Unlicensed and off-label drug use in children

Many commercially available drugs are only licensed for use in adults and for many drugs the available formulations are unsuitable for pediatric use.' This reality leads to use of drugs which are unlicensed or off -label for use in children. There are several reasons for this highly unsatisfactory situation. Firstly, children represent only a small market in an absolute sense but also relatively as most children are healthy. Hence, from a commercial perspective it may not be profitable to invest in pediatric drug research. Secondly, fear is growing for unforeseen adverse effects and long-term toxicity which may be difficult to study. Therefore, the current requirements for licensing of a drug may have become a barrier to make proper drugs available to a vulnerable group of patients. Thirdly, there are ethical problems to conduct drug studies in children. In Europe the problems in pediatric drug use and research receive relatively little interest and there is a substantial Jack of funding of pediatric drug research. N. a result, pediatric drug trials are relatively scarce and often include only a limited number of patients. Despite the well-known thalidomide disaster, which happened already forty years ago and caused an epidemic of congenital malformations, very little has changed regarding the labeling of drugs in infants and children. Although the disaster has stimulated legislation of drug licensing, children ironically remain 'therapeutic orphans'. This is difficult to accept because many diseases in adults can also occur in children while pharmacokinetics and pharmacodynamics often differ. Prescription of drugs should be proven to be equally safe in children as in adnlts, and efficacy of the product should be thoroughly assessed for all probable users. Exposure of infants and children to drugs which are not proven to be safe and efficacious during growth and development, cannot always be prevented. Hence, the health implications of this 'therapeutic orphanhood' may be larger than is sometimes assumed. The scope of this thesis was to assess the extent of the problem of unlicensed and offlabel drug use in children both in clinical care as well as in general practice. Although it is just a first step on a lengthy road, we hope that results of our studies may revive awareness of the problem and stimulate adequate regulatory actions

Unlicensed and off-label prescription of respiratory drugs to children

Many respiratory drugs are not available in formulations suitable for infants and toddlers. Efficacy and safety research is mostly restricted to older children. However, respiratory drugs are frequently used in children for common diseases like asthma, upper and lower respiratory tract infections, rhinitis and sinusitis. The unlicensed and off-label use of respiratory drugs in children were studied. A population-based cohor

Compressive 3D ultrasound imaging using a single sensor

Three-dimensional ultrasound is a powerful imaging technique, but it requires thousands of sensors and complex hardware. Very recently, the discovery of compressive sensing has shown that the signal structure can be exploited to reduce the burden posed by traditional sensing requirements. In this spirit, we have designed a simple ultrasound imaging device that can perform three-dimensional imaging using just a single ultrasound sensor. Our device makes a compressed measurement of the spatial ultrasound field using a plastic aperture mask placed in front of the ultrasound sensor. The aperture mask ensures that every pixel in the image is uniquely identifiable in the compressed measurement. We demonstrate that this device can successfully image two structured objects placed in water. The need for just one sensor instead of thousands paves the way for cheaper, faster, simpler, and smaller sensing devices and possible new clinical applications

Adverse drug reactions in a primary care population prescribed non-steroidal anti-inflammatory drugs

Objective. To determine how often patients with musculoskeletal (MSK) complaints prescribed a non-steroidal anti-inflammatory drug (NSAID) subsequently consult their general practitioner (GP) with a non-serious adverse drug reaction (ADR). Design. Cohort study. Setting. A healthcare database containing the electronic GP medical records of over 1.5 million patients throughout the Netherlands. Patients. A total of 16 626 adult patients with MSK complaints prescribed an NSAID. Main outcome measures. The patients' medical records were manually assessed for the duration of NSAID use for a maximum of two months, and consultations for complaints predefined as potential ADRs were identified. Subsequently, the likelihood of an association with the NSAID use was assessed and these potential ADRs were categorized as likely, possible, or unlikely ADRs. Results. In total, 961 patients (6%) consulted their GP with 1227 non-serious potential ADRs. In 174 patients (1%) at least one of these was categorized as a likely ADR, and in a further 408 patients (2.5%) at least one was categorized as a possible ADR. Dyspepsia was the most frequent likely ADR, followed by diarrhoea and dyspnoea (respectively 34%, 8%, and 8% of all likely ADRs). Conclusion. Of the patients with MSK complaints prescribed an NSAID, almost one in 30 patients re-consulted their GP with a complaint likely or possibly associated with the use of this drug. The burden of such consultations for non-serious ADRs should be taken into account by GPs when deciding whether treatment with an NSAID is appropriate

Antibiotic-Induced Liver Injury in Paediatric Outpatients: A Case-Control Study in Primary Care Databases

Introduction: Antibiotics are the most commonly prescribed drug class in children. Real-world data mining on the paediatric population showed potential associations between antibiotic use and acute liver injury. Objective: We assessed risk estimates of liver injury associated with antibiotic use in children and adolescent outpatients. Methods: A large, multi-database, population-based, case-control study was performed in people <18 years of age from two European countries (Italy and The Netherlands) during the period 2000–2008. All potential cases of liver injury were automatically extracted from three databases and then manually validated based on Council for International Organizations of Medical Sciences (CIOMS) criteria and by exclusion of all competing causes for liver injury. Up to 100 control participants were sampled for each case and were matched on index date of the event, age, sex and database. Based on prescription data, antibiotic exposure was categorized as current, recent or past use by calculating the time period between the end of prescription and the index date. Multivariate conditional logistic regression analyses were applied to calculate odds ratios (ORs) as a measure of the association (with 95% confidence interval [CI]). Results: We identified 938 cases of liver injury and matched to 93,665 controls. Current use of overall antibiotics is associated with a threefold increased risk of liver injury compared with past use (adjusted OR [ORadj] 3.22, 95% CI 2.57–4.03). With regard to individual antibiotics, the risk is significantly increased for current use of each antibiotic (p < 0.005), except for azithromycin. Risk estimates vary from the lowest ORadj of 1.86 (95% CI 1.08–3.21) for amoxicillin to the highest ORadj of 24.16 (95% CI 11.78–49.54) for cotrimoxazole (i.e. sulphamethoxa

Delineating morbillivirus entry, dissemination and airborne transmission by studying in vivo competition of multicolor canine distemper viruses in ferrets

Identification of cellular receptors and characterization of viral tropism in animal models have vastly improved our understanding of morbillivirus pathogenesis. However, specific aspects of viral entry, dissemination and transmission remain difficult to recapitulate in animal models. Here, we used three virologically identical but phenotypically

Micro-costing diagnostics in oncology:from single-gene testing to whole- genome sequencing

Purpose: Predictive diagnostics play an increasingly important role in personalized medicine for cancer treatment. Whole-genome sequencing (WGS)-based treatment selection is expected to rapidly increase worldwide. This study aimed to calculate and compare the total cost of currently used diagnostic techniques and of WGS in treatment of non-small cell lung carcinoma (NSCLC), melanoma, colorectal cancer (CRC), and gastrointestinal stromal tumor (GIST) in the Netherlands. Methods: The activity-based costing (ABC) method was conducted to calculate total cost of included diagnostic techniques based on data provided by Dutch pathology laboratories and the Dutch-centralized cancer WGS facility. Costs were allocated to four categories: capital costs, maintenance costs, software costs, and operational costs. Results: The total cost per cancer patient per technique varied from € 58 (Sanger sequencing, three amplicons) to € 2925 (paired tumor-normal WGS). The operational costs accounted for the vast majority (over 90%) of the total per cancer patient technique costs. Conclusion: This study outlined in detail all costing aspects and cost prices of current and new diagnostic modalities used in treatment of NSCLC, melanoma, CRC, and GIST in the Netherlands. Detailed cost differences and value comparisons between these diagnostic techniques enable future economic evaluations to support decision-making

An interdisciplinary multimodal integrative healthcare program for depressive and anxiety disorders

ObjectiveAlthough multimodal interventions are recommended in patients with severe depressive and/or anxiety disorders, available evidence is scarce. Therefore, the current study evaluates the effectiveness of an outpatient secondary care interdisciplinary multimodal integrative healthcare program, delivered within a transdiagnostic framework, for patients with (comorbid) depressive and/or anxiety disorders.MethodsParticipants were 3,900 patients diagnosed with a depressive and/or anxiety disorder. The primary outcome was Health-Related Quality of Life (HRQoL) measured with the Research and Development-36 (RAND-36). Secondary outcomes included: (1) current psychological and physical symptoms measured with the Brief Symptom Inventory (BSI) and (2) symptoms of depression, anxiety, and stress measured with the Depression Anxiety Stress Scale (DASS). The healthcare program consisted of two active treatment phases: main 20-week program and a subsequent continuation-phase intervention (i.e., 12-month relapse prevention program). Mixed linear models were used to examine the effects of the healthcare program on primary/secondary outcomes over four time points: before start 20-week program (T0), halfway 20-week program (T1), end of 20-week program (T2) and end of 12-month relapse prevention program (T3).ResultsResults showed significant improvements from T0 to T2 for the primary variable (i.e., RAND-36) and secondary variables (i.e., BSI/DASS). During the 12-month relapse prevention program, further significant improvements were mainly observed for secondary variables (i.e., BSI/DASS) and to a lesser extent for the primary variable (i.e., RAND-36). At the end of the relapse prevention program (i.e., T3), 63% of patients achieved remission of depressive symptoms (i.e., DASS depression score ≤ 9) and 67% of patients achieved remission of anxiety symptoms (i.e., DASS anxiety score ≤ 7).ConclusionAn interdisciplinary multimodal integrative healthcare program, delivered within a transdiagnostic framework, seems effective for patients suffering from depressive and/or anxiety disorders with regard to HRQoL and symptoms of psychopathology. As reimbursement and funding for interdisciplinary multimodal interventions in this patient group has been under pressure in recent years, this study could add important evidence by reporting on routinely collected outcome data from a large patient group. Future studies should further investigate the long-term stability of treatment outcomes after interdisciplinary multimodal interventions for patients suffering from depressive and/or anxiety disorders

Clinical Application of Radioembolization in Hepatic Malignancies: Protocol for a Prospective Multicenter Observational Study

Background: Radioembolization, also known as transarterial radioembolization or selective internal radiation therapy with yttrium-90 (90Y) resin microspheres, is an established treatment modality for patients with primary and secondary liver tumors. However, large-scale prospective observational data on the application of this treatment in a real-life clinical setting is lacking. Objective: The main objective is to collect data on the clinical application of radioembolization with 90Y resin microspheres to improve the understanding of the impact of this treatment modality in its routine practice setting. Methods: Eligible patients are 18 years or older and receiving radioembolization for primary and secondary liver tumors as part of routine practice, as well as have signed informed consent. Data is collected at baseline, directly after treatment, and at every 3-month follow-up until 24 months or study exit. The primary objective of the Cardiovascular and Interventional Radiological Society of Europe Registry for SIR-Spheres Therapy (CIRT) is to observe the clinical application of radioembolization. Secondary objectives include safety, effectiveness in terms of overall survival, progression-free survival (PFS), liver-specific PFS, imaging response, and change in quality of life. Results: Between January 2015 and December 2017, 1047 patients were included in the study. The 24-month follow-up period ended in December 2019. The first results are expected in the third quarter of 2020. Conclusions: The CIRT is the largest observational study on radioembolization to date and will provide valuable insights to the clinical application of this treatment modality and its real-life outcomes