Role of Nesprin-2 and RanBP2 in BICD2-associated brain developmental disorders.

Bicaudal D2 (BICD2) is responsible for recruiting cytoplasmic dynein to diverse forms of subcellular cargo for their intracellular transport. Mutations in the human BICD2 gene have been found to cause an autosomal dominant form of spinal muscular atrophy (SMA-LED2), and brain developmental defects. Whether and how the latter mutations are related to roles we and others have identified for BICD2 in brain development remains little understood. BICD2 interacts with the nucleoporin RanBP2 to recruit dynein to the nuclear envelope (NE) of Radial Glial Progenitor cells (RGPs) to mediate their well-known but mysterious cell-cycle-regulated interkinetic nuclear migration (INM) behavior, and their subsequent differentiation to form cortical neurons. We more recently found that BICD2 also mediates NE dynein recruitment in migrating post-mitotic neurons, though via a different interactor, Nesprin-2. Here, we report that Nesprin-2 and RanBP2 compete for BICD2-binding in vitro. To test the physiological implications of this behavior, we examined the effects of known BICD2 mutations using in vitro biochemical and in vivo electroporation-mediated brain developmental assays. We find a clear relationship between the ability of BICD2 to bind RanBP2 vs. Nesprin-2 in controlling of nuclear migration and neuronal migration behavior. We propose that mutually exclusive RanBP2-BICD2 vs. Nesprin-2-BICD2 interactions at the NE play successive, critical roles in INM behavior in RGPs and in post-mitotic neuronal migration and errors in these processes contribute to specific human brain malformations.

Sublingual immunotherapy persistence and adherence in real-world settings: A systematic review.

BACKGROUND: Sublingual immunotherapy (SLIT) adherence in the literature is often evaluated in closely monitored trials that may impact patient behavior; real-world SLIT adherence is relatively unknown. This systematic review intends to assess SLIT adherence in studies that reflect real-world settings. METHODS: A literature search of PubMed, Embase, Cochrane, Web of Science, and Scopus for real-world studies examining SLIT adherence was performed. Monitored clinical trials were excluded. Paired investigators independently reviewed all articles. For this review, "persistence" was defined as continuing therapy and not being lost to follow-up and "adherence" as persistence in accordance with prescribed SLIT dose, dosing schedule, and duration. Article quality was assessed using a modified Newcastle-Ottawa scale and then converted to AHRQ standards (good, fair, and poor). RESULTS: The search yielded 1596 nonduplicate abstracts, from which 32 articles (n = 63,683 patients) met criteria. Twenty-six (81%) studies reported persistence rates ranging from 7.0% to 88.7%, and 18 (56%) reported adherence rates ranging from 9.6% to 97.0%. Twenty-one (66%) studies surveyed reasons for discontinuing SLIT. All studies were Oxford level of evidence 2b and of good (n = 12) to fair (n = 20) quality. CONCLUSION: Reported rates of real-world SLIT persistence and adherence varied widely by study methodology (e.g., follow-up duration, objective vs. subjective assessment). Studies with longer follow-up generally reported lower rates; 3-year persistence ranged from 7% to 59.0% and 3-year adherence from 9.6% to 49.0%. Future studies of SLIT adherence would benefit from following concordant definitions of persistence/adherence and standardized reporting metrics.

Systematic review of real-world persistence and adherence in subcutaneous allergen immunotherapy.

BACKGROUND: Given that subcutaneous immunotherapy (SCIT) adherence in the literature is often studied in closely monitored trials, few studies report real-world SCIT adherence. The purpose of this review is to assess SCIT adherence in real-world settings. METHODS: A literature search of PubMed, Embase, Cochrane Library, Web of Science, and Scopus for real-world studies examining SCIT adherence was performed. Paired investigators independently reviewed all articles. For this review, "persistence" was defined as continuing therapy and not being lost to follow-up after initiating SCIT, and "adherence" defined as persistence in accordance with prescribed SCIT dose, dosing schedule, and duration. Article quality was first assessed using a modified Newcastle-Ottawa scale and then converted to Agency for Healthcare Research and Quality standards (good, fair, and poor). RESULTS: The search yielded 1596 nonduplicate abstracts, from which 17 articles (n = 263,221 patients) met inclusion criteria. Fourteen (82%) studies reported persistence rates, ranging from 16.0% to 93.7%. Seven (41%) studies reported adherence rates, ranging from 15.1% to 99%. Five (29%) studies (n = 416 patients) collected original data on reasons for discontinuing SCIT, of which inconvenience was most cited. All studies were Oxford level of evidence 2b and of good (n = 10) to fair (n = 7) quality. CONCLUSION: Real-world SCIT persistence and adherence rates are poor, with the majority of included studies reporting rates <80%; however, they range widely, explained in part by inter-study differences in measuring and reporting adherence-related findings. Future studies on SCIT adherence may benefit from following concordant definitions of persistence and adherence in addition to standardized reporting metrics.

In-hospital predictors of post-stroke depression for targeted initiation of Selective Serotonin Reuptake Inhibitors (SSRIs).

BACKGROUND: Although SSRIs are no longer widely prescribed for post-stroke motor recovery, fluoxetine demonstrated beneficial effects on post-stroke depression (PSD). Given the potential side effects of SSRIs, targeted initiation among individuals at highest risk for PSD warrants consideration. While previous studies have identified stroke severity and psychiatric history as factors associated with PSD, its predictability remains unknown. In this study, we investigate inpatient predictive factors to better identify individuals who might derive the most benefit from targeted initiation of SSRIs. METHODS: We performed a retrospective analysis of a prospectively-collected registry of adult patients presenting with acute ischemic stroke to a tertiary referral urban academic comprehensive stroke center between 2016-2020. Patients were seen 4-6 weeks post-discharge and administered the PHQ-9 (Patient Health Questionnaire-9) to screen for PSD (PHQ-9 ≥ 5). Demographics, history of depression, stroke severity, and inpatient PHQ-9 scores were abstracted. Logistic regression was used to determine factors associated with PSD and an ROC analysis determined the predictability of PSD in the inpatient setting. RESULTS: Three hundred seven individuals were administered the PHQ-9 at follow-up (mean age 65.5 years, 52% female). History of depression (OR = 4.11, 95% CI: 1.65-10.26) and inpatient PHQ-9 score (OR = 1.17, 95% CI: 1.06-1.30) were significantly associated with PSD. Stroke severity, marital status, living alone, employment, and outpatient therapy were not associated with PSD. The ROC curve using a positive inpatient PHQ-9 achieved an area under the curve (AUC) of 0.65 (95% CI: 0.60-0.70), while the AUC was 0.72 (95% CI: 0.66-0.77) after adding history of depression. CONCLUSIONS: History of depression and a positive inpatient PHQ-9 appear to be most strongly predictive of long-term PSD. Initiating SSRIs only in those individuals at highest risk for PSD may help reduce the burden of stroke recovery in this targeted population while minimizing adverse side effects.

Clinical presentation of paradoxical vocal fold motion or laryngeal dyskinesia in infants.

OBJECTIVES: Paradoxical vocal fold motion (PVFM) is not well-characterized in infants. Sex- and race/ethnicity-based differences have been described in older children with PVFM. This study's objectives are to characterize demographic and clinical characteristics of infants diagnosed with PVFM and investigate sex- and race-specific differences in presentation. METHODS: We retrospectively reviewed infants ≤1 year of age diagnosed with PVFM at our institution from 2009 to 2019. Patient demographics, symptoms, and findings on flexible laryngoscopy are described. Sex- and race/ethnicity-based differences were assessed using Fisher's exact test analyses. RESULTS: We identified 22 infants who were diagnosed with PVFM. The average age (range) at diagnosis was 5.7 (0.25-12.0) months, and 45.5% were male. The majority (54.6%) of patients identified as non-Hispanic White. Common comorbidities included GERD (45.5%) and chronic rhinitis (13.6%). Stridor was the only presenting symptom in the majority of patients (95.4%). The most common episode triggers were crying (45.5%), feeding (27.3%), and gastric reflux (9.1%). On flexible laryngoscopy, PVFM was observed in 95.5% of patients. A third of patients (31.8%) were misdiagnosed as having reactive airway disease or laryngomalacia prior to evaluation by otolaryngology. No sex- and race/ethnicity-based differences in presentation were identified. CONCLUSION: We present the largest case series of PVFM in infants. We found sparse clinical signs/symptoms other than stridor and a high incidence of misdiagnosis, which supports the importance of objective flexible laryngoscopy for the evaluation of stridor in this age group. Previously reported sex- and race/ethnicity-based differences in presentation of PVFM were not observed in this cohort of infants.

Magnetic Resonance Imaging as a Diagnostic and Research Tool in Patients with Olfactory Dysfunction: A Systematic Review.

BACKGROUND: Patients with acquired, idiopathic olfactory dysfunction (OD) commonly undergo magnetic resonance imaging (MRI) evaluation to rule out intracranial pathologies. This practice is highly debated given the expense of MRI relative to the probability of detecting a treatable lesion. This, combined with the increasing use of MRI in research to investigate the mechanisms underlying OD, provided the impetus for this comprehensive review. OBJECTIVE: The purpose of this systematic review was to both assess the utility of MRI in diagnosis of idiopathic OD and to describe MRI findings among mixed OD etiologies to better understand its role as a research tool in this patient population. METHODS: A literature search of PubMed, Embase, Cochrane, Web of Science, and Scopus for studies with original MRI data for patients with OD was completed. Studies exclusively investigating patients with neurocognitive deficits or those studying traumatic or congenital etiologies of OD were excluded. RESULTS: From 1758 candidate articles, 33 studies were included. Four studies reviewed patients with idiopathic OD for structural pathologies on MRI, of which 17 of 372 (4.6%) patients had a potential central cause identified, and 3 (0.8%) had an olfactory meningioma or olfactory neuroblastoma. Fourteen studies (42.4%) reported significant correlation between olfactory bulb volume and olfactory outcomes, and 6 studies (18.8%) reported gray matter volume reduction, specifically in the orbitofrontal cortex, anterior cingulate cortex, insular cortex, parahippocampal, and piriform cortex areas, in patients with mixed OD etiologies. Functional MRI studies reported reduced brain activation and functional connectivity in olfactory network areas. CONCLUSION: MRI uncommonly detects intracranial pathology in patients with idiopathic OD. Among patients with mixed OD etiologies, reduced olfactory bulb and gray matter volume are the most common abnormal findings on MRI. Further research is required to better understand the role of MRI and its cost-effectiveness in patients with acquired, idiopathic OD.

Racial and Ethnic Differences in Hearing Aid Use Among Medicare Beneficiaries.

OBJECTIVES: We examined individual-level factors associated with hearing aid use by race and ethnicity in a nationally representative sample of Medicare beneficiaries. METHODS: We used the Medicare Current Beneficiary Survey (cycles 2016-2018) for 10,301 older adults with hearing loss and hearing aid use as the primary outcome. Covariates included education, income, urban residence, chronic conditions, functional limitations, and Medicaid eligibility. Multivariable logistic regression stratified by race and ethnicity was used to identify factors associated with hearing aid use. RESULTS: Factors associated with hearing aid use included higher education among White (OR = 1.35, 95%CI:1.16, 1.58), Black (OR = 1.76, 95%CI:1.02, 3.05), and Hispanic (OR = 1.77, 95%CI:1.17, 2.68) beneficiaries. Urban residence was associated with hearing aid use for Black participants (OR = 3.06, 95%CI:1.17, 8.03) and Medicaid eligibility for Hispanic participants (OR = 1.58, 95%CI:0.97, 2.59), although the confidence interval included the null hypothesis. DISCUSSION: ndividual-level factors associated with hearing aid use differed by race and ethnicity among Medicare beneficiaries.

Individual Life-Course Socioeconomic Position and Hearing Aid Use in the Atherosclerosis Risk in Communities Study.

BACKGROUND: To measure the association between individual life-course socioeconomic position (SEP) and hearing aid use, we examined childhood and adulthood socioeconomic variables collected at the Atherosclerosis Risk in Communities (ARIC) study baseline visit (1987-1989)/Life Course Socioeconomic Status study (2001-2002) and hearing aid use data collected at visit 6 (2016-2017). METHODS: ARIC is a prospective cohort study of older adults (45-64 years) recruited from 4 U.S. communities. This analysis included a subset of 2 470 participants with hearing loss at visit 6 (≥25 decibels hearing level [dB HL] better-ear) with complete hearing aid use data. Childhood SEP variables included parental education, parental occupation, and parental home ownership. Young and older adulthood SEP variables included income, education, occupation, and home ownership. Each life epoch was assigned a score ranging from 0 to 5 and then summed to calculate the individual cumulative SEP score. Multivariable-adjusted logistic regression was used to estimate the association between individual cumulative SEP and hearing aid use. Missing SEP scores were imputed for participants with incomplete socioeconomic data. RESULTS: Of the 2 470 participants in the analytic cohort (median [interquartile interval] age 79.9 [76.7-84.0], 1 330 [53.8%] women, 450 [18.2%] Black), 685 (27.7%) participants reported hearing aid use. Higher cumulative SEP was positively associated with hearing aid use (odds ratio [OR] = 1.09, 95% confidence interval [CI]: 1.04-1.14), and slightly stronger for childhood (OR = 1.09, 95% CI: 1.00-1.20) than older adulthood SEP score (OR = 1.06, 95% CI: 0.95-1.18). CONCLUSIONS: In this community-based cohort of older adults with hearing loss, higher individual life-course SEP was positively associated with hearing aid use.

Systemic comorbidities of rosacea: practice gaps among dermatologists.

Rosacea is a chronic inflammatory skin condition that is associated with multiple systemic comorbidities, with the strongest evidence linking rosacea to hypertension, dyslipidemia, inflammatory bowel disease, and anxiety and depression. To assess dermatologists' awareness of and screening practices for rosacea comorbidities, we developed a survey that was distributed to attendings and residents across four academic dermatology departments in Massachusetts. A total of 73 dermatologists with varying experience participated in the study. Findings demonstrated significant knowledge and practice gaps among academic dermatologists in managing systemic comorbidities in rosacea. In addition, dermatologists' awareness of rosacea comorbidities was negatively correlated with number of years out of residency training, highlighting the need to address this knowledge gap through increased continuing medical education. Importantly, we observed a low screening frequency despite a high awareness of the association between rosacea and ocular comorbidities, suggesting that additional financial, institutional, or practice barriers likely contribute to the low screening rate.

Magnetic Resonance Imaging Findings Among Individuals With Olfactory and Cognitive Impairment.

OBJECTIVES: The underlying mechanism of the association between olfactory impairment and dementia may be explained by neurodegenerative changes detected on magnetic resonance imaging (MRI). The purpose of this systematic review is to describe neurodegenerative changes on MRI in patients with olfactory impairment and mild cognitive impairment (MCI) or dementia. STUDY DESIGN: Systematic review. METHODS: A literature search encompassing PubMed, Embase, Cochrane Library, Web of Science, Scopus, and Google Scholar for studies with MRI and olfactory testing among participants diagnosed with MCI or dementia was performed. Sample size, study design, cognitive impairment type, olfactory testing, and MRI findings were abstracted. Two investigators independently reviewed all articles. RESULTS: The search yielded 556 nonduplicate abstracts, from which 86 articles were reviewed and 24 were included. Seventeen (71%) of 24 studies reported hippocampal volume findings, with 14 studies reporting a relationship between hippocampal volume and olfactory performance. Two (50%) of four prospective studies reported the potential utility of baseline hippocampal volume as a marker of dementia conversion from MCI. Five (21%) of 24 studies reporting olfactory functional MRI (fMRI) findings highlighted the utility of olfactory fMRI to identify individuals in the early stages of cognitive decline. CONCLUSION: Current evidence suggests hippocampal volume correlates with olfactory performance in individuals with cognitive impairment, and that olfactory fMRI may improve early detection of AD. However, the predictive utility of these imaging markers is limited in prospective studies. MRI may be a useful modality for selecting patients at high risk of future cognitive decline for enrollment in early treatment trials. Laryngoscope, 132:177-187, 2022.

Moving forward with teledermatology: Operational challenges of a hybrid in-person and virtual practice.

Since the COVID-19 outbreak, teledermatology services have become an integral part of our daily practice. In this study, we compared three practice models of an academic department in an urban setting: 1) in-person only, 2) teledermatology only, and 3) hybrid of in-person and teledermatology. Our study demonstrated that older patients prefer in-person visits over teledermatology visits, while non-English-speaking patients prefer teledermatology visits over in-person visits. In addition, teledermatology services can be better utilized for evaluation of acne and psoriasis, as these diagnoses do not require in-person reevaluation, unlike the evaluation of concerning lesions. Considering these findings, our study highlights the need to continuously examine our practice models to understand patient preferences, overcome practice-driven barriers, and ensure the sound allocation of limited health care resources.

Demographic Differences in Clinical Presentation of Pediatric Paradoxical Vocal Fold Motion (PVFM).

OBJECTIVES: Paradoxical vocal fold motion (PVFM) is involuntary closure of the vocal folds during inspiration, often presenting in children and young adults. Although common symptoms and triggers are known, differences in clinical presentation based on patient demographics are unknown. This study characterizes differences in clinical presentation of pediatric PVFM based on age, sex, and race/ethnicity. METHODS: We reviewed electronic medical records of patients 0-21 years old with PVFM based on ICD codes from 2009 to 2019 within a tertiary academic health system. Demographics, symptoms, triggers, concurrent diagnoses, and laryngoscopy findings were abstracted. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Among 96 individuals the mean age was 10.6 years (standard deviation ±6.5) and 66 (69%) were female. In comparison to 13-21 year olds, those 0-2 years more often had PVFM observed on laryngoscopy (OR = 17.84, 95% CI: 3.14-101.51) and had less shortness of breath (OR = 0.01, 95% CI: 0.00-0.09). Those 3-12 years had more asthma (OR = 3.07, 95% CI: 1.07-8.81) and cough (OR = 6.12, 95% CI: 1.77-21.13). Both 0-2 (OR = 0.07, 95% CI: 0.02-0.24) and 3-12 year olds (OR = 0.13, 95% CI: 0.04-0.40) presented less with activity as a trigger. Racial/ethnic minorities were more likely to present with pharyngeal findings (eg mucosal inflammation, adenotonsillar hypertrophy) on laryngoscopy (OR = 4.58, 95% CI: 1.45-15.37) compared to non-Hispanic Whites. Differences in clinical presentation by sex were not observed. CONCLUSION: We identified several differences in symptoms, triggers, and laryngoscopy findings in pediatric PVFM based on age and race/ethnicity. Associations between sex and clinical presentation were not observed.

Painful scrotal dermatitis secondary to topical 5-fluorouracil.

5-Fluorouracil (5-FU) is an antineoplastic agent that is used topically to treat actinic keratoses. Although topical 5-FU frequently causes irritant contact dermatitis at the site of application, distant skin reactions are rare and could relate to accidental transfer or systemic absorption of the drug. We present a patient who developed a painful scrotal dermatitis after applying the topical cream to actinic keratoses on his chest. Upon discontinuation of topical 5-FU, the reaction resolved over a four-week period with oral prednisone and topical betamethasone ointment. The patient was re-challenged with topical 5-FU one year later and again developed scrotal pain and erythema similar to the initial reaction. Scrotal dermatitis is a rare adverse effect of topical 5-FU therapy that can be associated with significant distress and disruption of daily activities.