Variations in the sleep-related breathing disorder index on polysomnography between men with HIV and controls: a matched case-control study.

BACKGROUND: Both sleep-related breathing disorders (SRBDs) and HIV infection can interfere with normal sleep architecture, and also cause physical and psychological distress. We aimed to understand the differences in the obstructive patterns, sleep architecture, physical and psychological distress when compared between people living with HIV (PLWH) and matched the severity of SRBDs controls. METHODS: A comparative study using matched case-control design was conducted. Men with HIV infection (case group) were enrolled from 2016 to 2019. A control group with HIV seronegative men were matched for SRBDs severity, and were selected from sleep medicine center database for comparison. RESULTS: The mean age of the 108 men (including 54 cases and 54 matched controls) was 33.75 years. Central-apnea index (CI) was higher in the case group rather than matched controls (mean CI, 0.34 vs. 0.17, p = 0.049). PLWH had a lower mean percentage of stage 3 sleep (10.26% vs. 13.94%, p = 0.034) and a higher percentage of rapid eye movement sleep (20.59% vs. 17.85%, p = 0.011) compared to matched controls. Nocturnal enuresis and sleepiness causing traffic accidents were more frequent complaint in PLWH compared to controls. CONCLUSIONS: Early detected SRBDs and subtypes in PLWH to begin treatment for the underlying cause could reduce the risk of sleepiness-related traffic accidents.

Ribociclib leverages phosphodiesterase 4 inhibition in the treatment of neutrophilic inflammation and acute respiratory distress syndrome.

INTRODUCTION: Overwhelming neutrophil activation and oxidative stress significantly contribute to acute respiratory distress syndrome (ARDS) pathogenesis. However, the potential of repurposing ribociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor used clinically in cancer treatment, for treating neutrophilic ARDS remains uncertain. This study illustrated the ability and underlying mechanism of ribociclib for treating ARDS and neutrophilic inflammation. METHODS: Primary human neutrophils were used to determine the therapeutic effects of ribociclib on respiratory bursts, chemotactic responses, and inflammatory signaling. In vitro and silico analyses were performed to determine the underlying molecular mechanisms. The potential of ribociclib repurposing was evaluated using an in vivo ARDS model in lipopolysaccharide (LPS)-primed mice. RESULTS: We found that treatment using ribociclib markedly limited overabundant oxidative stress (reactive oxygen species [ROS]) production and chemotactic responses (integrin levels and adhesion) in activated human neutrophils. Ribociclib was also shown to act as a selective inhibitor of phosphodiesterase 4 (PDE4), thereby promoting the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, leading to the inhibition of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) phosphorylation, and calcium influx. Notably, prophylactic administration and post-treatment with ribociclib ameliorated neutrophil infiltration, lung inflammation, accumulation of oxidative stress, pulmonary destruction, and mortality in mice with LPS-induced ARDS. CONCLUSION: We demonstrated for the first time that ribociclib serves as a novel PDE4 inhibitor for treating neutrophilic inflammation and ARDS. The repurposing ribociclib and targeting neutrophilic PDE4 offer a potential off-label alternative for treating lung lesions and other inflammatory conditions.

Severity of tongue base collapse in various body positions in patients with obstructive sleep apnea: A trajectory analysis.

BACKGROUND: Drug-induced sleep endoscopy (DISE) is used for evaluating upper airway anatomy and determining airway obstruction patterns. It is typically performed with the patient in the supine position. Airway collapse severity is influenced by body position and level of consciousness; the resultant dynamic changes may vary across patients. In this study, we evaluated the severity of upper airway collapse through awake endoscopy and DISE and identified factors affecting the pattern of airway collapse severity. METHODS: This study included 66 patients with obstructive sleep apnea. The patients underwent type 1 polysomnography, tongue strength assessment, awake endoscopy in the sitting and supine positions, and DISE. Group-based trajectory modeling was performed to identify patients with different collapse severity patterns in different body positions and at different levels of consciousness. RESULTS: Patient with similar severity trajectory were assigned to the same group. Two different severity trajectories (group 1 and group 2) were identified at the tongue base level. Tongue depression strength varied significantly between groups 1 and 2 (47.00 vs. 35.00 kPa; P = .047). During awake endoscopy, collapse severity was significantly higher in group 2 than in group 1. Group 1 had lower rapid eye movement/nonrapid eye movement apnea-hypopnea index ratios and higher tongue depression strength than did group 2. CONCLUSION: In patients with obstructive sleep apnea, tongue strength may vary depending on body position. Our results should be interpreted with caution because of the limited sample size. Future studies should investigate the effect of oropharyngeal rehabilitation on tongue strength and collapse severity.

Two-stage deep-learning-based colonoscopy polyp detection incorporating fisheye and reflection correction.

BACKGROUND AND AIM: Colonoscopy is a useful method for the diagnosis and management of colorectal diseases. Many computer-aided systems have been developed to assist clinicians in detecting colorectal lesions by analyzing colonoscopy images. However, fisheye-lens distortion and light reflection in colonoscopy images can substantially affect the clarity of these images and their utility in detecting polyps. This study proposed a two-stage deep-learning model to correct distortion and reflections in colonoscopy images and thus facilitate polyp detection. METHODS: Images were collected from the PolypSet dataset, the Kvasir-SEG dataset, and one medical center's patient archiving and communication system. The training, validation, and testing datasets comprised 808, 202, and 1100 images, respectively. The first stage involved the correction of fisheye-related distortion in colonoscopy images and polyp detection, which was performed using a convolutional neural network. The second stage involved the use of generative and adversarial networks for correcting reflective colonoscopy images before the convolutional neural network was used for polyp detection. RESULTS: The model had higher accuracy when it was validated using corrected images than when it was validated using uncorrected images (96.8% vs 90.8%, P < 0.001). The model's accuracy in detecting polyps in the Kvasir-SEG dataset reached 96%, and the area under the receiver operating characteristic curve was 0.94. CONCLUSION: The proposed model can facilitate the clinical diagnosis of colorectal polyps and improve the quality of colonoscopy.

Neutrophil-targeted combinatorial nanosystems for suppressing bacteremia-associated hyperinflammation and MRSA infection to improve survival rates.

There is currently no specific and effective treatment for bacteremia-mediated sepsis. Hence, this study engineered a combinatorial nanosystem containing neutrophil-targeted roflumilast-loaded nanocarriers and non-targeted fusidic acid-loaded nanoparticles to enable the dual mitigation of bacteremia-associated inflammation and methicillin-resistant Staphylococcus aureus (MRSA) infection. The targeted nanoparticles were developed by conjugating anti-lymphocyte antigen 6 complex locus G6D (Ly6G) antibody fragment on the nanoparticulate surface. The particle size and zeta potential of the as-prepared nanosystem were about 200 nm and -25 mV, respectively. The antibody-conjugated nanoparticles showed a three-fold increase in neutrophil internalization compared to the unfunctionalized nanoparticles. As a selective phosphodiesterase (PDE) 4 inhibitor, the roflumilast in the nanocarriers largely inhibited cytokine/chemokine release from the activated neutrophils. The fusidic acid-loaded nanocarriers were vital to eliminate biofilm MRSA colony by 3 log units. The nanoparticles drastically decreased the intracellular bacterial count compared to the free antibiotic. The in vivo mouse bioimaging demonstrated prolonged retention of the nanosystem in the circulation with limited organ distribution and liver metabolism. In the mouse bacteremia model, the multifunctional nanosystem produced a 1‒2 log reduction of MRSA burden in peripheral organs and blood. The functionalized nanosystem arrested the cytokine/chemokine overexpression greater than the unfunctionalized nanocarriers and free drugs. The combinatory nanosystem also extended the median survival time from 50 to 103 h. No toxicity from the nanoformulation was found based on histology and serum biochemistry. Furthermore, our data proved that the active neutrophil targeting by the versatile nanosystem efficiently alleviated MRSA infection and organ dysfunction caused by bacteremia. STATEMENT OF SIGNIFICANCE: Bacteremia-mediated sepsis poses a significant challenge in clinical practice, as there is currently no specific and effective treatment available. In our study, we have developed a novel combinatorial nanosystem to address this issue. Our nanosystem consists of neutrophil-targeted roflumilast-loaded nanocarriers and non-targeted fusidic acid-loaded nanoparticles, enabling the simultaneous mitigation of bacteremia-associated inflammation and MRSA infection. Our nanosystem demonstrated the decreased neutrophil activation, effective inhibition of cytokine release, elimination of MRSA biofilm colonies, and reduced intracellular bacterial counts. In vivo experiments showed prolonged circulation, limited organ distribution, and increased survival rates in a mouse bacteremia model. Importantly, our nanosystem exhibited no toxicity based on comprehensive assessments.

Molecular characterization of rifabutin-resistance in refractory Helicobacter pylori infection in Taiwan.

OBJECTIVES: To explore the molecular characteristics of rpoB, encoding ß-subunit of DNA-directed RNA polymerase, and unravel the link to rifabutin-resistance in patients with refractory Helicobacter pylori infection. METHODS: From January 2018-March 2021, a total of 1590 patients were screened for eligibility to participate in the study. Patients with refractory H. pylori infection were confirmed by using the (13C)-urea breath assay. All enrolled patients underwent esophagogastroduodenoscopy, and biopsies were taken for H. pylori culture and antibacterial susceptibility testing. Sequence analysis of rpoB was conducted for all rifabutin-resistant isolates. RESULTS: In total, 70 patients were diagnosed with refractory H. pylori infection, and 39 isolates were successfully cultured. Amongst, 10 isolates were identified as rifabutin-resistance and nine isolates exhibited at least one amino acid substitution in RpoB. Isolates with a minimal inhibitory concentration >32 mg/l displayed a higher number of mutational changes in RpoB than the others. Additionally, more amino acid substitutions in RpoB correlated with developing a higher minimal inhibitory concentration for H. pylori rifabutin-resistance. CONCLUSION: Our findings highlight the relationship between rifabutin-resistance in refractory H. pylori infection and specific mutations in RpoB, which will aid the clinical selection of appropriate antibacterial agents with better therapeutic effects.

Polysomnography scoring-related training and quantitative assessment for improving interscorer agreement.

STUDY OBJECTIVES: To efficiently improve the scoring competency of scorers with varying levels of experience across regions in Taiwan, we developed a training program with a cloud-based polysomnography scoring platform to evaluate and improve interscorer agreement. METHODS: A total of 70 scorers from 34 sleep centers in Taiwan (job tenure: 0.5-39.0 years) completed a scoring test. All scorers scored a 742-epoch (30 s/epoch) overnight polysomnography recording of a patient with a moderate apnea-hypopnea index. Subsequently, 8 scoring experts delivered 8 interactive online lectures (each lasting 30 minutes). The training program included identifying scoring weaknesses, highlighting the latest scoring rules, and providing physicians' perspectives. Afterward, the scorers completed the second scoring test on the same participant. Changes in agreement from the first to second scoring test were identified. Sleep staging, sleep parameters, and respiratory events were considered for evaluating scoring agreement. RESULTS: The scorers' agreement in overall sleep stage scoring significantly increased from 74.6 to 82.3% (median score). The proportion of scorers with an agreement of ≥ 80% increased from 20.0% (14/70) to 58.6% (41/70) after the online training program. In addition, the scorers' agreement in overall respiratory-event scoring increased to 88.8% (median score) after training. The scorers with a job tenure of 2.0-4.9 years exhibited the highest level of improvement in overall sleep staging (their median agreement increased from 72.8 to 84.9%; P < .001). CONCLUSIONS: Our interactive online training program efficiently targeted the scorers' scoring weaknesses identified in the first scoring test, leading to substantial improvements in scoring proficiency. CITATION: Liao Y-S, Wu M-C, Li C-X, Lin W-K, Lin C-Y, Liang S-F. Polysomnography scoring-related training and quantitative assessment for improving interscorer agreement. J Clin Sleep Med. 2024;20(2):271-278.

Development of Physiologically Relevant Skin Organoids from Human Induced Pluripotent Stem Cells.

The development of skin organs for studying developmental pathways, modeling diseases, or regenerative medicine purposes is a major endeavor in the field. Human induced pluripotent stem cells (hiPSCs) are successfully used to derive skin cells, but the field is still far from meeting the goal of creating skin containing appendages, such as hair follicles and sweat glands. Here, the goal is to generate skin organoids (SKOs) from human skin fibroblast or placental CD34+ cell-derived hiPSCs. With all three hiPSC lines, complex SKOs with stratified skin layers and pigmented hair follicles are generated with different efficacies. In addition, the hiPSC-derived SKOs develop sebaceous glands, touch-receptive Merkel cells, and more importantly eccrine sweat glands. Together, physiologically relevant skin organoids are developed by direct induction of embryoid body formation, along with simultaneous inactivation of transforming growth factor beta signaling, activation of fibroblast growth factor signaling, and inhibition of bone morphogenetic protein signaling pathways. The skin organoids created in this study can be used as valuable platforms for further research into human skin development, disease modeling, or reconstructive surgeries.

Oral fecal transplantation enriches Lachnospiraceae and butyrate to mitigate acute liver injury.

While fecal microbiota transplantation (FMT) shows promise in treating human diseases, oral capsule FMT is more accepted and accessible to patients. However, microbe selection in the upper gastrointestinal tract (UGIT) through oral administration remains unclear. Here, we demonstrate that short-term oral fecal gavage (OFG) alleviates acetaminophen-induced acute liver injury (AILI) in mice, regardless of the divergent effects of commensal gut microbes. Pasteurized fecal gavage yields similar therapeutic effects. OFG enriches gut Lachnospiraceae and butyrate compared to donor feces. Butyrate mitigates AILI-induced ferroptosis via AMPK-ULK1-p62 signaling to simultaneously induce mitophagy and Nrf2 antioxidant responses. Combined N-acetylcysteine and butyrate administration significantly improves AILI mouse survival rates. These observations indicate the significance of the UGIT in modulating the implanted fecal microbes through oral administration and its potential biological and clinical impacts. Our findings also highlight a possible strategy for applying microbial metabolites to treat acute liver injury.

Combining augmented and virtual reality simulation training to improve geriatric oral care performance in healthcare assistants: A randomized controlled trial.

Objective: Healthcare assistants (HCAs) are frontline caregivers for older adults. This study evaluated the effectiveness of combining augmented reality (AR) and virtual reality (VR) to implement oral healthcare simulation training for HCAs. Methods: An experimental design was adopted. HCAs were recruited and randomly assigned to an AR/VR group (n = 40) or a control group (n = 40). The AR/VR group received 2.5 h of AR/VR training. Participants were trained on the Bass brushing technique through AR and on scenario-based oral care procedures for various physical and oral health conditions in older adults through VR. A self-administered questionnaire was employed to collect data before and after the training. Generalized estimating equations were used to analyze the differences between pretest and posttest results. Results: After the training, the HCAs in the AR/VR group achieved a significantly greater increase in their level of oral care-related knowledge (ß = 2.55, effect size [ES] = 1.62), self-efficacy (ß = 4.23, ES = 0.75), and behavioral intention (ß = 2.10, ES = 0.55) relative to the control group. Conclusion: This study revealed that the application of an AR/VR simulation system can effectively improve the geriatric oral care performance of HCAs.

Proteinase K/Retinoic Acid-Loaded Cationic Liposomes as Multifunctional Anti-Acne Therapy to Disorganize Biofilm and Regulate Keratinocyte Proliferation.

Background: Simultaneous anti-Cutibacterium acnes and anti-inflammatory actions are highly beneficial in treating acne vulgaris. In this study, we present novel anti-acne nanovesicles based on liposomes loaded with proteinase K (PK), retinoic acid (RA), and soyaethyl morpholinium ethosulfate (SME) to achieve an effective and safe treatment. Materials and Methods: This study examined in vitro planktonic and biofilm C. acnes elimination, as well as the keratinocyte proliferation suppression by liposomes. The multifunctional liposomes for treating C. acnes in mice were also evaluated. Results: We acquired multifunctional liposomes with a size of 71 nm and zeta potential of 31 mV. The antimicrobial activity of SME was enhanced after liposomal encapsulation according to the reduction of minimum bactericidal concentration (MBC) by 6-fold. The multifunctional liposomes exhibited a synergistically inhibitory effect on biofilm C. acnes colonization compared with the liposomes containing PK or those containing SME individually. The adhesive bacterial colony in the microplate was lessened by 62% after multifunctional liposome intervention. All liposomal formulations tested here demonstrated no cytotoxicity against the normal keratinocytes but inhibited C. acnes-stimulated cell hyperproliferation. The in vitro scratch assay indicated that the liposomal RA-but not free RA-restrained keratinocyte migration. The animal study showed that free RA combined with SME and multifunctional nanovesicles had a similar effect on diminishing C. acnes colonies in the skin. On the other hand, liposomes exhibited superior performance in recovering the impaired skin barrier function than the free control. We also found that RA-loaded nanovesicles had greater skin tolerability than free RA. Conclusion: The cationic liposomes containing dual PK and RA represented a potential treatment to arrest bacterial infection and associated inflammation in acne.

Digital health literacy and well-being among university students: Mediating roles of fear of COVID-19, information satisfaction, and internet information search.

Background: Digital health literacy (DHL) enables healthy decisions, improves protective behaviors and adherence to COVID-19 measures, especially during the era of the "infodemic", and enhances psychological well-being. Objective: We aimed to explore the mediating roles of fear of COVID-19, information satisfaction, and the importance of online information searching on the association between DHL and well-being. Methods: A cross-sectional web-based survey was conducted among 1631 Taiwanese university students, aged 18 years and above, from June 2021 to March 2022. The collected data include sociodemographic characteristics (sex, age, social status, and financial satisfaction), the importance of online information searching, information satisfaction, fear of COVID-19, DHL, and well-being. A linear regression model was utilized to investigate factors associated with well-being, followed by a pathway analysis to assess the direct and indirect relationship between DHL and well-being. Results: The scores of DHL and overall well-being were 3.1 ± 0.4 and 74.4 ± 19.7, respectively. Social status (B = 2.40, 95% confidence interval (CI) 1.73-3.07, p < 0.001), DHL (B 0.29, 95% CI 0.10-0.49, p < 0.001), importance of online information searching (B = 0.78, 95% CI 0.38-1.17, p < 0.001), and information satisfaction (B = 3.59, 95% CI 2.22-4.94, p < 0.001) were positively associated with well-being, whereas higher fear of COVID-19 scores (B = -0.38, 95% CI -0.55-(-0.21), p < 0.001) and female (B = -2.99, 95% CI -5.02-0.6, p = 0.004) were associated with lower well-being, when compared with lower fear scores and male, respectively. Fear of COVID-19 (B = 0.03, 95% CI 0.016-0.04, p < 0.001), importance of online information searching (B = 0.03, 95% CI 0.01-0.05, p = 0.005), and information satisfaction (B = 0.05, 95% CI 0.023-0.067, p < 0.001) were significantly mediated the relationship between DHL and well-being. Conclusion: Higher DHL scores show direct and indirect associations with higher well-being scores. Fear, importance of online information searching, and information satisfaction significantly contributed to the association.

The First-Water-Layer Evolution at the Graphene/Water Interface under Different Electro-Modulated Hydrophilic Conditions Observed by Suspended/Supported Field-Effect-Device Architectures.

Interfacial water molecules affect carrier transportation within graphene and related applications. Without proper tools, however, most of the previous works focus on simulation modeling rather than experimental validation. To overcome this obstacle, a series of graphene field-effect transistors (GFETs) with suspended (substrate-free, SF) and supported (oxide-supported, OS) configurations are developed to investigate the graphene-water interface under different hydrophilic conditions. With deionized water environments, in our experiments, the electrical transportation behaviors of the graphene mainly originate from the evolution of the interfacial water-molecule arrangement. Also, these current-voltage behaviors can be used to elucidate the first-water layer at the graphene-water interface. For SF-GFET, our experimental results show positive hysteresis in electrical transportation. These imply highly ordered interfacial water molecules with a separated-ionic distributed structure. For OS-GFET, on the contrary, the negative hysteresis shows the formation of the hydrogen-bond interaction between the interfacial water layer and the SiO2 substrate under the graphene. This interaction further promotes current conduction through the graphene/water interface. In addition, the net current-voltage relationship also indicates the energy required to change the orientation of the first-layer water molecules during electro-potential change. Therefore, our work gives an insight into graphene-water interfacial evolution with field-effect modulation. Furthermore, this experimental architecture also paves the way for investigating 2D solid-liquid interfacial features.

Objective multidisciplinary measurements of sleep disturbance and autonomic dysfunction as risk factors for chronic subjective tinnitus.

PURPOSE: This observational study assessed sleep disturbance and autonomic dysfunction as risk factors for chronic subjective tinnitus through polysomnography (PSG) and autonomic function tests. METHODS: Adult patients with chronic subjective tinnitus who visited the department of otolaryngology in our hospitals (n = 40), along with controls without tinnitus (n = 80), were recruited. Individuals with an average hearing threshold level (HL) exceeding 25 dB HL and a known diagnosis of insomnia were excluded. Objective assessments comprised pure-tone audiometry, PSG, and autonomic function tests (e.g., the cold pressor test). RESULTS: Patients with prolonged sleep latency, lower sleep efficiency, and sympathetic hyperactivity had significantly higher risks of developing tinnitus. No interaction effect between poor sleep quality and sympathetic hyperactivity on tinnitus was detected. CONCLUSION: This is the first study to administer PSG and autonomic function tests to patients with chronic subjective tinnitus. Poor sleep quality and autonomic dysfunction were implicated as risk factors for tinnitus. PSG and the autonomic function tests helped identify tinnitus-related comorbidities and inform tinnitus treatment. Sleep disturbance and autonomic dysfunction did not exert an interaction effect on tinnitus. Further studies with a larger sample size and the inclusion of patients with more severe tinnitus are warranted.

Targeting anti-inflammatory immunonanocarriers to human and murine neutrophils via the Ly6 antigen for psoriasiform dermatitis alleviation.

Psoriasis is a refractory and difficult-to-treat skin disorder. The neutrophil-targeting approach represents a promising option for psoriasis therapy. This study developed and examined NIMP-R14-conjugated immunonanoparticles for specific targeting to neutrophils associated with psoriasiform dermatitis. In the process, roflumilast (RFL), as a phosphodiesterase (PDE) 4 inhibitor, was encapsulated in the nanocarriers to assess the anti-inflammatory capability against primary neutrophil activation and murine psoriasiform lesion. The average size and surface charge of the immunonanocarriers were 305 ± 36 nm and -18 ± 6 mV, respectively. The monovalent antibody-conjugated nanoparticles offered precise uptake by both human and mouse neutrophils but failed to exhibit this effect in monocytes and lymphocytes. The intracellular RFL concentration of the immunonanocarriers was five-fold superior to that of the passive counterparts. The immunonanocarriers specifically recognized the neutrophils through the Ly6 antigen with no apparent cytotoxicity. The antibody-conjugated nanoparticles mitigated superoxide anion production and migration of the activated human neutrophils. The in vivo biodistribution in the psoriasiform mice, found using an in vivo imaging system (IVIS) and liquid chromatography (LC)-mass-mass analysis, showed that the antibody conjugation increased the nanoparticle residence in systemic circulation after intravenous administration. On the other hand, most of the nanoparticles were accumulated in the lesional skin after subcutaneous injection. The actively-targeted nanocarriers were better than the free RFL and unfunctionalized nanoparticles in suppressing psoriasiform inflammation. The immunonanocarriers reduced neutrophil recruitment and epidermal hyperplasia in the plaque. Intravenous and subcutaneous treatments with the immunonanocarriers significantly reduced the overexpressed cytokines and chemokines in the inflamed skin, demonstrating that the nanosystems could both systematically and locally alleviate inflammation. The results indicated that the NIMP-R14-conjugated RFL-loaded nanoparticles have potential as an anti-autoimmune disease delivery system for neutrophil targeting.

Multiple amino acid substitutions in penicillin-binding protein-1A confer amoxicillin resistance in refractory Helicobacter pylori infection.

BACKGROUND: Amoxicillin resistance in Helicobacter pylori is mainly associated with mutations in penicillin-binding protein-1A (PBP-1A). However, the specific amino acid substitutions in PBP-1A that confer amoxicillin resistance in H. pylori remain to be investigated. OBJECTIVE: This study aimed to investigate the molecular mechanism underlying amoxicillin resistance in patients with refractory H. pylori infection. METHODS: Esophagogastroduodenoscopy (EGD) was performed in patients with persistent H. pylori infection after at least two courses of H. pylori eradication therapy between January-2018 to March-2021. Refractory H. pylori was cultured from the gastric biopsy specimens. Antibiotic susceptibility testing was conducted to determine the minimum inhibitory concentrations (MICs). Sequence analysis of pbp-1A was performed for amoxicillin-resistant strains. RESULTS: Thirty-nine successfully cultured isolates were classified as refractory H. pylori isolates, and seventeen isolates were resistant to amoxicillin (MIC > 0.125 mg/L). Sequence analysis of resistant strains showed multiple mutations in the C-terminal region of PBP-1A that conferred amoxicillin resistance in H. pylori. However, the number of PBP-1A mutations did not correlate with the high MICs of amoxicillin-resistant isolates. Notably, some amino acid substitutions were identified in all Taiwanese isolates with history of eradication failure but not in published amoxicillin-susceptible strains, suggesting that the mutations may play a role in conferring antibiotic resistance to these strains. CONCLUSIONS: Our results show that amoxicillin resistance in refractory H. pylori is highly correlated with numerous PBP-1A mutations that are strain specific. Continuous improvements in diagnostic tools, particularly molecular analysis approaches, can help to optimize current antimicrobial regimens.

The effect of cumulative noise exposure on distortion product otoacoustic emissions.

OBJECTIVE: This study aimed to identify the characteristics of distortion product otoacoustic emissions (DPOAEs) that can be used to differentiate noise-induced hearing loss (NIHL) from age-related hearing loss. A potential index to detect NIHL was defined in terms of its susceptibility to cumulative noise exposure but not to age. DESIGN: In this cross-sectional cohort study, a job-exposure matrix was used to calculate the cumulative noise exposure. Multivariate linear regression models were used to examine how age and cumulative noise exposure associated with DPOAEs at individual frequencies after adjusting for hypertension, dyslipidaemia, tobacco use and alcohol consumption. STUDY SAMPLE: The pure-tone audiometry and DPOAEs data collected from 239 male workers in a steel factory. RESULTS: DPOAEs and DPOAE signal-to-noise ratios (SNRs) at all frequencies were found to be correlated with age, and those at 2, 3, 4 and 6 kHz were correlated with both age and noise exposure. The difference between DPOAE SNR at 1 and 3 kHz showed significant correlation with noise exposure but not with age. CONCLUSIONS: The results showed that this DPOAE index, the DPOAE SNR at 1 kHz minus the DPOAE SNR at 3 kHz, could add values to audiometric evaluation of NIHL.

Association of Digital Health Literacy with Future Anxiety as Mediated by Information Satisfaction and Fear of COVID-19: A Pathway Analysis among Taiwanese Students.

Digital Health Literacy (DHL) helps online users with navigating the infodemic and co-existing conspiracy beliefs to avoid mental distress and maintain well-being. We aimed to investigate the association between DHL and future anxiety (FA); and examine the potential mediation roles of information satisfaction and fear of COVID-19 (F-CoV). A web-based cross-sectional survey was carried out among 1631 Taiwanese university students aged 18 years and above from June 2021 to March 2022. Data collected were socio-demographic characteristics (sex, age, social status, university location), information satisfaction, F-CoV, DHL and FA (using Future Dark scale). The linear regression model was used to explore factors associated with FA. The pathway analysis was further used to evaluate the direct and indirect relationship between DHL and FA. A higher score of DHL (B = -0.21; 95% CI, -0.37, -0.06; p = 0.006), and information satisfaction (B = -0.16; 95% CI, -0.24, -0.08; p < 0.001) were associated with a lower FA score, whereas a higher F-CoV score was associated with a higher FA score (B = 0.43; 95% CI, 0.36, 0.50; p < 0.001). DHL showed the direct impact (B = -0.1; 95% CI, -0.17, -0.04; p = 0.002) and indirect impact on FA as mediated by information satisfaction (B = -0.04; 95% CI, -0.06, -0.01; p = 0.002) and F-CoV (B = -0.06, 95% CI, -0.08, -0.04; p < 0.001). Strategic approaches to promote DHL, information satisfaction, lower F-CoV are suggested to reduce FA among students.

A proposal for T1 subclassification in hepatocellular carcinoma: reappraisal of the AJCC 8th edition.

BACKGROUND: In the 8th edition of American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC), tumor size is not considered in T1 stage. The present study aimed to find out the optimal cutoff for tumor size to further stratify patients with T1 HCC. METHODS: Operated HCC patients were identified from the Chang Gung Research Database (CGRD), and the patients with T1bN0M0 tumors were further divided into two groups based on the tumor size. The resulting subgroups were denoted as T1b (≤ cutoff) and T1c (> cutoff). The survivals were compared between T1a/b and T1c as well as T1c and T2. RESULTS: From 2002 to 2018, a total of 2893 patients who underwent surgery for T1N0M0 HCC were identified from the CGRD. After excluding cases who died within 30 days of surgery, Kaplan-Meier survival analysis discovered that T1 tumors > 65 mm (T1c) had survivals similar to those of T2N0M0 tumors. Cox regression multivariate analysis further demonstrated that tumor size > 6.5 cm was an independent poor prognostic indicator for T1 HCC. Sensitivity tests also confirmed that tumors lager than 6.5 cm were significantly more likely to develop both tumor recurrence and liver-specific death after surgery. CONCLUSIONS: Our study demonstrated that tumor size would significantly impact the survival outcome of T1 HCC after surgery. Due to significantly worse survival, we proposed a subclassification within T1 HCC, T1c: solitary tumor > 6.5 cm without vascular invasion, to further stratify those patients at risk. Further studies are mandatory to validate our findings.

Mitochondrial brain proteome acetylation levels and behavioural responsiveness to amphetamine are altered in mice lacking Sirt3.

Post-translational modification of mitochondrial proteins represents one mechanism by which the functional activity of mitochondria can be regulated. In the brain, these modifications can influence the functional properties of different neural circuitries. Given that the sirtuin family member Sirt3 represents the primary protein deacetylase enzyme in mitochondria, we tested whether brain mitochondrial proteome acetylation would increase in male or female mice lacking Sirt3. Our results confirm that whole brain mitochondrial proteome acetylation levels are indeed elevated in both sexes of Sirt3-KO mice relative to controls. Consistently, we found the mitochondria of mouse embryonic fibroblast (MEF) cells derived from Sirt3-KO mice were smaller in size, and fewer in number than in wild-type MEFs, and that mitochondrial free calcium levels were elevated within the mitochondria of these cells. As protein acetylation can influence mitochondrial function, and changes in mitochondrial function have been linked to alterations in neural circuit function regulating motor activity and anxiety-like behavior, we tested whether Sirt3-deficient mice would display sensitized responsiveness to the stimulant amphetamine. Both male and female Sirt3-KO mice displayed hyper-locomotion and attenuated anxiety-like behavior in response to a dose of amphetamine that was insufficient to promote any behavioural responses in wild-type mice. Collectively, these results confirm that Sirt3 regulates mitochondrial proteome acetylation levels in brain tissue, and that the absence of Sirt3 increases the sensitivity of neural systems to amphetamine-induced behavioural responses.