systematic review. All randomised controlled trials were phase III, multicentre placebo-controlled trials including 3866 participants with moderate-to-severe psoriasis. Two trials also included an active comparator (etanercept). All randomised controlled trials showed statistically significant increases in two primary outcomes, static Physician Global Assessment (0,1) and improvement of 75% from baseline in the Psoriasis Area and Severity Index. Ixekizumab was generally well tolerated in the randomised controlled trials, with similar discontinuation rates because of adverse events as placebo or etanercept. The most frequent adverse events of special interest were infections and injection-site reactions. The company submission also included a network meta-analysis of relevant comparators. The Evidence Review Group highlighted some issues regarding the systematic review process and an issue with the generalisability of the findings in that the trials failed to include patients with moderate psoriasis according to a widely used definition. This issue was considered by the Appraisal Committee and the population was deemed generalisable to patients in England and Wales. Based on the network meta-analysis, the Appraisal Committee concluded that ixekizumab was more clinically effective than adalimumab and ustekinumab, and agreed it was likely that ixekizumab was similarly effective compared with secukinumab and infliximab while tolerability was similar to other biological treatments approved for treating psoriasis. The Evidence Review Group's critical assessment of the company's economic evaluation highlighted a number of concerns, including (1) the use of relative outcomes such as Psoriasis Area and Severity Index response to model the cost effectiveness; (2) the exclusion of the consequences of adverse events; (3) the assumption of no utility gain in the induction phase; (4) equal annual discontinuation rates for all treatments; (5) the selection of treatment sequences for consideration in the analyses and; (6) the transparency of the Visual Basic for Applications code used to develop the model. Although some of these issues were adjusted in the Evidence Review Group base case, the Evidence Review Group could not estimate the impact of all of these issues, and thus acknowledges that there are still uncertainties concerning the cost-effectiveness evidence. In the Evidence Review Group base-case incremental analysis, the treatment sequence incorporating ixekizumab in the second line has an incremental cost-effectiveness ratio of £25,532 per quality-adjusted life-year gained vs. the etanercept sequence. Ixekizumab in the first-line sequence has an incremental cost-effectiveness ratio of £39,129 per quality-adjusted life-year gained compared with the treatment sequence incorporating ixekizumab in the second line. Consistent with its conclusion regarding clinical effectiveness, the Appraisal Committee concluded that the cost effectiveness of ixekizumab for treating moderate-to-severe plaque psoriasis was similar to that of other biological treatments, already recommended in previous National Institute for Health and Care Excellence guidance. The committee concluded that the incremental cost-effectiveness ratio was within the range that could be considered a cost-effective use of National Health Service resources.

Background: Ten per cent of patients with obsessive-compulsive disorder (ocd) are resistant to treatment. For these patients, repetitive transcranial magnetic stimulation (rtms) may be an alternative form of treatment.
AIM: To clarify the effect and clinical application of rtms for treatment-resistant ocd.
METHOD: We searched the literature systematically and we discuss the relevant articles critically.
RESULTS: We included 17 randomised controlled trials (rcts) with 502 patients. The reported trials were small and heterogeneous. A small but consistent treatment effect was found for rtms (mean decrease y-bocs score 6.6 points) compared to placebo stimulation (mean decrease y-bocs score 2.4 points). However, the differences between the effects of rtms and the effects of placebo were often not statistically or clinically significant. The effect frequently disappeared within several weeks after ending rtms and the follow-up period was never longer than three months.
CONCLUSION: rtms is still not entirely suitable for inclusion in the regular treatment of resistant ocd. More information is needed about follow-up requirements and about the advisable length and intensity of the applied stimulation. Future developments may involve increasing the number of stimulation sessions, combining these with cognitive behavioral therapy and delivering a more personalised form of rtms.

Background: Compulsive movements, complex tics and stereotypies are frequent, especially among patients with autism or psychomotor retardation. These movements can be difficult to characterize and can mimic other conditions like epileptic seizures or paroxysmal dystonia, particularly when abnormal breathing and cerebral hypoxia are induced., Case Presentation: We describe an 18-year-old patient with Asperger syndrome who presented with attacks of tonic posturing of the trunk and neck. The attacks consisted of self-induced stereotypic stretching of the neck combined with a compulsive Valsalva-like maneuver. This induced cerebral hypoperfusion and subsequently dysautonomia and some involuntary movements of the arms., Conclusion: This patient suffered from a complex tic with compulsive respiratory stereotypies. His symptoms contain aspects of a phenomenon described in early literature as 'the fainting lark'.

Primary prevention of childhood obesity and related hypertension is warrant given that both risk factors are intertwined and track into adulthood. This systematic review and meta-analysis assess the impact of school-based lifestyle interventions on children's body mass index (BMI) and blood pressure. We searched databases and prior reviews. Eligibility criteria were the following: randomized controlled trial design, evaluation of a school-based intervention, targeting children aged 4-12 years, reporting on BMI and/or related cardiovascular risk factors, reporting data on at least one follow-up moment. The effects on BMI, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were evaluated by means of univariate and multivariate three-level random effects models. A total of 85 RCTs (91 papers) were included in the meta-analyses. In univariate models, the pooled effects were -0.072 (95%CI: -0.106; -0.038) for BMI, -0.183 (95%CI: -0.288; -0.078) for SBP and -0.071 (95%CI: -0.185; 0.044) for DBP. In multivariate analyses, the pooled effects of interventions were -0.054 (95%CI: -0.131; 0.022) for BMI, -0.182 (95%CI: -0.266; -0.098) for SBP and -0.144 (95%CI: -0.230; -0.057) for DBP. Parental involvement accentuated the beneficial effects of interventions. School-based lifestyle prevention interventions result in beneficial changes in children's BMI and blood pressure, and the effects on the latter may be stronger than and accrue independently from those in the former., (© 2016 World Obesity.)

Background: Unhealthy lifestyles in early childhood are a major global health challenge. These lifestyles often persist from generation to generation and contribute to a vicious cycle of health-related and social problems. This design article presents a study evaluating the effects of two novel healthy school interventions. The main outcome measure will be changes in children's body mass index (BMI). In addition, lifestyle behaviours, academic achievement, child well-being, socio-economic differences, and societal costs will be examined., Methods: In close collaboration with various stakeholders, a quasi-experimental study was developed, for which children of four intervention schools (n = 1200) in the southern part of the Netherlands are compared with children of four control schools (n = 1200) in the same region. The interventions started in November 2015. In two of the four intervention schools, a whole-school approach named 'The Healthy Primary School of the Future', is implemented with the aim of improving physical activity and dietary behaviour. For this intervention, pupils are offered an extended curriculum, including a healthy lunch, more physical exercises, and social and educational activities, next to the regular school curriculum. In the two other intervention schools, a physical-activity school approach called 'The Physical Activity School', is implemented, which is essentially similar to the other intervention, except that no lunch is provided. The interventions proceed during a period of 4 years. Apart from the effectiveness of both interventions, the process, the cost-effectiveness, and the expected legal implications are studied. Data collection is conducted within the school system. The baseline measurements started in September 2015 and yearly follow-up measurements are taking place until 2019., Discussion: A whole-school approach is a new concept in the Netherlands. Due to its innovative, multifaceted nature and sound scientific foundation, these integrated programmes have the potential to form a template for primary schools worldwide. The effects of this approach may extend further than the outcomes associated with well-being and academic achievement, potentially impacting legal and cultural aspects in our society., Trial Registration: The study protocol was registered in the database ClinicalTrials.gov on 14-06-2016 with the reference number NCT02800616 .

Background: Diagnostic biomarkers have multiple applications along the care process and have a large potential in optimizing treatment decisions. However, many diagnostic biomarkers struggle to gain market access and obtain appropriate coverage because of a lack of evidence on their health economic impact., Objectives: The aim was to review the (methodological) characteristics of recent economic evaluations on diagnostic biomarkers and examine whether these studies dealt with specific issues such as different payer perspectives, preference heterogeneity, and multiple applications in subpopulations., Methods: The PubMed database and the National Health Service Economic Evaluation Database were searched. Full economic evaluations published after 2009 assessing diagnostic biomarkers for the main non-communicable diseases in middle-income or high-income countries were considered eligible. Empirical and methodological study characteristics were summarized, as was the handling of specific issues related to the economic evaluation of personalized medicine., Results: Thirty-three economic evaluations were included, of which 25 were model-based analyses. The number of strategies compared ranged from two to 17 per study, and was especially large in studies assessing genetic testing in patients and their relatives. Cost-effectiveness results were most sensitive to test accuracy and costs of the biomarker (N = 7), the relative risk of an event (N = 4), and the proportion of people accepting genetic testing (N = 2). One study incorporated patient preferences, and none of the studies considered different payer perspectives, cost sharing arrangements or variable opportunity costs due to population density variability., Conclusions: Published health economic evaluations of biomarkers used for diagnosing, staging diseases, and guiding treatment selection are characterized by a large number of comparators to model the potential clinical applications and to determine their value. Assessing outcomes beyond health as well as specific issues, such as different payer perspectives and patient preferences, is crucial to fully capture the potential health economic impact of diagnostic biomarkers and to inform value-based reimbursement.

Background: The underlying mechanism of the juvenile head trauma syndrome (JHTS) is still uncertain, but it has been suggested that there is a role in cortical spreading depression, a phenomenon that is assumed to be a part of the pathophysiology of migraine., Hypothesis: We postulate that children affected by the JHTS are more susceptible to cortical spreading depression, caused by a genetic etiology similar to genetic factors in migraine., Methods: Children with the JHTS were selected and evaluated retrospectively in an observational case-control study in two Dutch trauma centers in the period between January 2008 and July 2012., Results: We included 33 patients with the JHTS, who were accounted for approximately 2.5% of the total number (1,342) of children seen at the emergency department with a mild head trauma. The prevalence of migraine in cases compared with controls did not differ. The proportion of patients with a first-degree relative with migraine was significantly higher in cases compared with controls (odds ratio, 2.69; 95% confidence interval, 1.16-6.22; p = 0.010)., Conclusion: The JHTS is a relatively rare phenomenon, seen in approximately 2.5% of all children seen at the emergency department with mild brain injury. This study demonstrates a significant relationship between the JHTS and a positive history of migraine in first-degree relatives., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Elevated D8/17 expression on B lymphocytes is a known susceptibility marker of rheumatic fever. Previous studies have reported higher than usual D8/17 expression on B lymphocytes of patients with tic disorders. The purpose of this study was to assess D8/17 expression on B lymphocytes of tic disorder patients by using an objective method in which no operator variability was involved., Method: D8/17 expression on B lymphocytes was assessed with flow cytometry by using an immunoglobulin M (IgM) monoclonal D8/17-specific antibody in an unselected group of Dutch patients with tic disorders (N=33) and healthy volunteers (N=20). Binding of this monoclonal antibody was compared with binding of an irrelevant IgM monoclonal antibody, and the shift in mean fluorescence intensity of the D8/17-specific antibody compared to that of the irrelevant IgM monoclonal antibody was used as a measure of D8/17 overexpression. For the patients, Yale Global Tic Severity Scale scores were used to assess disease severity., Results: D8/17 overexpression in the patient group (mean=16.8 arbitrary units, SD=30.5) was significantly higher than in the comparison group (mean=3.2, SD=3.0). A significant minority of the patients (N=13, 39.4%), however, had levels of D8/17 overexpression within the range of that of the healthy comparison subjects. Flow cytometric analysis did not indicate a separate subpopulation of D8/17-positive B cells., Conclusions: These data confirm the utility of D8/17 B cell overexpression as a peripheral blood marker in patients with tic disorders and are compatible with a streptococcus-related pathogenesis for at least a subgroup of patients with tic disorders.

Objective: The authors studied the effects of the alpha 2-receptor agonist clonidine on stuttering in children., Method: Using a double-blind crossover study, they gave placebo or 4 micrograms/kg body weight per day to 25 stuttering children who were 6-13 years old. Stuttering was measured by counting the occurrences of four elementary speech difficulties and by asking parents and teachers to give an overall impression of the amount of stuttering, as well as their impression of how troublesome the stuttering was to the children., Results: Clonidine did not improve stuttering., Conclusions: Clonidine cannot be recommended as a useful drug for treating children who stutter.