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Background: Vancomycin is a commonly prescribed antibiotic to treat serious Gram-positive infections in children. The efficacy of vancomycin is known to be directly related to the pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve (AUC) divided by the minimal inhibitory concentration (MIC) of the pathogen. In most countries, steady-state plasma concentrations are used as a surrogate parameter for this target AUC/MIC, but this practice has some drawbacks. Hence, AUC-based dosing using model-informed precision dosing (MIPD) tools has been proposed for increasing the target attainment rate and reducing vancomycin-related nephrotoxicity. Solid scientific evidence for these claimed benefits is lacking in children. This randomized controlled trial aims to investigate the large-scale utility of MIPD dosing of vancomycin in critically ill children., Methods: Participants from 14 neonatal intensive care, pediatric intensive care, and pediatric hemo-oncology ward units from 7 hospitals are randomly allocated to the intervention or standard-of-care comparator group. In the intervention group, a MIPD dosing calculator is used for AUC-based dosing, in combination with extra sampling for therapeutic drug monitoring in the first hours of treatment, as compared to standard-of-care. An AUC24h between 400 and 600 is targeted, assuming an MIC of 1 mg/L. Patients in the comparator group receive standard-of-care dosing and monitoring according to institutional guidelines. The primary endpoint is the proportion of patients reaching the target AUC24h/MIC of 400-600 between 24 and 48 h after the start of vancomycin treatment. Secondary endpoints are the proportion of patients with (worsening) acute kidney injury during vancomycin treatment, the proportion of patients reaching target AUC24h/MIC of 400-600 between 48 and 72 h after the start of vancomycin treatment, time to clinical cure, ward unit length-of-stay, hospital length-of-stay, and 30-day all-cause mortality., Discussion: This trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment in critically ill children., Trial Registration: Eudract number: 2019-004538-40. Registered on 2020-09-08 ClinicalTrials.gov NCT046666948. Registered on 2020-11-28., (© 2024. The Author(s).)

Poorly differentiated thyroid carcinoma (PDTC) is a rare malignancy, representing ~1% of all thyroid tumors. It is characterized by high-grade histologic features without the anaplastic characteristics observed in anaplastic thyroid carcinoma. Although rare in children and young adults, there is emerging evidence of clinical and genetic differences with PDTC in adults. We present a case of a 19-year-old female with a right thyroid lobe nodule classified as an EU-TIRADS 5 lesion. Subsequent FNAC showed a cellular aspirate of solitary cells and scant microfollicles with variable nuclear irregularities, which was designated a Bethesda class IV lesion. Thyroidectomy revealed histopathological features consistent with PDTC, including solid/trabecular growth, increased mitotic activity, central necrosis, and extensive vascular invasion. Molecular analysis identified germline and somatic DICER1 mutations in the absence of other established driver mutations of PDTC. This case report describes the fourth reported patient with a PDTC and germline DICER1 mutation. Our findings contribute to a limited body of literature on pediatric/young adult PDTC cases and highlight the pivotal role of DICER1 mutations. Emerging evidence suggests that pediatric PDTC may exhibit unique clinical and genetic characteristics, prompting further research into its molecular profile., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The COVID-19 pandemic required a significant response from global healthcare systems. In Belgium, the crisis began in March 2020, prompting quick action in hospitals. This study assesses the effectiveness of Belgium's hospital emergency plans and compares them with global standards for potential enhancements., Methodology: An online survey targeting CEOs of 60 Flemish general hospitals evaluated the deployment of hospital emergency coordination cells during the pandemic's first and fourth waves, utilizing various statistical analyses., Results: Findings indicate a high establishment rate of COVID-19 coordination cells before the government's deadline. Despite this readiness, differences in leadership, involvement, and communication strategies were noted among hospitals. There was a notable shift towards hybrid meetings and an evolving role for coordination cells, highlighting the need for a more structured crisis management approach., Conclusion: The study concludes that while Flemish hospitals were quick to respond, the lack of a standardized framework suggests the potential for adopting models like the Hospital Incident Command System (HICS) for improved crisis management. Future research should examine the long-term effects of these strategies and the integration of comprehensive emergency management systems in Belgium's healthcare.

Background: Augmented renal clearance (ARC) holds a risk of subtherapeutic drug concentrations. Knowledge of patient-, disease-, and therapy-related factors associated with ARC would allow predicting which patients would benefit from intensified dosing regimens. This study aimed to identify ARC predictors and to describe ARC time-course in critically ill children, using iohexol plasma clearance (CL iohexol ) to measure glomerular filtration rate (GFR)., Methods: This is a retrospective analysis of data from the "IOHEXOL" study which validated GFR estimating formulas (eGFR) against CL iohexol . Critically ill children with normal serum creatinine were included, and CL iohexol was performed as soon as possible after pediatric intensive care unit (PICU) admission (CL iohexol1 ) and repeated (CL iohexol2 ) after 48-72 h whenever possible. ARC was defined as CL iohexol exceeding normal GFR for age plus two standard deviations., Results: Eighty-five patients were included; 57% were postoperative patients. Median CL iohexol1 was 122 mL/min/1.73 m 2 (IQR 75-152). Forty patients (47%) expressed ARC on CL iohexol1 . Major surgery other than cardiac surgery and eGFR were found as independent predictors of ARC. An eGFR cut-off value of 99 mL/min/1.73 m 2 and 140 mL/min/1.73 m 2 was suggested to identify ARC in children under and above 2 years, respectively. ARC showed a tendency to persist on CL iohexol2 ., Conclusions: Our findings raise PICU clinician awareness about increased risk for ARC after major surgery and in patients with eGFR above age-specific thresholds. This knowledge enables identification of patients with an ARC risk profile who would potentially benefit from a dose increase at initiation of treatment to avoid underexposure., Trial Registration: ClinicalTrials.gov NCT05179564, registered retrospectively on January 5, 2022., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Fibroepithelial stromal polyps (FSPs) are benign mesenchymal lesions occurring in the vulvovaginal region. Following the identification of loss of Retinoblastoma 1 (RB1) on immunohistochemical staining in routine practice, we stained a series of FSPs and performed additional fluorescence in situ hybridization (FISH) and copy number variation (CNV) sequencing to detect losses/deletions in the Retinoblastoma transcriptional corepressor 1 (RB1) gene. Fifteen FSP cases were stained for RB1, and subsequently, 9 cases were examined by FISH to detect a loss of RB1 (13q). Next, CNV sequencing was performed to assess genomic alterations. The mean age of the patients was 50 years. Loss of RB1 expression on immunohistochemistry was seen in 13 cases, and heterogeneous RB1 staining in the remaining 2 cases. FISH showed deletion of RB1 in all of the cases. CNV sequencing failed in almost all cases due to a low tumor content. Based on our findings, we hypothesize that FSPs are part of a spectrum of genetically related lesions, namely the 13q/RB1 family of tumors (which includes pleomorphic fibromas and spindle cell/pleomorphic lipomas). Due to the clinical, morphologic, and molecular overlap, we suggest that FSPs are pleomorphic fibromas occurring in the specialized stroma of the genital region., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Background and Objective: Drug dosing should ideally be based on the drug concentrations at the target site, which, for most drugs, corresponds to the tissue. The exact influence of growth and development on drug tissue distribution is unclear. This systematic review compiles the current knowledge on the tissue distribution of systemically applied drugs in children, with the aim to identify priorities in tissue pharmacokinetic (PK) research in this population., Methods: A systematic literature search was performed in the MEDLINE and Embase databases., Results: Forty-two relevant articles were identified, of which 71% investigated antibiotics, while drug classes from the other studies were anticancer drugs, antifungals, anthelmintics, sedatives, thyreostatics, immunomodulators, antiarrhythmics, and exon skipping therapy. The majority of studies (83%) applied tissue biopsy as the sampling technique. Tonsil and/or adenoid tissue was most frequently examined (70% of all included patients). The majority of studies had a small sample size (median 9, range 1-93), did not include the youngest age categories (neonates and infants), and were of low reporting quality. Due to the heterogeneous data from different study compounds, dosing schedules, populations, and target tissues, the possibility for comparison of PK data between studies was limited., Conclusion: The influence of growth and development on drug tissue distribution continues to be a knowledge gap, due to the paucity of tissue PK data in children, especially in the younger age categories. Future research in this field should be encouraged as techniques to safely investigate drug tissue disposition in children are available., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

High-grade B-cell lymphoma (HGBL)/diffuse large B-cell lymphoma (DLBCL) with rearrangements (R) in MYC and BCL2 and/or BCL6 are correlated with poor prognosis. Little is known about the impact of other genetic alterations (gain (G) or amplification (A)) of these genes. The aim of the study was to investigate whether we can identify new prognostic subgroups. Fluorescence in situ hybridization (FISH) results from 169 HGBL/DLBCL were retrospectively categorized into: (1) concurrent MYC-R and BCL2-R and/or BCL6-R-samples with MYC-R and BCL2-R (+/- BCL6-R); n = 21, and HGBL/DLBCL with MYC-R and BCL6-R; n = 11; (2) concurrent R and G/A in MYC and BCL2 and/or BCL6 called "alternative HGBL/DLBCL"-samples with (n = 16) or without (n = 6) BCL2 involvement; (3) BCL2 and/or BCL6 alterations without MYC involvement (n = 35); (4) concurrent G/A in MYC and BCL2 and/or BCL6 without R (n = 25); and (5) "No alterations" (n = 55). Patients with HGBL/DLBCL-MYC/BCL2 and "alternative" HGBL/DLBCL (with BCL2 involvement) had significantly worse survival rates compared to the "no alterations" group. G/A of these genes in the absence of rearrangements did not show any prognostic significance. HGBL/DLBCL with MYC-R and BCL6-R without BCL2 involvement showed a better survival rate compared to HGBL/DLBCL-MYC/BCL2. According to immunohistochemistry, "double/triple" expression (DEL/TEL) did not show a significantly worse outcome compared to absent DEL/TEL. This study highlights the continued value of FISH assessment of MYC, BCL2, and BCL6 in the initial evaluation of HGBL/DLBCL with different survival rates between several genetic subgroups., (© 2023 Wiley Periodicals LLC.)

Summary: Primary hyperparathyroidism most commonly presents with hypercalcaemia. Rarely, parathyroid apoplexy or haemorrhage mimicking a thyroid bleeding cyst is the first presentation of a parathyroid adenoma. A woman presented with a sudden-onset painful 'goitre'. Ultrasound showed a cystic nodule located posterior to rather than in the right thyroid lobe, suggesting parathyroid adenoma bleeding. Biochemistry showed mild primary hyperparathyroidism. 99mTc-pertechnetate/sestamibi showed no uptake in the nodule, which was interpreted as a cold thyroid nodule. 18F-fluorocholine PET/CT showed uptake in the nodule, suggestive of a parathyroid adenoma. Persistent mild primary hyperparathyroidism complicated by nephrolithiasis and osteopenia favoured parathyroidectomy over a wait-and-see approach. The patient was referred for parathyroidectomy along with right thyroid lobectomy. Pathology showed an adenoma, with an eccentrically located cystic structure filled with red blood cells surrounded by a thickened fibrous capsule. In conclusion, cervical pain/haemorrhage with hypercalcaemia points to the diagnosis of parathyroid apoplexy, mimicking a thyroid bleeding cyst. Workup with ultrasound and, if available, 18F-choline PET/CT allows for timely surgery, minimizing the risk of recurrent and severe bleeding., Learning Points: A bleeding cyst may be located posterior to rather than in the thyroid, suggesting a parathyroid haemorrhage. Neck pain and/or haemorrhage along with primary hyperparathyroidism point to parathyroid apoplexy. A two-step presentation has been described, with a first phase of local symptoms to be followed by visible and possibly life-threatening compressing bleeding. Therefore, an expedited workup is needed, allowing for timely surgery.

Background: Diffuse large B-cell lymphoma (DLBCL) masquerading as a recurrent inguinal hernia is rare. We report the case of a 73-year-old male patient who presented with a symptomatic bulge in his left groin. Medical history revealed bilateral preperitoneal inguinal hernia repair, osteoporosis and atrial fibrillation. The patient's further history was not significant., Methods: Sonography revealed recurrence of an indirect inguinal hernia (4.5 cm × 2.3 cm) on the left, with bilateral subcutaneous lymph nodes that were deemed unremarkable. We planned an elective left-sided anterior inguinal repair. Apixaban was stopped two days prior to surgery., Results: During surgery we identified the bulge as a lump attached to the spermatic cord. No hernial sac was present. Together with the consulting urologist, we concluded a possible malignant etiology and performed an orchiectomy along with resection of the lump., Conclusion: Microscopic and immunohistochemical analysis revealed a DLBCL with non-germinal center phenotype and c-MYC rearrangement. Further staging confirmed stage IE disease with extranodal paratesticular involvement. The patient was subsequently treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine, prednisone and showed complete metabolic remission after two cycles. This case illustrates the broad differential diagnosis of inguinal swelling and (para)testicular tumors.

Objectives: Knowledge on the tissue penetration of piperacillin-tazobactam in children with sepsis is lacking. In this study, the feasibility and performance of microdialysis experiments were explored in septic piglets and children as part of a translational research project., Methods: Multiple-day microdialysis investigations were performed in muscle tissue of 22 piglets (of which 11 were septic) and 6 children with sepsis. An in vitro experiment preceded the (pre)clinical trials to derive optimal experimental settings and calibration technique. Linear mixed-effects models quantified the impact of sepsis on relative recovery (RR) and intercatheter, interindividual, interoccasion, and residual variability., Results: In vivo microdialysis was well tolerated in piglets and children, with no significant adverse events reported. Using identical experimental settings, lower RR values were recorded in healthy and septic piglets (range: piperacillin, 17.2-29.1% and tazobactam, 23.5-29.1%) compared with the in vitro experiment (piperacillin, 43.3% and tazobactam, 55.3%), and there were unacceptably low values in children with sepsis (<10%). As a result, methodological changes were made in the pediatric trial. Realistic tissue concentration-time curves were derived in piglets and children. In piglets, sepsis reduced the RR. The greatest contributors to RR variability were residual (>40%) and interoccasion (>30%) variability. The internal standard method was the preferred calibration technique in both piglets and children., Conclusions: Microdialysis is a safe and applicable method for the measurement of tissue drug concentrations in piglets and children. This study demonstrated the impact of experimental settings, sepsis, and target population on individual RR., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: The participation of health professionals in designing interventions is considered vital to effective implementation, yet in areas such as clinical coordination is rarely promoted and evaluated. This study, part of Equity-LA II, aims to analyse the design process of interventions to improve clinical coordination, taking a participatory-action-research (PAR) approach, in healthcare networks of Argentina, Brazil, Chile, Colombia, Mexico and Uruguay. This participatory process was planned in four phases, led by a local steering committee (LSC): (1) dissemination of problem analysis results and creation of professionals' platform, (2) selection of problems and intervention (3) intervention design and planning (4) adjustments after evaluation of first implementation stage., Methods: A descriptive qualitative study based on documentary analysis, using a topic guide, was conducted in each intervention network. Documents produced regarding the intervention design process were selected. Thematic content analysis was conducted, generating mixed categories taken from the topic guide and identified from data. Main categories were LSC characteristics, type of design process (phases, participants' roles, methods) and associated difficulties, coordination problems and interventions selected., Results: LSCs of similar composition (managers, professionals and researchers) were established, with increasing membership in Chile and high turnover in Argentina, Colombia and Mexico. Following results dissemination and selection of problems and interventions (more participatory in Chile and Colombia: 200-479 participants), the interventions were designed and planned, resulting in three different types of processes: (1) short initial design with adjustments after first implementation stage, in Colombia, Brazil and Mexico; (2) longer, more participatory process, with multiple cycles of action/reflection and pilot tests, in Chile; (3) open-ended design for ongoing adaptation, in Argentina and Uruguay. Professionals' time and the political cycle were the main barriers to participation. The clinical coordination problem selected was limited communication between primary and secondary care doctors. To address it, through discussions guided by context and feasibility criteria, interventions based on mutual feedback were selected., Conclusions: As expected in a flexible PAR process, its rollout differed across countries in participation and PAR cycles. Results show that PAR can help to design interventions adapted to context and offers lessons that can be applied in other contexts., (© 2023. The Author(s).)

Breast-implant associated (BIA) lymphoma is an infrequent type of cancer occurring in the fluid and fibrous capsule around a textured breast implant. Recently, both the 2022 WHO 5th edition classification of Haematological tumours (WHO HAEM5) and 2022 International Consensus Classification of Mature Lymphoid Neoplasms (22ICC), recognized breast implant-associated Anaplastic Large Cell Lymphoma (BIA-ALCL) as a definitive entity, defined as a mature CD30-positive T-cell lymphoma, confined by a fibrous capsule, in a breast implant setting. Only few B-cell lymphomas have been reported in the literature to be associated with breast implants. Here we report two EBV-positive Diffuse Large B-cell lymphomas (EBV + DLBCL) in relation to a breast implant, both expressing CD30 as well as EBV latency type 3. Both lesions were considered as DLBCL associated with chronic inflammation (CI-DLBCL), but one presented as a 7 cm solid mass, while the other presented as a fibrin-associated DLBCL (FA-DLBCL) in an HIV patient. Clinically, both are in complete remission 6 months or longer after capsulectomy and graft removal, without additional chemotherapy.Such cases, characterized by large CD30-positive cells, can easily be misdiagnosed as BIA-ALCL if the cell of origin is not further established. Therefore, a diagnostic panel including lineage-specific B-and T-cell markers and EBER in situ hybridization is essential to recognize this rare entity, to understand lymphomagenesis, to predict outcome and to define clinical approach., (© 2023. The Author(s).)

Background and Objective: (Patho)physiological changes in older people may influence the pharmacokinetics (PK), and consequently the target attainment, of ß-lactam antibiotics using standard dosing regimens. This systematic review compiles the current knowledge on the PK and target attainment of ß-lactam antibiotics in older people, with the aim to identify priorities for dose optimization in this patient population., Methods: A systematic literature search of the PubMed and EMBASE databases was conducted. Relevant articles published prior to 1 December 2021 were identified as eligible when they included data on the PK of ß-lactam antibiotics in adults ≥ 65 years of age. Extracted information included reported PK parameters (volume of distribution, clearance [CL], elimination rate constant, intercompartmental CL, elimination half-life, area under the concentration-time curve, maximum and trough concentration), covariates on PK parameters, target attainment rate, and dosing recommendations., Results: Ninety-one relevant articles were included in this review. Four main ß-lactam subclasses were represented: 59.3% on cephalosporins + cephamycins, 25.3% on penicillins, 15.4% on carbapenems, and 3.3% on monobactams; 65.9% of articles involved intravenous administration, 16.5% mixed administration routes, 12.1% oral administration, and 5.5% intramuscular administration. The majority of studies had a small sample size, often did not include detailed information on the study population and methods, and were fairly old. CL was, on average, decreased, while elimination half-life was prolonged in aged subjects compared with young subjects. Volume of distribution was generally similar between age groups. Most studies identified renal function as the most important contributor to altered drug CL. In only 30.8% of the articles, target attainment was studied, and in 35.7% of these articles, target attainment was found to be suboptimal. Dosing recommendations were incorporated in 87.9% of articles., Conclusion: Studies frequently fail to provide an evidence-based dosing recommendation for this diverse patient population. Model-based PK studies that address both physiological and disease-related changes are urgently needed. This review identified gaps of knowledge to set priorities for further research., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Cardiac amyloidosis (CA) is often overlooked or misdiagnosed. Effects of growing disease awareness, diagnostic ameliorations and novel treatment options on CA diagnosis and management are scarcely reported., Objective: To report trends in diagnosis, referral routes, clinical presentation, early onset diagnostic red flags and outcome in de novo CA subjects., Methods: An unselected cohort of 139 de novo CA patients over an 8-year period in a tertiary referral hospital was recruited., Results: Transthyretin (ATTR, 82%, n  = 114) was the most common CA form; Light-chain (AL, 15%, n  = 21) and secondary (AA, 3%, n  = 4) are less prevalent. Increased awareness over time led to a marked ATTR diagnostic surge, steep non-invasive diagnostic approach increment and increased nuclear medicine and external cardiologist referrals (all p  < 0.001). A total of 41% ( n  = 57/139) of patients were referred by non-cardiology specialist disciplines. Specific referral to rule out CA (24-36%) and diagnostic time lag from symptom onset (9 ± 12 to 8 ± 14 months), however, did not improve (all p  > 0.050). Multiple early red flag events preceded CA diagnose several years in ATTR: Left ventricular hypertrophy (LVH, 60%, 4.9 ± 4.3 y), heart failure (54%, 2.5 ± 3.5 y), atrial fibrillation (47%, 5.9 ± 6.7 y), bilateral carpal tunnel syndrome (43%, 9.5 ± 5.7 y) and spinal stenosis (40%, 7.4 ± 6.5 y). LVH ≥ 12 mm was absent in 11% ATTR ( n  = 13/114) and 5% AL ( n  = 1/21) patients. Hypertension was common in both ATTR ( n  = 70/114, 62%) and AL ( n  = 10/21, 48%). 56% ( n  = 78/139) of CA presented with heart failure. Cumulative 1 and 5-year mortality of 10%/66%, 40%/52% and 75%/75% for ATTR, AL, and AA, respectively, remains high., Conclusions: Although CA diagnostic uptake and referral improve, specialist-specific disease and diagnostic red flag ignorance result in non-timely diagnosis and unfavourable outcome.

Accurate renal function assessment is crucial to guide intensive care decision-making and drug dosing. Estimates of glomerular filtration rate (eGFR) are routinely used in critically ill children; however, these formulas were never evaluated against measured GFR (mGFR) in this population. We aimed to assess the reliability of common eGFR formulas compared to iohexol plasma clearance (CL iohexol ) in a pediatric intensive care (PICU) population. Secondary outcomes were the prevalence of acute kidney injury (AKI) (by pRIFLE criteria) and augmented renal clearance (ARC) (defined as standard GFR for age + 2 standard deviations (SD)) within 48 h after admission based on mGFR and eGFR by the revised Schwartz formula and the difference between these two methods to diagnose AKI and ARC. In children, between 0 and 15 years of age, without chronic renal disease, GFR was measured by CL iohexol and estimated using 26 formulas based on creatinine (Scr), cystatine C (CysC), and betatrace protein (BTP), early after PICU admission. eGFR and mGFR results were compared for the entire study population and in subgroups according to age, using Bland-Altman analysis with calculation of bias, precision, and accuracy expressed as percentage of eGFR results within 30% (P30) and 10% (P10) of mGFR. CL iohexol was measured in 98 patients. Mean CL iohexol (± SD) was 115 ± 54 ml/min/1.73m 2 . Most eGFR formulas showed overestimation of mGFR with large bias and poor precision reflected by wide limits of agreement (LoA). Bias was larger with CysC- and BTP-based formulas compared to Scr-based formulas. In the entire study population, none of the eGFR formulas showed the minimal desired P30 > 75%. The widely used revised Schwartz formula overestimated mGFR with a high percentage bias of - 18 ± 51% (95% confidence interval (CI) - 29; - 9), poor precision with 95% LoA from - 120 to 84% and insufficient accuracy reflected by P30 of only 51% (95% CI 41; 61), and P10 of 21% (95% CI 13; 66) in the overall population. Although performance of Scr-based formulas was worst in children below 1 month of age, exclusion of neonates and younger children did not result in improved agreement and accuracy. Based on mGFR, prevalence of AKI and ARC within 48 h was 17% and 45% of patients, respectively. There was poor agreement between revised Schwartz formula and mGFR to diagnose AKI (kappa value of 0.342, p < 0.001; sensitivity of 30%, 95% CI 5; 20%) and ARC (kappa value of 0.342, p < 0.001; sensitivity of 70%, 95% CI 33; 58)., Conclusion: In this proof-of-concept study, eGFR formulas were found to be largely inaccurate in the PICU population. Clinicians should therefore use these formulas with caution to guide drug dosing and therapeutic interventions in critically ill children. More research in subgroup populations is warranted to conclude on generalizability of these study findings., Clinicaltrials: gov NCT05179564, registered retrospectively on January 5, 2022., What Is Known: • Both acute kidney injury and augmented renal clearance may be present in PICU patients and warrant adaptation of therapy, including drug dosing. • Biomarker-based eGFR formulas are widely used for GFR assessment in critically ill children, although endogenous filtration biomarkers have important limitations in PICU patients and eGFR formulas have never been validated against measured GFR in this population., What Is New: • eGFR formulas were found to be largely inaccurate in the PICU population when compared to measured GFR by iohexol clearance. Clinicians should therefore use these formulas with caution to guide drug dosing and therapeutic interventions in critically ill children. • Iohexol plasma clearance could be considered an alternative for accurate GFR assessment in PICU patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: In critically ill children, severely altered pharmacokinetics may result in subtherapeutic β-lactam antibiotic concentrations when standard pediatric dosing regimens are applied. However, it remains unclear how to recognize patients most at risk for suboptimal exposure and their outcome. This study aimed to: 1) describe target attainment for β-lactam antibiotics in critically ill children, 2) identify risk factors for suboptimal exposure, and 3) study the association between target nonattainment and clinical outcome., Design: Post hoc analysis of the "Antibiotic Dosing in Pediatric Intensive Care" study (NCT02456974, 2012-2019). Steady-state trough plasma concentrations were classified as therapeutic if greater than or equal to the minimum inhibitory concentration of the (suspected) pathogen. Factors associated with subtherapeutic concentrations and clinical outcome were identified by logistic regression analysis., Setting: The pediatric and cardiac surgery ICU of a Belgian tertiary-care hospital., Patients: One hundred fifty-seven patients (aged 1 mo to 15 yr) treated intravenously with amoxicillin-clavulanic acid, piperacillin-tazobactam, or meropenem., Interventions: None., Measurements and Main Results: Three hundred eighty-two trough concentrations were obtained from 157 patients (median age, 1.25 yr; interquartile range, 0.4-4.2 yr). Subtherapeutic concentrations were measured in 39 of 60 (65%), 43 of 48 (90%), and 35 of 49 (71%) of patients treated with amoxicillin-clavulanic acid, piperacillin-tazobactam, and meropenem, respectively. Estimates of glomerular filtration rate (eGFR; 54% increase in odds for each sd increase in value, 95% CI, 0.287-0.736; p = 0.001) and the absence of vasopressor treatment (2.8-fold greater odds, 95% CI, 1.079-7.253; p = 0.034) were independently associated with target nonattainment. We failed to identify an association between antibiotic concentrations and clinical failure., Conclusions: Subtherapeutic β-lactam concentrations are common in critically ill children and correlate with renal function. eGFR equations may be helpful in identifying patients who may require higher dosing. Future studies should focus on the impact of subtherapeutic concentrations on clinical outcome., Competing Interests: Dr. Van Der Heggen received funding from Clinical Research Fund Ghent University Hospital, Belgium. Dr. De Cock received funding from a Clinical Research fund. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Mosaic RASopathies are a molecularly heterogeneous group of (neuro)cutaneous syndromes with high phenotypical variability. Postzygotic variants in KRAS have been described in oculoectodermal syndrome (OES), encephalocraniocutaneous lipomatosis (ECCL) and epidermal nevus syndrome (ENS). This study confirms the continuum of mosaic neurocutaneous RASopathies showing codon 146 KRAS variants in an individual with OES and, for the first time, in an individual with (isolated) epidermal nevus. The presence of a nevus psiloliparus in individuals with OES indicates that this finding is not specific for ECCL and highlights the phenotypical overlap between ECCL and OES. The presence of the somatic KRAS variant in the nevus psiloliparus resolves the underlying molecular etiology of this fatty-tissue nevus. In addition, this finding refutes the theory of non-allelic twin-spotting as an underlying hypothesis to explain the concurrent presence of two different mosaicisms in one individual. The identification of codon 146 KRAS variants in isolated epidermal nevus introduces a new hot spot for this condition, which is useful for increasing molecular genetic testing using targeted gene sequencing panels.

We report a case of a 19-year-old woman who ingested Digitalis purpurea leaves as a suicide attempt. She developed gastro-intestinal symptoms, loss of colour vision, cardiac conduction disturbances as well as an elevated serum potassium. Treatment was initiated in analogy to medicinal digoxin poisoning by means of digoxin-specific Fab-fragments with a good effect. However during the further course we faced difficulties of prolonged intestinal absorption and inability to estimate the ingested dose or half-life of the vegetal cardiac glycoside compounds. To prevent further absorption and interrupt enterohepatic recycling, multi-dose activated charcoal was administered. Because of a relapse of cardiac conduction disturbances and hyperkalemia, two supplementary doses of Fab-fragments were given, up to a total dose of nineteen vials (one vial containing 40 mg). The important diagnostic and therapeutic differences of vegetal digitalis intoxication as compared to medicinal intoxication and the applicability of existing guidelines on medicinal digitalis intoxication in the light of these differences will be discussed here.

Background: Trampoline injuries are a cause for concern and data from different countries indicate that these are increasing. The aim of this study was to collect data in a Belgian University Hospital emergency department., Methods: Medical files of patients admitted with a trampoline-related injury between 1st July 2011 and 30th June 2016 were retrospectively analyzed., Results: One hundred and sixty patients, aged between 2 and 64 years old and predominantly males (57%), were admitted most frequently during the months March until September. An increase was observed during the years 2013-2014. Most injuries (76%) occurred during activity on the trampoline. Fractures occurred in 40% of the patients with the extremities most frequently involved. An X-ray examination and a CT scan was performed in 82 and 3% of the cases, respectively. Surgery was carried out in 12% of the patients. 9% of the patients had to be admitted to hospital., Conclusions: Trampoline injuries are increasingly observed in the emergency department. These injuries are important and further research on the circumstances and causes for the accidents is needed. Preventive measures, as proposed in the literature, should be considered.

Background Correct dosing and therapeutic drug monitoring (TDM) practices are essential when aiming for optimal vancomycin treatment. Objective To assess target attainment after initial dosing and dose adjustments, and to determine compliance to dosing and TDM guidelines. Setting Tertiary care university hospital in Belgium. Method A chart review was performed in 150 patients, ranging from preterm infants to adults, treated intravenously with vancomycin. Patient characteristics, dosing and TDM data were compared to evidence-based hospital guidelines. Main outcome measures Target attainment of vancomycin after initial dosing and dose adjustments. Results Subtherapeutic concentrations were measured in 68% of adults, in 76% of children and in 52% of neonates after treatment initiation. Multiple dose adaptations (median 2, Q1 1-Q3 2) were required for target attainment, whilst more than 20% of children and neonates never reached targeted concentrations. Regarding compliance to the hospital guideline, some points of improvement were identified: omitted dose adjustment in adults with decreased renal function (53%), delayed sampling (16% in adults, 31% in children) and redundant sampling (34% of all samples in adults, 12% in children, 13% in neonates). Conclusion Target attainment for vancomycin with current dosing regimens and TDM is poor in all age groups. Besides, human factors should not be ignored when aiming for optimal treatment. This study reflects an ongoing challenge in clinical practice and highlights the need for optimization of vancomycin dosing strategies and improvement of awareness of all health care professionals involved., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives : To test the feasibility of an evidence-based protocol for procedural sedation in adults at our emergency department, using a mixture of ketamine and propofol ('ketofol') in a 1 to 4 ratio. We hypothesize that the protocol is safe and effective and can facilitate procedural sedation. Methods : During 14 months, adults in need of procedural sedation at our university hospital emergency department were included in a prospective convenience sample study. Patients with important comorbidity were discussed with the anaesthesiology department for feasibility of sedation in the emergency department setting. Outcome measures were procedural success, respiratory and hemodynamic events, vomiting, agitation or hallucinations, recall and physician's satisfaction. Results : Sixty-one patients between 18 and 89 years were included. All but one procedure were successful. Six respiratory events were registered in 6 patients (9.8%). These consisted of airway obstruction alleviated by airway repositioning and without influence on vital signs except for one brief episode of desaturation. Neither hemodynamic events nor vomiting were reported. Five patients (8.2%) experienced pleasant hallucinations and one patient (1.6%) became agitated upon awakening but recovered rapidly without medication. Three patients (4.9%) had recall and physician satisfaction rate was 93.4%. Conclusion : A feasibility trial of an implemented protocol for ketofol procedural sedation in adults showed only minor respiratory events, a low incidence of agitation or hallucinations, minimal recall and a high success and physician satisfaction rate. Despite a non-consecutive and limited sample used, ketofol in a 1 to 4 ratio appears safe and effective for use in the emergency department.

Objective: Aims were (1) to assess the characteristics, associated factors and compliance of patients with acute poisoning advised by the Belgian Poison Centre (BPC) to go (conditionally) to the hospital, (2) to assess the compliance and potential health-economic impact., Methods: Three types of referrals to the hospital of patients who called the BPC between 1 January and 30 June 2018 were analysed: referrals in case of deterioration in the patient's condition (Hosp-watchful-wait), referrals (Hosp-referral) or urgent referrals (Hosp-urgent-referral). Factors associated with type of recommendation were registered. A survey was conducted on a second dataset of patients who called the BPC between 1 March and 15 May 2019 and referred (conditionally) to the hospital., Results: 5476 referrals were included: 72.4% accidental poisoning, 25.3% intentional self-harm, 1.2% substance abuse and 1.1% unclear intentionality. There were 2368 (43.2%) Hosp-watchful-wait cases, 2677 (48.9%) Hosp-referrals and 431 (7.9%) Hosp-urgent-referrals. In Hosp-watchful-wait cases, soaps and detergents were represented most (20.5%). In Hosp-referrals and Hosp-urgent-referrals, benzodiazepines (12.7% and 15.1%, respectively) predominated. Factors associated with hospitalisation type were number of symptoms, intentionality, type of agent(s) involved and advising antidotes. The survey showed that 7.8% of Hosp-watchful-wait patients went to the hospital versus 57.3% of Hosp-referrals and 59.6% of Hosp-urgent-referrals. The mean cost for Hosp-watchful-wait patients, Hosp-referrals and Hosp-urgent-referrals was estimated at €127, €767 and €796, respectively., Conclusion: Only a small proportion of patients followed the advice of the BPC to go (conditionally) to the hospital. A systematic follow-up of cases is warranted to examine the appropriateness of referrals and the compliance of patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

To date, information on the ontogeny of renal transporters is limited. Here, we propose to estimate the in vivo functional ontogeny of transporters using a combined population pharmacokinetic (popPK) and physiology-based pharmacokinetic (PBPK) modeling approach called popPBPK. Clavulanic acid and amoxicillin were used as probes for glomerular filtration, combined glomerular filtration, and active secretion through OAT1,3, respectively. The predictive value of the estimated OAT1,3 ontogeny function was assessed by PBPK predictions of renal clearance (CL R ) of other OAT1,3 substrates: cefazolin and piperacillin. Individual CL R post-hoc values, obtained from a published popPK model on the concomitant use of clavulanic acid and amoxicillin in critically ill children between 1 month and 15 years, were used as dependent variables in the popPBPK analysis. CL R was re-parameterized according to PBPK principles, resulting in the estimation of OAT1,3-mediated intrinsic clearance (CL int,OAT1,3,invivo ) and its ontogeny. CL int,OAT1,3,invivo ontogeny was described by a sigmoidal function, reaching half of adult level around 7 months of age, comparable to findings based on renal transporter-specific protein expression data. PBPK-based CL R predictions including this ontogeny function were reasonably accurate for piperacillin in a similar age range (2.5 months-15 years) as well as for cefazolin in neonates as compared to published data (%RMSPE of 21.2 and 22.8%, respectively and %PE within ±50%). Using this novel approach, we estimated an in vivo functional ontogeny profile for CL int,OAT1,3,invivo that yields accurate CL R predictions for different OAT1,3 substrates across different ages. This approach deserves further study on functional ontogeny of other transporters.

The glomerular filtration rate (GFR) is considered the best overall index for the renal function. Currently, one of the most promising exogenous markers for GFR assessment is iohexol. In this study, the suitability of volumetric absorptive microsampling (VAMS) as alternative for the conventional blood sampling and quantification of iohexol in paediatric plasma was assessed. Therefore, a new, fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed. Subsequently, the clinical suitability was evaluated in 20 paediatric patients by comparing plasma iohexol concentrations and associated GFR values obtained by the VAMS method with those obtained by conventional blood sampling and quantification of iohexol in plasma. The developed, simple and cost-effective LC-MS/MS-method fulfilled all pre-set validation acceptance criteria. Iohexol could be accurately quantified within a haematocrit range of 20-60% and long-term stability of iohexol in VAMS was demonstrated up to 245 days under different storage temperatures. Both iohexol plasma concentrations (r = 0.98, mean bias: -4.20%) and derived GFR values (r = 0.99; mean bias: 1.31%), obtained by a conventional plasma and the VAMS method, demonstrated good correlation and acceptable bias. The agreement between the two methods was especially good for GFR values higher than 60 mL/min/1.73 m 2 . Nevertheless, for GFR values <60 mL/min/1.73 m 2 the accuracy compared to the plasma method was lower. However, small adjustments to the sampling protocol could probably solve this problem., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Augmented renal clearance (ARC) as observed in the critically ill (pediatric) population can have a major impact on the pharmacokinetics and posology of renally excreted drugs. Although sepsis has been described as a major trigger in the development of ARC in human critically ill patients, mechanistic insights on ARC are currently lacking. An appropriate ARC animal model could contribute to reveal these underlying mechanisms. In this exploratory study, a state of ARC was induced in 8-week-old piglets. Conscious piglets were continuously infused over 36 h with lipopolysaccharides (LPS) from Escherichia coli (O111:B4) to induce sepsis and subsequently trigger ARC. To study the dose-dependent effect of LPS on the renal function, three different doses (0.75, 2.0, 5.0 μg/kg/h) were administered (two ♂ piglets/dose, one sham piglet), in combination with fluid administration (0.9% NaCl) at 6 ml/kg/h. Single boluses of renal markers, i.e., creatinine [40 mg/kg body weight (BW)], iohexol (64.7 mg/kg BW), and para-aminohippuric acid (PAH, 10 mg/kg BW) were administered intravenously to evaluate the effect of LPS on the renal function. Clinical parameters were monitored periodically. Blood sampling was performed to determine the effect on hematology, neutrophil gelatinase-associated lipocalin, and prostaglandin E 2 plasma levels. All piglets that were continuously infused with LPS displayed an elevated body temperature, heart rhythm, and respiratory rate ~1-3 h after start of the infusion. After infusion, considerably higher total body clearances of iohexol, creatinine, and PAH were observed, independent of the administration of LPS and/or its dose. Since also the sham piglet, receiving no LPS, demonstrated a comparable increase in renal function, the contribution of fluid administration to the development of ARC should be further evaluated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dhondt, Croubels, Temmerman, De Cock, Meyer, Van Den Broeck, De Paepe and Devreese.)

Background and Objectives: Teicoplanin is a highly protein-bound antibiotic, increasingly used to treat serious Gram-positive infections in critically ill children. Maturational and pathophysiological intensive care unit-related changes often lead to altered pharmacokinetics. In this study, the objectives were to develop a pediatric population-pharmacokinetic model of unbound and total teicoplanin concentrations, to investigate the impact of plasma albumin levels and renal function on teicoplanin pharmacokinetics, and to evaluate the efficacy of the current weight-based dosing regimen., Methods: An observational pharmacokinetic study was performed and blood samples were collected for quantification of unbound and total concentrations of teicoplanin after the first dose and in assumed steady-state conditions. A population-pharmacokinetic analysis was conducted using a standard sequential approach and Monte Carlo simulations were performed for a probability of target attainment analysis using previously published pharmacokinetic-pharmacodynamic targets., Results: A two-compartment model with allometric scaling of pharmacokinetic parameters and non-linear plasma protein binding best described the data. Neither the inclusion of albumin nor the renal function significantly improved the model and no other covariates were supported for inclusion in the final model. The probability of target attainment analysis showed that the standard dosing regimen does not satisfactory attain the majority of the proposed targets., Conclusions: We successfully characterized the pharmacokinetics of unbound and total teicoplanin in critically ill pediatric patients. The highly variable unbound fraction of teicoplanin could not be predicted using albumin levels, which may support the use of therapeutic drug monitoring of unbound concentrations. Poor target attainment was shown for the most commonly used dosing regimen, regardless of the pharmacokinetic-pharmacodynamic target evaluated.

Augmented renal clearance (ARC) observed in the critically ill pediatric population has received an increased attention over the last years due to its major impact on the disposition and pharmacokinetics of mainly renally excreted drugs. Apart from an important inflammatory trigger, fluid administration has been suggested to contribute to the development of ARC. Therefore, the primary objective of this study was to evaluate the effect of continuous intravenous fluid administration on renal function using a conventional piglet animal model and to quantify the impact of fluid administration on the pharmacokinetics of renally excreted drugs. At baseline, twenty-four piglets (12 treatment/12 control; 7 weeks old, all ♂) received the marker drugs iohexol (64.7 mg/kg body weight (BW)) and para-aminohippuric acid (10 mg/kg BW) to quantify glomerular filtration rate and effective renal plasma flow, respectively. In addition, the hydrophilic antibiotic amikacin (7.5 mg/kg BW) was administered. Following this baseline measurement, the treatment group received fluid therapy as a constant rate infusion of 0.9% saline at 6 mL/kg/h over 36 h. After 24 h of fluid administration, the marker drugs and amikacin were administered again. When comparing both groups, a significant effect of fluid administration on the total body clearances of iohexol ( p = 0.032) and amikacin ( p = 0.0014) was observed. Clearances of iohexol and amikacin increased with on average 15 and 14%, although large interindividual variability was observed. This led to decreased systemic exposure to amikacin, which was manifested as decrease in area under the plasma concentration-time curve from time 0 h to infinity from 34,807 to 30,804 ng.h/mL. These results suggest that fluid therapy is a key factor involved in the development of ARC and should be taken into account when administering mainly renally excreted drugs. However, further research is necessary to confirm these results in children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dhondt, Croubels, De Paepe, Goethals, De Cock and Devreese.)

Introduction: Cardiopulmonary resuscitation (CPR) in patients with a poor prognosis increases the risk of perception of inappropriate care leading to moral distress in clinicians. We evaluated whether perception of inappropriate CPR is associated with intention to leave the job among emergency clinicians., Methods: A cross-sectional multi-centre survey was conducted in 24 countries. Factors associated with intention to leave the job were analysed by conditional logistic regression models. Results are expressed as odds ratios with 95% confidence intervals., Results: Of 5099 surveyed emergency clinicians, 1836 (36.0%) were physicians, 1313 (25.7%) nurses, 1950 (38.2%) emergency medical technicians. Intention to leave the job was expressed by 1721 (33.8%) clinicians, 3403 (66.7%) often wondered about the appropriateness of a resuscitation attempt, 2955 (58.0%) reported moral distress caused by inappropriate CPR. After adjustment for other covariates, the risk of intention to leave the job was higher in clinicians often wondering about the appropriateness of a resuscitation attempt (1.43 [1.23-1.67]), experiencing associated moral distress (1.44 [1.24-1.66]) and who were between 30-44 years old (1.53 [1.21-1.92] compared to <30 years). The risk was lower when the clinician felt valued by the team (0.53 [0.42-0.66]), when the team leader acknowledged the efforts delivered by the team (0.61 [0.49-0.75]) and in teams that took time for debriefing (0.70 [0.60-0.80])., Conclusion: Resuscitation attempts perceived as inappropriate by clinicians, and the accompanying moral distress, were associated with an increased likelihood of intention to leave the job. Interprofessional collaboration, teamwork, and regular interdisciplinary debriefing were associated with a lower risk of intention to leave the job. ClinicalTrials.gov; No.: NCT02356029., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: There is a paucity of data on the incidence and severity of tram tracks related cycling injuries. The aim of this study is to get insight into the incidence, severity and characteristics of tram tracks related cycling injuries, potentially defining significant 'hotspots' in the Ghent city area., Methods: A one-year, multicenter, prospective, observational study was conducted. Patients presenting to the emergency departments of all 4 Ghent hospitals with tram tracks related cycling injury, were included. Data on patient demographics, circumstances of the accident and type of injury were collected., Results: 149 patients were included, with a median age of 31 years. 42 patients had fractures, 39 patients required wound sutures, 79 and 49 patients suffered from bruising and abrasions respectively. Only 5 patients required admission. No patients died or suffered life-threatening injuries. Women (65.1%) presented more frequently than men (34.9%). Forty-tree percent of all accidents happened in autumn ( p  < 0.001). Accidents happened more frequently in rainy conditions ( p  < 0.001). Mean number of days off work was 2.7 days, significantly increasing to 6.56 days when sustaining a fracture or dislocation ( p  = 0.02)., Conclusion: Tram tracks are potentially dangerous and may lead to clinically important injuries and significant number of days off work.

Background: Since some form of dual clinical/public health practice is desirable, this paper explains why their ethics should be combined to influence medical practice and explores a way to achieve that., Main Text: In our attempt to merge clinical and public health ethics, we empirically compared the individual and collective health consequences of two illustrative lists of medical and public health ethical tenets and discussed their reciprocal relevance to praxis. The studied codes share four principles, namely, 1. respect for individual/collective rights and the patient's autonomy; 2. cultural respect and treatment that upholds the patient's dignity; 3. honestly informed consent; and 4. confidentiality of information. However, they also shed light on the strengths and deficiencies of each other's tenets. Designing a combined clinical and public health code requires fleshing out three similar principles, namely, beneficence, medical and public health engagement in favour of health equality, and community and individual participation; and adopting three stand-alone principles, namely, professional excellence, non-maleficence, and scientific excellence. Finally, we suggest that eco-biopsychosocial and patient-centred care delivery and dual clinical/public health practice should become a doctor's moral obligation. We propose to call ethics based on non-maleficence, beneficence, autonomy, and justice - the values upon which, according to Pellegrino and Thomasma, the others are grounded and that physicians and ethicists use to resolve ethical dilemmas - "neo-Hippocratic". The neo- prefix is justified by the adjunct of a distributive dimension (justice) to traditional Hippocratic ethics., Conclusion: Ethical codes ought to be constantly updated. The above values do not escape the rule. We have formulated them to feed discussions in health services and medical associations. Not only are these values fragmentary and in progress, but they have no universal ambition: they are applicable to the dilemmas of modern Western medicine only, not Ayurvedic or Shamanic medicine, because each professional culture has its own philosophical rationale. Efforts to combine clinical and public health ethics whilst resolving medical dilemmas can reasonably be expected to call upon the physician's professional identity because they are intellectual challenges to be associated with case management.

Background: Revisiting professionalism, both as a medical ideal and educational topic, this paper asks whether, in the rise of artificial intelligence, healthcare commoditisation and environmental challenges, a rationale exists for merging clinical and public health practices. To optimize doctors' impact on community health, clinicians should introduce public health thinking and action into clinical practice, above and beyond controlling nosocomial infections and iatrogenesis. However, in the interest of effectiveness they should do everything possible to personalise care delivery. To solve this paradox, we explore why it is necessary for the boundaries between medicine and public health to be blurred., Main Body: Proceeding sequentially, we derive standards for medical professionalism from care quality criteria, neo-Hippocratic ethics, public health concepts, and policy outcomes. Thereby, we formulate benchmarks for health care management and apply them to policy evaluation. During this process we justify the social, professional - and by implication, non-commercial, non-industrial - mission of healthcare financing and policies. The complexity of ethical, person-centred, biopsychosocial practice requires a human interface between suffering, health risks and their therapeutic solution - and thus legitimises the medical profession's existence. Consequently, the universal human right to healthcare is a right to access professionally delivered care. Its enforcement requires significant updating of the existing medical culture, and not just in respect of the man/machine interface. This will allow physicians to focus on what artificial intelligence cannot do, or not do well. These duties should become the touchstone of their practice, knowledge and ethics. Artificial intelligence must support medical professionalism, not determine it. Because physicians need sufficient autonomy to exercise professional judgement, medical ethics will conflict with attempts to introduce clinical standardisation as a managerial paradigm, which is what happens when industrial-style management is applied to healthcare., Conclusion: Public healthcare financing and policy ought to support medical professionalism, alongside integrated clinical and public health practice, and its management. Publicly-financed health management should actively promote ethics in publicly- oriented services. Commercialised healthcare is antithetical to ethical medical, and to clinical / public health practice integration. To lobby governments effectively, physicians need to appreciate the political economy of care.

Background: Strong relations between medicine and public health have long been advocated. Today, professional medical practice assumes joint clinical/public health objectives: GPs are expected to practice community medicine; Hospital specialists can be involved in disease control and health service organisation; Doctors can teach, coach, evaluate, and coordinate care; Clinicians should interpret protocols with reference to clinical epidemiology. Public health physicians should tailor preventive medicine to individual health risks. This paper is targeted at those practitioners and academics responsible for their teams' professionalism and the accessibility of care, where the authors argue in favour of the epistemological integration of clinical medicine and public health., Main Text: Based on empirical evidence the authors revisit the epistemological border of clinical and public health knowledge to support joint practice. From action-research and cognitive psychology, we derive clinical/public health knowledge categories that require different transmission and discovery techniques. The knowledge needed to support the universal human right to access professional care bridges both clinical and public health concepts, and summons professional ethics to validate medical decisions. To provide a rational framework for teaching and research, we propose the following categories: 'Know-how/practice techniques', corresponding a.o. to behavioural, communication, and manual skills; 'Procedural knowledge' to choose and apply procedures that meet explicit quality criteria; 'Practical knowledge' to design new procedures and inform the design of established procedures in new contexts; and Theoretical knowledge teaches the reasoning and theory of knowledge and the laws of existence and functioning of reality to validate clinical and public health procedures. Even though medical interventions benefit from science, they are, in essence, professional: science cannot standardise eco-biopsychosocial decisions; doctor-patient negotiations; emotional intelligence; manual and behavioural skills; and resolution of ethical conflicts., Conclusion: Because the quality of care utilises the professionals' skill-base but is also affected by their intangible motivations, health systems should individually tailor continuing medical education and treat collective knowledge management as a priority. Teamwork and coaching by those with more experience provide such opportunities. In the future, physicians and health professionals could jointly develop clinical/public health integrated knowledge. To this end, governments should make provision to finance non-clinical activities.

Background: Ethical medical practice requires managing health services to promote professionalism and secure accessibility to care. Commercially financed and industrially managed services strain the physicians' clinical autonomy and ethics because the industry's profitability depends on commercial, clinical standardisation. Private insurance companies also reduce access to care whilst fragmenting and segmenting health systems. Against this background, given the powerful, symbolic significance of their common voice, physicians' and patients' organisations could effectively leverage together political parties and employers' organisations to promote policies favouring access to professional care., Main Text: To provide a foundation for negotiations between physicians' and patients' organisations, we propose policy principles derived from an analysis of rights-holders and duty-bearers' stakes, i.e., patients, physicians and health professionals, and taxpayers. Their concerns are scrutinised from the standpoints of public health and right to health. Illustrated with post-WWII European policies, these principles are formulated as inputs for tentative action-research. The paper also identifies potential stumbling blocks for collective doctor/patient negotiations based on the authors' personal experience. The patients' concerns are care accessibility, quality, and price. Those of physicians and other professionals are problem-solving capacity, autonomy, intellectual progress, ethics, work environment, and revenue. The majority of taxpayers have an interest in taxes being progressive and public spending on health regressive. Mutual aid associations tend to under-estimate the physician's role in delivering care. Physicians' organisations often disregard the mission of financing care and its impact on healthcare quality., Conclusion: The proposed physicians-patients' alliance could promote policies in tune with professional ethics, prevent European policies' putting industrial concerns above suffering and death, bar care financing from the ambit of international trade treaties, and foster international cooperation policies consistent with the principles that inspire the design of healthcare policies at home and so reduce international migration. To be credible partners in this alliance, physicians' associations should promote a public health culture amongst their members and a team culture in healthcare services. To promote a universal health system, patients' organisations should strive to represent universal health interests rather than those of patients with specific diseases, ethnic groups, or social classes.

Background: Professional knowledge aims at improving practice. It reduces uncertainty in decision-making, improves effectiveness in action and relevance in evaluation, stimulates reflexivity, and subjects practice to ethical standards. Heuristics is an approach to problem-solving, learning, and discovery employing a practical methodology that, although not optimal, is sufficient for achieving immediate goals. This article identifies the desirable, heuristic particularities of research in professional, medical practice; and it identifies what distinguishes this research from scientific research., Main Text: We examine the limits of biomedical and sociological research to produce professional knowledge. Then, we derive the heuristic characteristics of professional research from a meta-analysis of two action-research projects aimed at securing access to essential generic drugs in Senegal and improving physicians' self-assessment and healthcare coordination in Belgium. To study healthcare, biomedical sciences ignore how clinical decisions are implemented. Decisions are built into an articulated knowledge system, such as (clinical) epidemiology, where those studied are standardisable - while taking care of patients is an idiosyncratic, value-based, person-to-person process that largely eludes probabilistic methodologies. Social sciences also reach their limits here because descriptive, interpretative methods cannot help with gesture and speech quality, while the management of the patient's suffering and risks makes each of them unique. Research into medical professionalism is normative as it is intended to formulate recommendations. Scientific data and descriptions are useful to the practitioner randomly, only from the similarities in the environment of the authors and their readers. Such recommendations can be conceived of as strategies, i.e., multi-resource and multi-stage action models to improve clinical and public health practice. Action learning and action-research are needed to design and implement these strategies, because their complexity implies trial and error. To validate a strategy, repeated experiences are needed. Its reproducibility assumes the description of the context. To participate in medical action-research, the investigator needs professional proficiency - a frequent difficulty in academic settings., Conclusion: Some criteria to assess the relevance of publicly funded clinical and public health research can be derived from the difference between scientific and professional knowledge, i.e. the knowledge gained with real-life experience in the field.

Background: Since the 1980s, markets have turned increasingly to intangible goods - healthcare, education, the arts, and justice. Over 40 years, the authors investigated healthcare commoditisation to produce policy knowledge relevant to patients, physicians, health professionals, and taxpayers. This paper revisits their objectives, methods, and results to enlighten healthcare policy design and research., Main Text: This paper meta-analyses the authors' research that evaluated the markets impact on healthcare and professional culture and investigated how they influenced patients' timely access to quality care and physicians' working conditions. Based on these findings, they explored the political economic of healthcare. In low-income countries the analysed research showed that, through loans and cooperation, multilateral agencies restricted the function of public services to disease control, with subsequent catastrophic reductions in access to care, health de-medicalisation, increased avoidable mortality, and failure to attain the narrow MDGs in Africa. The pro-market reforms enacted in middle-income countries entailed the purchaser-provider split, privatisation of healthcare pre-financing, and government contracting of health finance management to private insurance companies. To establish the materiality of a cause-and-effect relationship, the authors compared the efficiency of Latin American national health systems according to whether or not they were pro-market and complied with international policy standards. While pro-market health economists acknowledge that no market can offer equitable access to healthcare without effective regulation and control, the authors showed that both regulation and control were severely constrained in Asia by governance and medical secrecy issues. In high-income countries they questioned the interest for population health of healthcare insurance companies, whilst comparing access to care and health expenditures in the European Union vs. the U.S., the Netherlands, and Switzerland. They demonstrated that commoditising healthcare increases mortality and suffering amenable to care considerably and carries professional, cultural, and ethical risks for doctors and health professionals. Pro-market policies systems cause health systems inefficiency, inequity in access to care and strain professionals' ethics., Conclusion: Policy research methodologies benefit from being inductive, as health services and systems evaluations, and population health studies are prerequisites to challenge official discourse and to explore the historical, economic, sociocultural, and political determinants of public policies.

Objectives: Disulfiram is an adjunct in the treatment of alcohol use disorders, but case reports indicate that disulfiram ethanol reactions are not always recognized in the emergency department. Our first aim is to remind of this risk with two case reports of life-threatening reactions not immediately considered by the emergency physician. The second aim is to estimate the probability that a disulfiram reaction goes unrecognized with the use of a retrospective study of patients admitted to the emergency department., Methods: Clinical files of patients admitted between October 1, 2010 and September 30, 2014 to the emergency department were retrospectively screened for the key words "ethanol use" and "disulfiram". Their diagnoses were then scored by a panel regarding the probability of an interaction., Results: Seventy-nine patients were included, and a disulfiram-ethanol reaction was scored as either 'highly likely', 'likely' or 'possible' in 54.4% and as 'doubtful' or 'certainly not present' in 45.6% of the patients. The interrater agreement was 0.71 (95% CI: 0.64-0.79). The diagnosis was not considered or only after a delay in 44.2% of the patients with a 'possible' to 'highly likely' disulfiram interaction. One patient with a disulfiram overdose died and was considered as a 'possible' interaction., Discussion and Conclusions: A disulfiram ethanol interaction can be life threatening and failure to consider the diagnosis in the emergency department seems frequent. Prospective studies with documentation of the intake of disulfiram and evaluation of the value of acetaldehyde as a biomarker are needed to determine the precise incidence. Improving knowledge of disulfiram interactions and adequate history taking of disulfiram intake may improve the care for patients., Competing Interests: The authors have declared that no competing interests exist.

Healthcare coordination is considered key to improving care quality. Although participatory action research (PAR) has been used effectively to bridge the gap between evidence and practice in other areas, little is known about the key success factors of its use in healthcare organizations. This article analyses the factors influencing the implementation of PAR interventions to improve clinical coordination from the perspective of actors in public healthcare networks of Brazil, Chile, Colombia, Mexico and Uruguay. A qualitative, descriptive-interpretative study was conducted in each country's healthcare network. Focus groups and semi-structured individual interviews were conducted to a criterion sample of: local steering committee (LSC) (29), professional platform (PP) (28), health professionals (49) and managers (28). Thematic content analysis was conducted, segmented by country and themes. The PAR process led by the LSC covered the return of baseline results, selection of problems and interventions and design, implementation and adjustment of the intervention, with PP. Interventions were implemented to improve communication and clinical agreement between primary and secondary care. Results reveal that contextual factors, the PAR process and the intervention's content influenced their implementation, interacting across time. First, institutional support providing necessary resources, and professionals' and managers' willingness to participate, emerge as contextual pivotal factors, influenced by other factors related to: the system (alignment with policy and political cycle), networks (lack of time due to work overload and inadequate working conditions) and individuals (not knowing each other and mutual mistrust). Second, different characteristics of the PAR process have a bearing, in turn, on institutional support and professionals' motivation: participation, flexibility, consensual decision-making, the LSC's leadership and the facilitating role of researchers. Evidence is provided that implementation through an adequate PAR process can become a factor of motivation and cohesion that is crucial to the adoption of care coordination interventions, leading to better results when certain contextual factors converge., (© The Author(s) 2020. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Over recent years, pigs have been promoted as potential animal model due to their anatomical and physiological similarities with humans. However, information about the contribution of distinct renal elimination processes [glomerular filtration rate (GFR), effective renal plasma flow (ERPF), tubular secretion, and reabsorption] in pigs is currently limited. Therefore, a cocktail of renal markers, consisting of iohexol (GFR), para-aminohippuric acid (ERPF and net tubular anion secretion), pindolol (net tubular cation secretion), and fluconazole (net tubular reabsorption) was administered intravenously to 7-week-old male conventional pigs. Plasma and urinary concentrations were determined using validated analytical methods. The clearance of iohexol (GFR) was 97.87 ± 16.05 ml/min/m² (mean ± SD). The ERPF, calculated as the renal clearance of PAH, was 226.77 ± 62.45 ml/min/m², whereas the net tubular secretion of PAH was 130.28 ± 52.62 ml/min/m². The net tubular secretion of R-pindolol and S-pindolol was 13.53 ± 12.97 and 18.01 ± 39.23 ml/min/m², respectively. The net tubular reabsorption of fluconazole was 78.32 ± 13.52 ml/min/m². Overall, this cocktail of renal markers was considered to be safe for use in pigs since no adverse effects were observed. Iohexol, PAH and fluconazole were considered suitable renal marker to assess the porcine renal function. Pindolol seems less appropriate due to the high degree of nonrenal clearance in pigs. The values of GFR, ERPF, and anion secretion are within the same range for both human and pig. Regarding the tubular reabsorption of fluconazole, slightly higher values were obtained for pigs. Nevertheless, these results indicate the conventional pig could be an appropriate animal model to study renal drug elimination processes in humans., (Copyright © 2020 Dhondt, Croubels, De Paepe, Wallis, Pandey, Roberts, Lipman, De Cock and Devreese.)

Paracetamol (acetaminophen, APAP) is the most frequently used analgesic drug worldwide. However, patients in several specific populations can have an increased exposure to toxic APAP metabolites. Therefore, APAP-protein adducts have been proposed as an alternative marker for the assessment of APAP intoxications and as an effective tool to study and steer APAP treatment in patients with an increased risk of APAP-induced liver damage. These adducts have been determined in plasma or serum as a matrix. Blood microsampling allows the determination of a variety of analytes, including protein adducts, in a drop of blood, facilitating convenient follow-up of patients in a home-sampling context, as well as repeated sampling of pediatric patients. We therefore evaluated the use of blood-based volumetric microsamples for the quantification of APAP-protein adducts. Quantitative methods for the determination of APAP-protein adducts in dried blood and dried plasma volumetric absorptive microsamples were developed and validated. Also a preliminary evaluation of pediatric patient dried blood microsamples was conducted. Method validation encompassed the evaluation of selectivity, carry over, calibration model, accuracy and precision, matrix effect, recovery and the effect of the hematocrit on the recovery, dilution integrity, and stability. All pre-set acceptance criteria were met, except for stability. Spiking of blank blood with APAP revealed a concentration-dependent ex vivo formation of APAP-protein adducts, resulting in a response for the measurand APAP-Cys, with an apparent role for the red blood cell fraction. Analysis of authentic samples, following intake of APAP at therapeutic dosing, revealed much higher APAP-Cys concentrations in dried blood vs. dried plasma samples, making interpretation of the results in the context of published intervals difficult. In addition, in contrast to what was observed during method validation, the data obtained for the patient samples showed a high and unacceptable variation. We conclude that, for a combination of reasons, dried blood is not a suitable matrix for the quantification of APAP-protein adducts via the measurement of the APAP-Cys digestion product. The collection of plasma or serum, either in the form of a liquid sample or a dried microsample for this purpose is advised., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Aims were to (1) analyse the direct cost charged by a university hospital to the government and the patient in case of an admission for acute poisoning, (2) identify the factors associated with the cost, and (3) compare the cost in the hospital studied with national data from the government. Methods: Patient records and invoices of all poisoning-related episodes of patients 14 years or older admitted to the Emergency Department (ED) of Ghent University Hospital (GUH) in 2017 were analysed. A generalised linear model with gamma loglink was applied to assess the variables associated with the cost. Our GUH data collected in 2017 were compared with national data 2016 for all Belgian hospitals on the one hand, and for the subgroup of GUH 2016 data on the other hand. To do this, we used data provided by the Technical Unit of the Federal Public Service Health, containing All Patient Refined Diagnosis Related Groups 812 (poisoning by medicinal agents) and 816 (toxic effects by non-medicinal substances). Results: The total direct cost for the treatment of 1,175 poisoned patients amounted to $1,830,870. Median direct cost per patient was $512 per episode, with $199 for ambulatory patients, $1,575 for patients admitted to the ED-observation-unit, $3,398 for hospitalised patients and $4,859 for patients treated in the intensive care unit. Factors associated with the cost were gender, degree of severity, type of hospitalisation, intentionality, and involvement of ethanol, paracetamol, antidepressants or amphetamines. Median hospitalisation cost per admission in GUH for medicinal agents was 70.5% higher than the cost reported in national hospitalisation data. Median cost per admission in case of non-medicinal agents was 54.5% higher than the national median 2016. Conclusion: The type of hospitalisation has a high impact on the cost, a.o. primarily due to the length of hospital stay, with accommodation accounting for a large proportion of the costs. It is important to benchmark individual hospital data with (inter)national data to evaluate its own cost management in the context of continuous improvement.

Objective: The aim of this retrospective study was to externally validate the CRASH (Corticosteroid Randomisation After Significant Head Injury) clinical calculator as a prognostic tool. Mortality at 14 days and an unfavorable outcome (i.e., Glasgow Outcome Scale score <4) after 6 months were the primary endpoints., Methods: The study included adult patients admitted to the emergency department of Ghent University Hospital during 2010-2014 with traumatic brain injury. The CRASH score was calculated for every patient and compared with real-life outcome at 14 days and 6 months. Researchers were blinded for each other's results, and each observer either calculated the CRASH score or obtained clinical outcome. Receiver operating characteristic analysis was used to validate the CRASH calculator. The prognostic value of other variables was tested using logistic regression (P < 0.05 was significant)., Results: Of 417 included patients with traumatic brain injury, 94.7% were still alive at 14 days, and 65% had a Glasgow Outcome Scale score ≥4 at 6 months. Receiver operating characteristic analysis showed an area under the curve of 92.1% at 14 days and 90.7% at 6 months (P < 0.05). Calculated cutoff value for the CRASH score at 14 days was 31.50% (sensitivity 0.823, specificity 0.895). At 6 months, calculated cutoff value was 55.75% (sensitivity 0.793, specificity 0.830)., Conclusions: The CRASH calculator is a good predictor of outcome in traumatic brain injury at 14 days and 6 months with high sensitivity and specificity. It does not replace clinical judgment of the physician treating the patient in the emergency department, but it constitutes a useful additional tool., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Many critically ill patients display a supraphysiological renal function with enhanced renal perfusion and glomerular hyperfiltration. This phenomenon described as augmented renal clearance (ARC) may result in enhanced drug elimination through renal excretion mechanisms. Augmented renal clearance seems to be triggered by systemic inflammation and therapeutic interventions in intensive care. There is growing evidence that ARC is not restricted to the adult intensive care population, but is also prevalent in critically ill children. Augmented renal clearance is often overlooked due to the lack of reliable methods to assess renal function in critically ill children. Standard equations to calculate glomerular filtration rate (GFR) are developed for patients who have a steady-state creatinine production and a stable renal function. Those formulas are not reliable in critically ill patients with acutely changing GFR and tend to underestimate true GFR in patients with ARC. Tools for real-time, continuous, and non-invasive measurement of fluctuating GFR are most needed to identify changes in kidney function during critical illness and therapeutic interventions. Such devices are currently being validated and hold a strong potential to become the standard of practice. In the meantime, urinary creatinine clearance is considered the most reliable method to detect ARC in critically ill patients. Augmented renal clearance is clearly associated with subtherapeutic antimicrobial concentrations and subsequent therapeutic failure. This warrants the need for adjusted dosing regimens to optimize pharmacokinetic and pharmacodynamic target attainment. This review aims to summarize current knowledge on ARC in critically ill children, to give insight into its possible pathophysiological mechanism, to evaluate screening methods for ARC in the pediatric intensive care population, and to illustrate the effect of ARC on drug exposure, therapeutic efficacy, and clinical outcome.

Objectives: To determine the prevalence of clinician perception of inappropriate cardiopulmonary resuscitation (CPR) regarding the last out-of-hospital cardiac arrest (OHCA) encountered in an adult 80 years or older and its relationship to patient outcome., Design: Subanalysis of an international multicenter cross-sectional survey (REAPPROPRIATE)., Setting: Out-of-hospital CPR attempts registered in Europe, Israel, Japan, and the United States in adults 80 years or older., Participants: A total of 611 clinicians of whom 176 (28.8%) were doctors, 123 (20.1%) were nurses, and 312 (51.1%) were emergency medical technicians/paramedics., Results and Measurements: The last CPR attempt among patients 80 years or older was perceived as appropriate by 320 (52.4%) of the clinicians; 178 (29.1%) were uncertain about the appropriateness, and 113 (18.5%) perceived the CPR attempt as inappropriate. The survival to hospital discharge for the "appropriate" subgroup was 8 of 265 (3.0%), 1 of 164 (.6%) in the "uncertain" subgroup, and 2 of 107 (1.9%) in the "inappropriate" subgroup (P = .23); 503 of 564 (89.2%) CPR attempts involved non-shockable rhythms. CPR attempts in nursing homes accounted for 124 of 590 (21.0%) of the patients and were perceived as appropriate by 44 (35.5%) of the clinicians; 45 (36.3%) were uncertain about the appropriateness; and 35 (28.2%) perceived the CPR attempt as inappropriate. The survival to hospital discharge for the nursing home patients was 0 of 107 (0%); 104 of 111 (93.7%) CPR attempts involved non-shockable rhythms. Overall, 36 of 543 (6.6%) CPR attempts were undertaken despite a known written do not attempt resuscitation decision; 14 of 36 (38.9%) clinicians considered this appropriate, 9 of 36 (25.0%) were uncertain about its appropriateness, and 13 of 36 (36.1%) considered this inappropriate., Conclusion: Our findings show that despite generally poor outcomes for older patients undergoing CPR, many emergency clinicians do not consider these attempts at resuscitation to be inappropriate. A professional and societal debate is urgently needed to ensure that first we do not harm older patients by futile CPR attempts. J Am Geriatr Soc 68:39-45, 2019., (© 2019 The American Geriatrics Society.)

Objectives: This study evaluates the impact of the Belgian Poison Centre (BPC) on national healthcare expenses for calls from the public for unintentional poisonings., Methods: The probability of either calling the BPC, consulting a general practitioner (GP) or consulting an emergency department (ED) was examined in a telephone survey (February-March 2016). Callers were asked what they would have done in case of unavailability of the BPC. The proportion and cost for ED-ambulatory care, ED 24-h observation or hospitalisation were calculated from individual invoices. A cost-benefit analysis was performed., Results: Unintentional cases (n = 485) from 1045 calls to the BPC were included. After having called the BPC, 92.1% did not seek further medical help, 4.2% consulted a GP and 3.7% went to an ED. In the absence of the BPC, 13.8% would not have sought any further help, 49.3% would have consulted a GP and 36.9% would have gone to the hospital. The cost-benefit ratio of the availability of the BPC as versus its absence was estimated at 5.70., Conclusions: Financial savings can be made if people first call the BPC for unintentional poisonings.