Epidemiology of physician interventions in maritime environment by the Marseille Fire Brigade (BMPM) from 2005 to 2017.

BACKGROUND: Marseille is the second largest city in France. The Marseille Fire Brigade (BMPM) is the largestunity of the French Navy. This organization is in charge of rescue operations and medical intervention in theMarseille area. The aim of the study was to describe the epidemiology of interventions that required a physicianto be present that were performed by the BMPM between the years of 2005 to 2017. MATERIALS AND METHODS: The statistical office database of the BMPM and the medical interventions forms (FIM)acquired from the BMPM medical ambulances (SMUR) archives were analysed from the years 2005 to 2017. RESULTS: The BMPM performed a total of 2,375 interventions in the maritime environment between 2005and 2017. A physician was necessary for intervention a total of 186 times. The extraction and analysisreports of 107 medical intervention forms found the BMPM archives revealed a significant number ofinterventions (67%) in the southern bay of Marseille and Frioul, specifically from the If and Planier islands.The majority of interventions (77%) took place within the 300m band. The most common cause of medicalintervention was due to an accidental fall into the water, followed by boating (sailing and motor), and swimming.Drowning was the most common cause of mortality, consisting of 34% of all interventions. Divingaccidents represented 14% of interventions. Trauma affected 22% of the study population and 83% oftrauma patients were transported to the hospital under the supervision of a physician. CONCLUSIONS: Potential areas for improvement in the management of drowning victims are the use ofSzpilman's classification, sonography, and non-invasive ventilation. A recertification course for medicaleducation training of BMPM doctors on the management of diving accidents could help to optimize theinformation recorded on FIM. Accident prevention training should be continued and reinforced when itcomes to maritime activities.

Erythroid-Progenitor-Targeted Gene Therapy Using Bifunctional TFR1 Ligand-Peptides in Human Erythropoietic Protoporphyria.

Erythropoietic protoporphyria (EPP) is a hereditary disease characterized by a deficiency in ferrochelatase (FECH) activity. FECH activity is responsible for the accumulation of protoporphyrin IX (PPIX). Without etiopathogenic treatment, EPP manifests as severe photosensitivity. 95% of affected individuals present a hypomorphic FECH allele trans to a loss-of-function (LOF) FECH mutation, resulting in a reduction in FECH activity in erythroblasts below a critical threshold. The hypomorphic allele promotes the use of a cryptic acceptor splice site, generating an aberrant FECH mRNA, which is responsible for the reduced level of wild-type FECH mRNA and, ultimately, FECH activity. We have previously identified an antisense oligonucleotide (AON), AON-V1 (V1), that redirects splicing to the physiological acceptor site and reduces the accumulation of PPIX. Here, we developed a specific strategy that uses transferrin receptor 1 (TRF1) as a Trojan horse to deliver V1 to erythroid progenitors. We designed a bifunctional peptide (P1-9R) including a TFR1-targeting peptide coupled to a nine-arginine cell-penetrating peptide (CPP) that facilitates the release of the AON from TFR1 in endosomal vesicles. We demonstrated that the P1-9R/V1 nanocomplex promotes the efficient and prolonged redirection of splicing towards the physiological splice site and subsequent normalization of WT FECH mRNA and protein levels. Finally, the P1-9R/V1 nanocomplex increases WT FECH mRNA production and significantly decreases PPIX accumulation in primary cultures of differentiating erythroid progenitors from an overt EPP-affected individual. P1-9R is a method designed to target erythroid progenitors and represents a potentially powerful tool for the in vivo delivery of therapeutic DNA in many erythroid disorders.

From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria.

Acute intermittent porphyria (AIP) is a disease affecting the heme biosynthesis pathway caused by mutations of the hydroxymethylbilane synthase (HMBS) gene. AIP is thought to display autosomal dominant inheritance with incomplete penetrance. We evaluated the prevalence, penetrance and heritability of AIP, in families with the disease from the French reference center for porphyria (CFP) (602 overt patients; 1968 relatives) and the general population, using Exome Variant Server (EVS; 12 990 alleles) data. The pathogenicity of the 42 missense variants identified was assessed in silico, and in vitro, by measuring residual HMBS activity of the recombinant protein. The minimal estimated prevalence of AIP in the general population was 1/1299. Thus, 50 000 subjects would be expected to carry the AIP genetic trait in France. Penetrance was estimated at 22.9% in families with AIP, but at only 0.5-1% in the general population. Intrafamily correlation studies showed correlations to be strong overall and modulated by kinship and the area in which the person was living, demonstrating strong influences of genetic and environmental modifiers on inheritance. Null alleles were associated with a more severe phenotype and a higher penetrance than for other mutant alleles. In conclusion, the striking difference in the penetrance of HMBS mutations between the general population and the French AIP families suggests that AIP inheritance does not follow the classical autosomal dominant model, instead of being modulated by strong environmental and genetic factors independent from HMBS. An oligogenic inheritance model with environmental modifiers might better explain AIP penetrance and heritability.

Mitochondrial energetic defects in muscle and brain of a Hmbs-/- mouse model of acute intermittent porphyria.

Acute intermittent porphyria (AIP), an autosomal dominant metabolic disease (MIM #176000), is due to a deficiency of hydroxymethylbilane synthase (HMBS), which catalyzes the third step of the heme biosynthetic pathway. The clinical expression of the disease is mainly neurological, involving the autonomous, central and peripheral nervous systems. We explored mitochondrial oxidative phosphorylation (OXPHOS) in the brain and skeletal muscle of the Hmbs(-/-) mouse model first in the basal state (BS), and then after induction of the disease with phenobarbital and treatment with heme arginate (HA). The modification of the respiratory parameters, determined in mice in the BS, reflected a spontaneous metabolic energetic adaptation to HMBS deficiency. Phenobarbital induced a sharp alteration of the oxidative metabolism with a significant decrease of ATP production in skeletal muscle that was restored by treatment with HA. This OXPHOS defect was due to deficiencies in complexes I and II in the skeletal muscle whereas all four respiratory chain complexes were affected in the brain. To date, the pathogenesis of AIP has been mainly attributed to the neurotoxicity of aminolevulinic acid and heme deficiency. Our results show that mitochondrial energetic failure also plays an important role in the expression of the disease.

Humidified high flow nasal oxygen during respiratory failure in the emergency department: feasibility and efficacy.

OBJECTIVE: Heated and humidified high flow nasal cannula oxygen therapy (HFNC) represents a new alternative to conventional oxygen therapy that has not been evaluated in the emergency department (ED). We aimed to study its feasibility and efficacy in patients exhibiting acute respiratory failure presenting to the ED. METHODS: Prospective, observational study in a university hospital's ED. Patients with acute respiratory failure requiring > 9 L/min oxygen or with ongoing clinical signs of respiratory distress despite oxygen therapy were included. The device of oxygen administration was then switched from non-rebreathing mask to HFNC. Dyspnea, rated by the Borg scale and a visual analog scale, respiratory rate, and S(pO(2)) were collected before and 15, 30, and 60 min after beginning HFNC. Feasibility was assessed through caregivers' acceptance of the device in terms of practicality and perceived effect on the subjects, evaluated by questionnaire. RESULTS: Seventeen subjects, median age 64 y (46-84.7 y), were studied. Pneumonia was the most common reason for oxygen therapy (n = 9). HFNC was associated with a significant decrease in both dyspnea scores: Borg scale from 6 (5-7) to 3 (2-4) (P < .001), and visual analog scale from 7 (5-8) to 3 (1-5) (P < .01). Respiratory rate decreased from 28 breaths/min (25-32 breaths/min) to 25 breaths/min (21-28 breaths/min) (P < .001), and S(pO(2)) increased from 90% (88.5-94%) to 97% (92.5-100%) (P < .001). Fewer subjects exhibited clinical signs of respiratory distress (10/17 vs 3/17, P = .03). HFNC was well tolerated and no adverse event was noted. Altogether, 76% of healthcare givers declared preferring HFNC, as compared to conventional oxygen therapy. CONCLUSIONS: HFNC is possible in the ED, and it alleviated dyspnea and improved respiratory parameters in subjects with acute hypoxemic respiratory failure.

Impact of high-flow nasal cannula oxygen therapy on intensive care unit patients with acute respiratory failure: a prospective observational study.

PURPOSE: The purpose of this study was to determine the impact of high-flow nasal cannula oxygen (HFNC) on patients with acute respiratory failure (ARF) in comparison with conventional oxygen therapy. MATERIALS AND METHODS: This was a prospective observational study. Patients with persistent ARF despite oxygen with conventional facemask without indication for immediate intubation were treated with HFNC oxygen. Clinical respiratory parameters and arterial blood gases were compared under conventional and HFNC oxygen therapy. RESULTS: Twenty patients, aged 59 years (38-75 years) and SAPS2 (simplified acute physiology score) 33 (26.5-38), were included in the study. Etiology of ARF was mainly pneumonia (n = 11), sepsis (n = 3), and miscellaneous (n = 6). Use of HFNC enabled a significant reduction of respiratory rate, 28 (26-33) vs 24.5 (23-28.5) breath per minute (P = .006), and a significant increase in oxygen saturation, oxygen saturation as measured by pulse oximetry 93.5% (90-98.5) vs 98.5% (95.5-100) (P = .0003). Use of HFNC significantly increased Pao(2) from 8.73 (7.13-11.13) to 15.27 (9.66-25.6) kPa (P = .001) and moderately increased Paco(2), 5.26 (4.33-5.66) to 5.73 (4.8-6.2) kPa (P = .005) without affecting pH. Median duration of HFNC was 26.5 (17-121) hours. Six patients were secondarily intubated, and 3 died in the intensive care unit. CONCLUSION: Use of HFNC in patients with persistent ARF was associated with significant and sustained improvement of both clinical and biologic parameters.