Uncovering the WWTR1::NCOA2 Gene fusion in low-grade myoepithelial-rich neoplasm with HMGA2 expression: A case report.

We describe a case of a pleomorphic adenoma (PA) arising from the para-tracheal accessory salivary gland in a 44-year-old male harboring a novel WWTR1::NCOA2 gene fusion. To our knowledge, this novel gene fusion has not been described previously in salivary gland tumors. The patient presented with hoarseness of voice. The radiological exam revealed a mass in the upper third of the trachea involving the larynx. Histologically, the tumor consisted of bland-looking monocellular eosinophilic epithelial cells arranged in cords and sheets separated by thin fibrous stroma, focally forming a pseudo-tubular pattern. In immunohistochemistry, the tumor cells demonstrated positivity for CK7, PS100, SOX10, and HMGA2; and negativity for CK5/6, p40 p63, and PLAG1. In addition, the clustering analysis clearly demonstrates a clustering of tumors within the PA group. In addition to reporting this novel fusion in the PA spectrum, we discuss the relevant differential diagnoses and briefly review of NCOA2 and WWTR1 gene functions in normal and neoplastic contexts.

Vestibular Assessment with the vHIT and Skull Vibration-Induced Nystagmus Test in Patients with Nonprogressive Vestibular Schwannoma.

Background: Our primary objective was to monitor nonprogressive unilateral vestibular schwannomas (VSs) to assess the efficiency of rapid bedside examinations, such as the video head impulse test (vHIT) and skull vibration-induced nystagmus test (SVINT), in identifying vestibular damage. Methods: An observational study was conducted from March 2021 to March 2022 on all adult patients (>18 years old) with a confirmed nonprogressive VS (no active treatment). The SVINT (using a 100 Hz vibrator with two (SVINT2) or three (SVINT3) stimulation locations) and vHIT (for the six semicircular canals (SCCs)) were performed on all patients. The asymmetry of function between the vestibules was considered significant when the gain asymmetry was greater than 0.1. Rapid and repeatable assessment of VSs using two- and three-stimulation SVINT plus vHIT was performed to quantify intervestibular asymmetry. Results: SVINT3 and SVINT2 triggered VIN in 40% (24/60) and 65% (39/60) of patients, respectively. There was significant asymmetry in the vestibulo-ocular reflex (VOR), as shown by a VS-side gain < healthy-side gain in 58% (35/60) of the patients. Among the patients with significant gain asymmetry between the two vestibules according to the vHIT (VS-side gain < healthy-side gain), the proportion of patients expressing vestibular symptomatology was significantly greater than that of patients without any symptoms [67% (29/43) vs. 35% (6/17), respectively; p = 0.047]. Conclusions: The SVINT2 can be combined with the vHIT to form an interesting screening tool for revealing vestibular asymmetry. This work revealed the superiority of mastoid stimulation over vertex stimulation for SVINT in patients with unilateral vestibular loss.

Study protocol: the biologics in severe chronic rhinosinusitis with nasal polyps survey.

INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a frequent condition affecting approximately 2% of the population. Medical treatment consists long-term use of intranasal corticosteroids and short-term use of oral corticosteroids, in adjunct with saline solution rinses. Surgical management is proposed in patients who failed after medical treatment. In France, two biologics are reimbursed in case of severe uncontrolled CRSwNP despite medical treatment and endoscopic sinus surgery. Waiting for head-to-head biologics comparison, studies should report the efficacy and safety of biologics in large real-life cohorts. This study protocol describes the aims and methods of a prospective, observational, national, multicentric cohort of patients with CRSwNP treated with biologics. METHODS AND ANALYSIS: The BIOlogics in severe nasal POlyposis SurvEy is a French multicentre prospective observational cohort study. The main aim is to assess the efficacy and tolerance of biologics in patients with CRSwNP, with or without association with other type 2 diseases, and to determine the strategies in case of uncontrolled disease under biologics. Patients over 18 years old requiring biologics for CRSwNP in accordance with its marketing approval in France (ie, severe nasal polyposis, with lack of control under nasal corticosteroid, systemic corticosteroids and surgery) are invited to participate. Collected data include topical history of surgical procedures and biologics, medication and use of systemic corticosteroids, visual analogical scales for specific symptoms, Sino-Nasal Outcome Test-22 questionnaire, nasal polyp score, asthma control test, Lund-Mackay score on CT scan and IgE concentration and eosinophilic count on blood sample. TRIAL REGISTRATION: NCT05228041/DRI_2021/0030.

Peculiar nuclear atypia associated with MDM2 gene amplification in carcinoma ex-pleomorphic adenoma harbouring an alteration of HMGA2.

AIMS: Salivary gland neoplasms (SGN) exhibiting the HMGA2::WIF1 fusion are recognized by their resemblance to histology found in canalicular adenoma. Recently, ~20% of cases among 28 HMGA2::WIF1-rearranged-SGN showed malignancy and adverse outcomes (recurrence, distant metastasis, and disease-specific mortality). Among them, MDM2/CDK4 amplifications were identified in one case. This outcome suggests that the MDM2/CDK4 amplifications could be useful to predict an aggressive course of carcinoma ex-pleomorphic adenoma (CEPA). METHODS AND RESULTS: We investigated the correlation between HMGA2 fusion and MDM2 amplification in four salivary gland neoplasms, providing detailed clinicopathological features and outcomes. Cases were selected from different institutions. Histological examination, immunohistochemistry, fluorescence in situ hybridization (FISH), RNA sequencing, and whole-exome capture were performed. The cohort included four CEPA cases, all female, aged between 32 and 89 years. Tumours arose from the parotid gland with an average size of 24.5 mm. None exhibited recurrence or distant metastases during the 4-5 months of follow-up. Pathologically, all cases displayed a peculiar atypical nuclei with 'gear-like appearance'. Immunohistochemically, tumours exhibited a biphasic pattern with myoepithelial and ductal differentiation markers. All cases showed HMGA2 overexpression and MDM2 amplification by FISH and RNA sequencing. In a control cohort of MDM2 nonamplified CEPA cases, not exhibiting the peculiar nuclear atypia. CONCLUSIONS: Our findings suggest a strong correlation between HMGA2 alteration/MDM2 amplification and a peculiar nuclear atypia, advocating for their evaluation in biphasic tumours to facilitate accurate diagnosis and tailored posttumour removal monitoring. Further studies are warranted to validate these observations and elucidate their prognostic implications.

The Prognostic Value of Olfactory Dysfunction in Patients with COVID-19: The COVIDORA Study.

BACKGROUND: Among all studies describing COVID-19 clinical features during the first wave of the pandemic, only a few retrospective studies have assessed the correlation between olfac-tory dysfunction (OD) and the evolution of disease severity. The main aim was to assess whether OD is a predictive factor of COVID-19 severity based on the patient's medical management (outpa-tient care, standard hospital admission, and ICU admission). METHODS: A national, prospective, mul-ticenter cohort study was conducted in 20 public hospitals and a public center for COVID-19 screen-ing. During the first wave of the pandemic, from 6 April to 11 May 2020, all patients tested positive for COVID-19 confirmed by RT-PCR underwent two follow-up ENT consultations within 10 days of symptom onset. The main outcome measures were the evolution of medical management (out-patient care, standard hospital admission, and ICU admission) at diagnosis and along the clinical course of COVID-19 disease. RESULTS: Among 481 patients included, the prevalence of OD was 60.7%, and it affected mostly female patients (74.3%) under 65 years old (92.5%), with fewer comor-bidities than patients with normal olfactory function. Here, 99.3% (290/292) of patients with OD presented with non-severe COVID-19 disease. Patients reporting OD were significantly less hospi-talized than the ones managed as outpatients, in either a standard medical unit or an ICU. Conclu-sions: As regards the clinical course of COVID-19 disease, OD could predict a decreased risk of hospitalization during the first wave of the pandemic.

Dupilumab prevents nasal epithelial function alteration by IL-4 in vitro: Evidence for its efficacy.

BACKGROUND: Chronic rhinosinusitis with nasal polyp (CRSwNP) is a typical type 2 inflammation involving interleukin (IL)-4 and IL-13. Dupilumab is a fully human monoclonal antibody targeting IL-4 receptor α subunit, thereby blocking signaling by both cytokines. Our hypothesis was that IL-4 and IL-13, by inducing a severe epithelial dysregulation, are involved in CRSwNP pathogenesis. This study aimed to evaluate the in vitro direct effect of IL-4, IL-13, and dupilumab on nasal epithelial functions. METHODS: Nasal polyps and control mucosa from 28 patients, as well as human nasal epithelial cells (HNEC) from 35 patients with CRSwNP were used. Three major epithelial functions were investigated: the epithelial barrier function (characterized by transepithelial electrical resistance measurements and tight junction protein expression), the ciliary motion (characterized by the ciliary beating efficiency index), and wound healing (characterized by the wound repair rate) under various stimulations (IL-4, IL-13, and dupilumab). The main outcome was a significant change in epithelial functions following exposure to IL-4, IL-13, and dupilumab for 48 h in the basal media. RESULTS: IL-4 (1, 10, and 100 ng/mL) but not IL-13 induced a significant decrease in occludin and zonula-occludens protein expression, ciliary beating efficiency, and wound repair rate in HNEC. Dupilumab (0.04 mg/mL) had no effect on HNEC and specifically restored all epithelial functions altered when cells were exposed to a 48-h IL-4 stimulation. CONCLUSION: Dupilumab, in vitro, restored epithelial integrity by counteracting the effect of IL-4 on the epithelial barrier (increased epithelial permeability, decreased ciliary beating efficiency, and decreased wound repair rate).

SimLife®: A New Dynamic Model for Head and Neck Surgical Oncology Simulation.

The SimLife® model consists in a human cadaver dynamized by pulsatile vascularization. The objective was to evaluate the face, contents, and constructs validity of the SimLife® model in head and neck surgical oncology simulation. Head and neck surgical oncology simulation sessions on SimLife® models were organized with lateral neck dissection and total laryngectomy. Face and contents validity were addressed by questionnaires. Constructs validity was assessed by objective structured assessment of technical skills (OSATS) score. High realism was demonstrated for consistency of tissues (7.1 ± 1.4), color of arteries and veins (7.3 ± 1.9, 8.5 ± 1.1, respectively), and vein consistency (8.5 ± 1.2). The mean OSATS score was 19.7 ± 5.4 for residents and 32.7 ± 1.9 for senior surgeon (P = .0022). SimLife® is a hyperrealistic model for head and neck surgical oncology simulation and it might become a core component of the surgical resident curriculum.

Cross-cultural adaptation of the CRS-PRO questionnaire into French.

BACKGROUND: Chronic rhinosinusitis (CRS), encompasses many different clinical patterns with variable response to treatment. Precise criteria specifying disease severity and control are lacking in the current literature. Our aim was to perform a cross-cultural adaptation of the CRS-PRO, creating a French version for use as a routine questionnaire in the assessment of patients with CRS. METHODS: The CRS-PRO questionnaire was translated according to the recommendations of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) through a three-step procedure including a backward translation. RESULTS: Seven of 12 items were initially discordant between the three translators before achieving consensus (Step 1). Two of 12 items were discordant between the backward translation and the initial CRS-PRO version regarding the word "mucus"(Step 2). Step 3 allowed the creation of a French proof-read version of the CRS-PRO questionnaire. Thirty patients were included for initial validation, mean age of 49.2 ± 15 years and 63.3% (19/30) male. It took them 67 ± 23 s to complete the questionnaire without any patients requiring more than 2 min. CONCLUSION: This study presents the French version of the CRS-PRO questionnaire-an adapted, validated, and well-accepted instrument to evaluate the CRS symptoms in the French speaking population.

Allograft bone vs. bioactive glass in rehabilitation of canal wall-down surgery.

Canal wall-down (CWD) mastoidectomy creates a radical cavity that modifies the anatomy and physiology of the middle ear, thus preventing it from being self-cleaning and causing epidermal stagnation in the posterior cavities. Canal wall-down tympanomastoidectomy with reconstruction (CWDTwR) can obliterate such radical cavities. The main objective of this study was to compare postoperative results after CWDTwR by using either bone allografts or 45S5 bioactive glass as a filling tissue with an 18-month follow-up. This was a single-center observational trial including all patients undergoing CWDTwR. Patients were divided into two groups according to the filling material used: allograft bone (AB group) or 45S5 bioactive glass (BG group). Clinical monitoring was performed regularly, with control imaging performed at 18 months (CT scan and DW MRI). The two groups were compared with the t test for quantitative variables and the chi square test for qualitative variables (no revision surgery, audiometric results, complications, mastoid obliteration volume). Thirty-two patients underwent CWDTwR between October 2015 and 2018. The mean age was 48 years, and 71.9% (23/32) were men. A total of 46.9% (15/32) of the patients had undergone at least 3 middle-ear surgeries prior to CWDTwR. The most frequent preoperative symptom was otorrhea (100.0%, 32/32), and only 12.5% (4/32) experienced dizziness. Fifteen and 17 patients underwent surgery with bone allografts and 45S5 bioactive glass, respectively. At 18 months post-operation, 53.3% of the patients (8/15) in the AB group presented with recurrent otorrhea versus 5.9% (1/17) of patients in the BG group (p = 0.005). Seventy-eight percent (7/9) of symptomatic patients had undergone revision surgery at 18 months postoperation: 40.0% (6/15) in the AB group and 5.9% (1/17) in the BG group (p = 0.033). One patient's surgery was cancelled due to the COVID-19 pandemic, and one patient refused surgery. The effects of CWDTwR with bone allografts are disappointing in early follow-up, with significant resorption leading to a 40.0% revision surgery rate. 45S5 BG is a simple solution, with preliminary results that are superior to those of AB. However, prospective controlled studies with longer follow-up times are needed to evaluate the value of BG versus other synthetic materials (such as hydroxyapatite) in surgical management of CWDTwR.Trial registration: retrospectively registered.

In vivo intranasal delivery of coagulation factor IX: a proof-of-concept study.

BACKGROUND: Hemophilia B (HB) is a bleeding disorder characterized by coagulation factor (F) IX (FIX) deficiency. The current standard-of-care for severe HB is prophylaxis with long-term repetitive intravenous (i.v.) infusions of recombinant FIX (rFIX) with standard half-life or extended half-life. Unmet needs remain regarding the development of non-invasive administration routes for coagulation factors. The aim of this study was to evaluate the effectiveness of intranasal delivery (IND) of rFIX and rFIX fused to Fc fragment (rFIX-Fc) in mice. METHODS: Drops of rFIX and rFIX-Fc were deposited in the nostrils of wild-type, FcRn knock-out, FcRn humanized, and FIX knock-out mice. rFIX mucosal uptake was evaluated by measuring plasma FIX antigen and FIX activity (FIX:C) levels, and by performing histologic analysis of the nasal mucosa following IND. RESULTS: After IND, both rFIX and rFIX-Fc were equally delivered to the blood compartment, irrespective of the mouse strain studied, mostly through a passive mechanism of transportation across the mucosal barrier, independent of FcRn receptor. Both plasma FIX antigen and FIX:C activity levels increased following IND in FIX knock-out mice. CONCLUSION: This proof-of-concept study describes evidence supporting the nasal route as an alternative to FIX i.v. infusion for the treatment of HB.

Transverse Venous Sinus Stenosis in Patients With Nasal Cerebrospinal Fluid Leak and Idiopathic Intracranial Hypertension.

OBJECTIVE: Spontaneous nasal cerebrospinal fluid (CSF) leaks are frequently linked to idiopathic intracranial hypertension (IIH). The objectives of our study were: (1) to determine the rate of transverse venous sinus stenosis (TVSS) in patients with spontaneous nasal CSF leak and in patients with IIH without CSF (controls), and (2) to study the correlation between spontaneous nasal CSF leak and brain imaging features. STUDY DESIGN: A multicenter retrospective case-control study. SETTING: Six French tertiary hospitals. METHODS: Patients with spontaneous nasal CSF leaks and patients with IIH without nasal CSF leaks (controls) were included. The transverse venous sinus patency was analyzed by magnetic resonance imaging to identify possible stenosis or hypoplasia. RESULTS: Thirty-two patients with spontaneous nasal CSF leaks and 32 controls were included. TVSS was significantly more frequent in patients with spontaneous nasal CSF leaks than in controls (p = .029). Univariate analysis indicated that TVSS (odds ratio, OR: 4.2; 95% confidence interval, CI [1.352-14.915]; p = .017) and arachnoid granulations (OR: 3; 95% CI [1.065-8.994]; p = .042) were risk factors for spontaneous nasal CSF leak. In multivariate analysis, TVSS and arachnoid granulations were independent risk factors of nasal CSF leak (OR: 5.577, 95% CI [1.485-25.837], p = .016; and OR: 4.35, 95% CI [1.234-17.756], p = .029, respectively). CONCLUSION: This multicenter case-control study shows that TVSS is an independent risk factor for CSF leak in patients with IIH. Stenosis management by interventional radiology may be proposed postoperatively to increase the success of IIH surgical treatment or preoperatively to reduce the need for surgery.

Definition of severity and treatment response in chronic rhinosinusitis with nasal polyps: a Delphi study among French experts.

INTRODUCTION: The introduction of biotherapies has significantly changed the management of patients with chronic rhinosinusitis with nasal polyps (CRSwNP). These drugs are generally reserved for severe or recurrent CRSwNP. Thus, the concepts of severity of the disease and treatment response must be mastered by otorhinolaryngologists. However, a clear definition of these concepts in CRSwNP is missing. METHODS: This article focuses on definitions of severity and treatment response in CRSwNP by providing an expert consensus among French rhinologists, using a Delphi study. RESULTS: The severity assessment should seek the presence of uncontrolled asthma, olfactory disorders, nasal blockage, impaired quality of life (QOL) and cumulative annual dose of systemic corticosteroids.The treatment response should assess the presence of olfactory disorders, nasal blockage, QOL impairment, response to background therapy, resistance and/or dependence to oral corticosteroids, cumulative annual dose of systemic corticosteroids, response to surgery and to biologics.A failure after polypectomy should not be considered as a failure of surgical management of CRSwNP and must discuss the realization of an extended sinus surgery procedure before the prescription of biologics. CONCLUSION: Definitions of severity, control of CRSwNP, as well as therapeutic strategies to improve patients' QOL achieved high level of consensus.

Incidence of Underlying Abnormal Findings on Routine Magnetic Resonance Imaging for Bell Palsy.

Importance: There is no consensus on the benefits of routine magnetic resonance imaging (MRI) of the facial nerve in patients with suspected idiopathic peripheral facial palsy (PFP) (ie, Bell palsy [BP]). Objectives: To estimate the proportion of adult patients in whom MRI led to correction of an initial clinical diagnosis of BP; to determine the proportion of patients with confirmed BP who had MRI evidence of facial nerve neuritis without secondary lesions; and to identify factors associated with secondary (nonidiopathic) PFP at initial presentation and 1 month later. Design, Setting, and Participants: This retrospective multicenter cohort study analyzed the clinical and radiological data of 120 patients initially diagnosed with suspected BP from January 1, 2018, to April 30, 2022, at the emergency department of 3 tertiary referral centers in France. Interventions: All patients screened for clinically suspected BP underwent an MRI of the entire facial nerve with a double-blind reading of all images. Main Outcomes and Measures: The proportion of patients in whom MRI led to a correction of the initial diagnosis of BP (any condition other than BP, including potentially life-threating conditions) and results of contrast enhancement of the facial nerve were described. Results: Among the 120 patients initially diagnosed with suspected BP, 64 (53.3%) were men, and the mean (SD) age was 51 (18) years. Magnetic resonance imaging of the facial nerve led to a correction of the diagnosis in 8 patients (6.7%); among them, potentially life-threatening conditions that required changes in treatment were identified in 3 (37.5%). The MRI confirmed the diagnosis of BP in 112 patients (93.3%), among whom 106 (94.6%) showed evidence of facial nerve neuritis on the affected side (hypersignal on gadolinium-enhanced T1-weighted images). This was the only objective sign confirming the idiopathic nature of PFP. Conclusions and Relevance: These preliminary results suggest the added value of the routine use of facial nerve MRI in suspected cases of BP. Multicentered international prospective studies should be organized to confirm these results.

Oncostatin M Contributes to Airway Epithelial Cell Dysfunction in Chronic Rhinosinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a typical type-2 inflammation involving several cytokines and is associated with epithelial cell dysfunction. Oncostatin M (OSM) (belonging to the interleukin(IL)-6 family) could be a key driver of epithelial barrier dysfunction. Therefore, we investigated the presence of OSM and IL-6 and the expression pattern of tight junctions (TJs) in the nasal tissue of CRSwNP patients and controls using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Then, their potential role in the epithelial barrier was evaluated in vitro in 27 different primary cultures of human nasal epithelial cells (HNECs) by measuring TJ expression and transepithelial electric resistance (TEER) with or without OSM or IL-6 (1, 10, and 100 ng/mL). The effect on ciliary beating efficiency was evaluated by high-speed videomicroscopy and on repair mechanisms with a wound healing model with or without OSM. OSM and IL-6 were both overexpressed, and TJ (ZO-1 and occludin) expression was decreased in the nasal polyps compared to the control mucosa. OSM (100 ng/mL) but not IL-6 induced a significant decrease in TJ expression, TEER, and ciliary beating efficiency in HNECs. After 24 h, the wound repair rate was significantly higher in OSM-stimulated HNECs at 100 ng/mL. These results suggest that OSM could become a new target for monoclonal antibodies.

Disabling hearing loss after Lefort I osteotomies in patients with history of Eustachian tube dysfunction: An unknown complication.

INTRODUCTION: The aim of this study was to determine the predisposing factors of this deafness after orthognathic surgery for a population with no history of cleft palate. MATERIAL AND METHODS: All patients with significant auditory symptoms after orthognathic surgery performed in the department of Craniomaxillofacial surgery in the Croix Rousse Hospital, Lyon, France, since 2012 were included in the study. The exclusion criterion was a history of cleft palate. Bone movements performed during orthognathic surgery were analyzed. An audiometric assessment, including Pure Tone Audiometry and tympanometry, was performed at day 30 (D30), day 60 (D60) and day 90 (D90). RESULTS: Six patients were included in the study. All patients were women with a mean age of 33.5 years and suffered from class III skeletal deformities. The average hearing loss was 40 dB at D30, 20 dB at D60 and 5 dB at D90 with sometimes differences between the two ears. Five patients had a type C tympanogram suggesting Eustachian tube dysfunction and one patient had a type B tympanogram. All patients benefited from maxillary advancement of 5 mm on average. DISCUSSION: This study allows to conclude that female patients with a history of allergy or catarrhal tubal deafness are at risk of deafness after orthognathic surgery. These patients must be informed of this complication before surgery and be reassured about its reversibility.

Systematic MRI in persistent post-Covid-19 olfactory dysfunction should be reassessed.

BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard in the etiological assessment of a persistent olfactory dysfunction (OD). While the utility of imaging in COVID-19-related OD has yet to be established, MRI is recommended in all patients with persistent OD. The high prevalence of the latter after SARS-CoV-2 infection means evaluating this strategy is an important public health matter. METHODS: The main objective was to examine the impact of systematic MRI on the management of patients with OD. All adult patients consulting for persistent OD (>2 months) after primary SARS-COV-2 infection (PCR) between March 2020 and December 2021 were included (n = 67). The secondary objective was to evaluate the relationship between the severity of the OD as measured by psychophysical testing (ETOC) and the volume of the olfactory bulb (OB) measured by MRI. RESULTS: All patients underwent MRI, and none led to a change in diagnosis or treatment. Among them, 82% (55/67) were considered normal by the radiologist on initial interpretation. There were no significant differences (visual analysis or OB volume) between groups (mild, moderate, and severe hyposmia). CONCLUSION: Systematic MRI may be unnecessary in patients whose persistent OD began soon (a few days) after confirmed SARS-CoV-2 infection.

Pre-referral intranasal artesunate powder for cerebral malaria: a proof-of-concept study.

BACKGROUND: Malaria still kills young children in rural endemic areas because early treatment is not available. Thus, the World Health Organization recommends the administration of artesunate suppositories as pre-referral treatment before transportation to the hospital in case of severe symptoms with an unavailable parenteral and oral treatment. However, negative cultural perception of the rectal route, and limited access to artesunate suppositories, could limit the use of artesunate suppositories. There is, therefore, a need for an alternative route for malaria pre-referral treatment. The aim of this study was to assess the potential of intranasal route for malaria pre-referral treatment. METHODS: The permeability of artesunate through human nasal mucosa was tested in vitro. The Transepithelial Electrical Resistance (TEER) of the nasal mucosa was followed during the permeation tests. Beside, regional deposition of artesunate powder was assessed with an unidose drug delivery device in each nostril of a nasal cast. Artesunate quantification was performed using Liquid Chromatography coupled to tandem Mass Spectrometry. RESULTS: The experimental model of human nasal mucosa was successfully implemented. Using this model, artesunate powder showed a much better passage rate through human nasal mucosa than solution (26.8 ± 6.6% versus 2.1 ± 0.3%). More than half (62.3%) of the artesunate dose sprayed in the nostrils of the nasal cast was recovered in the olfactory areas (44.7 ± 8.6%) and turbinates (17.6 ± 3.3%) allowing nose-to-brain and systemic drug diffusion, respectively. CONCLUSION: Artesunate powder showed a good permeation efficiency on human nasal mucosa. Moreover it can be efficiently sprayed in the nostrils using unidose device to reach the olfactory area leading to a fast nose-to-brain delivery as well as a systemic effect. Taken together, those results are part of the proof-of-concept for the use of intranasal artesunate as a malaria pre-referral treatment.

Long term outcome of laryngeal mobility disorder and quality of life after pediatric cardiac surgery.

INTRODUCTION: Laryngeal mobility disorder after a pediatric heart surgery is common (between 5 and 10% of cases), and has important consequences on swallowing, breathing and speaking. After reviewing the literature, the recovery rate is variable and the postoperative follow-up is often done on a short time frame. The primary objective of the study is to describe the recovery from laryngeal mobility disorder with a follow-up time of at least 5 years. The secondary objective is to describe of the quality of life of the child in terms of phonation and swallowing, and to identify potential risk factors for a lasting laryngeal mobility disorder. METHODS: We collected data (morphological characteristics and details of the procedures and medical care) on children who had undergone a heart surgery with risks of complications, between 2010 and 2015, and with a laryngeal mobility disorder detected after the surgery through nasal flexible laryngoscopy. During a follow-up consultation, carried at least 5 years after the surgery, we performed a nasal flexible laryngoscopy to assess whether or not the patient had recovered a full mobility of the larynx. Two questionnaires were also given to the patients, the pVHI and the PEDI EAT-10, to assess respectively the quality of their speech and of their swallowing function. RESULTS: The recovery rate for a laryngeal mobility disorder more than 5 years after surgery was found to be 65% (9 children out of the 14 included in the study). We identified a risk factor for the persistence of a laryngeal mobility disorder after surgery: the presence of an associated genetic syndrome, p = 0.025. Children with persistent laryngeal mobility disorder have an impaired quality of life score, using the pVHI scale, which correlates well with the flexible laryngoscopy findings, p = 0.033. CONCLUSION: Children with a lasting laryngeal mobility disorder have disabling respiratory and vocal symptoms in their daily lives. Nasal flexible laryngoscopy should therefore be systematically performed postoperatively after a surgery carrying risks. For improved patient management, early detection of these disorders by pharyngolaryngeal nasal flexible laryngoscopy in the aftermath of high-risk cardiac surgery is strongly advised, with prolonged follow-up.