Three years pilot of spinal muscular atrophy newborn screening turned into official program in Southern Belgium.

Three new therapies for spinal muscular atrophy (SMA) have been approved by the United States Food and Drug Administration and the European Medicines Agency since 2016. Although these new therapies improve the quality of life of patients who are symptomatic at first treatment, administration before the onset of symptoms is significantly more effective. As a consequence, newborn screening programs have been initiated in several countries. In 2018, we launched a 3-year pilot program to screen newborns for SMA in the Belgian region of Liège. This program was rapidly expanding to all of Southern Belgium, a region of approximately 55,000 births annually. During the pilot program, 136,339 neonates were tested for deletion of exon 7 of SMN1, the most common cause of SMA. Nine SMA cases with homozygous deletion were identified through this screen. Another patient was identified after presenting with symptoms and was shown to be heterozygous for the SMN1 exon 7 deletion and a point mutation on the opposite allele. These ten patients were treated. The pilot program has now successfully transitioned into the official neonatal screening program in Southern Belgium. The lessons learned during implementation of this pilot program are reported.

Impact of perceived inappropiate cardiopulmonary resuscitation on emergency clinicians' intention to leave the job: Results from a cross-sectional survey in 288 centres across 24 countries.

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.

Cardiopulmonary Resuscitation in Adults Over 80: Outcome and the Perception of Appropriateness by Clinicians.

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.

Perception of inappropriate cardiopulmonary resuscitation by clinicians working in emergency departments and ambulance services: The REAPPROPRIATE international, multi-centre, cross sectional survey.

INTRODUCTION: Cardiopulmonary resuscitation (CPR) is often started irrespective of comorbidity or cause of arrest. We aimed to determine the prevalence of perception of inappropriate CPR of the last cardiac arrest encountered by clinicians working in emergency departments and out-of-hospital, factors associated with perception, and its relation to patient outcome. METHODS: A cross-sectional survey was conducted in 288 centres in 24 countries. Factors associated with perception of CPR and outcome were analyzed by Cochran-Mantel-Haenszel tests and conditional logistic models. RESULTS: Of the 4018 participating clinicians, 3150 (78.4%) perceived their last CPR attempt as appropriate, 548 (13.6%) were uncertain about its appropriateness and 320 (8.0%) perceived inappropriateness; survival to hospital discharge was 370/2412 (15.3%), 8/481 (1.7%) and 8/294 (2.7%) respectively. After adjusting for country, team and clinician's characteristics, the prevalence of perception of inappropriate CPR was higher for a non-shockable initial rhythm (OR 3.76 [2.13-6.64]; P < .0001), a non-witnessed arrest (2.68 [1.89-3.79]; P < .0001), in older patients (2.94 [2.18-3.96]; P < .0001, for patients >79 years) and in case of a "poor" first physical impression of the patient (3.45 [2.36-5.05]; P < .0001). In accordance, non-shockable and non-witnessed arrests were both associated with lower survival to hospital discharge (0.33 [0.26-0.41]; P < 0.0001 and 0.25 [0.15-0.41]; P < 0.0001, respectively), as were older patient age (0.25 [0.14-0.44]; P < 0.0001 for patients >79 years) and a "poor" first physical impression (0.26 [0.19-0.35]; P < 0.0001). CONCLUSIONS: The perception of inappropriate CPR increased when objective indicators of poor prognosis were present and was associated with a low survival to hospital discharge. Factoring clinical judgment into the decision to (not) attempt CPR may reduce harm inflicted by excessive resuscitation attempts.

Quality of resuscitation by first responders using the 'public access resuscitator': a randomized manikin study.

AIM: The CAREvent Public Access Resuscitator (PAR) is an electronic, oxygen-driven cardiopulmonary resuscitation (CPR) device allowing volume-controlled ventilation with a face mask and guiding the rescuer through the resuscitation with voice prompts and visual indications. We hypothesized that 1 year after initial training, the efficacy of ventilation skills (primary outcome) and compression skills (secondary outcome) by first responders using the PAR would be superior compared with CPR with only a face mask. METHODS: Seventy-one first responders were randomized to a group using the PAR (n=35) and a control group using only a face mask (n=36). CPR skills were assessed immediately after training and after 3, 7 and 12 months using a Skill Reporter manikin. Differences between groups over time and the interaction between time and groups were assessed using repeated measures models. Results are reported as mean values and number of participants with good ventilation or compression skills. RESULTS: Twelve months after training, there were more PAR users with adequate tidal volume than face mask users. Other ventilations skills did not differ between groups. There were more PAR users with an adequate number of compressions and with good hand position. Skill decay over 12 months did not differ between groups, except for hand position, where no decline was observed in the PAR group. CONCLUSION: Compared with the face mask, PAR improved tidal volume, compressions per minute and hand position in a manikin setting.

Patients with cardiac arrest are ventilated two times faster than guidelines recommend: an observational prehospital study using tracheal pressure measurement.

AIM: To measure ventilation rate using tracheal airway pressures in prehospitally intubated patients with and without cardiac arrest. METHODS: Prospective observational study. In 98 patients (57 with and 41 without cardiac arrest) an air-filled catheter was inserted into the endotracheal tube and connected to a custom-made portable device allowing tracheal airway pressure recording and subsequent calculation of ventilation rate. RESULTS: In manually ventilated patients with cardiac arrest 39/43 (90%) had median ventilation rates higher than 10/min (overall median 20, min 4, max 74). During mechanical ventilation, 35/38 (92%) had ventilation rates higher than 10/min. The ventilation rate in patients with cardiac arrest was higher than in patients without cardiac arrest, both for manual and mechanical ventilation. Subanalysis comparing episodes with and without compression in cardiac arrest patients showed no clinically significant difference in ventilation rate after compressions were terminated. CONCLUSION: Cardiac arrest patients were ventilated two times faster than recommended by the guidelines. Tracheal airway pressure measurement is feasible during resuscitation and may be developed further to provide real-time feedback on airway pressure and ventilation rate during resuscitation.

Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity.

Stiffness of elastic arteries like the aorta predicts cardiovascular risk. By directly reflecting arterial stiffness, having the best predictive value for cardiovascular outcome and the ease of its measurement, carotid-femoral pulse wave velocity is now considered the gold standard for arterial stiffness assessment in daily practice. Many different measurement procedures have been proposed. Therefore, standardization of its measurement is urgently needed, particularly regarding the distance measurement. This consensus document advises on the measurement procedures in general and provides arguments for the use of 80% of the direct carotid-femoral distance as the most accurate distance estimate. It also advises the use of 10 m/s as new cut-off value for carotid-femoral pulse wave velocity.

Nurse-led education and counselling to enhance adherence to phosphate binders.

AIMS AND OBJECTIVES: To investigate whether nurse-led education and counselling enhance phosphate binder adherence in chronic dialysis patients. BACKGROUND: One in two chronic dialysis patients experiences difficulties in adhering to phosphate binders. The reasons for non-adherence are multifactorial and accordingly require a multifaceted strategy. To date, investigations have been confined primarily to single interventions to promote adherence. This study examines the effect of a multifaceted approach. DESIGN: The design was interventional. METHOD: Adherence to phosphate binders was blindly and electronically monitored for 17 consecutive weeks with the Medication Event Monitoring System (MEMS). After four weeks baseline monitoring, the effects of the intervention were studied for an additional 13 weeks. In week 5, the study nurse gave all 41 participating patients education on phosphate binders. Thereafter, the study nurse gave bi-weekly personalised counselling to enhance adherence to phosphate binders. The evolution of adherence over time was assessed and compared with historical control data. Secondary outcome variables included serum values of phosphate, calcium and parathyroid hormone and phosphate binder knowledge. RESULTS: In week 1, mean adherence was 83% in this study (intervention group), compared with 86% in the historical control group. In the intervention group, mean adherence increased from 83-94% after 13 weeks. By contrast, in the historical control group, mean adherence declined from 86-76%. In the intervention group, serum phosphate values decreased from 4·9-4·3 mg/dl and phosphate binder knowledge increased from a mean score of 53-75%. CONCLUSIONS: Combining education and continuous counselling holds promise in enhancing phosphate binder adherence. Large-scaled and long-term field studies are indicated to determine which nurse-led practices lead to an integral and sustained medication adherence management. RELEVANCE TO CLINICAL PRACTICE: Nursing strategies to scale up adherence should at least include educating patients and regularly reinforcing adherence behaviour.

Carotid to femoral pulse wave velocity: a comparison of real travelled aortic path lengths determined by MRI and superficial measurements.

OBJECTIVES: Carotid-femoral pulse wave velocity (PWV) is the gold standard method for determination of arterial stiffness. PWV is assessed by dividing travelled distance by travel time. Standardization and validation of the methodology for travelled distance measurement is of crucial importance. The aim of the current investigation was to standardize and validate the methodology for travelled distance measurement. METHODS: Real travelled carotid-femoral path lengths were measured with MRI in 98 healthy men/women (50% men, age 21-76 years) and are used as reference distance. This reference distance was compared with 11 estimates of aortic path length from body surface distances commonly used in PWV measurement, nine of them based on tape measures and two based on body height. Determinants of the difference between reference distance and the best body surface distance were determined. Additionally, the influence of body contours was identified. RESULTS: The tape measure distance from carotid to femoral artery (CA-FA), multiplied by 0.8, yielded the best agreement with the reference aortic path length [difference 0.26 cm (SD 3.8), not statistically significant]. Thirty percent of the variation in difference between the reference distance and tape measure distance (CA-FA × 0.8) was explained by age. Adding BMI increased this number to 34%. CONCLUSION: The tape measure distance from CA-FA, multiplied by 0.8, corresponds best with the real travelled aortic path length. This distance is moderately (yet statistically significantly) influenced by age and minimally by BMI.

Peroxisome dynamics in cultured mammalian cells.

Despite the identification and characterization of various proteins that are essential for peroxisome biogenesis, the origin and the turnover of peroxisomes are still unresolved critical issues. In this study, we used the HaloTag technology as a new approach to examine peroxisome dynamics in cultured mammalian cells. This technology is based on the formation of a covalent bond between the HaloTag protein--a mutated bacterial dehalogenase which is fused to the protein of interest--and a synthetic haloalkane ligand that contains a fluorophore or affinity tag. By using cell-permeable ligands of distinct fluorescence, it is possible to image distinct pools of newly synthesized proteins, generated from a single genetic HaloTag-containing construct, at different wavelengths. Here, we show that peroxisomes display an age-related heterogeneity with respect to their capacity to incorporate newly synthesized proteins. We also demonstrate that these organelles do not exchange their protein content. In addition, we present evidence that the matrix protein content of pre-existing peroxisomes is not evenly distributed over new organelles. Finally, we show that peroxisomes in cultured mammalian cells, under basal growth conditions, have a half-life of approximately 2 days and are mainly degraded by an autophagy-related mechanism. The implications of these findings are discussed.

Small G proteins in peroxisome biogenesis: the potential involvement of ADP-ribosylation factor 6.

BACKGROUND: Peroxisomes execute diverse and vital functions in virtually every eukaryote. New peroxisomes form by budding from pre-existing organelles or de novo by vesiculation of the ER. It has been suggested that ADP-ribosylation factors and COPI coatomer complexes are involved in these processes. RESULTS: Here we show that all viable Saccharomyces cerevisiae strains deficient in one of the small GTPases which have an important role in the regulation of vesicular transport contain functional peroxisomes, and that the number of these organelles in oleate-grown cells is significantly upregulated in the arf1 and arf3 null strains compared to the wild-type strain. In addition, we provide evidence that a portion of endogenous Arf6, the mammalian orthologue of yeast Arf3, is associated with the cytoplasmic face of rat liver peroxisomes. Despite this, ablation of Arf6 did neither influence the regulation of peroxisome abundance nor affect the localization of peroxisomal proteins in cultured fetal hepatocytes. However, co-overexpression of wild-type, GTP hydrolysis-defective or (dominant-negative) GTP binding-defective forms of Arf1 and Arf6 caused mislocalization of newly-synthesized peroxisomal proteins and resulted in an alteration of peroxisome morphology. CONCLUSION: These observations suggest that Arf6 is a key player in mammalian peroxisome biogenesis. In addition, they also lend strong support to and extend the concept that specific Arf isoform pairs may act in tandem to regulate exclusive trafficking pathways.

Properties of the ubiquitin-pex5p thiol ester conjugate.

Pex5p, the peroxisomal protein cycling receptor, binds newly synthesized peroxisomal matrix proteins in the cytosol and promotes their translocation across the organelle membrane. During its transient passage through the membrane, Pex5p is monoubiquitinated at a conserved cysteine residue, a requisite for its subsequent ATP-dependent export back into the cytosol. Here we describe the properties of the soluble and membrane-bound monoubiquitinated Pex5p species (Ub-Pex5p). Our data suggest that 1) Ub-Pex5p is deubiquitinated by a combination of context-dependent enzymatic and nonenzymatic mechanisms; 2) soluble Ub-Pex5p retains the capacity to interact with the peroxisomal import machinery in a cargo-dependent manner; and 3) substitution of the conserved cysteine residue of Pex5p by a lysine results in a quite functional protein both in vitro and in vivo. Additionally, we show that MG132, a proteasome inhibitor, blocks the import of a peroxisomal reporter protein in vivo.

Identification of a novel PEX14 mutation in Zellweger syndrome.

Here we report a patient with Zellweger syndrome, who presented at the age of 3 months with icterus, dystrophy, axial hypotonia, and hepatomegaly. Abnormal findings of metabolic screening tests included hyperbilirubinaemia, hypoketotic dicarboxylic aciduria, increased C(26:0) and decreased C(22:0) plasma levels, and strongly reduced plasmalogen concentrations. In fibroblasts, both peroxisomal α- and ß-oxidation were impaired. Liver histology revealed bile duct paucity, cholestasis, arterial hyperplasia, very small branches of the vena portae, and parenchymatic destruction. Immunocytochemical analysis of cultured fibroblasts demonstrated that the cells contain peroxisomal remnants lacking apparent matrix protein content and PEX14, a central membrane component of the peroxisomal matrix protein import machinery. Transfection of fibroblasts with a plasmid coding for wild-type PEX14 restored peroxisomal matrix protein import. Mutational analysis of this gene revealed a genomic deletion leading to the deletion of exon 3 from the coding DNA (c.85-?_170+?del) and a concomitant change of the reading frame (p.[Ile29_Lys56del;Gly57GlyfsX2]).