Natural History of Untreated Idiopathic Sudden Sensorineural Hearing Loss.

OBJECTIVE: Although corticosteroids and other treatments for idiopathic sudden sensorineural hearing loss (ISSNHL) have been described, understanding its prognosis without intervention provides valuable information for patient management. The objective of this study is to provide a comprehensive, quantitative statistical analysis of the natural history of untreated idiopathic sudden sensorineural hearing loss (ISSNHL). STUDY TYPE AND DESIGN: A systematic review and meta-analyses. METHODS: Two independent searches of PubMed, Scopus, Web of Science, and Cochrane Library databases up to June 30, 2022, were performed. Adults with idiopathic sudden sensorineural hearing loss who received placebo or were untreated and had audiometric outcome measures in all study types were reviewed. These data indicative of the natural history of ISSNHL were analyzed, as were study characteristics related to risk of bias. Heterogeneity as assessed via I2 and random effects analyses were performed. RESULTS: Six studies meeting the inclusion criteria yielded 319 untreated patients whose natural history could be assessed. Heterogeneity among studies was moderate, with a variety of reported outcomes. A hearing improvement of at least 30 dB HL was observed in 36% (95% CI 0.28-0.44) of untreated patients, and of at least 10 dB HL was observed in 70% (95% CI 0.57-0.82) of untreated patients at 3 months. The mean hearing gain among untreated patients was 24.0 dB HL (95% CI 2.65-45.37) at 2-3 months. CONCLUSIONS: The observed natural history of ISSNHL suggests that patients can regain some hearing without active treatment. In the absence of future studies collecting prospective natural history data from untreated or placebo-treated ISSNHL patients, the data presented here provide the best available historical control data for reconsideration of results in past ISSNHL studies, as well as a roadmap for design and interpretation of future ISSNHL treatment clinical trials. Furthermore, knowing there is a statistically significant mean hearing gain of 24.0 dB HL in the untreated/placebo group provides an ethical basis for future placebo study of ISSNHL. The current status on ISSNHL management calls for a multi-institutional, randomized, double-blind placebo-controlled trial with validated outcome measures to provide science-based treatment guidance. Laryngoscope, 2024.

Targeting Oncostatin M Receptor to Attenuate Carotid Artery Plaque Vulnerability in Hypercholesterolemic Microswine.

Atherosclerosis is a chronic inflammatory disease that leads to acute embolism via the formation of atherosclerotic plaques. Plaque formation is first induced by fatty deposition along the arterial intima. Inflammation, bacterial infection, and the released endotoxins can lead to dysfunction and phenotypic changes of vascular smooth muscle cells (VSMCs), advancing the plaque from stable to unstable form and prone to rupture. Stable plaques are characterized by increased VSMCs and less inflammation while vulnerable plaques develop due to chronic inflammation and less VSMCs. Oncostatin M (OSM), an inflammatory cytokine, plays a role in endothelial cells and VSMC proliferation. This effect of OSM could be modulated by p27KIP1, a cyclin-dependent kinase (CDK) inhibitor. However, the role of OSM in plaque vulnerability has not been investigated. To better understand the role of OSM and its downstream signaling including p27KIP1 in plaque vulnerability, we characterized the previously collected carotid arteries from hyperlipidemic Yucatan microswine using hematoxylin and eosin stain, Movat Pentachrome stain, and gene and protein expression of OSM and p27KIP1 using immunostaining and real-time polymerase chain reaction. OSM and p27KIP1 expression in carotid arteries with angioplasty and treatment with either scrambled peptide or LR12, an inhibitor of triggering receptor expressed on myeloid cell (TREM)-1, were compared between the experimental groups and with contralateral carotid artery. The results of this study elucidated the presence of OSM and p27KIP1 in carotid arteries with plaque and their association with arterial plaque and vulnerability. The findings suggest that targeting OSM and p27KIP1 axis regulating VSMC proliferation may have therapeutic significance to stabilize plaque.

Therapeutic Potential of Targeting p27kip1 in Plaque Vulnerability.

Atherosclerosis, a critical contributor to coronary artery diseases, involves the accumulation of cholesterol, fibrin, and lipids within arterial walls, inciting inflammatory reactions culminating in plaque formation. This multifaceted interplay encompasses excessive fibrosis, fatty plaque development, vascular smooth muscle cell (VSMC) proliferation, and leukocyte migration in response to inflammatory pathways. While stable plaques demonstrate resilience against complications, vulnerable ones, with lipid-rich cores, necrosis, and thin fibrous caps, lead to thrombosis, myocardial infarction, stroke, and acute cerebrovascular accidents. The nuanced phenotypes of VSMCs, modulated by gene regulation and environmental cues, remain pivotal. Essential markers like alpha-SMA, myosin heavy chain, and calponin regulate VSMC migration and contraction, exhibiting diminished expression during VSMC de-differentiation and proliferation. p27kip, a CDK inhibitor, shows promise in regulating VSMC proliferation and appears associated with TNF-α-induced pathways impacting unstable plaques. Oncostatin M (OSM), an IL-6 family cytokine, correlates with MMP upregulation and foam cell formation, influencing plaque development. Efforts targeting mammalian target of rapamycin (mTOR) inhibition, notably using rapamycin and its analogs, demonstrate potential but pose challenges due to associated adverse effects. Exploration of the impact of p27kip impact on plaque macrophages presents promising avenues, yet its complete therapeutic potential remains untapped. Similarly, while OSM has exhibited potential in inducing cell cycle arrest via p27kip, direct links necessitate further investigation. This critical review discusses the role of mTOR, p27kip, and OSM in VSMC proliferation and differentiation followed by the therapeutic potential of targeting these mediators in atherosclerosis to attenuate plaque vulnerability.

Mitigation of Effect Modification by Psychological Status in Patients with Hearing Loss.

Importance: Although patient-reported outcomes provide valuable insights, these subjective data may not align with objective test results. Hearing loss is a pervasive problem, such that concordance between subjective perceptions of hearing ability and objective audiogram assessments would be beneficial. Objectives: To determine (1) whether psychological status is an effect modifier of the association between subjective patient reports of hearing ability and objective audiometry results, and (2) whether any effect modification observed in standard static questionnaires would be either mitigated or exacerbated by adaptive testing based on Item Response Theory analyses. Design, Setting, and Participants: This diagnostic study at a tertiary care center and community-based practice included consecutive adults who presented with queries related to hearing loss. Participants were recruited and enrolled and data analyses occurred from 2022 to 2024. Exposures: Participants prospectively reported their hearing-specific abilities through either a standard static or adaptive version of the Inner Effectiveness of Auditory Rehabilitation (EAR) scale, alongside validated measures of their mental health and audiometry. Word recognition scores (WRS) and pure tone averages (PTA) were used to analyze audiometric testing. Main Outcomes and Measures: The association between subjective Inner EAR results and audiometry was evaluated. Stratified analyses were used to assess for effect modification by psychological status. The results of standard static and adaptive testing were compared. Results: In this study of 395 patients (mean [range] age, 55.9 [18-89] years; 210 [53.2%] female), standard static Inner EAR mean scores were appropriately higher in patients with higher (better) WRS (50.7, 95% CI, 46.4-54.9), compared with patients with lower (worse) WRS (34.7, 95% CI, 24.3-45.1). However, among patients with worse mental health, there was no association between standard static Inner EAR scores and WRS. In contrast, adaptive Inner EAR mean scores were significantly higher for those with better WRS, regardless of mental health status. Thus, effect modification was observed in standard static assessments, whereas adaptive testing remained durably associated with audiometry, regardless of mental health. Conclusions and Relevance: Psychological status was an effect modifier of the association between standard Inner EAR scale scores and audiometry, with a positive association observed only in those with better mental health. Adaptive testing scores, however, remained significantly associated with audiometry, even when mental status was worse. Adaptive testing may stabilize the association between subjective and objective hearing outcomes.

Silk-Hyaluronic Acid for Vocal Fold Augmentation: Safety Profile and Long-Term Voice Outcomes.

OBJECTIVES: Silk-hyaluronic acid (silk-HA) is a novel vocal fold augmentation material used in humans since July 2020. We aim to describe indications, voice outcomes, and longevity data for silk-HA injectable when used for vocal fold injection (VFI) augmentation in a large cohort of patients with longer-term follow-up than preliminary clinical studies. METHODS: Retrospective chart review of Silk-HA injections for glottic insufficiency (GI) and follow-up between July 2020 and November 2023. Subject demographics, diagnoses, volume of material injected, VHI-10 data, time from injection, need for reinjection, and complications were collected. Blinded perceptual voice analysis of randomly selected pre- and post-intervention voice samples for unilateral vocal fold paralysis patients was performed by three voice-specialized speech-language pathologists, and changes in VHI-10 determined at various time intervals up to 1year and beyond. RESULTS: A total of 160 silk-HA injection procedures were performed: 59% female, with a mean age of 66± 13 (range 21-90) years. Ninety-four subjects had unilateral paralysis (58.4%); the remainder had scar, atrophy, paresis, or a combination thereof. Mean volume of silk-HA injected was 0.24± 0.14 cc. Major complications were rare, most notable for laryngoscopic evidence of hemilaryngeal edema (n = 6, 3.8%), with a readmission rate to hospital of 1.3% (n = 2). There was a statistically significant decrease in paired ΔVHI-10 and CAPE-V ratings for each of the postoperative follow-up intervals. A total of 24 (27.2%) repeat medialization procedures were recommended following silk-HA injection for unilateral paralysis. CONCLUSIONS: This study demonstrates that silk-HA is a safe product for VFI augmentation, and effective injectable for the treatment of GI due to unilateral vocal fold paralysis. Based on the current data, it is reasonable to counsel patients that they should expect benefit for several months following the injection. If patients reach 1year from their injection with a stable and satisfactory outcome, the majority experience ongoing benefit without need for additional procedures, however, the final duration of clinical effect appears to be years, but it is yet to be determined.

YouTube Video Analytics for Patient Education: An Exploratory Clustering of Obstructive Sleep Apnea Videos.

With the growing popularity of content-sharing platforms, patients are increasingly using the Internet as a critical source of health information. As one of the most popular video-sharing sites, YouTube provides easy access to health information seekers, but it is difficult and time-consuming to identify and retrieve high-quality videos that may serve as engaging patient education materials. This paper reports on an exploratory analysis of 317 YouTube videos on Obstructive Sleep Apnea (OSA) to better understand some key features of the videos and the relationships between them to facilitate subsequent video classification and recommendation. Features intrinsic to a video, such as video duration, and extrinsic, such as the number of views, are analyzed using unsupervised clustering methods and the Sankey diagram to discover the relationship between the clusters and their significance across different clusters, providing promising insights for the assessment of video quality.

High-resolution assessment of multidimensional cellular mechanics using label-free refractive-index traction force microscopy.

A critical requirement for studying cell mechanics is three-dimensional assessment of cellular shapes and forces with high spatiotemporal resolution. Traction force microscopy with fluorescence imaging enables the measurement of cellular forces, but it is limited by photobleaching and a slow acquisition speed. Here, we present refractive-index traction force microscopy (RI-TFM), which simultaneously quantifies the volumetric morphology and traction force of cells using a high-speed illumination scheme with 0.5-Hz temporal resolution. Without labelling, our method enables quantitative analyses of dry-mass distributions and shear (in-plane) and normal (out-of-plane) tractions of single cells on the extracellular matrix. When combined with a constrained total variation-based deconvolution algorithm, it provides 0.55-Pa shear and 1.59-Pa normal traction sensitivity for a 1-kPa hydrogel substrate. We demonstrate its utility by assessing the effects of compromised intracellular stress and capturing the rapid dynamics of cellular junction formation in the spatiotemporal changes in non-planar traction components.

'If I Knew More I Would Feel Less Worried': Filipino Americans' Attitudes and Knowledge of Genetic Disease, Counseling, and Testing.

INTRODUCTION: The field of genetics is rapidly expanding and people are increasingly utilizing genetic testing and counseling services. However, the current literature on genetic health topics and Filipinos remains limited, as many minority populations are not adequately studied. This study describes Filipino Americans' attitudes and knowledge of genetic disease, genetic testing, and genetic counseling. To address these knowledge gaps and reduce the burden of health disparities, the informational needs of Filipino Americans regarding genetic disease and genetic services must be understood in order to better tailor these services and outreach methods. METHODS: Fifteen semi-structured, qualitative interviews were held with individuals who self-identified as Filipino American between November 2022 and January 2023. Interviews were transcribed and coded using an iterative process. RESULTS: Most participants were familiar with genetic disease and believed that factors such as biology, as well as cultural factors such as upbringing and food, contributed to its development. The majority of participants had previously heard of genetic testing; however, most participants either did not know much or were only familiar with ancestry direct-to-consumer genetic testing (DTC-GT). Most participants had not heard of genetic counseling and those that had heard of genetic counseling before did not understand its purpose. Overall, most participants had a positive attitude toward genetic testing and counseling. Participants identified the benefits of these services including genetic disease prevention, management, and treatment. Participants stressed the importance of educating the Filipino community and shared their ideas for how to implement outreach efforts. DISCUSSION/CONCLUSION: This study found that Filipino Americans generally had a positive outlook on genetic testing and genetic counseling. We propose participant-generated ideas for outreach and education that may help inform future public health efforts that aim to educate this population about genetic disease, testing and counseling.

Validation of a Novel Allergy-Specific Domain for the 22-Item Sino-Nasal Outcomes Test.

OBJECTIVES: To develop and assess the validity of a novel allergy-specific domain for the 22-item sino-nasal outcomes test (SNOT-22), to provide a new tool that efficiently quantifies the impact of allergic rhinitis (AR) concurrent with chronic rhinosinusitis. STUDY DESIGN: Prospective validation study. SETTING: Tertiary care hospital and community-based clinic. METHODS: Proposed items were developed based on clinician and patient input, and further assessed via factor analysis and for internal consistency (n = 1987). Items were then additionally assessed for convergent and discriminant validity (n = 415), applying data from concurrent completions of the Nasal Obstruction and Septoplasty Effectiveness Scale (NOSE), Mini-Rhinoconjunctivitis Quality-of-Life Questionnaire (MiniRQLQ), and validated global health assessments. Assessments of intra-rater reliability, responsiveness to change, and qualitative input were also performed. RESULTS: Factor analysis demonstrated that proposed allergy items mapped to a single domain. Items were internally consistent (Cronbach α: 0.80 within domain, 0.91 within all SNOT). In assessments of convergent validity, domain scores were associated with MiniRQLQ (Spearman's ρ: 0.46, 95% confidence interval [CI]: 0.30-0.59) and NOSE scores (0.36, 95% CI: 0.27-0.44). The novel items also discriminated among clinical states: a 1-point increase in domain score was associated with an 8.32 (95% CI: 5.43-12.75) increase in the odds of prompting a visit for allergy-related symptoms and a 1.52 (95% CI: 1.13-2.05) increase in the odds of positive allergy testing. Intra-rater reliability was substantial (Cohen's κ: 0.8, 95% CI: 0.8-0.9), and responsiveness to change was demonstrated (mean difference: -0.6, 95% CI: -0.8 to -0.4). CONCLUSIONS: This novel domain is a valid, efficient measure of AR alongside rhinosinusitis.

Circulating tumor-tissue modified HPV DNA testing in the clinical evaluation of patients at risk for HPV-positive oropharynx cancer: The IDEA-HPV study.

OBJECTIVES: While survival outcomes are favorable for Human Papillomavirus (HPV)-positive oropharyngeal squamous cell carcinomas (OPSCCs), early diagnosis may minimize treatment-related morbidity and mortality. This study evaluated circulating tumor tissue-modified viral (TTMV)-HPV DNA plasma testing to facilitate early diagnosis of HPV-positive OPSCCs. METHODS: In this prospective exploratory cohort study, patients presenting to an Otolaryngology-Head and Neck Surgery clinic with unexplained signs or symptoms considered high-risk for HPV-positive OPSCC were recruited between March 2021-October 2022. Circulating TTMV-HPV DNA testing was performed, and results were shared with subjects and treating clinicians. Clinicians were surveyed regarding the perceived clinical utility of the test. RESULTS: Thirty-nine subjects were included. Most subjects were women (N = 23, 59 %), white (N = 32, 82 %) and never-smokers (N = 20, 51 %) with median age 60 years. Circulating TTMV-HPV DNA was detected in 2/39 subjects, both subsequently diagnosed with HPV-positive OPSCC. Both were white men aged 70-80 years with a neck mass. One subject with undetectable TTMV-HPV DNA was also diagnosed with HPV-positive OPSCC through excisional neck mass biopsy. Other eventual diagnoses included 3 HPV-negative head and neck squamous cell carcinomas and 4 other malignancies. Testing was perceived as helpful in clinical decision-making for 26/38 (68 %) subjects, and useful for similar future patients for 32/37 (86 %) subjects. CONCLUSION: Circulating TTMV-HPV DNA testing is feasible and holds potential as a diagnostic aid for HPV-positive OPSCC alongside standard clinical workup. Clinicians should be cognizant of its limitations, as a negative test does not necessarily indicate the absence of disease. Further studies to evaluate its utility are warranted.

Evidence-Based Medicine in Otolaryngology Part 16: Qualitative and Quantitative Methods-Contrasting and Complementary Approaches.

Qualitative methods have been increasingly applied in our literature, providing richness to data and incorporating the nuances of patient and family perspectives. These qualitative research techniques provide breadth and depth beyond what can be gleaned through quantitative methods alone. When both quantitative and qualitative approaches are coupled, their findings provide complementary information which can further substantiate study conclusions. We thus aim to provide insight into qualitative and quantitative methods in comparison and contrast to each other, as well as guidance on when each approach is most apt. In relation, we also describe mixed methods and the theory supporting their framework. In doing so, we provide the foundation for an ensuing, more detailed exposition of qualitative methods.

Surface tension-induced biomimetic assembly of cell-laden fibrous bundle construct for muscle tissue engineering.

The field of tissue engineering has been long seeking to develop functional muscle tissue that closely resembles natural muscle. This study used a bio-inspired assembly based on the surface tension mechanism to develop a novel method for engineering muscle tissue. This approach enabled uniaxially ordered electrospun fibers to naturally collide into an aligned bundle without the need for manual handling, thereby reducing cell damage during the cell culture procedure. During the assembly procedure, C2C12 myoblasts were cultured in a viscous collagen hydrogel that caused wetting while providing adequate structural stability for the cell-fiber construct. In addition, gene expression analysis of the resulting muscle-like fibril bundle revealed improved myogenic differentiation. These findings highlight the potential of using a collagen hydrogel and the surface tension mechanism to construct biologically relevant muscle tissue, offering a promising strategy that may outperform existing approaches. Overall, this study contributes to the development of advanced tissue engineering methods and brings us a step closer to creating functional muscle tissue for therapeutic and regenerative medicine applications.

The Impact of Sinonasal Symptoms in Relation to Potentially Life-Threatening Comorbidities.

OBJECTIVE: While general health may be influenced by sinonasal symptoms, their effects may be overshadowed by comorbid states which may be more serious. To assess the validity of this postulate, we measured the extent to which sinonasal symptoms and concurrent conditions influenced general health. STUDY DESIGN: Observational outcomes study. SETTING: Academic medical center, community care sites. METHODS: Adults with sinonasal symptoms completed the 22-item Sinonasal Outcome Test, along with the Patient-Reported Outcomes Measurement Information System global health short form. Comorbidities were categorized with the Deyo modification of the Charlson comorbidity index. Multivariate regression analyses were utilized to determine the relative impact of sinonasal symptoms and concurrent comorbid conditions on general health. RESULTS: Data from 219 consecutive patients demonstrated that sinonasal symptoms were associated with significantly diminished general physical (ß = -1.431, p < .001), mental (ß = -1.000, p < .001), overall (ß = -1.026, p < .001), and social health (ß = -0.872, p = .003), regardless of the presence of potentially life-threatening comorbid conditions. Comorbid conditions included cardiovascular disease, chronic obstructive pulmonary disease, connective tissue disease, peptic ulcer, diabetes mellitus, and hepatic disease. The effect of sinonasal symptoms was neither subsumed nor overshadowed by the effects of comorbid states. Nasal, ear, sleep, and psychological domain scores were also associated with general physical, mental, and global health while adjusting for the impact of comorbidities. CONCLUSION: Sinonasal symptoms have a substantial effect on general health which is not subsumed by the presence of potentially life-threatening concurrent comorbidities. These data may help support the importance of funding and resource allocation for conditions causing sinonasal symptoms.

Can EAT-10 Become EAT-5? Improving Measurement Efficiency of Dysphagia with Item Response Theory.

OBJECTIVES: To assess: (1) the Eating Assessment Tool (EAT-10) with item response theory (IRT) to determine which individual items provide the most information, (2) the extent to which dysphagia is measured with subsets of items while maintaining precise score estimates, and (3) if 5-item scales have the differing discriminatory ability, as compared to the parent 10-item instrument. METHODS: Prospectively collected data from 2,339 patients who completed the EAT-10 questionnaire during evaluation at a tertiary care otolaryngology clinic were utilized. IRT analyses provided discrimination and location parameters associated with individual questions. Residual item correlations were also assessed for redundant information. Based on these results, three 5-item subsets were further evaluated using item information function curves. Areas under receiver-operator characteristic curves (ROC-AUC) were also calculated to evaluate the discriminatory ability for dysphagia-related clinical diagnoses. RESULTS: Item discrimination parameter estimates ranged from 1.71 to 5.46, with higher values indicating more information. Residual item correlations were determined within item pairs, and location parameters were calculated. Based on these data, in combination with clinical utility, three 5-item subsets were proposed and assessed. ROC-AUC analyses demonstrated no significant difference between the EAT-5-Alpha subset and the original 10-item instrument for discriminating dysphagia as a primary diagnosis (0.88, 0.88). The EAT-5-Clinical subset outperformed the original 10 instruments in ROC-AUC for aspiration. The EAT-5-Range subset was significantly associated with problems with thin liquids. CONCLUSIONS: IRT analyses distinguished three proposed 5-item subsets of the EAT-10 instrument, supporting shorter survey options, while still reflecting the impact of dysphagia without significant loss of discrimination. LEVEL OF EVIDENCE: 3 (Diagnostic testing with consistently applied reference standards, partial blinding). Laryngoscope, 133:3327-3333, 2023.

Normative Values for the Inner EAR Scale.

OBJECTIVE: To determine normative values for the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) scale, a validated instrument utilized to study the impact of hearing loss and potential treatments. STUDY DESIGN: Observational outcomes study. SETTING: Academic medical center and community care sites. METHODS: We included patients who were at least 18 years of age and completed the Inner EAR scale, pure-tone audiometry, and word recognition score assessment. Based on audiometry results, patients were categorized as having: (1) normal bilateral hearing, (2) unilateral hearing loss, and (3) bilateral hearing loss. The distributions of Inner EAR scale scores were assessed within each category. Fisher's exact test was utilized to determine whether data-driven threshold values could discriminate among the 3 clinical groups. RESULTS: Two hundred and twenty-two consecutive patients with hearing-related complaints met inclusion criteria. Mean Inner EAR scores for patients with bilateral hearing loss (29.2, interquartile range [IQR] 10-41.5), unilateral hearing loss (38.9, IQR 23-49), and normal hearing (46.6, IQR 31-62) were significantly different (analysis of variance F < 0.0001). An Inner EAR score threshold of 50 supported the ability to statistically significantly discriminate between bilateral hearing loss and normal hearing (p = .003), as well as between unilateral hearing loss and normal hearing (p = .015). CONCLUSION: An Inner EAR score normative threshold value of 50 provides significant discriminatory ability between normal hearing and unilateral or bilateral hearing loss on audiometry. Normative values provide useful, frequently referenced data when assessing responses to treatment. Based on these data, this threshold may help distinguish patients with and without perceived functional impact from hearing loss.

Early Biliary Decompression Reduces Morbidity but Not Mortality in Acute Ascending Cholangitis.

Background Acute ascending cholangitis is a life-threatening infection due to biliary obstruction. Decompression via endoscopic retrograde cholangiography (ERC) or interventional radiologic (IR) drainage controls the source of the sepsis. Numerous studies have been published with conflicting data on whether earlier drainage affects morbidity and mortality. We sought to publish our experience at two Las Vegas community hospitals. Methods After IRB approval, over 4000 inpatient non-elective ERCs were analyzed between 2010 and 2019. Six-hundred and twenty-five patients met the 2018 Tokyo criteria for a "definitive diagnosis" of acute ascending cholangitis. A univariate and multivariate analysis was conducted to identify factors significantly associated with length of stay and mortality. Results On univariate analysis, patients who had drainage conducted within 24 hours had significantly shorter lengths of stay (p = 0.0012 95% CI [-88.1 to -21.8 hrs]), higher mean diastolic blood pressure (p=0.0029 95% CI [1.03 to 5.01 mm Hg]), and lower mean maximum temperature (p=0.0001 95% CI [-0.842 to -0.382 oC]) when compared to patients who underwent decompression more than 24 hours after admission. There were no statistically significant differences in mortality between patients who underwent decompression within 24 hours of admission versus patients who underwent decompression beyond 24 hours of admission. On multivariate analysis, earlier decompression reduced the length of stay for patients with mild (p<0.0001), moderate (p<0.0001), and severe cholangitis (p=0.0023). Mortality was significantly associated with the worsening severity of the cholangitis (moderate [p=0.0001] and severe [p<0.0001], but not mild disease) and the use of vasopressors. Conclusions Timely biliary decompression within 24 hours of admission significantly reduces the length of stay, pyrexia, and hemodynamic abnormalities. In addition, our data corroborate the 2018 Tokyo guidelines that correlate the severity of cholangitis with mortality.

Shear-induced phenotypic transformation of microglia in vitro.

The brain cells are affected by continuous fluid shear stress that is driven by varying hydrostatic and osmotic pressure conditions, depending on the brain's pathophysiological conditions. Although all brain cells are sensitive to the subtle changes in various physicochemical factors in the microenvironment, microglia, the resident brain immune cells, exhibit the most significant morphodynamic transformation. However, little is known about the phenotypic alterations in microglia in response to changes in fluid shear stress. In this study, we established a flow-controlled microenvironment to investigate the effects of shear flow on microglial phenotypes, including morphology, motility, and activation states. We observed two distinct morphologies of microglia in a static condition: bipolar cells that oscillate along their long axis and unipolar cells that migrate persistently. When exposed to flow, a significant fraction of bipolar cells showed unstable oscillation with an increased amplitude of oscillation and a decreased frequency, which consequently led to the phenotypic transformation of oscillating cells into migrating cells. Furthermore, we observed that the level of proinflammatory genes increased in response to shear stress, although there were no significant changes in the level of antiinflammatory genes. Our findings suggest that an interstitial fluid-level stimulus can cause a dramatic phenotypic shift in microglia toward proinflammatory states, shedding light on the pathological outbreaks of severe brain diseases. Given that the fluidic environment in the brain can be locally disrupted in pathological circumstances, the mechanical stimulus by fluid flow should also be considered a crucial element in regulating the immune activities of the microglia in brain diseases.

Light-stimulated insulin secretion from pancreatic islet-like organoids derived from human pluripotent stem cells.

Optogenetic techniques permit non-invasive, spatiotemporal, and reversible modulation of cellular activities. Here, we report a novel optogenetic regulatory system for insulin secretion in human pluripotent stem cell (hPSC)-derived pancreatic islet-like organoids using monSTIM1 (monster-opto-Stromal interaction molecule 1), an ultra-light-sensitive OptoSTIM1 variant. The monSTIM1 transgene was incorporated at the AAVS1 locus in human embryonic stem cells (hESCs) by CRISPR-Cas9-mediated genome editing. Not only were we able to elicit light-induced intracellular Ca2+ concentration ([Ca2+]i) transients from the resulting homozygous monSTIM1+/+-hESCs, but we also successfully differentiated them into pancreatic islet-like organoids (PIOs). Upon light stimulation, the ß-cells in these monSTIM1+/+-PIOs displayed reversible and reproducible [Ca2+]i transient dynamics. Furthermore, in response to photoexcitation, they secreted human insulin. Light-responsive insulin secretion was similarly observed in monSTIM1+/+-PIOs produced from neonatal diabetes (ND) patient-derived induced pluripotent stem cells (iPSCs). Under LED illumination, monSTIM1+/+-PIO-transplanted diabetic mice produced human c-peptide. Collectively, we developed a cellular model for the optogenetic control of insulin secretion using hPSCs, with the potential to be applied to the amelioration of hyperglycemic disorders.