Citations

Objectives: This article describes key data sources and methods used to estimate hearing loss in the United States, in the Global Burden of Disease study. Then, trends in hearing loss are described for 2019, including temporal trends from 1990 to 2019, changing prevalence over age, severity patterns, and utilization of hearing aids. Design: We utilized population-representative surveys from the United States to estimate hearing loss prevalence for the Global Burden of Disease study. A key input data source in modeled estimates are the National Health and Nutrition Examination Surveys (NHANES), years 1988 to 2010. We ran hierarchical severity-specific models to estimate hearing loss prevalence. We then scaled severity-specific models to sum to total hearing impairment prevalence, adjusted estimates for hearing aid coverage, and split estimates by etiology and tinnitus status. We computed years lived with disability (YLDs), which quantifies the amount of health loss associated with a condition depending on severity and creates a common metric to compare the burden of disparate diseases. This was done by multiplying the prevalence of severity-specific hearing loss by corresponding disability weights, with additional weighting for tinnitus comorbidity. Results: An estimated 72.88 million (95% uncertainty interval (UI) 68.53 to 77.30) people in the United States had hearing loss in 2019, accounting for 22.2% (20.9 to 23.6) of the total population. Hearing loss was responsible for 2.24 million (1.56 to 3.11) YLDs (3.6% (2.8 to 4.7) of total US YLDs). Age-standardized prevalence was higher in males (17.7% [16.7 to 18.8]) compared with females (11.9%, [11.2 to 12.5]). While most cases of hearing loss were mild (64.3%, 95% UI 61.0 to 67.6), disability was concentrated in cases that were moderate or more severe. The all-age prevalence of hearing loss in the United States was 28.1% (25.7 to 30.8) higher in 2019 than in 1990, despite stable age-standardized prevalence. An estimated 9.7% (8.6 to 11.0) of individuals with mild to profound hearing loss utilized a hearing aid, while 32.5% (31.9 to 33.2) of individuals with hearing loss experienced tinnitus. Occupational noise exposure was responsible for 11.2% (10.2 to 12.4) of hearing loss YLDs. Conclusions: Results indicate large burden of hearing loss in the United States, with an estimated 1 in 5 people experiencing this condition. While many cases of hearing loss in the United States were mild, growing prevalence, low usage of hearing aids, and aging populations indicate the rising impact of this condition in future years and the increasing importance of domestic access to hearing healthcare services. Large-scale audiometric surveys such as NHANES are needed to regularly assess hearing loss burden and access to healthcare, improving our understanding of who is impacted by hearing loss and what groups are most amenable to intervention.

Abstract Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function.

Abstract Background Invasive fungal infections have been described throughout the COVID-19 pandemic. Cryptococcal disease after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in several isolated case reports and 1 larger case series. We sought to describe cryptococcal infections following SARS-CoV-2 through establishing a database to investigate underlying risk factors, disease manifestations, and outcomes. Methods We created a crowdsourced call for cases solicited through the Mycoses Study Group Education and Research Consortium, the Centers for Disease Control and Prevention Emerging Infectious Diseases Network, and infectious diseases Twitter groups. Data were collected in a web-based and secure REDCap survey without personal identifiers. Results Sixty-nine cases were identified and submitted by 29 separate institutional sites. Cryptococcosis was diagnosed a median of 22 days (interquartile range, 9–42 days) after SARS-CoV-2 infection. Mortality among those with available follow-up was 72% (26/36) for the immunocompetent group and 48% (15/31) for the immunocompromised group (likelihood ratio, 4.01; P = .045). We observed a correlation between disease manifestation (central nervous system infection, proven/probable disseminated disease, and respiratory) and mortality (P = .002). Conclusions The mortality rate of 59% for patients with cryptococcosis following SARS-CoV-2 is higher than that of modern Cryptococcus cohorts. There was an association between immunocompromised status and cryptococcal disease manifestations as well as mortality. Moreover, our series emphasizes the need for clinical and laboratory assessment of opportunistic infections beyond 30 days when concerning symptoms develop.

INTRODUCTION: The American Gastroenterological Association (AGA) has compiled risk factors that may be predictive of disease complications in Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to evaluate the performance of the AGA risk factors for risk stratification in UC and CD. METHODS: We included participants of 2 cohorts: the Ocean State Crohn's and Colitis Area Registry cohort and the Mayo Clinic cohort. Baseline clinical risk factors were extracted according to the AGA pathway. Our primary end point was defined as follows: (i) any inflammatory bowel disease related–hospitalization, (ii) any inflammatory bowel disease–related bowel surgery, or (iii) any progression of disease. We analyzed the association of the number of AGA risk factors with our end point. Statistical multivariable modeling was performed with Cox proportional hazards model. RESULTS: A total of 412 patients with CD were included. Comparing ≥3 risk factors with 0–1 risk factor, we found a significantly increased risk of complications in both the Ocean State Crohn's and Colitis Area Registry cohort (hazard ratio [HR] 2.75, 95% confidence interval 1.71–4.41) and Mayo Clinic cohort (HR 2.07, 95% confidence interval 1.11–3.84). Diagnosis at younger age (HR 2.07), perianal disease (HR 1.99), and B2/B3 behavior (HR 1.92) were significantly associated with disease complications. We did not observe a consistent association between number of risk factors nor any specific individual risk factors and risk of disease complications in the 265 patients with UC included. DISCUSSION: We found a significant association between the number of AGA risk factors and the risk of disease complication in CD; this association was not significant in UC. The presence of ≥ 3 risk factors in CD leads to the highest risk of complications. The AGA care pathway is a useful tool to stratify patients who are at higher risk of disease complications in patients with CD.

AbstractBackgroundPrior implementations of the channelized Hotelling observer (CHO) model have succeeded in assessing the performance of X‐ray angiography systems under a variety of imaging conditions. However, often times these conditions do not resemble those present in routine clinical imaging scenarios, such as having complex anthropomorphic backgrounds in conjunction with moving test objects.PurposeThis work builds up on prior established CHO methods and introduces a new approach to switch from the already established “multiple‐sample” CHO implementation to a “single‐sample” technique. The proposed implementation enables the inclusion of moving test objects upon nonuniform backgrounds by allowing only a single sample to represent the test object present condition that is to be used within the statistical test to estimate the detectability index.MethodsTo assess the proposed method, two image data sets were acquired with a clinical X‐ray angiography system. The first set consisted of a uniform background in combination with static test objects while the second consisted of an anthropomorphic chest phantom in conjunction with moving test objects. The first set was used to validate the proposed approach against the multiple‐sample method while the second was used to assess the feasibility of the proposed method under a variety of imaging conditions, including seven object sizes and seven detector target dose (DTD) levels.ResultsFor the uniform background data set, considering all detectability indices greater or equal than 1, the ratio between the detectability indices of the proposed single‐sample approach versus the multiple‐sample method was 0.997 ± 0.056 (range 0.884–1.159). The average single‐direction width of the 95% confidence intervals (CIs) of the detectability index estimates for the multiple‐sample method was 0.38 ± 0.43 (range 0.03–2.20). For the single‐sample approach, the average width was 2.52 ± 0.63 (range 1.11–5.44). For the anthropomorphic background image set, the results were consistent with classical quantum‐limited signal‐to‐noise ratio (SNR) theory. The magnitude of the detectability indices varied predictably with changes in both object size and DTD, with the highest value associated with the highest dose and the largest object size. Additionally, the proposed method was able to capture differences in the imaging performance for a given test object across the field of view, which was associated with the attenuation levels provided by different features of the anthropomorphic background.ConclusionsA new single‐sample variant of the CHO model to assess the performance of X‐ray angiography imaging systems is proposed. The new approach is consistent with quantum‐limited image quality theory and with a standard implementation of the CHO model. The proposed method enables the assessment of moving test objects in combination with complex, nonuniform image backgrounds, thereby opening the possibility to assess imaging conditions which more closely resemble those used in clinical care.

Neuron-derived extracellular vesicles (NDEVs) are potential biomarkers of neurological diseases although their reliable molecular target is not well established. Here, we demonstrate that ATPase Na + /K + transporting subunit alpha 3 (ATP1A3) is abundantly expressed in extracellular vesicles (EVs) isolated from induced human neuron, brain, cerebrospinal fluid, and plasma in comparison with the presumed NDEV markers NCAM1 and L1CAM by using super-resolution microscopy and biochemical assessments. Proteomic analysis of immunoprecipitated ATP1A3 + brain-derived EVs shows higher enrichment of synaptic markers and cargo proteins relevant to Alzheimer’s disease (AD) compared to NCAM1 + or LICAM + EVs. Single particle analysis shows the elevated amyloid-β positivity in ATP1A3 + EVs from AD plasma, providing better diagnostic prediction of AD over other plasma biomarkers. Thus, ATP1A3 is a reliable target to isolate NDEV from biofluids for diagnostic research.

Abstract Purpose We describe the case of a 22-year-old male who developed thyroid storm necessitating therapeutic plasma exchange (TPE). The patient’s past medical history was complicated by epilepsy, for which he took lacosamide. Little evidence was available to guide lacosamide dosing during TPE. Because of an exacerbation of the patient’s underlying epilepsy in the context of the thyroid storm, we conducted therapeutic medication monitoring of lacosamide concentrations to guide management. Summary We arranged for measurement of the lacosamide concentration immediately before TPE (5.1 μg/mL) and 2.5 hours after the initial measurement (3.4 μg/mL) to determine the amount of lacosamide removed by TPE. Utilizing population pharmacokinetic parameters, we calculated the expected concentration and compared this to the measured concentration. The difference between these values was used to determine the percentage removed via TPE compared to the expected post-TPE concentration. We found that one TPE session removed an additional 20% of serum lacosamide. Conclusion TPE appeared to remove an additional 20% of lacosamide when compared to the expected post-TPE concentration.

BACKGROUND: Whether volatile anesthetic solubility affects postanesthesia recovery time in clinical practice is unclear. We investigated the association among 3 volatile agents and 2 clinically relevant outcomes—postanesthesia care unit (PACU) recovery time (time from PACU admission to fulfillment of discharge criteria) and oversedation (Richmond Agitation-Sedation Scale score ≤−3)—as a potential contributor to delaying PACU discharge. The volatile agents studied were isoflurane, desflurane, and sevoflurane. We hypothesized that increased solubility of the volatile agent (isoflurane versus desflurane or sevoflurane) would be associated with longer PACU recovery time and higher rates of oversedation. METHODS: This retrospective observational study included adults (≥18 years) who underwent surgical procedures under general anesthesia with a volatile agent and were admitted to the PACU from May 5, 2018, to December 31, 2020. The primary outcome was PACU recovery time, and the secondary outcome was oversedation. PACU recovery time was log-transformed and analyzed with linear regression. Oversedation was analyzed by using logistic regression. To account for potential confounding, inverse probability of treatment weighting (IPTW) was used. Pairwise comparisons of the 3 agents were performed, with P < .017 (Bonferroni-adjusted) considered significant. RESULTS: Of 47,847 patients included, 11,817 (24.7%) received isoflurane, 11,286 (23.6%) received desflurane, and 24,744 (51.7%) received sevoflurane. Sevoflurane had an estimated 4% shorter PACU recovery time (IPTW-adjusted median [interquartile range {IQR}], 61 [42–89] minutes) than isoflurane (64 [44–92] minutes) (ratio of geometric means [98.3% confidence interval {CI}], 0.96 [0.95–0.98]; P < .001). Differences in PACU recovery time between desflurane and the other agents were not significant. The IPTW-adjusted frequency of oversedation was 8.8% for desflurane, 12.2% for sevoflurane, and 16.7% for isoflurane; all pairwise comparisons were observed to be significant (odds ratio [98.3% CI], 0.70 [0.62–0.79] for desflurane versus sevoflurane, 0.48 [0.42–0.55] for desflurane vs isoflurane, and 0.69 [0.63–0.76] for sevoflurane versus isoflurane; all P < .001). Although oversedated patients had longer PACU recovery time, differences in the oversedation rate across agents did not result in meaningful differences in time to PACU recovery. CONCLUSIONS: In clinical practice, only small, clinically unimportant differences in PACU recovery time were observed between the volatile anesthetics. Although oversedation was associated with increased PACU recovery time, differences in the rate of oversedation among agents were insufficient to produce meaningful differences in overall PACU recovery time across the 3 volatile agents. Practical attempts to decrease PACU recovery time should address factors other than volatile agent selection.