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Background and Objectives: Discharge from the emergency department (ED) involves a complex series of steps to ensure a safe transition to home and follow-up care. Preventable, discharge-related serious safety events (SSEs) in our ED highlighted local vulnerabilities. We aimed to improve ED discharge by implementing a standardized discharge process with emphasis on multidisciplinary communication and family engagement., Methods: At a tertiary children's hospital, we used the model for improvement to revise discharge care. Interventions included a new discharge checklist, a provider huddle emphasizing discharge vital signs, and a scripted discharge review of instructions with families. We used statistical process control to evaluate performance. Primary outcomes included elimination of preventable, discharge-related SSEs and Press Ganey survey results assessing caregiver information for care of child at home. A secondary outcome was number of days between preventable low-level (near-miss, no or minimal harm) events. Process measures included discharge checklist adoption and vital sign acquisition. Balancing measures were length of stay (LOS) and return rates., Results: Over the study period, there were no preventable SSEs and low-level event frequency improved to a peak of >150 days between events. Press Ganey responses regarding quality of discharge information did not change (62%). Checklist use was rapidly adopted, reaching 94%. Vital sign acquisition increased from 67% to 83%. There was no change in the balancing measures of median LOS or return visit rates., Conclusions: The development and implementation of a standardized discharge process led to the elimination of reported discharge-related events, without increasing LOS or return visits., (Copyright © 2022 by the American Academy of Pediatrics.)

Anderson-Fabry Disease (AFD) is a rare, X-linked inborn error of glycosphingolipid catabolism caused by a deficient or absent activity of the lysosomal enzyme, α-galactosidase A, resulting in the progressive multisystem lysosomal accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3). Among the wide spectrum of clinical signs and symptoms and the life-threatening complications of Fabry disease, renal failure causes significant morbidity and mortality. Various evidence shows that the accumulation of Gb3 in different renal cells is present since the first years of life, many years and usually decades before manifest symptoms and signs of renal involvement. Early renal damage can be demonstrated by clinical signs as microalbuminuria and proteinuria, developing as early as in the second decade of life. A decline in GFR is uncommon at paediatric ages but may be seen as early as adolescence. Renal biopsy is rarely used in paediatric patients with Fabry disease although evidence shows that it may be considered a valid tool for the diagnosis of early and potentially reversible nephropathy, as well as for the evaluation of the effectiveness of enzyme replacement therapy (ERT). Although there is consensus in considering the early initiation of ERT as the only tool able to prevent the progression of nephropathy, the issue on the correct timing for the onset of ERT in pediatric age remains open in the management of this chronic and progressive disease., (Copyright 2019 Biolife Sas. www.biolifesas.org.)

Alport's syndrome (AS, OMIM 301050) is a hereditary disorder characterized by progressive renal failure, hearing impairment and ocular changes. It is clinically and genetically heterogeneous and in its natural history, renal disease progresses from microscopic haematuria to proteinuria, and finally to progressive renal insufficiency. AS is caused by an inherited defect in a type IV collagen, a structural material, expressed in many tissues that is essential for the normal function of different parts of the body. In most of cases, about the 85%, Alport's syndrome is X-linked and is originated by mutations in the COL4A5 gene. In the remaining cases, it may be inherited in either an autosomal recessive, or rarely in an autosomal dominant manner. Mostly, the condition is caused by mutations in the COL4A3 or COL4A4 genes. Coexisting mutations in COL4A3, COL4A4, COL4A5 or COL4A6 were found to cause an Alport's syndrome phenotype with digenic inheritance. Diagnosis of the condition is based on family history, clinical signs, and specific procedures such as a kidney biopsy. The diagnosis can be confirmed by genetic testing. Treatment may include use of a hearing aid, hemodialysis, and peritoneal dialysis to treat those with end-stage renal failure, and, as the last step, kidney transplantation. Firstly described by Arthur C. Alport's, in 1927, over the years it has become a pathology of high scientific interest. At the moment, thanks to advances in diagnostic techniques, it is possible to make an early diagnosis avoiding irreversible damages and life -threatening complications., (Copyright 2019 Biolife Sas. www.biolifesas.org.)

Clericuzio-type poikiloderma with neutropenia is a well-defined nosological entity, but despite a remarkable number of clinical reports, no long term follow-up data has been presented to date regarding patients with this rare condition. Here we describe the results of clinical follow-up of three siblings, one male (Patient 1) and two females (Patients 2 and 3), subsequent to their first clinical and then molecular diagnosis of Clericuzio-type poikiloderma with neutropenia syndrome due to mutation of USB1gene. Patient 1 always expressed the most severe phenotype, while patients 2 and 3 showed an intermediate and mild phenotype, respectively, as observed since their first clinical evaluation. None of the patients developed skin cancer and/or myelodysplastic disorders considering the peripheral haematological findings. Lens opacity, never reported before, was found in two of the three patients. The long term follow-up observations confirm the stability over time of the pronounced intra-familial heterogeneity of clinical manifestations observed prior to and upon molecular diagnosis. We conclude that prolonged follow-up is an adjunct tool to monitor intra-familial variability of PN clinical spectrum which may favour surveillance of more serious complications of the disease among siblings, when a patient-specific clinical expressivity is present., (Copyright © 2018. Published by Elsevier Masson SAS.)

Enzyme replacement therapy (ERT) has been widely used for the treatment of Fabry disease, a rare X-linked recessive disorder due to absent or reduced activity of lysosomal enzyme α-galactosidase A. It is still unclear why some patients under ERT show disease progression typically with renal, cardiovascular and cerebrovascular dysfunctions. Here, we investigated the involvement of drug absorption, distribution, metabolism, and excretion gene variants in response variability to ERT, genotyping 37 patients with the Affymetrix Drug Metabolizing Enzyme and Transporters (DMET) Plus microarray. We found three single nucleotide polymorphisms in human alcohol dehydrogenase (ADH)4 gene (rs1126670, rs1126671, rs2032349) and one in ADH5 gene (rs2602836) associated with disease progression ( p < 0.05). Our data provide a basic tool for identification of patient with ERT non-response risk that may represent a framework for personalized treatment of this rare disease., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

The chemical cross-linking/mass spectrometry (MS) approach is gaining increasing importance as an alternative method for studying protein conformation and for deciphering protein interaction networks. This study is part of our ongoing efforts to develop innovative cross-linking principles for a facile and efficient assignment of cross-linked products. We evaluate two homobifunctional, amine-reactive, and MS-cleavable cross-linkers regarding their potential for automated analysis of cross-linked products. We introduce the bromine phenylurea (BrPU) linker that possesses a unique structure yielding a distinctive fragmentation pattern on collisional activation. Moreover, BrPU delivers the characteristic bromine isotope pattern and mass defect for all cross-linker-decorated fragments. We compare the fragmentation behavior of the BrPU linker with that of our previously described MS-cleavable TEMPO-Bz linker (which consists of a 2,2,6,6-tetramethylpiperidine-1-oxy moiety connected to a benzyl group) that was developed to perform free-radical-initiated peptide sequencing. Comparative collisional activation experiments (collision-induced dissociation and higher-energy collision-induced dissociation) with both cross-linkers were conducted in negative electrospray ionization mode with an Orbitrap Fusion mass spectrometer using five model peptides. As hypothesized in a previous study, the presence of a cross-linked N-terminal aspartic acid residue seems to be the prerequisite for the loss of an intact peptide from the cross-linked products. As the BrPU linker combines a characteristic mass shift with an isotope signature, it presents a more favorable combination for automated assignment of cross-linked products compared with the TEMPO-Bz linker. ᅟ.

The Norrbottnian type of Gaucher disease (GD), as described many years ago, is due to a unique neuronopathic variant (c.1448T>G; L444P) that may have appeared during or before the sixteenth century in northern Sweden. It is a well-defined nosological entity with a characteristic course of clinical manifestations. In particular, Norrbottnian patients described in Sweden and Poland seem to share identical clinical histories characterized by the early onset of significant hepatosplenomegaly, often requiring splenectomy at an early age. Neurological involvement generally appears during the first or second decade of life, and includes horizontal gaze palsy, epilepsy, myoclonic movements, ataxia, dementia and cognitive impairment. Osteopenia occurs primarily in the spine, causing a severe and progressive thoracic kyphosis, although the involvement of other skeletal sites cannot be excluded. Here, we report on four Gaucher type 3 patients with Southern Italian ancestry presenting with clinical features and disease progression comparable to those of the 'Norrbottnian' Swedish phenotype, particularly regarding skeletal involvement with poor responsiveness to any therapeutical approach. Although a common ancestry among Southern Italian and Swedish Norrbottnian GD patients could not be investigated, the genotype [L444P]+[L444P] is the most frequently encountered in Southern Italy.

Background: The variants of neuronopathic Gaucher disease may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The chronic neuronopathic form of Gaucher disease is characterized by a later onset of neurological symptoms and protracted neurological and visceral involvement. The first-choice treatment for nonneuronopathic Gaucher disease is enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase. Enzyme replacement therapy has been shown to improve hematological and bone manifestations associated with Gaucher disease, but, as with most proteins, recombinant enzymes cannot cross the blood-brain barrier, which prevents effects on neurological manifestations. Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin) inhibits glucosylceramide synthase, which catalyzes the first step in glycosphingolipid synthesis. Because miglustat can cross the blood-brain barrier, it has been suggested that, combined with enzyme replacement therapy, it might be effective in treating neurological symptoms in patients with neuronopathic Gaucher disease., Case Presentation: We report observed effects of combined enzyme replacement therapy and substrate reduction therapy in a 7-year-old Caucasian boy with neuronopathic Gaucher disease who was homozygous for L444P mutations. He had received enzyme replacement therapy from the age of 18 months, and concomitant miglustat treatment was commenced, with dosing according to body surface area uptitrated over 1 month with dietary modifications when he reached the age of 30 months. He experienced mild diarrhea after commencing miglustat therapy, which decreased in frequency/severity over time. His splenomegaly was reduced, and his hematological values and plasma angiotensin-converting enzyme activity normalized. Plasma chitotriosidase also showed substantial and sustained decreases. After 5 years of combination therapy, the patient showed no signs of neurological impairment., Conclusions: This case supports the concept that oral miglustat in combination with intravenous enzyme replacement therapy may be beneficial in preventing neurological signs in patients with chronic neuronopathic Gaucher disease. The importance of dietary modifications has also been confirmed. Further follow-up studies are needed to better define the therapeutic effect of combined treatment in this Gaucher disease subtype.

We have synthesized a homobifunctional active ester cross-linking reagent containing a TEMPO (2,2,6,6-tetramethylpiperidine-1-oxy) moiety connected to a benzyl group (Bz), termed TEMPO-Bz-linker. The aim for designing this novel cross-linker was to facilitate MS analysis of cross-linked products by free radical initiated peptide sequencing (FRIPS). The TEMPO-Bz-linker was reacted with all 20 proteinogenic amino acids as well as with model peptides to gain detailed insights into its fragmentation mechanism upon collision activation. The final goal of this proof-of-principle study was to evaluate the potential of the TEMPO-Bz-linker for chemical cross-linking studies to derive 3D-structure information of proteins. Our studies were motivated by the well documented instability of the central NO-C bond of TEMPO-Bz reagents upon collision activation. The fragmentation of this specific bond was investigated in respect to charge states and amino acid composition of a large set of precursor ions resulting in the identification of two distinct fragmentation pathways. Molecular ions with highly basic residues are able to keep the charge carriers located, i.e. protons or sodium cations, and consequently decompose via a homolytic cleavage of the NO-C bond of the TEMPO-Bz-linker. This leads to the formation of complementary open-shell peptide radical cations, while precursor ions that are protonated at the TEMPO-Bz-linker itself exhibit a charge-driven formation of even-electron product ions upon collision activation. MS(3) product ion experiments provided amino acid sequence information and allowed determining the cross-linking site. Our study fully characterizes the CID behavior of the TEMPO-Bz-linker and demonstrates its potential, but also its limitations for chemical cross-linking applications utilizing the special features of open-shell peptide ions on the basis of selective tandem MS analysis., (Copyright © 2015 John Wiley & Sons, Ltd.)