Raloxifene for women with Alzheimer disease: A randomized controlled pilot trial

OBJECTIVE: To determine whether raloxifene, a selective estrogen receptor modulator, improves cognitive function compared with placebo in women with Alzheimer disease (AD) and to provide an estimate of cognitive effect. METHODS: This pilot study was conducted as a randomized, double-blind, placebo-controlled trial, with a planned treatment of 12 months. Women with late-onset AD of mild to moderate severity were randomly allocated to high-dose (120 mg) oral raloxifene or identical placebo provided once daily. The primary outcome compared between treatment groups at 12 months was change in the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog). RESULTS: Forty-two women randomized to raloxifene or placebo were included in intent-to-treat analyses (mean age 76 years, range 68-84), and 39 women contributed 12-month outcomes. ADAS-cog change scores at 12 months did not differ significantly between treatment groups (standardized difference 0.03, 95% confidence interval -0.39 to 0.44, 2-tailed p = 0.89). Raloxifene and placebo groups did not differ significantly on secondary analyses of dementia rating, activities of daily living, behavior, or a global cognition composite score. Caregiver burden and caregiver distress were similar in both groups. CONCLUSIONS: Results on the primary outcome showed no cognitive benefits in the raloxifene-treated group. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for women with AD, raloxifene does not have a significant cognitive effect. The study lacked the precision to exclude a small effect

Longitudinal trajectories of quality of life among people with mild-to-moderate dementia: a latent growth model approach with IDEAL cohort study data

Objectives We aimed to examine change over time in self-rated quality of life (QoL) in people with mild-to-moderate dementia and identify sub-groups with distinct QoL trajectories. Method We used data from people with mild-to-moderate dementia followed up at 12 and 24 months in the IDEAL cohort study (baseline n=1537). A latent growth model approach examined mean change over time in QoL, assessed with the QoL-AD scale, and investigated associations of baseline demographic, cognitive and psychological covariates with the intercept and slope of QoL. We employed growth mixture modelling to identify multiple growth trajectories. Results Overall mean QoL scores were stable and no associations with change over time were observed. Four classes of QoL trajectories were identified: two with higher baseline QoL scores, labelled Stable (74.9%) and Declining (7.6%), and two with lower baseline QoL scores, labelled Stable Lower (13.7%) and Improving (3.8%). The Declining class had higher baseline levels of depression and loneliness, and lower levels of self-esteem and optimism, than the Stable class. The Stable Lower class was characterised by disadvantage related to social structure, poor physical health, functional disability, and low psychological well-being. The Improving class was similar to the Stable Lower class but had lower cognitive test scores. Discussion Understanding individual trajectories can contribute to personalised care planning. Efforts to prevent decline in perceived QoL should primarily target psychological well-being. Efforts to improve QoL for those with poorer QoL should additionally address functional impairment, isolation, and disadvantage related to social structure

A comprehensive model of factors associated with subjective perceptions of living well with dementia: findings from the IDEAL study

Background: The concept of ‘living well’ is increasingly used to indicate that it is, or should be, possible for a person living with dementia to experience a subjective sense of ‘comfort, function and contentment with life.’ We used a theoretically-derived conceptual framework to investigate capability to ‘live well’ with dementia through identifying the relative contribution of domains associated with the subjective experience of living well. Methods: We analysed data from 1550 community-dwelling individuals with mild to moderate dementia participating in the baseline wave of the Improving the experience of Dementia and Enhancing Active Life (IDEAL) cohort study. Subjective perceptions of ability to live well were obtained by generating a living well latent factor from responses on the Quality of Life in Alzheimer’s disease (QoL-AD), Satisfaction with Life and WHO-5 Well-being scales. Multivariate modelling and structural equation modelling was used to investigate variables potentially associated with living well. Variables were grouped into five domains, latent variables were constructed representing Social Location, Capitals, Assets and Resources, Psychological Characteristics and Psychological Health, Physical Fitness and Health, and Managing Everyday Life with Dementia, and associations with living well were examined. All models were adjusted for age, sex and dementia sub-type. Results: Considering the domains singly, the Psychological Characteristics and Psychological Health domain was most strongly associated with living well (3.56; 95% CI: 2.25, 4.88), followed by Physical Fitness and Physical Health (1.10, 95% CI: -2.26, 4.47). Effect sizes were smaller for Capitals, Assets and Resources (0.53; 95% CI: -0.66, 1.73), Managing Everyday Life with Dementia (0.34; 95% CI: 0.20, 0.87), and Social Location (-0.12; 95% CI: -5.72, 5.47). Following adjustment for the Psychological Characteristics and Psychological Health domain, other domains did not show independent associations with living well. Conclusions: Psychological resources are central to subjective perceptions of living well and offer important targets for immediate intervention. Availability of social and environmental resources, and physical fitness, underpin these positive psychological states, and also offer potential targets for interventions and initiatives aimed at improving the experience of living with dementia

A comprehensive model of factors associated with subjective perceptions of living well with dementia: findings from the IDEAL study

Background: The concept of ‘living well’ is increasingly used to indicate that it is, or should be, possible for a person living with dementia to experience a subjective sense of ‘comfort, function and contentment with life.’ We used a theoretically-derived conceptual framework to investigate capability to ‘live well’ with dementia through identifying the relative contribution of domains associated with the subjective experience of living well. Methods: We analysed data from 1550 community-dwelling individuals with mild to moderate dementia participating in the baseline wave of the Improving the experience of Dementia and Enhancing Active Life (IDEAL) cohort study. Subjective perceptions of ability to live well were obtained by generating a living well latent factor from responses on the Quality of Life in Alzheimer’s disease (QoL-AD), Satisfaction with Life and WHO-5 Well-being scales. Multivariate modelling and structural equation modelling was used to investigate variables potentially associated with living well. Variables were grouped into five domains, latent variables were constructed representing Social Location, Capitals, Assets and Resources, Psychological Characteristics and Psychological Health, Physical Fitness and Health, and Managing Everyday Life with Dementia, and associations with living well were examined. All models were adjusted for age, sex and dementia sub-type. Results: Considering the domains singly, the Psychological Characteristics and Psychological Health domain was most strongly associated with living well (3.56; 95% CI: 2.25, 4.88), followed by Physical Fitness and Physical Health (1.10, 95% CI: -2.26, 4.47). Effect sizes were smaller for Capitals, Assets and Resources (0.53; 95% CI: -0.66, 1.73), Managing Everyday Life with Dementia (0.34; 95% CI: 0.20, 0.87), and Social Location (-0.12; 95% CI: -5.72, 5.47). Following adjustment for the Psychological Characteristics and Psychological Health domain, other domains did not show independent associations with living well. Conclusions: Psychological resources are central to subjective perceptions of living well and offer important targets for immediate intervention. Availability of social and environmental resources, and physical fitness, underpin these positive psychological states, and also offer potential targets for interventions and initiatives aimed at improving the experience of living with dementia

Reconsidering the Barefoot Doctor Programme

This paper examines the widely acclaimed Barefoot Doctor campaign in China. The Barefoot Doctor Campaign has come to symbolize the success of Chinese health care to the extent that it has become a model for WHO public health strategy. Yet little has been done to understand how or whether it worked on the ground and what difficulties and contradictions emerged in its implementation. Using previously unexplored party archives as well as newly collected oral interviews, this paper moves away from a narrow focus on party politics and policy formulation by examining the reality of health care at the local level and the challenges faced by local authorities and individuals as the campaigns evolved

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment