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Alkaptonuria is characterized by the accumulation of homogentisic acid which causes dark coloration of urine upon standing, ochronosis, and arthritis. A 4-year old child was referred to our pediatric nephrologist with hyperoxaluria and a history of unexplained pink-to-brown discolouration of his diapers associated with a brown-staining of clothes and skin since he was six months old. He had no other symptoms and his past medical history only included minor child illnesses. His 11-month-old brother had the same dark discoloration of his diapers. Laboratory testing on a spot urine sample showed hyperoxaluria and nephrotic range proteinuria with low creatinine and normal albumin concentrations. Considered causes were hyperoxaluria, alkaptonuria, interfering substance, adulteration. The further diagnostic work-up revealed increased homogentisic acid in urine, compatible with alkaptonuria. Urinary creatinine and total protein measurements on Roche Cobas were, respectively, falsely decreased and increased in the presence of homogentisic acid. The false-low creatinine resulted in an elevated oxalate/creatinine ratio. Alkaptonuria can cause a false increase of results expressed per creatinine and should be excluded in case of an unexplained marked increase of urine total protein without a concomitant increase of albumin.

Background: Apraglutide is a novel long-acting GLP-2 analog in development for short bowel syndrome with intestinal failure (SBS-IF). This multicenter, open-label, phase 2 study in SBS-IF and colon-in-continuity (CiC) investigates the safety and efficacy of apraglutide. Methods: This was a 52-week phase 2 metabolic balance study (MBS) in 9 adult patients with SBS-IF-CiC receiving once-weekly subcutaneous apraglutide injections. Safety was the primary endpoint. Secondary endpoints included changes in absorption parameters (MBS at baseline, after 4 weeks with stable parenteral support (PS), and 48 weeks), PS needs (48-week PS adjustment period based on monthly 48-h fluid balances) and intestinal morphology and motility (static and cine MRI at baseline and 4, 24 and 48 weeks). Results: PS volume decreased by −4702 mL/week (−52 %; p < 0.001) at week 52. Seven patients (78 %) achieved ≥1 day off PS at week 52. At 4 weeks, fecal output was reduced by 253 g/day (p = 0.013). At 48 weeks, increases in wet weight absorption by 316 g/day (p = 0.039), energy absorption by 1134 kJ/day (p = 0.041) and carbohydrate absorption by 56.1 g/day (p = 0.024) were observed. Moreover, small bowel length increased from 29.7 to 40.7 cm (p = 0.012), duodenal wall thickness increased by 0.8 mm (p = 0.02) and motility in the proximal colon was reduced (p = 0.031). A total of 127 adverse events was reported, which were mostly mild to moderate. Conclusion: Apraglutide had an acceptable safety profile and was associated with significant reductions in PS needs and days off PS, improvements in intestinal absorption, and structural and functional intestinal changes in patients with SBS-IF-CiC. ClinicalTrials.gov, Number NCT04964986.

Background: Human serum albumin (HSA) concentrations may alter HSA-bound drug distribution. This study aims to describe longitudinal real-world HSA trends, and to develop a prediction model for HSA concentrations using a large neonatal cohort. Methods: Patients admitted to the neonatal intensive care unit of the University Hospitals Leuven (postnatal age (PNA) ≤28days) were retrospectively included. Using linear mixed models, covariate effects on HSA were explored. A multivariable prediction model was developed (backward model selection procedure, 1% significance level). Results: In total, 848 neonates were included [median(interquartile range) gestational age (GA) 35(32–38)weeks, birth weight (BW) 2400(1640–3130)grams]. Median HSA concentration was 32.3(28.7–35.6)g/L. Longitudinal analyses demonstrated increasing HSA concentrations with PNA and GA for most GA groups. Univariable analyses revealed significant associations of HSA with PNA, GA, BW, current weight, total and direct bilirubin, total plasma proteins, respiratory support, mechanical ventilation, sepsis, ibuprofen use, and C-reactive protein (p-values < 0.05). A high-performance (R 2 = 76.3%) multivariable HSA prediction model was developed, and PNA- and GA-dependent HSA centiles were provided. Conclusion: Population-specific HSA centiles and an accurate neonatal HSA prediction model were developed, incorporating both maturational and non-maturational covariates. These results can enhance future clinical care and pharmacokinetic analyses to improve pharmacotherapy of HSA-bound drugs in neonates, respectively. Impact: To improve future pharmacokinetic modeling initiatives, a high-performance human serum albumin (HSA) prediction model was developed for (pre)term neonates, using a large, single-center cohort of real-world data. This prediction model integrates both maturational and non-maturational covariates, resulting in accurate HSA predictions in neonates. Additionally, HSA centiles based

AIM: Blood Sampling Guidelines have been developed to target European emergency medicine-related professionals involved in the blood sampling process (e.g. physicians, nurses, phlebotomists working in the ED), as well as laboratory physicians and other related professionals. The guidelines population focus on adult patients. The development of these blood sampling guidelines for the ED setting is based on the collaboration of three European scientific societies that have a role to play in the preanalytical phase process: EuSEN, EFLM, and EUSEM. The elaboration of the questions was done using the PICO procedure, literature search and appraisal was based on the GRADE methodology. The final recommendations were reviewed by an international multidisciplinary external review group. RESULTS: The document includes the elaborated recommendations for the selected sixteen questions. Three in pre-sampling, eight regarding sampling, three post-sampling, and two focus on quality assurance. In general, the quality of the evidence is very low, and the strength of the recommendation in all the questions has been rated as weak. The working group in four questions elaborate the recommendations, based mainly on group experience, rating as good practice. CONCLUSIONS: The multidisciplinary working group was considered one of the major contributors to this guideline. The lack of quality information highlights the need for research in this area of the patient care process. The peculiarities of the emergency medical areas need specific considerations to minimise the possibility of errors in the preanalytical phase.

Coronavirus Disease 2019 (COVID-19) vaccination has resulted in excellent protection against fatal disease, including in older adults. However, risk factors for post-vaccination fatal COVID-19 are largely unknown. We comprehensively studied three large nursing home outbreaks (20-35% fatal cases among residents) by combining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) aerosol monitoring, whole-genome phylogenetic analysis and immunovirological profiling of nasal mucosa by digital nCounter transcriptomics. Phylogenetic investigations indicated that each outbreak stemmed from a single introduction event, although with different variants (Delta, Gamma and Mu). SARS-CoV-2 was detected in aerosol samples up to 52 d after the initial infection. Combining demographic, immune and viral parameters, the best predictive models for mortality comprised IFNB1 or age, viral ORF7a and ACE2 receptor transcripts. Comparison with published pre-vaccine fatal COVID-19 transcriptomic and genomic signatures uncovered a unique IRF3 low/IRF7 high immune signature in post-vaccine fatal COVID-19 outbreaks. A multi-layered strategy, including environmental sampling, immunomonitoring and early antiviral therapy, should be considered to prevent post-vaccination COVID-19 mortality in nursing homes., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

IntroductionThe presence of macroenzymes in blood can cause diagnostic confusion. Therefore, confirming the presence of macroenzymes is important to reduce unnecessary (non-)invasive investigations. Polyethylene glycol (PEG) precipitation is a simple and fast first-line method for the detection of macroenzymes. However, there is no consensus on the upper reference limit for the PEG-precipitable activity (%PPA) of monomeric enzymes. The aim of this study was to verify a PEG precipitation protocol for the detection of macroenzymes in our laboratory by establishing upper reference limits (URLs) and determining imprecision for eight enzymes after PEG precipitation. In addition, we aimed to clinically verify the URLs using samples containing macroenzymes as identified by electrophoresis. Materials and methodsPer enzyme, at least 40 leftover blood samples from adult patients with either normal or increased enzyme activities were diluted 1:1 with 25% PEG 6000 and 1:1 with 0.9% NaCl. Mixtures were incubated for 10 min at 37°C and centrifuged. Supernatant enzyme activity was measured on Cobas c702 and the %PPA was calculated. ResultsThe following URLs were obtained: 26% PPA for amylase, 29% PPA for alkaline phosphatase (ALP), 61% PPA for alanine aminotransferase, 48% PPA for aspartate aminotransferase, 24% PPA for creatine kinase (CK), 55% PPA for gamma-glutamyltransferase, 65% PPA for lactate dehydrogenase, and 56% PPA for lipase. The within-lab imprecision was < 15%. Regarding the clinical verification, the two historical samples with proven macroCK showed a %PPA of 69% and 43%, respectively, and a sample with proven macroALP had a %PPA of 52%. ConclusionIn this study, URLs for monomeric enzyme activities after PEG precipitation for eight different enzymes were established. The URLs are suitable for clinical use, but are only partially in line with other studies. Therefore, our data highlight the importance of establishing laboratory-specific upper reference limits for %PP

Neuronal development in the human cerebral cortex is considerably prolonged compared with that of other mammals. We explored whether mitochondria influence the species-specific timing of cortical neuron maturation. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower mitochondria development in human cortical neurons compared with that in the mouse, together with lower mitochondria metabolic activity, particularly that of oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated development in vitro and in vivo, leading to maturation of cells weeks ahead of time, whereas its inhibition in mouse neurons led to decreased rates of maturation. Mitochondria are thus important regulators of the pace of neuronal development underlying human-specific brain neoteny., SCOPUS: ar.j, info:eu-repo/semantics/published