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Abstract Prescribing cascade is a significant clinical problem but is often overlooked. We explore the incidence of the prescribing cascades of antigout medications related to thiazide treatment in gout-naïve hypertensive adults newly exposed to the pharmacological treatment. This population-based, retrospective cohort study used the Taiwan National Health Insurance Registry Database. Gout-naïve hypertensive adults who were newly dispensed first-line antihypertensive drugs between January 1, 2000, and December 31, 2016, were enrolled. Patients were divided into the thiazide group (n = 4192) and the non-thiazide group (n = 81,083). The non-thiazide group included patients who received an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, calcium channel blocker, or beta-blocker. The study utilized propensity score matching and multivariable Cox regression models to investigate the prescribing cascade of antigout agents following antihypertensive treatment, adjusting for factors like age, sex, comorbidities, and concurrent medications. After propensity score matching, each group consisted of 4045 patients, with the thiazide group exhibiting a higher risk of being prescribed antigout medications across different time intervals post-treatment initiation. Specifically, adjusted hazard ratios (aHRs) for the thiazide group were 2.23, 2.07, and 2.41 for 180 days, respectively, indicating a sustained and significant risk over time. Comparative analyses revealed thiazide diuretics were associated with a higher risk of antigout medication prescriptions compared to other antihypertensive classes, particularly evident after 180 days. Subgroup analyses across various demographics and comorbidities consistently showed an increased risk in the thiazide cohort. Gout-naïve hypertensive adults newly dispensed thiazide had a higher risk of subsequently adding antigout agents than those taking other first-line antihypertensive medications. The awareness and interruption of these prescribing cascades are critical to improving patient safety.

Exposure to air pollutants has been associated with DNA damage and increases the risks of respiratory diseases, such as asthma and COPD; however short- and long-term effects of air pollutants on telomere dysfunction remain unclear. We investigated the impact of short- and long-term exposure to fine particulate matter with an aerodynamic diameter below 2.5 μm (PM2.5) on telomere length in human bronchial epithelial BEAS-2B cells, and assessed the potential correlation between PM2.5 exposure and telomere length in the LIGHTS childhood cohort study. We observed that long-term, but not short-term, PM2.5 exposure was significantly associated with telomere shortening, along with the downregulation of human telomerase reverse transcriptase (hTERT) mRNA and protein levels. Moreover, long-term exposure to PM2.5 induced proinflammatory cytokine secretion, notably interleukin 6 (IL-6) and IL-8, triggered subG1 cell cycle arrest, and ultimately caused cell death. Long-term exposure to PM2.5 upregulated the LC3-II/ LC3-I ratio but led to p62 protein accumulation in BEAS-2B cells, suggesting a blockade of autophagic flux. Moreover, consistent with our in vitro findings, our epidemiological study found significant association between annual average exposure to higher PM2.5 and shortening of leukocyte telomere length in children. However, no significant association between 7-day short-term exposure to PM2.5 and leukocyte telomere length was observed in children. By combining in vitro experimental and epidemiological studies, our findings provide supportive evidence linking potential regulatory mechanisms to population level with respect to long-term PM2.5 exposure to telomere shortening in humans.

Abstract Background Patients with idiopathic normal-pressure hydrocephalus (iNPH) are predisposed to developing dementing disorders. Cerebrospinal fluid (CSF) shunt implantation is a treatment used to improve the motor and cognitive disabilities of these patients; however, its effect on the risk of developing dementing disorders remains unclear. We conducted a population-based propensity-weighted cohort study to investigate whether CSF shunt surgery may reduce the risk of subsequently developing dementia, Alzheimer’s disease (AD), and vascular dementia in iNPH patients. Methods Patients aged ≥ 60 years who were diagnosed with iNPH (n = 2053) between January 2001 and June 2018 were identified from the Taiwan National Health Insurance Research Database. Various demographic characteristics (age, sex, and monthly income) and clinical data (incidence year, comorbidities, and Charlson comorbidity index) were collected and divided into the shunt surgery group (SSG) and the non-shunt surgery group (NSSG). Stabilized inverse probability of treatment weighting by using the propensity score was performed to achieve a balanced distribution of confounders across the two study groups. The cumulative incidence rate and risk of dementing disorders were estimated during a 16-year follow-up period. Results After weighting, the data of 375.0 patients in SSG and 1677.4 patients in NSSG were analyzed. Kaplan–Meier curve analysis indicated that the cumulative incidence rate of AD (p = 0.009), but not dementia (p = 0.241) and vascular dementia (p = 0.761), in SSG was significantly lower than that in NSSG over the 16-year follow-up period. Cox proportional hazards regression analysis revealed that SSG had a reduced hazard ratio (HR) for developing AD [HR (95% CI) 0.17 (0.04–0.69)], but not for dementia [HR (95% CI) 0.83 (0.61–1.12)] and vascular dementia [HR (95% CI) 1.18 (0.44–3.16)], compared with NSSG. Further Fine–Gray hazard regression analysis with death as a competing event demonstrated that SSG had a reduced subdistribution HR (sHR) for developing dementia [sHR (95% CI) 0.74 (0.55–0.99)] and AD [sHR (95% CI) 0.15 (0.04–0.61)], but not for vascular dementia [sHR (95% CI) 1.07 (0.40–2.86)]. Conclusion CSF shunt surgery is associated with reduced risks of the subsequent development of dementia and AD in iNPH patients. Our findings may provide valuable information for assessing the benefit-to-risk profile of CSF shunt surgery.

Abstract Elevated levels of interleukin 1β (IL‐1β) have been identified in patients with chronic viral hepatitis and have been associated with depressive symptoms. Given the high prevalence of depression in this patient population, this study sought to explore the potential influence of IL‐1β genetic variations on the severity of depressive symptoms. In a cohort of 181 Taiwanese patients with chronic viral hepatitis, we investigated the impact of five common IL‐1β single nucleotide polymorphisms (SNPs), including rs16944, rs1143627, rs1143630, rs1143643, and rs3136558, on depressive symptoms using the Beck's Depression Inventory‐II. Additionally, we analyzed the primary domains of IL‐1β‐related depressive symptoms according to Beck's six symptom categories of depression. Our analysis revealed significant associations between depressive symptoms and three intronic IL‐1β SNPs. After controlling for age, sex, marital status, and education level, patients with the rs1143630 GG, rs1143643 CC, and rs3136558 AA genotypes demonstrated higher severity of depressive symptoms in the domains of indecision (p = 0.004), agitation (p = 0.001), and feelings of punishment (p = 0.005), respectively, compared to rs1143630 GA+AA, rs1143643 CT, and rs3136558 AG+GG genotypes. According to Beck's categorization, these symptoms can be classified into three dimensions: disturbances in emotion regulation, energy, and cognition. Our findings demonstrate the association between IL‐1β polymorphisms and depressive symptoms and suggest a potential underlying mechanism for specific depressive symptoms within the chronic viral hepatitis population. These insights could improve our understanding and treatment of depressive symptoms in individuals with viral hepatitis.

Targeting inflammatory pathways is considered a common strategy to control type 2 diabetes (T2D) and periodontitis. This overview was to validate systemic antibiotics as an adjuvant to scaling and root planing (SRP) for the treatments of periodontal patients with T2D. Literature searches were conducted using Web of Science, PubMed, Cochrane, and EMBASE. Randomized trials comparing SRP and systemic antibiotics on glycated hemoglobin (HbA1c) and probing pocket depth (PPD) in adults with T2D and periodontitis were analyzed using network meta-analysis and meta-regression. At 3-month postintervention, meta-analyses of 16 studies revealed that SRP and SRP plus systemic antibiotics (SRPa) had similar significant effects in reducing HbA1c levels of − 0.72% and − 0.96% respectively. While SRP and SRPa also, respectively, reduced PPD of − 0.67 and − 0.89 mm, SRPa showed a better reduction than SRP. At 6-month postintervention, meta-analyses of 7 trials revealed that only SRP was effective in reducing HbA1c levels (−0.29%) but not SRPa. Although both SRP and SRPa still significantly reduced PPD by − 0.56 and − 0.81 mm, respectively, there was no difference between them. The current overview suggested that routine SRP alone is highly recommended for patients with T2D and periodontitis, since systemic antibiotics as an adjuvant provide a rather short-term effect.

Abstract Essential hypertension involves complex cardiovascular regulation. The autonomic nervous system function fluctuates throughout the sleep–wake cycle and changes with advancing age. However, the precise role of the autonomic nervous system in the development of hypertension during aging remains unclear. In this study, we characterized autonomic function during the sleep–wake cycle in different age groups with essential hypertension. This study included 97 men (53 with and 44 without hypertension) aged 30–79 years. They were stratified by age into young (

This study developed a MgBi2O6-based photocatalyst via low-temperature hydrothermal synthesis. AgBr was co-precipitated onto MgBi2O6, and silver nanoparticles (AgNPs) were photo-reduced onto the surface. The photocatalytic performance, assessed by methylene blue (MB) degradation under white-light LED irradiation (2.5 W, power density = 0.38 W/cm2), showed that Ag/AgBr/MgBi2O6 achieved 98.6% degradation in 40 min, outperforming MgBi2O6 (37.5%) and AgBr/MgBi2O6 (85.5%). AgNPs boosted electron-hole separation via surface plasmon resonance, reducing recombination. A Z-scheme photocatalytic mechanism was suggested, where photogenerated carriers transferred across the p–n heterojunction between AgBr and MgBi2O6, producing reactive oxygen species like superoxide and hydroxyl radicals critical for dye degradation. Thus, the Ag/AgBr/MgBi2O6 composites possessed excellent photocatalytic performance regarding dyestuff degradation (85.8–99.9% degradation within 40 min) under white-light LED irradiation.

Abstract Background Human polyomavirus BK (BKPyV) causes associated nephropathy and contributes to urinary tract cancer development in renal transplant recipients. Large tumor antigen (LT) is an early protein essential in the polyomavirus life cycle. Protein acetylation plays a critical role in regulating protein stability, so this study investigated the acetylation of the BKPyV LT protein. Methods The BKPyV LT nucleotide was synthesized, and the protein was expressed by transfection into permissive cells. The BKPyV LT protein was immunoprecipitated and subjected to LC-MS/MS analysis to determine the acetylation residues. The relative lysine was then mutated to arginine in the LT nucleotide and BKPyV genome to analyze the role of LT lysine acetylation in the BKPyV life cycle. Results BKPyV LT acetylation sites were identified at Lys3 and Lys230 by mass spectrometry. HDAC3 and HDAC8 and their deacetylation activity are required for BKPyV LT expression. In addition, mutations of Lys3 and Lys230 to arginine increased LT expression, and the interaction of HDAC3 and LT was confirmed by coimmunoprecipitation. Conclusions HDAC3 is a newly identified protein that interacts with BKPyV LT, and LT acetylation plays a vital role in the BKPyV life cycle.

Well-being can reflect people’s psychological conditions and be used alongside physiological parameters to evaluate patients’ physical and mental health. The modern medical environment increasingly incorporates digital carriers, human–computer interaction devices, sensible spaces, and the execution of suitable algorithms. Slow design in healthy human–computer interaction is often used to reflect people’s dependence on or support from behaviors or objects, promoting the stability of behaviors as well as meaningful and positive changes. Therefore, in this study, we propose a slow sensing model, develop a Slow Well-Being Gardening system, and use it to evaluate behavioral data from radiation therapy patients during treatment sessions and horticultural therapy. This study is based on SENS and slow design, setting the hospital lounge as a sensible space and establishing a sensor system. After a 10-day inspection, the process was evaluated and verified. Ultimately, data from facial detection (smile) and HRV showed that the patients in the experimental group experienced a significant improvement in their well-being, feeling better than those in the control group who maintained the most common state in normal treatment. Therefore, it can be inferred that the Slow Well-Being Gardening model is indeed valid and can be further developed.

Abstract Background Hematoxylin and Eosin (H&E)-based frozen section (FS) pathology is presently the global standard for intraoperative tumor assessment (ITA). Preparation of frozen section is labor intensive, which might consume up-to 30 minutes, and is susceptible to freezing artifacts. An FS-alternative technique is thus necessary, which is sectioning-free, artifact-free, fast, accurate, and reliably deployable without machine learning and/or additional interpretation training. Methods We develop a training-free true-H&E Rapid Fresh digital-Pathology (the-RFP) technique which is 4 times faster than the conventional preparation of frozen sections. The-RFP is assisted by a mesoscale Nonlinear Optical Gigascope (mNLOG) platform with a streamlined rapid artifact-compensated 2D large-field mosaic-stitching (rac2D-LMS) approach. A sub-6-minute True-H&E Rapid whole-mount-Soft-Tissue Staining (the-RSTS) protocol is introduced for soft/frangible fresh brain specimens. The mNLOG platform utilizes third harmonic generation (THG) and two-photon excitation fluorescence (TPEF) signals from H and E dyes, respectively, to yield the-RFP images. Results We demonstrate the-RFP technique on fresh excised human brain specimens. The-RFP enables optically-sectioned high-resolution 2D scanning and digital display of a 1 cm2 area in 700 M bits/sec, with zero post-acquisition data/image processing. Training-free blind tests considering 50 normal and tumor-specific brain specimens obtained from 8 participants reveal 100% match to the respective formalin-fixed paraffin-embedded (FFPE)-biopsy outcomes. Conclusions We provide a digital ITA solution: the-RFP, which is potentially a fast and reliable alternative to FS-pathology. With H&E-compatibility, the-RFP eliminates color- and morphology-specific additional interpretation training for a pathologist, and the-RFP-assessed specimen can reliably undergo FFPE-biopsy confirmation.

Knockout of Mir125b-2 in mice leads to defects in hippocampus-related behaviors and affects hippocampal expression of Grin2a and NMDAR-mediated currents.

Traditional Chinese medicine (TCM) has the characteristics of multi-component, multi-target, and biological systems coordination, which meet the criteria of the network pharmacological application. Therefore, using network pharmacology to discover the relationship between TCM, diseases, and cellular responses is easily achievable. Aging-induced imbalanced homeostasis is a risk factor for Alzheimer's disease (AD), a neuronal disease regulated by multiple genes. Meta-analysis of TCM in metabolic regulation to improve symptoms of AD helps understand the pharmacological effects. The drug targets of TCM can be investigated using a holistic network pharmacology approach to find potential modulators involved in AD-related metabolic pathways. Based on the theoretical prediction of TCM for AD, experimental validation is needed to develop pure compounds for specific treatments.

Abstract Cardiovascular function is related to age, sex, and state of consciousness. We hypothesized that cardiovagal baroreflex sensitivity (BRS) demonstrates different patterns in both sexes before and after 50 years of age and that these patterns are associated with patterned changes during the sleep–wake cycle. We recruited 67 healthy participants (aged 20–79 years; 41 women) and divided them into four age groups: 20–29, 30–49, 50–69, and 70–79 years. All the participants underwent polysomnography and blood pressure measurements. For each participant, we used the average of the arterial pressure variability, heart rate variability (HRV), and BRS parameters during the sleep–wake stages. BRS and HRV parameters were significantly negatively correlated with age. The BRS indexes were significantly lower in the participants aged ≥ 50 years than in those aged

Exposure to environmental metals has been associated with health outcomes including respiratory health. Little is known about the impact of exposure to environmental metals on lung function among young children in general population. This study aimed to investigate the associations of exposure to metals with lung function among young children in a population-based cohort. A total of 1488 children aged 5–8 years attended a follow-up visit as part of the Longitudinal Investigation of Global Health in Taiwanese Schoolchildren (LIGHTS) cohort. We measured urinary samples of vanadium (median: 1.21 ng/mL; interquartile range (IQR): 0.73–1.98), manganese (median: 0.23 ng/mL; IQR: 0.13–0.47), arsenic (median: 40.51 ng/mL; IQR: 21.66–70.49), nickel (median: 1.09 ng/mL; IQR: 0.31–3.60), and cadmium (median: 0.26 ng/mL; IQR: 0.11–0.43) and performed lung function tests. Urinary vanadium concentrations were inversely associated with FVC (β coefficient for the highest quartile versus the other quartiles: −33.40, p = 0.001), FEV1 (β: −41.31, p

Abstract Background Epidemiological studies suggest that advanced paternal age impact offspring health, but its impact on respiratory health is unclear. This study aimed to investigate the association of paternal age with lung function and fraction of exhaled nitric oxide (FeNO) in children. Methods We analyzed data from 1330 single-born children (576 girls, 43.3%; mean age, 6.4 years), who participated in the Longitudinal Investigation of Global Health in Taiwanese Schoolchildren (LIGHTS) cohort and received measurements of lung function and FeNO at 6-year follow-up visits. Covariate-adjusted regression analyses were applied. Results Every 5-year increase in paternal age at birth was associated with 0.51% decrease in FEV1/FVC ratio (95% CI − 0.86 to − 0.15; p = 0.005) and 19.86 mL/s decrease in FEF75 (95% CI: − 34.07 to − 5.65; p = 0.006). Stratified analyses revealed that increasing paternal age at birth was associated with decreasing FEV1/FVC ratio and FEF75 only among children with prenatal exposure to environmental tobacco smoke (ETS) or not being breastfed. Sensitivity analyses using paternal age as a categorical variable found decreasing FEV1/FVC ratio and FEF75 in the groups of paternal age 35–39 and ≥ 40 years. There was no association of paternal age at birth with FeNO. Conclusion Our findings provide novel evidence linking advanced paternal age at birth with decreasing lung function in children at school age. Children with prenatal exposure to ETS or not being breastfed are more vulnerable to the adverse effect of advanced paternal age on childhood lung function. Further studies are warranted to confirm this novel adverse effect of advanced paternal age.

Abstract Introduction The human JC polyomavirus (JCPyV) has been detected in colorectal cancer (CRC) tissues and is suggested to contribute to CRC tumorigenesis. The rearrangement of the JCPyV regulatory region is supposedly associated with CRC development. The progression of CRC involves the stepwise accumulation of mutations. The large tumor antigen (LT) of JCPyV can trigger uncontrolled cell cycle progression by targeting oncogenes, and tumor suppressor genes, and causing chromosome instability. Few studies have focused on the presence of JCPyV DNA in the higher grade of CRC tissues. Methods We collected 95 tissue blocks from samples of stages I, II, III, and IV CRC. Nested PCR targeting the regulatory region of the viral genome was performed to determine the presence of JCPyV DNA in the various stages of colorectal cancer tissues. Results The nested PCR results showed that the positive rate of JCPyV DNA increased with the progression of CRC stages. The archetypal-like, non-rearrangement genotype of JCPyV with subtle mutations was the major genotype found in CRC samples. Conclusions This finding in our study suggests that there may be an association between JCPyV and CRC progression.

The elementary school system in Taiwan currently does not have dedicated learning content for the resource classes. As the existing worksheets and online resources designed for regular classes are often not applicable for resource classes, the teachers of resource classes need to develop their own materials to accommodate the diverse needs of students with various situations. To address the issue, this research aims to design a motion infographics system that serves as an additional resource for the resource classes, to improve the students’ learning. Motion infographics combines the quality of infographics and motion graphic, in order to simplify the information presented and to create a deeper impression in the audience. The topic used in this study is carbon footprint, a highly recognized and commonly adopted concept across the globe. The experiment conducted in this research indicates that motion infographics are effective in teaching resource classes. Compared to the control group of the resource class, the experimental group of the resource class using the motion infographics system showed greatly improved exam scores and learning effectiveness. The experimental group from the resource class also demonstrated greater command and comprehension of the image shapes than that from the regular class.

Objectives: Normal-pressure hydrocephalus is a clinical syndrome consisting of dilated cerebral ventricles with the clinical triad of gait disturbance, cognitive impairment and/or urinary dysfunction. Lumbar-peritoneal (LP) shunt could improve idiopathic normal pressure hydrocephalus (iNPH) while its effectiveness on secondary NPH (sNPH) is elusive. We compared the clinical results of the patients who received LP shunt surgery between iNPH and sNPH. Materials and Methods: We retrospectively analyzed the patients who received LP shunt surgery in a single center from January 1, 2017, to June 30, 2017. Patients selected for LP shunt placement had at least two of three cardinal symptoms of iNPH. The symptoms should persist for more than 3 months with compatible brain magnetic resonance imaging findings. All patients were followed up with iNPH grading scale (iNPHGS) and Modified Rankin Scale (MRS) for evaluation. Results: Thirty-three patients (23 male and 10 female patients) with mean age 76-year-old completed follow-up in this study, and 17 patients received lumbar drainage tests and intracranial pressure measurements. Both iNPH (n = 22) and sNPH (n = 11) groups did not have major complications such as infection, nerve root injury, or shunt failure. Both groups have significant improvement in iNPHGS and MRS. Interestingly, we found the correlation between both opening intracranial pressure and pressure gradient difference to the improvement percentage from LP shunt. Conclusion: The safety and effectiveness for sNPH patients who received LP shunt placement are equivalent to the iNPH patients. Lumbar drainage test provides prerequisite outcome prediction and should be considered to identify NPH patients planned to receive LP shunt.

Sjögren's syndrome (SS) is a chronic autoimmune rheumatic disease characterized by a progressive lymphocytic infiltration of salivary glands, resulting in xerostomia and other oral diseases. The pathogenesis and mechanisms of SS on periodontal tissues are not well understood. Furthermore, results of two systemic reviews and meta-analyses in which compared periodontal parameters of patients with SS to healthy subjects were different. To determine whether periodontal conditions in SS were different from healthy controls, we re-examined the issue with a random-effect model, avoiding recruiting active controls and inadequate data conversion. Outcome measures included probing pocket depth (PPD), clinical attachment loss (CAL), plaque index (PI), and gingival index (GI). Recruited individuals comprised 198 patients with SS and 180 subjects for healthy controls. Quantitative analysis revealed higher PI (WMD = 0.76, 95% CI: 0.30, 1.23) and GI (WMD of total = 0.50, 95% CI: 0.01, 0.98) in SS patients who were not categorized into primary or secondary types of SS. PPD and CAL in SS patients was comparable with control subjects. However, heterogeneity was observed among included studies. Thus, results from this and previous analyses should be interpretated carefully, and a well-designed observational study regarding this issue should be conducted.

Background: Health-care providers typically undergo shift work and are subjected to increased stress. Night shift work may induce disturbed sleep cycles and circadian rhythm. The objective of this study was to explore if night shift workers (NSWs) show an increased risk of abnormal thyroid-stimulating hormone (TSH). Methods: We conducted a retrospective cohort study of 574 employees without thyroid disease and abnormal TSH at baseline who underwent annual check-ups between 2007 and 2016 in a medical center. NSWs were defined as those with working time schedules other than daytime hours. We calculated the incidence rate and estimated the adjusted hazard ratio (HR) for incident abnormal TSH and subclinical hypothyroidism compared with non-NSWs using a Cox regression model. Results: A total of 56 incident abnormal TSH cases and 39 subclinical hypothyroidism cases in NSWs were identified during 3000 person-years of follow-up. In models adjusted for age, sex, obesity, and working departments, we found no increased relative risk for incident abnormal TSH (HR: 0.72, 95% confidence interval: 0.33–1.60) or subclinical hypothyroidism (HR: 0.52, 95% confidence interval: 0.19–1.45) when comparing NSWs to non-NSWs; nor were incidence rates significantly different among exclusively medical employees after excluding administrative staff. Conclusion: In this hospital-based nine-year follow-up retrospective cohort study, NSWs were not associated with increased relative risk of incident abnormal TSH and subclinical hypothyroidism, in contrast to previous cross-sectional studies.

PurposeDiabetic macular edema (DME) is one of the leading causes of visual impairment in diabetic retinopathy (DR). Physicians rely on optical coherence tomography (OCT) and baseline visual acuity (VA) to tailor therapeutic regimen. However, best-corrected visual acuity (BCVA) from chart-based examinations may not wholly reflect DME status. Chart-based examinations are subjected findings dependent on the patient’s recognition functions and are often confounded by concurrent corneal, lens, retinal, optic nerve, or extraocular disorders. The ability to infer VA from objective optical coherence tomography (OCT) images provides the predicted VA from objective macular structures directly and a better understanding of diabetic macular health. Deviations from chart-based and artificial intelligence (AI) image-based VA will prompt physicians to assess other ocular abnormalities affecting the patients VA and whether pursuing anti-VEGF treatment will likely yield increment in VA.Materials and methodsWe enrolled a retrospective cohort of 251 DME patients from Big Data Center (BDC) of Taipei Veteran General Hospital (TVGH) from February 2011 and August 2019. A total of 3,920 OCT images, labeled as “visually impaired” or “adequate” according to baseline VA, were grouped into training (2,826), validation (779), and testing cohort (315). We applied confusion matrix and receiver operating characteristic (ROC) curve to evaluate the performance.ResultsWe developed an OCT-based convolutional neuronal network (CNN) model that could classify two VA classes by the threshold of 0.50 (decimal notation) with an accuracy of 75.9%, a sensitivity of 78.9%, and an area under the ROC curve of 80.1% on the testing cohort.ConclusionThis study demonstrated the feasibility of inferring VA from routine objective retinal images.Translational relevanceServes as a pilot study to encourage further use of deep learning in deriving functional outcomes and secondary surrogate endpoints for retinal diseases.

Background Small cell lung cancer (SCLC) is a deadly disease with a 5-year survival of less than 7%. The addition of immunotherapy to chemotherapy was recently approved as first-line treatment; however, the improved clinical benefit is modest, highlighting an urgent need for new treatment strategies. Nemvaleukin alfa, a novel engineered interleukin-2 fusion protein currently in phase I–III studies, is designed to selectively expand cytotoxic natural killer (NK) cells and CD8+ T cells. Here, using a novel SCLC murine model, we investigated the effects of a mouse version of nemvaleukin (mNemvaleukin) on tumor growth and antitumor immunity.Methods A novel Rb1−/−p53−/−p130−/− SCLC model that mimics human disease was generated. After confirming tumor burden by MRI, mice were randomized into four treatment groups: vehicle, mNemvaleukin alone, chemotherapy (cisplatin+etoposide) alone, or the combination of mNemvaleukin and chemotherapy. Tumor growth was measured by MRI and survival was recorded. Tumor-infiltrating lymphocytes and peripheral blood immune cells were analyzed by flow cytometry. Cytokine and chemokine secretion were quantified and transcriptomic analysis was performed to characterize the immune gene signatures.Results mNemvaleukin significantly inhibited SCLC tumor growth, which was further enhanced by the addition of chemotherapy. Combining mNemvaleukin with chemotherapy provided the most significant survival benefit. Profiling of tumor-infiltrating lymphocytes revealed mNemvaleukin expanded the total number of tumor-infiltrating NK and CD8+ T cells. Furthermore, mNemvaleukin increased the frequencies of activated and proliferating NK and CD8+ T cells in tumors. Similar immune alterations were observed in the peripheral blood of mNemvaleukin-treated mice. Of note, combining mNemvaleukin with chemotherapy had the strongest effects in activating effector and cytotoxic CD8+ T cells. mNemvaleukin alone, and in combination with chemotherapy, promoted proinflammatory cytokine and chemokine production, which was further confirmed by transcriptomic analysis.Conclusions mNemvaleukin, a novel cytokine-based immunotherapy, significantly inhibited murine SCLC tumor growth and prolonged survival, which was further enhanced by the addition of chemotherapy. mNemvaleukin alone, and in combination with chemotherapy, drove a strong antitumor immune program elicited by cytotoxic immune cells. Our findings support the evaluation of nemvaleukin alone or in combination with chemotherapy in clinical trials for the treatment of SCLC.

Abstract The proportion of allergic diseases attributable to atopy remains a subject of controversy. This study aimed to estimate the population risk of physician-diagnosed asthma, rhinitis and eczema attributed to atopy among a population sample of Asian school-age children. Asian children aged 5–18 years (n = 1321) in the Prediction of Allergies in Taiwanese CHildren (PATCH) study were tested for serum allergen-specific immunoglobulin E. Physician-diagnosed asthma, rhinitis and eczema were assessed by a modified International Study of Asthma and Allergies in Childhood questionnaire. Atopy was defined as the presence of serum allergen-specific immunoglobulin E. In this population-based study, 50.4% of the subjects with asthma, 46.3% with rhinitis, and 46.7% with eczema were attributable to atopy. The population attributable risk (PAR) of atopy for three allergic diseases was higher in adolescents (asthma, 54.4%; rhinitis, 59.6%; eczema, 49.5%) than younger children aged less than 10 years (asthma, 46.9%; rhinitis, 39.5%; eczema, 41.9%). Among the seven allergen categories, sensitization to mites had the highest PARs for all three allergic diseases (51.3 to 64.1%), followed by sensitization to foods (asthma, 7.1%; rhinitis, 10.4%; eczema 27.7%). In conclusion, approximately half (46.3 to 50.4%) of Asian children in Taiwan with allergic diseases are attributable to atopy.

Abstract Background Lung adenocarcinoma (LUAD) is a highly malignant and heterogeneous tumor that involves various oncogenic genetic alterations. Epigenetic processes play important roles in lung cancer development. However, the variation in enhancer and super-enhancer landscapes of LUAD patients remains largely unknown. To provide an in-depth understanding of the epigenomic heterogeneity of LUAD, we investigate the H3K27ac histone modification profiles of tumors and adjacent normal lung tissues from 42 LUAD patients and explore the role of epigenetic alterations in LUAD progression. Results A high intertumoral epigenetic heterogeneity is observed across the LUAD H3K27ac profiles. We quantitatively model the intertumoral variability of H3K27ac levels at proximal gene promoters and distal enhancers and propose a new epigenetic classification of LUAD patients. Our classification defines two LUAD subgroups which are highly related to histological subtypes. Group II patients have significantly worse prognosis than group I, which is further confirmed in the public TCGA-LUAD cohort. Differential RNA-seq analysis between group I and group II groups reveals that those genes upregulated in group II group tend to promote cell proliferation and induce cell de-differentiation. We construct the gene co-expression networks and identify group-specific core regulators. Most of these core regulators are linked with group-specific regulatory elements, such as super-enhancers. We further show that CLU is regulated by 3 group I-specific core regulators and works as a novel tumor suppressor in LUAD. Conclusions Our study systematically characterizes the epigenetic alterations during LUAD progression and provides a new classification model that is helpful for predicting patient prognosis.

Background: Previous studies suggest the association between early-life weight gain and asthma. It remains unclear whether early-life weight gain is associated with atopic or non-atopic asthma. This study aimed to investigate whether early-life weight gain is associated with atopic or non-atopic asthma. Methods: Included in this study were 1343 singleton-birth children (761 boys, 57%) born between January 2010 and December 2011 participating in the Longitudinal Investigation of Global Health in Taiwanese Schoolchildren (LIGHTS) cohort were evaluated by a modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and interviewed by pediatricians between July 1, 2016 and May 31, 2018 at the mean age of 6.4 years. Weight gain z-scores during the first 6, 12, and 18 months of life were classified into 4 groups: slow (below −0.67), on track (−0.67 to 0.67), rapid (0.67 to 1.28), and extremely rapid (above 1.28). The main outcomes were atopic and non-atopic asthma. Asthma was defined as having physician-diagnosed asthma and the presence of wheeze or asthma exacerbations in the last 12 months. Atopy was determined by Phadiatop Infant. Results: The extremely rapid weight gain group of children during the first 6, 12, and 18 months of life was significantly associated with an increased risk of non-atopic asthma (adjusted odd ratio [AOR], 2.14, 95% confidence interval [CI], 1.01–4.53 for the first 6 months; AOR, 2.86, 95% CI, 1.34–6.14 for the first 12 months; AOR, 3.26, 95% CI 1.49–7.15 for the first 18 months) compared with the on track group. No significant association was found in atopic asthma. A sex-stratified analysis revealed the association of early-life weight gain with non-atopic asthma was statistically significant only in boys (AOR, 4.24, 95% CI, 1.44–12.50). Conclusion: Extremely rapid weight gain during the first 6–18 months of life was significantly associated with 2.1- to 3.3-fold increased risk of non-atopic asthma, with a more pronounced risk found in boys.

Purpose: Early-life antibiotic use may be associated with asthma, yet whether this association also exists in patients with allergic rhinitis (AR) remains unknown. We investigated the association between antibiotic exposure and asthma development in AR children. Methods: AR patients less than 18 year-old were enrolled from the Taiwan National Health Insurance Database, which reported information from 2005 to 2010. The case group was defined as having newly developed asthma, and the control group was defined as never having an asthma diagnosis. The age of first exposure to antibiotic prescriptions and antibiotic exposure records preceding 5 years before the first asthma diagnosis were obtained from drug prescription records. The odds ratio (OR) was examined after adjusting for age, gender, resident urbanization, underlying medical disorders and medications. Results: A total of 3236 AR patients with newly developed asthma and 9708 AR patients without asthma were included in this study. Antibiotic exposure before the age of 3 years was not associated with asthma development. Preceding 5-year antibiotic exposure increased the risk of asthma development with a dose-response relationship, even for antibiotics with low cumulative defined daily doses (adjusted OR 1.40, 95% CI 1.12–1.75). Preceding 5-year exposure to penicillin and macrolide significantly increased the risk of asthma when diagnosed before age 12 in AR patients, but this was not statistically significant when asthma diagnosed after age 12. Conclusion: Preceding 5-year antibiotic exposure, particularly to penicillin group of amoxicillin and macrolides, is associated with the risk of asthma development before age 12 in AR children.

In factories, energy conservation is a crucial issue. The co-fabrication space is a modern-day equivalent of a new factory type, and it makes use of Internet of Things (IoT) devices, such as sensors, software, and online connectivity, to keep track of various building features, analyze data, and produce reports on usage patterns and trends that can be used to improve building operations and the environment. The co-fabrication user requires dynamic and flexible space, which is different from the conventional user’s usage. Because the user composition in a co-fabrication space is dynamic and unstable, we cannot use the conventional approach to assess their usage and rentals. Prototyping necessitates a specifically designed energy-saving strategy. The research uses a “seeing–moving–seeing” design thinking framework, which enables designers to more easily convey their ideas to others through direct observation of the outcomes of their intuitive designs and the representation of their works through design media. The three components of human behavior, physical manufacture, and digital interaction are primarily the focus of this work. The computing system that connects the physical machine is created through communication between the designer and the digital interface, giving the designer control over the physical machine. It is an interactive fabrication process formed by behavior. The Sensible Energy System+ is an interactive fabrication process of virtual and real coexistence created by combining the already-existing technology, the prototype fabrication machine, and SENS. This process analyzes each step of the fabrication process and energy, fits it into the computing system mode to control the prototype fabrication machine, and reduces the problem between virtual and physical fabrication and energy consumption.

Background During the COVID-19 surge in Taiwan, the Far East Memorial Hospital established a system including a centralized quarantine unit and triage admission protocol to facilitate acute care surgical inpatient services, prevent nosocomial COVID-19 infection and maintain the efficiency and quality of health care service during the pandemics. Materials and methods This retrospective cohort study included patients undergoing acute care surgery. The triage admission protocol was based on rapid antigen tests, Liat® PCR and RT-PCT tests. Type of surgical procedure, patient characteristics, and efficacy indices of the centralized quarantine unit and emergency department (ED) were collected and analyzed before (Phase I: May 11 to July 2, 2021) and after (Phase II: July 3 to July 31, 2021) the system started. Results A total of 287 patients (105 in Phase I and 182 in Phase II) were enrolled. Nosocomial COVID-19 infection occur in 27 patients in phase I but zero in phase II. More patients received traumatological, orthopedic, and neurologic surgeries in phase II than in phase I. The patients’ surgical risk classification, median total hospital stay, intensive care unit (ICU) stay, intraoperative blood loss, operation time, and the number of patients requiring postoperative ICU care were similar in both groups. The duration of ED stay and waiting time for acute care surgery were longer in Phase II (397 vs. 532 minutes, p < 0.0001). The duration of ED stay was positively correlated with the number of surgical patients visiting the ED (median = 66 patients, Spearman’s ρ = 0.207) and the occupancy ratio in the centralized quarantine unit on that day (median = 90.63%, Spearman’s ρ = 0.191). Conclusions The triage admission protocol provided resilient quarantine needs and sustainable acute care surgical services during the COVID-19 pandemic. The efficiency was related to the number of medical staff dedicated to the centralized quarantine unit and number of surgical patients visited in ED.

Cinnamic acid is one of the phenolic compounds that is isolated from cinnamon, or other natural plants, and has a wide range of physiological activities. However, the application of cinnamic acid is limited due to its poor solubility and low oral bioavailability. In this study, the feasibility of producing octyl cinnamate by ultrasonic assistance, combined with a rotary evaporation under vacuum, was studied using methyl cinnamate and octanol as the starting materials. A Box–Behnken design (BBD) was employed to evaluate the effects of the operation parameters, including reaction temperature (55–75 °C), reaction time (4–12 h), and ultrasonic power (90–150 W) on the production of octyl cinnamate. Meanwhile, the synthesis process was further optimized by the modeling response surface methodology (RSM). The data indicated that octyl cinnamate was efficiently synthesized from methyl cinnamate and octanol using the ultrasound plus vacuum system; further, this system was superior to the conventional method. According to the RSM model for the actual experiments, a reaction temperature of 74.6 °C, a reaction time of 11.1 h, and an ultrasound power of 150 W were determined to be the best conditions for the maximum molar conversion of octyl cinnamate (93.8%). In conclusion, the highly efficient synthesis of octyl cinnamate by a rotary evaporator with an ultrasound plus vacuum system was achieved via RSM optimization.

MicroRNAs (miRNAs) play important roles in the development of various cancers including lung cancer which is one of the devastating diseases worldwide. How miRNAs function in de novo lung tumorigenesis remains largely unknown. We here developed a CRISPR/Cas9-mediated dual guide RNA (dgRNA) system to knockout miRNAs in genetically engineered mouse model (GEMM). Through bioinformatic analyses of human lung cancer miRNA database, we identified 16 downregulated miRNAs associated with malignant progression and performed individual knockout with dgRNA system in KrasG12D/Trp53L/L (KP) mouse model. Using this in vivo knockout screening, we identified miR-30b and miR-146a, which has been previously reported as tumor suppressors and miR-190b, a new tumor-suppressive miRNA in lung cancer development. Over-expression of miR-190b in KP model as well as human lung cancer cell lines significantly suppressed malignant progression. We further found that miR-190b targeted the Hus1 gene and knockout of Hus1 in KP model dramatically suppressed lung tumorigenesis. Collectively, our study developed an in vivo miRNA knockout platform for functionally screening in GEMM and identified miR-190b as a new tumor suppressor in lung cancer.

Background: Some studies have shown associations of maternal age at delivery with asthma and food allergy in offspring. However, the relationship between maternal age at delivery and allergic rhinitis is largely unclear. This study aimed to investigate the association between maternal age at delivery and allergic rhinitis in a population sample of Asian children, and to explore potential effect modifiers. Methods: A total of 1344 singleton-birth children (763 boys, 56.8%; mean age, 6.4 years) participating in the Longitudinal Investigation of Global Health in Taiwanese Schoolchildren (LIGHTS) cohort were evaluated by a modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and interviewed by pediatricians. Allergic sensitization was determined by using Phadiatop Infant. Multiple logistic regression models with covariates adjustment were performed to investigate the association of maternal age at delivery with allergic rhinitis and allergic sensitization in offspring. Results: Among 1344 study children, 793 (59%) had physician-diagnosed allergic rhinitis. Advanced maternal age at delivery (≥40 years) was significantly associated with increased odds of allergic rhinitis (adjusted odds ratio [AOR] = 4.58, 95% confidence interval [CI]: 1.90–11.03) and allergic sensitization (AOR = 2.86, 95% CI: 1.13–7.22) in offspring. A sex-stratified analysis revealed that the association of advanced maternal age with allergic rhinitis was statistically significant only in female offspring (AOR = 7.02, 95% CI: 1.89–26.14). Stratified analyses by birth order or environmental tobacco smoke exposure during pregnancy did not reveal any significant differences. Conclusion: Advanced maternal age at delivery was associated with increased risk of allergic rhinitis in Asian children, probably more pronounced among girls.

Diabetic macular edema (DME) is a highly common cause of vision loss in patients with diabetes. Optical coherence tomography (OCT) is crucial in classifying DME and tracking the results of DME treatment. The presence of intraretinal cystoid fluid (IRC) and subretinal fluid (SRF) and the disruption of the ellipsoid zone (EZ), which is part of the photoreceptor layer, are three crucial factors affecting the best corrected visual acuity (BCVA). However, the manual segmentation of retinal fluid and the EZ from retinal OCT images is laborious and time-consuming. Current methods focus only on the segmentation of retinal features, lacking a correlation with visual acuity. Therefore, we proposed a modified U-net, a deep learning algorithm, to segment these features from OCT images of patients with DME. We also correlated these features with visual acuity. The IRC, SRF, and EZ of the OCT retinal images were manually labeled and checked by doctors. We trained the modified U-net model on these labeled images. Our model achieved Sørensen–Dice coefficients of 0.80 and 0.89 for IRC and SRF, respectively. The area under the receiver operating characteristic curve (ROC) for EZ disruption was 0.88. Linear regression indicated that EZ disruption was the factor most strongly correlated with BCVA. This finding agrees with that of previous studies on OCT images. Thus, we demonstrate that our segmentation network can be feasibly applied to OCT image segmentation and assist physicians in assessing the severity of the disease.

Objective: To determine the normal values of flow mediated dilatation (FMD) in Taiwanese women with normal singleton pregnancies for the early detection of preeclampsia. Materials and methods: Data of women with normal singleton pregnancies seen at the Tri-Service General Hospital and Taiji Clinic between January 2014 and December 2015 were collected and analyzed. FMD was measured using high-resolution ultrasonography of the brachial artery for the assessment of endothelial function at the first and second trimester. The relationship between the FMD values and maternal gestational age was analyzed. Results: A total of 122 pregnant women were included in the study. Systole FMD values first and second trimester were 9.05 ± 3.72 and 10.93 ± 3.74, respectively; and the diastole were 9.24 ± 3.64 and 11.18 ± 3.93, respectively. FMD and gestational age were positively correlated (systole, p = 0.0175; diastole, p = 0.0149). Conclusion: The normal values of FMD in Taiwanese women with normal singleton pregnancies were established, and data suggests that both systolic and diastolic FMD increase with gestational age. Because of the high failure rate, measurement of FMD may not be suitable as a routine clinical examination. Keywords: Flow mediated dilatation, Pregnancy, Taiwanese