Population pharmacokinetics of lisinopril in hypertensive children and adolescents with normal to mildly reduced kidney function.

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.

Circadian rhythm of water and solute excretion in nocturnal enuresis.

BACKGROUND: Nocturnal polyuria (NP) due to a suppressed vasopressin circadian rhythm is a well-documented pathogenetic mechanism in enuresis, mainly studied in monosymptomatic enuresis. A substantial percentage of patients do not respond to desmopressin. This suggests that NP may not only be related to vasopressin, but that other kidney components play a role. Solute handling and osmotic excretion have been investigated in the past, especially in refractory patients. Nevertheless, data in treatment-naïve populations with information on timing overnight are sparse. This study aims to investigate the diuresis and solute excretion in treatment-naïve patients with or without NP, with emphasis on circadian rhythms. METHODS: Retrospective analysis of 403 treatment-naïve children 5-18 years with severe enuresis (> 8 nights/2 weeks). Circadian rhythms were evaluated by a 24-h urine collection in 8 timed portions (4 day, 4 nighttime) at in-home settings. Urine volume, osmolality, and creatinine were measured. Patients were subdivided into three groups according to nocturnal diuresis (ND) and Expected Bladder Capacity (EBCage) ratio: (a) < 100%, (b) 100-129%, (c) > 130%. RESULTS: All groups maintained circadian rhythm for diuresis and diuresis rates. Patients with higher ND (100-129% and > 130% EBCage) had higher daytime volumes and less pronounced circadian rhythm. In the ND group > 130% EBCage, the ND rate was higher during the first night collection and osmotic excretion was significantly higher overnight. CONCLUSIONS: Overall 24-h fluid intake (reflected by 24-h diuresis) and nutritional intake (24-h osmotic excretion) might play a role in enuresis. Increased diuresis rate early in the night can be important in some patients, whereas the total night volume can be important in others. A higher resolution version of the Graphical abstract is available as Supplementary Information.

Global surgery education in Belgium: Student's knowledge, attitudes and exposure.

PURPOSE: Understanding how medical students perceive global surgery will be essential in strengthening the global surgery workforce by 2030. This study investigated the knowledge, attitudes and exposure of Belgian medical students towards global surgery and identified avenues for medical institutions to include meaningful educational opportunities. METHODS: An online survey was distributed to first to final year medical students across Belgian universities using social media. Data were collected on demographics, exposure, knowledge and attitudes towards global surgery. Odds ratios with 95% confidence intervals were calculated. RESULTS: A total of 304 medical students participated from four Belgian universities. A minority reported having exposure to global surgery (24.7%), and most wanted more exposure (75.3%). Almost all respondents agreed (94.4%) that it is a relevant topic for medical students, and most agreed (71%) more compulsory education on the topic is needed. Only 13 to 44% of students could correctly answer questions testing global surgery knowledge. Personal/family responsibilities were the most important barrier to pursuing global surgery careers. CONCLUSIONS: Global surgery knowledge and exposure is limited among Belgian medical students despite interest in the field. These results advocate for the inclusion of decolonised global surgery education alongside equitable international clinical internships in medical education worldwide.

Hemolytic Uremic Syndrome Associated With Non-Shigatoxin-producing Infectious Agents: Expanding the Shigatoxin Theory.

Diarrhea-associated hemolytic uremic syndrome (HUS) is usually associated with shigatoxin-producing Escherichia coli or shigella infections. We report 2 cases of HUS, respectively, caused by salmonella and Campylobacter jejuni infections. None of these bacteria produce shigatoxins, and the underlying mechanism of HUS development remains unknown. In streptococcus pneumoniae-associated HUS, bacterial neuraminidase cleaves neuraminic acid and causes exposure of Thomsen-Friedenreich cryptantigen on the cell surface of, for example, erythrocytes, which induces an inflammatory response caused by binding of preformed IgM. Both campylobacter and salmonella bacteria also produce neuraminidase, and HUS development could be explained by a similar mechanism.

Development of the CDISC Pediatrics User Guide: a CDISC and conect4children collaboration.

Introduction: The conect4children (c4c) project aims to facilitate efficient planning and delivery of paediatric clinical trials. One objective of c4c is data standardization and reuse. Interoperability and reusability of paediatric clinical trial data is challenging due to a lack of standardization. The Clinical Data Interchange Standards Consortium (CDISC) standards that are required or recommended for regulatory submissions in several countries lack paediatric specificity with limited awareness within academic institutions. To address this, c4c and CDISC collaborated to develop the Pediatrics User Guide (PUG) consisting of cross-cutting data items that are routinely collected in paediatric clinical trials, factoring in all paediatric age ranges. Methods and Results: The development of the PUG consisted of six stages. During the scoping phase, subtopics (each containing several clinically relevant concepts) were suggested and debated for inclusion in the PUG. Ninety concepts were selected for the modelling phase. Concept maps describing the Research Topic and representation procedure were developed for the 19 concepts that had no (or partial) previous modelling in CDISC. Next, metadata and implementation examples were developed for concepts. This was followed by a CDISC internal review and a public review. For both these review stages, the feedback comments were either implemented or rejected based on budget, timelines, expert review, and scope. The PUG was published on the CDISC website on February 23, 2023. Discussion: The PUG is a first step in bridging the lack of child specific CDISC standards, particularly within academia. Several academic and industrial partners were involved in the development of the PUG, and c4c has undertaken multiple steps to publicize the PUG within its academic partner organizations - in particular, the European Reference Networks (ERNs) that are developing registries and dictionaries in 24 disease areas. In the long term, continued use of the PUG in paediatric clinical trials will enable the pooling of data from multiple trials, which is particularly important for medical domains with small populations.

A roadmap to building first responder networks: Lessons learned and best practices from Belgium and Switzerland.

Background/Aims: Limited bystander assistance and delayed emergency medical service arrival reduce the chances of survival in cardiac arrest victims. Early basic life support through trained first responders (FR) and automatic external defibrillation both improve the outcome. Well-organized FR networks have shown promise, but guidance on effective implementation is lacking. This study evaluates two FR networks, in Belgium and in Switzerland, to identify main advancements in the development of such systems. Method: Direct comparison is made of the barriers and facilitators in the development of both FR systems from 2006 up until December 2022, and summarized within a roadmap. Results: The Roadmap comprises four integral steps: exploration, installation, initiation, and implementation. Exploration involves understanding the national legislation, engaging with advisory bodies, and establishing local steering committees. The installation phase focuses on FR recruitment, engaging specific professional groups such as firemen, registering public Automated External Defibrillators (AEDs), and requesting feedback. The initiation step includes implementing improvement cycles and fidelity measures. Finally, implementation expands the network, leading to increased survival rates and the integration of these practices into legislation. A significant focus is placed on FR's psychological wellbeing. Moreover, the roadmap highlights the use of efficient geo-mapping to simplify optimal AED placement and automatically assign FRs to tasks. Conclusion: The importance of FR networks for early resuscitation is increasingly recognized and various systems are being developed. Key developmental strategies of the EVapp and Ticino Cuore app system may serve as a roadmap for other systems and implementations within Europe and beyond.

Development and performance of the c4c national clinical trial networks for optimizing pediatric trial facilitation.

Introduction: The high failure rate of industry-driven pediatric clinical trials leads to insufficient timely labeling of drugs in children and a lack of scientific evidence, resulting in the persistently high off-label drug use. National clinical trial networks can facilitate collaboration between sites, investigators, and experts, increasing the likelihood of successful trials. Within the conect4children (c4c) network, an Innovative Medicines Initiative 2-funded project, National Hubs hosted by National Clinical Trials Networks were set up across 21 European countries to facilitate the setup and execution of pediatric clinical trials. In this paper, we aim to present the performance metrics of the trial feasibility process as well as learnings and challenges encountered by the Belgian and Dutch Networks in working within the European c4c project. Method: The c4c National Hubs streamline pediatric clinical trials by initiating early country outreach, identifying overlapping studies, recommending quality trial sites, and supporting trial budgeting for both industry and academic settings. To show the impact of Pedmed-NL and Belgian Pediatric Clinical Research Network (BPCRN), internal metrics were collected from 2019 to 2022 on four industry-sponsored and three academic trials performed within the c4c network. Timelines and outcomes of the site identification were collected and analyzed for industry trials. A qualitative analysis was conducted through c4c platforms, sponsor interactions, and stakeholder engagement to evaluate the added value of a research network. Results: In industry-sponsored trials, full feasibility questionnaires were completed within 2 weeks (n = 48), and inclusion rates were up to 80% of clinical sites. Before committing to c4c, 14% of sites were contacted by industry, leading to communication burdens. Utilizing national infrastructure knowledge and therapeutic environment insights helped optimize trial timelines and address feasibility challenges. In addition, national adaptations, such as bilingual staff and site development, played a role in streamlining trial operations in both academic and industry settings. Performance and experiences were similar for both networks. Conclusion: The early-facilitation examples from the c4c trials demonstrated promising metrics for two National Hubs, including optimized start-up timelines and aiding site selection quality. The learnings and challenges of the Belgian and Dutch Networks provided insights for the development of clinical research networks.

A case of Graves' disease associated with membranoproliferative glomerulonephritis and leukocytoclastic vasculitis.

Background The association of hyperthyroidism with renal disease is very rare and the importance of timely clinical recognition cannot be overemphasized. Case presentation An 11-year-old girl presented with gastrointestinal symptoms while hypertension, edema and abdominal pain were noticed on clinical examination. Laboratory investigation revealed: hemoglobin 9.4 (11.5-15.5) g/dL, total white cell count 16 (4.5-12)×109/L, platelets 247 (150-450)×109/L, C-reactive protein (CRP) 31.8 (<5) mg/L, blood urea nitrogen (BUN) 126 (13-43) mg/dL, creatinine 0.98 (0.53-0.79) mg/dL, albumin 25 (35-52) g/dL, complement factor C3 0.7 (0.9-1.8) g/L, complement factor C4 0.1 (0.1-0.4) g/L, tri-iodothyronine 6.5 (2.5-5.2) pg/mL, free thyroxine 2.4 (1-1.7) ng/dL, thyroid stimulating hormone (TSH) <0.02 (0.5-4.3) mU/L. Urinalysis showed nephrotic range proteinuria. Renal function deteriorated necessitating hemodialysis (HD). A renal biopsy revealed an immune complex-mediated membranoproliferative glomerulonephritis (MPGN). Elevated thyroid hormones and suppressed TSH levels with elevated thyroperoxidase antibodies and thyroid stimulating immunoglobulins confirmed the diagnosis of Graves' disease. Corticosteroids were commenced and eventually thiamazole was added with gradual improvement of renal function, cessation of HD and discharge from the hospital. Conclusions Graves' disease complicated by MPGN is extremely rare, but can cause life-threatening complications.