Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are ...often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hypermutation and affinity maturation, plasmablast differentiation and class-switch recombination. We use this system to define the essential cellular components necessary to produce an influenza vaccine response. We also show that it can be used to evaluate humoral immune responses to two priming antigens, rabies vaccine and an adenovirus-based severe acute respiratory syndrome coronavirus 2 vaccine, and to assess the effects of different adjuvants. This system should prove useful for studying critical mechanisms underlying adaptive immunity in much greater depth than previously possible and to rapidly test vaccine candidates and adjuvants in an entirely human system.
Otitis media, a common disease marked by the presence of fluid within the middle ear space, imparts a significant global health and economic burden. Identifying an effusion through the tympanic ...membrane is critical to diagnostic success but remains challenging due to the inherent limitations of visible light otoscopy and user interpretation. Here we describe a powerful diagnostic approach to otitis media utilizing advancements in otoscopy and machine learning. We developed an otoscope that visualizes middle ear structures and fluid in the shortwave infrared region, holding several advantages over traditional approaches. Images were captured in vivo and then processed by a novel machine learning based algorithm. The model predicts the presence of effusions with greater accuracy than current techniques, offering specificity and sensitivity over 90%. This platform has the potential to reduce costs and resources associated with otitis media, especially as improvements are made in shortwave imaging and machine learning.
Early detection and intervention of pediatric hearing loss is critical for language development and academic achievement. However, variations in the diagnostic workup and management of pediatric ...sensorineural hearing loss (SNHL) exist.
To identify patient and clinician factors that are associated with variation in practice on a national level.
This cross-sectional study used the Optum claims database to identify 53 711 unique children with SNHL between January 1, 2008, and December 31, 2018.
National use rates and mean costs for diagnostic modalities (electrocardiogram, cytomegalovirus testing, magnetic resonance imaging, computed tomography, and genetic testing) and interventions (speech-language pathology, billed hearing aid services, and cochlear implant surgery) were reported. The associations of age, sex, SNHL laterality, clinician type, race/ethnicity, and household income with diagnostic workup and intervention use were measured in multivariable analyses.
Of 53 711 patients, 23 735 (44.2%) were girls, 2934 (5.5%) were Asian, 3797 (7.1%) were Black, 5626 (10.5%) were Hispanic, 33 441 (62.3%) were White, and the mean (SD) age was 7.3 (5.3) years. Of all patients, 32 200 (60.0%) were seen by general otolaryngologists, while 7573 (14.10%) were seen by pediatric otolaryngologists. Diagnostic workup was received by 14 647 patients (27.3%), while 13 482 (25.1%) received intervention. Use of genetic testing increased (odds ratio, 1.22 per year; 95% CI, 1.20-1.24), whereas use of computed tomography decreased (odds ratio, 0.93 per year; 95% CI, 0.92-0.94) during the study period. After adjusting for relevant covariables, children who were seen by pediatric otolaryngologists and geneticists had the highest odds of receiving workup and intervention. Additionally, racial/ethnic and economic disparities were observed in the use of most modalities of diagnostic workup and intervention for pediatric SNHL.
This cross-sectional study identified factors associated with disparities in the diagnostic workup and intervention of pediatric SNHL, thus highlighting the need for increased education and standardization in the management of this common sensory disorder.
To assess the utility of diffusion tensor imaging of the auditory pathway in children with sensorineural hearing loss (SNHL).
Retrospective cohort study.
A single academic tertiary children's ...hospital.
Sixteen pediatric patients with bilateral SNHL of at least moderate severity in the poorer ear (eight male; mean age, 5.3 ± 4.9 yrs). Controls consisted of age- and sex-matched children with normal hearing who were imaged for nonotologic, non-neurologic medical concerns and found to have normal magnetic resonance imaging (MRI).
Three Tesla MRI scanners were used for diffusion tensor imaging.
Quantitative diffusion tensor metrics were extracted from the superior olivary nucleus (SON), inferior colliculus (IC), and ipsilateral fiber tracts between the SON and IC delineated by tractography.
We identified differences in fractional anisotropy of the SON between the SNHL cohort and controls (0.377 ± 0.056 vs. 0.422 ± 0.052; p = 0.009), but not in the IC. There were no differences in the mean diffusivity (MD) values in the IC and SON. Among younger children (≤5 yrs), MD was decreased in the SNHL cohort compared with controls in the IC (0.918 ± 0.051 vs. 1.120 ± 0.142; p < 0.001). However, among older children (>5 yrs), there were no differences in MD (1.124 ± 0.198 vs. 0.997 ± 0.103; p = 0.119). There were no differences in MD or fractional anisotropy in the white matter fibers of the IC-SON tract.
Our results suggest abnormal neural tracts along the central auditory pathway among children with SNHL. Longitudinal studies should assess the prognostic value of these MRI-based findings for assessing long-term outcomes and determining intervention efficacy.
To introduce a novel intubation technique for difficult pediatric airways.
This two-provider technique requires a direct laryngoscope and a flexible fiberoptic laryngoscope. One provider performs ...direct laryngoscopy which allows for introduction of the flexible laryngoscope. The second provider inserts the flexible laryngoscope with the endotracheal tube loaded, through the oropharynx in to the subglottis.
We report three pediatric patients that were initially unable to be intubated by conventional methods. We were ultimately able to successfully intubate these patients with difficult airways using our novel technique.
We found that this technique of direct laryngoscopy assisted flexible fiberoptic intubation is a useful adjunct in select pediatric difficult airway patients.
To describe national trends in cholesteatoma management.
Retrospective analysis Optum Clinformatics® Database from 2003 to 2019.
16,179 unique adult and pediatric patients who received cholesteatoma ...surgery.
Patients were categorized into three groups by initial surgical modality: canal wall down (CWD), canal wall up (CWU), and tympanoplasty without mastoidectomy (TnoM). Three major comparisons between groups were performed: 1) temporal trends, 2) clinical and sociodemographic determinants, and 3) healthcare use in terms of total costs and incidence of postoperative imaging and subsequent surgery.
Overall, 23.2% received initial CWD surgery, 44.3% CWU, and 32.5% TnoM. 1) The incidence of initial CWD surgery decreased (odds ratios OR = 0.98, 95% confidence intervals CI 0.97,0.99), while CWU increased (OR = 1.02, 95% CI 1.01,1.03), and TnoM remained stable over the study period (OR = 0.99, 95% CI 0.98,1.00). 2) Relative to CWU, TnoM surgery was less likely in adults, patients with prior complications, and non-White patients, while being more likely in patients with higher household income. CWD was more likely than CWU in adults, patients with prior complications, and non-White patients, while income had no effect. 3) Postoperative costs for CWU and CWD were similar. In 2 years following initial surgery, postoperative imaging and/or subsequent surgery was performed in 45.48% of CWD, 57.42% of CWU, and 41.62% of TnoM patients.
Incidence of initial CWD surgery decreased and social disparities in cholesteatoma management were observed. Postoperative imaging or second-look surgery were performed in less than 60% of patients with initial CWU surgery and over 40% of patients with initial CWD.
To assess diffusion and perfusion changes of the auditory pathway in pediatric medulloblastoma patients exposed to ototoxic therapies.
Retrospective cohort study.
A single academic tertiary ...children's hospital.
Twenty pediatric medulloblastoma patients (13 men; mean age 12.0 ± 4.8 yr) treated with platinum-based chemotherapy with or without radiation and 18 age-and-sex matched controls were included. Ototoxicity scores were determined using Chang Ototoxicity Grading Scale.
Three Tesla magnetic resonance was used for diffusion tensor and arterial spin labeling perfusion imaging.
Quantitative diffusion tensor metrics were extracted from the Heschl's gyrus, auditory radiation, and inferior colliculus. Arterial spin labeling perfusion of the Heschl's gyrus was also examined.
Nine patients had clinically significant hearing loss, or Chang grades more than or equal to 2a; 11 patients had mild/no hearing loss, or Chang grades less than 2a. The clinically significant hearing loss group showed reduced mean diffusivity in the Heschl's gyrus (p = 0.018) and auditory radiation (p = 0.037), and decreased perfusion in the Heschl's gyrus (p = 0.001). Mild/no hearing loss group showed reduced mean diffusivity (p = 0.036) in Heschl's gyrus only, with a decrease in perfusion (p = 0.008). There were no differences between groups in the inferior colliculus. There was no difference in fractional anisotropy between patients exposed to ototoxic therapies and controls.
Patients exposed to ototoxic therapies demonstrated microstructural and physiological alteration of the auditory pathway. The present study shows proof-of-concept use of diffusion tensor imaging to gauge ototoxicity along the auditory pathway. Future larger cohort studies are needed to assess significance of changes in diffusion tensor imaging longitudinally, and the relationship between these changes and hearing loss severity and longitudinal changes of the developing auditory white matter.
The optimal surgical management of cholesteatoma remains controversial. Within pediatric otolaryngology, one of the most vital points of contention is the selection of canal wall-up (CWU) versus ...canal wall-down (CWD) procedures. Pediatric cholesteatoma has high rates of recurrence (16%–54%). In adults, there is evidence that the selection of surgical techniques affects recurrence rates. This has not been shown in children.
1. To systematically review the literature on recurrent and residual cholesteatoma after CWU and CWD in children and perform a meta-analysis of the data. 2. To assess the rates of recurrent and residual cholesteatoma between CWU and CWD techniques in pediatric patients. 3. To assess hearing outcomes by evaluating postoperative differences in the air-bone gap (ABG) between CWU and CWD techniques.
A systematic search of PubMed, Embase, Scopus, and Cochrane Collaboration was performed from inception to May 1st, 2020, to identify studies that compared CWU and CWD procedures for acquired cholesteatoma in children.
Search records were screened in duplicate by four reviewers. Inclusion criteria consisted of comparative randomized clinical trials and observational studies assessing outcomes of CWU and CWD techniques in the pediatric population. Studies involving patients with congenital cholesteatoma were excluded.
Four reviewers working independently and in duplicate systematically reviewed and extracted study data. Dichotomous variables were analyzed as risk ratios (RR), while continuous variables were compared using weighted mean differences (MD). The risk of bias was assessed using the CLARITY Scale.
The outcomes were recurrence, residual disease, air-bone gap (ABG), and air conductive (AC) thresholds.
After screening 1036 publications, 17 retrospective cohort studies were selected. 1333 children were included; the overall mean age was ten years (SD 7.9), and the overall mean follow-up time was 5.9 years (SD 6.6). CWU and CWD techniques were performed in 60% (796) and 40% (537) cases. We did not find differences in cholesteatoma recurrence (RR: 1.50, 95% CI 0.94; 2.40; n = 544; I2 0%; Tau 2: 0.00), or rates of residual cholesteatoma (RR 1.51, 95% CI 0.96; 2.38, n = 506; I2: 0%; Tau 2: 0.00) in patients who underwent CWU and CWD mastoidectomy. The mean air-bone gap was lower with CWU than CWD (mean difference: 7.60, 95% CI -10.65; −4.54; n = 242; I2: 71%; Tau 2: 5.98).
and relevance: We show similar rates of recurrence and residual disease after either CWU or CWD tympanoplasty. Our results challenge the fundamental principle of CWD surgery as a standard technique, as there is no difference in rates of recurrence and residual disease in CWU and CWD. Moreover, audiometric results support CWU with improved hearing outcomes.
PROSPERO identifier: CRD42020184029.
► Rapid increase in environmental contamination with toxic metals (TMs) and metalloids. ► TMs and metalloids-stress impacts cause either directly of indirectly excessive generation of ROS leading to ...oxidative stress in plants. ► GSH (γ-Glu-Cys-Gly) is a significant component of AsA-GSH pathway. ► GSH is involved in both direct and indirect control of ROS concentrations in cells. ► TMs and metalloids modulate differentially the total GSH, its redox couple (GSH/GSSG) and related major enzymes (such as, GR, GPXs, GSTs) in plants which in turn, cumulatively control plants’ adaptation and tolerance to TMs and metalloids stress.
The rapid increase in the contamination of the environment by toxic metals (TMs) and metalloids is posing serious threats to biotic communities. Plants are among the organisms most vulnerable to TMs and metalloids due to their sedentary and stationary existence under changing environmental conditions. Toxic metals- and metalloids-stress-impacts cause either directly or indirectly excessive generation of reactive oxygen species (ROS) leading to oxidative stress in plants. Being a significant component of ascorbate-glutathione (AsA-GSH) pathway, tripeptide glutathione (GSH, γ-Glu-Cys-Gly) is involved in both direct and indirect control of ROS and their reaction products concentrations in cells and thus, protects plants against TMs- and metalloids-mediated oxidative stress. Additionally, several GSH-related enzymes such as GSH reductase (GR, EC 1.6.4.2), GSH peroxidases (GPXs, EC 1.11.1.9) and GSH sulfo-transferases (GSTs, EC 2.5.1.18) cumulatively form an efficient defense system to protect plants against ROS-induced effects in addition to their significance for the detoxification, chelation and compartmentalization of major TMs and metalloids in plants. The present review critically evaluates the recent studies on the modulation of total reduced GSH, GSH/GSSG redox couple, the major GSH-related enzymes and their cumulative significance in plants’ adaptation and/or tolerance to TMs and metalloids in detail.
Metoclopramide is mainly metabolized by CYP2D6, CYP3A4, CYP2C19, and CYP1A2 enzymes, while cilostazol is also metabolized by CYP3A4, CYP2C19, and CYP1A2 enzymes.
This study evaluates the effect of ...cilostazol on the pharmacokinetics of oral metoclopramide.
This was a randomized, two-phase cross-over pharmacokinetic study separated by a 4-week wash-out time period, 12 healthy non-smoking volunteers received metoclopramide 20 mg as a single oral dose and after 4 weeks, cilostazol 100 mg twice daily for 4 days then with metoclopramide 20 mg on test day. Serial blood samples were analyzed by using a validated high-performance liquid chromatography-ultraviolet method to determine maximum plasma drug concentration (Cmax), time to reach (Tmax), and area under the curve (AUC0-∞) of metoclopramide.
Cilostazol increased the mean Cmax, AUC0-∞ and half-life (T1/2) of metoclopramide by 6%, 27% and by 0.79 %, respectively. In addition, Tmax of metoclopramide was delayed by cilostazol.
The results showed delayed Tmax of metoclopramide by cilostazol, which could lead to the conclusion that cilostazol affects the absorption of metoclopramide. Both drugs when necessary to administer together must not be administered at the same time especially when given in gastroparesis patients.
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