Force-induced conformational changes in PIEZO1.

PIEZO1 is a mechanosensitive channel that converts applied force into electrical signals. Partial molecular structures show that PIEZO1 is a bowl-shaped trimer with extended arms. Here we use cryo-electron microscopy to show that PIEZO1 adopts different degrees of curvature in lipid vesicles of different sizes. We also use high-speed atomic force microscopy to analyse the deformability of PIEZO1 under force in membranes on a mica surface, and show that PIEZO1 can be flattened reversibly into the membrane plane. By approximating the absolute force applied, we estimate a range of values for the mechanical spring constant of PIEZO1. Both methods of microscopy demonstrate that PIEZO1 can deform its shape towards a planar structure. This deformation could explain how lateral membrane tension can be converted into a conformation-dependent change in free energy to gate the PIEZO1 channel in response to mechanical perturbations.

An expedited model for identifying potential patients with periodic leg movements.

Periodic leg movements during sleep (PLMS) may have crucial consequences in adults. This study aimed to identify baseline characteristics, symptoms, or questionnaires that could help to identify sleep-disordered breathing patients with significant PLMS. Patients aged 20-80 years who underwent polysomnography for assessing sleep disturbance were included. Various factors such as sex, age, body measurements, symptoms, apnea-hypopnea index (AHI), and sleep quality scales were analysed to determine the presence of PLMS. The study included 1480 patients with a mean age of 46.4 ± 13.4 years, among whom 110 (7.4%) had significant PLMS with a PLM index of 15 or higher. There were no significant differences observed in terms of sex or BMI between patients with and without significant PLMS. However, the odds ratios (OR) for PLMS were 4.33, 4.41, and 4.23 in patients who were aged over 50 years, had insomnia, or had an ESS score of less than 10, respectively. Notably, the OR increased up to 67.89 times in patients who presented with all three risk factors. Our analysis identified significant risk factors for PLMS: age over 50, self-reported insomnia, and lower daytime sleepiness levels. These findings aid in identifying potential PLMS patients, facilitating confirmatory examinations and managing associated comorbidities.

Completion and Adverse Drug Events of Latent Tuberculosis Infection Treatment in Patients Receiving Dialysis: Predictors and Impacts of Different Regimens in a Prospective Cohort Study.

Although patients with end-stage renal disease receiving maintenance hemodialysis are at high risk for tuberculosis, the optimal treatment regimen for latent tuberculosis infection (LTBI) in this group has scarcely been studied for predictors of completion rate and adverse drug events (ADE). We prospectively enrolled dialysis patients for LTBI intervention from three medical centers in Taiwan. LTBI treatments were 3 months of weekly rifapentine plus isoniazid (3HP) and 9 months of daily isoniazid (9H). Completion rate, ADE, and reasons for treatment termination were recorded. Factors associated with treatment termination and ADE were analyzed using multivariate logistic regression. In all, 91 treatment courses (41 9H and 50 3HP) were surveyed. The completion rates were 61% for 9H and 82% for 3HP (P = 0.046). Use of 9H and development of ADE with a grade of ≥2 (≥grade 2 ADE) were associated with treatment termination. Hypersensitivity occurred in 29.2% of subjects in the 3HP group and 10.8% in the 9H group (P = 0.035) and independently correlated with 3HP regimen, diabetes mellitus (DM), and peritoneal dialysis (PD). Similarly, the independent predictors of ≥grade 2 ADE were use of 3HP regimen, presence of DM, and use of PD, whereas ≥grade 3 ADE were associated with eosinophil counts of >700/mm3 after 2 weeks of LTBI treatment even after adjustment for age and gender. In conclusion, for patients on dialysis, 3HP showed a higher rate of completion but also a higher rate of ≥grade 2 ADE than 9H. In addition, DM and PD were risk factors for ≥grade 2 ADE. Eosinophilia after 2-week treatment might be an alert for severe ADE.

Treatment and revaccination of children with paraneoplastic opsoclonus-myoclonus-ataxia syndrome and neuroblastoma: The Memorial Sloan Kettering experience.

OBJECTIVE: To review the treatment and revaccination of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome (OMAS) patients at Memorial Sloan Kettering Cancer Center (MSK). PROCEDURE: Institutional Review Board approval was obtained for this retrospective study of patients with neuroblastoma-associated OMAS followed at MSK from 2000 to 2016. RESULTS: Fourteen patients (nine female) were 9-21 (median 17) months old at diagnosis of neuroblastoma and OMAS syndrome. They had stage 1 (n = 12), stage 2B, or intermediate-risk stage 4. Tumor histology was favorable in 11 patients, unfavorable in two, and unknown in one patient. No patient had amplified MYCN. All patients underwent tumor resection at diagnosis. Anti-neuroblastoma treatment was limited to chemotherapy in one patient. Overall survival is 100% at 3-16 (median 10) years. For OMAS, 13 patients received intravenous immune globulin (IVIg), adrenocorticotropic hormone (ACTH), and rituximab, and one received ACTH and IVIg. Seven patients experienced OMAS relapse. For these relapses, five patients received low-dose cyclophosphamide and two received rituximab. The mean total OMAS treatment was 20-96 (median 48) months. Seven patients started rituximab ≤3 months from diagnosis and did not relapse. The other six experienced OMAS relapse. To date, six patients have been revaccinated at a minimum of 2 years after completion of OMAS therapy without OMAS recurrence. CONCLUSIONS: Patients with neuroblastoma-associated OMAS had excellent overall survival. Early initiation of rituximab, IVIg, and ACTH may reduce risks of OMAS relapse. Revaccination can be resumed without exacerbation of OMAS. Further investigation with a larger cohort of patients is needed.

Emergency department utilization and resuscitation rate among patients receiving maintenance hemodialysis.

BACKGROUND: End-stage renal disease (ESRD) is a growing global health concern with increased disease burden and high medical costs. Utilization of the emergency department (ED) among dialyzed patients and the associated risk factors remain unknown. METHODS: Participants of this study, selected from the National Health Insurance Database in Taiwan, were aged 19-90 years and received maintenance hemodialysis from January 1, 2010, to December 31, 2010. A control group consisting of individuals who did not receive dialysis, selected from the same data source, were matched for age, sex, and the Charlson Comorbidity Index (CCI). Subgroup analysis with hemodialysis frequency was also performed. ED utilization among enrolled individuals was assessed in 2012. Generalized estimating equations with multiple variable adjustments were used to identify risk factors associated with resuscitation during ED visits. RESULTS: One group of 2985 individuals who received maintenance hemodialysis, and another group of 2985 patients that did not receive hemodialysis, between January 1, 2010, and December 31, 2010, were included in this study. There were 4822 ED visits in the hemodialysis group, and 1755 ED visits in the non-dialysis group between January 1, 2012, and December 31, 2012. Analysis of multivariable generalized estimating equations identified the risk associated with resuscitation during ED visits to be greater in individuals who were receiving maintenance hemodialysis, aged older than 55 years, hospitalized in the past year, and assigned first and second degree of triage. CONCLUSION: Patients receiving maintenance hemodialysis had higher ED utilization and a significantly higher risk of resuscitation during ED visits than those without hemodialysis.

Using a FRET Library with Multiple Probe Pairs To Drive Monte Carlo Simulations of α-Synuclein.

We describe a strategy for experimentally-constraining computational simulations of intrinsically disordered proteins (IDPs), using α-synuclein, an IDP with a central role in Parkinson's disease pathology, as an example. Previously, data from single-molecule Förster Resonance Energy Transfer (FRET) experiments have been effectively utilized to generate experimentally constrained computational models of IDPs. However, the fluorophores required for single-molecule FRET experiments are not amenable to the study of short-range (<30 Å) interactions. Using ensemble FRET measurements allows one to acquire data from probes with multiple distance ranges, which can be used to constrain Monte Carlo simulations in PyRosetta. To appropriately employ ensemble FRET data as constraints, we optimized the shape and weight of constraining potentials to afford ensembles of structures that are consistent with experimental data. We also used this approach to examine the structure of α-synuclein in the presence of the compacting osmolyte trimethylamine-N-oxide. Despite significant compaction imparted by 2 M trimethylamine-N-oxide, the underlying ensemble of α-synuclein remains largely disordered and capable of aggregation, also in agreement with experimental data. These proof-of-concept experiments demonstrate that our modeling protocol enables one to efficiently generate experimentally constrained models of IDPs that incorporate atomic-scale detail, allowing one to study an IDP under a variety of conditions.

Kinetics of Surface-Mediated Fibrillization of Amyloid-ß (12-28) Peptides.

Surfaces or interfaces are considered to be key factors in facilitating the formation of amyloid fibrils under physiological conditions. In this report, we study the kinetics of the surface-mediated fibrillization (SMF) of an amyloid-ß fragment (Aß12-28) on mica. We employ a spin-coating-based drying procedure to control the exposure time of the substrate to a low-concentration peptide solution and then monitor the fibril growth as a function of time via atomic force microscopy (AFM). The evolution of surface-mediated fibril growth is quantitatively characterized in terms of the length histogram of imaged fibrils and their surface concentration. A two-dimensional (2D) kinetic model is proposed to numerically simulate the length evolution of surface-mediated fibrils by assuming a diffusion-limited aggregation (DLA) process along with size-dependent rate constants. We find that both monomer and fibril diffusion on the surface are required to obtain length histograms as a function of time that resemble those observed in experiments. The best-fit simulated data can accurately describe the key features of experimental length histograms and suggests that the mobility of loosely bound amyloid species is crucial in regulating the kinetics of SMF. We determine that the mobility exponent for the size dependence of the DLA rate constants is α = 0.55 ± 0.05, which suggests that the diffusion of loosely bound surface fibrils roughly depends on the inverse of the square root of their size. These studies elucidate the influence of deposition rate and surface diffusion on the formation of amyloid fibrils through SMF. The method used here can be broadly adopted to study the diffusion and aggregation of peptides or proteins on various surfaces to investigate the role of chemical interactions in two-dimensional fibril formation and diffusion.

Update of pathophysiology and management of diabetic kidney disease.

Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in patients with diabetes mellitus and the leading cause of end-stage renal disease in the world. The most characteristic marker of DKD is albuminuria, which is associated with renal disease progression and cardiovascular events. Renal hemodynamics changes, oxidative stress, inflammation, hypoxia and overactive renin-angiotensin-aldosterone system (RAAS) are involved in the pathogenesis of DKD, and renal fibrosis plays the key role. Intensified multifactorial interventions, including RAAS blockades, blood pressure and glucose control, and quitting smoking, help to prevent DKD development and progression. In recent years, novel agents are applied for preventing DKD development and progression, including new types of glucose-lowering agents, pentoxifylline, vitamin D analog paricalcitol, pyridoxamine, ruboxistaurin, soludexide, Janus kinase inhibitors and nonsteroidal minerocorticoid receptor antagonists. In this review, recent large studies about DKD are also summarized.

The effect of chemical structure on the stability of physical vapor deposited glasses of 1,3,5-triarylbenzene.

We detail the formation and properties associated with stable glasses (SG) formed by a series of structural analogues of 1,3-bis(1-naphthyl)-5-(2-naphthyl)benzene (α,α,ß-TNB), a well-studied SG former. Five compounds with similar structural properties were synthesized and physical vapor-deposited with a constant deposition rate at various substrate temperatures (Tdep) in the range between 0.73 Tg and 0.96 Tg. These molecules include α,α,ß-TNB, 3,5-di(naphthalen-1-yl)-1-phenylbenzene (α,α-P), 9-(3,5-di(naphthalen-1-yl)phenyl)anthracene (α,α-A), 9,9'-(5-(naphthalen-2-yl)-1,3-phenylene)dianthracene (ß-AA), and 3,3',5,5'-tetra(naphthalen-1-yl)-1,1'-biphenyl (α,α,α,α-TNBP). Ellipsometry was used to study the transformations from the as-deposited glasses into ordinary glasses (OG). The stability of each film was evaluated by measuring the fictive temperature (Tf) and density difference between the as-deposited glass and OG. It is demonstrated that all five molecules can form SGs upon vapor deposition in this temperature range. In-depth studies on the dependence of the stability of as-deposited glasses upon Tdep were performed with three molecules, α,α,ß-TNB, α,α-P, and α,α-A. The general trends of stability were comparable at the same Tdep/Tg for these three compounds. Similar to previous studies on α,α,ß-TNB, vapor-deposited glasses of α,α-P and α,α-A formed the most stable structures around Tdep = 0.8-0.85 Tg. The most stable glass of each molecule showed the lowest thermal expansion coefficient compared to OG and a positive optical birefringence. However, the SGs of α,α-A were less stable compared to α,α-P and α,α,ß-TNB at the relative Tdep/Tg. Based on Arrhenius extrapolation of the aging time, as a measure of stability, the most stable α,α-A glass was only aged for a few years as opposed to hundreds or thousands of years for other glasses. We hypothesize that the reduced stability is due to slower mobility at the free surface of α,α-A glass compared to the other two molecules.

Correction: REM-related obstructive sleep apnea and vertigo: A retrospective case-control study.

[This corrects the article DOI: 10.1371/journal.pone.0252844.].

Dehydrated Biomimetic Membranes with Skinlike Structure and Function.

Novel vapor-permeable materials are sought after for applications in protective wear, energy generation, and water treatment. Current impermeable protective materials effectively block harmful agents but trap heat due to poor water vapor transfer. Here we present a new class of materials, vapor permeable dehydrated nanoporous biomimetic membranes (DBMs), based on channel proteins. This application for biomimetic membranes is unexpected as channel proteins and biomimetic membranes were assumed to be unstable under dry conditions. DBMs mimic human skin's structure to offer both high vapor transport and small molecule exclusion under dry conditions. DBMs feature highly organized pores resembling sweat pores in human skin, but at super high densities (>1012 pores/cm2). These DBMs achieved exceptional water vapor transport rates, surpassing commercial breathable fabrics by up to 6.2 times, despite containing >2 orders of magnitude smaller pores (1 nm vs >700 nm). These DBMs effectively excluded model biological agents and harmful chemicals both in liquid and vapor phases, again in contrast with the commercial breathable fabrics. Remarkably, while hydrated biomimetic membranes were highly permeable to liquid water, they exhibited higher water resistances after dehydration at values >38 times that of commercial breathable fabrics. Molecular dynamics simulations support our hypothesis that dehydration induced protein hydrophobicity increases which enhanced DBM performance. DBMs hold promise for various applications, including membrane distillation, dehumidification, and protective barriers for atmospheric water harvesting materials.

Prognostic Factors for the Outcome of Salivary Gland Holmium: YAG Laser Intraductal Lithotripsy.

OBJECTIVES: Holmium: YAG laser has gained its popularity throughout the years and is used to treat sialolithiasis, which helps to overcome the limitations of traditional sialendoscopic lithotripsy for larger-sized salivary stones. However, little information is available regarding factors predicting the success rate of Holmium: YAG laser intraductal lithotripsy. The purpose of this study is to investigate the factors affecting the success rates of Holmium: YAG laser lithotripsy for salivary stones treatment in a tertiary care hospital. METHODS: A retrospective study conducted in patients receiving sialolithiasis surgery under sialendoscopy from May 2013 to March 2015 at Mackay Memorial Hospital, Taiwan. Data on various factors, including patients' age, gender, glands, size of largest stone, multiple stones (≥2 stones), location of the stone (distal duct, middle duct, proximal duct, and hilum), and operative time. The success of the surgery defined as patients without any complaints such as swelling or tenderness. Logistic regression and Fisher exact tests were employed to examine these factors on the success rate. RESULTS: Fifty-four patients who received sialendoscopy surgery with a mean age of 35.74 years old recruited. Logistic regression identified the operation time exceeding 210 minutes showed 23.497 folds higher odd ratio of having a result of operation failure (P < .05). CONCLUSION: The prolonged operation time is the sole independent factor affecting the successful outcome for salivary gland intraductal laser lithotripsy. We recommend operative time be no more than 210 minutes to increase the success rate in salivary gland Holmium: YAG laser intraductal lithotripsy.

Factors Related to Ventilation Tube Extrusion Time in Children and Adults.

BACKGROUND AND OBJECTIVE: The aim of this study was to investigate the factors affecting extrusion time in both children and adults with ventilation tube (VT) insertion, providing useful information for clinicians for better decision-making, follow strategy, and potentially improve clinical outcomes for these patients. METHODS: Data from patients receiving myringotomy with VT insertion from January 1, 2007, to June 30, 2012, were retrospectively collected and analyzed by the end of 2018. Various factors, including age, gender, history of VT insertion, tympanogram, size of VT used, local finding of tympanic membrane, hypertension, diabetes mellitus, hyperlipidemia, and postoperative ear infection, were included and analyzed to examine the effects of these factors on extrusion time. RESULTS: A total of 447 patients were included in this study (Child group-Adult group = 237:210). The overall average extrusion time was 225.85 days. In the subgroup analysis, the average time was 221.3 days and 231.0 days for children and adults, respectively. The results showed that the VT extrusion time was significantly longer in participants without a history of VT insertion and in those where larger sized VTs were inserted in both age-groups. Male gender had an influence on extrusion time in children. In addition, a history of VT insertion and VT size were determined to be factors related to extrusion before 12 months in children. CONCLUSION: History of VT insertion and VT size were significantly related to VT extrusion time in both children and adults and defined as factors associated with extrusion before 12 months in children. The findings suggest avoiding VT with a diameter < 1 mm and considering an appropriately larger size in patients with a history of VT insertion to optimize VT retention.

Age-Dependent Effects of Acute Kidney Injury on End-Stage Kidney Disease and Mortality in Patients with Moderate to Severe Chronic Kidney Disease.

INTRODUCTION: Old age has been considered as a positive modifier of chronic kidney disease (CKD), but the progression of CKD is often accelerated by acute kidney injury (AKI) in older adults. This study aimed to investigate this paradoxical interplay and identify age-specific predictors of end-stage kidney disease (ESKD). METHODS: This retrospective cohort included 6,101 patients with CKD stage 3B-5 followed at a single center during 2005-2018. Participants were stratified into four age groups to explore age-dependent influences on the risk of ESKD and all-cause mortality. Multivariate Cox proportional hazard regression model with competing risk analysis was used to identify predictors of outcomes. RESULTS: During a median follow-up of 2.68 years, 1,650 (27.0%) patients developed ESKD and 541 (8.9%) patients died. The rate of ESKD decreased with advancing age, being lowest in the very old-aged (>75 years) group who displayed the slowest rate of estimated glomerular filtration rate (eGFR) decline. Multivariate Cox proportional hazard regression adjusted for competing death showed that younger ages, compared with patients aged >75 years, together with AKI episodes and several traditional risk factors were identified as predictors for ESKD. The impact of AKI episodes on ESKD development was most prominent in patients aged >75 years. These results were confirmed with subgroup analyses in patients with outcomes of different ages. CONCLUSION: Older adults with CKD exhibited a slower decline rate of eGFR, yet they were more likely to develop ESKD following AKI episodes. These results suggest tackling AKI is needed to prevent accelerated initiation of renal replacement therapy in elderly patients with pre-existing CKD.

The firstly visited department affects the acceptance of CPAP in patients with obstructive sleep apnea: a cohort study.

BACKGROUND: Continuous positive airway pressure (CPAP) therapy is the first-line treatment for obstructive sleep apnea (OSA). However, the low acceptance rate of CPAP remains a challenging clinical issue. This study aimed to determine the factors that influence the acceptance rate of CPAP. METHODS: This retrospective cohort study was conducted at the sleep center of Shuang-Ho Hospital. Initially, 1186 OSA patients who received CPAP therapy between December 2013 and December 2017 were selected, and finally, 1016 patients were analyzed. All patients with OSA received CPAP therapy for at least 1 week, and their acceptance to treatment was subsequently recorded. Outcome measures included patients' demographic and clinical characteristics (sex, age, BMI, comorbidities, history of smoking, and the medical specialist who prescribed CPAP treatment), polysomnography (PSG) results, and OSA surgical records. RESULTS: Patients with a lower CPAP acceptance rate were referred from otolaryngologists (acceptance rate of otolaryngology vs. others: 49.6% vs. 56.6%, p = .015), in addition to having a lower apnea-hypopnea index (AHI) (acceptance vs. non-acceptance: 55.83 vs. 40.79, p = .003), rapid eye movement AHI (REM-AHI) (acceptance vs. non-acceptance: 51.21 vs. 44.92, p = .014), and arousal index (acceptance vs. non-acceptance: 36.80 vs. 28.75, p = .011). The multiple logistic regression model showed that patients referred from otolaryngology had a lower CPAP acceptance rate (odds ratio 0.707, p = .0216) even after adjusting for age, sex, BMI, AHI, REM-AHI, arousal index, comorbidities, and smoking status. CONCLUSIONS: Before their initial consultation, patients may already have their preferred treatment of choice, which is strongly linked to the type of medical specialists they visit, and consequently, affects their rate of acceptance to CPAP therapy. Therefore, physicians should provide personalized care to patients by exploring and abiding by their preferred treatment choices.

Screening the risk of obstructive sleep apnea by utilizing supervised learning techniques based on anthropometric features and snoring events.

Objectives: Obstructive sleep apnea (OSA) is typically diagnosed by polysomnography (PSG). However, PSG is time-consuming and has some clinical limitations. This study thus aimed to establish machine learning models to screen for the risk of having moderate-to-severe and severe OSA based on easily acquired features. Methods: We collected PSG data on 3529 patients from Taiwan and further derived the number of snoring events. Their baseline characteristics and anthropometric measures were obtained, and correlations among the collected variables were investigated. Next, six common supervised machine learning techniques were utilized, including random forest (RF), extreme gradient boosting (XGBoost), k-nearest neighbor (kNN), support vector machine (SVM), logistic regression (LR), and naïve Bayes (NB). First, data were independently separated into a training and validation dataset (80%) and a test dataset (20%). The approach with the highest accuracy in the training and validation phase was employed to classify the test dataset. Next, feature importance was investigated by calculating the Shapley value of every factor, which represented the impact on OSA risk screening. Results: The RF produced the highest accuracy (of >70%) in the training and validation phase in screening for both OSA severities. Hence, we employed the RF to classify the test dataset, and results showed a 79.32% accuracy for moderate-to-severe OSA and 74.37% accuracy for severe OSA. Snoring events and the visceral fat level were the most and second most essential features of screening for OSA risk. Conclusions: The established model can be considered for screening for the risk of having moderate-to-severe or severe OSA.

Effect of Lipid-Lowering Drugs on Renal and Cardiovascular Outcomes in Patients with Chronic Kidney Disease and Dyslipidemia: A Retrospective Cohort Study.

The effects of lipid-lowering drugs (LLDs) on cardiovascular and renal outcomes in patients with advanced chronic kidney disease (CKD) and dyslipidemia are not completely understood. We conducted a retrospective cohort study to evaluate the effect of LLDs on end-stage kidney disease (ESKD), major adverse cardiovascular events (MACEs), and mortality in adult patients with CKD stage 3b, 4, or 5, and dyslipidemia. Participants were recruited between January 1, 2008, and December 31, 2018, and classified as LLD or non-LLD users; the final follow-up date was December 31, 2020. The primary outcome was time to ESKD or death due to renal failure. Sub-distribution hazard regression models adjusted for multivariables, including time-varying lipid profile covariates, were used for the analysis. Among the 6,740 participants, 4,280 patients with CKD and dyslipidemia, including 872 using LLDs and 3,408 not using LLDs, completed the primary analysis. The multivariable analyses showed that LLD users had a significantly lower risk of time to the composite renal outcome (adjusted hazard ratio [aHR], 0.76, 95% confidence interval [CI], 0.65-0.89), and MACE incidence (aHR, 0.75, 95% CI, 0.62-0.93) than did non-LLD users. After adjusting for time-varying covariates of the lipid profile, there was a significant difference in the composite renal outcome (aHR, 0.78, 95% CI, 0.65-0.93) and MACEs (aHR, 0.77, 95% CI, 0.60-0.98). Among adult patients with advanced CKD and dyslipidemia, LLD users had a significantly lower risk of composite renal outcomes and MACEs than non-LLD users. In addition to reducing lipid profile, the use of LLD is associated with renal and cardiovascular protective effects.

Anti-tumor effects of deubiquitinating enzyme inhibitor PR-619 in human chondrosarcoma through reduced cell proliferation and endoplasmic reticulum stress-related apoptosis.

Chondrosarcoma, a treatment-resistant cancer with limited therapeutic options, lacks significant advancements in treatment methods. However, PR-619, a novel inhibitor of deubiquitinating enzymes, has demonstrated anti-tumor effects in various malignancies. This study aimed to investigate the impact of PR-619 on chondrosarcoma both in vitro and in vivo. Two human chondrosarcoma cell lines, SW11353 and JJ012, were utilized. Cell viability was assessed using an MTT assay, while flow cytometry enabled the detection of apoptosis and cell cycle progression. Western blotting analyses were conducted to evaluate apoptosis, cell stress, and endoplasmic reticulum (ER) stress. Furthermore, the in vivo anti-tumor effects of PR-619 were examined using a xenograft mouse model. The results revealed that PR-619 induced cytotoxicity, apoptosis, and cell cycle arrest at the G0/G1 stage by activating caspases, PARP cleavage, and p21. Moreover, PR-619 increased the accumulation of polyubiquitinated proteins and ER stress by activating IRE1, GRP78, caspase-4, CHOP, and other cellular stress responses, including JNK activation. In vivo analysis demonstrated that PR-619 effectively inhibited tumor growth with minimal toxicity in the xenograft mouse model. These findings provide evidence of the anti-tumor effects and induction of cellular and ER stress by PR-619 in human chondrosarcoma, suggesting its potential as a novel therapeutic strategy for in human chondrosarcoma.

Prevention of Incident Hypertension in Patients With Obstructive Sleep Apnea Treated With Uvulopalatopharyngoplasty or Continuous Positive Airway Pressure: A Cohort Study.

Purpose: To determine whether treatment with uvulopalatopharyngoplasty (UPPP) or continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) prevents hypertension, compared to those not receiving any treatment. Methods: A retrospective cohort study was conducted among 413 patients with OSA (age ≥ 35 years) at the Shuang Ho Hospital between 2009 and 2016. The patients were divided into three groups: UPPP, CPAP, and non-treatment groups. Data about the personal characteristics, history of comorbidities, and polysomnography (PSG) reports were collected at baseline. A Cox model with inverse probability of treatment weighting was used to adjust for confounders and baseline diversity. Results: After multivariate adjustment and weighting for incident hypertension, patients in both the CPAP and UPPP groups showed a significant preventive effect on hypertension than in the non-treatment group. Moreover, patients in the CPAP group had lower event rates than those in the UPPP group. Conclusion: UPPP can prevent the development of new-onset hypertension in patients with OSA. CPAP had a better preventive effect than UPPP. UPPP might be a good alternative for reducing the risk of the onset of hypertension when compliance to CPAP is poor.

The Additive Effectiveness of Inspiratory Muscle Training on Glottic Closure and Subjective Voice Outcomes of Patients With Benign Lesion After Hyaluronic Acid Laryngoplasty.

OBJECTIVES: For patients with glottic insufficiency disease, injection laryngoplasty is a rapid and efficient management option that complements voice therapy. Some studies have indicated that respiratory muscle training may also show promise in patients with voice disorders. However, the effect of respiratory muscle training in patients with glottic insufficiency was reported to be limited, and whether it provides additional benefit after standard management requires further evaluation. We aimed to investigate the effectiveness of inspiratory muscle training on glottis closure and patient-reported voice quality in glottic insufficiency patients who had been treated with hyaluronic acid injection. STUDY DESIGN: Retrospective observational study. METHODS: We included 46 patients with glottic insufficiency who had undergone hyaluronic acid injection. Twenty of them had undergone inspiratory muscle training during three months. We measured patients' changes in glottic status according to the normalized glottal gap area and bowing index, as well as voice quality of life according to the voice handicap index 10 and the voice outcome survey, before and after training. RESULTS: Patients who underwent inspiratory muscle training had higher odds of experiencing better improvement in all scores. The range of odds ratios ranged from 2.5 to 6.3 for changes in scores, and from 3.8 to 22.2 for changes in score percentages. Of note, the effect of training on percentage changes in the normalized glottal gap area score was significant (P= 0.0127) after adjustment for the duration of vocal disease, body mass index and BMI, and history of gastroesophageal reflux disease. CONCLUSIONS: Inspiratory muscle training can improve the glottal gap after injection laryngoplasty, and may be applied in clinical practice.