Protein-enriched soup and weekly exercise improve muscle health: A randomized trial in mid-to-old age with inadequate protein intake.

BACKGROUND: Prior research has highlighted the synergistic impact of protein supplementation on muscle function post-exercise in adults; however, evidence supporting the combined effects were less robust and inconsistent on those with protein insufficiency. This investigation aims to explore efficacy of protein-enriched soup coupled with exercise on muscle health and metabolism in middle-aged and older adults with suboptimal protein intake. METHODS: An open-label, 12-week, randomized controlled trial involving participants with insufficient protein intake (<1.0 g/kg/day) was done. The intervention group consumed protein-enriched soup (24-30 g protein daily) and 1-h weekly exercise, while controls received health education. Assessments included laboratory tests, functional assessments, and body composition. RESULTS: In this trial, 97 out of 100 randomized participants (mean age: 64.65 ± 4.84 years, 81.8% female) completed the study (47 in intervention group and 50 in control group). Compared results of baselines, at 1 and 3 months of intervention, significant improvements in waist circumference (83.48 ± 10.22 vs. 82.5 ± 9.88 vs. 82.37 ± 9.42 cm, P for trend = 0.046), 6-min walking distance (525.65 ± 58.46 vs. 534.47 ± 51.87 vs. 552.02 ± 57.66 m, P for trend = 0.001), five-time sit-to-stand time (7.63 ± 1.63 vs. 6.81 ± 1.8 vs. 6.4 ± 1.42 s, P for trend <0.001), grip strength (26.74 ± 6.54 vs. 27.53 ± 6.99 vs. 28.52 ± 7.09 kg, P for trend <0.001), and MNA score (26.8 ± 2.14 vs. 27.73 ± 1.74 vs. 27.55 ± 1.72, P for trend <0.001) were discerned within the intervention group. The intervention demonstrated a significant reduction in serum triglyceride (105.32 ± 49.84 vs. 101.36 ± 42.58 vs. 93.43 ± 41.49 mg/dL, P for trend = 0.023), increased HDL-C (60.04 ± 16.21 vs. 60 ± 17.37 vs. 62.55 ± 18.27 mg/dL, P for trend = 0.02), and DHEA-S levels (97.11 ± 54.39 vs. 103.39 ± 56.75 vs. 106.83 ± 60.56 µg/dL, P for trend = 0.002). Serum myostatin did not differ in both groups, but serum leptin levels significantly increased (9118.88 ± 5811.68 vs. 11508.97 ± 7151.08 vs. 11220.80 ± 7190.71 pg/mL, P for trend = 0.016) in controls. The intervention group showed greater improvements in 6 min walking distance (ß = 0.71, 95% CI: 6.88 to 40.79, P = 0.006), five-time sit-to-stand test (ß = -0.87, 95% CI: -1.59 to -0.15, P = 0.017), MNA score (ß = 0.96, 95% CI: 0.20 to 1.71, P = 0.013), serum triglycerides (ß = -15.01, 95% CI: -27.83 to -2.20, P = 0.022), LDL-C (ß = -9.23, 95% CI: -16.98 to -1.47, P = 0.020), and DHEA-S levels (ß = 9.98, 95% CI: 0.45 to 19.51, P = 0.04) than controls. CONCLUSIONS: Protein-enriched soup with weekly exercise over 12 weeks significantly improved physical performance, lipid profile, and DHEA-S levels among middle-aged and older adults with inadequate protein intake, while studies assessing long-term benefits of the intervention are needed.

Risks of maternal cardiopulmonary events associated with ritodrine for tocolysis: A national database linkage study in 1 831 564 pregnant women.

OBJECTIVE: Real-world data on cardiopulmonary events among pregnant women receiving ß-agonist therapy are scarce. In the present study, we aimed to examine the absolute and relative risks of maternal cardiopulmonary events associated with the use of ß-agonist ritodrine during pregnancy. METHODS: By linking Taiwan's National Birth Certificate Application Database with National Health Insurance data, 1 831 564 pregnancies at ≥20 weeks' gestation were identified. Age-standardized incidence rates of cardiopulmonary events among pregnant women exposed to ritodrine were estimated. Nested case-control analyses were conducted to evaluate the relative risk of pulmonary edema, heart failure, and arrhythmia associated with prior ritodrine use. Cases and controls were matched using risk set sampling, and adjusted odds ratios were estimated using conditional logistic regression models. RESULTS: A total of 189 cases of pulmonary edema, 126 cases of heart failure, and 162 cases of arrhythmia were identified (corresponding age-standardized incidence rates: 20.90, 8.35, and 16.63 per 100 000 among pregnant women only exposed to oral ritodrine; 91.28, 36.01, and 14.61 per 100 000 among those ever exposed to intravenous ritodrine). Exposure to oral ritodrine was associated with a lower increased risk of pulmonary edema (aOR 1.76; 95% CI: 1.12-2.76) and arrhythmia (2.21; 1.47-3.32) whereas exposure to ritodrine injection was associated with a significantly higher risk of pulmonary edema (10.56; 6.39-17.45), arrhythmia (4.15; 1.99-8.64), and heart failure (5.58; 2.27-13.74). CONCLUSIONS: Pregnant women receiving intravenous ritodrine therapy had higher cardiopulmonary risks and should be intensively monitored. While the relative risk associated with oral ritodrine is not pronounced, it should be used judiciously among pregnant women as well.

The Impact of Social Vulnerability on Alcohol Consumption and Mortality: A 20-year Age, Sex-stratified Analysis From the Taiwan Longitudinal Study of Aging.

OBJECTIVE: This study aimed to use the Social Vulnerability Index (SVI) to encapsulate the complex and multidimensional nature of social determinants and their influence on alcohol intake and mortality in middle-aged and older individuals. DESIGN: Cohort study. SETTING AND PARTICIPANTS: Data were obtained from the Taiwan Longitudinal Study on Aging (TLSA), with 3945 study participants aged 50 years and older. METHODS: The TLSA questionnaire defined SVI (51 items including living conditions, social support, socially oriented activities of daily living, social engagement and leisure, empowerment of life, satisfaction about life, and socioeconomic status) and alcohol intake (behavior as well as type and frequency of alcohol intake). Multivariate Cox proportional hazard models were used to estimate the association between alcohol intake and mortality, stratified by gender and SVI groups. RESULTS: Men with high social vulnerability and high alcohol intake exhibit an elevated mortality risk (adjusted hazard ratio [aHR], 1.51; 95% CI, 1.01-2.24), whereas notably, women in similar social circumstances but with moderate alcohol intake face a quintupled mortality risk (>35 g/wk; aHR, 5.67; 95% CI, 2.37-13.61). The impact of alcohol and social vulnerability on mortality was more pronounced in men younger than 65. Among them, those with high social vulnerability and moderate (35-140 g/wk; aHR, 2.83; 95% CI, 1.50-5.36) to high (>140 g/wk; aHR, 2.24; 95% CI, 1.15-4.35) alcohol intake was associated with an increased risk of mortality. CONCLUSIONS AND IMPLICATIONS: Various factors throughout the life course of both men and women significantly impact the risk of all-cause mortality due to alcohol intake, underscoring the importance of social vulnerability as a determinant of both alcohol intake behavior and mortality risk.

Ten-year epidemiology and risk factors of cytomegalovirus infection in hematopoietic stem cell transplantation patients in Taiwan.

BACKGROUND: Cytomegalovirus (CMV) can cause infection and critical diseases in hematopoietic stem cell transplantation (HSCT) recipients. This study aimed to explore the cumulative incidence and risk factors for CMV infection and disease among HSCT recipients in Taiwan. METHODS: This retrospective cohort study using the Taiwan Blood and Marrow Transplantation Registry (TBMTR) included HSCT recipients between 2009 and 2018 in Taiwan. The primary outcome was cumulative incidence of CMV infection or disease at day 100 after HSCT. Secondary outcomes included day 180 cumulative incidence of CMV infection or disease, infection sites, risk factors for CMV infection or disease, survival analysis, and overall survival after CMV infection and disease. RESULTS: There were 4394 HSCT recipients included in the study (2044 auto-HSCT and 2350 allo-HSCT). The cumulative incidence of CMV infection and disease was significantly higher in allo-HSCT than in auto-HSCT patients at day 100 (53.7% vs. 6.0%, P < 0.0001 and 6.1% vs. 0.9%, P < 0.0001). Use of ATG (HR 1.819, p < 0.0001), recipient CMV serostatus positive (HR 2.631, p < 0.0001) and acute GVHD grades ≥ II (HR 1.563, p < 0.0001) were risk factors for CMV infection, while matched donor (HR 0.856, p = 0.0180) and myeloablative conditioning (MAC) (HR 0.674, p < 0.0001) were protective factors. CONCLUSION: The study revealed a significant disparity in terms of the incidence, risk factors, and clinical outcomes of CMV infection and disease between auto and allo-HSCT patients. These findings underscore the importance of considering these factors in the management of HSCT recipients to improve outcomes related to CMV infections.

Non-steroidal anti-inflammatory drugs, renin-angiotensin system blockade or diuretics and risk of acute kidney injury: A case-crossover study.

BACKGROUND: Aging-related physiological changes, such as decline in renal function, not only exacerbates pre-existing comorbidities but also escalate the susceptibility to adverse events. Previous studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI), and the concomitant use of renin-angiotensin system blockade or diuretics may further potentiate the risk. However, studies evaluating the risk of AKI associated with NSAIDs (including routes, concomitant use of different NSAIDs, categories (traditional NSAIDs or COX-2 inhibitors), and cumulative doses of NSAIDs) are limited, particularly the risk of AKI associated with the dual or triple combination of NSAIDs with renin-angiotensin system blockade (RAS blockades) and/or diuretics. METHODS: A case-crossover study utilized two sets of longitudinal data from Taiwan's National Health Insurance Research Database (NHIRD). Newly admitted patients with a primary AKI diagnosis were included, with the index date defined as the first admission date. The 1-7 days and 181-187 days prior to the index date served as the case and control periods. Exposure to NSAIDs and co-exposures of RAS blockade and/or diuretics were assessed in both periods. Multivariable conditional logistic regression models, adjusting for potential confounders, estimated adjusted odds ratios (aORs) and 95 % confidence intervals (CIs) for AKI associated with NSAIDs, dual, or triple combinations. Sensitivity analyses explored result robustness by varying case and control period lengths. RESULTS: The study included 1,284 newly diagnosed AKI patients. NSAIDs showed a 3.55-fold increased risk of AKI (aOR: 3.55; 95 % CI 2.70-4.65), with similar risks for traditional NSAIDs and COX-2 inhibitors. Use of multiple NSAIDs, parenteral dosage forms, and higher cumulative doses increased AKI risk. Dual combination with either RAS blockade or diuretics resulted in a 2.90-fold (aOR: 2.90; 95 %CI 1.47-5.70) and 12.68-fold (aOR: 12.68; 95 %CI 6.15-26.12) risk, respectively. The highest risk occurred with triple combination (aOR: 29.22; 95 %CI 12.82-66.64). CONCLUSIONS: NSAIDs, including both non-selective NSAIDs and COX2 inhibitors, elevate the risk of AKI. Increased AKI risk is linked to using multiple NSAIDs, the parenteral dosage form, and higher cumulative doses. Dual combination of RAS blockade with NSAIDs or diuretics with NSAIDs, as well as triple therapy, heightens the risk, with the latter associated with the highest risk of AKI.

Intrinsic capacity and multimorbidity predicting incident disability-Insights from the I-Lan Longitudinal Aging Study.

OBJECTIVES: This longitudinal cohort study aimed to examine the effect of intrinsic capacity (IC) and multimorbidity on the development of new disabilities. METHODS: The study utilized data from 1,009 participants without disabilities from the I-Lan Longitudinal Aging Study. Multivariable logistic regressions were employed to assess the predictive capability of IC (ranging from 0 to 100) and multimorbidity for incident disability over a 7-year follow-up period. RESULTS: Both low IC (OR 4.9, 95 % CI 2.1-11.1, p < 0.001) and multimorbidity (OR 4.5, 95 % CI 2.2-9.2, p < 0.001) significantly predicted incident disability over the 7-year period. A one-point increase in IC reduced the risk of incident disability by 10 % (OR 0.9, 95 % CI 0.8-0.9, p < 0.001). Among IC subdomains, both better locomotion (OR 0.96, 95 % CI 0.94-0.99, p = 0.014) and psychology (OR 0.97, 95 %CI 0.94-1.00, p = 0.049) significantly reduced the risk of incident disability. Rapid declines in IC significantly predicted incident disability (OR 4.1, 95 % CI 1.8-9.3, p = 0.001), whereas the onset of new multimorbidity or changes in the number of chronic conditions did not demonstrate a significant association with incident disability. The interaction terms between IC and multimorbidity, both categorically (low IC * multimorbidity, p = 0.959) and numerically (IC (per point) * multimorbidity, p = 0.660) were all statistically insignificant. CONCLUSIONS: IC exhibited better predictive capacity for 7-year incident disability compared to multimorbidity, so health care services targeting older adults should adopt an integrated care approach that combines both function- and disease-centric strategies.

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.

Advancing nutrition risk assessment in middle-aged and older individuals with diverse food cultures: A data-driven personalized approach to predict incident hypertension, diabetes and mortality.

BACKGROUND: Personalized nutrition risk assessment is crucial in addressing the association between healthy dietary habits across the life course and the development of disease, functional capacity, and healthy aging, as specific dietary pattern recommendations may not be suitable for diverse food cultures. OBJECTIVE: To develop a data-driven, personalized nutrition risk assessment algorithm linked to incident hypertension, diabetes, and all-cause mortality utilizing the food frequency questionnaire among middle-aged and older individuals. METHODS: A retrospective, population-based cohort study conducted between 1999 and 2015 utilized the nationally representative Taiwan Longitudinal Study on Aging (TLSA) survey to examine personalized dietary risk clusters and their associations with health outcomes. Latent class analysis was performed to derive the dietary diversity clusters among community-dwelling middle-aged and older individuals. Outcomes were defined as new-onset hypertension, diabetes mellitus and all-cause mortality at 4-, 8-, 12- and 16-year follow-ups. RESULTS: Data from 1,811 participants (58.14% males, 43.90% aged 50-64 years) showed that around one-third of participants reported being illiterate, 21.98% widowed, and 51.46% engaging in regular physical exercise. Four dietary diversity clusters were identified: "least diverse", "fish and meat", "dairy, fruit, and vegetable", and "most diverse". The "most diverse" cluster was characterized by a high consumption of protein-rich foods, while the "dairy, fruit, and vegetable" cluster had the highest consumption of dairy products and beans/legumes. The "least diverse" cluster had the lowest intake of protein-rich foods, and dark-colored vegetables and fruits. The "most diverse" cluster had a significantly lower risk of hypertension development at the 4-year (aOR 0.58; p < 0.02) and 8-year (aOR 0.57; p < 0.01) follow-up and diabetes at the 4-year (aOR 0.44; p < 0.03) follow-up. Participants in the "most diverse" clusters exhibited lower risks of 8-year, 12-year, and 16-year mortality than those in the "least diverse" cluster (aOR 0.67, p < 0.05; 0.67, p < 0.03; and 0.50, p < 0.01, respectively). CONCLUSION: The personalized nutrition risk assessment algorithm from the food frequency questionnaire can effectively stratify personal health risks among diverse middle-aged and older individuals, making it a valuable tool in lifestyle modification and intervention studies.

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.

Long-term effects of the global budget program and periodic price adjustment on antibacterial agents: A nationwide decomposition analysis between 2001 and 2016.

BACKGROUND: Previous studies have shown that financial strategies are beneficial for improving the appropriate use of antibiotics within a limited period of time. Long-term effects have rarely been explored. METHODS: This study evaluated the changes in expenditure and prescription patterns of antibacterial agents under the global budget (GB) program and drug price adjustment of a National Health Insurance scheme. Two structural methods, that is, the Laspeyres method and Fisher's Ideal Index decomposition method, were used to illustrate the impacts of price, volume, and drug change. RESULTS: During the first 5 years of the GB program (ie, 2001-2006), the expenses of antibacterial agents increased by 54.1%, while the volume decreased by 11% to 21.3%. Therapeutic choice was the predominant cause of expense growth. In the second and third 5-year periods (ie, 2006-2011 and 2011-2016), the driving force of therapeutic choice gradually decreased. The antibacterial expense remained stable with a slight increase in prescription volume. Periodic price adjustment contributed steadily to cost containment, by 21.9% to 39.9%. CONCLUSIONS: The GB program led to a remarkable increase in antibacterial expenses mainly attributed to therapeutic choice, especially in the early stage. In contrast, periodic price adjustment, provided steady benefits to pharmaceutical budget control without a noticeable increase in drug volume.

Benzodiazepine Use During Pregnancy and Risk of Miscarriage.

Importance: Benzodiazepine use during pregnancy has raised significant concerns due to the potential harmful effects of this drug class on neonates. Studies on the association between benzodiazepine use and the risk of miscarriage are limited. Objective: To quantify the risk of miscarriage associated with benzodiazepine use during pregnancy after controlling for unmeasured confounders and exposure time trends. Design, Setting, and Participants: This was a nationwide, population-based case-time-control study using Taiwan's National Birth Certificate Application database and the National Health Insurance database. Pregnancies resulting in miscarriage between 2004 and 2018 were included in the case group and were 1:1 matched with exposure time-trend control individuals using disease risk score, considering demographic characteristics and prepregnancy comorbidities. Data were analyzed from August 2022 to March 2023. Exposures: Discordant exposures to benzodiazepines during risk period (1-28 days before miscarriage) and 2 reference periods (31-58 days and 181-208 days before the last menstrual period) were compared for each pregnancy. Main Outcomes and Measures: Miscarriage was defined as any pregnancy loss occurring between the first prenatal care visit (usually 8 weeks) and the 19th completed week of pregnancy. Results: This study comprised a total of 3 067 122 pregnancies among 1 957 601 women, 136 134 of which (4.4%) resulted in miscarriage. The mean (SD) age of the study population was 30.61 (5.91) years. The use of benzodiazepines during pregnancy was associated with an increased risk of miscarriage (odds ratio [OR], 1.69; 95% CI, 1.52-1.87), and consistent findings were observed across multiple sensitivity analyses considering different time windows and accounting for misclassification. In subgroup analyses, an increased risk of miscarriage was associated with each commonly used individual benzodiazepine, ranging from case-time-control ORs of 1.39 (95% CI, 1.17-1.66) for alprazolam to 2.52 (95% CI, 1.89-3.36) for fludiazepam. Conclusions and Relevance: This nationwide case-time-control study revealed an increased risk of miscarriage associated with benzodiazepine use during pregnancy after accounting for measurable confounders, and results were unlikely to be due to unmeasured confounding. These findings underscore the necessity for health care professionals to meticulously balance the risk-benefit ratio when considering the use of benzodiazepines to treat psychiatric and sleep disorders during pregnancy.

Unveiling the multifaceted nexus of subjective aging, biological aging, and chronological age: Findings from a nationally representative cohort study.

OBJECTIVES: This study aims to investigate how subjective aging influences the psychological and behavioral responses of older individuals, specifically focusing on the associations between subjective aging and longitudinal changes in biological age. METHODS: This is a retrospective cohort study retrieving data from the Taiwan Longitudinal Study on Aging (TLSA), over a 4-year follow-up period. Subjective aging is assessed by asking participants if they perceive themselves as old, while frailty is measured using a frailty index comprising 34 deficits from various domains. Participants are categorized into three groups based on their chronological age. The association between subjective aging and transition of biological age (as indicated by an increased frailty index) from 2011 to 2015 is examined using logistic regression models. RESULTS: The study consisted of 2412 participants, who were categorized into middle-age (n = 1,082), young-old (n = 779), and old-old (n = 551) groups. Among them, individuals exhibiting subjective aging at baseline were more likely to be older in chronological age, female, illiterate, and unemployed, compared to those without subjective aging. The adjusted odds ratios (aORs) for the association between subjective aging and an increased biological age were 1.72 [95% CI: 0.88-3.34], 1.61 [0.77-3.37], and 1.08 [0.65-1.80], in the middle-age, young-old, and old-old groups, respectively. DISCUSSIONS: No significant associations were found between changes in biological age and subjective aging across various chronological age groups. Notably, within the younger age group, a discernible trend towards an association was observed, indicating the potential age-related nuances in the complex interrelation between subjective age, biological aging, and chronological aging.

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.

Effects of declines in personal mastery on self-perceived mobility, physical function, cognitive function, and depressive symptoms: a 6-year follow-up study from the Social Environment and Biomarkers of Aging Study.

OBJECTIVES: As the psychosocial competence, personal mastery helps individuals to cope with stressful life events, and this study aims to examine impacts of declines in personal mastery on healthy aging among community-dwelling middle-aged and older adults using a nationally representative cohort. METHODS: Data from 648 study participants in the Social Environment and Biomarkers of Aging Study (SEBAS) were retrieved for analysis. All participants were divided into four groups based on their baseline and changes of personal mastery (measured by the Pearlin mastery score) during the 6-year follow-up. Multivariate logistic regression models were adopted to examine associations between declines in personal mastery and indicators for healthy aging (declines in self-perceived mobility, physical function (activities of daily living (ADLs) and instrumental activities of daily living (IADLs)), cognitive function and depressive symptoms). RESULTS: After adjustments for demographics and comorbidities, those with declines in personal mastery were associated with greater risks of declines in self-perceived mobility (adjusted odds ratio (aOR) 1.50 [95% confidence interval 1.01-2.22], p < 0.05). Although the point estimate in the unadjusted models indicated similar associations between declines in personal mastery and declines in ADLs, IADLs, cognitive function or depressive symptoms, these outcomes did not reach statistical significance in the adjusted model. CONCLUSIONS: Declines in personal mastery were negatively associated with indicators related to healthy aging (particularly locomotion) in a 6-year follow-up. Further investigations are needed to explore the effects of preventing declines in personal mastery in promoting healthy aging over time.

Enhancing Intrinsic Capacity and Related Biomarkers in Community-Dwelling Multimorbid Older Adults Through Integrated Multidomain Interventions: Ancillary Findings From the Taiwan Integrated Geriatric (TIGER) Trial.

OBJECTIVE: This study aimed to evaluate the efficacy of integrated multidomain interventions and primary health care on intrinsic capacity (IC) and related biomarkers. DESIGN: An ancillary analysis from the Taiwan Integrated Geriatric Care (TIGER) study: a randomized controlled trial. SETTING AND PARTICIPANTS: A total of 398 community-dwelling older adults aged ≥65 years with ≥3 chronic conditions. METHODS: Participants were randomized into the 12-month pragmatic multidomain intervention or usual care groups. The primary outcome was the change in IC and its subdomains (locomotion, cognition, vitality, psychological, and sensory) at baseline and 3-, 6-, 9-, and 12-month follow-ups. Generalized linear mixed models were used to evaluate the multidomain intervention effects on these changes. RESULTS: The intervention arm had greater improvement in IC than the usual care arm (overall difference 1.5; 95% CI 0.5-2.5; P = .005), mainly from subdomains of locomotion (overall difference 1.4; 95% CI 0.5-2.4; P = .004) and cognition (2.9; 95% CI 2.1-3.7; P < .001). Changes in neutrophil-to-lymphocyte ratio (NLR -2.4; 95% CI -3.9 to -0.8, P = .003), serum levels of albumin (35.1; 95% CI 23.1-47.2; P < .001), dehydroepiandrosterone sulfate (DHEA-S 2.8; 95% CI 1.9-3.8; P < .001), free androgen index (FAI 1.5; 95% CI 1.1-1.9; P < .001), and vitamin D (4.0; 95% CI 2.0-6.1; P < .001) were associated with changes in IC over time. CONCLUSIONS AND IMPLICATIONS: The incorporation of multidomain interventions into primary health care significantly enhanced IC over the 12-month program. Changes in NLR, FAI, and serum levels of albumin, DHEA-S, vitamin D were associated with changes in IC over time. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03528005.

Multi-Trajectories of Intrinsic Capacity Decline and Their Impact on Age-Related Outcomes: A 20-Year National Longitudinal Cohort Study.

The existence of intrinsic capacity (IC) subtypes and their distinct impacts on age-related outcomes remain unexplored. This study sought to investigate IC impairment trajectories across domains and their associations with the risk of age-related outcomes, including falls, functional limitations, reduced quality of life (QoL) and mortality at 4- and 8-year follow-ups. The study sample comprised 1,782 older adults residing in the community from the Taiwan Longitudinal Study on Ageing (TLSA). Utilizing group-based multitrajectory modeling, distinct subtypes of IC decline trajectories across various domains were identified. Cox proportional hazard models and multivariable logistic regression analyses were employed to assess the associations between the identified subtypes and age-related outcomes. We identified four subtypes of IC decline: robust with mild decline (n=902), hearing loss with cognitive decline (n=197), physio-cognitive decline (PCD) with depression (n=373), and severe IC decline (n=310). Over the 4-year study period, compared to the robust with mild decline group, hearing loss with cognitive decline group exhibited a significantly higher risk of diminished QoL (OR=2.53 [1.66-3.86], p>0.01), whereas those in the PCD with depression group experienced an elevated risk of falls (OR=1.62 [1.18-2.23], p>0.01), as well as functional limitation (OR=2.61 [1.81-3.75], p>.01). Individuals in the severe IC decline group faced a substantially increased risk of all outcomes of interest. Distinct subtypes of IC decline across different domains have varying impacts on age-related outcomes, highlighting the need for a personalized approach to promote healthy ageing at the population level, while further investigation into specific pathophysiological mechanisms is warranted as well.

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.

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.

Highly reproducible and cost-effective one-pot organoid differentiation using a novel platform based on PF-127 triggered spheroid assembly.

Organoid technology offers sophisticatedin vitrohuman models for basic research and drug development. However, low batch-to-batch reproducibility and high cost due to laborious procedures and materials prevent organoid culture standardization for automation and high-throughput applications. Here, using a novel platform based on the findings that Pluronic F-127 (PF-127) could trigger highly uniform spheroid assembly through a mechanism different from plate coating, we develop a one-pot organoid differentiation strategy. Using our strategy, we successfully generate cortical, nephron, hepatic, and lung organoids with improved reproducibility compared to previous methods while reducing the original costs by 80%-95%. In addition, we adapt our platform to microfluidic chips allowing automated culture. We showcase that our platform can be applied to tissue-specific screening, such as drug toxicity and transfection reagents testing. Finally, we generateNEAT1knockout tissue-specific organoids and showNEAT1modulates multiple signaling pathways fine-tuning the differentiation of nephron and hepatic organoids and suppresses immune responses in cortical organoids. In summary, our strategy provides a powerful platform for advancing organoid research and studying human development and diseases.

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.