Αρχειοθήκη ιστολογίου

Πέμπτη 7 Ιουλίου 2022

Pharmacokinetics, Safety, and Efficacy of Gadopiclenol in Pediatric Patients Aged 2 to 17 Years

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imageObjectives The aim of this study was to evaluate the pharmacokinetic (PK) profile, safety, and efficacy of gadopiclenol, a new high-relaxivity gadolinium-based contrast agent, in children aged 2 to 17 years. Materials and Methods Children scheduled to undergo contrast-enhanced magnetic resonance imaging of the central nervous system (CNS cohort) or other organs (body cohort) were included sequentially into 3 age groups (12–17, 7–11, and 2–6 years). Gadopiclenol was administered at the dose of 0.05 mmol/kg. A sparse sampling approach was applied, with 4 blood samples per child collected up to 8 hours postinjection. Population PK modeling was used for the analysis, including the CNS cohort and adult subjects from a previous study. Adverse events were recorded, and efficacy was assessed for all children. Results Eighty children were included, 60 in the CNS cohort and 20 in the body cohort. The 2-compartment model with linear elimination from the central compartment developed in adults was also suitable for children. Pharmacokinetic parameters were very similar between adults and children. Terminal elimination half-life was 1.82 hours for adults and 1.77 to 1.29 hours for age groups 12–17 to 2–6 years. The median clearance ranged from 0.08 L/h/kg in adults and 12–17 years to 0.12 L/h/kg in 2–6 years. The median central and peripheral volumes of distribution were 0.11 to 0.12 L/kg and 0.06 L/kg, respectively, for both adults and children. Simulations of plasma concentrations showed minor differences, and median area under the curve was 590 mg·h/L for adults and 582 to 403 mg·h/L for children. Two patients (2.5%) experienced nonserious adverse events considered related to gadopiclenol: a mild QT interval prolongation and a moderate maculopapular rash. Despite the limited number of pat ients, this study showed that gadopiclenol improved lesion detection, visualization, and diagnostic confidence. Conclusions The PK profile of gadopiclenol in children aged 2 to 17 years was similar to that observed in adults. Thus, there is no indication for age-based dose adaptation, and comparable plasma gadopiclenol concentrations are predicted to be achieved with body weight–based dosing in this population. Gadopiclenol at 0.05 mmol/kg seems to have a good safety profile in these patients and could improve lesion detection and visualization, therefore providing better diagnostic confidence.
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Severity of SARS-CoV-2 Infection in Pregnancy

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Abstract
Background
Pregnancy represents a physiological state associated with increased vulnerability to severe outcomes from infectious diseases, both for the pregnant person and developing infant. The SARS-CoV-2 pandemic may have important health consequences for pregnant individuals, who may also be more reluctant than non-pregnant people to accept vaccination.
Methods
We sought to estimate the degree to which increased severity of SARS-CoV-2 outcomes can be attributed to pregnancy using a population-based SARS-CoV-2 case file from Ontario, Canada. Due to varying propensity to receive vaccination, and changes in dominant circulating viral strains over time, a time-matched cohort study was performed to evaluate the relative risk of severe illness in pregnant women with SARS-CoV-2 compared to other SARS-CoV-2 infected women of childbearing age (10 to 49 years old). Risk of severe SARS-CoV-2 outcomes was evaluated in pregnant women and time-matched non-pregnant controls using multivariable conditional logistic regression.
Results
Compared to the rest of the population, non-pregnant women of childbearing age had an elevated risk of infection (standardized morbidity ratio (SMR) 1.28), while risk of infection was reduced among pregnant women (SMR 0.43). After adjustment for confounding pregnant women had a markedly elevated risk of hospitalization (adjusted OR 4.96, 95% CI 3.86 to 6.37) and ICU admission (adjusted OR 6.58, 95% CI 3.29 to 13.18). The relative increase in hospitalization risk associated with pregnancy was greater in women without comorbidities than in those with comorbidities (P for heterogeneity 0.004).
Conclusions
Given the safety of SARS-CoV-2 vaccines in pregnancy, risk-benefit calculus strongly favours SARS-CoV-2 vaccination in pregnant women.
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Antibody and T-cell responses 6 months after COVID-19 mRNA-1273 vaccination in patients with chronic kidney disease, on dialysis, or living with a kidney transplant

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Abstract
Background
The immune response to COVID-19 vaccination is inferior in kidney transplant recipients (KTR), and to a lesser extent in patients on dialysis or with chronic kidney disease (CKD). We assessed the immune response 6 months after mRNA-1273 vaccination in kidney patients and compared this to controls.
Methods
152 participants with CKD stages G4/5 (eGFR <30  mL/min/1.73m2), 145 participants on dialysis, 267 KTR, and 181 controls were included. SARS-CoV-2 Spike S1-specific IgG antibodies were measured by fluorescent bead-based multiplex-immunoassay, neutralizing antibodies to ancestral, Delta and Omicron (BA.1) variants by plaque reduction, and T-cell responses by IFN-γ release assay.
Results
At 6 months after vaccination S1-specific antibodies were detected in 100% of controls, 98.7% of CKD G4/5 patients, 95.1% of dialysis patients, and 56.6% of KTR. These figures were comparable to the respons e rates at 28 days, but antibody levels waned significantly. Neutralization of the ancestral and Delta variant was detected in most participants, whereas neutralization of Omicron was mostly absent. S-specific T-cell responses were detected 6 months in 75.0% of controls, 69.4% of CKD G4/5 patients, 52.6% of dialysis patients, and 12.9% of KTR. T-cell responses at 6 months were significantly lower than responses at 28 days.
Conclusions
Although seropositivity rates at 6 months were comparable to that at 28 days after vaccination, significantly decreased antibody levels and T-cell responses were observed. The combination of low antibody levels, reduced T-cell responses, and absent neutralization of the newly-emerging variants indicates the need for additional boosts or alternative vaccination strategies in KTR.
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Strategies for Evaluating Anosmia Therapeutics in the COVID-19 Era

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jamanetwork.com

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

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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.
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Safety of High-Dose Nasal Theophylline Irrigation in the Treatment of Postviral Olfactory Dysfunction

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jamanetwork.com

This case series aims to determine the maximum tolerable dose of theophylline delivered via high-volume, low-pressure nasal saline irrigation for treatment of postviral olfactory dysfunction.
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Surgeon Thyroidectomy Case Volume Impacts Disease‐free Survival in the Management of Thyroid Cancer

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Surgeon Thyroidectomy Case Volume Impacts Disease-free Survival in the Management of Thyroid Cancer

In this population-based cohort study involving 37,233 thyroidectomies performed in Ontario, Canada between 1993 and 2017, we found both high-volume surgeons and hospitals to be predictors of better disease-free survival (DFS) in patients with well-differentiated thyroid cancer. DFS is higher among surgeons performing more than 40 thyroidectomies a year.


Objectives

To assess the association between surgeons thyroidectomy case volume and disease-free survival (DFS) for patients with well-differentiated thyroid cancer (WDTC). A secondary objective was to assess a surgeon volume cutoff to optimize outcomes in those with WDTC. We hypothesized that surgeon volume will be an important predictor of DFS in patients with WDTC after adjusting for hospital volume and sociodemographic and clinical factors.

Methods

In this retrospective population-based cohort study, we identified WDTC patients in Ontario, Canada, who underwent thyroidectomy confirmed by both hospital-level and surgeon-level administrative data between 1993 and 2017 (N = 37,233). Surgeon and hospital volumes were calculated based on number of cases performed in the year prior by the physician and at an institution performing each case, respectively and divided into quartiles. A multilevel hierarchical Cox regression model was used to estimate the effect of volume on DFS.

Results

A crude model without patient or treatment characteristics demonstrated that both higher surgeon volume quartiles (p < 0.001) and higher hospital volume quartiles (p < 0.001) were associated with DFS. After controlling for clustering and patient/treatment covariates and hospital volume, moderately low (18–39/year) and low (0–17/year) volume surgeons (hazard ratios [HR]: 1.23, 95% confidence interval [CI]: 1.09–1.39 and HR: 1.34, 95% CI: 1.17–1.53 respectively) remained an independent statistically significant negative predictor of DFS.

Conclusion

Both high-volume surgeons and hospitals are predictors of better DFS in patients with WDTC. DFS is higher among surgeons performing more than 40 thyroidectomies a year.

Level of Evidence

3 Laryngoscope, 2022

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Characterizing Pediatric Bilateral Vocal Fold Dysfunction: Analysis with the Pediatric Health Information System Database

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Characterizing Pediatric Bilateral Vocal Fold Dysfunction: Analysis with the Pediatric Health Information System Database

This database study represents the largest cohort analysis to date characterizing bilateral vocal fold dysfunction. The majority of pediatric patients with bilateral vocal fold dysfunction (BVFD) have a complex chronic condition, with respiratory conditions being the most common followed by gastrointestinal conditions. Prognostic indicators of improved hospital survival include gastrointestinal comorbidities and presence of tracheostomy.


Objectives

The purpose of this study was to characterize pediatric bilateral vocal fold dysfunction and to examine the overall inpatient mortality.

Methods

Retrospective cohort analysis. Data from the Pediatric Health Information System was gathered for all pediatric patients with a diagnosis of bilateral vocal fold dysfunction between January 2008 and September 2020. Univariate and multivariate analyses were performed using Cox proportional hazard models.

Results

2395 patients accounted for 4799 hospitalizations with bilateral vocal fold dysfunction. Inpatient mortality occurred in 2.9% of the study sample. Chiari 2 was found in 2.8% of patients. The most common associated diagnoses were related to comorbid respiratory conditions (61.1%). The median adjusted ratio of cost to charges was $76,569. Aspiration was noted in 28 patients (1.2%). Gastrostomy was performed in 607 patients (25.3%). Tracheostomy was performed in 27% of patients. The overall 90-day readmission rate was 61%. On multivariate analysis, prognostic factors associated with increased hospital survival include gastrointestinal comorbidities (hazard ratio [HR]: 0.29; 95% confidence interval [CI]: 0.18–0.49) and tracheostomy (HR: 0.21; 95% CI: 0.12–0.37).

Conclusion

This database study represents the largest cohort analysis to date characterizing bilateral vocal fold dysfunction. Favorable prognostic indicators of overall hospital survival include gastrointestinal comorbidities and the presence of tracheostomy. Tracheostomy is associated with an increase in hospital costs, comorbidities, gastrostomy tube placement, and Chiari diagnosis.

Level of Evidence

4 Laryngoscope, 2022

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Tooth Preservation vs. Extraction and Implant Placement in Periodontally Compromised Patients: A Systematic Review and Analysis of Studies

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Abstract

Purpose

: The aim of this systematic review was to identify studies with a minimum of 5-years follow-up, reporting on the management of periodontally compromised teeth with either extraction and subsequent implant placement or teeth preservation with conventional periodontal treatment and application of regenerative procedures. The outcomes of these two approaches, based on clinical and radiographic data and the incidence of tooth- and implant-loss, were also investigated.

Material and methods

: A systematic search for studies reporting on clinical and radiographic outcomes of periodontal treatment or replacement of periodontally compromised teeth with implants was conducted in 3 electronic databases, followed by a hand-search in 8 journals. Only randomized controlled trials (RCTs), cohort studies, and case series with prospective design were included.

Results

: The initial search resulted in 1080 papers. After the first two screenings, 24 publications were selected for inclusion in this systematic review. The treatment protocols for the teeth preservation group contained non-surgical and/or surgical periodontal treatment with or without regeneration procedures. The implant studies included extraction of periodontally involved teeth and implant placement with or without bone and soft tissue augmentation, followed by restoration with fixed dental prostheses (FDPs). Survival rates ranged between 81.8% and 100% in the tooth retention group, and between 94.8% and 100% in the implant group. In the extraction group, no complications were reported for 76.09% of the implants. Similarly, no complications were reported for 86.83% of the tooth retention group. The lack of standardized comparable studies prohibited conduction of a meta-analysis.

Conclusion

: Both treatment approaches, treatment of periodontally compromised teeth, or tooth extraction followed by implant placement, present high survival rates. The application of bone regeneration techniques improves the long-term prognosis of periodontally involved teeth. Hence, treatment of periodontally involved teeth with subsequent application of a rigorous maintenance protocol can be a viable alternative for a number of years, before proceeding to extraction and replacement with dental implants. More well-designed randomized controlled trials are needed in order to draw definite conclusions on the subject.

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