Norepinephrine Drives Sleep Fragmentation Activation of Asparagine Endopeptidase, Locus Ceruleus Degeneration, and Hippocampal Amyloid-ß42 Accumulation.

Chronic sleep disruption (CSD), from insufficient or fragmented sleep and is an important risk factor for Alzheimer's disease (AD). Underlying mechanisms are not understood. CSD in mice results in degeneration of locus ceruleus neurons (LCn) and CA1 hippocampal neurons and increases hippocampal amyloid-ß42 (Aß42), entorhinal cortex (EC) tau phosphorylation (p-tau), and glial reactivity. LCn injury is increasingly implicated in AD pathogenesis. CSD increases NE turnover in LCn, and LCn norepinephrine (NE) metabolism activates asparagine endopeptidase (AEP), an enzyme known to cleave amyloid precursor protein (APP) and tau into neurotoxic fragments. We hypothesized that CSD would activate LCn AEP in an NE-dependent manner to induce LCn and hippocampal injury. Here, we studied LCn, hippocampal, and EC responses to CSD in mice deficient in NE [dopamine ß-hydroxylase (Dbh)-/-] and control male and female mice, using a model of chronic fragmentation of sleep (CFS). Sleep was equally fragmented in Dbh -/- and control male and female mice, yet only Dbh -/- mice conferred resistance to CFS loss of LCn, LCn p-tau, and LCn AEP upregulation and activation as evidenced by an increase in AEP-cleaved APP and tau fragments. Absence of NE also prevented a CFS increase in hippocampal AEP-APP and Aß42 but did not prevent CFS-increased AEP-tau and p-tau in the EC. Collectively, this work demonstrates AEP activation by CFS, establishes key roles for NE in both CFS degeneration of LCn neurons and CFS promotion of forebrain Aß accumulation, and, thereby, identifies a key molecular link between CSD and specific AD neural injuries.

The Effects of Angiotensin II versus Norepinephrine on Pulmonary Vascular Resistance in Cardiac Surgery: Post Hoc Analysis of a Randomized Controlled Trial.

OBJECTIVES: To assess whether angiotensin II infusion increases pulmonary vascular resistance (PVR) relative to norepinephrine. DESIGN: Secondary analysis of a double-blinded randomized feasibility study. SETTING: Two tertiary metropolitan hospitals in Melbourne, Australia. PARTICIPANTS: Fifty-eight adult patients undergoing cardiac surgery using cardiopulmonary bypass with an elevated risk of acute kidney injury (AKI). INTERVENTIONS: Angiotensin II infusion compared with norepinephrine infusion. MEASUREMENTS AND MAIN RESULTS: There was no significant difference in the primary outcome of PVR both intraoperatively and postoperatively between the angiotensin II group and the norepinephrine group. The study drug (angiotensin II or norepinephrine) infusion rate was associated with a small increase in PVR (ß = 0.08; p = 0.01). The strongest association with PVR was the random effect (ie, patient effect) (p < 0.001). This effect was consistent across secondary outcomes. Randomization to norepinephrine instead of to angiotensin II was associated with reduced mean systemic arterial to mean pulmonary arterial pressure ratio postoperatively (ß = -0.65; p = 0.01). CONCLUSIONS: The results of this study suggest that in cardiac surgery patients and at doses used in the prior feasibility study, angiotensin II did not have significant effects on the pulmonary vasculature compared with norepinephrine. Moreover, at doses used in this study, neither drug appeared to have a substantial effect on the pulmonary circulation relative to surgical and patient factors.

Photoreceptive Ganglion Cells Drive Circuits for Local Inhibition in the Mouse Retina.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) exhibit melanopsin-dependent light responses that persist in the absence of rod and cone photoreceptor-mediated input. In addition to signaling anterogradely to the brain, ipRGCs signal retrogradely to intraretinal circuitry via gap junction-mediated electrical synapses with amacrine cells (ACs). However, the targets and functions of these intraretinal signals remain largely unknown. Here, in mice of both sexes, we identify circuitry that enables M5 ipRGCs to locally inhibit retinal neurons via electrical synapses with a nonspiking GABAergic AC. During pharmacological blockade of rod- and cone-mediated input, whole-cell recordings of corticotropin-releasing hormone-expressing (CRH+) ACs reveal persistent visual responses that require both melanopsin expression and gap junctions. In the developing retina, ipRGC-mediated input to CRH+ ACs is weak or absent before eye opening, indicating a primary role for this input in the mature retina (i.e., in parallel with rod- and cone-mediated input). Among several ipRGC types, only M5 ipRGCs exhibit consistent anatomical and physiological coupling to CRH+ ACs. Optogenetic stimulation of local CRH+ ACs directly drives IPSCs in M4 and M5, but not M1-M3, ipRGCs. CRH+ ACs also inhibit M2 ipRGC-coupled spiking ACs, demonstrating direct interaction between discrete networks of ipRGC-coupled interneurons. Together, these results demonstrate a functional role for electrical synapses in translating ipRGC activity into feedforward and feedback inhibition of local retinal circuits.SIGNIFICANCE STATEMENT Melanopsin directly generates light responses in intrinsically photosensitive retinal ganglion cells (ipRGCs). Through gap junction-mediated electrical synapses with retinal interneurons, these uniquely photoreceptive RGCs may also influence the activity and output of neuronal circuits within the retina. Here, we identified and studied an electrical synaptic circuit that, in principle, could couple ipRGC activity to the chemical output of an identified retinal interneuron. Specifically, we found that M5 ipRGCs form electrical synapses with corticotropin-releasing hormone-expressing amacrine cells, which locally release GABA to inhibit specific RGC types. Thus, ipRGCs are poised to influence the output of diverse retinal circuits via electrical synapses with interneurons.

Phase 1A/1B dose-escalation and -expansion study to evaluate the safety, pharmacokinetics, food effects and antitumor activity of pamiparib in advanced solid tumours.

BACKGROUND: Pamiparib, a PARP1/2 inhibitor, demonstrated antitumor activity in preclinical models. METHODS: This Phase 1A/1B dose-escalation/dose-expansion study enrolled adults (≥18 years) with advanced/metastatic cancer. The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food effects. RESULTS: Patients (N = 101) were enrolled in dose-escalation (n = 64) and dose-expansion (n = 37). During BID dose-escalation, dose-limiting toxicities were Grade 2 nausea (n = 1, 40 mg; n = 1, 80 mg); Grade 2 nausea and Grade 2 anorexia (n = 1, 120 mg), Grade 2 nausea, Grade 3 fatigue and Grade 3 paraesthesia (n = 1, 120 mg); MTD was 80 mg BID and RP2D was 60 mg BID. Common adverse events (AEs) were nausea (69.3%), fatigue (48.5%) and anaemia (35.6%); the most common Grade ≥3 AE was anaemia (24.8%). There was a dose-proportional increase in pamiparib exposure; no food effects on pharmacokinetics were observed. In the efficacy-evaluable population (n = 77), objective response rate (ORR) was 27.3% (95% CI, 17.7-38.6%). Median duration of response was 14.9 months (95% CI, 8.7-26.3). In the epithelial ovarian cancer (EOC)-evaluable population (n = 51), ORR was 41.2% (95% CI, 27.6-55.8%). CONCLUSIONS: Pamiparib was tolerated with manageable AEs, and antitumor activity was observed in patients with EOC. CLINICALTRIALS. GOV IDENTIFIER: NCT02361723.

Dysfunction of the Auditory System in Children With Hypothyroidism: A Systematic Review and Meta-Analysis.

OBJECTIVE: To examine the prevalence of hearing impairment in children with hypothyroidism, and to characterize clinical and subclinical hearing loss by examining cochlear function, auditory brainstem pathways, and integration of the auditory system as a whole. DESIGN: An electronic search was conducted using PubMed, Scopus, and Cochrane Library databases. This systematic review was performed in accordance with the PRISMA guidelines. Original observational studies that utilized audiological tests for auditory system evaluations in hypothyroidism were included. A total of 2004 studies were found in the search, with 23 studies meeting the inclusion criteria. RESULTS: The pooled prevalence of hearing loss was 16.1% [95% confidence interval 10.7, 22.4] for children with congenital hypothyroidism. Hearing thresholds at pure-tone averages (0.5-2 kHz) were 1.6 dB [95% confidence interval 1.7, 4.8] higher for children with hypothyroidism compared to age-matched controls. Cochlear dysfunction was detected at middle frequencies (1-3 kHz) by otoacoustic emission testing, indicating abnormalities of hair cell function or cochlear integration. Retrocochlear involvement was detected on auditory brainstem response (ABR), with prolonged Wave I indicating a peripheral conduction abnormality localized to the middle or inner ear and eighth cranial nerve. CONCLUSIONS: Children with hypothyroidism have a higher prevalence of hearing loss than children without hypothyroidism. For children with congenital hypothyroidism, evidence of subclinical abnormalities at the level of the cochlea and eighth cranial nerve are present despite early initiation of levothyroxine therapy. Dysfunction of the auditory system might begin with predominance of peripheral conduction abnormalities early in development.

Outcomes and Disposition of Patients After Case Cancellation on Day of Surgery for Reasons Attributed to Medical or Anesthetic Care: A Retrospective Cohort Analysis.

BACKGROUND: Many day-of-surgery cancellations are avoidable, and different strategies are used to prevent these costly adverse events. Despite these past analyses and evaluations of positive interventions, studies have not examined the final disposition of patients whose cases were canceled in this late manner. This study sought to determine whether surgical procedures canceled for medical or anesthetic reasons were ultimately rescheduled, and the time elapsed between cancellation and completion. In addition, the resolution of the underlying issue leading to cancellation was examined. METHODS: Two years of surgical case data were reviewed in the electronic health record to isolate all procedures canceled on the intended operative date. These cases were then filtered by the documented reason for cancellation into 2 categories: 1 for cases related to medical or anesthetic care and 1 for unrelated cases. Medical- or anesthetic-related cases were further categorized to better elucidate the underlying reason for cancellation. Cases were then traced to determine if and when the procedure was ultimately completed. If a case was rescheduled, the record was reviewed to determine whether the underlying reason for cancellation was resolved. RESULTS: A total of 4472 cases were canceled in the study period with only 20% associated with medical or anesthetic causes. Of these, 72% were rescheduled and 83% of all rescheduled cases resolved the underlying issue before the rescheduled procedure. Nearly half of all cases (47.8%) canceled on the day of surgery for reasons linked to medical and/or anesthetic care were due to acute conditions. CONCLUSIONS: Nearly a fifth of cases that are canceled on the date of surgery are never rescheduled and, if they are rescheduled, the delay can be substantial. Although the majority of patients whose procedure are canceled for reasons related to medical or anesthetic care have resolved the underlying issue that led to initial postponement, a significant portion of patients have no change in their status before the ultimate completion of their surgical procedure.

Frailty Is Associated With Postoperative Delirium But Not With Postoperative Cognitive Decline in Older Noncardiac Surgery Patients.

BACKGROUND: Postoperative cognitive dysfunction (POCD) and delirium are the most common perioperative cognitive complications in older adults undergoing surgery. A recent study of cardiac surgery patients suggests that physical frailty is a risk factor for both complications. We sought to examine the relationship between preoperative frailty and postoperative delirium and preoperative frailty and POCD after major noncardiac surgery. METHODS: We performed a prospective cohort study of patients >65 years old having major elective noncardiac surgery with general anesthesia. Exclusion criteria were preexisting dementia, inability to consent, cardiac, intracranial, or emergency surgery. Preoperative frailty was determined using the FRAIL scale, a simple questionnaire that categorizes patients as robust, prefrail, or frail. Delirium was assessed with the Confusion Assessment Method for the intensive care unit (CAM-ICU) twice daily, starting in the recovery room until hospital discharge. All patients were assessed with neuropsychological tests (California Verbal Learning Test II, Trail Making Test, subtests from the Wechsler Adult Intelligence Scale, Logical Memory Story A, Immediate and Delayed Recall, Animal and Vegetable verbal fluency, Boston Naming Test, and the Mini-Mental Status Examination) before surgery and at 3 months afterward. RESULTS: A total of 178 patients met inclusion criteria; 167 underwent major surgery and 150 were available for follow-up 3 months after surgery. The median age was 70 years old. Thirty-one patients (18.6%) tested as frail, and 72 (43.1%) prefrail before surgery. After adjustment for baseline cognitive score, age, education, surgery duration, American Society of Anesthesiologists (ASA) physical status, type of surgery, and sex, patients who tested frail or prefrail had an estimated 2.7 times the odds of delirium (97.5% confidence interval, 1.0-7.3) when compared to patients who were robust. There was no significant difference between the proportion of POCD between patients who tested as frail, prefrail, or robust. CONCLUSIONS: After adjustment for baseline cognition, testing as frail or prefrail with the FRAIL scale is associated with increased odds of postoperative delirium, but not POCD after noncardiac surgery.

YouTube for Cosmetic Plastic Surgery: An Effective Patient Resource?

BACKGROUND: YouTube is increasingly being utilized as a major educational resource by patients. It is important for plastic surgeons to understand the quality and characteristics of videos that patients are likely to view about procedures of interest. OBJECTIVES: The aim of this study was to evaluate the quality of the videos that patients are most likely to encounter when searching YouTube for the most common cosmetic plastic surgery procedures. METHODS: Based on Google Trends data, the most searched medical and colloquial terms were identified for common cosmetic surgery procedures: "abdominoplasty," "tummy tuck," "breast augmentation," "boob job," "liposuction," "lipo," "mastopexy," "breast lift," "reduction mammoplasty," and "breast reduction." On YouTube, videos were searched by relevance (default) and view count; the top 10 results were collected in each group and rated according to the DISCERN criteria. Each video was assigned an overall and bias DISCERN score (DS). A score of 1 indicates high bias and low overall quality and a score of 5 indicates the opposite. RESULTS: In total, 143 unique videos were identified, which resulted in a mean bias DS of 2.29 and mean overall DS of 2.44. Seventy-two videos included US board-certified plastic surgeons and 58 were classified as patient experience. Videos had 667,373,209 total views and were an average of 4.27 years old. Videos including US board-certified plastic surgeons were of significantly higher quality and showed lower bias than videos without these practitioners (P < 0.05). CONCLUSIONS: Overall, YouTube videos showed high bias and low quality. Plastic surgeons should be aware of this popular resource and counsel patients about the bias that is often present. Plastic surgeons and academic plastic surgery organizations should strive to upload high-quality, unbiased videos to provide patients with a more appropriate resource.

Statistical design of noninferiority multiple region clinical trials to assess global and consistent treatment effects.

Noninferiority multiregional clinical trials (MRCTs) have recently received increasing attention in drug development. While a major goal in an MRCT is to estimate the global treatment effect, it is also important to assess the consistency of treatment effects across multiple regions. In this paper, we propose an intuitive definition of consistency of noninferior treatment effects across regions under the random-effects modeling framework. Specifically, we quantify the consistency of treatment effects by the percentage of regions that meet a predefined treatment margin. This new approach enables us to achieve both goals in one modeling framework. We propose to use a signed likelihood ratio test for testing the global treatment effect and the consistency of noninferior treatment effects. In addition, we provide guidelines for the allocation rule to achieve optimal power for testing consistency among multiple regions. Extensive simulation studies are conducted to examine the performance of the proposed methodology. An application to a real data example is provided.

Serial dependence promotes object stability during occlusion.

Object identities somehow appear stable and continuous over time despite eye movements, disruptions in visibility, and constantly changing visual input. Recent results have demonstrated that the perception of orientation, numerosity, and facial identity is systematically biased (i.e., pulled) toward visual input from the recent past. The spatial region over which current orientations or face identities are pulled by previous orientations or identities, respectively, is known as the continuity field, which is temporally tuned over the past several seconds (Fischer & Whitney, 2014). This perceptual pull could contribute to the visual stability of objects over short time periods, but does it also address how perceptual stability occurs during visual discontinuities? Here, we tested whether the continuity field helps maintain perceived object identity during occlusion. Specifically, we found that the perception of an oriented Gabor that emerged from behind an occluder was significantly pulled toward the random (and unrelated) orientation of the Gabor that was seen entering the occluder. Importantly, this serial dependence was stronger for predictable, continuously moving trajectories, compared to unpredictable ones or static displacements. This result suggests that our visual system takes advantage of expectations about a stable world, helping to maintain perceived object continuity despite interrupted visibility.

Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study.

BACKGROUND: The anti-EGFR monoclonal antibodies panitumumab and cetuximab are effective in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer. We assessed the efficacy and toxicity of panitumumab versus cetuximab in these patients. METHODS: For this randomised, open-label, phase 3 head-to-head study, we enrolled patients (from centres in North America, South America, Europe, Asia, Africa, and Australia) aged 18 years or older with chemotherapy-refractory metastatic colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and wild-type KRAS exon 2 status. Using a computer-generated randomisation sequence, we assigned patients (1:1; stratified by geographical region and ECOG performance status, with a permuted block method) to receive panitumumab (6 mg/kg once every 2 weeks) or cetuximab (initial dose 400 mg/m(2); 250 mg/m(2) once a week thereafter). The primary endpoint was overall survival assessed for non-inferiority (retention of ≥ 50% of the cetuximab treatment effect; historical hazard ratio [HR] for cetuximab plus best supportive care vs best supportive care alone of 0.55). The primary analysis included patients who received one or more dose of panitumumab or cetuximab, analysed per allocated treatment. Recruitment for this trial is closed. The trial is registered with ClinicalTrials.gov, number NCT01001377. FINDINGS: Between Feb 2, 2010, and July 19, 2012, we enrolled and randomly allocated 1010 patients, 999 of whom began study treatment: 499 received panitumumab and 500 received cetuximab. For the primary analysis of overall survival, panitumumab was non-inferior to cetuximab (Z score -3.19; p=0.0007). Median overall survival was 10.4 months (95% CI 9.4-11.6) with panitumumab and 10.0 months (9.3-11.0) with cetuximab (HR 0.97; 95% CI 0.84-1.11). Panitumumab retained 105.7% (81.9-129.5) of the effect of cetuximab on overall survival seen in this study. The incidence of adverse events of any grade and grade 3-4 was similar across treatment groups. Grade 3-4 skin toxicity occurred in 62 (13%) patients given panitumumab and 48 (10%) patients given cetuximab. The occurrence of grade 3-4 infusion reactions was lower with panitumumab than with cetuximab (one [<0.5%] patient vs nine [2%] patients), and the occurrence of grade 3-4 hypomagnesaemia was higher in the panitumumab group (35 [7%] vs 13 [3%]). We recorded one treatment-related fatal adverse event: a lung infection in a patient given cetuximab. INTERPRETATION: Our findings show that panitumumab is non-inferior to cetuximab and that these agents provide similar overall survival benefit in this population of patients. Both agents had toxicity profiles that were to be expected. In view of the consistency in efficacy and toxicity seen, small but meaningful differences in the rate of grade 3-4 infusion reactions and differences in dose scheduling can guide physician choice of anti-EGFR treatment.

Acetylcholine Promotes Directionally Biased Glutamatergic Retinal Waves.

Spontaneous retinal waves are a critical driving force for the self-organization of the mouse visual system prior to eye-opening. Classically characterized as taking place in three distinct stages defined by their primary excitatory drive, Stage II waves during the first postnatal week are propagated through the volume transmission of acetylcholine while Stage III retinal waves during the second postnatal week depend on glutamatergic transmission from bipolar cells. However, both late Stage II and early Stage III retinal waves share a defining propagation bias toward the temporal-to-nasal direction despite developmental changes in the underlying cholinergic and glutamatergic retinal networks. Here, we leverage genetic and pharmacological manipulations to investigate the relationship between cholinergic and glutamatergic neurotransmission during the transition between Stage II and Stage III waves in vivo. We find that the cholinergic network continues to play a vital role in the propagation of waves during Stage III after the primary mode of neurotransmission changes to glutamate. In the absence of glutamatergic waves, compensatory cholinergic activity persists but lacks the propagation bias typically observed in Stage III waves. In the absence of cholinergic waves, gap junction-mediated activity typically associated with Stage I waves persists throughout the developmental window in which Stage III waves usually emerge and lacks the spatiotemporal profile of normal Stage III waves, including a temporal-to-nasal propagation bias. Finally, we show that cholinergic signaling through ß2 subunit-containing nicotinic acetylcholine receptors, essential for Stage II wave propagation, is also critical for Stage III wave directionality.

Systematic Review of Surgical Interventions for Inferior Turbinate Hypertrophy.

BACKGROUND: Various surgical interventions exist for treatment of inferior turbinate hypertrophy (ITH). Though mucosal-sparing techniques are generally preferred, there is lack of consensus on the optimal technique. OBJECTIVE: This systematic review sought to evaluate the evidence for treatment of bilateral nasal obstruction via inferior turbinate reduction (ITR) and provide a meta-analysis of expected results of various techniques. METHODS: PubMed, Scopus, Cochrane Library databases were queried to include articles describing surgical treatment for ITH. Exclusion criteria were concurrent nasal procedures or non-mucosal ITH. Primary outcomes included visual analog scale for nasal obstruction, nasal cavity volume by acoustic rhinometry, and resistance by anterior rhinomanometry. Subgroup analyses assessed outcomes by rhinitis diagnosis and length of follow-up, and radiofrequency ablation (RFA) was compared to microdebrider-assisted turbinoplasty (MAIT). RESULTS: A total of 1870 studies were identified with 62 meeting inclusion criteria. Reported techniques included turbinectomy, submucosal resection, RFA, MAIT, laser, or electrocautery.All techniques demonstrated significant improvements in nasal obstruction using the visual analog scale. Further comprehensive physiologic data for RFA, MAIT, and laser was available and, compared to baseline, these techniques resulted in significant improvements in nasal resistance, nasal cavity volume, and nasal airflow. Six studies directly compared RFA and MAIT with statistically similar results on VAS, nasal cavity volume, and resistance with median follow-up time of 3.5 months. Assessment of VAS congestion over time reveals peak benefit is achieved between 3-6 months follow-up. CONCLUSIONS: All reviewed ITR techniques improve patient-reported nasal obstruction. RFA and MAIT provide comparable improvements in patient-reported and physiologic nasal airflow outcomes and while benefits are sustained long-term, the peak benefit for both techniques appears to be achieved within the first year.

Hyperspectral imaging to accurately segment skin erythema and hyperpigmentation in cutaneous chronic graft-versus-host disease.

In 51 lesions from 15 patients with the inflammatory skin condition chronic graft-versus-host-disease, hyperspectral imaging accurately delineated active erythema and post-inflammatory hyperpigmentation. The method was validated by dermatologist-approved confident delineations of only definitely affected and definitely unaffected areas in photographs. A prototype hyperspectral imaging system acquired a 2.5 × 3.5 cm2 area of skin at 120 wavelengths in the 450-850 nm range. Unsupervised extraction of unknown absorbers by endmember analysis achieved a comparable accuracy to that of supervised extraction of known absorbers (melanin, hemoglobin) by chromophore mapping: 0.78 (IQR: 0.39-0.85) vs. 0.83 (0.53-0.91) to delineate erythema and 0.74 (0.57-0.87) vs. 0.73 (0.52-0.84) to delineate hyperpigmentation. Both algorithms achieved higher specificity than sensitivity. Whereas a trained human confidently marked a median of 7% of image pixels, unsupervised and supervised algorithms delineated a median of 14% and 27% pixels. Hyperspectral imaging could overcome a fundamental practice gap of distinguishing active from inactive manifestations of inflammatory skin disease.

Secondary autoimmune immune ear disease (AIED): a systematic review and meta-analysis on vestibular manifestations of systemic autoimmune and inflammatory disorders.

Secondary autoimmune inner ear disease (AIED) is often bilateral and asymmetric in patients presenting with audiovestibular symptoms due to a systemic autoimmune disease. This systematic review and meta-analysis are aimed at identifying and highlighting patterns in prevalence of vestibular dysfunction, symptom presentation, and diagnostic methods in extant literature by combining clinical context from case reports with quantitative analyses from cohort studies. Screening of articles by title, abstract, and full text was completed by four reviewers (K.Z., A.L., S.C., and S.J.). In this study, we grouped secondary AIED and systemic autoimmune diseases by pathophysiologic mechanism: (1) connective tissue disease (CTD), (2) vasculitides (VAS), (3) systemic inflammatory disorders (SID), and (4) other immune-mediated disorders (OIMD). The search for AIED disease identified 120 articles (cohorts and case reports) that met the final inclusion criteria. All 120 were included in the qualitative review, and 54 articles were included for meta-analysis. Of these 54 articles, 22 included a control group (CwC). Ninety individual cases or patient presentations from 66 articles were included for analysis in addition to the 54 cohort articles. Secondary AIED does not have a diagnostic algorithm for managing vestibular symptoms. The management of audiovestibular symptoms requires close collaboration between otolaryngologists and rheumatologists to preserve end-organ function of the ear. To improve our ability to understand the impact on the vestibular system, vestibular clinicians need to develop a standardized reporting method. Clinical presentation should frequently be paired with vestibular testing to contextually investigate symptom severity and provide higher quality care.

Interrater reproducibility of the Myoton and durometer devices to quantify sclerotic chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a severe complication in long-term survivors of allogeneic hematopoietic stem cell transplantation. This disease is challenging to manage clinically due to a lack of validated tools to quantitatively measure skin sclerosis. The current gold standard for measuring skin sclerosis is the NIH Skin Score which has only moderate agreement among clinicians and experts. To more accurately assess skin sclerosis in cGVHD, the Myoton and durometer devices can be used to directly measure biomechanical parameters of the skin. However, the reproducibility of these devices is not known in patients with cGVHD. To determine this reproducibility, three observers independently measured 10 anatomic sites in each of seven patients with sclerotic cGVHD using the Myoton and durometer. Clinical reproducibility was measured by mean pairwise differences (U-statistic) and intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs). Mean pairwise differences, expressed in true physical units, were used to report typical errors for each anatomic site and device. Mean pairwise differences were less than 11% of the average overall values for all five Myoton parameters and durometer hardness. These were lower for Myoton creep (4.1%), relaxation time (4.7%), and frequency (5.1%) than decrement (9.0%), stiffness (10.4%), and durometer hardness (9.0%). Myoton parameters creep, relaxation time, and frequency showed promise for capturing skin biomechanics more accurately than Myoton stiffness, decrement, or durometer hardness. Mean pairwise differences trended highest in the shin and volar forearm and lowest in the dorsal forearm. The interobserver ICC for overall (averaged across all measured body sites of a patient) creep (0.94; 95% CI 0.87-1.00), relaxation time (0.96; 95% CI 0.90-1.00), and frequency (0.95; 95% CI 0.88-1.00), trended higher than that for decrement (0.43; 95% CI 0.00-0.88), stiffness (0.92; 95% CI 0.81-1.00), and durometer hardness (0.82; 95% CI 0.61-1.00). Similar trends were observed in healthy participants. These findings can help clinicians design better studies to assess therapeutic response to new cGVHD treatments and support the interpretation of future measurements.

Identifying barriers to obstructive sleep-disordered breathing care: Parental perspectives.

OBJECTIVE: Despite established clinical practice guidelines for pediatric obstructive sleep-disordered breathing (SDB), disparities persist for this common condition. Few studies have investigated parental experiences about challenges faced in obtaining SDB evaluation and tonsillectomy for their children. To better understand parent-perceived barriers to treatment of childhood SDB, we administered a survey to assess parental knowledge of this condition. MATERIALS & METHODS: A cross-sectional survey was designed to be completed by parents of children diagnosed with SDB. Two validated surveys were administered: 1) Barriers to Care Questionnaire and 2) Obstructive Sleep-Disordered Breathing and Adenotonsillectomy Knowledge Scale for Parents. Logistic regression modeling was performed to assess for predictors of parental barriers to SDB care and knowledge. RESULTS: Eighty parents completed the survey. Mean patient age was 7.4 ± 4.6 years, and 48 (60%) patients were male. The survey response rate was 51%. Patient racial/ethnic categories included 48 (60.0%) non-Hispanic White, 18 (22.5%) non-Hispanic Black, and 14 (17.5%) Other. Parents reported challenges in the 'Pragmatic' domain, including appointment availability and cost of healthcare, as the most frequently described barrier to care. Adjusting for age, sex, race, and education, parents in the middle-income bracket ($26,500 - $79,500) had higher odds of reporting greater barriers to care than parents in the highest (>$79,500) income tier (OR 5.536, 95% CI 1.312-23.359, P = 0.020) and lowest income tier (<$26,500) (OR 3.920, 95% CI 1.096-14.020). Parents whose children had tonsillectomy (n = 40) answered only a mean 55.7% ± 13.3% of questions correctly on the knowledge scale. CONCLUSION: Pragmatic challenges were the most encountered barrier that parents reported in accessing SDB care. Families in the middle-income tier experienced the greatest barriers to SDB care compared to lower and higher income families. In general, parental knowledge of SDB and tonsillectomy was relatively low. These findings represent potential areas of improvement to target interventions to promote equitable care for SDB.