Methyl 2-hy-droxy-4-iodo-benzoate.

The structure of the title compound, C8H7IO3, at 90 K has monoclinic (P21/c) symmetry. The extended structure is layered and displays inter-molecular and intra-molecular hydrogen bonding arising from the same OH group.

Randomised clinical trial: First-line infliximab biosimilar is cost-effective compared to conventional treatment in paediatric Crohn's disease.

BACKGROUND: Data on cost-effectiveness of first-line infliximab in paediatric patients with Crohn's disease are limited. Since biologics are increasingly prescribed and accompanied by high costs, this knowledge gap needs to be addressed. AIM: To investigate the cost-effectiveness of first-line infliximab compared to conventional treatment in children with moderate-to-severe Crohn's disease. METHODS: We included patients from the Top-down Infliximab Study in Kids with Crohn's disease randomised controlled trial. Children with newly diagnosed moderate-to-severe Crohn's disease were treated with azathioprine maintenance and either five induction infliximab (biosimilar) infusions or conventional induction treatment (exclusive enteral nutrition or corticosteroids). Direct healthcare consumption and costs were obtained per patient until week 104. This included data on outpatient hospital visits, hospital admissions, drug costs, endoscopies and surgeries. The primary health outcome was the odds ratio of being in clinical remission (weighted paediatric Crohn's disease activity index<12.5) during 104 weeks. RESULTS: We included 89 patients (44 in the first-line infliximab group and 45 in the conventional treatment group). Mean direct healthcare costs per patient were €36,784 for first-line infliximab treatment and €36,874 for conventional treatment over 2 years (p = 0.981). The odds ratio of first-line infliximab versus conventional treatment to be in clinical remission over 104 weeks was 1.56 (95%CI 1.03-2.35, p = 0.036). CONCLUSIONS: First-line infliximab treatment resulted in higher odds of being in clinical remission without being more expensive, making it the dominant strategy over conventional treatment in the first 2 years after diagnosis in children with moderate-to-severe Crohn's disease. TRIAL REGISTRATION NUMBER: NCT02517684.

Risk factors associated with symptoms of temporomandibular disorders among women with hypermobile Ehlers-Danlos syndrome: Questionnaire-based study in Finland and Sweden.

BACKGROUND: Generalized joint hypermobility as a characteristic feature of Ehlers-Danlos syndromes (EDS) is among the factors contributing to temporomandibular disorders (TMD). OBJECTIVE: To evaluate the prevalence of TMD symptoms and their risk factors among women born in Sweden or Finland who were 27- to 78-year-olds with diagnosed hypermobile EDS (hEDS). METHODS: A cohort of women with confirmed hEDS (n = 185) was constructed from the members of the National EDS Associations in both countries. Based on questionnaire data, frequency of independent variables in terms of socio-demographic, general health and oral health-related factors, comorbid symptoms and psychological distress for self-reported TMD symptoms as the dependent variables, were calculated first. Prevalence ratios (PR) and their 95% confidence interval (95% CI) were estimated for the association between independent and dependent variables. RESULTS: Nearly all participants reported TMD symptoms (98%) with TMD pain (95%), TMJ clicking (90%) and jaw fatigue (80%) as the most common symptoms and TMJ crepitation (63%) and luxation (44%) as the least common symptoms. Risk factors for TMD among 27- to 50-year-olds participants were Finland as a country of birth, living alone and self-reported worst pain in the body (not the joints). The respective risk factors among the 51- to 78-year-olds were Finland as a country of birth, family history of EDS, tinnitus and regularly taking contraceptives. CONCLUSIONS: Among adult women with confirmed hEDS, socio-demographic and health-related factors and comorbid symptoms were significantly associated with TMD but with differences regarding age group. Therefore, management of TMD requires a multidisciplinary approach among the affected.

Ultra-brief acceptance & commitment therapy for inpatients with psychosis - a single-case experimental design investigating processes of change.

People with primary psychosis are among the most seen in inpatient psychiatry. Treatment guidelines recommend both pharmacological and psychological treatments. However, psychological treatments are not routinely offered in many settings. There is also a lack of research on psychological treatments for this vulnerable population in the inpatient setting. The first aim of the current study was to examine treatment effects of a brief form of Acceptance and Commitment Therapy on outcomes valued by the treatment recipients. The second aim was to explore hypothetical processes of change in relation to outcomes over time. Three people with primary psychosis were treated for two to four sessions. A replicated single-case experimental design with multiple baselines across subjects (Clinical Trials registration number ID NCT04704973) was employed to examine treatment effects. The Personal Questionnaire (PQ) was used as primary outcome, symptom believability and preoccupation as proposed processes of change. Data were analyzed using visual inspection, calculation of Tau-U values, and cross-lagged correlation. All participants improved significantly on PQ and the symptom preoccupation measure. Two improved significantly on the symptom believability measure. Cross-lagged correlation analyses showed no clear mediation. Change in proposed processes of change and primary outcome predominantly happened concomitantly, although patterns of results reflected individual differences.

Psychotherapist variables that may lead to treatment failure or termination-A qualitative analysis of patients' perspectives.

A substantial number of patients do not improve from psychotherapy, some even deteriorate, and some terminate treatment prematurely. Identifying therapist variables that may lead to treatment failures from patients' perspectives can inform how psychotherapists can increase effectiveness. Using a semistructured protocol, we interviewed 24 patients who had experienced unsatisfying individual face-to-face psychotherapy within the last 2 years. The study procedures were guided by the consolidated criteria for reporting qualitative research. The manifest content analysis provided 13 subcategories grouped into four categories: (a) psychotherapists' negative traits (inflexible, unengaged, unemphatic, insecure), (b) unprofessionalism (superficial, violating personal boundaries, breaking confidentiality, nontransparent), (c) incompetence (unstructured, poor assessment or understanding, poor knowledge, too passive), and (d) mismatch (therapist-patient mismatch). To reduce the risk of treatment failure, psychotherapists may need a multifaceted set of relational skills, theoretical and technical competence, ethical sensitivity, and engagement. Some of the identified subcategories were complex constructs (e.g., unengaged) that may need time and effort to develop for psychotherapists. Other identified subcategories were obvious inappropriate behaviors in professional psychotherapy (e.g., breaking confidentiality). However, the categories found in this study need further quantitative investigation to assess the validity, frequency, and relative impact on treatment outcomes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial).

BACKGROUND: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. METHODS: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. DISCUSSION: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.

Promoting Healthy Behaviors Among Adolescents and Young Adults With Intellectual Disability: Protocol for Developing a Digital Intervention With Co-Design Workshops.

BACKGROUND: Intellectual disability (ID) is a neurodevelopmental disorder associated with a poorer health profile and higher mortality. Young people with ID have more sedentary lifestyles than their typically developing peers. Consequently, this group is at significant risk of developing lifestyle diseases (ie, noncommunicable diseases) later in life. Increasing physical activity and eating a healthier diet have been argued to be effective ways to improve the health of adolescents and young adults with ID. Digital interventions are a viable option for improving health behaviors. OBJECTIVE: This research protocol describes a co-design approach using workshops to develop a digital intervention that promotes healthy behaviors, including increasing physical activity and eating a healthier diet, among adolescents and young adults with ID. METHODS: A participatory design using a co-design approach will be applied as a strategy to include potential users of the digital intervention and other stakeholders in the research process, comprising research design, data collection, and data analysis. A total of 7 to 10 workshops will be conducted aimed at developing a digital intervention and will include procedures for assessing needs; facilitators and barriers to health promotion; physical, mental, and social well-being; participation; and relationships. The workshops will include 12 to 18 stakeholders with experience of clinical practice and research related to young people with ID, including relatives, as well as adolescents and young adults (aged 16-25 years) with mild to moderate ID. Participants will perform a mixture of individual and group work using whiteboards, sticky notes, felt-tip pens, cards, balls, stickers, and wireframe templates. Data analysis will take place concurrently with data collection as an iterative process. Transcribed data from the audio and video recordings of the groups' discussions will be analyzed following a qualitative methodological procedure. RESULTS: This study protocol provides a systematic record of the scientific methodologies used when developing the digital intervention and provides insights into the potential practical solutions and challenges when following a co-design approach in which relatives and professionals, as well as adolescents and young adults with ID, are included as research partners. Recruitment of participants started in April 2023. Data collection, analysis, and reporting will be completed in December 2023. CONCLUSIONS: This study will explore the effectiveness of workshops at gathering rich, reliable, and valid data in a co-design approach with participants. The results will provide increased knowledge in how to use technology to develop novel, evidence-based, and scalable interventions that adolescents and young adults with ID can and want to use to motivate physical activity and a healthier diet. The project will provide a simple and cognitively accessible digital solution for promoting lifestyle behaviors tailored to the needs of adolescents and young adults with ID. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/47877.

Single-use duodenoscopes compared with reusable duodenoscopes in patients carrying multidrug-resistant microorganisms: a break-even cost analysis.

Background and study aims Single-use duodenoscopes can prevent transmission of microorganisms through contaminated reusable duodenoscopes. Concerns regarding their economic and environmental impact impede the transition to single-use duodenoscopes. This study investigated the costs associated with two scenarios in which single-use duodenoscopes are used in patients carrying multidrug-resistant microorganisms (MDROs). Methods Break-even costs for single-use duodenoscopes were calculated for two scenarios in which patients were screened for MDRO carriage before undergoing endoscopic retrograde cholangiopancreatography (ERCP). Only direct costs related to the endoscopy were taken into consideration. In Scenario 1, patients were screened through microbiological culturing with a lag time in receiving the test result. In Scenario 2, screening was performed using GeneXpert analysis providing a rapid read-out. Calculations were performed using data from a Dutch tertiary care center and also with US healthcare data. Results In the Dutch situation, single-use duodenoscopes needed to be priced at a maximum of €â€Š140 to €â€Š250 to break-even. In the US analyses, break-even costs varied widely, depending on the duodenoscope-associated infection costs used, ERCP volume, and infection risk. The break-even costs in Scenario 1 ranged between $78.21 and $2,747.54 and in Scenario 2, between $248.89 and $2,209.23. Conclusions This study showed that a crossover scenario in which single-use duodenoscopes are only used in patients carrying MDROs could be an economically viable alternative to a complete transition to single-use duodenoscopes. In the Dutch setting, single-use duodenoscopes need to be priced much lower than in the United States to reach a per-procedure cost that is comparable with a scenario using reusable duodenoscopes exclusively.

Music to prevent deliriUm during neuroSurgerY (MUSYC): a single-centre, prospective randomised controlled trial.

OBJECTIVES: Delirium is a serious complication following neurosurgical procedures. We hypothesise that the beneficial effect of music on a combination of delirium-eliciting factors might reduce delirium incidence following neurosurgery and subsequently improve clinical outcomes. DESIGN: Prospective randomised controlled trial. SETTING: Single centre, conducted at the neurosurgical department of the Erasmus Medical Center, Rotterdam, the Netherlands. PARTICIPANTS: Adult patients undergoing craniotomy were eligible. INTERVENTIONS: Patients in the intervention group received preferred recorded music before, during and after the operation until day 3 after surgery. Patients in the control group were treated according to standard of clinical care. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was presence or absence of postoperative delirium within the first 5 postoperative days measured with the Delirium Observation Screening Scale (DOSS) and, in case of a daily mean score of 3 or higher, a psychiatric evaluation with the latest Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria. Secondary outcomes included anxiety, heart rate variability (HRV), depth of anaesthesia, delirium severity and duration, postoperative complications, length of stay and location of discharge. RESULTS: We enrolled 189 patients (music=95, control=94) from July 2020 through September 2021. Delirium, as assessed by the DOSS, was less common in the music (n=11, 11.6%) than in the control group (n=21, 22.3%, OR:0.49, p=0.048). However, after DSM-5 confirmation, differences in delirium were not significant (4.2% vs 7.4%, OR:0.47, p=0.342). Moreover, music increased the HRV (root mean square of successive differences between normal heartbeats, p=0.012). All other secondary outcomes were not different between groups. CONCLUSION: Our results support the efficacy of music in reducing the incidence of delirium after craniotomy, as found with DOSS but not after DSM-5 confirmation, substantiated by the effect of music on preoperative autonomic tone. Delirium screening tools should be validated and the long-term implications should be evaluated after craniotomy. TRIAL REGISTRATION NUMBER: Trialregister.nl: NL8503 and ClinicalTrials.gov: NCT04649450.

COllaborative Neonatal Network for the first European CPAM Trial (CONNECT): a study protocol for a randomised controlled trial.

INTRODUCTION: Consensus is lacking on the optimal management of asymptomatic congenital pulmonary airway malformation (CPAM). For future studies, the CONNECT consortium (the COllaborative Neonatal Network for the first European CPAM Trial)-an international collaboration of specialised caregivers-has established consensus on a core outcome set of outcome parameters concerning respiratory insufficiency, surgical complications, mass effect and multifocal disease. These outcome parameters have been incorporated in the CONNECT trial, a randomised controlled trial which, in order to develop evidence-based practice, aims to compare conservative and surgical management of patients with an asymptomatic CPAM. METHODS AND ANALYSIS: Children are eligible for inclusion after the CPAM diagnosis has been confirmed on postnatal chest CT scan and they remain asymptomatic. On inclusion, children are randomised to receive either conservative or surgical management. Subsequently, children in both groups are enrolled into a standardised, 5-year follow-up programme with three visits, including a repeat chest CT scan at 2.5 years and a standardised exercise tolerance test at 5 years.The primary outcome is exercise tolerance at age 5 years, measured according to the Bruce treadmill protocol. Secondary outcome measures are molecular genetic diagnostics, validated questionnaires-on parental anxiety, quality of life and healthcare consumption-, repeated imaging and pulmonary morbidity during follow-up, as well as surgical complications and histopathology. This trial aims to end the continuous debate surrounding the optimal management of asymptomatic CPAM. ETHICS AND DISSEMINATION: This study is being conducted in accordance with the Declaration of Helsinki. The Medical Ethics Review Board of Erasmus University Medical Centre Rotterdam, The Netherlands, has approved this protocol (MEC-2022-0441). Results will be disseminated through peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT05701514.

Better assessment of neonatal jaundice at home (BEAT Jaundice @home): protocol for a prospective, multicentre diagnostic study.

INTRODUCTION: Severe neonatal hyperbilirubinaemia can place a neonate at risk for acute bilirubin encephalopathy and kernicterus spectrum disorder. Early diagnosis is essential to prevent these deleterious sequelae. Currently, screening by visual inspection followed by laboratory-based bilirubin (LBB) quantification is used to identify hyperbilirubinaemia in neonates cared for at home in the Netherlands. However, the reliability of visual inspection is limited. We aim to evaluate the effectiveness of universal transcutaneous bilirubin (TcB) screening as compared with visual inspection to: (1) increase the detection of hyperbilirubinaemia necessitating treatment, and (2) reduce the need for heel pricks to quantify bilirubin levels. In parallel, we will evaluate a smartphone app (Picterus), and a point-of-care device for quantifying total bilirubin (Bilistick) as compared with LBB. METHODS AND ANALYSIS: We will undertake a multicentre prospective cohort study in nine midwifery practices across the Netherlands. Neonates born at a gestational age of 35 weeks or more are eligible if they: (1) are at home at any time between days 2 and 8 of life; (2) have their first midwife visit prior to postnatal day 6 and (3) did not previously receive phototherapy. TcB and the Picterus app will be used after visual inspection. When LBB is deemed necessary based on visual inspection and/or TcB reading, Bilistick will be used in parallel. The coprimary endpoints of the study are: (1) hyperbilirubinaemia necessitating treatment; (2) the number of heel pricks performed to quantify LBB. We aim to include 2310 neonates in a 2-year period. Using a decision tree model, a cost-effectiveness analysis will be performed. ETHICS AND DISSEMINATION: This study has been approved by the Medical Research Ethical Committee of the Erasmus MC Rotterdam, Netherlands (MEC-2020-0618). Parents will provide written informed consent. The results of this study will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Dutch Trial Register (NL9545).

Genetics tools for corpora allata specific gene expression in Aedes aegypti mosquitoes.

Juvenile hormone (JH) is synthesized by the corpora allata (CA) and controls development and reproduction in insects. Therefore, achieving tissue-specific expression of transgenes in the CA would be beneficial for mosquito research and control. Different CA promoters have been used to drive transgene expression in Drosophila, but mosquito CA-specific promoters have not been identified. Using the CRISPR/Cas9 system, we integrated transgenes encoding the reporter green fluorescent protein (GFP) close to the transcription start site of juvenile hormone acid methyl transferase (JHAMT), a locus encoding a JH biosynthetic enzyme, specifically and highly expressed in the CA of Aedes aegypti mosquitoes. Transgenic individuals showed specific GFP expression in the CA but failed to reproduce the full pattern of jhamt spatiotemporal expression. In addition, we created GeneSwitch driver and responder mosquito lines expressing an inducible fluorescent marker, enabling the temporal regulation of the transgene via the presence or absence of an inducer drug. The use of the GeneSwitch system has not previously been reported in mosquitoes and provides a new inducible binary system that can control transgene expression in Aedes aegypti.

Assessment, management, and incidence of neonatal jaundice in healthy neonates cared for in primary care: a prospective cohort study.

Jaundice caused by hyperbilirubinaemia is a common phenomenon during the neonatal period. Population-based studies evaluating assessment, management, and incidence of jaundice and need for phototherapy among otherwise healthy neonates are scarce. We prospectively explored these aspects in a primary care setting via assessing care as usual during the control phase of a stepped wedge cluster randomised controlled trial.We conducted a prospective cohort study embedded in the Screening and TreAtment to Reduce Severe Hyperbilirubinaemia in Infants in Primary care (STARSHIP) Trial. Healthy neonates were included in seven primary care birth centres (PCBCs) in the Netherlands between July 2018 and March 2020. Neonates were eligible for inclusion if their gestational age was ≥ 35 weeks, they were admitted in a PCBC for at least  2 days during the first week of life, and if they did not previously receive phototherapy. Outcomes were the findings of visual assessment to detect jaundice, jaundice incidence and management, and the need for phototherapy treatment in the primary care setting.860 neonates were included of whom 608 (71.9%) were visibly jaundiced at some point during admission in the PCBC, with 20 being 'very yellow'. Of the latter, four (20%) did not receive total serum bilirubin (TSB) quantification. TSB levels were not associated with the degree of visible jaundice (p = 0.416). Thirty-one neonates (3.6%) received phototherapy and none received an exchange transfusion. Five neonates did not receive phototherapy despite having a TSB level above phototherapy threshold.Jaundice is common in otherwise healthy neonates cared for in primary care. TSB quantification was not always performed in very jaundiced neonates, and not all neonates received phototherapy when indicated. Quality improvement initiatives are required, including alternative approaches to identifying potentially severe hyperbilirubinaemia.Trial registration: NL6997 (Dutch Trial Register; Old NTR ID 7187), registered 3 May 2018.

Effect of music on clinical outcome after hip fracture operations (MCHOPIN): study protocol of a multicentre randomised controlled trial.

BACKGROUND: Patients undergoing proximal femur fracture surgery are at high risk of postoperative complications, with postoperative delirium occurring in 25%-40% of patients. Delirium has profound effects on patient outcome and recovery, the patient's family, caregivers and medical costs. Perioperative music has a beneficial effect on eliciting modifiable risk factors of delirium. Therefore, the aim of this trial was to evaluate the effect of perioperative recorded music on postoperative delirium in patients with proximal femur fracture undergoing surgery. METHODS AND ANALYSIS: The Music on Clinical Outcome after Hip Fracture Operations study is an investigator-initiated, multicentre, randomised controlled, open-label, clinical trial. Five hundred and eight patients with proximal femur fracture meeting eligibility criteria will be randomised to the music intervention or control group with concealed allocation in a 1:1 ratio, stratified by hospital site. The perioperative music intervention consists of preselected lists totalling 30 hours of music, allowing participants to choose their preferred music from these lists (classical, jazz and blues, pop and Dutch). The primary outcome measure is postoperative delirium rate. Secondary outcome measures include pain, anxiety, medication requirement, postoperative complications, hospital length of stay and 30-day mortality. A 90-day follow-up will be performed in order to assess nursing home length of stay, readmission rate and functional ability to perform daily living activities. Furthermore, the cost and cost-effectiveness of the music intervention will be assessed. Data will be analysed according to an intention-to-treat principle. ETHICS AND DISSEMINATION: The study protocol has been approved by the Medical Research Ethics Committee Erasmus MC on 8 October 2018 (MEC-2018-110, NL64721.078.18). The trial will be carried out following the Declaration of Helsinki principles, Good Clinical Practice guidelines and Dutch Medical Research Involving Human Subjects Act. Research data will be reported following Consolidated Standards of Reporting Trials guidelines and study results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NTR7036.

Epoxidation of juvenile hormone was a key innovation improving insect reproductive fitness.

Methyl farnesoate (MF) plays hormonal regulatory roles in crustaceans. An epoxidated form of MF, known as juvenile hormone (JH), controls metamorphosis and stimulates reproduction in insects. To address the evolutionary significance of MF epoxidation, we generated mosquitoes completely lacking either of the two enzymes that catalyze the last steps of MF/JH biosynthesis and epoxidation, respectively: the JH acid methyltransferase (JHAMT) and the P450 epoxidase CYP15 (EPOX). jhamt-/- larvae lacking both MF and JH died at the onset of metamorphosis. Strikingly, epox-/- mutants, which synthesized MF but no JH, completed the entire life cycle. While epox-/- adults were fertile, the reproductive performance of both sexes was dramatically reduced. Our results suggest that although MF can substitute for the absence of JH in mosquitoes, it is with a significant fitness cost. We propose that MF can fulfill most roles of JH, but its epoxidation to JH was a key innovation providing insects with a reproductive advantage.

Music to prevent deliriUm during neuroSurgerY (MUSYC) Clinical trial: a study protocol for a randomised controlled trial.

INTRODUCTION: Delirium is a neurocognitive disorder characterised by an acute and temporary decline of mental status affecting attention, awareness, cognition, language and visuospatial ability. The underlying pathophysiology is driven by neuroinflammation and cellular oxidative stress.Delirium is a serious complication following neurosurgical procedures with a reported incidence varying between 4% and 44% and has been associated with increased length of hospital stay, increased amount of reoperations, increased costs and mortality.Perioperative music has been reported to reduce preoperative anxiety, postoperative pain and opioid usage, and attenuates stress response caused by surgery. We hypothesize that this beneficial effect of music on a combination of delirium eliciting factors might reduce delirium incidence following neurosurgery and subsequently improve clinical outcomes. METHODS: This protocol concerns a single-centred prospective randomised controlled trial with 6 months follow-up. All adult patients undergoing a craniotomy at the Erasmus Medical Center in Rotterdam are eligible. The music group will receive recorded music through an overear headphone before, during and after surgery until postoperative day 3. Patients can choose from music playlists, offered based on music importance questionnaires administered at baseline. The control group will receive standard of clinical careDelirium is assessed by the Delirium Observation Scale and confirmed by a delirium-expert psychiatrist according to the DSM-5 criteria. Risk factors correlated with the onset of delirium, such as cognitive function at baseline, preoperative anxiety, perioperative medication use, depth of anaesthesia and postoperative pain, and delirium-related health outcomes such as length of stay, daily function, quality of life (ie, EQ-5D, EORTC questionnaires), costs and cost-effectiveness are collected. ETHICS AND DISSEMINATION: This study is being conducted in accordance with the Declaration of Helsinki. The Medical Ethics Review Board of Erasmus University Medical Center Rotterdam, The Netherlands, approved this protocol. Results will be disseminated via peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBERS: NL8503 and NCT04649450.

Effectiveness of Simulation Training and Assessment of PICU Nurses' Resuscitation Skills: A Mixed Methods Study from the Netherlands.

PURPOSE: The quality of resuscitation and effective leadership are decisive for the outcome of a resuscitation. Nurses are usually the first responders upon cardiac arrest. Therefore, we started the "proficiency check" project, which aims to improve nurses' resuscitation and teamwork skills. This article describes the effectiveness of the proficiency check and nurses' experiences with it. DESIGN AND METHODS: This study was done among intensive care nurses working on a pediatric ICU (PICU) in the Netherlands. It was designed as a mixed-methods study combining a quantitative and a qualitative approach. Quantitative data were obtained through a pre-posttest comparison of nurses' resuscitation and teamwork skills, in a simulation setting. Qualitative data on nurses' experiences were collected through semi-structured individual interviews. RESULTS: Both resuscitation and teamwork skills improved significantly. In 39 nurses (32%), the improvement of both resuscitation and teamwork skills after the intervention was large (effect size >0.8). The experiences of nurses regarding the proficiency check were diverse: on the positive side, increased knowledge and confidence were reported, whereas negative experiences related, among other things, to stress and anxiety. CONCLUSIONS: Resuscitation and teamwork skills of PICU nurses can be enhanced by the 'proficiency check' studied here. This simulation-based training can be further improved by incorporating the nurses' experiences. PRACTICE IMPLICATIONS: A simulation-based assessment for resuscitation may play an important role in a PICU, and possibly for other skills and in other settings as well. Particular attention should be paid to the stress that many nurses experience due to skills assessment.

Interventions with Music in PECTus excavatum treatment (IMPECT trial): a study protocol for a randomised controlled trial investigating the clinical effects of perioperative music interventions.

INTRODUCTION: Pectus excavatum repair is associated with substantial postoperative pain, despite the use of epidural analgesia and other analgesic regimens. Perioperative recorded music interventions have been shown to alleviate pain and anxiety in adults, but evidence for children and adolescents is still lacking. This study protocol describes a randomised controlled trial that evaluates the effects of recorded music interventions on postoperative pain relief in children and adolescents after pectus excavatum repair. METHODS: A multicentre randomised controlled trial was set up comparing the effects of perioperative recorded music interventions in addition to standard care with those of standard care only in patients undergoing a Nuss procedure for pectus excavatum repair. One hundred and seventy subjects (12-18 years of age) will be included in three centres in the Netherlands. Patient inclusion has started in November 2018, and is ongoing. The primary outcome is self-reported perceived pain measured on the visual analogue scale. Secondary outcomes are anxiety level, analgesics consumption, vital parameters such as heart rate, blood pressure and respiratory rate, length of hospital stay, postoperative complications, quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: This study is being conducted in accordance with the Declaration of Helsinki. The Medical Ethics Review Board of Erasmus University Medical Centre Rotterdam, The Netherlands, has approved this protocol. Results will be disseminated via peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: NL6863.

Intralesional steroid injections to prevent refractory strictures in patients with oesophageal atresia: study protocol for an international, multicentre randomised controlled trial (STEPS-EA trial).

INTRODUCTION: Anastomotic stricture formation is the most common postoperative complication after oesophageal atresia (OA) repair. The standard of care is endoscopic dilatation. A possible adjuvant treatment is intralesional steroid injection, which is thought to inhibit scar tissue formation and thereby to prevent stricture recurrence. We hypothesise that this intervention could prevent refractory strictures and reduce the total number of dilatations needed in these children. METHODS AND ANALYSIS: This is an international multicentre randomised controlled trial. Children with OA type C (n=110) will be randomised into intralesional steroid injection followed by balloon dilatation or dilatation only. Randomisation and intervention will take place when a third dilatation is performed. The indication for dilatation will be confirmed with an oesophagram. One radiologist-blinded for randomisation-will review all oesophagrams. The primary outcome parameter is the total number of dilatations needed with <28 days' interval, which will be analysed with a linear-by-linear χ2 association test. Secondary outcome parameters include the level of dysphagia, the luminal oesophageal diameter and stricture length (measured on the oesophagrams), the influence of comedication on stricture formation, systemic effects of intralesional steroids (cortisol levels, length and weight) and the cost-effectiveness. Patients will undergo a second oesophagram; length and weight will be measured repeatedly; a scalp hair sample will be collected; and three questionnaires will be administered. The follow-up period will be 6 months, with evaluation at 2-3 weeks, 3 and 6 months after the intervention. ETHICS AND DISSEMINATION: Patients will be included after written parental informed consent. The risks and burden associated with this trial are minimal. The institutional review board of the Erasmus Medical Centre approved this protocol (MEC-2018-1586/NL65364.078.18). The results of the trial will be published in a peer-reviewed scientific journal and will be presented at international conferences. TRIAL REGISTRATION NUMBERS: 2018-002863-24 and NTR7726/NL7484.

Outpatient initiation of the ketogenic diet in children with pharmacoresistant epilepsy: An effectiveness, safety and economic perspective.

BACKGROUND: Children with pharmacoresistant epilepsy usually receive ketogenic diet (KD) as an inpatient, which makes it an expensive treatment. OBJECTIVE: To compare the effectiveness, safety, and costs of outpatient versus inpatient initiated KD. DESIGN: Retrospective observational non-inferiority study. PATIENTS/SETTING: Patients (1-18 years of age) who started KD either inpatient or outpatient. MAIN OUTCOME MEASURES: Effectiveness was defined as ≥50% seizure reduction. Safety was measured by the numbers of emergency visits and complications. Economic impact was analyzed by calculating total costs of treatment. STATISTICAL ANALYSES: Non-inferiority of outpatient initiation was tested using 95% confidence intervals of the differences in effectiveness and safety endpoints between groups with non-inferiority margins of 10%. Nonparametric bootstrap techniques were used to derive a 95% confidence interval for the mean difference in total costs between the groups. RESULTS: Hundred and five patients started KD in the period 2001 to 2017: 43 inpatient and 62 outpatient. At three months, the KD was effective in 61% of outpatients versus 63% of inpatients. The KD was considered safe in 36% of the outpatients, as compared to 29% in the inpatients. Outpatient initiation was shown to be non-inferior to inpatient initiation in terms of safety. Total health care costs of outpatient initiation were € 2901, as compared to € 8195 of inpatient initiation per patient (mean difference € 5294, 95% CI; -€ 7653 to -€ 2935). CONCLUSIONS: Our study suggests that outpatient KD initiation is no worse than inpatient initiation in terms of effectiveness and safety, while carrying lower health care costs.