There is a recent consensus proposal of “cognitive frailty” defined by the presence of both physical frailty and cognitive impairment in the absence of dementia. The relevance, validity, and ...utilization of cognitive frailty, however, is presently unclear. We determine whether concurrent physical frailty and cognitive impairment, compared with physical frailty alone substantially increased adverse health outcomes (functional disability, hospitalization, poor quality of life QOL, and mortality).
Longitudinal study.
Population-based cohort (Singapore Longitudinal Ageing Study, SLAS).
Two thousand three hundred seventy-five Chinese Singaporeans aged 55 and above without dementia and degenerative disorders.
The associations of physical frailty (Cardiovascular Health Study criteria: 0 = robust, 1-2 = pre-frail, 3-5 = frail) with and without cognitive impairment (mini-mental state examination <26) and adverse outcomes were estimated, controlling for age, gender, education, comorbidity, smoking, alcohol consumption, depressive symptoms, baseline activities of daily living-instrumental and basic activities of daily living disability or QOL score.
Compared to robust noncognitively impaired individuals, physical pre-frailty with cognitive impairment was associated with a twofold increased prevalence and incidence of functional disability, a twofold increased incidence of poor QOL, and 1.8-fold increased mortality risks. Cognitively impaired frail individuals stood out with 12- to 13-fold increased prevalence and incidence of functional disability, a five- and 27-fold increased prevalence and incidence of low QOL, and a fivefold increased mortality risk. The estimated prevalence of physical frailty with cognitive impairment was 1.8%, and physical pre-frailty with cognitive impairment was 8.9%.
Pre-frailty and frailty with impaired cognitive function, found in 10.7% of this dementia-free population, was associated with an evidently high risk of adverse health outcomes.
To examine the association between the social frailty (SF) phenotype and functional disability, independently of the physical frailty (PF) phenotype, and compare the abilities of the PF, SF, and ...combined social and physical (PSF) indexes for predicting functional disability.
Cross-sectional and longitudinal analyses of a population-based cohort (Singapore Longitudinal Ageing Study, SLAS-1) of 2406 community-dwelling older adults with 3 years of follow-up (N = 1254 and N = 1557 for instrumental activity of daily living (IADL) disability and severe disability (≥3 basic ADL) respectively).
Seven-item social frailty index (living arrangements, education, socioeconomic status, and social network and support, 0 = nil SF, 1 = low, 2-7 = high), PF phenotype (Fried criteria), and instrumental activities of daily living (IADLs) disability and severe disability (≥3 basic ADLs).
Compared to nil SF, low and high SF were significantly associated with 1.3 to 2.4 fold increased prevalence and incidence of IADL disability, and 6.3 fold increase in severe disability. Frail individuals with and without SF stood out with 5-11 fold increased prevalence and incidence of IADL disability and 21-25 fold increased prevalence and incidence of severe disability, compared to robust individuals without SF. A combined PSF index more accurately identified individuals with increased risk of functional disability (ROC = 64%) and severe disability (ROC = 81%) than either the SF or the PF indexes alone (55% to 68%).
The SF index alone or in combination with the PF index has clinical relevance and utility for identifying and stratifying older people at risk of disability. The mental frailty construct is closely related to SF and should be further investigated in future studies.
Background Over 20% of pregnancies in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL) result in an adverse pregnancy outcome (APO) related to abnormal ...placentation. The ability to identify, early in pregnancy, patients who are destined for poor outcomes would significantly impact care of this high-risk population. In nonautoimmune patients, circulating angiogenic factors are dysregulated in disorders of placentation, such as preeclampsia (PE) and fetal growth restriction. Objective We sought to determine whether early dysregulation of circulating angiogenic factors can predict APO in high-risk SLE and/or APL pregnancies. Study Design We used data and samples from the Predictors of Pregnancy Outcome: Biomarkers in APL Syndrome and SLE (PROMISSE), a multicenter prospective study that enrolled 492 pregnant women with SLE and/or APL from September 2003 through August 2013. Patients were followed through pregnancy from <12 weeks gestation. Circulating levels of soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin were measured monthly and subjects followed up for APO, classified as severe (PE <34 weeks, fetal/neonatal death, indicated preterm delivery <30 weeks) or moderate (PE ≥34 weeks, indicated preterm delivery 30-36 weeks, growth restriction without PE). Results Severe APOs occurred in 12% and moderate APOs in 10% of patients. By 12-15 weeks, sFlt1, PlGF, and soluble endoglin levels were markedly altered in women who developed severe APO. After adjusting for clinical risk factors, sFlt1 was the strongest predictor of severe APO among 12-15 week measures (odds ratio, 17.3 comparing highest and lowest quartiles; 95% confidence interval CI, 3.5–84.8; positive predictive value PPV, 61%; negative predictive value NPV, 93%). At 16-19 weeks, the combination of sFlt1 and PlGF was most predictive of severe APO, with risk greatest for subjects with both PlGF in lowest quartile (<70.3 pg/mL) and sFlt1 in highest quartile (>1872 pg/mL; odds ratio, 31.1; 95% CI, 8.0–121.9; PPV, 58%; NPV, 95%). Severe APO rate in this high-risk subgroup was 94% (95% CI, 70–99.8%), if lupus anticoagulant or history of high blood pressure was additionally present. In contrast, among patients with both sFlt1 <1872 pg/mL and PlGF >70.3 pg/mL, rate of severe APO was only 4.6% (95% CI, 2.1–8.6%). Conclusion Circulating angiogenic factors measured during early gestation have a high NPV in ruling out the development of severe adverse outcomes among patients with SLE and/or APL syndrome. Timely risk stratification of patients is important for effective clinical care and optimal allocation of health care resources.
Background: Malignant glioma is a lethal brain tumor that is highly resistant to standard therapy. Our research aims to explore the suppressive effects of nitidine chloride (NC) on gliomas and the ...mechanisms involved, showing that it is a potential agent for integrative therapy of gliomas. Methods: After glioma cells were treated with NC, several experiments were performed to evaluate NC’s antitumor effects. CCK-8 assay was used to detect viability. Transwell and 3-dimensional spheroid invasion assays were used to evaluate motility of glioma in vitro, and the sphere-formation assay showed NC’s influence on glioma stem cells. Apoptosis and intracellular reactive oxygen species were measured by means of flow cytometry. Subcellular structures were observed through transmission electron microscopy. Western blot analysis reflected expression of endoplasmic reticulum (ER) stress and epithelial-mesenchymal transition (EMT) marker proteins. An orthotopic xenograft model was established to investigate the tumor suppressive effects in vivo. Results: Nitidine chloride inhibited glioma cell migration and invasion in vitro, downregulated the EMT proteins, and suppressed sphere formation of glioma stem cells. Furthermore, NC induced persistent ER stress that contributed to apoptosis and reactive oxygen species production. The xenograft model showed that NC effectively restricted glioma growth and invasion in vivo. Furthermore, we confirmed the signaling pathways that ER stress downregulates C/EBPβ and slug, as well as inhibition of the AKT/GSK3β/β-catenin axis caused by NC, in U-87 MG. Conclusion: We demonstrated that NC inhibits gliomas in vitro and in vivo by activating ER stress and downregulating EMT, which provides a basis for glioma therapy.
Most radiomic studies use the features extracted from the manually drawn tumor contours for classification or survival prediction. However, large interobserver segmentation variations lead to ...inconsistent features and hence introduce more challenges in constructing robust prediction models. Here, we proposed an automatic workflow for glioblastoma (GBM) survival prediction based on multimodal magnetic resonance (MR) images.
Two hundred eighty-five patients with glioma (210 GBM, 75 low-grade glioma) were included. One hundred sixty-three of the patients with GBM had overall survival data. Every patient had 4 preoperative MR images and manually drawn tumor contours. A 3-dimensional convolutional neural network, VGG-Seg, was trained and validated using 122 patients with glioma for automatic GBM segmentation. The trained VGG-Seg was applied to the remaining 163 patients with GBM to generate their autosegmented tumor contours. The handcrafted and deep learning (DL)–based radiomic features were extracted from the autosegmented contours using explicitly designed algorithms and a pretrained convolutional neural network, respectively. One hundred sixty-three patients with GBM were randomly split into training (n = 122) and testing (n = 41) sets for survival analysis. Cox regression models were trained to construct the handcrafted and DL-based signatures. The prognostic powers of the 2 signatures were evaluated and compared.
The VGG-Seg achieved a mean Dice coefficient of 0.86 across 163 patients with GBM for GBM segmentation. The handcrafted signature achieved a C-index of 0.64 (95% confidence interval, 0.55-0.73), whereas the DL-based signature achieved a C-index of 0.67 (95% confidence interval, 0.57-0.77). Unlike the handcrafted signature, the DL-based signature successfully stratified testing patients into 2 prognostically distinct groups.
The VGG-Seg generated accurate GBM contours from 4 MR images. The DL-based signature achieved a numerically higher C-index than the handcrafted signature and significant patient stratification. The proposed automatic workflow demonstrated the potential of improving patient stratification and survival prediction in patients with GBM.
Summary The marginal costs and benefits of converting malaria programmes from a control to an elimination goal are central to strategic decisions, but empirical evidence is scarce. We present a ...conceptual framework to assess the economics of elimination and analyse a central component of that framework—potential short-term to medium-term financial savings. After a review that showed a dearth of existing evidence, the net present value of elimination in five sites was calculated and compared with effective control. The probability that elimination would be cost-saving over 50 years ranged from 0% to 42%, with only one site achieving cost-savings in the base case. These findings show that financial savings should not be a primary rationale for elimination, but that elimination might still be a worthy investment if total benefits are sufficient to outweigh marginal costs. Robust research into these elimination benefits is urgently needed.
Infants with hypoplastic left heart syndrome after palliation have the worst survival among heart transplant recipients. Heart transplantation is often reserved for use in patients with sub-optimal ...results after palliative surgery. This study characterized outcomes after listing in infants with a single ventricle who had undergone the Norwood procedure and identified predictors of the decision to list for heart transplantation.
The public-use database from the multicenter, prospective randomized Single Ventricle Reconstruction trial was used to identify patients who were listed for heart transplantation. Outcomes on the waiting list and after transplantation were determined. Risk factors were compared between those who were listed and those who survived without listing.
Among 555 patients, 33 patients (5.9%) were listed and 18 underwent heart transplantation. Mortality was 39% while waiting for a heart and was 33% after heart transplantation. Overall, 1-year survival after listing (including death after transplantation) was 48%. Factors associated with listing were a lower right ventricular fractional area change at birth, non-hypoplastic left heart syndrome diagnosis, and a more complicated post-Norwood course, defined as a higher need for extracorporeal membrane oxygenation, longer intensive care unit stay, more complications, and a higher number of discharge medications.
Worse right ventricular function, non-hypoplastic left heart syndrome diagnosis, and complex intensive care unit stay were significant risk factors for listing for heart transplantation after the Norwood procedure. Heart transplantation as a rescue procedure after the Norwood procedure in the first year of life carries a significant risk of mortality.
The Montreal Cognitive Assessment (MOCA) is a screening tool for mild cognitive impairment (MCI) and dementia. The new criteria for Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition ...(DSM-5) mild neurocognitive disorder (NCD) define participants with cognitive decline but no dementia, and major NCD (dementia). We explored the usefulness of MOCA to detect major and mild NCD.
Cross-sectional test research.
Tertiary hospital memory clinic and community-based Singapore Longitudinal Aging Study (SLAS).
Participants with questionable dementia (clinical dementia rating, CDR = 0.5) and early dementia (CDR ≤1) over a period of 1 year were identified from the memory clinic registry. The patient records were reviewed and the diagnostic labels of major and mild NCD were applied accordingly. Healthy controls (HC) (CDR = 0, Mini-Mental State Examination >26) were recruited from the on-going SLAS.
Major and mild NCD were diagnosed based on medical history, clinical examination, basic and instrumental activities of daily living, locally validated bedside cognitive tests (Mini-Mental State Examination, Frontal Assessment Battery, and Clock Drawing Test), relevant laboratory investigations and standardized neuropsychological assessment.
Two hundred fifty-one participants were included (41 mild NCD, 64 major NCD, 146 HC). On receiver operating characteristic curve analysis, the diagnostic performance by area under the curve (AUC) for MOCA was 0.99 95% confidence interval (CI) 0.98-1.0 for major NCD and 0.77 (95% CI 0.67-0.86) for mild NCD. For diagnosis of mild NCD, MOCA performed better in those with lower education (primary and below) (AUC 0.90) compared with those with secondary education and beyond (AUC 0.66).
MOCA has high diagnostic utility for major NCD but its usefulness in detecting mild NCD is more modest. Possible reasons include greater heterogeneity in participants with mild NCD and how "quantified clinical assessment" in the DSM-5 mild NCD criteria is interpreted and operationalized.
Background In patients with vitiligo, an increased reactive oxygen species (ROS) level has been proved to be a key player during disease initiation and progression in melanocytes. Nevertheless, ...little is known about the effects of ROS on other cells involved in the aberrant microenvironment, such as keratinocytes and the following immune events. CXCL16 is constitutively expressed in keratinocytes and was recently found to mediate homing of CD8+ T cells in human skin. Objective We sought to explicate the effect of oxidative stress on human keratinocytes and its capacity to drive CD8+ T-cell trafficking through CXCL16 regulation. Methods We first detected putative T-cell skin-homing chemokines and ROS in serum and lesions of patients with vitiligo. The production of candidate chemokines was detected by using quantitative real-time PCR and ELISA in keratinocytes exposed to H2 O2 . Furthermore, the involved mediators were analyzed by using quantitative real-time PCR, Western blotting, ELISA, and immunofluorescence. Next, we tested the chemotactic migration of CD8+ T cells from patients with vitiligo mediated by the CXCL16-CXCR6 pair using the transwell assay. Results CXCL16 expression increased and showed a positive correlation with oxidative stress levels in serum and lesions of patients with vitiligo. The H2 O2 -induced CXCL16 expression was due to the activation of 2 unfolded protein response pathways: kinase RNA (PKR)–like ER kinase–eukaryotic initiation factor 2α and inositol-requiring enzyme 1α–X-box binding protein 1. CXCL16 produced by stressed keratinocytes induced migration of CXCR6+ CD8+ T cells derived from patients with vitiligo. CXCR6+ CD8+ T-cell skin infiltration is accompanied by melanocyte loss in lesions of patients with vitiligo. Conclusion Our study demonstrated that CXCL16-CXCR6 mediates CD8+ T-cell skin trafficking under oxidative stress in patients with vitiligo. The CXCL16 expression in human keratinocytes induced by ROS is, at least in part, caused by unfolded protein response activation.
BACKGROUND:Although the mechanisms and pathways mediating ARDS have been studied extensively, less attention has been given to the mechanisms and pathways that counteract injury responses. This study ...found that the apelin-APJ pathway is an endogenous counterinjury mechanism that protects against ARDS. METHODS:Using a rat model of oleic acid (OA)-induced ARDS, the effects of ARDS on apelin and APJ receptor expressions and on APJ receptor binding capacity were examined. The protective effect of activating the apelin-APJ pathway against OA- or lipopolysaccharide (LPS)-induced ARDS was evaluated. RESULTS:ARDS was coupled to upregulations of the apelin and APJ receptor. Rats with OA-induced ARDS had higher lung tissue levels of apelin proprotein and APJ receptor expressions; elevated plasma, BAL fluid (BALF), and lung tissue levels of apelin-36 and apelin-12/13; and an increased apelin-APJ receptor binding capacity. Upregulation of the apelin-APJ system has important pathophysiologic function. Stimulation of the apelin-APJ signaling using receptor agonist apelin-13 alleviated, whereas inhibition of the apelin-APJ signaling using receptor antagonist Ala-apelin-13 exacerbated, OA-induced lung pathologies, extravascular lung water accumulation, capillary-alveolar leakage, and hypoxemia. The APJ receptor agonist inhibited, and the APJ receptor antagonist augmented, OA-induced lung tissue and BALF levels of tumor necrosis factor-α and monocyte chemoattractant protein-1, and plasma and lung tissue levels of malondialdehyde. Postinjury treatment with apelin-13 alleviated lung inflammation and injury and improved oxygenation in OA- and LPS-induced lung injury. CONCLUSIONS:The apelin-APJ signaling pathway is an endogenous anti-injury and organ-protective mechanism that is activated during ARDS to counteract the injury response and to prevent uncontrolled lung injury.
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