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Objectives: Paediatric and adult inflammatory bowel disease (pIBD, aIBD) patients may lose response to anti-tumour necrosis factor (TNF) treatment within the first year. Adult-extrapolated weight-based dosing is incorrect in children, due to age-related pharmacokinetic differences. We investigated biomarkers for initial and maintenance of response to infliximab (IFX) or adalimumab (ADA), comparing pIBD and aIBD patients., Methods: In this prospective, observational study, pIBD (n = 24) and aIBD (n = 21) patients were included when initiating anti-TNF. Escalation from standard dosing and continued anti-TNF at 12 and 18 months were assessed. Biomarkers included clinical laboratory parameters, faecal calprotectin (FCP) and IFX trough levels (TLs). Plasma proteomics was performed in pIBD., Results: During our study, treatment escalation (in clinical loss of response) occurred more common in pIBD versus aIBD (p = 0.02). We established that IFX therapy escalation in pIBD patients was not due to low infliximab levels. We identified 9 pro-inflammatory proteins that were elevated in patients losing response., Conclusion: Anti-TNF exposure-response relationship may be different in pIBD versus aIBD. No biomarkers for maintained response were identified, but 9 inflammatory proteins were of interest as potential predictors for loss of response in pIBD., (© 2024 The Authors. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Aim: Paediatric patients with high-output ileostomies (HOI) face an elevated risk of complications. This study aimed to comprehensively review the existing literature and offer nutritional management recommendations for paediatric patients with an HOI., Methods: PubMed and Embase were searched for relevant English or French language papers up to 31 June 2022. The emphasis was placed on studies involving paediatric ileostomy patients, but insights were obtained from adult literature and other intestinal failure pathologies when these were lacking., Results: We identified 16 papers that addressed nutritional issues in paediatric ileostomy patients. Currently, no evidence supports a safe paediatric HOI threshold exceeding 20 mL/kg/day on two consecutive days. Paediatric HOI patients were at risk of dehydration, electrolyte disturbances, micronutrient deficiencies and growth failure. The primary dietary choice for neonates is bolus feeding with breastmilk. In older children, an enteral fluid restriction should be installed favouring isotonic or slightly hypotonic glucose-electrolyte solutions. A diet that is high in calories, complex carbohydrates and proteins, low in insoluble fibre and simple carbohydrates, and moderate in fat is recommended., Conclusion: Adequate nutritional management is crucial to prevent complications in children with an HOI. Further research is needed to establish more evidence-based guidelines., (© 2024 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Competing Interests: The authors declare that they have no conflict of interest

Aims: Lisinopril, an angiotensin-converting enzyme inhibitor, is a frequently prescribed antihypertensive drug in the paediatric population, while being used off-label under the age of 6 years in the USA and for all paediatric patients globally. The SAFEPEDRUG project (IWT-130033) investigated lisinopril pharmacokinetics in hypertensive paediatric patients corresponding with the day-to-day clinical population., Methods: The dose-escalation pilot study included 13 children with primary and secondary hypertension who received oral lisinopril once daily in the morning; doses ranged from 0.05 to 0.2 mg kg -1 . Patients were aged between 1.9 and 17.9 years (median 13.5 years) and weight ranged between 9.62 and 97.2 kg (median 53.2 kg). All data were analysed using Monolix version 2020R1 (Lixoft, France) and R version 3.6.2., Results: A 1-compartment model with first-order absorption and first-order elimination optimally describes the data. Parameter estimates of absorption rate constant (0.075 h -1 [0.062, 0.088], typical value [95% confidence interval]), volume of distribution (31.38 L 70 kg -1 [10.5, 52.3]) and elimination clearance (24.2 L h -1 70 kg -1 [19.5, 28.9]) show good predictive ability. Significant covariate effects include total body weight on elimination clearance, and distribution volume and estimated glomerular filtration rate (eGFR) on elimination clearance. The effects of eGFR on the elimination clearance are optimally described by a linear effect centred around 105 mL min -1  1.73 m -2 . The effects of body weight were implemented using fixed allometric exponents centred around an adult weight of 70 kg., Conclusion: Lisinopril dose and regimen adjustments for paediatric patients should include eGFR on top of weight adjustments. An expanded model characterizing the pharmacodynamic effect is required to identify the optimal dose and dosing regimen., (© 2023 British Pharmacological Society.)

Competing Interests: Declaration if interests We declare no competing interests.

Objective: To study the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of desmopressin (dDAVP) oral lyophilisate in children below the age of 8 years with special emphasis on age-related and size-related differences in bioavailability., Design: Open label, non-randomised, interventional PK and PD trial., Setting: Single-centre study., Patients: Children (age: 6 months to 8 years) with nocturnal polyuria, including both children with uropathy or nephropathy (glomerular filtration rate >60 mL/min/1.73 m²) and children (age: 5-8 years) with severe monosymptomatic nocturnal enuresis, who were unresponsive to treatment with 400 µg of the dDAVP tablet for at least 1 month., Interventions: After a water load, dDAVP was administered sublingually as a single dose of oral lyophilisate. Subsequently, blood and urine samples were collected until 7 hours post-administration., Main Outcome Measures: Non-compartmental analysis of PK parameters was performed based on dDAVP concentrations in both plasma and urine. To evaluate the effect of dDAVP lyophilisate (PD parameters), the urinary concentration capacity (urine osmolality (mOsm/kg)) and antidiuretic effect (diuresis rate (mL/kg/h)) were calculated., Results: The PK data support the need for size-dependent dosing in children. Body weight was shown to be a significant covariate for apparent clearance (CL/F) and apparent volume of distribution (V d /F). A double absorption peak of dDAVP lyophilisate in the first 2 hours post-administration was demonstrated., Conclusions: For the first time, a double absorption profile of dDAVP lyophilisate was found in children, questioning extrapolation of bioequivalence from adults towards children. Moreover, the need for size-adapted dosing regimens of dDAVP lyophilisate in young children is indicated., Trial Registration Number: NTC02584231., Competing Interests: Competing interests: LD, CVH, EG and PDB received a travel reimbursement from Ferring Pharmaceuticals for a presentation at the Ghent-Aarhus Springschool. SR and JvdW received consulting fees and travel reimbursements from Ferring Pharmaceuticals. AV is an employee of Johnson & Johnson and holds stock/stock options from J&J. RM has no potential conflicts of interest that might be relevant to this manuscript., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Medical devices (MedDevs) and medicines are assessed (and monitored) differently before and after launch. There are products for repeated oral ingestion that are marketed in the European Union as MedDevs., Objectives and Methods: To illustrate the consequences of these differences in assessment, we compared the leaflet information of three MedDevs with the standards for medicines and with published evidence at launch. As examples, gelatin tannate (GT), its combination with tyndalised probiotics (TP) (GTTP) for diarrhoea and a gel containing hyaluronic acid (HA)/chondroitin sulfate (CS)/poloxamer (Pol407) (HACSPol) for gastro-oesophageal reflux disease were examined., Results: Applying standards for medicines, product composition is insufficiently defined in the MedDev leaflet (eg, plant origin, polymerisation grade, dose and ratio of the relevant constituents). As no age limit is mentioned in the leaflets, all 3 products allow use in children from birth onwards, although published clinical documentation in children was poor (GT) or lacking (GTTP and HACSPol). MedDev leaflets do not mention adverse events (AEs), while literature search suggests safety concerns such as tannic acid (TA) cytotoxicity, potentially more diarrhoea/AEs with TP, use of doses higher than established safe (TA and HA) and lack of chronic toxicity studies for oral Pol407. None refers to interactions with medicines, although some ingredients may affect medicine absorption., Conclusion: Although these MedDevs require repeated oral intake as do medicines, their assessment and monitoring differ significantly from the standards for medicines. Compared with medicines, MedDevs for repeated oral use are poorly labelled and rely on very limited clinical information at market release., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The bioequivalence of two formulations of desmopressin (dDAVP), a vasopressin analogue prescribed for nocturnal enuresis treatment in children, has been previously confirmed in adults but not in children. In this study, we aimed to study the pharmacokinetics (PK) and pharmacodynamics (PD) of these two formulations, in both fasted and fed children, including patients younger than 6 years of age., Methods: Previously published data from one PK study and one PK/PD study in children aged between 6 and 16 years were combined with a new PK/PD study in children aged between 6 months and 8 years, and analysed using population PK/PD modelling. Simulations were performed to further explore the relative bioavailability of both formulations and evaluate current dosing strategies., Results: The complex absorption behaviour of the lyophilizate was modelled using a double input, linked to a one-compartmental model with linear elimination and an indirect response model linking dDAVP concentration to produced urine volume and osmolality. The final model described the observed data well and elucidated the complexity of bioequivalence and therapeutic equivalence of the two formulations. Simulations showed that current dosing regimens using a fixed dose of lyophilizate 120 μg is not adequate for children, assuming children to be in the fed state when taking dDAVP. A new age- and weight-based dosing regimen was suggested and was shown to lead to improved, better tailored effects., Conclusions: Bioequivalence and therapeutic equivalence data of two formulations of the same drug in adults cannot be readily extrapolated to children. This study shows the importance of well-designed paediatric clinical trials and how they can be analysed using mixed-effects modelling to make clinically relevant inferences. A follow-up clinical trial testing the proposed dDAVP dosing regimen should be performed., Clinical Trial Registration: This trial has been registered at www.clinicaltrials.gov (identifier NCT02584231; EudraCT 2014-005200-13).

As children are unable to make health-related decisions themselves, parents play a central role in consultations with healthcare providers. Parents' perspectives are therefore the focus of this study. Our first aim was to determine parents' expectations of a healthcare visit with a general practitioner and a community pharmacist. The second aim was to determine the general practitioners' and community pharmacists' perspectives about consultations with children. An observational cross-sectional study was conducted in April and May 2018. We developed three questionnaires: one for parents, one for general practitioners, and one for community pharmacists. The questionnaire for parents was only available through an online platform. The healthcare providers were questioned face-to-face and through an online platform. The study included 380 respondents. Parents considered prescribing or proposing medication the least important action by a general practitioner or community pharmacist, respectively. As well, parents expect information in most cases from both healthcare providers. The questionnaire for general practitioners and community pharmacists revealed that prescribing or proposing medication was regarded the least important action.Conclusion: Considering parents' expectations for a consultation with a general practitioner or community pharmacist, there is a substantial resemblance with the healthcare providers' perspective.What is Known:• The previous studies focusing on parents' perspectives were carried out in a hospital setting or focused on a specific disorder.• Parents consider reassurance and advice from their general practitioner to be very important; the treatment is considered less important.What is New:• Parents considered for both general practitioners' and community pharmacists' verbal information, answers to their questions, and reassurance as more important than receiving pharmacological treatment, while general practitioners and community pharmacists consider prescribing/proposing medication and providing written information as less important.• The expectations of the different groups (parents in relation to not only the healthcare providers but also the general practitioners and community pharmacists compared to each other) know a great resemblance.

Background: Apical dissection in robot-assisted radical prostatectomy (RARP) affects not only cancer control, but also continence recovery., Objective: To describe a novel approach for apical dissection, the collar technique, to reduce apical positive surgical margins (PSMs)., Design, Setting, and Participants: A total of 189 consecutive patients (81 in the control group, 108 in the collar technique group) underwent RARP at a single center., Primary Outcome: rates of apical PSMs; secondary outcome: urinary continence., Intervention: The urethral sphincter complex is incised 2-3mm distally to the apex, to stay farther from it and reduce PSMs; the underlying smooth muscle is exposed and incised closer to the apex to preserve the maximal length of the lissosphincter., Outcome Measurements and Statistical Analysis: Mann-Whitney U and chi-square tests compared median and proportions between the two groups, respectively. Univariate logistic regression tested the association between technique employed and risk of apical PSMs., Results and Limitations: Fourteen patients (7.4%) revealed apical PSMs (9.9% in the control group, 5.6% in the collar group; p=0.7). When the collar technique was used, significantly lower rates of apical PSMs occurred in pT2 disease (0% vs 7.1%; p=0.03). In case of apical tumor at preoperative magnetic resonance imaging (MRI; n=43), the collar technique determined significantly lower overall (9.7% vs 42%) and apical (3.2% vs 42%) PSMs (all p≤0.02). Continence recovery in the collar and control groups was similar. When preoperative MRI showed an apical tumor, the collar technique had a significantly lower risk of apical PSMs (odds ratio: 0.05, p=0.009)., Conclusions: The collar technique reduces the rates of apical PSMs in case of apical tumor, preserving the length of the lissosphincter., Patient Summary: We describe a novel approach for apical dissection during robot-assisted radical prostatectomy. Our technique reduces the rates of apical surgical margins in case of apical tumor at preoperative magnetic resonance imaging and leads to optimal continence recovery., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

There is a general consensus about the underlying theoretical ethical principles that ground the practice of pediatric clinical trials: scientific necessity, good risk/benefit ratio, minimized burden, and parental consent/child assent. However, these principles are so broadly construed that it is not always clear how they should be applied in clinical practice. We conducted a qualitative study at Ghent University Hospital and the hospital of the Dutch-speaking university of Brussels on how researchers weigh ethical principles, assess the risk/benefit balance, estimate patient experience, and experience informed consent procedures in pediatric drug studies. Based on our assessment of the burden and risk versus benefit ratio in 62 pediatric drug research protocols, we selected 21 studies for further study to maximize diversity. Twenty-seven researchers (17 physicians, 10 study nurses) completed a qualitative survey about their study. We compared their responses to our assessments. The risk benefit assessment of our participants about their own research projects resembled our assessment almost perfectly. Assessing burden appeared to be more subjective. The researchers were confident in their ability to obtain valid consent. However, we question whether this confidence is warranted., Conclusion: We argue for constant ethical reflexivity in pediatric clinical trials, because broad ethical principles are not always easy to apply to specific situations. What is Known: • Several international guidelines and a large body of scientific literature indicate a broad consensus about the basic ethical framework for pediatric clinical trials, based on risk benefit assessment and respect for autonomy. • Little is known about how researchers implement these broad principles in practice. What is New: • Researchers' risk/benefit assessments about their own studies resembled the assessment of neutral peers, assessing burden was more subjective. • Researchers were very confident in their ability to obtain valid informed consent.

Background: Fluoroquinolones (FQ) are increasingly prescribed for children, despite being labeled for only a limited number of labeled pediatric indications. In this multicenter retrospective drug utilization study, we analyzed indications for systemic FQ prescriptions in hospitalized children and the appropriateness of the prescribed dose., Methods: Using data obtained from electronic medical files, the study included all children who received a systemic FQ prescription in two Belgian university children's hospitals between 2010 and 2013. Two authors reviewed prescribed daily doses. Univariate and multivariate logistic regression models were used to analyze risk factors for inadequately dosing. Results262 FQ prescriptions for individual patients were included for analysis. 16.8% of these prescriptions were for labeled indications, and 35.1% were guided by bacteriological findings. Prescribed daily dose was considered to be inappropriate in 79 prescriptions (30.2%). Other FQ than ciprofloxacin accounted for 9 prescriptions (3.4%), of which 8 were correctly dosed. Underdosing represented 45 (56.9%) dosing errors. Infants and preschool children were at particular risk for dosing errors, with associated adjusted OR of 0.263 (0.097-0.701) and 0.254 (0.106-0.588) respectively., Conclusions: FQ were often prescribed off-label and not guided by bacteriological findings in our study population. Dosing errors were common, particularly in infants and preschool children. FQ prescriptions for children should be improved by specific pediatric antimicrobial stewardship teams. Furthermore, pharmacokinetic studies should optimise dosing recommendations for children.

Desmopressin is used to treat primary nocturnal enuresis in children. Over the years, various formulations of desmopressin were commercialized of which the sublingual melt tablet is preferred in the pediatric population, despite the lack of full PK studies in this population. A full PK study was performed in growing conventional piglets to evaluate if this juvenile animal model can provide supplementary information to complement the information gap in the pediatric population. A desmopressin sublingual melt tablet (120 μg) was administered to 32 male piglets aged 8 days, 4 weeks, 7 weeks, and 6 months (each group n = 8). Population PK (pop-PK) analysis was performed to derive the PK parameters, the between- and within-subject variabilities and the effects of covariates. Desmopressin demonstrated two-compartmental PK, with a dual, sequential absorption process, and linear elimination. Body weight was the only significant covariate on clearance and on apparent volume of distribution of the central compartment. In human pediatric trials, no double peak in the absorption phase was observed in the plasma concentration-time curves, possibly due to the sparse sampling strategy applied in those pediatric studies. Therefore, it is recommended to perform additional studies, based on the sampling protocol applied in the current study.

Proton pump inhibitor (PPI) use is becoming increasingly common. Although the toxicity profiles of PPIs are not well understood particularly in children, PPIs have been associated with increased risks of gastrointestinal and respiratory tract infection, vitamin B 12 deficiency, hypomagnesaemia, bone fractures, and rebound hyperacidity after discontinuation. Prescribers should take into account that PPI uses pose toxicity risks, which remain to be fully characterised in infants and children., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

We present a 4-year-old girl with delayed neuromotor development, short stature of prenatal onset, and specific behavioral and craniofacial features harboring an intragenic deletion in the ARID2 gene. The phenotype confirmed the major features of the recently described ARID2-related intellectual disability syndrome. However, our patient showed overlapping features with Nicolaides-Baraitser syndrome and Coffin-Siris syndrome, providing further arguments to reclassify these disorders as "SWI/SNF-related intellectual disability syndromes.", (© 2017 Wiley Periodicals, Inc.)

Purpose: Since 1997, strong incentives have been introduced worldwide to improve access to safe and effective medicines addressing the therapeutic needs of children. ACE inhibitors, the most prescribed antihypertensive drugs in the paediatric population, are one of the prototype drugs targeted by the legislation initiatives. Our purpose in assembling this review is to evaluate and describe the current evidence for the efficacy and safety profile of ACE inhibitors in the paediatric population., Methods: The authors made a descriptive review of the literature from 1980 to 2015 using the following search terms: hypertension, child, paediatric, ACE (inhibitors), renin-angiotensin aldosterone system, captopril, lisinopril, enalapril, ramipril and fosinopril., Results: A total of 16 studies evaluating efficacy and safety of ACE inhibitors were included in this review. The included studies demonstrate that ACE inhibitors have the potency to decrease the systolic and/or diastolic blood pressure with an overall favourable safety profile in a short-term period. More importantly, the incentives resulted in an improvement of the overall availability of paediatric labelling, dosing and safety information for ACE inhibitors. However, they failed to fulfil several of paediatric needs: absence of long-term safety data on growth and maturation, absence of commercially available child-friendly formulations and incomplete evaluation of the entire paediatric hypertension population., Conclusion: Additional efforts are needed to close the gap between the availability of drugs that are labelled and indicated for paediatric use and the actual drug usage in children, especially in young children, neonates and children with severe hypertension, renal transplantation or severe renal impairment., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background and Aims: During the last decades, much attention has been paid to off-label and unlicensed prescriptions in paediatrics. However, on-label prescribing can also cause health issues. In this paper, the case of first-generation H 1 -antihistamines is investigated, notably the range of indications for which products are licensed in different European countries and the evidence base (or lack thereof) for each indication, as well as reported adverse drug reactions., Methods: Review of the Summary of Product Characteristics of first-generation H 1 -antihistamines with a focus on paediatric use. This is plotted against the evidence available in the literature., Results: This investigation shows a large variability in labelled indications and licensing ages when compared in five different European countries. Moreover, most of the indications are not based on clinical trials evaluating efficacy and safety of these drugs in children., Conclusions: Many of the licensed indications of first-generation antihistamines do not appear to be evidence based., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Introduction: Desmopressin is used for treatment of nocturnal enuresis in children. In this study, we investigated the pharmacokinetics of two formulations-a tablet and a lyophilisate-in both fasted and fed children., Methods: Previously published data from two studies (one in 22 children aged 6-16 years, and the other in 25 children aged 6-13 years) were analyzed using population pharmacokinetic modeling. A one-compartment model with first-order absorption was fitted to the data. Covariates were selected using a forward selection procedure. The final model was evaluated, and sensitivity analysis was performed to improve future sampling designs. Simulations were subsequently performed to further explore the relative bioavailability of both formulations and the food effect., Results: The final model described the plasma desmopressin concentrations adequately. The formulation and the fed state were included as covariates on the relative bioavailability. The lyophilisate was, on average, 32.1 % more available than the tablet, and fasted children exhibited an average increase in the relative bioavailability of 101 % in comparison with fed children. Body weight was included as a covariate on distribution volume, using a power function with an exponent of 0.402. Simulations suggested that both the formulation and the food effect were clinically relevant., Conclusion: Bioequivalence data on two formulations of the same drug in adults cannot be readily extrapolated to children. This was the first study in children suggesting that the two desmopressin formulations are not bioequivalent in children at the currently approved dose levels. Furthermore, the effect of food intake was found to be clinically relevant. Sampling times for a future study were suggested. This sampling design should result in more informative data and consequently generate a more robust model.

Purpose: Although nocturnal polyuria in patients with monosymptomatic enuresis can largely be explained by the decreased nocturnal vasopressin secretion hypothesis, other circadian rhythms in the kidney also seem to have a role. We recently documented an absent day/night rhythm in a subgroup of desmopressin refractory cases. We explore the importance of abnormal circadian rhythm of glomerular filtration and tubular (sodium, potassium) parameters in patients with monosymptomatic enuresis., Materials and Methods: In this retrospective study of a tertiary enuresis population we collected data subsequent to a standardized screening (International Children's Continence Society questionnaire), 14-day diary for nocturnal enuresis and diuresis, and 24-hour concentration profile. The study population consisted of 139 children with nocturnal enuresis who were 5 years or older. Children with nonmonosymptomatic nocturnal enuresis were used as controls., Results: There was a maintained circadian rhythm of glomerular filtration, sodium, osmotic excretion and diuresis rate in children with monosymptomatic and nonmonosymptomatic nocturnal enuresis, and there was no difference between the 2 groups. Secondary analysis revealed that in patients with nocturnal polyuria (with monosymptomatic or nonmonosymptomatic nocturnal enuresis) circadian rhythm of glomerular filtration, sodium and osmotic excretion, and diuresis rate was diminished in contrast to those without nocturnal polyuria (p <0.001)., Conclusions: Circadian rhythm of the kidney does not differ between patients with nonmonosymptomatic and monosymptomatic enuresis. However, the subgroup with enuresis and nocturnal polyuria has a diminished circadian rhythm of nocturnal diuresis, sodium excretion and glomerular filtration in contrast to children without nocturnal polyuria. This observation cannot be explained by the vasopressin theory alone., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Pediatric drug research is still substandard, not reaching the same quality level as adult drug research. Despite the efforts made by the Food and Drug Administration and European Medicines Agency to reduce off-label use in children, the lack of clinical studies involving the pediatric population still stands. Pharmacokinetic and pharmacodynamics studies (PK/PD) taking growth and maturation into account are necessary to rationalize dosing strategies in children. Currently, traditional animal models such as rats, mice, dogs and primates are used to conduct pharmacokinetic and pharmacodynamic studies, however age-related trials are rather uncommon. Moreover, these species have several shortcomings as animal models, such as a different physiology and anatomy of the gastrointestinal tract in dogs or the ethical aspects for the use of primates. In contrast, piglets might be potential biomedical pediatric animal models because of the good resemblance with humans, anatomically, physiologically and biochemically. This review summarizes the comparative anatomy and physiology and postnatal development of piglets and infants, focusing on six major topics, namely growth, cardiovascular system, gastrointestinal tract, liver, kidney and integument. Furthermore, the application of piglets as animal model in pediatric PK/PD research is discussed.

The evidence for organic pathogenetic factors in enuresis and the discovery of effective therapies targeting the bladder and/or nocturnal diuresis have overwhelmed every potential role of psychological factors in pathogenesis and treatment. However, psychopathology is still important in enuresis because according to the document of the International Children's Continence Society (ICCS) 20-30% of the children with enuresis have at least one psychological/psychiatric disorder at rates two times higher than non-wetting children. The most common comorbid disorder with enuresis is attention deficit hyperactivity disorder. The aim of this review is to translate the existing evidence on the importance of a psychological screening into daily clinical practice of the medical practitioner. The use of the minimal psychological screening tool should be considered mandatory in each primary setting. If psychological problems are indicated, referral of the patient to a multidisciplinary setting should be considered, not only to allow psychological assessment to screen for a possible psychopathology, but also since therapy resistance might be expected. This review concentrates on two items from psychopathology/psychotherapy that might predict insufficient treatment response: the psychological comorbidities as described according to the DSM-5 criteria and the underestimated importance of therapy adherence. Adherence is a cornerstone of effective therapy in enuresis. It is a problem involving the doctor, the patient, and the parents. Increasing adherence takes effort and is time-consuming. But it is worthwhile knowing that several studies have demonstrated that high adherence is associated with high therapy success of enuresis. Eventually, this is the ultimate goal of treatment., (Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Port-site metastasis of prostatic adenocarcinoma is rare and usually associated with poor prognosis. We report a case of a young man with a rising prostate-specific antigen (PSA) 4.5 years after robot-assisted laparoscopic prostatectomy (RALP) and extended pelvic lymphadenectomy (ePLND) for a Gleason 7 (4+3) prostate cancer (pT3b pN0 cM0). Choline positron emission tomography-computed tomography (PET-CT) demonstrated a PET positive subcutaneous recurrence in a previous trocar site accompanied by a PET positive ipsilateral inguinal lymph node. Excision of both lesions was performed, confirming the diagnosis of metastatic prostate cancer. The patient's PSA dropped significantly postoperatively enabling postponement of androgen deprivation treatment up to this date. The etiology of port-site metastasis is multifactorial, including patient and surgery related factors. Such metastases have been scarcely reported following ePLND with or without RALP. Certain surgical precautions can be made to prevent the occurrence. We summarize previously reported mechanisms of development and possible precautionary measures.

Dissection of the subclavian artery usually occurs as a result of trauma, endovascular interventions or connective tissue disorders. Only rarely has it been described occurring spontaneously. The treatment can be endovascular, open surgery, conservative or a combination of the above. There are no guidelines. The best approach is the one tailored to the lesion itself. This case presents a 73-year-old man with a tiresome and heavy feeling in the right arm. He was diagnosed having a spontaneous dissection of the right subclavian artery, accompanied by a complete occlusion more distally. Because of the relatively minor symptoms he was treated conservatively using anticoagulants. After 6 months of treatment there was complete revascularisation with good pulsations at the right wrist.

Dissection of the subclavian artery usually occurs as a result of trauma, endovascular interventions or connective tissue disorders. Only rarely has it been described occurring spontaneously. The treatment can be endovascular, open surgery, conservative or a combination of the above. There are no guidelines. The best approach is the one tailored to the lesion itself. This case presents a 73-year-old man with a tiresome and heavy feeling in the right arm. He was diagnosed having a spontaneous dissection of the right subclavian artery, accompanied by a complete occlusion more distally. Because of the relatively minor symptoms he was treated conservatively using anticoagulants. After 6 months of treatment there was complete revascularisation with good pulsations at the right wrist., (Copyright© Acta Chirurgica Belgica.)

Introduction: This pre-specified sub-study of the desmopressin response in primary nocturnal enuresis study (DRIP study) evaluates the safety profile of the oral desmopressin tablet in children with primary nocturnal enuresis. Endpoints are adverse events and change in body mass index., Methods: The DRIP study was an open-label, intention-to-treat, phase IV, multi-national study. Overall, 936 patients were screened and 744 children aged 5-15 years with previously untreated primary nocturnal enuresis were eligible to receive the study medication desmopressin once daily as an oral tablet formulation. At each visit, adverse events were questioned and observed signs or symptoms were recorded., Results: Overall, 222 (30%) patients experienced 404 treatment-emergent adverse events. The proportion of patients experiencing treatment-emergent adverse events was similar regardless of patient gender or age. Most treatment-emergent adverse events were experienced in three system organ classes: gastrointestinal disorders; infections and infestations; and respiratory, thoracic and mediastinal disorders and were considered unrelated to the study drug. There was a slight increase in body mass index from screening levels during the study, however, clinically not significant., Conclusion: Desmopressin tablet treatment is well tolerated in children with primary nocturnal enuresis, regardless of patient gender or age., Funding: The desmopressin response in primary nocturnal enuresis study (DRIP- study) was funded by Ferring.

Objective: The aim of this study was to examine the trend in the prescribing of proton pump inhibitors (PPIs) and histamine 2-receptor antagonists (H2-RAs) for children in Belgium from 1997 to 2009 to encourage discussion regarding appropriate clinical use., Methods: Monthly claim-based data for PPIs and H2-RAs were obtained from the national health insurance database (Pharmanet 1997-2009)., Results: The total monthly volume of all reimbursed antireflux medications, prescribed by Belgian pediatricians, increased 7-fold from 20,782 daily defined doses (DDDs) in January 1997 to 142,912 DDDs in June 2009. During this study period, reimbursed volume of H2-RAs increased from 2575 to 38,996 DDDs and of PPIs from 3472 to 103,926 DDDs per month., Conclusions: PPI use has increased substantially in children. Its use does not seem to be commensurate with the prevalence of gastroesophageal reflux disease in children. This study encourages clinical discussion regarding well-considered use of these drugs in children.

Desmopressin 120 μg oral lyophilisate and 200 μg tablet are considered bioequivalent, based on extrapolation of studies in a limited number of adults and on one dose-finding study of desmopressin oral lyophilisate in children. However, no comparative pharmacokinetic study in children was executed confirming this statement. No data are available on the influence of food intake on the bioavailability of desmopressin tablet in a pediatric setting, although studies in adults have documented that food intake results in a significantly lower desmopressin plasma concentration. In this study, we analyzed plasma concentrations of desmopressin oral lyophilisate and tablet with concomitant food intake. Twenty-three children with monosymptomatic nocturnal enuresis (mean age, 12.7 years) were recruited. Two tests were performed on two separate days in identical conditions with a standardized food and fluid intake. Desmopressin was administered as desmopressin tablet or desmopressin oral lyophilisate immediately after a meal. Desmopressin plasma concentration was measured at 1 h, 2 h, and 6 h postdosing. No significant difference in plasma concentration of 120 μg desmopressin oral lyophilisate and 200 μg tablet was demonstrated, even with concomitant food intake. A significant difference in variability was found, identifying a smaller variance for desmopressin oral lyophilisate plasma concentrations at all time points. This study demonstrates comparable plasma levels for desmopressin oral lyophilisate, despite the lower dose. The dosage for desmopressin oral lyophilisate is more predictable due to the significantly smaller variance. Therefore, desmopressin oral lyophilisate seems more suitable, especially in the younger age group for which time interval between dinner and drug administration is limited.

Unlabelled: Primary nocturnal enuresis is a prevalent childhood condition that can persist into adulthood. Desmopressin is an antidiuretic available as orally disintegrating lyophilisate (melt) or solid tablet. Recent findings suggesting different food interactions and clinical characteristics, including compliance, between desmopressin melt and tablet motivated a post hoc analysis of a previously reported randomised, crossover study. The efficacy of desmopressin melt compared with tablet was evaluated using the International Children's Continence Society (ICCS) responder definitions. Compliance was further analysed using detailed criteria, and the association between efficacy and compliance was examined. In total, 221 patients aged 5-15 years, already receiving desmopressin tablets were randomised to the treatment sequence melt (120/240 μg)/tablet (0.2/0.4 mg) or tablet/melt in two consecutive 3-week periods. The probability of being a responder (partial or full) during either period was significantly more likely with desmopressin melt compared with tablet (odds ratio, 2.0; confidence intervals, 1.07-3.73; p = 0.03). There was no period effect on compliance in the tablet/melt sequence and no difference in the number of completely compliant patients in each formulation group; however, more patients were >75 % compliant in period 1 compared with period 2 in the melt/tablet sequence. Increased compliance was associated with greater reductions in the number of wet nights for both formulations., Conclusions: Desmopressin melt, compared with tablet, improves the probability of being a responder. Switching from tablet to melt formulation increased patient compliance. Increased compliance was associated with increased efficacy. Switching to desmopressin melt may benefit patients with suboptimal responses to desmopressin tablet.