Sex-specific implications of inflammation in covert cerebral small vessel disease.

BACKGROUND: The relationship between inflammation and covert cerebral small vessel disease (SVD) with regards to sex difference has received limited attention in research. We aim to unravel the intricate associations between inflammation and covert SVD, while also scrutinizing potential sex-based differences in these connections. METHODS: Non-stroke/dementia-free study population was from the I-Lan longitudinal Aging Study. Severity and etiology of SVD were assessed by 3T-MRI in each participant. Systemic and vascular inflammatory-status was determined by the circulatory levels of high-sensitivity C-reactive protein (hsCRP) and homocysteine, respectively. Sex-specific multivariate logistic regression to calculate odds ratios (ORs) and interaction models to scrutinize women-to-men ratios of ORs (RORs) were used to evaluate the potential impact of sex on the associations between inflammatory factors and SVD. RESULTS: Overall, 708 participants (62.19 ± 8.51 years; 392 women) were included. Only women had significant associations between homocysteine levels and covert SVD, particularly in arteriosclerosis/lipohyalinosis SVD (ORs[95%CI]: 1.14[1.03-1.27] and 1.15[1.05-1.27] for more severe and arteriosclerosis/lipohyalinosis SVD, respectively). Furthermore, higher circulatory levels of homocysteine were associated with a greater risk of covert SVD in women compared to men, as evidenced by the RORs [95%CI]: 1.14[1.01-1.29] and 1.14[1.02-1.28] for more severe and arteriosclerosis/lipohyalinosis SVD, respectively. No significant associations were found between circulatory hsCRP levels and SVD in either sex. CONCLUSION: Circulatory homocysteine is associated with covert SVD of arteriosclerosis/lipohyalinosis solely in women. The intricacies underlying the sex-specific effects of homocysteine on SVD at the preclinical stage warrant further investigations, potentially leading to personalized/tailored managements. TRIAL REGISTRATION: Not applicable.

Sex differences in the frailty phenotype and mortality in the I-Lan longitudinal aging study cohort.

BACKGROUND: Frailty is a common geriatric syndrome related to multiple adverse outcomes. Sex differences in its prevalence and impact on mortality remain incompletely understood. METHODS: This study was conducted with data from the I-Lan Longitudinal Aging Study, in which community-dwelling subjects aged > 50 years without coronary artery disease or diabetes were enrolled. Sex disparities in phenotypically defined frailty and sex-morality predictor interactions were evaluated. Sex- and frailty-stratified analyses of mortality were performed. RESULTS: The sample comprised 1371 subjects (51.4% women, median age 61 years). The median follow-up period was 6.3 (interquartile range, 5.8-7.0) years. The frailty prevalence did not differ between men (5.3%) and women (5.8%). Frail individuals were older and less educated and had poorer renal function than did non-frail individuals. Body composition trends differed between sexes, regardless of frailty. Relative to non-frail men, frail men had significantly lower body mass indices (BMIs; 24.5 vs. 23.4 kg/m2, p = 0.04) and relative appendicular skeletal muscle masses (7.87 vs. 7.05 kg/m2, p < 0.001). Frail women had significantly higher BMIs (25.2 vs. 23.9 kg/m2, p = 0.02) and waist circumferences (88 vs. 80 cm, p < 0.001) than did non-frail women. Frailty was an independent mortality predictor for men only [hazard ratio (95% confidence interval) = 3.395 (1.809-6.371), psex-frailty interaction = 0.03]. CONCLUSION: Frailty reflected poorer health in men than in women in the present cohort. This study revealed sex disparities in the impact of frailty on mortality among relatively healthy community-dwelling older adults.

Altered cerebellar and caudate gray-matter volumes and structural covariance networks preceding dual cognitive and mobility impairments in older people.

INTRODUCTION: The neuroanatomical changes driving both cognitive and mobility impairments, an emerging preclinical dementia syndrome, are not fully understood. We examined gray-matter volumes (GMVs) and structural covariance networks (SCNs) abnormalities in community-based older people preceding the conversion to physio-cognitive decline syndrome (PCDS). METHODS: Voxel-wise brain GMV and established SCNs were compared between PCDS and non-PCDS converters. RESULTS: The study included 343 individuals (60.2 ± 6.9 years, 49.6% men) with intact cognitive and mobility functions. Over an average 5.6-year follow-up, 116 transitioned to PCDS. Identified regions with abnormal GMVs in PCDS converters were over cerebellum and caudate, which served as seeds for SCNs establishment. Significant differences in cerebellum-based (to right frontal pole and left middle frontal gyrus) and caudate-based SCNs (to right caudate putamen, right planum temporale, left precentral gyrus, right postcentral gyrus, and left parietal operculum) between converters and nonconverters were observed. DISCUSSION: This study reveals early neuroanatomic changes, emphasizing the cerebellum's role, in dual cognitive and mobility impairments. HIGHLIGHTS: Neuroanatomic precursors of dual cognitive and mobility impairments are identified. Cerebellar GMV reductions and increased right caudate GMV precede the onset of PCDS. Altered cerebellum- and caudate-based SCNs drive PCDS transformation. This research establishes a foundation for understanding PCDS as a specific dementia syndrome.

Neuronal intranuclear inclusion disease in patients with adult-onset non-vascular leukoencephalopathy.

Neuronal intranuclear inclusion disease (NIID), caused by an expansion of GGC repeats in the 5'-untranslated region of NOTCH2NLC, is an important but underdiagnosed cause of adult-onset leukoencephalopathies. The present study aimed to investigate the prevalence, clinical spectrum and brain MRI characteristics of NIID in adult-onset nonvascular leukoencephalopathies and assess the diagnostic performance of neuroimaging features. One hundred and sixty-one unrelated Taiwanese patients with genetically undetermined nonvascular leukoencephalopathies were screened for the NOTCH2NLC GGC repeat expansions using fragment analysis, repeat-primed PCR, Southern blot analysis and/or nanopore sequencing with Cas9-mediated enrichment. Among them, 32 (19.9%) patients had an expanded NOTCH2NLC allele and were diagnosed with NIID. We enrolled another two affected family members from one patient for further analysis. The size of the expanded NOTCH2NLC GGC repeats in the 34 patients ranged from 73 to 323 repeats. Skin biopsies from five patients all showed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and dermal adipocytes. Among the 34 NIID patients presenting with nonvascular leukoencephalopathies, the median age at symptom onset was 61 years (range, 41-78 years) and the initial presentations included cognitive decline (44.1%; 15/34), acute encephalitis-like episodes (32.4%; 11/34), limb weakness (11.8%; 4/34) and parkinsonism (11.8%; 4/34). Cognitive decline (64.7%; 22/34) and acute encephalitis-like episodes (55.9%; 19/34) were also the most common overall manifestations. Two-thirds of the patients had either bladder dysfunction or visual disturbance. Comparing the brain MRI features between the NIID patients and individuals with other undetermined leukoencephalopathies, corticomedullary junction curvilinear lesions on diffusion weighted images were the best biomarkers for diagnosing NIID with high specificity (98.4%) and sensitivity (88.2%). However, this diffusion weighted imaging abnormality was absent in 11.8% of the NIID patients. When only fluid-attenuated inversion recovery images were available, the presence of white matter hyperintensity lesions either in the paravermis or middle cerebellar peduncles also favoured the diagnosis of NIID with a specificity of 85.3% and sensitivity of 76.5%. Among the MRI scans of 10 patients, performed within 5 days of the onset of acute encephalitis-like episodes, five showed cortical hyperintense lesions on diffusion weighted images and two revealed focal brain oedema. In conclusion, NIID accounts for 19.9% (32/161) of patients with adult-onset genetically undiagnosed nonvascular leukoencephalopathies in Taiwan. Half of the NIID patients developed encephalitis-like episodes with restricted diffusion in the cortical regions on diffusion weighted images at the acute stage. Corticomedullary junction hyperintense lesions, white matter hyperintensities in the paravermis or middle cerebellar peduncles, bladder dysfunction and visual disturbance are useful hints to diagnosing NIID.

The Clinical and Genetic Characteristics of Streptococcus agalactiae Meningitis in Neonates.

Streptococcus agalactiae (Group B Streptococcus, GBS) is an important pathogen of bacterial meningitis in neonates. We aimed to investigate the clinical and genetic characteristics of neonatal GBS meningitis. All neonates with GBS meningitis at a tertiary level medical center in Taiwan between 2003 and 2020 were analyzed. Capsule serotyping, multilocus sequence typing, antimicrobial resistance, and whole-genome sequencing (WGS) were performed on the GBS isolates. We identified 48 neonates with GBS meningitis and 140 neonates with GBS sepsis. Neonates with GBS meningitis had significantly more severe clinical symptoms; thirty-seven neonates (77.8%) had neurological complications; seven (14.6%) neonates died; and 17 (41.5%) survivors had neurological sequelae at discharge. The most common serotypes that caused meningitis in neonates were type III (68.8%), Ia (20.8%), and Ib (8.3%). Sequence type (ST) is highly correlated with serotypes, and ST17/III GBS accounted for more than half of GBS meningitis cases (56.3%, n = 27), followed by ST19/Ia, ST23/Ia, and ST12/Ib. All GBS isolates were sensitive to ampicillin, but a high resistance rates of 72.3% and 70.7% to erythromycin and clindamycin, respectively, were noted in the cohort. The virulence and pilus genes varied greatly between different GBS serotypes. WGS analyses showed that the presence of PezT; BspC; and ICESag37 was likely associated with the occurrence of meningitis and was documented in 60.4%, 77.1%, and 52.1% of the GBS isolates that caused neonatal meningitis. We concluded that GBS meningitis can cause serious morbidity in neonates. Further experimental models are warranted to investigate the clinical and genetic relevance of GBS meningitis. Specific GBS strains that likely cause meningitis requires further investigation and clinical attention.

Determinants of long-term care service use by persons with dementia: A national dementia registry study conducted in Taiwan.

BACKGROUND: This study investigated the determinants and use of Taiwan's long-term care (LTC) Plan Version 2.0 (LTC 2.0) services by persons with dementia (PWDs) and their caregivers. METHODS: In total, 1268 PWD-caregiver dyads were enrolled for analysis from a national dementia registry. Andersen's Behavioral Model of Health Services Use was used to investigate the association of LTC service use with several factors, namely the demographic data of PWDs and their caregivers, migrant caregiver employment, monthly household income, caregiver burden as determined by the Zarit Burden Interview (ZBI), Mini-Mental State Examination score, Clinical Dementia Rating scores, neuropsychiatric inventory scores for the behavioral and psychological symptoms of dementia, and PWDs' activities of daily living (ADLs). RESULTS: Among the studied family caregivers, 81.4% did not use LTC resources. A multivariable logistic analysis revealed that aberrant motor behaviors (odd ratio [OR] = 1.31, 95% confidence interval [CI] = 1.10-1.56, p = 0.003), dysfunction in ADLs (OR = 1.06, 95% CI = 1.02-1.10, p = 0.002), higher ZBI scores (OR = 1.02, 95% CI = 1.01-1.03, p = 0.004), not residing with family members (OR = 1.88, 95% CI = 1.32-2.66, p < 0.001), and not employing a migrant caregiver (OR = 4.41, 95% CI = 2.59-7.51, p < 0.001) were the factors most significantly associated with LTC service use. CONCLUSION: Factors such as whether PWDs live alone, specific neuropsychiatric symptoms, and impaired function should be considered in future policy amendments to provide required activities and care resources for PWDs and their caregivers.

Brain white matter hyperintensities-predicted age reflects neurovascular health in middle-to-old aged subjects.

BACKGROUND: age-related neurovascular structural and functional impairment is a major aetiology of dementia and stroke in older people. There is no single marker representative of neurovascular biological age yet. OBJECTIVE: this study aims to develop and validate a white matter hyperintensities (WMH)-based model for characterising individuals' neurovascular biological age. METHODS: in this prospective single-site study, the WMH-based age-prediction model was constructed based on WMH volumes of 491 healthy participants (21-89 years). In the training dataset, the constructed linear-regression model with log-transformed WMH volumes showed well-balanced complexity and accuracy (root mean squared error, RMSE = 10.20 and mean absolute error, MAE = 7.76 years). This model of neurovascular age estimation was then applied to a middle-to-old aged testing dataset (n = 726, 50-92 years) as the testing dataset for external validation. RESULTS: the established age estimator also had comparable generalizability with the testing dataset (RMSE = 7.76 and MAE = 6.38 years). In the testing dataset, the WMH-predicted age difference was negatively associated with visual executive function. Individuals with older predicted-age for their chronological age had greater cardiovascular burden and cardiovascular disease risks than individuals with normal or delayed predicted age. These associations were independent of chronological age. CONCLUSIONS: our model is easy to use in clinical practice that helps to evaluate WMH severity objective to chronological age. Current findings support our WMH-based age measurement to reflect neurovascular health and have potential diagnostic and prognostic value for clinical or research purposes in age-related neurovascular disorders.

Neuropsychiatric symptoms and mortality among patients with mild cognitive impairment and dementia due to Alzheimer's disease.

BACKGROUND: Neuropsychiatric symptoms (NPS) could increase mortality risk in people with dementia due to Alzheimer's disease (AD). However, whether NPS affects mortality risk in people with mild cognitive impairment (MCI) and whether any specific syndrome of NPS influences this risk are still unclear. METHODS: In total, 984 participants with dementia due to AD, 338 with MCI, and 365 controls were enrolled. Over a mean of 5-year follow-up, cause of death data were obtained from the Ministry of Health and Welfare in Taiwan. NPS were assessed using Neuropsychiatric Inventory Questionnaire (NPI-Q), and psychosis, mood, and frontal domain scores were determined. Survival analyses were conducted to determine the hazard ratio (HR) of death. RESULTS: In controlled analyses, HR of death for AD was 2.19 (95% confidence interval [CI] = 1.29-3.71) compared with the control group, whereas no statistical significance was noted for the MCI group. A high NPI-Q score (above the median score) increased mortality risk for both the MCI and AD groups, with HRs of 2.32 (95% CI = 1.07-5.03) and 2.60 (95% CI = 1.51-4.47), respectively. Among NPI-Q domain scores, only high mood domain, but not psychosis or frontal domain, scores increased death risk for both the MCI (HR = 2.89, 95% CI = 1.00-8.51) and AD (HR = 2.59, 95% CI = 1.47-4.55) groups. CONCLUSION: Mortality risk is high for patients with AD. Not only for AD, patients with MCI presenting with NPS, particularly mood symptoms, have high death risk.

Large-Scale Structural Covariance Networks Predict Age in Middle-to-Late Adulthood: A Novel Brain Aging Biomarker.

The aging process is accompanied by changes in the brain's cortex at many levels. There is growing interest in summarizing these complex brain-aging profiles into a single, quantitative index that could serve as a biomarker both for characterizing individual brain health and for identifying neurodegenerative and neuropsychiatric diseases. Using a large-scale structural covariance network (SCN)-based framework with machine learning algorithms, we demonstrate this framework's ability to predict individual brain age in a large sample of middle-to-late age adults, and highlight its clinical specificity for several disease populations from a network perspective. A proposed estimator with 40 SCNs could predict individual brain age, balancing between model complexity and prediction accuracy. Notably, we found that the most significant SCN for predicting brain age included the caudate nucleus, putamen, hippocampus, amygdala, and cerebellar regions. Furthermore, our data indicate a larger brain age disparity in patients with schizophrenia and Alzheimer's disease than in healthy controls, while this metric did not differ significantly in patients with major depressive disorder. These findings provide empirical evidence supporting the estimation of brain age from a brain network perspective, and demonstrate the clinical feasibility of evaluating neurological diseases hypothesized to be associated with accelerated brain aging.

Longitudinal changes of frailty in 8 years: comparisons between physical frailty and frailty index.

BACKGROUND: Few studies have made longitudinal comparisons between frailty phenotype (FP) and frailty index (FI) changes. We aimed to investigate frailty status changes defined by FP and FI concurrently, and to compare the associated factors and incident disability among different combination of FI and FP trajectory groups. METHODS: Data on respondents aged over 50 who completed the 1999, 2003 and 2007 Taiwan Longitudinal Study on Aging (TLSA) surveys (n = 2807) were excerpted. Changes of FI, FP and major time-dependent variables were constructed by group-based trajectory modeling. Logistic regression was used to investigate the associated factors and relationships with incident disability among different frailty trajectories. RESULTS: We identified four FP trajectories - stably robust, worsened frailty, improved frailty, and stably frail and three FI trajectories - stable FI, moderate increase FI and rapid increase FI. Lower self-rated health, mobility impairment, and depressed mood were associated with unfavorable FP and FI changes (all p < 0.001). Regardless of FP trajectory groups, the moderate and rapid increase FI group had significantly more comorbidities than the stable FI group, and more visual, hearing, oral intake impairment, more difficulty in meeting living expenses, and poorer cognitive function in ≥65-year-olds (all p < 0.05). In addition, the worsened frailty, improved frailty, and stably frail groups had ORs for incident disability of 10.5, 3.0, and 13.4, respectively, compared with the stably robust group (all p < 0.01); the moderate and rapid increase FI groups had 8.4-fold and 77.5-fold higher risk than the stable FI group (both p < 0.001). When combining FI and FP trajectories, risk increased with FI trajectory steepness, independent of FP change (all p < 0.01 in rapid increase FI vs stable FI). CONCLUSIONS: Four FP trajectories (stably robust, worsened frailty, improved frailty, and stably frail) and three FI trajectories (stable FI, moderate increase FI and rapid increase FI) were identified. Lower self-rated health, mobility impairment, and depressed mood were associated with both unfavorable FP and FI trajectories. Nevertheless, even for individuals in stably robust or improved frailty FP groups, moderate or rapid increase in FI, either due to comorbidities, sensory impairment, cognitive deficits, or financial challenges, may still increase the risk of incident disability.

Predictors of caregiver burden in aged caregivers of demented older patients.

BACKGROUND: Dementia in the oldest-old is projected to increase exponentially as is the burden of their caregivers who may experience unique challenges and suffering. Thus, we aim to investigate which factors are associated with older caregivers' burden in caring demented outpatients in a multicenter cohort. METHODS: Patients and their caregivers, both aged ≧65 years, in the National Dementia Registry Study in Taiwan (T-NDRS) were included in this study. Caregiver burden was measured with the short version of the Zarit Burden Interview (ZBI). The correlations between the ZBI scores and characteristics of caregivers and patients, including severity of dementia, physical comorbidities, instrumental activities of daily living (IADL), neuropsychiatric symptoms assessed by the Neuropsychiatric Inventory (NPI), and family monthly income, were analyzed. RESULTS: We recruited 328 aged informal caregiver-patient dyads. The mean age of caregivers was 73.7 ± 7.0 years, with female predominance (66.8%), and the mean age of patients was 78.8 ± 6.9 years, with male predominance (61.0%). Multivariable linear regression showed that IADLs (ß = 0.83, p < 0.001) and NPI subscores of apathy (ß = 3.83, p < 0.001)and irritability (ß = 4.25, p < 0.001) were positively associated with ZBI scores. The highest family monthly income (ß = - 10.92, p = 0.001) and caregiver age (ß = - 0.41, p = 0.001) were negatively correlated with ZBI scores. CONCLUSIONS: Older caregivers of older demented patients experience a higher care burden when patients had greater impaired functional autonomy and the presence of NPI symptoms of apathy and irritability. Our findings provide the direction to identify risky older caregivers, and we should pay more attention to and provide support for these exhausted caregivers.

Real-world evidence on the safety and effectiveness of fingolimod in patients with multiple sclerosis from Taiwan.

BACKGROUND/PURPOSE: Multiple sclerosis is classified as a rare disease in Taiwan. This study evaluated the safety and effectiveness of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) from routine clinical practice in Taiwan. METHODS: In this retrospective, multicentre, observational study, we collected clinical data of patients treated with fingolimod 0.5 mg/day in routine clinical practice between September 2012 and December 2015. Primary outcome was the overall safety of fingolimod; secondary outcome was the annualized relapse rate (ARR). RESULTS: Overall, 62/69 (86.1%) patients were on fingolimod by the end of data collection period. Mean age (±standard deviation [SD]) at inclusion was 37.7 ± 10.10 years; mean duration of MS was 5.4 ± 4.52 years and mean duration of fingolimod exposure was 135.8 patient-years. The most common adverse events (AEs) were bradycardia (21.7%; first-dose related), upper respiratory tract infection, dizziness, and hypoaesthesia (numbness) (11.6% each), followed by urinary tract infection and back pain (7.2% each). Seven patients had liver enzyme-related AEs. Eight patients had absolute lymphocyte counts <0.2 × 103/uL over the study period. One patient developed second degree AV block after first-dosing. Serious AEs were observed in 11 patients (15.9%; mild-to-moderate). No newly developed macular oedema was detected. The ARR was 0.3 ± 0.74 in fingolimod-treated patients and 66.7% of patients were relapse-free. The mean (SD) change from baseline in expanded disability status scale score was -0.30 ± 1.353. CONCLUSION: Fingolimod 0.5 mg/day treatment with an average of 2 years of exposure was associated with a manageable safety profile, and maintained/improved effectiveness in RRMS patients from Taiwan.

First Determination of Glycidyl Ester Species in Edible Oils by Reverse-Phase Ultra-Performance Liquid Chromatography Coupled with an Evaporative Light-Scattering Detector.

In this work, a new ultra-performance liquid chromatograph-evaporative light-scattering detector (UPLC-ELSD) method for quantitation of glycidyl esters (GE) contents in edible oils is presented. The method features complete separation of five GE species within 20 min by a C18 column and gradient elution with a mobile phase consisting of 85% and 2.5% methanol aqueous solutions. The coefficients of regression (R2) were all ≥0.9999 for the linear-quadratic regression curves of GE species in a concentration range of 5~80 µg/mL. The intraday and interday recoveries (%) of GE species in solvent were in a range of 81.3~107.3%, and the intraday and interday coefficients of variation (CVs, %) were all ≤8.6%. The average recovery (%) of GE species spiked in extra-virgin olive oil samples ranged from 88.3~107.8% and the intermediate precision (CV, %) of ≤14% indicated acceptable accuracy and precision. The method exhibited limit of quantification (LOQ) for each GE species (0.6 µg glycidol equivalents/g oil). The method was applied to determine GE concentrations of six commercial oil samples, and total glycidol equivalents were consistent with data obtained by GC-MS method. This UPLC-ELSD method could be adopted for precursory screening and research purposes to improve food safety when MS detectors are unavailable.

Therapeutic Effects of Exercise Training on Elderly Patients With Dementia: A Randomized Controlled Trial.

OBJECTIVE: To investigate whether strength or aerobic training can offer significantly more benefits with regarding the activities of daily living of elderly patients with dementia as well as to determine the effects of exercise on cognition, depression, and biochemical markers. DESIGN: Single-blind randomized controlled trial. SETTING: A nursing home for veterans. PARTICIPANTS: A volunteer sample of participants (N=80) whose scores on the Mini-Mental State Examination were between 15 and 26 were included. Because of cardiopulmonary or orthopedic conditions that prohibit exercise training, along with any cognitive problems that may impede answering the contents of our questionnaires, 11 participants were excluded. During the exercise training period, 8 participants voluntarily dropped out of the study. INTERVENTIONS: The participants were randomly assigned to perform either strength or aerobic training for a total of 4 weeks. MAIN OUTCOME MEASURES: The main outcome measure was the Barthel Index. Other outcome measures included the Mini-Mental State Examination, Montreal Cognitive Assessment, Geriatric Depression Scale, plasma monocyte chemotactic protein-1 levels, insulin-like growth factor-1 levels, and serum brain-derived neurotrophic factor levels. RESULTS: After completion of the program, we discovered a significant improvement in the patients' Barthel Index, Mini-Mental State Examination, Montreal Cognitive Assessment, and plasma monocyte chemotactic protein-1 levels in the strength-training group. For the patients who had received aerobic training, their serum brain-derived neurotrophic factor also improved significantly. However, the degree of improvement regarding these outcome measures did not achieve significant statistical difference between the 2 groups. CONCLUSIONS: Through our study, an intensive 4-week exercise program, whether it be strength or aerobic training, is evidenced to bring significant benefits to elderly patients with dementia, while the serum brain-derived neurotrophic factor was additionally improved through aerobic training.

First insights on value-based healthcare of elders using ICHOM older person standard set reporting.

BACKGROUND: Clinical guidelines for specific conditions fragment care provision for elders. The International Consortium for Health Outcomes Measurement (ICHOM) has developed a global standard set of outcome measures for comprehensive assessment of older persons. The goal of this study was to report value-based health metrics in Taiwan using this ICHOM toolset. METHODS: The cross-sectional study of baseline data excerpted from a prospective longitudinal cohort, which recruited people ≥65 years old with ≥3 chronic medical conditions between July and December 2018. All participants received measurements of physical performance, anthropometric characteristics, health-related behaviors, Charlson Comorbidity Index, and Montreal Cognitive Assessment. The ICHOM toolset comprises three tiers: 1 includes frailty and having chosen a preferred place of death; 2 includes polypharmacy, falls, and participation in decision-making; and 3 includes loneliness, activities of daily living, pain, depression, and walking speed. These items were converted into a 0-10 point value-based healthcare score, with high value-based health status defined as ≥8/10 points. RESULTS: Frequencies of individual ICHOM indicators were: frail 11.7%, chose preferred place of death 14.4%, polypharmacy 31.5%, fell 17.1%, participated in decision-making 81.6%, loneliness 26.8%, limited activities of daily living 22.4%, pain 10.4%, depressed mood 13.0%, and slowness 38.5%. People with high disease burden (OR 0.40, 95% CI 0.21-0.76, p = 0.005) or cognitive impairment (OR 0.49, 95%CI 0.27-0.87, p = 0.014) were less likely to have high value-based healthcare status. CONCLUSIONS: The ICHOM Standard Set Older Person health outcome measures provide an opportunity to shift from a disease-centric medical paradigm to whole person-focused goals. This study identified advanced age, chronic disease burden and cognitive impairment as important barriers to achieving high value-based healthcare status.

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.

Genetics of neuropsychiatric symptoms in patients with Alzheimer's disease: A 1-year follow-up study.

AIM: The aim of this study was to investigate the associations between candidate gene variants and domains of neuropsychiatric symptoms (NPS) and the changes in these associations over a 1-year period. METHODS: Seven hundred and ninety-three Taiwanese participants (47.8% female) with Alzheimer's disease (AD) were enrolled. Genes associated with a risk of developing AD were selected as candidate genes. NPS were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q), and the NPI-Q total score and sub-scores for the Psychosis, Mood, and Frontal Syndrome domains were calculated. RESULTS: Patients with AD and the APOE ε4 allele exhibited more obvious symptoms of psychosis. Mood symptoms were associated with CD33 rs3865444 and EPHA1 rs11767557, and frontal symptoms were associated with SORL1 rs3824968. A 1-year Time × Alleles interaction effect of CD33 rs3865444 on mood symptoms was discerned. CONCLUSION: Risk genes of AD, which are also associated with NPS, are APOE ε4 for psychosis, CD33 and EPHA1 for mood symptoms, and SORL1 for frontal symptoms. The association between CD33 and mood symptoms is dynamic and could change over 1 year; however, the results should be interpreted with caution because corrections for multiple comparisons were not performed.

A Case Report: An Acute Spinal Epidural Hematoma after Acupuncture Mimicking Stroke.

BACKGROUND: Spinal epidural hematoma (SEH) after acupuncture is rare and may present with acute or subacute onset and varied symptoms, making it difficult to diagnose. This condition can mimic acute stroke, so it is vital to establish a clear diagnosis before considering thrombolytic therapy, which could be disastrous if applied inappropriately. CASE REPORT: We describe a 52-year-old man who presented to our emergency department (ED) with acute onset of unilateral weakness of the limbs for 3.5 h immediately after receiving acupuncture at the bilateral neck and back. The acute stroke team was activated. In the ED, computer tomography angiography from the aortic arch to the head revealed spinal epidural hematoma. The patient was admitted to the ward for conservative treatment and was discharged with subtle residual symptoms of arm soreness 5 days later. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Acute spinal epidural hematoma rarely presents with unilateral weakness of the limbs, mimicking a stroke. Because inappropriate thrombolysis can lead to devastating symptoms, spinal epidural hematoma should be excluded when evaluating an acute stroke patient with a history of acupuncture who is a possible candidate for thrombolytic therapy.

1,25(OH)2D3 Alleviates Aß(25-35)-Induced Tau Hyperphosphorylation, Excessive Reactive Oxygen Species, and Apoptosis Through Interplay with Glial Cell Line-Derived Neurotrophic Factor Signaling in SH-SY5Y Cells.

Amyloid beta (Aß) accumulation in the brain is one of the major pathological features of Alzheimer's disease. The active form of vitamin D (1,25(OH)2D3), which acts via its nuclear hormone receptor, vitamin D receptor (VDR), has been implicated in the treatment of Aß pathology, and is thus considered as a neuroprotective agent. However, its underlying molecular mechanisms of action are not yet fully understood. Here, we aim to investigate whether the molecular mechanisms of 1,25(OH)2D3 in ameliorating Aß toxicity involve an interplay of glial cell line-derived neurotrophic factor (GDNF)-signaling in SH-SY5Y cells. Cells were treated with Aß(25-35) as the source of toxicity, followed by the addition of 1,25(OH)2D3 with or without the GDNF inhibitor, heparinase III. The results show that 1,25(OH)2D3 modulated Aß-induced reactive oxygen species, apoptosis, and tau protein hyperphosphorylation in SH-SY5Y cells. Additionally, 1,25(OH)2D3 restored the decreasing GDNF and the inhibited phosphorylation of the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3ß (GSK-3ß) protein expressions. In the presence of heparinase III, these damaging effects evoked by Aß were not abolished by 1,25(OH)2D3. It appears 1,25(OH)2D3 is beneficial for the alleviation of Aß neurotoxicity, and it might elicit its neuroprotection against Aß neurotoxicity through an interplay with GDNF-signaling.

Conversion and Hydrothermal Decomposition of Major Components of Mint Essential Oil by Small-Scale Subcritical Water Treatment.

Thermal stabilities of four major components (l-menthol, l-menthone, piperitone, and l-menthyl acetate) of Japanese mint essential oil were evaluated via subcritical water treatment. To improve experimental throughput for measuring compound stabilities, a small-scale subcritical water treatment method using ampoule bottles was developed and employed. A mixture of the four major components was treated in subcritical water at 180-240 °C for 5-60 min, and then analyzed by gas chromatography. The results indicated that the order of thermal resistance, from strongest to weakest, was: l-menthyl acetate, l-menthol, piperitone, and l-menthone. In individual treatments of mint flavor components, subsequent conversions of l-menthyl acetate to l-menthol, l-menthol to l-menthone, l-menthone to piperitone, and piperitone to thymol were observed in individual treatments at 240 °C for 60 min. As the mass balance between piperitone and thymol was low, the hydrothermal decomposition of the components was considered to have occurred intensely during, or after the conversion. These results explained the degradation of mint essential oil components under subcritical water conditions and provided the basis for optimizing the extraction conditions of mint essential oils using subcritical water.