Model-based clustering of high-dimensional longitudinal data via regularization.

We propose a model-based clustering method for high-dimensional longitudinal data via regularization in this paper. This study was motivated by the Trial of Activity in Adolescent Girls (TAAG), which aimed to examine multilevel factors related to the change of physical activity by following up a cohort of 783 girls over 10 years from adolescence to early adulthood. Our goal is to identify the intrinsic grouping of subjects with similar patterns of physical activity trajectories and the most relevant predictors within each group. The previous analyses conducted clustering and variable selection in two steps, while our new method can perform the tasks simultaneously. Within each cluster, a linear mixed-effects model (LMM) is fitted with a doubly penalized likelihood to induce sparsity for parameter estimation and effect selection. The large-sample joint properties are established, allowing the dimensions of both fixed and random effects to increase at an exponential rate of the sample size, with a general class of penalty functions. Assuming subjects are drawn from a Gaussian mixture distribution, model effects and cluster labels are estimated via a coordinate descent algorithm nested inside the Expectation-Maximization (EM) algorithm. Bayesian Information Criterion (BIC) is used to determine the optimal number of clusters and the values of tuning parameters. Our numerical studies show that the new method has satisfactory performance and is able to accommodate complex data with multilevel and/or longitudinal effects.

Clustering of longitudinal physical activity trajectories among young females with selection of associated factors.

We examined multi-level factors related to the longitudinal physical activity trajectories of adolescent girls to determine the important predictors for physical activity. The Trial of Activity in Adolescent Girls (TAAG) Maryland site recruited participants at age 14 (n = 566) and followed up with these girls at age 17 (n = 553) and age 23 (n = 442). Individual, social factors and perceived environmental factors were assessed by questionnaire; body mass index was measured at age 14 and age 17, and self-reported at age 23. Neighborhood factors were assessed by geographic information systems. The outcome, moderate-to-vigorous physical activity (MVPA) minutes in a day, was assessed from accelerometers. A mixture of linear mixed-effects models with double penalization on fixed effects and random effects was used to identify the intrinsic grouping of participants with similar physical activity trajectory patterns and the most relevant predictors within the groups simultaneously. Three clusters of participants were identified. Two hundred and forty participants were clustered as "maintainers" and had consistently low MVPA over time; 289 participants were clustered as "decreasers" who had decreasing MVPA over time; 39 participants were grouped as "increasers" and had increasing MVPA over time. Each of the three clusters has its own cluster-specific factors identified using the clustering method, indicating that each cluster has unique characteristics.

Pseudoepitheliomatous hyperplasia of the auricle: two case reports and experiences of reconstruction.

BACKGROUND: It is rare to find pseudoepitheliomatous hyperplasia (PEH) on the auricle. PEH should be differentiated from squamous cell carcinoma (SCC). Diagnosis is made after surgery as a biopsy is often inconclusive. A free or pedicled skin flap is needed to avoid deformation of the auricle. METHODS: Adjacent pedicled skin flap is a good option for reconstruction. Moreover, it was shown how to repair the wound in the following two cases. RESULTS: The flaps grew well after surgery, and the wound healed well. CONCLUSION: PEH is a benign lesion. Adjacent pedicled skin flap is a good option for reconstruction, which can avoid deformation of the auricle.

Experimental animal models of drug-induced sensorineural hearing loss: a narrative review.

OBJECTIVE: This narrative review describes experimental animal models of sensorineural hearing loss (SNHL) caused by ototoxic agents. BACKGROUND: SNHL primarily results from damage to the sensory organ within the inner ear or the vestibulocochlear nerve (cranial nerve VIII). The main etiology of SNHL includes genetic diseases, presbycusis, ototoxic agents, infection, and noise exposure. Animal models with functional and anatomic damage to the sensory organ within the inner ear or the vestibulocochlear nerve mimicking the damage seen in humans are employed to explore the mechanism and potential treatment of SNHL. These animal models of SNHL are commonly established using ototoxic agents. METHODS: A literature search of PubMed, Embase, and Web of Science was performed for research articles on hearing loss and ototoxic agents in animal models of hearing loss. CONCLUSIONS: Common ototoxic medications such as aminoglycoside antibiotics (AABs) and platinum antitumor drugs are extensively used to induce SNHL in experimental animals. The effect of ototoxic agents in vivo is influenced by the chemical mechanisms of the ototoxic agents, the species of animal, routes of administration of the ototoxic agents, and the dosage of ototoxic agents. Animal models of drug-induced SNHL contribute to understanding the hearing mechanism and reveal the function of different parts of the auditory system in humans.

Moderate to Severe Chronic Pain in Later Life: Risk and Resilience Factors for Recovery.

Despite extensive research on the development and risk factors of chronic pain, the process of recovery from chronic pain in later life has been rarely studied. We estimated the recovery rate of moderate to severe chronic pain (chronic pain of moderate or severe severity or interfering with usual activities) among older adults and investigated predictors of recovery. Leveraging the longitudinal Health and Retirement Study 2006-2016 data (6 waves), we estimated the biennial national attrition-adjusted recovery rate of moderate to severe chronic pain among 6,132 US adults aged 65-75 at baseline. Generalized estimating equation Poisson models examined pain-related, sociodemographic, psychosocial and health-related factors in relation to recovery within any 2-year interval using longitudinal lagged design. Between 2006-2016, the prevalence of moderate to severe chronic pain increased from 28% to 33% with the incidence increasing from 14% to 18% and the recovery rate approximately 30%. Previous chronic pain duration, age, chronic diseases and a personality trait (agreeableness) were associated with a lower probability of recovery. Greater financial wealth and physical activity, better sleep quality and self-reported health were associated with a greater probability of recovery. Interventions that improve physical activity and sleep quality may be important avenues for reducing chronic pain burden among older adults. PERSPECTIVE: Our longitudinal findings suggested that recovery from moderate to severe chronic pain is common in later life and we further identified several key factors associated with this recovery process. Future research should consider the potential of interventions that improve physical activity and sleep quality to enhance recovery among older adults.

Endoscopic Transcanal Push-Trough Myringoplasty for Different Types of Tympanic Membrane Perforations.

OBJECTIVE: This study aims to explore the feasibility of endoscopic transcanal push-trough myringoplasty (ETPM) for all types of tympanic membrane perforations (TMPs), and compare the outcomes with those of endoscopic type 1 tympanoplasty (ETT) with meatal flap elevation. STUDY DESIGN: A prospective, controlled study. METHODS: In the present study, inpatients with TMPs were divided into two groups according to the manner of tympanic membrane repair: one group received ETPM without raising the meatal flap, and the other received ETT. The operation duration, postoperative healing rate, visual analogue scale (VAS) of pain, and complication rates were compared between these two groups. RESULTS: Regardless of the size and location of the perforation, and its relationship with the malleus manubrium, myringoplasty can be completed using the ETPM method. The operation duration for different types of TMPs was shorter in the ETPM group than in the ETT group, and the difference was statistically significant (p<0.05). However, there was no statistical difference in the short-term healing rate (p>0.05) and pain VAS score (p>0.05) between these two groups. Furthermore, no intraoperative or postoperative complications occurred in both groups. CONCLUSION: ETPM without raising the meatal flap can be applied for all types of TMPs, regardless of how large the perforation is, or where it is located. This can shorten the operation duration, and has a high healing rate comparable to ETT and mild postoperative pain. Mastering some essential surgical skills under the endoscope would be helpful to ensure the success of the surgery.

Isradipine plasma pharmacokinetics and exposure-response in early Parkinson's disease.

OBJECTIVES: Isradipine is a dihydropyridine calcium channel inhibitor that has demonstrated concentration-dependent neuroprotective effects in animal models of Parkinson's disease (PD) but failed to show efficacy in a phase 3 clinical trial. The objectives of this study were to model the plasma pharmacokinetics of isradipine in study participants from the phase 3 trial; and, to investigate associations between drug exposure and longitudinal clinical outcome measures of PD progression. METHODS: Plasma samples from nearly all study participants randomized to immediate-release isradipine 5-mg twice daily (166 of 170) were collected for population pharmacokinetic modeling. Estimates of isradipine exposure included apparent oral clearance and area under the concentration-time curve. Isradipine exposure parameters were tested for correlations with 36-month changes in disease severity clinical assessment scores, and time-to-event analyses for initiation of antiparkinson therapy. RESULTS: Isradipine exposures did not correlate with the primary clinical outcome, changes in the antiparkinson therapy-adjusted Unified Parkinson's Disease Rating Scale parts I-III score over 36 months (Spearman rank correlation coefficient, rs : 0.09, P = 0.23). Cumulative levodopa equivalent dose at month 36 was weakly correlated with isradipine plasma clearance (rs : 0.18, P = 0.035). This correlation was sex dependent and significant in males, but not females. Those with higher isradipine exposure had decreased risk of needing antiparkinson treatment over 36 months compared with placebo (hazard ratio: 0.87, 95% CI: 0.78-0.98, P = 0.02). INTERPRETATION: In this clinical trial, higher isradipine plasma exposure did not affect clinical assessment measures of PD severity but modestly decreased cumulative levodopa equivalent dose and the time needed for antiparkinson treatment initiation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02168842.

Impacts of different methylprednisolone administration routes in patients with sudden hearing loss or Meniere's disease.

BACKGROUND: Evidence suggests that glucocorticoids are important in the treatment of sudden hearing loss (SHL) and Meniere's disease (MD). However, different glucocorticoid administration methods may have a significant impact on treatment outcomes. OBJECTIVE: This study aimed to investigate effects of different glucocorticoid administration methods on sudden hearing loss and Meniere's disease. METHODS: In this study, glucocorticoids were administered orally in 18 patients, by retroauricular injection in 15 patients and by intratympanic injection in 15 patients. White blood cell (WBC) count, serum K+, fasting plasma glucose (FPG), body temperature, heart rate and blood pressure were used to evaluate effects of glucocorticoids on patients with hearing loss. Visual analog scale (VAS) of pain and sleep disorders were also surveyed, and pure tone audiometry (PTA) results were compared among groups to evaluate efficacy of different glucocorticoids administration methods. RESULT: WBC count, heart rate and blood pressure were higher in patients taking oral glucocorticoids, while body temperature, serum K+ and FPG levels did not change in all three groups. However, patients who received intratympanic injection of glucocorticoids experienced more pain, while those taking oral glucocorticoids reported more sleep impairment. Treatment efficacy on hearing loss was not significantly different among the three groups. CONCLUSION: These findings suggest that systemic glucocorticoid administration can result in greater whole body responses than local administration, but with similar hearing treatment efficacy.

Chinese Society of Allergy and Chinese Society of Otorhinolaryngology-Head and Neck Surgery Guideline for Chronic Rhinosinusitis.

The current document is based on a consensus reached by a panel of experts from the Chinese Society of Allergy and the Chinese Society of Otorhinolaryngology-Head and Neck Surgery, Rhinology Group. Chronic rhinosinusitis (CRS) affects approximately 8% of Chinese adults. The inflammatory and remodeling mechanisms of CRS in the Chinese population differ from those observed in the populations of European descent. Recently, precision medicine has been used to treat inflammation by targeting key biomarkers that are involved in the process. However, there are no CRS guidelines or a consensus available from China that can be shared with the international academia. The guidelines presented in this paper cover the epidemiology, economic burden, genetics and epigenetics, mechanisms, phenotypes and endotypes, diagnosis and differential diagnosis, management, and the current status of CRS in China. These guidelines-with a focus on China-will improve the abilities of clinical and medical staff during the treatment of CRS. Additionally, they will help international agencies in improving the verification of CRS endotypes, mapping of eosinophilic shifts, the identification of suitable biomarkers for endotyping, and predicting responses to therapies. In conclusion, these guidelines will help select therapies, such as pharmacotherapy, surgical approaches and innovative biotherapeutics, which are tailored to each of the individual CRS endotypes.

γδT cells contribute to type 2 inflammatory profiles in eosinophilic chronic rhinosinusitis with nasal polyps.

Eosinophilic chronic rhinosinusitis with nasal polyps (ECRS) is a condition linked with type 2 inflammation, poor treatment outcomes, and high recurrence tendency. Although γδT cells have been reported to induce type 2 immune responses and eosinophilic infiltration in several diseases, their role in ECRS has not been fully explored. We aimed to evaluate the association of γδT cells with the type 2 inflammatory profiles in ECRS. Nasal tissue samples obtained from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) (51 eosinophilic and 48 non-eosinophilic), 50 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 58 control subjects were examined for γδT cells, inflammatory markers and eosinophils using HE, RT-qPCR, ELISA, immunofluorescence, and flow cytometry. In parallel, studies were also conducted in an ECRS murine model induced by anti-γδT cells neutralizing antibody administration. γδT cells expression was significantly increased in tissues from patients with ECRS compared with non-ECRS, CRSsNP and control subjects. Moreover, inflammatory markers including type 2 proinflammatory cytokines (IL-4, IL-5, IL-13), GATA3, eosinophil cationic protein (ECP), and eotaxin levels were also increased in nasal tissues of patients with ECRS, and Vγ1+ γδT cells mRNA expression was positively correlated with type 2 cytokines, GATA3, and ECP. In the ECRS murine model, anti-Vγ1+ γδT antibody treatment reduced the infiltration of eosinophils and expression of type 2 cytokines, GATA3, and ECP in nasal mucosae. In conclusion, the results of the present study suggest that γδT cells play a crucial role in the type 2 inflammatory profiles and nasal tissue eosinophilic infiltration in patients with ECRS.

IL-19 Up-Regulates Mucin 5AC Production in Patients With Chronic Rhinosinusitis via STAT3 Pathway.

The mucin gene, MUC5AC, is highly expressed both in chronic respiratory inflammatory diseases and inflammatory bowel disease where mucin secretion is regulated by members of the interleukin IL-20 subfamily. This study was conducted to determine the roles and mechanisms of IL-19, a member of the IL-20 subfamily, in regulating MUC5AC production in chronic rhinosinusitis (CRS). We analyzed the expression of mucin and MUC5AC in the nasal mucosa of patients with CRS through periodic acid Schiff (PAS) staining and immunohistochemical examination. Real-time quantitative PCR, ELISA, confocal microscopy and western blotting were used to measure MUC5AC expression in primary human nasal epithelium cells (PHNECs) stimulated with recombinant human IL-19 (rhIL-19), IL-19 receptor siRNA transfection or a control. The involvement of the STAT3 signaling pathway was examined using cryptotanshinone (CRY, an inhibitor of STAT3). Mucin and MUC5AC were significantly increased in mucosa of CRS patients with/without nasal polyps compared to mucosa isolated from controls who had no CRS, but there were no significant differences between these two groups. Pretreatment with rhIL-19 up-regulated the expression of MUC5AC levels in PHNECs. Knockdown of IL-20R2 and pretreatment with CRY attenuated MUC5AC production induced by rhIL-19. We propose that IL-19 up-regulates MUC5AC-induced mucin production via the STAT3 pathway in CRS, highlighting the important role IL-19 may play in mucin production in chronic respiratory diseases.

Tc17/IL-17A Up-Regulated the Expression of MMP-9 via NF-κB Pathway in Nasal Epithelial Cells of Patients With Chronic Rhinosinusitis.

Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease of the upper airways involving nasal cavity and sinus. Deriving both from its clinical complexity with protean clinical manifestations as well its pathogenetic heterogeneity, the molecular mechanisms contributing to the pathogenesis of CRS remain unclear, and attract a wide interest in the field. Current evidences indicate that IL-17A is highly expressed in chronic rhinosinusitis with nasal polyps (CRSwNP). However, its pathogenetic role in regulation of tissue remodeling of CRSwNP remains unknown. The present study aimed to investigate the cellular origins and functions of IL-17A cytokine in CRSwNP, and further determined whether IL-17A could affect the expression of metalloproteinases (MMPs), the remodeling factors of CRSwNP. The results showed that the expression of IL-17A was upregulated in nasal tissues of patients with CRSwNP compared to those with chronic rhinosinusitis without nasal polyps (CRSsNP) and controls. CD8+ cytotoxic T lymphocytes (Tc) were major IL-17A producers in nasal tissues of CRSwNP. Interleukin (IL)-17-producing CD8+ T cells (Tc17) was significantly higher in nasal tissues of CRSwNP than CRSsNP and controls. Nonetheless, no difference was observed among the IL-17A in peripheral blood lymphocytes of these three groups. Moreover, in the same patients, IL-17A expression was negligible in lymphocytes of peripheral blood when compared with nasal tissues. Increased gene and protein expression of MMP-7 and MMP-9 in patients with CRSwNP compared with controls were observed. In CRSwNP samples, IL-17A receptor (IL-17AR) co-localized with MMP-9 and they were mainly expressed in the epithelial cells. MMP-9 expression was up-regulated both in Primary human nasal epithelial cells (PHNECs) and a nasal epithelial cell line (RPMI 2650) by IL-17A treatment, and diminished by anti-IL-17AR treatment. Furthermore, IL-17A promoted the expression of MMP-9 by activating the NF-κB signal pathway. Thus, our results have revealed a crucial role of IL-17A and Tc cells on pathogenesis and tissue remodeling of CRSwNP.

A Retrospective Analysis of γδ T Cell Expression in Chronic Rhinosinusitis and Its Association with Recurrence of Nasal Polyps.

BACKGROUND/AIMS: To examine whether γδ T cell is expressed in the nasal mucosa of chronic rhinosinusitis (CRS) patients and its potential association with recurrence of nasal polyps. METHODS: Thirty-six patients with CRS with nasal polyps (CRSwNP) and 25 patients with CRS without nasal polyps (CRSsNP) were recruited. Twenty-six patients with other nasal diseases served as controls. The CRSwNP group was divided into the eosinophilic CRSwNP and noneosinophilic CRSwNP groups. The expression of γδ T cells was detected by immunohistochemistry. The expression of each subtype of γδ T cells was detected by using qRT-PCR. All patients underwent nasal endoscopy, and postoperative follow-up lasted over 12 months. CRS patients were evaluated by preoperative VAS scores of symptoms and nasal endoscopy Lund-Kennedy scores. RESULTS: The expression of γδ T cells in the CRSwNP groups was stronger than in the CRSsNP and the control group (p < 0.05, p < 0.05). The expression of Vγ1+γδ T cells in the eosinophilic CRSwNP group was higher than that in the CRSsNP group and the control group (p < 0.05, p < 0.05). The expression of γδ T cells was associated with high rate of recurrence, tissue eosinophil infiltration, worse symptom score of nasal obstruction, and higher Lund-Kennedy score (all p < 0.05). CONCLUSIONS: Increased expression of γδ T cells in CRSwNP may be associated with recurrence of nasal polyps.