HDGF stimulates liver tumorigenesis by enhancing reactive oxygen species generation in mitochondria.

Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis.

The incidences and clinical outcomes of cryptococcosis in Taiwan: A nationwide, population-based study, 2002-2015.

Large-scale epidemiological data on cryptococcosis other than cryptococcal meningitis (CM), human immunodeficiency virus (HIV)- or solid organ transplantation (SOT)-associated cryptococcosis are limited. This study investigated the disease burden of cryptococcosis in Taiwan over 14 years. Incident episodes of cryptococcosis, comorbidities, treatment, and outcomes were captured from Taiwan's National Health Insurance Research Database and National Death Registry between 2002 and 2015. Of 6647 episodes analyzed, the crude incidence rate per 100 000 population increased from 1.48 in 2002 to 2.76 in 2015, which was driven by the growing trend in the non-CM group (0.86-2.12) but not in the CM group (0.62-0.64). The leading three comorbidities were diabetes mellitus (23.62%), malignancy (22.81%), and liver disease (17.42%). HIV accounted for 6.14% of all episodes and was associated with the highest disease-specific incidence rate (269/100 000 population), but the value dropped 16.20% biennially. Within 90 days prior to cohort entry, 30.22% of episodes had systemic corticosteroid use. The in-hospital mortality of all episodes was 10.80%, which varied from 32.64% for cirrhosis and 13.22% for HIV to 6.90% for SOT. CM was associated with a higher in-hospital mortality rate than non-CM (19.15% vs. 6.33%). At diagnosis, only 48.53% of CM episodes were prescribed an amphotericin-based regimen. The incidence rate of cryptococcosis was increasing, especially that other than meningitis and in the non-HIV population. A high index of clinical suspicion is paramount to promptly diagnose, treat, and improve cryptococcosis-related mortality in populations other than those with HIV infection or SOT.

This nationwide study showed that the incidence rate of cryptococcosis doubled from 2002 to 2015. Non-meningeal cryptococcosis and non-HIV/nontransplant (NHNT)-associated cryptococcosis contributed to this increase. Our study highlighted the underestimated burden of cryptococcosis in the NHNT hosts.

Clinical impacts of frailty on 123,172 people with diabetes mellitus considering the age of onset and drugs of choice: a nationwide population-based 10-year trajectory analysis.

AIMS: Frailty substantially increased the risk of adverse clinical outcomes, which was also critical in diabetes management. This study aimed to investigate the interrelationships between the age of onset, frailty, anti-diabetic medications and clinical outcomes in people with diabetes mellitus (DM). METHODS: A total of 123,172 people aged 40 years and older who were newly diagnosed with DM were identified and categorised into four frailty subgroups (robust, mild, moderate and severe) based on the multimorbidity frailty index (mFI). Cox proportional hazards models were used to examine associations between frailty and clinical outcomes at different ages of DM onsets (40-64, 65-74, 75-84 and 85+ years). Outcomes of interest included generic outcomes (mortality and unplanned hospitalisation) and DM-related outcomes (cardiovascular disease-related mortality, major adverse cardiovascular events (MACEs), diabetes-related hospitalisation and hypoglycaemia). RESULTS: The proportion of frailty increased with age at diagnosis amongst people with incident DM and the mFI scores increased significantly during the 10-year follow-up. Amongst people with diabetes, those with mild, moderate and severe frailty were associated with greater risks of all-cause mortality (mild: adjusted hazard ratio (aHR) 1.69 [95% confidence interval (CI) 1.60-1.80], P < 0.01; moderate: aHR 2.46 [2.29-2.65], P < 0.01; severe frailty: aHR 3.40 [3.16-3.65], P < 0.01) compared with the robust group. Similar results were found in unplanned hospitalisations, cardiovascular disease-related mortality, MACEs and hypoglycaemia. CONCLUSIONS: Our study quantified the prevalence of frailty, captured its dynamic changes and examined its impacts on various clinical outcomes amongst people with diabetes at different ages at onset. Frailty assessment and management should be implemented into routine diabetes care.

Risk of thromboembolic events associated with different multiple myeloma regimens in Taiwan: a nested case-control study.

Although novel agents for multiple myeloma (MM) have a better response rate and survival in both newly diagnosed and relapsed/refractory MM patients, concerns regarding the association between MM treatments and thromboembolic events have been raised. The aim of this population-based study was to examine the association between different combinations of MM treatments and the risk of thromboembolic events. We conducted a nested case-control study using the Taiwan Cancer Registry (TCR) and National Health Insurance Research Database (NHIRD). Adult patients newly diagnosed with MM and treated with at least one of the immunomodulatory agents between 2008 and 2016 were identified. Among them, we further identified patients who developed thromboembolic events as cases and selected controls matched by age, sex and duration of MM diagnosis at a ratio of 1:5. The index date was defined as the day one year before the diagnosis date of thromboembolic events in the case group and the corresponding date in the control group. Conditional logistic regression was used to examine the association between different MM treatment regimens and the risk of thromboembolic events. A total of 4,180 newly diagnosed MM patients treated with at least one of the immunomodulatory agents were identified (mean age: 67.2 years; male: 55.7%). In this MM cohort, we further identified 388 cases and 1,940 matched controls (mean age: 71 years; male: 64.2%). The use of a thalidomide/bortezomib/steroid combination (odds ratio (OR) 2.95 [95% confidence interval (CI) 1.47-5.95]), thalidomide monotherapy (OR 3.33; 95% CI, 1.59-6.94), and a thalidomide/steroid combination (OR 4.24; 95% CI, 2.00-8.98) were associated with an increased risk of thromboembolic events. Other risk factors, particularly a history of thromboembolic events, including ischemic heart disease and pulmonary embolism, were significantly associated with increased risk of thromboembolic events. We found that the use of thalidomide alone and in specific combinations was associated with an increased risk of thromboembolic events.

Using Hypothesis-Led Machine Learning and Hierarchical Cluster Analysis to Identify Disease Pathways Prior to Dementia: Longitudinal Cohort Study.

BACKGROUND: Dementia development is a complex process in which the occurrence and sequential relationships of different diseases or conditions may construct specific patterns leading to incident dementia. OBJECTIVE: This study aimed to identify patterns of disease or symptom clusters and their sequences prior to incident dementia using a novel approach incorporating machine learning methods. METHODS: Using Taiwan's National Health Insurance Research Database, data from 15,700 older people with dementia and 15,700 nondementia controls matched on age, sex, and index year (n=10,466, 67% for the training data set and n=5234, 33% for the testing data set) were retrieved for analysis. Using machine learning methods to capture specific hierarchical disease triplet clusters prior to dementia, we designed a study algorithm with four steps: (1) data preprocessing, (2) disease or symptom pathway selection, (3) model construction and optimization, and (4) data visualization. RESULTS: Among 15,700 identified older people with dementia, 10,466 and 5234 subjects were randomly assigned to the training and testing data sets, and 6215 hierarchical disease triplet clusters with positive correlations with dementia onset were identified. We subsequently generated 19,438 features to construct prediction models, and the model with the best performance was support vector machine (SVM) with the by-group LASSO (least absolute shrinkage and selection operator) regression method (total corresponding features=2513; accuracy=0.615; sensitivity=0.607; specificity=0.622; positive predictive value=0.612; negative predictive value=0.619; area under the curve=0.639). In total, this study captured 49 hierarchical disease triplet clusters related to dementia development, and the most characteristic patterns leading to incident dementia started with cardiovascular conditions (mainly hypertension), cerebrovascular disease, mobility disorders, or infections, followed by neuropsychiatric conditions. CONCLUSIONS: Dementia development in the real world is an intricate process involving various diseases or conditions, their co-occurrence, and sequential relationships. Using a machine learning approach, we identified 49 hierarchical disease triplet clusters with leading roles (cardio- or cerebrovascular disease) and supporting roles (mental conditions, locomotion difficulties, infections, and nonspecific neurological conditions) in dementia development. Further studies using data from other countries are needed to validate the prediction algorithms for dementia development, allowing the development of comprehensive strategies to prevent or care for dementia in the real world.

Tyrosine Kinase Inhibitors and Vascular Adverse Events in Patients with Chronic Myeloid Leukemia: A Population-Based, Propensity Score-Matched Cohort Study.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have shown long-term survival benefits in patients with chronic myeloid leukemia (CML). Nevertheless, significant concern has been raised regarding long-term TKI-associated vascular adverse events (VAEs). The objective of this retrospective cohort study was to investigate the incidence of VAEs in Taiwanese patients with CML treated with different TKIs (imatinib, nilotinib, and dasatinib) as well as potential risk factors. MATERIALS AND METHODS: We conducted a retrospective cohort study using the Taiwan Cancer Registry Database and National Health Insurance Research Database. Adult patients diagnosed with CML from 2008 to 2016 were identified and categorized into three groups according to their first-line TKI treatment (imatinib, nilotinib, and dasatinib). Propensity score matching was performed to control for potential confounders. Cox regressions were used to estimate the hazard ratio (HR) of VAEs in different TKI groups. RESULTS: In total, 1,111 patients with CML were included in our study. We found that the risk of VAEs in nilotinib users was significantly higher than that in imatinib users, with an HR of 3.13 (95% confidence interval (CI), 1.30-7.51), whereas dasatinib users also showed a nonsignificant trend for developing VAEs, with an HR of 1.71 (95% CI, 0.71-4.26). In multivariable logistic regression analysis, only nilotinib usage, older age, and history of cerebrovascular diseases were identified as significant risk factors. The annual incidence rate of VAEs was highest within the first year after the initiation of TKIs. CONCLUSION: These findings can support clinicians in making treatment decisions and monitoring VAEs in patients with CML in Taiwan. IMPLICATIONS FOR PRACTICE: This study found that patients with chronic myeloid leukemia (CML) treated with nilotinib and dasatinib may be exposed to a higher risk of developing vascular adverse events (VAEs) compared with those treated with imatinib. Thus, this study suggests that patients with CML who are older or have a history of cerebrovascular diseases should be under close monitoring of VAEs, particularly within the first year after the initiation of tyrosine kinase inhibitors.

Hepatoma-derived growth factor participates in concanavalin A-induced hepatitis.

Hepatitis is an important health problem worldwide. Novel molecular targets are in demand for detection and management of hepatitis. Hepatoma-derived growth factor (HDGF) has been delineated to participate in hepatic fibrosis and liver carcinogenesis. However, the relationship between hepatitis and HDGF remains unclear. This study aimed to elucidate the role of HDGF during hepatitis using concanavalin A (ConA)-induced hepatitis model. In cultured hepatocytes, ConA treatment-elicited HDGF upregulation at transcriptional level and promoted HDGF secretion while reducing intracellular HDGF protein level and cellular viability. Similarly, mice receiving ConA administration exhibited reduced hepatic HDGF expression and elevated circulating HDGF level, which was positively correlated with serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. By using HDGF knockout (KO) mice, it was found the ConA-evoked cell death was prominently alleviated in KO compared with control. Besides, it was delineated HDGF ablation conferred protection by suppressing the ConA-induced neutrophils recruitment in livers. Above all, the ConA-mediated activation of tumor necrosis factor-α (TNF-α)/interleukin-1ß (IL-1ß)/interleukin-6 (IL-6)/cyclooxygenase-2 (COX-2) inflammatory signaling was significantly abrogated in KO mice. Treatment with recombinant HDGF (rHDGF) dose-dependently stimulated the expression of TNF-α/IL-1ß/IL-6/COX-2 in hepatocytes, further supporting the pro-inflammatory function of HDGF. Finally, application of HDGF antibody not only attenuated the ConA-mediated inflammatory cascade in hepatocytes, but also ameliorated the ConA-induced hepatic necrosis and AST elevation in mice. In summary, HDGF participates in ConA-induced hepatitis via neutrophils recruitment and may constitute a therapeutic target for acute hepatitis.

All-cause mortality, cardiovascular mortality, major cardiovascular events and hypoglycaemia of patients with diabetes onset at an older age: results from the 10-year nationwide cohort study.

BACKGROUND: Longitudinal adverse outcomes are unclear among adults with diabetes according to the age of onset. OBJECTIVE: To investigate the longitudinal diabetes-related outcomes in adults with new-onset diabetes stratified by age. DESIGN: Retrospective cohort study. SETTING: Taiwan National Health Insurance Research Database claims data from 2000 to 2015. SUBJECTS: In total, 115,751 participants aged ≥40 years with new-onset diabetes in 2003 were recruited and stratified by the ages 40-64 (64.3%), 65-74 (21.2%), 75-84 (11.8%) and ≥85 years (2.7%) at the time of diagnosis. METHODS: Time-varying multivariate Cox proportional hazards model adjusted for covariates was used to examine the associations between the ages of the patients at diabetes onset and the outcomes of interest [all-cause mortality, cardiovascular (CV) mortality, major cardiovascular events (MACE) and hypoglycaemia] during a 10-year follow-up period. RESULTS: The results showed that compared with those patients aged 40-64 at diagnosis, patients with older-onset diabetes had significantly higher comorbidities (P < 0.01) and a higher diabetes severity (P < 0.01). Patients with older-onset diabetes had a higher risk of all-cause mortality [adjusted hazard ratio (aHR) 2.28, 4.48 and 10.07 in 65-74, 75-84 and ≥85 years old, respectively], CV mortality (aHR = 2.82, 6.06 and 15.91), MACE (aHR = 2.19, 3.01 and 4.15) and hypoglycaemia (aHR = 2.41, 3.59 and 4.62) than patients aged 40-64 during a 10-year follow-up period. CONCLUSIONS: Patients with diabetes onset at an older age was associated with increased risks of all-cause mortality, CV mortality, MACE and hypoglycaemia after adjusting for the severity of diabetes and anti-diabetic treatment.

A phase 3, open-label, multicenter study of a 6-month pre-mixed depot formulation of leuprolide mesylate in advanced prostate cancer patients.

OBJECTIVES: To determine the safety, efficacy and pharmacokinetic (PK) profile of a pre-mixed depot formulation of leuprolide mesylate subcutaneous injectable suspension (LMIS) 50 mg for up to 1 year of treatment for subjects with advanced prostate cancer. PATIENTS AND METHODS: In this open-label, multicenter study, prostate cancer patients with indication for androgen ablation therapy received two subcutaneous injection of LMIS 50 mg 6 months apart and were followed for an additional 6 months. Two efficacy primary end points were the percentage of subjects with a serum testosterone level ≤ 50 ng/dL by Day 28 as well as the percentage of subjects with similar testosterone suppression from Day 28 to Day 336. RESULTS: Of the 137 enrolled subjects, 15 (10.9%) subjects did not complete the study, including 5 subjects who terminated early due to an adverse event. By Day 28, 98.5% (95% confidence interval 94.8-99.8) of the subjects achieved a castrate testosterone level. At the end of the study, 97% and 95.9% of the subjects had serum testosterone level ≤ 50 ng/dL and ≤ 20 ng/dL, respectively. LMIS 50 mg significantly reduced serum prostate-specific antigen levels after its first injection and this PSA declination effect remained until the end of the study. No statistically significant change was observed in worsening bone pain or urinary symptom assessments during the study. Hot flush (48.9%) and hypertension (14.6%) were the two most common adverse events reported. CONCLUSIONS: LMIS 50 mg, administered at 6-month intervals, effectively suppressed serum testosterone level, and demonstrated a consistent safety profile.

Comparisons Between Hypothesis- and Data-Driven Approaches for Multimorbidity Frailty Index: A Machine Learning Approach.

BACKGROUND: Using big data and the theory of cumulative deficits to develop the multimorbidity frailty index (mFI) has become a widely accepted approach in public health and health care services. However, constructing the mFI using the most critical determinants and stratifying different risk groups with dose-response relationships remain major challenges in clinical practice. OBJECTIVE: This study aimed to develop the mFI by using machine learning methods that select variables based on the optimal fitness of the model. In addition, we aimed to further establish 4 entities of risk using a machine learning approach that would achieve the best distinction between groups and demonstrate the dose-response relationship. METHODS: In this study, we used Taiwan's National Health Insurance Research Database to develop a machine learning multimorbidity frailty index (ML-mFI) using the theory of cumulative diseases/deficits of an individual older person. Compared to the conventional mFI, in which the selection of diseases/deficits is based on expert opinion, we adopted the random forest method to select the most influential diseases/deficits that predict adverse outcomes for older people. To ensure that the survival curves showed a dose-response relationship with overlap during the follow-up, we developed the distance index and coverage index, which can be used at any time point to classify the ML-mFI of all subjects into the categories of fit, mild frailty, moderate frailty, and severe frailty. Survival analysis was conducted to evaluate the ability of the ML-mFI to predict adverse outcomes, such as unplanned hospitalizations, intensive care unit (ICU) admissions, and mortality. RESULTS: The final ML-mFI model contained 38 diseases/deficits. Compared with conventional mFI, both indices had similar distribution patterns by age and sex; however, among people aged 65 to 69 years, the mean mFI and ML-mFI were 0.037 (SD 0.048) and 0.0070 (SD 0.0254), respectively. The difference may result from discrepancies in the diseases/deficits selected in the mFI and the ML-mFI. A total of 86,133 subjects aged 65 to 100 years were included in this study and were categorized into 4 groups according to the ML-mFI. Both the Kaplan-Meier survival curves and Cox models showed that the ML-mFI significantly predicted all outcomes of interest, including all-cause mortality, unplanned hospitalizations, and all-cause ICU admissions at 1, 5, and 8 years of follow-up (P<.01). In particular, a dose-response relationship was revealed between the 4 ML-mFI groups and adverse outcomes. CONCLUSIONS: The ML-mFI consists of 38 diseases/deficits that can successfully stratify risk groups associated with all-cause mortality, unplanned hospitalizations, and all-cause ICU admissions in older people, which indicates that precise, patient-centered medical care can be a reality in an aging society.

Novel HDGF/HIF-1α/VEGF axis in oral cancer impacts disease prognosis.

BACKGROUND: Hepatoma-derived growth factor (HDGF) participates in angiogenesis and represents a negative prognostic factor in oral cancer. The current study was designed to elucidate the regulatory mechanism between HDGF and vascular endothelial growth factor (VEGF) and the clinical impact of oral cancer. METHODS: TCGA data and surgical samples from oral cancer patients were used for the clinicopathological parameter and survival analysis. Human oral cancer SCC4 and SAS cells were treated with recombinant HDGF protein. VEGF gene expression and protein level were analyzed by RT-PCR, Western blotting, and enzyme-linked immunosorbent assay. The signaling pathways for regulating VEGF expression were investigated. The nucleolin neutralizing antibody and HIF-1α inhibitor were applied to SCC4 cells to investigate their effects on the HDGF-stimulated VEGF pathways. RESULTS: TCGA and immunohistochemical analysis revealed a positive correlation between HDGF and VEGF expression in oral cancer tissues. Recombinant HDGF significantly increased VEGF gene and protein expression in oral cancer SCC4 cells in a dose-dependent manner. HDGF enhanced the phosphorylation levels of AKT and IkB and the protein level of HIF-1α and NF-κB. The nucleolin-neutralizing antibody abolished HDGF-stimulated HIF-1α, NF-κB and VEGF protein expression in SCC4 cells. The HIF-1α inhibitor antagonized the HDGF-induced VEGF gene expression. High VEGF expression was strongly correlated with HDGF expression, advanced disease, and poor survival. CONCLUSION: This study postulated a new pathway in which HDGF activated HIF-1α and then induced VEGF expression through binding to membrane nucleolin under normoxic conditions, leading to poor disease control. The HDGF/HIF-1α/VEGF axis is important for developing future therapeutic strategies.

Prognostic factors for successful varicocelectomy to treat varicocele-associated male infertility.

The present study identified prognostic factors for successful varicocelectomy for the treatment of varicocele-induced male infertility. All varicoceles were diagnosed and graded by physical examination and ultrasound. Pre- and postoperative analysis of semen specimens measured sperm density, morphology and motility. 'Responder' and 'non-responder' status was determined by semen analyses at 3, 6 and 12 months postoperatively. Varicocele Grades 1, 2 and 3 were found in 16, 36 and 28 patients, respectively; 49 patients (61.3%) were responders based on improved seminograms. Significant postoperative increases were noted in sperm density (from 18.20 ± 14.76 × 10(6) to 32.36 ± 24.81 × 10(6)mL(-1); P<0.001), sperm morphology (from 57.21 ± 17.35% to 62.66 ± 15.18%; P=0.006) and percentage motility (from 29.89 ± 14.71% to 50.92 ± 19.30%; P<0.001). Multivariate logistic regression indicated that age (odds ratio (OR) 0.56; P<0.001) and preoperative sperm density (OR 1.22; P=0.001) had significant unfavourable and favourable associations, respectively, with the likelihood of successful varicocelectomy. Furthermore, a preoperative sperm density of 12 × 10(6)mL(-1) as a cut-off point was able to predict successful varicocelectomy with a sensitivity of 77.6% and specificity of 77.4% (area under the curve=0.85; P<0.001; 95% confidence interval 0.76-0.92). Age and preoperative sperm density are prognostic factors for successful varicocelectomy. The results of the present study may allow clinicians to predict surgical improvement in fertility in patients with varicocele.

The translation and validation of Chinese overactive bladder symptom score for assessing overactive bladder syndrome and response to solifenacin treatment.

BACKGROUND/PURPOSE: Overactive bladder symptom score (OABSS) was developed by a Japanese urologist and is widely used in Asian countries. The aim of this study was to develop and validate a Chinese OABSS for assessing overactive bladder (OAB) and treatment outcome after solifenacin. METHODS: The Chinese OABSS was developed by linguistic validation of the original version. Its reliability and validity, and correlations with a three-day bladder diary were tested. Patients answered the Chinese OABSS at enrollment and repeated the questionnaire after a non-treatment period of 2 weeks, and at 4 and 12 weeks after solifenacin (5mg/day). Patients also completed a three-day bladder diary and forms including patient perception of bladder condition, International Prostatic Symptom Score and quality of life index at each study visit (for a total of four visits). An analysis was conducted to evaluate the reliability and validity of the Chinese OABSS and the correlations with a three-day bladder diary and a patient perception of bladder condition, respectively. RESULTS: A total of 60 patients with OAB, including 31 OAB wet and 29 OAB dry, were enrolled. The test-retest reliability of Chinese OABSS was moderate to good with weighted kappa coefficients of 0.515-0.721 for each symptom score and 0.610 for total symptom score. Forty-eight (80%) patients completed the responsiveness study and were followed-up at all time points. Patients' OAB symptoms improved significantly from baseline to 3 months after solifenacin treatment. The changes in OABSS decreased gradually with time within the three months of solifenacin treatment. CONCLUSION: The Chinese OABSS has been validated as a reliable instrument for assessing OAB. Solifenacin 5mg once daily improved urgency and other symptoms of OAB including frequency, urge incontinence, OABSS and International Prostatic Symptom Score. The adverse effects were acceptable and became less significant with time in the three months of treatment.

Trends in dementia incidence and mortality, and dynamic changes in comorbidity and healthcare utilization from 2004 to 2017: A Taiwan national cohort study.

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∼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.

The burden of frailty in heart failure: Prevalence, impacts on clinical outcomes and the role of heart failure medications.

BACKGROUND: Frailty often coexists with heart failure (HF), which significantly aggravates the clinical outcomes of older adults. However, studies investigating the interplay between frailty and HF in older adults are scarce. We aimed to assess the prevalence of frailty using the cumulative deficit approach and evaluate the impacts of frailty on health utilization, use of HF-related medications and adverse clinical outcomes (all-cause mortality, all-cause readmissions and HF readmissions) among older HF patients. METHODS: A total of 38 843 newly admitted HF patients were identified from Taiwan's National Health Insurance Research Database and categorized into three frailty subgroups (fit, mild frailty and severe frailty) based on the multimorbidity frailty index. Cox regression models and Fine and Gray subdistribution hazard models were used to estimate the impacts of frailty on clinical outcomes at 1 and 2 years of follow-up. Generalized estimating equation models were further conducted to evaluate the associations between longitudinal and time-varying use of HF-related medications and clinical outcomes among distinct frailty subgroups. RESULTS: Of 38 843 older HF patients (mean age 80.4 ± 8.5 years, 52.3% females) identified, 68.3% were categorized as frail (47.5% of mild frailty and 20.8% of severe frailty). The median number of readmissions (fit: 1 [inter-quartile range-IQR 2], mild frailty: 1 [IQR 2] and severe frailty: 2 [IQR 3]) increased with the severity of frailty. Only 27.3% of HF patients died of cardiovascular diseases regardless of their frailty status. Compared with the fit group, the severe frailty group was associated with increased risk of all-cause mortality (adjusted hazard ratio 1.16, 95% confidence interval [CI] 1.11-1.21), all-cause readmissions (subdistributional hazard ratio (sHR) 1.21, 95% CI 1.16-1.25) and HF-related readmissions (sHR 1.14, 95% CI 1.09-1.20) at 2 years of follow-up. Those who used triple or more HF-related medications were at lower risk for all-cause readmissions (adjusted odds ratio [aOR] 0.49, 95% CI 0.44-0.54) and HF-related readmissions (aOR 0.42, 95% CI 0.37-0.47) at 2 years of follow-up even in the severe frailty group. CONCLUSIONS: Frailty is highly prevalent and associated with increased risk of all-cause mortality, all-cause readmissions and HF readmissions among older HF patients. Those who were using triple or more HF-related medications were at lower risk of adverse clinical outcomes across distinct frailty subgroups. Further studies are needed to optimize the treatment strategies for older HF patients with distinct frailty status.

Development and validation of the Chinese Overactive Bladder Symptom Score for assessing overactive bladder syndrome in a RESORT study.

BACKGROUND/PURPOSE: This study aimed to develop and validate the Chinese Overactive Bladder Symptom Score (OABSS) for assessing overactive bladder (OAB) symptoms and compare it with a 3-day bladder diary. METHODS: The Chinese OABSS was developed by linguistic validation of the original version. Its reliability and validity and correlations with a 3-day bladder diary were tested on patients with OAB in a multicenter study conducted in Taiwan (the RESORT study). RESULTS: A total of 60 patients with OAB, either incontinent (OAB wet, n=31) or continent (OAB dry, n=29), were enrolled consecutively in this study. The test-retest reliability of the Chinese OABSS was moderate to good, with weighted kappa coefficients of 0.515-0.721 for each symptom score and 0.610 for the total symptom score. Each symptom score correlated positively with the total OABSS (Spearman's rho 0.365-0.793) and was internally consistent (Cronbach's alpha 0.674). The distribution of the OABSS showed a clear separation between OAB wet (average 11.4, range 7-15) and OAB dry (average 7.97, range 4-10) subgroups (Wilcoxon exact test, p<0.05). In addition, the OABSS items correlated positively with the corresponding bladder diary variables (Spearman's rho 0.504-0.879) and the degrees of agreement improved with study visits except for nighttime frequency. The Chinese OABSS tended to underestimate the frequency of nighttime voiding. CONCLUSION: The Chinese OABSS has been developed and validated as a reliable instrument for assessing OAB symptoms. OABSS can be an alternative to, but not a replacement for, a 3-day bladder diary for assessing patients.

Health care utilization and potentially preventable adverse outcomes of high-need, high-cost middle-aged and older adults: Needs for integrated care models with life-course approach.

PURPOSE OF THE RESEARCH: The success of modern health care increases life expectancy and prolongs the days of having multimorbidity and functional limitations; the so-defined "high need, high cost (HNHC)" state represents the extreme scenarios of care burden and complexity. This study aims to explore health care utilization and the risk of preventable adverse outcomes stratified by age and HNHC state. MATERIALS AND METHODS: We conducted a retrospective cohort study using the National Health Insurance (NHI) database. People aged ≥40 years were included and further stratified by age (middle-aged: 40-64 and older adults: 65) and HNHC state (top 10% of spending). Health care utilization and drug consumption across different groups were obtained. The multimorbidity frailty index (mFI) was developed for further analysis. Cox regression models were used to examine the associations between HNHC and adverse clinical outcomes (preventable hospitalizations, preventable emergency department visits, and mortality). RESULTS: HNHC participants were older, had a higher mFI and drug consumption, and had higher health care utilization. Compared with non-HNHC participants, HNHC participants exhibited a 4.4-fold and 2.4-fold higher risk of preventable hospitalizations in middle-aged (HR=4.41; 95% CI, 4.17-4.65, p<0.01) and older adults (HR=2.44; 95% CI, 2.34-2.55, p<0.01). Similar risks were observed for preventable emergency department visits and mortality (all p<0.01). CONCLUSIONS: The HNHC state substantially increased health care utilization, polypharmacy, and potentially preventable adverse outcomes after adjustment for frailty. Intervention studies developing integrated care models using the life-course approach are needed to improve the quality of health care systems in super-aged societies.

Longitudinal impact of distinct infection trajectories on all-cause mortality of older people in Taiwan: a retrospective, nationwide, population-based study.

BACKGROUND: Infectious diseases are the leading cause of deaths in adults aged 65 years or older. Studies of adverse infection outcomes have been limited to specific infections and acute episodes and have not investigated longitudinal trends of cumulative infections. We aimed to identify distinct trajectories of longitudinal infection episodes in older adults and to assess their corresponding risk of all-cause mortality. METHODS: In this retrospective cohort study, we included people aged 65 years or older who were admitted to hospital between Jan 1 and Dec 31, 2011, with one of the following infections: urinary tract, pneumonia, sepsis, cellulitis, cholecystitis, peritonitis, endocarditis, and meningitis. Participants were identified from Taiwan's National Health Insurance Research Database. We analysed infection episodes on a quarterly basis during a 5-year period (2011-15) and used group-based trajectory modelling to identify distinct trajectories. We examined the associations between infection trajectories and all-cause mortality using Kaplan-Meier curves and the Cox proportional hazard model. FINDINGS: Among 79 666 eligible older adults, we identified four distinct infection trajectories over the 5-year follow-up: infrequent (58 619 [73·6%]), increasing (9746 [12·2%]), decreasing (9069 [11·4%]), and frequent (2232 [2·8%]). Compared with people with infrequent infections, the adjusted hazard ratios for all-cause mortality were 2·96 (95% CI 2·82-3·11) in participants with frequent infections, 2·15 (2·09-2·22) in those with increasing infections, and 1·85 (1·80-1·91) in those with decreasing infections. INTERPRETATION: Older adults with multiple infection episodes, irrespective of type, pathogens, and distinct infection pattern, had greater risk of all-cause mortality compared with those with infrequent infections. Further research to define the overall infection burden in older adults is needed for risk stratification and to inform prevention strategies. FUNDING: The Interdisciplinary Research Center for Healthy Longevity of National Yang Ming Chiao Tung University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education, the National Science and Technology Council, and the Ministry of Science and Technology in Taiwan.

Medication overload: A closer look at polypharmacy and potentially inappropriate medications among older people in Taiwan and Japan.

BACKGROUND: Polypharmacy and potentially inappropriate medications (PIM) are widely recognized as vital quality indicators of pharmacotherapy in older adults. As Taiwan and Japan grapple with the ongoing challenges of population aging, obtaining an accurate understanding of the prevalence of these indicators is crucial for developing effective strategies to optimize pharmacotherapy in older populations. The present study aims to comprehensively evaluate the prevalence of polypharmacy and PIMs in Taiwan and two Japanese cohorts, shedding light on the similarities and differences in prescribing practices across these populations. METHODS: This study employed a cross-sectional design to investigate individuals aged ≥65 years in Taiwan, as well as two Japanese cohorts: Japan Cohort 1 (dispensing data from chain pharmacies; year 2014 and 2019) and Japan Cohort 2 (claims data; year 2017 and 2019). The prescription records of these participants were collected from the national claims database in Taiwan for the years 2014, 2017, and 2019. To identify polypharmacy and hyper-polypharmacy, the study defined the use of 5-9 and 10+ drugs, respectively. Furthermore, the study identified PIMs based on the STOPP-J criteria. Notably, the study further explored the most frequently used PIMs (by categories) in Taiwan. RESULTS: In the year 2019, the prevalence of polypharmacy exhibited similar rates in Taiwan (35.4%) and Japan Cohort 2 (33.1%), while surpassing that of Japan Cohort 1 (25.6%). Nonetheless, the incidence of PIMs in Taiwan was the highest (66.5%), exceeding those of the two Japanese cohorts (Cohort 1: 43.7% and Cohort 2: 40.2%) in the same year. Notably, the top three categories of commonly used PIMs in Taiwan comprised non-steroidal anti-inflammatory drugs (NSAIDs), antithrombotic drugs, and benzodiazepines. CONCLUSIONS: This study highlights the varying prevalence of polypharmacy and PIMs between Taiwan and Japan, but emphasizes the need for collaborative efforts towards optimizing pharmacotherapy in older adults.

Association between maternal benzodiazepine or Z-hypnotic use in early pregnancy and the risk of stillbirth, preterm birth, and small for gestational age: a nationwide, population-based cohort study in Taiwan.

BACKGROUND: Benzodiazepines and Z-hypnotics are commonly prescribed for anxiety and insomnia during pregnancy, but the evidence regarding potential adverse neonatal outcomes is insufficient because of poor control for confounding factors in previous studies. We therefore aimed to evaluate the association between the use of benzodiazepines or Z-hypnotics during early pregnancy and adverse neonatal outcomes (stillbirth, preterm birth, and small for gestational age). METHODS: We did a nationwide, population-based cohort study in Taiwan using three data sources: Taiwan's National Birth Certificate Application database, the National Health Insurance database, and the Maternal and Child Health Database. The study cohort included all singleton pregnancies of females aged 15-50 years who gave birth between Jan 1, 2004, and Dec 31, 2018. Pregnancies without valid information were excluded. Benzodiazepine and Z-hypnotic use was defined as at least one benzodiazepine or Z-hypnotic prescription during early pregnancy (the first 20 weeks of pregnancy). The primary outcomes were stillbirth (fetal death at or after 20 weeks' gestation), preterm birth (<37 weeks' gestation), and small for gestational age (birthweight below the 10th percentile for gestational age by sex). Logistic regression models with propensity score fine stratification weighting were used to control for potential confounders and examine the association between benzodiazepines or Z-hypnotics use during early pregnancy and the risk of adverse neonatal outcomes. Odds ratios (ORs) and 95% CIs were reported. We used confounding by indication control analyses, a sibling control study, and a paternal negative control design to account for unmeasured confounders. The risk associated with exposure during late pregnancy was also assessed. FINDINGS: Between Oct 7, 2021, and June 10, 2022, we analysed the study data. The cohort included 2 882 292 singleton pregnancies; of which, 75 655 (2·6%) of the mothers were dispensed one or more benzodiazepines or Z-hypnotics during early pregnancy. Women exposed during pregnancy were older (mean age at delivery was 31·0 years [SD 5·3] for exposed women vs 30·6 years [4·9] for unexposed women), had a higher prevalence of psychiatric disorders, and were more likely to have unhealthy lifestyle behaviours than unexposed women. Information about ethnicity was not available. Early pregnancy exposure was associated with adverse neonatal outcomes compared with non-exposure. The propensity score-weighted OR was 1·19 (95% CI 1·10-1·28) for stillbirth, 1·19 (1·16-1·23) for preterm birth, and 1·16 (1·13-1·19) for small for gestational age. After controlling for confounding by indication, there was no significant association between drug exposure and stillbirth risk; however, this attenuation was not observed for preterm birth and small for gestational age. In models with sibling controls that accounted for familial confounding and genetic factors, early exposure to benzodiazepines or Z-hypnotics was not associated with an increased risk of stillbirth and preterm birth, but it remained significantly associated with small for gestational age. The paternal negative control analyses with point estimates close to the null indicated no strong evidence of unmeasured confounding shared by the mother and the father. Substantially increased risks of stillbirth and preterm birth were observed for late pregnancy exposure. INTERPRETATION: Benzodiazepine or Z-hypnotic use in early pregnancy is not associated with a substantial increase in the risk of stillbirth and preterm birth after accounting for unmeasured confounding factors. Clinicians should be aware of the increased risk of small for gestational age and caution should be taken when prescribing these medications during late pregnancy. FUNDING: National Science and Technology Council, Taiwan. TRANSLATION: For the Taiwanese translation of the abstract see Supplementary Materials section.