Atoh1 Directs Regeneration and Functional Recovery of the Mature Mouse Vestibular System

Utricular hair cells (HCs) are mechanoreceptors required for vestibular function. After damage, regeneration of mammalian utricular HCs is limited and regenerated HCs appear immature. Thus, loss of vestibular function is presumed irreversible. Here, we found partial HC replacement and functional recovery in the mature mouse utricle, both enhanced by overexpressing the transcription factor Atoh1. Following damage, long-term fate mapping revealed that support cells non-mitotically and modestly regenerated HCs displaying no or immature bundles. By contrast, Atoh1 overexpression stimulated proliferation and widespread regeneration of HCs exhibiting elongated bundles, patent mechanotransduction channels, and synaptic connections. Finally, although damage without Atoh1 overexpression failed to initiate or sustain a spontaneous functional recovery, Atoh1 overexpression significantly enhanced both the degree and percentage of animals exhibiting sustained functional recovery. Therefore, the mature, damaged utricle has an Atoh1-responsive regenerative program leading to functional recovery, underscoring the potential of a reprogramming approach to sensory regeneration

Modeling drug response using network-based personalized treatment prediction (NetPTP) with applications to inflammatory bowel disease.

For many prevalent complex diseases, treatment regimens are frequently ineffective. For example, despite multiple available immunomodulators and immunosuppressants, inflammatory bowel disease (IBD) remains difficult to treat. Heterogeneity in the disease across patients makes it challenging to select the optimal treatment regimens, and some patients do not respond to any of the existing treatment choices. Drug repurposing strategies for IBD have had limited clinical success and have not typically offered individualized patient-level treatment recommendations. In this work, we present NetPTP, a Network-based Personalized Treatment Prediction framework which models measured drug effects from gene expression data and applies them to patient samples to generate personalized ranked treatment lists. To accomplish this, we combine publicly available network, drug target, and drug effect data to generate treatment rankings using patient data. These ranked lists can then be used to prioritize existing treatments and discover new therapies for individual patients. We demonstrate how NetPTP captures and models drug effects, and we apply our framework to individual IBD samples to provide novel insights into IBD treatment

Presence of Anxiety and Depression Symptoms Affects the First Time Treatment Efficacy and Recurrence of Benign Paroxysmal Positional Vertigo

ObjectivesTo investigate the possible effects of anxiety and/or depression symptoms on the treatment outcomes and recurrence of benign paroxysmal positional vertigo (BPPV).MethodsThis is a retrospective study conducted at a single institution. 142 consecutive patients diagnosed with idiopathic BPPV at the Department of Otology in Shengjing Hospital of China Medical University between October 2016 and July 2017 were retrospectively reviewed. 127 patients were finally included in this study. Zung self-rating anxiety scale (SAS) and Zung self-rating depression scale (SDS) were used to evaluate the presence of anxiety and/or depression, respectively, in our BPPV patients. A significant score (at or above 50 for SAS and 53 for SDS) represents the presence of clinically significant symptoms. Two-tailed Student’s t-test, χ2 test, and logistic regression analysis were used as appropriate. A p value less than 0.05 was considered statistically significant.ResultsThe prevalence of anxiety and/or depression symptoms in BPPV patients in the present study was 49.61%. The effectiveness of the first time canalith repositioning maneuver (CRM) was 70.08%. With weekly follow-up treatments of CRM, the success rate increased to 97.64% by 1 month. The total recurrence rate at 6-month follow-up post-cure was 14.17%. Holding all other variables constant, patients with psychiatric symptoms (Relative-risk ratio: 3.160; p = 0.027) and patients with non-posterior semicircular canal (PSC) involvement (Relative-risk ratio: 7.828, p = 0.013) were more likely to experience residual dizziness (RD) even after effective CRM treatment. Psychiatric symptoms (Relative-risk ratio: 6.543; p = 0.001) and female gender (Relative-risk ratio: 4.563; p = 0.010) are risk factors for the failure of first time CRM. In addition, BPPV patients with psychiatric symptoms (Odds ratio: 9.184, p = 0.008) were significantly more likely to experience recurrences within the first 6 months after a successful maneuver.ConclusionAnxiety-depression status significantly reduced the efficacy of the first time CRM and increased the risk for recurrence. Other factors, such as female gender and non-PSC involvement are also susceptible risk factors for BPPV patients to require multiple treatments and experience delayed recovery. A screening for psychiatric symptoms in BPPV patients and active treatment of these symptoms would benefit both physicians and patients in understanding and improving the prognosis of the disease and treatment options

Uncoordinated maturation of developing and regenerating postnatal mammalian vestibular hair cells

Sensory hair cells are mechanoreceptors required for hearing and balance functions. From embryonic development, hair cells acquire apical stereociliary bundles for mechanosensation, basolateral ion channels that shape receptor potential, and synaptic contacts for conveying information centrally. These key maturation steps are sequential and presumed coupled; however, whether hair cells emerging postnatally mature similarly is unknown. Here, we show that in vivo postnatally generated and regenerated hair cells in the utricle, a vestibular organ detecting linear acceleration, acquired some mature somatic features but hair bundles appeared nonfunctional and short. The utricle consists of two hair cell subtypes with distinct morphological, electrophysiological and synaptic features. In both the undamaged and damaged utricle, fate-mapping and electrophysiology experiments showed that Plp1+ supporting cells took on type II hair cell properties based on molecular markers, basolateral conductances and synaptic properties yet stereociliary bundles were absent, or small and nonfunctional. By contrast, Lgr5+ supporting cells regenerated hair cells with type I and II properties, representing a distinct hair cell precursor subtype. Lastly, direct physiological measurements showed that utricular function abolished by damage was partially regained during regeneration. Together, our data reveal a previously unrecognized aberrant maturation program for hair cells generated and regenerated postnatally and may have broad implications for inner ear regenerative therapies

Association Between Retinal Pathology and Hearing in Older Adults

Abstract We investigated the association between retinal microvascular changes and hearing loss based on the hypothesis that both may result from shared microvascular pathology. Data from 536 older adults from the National Health and Nutritional Examination Survey 2005 to 2006 including sociodemographic and health characteristics, pure‐tone hearing thresholds, and retinal pathologies were collected and analyzed. Associations between retinal and hearing pathologies were modeled with multivariable‐adjusted linear regressions. 75% of participants had hearing loss and 15% of participants had retinopathy. The association between retinopathy, microaneurysms, and blot hemorrhages with better speech‐frequency pure tone average was −2.81 (95% confidence interval [CI]: −5.72 to 0.10), −4.75 (95% CI: −8.73 to −0.78), and −5.34 (95% CI: −8.68 to −2.00), respectively. The presence of retinopathy, microaneurysms, and blot hemorrhages was inversely associated with hearing loss. Further studies are needed to better understand the potential relationship between microvascular pathologies of the eye and ear

Uncoordinated maturation of developing and regenerating postnatal mammalian vestibular hair cells.

Sensory hair cells are mechanoreceptors required for hearing and balance functions. From embryonic development, hair cells acquire apical stereociliary bundles for mechanosensation, basolateral ion channels that shape receptor potential, and synaptic contacts for conveying information centrally. These key maturation steps are sequential and presumed coupled; however, whether hair cells emerging postnatally mature similarly is unknown. Here, we show that in vivo postnatally generated and regenerated hair cells in the utricle, a vestibular organ detecting linear acceleration, acquired some mature somatic features but hair bundles appeared nonfunctional and short. The utricle consists of two hair cell subtypes with distinct morphological, electrophysiological and synaptic features. In both the undamaged and damaged utricle, fate-mapping and electrophysiology experiments showed that Plp1+ supporting cells took on type II hair cell properties based on molecular markers, basolateral conductances and synaptic properties yet stereociliary bundles were absent, or small and nonfunctional. By contrast, Lgr5+ supporting cells regenerated hair cells with type I and II properties, representing a distinct hair cell precursor subtype. Lastly, direct physiological measurements showed that utricular function abolished by damage was partially regained during regeneration. Together, our data reveal a previously unrecognized aberrant maturation program for hair cells generated and regenerated postnatally and may have broad implications for inner ear regenerative therapies

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit