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The independent role of fine particulate matter and genetic liability on cognition in older adults
No full text[[abstract]]Background Genetic susceptibility to mental health and cognitive traits, as well as air pollution, significantly impact cognition. The interplay between polygenic liability and fine particulate matter (PM2.5) remains unclear due to the limited number of large-scale studies in Asia. This study utilized the Taiwan Biobank, a nationwide community-based database, to investigate the main and modified effect of PM2.5 on individuals' polygenic susceptibility in cognition. Methods Polygenic risk score (PRS) for cognitive performance (CP PRS), Alzheimer's disease (AD PRS), schizophrenia (SCZ PRS), and major depression (MDD PRS) were computed representing genetic susceptibility for an individual. APOE genotype was classified into E3/E3, E3/E4, and E4/E4. The five-year average concentration of PM2.5 from satellite images was used for defining environmental exposure. Cognitive performance was evaluated via the Mini-Mental State Examination (MMSE) score. The association between personal genetic susceptibility, PM2.5, and cognitive performance was examined using multilevel linear regression with the adjustment of age, sex, batch effect, and population stratification effect. The gene-environment synergism was examined with the inclusion of product term of PM2.5 and PRS in the multivariate model. Results Our analyses included 25,593 participants from 164 townships. Participants exposed to higher PM2.5 concentrations had a lower MMSE score (Beta=-0.0830 corresponding to a 1 mu g/m3 increase in PM2.5 concentration, 95% CI, -0.0973 to -0.0688, p-value < 0.0001). After controlling for PM2.5 concentration, CP PRS (Beta = 0.1729, 95% CI, 0.1470 to 0.1988, p-value < 0.0001), SCZ PRS (Beta=-0.0632, 95% CI, -0.0891 to -0.0374, p-value < 0.0001), and AD PRS (Beta=-0.0321, 95% CI, -0.0580 to -0.0062, p-value = 0.0153) were associated with MMSE score. After further examination of gene-environment synergism, no interaction effect was identified, indicating different mechanism of PM2.5 and genetic liability to influence cognitive performance. Conclusions Human polygenic loading and PM2.5 may impact cognition via an independent pathway. A prevention strategy targeting air pollution reduction may effectively improve the cognitive performance. Multiple exposures and their influences on the long-term change of cognition were required in future research
Opioid substitution therapy programs and the national campaign to eliminate hepatitis C virus in Taiwan: Current status and perspectives in a 2022 national survey among medical institutions
No full text[[abstract]]Aim: In Taiwan’s national campaign to eliminate hepatitis C virus (HCV) by 2025, HCV infection care cascade among opioid substitution therapy (OST) programs plays a crucial role. By employing a national survey among medical institutions, we aim to examine the current status and perspectives expressed by appropriate personnel in the OST program-affiliated institutions. Methods: We conducted a national survey in 2022 among government-contracted OST programs. The questionnaire consists of items about the running costs, hepatitis care cascade, and other issues in the OST programs to be answered by either case managers or directors. Within the 185 OST programs in the nation, 125 programs (68%) had responses from both types of personnel and were included for subsequent analyses. Results: Of 125 programs, 74 (59%) offered HCV screening and 69 (55%) offered HCV treatment. The correlates of both HCV screening and treatment were similar, including greater urbanity level, providing both methadone and buprenorphine (vs either one alone), hospital-based (vs satellite dispensing), smaller size of daily participants (≤ 500, having 2 or more physicians, having 2 or more nurses, and a team consisting of physician plus ≥2 dedicated staff). Regarding the integration of HCV care with OST program, institutions’ concerns included financial incentive for the patients and the doctors, the accessible resources of equipment and relative training, and the service matching platform to enhance the collaboration between OST and other medical institutes are mentioned. Regarding on-site HCV treatment, the percentage of future willingness to offer was 42% for those OST program with current HCV care cascade but only 11% for those without. Conclusions: The establishment of the HCV care cascade in the OST programs was mainly influenced by the resources of medical collaboration and the human resources. Future investments in these aspects are needed to enhance HCV infection care in the OST programs
Phase I study of oral metronomic gemcitabine (D07001) in patients with advanced solid tumors
No full text[[abstract]]Background: D07001-F4 is an absorption-enhanced oral gemcitabine developed in liquid formulation and adjusted to D07001-softgel capsules. We conducted 2 phase 1 studies to evaluate the dose-limiting toxicity (DLT), pharmacokinetics (PK), and maximum tolerated dose (MTD) of the 2 formulations of D07001 in patients with advanced solid tumors. Materials and methods: Initially, patients received escalating doses (2-80 mg) of D07001-F4 thrice a week for 2 weeks, followed by 1-week rest. Since no DLT was observed in the phase 1 study, the phase 1b study was conducted with D07001-softgel capsules (dose range: 40-120 mg) in patients with refractory gastrointestinal malignancies. A bridging dose of 40 mg was administered in the phase 1b study to achieve an equivalent intake of 80 mg of D07001-F4. Results: Fifty-three patients (phase 1, n = 34; phase 1b, n = 19) were enrolled. The mean oral bioavailability of D07001-F4 was similar to 39%. Two patients receiving 120 mg of D07001-softgel capsules experienced grade 3 hepatotoxicity and anorexia, respectively. Therefore, an additional 100 mg dose was tested and determined as the MTD. The C-max and area under the curve of gemcitabine and its metabolite, 2 ', 2 '-difluoro deoxyuridine, have a dose-dependent manner and comparable between the 2 formulations. Grade >= 3 anorexia (10.5%) and diarrhea (10.5%) were observed in the phase 1b extension study. Conclusion: Our study demonstrated that D07001-softgel capsules can be safely administered as continuous dosing of up to 100 mg in patients with advanced solid tumors. Further studies are warranted to determine the appropriate dose in combination with other chemotherapy drugs
Clinical and hospital environmental fusarium in Taiwan: Molecular identification, antifungal susceptibilities, and phylogenetic analyses
No full text[[abstract]]BackgroundFusarium species are emerging pathogens known to cause both superficial and disseminated human infections. Aerosolized Fusarium species in healthcare settings have been associated with nosocomial fusariosis, particularly in patients with severe immunosuppression.ObjectivesTo analyse the phylogenetic relationships of clinical and hospital environmental Fusarium isolates and assess their susceptibility to available antifungal agents.MethodsClinical Fusarium isolates were procured from four hospitals in Taiwan, with environmental air and water sampling collected at Kaohsiung Chang Gung Memorial Hospital (KCGMH). All clinical and hospital environmental Fusarium isolates were identified through gene sequencing of translation elongation factor 1-alpha and internal transcribed spacer regions of ribosomal DNA. Antifungal susceptibility testing followed the CLSI M38-A3 broth microdilution method.ResultsA total of 41 clinical and 4 hospital environmental Fusarium isolates were identified, belonging to five species complexes (SC): F. solani SC (FSSC) (62.8%), F. fujikuroi SC (FFSC) (14.0%), F. incarnatum-equiseti SC (11.6%), F. dimerum SC (7.0%), and F. oxysporum SC (4.7%). Phylogenetic analysis revealed that clinical Fusarium isolates from KCGMH were closely related to environmental Fusarium isolates from air samples at the same hospital. Amphotericin B exhibited high activity against most Fusarium species. With the exception of FFSC, other Fusarium SC demonstrated significantly elevated MIC values to itraconazole, voriconazole, posaconazole, and isavuconazole.ConclusionsFSSC was the most prevalent SC in Taiwan, exhibiting higher MIC values for azoles than FFSC isolates. The clinical Fusarium isolates were observed to form clusters with the corresponding environmental isolates. The potential of airborne nosocomial infections in the healthcare environment cannot be overlooked
Emerging roles of ACTL6A as an oncogenic hub: Transcriptional regulation and beyond
No full text[[abstract]]The malignant progression of human cancer is dictated by specific regulatory hubs coordinating multiple signaling modules. Identifying key oncogenic hubs of human cancers may lay the groundwork for developing breakthrough therapeutic strategies. Actin-like 6A (ACTL6A; BAF53A) was originally identified as a chromatin remodeling factor involved in the transcriptional regulation of genes, especially in stem and progenitor cells. The preponderance of evidence revealed the overexpression of ACTL6A in most cancers and its crucial role in various malignant phenotypes, including cell cycle progression, cancer stemness, epithelial-to-mesenchymal transition, redox and glucose metabolism, and DNA replication and repair. Interestingly, emerging data suggest that the oncogenic function of ACTL6A is mediated through diverse mechanisms beyond its canonical function in transcriptional regulation, including notably the stabilization of oncoproteins and stemness factors, such as YAP, VPS72, and MYC. Here, we describe the isoforms and the putative functional domains of ACTL6A. We summarize the expression pattern and prognostic significance of ACTL6A in human cancers and the upstream regulatory mechanisms of its expression. We summarize recent progress in understanding the diverse pro-oncogenic functions of ACTL6A and emphasize its pleiotropic mechanisms of action as a regulatory hub of cancer stemness and progression. The review highlights the importance and the potential utilities of characterizing ACTL6A, which may imply molecularly informed diagnostics and therapeutics to improve the outcome of cancer patients
Medical accessibility and underreporting of occupational diseases: effect of travel distance and travel time
No full text[[abstract]]OBJECTIVES: Underreporting of occupational diseases (ODs) could be attributed to poor medical accessibility, which is rarely discussed previously. Our cross-sectional study aims to evaluate how OD reporting is impeded by long travel distance/time (TD/TT) to the nearest major occupational medicine clinics. METHODS: Using data from the Network of Occupational Diseases and Injuries Service (NODIS), Taiwan's OD surveillance system, and the annual Manpower Survey from 2008 to 2018, we calculate each district's incidence rate of ODs (IROD) and expected IROD based on industries and job titles. Each town's TD/TT to the nearest major occupational medicine clinics is estimated by Google Maps' Distance Matrix API. The quasi-Poisson regression model is used to investigate the effect of TD and TT on IROD, while industries and job titles are adjusted by offsetting expected IROD. A subgroup analysis is then carried out to check the effect of employment status, sickness absence, and reporting years. RESULTS: A total of 3,420 cases of definite ODs are included in our study. Using the quasi-Poisson regression model, after adjusting industry types and job titles, TD and TT have a significant effect on IROD. As TD/TT increases by 10 km/10 min, IROD decreases by 10.90%/10.73%. It is estimated that ∼200 OD cases per year or 40% of ODs are therefore underreported. In the subgroup analysis, only mildly sick workers are still significantly affected by TD and TT. CONCLUSIONS: Our study shows how poor medical accessibility leads to underreporting, especially for mildly sick cases, and up to 40% of ODs could be underreported. Using this method, we can evaluate the cost-effectiveness of adding reporting hospitals in areas with poor medical accessibility
Performance of the Brain Health Test-7, Mini-Mental State Examination, and Montreal Cognitive Assessment for detecting subjects with mild cognitive impairment
No full text[[abstract]]OBJECTIVES: The Brain Health Test-7 (BHT-7), Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA) are valid dementia and mild cognitive impairment (MCI) screening tools. Relevant validation studies have usually used receiver operating characteristic (ROC) curve analysis or a fixed-threshold approach. In this study, we adopted stratum-specific likelihood ratio (SSLR) analysis to capture more information about their performance in detecting MCI. DESIGN: Cross-sectional multi-site study. SETTING: Hospitals in northern and southern Taiwan. PARTICIPANTS: 1090 subjects aged 50 years or older were assigned to a cognitively normal group, an MCI group, or a dementia group. MEASUREMENTS: BHT-7, MMSE, and MoCA to differentiate cognitively normal subjects from those with MCI or dementia. RESULTS: The three cognitive assessment tools were valid for detecting subjects with MCI or dementia according to ROC analysis. The overall area under the ROC curve (AUC) of the BHT-7 was significantly higher than that of the MoCA and MMSE in differentiating MCI or dementia from controls. Five strata were generated by SSLR analysis for the BHT-7 and MoCA, while 4 for the MMSE. The five strata of the BHT-7 and MoCA well represented the different degrees of probabilities of having MCI. However, it was still difficult to rule out the presence of MCI even by a test score within the highest-score stratum of the MMSE. CONCLUSIONS: The BHT-7 performed slightly better than MoCA and MMSE in detecting subjects with MCI. The strata generated from the SSLR analysis were more informative than single cutoff values
Identification of chicken-derived antibodies targeting the Candida albicans Als3 protein
No full text[[abstract]]Candida albicans is a major opportunistic pathogen, responsible for nearly half of clinical candidemia cases. The rising prevalence of azole-resistant Candida species represents a significant clinical challenge, underscoring the urgent need for alternative therapeutic strategies. Monoclonal antibody-based therapies have emerged as a promising and cost-effective approach to combating Candida infections. Agglutinin-like sequence protein 3 (Als3), a key cell surface protein of C. albicans, plays a pivotal role in adherence and biofilm formation, both of which are essential for its pathogenesis. In this study, recombinant Als3 protein was purified and utilized to immunize chickens, resulting in the production of Als3-specific immunoglobulin Y (IgY) antibodies. Two single-chain variable fragment (scFv) antibody libraries were subsequently constructed using phage display technology, yielding transformant counts of 5.3 × 107 and 2.8 × 107, respectively. Phage-based enzyme-linked immunosorbent assay (ELISA) revealed enhanced signals following bio-panning, enabling the identification and sequence validation of three scFv antibodies. These scFv antibodies exhibited strong binding activities to Als3, as confirmed through ELISA and western blot analyses. Binding affinities were determined to be ~ 10⁻⁸ M via serial titration ELISA and competitive ELISA. Additionally, the selected scFv antibodies specifically recognized endogenous Als3 protein in C. albicans, as demonstrated by western blot and cell-based ELISA assays. In conclusion, this study successfully generated and characterized high-affinity scFv antibodies targeting Als3, which exhibited exceptional specificity and binding activity. These findings highlight their potential as promising immunotherapeutic candidates for the treatment of C. albicans infections. KEY POINTS: • The Als3 protein of C. albicans is a critical biomarker and therapeutic target • Chicken-derived scFv antibodies against Als3 were developed via phage display • The scFv antibodies showed strong binding to endogenous Als3 in C. albicans
Chronic blue light exposure induced spatial anxiety in an adolescent mouse model: Per2 upregulation and altered brain resting-state functional activity
No full text[[abstract]]Background: Blue light (BL) is the primary component of light emitted from 3C devices. The use of 3C (computers, consumer electronics, and communication) devices has been increasing among all age groups. How social interaction and spatial cognition are affected in adolescents after long-term 3C device usage at night remains unclear. Methods: Five-week-old mice were exposed to BL. Subsequently, these mice were subjected to social behavior tests, functional magnetic resonance imaging, and histopathologic analyses. Results: BL exposure increased spatial anxiety but did not affect sociability, social novelty, or motor coordination. Also, BL exposure altered brain connectivity in the hippocampus (Hip), thalamus, and striatum, and it reduced brain activity in the retrosplenial cortex and dorsal part of the Hip. Spatial anxiety was associated with brain alterations. Although BL exposure reduced the size of retinal oligodendrocytes and increased the expression of the Period 2 circadian protein, it did not result in brain inflammation, at least not in the Hip. Conclusion: Our findings highlight that long-term BL exposure in adolescents induces spatial anxiety. The underlying mechanisms include changes in brain activity and connectivity and the disruption of the circadian rhythm