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Background: In assessing the levels of clinical impairment in dementia, a summary index of neuropsychological batteries has been widely used in describing the overall functional status. Objective: It remains unexamined how complex patterns of the test performances can be utilized to have specific predictive meaning when the machine learning approach is applied. Methods: In this study, the neuropsychological battery (CERAD-K) and assessment of functioning level (Clinical Dementia Rating scale and Instrumental Activities of Daily Living) were administered to 2,642 older adults with no impairment (n = 285), mild cognitive impairment (n = 1,057), and Alzheimer’s disease (n = 1,300). Predictive accuracy on functional impairment level with the linear models of the single total score or multiple subtest scores (Model 1, 2) and support vector regression with low or high complexity (Model 3, 4) were compared across different sample sizes. Results: The linear models (Model 1, 2) showed superior performance with relatively smaller sample size, while nonlinear models with low and high complexity (Model 3, 4) showed an improved accuracy with a larger dataset. Unlike linear models, the nonlinear models showed a gradual increase in the predictive accuracy with a larger sample size (n > 500), especially when the model training is allowed to exploit complex patterns of the dataset. Conclusion: Our finding suggests that nonlinear models can predict levels of functional impairment with a sufficient dataset. The summary index of the neuropsychological battery can be augmented for specific purposes, especially in estimating the functional status of dementia.

Background and Objectives: Although the need for anticoagulation to prevent thromboembolism is increasing and non-vitamin K antagonist oral anticoagulants (NOACs) have been tried, there is still controversy about the efficacy of anticoagulation in patients with dialysis. Materials and Methods: We retrospectively analyzed the risk and benefit of anticoagulation in dialysis patients with atrial fibrillation (AF). We retrospectively analyzed all data of 89 patients who received dialysis therapy and were diagnosed with AF. Among them, 27 received anticoagulation (11 warfarin and 16 apixaban 2.5 mg twice a day), while 62 received no anticoagulation. Results: In multivariate Cox regression analysis, compared to no anticoagulation treatment, anticoagulation treatment was associated with a low incidence of all-cause mortality (hazard ratios (HR) 0.36; 95% confidence interval (CI) 0.15–0.88). Compared to no anticoagulation treatment, more anticoagulation treatment patients experienced severe bleeding (HR 4.67; 95% CI 1.26–17.25) and any bleeding (HR 2.79; 95% CI 1.01–7.74). Compared to no anticoagulation, warfarin treatment patients were associated with a low incidence of all-cause mortality (HR 0.26; 95% CI 0.09–0.81) and a high incidence of severe bleeding (HR 4.85; 95% CI 1.12–21.10). All-cause mortality and bleeding were not significantly different between no anticoagulation and apixaban treatment patients. Conclusions: In dialysis patients with AF, anticoagulation therapy is associated with an increased incidence of severe bleeding, but anticoagulation therapy is associated with a low incidence of all-cause mortality. Individualized anticoagulation therapy with careful bleeding monitoring is needed in dialysis patients with AF.

BACKGROUND Research outcomes on intellectual development and related disabilities in North Korea are not widely known. Therefore, the current scoping review aimed to provide preliminary insight on research topics concerning intellectual disabilities in North Korea. METHOD A six-stage framework for scoping review was adopted to examine research trends. Articles were categorised based on the era of supreme leader and research topic. RESULTS There is a greater amount of research regarding intellectual disabilities in the recent Kim Jong-un era compared to the period of the previous leader where research outcomes on general intelligence were the focus. Significant qualitative progress was similarly found. CONCLUSIONS The current analysis on research outcomes provides meaningful insights to aid in understanding the atmosphere in North Korea surrounding intellectual disabilities. Follow-up studies and open discussions are necessary for further progress.

Objective:Functional impairment in daily activity is a cornerstone in distinguishing the clinical progression of dementia. Multiple indicators based on neuroimaging and neuropsychological instruments are used to assess the levels of impairment and disease severity; however, it remains unclear how multivariate patterns of predictors uniquely predict the functional ability and how the relative importance of various predictors differs.Method:In this study, 881 older adults with subjective cognitive complaints, mild cognitive impairment (MCI), and dementia with Alzheimer’s type completed brain structural magnetic resonance imaging (MRI), neuropsychological assessment, and a survey of instrumental activities of daily living (IADL). We utilized the partial least square (PLS) method to identify latent components that are predictive of IADL.Results:The result showed distinct brain components (gray matter density of cerebellar, medial temporal, subcortical, limbic, and default network regions) and cognitive–behavioral components (general cognitive abilities, processing speed, and executive function, episodic memory, and neuropsychiatric symptoms) were predictive of IADL. Subsequent path analysis showed that the effect of brain structural components on IADL was largely mediated by cognitive and behavioral components. When comparing hierarchical regression models, the brain structural measures minimally added the explanatory power of cognitive and behavioral measures on IADL.Conclusion:Our finding suggests that cerebellar structure and orbitofrontal cortex, alongside with medial temporal lobe, play an important role in the maintenance of functional status in older adults with or without dementia. Moreover, the significance of brain structural volume affects real-life functional activities via disruptions in multiple cognitive and behavioral functions.

The aim of this study is to provide a more accurate representation of COVID-19's case fatality rate (CFR) by performing meta-analyses by continents and income, and by comparing the result with pooled estimates. We used multiple worldwide data sources on COVID-19 for every country reporting COVID-19 cases. On the basis of data, we performed random and fixed meta-analyses for CFR of COVID-19 by continents and income according to each individual calendar date. CFR was estimated based on the different geographical regions and levels of income using three models: pooled estimates, fixed- and random-model. In Asia, all three types of CFR initially remained approximately between 2.0% and 3.0%. In the case of pooled estimates and the fixed model results, CFR increased to 4.0%, by then gradually decreasing, while in the case of random-model, CFR remained under 2.0%. Similarly, in Europe, initially, the two types of CFR peaked at 9.0% and 10.0%, respectively. The random-model results showed an increase near 5.0%. In high-income countries, pooled estimates and fixed-model showed gradually increasing trends with a final pooled estimates and random-model reached about 8.0% and 4.0%, respectively. In middle-income, the pooled estimates and fixed-model have gradually increased reaching up to 4.5%. in low-income countries, CFRs remained similar between 1.5% and 3.0%. Our study emphasizes that COVID-19 CFR is not a fixed or static value. Rather, it is a dynamic estimate that changes with time, population, socioeconomic factors, and the mitigatory efforts of individual countries.

Metabolic syndrome (MetS) is characterized by insulin resistance, high blood pressure/sugar, dyslipidemia, and obesity. Whether MetS and its components affect the development of Behçet's disease (BD) remains unclear. This study was performed to investigate the associations between metabolic syndrome and risk of BD using nationwide population data. We conducted a retrospective cohort study of 10 505 818 Korean subjects who received health checkups in 2009-2012. Patients were classified into a MetS and its components group and were followed-up until 2016 for new-onset BD. A Cox proportional hazards model was used to assess the independent or synergistic effects of MetS and its components on the risk of incident BD. Compared to subjects without MetS components, the hazard ratio (HR) for development of BD in patients with MetS was 0.874 (95% confidence interval [CI]: 0.819-0.933) and this association was more prominent when all components of MetS were present (HR = 0.675, 95% CI = 0.571-0.798). Subjects with low high density lipoprotein (HDL) has a significantly increased risk of the development of BD (HR = 1.51, 95% CI = 1.4-1.594) compared to controls. This study showed that the incidence of Behçet's disease was reduced in subjects with MetS. Moreover, the presence of MetS components, with the exception of HDL, was negatively related to the development of BD.

BACKGROUND: Joint loads in different walking strategies during stair descent have been investigated in terms of the joint moment in association with the risk of osteoarthritis. However, the absorption mechanisms of the potential energy loss are not known. OBJECTIVE: This study aims to compare the mechanical energy absorptions in lower limb joints in different initial foot contact strategies. METHODS: Nineteen young subjects walked down on instrumented stairs with two different strategies, i.e., forefoot and rearfoot strike. Power and energy at lower limb joints during stance phase were compared between strategies. RESULTS: Lower limb joints absorbed 73 ± 11% of the potential energy released by descending stairs and there was no difference between strategies. Rearfoot strategy absorbed less energy than forefoot strategy at the ankle joint in the 1st phase, which was compensated mainly by more energy absorption at the knee in the 2nd phase and less energy generation at the hip joints in the 3rd phase. CONCLUSION: The results suggest that a leg absorbs most of the potential energy while descending stairs irrespective of the walking strategies and that any reduction of energy absorption at one joint is compensated by other joints. Greater energy absorption at the knee joint compared to the other joints suggests high burden of knee joint muscles and connective tissues during stair-descent, which is even more significant for the rearfoot strike strategy.

International audience; Rationale: Coronavirus disease 2019 (COVID-19) has spread worldwide and poses a threat to humanity. However, no specific therapy has been established for this disease yet. We conducted a systematic review to highlight therapeutic agents that might be effective in treating COVID-19. Methods: We searched Medline, Medrxiv.org, and reference lists of relevant publications to identify articles of in vitro, in vivo, and clinical studies on treatments for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19 published in English until the last update on October 11, 2020. Results: We included 36 studies on SARS, 30 studies on MERS, and 10 meta-analyses on SARS and MERS in this study. Through 12,200 title and 830 full-text screenings for COVID-19, eight in vitro studies, 46 randomized controlled trials (RCTs) on 6,886 patients, and 29 meta-analyses were obtained and investigated. There was no therapeutic agent that consistently resulted in positive outcomes across SARS, MERS, and COVID-19. Remdesivir showed a therapeutic effect for COVID-19 in two RCTs involving the largest number of total participants (n = 1,461). Other therapies that showed an effect in at least two RCTs for COVID-19 were sofosbuvir/daclatasvir (n = 114), colchicine (n = 140), IFN-β1b (n = 193), and convalescent plasma therapy (n = 126). Conclusions: This review provides information to help establish treatment and research directions for COVID-19 based on currently available evidence. Further RCTs are required.

We evaluated the efficacy and safety of MS-10

It is widely known that exposure to residential greenness is beneficial for health. However, few studies have analyzed the association between greenery and Parkinson’s disease (PD). We selected 313,355 participants who matched the inclusion criteria from the National Health Insurance Service-National Sample Cohort, followed up from 2007 to 2015. Residential greenness, represented by the normalized difference vegetation index (NDVI), was obtained from satellite measurements. We estimated hazard ratios of PD associated with a 0.1-unit increase in long-term greenness exposure at the district level for the previous 1 year of each year until a censoring/event occurred, using time-varying Cox proportional hazard models, adjusted for individual- and area-level characteristics. During the 2,745,389 person-years of follow-up, 2621(0.8%) participants developed PD. Exposure to higher levels of residential greenness was found to be associated with a decreased risk of PD incidence (21% per 0.1-unit increase, 95% confidence interval (CI): 0.74–0.84). In subgroup analyses, stronger protective effects were observed in participants aged over 50 years, females, overweight/obese participants, non-urban residents, non-smokers, alcoholics, and those with comorbidities. Long-term exposure to greenness was beneficial to incident PD, and our findings could aid in the development of public-health strategies.

Background: Previous studies indicated an association between Alzheimer’s disease (AD) dementia and air particulate matter (PM) with aerodynamic diameter

Background: Although the existence of proteasomes in human blood, termed circulating proteasomes (c-proteasomes), has been reported previously, their origin and pathophysiological functions remain largely unknown. Objective: Given that c-proteasome activity was significantly reduced in Alzheimer’s disease model mice and relatively high frequency of mild cognitive impairment (MCI) is accompanied by chronic tinnitus in aged patients, we examined whether c-proteasome activity in human plasma was associated with cognitive function in patients with chronic tinnitus. Methods: c-Proteasome activity in the plasma of tinnitus patients (N = 55) was measured with fluorogenic reporter substrate, suc-LLVY-AMC. To assess MCI, the Montreal Cognitive Assessment was conducted with a cut-off score of 22/23. All patients underwent audiological and psychoacoustic analyses. Levels of c-proteasomes, Aβ42, and Aβ40 were measured using ELISA, and their association with c-proteasome activity was evaluated. Results: The activity of circulating proteasomes was significantly lower in patients with chronic tinnitus and MCI (p = 0.042), whereas activities of other plasma enzymes showed little correlation. In addition, c-proteasome activity was negatively associated with the level of plasma Aβ and was directly dependent on its own concentration in the plasma of patients with chronic tinnitus. Conclusion: Our current work provides a new perspective for understanding the potential relationship between circulating proteasomes in the plasma and cognitive dysfunction, suggesting a novel, non-invasive biomarker in the context of MCI diagnosis.

The association between blood pressure (BP) defined by the 2017 American College of Cardiology/American Heart Association Hypertension Clinical Practice Guidelines with cardiovascular disease (CVD) and chronic kidney disease in patients with diabetes mellitus remains unclear. This study used the National Health Insurance Database of Korea that has health information of 8 922 940 persons who were screened from 2009 to 2014. We determined the BP status of 490 352 diabetes mellitus: level 1 (systolic

ObjectivesTo investigate the relationships of serum albumin with in vivo Alzheimer disease (AD) pathologies, including cerebral β-amyloid (Aβ) protein deposition, neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMH), in the human brain.MethodsA total of 396 older adults without dementia underwent comprehensive clinical assessments, measurement of serum albumin level, and multimodal brain imaging, including [11C] Pittsburgh compound B-PET,18F-fluorodeoxyglucose-PET, and MRI. Serum albumin was categorized as follows: 4.5 g/dL (high albumin; used as a reference category). Aβ positivity, AD-signature region cerebral glucose metabolism (AD-CM), AD-signature region cortical thickness (AD-CT), and WMH volume were used as outcome measures.ResultsSerum albumin level (as a continuous variable) was inversely associated with Aβ deposition and Aβ positivity. The low albumin group showed a significantly higher Aβ positivity rate compared to the high albumin group (odds ratio 3.40, 95% confidence interval 1.67–6.92,p= 0.001), while the middle albumin group showed no difference (odds ratio 1.74, 95% confidence interval 0.80–3.77,p= 0.162). Neither serum albumin level (as a continuous variable) nor albumin categories were related to AD-CM, AD-CT, or WMH volume.ConclusionsLow serum albumin may increase the risk of AD dementia by elevating amyloid accumulation. In terms of AD prevention, more attention needs to be paid to avoid a low serum albumin level, even within the clinical normal range, by clinicians.

Background Although recent studies indicate that the relationship between body mass index (BMI) and Alzheimer's disease (AD) may differ by both sex and age of BMI measurement, little information is available on sex- or age-specific associations between BMI and AD neuropathologies. Objective To examined whether sex-specific BMIs measured at different life-stages (in early adulthood, midlife, and late life) were associated with cerebral amyloid-β (Aβ) deposition and AD-signature region cortical thickness (AD-CT) in cognitively normal (CN) older adults. Methods A total of 212 CN subjects aged 60-90 years (females 108, males 104), who participated in the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), an ongoing prospective cohort study, were included. All participants underwent comprehensive clinical and neuropsychological assessments, [11C] Pittsburgh Compound B positron emission tomography, and brain magnetic resonance imaging. BMIs at different life stages were calculated. Multiple regression analyses were performed separately for either sex. Results In males, lower early adulthood or midlife BMI was associated with greater cerebral Aβ deposition, but late life BMI was not. Lower midlife BMI was associated with reduced AD-CT, but the BMI in early adulthood and late life was not. In females, no significant association was observed between any lifetime BMI and Aβ deposition or AD-CT. Conclusion Our results support a male-specific association between BMI prior to late life, and in vivo AD pathologies. Avoiding underweight status early in life may be important to prevent AD dementia in males, but not females.

Aim It has been suggested that personality traits, particularly neuroticism and conscientiousness, are risk factors for Alzheimer's disease (AD) and related cognitive decline. However, the underlying pathological links between personality traits and AD-related cognitive impairments remain unclear. Thus, the present study investigated associations of neuroticism and conscientiousness with in vivo cerebral amyloid-beta (Aβ) burden, AD-signature regional neurodegeneration, and white matter hyperintensities (WMH) in non-demented middle- and old-aged adults. Methods A total of 397 non-demented participants underwent comprehensive clinical and neuropsychological assessments, 11 C-labeled Pittsburgh Compound B positron emission tomography, and magnetic resonance imaging. Additionally, the NEO Five-Factor Inventory was administered to both the participants and their informants to measure neuroticism and conscientiousness. Results Neither neuroticism nor conscientiousness was associated with cerebral Aβ deposition or WMH. In contrast, higher neuroticism and lower conscientiousness, reported by informants in particular, were significantly associated with reduced AD-signature region cortical thickness. In regards to the direct and indirect effect of each personality on AD-signature region cortical thickness, only the direct effects were found, whereas indirect effects via Aβ deposition or WMH were not. Conclusion The present findings suggest that amyloid-independent regional neurodegeneration might underlie relations of neuroticism and conscientiousness with AD.

Imatinib (Gleevec) is a multiple tyrosine kinase inhibitor that decreases the activity of the fusion oncogene called BCR-ABL (breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog) and is clinically used for the treatment of chronic myelogenous leukemia and acute lymphocytic leukemia. Small molecule drugs, such as imatinib, can bind to several cellular proteins including the target proteins in the cells, inducing undesirable effects along with the effects against the disease. In this study, we report the synthetic optimization for 14 C-labeling and radiosynthesis of [14 C]imatinib to analyze binding with cellular proteins using accelerator mass spectroscopy. 14 C-labeling of imatinib was performed by the synthesis of 14 C-labeld 2-aminopyrimidine intermediate using [14 C]guanidine·HCl, which includes an in situ reduction of an inseparable byproduct for easy purification by HPLC, followed by a cross-coupling reaction with aryl bromide precursor. The radiosynthesis of [14 C]imatinib (specific activity, 631 MBq/mmol; radiochemical purity, 99.6%) was achieved in six steps with a total chemical yield of 29.2%.

Aims: The aim of the current study was to develop and validate a short-form of the internet overuse screening questionnaire (IOS-Qs). Methods: A total of 571 adults were recruited from a representative, stratified, and multistage cluster sample. Among participants, 188 and 383 were used in the development and validation of the IOS-Qs, respectively. Results: Experts’ ratings and Rasch model analyses led to the selection of 8 items from the IOS-Qs; latent-class analysis using these 8 items revealed an estimated prevalence of 8.6% (33 out of 383) of problematic internet over-users. Problematic internet over-users were positively associated with a 1-year prevalence rate of any mental disorder (OR 3.08, p = 0.008), mood disorder (OR 7.11, p = 0.003), and depressive disorder (OR 5.22, p = 0.016). The receiver operating characteristic curves identified an optimal cutoff score of 9.5 for differentiating problematic internet over-users from unproblematic internet users with 94% sensitivity and 94% specificity. Conclusion: The results suggest that the IOS-Qs was valid, and items including social isolation were crucial to the brief distinction of at-risk internet users. Because of its brevity, the questionnaire can be effectively administered as a large-scale survey.

Late-life depression (LDD) results from multiple psychosocial and neurobiological changes occurring in later life. The current study investigated how patterns of clinical symptoms and brain structural features are classified into LDD subtypes.Self-report scale of depression, behavioral rating of affective symptoms, and brain structural imaging of white matter change and cortical thickness were assessed in 541 older adults with no cognitive impairment or mild cognitive impairment. Latent profile analysis was used to identify distinct subtypes of depression.The latent profile analysis identified four classes with mild to severe depressive symptoms and two classes with minimal symptoms. While the classes primarily differed in the overall severity, the combinatory patterns of clinical symptoms and neuropathological signature distinguished the classes with similar severity. The classes were distinguished in terms of whether or not neurodegenerative risk accompanied the corresponding depressive symptoms. The presence of the negative self-scheme and cortical thinning pattern notably characterized the subtypes of LDD.The underlying etiologies of the biological subtypes are still speculative, and the current study lacks clinical history that differentiates late- and early-onset depression.Our finding provides insight in identifying heterogeneities of depressive disorder in later life and suggests that self-report and behavioral symptom profile in combination with white matter lesion and cortical thickness effectively characterizes distinct subtypes of LDD.

BACKGROUND: Physical activities (PA) have been suggested to reduce the risk of Alzheimer’s disease (AD) dementia. However, information on the neuropathological links underlying the relationship is limited. OBJECTIVE: We investigated the role of midlife and late-life PA with in vivo AD neuropathologies in old adults without dementia. METHODS: This study included participants from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s disease (KBASE). The participants underwent comprehensive clinical and neuropsychological assessment, [(11)C] Pittsburgh Compound B positron emission tomography (PET), [(18)F] fluorodeoxyglucose PET, and magnetic resonance imaging. Using the multi-modal brain imaging data, in vivo AD pathologies including global amyloid deposition, AD-signature region cerebral glucose metabolism (AD-CM), and AD-signature region cortical thickness (AD-CT) were quantified. Both midlife and late-life PA of participants were measured using the Lifetime Total Physical Activity Questionnaire. RESULTS: This study was performed on 260 participants without dementia (195 with normal cognitive function and 65 with mild cognitive impairment). PA of neither midlife nor late-life showed direct correspondence with any neuroimaging biomarker. However, late-life PA moderated the relationship of brain amyloid-β (Aβ) deposition with AD-CM and AD-CT. Aβ positivity had a significant negative effect on both AD-CM and AD-CT in individuals with lower late-life PA, but those with higher late-life PA did not show such results. Midlife PA did not have such a moderation effect. CONCLUSION: The findings suggest that physically active lifestyle in late-life, rather than that in midlife, may delay AD-associated cognitive decline by decreasing Aβ-induced neurodegenerative changes in old adults.

A considerable proportion of patients warranting total knee arthroplasty (TKA) have night pain, neuropathic pain, and/or depressive disorder, which may not be resolved by TKA. This prospective, longitudinal cohort study aimed to document the prevalence of night pain, neuropathic pain, and depressive disorder in patients with advanced knee osteoarthritis undergoing TKA and to determine whether the specific coexisting pain and/or disorder at the time of TKA adversely affected postoperative outcomes.In this study, 148 patients undergoing TKA were longitudinally evaluated. The presence of night pain, neuropathic pain (determined using Douleur Neuropathique 4 [DN4]) and depressive disorder (determined using the Patient Health Questionnaire-9 [PHQ-9]) was determined before and 6 weeks, 3 months and 1 year after TKA. In addition, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and EuroQol-5 Dimension (EQ-5D) scores were assessed before and 1 year after TKA. Potential associations of night pain, neuropathic pain, and/or depressive disorder with pre- and postoperative WOMAC and EQ-5D scores were examined in subgroup analyses.Preoperatively, 72% (n = 106) of patients reported night pain, and the prevalences of neuropathic pain and depressive disorder were 15% and 17%, respectively. Preoperatively, compared with patients without night pain, those with night pain had significantly poorer preoperative WOMAC scores, but no significant difference was seen between groups 1 year after TKA. Preoperatively, the WOMAC, EQ-5D, and EQ-5D health scores of patients with neuropathic pain were not significantly different from those of patients without neuropathic pain, and there was no difference in clinical outcome scores 1 year after TKA between these groups. Preoperatively, the patients with depressive disorder showed significantly poorer preoperative WOMAC, EQ-5D, and EQ-5D health scores than those without depressive disorder, but no significant differences in scores were observed 1 year after TKA between these groups.This study revealed a considerable prevalence of night pain, neuropathic pain, and depressive disorder in patients undergoing TKA and that patients with these specific conditions reported poorer functional and quality of life scores preoperatively. However, such adverse effects disappeared after TKA. Our study findings suggest that TKA can provide satisfactory outcomes for patients with these specific conditions.

Nickel allergy is the most common contact allergy, and a nickel salt is, therefore, included in most baseline patch test series. In the baseline series of the International Contact Dermatitis Research Group and the American Contact Dermatitis Society, nickel sulfate hexahydrate (NSH) in petrolatum at 2.5% is included, whereas NSH at 5.0% is included in many other baseline series, such as the European and Swedish ones. The aim of the study is to investigate whether NSH at 5.0% detects significantly more contact allergy than NSH 2.5% when both preparations are tested simultaneously in consecutive dermatitis patients. Two thousand two hundred eighty-seven consecutive dermatitis patients were patch tested simultaneously with NSH in petrolatum at 2.5% and 5.0%. The allergy rates were compared for all clinics individually and combined using McNemar test, 2-sided. Contact allergy to NSH 5.0% and 2.5% was found in 20.3% and 16.8%, respectively ( P < 0.0001). In 6 of 11 clinics, significantly more patients tested positive to the higher NSH concentration. For the 2 clinics in North America combined, significantly more patients tested positive to NSH 5.0%. The NSH preparation in the International Contact Dermatitis Research Group baseline patch test series should be considered to be changed from NSH 2.5% (1 mg NSH/cm2) to 5.0% (2 mg NSH/cm2).

Layered double hydroxide is a family of two-dimensional materials with wide range of compositions. Recently, its ability to accommodate various chemical species and biocompatibility have been attracted in the biomedical applications to develop drug delivery system and nanodiagnostics. In this review, we categorized biomedical approaches of layered double hydroxide with respect to the three topologies of, namely, interlayer space, outer surface with particle edge, and the lattice points. There have been extensive researches on the intercalation of drug or tracing to make use of interlayer space of layered double hydroxide for drug stabilization, sustained release, cellular delivery and etc. Outer surface or edge has been utilized to immobilization of large therapeutic moieties and to attach tracing moiety. Lattice points consisting of various metal species could be utilized for the specific metal species like paramagnetic elements or radioisotopes. Based on these topologies in layered double hydroxide, both the synthetic routes and the achieved functionalities in terms of biomedical application will be discussed.

Background This study investigated trends in the prevalence of major depressive disorder (MDD) by sociodemographic factors in South Korea. Methods National samples of the general population aged 18 years or older collected from the nationwide Korean Epidemiologic Catchment Area surveys conducted in 2001 (n = 6,206), 2006 (n = 6,466), and 2011 (n = 5,986) were used. For MDD diagnosis, we conducted face-to-face interviews using the Korean version of the Composite International Diagnostic Interview. We performed logistic regression analyses stratified by gender, after adjusting for other sociodemographic variables, to calculate the 2006-to-2001 odds ratio (OR) and 2011-to-2001 OR by subgroups of sociodemographic factors to explore the association of MDD prevalence with sociodemographic factors over time. Results The prevalence of MDD in the general population of South Korea increased steadily from 2001, to 2006, and to 2011 (1.6%, 2.5%, and 3.1%, respectively). Among the men, the prevalence of MDD continued to increase significantly in 18–29 years of age group (2006: adjusted OR [AOR], 3.32; 2011: AOR, 7.42), at-risk drinking group (2006: AOR, 3.56; 2011: AOR, 4.77), and not living with a partner group (2006: AOR, 3.24; 2011: AOR, 3.25). Meanwhile, among the women, the prevalence of MDD continued to significantly increase in the below-average household income group (2006: AOR, 2.58; 2011: AOR, 2.59), at-risk drinking group (2006: AOR, 2.02; 2011: AOR, 2.47), and unemployed group (2006: AOR, 1.48; 2011: AOR, 2.04). Conclusion This study may provide significant information for public policymakers to allocate sufficient health resources on MDD to vulnerable groups, particularly, men aged 18–29 years and women living in households with below-average income, and for clinicians to develop appropriate screening and treatment modalities for MDD., Graphical Abstract

Background Despite the known associations between zinc levels and Alzheimer’s disease (AD) dementia and related cognitive impairment, the underlying neuropathological links remain poorly understood. We tested the hypothesis that serum zinc level is associated with cerebral beta-amyloid protein (Aβ) deposition. Additionally, we explored associations between serum zinc levels and other AD pathologies [i.e., tau deposition and AD-signature cerebral glucose metabolism (AD-CM)] and white matter hyperintensities (WMHs), which are measures of cerebrovascular injury. Methods A total of 241 cognitively normal older adults between 55 and 90 years of age were enrolled. All the participants underwent comprehensive clinical assessments, serum zinc level measurement, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging. Zinc levels were stratified into three categories: 90 μg/dL (high). Results A low serum zinc level was significantly associated with increased Aβ retention. In addition, apolipoprotein E ε4 allele (APOE4) status moderated the association: the relationship between low zinc level and Aβ retention was significant only in APOE4 carriers. Although a low zinc level appeared to reduce AD-CM, the relationship became insignificant on sensitivity analysis including only individuals with no nutritional deficiency. The serum zinc level was associated with neither tau deposition nor the WMH volume. Conclusions Our findings suggest that decreased serum zinc levels are associated with elevation of brain amyloid deposition. In terms of AD prevention, more attention needs to be paid to the role of zinc.

Facial expressions are well known to change with age, but the quantitative properties of facial aging remain unclear. In the present study, we investigated the differences in the intensity of facial expressions between older (n = 56) and younger adults (n = 113). In laboratory experiments, the posed facial expressions of the participants were obtained based on six basic emotions and neutral facial expression stimuli, and the intensities of their faces were analyzed using a computer vision tool, OpenFace software. Our results showed that the older adults expressed strong expressions for some negative emotions and neutral faces. Furthermore, when making facial expressions, older adults used more face muscles than younger adults across the emotions. These results may help to understand the characteristics of facial expressions in aging and can provide empirical evidence for other fields regarding facial recognition.

Adenovirus (Ad) has risen to be a promising alternative to conventional cancer therapy. However, systemic delivery of Ad, which is necessary for the treatment of metastatic cancer, remains a major challenge within the field, owing to poor tumor tropism and nonspecific hepatic tropism of the virus. To address this limitation of Ad, we have synthesized two variants of folic acid (FA)-conjugated methoxy poly(ethylene glycol)-b-poly{N-[N-(2-aminoethyl)-2-aminoethyl]-L-glutamate (P5N2LG-FA and P5N5LG-FA) using 5 kDa poly(ethylene glycol) (PEG) with a different level of protonation (N2 &lt, N5 in terms of charge), along with a P5N5LG control polymer without FA. Our findings demonstrate that P5N5LG, P5N2LG-FA, and P5N5LG-FA exert a lower level of cytotoxicity compared to 25 kDa polyethyleneimine. Furthermore, green fluorescent protein (GFP)-expressing Ad complexed with P5N2LG-FA and P5N5LG-FA (Ad/P5N2LG-FA and Ad/P5N5LG-FA, respectively) exerted superior transduction efficiency compared to naked Ad or Ad complexed with P5N5LG (Ad/P5N5LG) in folate receptor (FR)-overexpressing cancer cells (KB and MCF7). All three nanocomplexes (Ad/P5N5LG, Ad/P5N2LG-FA, and Ad/P5N5LG-FA) internalized into cancer cells through coxsackie adenovirus receptor-independent endocytic mechanism and the cell uptake was more efficient than naked Ad. Importantly, the cell uptake of the two FA functionalized nanocomplexes (Ad/P5N2LG-FA and Ad/P5N5LG-FA) was dependent on the complementary interaction of FA–FR. Systemically administered Ad/P5N5LG, Ad/P5N2LG-FA, and Ad/P5N5LG-FA showed exponentially higher retainment of the virus in blood circulation up to 24 h post-administration compared with naked Ad. Both tumor-targeted nanocomplexes (Ad/P5N2LG-FA and Ad/P5N5LG-FA) showed significantly higher intratumoral accumulation than naked Ad or Ad/P5N5LG via systemic administration. Both tumor-targeted nanocomplexes accumulated at a lower level in liver tissues compared to naked Ad. Notably, the nonspecific accumulation of Ad/P5N2LG-FA was significantly lower than Ad/P5N5LG-FA in several normal organs, while exhibiting a significantly higher intratumoral accumulation level, showing that careful optimization of polyplex surface charge is critical to successful tumor-targeted systemic delivery of Ad nanocomplexes.

Age-related white matter lesion (WML) is considered a manifestation of sporadic cerebral small vessel disease and an important pathological substrate for dementia. Asia is notable for its large population with a looming dementia epidemic. Yet, the burden of WML and its associated risk factors across different Asian societies are unknown. Subjects from 9 Asian cities (Bangkok, Bandung, Beijing, Bengaluru, Hong Kong, Kaohsiung, Manila, Seoul, and Singapore) were recruited (n = 5701) and classified into (i) stroke/transient ischemic attack (TIA), (ii) Alzheimer’s disease (AD)/mild cognitive impairment (MCI), or (iii) control groups. Data on vascular risk factors and cognitive performance were collected. The severity of WML was visually rated on MRI or CT. The prevalence of moderate-to-severe WML was the highest in subjects with stroke/TIA (43.3%). Bandung Indonesia showed the highest prevalence of WML, adjusted for age, sex, education, disease groups, and imaging modality. Hypertension and hyperlipidemia were significant risk factors for WML, and WML was negatively associated with MMSE in all groups. WML is highly prevalent in Asia and is associated with increasing age, hypertension, hyperlipidemia, and worse cognitive performance. Concerted efforts to prevent WML will alleviate the huge dementia burden in the rapidly aging Asian societies.

Psoriasis is a chronic inflammatory skin disease known to be associated with a variety of systemic comorbidities, such as metabolic syndrome and obesity. Obesity represents a major comorbidity and has been suggested to be related to psoriasis. This nationwide population-based prospective cohort study was performed to investigate the impacts of body mass index (BMI) and waist circumference (WC) on psoriasis. We used the health check-up database and the study population consisted of subjects who had undergone health screening between January 2009 and December 2012. This study investigated patients newly diagnosed with psoriasis (International Classification of Disease, Tenth Revision, code L40) by dermatologists during the follow-up period (5.32 years), based on claims data. The total population consisted of 22 633 536 subjects, among whom 399 461 had newly developed psoriasis. Subjects with BMI of more than 30 had a higher risk of psoriasis (hazards ratio [HR], 1.118; 95% confidence interval [CI], 1.100-1.137) compared with the BMI 18.5-23 group. WC showed a dose-dependent association with psoriatic risk. Subjects with WC over 105 cm showed the highest risk of psoriasis (HR, 1.305; 95% CI, 1.261-1.349) compared with subjects with WC lower than 80/75 after adjusting for confounding factors, including BMI. The risk of psoriasis was highest in males with normal BMI and abdominal obesity (HR, 1.175; 95% CI, 1.150-1.200). Our study indicates that WC is a specific factor affecting psoriatic risk and highlights the association between abdominal obesity and psoriasis, thus increasing awareness of the role of abdominal obesity in the pathogenesis and comorbidities of psoriasis.

This study tested the efficacy of the phosphodiesterase type III inhibitor cilostazol in Alzheimer’s disease patients with white matter lesions treated with donepezil in comparison with donepezil monotherapy using fluorodeoxyglucose ((18)F) positron-emission tomography (FDG PET). A 24-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted. Thirty-six Alzheimer’s disease patients with white matter lesions who received donepezil (n = 18 each in the cilostazol and placebo groups) were enrolled. Participants underwent pre and post FDG PET imaging scans and three rounds of clinical and neuropsychological tests. The cilostazol group did not show a significant decrease of regional glucose metabolism; however, regional glucose metabolism was significantly decreased in the parietal and frontal lobes of the placebo group. The repeated measures ANOVA measuring differences in uptake change revealed that regional glucose metabolism in the left inferior frontal gyrus was significantly more preserved in the cilostazol group than that in the placebo group (p

The aim of this study was to investigate distinct neurometabolites in the right and left thalamus and insula of patients with complex regional pain syndrome (CRPS) compared with healthy controls using proton magnetic resonance spectroscopy. Levels of N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG), myo-inositol (ml), glutamine (Gln), glycerophosphocholine (GPC), glutathione (GSH), and alanine (Ala) relative to total creatine (tCr) levels, including creatine and phosphocreatine, were determined in the right and left thalamus and insula in 12 patients with CRPS compared with 11 healthy controls using magnetic resonance spectroscopy. Levels of NAAG/tCr and Ala/tCr were higher in patients with CRPS than in controls in the left thalamus. NAAG/tCr, ml/tCr, and Gln/tCr levels were higher but NAA/tCr levels were lower in the right insula of patients with CRPS compared with controls. There were negative correlations between GSH/tCr and pain score (McGill Pain Questionnaire) in the left thalamus. These findings are paramount to understand and determine all aspects of the complex pathophysiological mechanisms that underlie CRPS, including involvement of the central and parasympathetic nervous systems as well as oxidative stress and antioxidants. Thus, the distinct metabolites presented herein may be essential to understand a strong diagnostic and prognostic potential for CRPS and to develop effective medical treatments.

Post-exposure prophylaxis (PEP) is highly effective in preventing disease progression of rabies when used in timely and appropriate manner. The key treatment for PEP is infiltration of rabies immune globulin (RIG) into lesion site after bite exposure, besides wound care and vaccination. Unfortunately, however, RIG is expensive and its supply is limited. Currently, several anti-rabies virus monoclonal antibody (mAb) products are under development as alternatives to RIG, and two recently received regulatory approval in India. In this study, fully human mAbs that recognize different rabies virus glycoprotein conformational antigenic site (II and III) were created from peripheral blood mononuclear cells of heathy vaccinated subjects. These mAbs neutralized a diverse range of lyssavirus types. As at least two anti-rabies virus mAbs are recommended for use in human PEP to ensure broad coverage against diverse lyssaviruses and to minimize possible escape variants, two most potent mAbs, NP-19-9 and 11B6, were selected to be used as cocktail treatment. These two mAbs were broadly reactive to different types of lyssaviruses isolates, and were shown to have no interference with each other. These results suggest that NP-19-9 and 11B6 are potent candidates to be used for PEP, suggesting further studies involving clinical studies in human.

Background: Both elevated blood homocysteine and diabetes mellitus (DM) are related to cognitive impairments or dementia. A previous study also demonstrated that the association between homocysteine and cognitive decline was much stronger in individuals with DM than in those without DM. Objective: This study aimed to examine the interactive effect of blood homocysteine and DM on brain pathological changes including brain atrophy, amyloid-β and tau deposition, and small vessel disease (SVD) related to cognitive impairments. Methods: A total of 430 non-demented older adults underwent comprehensive clinical assessment, measurement of serum homocysteine level, [11C] Pittsburgh Compound B (PiB) PET, [18F] AV-1451 PET, and brain MRI. Results: The interactive effect of homocysteine with the presence of DM on brain atrophy, especially in aging-related brain regions, was significant. Higher homocysteine concentration was associated with more prominent brain atrophy in individuals with DM, but not in those without DM. In contrast, interaction effect of homocysteine and DM was found neither on Alzheimer’s disease (AD) pathologies, including amyloid-β and tau deposition, nor white matter hyperintensity volume as a measure of SVD. Conclusion: The present findings suggest that high blood homocysteine level and DM synergistically aggravate brain damage independently of AD and cerebrovascular disease. With regard to preventing dementia or cognitive decline in older adults, these results support the importance of strictly controlling blood glucose in individuals with hyperhomocysteinemia and lowering blood homocysteine level in those with DM.

Scoring atopic dermatitis (AD) severity with the Eczema Area and Severity Index (EASI) in an objective and reproducible manner is challenging. Automated measurement of erythema, papulation, excoriation, and lichenification severity using images has not yet been investigated. Our aim was to determine whether convolutional neural networks (CNNs) could assess erythema, papulation, excoriation, and lichenification severity at a level of competence comparable to dermatologists. We created a standard dataset of 8,000 clinical images showing AD. Each component of the EASI was scored from 0 to 3 by three dermatologists. We trained four CNNs (ResNet V1, ResNet V2, GoogLeNet, and VGG-Net) with the image dataset and determined which CNN was the most suitable for erythema, papulation, excoriation, and lichenification scoring. The brightness of the images in each dataset was adjusted to − 80% to + 80% of the original brightness (i.e., 9 levels by 20%) to investigate if the CNNs accurately measured scores if image brightness levels were changed. Compared to the dermatologists’ scoring, accuracy rates of the CNNs were 99.17% for erythema, 93.17% for papulation, 96.00% for excoriation, and 97.17% for lichenification. CNNs trained with brightness-adjusted images achieved a high accuracy without the need to standardize camera settings. These results suggested that CNNs perform at level of competence comparable to dermatologists for scoring erythema, papulation, excoriation, and lichenification severity.

BackgroundMetamemory training (MMT) is a useful training strategy for improving cognitive functioning in the older adult population. Despite the advantages, there are limitations imposed by location and time constraints.ObjectiveThis study aimed to develop a smart speaker–based MMT program and evaluate the efficacy of the program in older adults without cognitive impairment.MethodsThis study used a case-control cohort design. The smart speaker–based MMT program comprised 3 training sessions per day, 5 days a week, for 8 weeks. Each training session took approximately 15 minutes. This program was implemented using smart speakers, not human trainers. All participants completed the Mini-Mental State Examination, Subjective Memory Complaints Questionnaire, Verbal Learning Test, Digit Span Test, fluency tests, and a short-form version of the Geriatric Depression Scale before and after training.ResultsA total of 60 subjects (29 in the MMT group and 31 in the control group) participated in the study. The training group showed significant increases in the delayed free recall, digit span forward, digit span backward, and fluency test scores compared with the control group.ConclusionsThis study confirmed the efficacy of smart speaker–based MMT in older adults. Home-based smart speaker–based MMT is not limited with respect to location or constrained by space and may help older adults with subjective cognitive decline without requiring intervention by human professionals.

Occupational attainment, which represents middle-age cognitive activities, is a known proxy marker of cognitive reserve for Alzheimer's disease. Previous genome-wide association studies have identified numerous genetic variants and revealed the genetic architecture of educational attainment, another marker of cognitive reserve. However, the genetic architecture and heritability for occupational attainment remain elusive. We performed a large-scale genome-wide association study of occupational attainment with 248 847 European individuals from the UK Biobank using the proportional odds logistic mixed model method. In this analysis, we defined occupational attainment using the classified job levels formulated in the UK Standard Occupational Classification system considering the individual professional skill and academic level. We identified 30 significant loci (P < 5 × 10−8); 12 were novel variants, not associated with other traits. Among them, four lead variants were associated with genes expressed in brain tissues by expression quantitative trait loci mapping from 10 brain regions: rs13002946, rs3741368, rs11654986 and rs1627527. The single nucleotide polymorphism-based heritability was estimated to be 8.5% (standard error of the mean = 0.004) and partitioned heritability was enriched in the CNS and brain tissues. Genetic correlation analysis showed shared genetic backgrounds between occupational attainment and multiple traits, including education, intelligence, leisure activities, life satisfaction and neuropsychiatric disorders. In two-sample Mendelian randomization analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.65–0.92 in inverse variance weighted method; OR = 0.73, 95% CI = 0.57–0.92 in the weighted median method]. This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic single nucleotide polymorphisms (OR = 0.72, 95% CI = 0.57–0.91 in the inverse variance weighted method; OR = 0.72, 95% CI = 0.53–0.97 in the weighted median method). Multivariable Mendelian randomization confirmed that occupational attainment had an independent effect on the risk for Alzheimer’s disease even after taking educational attainment into account (OR = 0.72, 95% CI = 0.54–0.95 in the inverse variance weighted method; OR = 0.68, 95% CI = 0.48–0.97 in the weighted median method). Overall, our analyses provide insights into the genetic architecture of occupational attainment and demonstrate that occupational attainment is a potential causal protective factor for Alzheimer's disease as a proxy marker of cognitive reserve.

Immunotherapy via interleukin-2 (IL-2) mediated activation of anti-tumor immune response is a promising approach for cancer treatment. The multi-potent cytokine, IL-2 has a central role in immune cell activation and homeostasis. Since IL-2 preferentially activates immunosuppressive T regulatory cells by IL-2Rα dependent manner, blocking IL-2:IL-2Rα interaction is a key to amplify the IL-2 activity in effector T cells toward anti-tumor response. Anti-IL-2 monoclonal antibodies are good candidates to control the IL-2:IL-2Rα interaction. In a previous study, we developed a new IL-2Rα mimetic antibody, TCB2, and showed that the human IL-2(hIL-2):TCB2 complex can stimulate T effector cells specifically and elicit potent anti-cancer immunotherapeutic effect, especially when administered in combination with immune checkpoint inhibitors. To understand the molecular mechanism, we determined the crystal structure of TCB2-Fab in a complex with hIL-2 at 2.5 Å resolution. Our structural analysis reveals that TCB2 binds to the central area of the hIL-2Rα binding region on hIL-2, and binding angle and epitope are different from previously known hIL-2Rα mimicking antibody NARA1 which recognizes the top part of hIL-2. TCB2 binding to hIL-2 also induces an allosteric effect that increases the affinity for the hetero-dimeric hIL-2 receptor, IL-2R(β + γ), on effector T cells.

In a previous study, we found that higher waist circumference (WC) and higher body mass index (BMI) both increase the risk of chronic spontaneous urticaria (CSU). The aim of this study was to determine whether WC and BMI also increase the duration of CSU. We used multivariable Cox proportional hazards models to determine the hazard ratio (HR) for longer disease duration (longer than 3 years) according to WC and BMI. A total of 52,667 subjects were enrolled and their mean age was 54.5. After adjustments for other confounding variables the high WC/high BMI group had 1.062 times higher HR (95% CI, 1.028–1.098) than the normal WC/normal BMI group. Interestingly, the high WC/normal BMI group showed a significantly higher HR (1.053; 95% CI, 1.008–1.101) than the normal WC/normal BMI group, but not the normal WC/high BMI group (0.998; 95% CI, 0.951–1.046). Taken together, our results suggest that high WC rather than high BMI is a predictive risk factor for the longer disease duration of CSU.

Graphical abstract, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) continues to spread worldwide, with 25 million confirmed cases and 800 thousand deaths. Effective treatments to target SARS-CoV-2 are urgently needed. In the present study, we have identified a class of cyclic sulfonamide derivatives as novel SARS-CoV-2 inhibitors. Compound 13c of the synthesized compounds exhibited robust inhibitory activity (IC50 = 0.88 μM) against SARS-CoV-2 without cytotoxicity (CC50 > 25 μM), with a selectivity index (SI) of 30.7. In addition, compound 13c exhibited high oral bioavailability (77%) and metabolic stability with good safety profiles in hERG and cytotoxicity studies. The present study identified that cyclic sulfonamide derivatives are a promising new template for the development of anti-SARS-CoV-2 agents.

Graphical abstract, Despite the rising threat of fatal coronaviruses, there are no general proven effective antivirals to treat them. 2-Aminoquinazolin-4(3H)-one derivatives were newly designed, synthesized, and investigated to show the inhibitory effects on SARS-CoV-2 and MERS-CoV. Among the synthesized derivatives, 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (9g) and 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4 (3H)-one (11e) showed the most potent anti-SARS-CoV-2 activities (IC50 < 0.25 μM) and anti-MERS-CoV activities (IC50 < 1.1 μM) with no cytotoxicity (CC50 > 25 μM). In addition, both compounds showed acceptable results in metabolic stabilities, hERG binding affinities, CYP inhibitions, and preliminary PK studies.

BackgroundLimited information is available regarding which of the commonly used cognitive reserve (CR) proxies are more appropriate to precisely reflect moderation effect for the relationship between a specific Alzheimer’s disease (AD) pathology and cognitive decline. We examined the moderating effects of the frequently used four CR proxies [i.e., education, premorbid intelligence quotient (pIQ), occupational complexity (OC), and lifetime cognitive activity (LCA)] on the relationships between various in vivo AD pathologies and cognitive decline. MethodsThis study included 361 older adults (268 cognitively unimpaired, 52 mild cognitive impairment with beta-amyloid (Aβ) deposition, 41 AD dementia with Aβ deposition). All participants underwent multi-modal brain imaging including [11C] Pittsburgh Compound B positron emission tomography (PET), [18F] Fluorodeoxyglucose-PET, and magnetic resonance imaging to measure AD pathologies as well as comprehensive clinical and neuropsychological assessments. Information on education, pIQ estimated with an adult reading test, OC, and LCA was obtained. The Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery total score (CERAD-TS) was used as the cognitive measure. We used linear regression model predicting cognition to examine the interactions of each CR proxy and each AD pathology.ResultsAmong the CR proxies, only education significantly moderated the relationship between Aβ deposition and CERAD-TS. Education, pIQ, and LCA, but not OC, showed moderating effect on the relationship between AD-signature cerebral hypometabolism and CERAD-TS. In contrast, only OC had a significant moderating effect on the relationship between cortical atrophy of the AD-signature regions and CERAD-TS. ConclusionsThe present findings suggest that the proposed CR proxies have different moderating effects on the relationships between specific AD pathologies and cognitive decline. To investigate CR or related issues, it is necessary to select a proper CR proxy considering the target brain pathology.

Patients with chronic kidney disease (CKD) have a high prevalence of left ventricular hypertrophy (LVH), which increases as kidney function decreases. LVH pathophysiology is complex, making it difficult to generalise its evolution in CKD. Therefore, early detection and prevention of risk factors are critical. Assessment and management of volume status can minimise cardiovascular complications including LVH. We retrospectively investigated the associations between fluid overload and LVH in patients with stage 5 CKD not undergoing dialysis in prospective cohort of 205 patients (age: 59.34 ± 13.51 years; women: 43.4%). All patients, free of intrinsic heart disease, were assessed for relative overhydration/extracellular water (OH/ECW) by bioimpedance spectroscopy. Our results show that markers reflecting fluid balance were significantly higher in the LVH group and as OH/ECW increased, the left ventricular mass index (LVMI) trended higher. Furthermore, our results show that systolic blood pressure, serum phosphorus levels, and OH/ECW were independently associated with LVMI and that OH/ECW was independently associated with LVH. Structural and functional evaluation of the heart using echocardiography and volume status assessment using bioimpedance should be performed simultaneously in patients with early-stage CKD, even in those without evident cardiovascular disease.

Background Cognitive training can potentially prevent cognitive decline. However, the results of recent studies using semi-immersive virtual reality (VR)-assisted cognitive training are inconsistent. Objective We aimed to examine the hypothesis that cognitive training using fully immersive VR, which may facilitate visuospatial processes, could improve visuospatial functioning, comprehensive neuropsychological functioning, psychiatric symptoms, and functional connectivity in the visual brain network in predementia. Methods Participants over 60 years old with subjective cognitive decline or mild cognitive impairment from a memory clinic were randomly allocated to the VR (n=23) or the control (n=18) group. The VR group participants received multidomain and neuropsychologist-assisted cognitive training in a fully immersive VR environment twice a week for 1 month. The control group participants did not undergo any additional intervention except for their usual therapy such as pharmacotherapy. Participants of both groups were evaluated for cognitive function using face-to-face comprehensive neuropsychological tests, including the Rey-Osterrieth Complex Figure Test (RCFT) copy task; for psychiatric symptoms such as depression, apathy, affect, and quality of life; as well as resting-state functional magnetic resonance imaging (rsfMRI) at baseline and after training. Repeated-measures analysis of variance was used to compare the effect of cognitive training between groups. Seed-to-voxel–based analyses were used to identify the cognitive improvement–related functional connectivity in the visual network of the brain. Results After VR cognitive training, significant improvement was found in the total score (F1,39=14.69, P=.001) and basic components score of the RCFT copy task (F1,39=9.27, P=.005) compared with those of the control group. The VR group also showed improvements, albeit not significant, in naming ability (F1,39=3.55, P=.07), verbal memory delayed recall (F1,39=3.03, P=.09), and phonemic fluency (F1,39=3.08, P=.09). Improvements in psychiatric symptoms such as apathy (F1,39=7.02, P=.01), affect (F1,39=14.40, P=.001 for positive affect; F1,39=4.23, P=.047 for negative affect), and quality of life (F1,39=4.49, P=.04) were found in the VR group compared to the control group. Improvement in the RCFT copy task was associated with a frontal-occipital functional connectivity increase revealed by rsfMRI in the VR group compared to the control group. Conclusions Fully immersive VR cognitive training had positive effects on the visuospatial function, apathy, affect, quality of life, and increased frontal-occipital functional connectivity in older people in a predementia state. Future trials using VR cognitive training with larger sample sizes and more sophisticated designs over a longer duration may reveal greater improvements in cognition, psychiatric symptoms, and brain functional connectivity. Trial Registration Clinical Research Information Service KCT0005243; https://tinyurl.com/2a4kfasa

Background: Physical frailty and impaired executive function of the brain show similar pathophysiology. Both of these factors lead to dysfunction of neuromuscular and abilities in elderly. High-speed power training (HSPT) has been determined to have positive effects on neuromuscular function and gait performance, as well as executive function in the elderly. Objectives: The purpose of this study was to investigate the effects of 8-week HSPT on neuromuscular, gait and executive functions in frail elderly with mild cognitive impairment (MCI). Design, setting and participants: We performed a randomized controlled trial of frail elderly from community and medical center in republic of Korea. Forty-two physically frail elderly with MCI were randomly allocated to control (n=22, age=74.22±4.46) and intervention groups (n=18, age=73.77±4.64). The intervention group was subjected to HSPT, 3 times weekly for 8 weeks. Measurements: Isometric contraction of knee extension and flexion with electromyography (EMG) was measured to determine the neuromuscular function such as knee extensor strength, rate of torque development, movement time, pre-motor time, motor time, rate of EMG rise, and hamstrings antagonist co-activation. Additionally, the 4.44-meter gait and timed up-and-go (TUG) test were administered to assess gait performance. A frontal assessment battery was measured in this study. Results: The 8-week HSPT regimen improved the knee extensor strength from 1.13±0.08 to 1.25±0.07 (p

Background:Regular monitoring of vascular access in patients on maintenance hemodialysis is important to detect early vascular access complications. We compared vascular access blood flow determined by blood temperature monitor and Doppler ultrasonography to evaluate the usefulness of blood temperature monitor.Methods:In total, 70 patients on maintenance hemodialysis were enrolled from three dialysis centers. Vascular access blood flow was measured thrice at 6-month intervals using Doppler ultrasonography to determine arterial inflow (Q-DUa), venous outflow (Q-DUv), and flow between punctures (Q-DUb) using BTM® (Q-BTM). Twister® was placed between the hemodialysis needle and blood lines, allowing simple reversal of flow without stopping the hemodialysis pump.Results:In total, 203 measurements were recorded, with median values (interquartile range) for Q-BTM, Q-DUa, Q-DUv, and Q-DUb of 1139.0 (868.0–1588.0) mL/min, 960.3 (658.7–1380.4) mL/min, 946.0 (552.0–1515.0) mL/min, and 1067.7 (544.8–1635.0) mL/min, respectively. For all measurements, the mean intraclass correlation coefficients were 0.52 (95% confidence interval, 0.36–0.64) for Q-DUa; 0.37 (95% confidence interval, 0.15–0.53) for Q-DUv; and 0.45 (95% confidence interval, 0.26–0.59) for Q-DUb. Analysis of a receiver operating characteristics curve yielded a cut-off of 627 mL/min for Q-BTM to predict stenosis.Conclusion:In patients on maintenance hemodialysis, blood flow measured by blood temperature monitor moderately correlated with Doppler blood flow. It was more related to arterial inflow than venous outflow or flow between punctures. The blood temperature monitor method was not inferior to Doppler ultrasonography. Therefore, blood temperature monitor could be recommended for routine vascular access monitoring because it can be done quickly without interrupting dialysis.

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.

Background and objective: Despite medical advances, we are facing the unprecedented disaster of the coronavirus disease 2019 (COVID-19) pandemic without available treatments and effective vaccines. As the COVID-19 pandemic has approached its culmination, desperate efforts have been made to seek proper treatments and response strategies, and the number of clinical trials has been rapidly increasing. In this time of the pandemic, it is believed that learning lessons from it would be meaningful in preparing for future pandemics. Thus, this study aims at providing a comprehensive landscape of COVID-19 related clinical trials based on the ClinicalTrials.gov database. Materials and methods: Up to 30 March 2020, we identified a total of 147 eligible clinical trials and reviewed the overview of the studies. Results: Until then, the most clinical trials were set up in China. Treatment approaches are the most frequent purpose of the registered studies. Chloroquine, interferon, and antiviral agents such as remdesivir, lopinavir, and ritonavir are agents under investigation in these trials. Conclusions: In this study, we introduced the promising therapeutic options that many researchers and clinicians are interested in, and to address the hidden issues behind clinical trials in this COVID-19 pandemic.

In this study, we investigated the tumor targeting effect in cancer cells using triphenylphosphonium (TPP) cations, which are accumulated by differences in membrane potential, and folic acid (FA), which is selectively bound to overexpressed receptors on various cancer cells. We used Food and Drug Administration (FDA)-approved silica nanoparticles (SNPs) as drug carriers, and SNPs conjugated with TPP and FA (STFs) samples were prepared by introducing different amounts of TPP and FA onto the nanoparticle surfaces. STF-1, 2, 3, 4 and 5 are named according to the combination ratio of TPP and FA on the particle surface. To confirm the tumor targeting effect, 89Zr (t1/2 = 3.3 days) was coordinated directly to the silanol group of SNP surfaces without chelators. It was shown that the radiochemical yield was 69% and radiochemical purity was &gt, 99%. In the cellular uptake evaluation, SNPs with the most TPP (SFT-5) and FA (SFT-1) attached indicated similar uptake tendencies for mouse colon cancer cells (CT-26). However, the results of the cell internalization assay and measurement of positron emission tomography (PET) images showed that SFT-5 had more affinity for the CT-26 tumor than other samples the TPP ratio of which was lower. Consequently, we confirmed that TPP ligands affect target cancer cells more than FA, which means that cell membrane potential is significantly effective for tumor targeting.

Kidney transplantations using expanded criteria donors (ECD) are being increasingly adopted, but no consensus tools are available to evaluate donor kidney status. Beta-2 microglobulin (B2MG) is a marker of kidney function, and herein, we evaluate the usefulness of assessing B2MG to evaluate donor kidney status. Fifty-seven kidney transplantations were performed from March 2017 to April 2019. Medical records were retrospectively reviewed, and relationships between clinical and laboratory variables and transplant outcomes were investigated. Thirty-eight patients received a standard criteria donor kidney and 19 patients an ECD kidney. Ten patients experienced delayed graft function (DGF), but no patient experienced primary nonfunction. Of the parameters studied, only donor renal replacement therapy (RRT) [odds ratio (OR) 24.162; p = 0.018] and donor serum B2MG (OR 22.685; p = 0.022) significantly predicted DGF. The presence of either of these two risk factors can better reflect the condition of the donor than previous classification. However, on their last follow-up creatinine and estimated glomerular filtration rate values in those with or without these risk factors were not significantly different. For an ECD with a B2MG level of