Pharmacokinetics of d- and l-norfenfluramine following their administration as individual enantiomers in rats.

The effect of fenfluramine and norfenfluramine enantiomers in rodent seizure models and their correlation with the pharmacokinetics of d- and l-fenfluramine in rats have been reported recently. To complement these findings, we investigated the pharmacokinetics of d- and l- norfenfluramine in rat plasma and brain. Sprague-Dawley rats were injected intraperitoneally with 20 mg/kg and 1 mg/kg l- norfenfluramine. A 1 mg/kg dose of d-norfenfluramine was used because higher doses caused severe toxicity. The concentration of each enantiomer in plasma and brain was determined at different time points by liquid chromatography/mass spectrometry. Pharmacokinetic parameters were compared between norfenfluramine enantiomers, and with those reported previously for fenfluramine enantiomers after a 20 mg/kg, i.p., dose. All enantiomers were absorbed rapidly and eliminated, with half-lives ranging from 0.9 h (l-fenfluramine) to 6.1 h (l- norfenfluramine, 20 mg/kg) in plasma, and from 3.6 h (d-fenfluramine) to 8.0 h (l-fenfluramine) in brain. Brain-to-plasma concentration ratios ranged from 15.4 (d-fenfluramine) to 27.6 (d-norfenfluramine), indicating extensive brain penetration. The fraction of d- and l-fenfluramine metabolized to norfenfluramine was estimated to be close to unity. This work is part of ongoing investigations to determine the potential value of developing enantiomerically pure l-fenfluramine or l-norfenfluramine as follow-up compounds to the marketed racemic fenfluramine.

Trans-mastoid plugging of superior semicircular canal dehiscence: long-term follow-up.

OBJECTIVE: To evaluate the long-term outcomes of trans-mastoid plugging of superior semicircular canal dehiscence (SSCD), focusing on complicated cases. METHODS: In this cohort study, we included all patients who underwent trans-mastoid plugging of SSCD between 2009 and 2019. We evaluated the symptoms (autophony, sound-/pressure-induced vertigo, disequilibrium, aural fullness and pulsatile tinnitus) before and 1 year after surgery in the medical records. We systematically assessed the current symptoms 6.2 ± 3 years postoperative (range 2.2-12.3 years) using questionnaires sent by post and validated by telephone interviews. We also documented any complications and the need for further procedures. We compared pure tone and speech audiometry before and 1 year after surgery. Finally, the degree of mastoid pneumatisation and mastoid tegmen anatomy were reviewed on preoperative CT scans. RESULTS: We included 24 ears in 23 patients. No complications were recorded, and none required a second procedure for SSCD. Following surgery, oscillopsia and Tullio phenomena resolved in all patients. Hyperacusis, autophony, and aural fullness were also settled in all patients except one. Balance impairment persisted to some degree in 35% of patients. No deterioration over the years was reported regarding the above symptoms. On average, bone conduction pure tone average pre- and 1 year postoperative were 13.7 ± 17 and 20.5 ± 18 dB, respectively (P = 0.002). Air bone gaps were reduced from 12.7 ± 8 to 5.9 ± 6 (P = 0.001). Two patients had a significant sclerotic mastoid, three had a prominent low-lying mastoid tegmen, and two had both. Anatomy had no effect on outcome. CONCLUSION: Trans-mastoid plugging of SSCD is a reliable and effective technique which achieves long-lasting symptom control, even in cases with sclerotic mastoid or low-lying mastoid tegmen.

Comparative activity of the enantiomers of fenfluramine and norfenfluramine in rodent seizure models, and relationship with their concentrations in plasma and brain.

OBJECTIVES: To investigate the comparative antiseizure activity of the individual enantiomers of fenfluramine and its major active primary metabolite norfenfluramine in rodent seizure models, and its relationship with the pharmacokinetics of these compounds in plasma and brain. METHODS: The antiseizure potency of d,l-fenfluramine (racemic fenfluramine) was compared with the respective potencies of its individual enantiomers and the individual enantiomers of norfenfluramine using the maximal electroshock (MES) test in rats and mice, and the 6-Hz 44 mA test in mice. Minimal motor impairment was assessed simultaneously. The time course of seizure protection in rats was compared with the concentration profiles of d-fenfluramine, l-fenfluramine, and their primary active metabolites in plasma and brain. RESULTS: All compounds tested were active against MES-induced seizures in rats and mice after acute (single-dose) administration, but no activity against 6-Hz seizures was found even at doses up to 30 mg/kg. Estimates of median effective doses (ED50 ) in the rat-MES test were obtained for all compounds except for d-norfenfluramine, which caused dose-limiting neurotoxicity. Racemic fenfluramine had approximately the same antiseizure potency as its individual enantiomers. Both d- and l-fenfluramine were absorbed and distributed rapidly to the brain, suggesting that seizure protection at early time points (≤2 h) was related mainly to the parent compound. Concentrations of all enantiomers in brain tissue were >15-fold higher than those in plasma. SIGNIFICANCE: Although there are differences in antiseizure activity and pharmacokinetics among the enantiomers of fenfluramine and norfenfluramine, all compounds tested are effective in protecting against MES-induced seizures in rodents. In light of the evidence linking the d-enantiomers to cardiovascular and metabolic adverse effects, these data suggest that l-fenfluramine and l-norfenfluramine are potentially attractive candidates for a chiral switch approach leading to development of a novel, enantiomerically-pure antiseizure medication.

The value of tracheostomy of critically ill COVID-19 patients - A multicentral study.

PURPOSE: Tracheostomy is an aerosol-generating procedure, thus performing it during the COVID-19 pandemic arises considerations such as the most appropriate timing and the patients to whom it is suitable. Medical teams lack sufficient data to assist determining whether or not to conduct tracheostomy, its short- and long-term implications are not fully understood. This study aims to shed light on the critically ill COVID-19 patients that require tracheostomy, and to investigate its value. METHODS: A retrospective multicentral case-control study of 157 hospitalized critically ill COVID-19 patients, among whom 30 patients went through tracheostomy and consisted of our study group. RESULTS: The mean age was similar between study and control groups (68.9 ± 12.7 years vs 70.5 ± 15.8 years, p = 0.57), as well as comorbidity prevalence (56.7% vs 67.7%, p = 0.25). Patients in the study group were hospitalized for longer duration until defined critically ill (5 ± 4.3 vs 3 ± 3.9 days; p = 0.01), until admitted to the intensive care unit (6 ± 6.6 vs 2.5 ± 3.7 days respectively; p = 0.005), and until discharged (24 ± 9.7 vs 10.7 ± 9.1 days, p < 0.001). Mortality rate was lower in the study group (30% vs 59.8%, p = 0.003). Kaplan Meier survival analysis revealed a statistically significant difference in survival time between groups (Log rank chi-sq = 20.91, p < 0.001) with mean survival time of 41 ± 3.1 days vs 21 ± 2.2 days. Survival was significantly longer in the study group (OR = 0.37, p = 0.004). CONCLUSION: Tracheostomy allows for more prolonged survival for gradually deteriorating critically ill COVID-19 patients. This should be integrated into the medical teams' considerations when debating whether or not to conduct tracheostomy.

The management of acute supraglottitis patients at the intensive care unit.

INTRODUCTION: Acute supraglottitis is a potentially life-threatening condition that often necessitates intensive care unit (ICU) admission for airway monitoring. The objective of this study was to identify clinical criteria that predict a benign course for patients with acute supraglottitis. METHODS: A prospective observational study was performed. Adult patients hospitalized in the ICU between 2007 and 2019 diagnosed with acute supraglottitis were included. All patients were treated with antibiotics and corticosteroids. Fiber optic laryngoscopy (FOL) was performed every 12 h, with each exam defined as "improving", "no change" or "deteriorating" based on the presence of airway edema. Need for airway intervention was correlated to changes in the FOL exam. RESULTS: Of 146 patients included, 14 (10%) required intubation, ten on admission, and four during the first 6 h of ICU admission. FOL follow-up was performed on 528 occasions-427 (81%) exams showed improvement, 16 (3%) deterioration, and 85 (16%) with no change. On no occasions was improvement in FOL followed by deterioration. The median ICU length of stay was 3 (IQR 2-3.5) vs. 1 (IQR 1.0-1.25) day for patients who did or did not require intubation (p < 0.001), respectively. CONCLUSION: Improvement in FOL exam accurately predicted the absence of need for intubation and might represent a criterion for early ICU discharge.

Synthesis and Enantioselective Pharmacokinetic/Pharmacodynamic Analysis of New CNS-Active Sulfamoylphenyl Carbamate Derivatives.

We recently reported a new class of carbamate derivatives as anticonvulsants. Among these, 3-methylpentyl(4-sulfamoylphenyl)carbamate (MSPC) stood out as the most potent compound with ED50 values of 13 mg/kg (i.p.) and 28 mg/kg (p.o.) in the rat maximal electroshock test (MES). 3-Methylpropyl(4-sulfamoylphenyl)carbamate (MBPC), reported and characterized here, is an MSPC analogous compound with two less aliphatic carbon atoms in its structure. As both MSPC and MBPC are chiral compounds, here, we studied the carbonic anhydrase inhibitory and anticonvulsant action of both MBPC enantiomers in comparison to those of MSPC as well as their pharmacokinetic properties. Racemic-MBPC and its enantiomers showed anticonvulsant activity in the rat maximal electroshock (MES) test with ED50 values in the range of 19-39 mg/kg. (R)-MBPC had a 65% higher clearance than its enantiomer and, consequently, a lower plasma exposure (AUC) than (S)-MSBC and racemic-MSBC. Nevertheless, (S)-MBPC had a slightly better brain permeability than (R)-MBPC with a brain-to-plasma (AUC) ratio of 1.32 (S-enantiomer), 1.49 (racemate), and 1.27 (R-enantiomer). This may contribute to its better anticonvulsant-ED50 value. The clearance of MBPC enantiomers was more enantioselective than the brain permeability and MES-ED50 values, suggesting that their anticonvulsant activity might be due to multiple mechanisms of action.

Toward a Better Understanding of Electrocochleography: Analysis of Real-Time Recordings.

OBJECTIVES: Real-time electrocochleography (ECochG) has been used as a monitoring tool during cochlear implantation (CI), whereby, amplitude drops have been correlated with postoperative acoustic hearing results. However, no consensus has been reached as to how a single event of an amplitude drop should be characterized. The aim of this study was to identify ECochG events that predict loss of hearing 1 month after surgery. DESIGN: Fifty-five patients were included in this prospective cohort study. Real-time ECochG measurements were performed during CI electrode insertion. Single ECochG events were characterized according to their amplitude loss and slope steepness. RESULTS: Using receiver operating characteristic analyses, the most efficient cut-off criterion for a relative hearing loss of 25% was an amplitude loss of 61% at a fixed slope steepness of 0.2 µV/sec. Three-quarters of our population had at least one such event during implantation. Most events occurred shortly before full insertion. With increasing number of events, median residual hearing thresholds deteriorated for all frequencies. Larger amplitude drops trended toward worse hearing preservation. Signal recovery after an ECochG event could not be correlated to acoustic hearing outcomes. CONCLUSIONS: Our data suggest that amplitude drops exceeding 61% of the ongoing signal at a slope steepness of 0.2 µV/sec are correlated with worse acoustic hearing preservation. Clearly defined ECochG events have the potential to guide surgeons during CI in the future. This is essential if a fully automated data analysis is to be employed or benchmarking undertaken.

The impact of R353Q genetic polymorphism in coagulation factor VII on the initial anticoagulant effect exerted by warfarin.

BACKGROUND: The initial rise in INR following warfarin is attributed to rapid decline in coagulation factor VII (F7). The R353Q polymorphism in F7 accounts for approximately 1/3 of the variability in F7 activity (FVIIc). OBJECTIVE: Evaluate the role of R353Q in the initial response to warfarin. METHODS: Twenty-eight healthy, males, carrying CYP2C9*1/*1 (n = 14), CYP2C9*1/*2 (n = 4) or CYP2C9*1/*3 (n = 10) genotypes, received single 20 mg warfarin. S&R-warfarin concentrations, INR, and FVIIc were monitored periodically for 7 days. RESULTS: Baseline and maximal INR were 5.6% and 33.5% higher among carriers of the RQ (n = 12) as compared with those carrying the RR (n = 16) genotype (p = 0.032, p = 0.003, respectively). Baseline and nadir FVIIc were 21.6% and 42.0% lower among subjects carrying the RQ as compared with carriers of the RR genotype (p = 0.001, p = 0.007 respectively). In multiple regression analysis, R353Q predicted 36.6% of the variability in peak INR whereas 20.2%, 9.9%, and 5.9% were attributed to VKORC1 genetic polymorphism, cholesterol concentration, and S Warfarin concentration after 24 h, respectively. CONCLUSIONS: R353Q genetic polymorphism plays a key role in determining the initial response to warfarin. The incorporation of this genetic variant into warfarin loading algorithm should be further investigated.

English translation and validation of the Zurich chronic middle ear inventory (ZCMEI-21-E) assessing quality of life in chronic otitis media: A prospective international multicentre study.

OBJECTIVES: To translate and validate the Zurich Chronic Middle Ear Inventory (ZCMEI-21) for the English language in order to provide an English instrument to assess health-related quality of life in chronic otitis media (COM). DESIGN: Pilot translation study including cognitive debriefings, prospective multicentre cross-sectional psychometric validation study. SETTING: Four tertiary referral centres in three different English-speaking countries (UK, USA and Australia). PARTICIPANTS: Adult patients suffering from COM. MAIN OUTCOME MEASURES: The English translation of the ZCMEI-21 (ZCMEI-21-E) and the five-level version of the EQ-5D questionnaire. The EQ-5D, which constitutes a generic measure of health-related quality of life, consists of a descriptive system score and a visual analogue scale. Statistical outcomes included single-item descriptive statistics, internal consistency (Cronbach's α) as an indicator of reliability, as well as construct validity. RESULTS: A total of 124 patients suffering from COM were included. The mean age was 50.1 years (SD 16.9 years), and 72 (58.1%) were males. The Cronbach's α of the ZCMEI-21-E was 0.91, suggesting an excellent internal consistency. The Spearman's correlation coefficient of the ZCMEI-21-E total score was 0.55 (P < 0.0001) for convergent construct validity with EQ-5D descriptive system score and 0.57 (P < 0.0001) with the EQ-5D visual analogue scale. CONCLUSIONS: The ZCMEI-21-E is a new validated questionnaire that provides clinicians with a short, comprehensive and reliable instrument to quantify health-related quality of life in patients suffering from COM. The ZCMEI-21-E may be of use in clinical routine as well as in outcome research and monitoring.

Starplasty tracheostomy: case series and literature review.

OBJECTIVES: The starplasty tracheostomy (SPT) technique has been suggested to reduce the short-term complications of tracheostomy, including accidental decannulation and pneumothorax. The aim of the present study was to conduct a review of key parameters prior to and following treatment of neonates and children with the SPT technique, including indications, complications, perioperative department stay, and overall length of stay in one University-Affiliated Medical Center. METHODS: A retrospective chart review of all children under the age of 18 underwent SPT in a single center between February 2006 and January 2012. RESULTS: Among the 39 patients reviewed, the median age at the time of surgery was 14.5 months, ranging from 3 days to 8.8 years. The most common indication for SPT was respiratory insufficiency resulting from central nervous system disorders (15, 38.4%) followed by neuromuscular disorders (14, 35.9%). Ten (25.6%) operations were performed on neonatal intensive care unit (NICU) patients and 29 (74.4%) on pediatric intensive care unit (PICU) patients. The median postoperative hospital stay was 19.5 days (range of 3-207 days); however, the median postoperative stay in the PICU was 13.5 days. There were no decannulations or any other short-term complications after SPT, and no SPT-related deaths occurred. CONCLUSIONS: In our series, pediatric SPT was not associated with any major complications. Therefore, we conclude that SPT should be considered as a safe and advantageous alternative for traditional tracheotomy, especially in patients with low probability of future decannulation, and, therefore, at low risk of a persistent tracheocutaneous fistula.

Pharmacokinetic-Pharmacodynamic Correlation and Brain Penetration of sec-Butylpropylacetamide, a New CNS Drug Possessing Unique Activity against Status Epilepticus.

sec-Butylpropylacetamide (SPD) is the amide derivative of valproic acid (VPA). SPD possess a wide-spectrum anticonvulsant profile better than that of VPA and blocks status epilepticus (SE) induced by pilocarpine and organophosphates. The activity of SPD on SE is better than that of benzodiazepines (BZDs) in terms of the ability to block SE when given 20-60 min after the beginning of a seizure. However, intraperitoneal (i.p.) administration to rats cannot be extrapolated to humans. Consequently, in the current study a comparative pharmacokinetic (PK)-pharmacodynamic analysis of SPD was conducted following i.p., intramuscular (i.m.), and intravenous (i.v.) administrations to rats. SPD brain and plasma levels were quantified at various times after dosing following i.p. (60 mg/kg), i.v. (60 mg/kg), and i.m. administrations (120 mg/kg) to rats, and the major PK parameters of SPD were estimated. The antiseizure (SE) efficacies of SPD and its individual stereoisomers were assessed in the pilocarpine-induced BZD-resistant SE model following i.p. and i.m. administrations to rats at 30 min after seizure onset. The absolute bioavailabilities of SPD following i.p. and i.m. administrations were 76% (i.p.) and 96% (i.p.), and its clearance and half-life were 1.8-1.5 L h(-1) kg(-1) and 0.5-1.7 h, respectively. The SPD brain-to-plasma AUC ratios were 1.86 (i.v.), 2.31 (i.p.), and 0.77 (i.m.). Nevertheless, the ED50 values of SPD and its individual stereoisomers were almost identical in the rat pilocarpine-induced SE model following i.p. and i.m. administrations. In conclusion, in rats SPD is completely or almost completely absorbed after i.m. and i.p. administration and readily penetrates into the brain. Consequently, in spite of PK differences, the activities of SPD in the BZD-resistant SE model following i.m. and i.p. administrations are similar.

Hearing Loss in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) has many characteristics of autoimmune diseases. Sensorineural hearing loss has been reported in many autoimmune diseases. Little is known about hearing loss in patients with IBD. METHODS: A prospective blinded comparative study was conducted over a 3-year period. IBD patients and controls underwent a complete otorhinolaryngeal examination and eudiometry test. RESULTS: Altogether 105 participants (76 patients and 29 controls) took part in this study. Mean age was 36, 51 % were males, and 40 % of the patients were presently hospitalized due to IBD exacerbation. Audiometric examination revealed that any hearing loss (mild to severe) was found in 29 (38 %) of the IBD population, compared to 4 (14 %) of the control group (p = 0.02). Extraintestinal manifestation (EIM) was present in 33/76 (43 %) of IBD patients. Any hearing loss and moderate to severe hearing loss were found in 17/33 (52 %) and 7/33 (21 %) in the EIM-positive group compared to 12/43 (28 %) and 4/43 (9 %) in the EIM-negative group (p = 0.036 and p = 0.14, respectively). Out of patients over the age of 40 with other EIMs, all 11/11 (100 %) of patients had any hearing loss compared to 8/12 (66 %) of patients over the age of 40 without other EIMs, p = 0.035. CONCLUSIONS: Hearing loss may be another EIM of IBD. It is found in 38 % of IBD patients and in up to 52 % of patients with other EIMs and increases over the age of 40. Early hearing evaluation should be recommended to these high-risk IBD patients.

Is Needle Aspiration for Peritonsillar Abscess Still as Good as We Think? A Long-term Follow-up.

OBJECTIVE: The aim was to study the therapeutic management, recurrence, and need for tonsillectomy in patients who underwent needle aspiration for peritonsillar abscess (PTA). METHODS: A prospective observational design study was performed. Patients hospitalized in Shaare Zedek Medical Center between the years 2004 and 2007 with a diagnosis of PTA who underwent needle aspiration obtaining pus were included. A minimum 5-year follow-up was required for all patients. Recurrences, complications, the need for a repeated surgical procedure, length of hospital admission, and tonsillectomy were the primary end points. RESULTS: The study included 117 patients. One hundred four patients (88.9%) improved after 1 needle aspiration without any other intervention, whereas 13 patients (11.1%) required an additional procedure. Broad spectrum antibiotics showed a statistical advantage over penicillin only, regarding need for recurrent procedure (14.7% vs 4.7%, P = .02). No short- or long-term complications were documented. Seventeen patients (14.5%) had any recurrence. Primary recurrent tonsillitis, female sex, and younger age were predictive risk factors for recurrent events of PTA (32% vs 10%, P < .01). A total of 18 patients (15.4%) eventually underwent tonsillectomy. CONCLUSION: Needle aspiration is an effective first line procedure for patients with PTA. Tonsillectomy is not necessary in most cases. In our study, young age, female sex, and recurrent tonsillitis are negative prognostic factors for recurrence. These patients should be managed accordingly. Broad spectrum antibiotics may offer additional advantages when compared to penicillin only.

The Effect of Delay Following the Clinical Decision to Perform Tracheostomy in the Critical Care Setting.

BACKGROUND: Tracheostomy in patients who are critically ill is generally performed due to prolonged mechanical ventilation and expected extubation failure. However, tracheostomy criteria and ideal timing are poorly defined, including equivocal data from randomized controlled trials and median intubation to tracheostomy times that range from 7-21 d. However, a consistent finding is that only ∼50% of late tracheostomy groups actually undergo tracheostomy, with non-performance due to recovery or clinical deterioration. Unlike in many jurisdictions, elective surgical procedures in our institution require a court-appointed guardian, which necessitates an approximately 1-week delay between the decision to perform tracheostomy and surgery. This offers a unique opportunity to observe patients with potential tracheostomy during a delay between the decision and the performance. METHODS: ICU patients who were ventilated were identified for inclusion retrospectively by an application for guardianship relating to tracheostomy, the intention-to-treat point. The main outcomes of tracheostomy, extubation, or death/palliative care after inclusion were noted. Demographics, outcomes, and event timing were compared for the 3 outcome groups. RESULTS: Tracheostomy-related guardianship requests were made for 388 subjects. Of these, 195 (50%) underwent tracheostomy, whereas 127 (33%) were extubated and 66 (17%) either died before tracheostomy (46 [12%]) or were transitioned to palliative care (20 [5%]). The median time (interquartile range) from guardianship request until a defining event was the following: 6.2 (4.0-11) d for tracheostomy, 5.0 (2.9-8.2) d for extubation (P < .001 as compared to tracheostomy group), and 6.5 (2.5-11) d for death/palliative care (P = .55 as compared to tracheostomy). Neurological admissions were more common in the tracheostomy group and less common in the palliative group. Other admission demographics and hospitalization characteristics were similar. Hospital mortality was higher for subjects undergoing tracheostomy (58/195 [30%]) versus extubation (24/127 [19%]) (P = .03). CONCLUSIONS: Delay in performing tracheostomy due to legal requirements was associated with a 50% decrease in the need for tracheostomy. This suggests that decision-making with regard to ideal tracheostomy timing could be improved, saving unnecessary procedures.

Conscious sedation for the management of peritonsillar abscess in pediatric patients: A prospective case series and literature review.

OBJECTIVE: Peritonsillar abscess (PTA) is a common pediatric infection requiring drainage. Conscious Sedation (CS) can facilitate drainage in uncooperative children. However, it carries risks, especially if the airway is compromised. Moreover, evidence on its safety and efficacy is limited. This study examined the safety, pain reduction, and anxiety management of hospitalized pediatric patients treated for PTA under CS. MATERIALS AND METHODS: We performed a prospective observational case series of 118 children aged 2-15 years with 155 PTA episodes, managed from 2016 to 2023. Conscious sedation was used in 42 episodes. Outcomes were compared among CS and non-CS (local anesthesia only). Complications assessed safety. Efficacy was evaluated by the amount of pus, hospitalization parameters, pain scores, and recurrence. RESULTS: No significant differences were found regarding the demographic and presentation parameters except for younger age among the CS group (9 vs 11 years p = 0.001). One minor oxygen desaturation (2 %) event occurred with CS. Abscess drainage amount was greater with CS than non-CS, 4.9±4 mL vs. 3.2±2 mL, respectively (p = 0.03). Hospitalization stays were similar among groups. Maximum pain scores were lower with CS than non-CS, 1.4 ± 2 vs 4.2 ± 3 (p < 0.001); similarly, IV pain medication was used less frequently, 0.9 ± 1 vs. 1.6 ± 3 (p = 0.045), and the need for re-aspiration was less common 14 % vs. 28 % (p = 0.04), with CS than non-CS, respectively. The three-month recurrence rate was numerically lower with CS (5 % vs. 14 % non-CS). CONCLUSIONS: Conscious sedation facilitates PTA drainage with excellent safety and improved efficacy compared to local anesthesia in children. Pain scores are reduced both during drainage and hospitalization. Our prospective data add to the limited evidence supporting CS as a viable option for abscess drainage in uncooperative pediatric patients. Further study is warranted to confirm potential long-term reductions in recurrence.

Risk Factors for Severe Clinical Course in Epistaxis Patients.

Purpose: Epistaxis is a common medical emergency that may require admission to the emergency department (ED) and treatment by an otolaryngologist. Currently, there are no widely accepted indications for hospitalization, and the decision is based on personal experience. Methods: A retrospective study of 1171 medical records of patients with epistaxis treated at our tertiary medical center ED from 2013 to 2018 with no age limit. The presence of recurrent epistaxis, a posterior source of bleeding, the need for hospitalization, the need for blood transfusion, or surgical intervention defined severe clinical course. Results: The 1171 admissions included 230 recurrent admissions for a total of 941 patients (60% males) who were treated by an otolaryngologist. The average age was 57.6 in the adult population (>15) and 6.6 in the pediatric population (≤15). Of all patients, 39% had hypertension; 39% took antiplatelet/anticoagulation therapy; 63% came during winter-a significant risk factor; 34 (2.9%) had reduced hemoglobin levels of >1gr%, but only 7 received a blood transfusion; 131 (11%) were hospitalized, and 21 (1.8%) required surgical control of the bleeding. Age (OR 1.02; CI 1.01-1.023), male sex (OR 2.07; CI 1.59-2.69), hypertension (OR 1.76; CI 1.27-2.45), and antiplatelet/anticoagulation therapy (OR 2.53; CI 1.93-3.33, OR 1.65; CI 1.11-2.44, respectively), were significantly correlated with severe clinical course. Conclusion: Epistaxis is significantly more common and severe in older male patients with hypertension or antiplatelet/anticoagulation therapy. However, few need a blood transfusion or surgical intervention. In borderline cases with no definitive indication for hospitalization, we suggest adopting these factors as indications for hospitalization due to their marked influence on the clinical course. Routine coagulation tests are indicated in patients treated with warfarin or combined antiplatelet + anticoagulation therapy.

Time from sudden sensory neural hearing loss to treatment as a prognostic factor.

Introduction: The widely accepted treatment for sudden sensorineural hearing loss (SSNHL) is corticosteroid treatment (oral or intratympanic). The main goal of this work is to define the significance of the time between symptom onset and treatment initiation, as well as other prognostic factors, for hearing improvement. Methods: This retrospective study included 666 patients treated for SSNHL. Demographic data, audiometry, treatment method, time since symptom onset, and associated symptoms were recorded for each patient. The patients were divided into five groups according to the treatment initiation time-half a week, one week, 2 weeks, 3 weeks, or 4 weeks and over-after symptom onset. The degree of improvement was assessed by comparing the audiometry at the beginning and the end of the treatment. Results: The average period of hearing loss from symptom onset to treatment initiation was 10.8 days. Significant differences were found between the groups of half a week, one week, and 2 weeks and the groups of 3 weeks and 4 weeks and over (each separately, p < 0.001). No difference was found between the half-week, one-week, and two-week groups, nor was there a difference between the three-week and four-week-and-over groups. A correlation was found between the treatment initiation time in days and the degree of improvement in hearing for both speech recognition threshold (SRT) and discrimination, R = 0.26 p < 0.001 and R = 0.17 p < 0.001, respectively. No correlation was found for gender, age of the patients, comorbidities, or associated symptoms. Conclusion: The threshold for treatment initiation time is up to 2 weeks, after which the amplitude of hearing improvement decreases significantly. The other prognostic factors measured were not found to be statistically significant predictors.

The Impact of CYP2C9*11 Allelic Variant on the Pharmacokinetics of Phenytoin and (S)-Warfarin.

Cytochrome P450 2C9 (CYP2C9) is responsible for the oxidative metabolism of about 15% of commonly used drugs, some of which are characterized by a narrow therapeutic window. CYP2C9 is highly polymorphic, and over 60 alleles have been described. CYP2C9*2 and CYP2C9*3 are the most common polymorphisms among White patients and both are associated with decreased activity. The evidence concerning the functional importance of less frequent variant alleles is scarce. The objective of the current study was to characterize the in vivo activity of CYP2C9 among carriers of CYP2C9*11, one of the "African" alleles and the fourth most common CYP2C9 variant allele among White patients by using two prototype substrates, phenytoin and (S)-warfarin. Single 300-mg phenytoin and 20-mg warfarin doses were given to 150 healthy Ethiopian Jewish participants who were nonsmokers, at least one week apart. (S)-warfarin oral clearance and phenytoin metabolic ratio (PMR) derived from the ratio of 5-(4-hydroxyphenyl)-5-phenylhydantoin in 24-hour urine collection to plasma phenytoin 12 hours (PMR 24/12) or 24 hours (PMR 24/24) post dosing, were used as markers of CYP2C9 activity. PMR 24/12 and PMR 24/24 were reduced by 50% and 62.2%, respectively, among carriers of CYP2C9*1/*11 (n = 13) as compared with carriers of CYP2C9*1/*1 (n = 127) (false discovery rate (FDR) q < 0.001). The respective decrease in (S)-warfarin oral clearance was 52.6% (FDR q < 0.001). In conclusion, the enzyme encoded by CYP2C9*11 is characterized by a more than 50% decrease in the enzymatic activity, resembling the extent of decrease associated with CYP2C9*3 ("no-function allele"). Among patients of African ancestry, CYP2C9*11 genetic analysis should be considered prior to prescribing of narrow therapeutic window drugs such as phenytoin, warfarin, nonsteroidal anti-inflammatory drugs, or siponimod.

Phenytoin Metabolic Ratio, a Marker of CYP2C9 Activity, is Superior to the CYP2C9 Genotype as a Predictor of (S)-Warfarin Clearance.

BACKGROUND: CYP2C9 is a member of the cytochrome P450 (CYP) superfamily responsible for the metabolism of 16% of drugs that undergo oxidative metabolism. The activity of CYP2C9 exhibits marked inter-individual variability, which translates into prominent differences in the pharmacokinetics of CYP2C9 substrates, some of which are characterized by a narrow therapeutic window. Genetic polymorphisms in the gene encoding for CYP2C9 account for a fraction of the variability in CYP2C9 activity. The phenytoin metabolic ratio (PMR) is a marker of CYP2C9 activity in vivo, which correlates with CYP2C9 genetic polymorphisms. OBJECTIVE: The purpose of the current study was to evaluate the ability of the PMR to predict the oral clearance of (S)-warfarin (SWOCL) and its formation clearance towards its CYP2C9-mediated metabolites (SWCLf) [i.e., 6- and 7-hydroxy-(S)-warfarin]. METHODS: The study was conducted in 150 healthy non-smoker subjects (segment 1) and 60 patients treated with warfarin (segment 2). In the first segment, the participants received on two separate occasions a single 300-mg dose of phenytoin and at least 7 days later a single dose of warfarin (5 or 10 mg). The same PMR procedure was performed in the second segment, except that it was performed either before warfarin initiation or after the patients had reached stable anticoagulation. The PMR was derived from the ratio of 5-(4-hydroxyphenyl)-5-phenyl-hydantoin content in a 24-hour urine collection to plasma phenytoin concentration 12- (PMR24/12) or 24- (PMR24/24) post-dosing. In segment 1, SWOCL was calculated from the ratio of (S)-warfarin dose to the warfarin area under the plasma concentration-time curve extrapolated to infinity and the SWCLf from the ratio of urine content of 6- and 7-hydroxy-(S)-warfarin to (S)-warfarin area under the (S)-warfarin plasma concentration-time curve until the last measured timepoint. In segment 2, estimated SWOCL was derived from the ratio of (S)-warfarin dose to the mid-interval plasma concentration of (S)-warfarin. RESULTS: The PMR, SWOCL, and SWCLf varied significantly between carriers of different CYP2C9 genotypes in both healthy subjects (p < 0.001) and patients (p < 0.005). However, PMR and SWOCL values exhibited substantial intra-genotypic variability. PMR24/12 and PMR24/24 were significantly correlated with SWOCL both in healthy subjects (r = 0.62 and r = 0.67, respectively, p < 0.001) and in patients (r = 0.57 and r = 0.61, respectively, p < 0.001). In a multiple regression model that included all variables that correlated with SWOCL, PMR was the strongest predictor, explaining 44% and 38% of the variability in SWOCL among healthy subjects and patients, respectively, and accounting for 95.7% (44%/46%) and 90.5% (38%/42%) of the total explained variability in SWOCL among healthy subjects and patients, respectively. CONCLUSIONS: The PMR is the strongest predictor of SWOCL, and as such, it exhibits a significant advantage over the CYP2C9 genotype. The inclusion of PMR in future dosing algorithms of CYP2C9 substrates characterized by a narrow therapeutic window should be encouraged and further investigated.

Real Time Monitoring During Cochlear Implantation: Increasing the Accuracy of Predicting Residual Hearing Outcomes.

OBJECTIVES: Real-time electrocochleography (rt-ECochG) is a method to detect intracochlear potential changes during cochlear implantation (CI). Steep amplitude drops of the cochlear microphonic (CM) signal (so called "ECochG events") have been correlated with worse residual hearing outcomes. However, the sensitivity and specificity of monitoring CM amplitude on its own are too low to use it as a biomarker. The aim of this article was to establish if additional signal components would help to better predict postoperative hearing outcomes. DESIGN AND SETTING: Single-center, prospective cohort study at a tertiary referral hospital. PARTICIPANTS AND INTERVENTIONS: Between 2017 and 2020, we included 73 adult patients receiving a lateral wall cochlear implant electrode. During electrode insertion, rt-ECochG measurements were performed. MAIN OUTCOMES: We calculated a multiple regression analysis for patients with one ECochG event. The dependant variable was the relative acoustic hearing result 4 weeks after surgery. Independent variables were CM latency, a ratio of the auditory nerve neurophonic to the CM (the ANN/CM index) as well as CM signal recovery. RESULTS: The change of the ANN/CM index linearly correlated with acoustic hearing outcomes 4 weeks after surgery. Adding this factor led to a statistically significant increase in the variance accounted for by the regression model. CONCLUSIONS: When monitoring the implantation process with rt-ECochG, prediction of postoperative hearing thresholds is improved by addition of the ANN/CM index to a model that includes CM amplitude fluctuation.