The integration of medical open databases with artificial intelligence (AI) technologies marks a transformative era in biomedical research and health care innovation. Over the past 25 years, initiatives like PhysioNet have revolutionized data access, fostering unprecedented levels of collaboration and accelerating medical discoveries. This rise of medical open databases presents challenges, particularly in harmonizing research enablement with patient confidentiality. In response, privacy laws such as the Health Insurance Portability and Accountability Act have been established, and privacy-enhancing technologies have been adopted to maintain this delicate balance. Privacy-enhancing technologies, including differential privacy, secure multiparty computation, and notably, federated learning (FL), have become instrumental in safeguarding personal health information. FL, in particular, represents a significant advancement by enabling the development and training of AI models on decentralized data. In Taiwan, significant strides have been made in aligning with these global data-sharing and privacy standards. We have actively promoted the sharing of medical data through the development of dynamic consent systems. These systems enable individuals to control and adjust their data-sharing preferences, ensuring transparency and continuity of consent in the ever-evolving landscape of digital health. Despite the challenges associated with privacy protections, the benefits, including improved diagnostics and treatment, are substantial. The availability of open databases has notably accelerated AI research, leading to significant advancements in medical diagnostics and treatments. As the landscape of health care research continues to evolve with open science and FL, the role of medical open databases remains crucial in shaping the future of medicine, promising enhanced patient outcomes and fostering a global research community committed to ethical integrity and privacy.

Aims: This study aims to ascertain dementia incidence from 2004 to 2017 in Taiwan, and to examine the disease course in comorbidity, treatments, healthcare usage, and mortality among older people with incident dementia preceding the diagnosis of dementia and afterwards. Methods: Taiwan National Health Insurance data on people aged >= 65 years with incident dementia from January 2004 to December 2017 were excerpted to estimate annual incidence rates and annualized percentage changes (APCs). For people diagnosed before 2013, annual mortality rates and causes of death during 5 -years' follow-up were determined. Changes in 22 diseases/conditions, hospital visits and admissions, and psychotropic medication prescriptions commonly associated with dementia, were examined from 3 years preceding the index diagnosis until 5 years afterwards. Results: From 2004 to 2017, the annual incidence of dementia in Taiwan increased from 30,606 to 50,651, and by > 90 % in women; age-standardized annual incidence increased significantly, with an APC of 0.4 %(p = 0.02). For 372,203 incident cases from 2004 to 2013, annual mortality was similar to 12 % during 5 -years' follow-up. The prevalence of most comorbidities increased by 65-150 % after being diagnosed with dementia. People with incident dementia had increased healthcare usage 1 year before diagnosis, which peaked 1 year afterwards. Psychotropic medication prescriptions increased gradually over 3 years before diagnosis, peaked 3 months afterwards, gradually declined during the next 2 years, then remained stable. Conclusion: The incidence of dementia in Taiwan has increased gradually over time, with an annual mortality risk of -12 %. Older people with dementia had more healthcare needs and comorbid conditions after dementia diagnosis, highlighting the exigency of person -centered dementia care.

Surface-enhanced Raman spectroscopy (SERS) is widely utilized in bacterial analyses, with the dominant SERS peaks attributed to purine metabolites released during sample preparation. Although adenosine triphosphate (ATP) and nucleic acids are potential molecular origins of these metabolites, research on their exact contributions remains limited. This study explored purine metabolite release from E. coli and RNA integrity following various sample preparation methods. Standard water washing generated dominant SERS signals within 10 s, a duration shorter than the anticipated RNA half-lives under starvation. Evaluating RNA integrity indicated that the most abundant ribosomal RNA species remained intact for hours post-washing, whereas messenger RNA and transfer RNA species degraded gradually. This suggests that bacterial SERS signatures observed after the typical washing step could originate from only a small fraction of endogenous purine-containing molecules. In contrast, acid depurination led to degradation of most RNA species, releasing about 40 times more purine derivatives than water washing. Mild heating also instigated the RNA degradation and released more purine derivatives than water washing. Notably, differences were also evident in the dominant SERS signals following these treatments. This work provides insights into SERS-based studies of purine metabolites released by bacteria and future development of methodologies.

Background: Changing the course duration or timing of subjects in learning pathways would influence medical students’ learning outcomes. Curriculum designers need to consider the strategy of reducing cognitive load and evaluate it continuously. Our institution underwent gradual curricular changes characterized by reducing cognitive load since 2000. Therefore, we wanted to explore the impact of this strategy on our previous cohorts. Methods: This cohort study explored learning pathways across academic years of more than a decade since 2000. Eight hundred eighty-two medical students between 2006 and 2012 were included eventually. Learning outcomes included an average and individual scores of subjects in different stages. Core subjects were identified as those where changes in duration or timing would influence learning outcomes and constitute different learning pathways. We examined whether the promising learning pathway defined as the pathway with the most features of reducing cognitive load has higher learning outcomes than other learning pathways in the exploring dataset. The relationship between features and learning outcomes was validated by learning pathways selected in the remaining dataset. Results: We found nine core subjects, constituting four different learning pathways. Two features of extended course duration and increased proximity between core subjects of basic science and clinical medicine were identified in the promising learning pathway 2012, which also had the highest learning outcomes. Other pathways had some of the features, and pathway 2006 without such features had the lowest learning outcomes. The relationship between higher learning outcomes and cognitive load-reducing features was validated by comparing learning outcomes in two pathways with and without similar features of the promising learning pathway. Conclusion: An approach to finding a promising learning pathway facilitating students’ learning outcomes was validated. Curricular designers may implement similar design to explore the promising learning pathway while considering potential confounding factors, including students, medical educators, and learning design of the course.

Background: Interleukin-17 (IL-17) is a pro-inflammatory cytokine that plays a vital role in the promotion of tumorigenesis in various cancers, including colorectal cancer (CRC). Based on current evidence, IL-17 binds to interleukin-17 receptor A (IL-17RA); however, the role of IL-17RA has not been elucidated in previous studies on CRC. In this study, we explored the role of IL-17RA in human CRC tissues and the progression of CRC in humans and mice. Methods: The expressions of IL-17RA and epithelial-mesenchymal transition (EMT)-related genes were examined in CRC cells and tissue samples by quantitative real-time polymerase chain reaction. The role of IL-17RA in pathogenesis and prognosis was evaluated using a Chi-squared test, Kaplan-Meier analysis, univariate, and multivariate Cox regression analysis in 133 CRC patients. A tumor-bearing mice model was executed to evaluate the role of IL-17RA in tumor growth, vascularity and population of infiltrating immune cells. Results: IL-17RA expression was found to be significantly higher in CRC tissues than in adjacent normal tissues. The expression of IL-17RA in Stage IV patients was significantly higher than that in Stages I and II patients. Patients with high IL-17RA expression exhibited significantly worse overall and CRC-specific survival than those with low IL-17RA expression. Functional assessment suggested that the knockdown of IL-17RA expression distinctly suppressed cellular proliferation, migration, invasion, and EMT-related gene expression. In a tumor-bearing mouse model, decreased IL-17RA expression significantly repressed tumor growth and vascularity and reduced the population of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Conclusion: Reduced IL-17RA expression also suppressed cellular proliferation, migration, and invasion, and the expression of EMT genes. Knockdown of IL-17RA inhibited tumor growth and vascularity and decreased the population of Tregs and MDSCs in mouse tumors. Overall, IL-17RA expression was identified to be independently associated with the prognosis of patients with CRC.

Background: Circulating tumor cells (CTCs) have been investigated as a potential biomarker for predicting prognosis and monitoring therapeutic responses in colorectal cancer (CRC). However, the sensitivity of CTCs detection is low, thus limiting the clinical utility of CTCs. We aim to examine the clinicopathological parameters that improve prognosis prediction for CRC using CTCs as a biomarker. Methods: We enumerated CTCs in 186 CRC patients and associated the number of CTCs with the clinicopathological features and overall survival (OS) using a univariate and multivariate Cox regression model and Kaplan–Meier survival analysis. Results: The presence of CTCs from 186 CRC patients was significantly associated with stage, preoperational carcinoembryonic antigen (CEA), and CA19-9 levels. Using Kaplan–Meier survival and Cox regression analysis, patients with five or more CTCs exhibited significantly worse OS compared to patients with fewer than five CTCs. The combination of CTCs with tumor marker CEA has a better OS prediction than individual CTCs or CEA and serves as a more effective prediction model in patients with CRC. Conclusion: We identified that patients with more than five CTCs exhibited significantly worse OS. Additionally, patients with the normal level of CEA, but who also had more than five CTCs trended towards a worse OS.

PDF file - 846KB, Expression of IL-17A was higher CRC with recurrence.

PDF file - 116KB, Expression of IL-17A was positively correlated with MMP9 and VEGF.

PDF file - 65KB, Pretherapy serum levels of cytokines in patients with and without recurrence.

PDF file - 590KB, CTCs are more abundant in blood from the mesenteric vein than in blood from the forearm vein.

Background: Metabolic acidosis is a common complication in patients with chronic kidney disease (CKD). Oral sodium bicarbonate is often used to treat metabolic acidosis and prevent CKD progression. However, there is limited information about the effect of sodium bicarbonate on major adverse cardiovascular events (MACE) and mortality in patients with pre-dialysis advanced CKD.Method: 25599 patients with CKD stage V between January 1, 2001 and December 31, 2019 were identified from the Chang Gung Research Database (CGRD), a multi-institutional electronic medical record database in Taiwan. The exposure was defined as receiving sodium bicarbonate or not. Baseline characteristics were balanced using propensity score weighting between two groups. Primary outcomes were dialysis initiation, all-cause mortality, and major adverse cardiovascular events (MACE) (myocardial infarction, heart failure, stroke). The risks of dialysis, MACE, and mortality were compared between two groups using Cox proportional hazards models. In addition, we performed analyzes using Fine and Gray sub-distribution hazard models that considered death as a competing risk.Result: Among 25599 patients with CKD stage V, 5084 patients (19.9%) were sodium bicarbonate users while 20515 (80.1%) were sodium bicarbonate non-users. The groups had similar risk of dialysis initiation (hazard ratio (HR): 0.98, 95% confidence interval (CI): 0.95-1.02, p < 0.379). However, taking sodium bicarbonate was associated with a significantly lower risks of MACE (HR: 0.95, 95% CI 0.92–0.98, p < 0.001) and hospitalizations for acute pulmonary edema (HR: 0.92, 95% CI 0.88–0.96, p < 0.001) compared with non-users. The mortality risks were significantly lower in sodium bicarbonate users compared with sodium bicarbonate non-users (HR: 0.75, 95% CI 0.74–0.77, p < 0.001).Conclusion: This cohort study revealed that in real world practice, use of sodium bicarbonate was associated with similar risk of dialysis compared with non-users among patients with advanced CKD stage V. Nonetheless, use of sodium bicarbonate was associated with significantly lower rate of MACE and mortality. Findings reinforce the benefits of sodium bicarbonate therapy in the expanding CKD population. Further prospective studies are needed to confirm these findings.

Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine involved in the pathogenesis of sarcopenia, but its short half-life and inconsistent reproducibility limit the potential of TNF-alpha to be an ideal sarcopenia biomarker. Anti-TNF-alpha, a natural consequent autoantibody to TNF-alpha, is an indicator of relatively prolonged TNF-alpha exposure, has more stable concentrations than TNF-alpha and should be a better alternative as a biomarker of sarcopenia. Data from 484 participants from the I-Lan Longitudinal Aging Study were used for this study, and sarcopenia was defined by the Asian Working Group for Sarcopenia 2019 consensus. Plasma levels of anti-TNF-alpha were deter-mined by a sandwich ELISA approach, and levels of TNF-alpha were determined by an immunoassay. Compared to nonsarcopenic participants, 43 sarcopenic participants had higher levels of anti-TNF-alpha (0.73 +/- 0.19 vs. 0.79 +/- 0.25 OD, p = 0.045). Plasma levels of anti-TNF-alpha were positively correlated with TNF-alpha (r = 0.24, p < 0.001), and plasma levels of anti-TNF-alpha were positively correlated with adiposity (r = 0.16, p < 0.001) and negatively correlated with lean body mass (r =-0.14, p = 0.003). Individuals with increasing levels of anti-TNF-alpha had higher odds of being sarcopenic (OR 5.4, 95 % CI: 1.1-25.8, p = 0.035), and these associations were stronger among women and younger adults. An association between TNF-alpha and sarcopenia was noted only in middle-aged adults (OR 6.2, 95 % CI: 1.8-21.7, p = 0.004). Plasma anti-TNF-alpha levels were positively correlated with TNF-alpha and were significantly associated with sarcopenia. Anti-TNF-alpha may be a more appropriate biomarker than TNF-alpha for sarcopenia, but further investigations are needed to confirm its roles in sarcopenia diagnosis and treatment response evaluation.

PDF file - 46KB, The serum profiles of GM-CSF in mice with or without metastasis.

Circulating tumor cells (CTCs) in blood are accepted as a prognostic marker for patients with metastatic colorectal cancer (CRC). However, there is limited data on the use of CTCs as a prognostic marker for non-metastatic patients. In the current study, we used a rare cell automated analysis platform, the MiSelect R System, to enumerate CTCs from blood in non-metastatic CRC patients, and corelated the number of CTCs with the clinical staging and survival. The presence of CTCs in mesenteric vein blood (MVB) samples from 101 CRC patients was significantly associated with T stage. Patients with 1 or more CTCs per 8 mL of MVB exhibited significantly worse disease-free survival (DFS) and cancer-specific survival (CSS) compared to patient without CTCs. The presence of CTCs before surgery is an independent marker for both DFS and CSS. CTC presence after surgical resection is also a prognostic marker. CTCs are a potentially useful prognostic and predictive biomarker in non-metastatic CRC patients that may further stratify patient's risk status within different stages of disease.

PDF file - 76KB, GM-CSF facilitates CTC clearance by boosting host immunity.

In the current study, we found that among patients who achieve pCR, OS does not depend on the time interval between the completion of RT and receipt of surgery, while among patients who do not achieve pCR, delaying surgery >12 weeks is associated with reduced OS. An interval of 9-12 weeks was the best optimal time as it was associated with the highest OR of achieving pCR and better OS compared to other interval times.

PDF file - 64KB, Treatment with rGM-CSF decreased CTCs and inhibited metastasis.

Figure S1: R1 does not affect contact inhibition during prostate cancer cell proliferation; Figure S2: R1 does not affect cell apoptosis in prostate cancer cells under both steady state and dynamic conditions; Figure S3: R1 promotes prostate cancer cell migration and invasion; Figure S4: R1/c-Myc physical interaction is not required for R1 regulation of c-Myc ubiquitination; Figure S5: R1 does not affect MIZ-1 and p53 protein expression in prostate cancer cells.

PDF file - 126KB, Clinicopathological characteristics of the patients analyzed in this study.