Utilization of mechanistic modelling and simulation to analyse fenspiride proarrhythmic potency – Role of physiological and other non‐drug related parameters

alexandrossfakianakis shared this article with you from Inoreader Utilization of mechanistic modelling and simulation to analyse fenspiride proarrhythmic potency – Role of physiological and other non‐drug related parameters via Journal of Clinical Pharmacy and Therapeutics In this study, we investigated the cardiac risk of fenspiride, the drug that has recently been withdrawn after decades of market presence. In the simulation study using PBPK-PD model, arrhythmia was not observed even in the extreme conditions in terms of exposure, age, heart rate, and plasma potassium concentration. In addition, qNet metric value positioned fenspiride in the intermediate proarrhythmic risk class. Thus, it can be hypothesized that the clinically observed arrhythmia cases were not directly caused by fenspiride but a combination of multiple factors, including comedications was needed. Abstract What is known and objective Fenspiride, a drug that had been used for decades for the treatment of respiratory diseases, was recently withdrawn from the market due to the potential risk of QT prolongation and proarrhythmia. This is the first such withdrawal for many years and hence poses a question whether such risk could have been predicted and to what degree non-drug-specific parameters play a role in the reported QT prolongation and cases of TdP. The study aim was to test various 'what–if' scenarios to assess the influence of age, gender, heart rate, and plasma potassium concentration on QT interval prolongation due to various doses of fenspiride with the use of mechanistic mathematical modelling. Methods Concentration-time profiles were simulated with the use of a PBPK model developed based on published physico-chemical data, data from in vitro ADME experiments, and in vivo PK study results. Pharmacodynamic effect, that is, drug-triggered pseudoECG signal modification was simulated using a biophysically detailed model of human cardiac myocytes. Analysis of the qNet metric was also performed to classify proarrhythmic risk related to fenspiride. Results In the simulation study, arrhythmia was not observed even in the 'what–if' scenarios with extreme exposure, age, heart rate, and plasma potassium concentration. The qNet metric value positioned fenspiride in the intermediate risk class. What is new and conclusion It can be hypothesized that the clinically observed arrhythmia cases were not directly caused by fenspiride alone but a combination of multiple factors, including comedications. View on Web

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SARS‐CoV‐2 IgG “heritage” in newborn: a credit of maternal natural infection

alexandrossfakianakis shared this article with you from Inoreader SARS‐CoV‐2 IgG "heritage" in newborn: a credit of maternal natural infection via Journal of Medical Virology Abstract Introduction Description of transplacental passage of specific SARS-CoV-2 IgG from mothers who contracted natural infection to their newborns. Methods Retrospective cohort analysis including pregnant women diagnosed with SARS-CoV-2and their newborns both tested for SARS-CoV2 specific IgG and IgM with antibody titration at delivery. NPS were taken from both mothers and neonates, and tested for SARS-CoV-2 using PCR. Results IgM and IgG were analyzed in maternal and neonatal serum of 143 mother-infant dyads. 86% of women with a positive SARS-CoV-2 PCR > 14 days before delivery developed specific IgG and 84% of their infants showed transplacental passage of IgG. Conclusions Pregnant women infected with SARS-CoV-2 achieve antibody seroconversion following the kinetics described in the general population, and transplacental transfer of IgG specific antibodies occurs. No conclusion can be drawn on passive immunity efficacy or duration. This article is protected by copyright. All rights reserved. View on Web

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Correlation between radiologic and pathologic extranodal extension in HPV‐associated oropharyngeal cancer: Systematic review

alexandrossfakianakis shared this article with you from Inoreader Correlation between radiologic and pathologic extranodal extension in HPV‐associated oropharyngeal cancer: Systematic review via Head & Neck Abstract Pretreatment determination of extranodal extension (ENE) has significant clinical implications in human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC). Unfortunately there is no gold-standard imaging modality for radiological assessment of ENE in HPV+ OPSCC, leading to subjective assessments and complex decision making concerning ENE. A systematic review of diagnostic test accuracy was therefore undertaken, with five databases systemically searched to evaluate the diagnostic performance of an imaging modality for detection of ENE in HPV+ OPSCC. A meta-analysis was conducted on four CT studies using a random-effects model. While a narrative synthesis was provided for the studies using PET/CT and "CT and MRI." Out of 1772 hits, six studies were included in the review. Meta-analysis on four CT studies showed CT had an overall sensitivity of 77% and specificity of 60%. PET/CT had a sensitivity of 37.5% and specificity of 97%. "CT and MRI" had a se nsitivity of 62% and specificity of 78%. Further diagnostic studies involving CT, PET/CT and MRI are ultimately required. View on Web

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Fully digital versus conventional workflow for horizontal ridge augmentation with intraoral block bone: A randomized controlled clinical trial

alexandrossfakianakis shared this article with you from Inoreader Fully digital versus conventional workflow for horizontal ridge augmentation with intraoral block bone: A randomized controlled clinical trial via Clinical Implant Dentistry and Related Research Abstract Objectives To compare the outcome and efficiency of the computer-aided intraoral block bone grafting procedure with those of the conventional technique for the augmentation of horizontal ridge defects. Materials and Methods A total of 28 patients with single missing tooth in esthetic zone with class IV horizontal alveolar bone defect in need of dental implant restoration were recruited. Computer-aided design of the implant restoration and intraoral block bone grafting was performed for all the participants. The patients were randomly and equally divided into guide and control groups. A fully guided bone harvesting, trimming, and grafting surgery was executed in the guide group. The control group patients underwent surgery without any guide. After 6 months, all the patients underwent implant placement. The primary outcomes were the root mean square estimate (RMSE) values between the outer contours of the actual implanted and planned bone block as well as the RMSE values between the inner surface of the implanted bone block and the original bone surface of the recipient site immediately after surgery. The secondary outcomes were the trimming time of bone block and the surgery-associated complications. The postoperative visual analog scale (VAS) of pain, swelling, and mouth opening difficulty was recorded. Results All 28 patients underwent intraoral block bone grafting, followed by the placement of implant after 191.8 ± 19.69 days. The RMSE values between the outer contours of the implanted and planned bone blocks were significantly lower in the guide group (0.37 ± 0.16 mm) as compared to those in the control group (0.72 ± 0.29 mm) (p = 0.0007). The RMSE values between the inner contours of the graft block and original bone at the recipient site were lower in the guide group (0.35 ± 0.15 mm) as compared to those in the control group (0.48 ± 0.17 mm) (p = 0.043). The duration of bone block trimming was shorter in the guide group (401.51 ± 97.60 s) as compared to the control group (602.36 ± 160.57 s) (p = 0.0005). In the control group, two patients received secondary bone grafting, one patient experienced bleeding of donor site and temporary hypoesthesia of the lower lip and chin skin, and one patient developed temporary sensitivity of the adjacent tooth. Conclusions As compared to the conventional procedure, the fully digital workflow in the present study seemed to be a more accuracy and effective protocol for horizontal ridge augmentation with intraoral block bone. Trial registration: Chictr.org.cn (ChiCTR2000036390). View on Web

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Perioperative Outcomes in Fibula, Osteocutaneous Radial Forearm, and Scapula Free Flaps

alexandrossfakianakis shared this article with you from Inoreader Perioperative Outcomes in Fibula, Osteocutaneous Radial Forearm, and Scapula Free Flaps via JAMA Otolaryngology–Head & Neck Surgery Online First This cohort study assesses whether fibula free flaps, osteocuta neous radial forearm free flaps, and scapula free flaps are associated with differences in perioperative outcomes in patients undergoing osseous head and neck reconstruction. View on Web

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A Novel Molecular Test for Determining HPV Integration Status in HPV-Positive Oropharynx Cancers

alexandrossfakianakis shared this article with you from Inoreader A Novel Molecular Test for Determining HPV Integration Status in HPV-Positive Oropharynx Cancers via JAMA Otolaryngology–Head & Neck Surgery Online First This diagnostic study describes the development of an assay fo r human papillomavirus–driven cancers of the oropharynx and the role viral integration could play in the process. View on Web

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Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for COVID-19–Related Olfactory Dysfunction

alexandrossfakianakis shared this article with you from Inoreader Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for COVID-19–Related Olfactory Dysfunction via JAMA Otolaryngology–Head & Neck Surgery Current Issue This randomized clinical trial evaluates the efficacy and safety of theophylline added to saline nasal irrigation compared with placebo for COVID-19–related olfactory dysfunction. View on Web

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Strategies for Evaluating Anosmia Therapeutics in the COVID-19 Era

alexandrossfakianakis shared this article with you from Inoreader Strategies for Evaluating Anosmia Therapeutics in the COVID-19 Era via JAMA Otolaryngology–Head & Neck Surgery Current Issue Two studies in this issue of JAMA Otolaryngology–Head & Neck Surgery evaluate the use of nasal theophylline, a phosphodiesterase inhibitor that may promote neural olfactory signaling and recovery for postviral olfactory dysfunction (OD). The first, a dose-modification Research Letter by Lee et al was conducted in patients with non-COVID-19–related hyposmia or anosmia secondary to viral infection and confirmed by the objective University of Pennsylvania Smell Identification Test. This open-label, dose-escalation trial provides an educ ational description of how to evaluate the appropriate dose for an emerging pharmacologic intervention. Specifically, the authors identified 400 mg of theophylline twice daily as a tolerated dosage. This was calculated as an equivalent oral dose of 20 mg. A phase 2 pilot study by Gupta et al was designed using this valuable information. Patients with suspected COVID-19–related OD completed the University of Pennsylvania Smell Identification Test and were randomized to either theophylline or placebo nasal irrigations for 6 weeks. This study was inconclusive regarding the clinical benefit of theophylline nasal irrigations, although there was suggested improvement by subjective assessments. The authors acknowledge several limitations, including small sample size, the virtual nature of the study design and subsequent inability to conduct endoscopic nasal examinations, lack of information regarding participant COVID-19 vaccination status, lack of polymerase chain reaction–confirmed C OVID-19 infection, and short-term participant follow-up. These acknowledgments are justified, and many can be overcome in subsequent studies with adequate funding and time. However, the heterogeneous nature of COVID-19 and associated research make this area of work particularly challenging. Herein, we propose several approaches to improve the rigor of OD research in the COVID-19 era. View on Web

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Muscle Tension Dysphonia

alexandrossfakianakis shared this article with you from Inoreader Muscle Tension Dysphonia via JAMA Otolaryngology–Head & Neck Surgery Current Issue This Patient Page describes the causes, symptoms, and tre atment options for muscle tension dysphonia. View on Web

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Well-Differentiated Hypopharyngeal Liposarcoma–Associated Airway Obstruction

alexandrossfakianakis shared this article with you from Inoreader Well-Differentiated Hypopharyngeal Liposarcoma–Associated Airway Obstruction via JAMA Otolaryngology–Head & Neck Surgery Current Issue This case report describes a man in his 70s who presented with a bilobed, cylindrical mucosal mass that had been expelled from his mouth after an episode of nausea and violent vomiting. View on Web

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