Transcriptional Dysregulation and Impaired Neuronal Activity in FMR1 Knock-Out and Fragile X Patients' iPSC-Derived Models.

Fragile X syndrome (FXS) is caused by a repression of the FMR1 gene that codes the Fragile X mental retardation protein (FMRP), an RNA binding protein involved in processes that are crucial for proper brain development. To better understand the consequences of the absence of FMRP, we analyzed gene expression profiles and activities of cortical neural progenitor cells (NPCs) and neurons obtained from FXS patients' induced pluripotent stem cells (IPSCs) and IPSC-derived cells from FMR1 knock-out engineered using CRISPR-CAS9 technology. Multielectrode array recordings revealed in FMR1 KO and FXS patient cells, decreased mean firing rates; activities blocked by tetrodotoxin application. Increased expression of presynaptic mRNA and transcription factors involved in the forebrain specification and decreased levels of mRNA coding AMPA and NMDA subunits were observed using RNA sequencing on FMR1 KO neurons and validated using quantitative PCR in both models. Intriguingly, 40% of the differentially expressed genes were commonly deregulated between NPCs and differentiating neurons with significant enrichments in FMRP targets and autism-related genes found amongst downregulated genes. Our findings suggest that the absence of FMRP affects transcriptional profiles since the NPC stage, and leads to impaired activity and neuronal differentiation over time, which illustrates the critical role of FMRP protein in neuronal development.

Cardiac Arrest Management in the Workplace: Improving but Not Enough?

The aim was to describe out-of-hospital cardiac arrest (OHCA) occurring in the workplace of a large emergency network, and compare the evolution of their management in the last 15 years. A retrospective study based on data from the Northern Alps Emergency Network compared characteristics of OHCA between cases in and out the workplace, and between cases occurring from January 2004 to December 2010 and from January 2011 to December 2017. Among the 15,320 OHCA cases included, 320 occurred in the workplace (2.1%). They were more often in younger men, and happened more frequently in an area with access to public defibrillation, had more often a shockable rhythm, had a cardiopulmonary resuscitation started by a bystander more frequently, and had a better outcome. Cardiopulmonary resuscitation started by a bystander was the only chain of survival link that improved for cases occurring after December 2010. Workplace OHCA seems to be managed more effectively than others; however, only a slight survival improvement was observed, suggesting that progress is still needed.

Door-in to door-out times in acute ST-segment elevation myocardial infarction in emergency departments of non-interventional hospitals: A cohort study.

In France, one in eight patients with acute ST-segment elevation myocardial infarction (STEMI) is admitted direct to an emergency department (ED) in a hospital without percutaneous coronary intervention (PCI) facilities. Guidelines recommend transfer to a PCI center, with a door-in to door-out (DI-DO) time of ≤30 min. We report DI-DO times and identify the main factors affecting them.RESURCOR is a French Northern Alps registry of patients with STEMI of <12 h duration. We focused on patients admitted direct, without prehospital medical care, to EDs in 19 non-PCI centers from 2012 to 2014. We divided DI-DO time into diagnostic time (ED admission to call for transfer) and logistical time (call for transfer to ED discharge).Among 2007 patients, 240 were admitted direct to EDs in non-PCI centers; 57.9% were treated with primary angioplasty and 32.9% received thrombolysis. Median (interquartile range) DI-DO time was 92.5 (67-143) min, with a diagnostic time of 41 (23-74) min and a logistical time of 47.5 (32-69) min. Five patients (2.1%) had a DI-DO time ≤30 min. Five variables were independently associated with a shorter DI-DO time: local transfer (mobile intensive care unit [MICU] team available at referring ED) (P = .017) or transfer by air ambulance (P = .004); shorter distance from referring ED to PCI center (P < .001); shorter time from symptom onset to ED admission (P = .002); thrombolysis (P = .006); and extended myocardial infarction (P = .007).In view of longer-than-recommended DI-DO times, efforts are required to promote urgent local transfer and use of thrombolysis.

Age-Related Differences in Reperfusion Therapy and Outcomes for ST-Segment Elevation Myocardial Infarction.

OBJECTIVES: To compare timely access to reperfusion therapy and outcomes according to age of older adults with ST-segment elevation myocardial infarction (STEM) managed within an integrated regional system of care. DESIGN: Ongoing, prospective, regional, hospital-based clinical registry. SETTING: Twenty-three public and private hospitals in the Northern Alps in France. PARTICIPANTS: Individuals presenting with STEMI evolving for less than 12 hours from symptom onset between January 2009 and December 2015 (N=4,813; 3,716 (77.2%) <75, 782 (16.2%) 75-84, 315 (6.5%) ≥85). MEASUREMENTS: Delivery of any reperfusion therapy (primary percutaneous coronary intervention (PCI), intravenous fibrinolysis), primary PCI, and timely reperfusion therapy and in-hospital outcomes. RESULTS: The percentages of patients receiving any reperfusion therapy were 92.9% for those younger than 75, 89.0% for those aged 75 to 84, and 78.7% for those aged 85 and older (P < .001). The percentages of patients undergoing primary PCI were 63.7%, 70.3%, 72.4% (P < .001); and the percentages of patients receiving timely delivery of reperfusion therapy were 44.6%, 36.8%, 29.9% (P < .001). In-hospital all-cause mortality was 3.4% for those younger than 75, 10.2% for those aged 75 to 84, and 19.8% for those aged 85 and older (P <.001). In multivariable analysis adjusting for baseline characteristics, timely delivery of reperfusion therapy was associated with lower in-hospital mortality (adjusted odds ratio=0.63, 95% confidence interval=0.46-0.85) with no significant heterogeneity between age groups (P-value for interaction = .45). CONCLUSION: Older adults meeting contemporary eligibility criteria for reperfusion therapy continue to receive delayed reperfusion therapy and experience higher mortality than their younger counterparts.

Survival of cardiac arrest patients on ski slopes: A 10-year analysis of the Northern French Alps Emergency Network.

AIM: Intense physical activity, cold and altitude make mountain sports a cause of increased risk of out-of-hospital cardiac arrest (OHCA). The difficulties of pre-hospital management related to this challenging environment could be mitigated by the presence of ski-patrollers in ski areas and use of helicopters for medical rescue. We assess whether this particular situation positively impacts the chain of survival compared to the general population. METHODS: Analysis of prospectively collected data from the cardiac arrest registry of the Northern French Alps Emergency Network (RENAU) from 2004 to 2014. RESULTS: 19,341 OHCAs were recorded during the period, including 136 on-slope events. Compared to other OHCAs, on-slope patients were younger (56 [40-65] vs. 66 [52-79] years, p<0.001) and more often in shockable initial rhythm (41.2% vs 20.1%, p<0.001). Resuscitation was more frequently started by a witness (43.4% vs 26.8%, p<0.001) and the time to the first electric shock was shorter (7.5min vs 14min, p<0.001), whereas time to the advanced life support (ALS) rescue arrival did not differ. The 30-day survival rate was higher for on-slope arrests (21.3% vs 5.9%, p<0.001, RR=3.61). In multivariate analysis, on-slope CA remained a positive 30-day survival factor with a 2.6 odds ratio (95% confidence interval, 1.42-4.81, p=0.002). CONCLUSION: Despite difficult access and management conditions, patients undergoing OHCAs on ski slopes presented a higher survival rate, possibly explained by a healthier population, the efficiency of resuscitation by ski-patrols and similar time to ALS facilities compared to other cardiac arrests.