Previous cohort studies have investigated the relationship between self-reported physical activity (PA) and dementia. Evidence from objective device-measured PA data is lacking. This study aimed to explore the association of device-measured PA with the risk of dementia incidence and common subtypes (Alzheimer’s disease [AD] and vascular dementia) using the UK Biobank study.
84,854 participants (55.8% women), invited to participate in the device-measured PA between 2013 and 2015, were included in this prospective cohort study. Wrist accelerometers were used to measure light, moderate, vigorous, moderate-to-vigorous PA (MVPA) and total PA intensity and duration (MET/min/week). Incident dementia (fatal and non-fatal) was extracted from hospital episodes records for incidence and death register for mortality. Incidence follow-up was carried out until the end of March 2021in England and Scotland and the end of March 2018 in Wales. Mortality data were available until February 2021. Nonlinear associations were first investigated using penalised cubic splines fitted in the Cox proportional hazard models. In addition, using MVPA, five categories were created. Associations of these categories with the outcomes were investigated using Cox proportional hazard models. Analyses were adjusted for sociodemographic, lifestyle and health-related factors.
After a median follow-up of 6.3 years, 678 individuals were diagnosed with dementia. Evidence of nonlinearity was observed for all PA modes and all-cause dementia. For categories of MVPA, there was a significant trend towards a low risk of overall dementia when higher levels of MVPA were achieved (HRtrend 0.66 [95% CI 0.62 to 0.70]. The lowest risk was identified in individuals who performed more than 1200 MET/min/week, those who had 84% (95% CI 0.12 to 0.21) lower risk of incident dementia compared to those who performed < 300 MET/min/week.
Participants with higher PA levels had a lower risk of incident dementia than those less active, independently of sociodemographic, lifestyle factors and comorbidity. Considering that the majority of previous studies have reported this association using self-reported data, our findings highlight the strong inverse association between PA objectively measured and incident dementia.
Gemtuzumab Ozogamicin (GO) is a CD33-directed antibody conjugated to calicheamicin used in AML immunotherapy. Children's Oncology Group led pediatric AML phase II trial COG-AAML03P1 (NCT00070174) established that GO could be safely added to the standard chemotherapy regimen consisting of ara-C, daunorubicin and etoposide (ADE+GO) and improved outcome(Cooper et al., 2012). Subsequent COG-AAML0531 phase III trial (NCT00372593) randomized patients to receive either standard chemotherapy alone (ADE) or with addition of two doses of GO (ADE+GO) and showed that addition of GO improved outcome in newly diagnosed AML patients (Gamis et al., 2014). Our group previously established that CD33 genetic variation impacts GO response in AML patients (Lamba et al., 2017). Given that the antileukemic effect of GO is primarily driven by calicheamicin induced DNA damage, in this study we investigated pharmacogenomic impact of SNPs in DNA damage response (DDR) pathway genes on GO treatment response. We genotyped 132 SNPs in 42 genes involved in DNA damage repair pathway in DNA samples from 470 patients treated with standard chemotherapy in AAML0531 trial (ADE arm) and 755 patients treated with addition of GO to standard therapy in AAML03P1 and AAAML0531 trials (ADE+GO arm). Univariate analysis to test for association between OS, EFS, DFS and RR after induction 1 in both ADE+GO and ADE arms identified 20 SNPs in 16 genes that were significantly associated with at least one of the clinical endpoints tested in the only ADE+GO arm but not in ADE arm of the trials. We tested these 20 SNPs in all possible combinations with a maximum of 3 SNP/model using multivariable Cox proportional hazard models for association with EFS and OS in patients treated with ADE+GO. Drastically increased number of models arising from higher SNP combination numbers was a computational challenge thus we restricted our analysis to a maximum of 3 SNP combinations. We performed 1000 permutation tests per model to determine the likelihood of obtaining them falsely. Models were ordered according to their Bayesian Information Criterion (BIC) and weight in favor of each model. Those withleast BIC and a 1000 permutation p≤0.05 were selected for development of DDR pharmacogenomics score. DDR_PGx8 score was defined by adding the genotype scores of 8 SNPs in 7 genes (AKT1, ATR, DDB2, PARP1, PI3KCA, PTEN and RAD51) accounting for mode of inheritance (additive, dominant or recessive) and direction of their association with outcome (positive for beneficial and negative for detrimental association) Fig 1A shows overall study design. The DDR_PGx8 score ranged from -5 to 3 in patients treated with ADE+GO (n=755) or ADE alone (N=470). Based on the distribution, the scores were stratified into high (score ≥0, n=212 in ADE group and n=357 in ADE+GO group) and low score (score <0, n=241 in ADE group and n=329 in ADE+GO group) groups. The distribution of DDR_PGx8 score groups did not differ by risk groups or MRD1 status. However, it differed significantly within race with 81.81% (108/132) of black or African American patients compared to 43.75% (364/832) of white patients in the low DDR_PGx8 score group. Patients with low-DDR-PGx8 score had significantly worse EFS (HR=1.52, 95%CI (1.22-1.90), p<0.001; Fig 1B), OS (HR=1.62, 95%CI(1.24-2.11), p<0.001), DFS (HR=1.88, 95%CI(1.42-2.50), p<0.00001;), and higher RR1 (HR=1.89, 95%CI(1.40-2.40), p<0.00001) compared to high-DDR-PGx8 score patients when treated with GO (ADE+GO cohort). This impact of DDR_PGx8 was not observed in patients treated with standard chemotherapy alone (ADE arm), with no difference between low and high DDR_PGx8 score groups in EFS (Fig 1B), OS, DFS and RR (all p>0.28). In multivariable Cox proportional hazard models for DDR-PGx8 score groups, initial risk group assignment, WBC at diagnosis and age, low-DDR-PGx8 score remained a significant and independent predictor of inferior EFS (HR=1.6, 95%CI=1.21-2.02, p<0.001; Fig 1C) and OS (HR=1.6, 95%CI=1.17-2.22, p=0.003) in ADE+GO arm but not in ADE arm. We establish a DNA damage repair response-based pharmacogenomics score predicting outcome in patients treated with addition of GO to standard chemotherapy. The score was not predictive of outcome in patients treated with standard chemotherapy alone implying its impact is GO-specific. Our results in conjunction with existing CD33 SNPs provide a rationale for use of pharmacogenomics in personalizing GO treatment.
Figure 1 Figure 1.
No relevant conflicts of interest to declare.
AbstractLeft atrial (LA) features are altered when diastolic dysfunction (DD) is present. The relations of LA features to the DD severity and to adverse outcomes remain unclear using CMR images. We sought to compare LA features including volumes, emptying fraction, and strains as predictors of left ventricular (LV) DD and adverse outcomes. We compared four groups including normal controls (n = 32), grade I DD (n = 69), grade II DD (n = 42), and grade III DD (n = 21). DD was graded by echocardiography following the current ASE guidelines. Maximum LA volume (LAVmax), minimum LA volume (LAVmin), and LA emptying fraction (LAEF) were assessed using CMR cine images. Phasic LA strains including reservoir, conduit, and booster pump strain were assessed by feature tracking. The outcome was a composite of hospital admissions for heart failure and all-cause mortality analyzed using Cox proportional hazard models. LAVmax and LAVmin were progressively larger while LAEF and LA strain measures were lower with worsening degree of DD (all p < 0.001). Among 132 patients with DD, 61 reached the composite outcome after on average 36-months of follow-up. Each of the LA parameters except for LA conduit strain was an independent predictor of the outcome in the adjusted Cox proportional hazard models (all p < 0.001). They remained significant outcome predictors after the model additionally adjusted for LV longitudinal strain. The AUC of outcome prediction was highest by LAEF (0.760) followed by LA reservoir strain (0.733) and LAVmin (0.725). Among all the LA features, increased LA volumes, reduced LAEF, reduced LA reservoir and booster pump strains were all associated with DD and DD severity. While LA strains are valuable, conventional parameters such as LAEF and LAVmin remain to be highly effective in outcome prediction with comparable performance.
Using observational data and variation in hospital admissions across days of the week, we examined the association between ED boarding time and development of delirium within 72 hours of admission among patients aged 65+ years admitted to an inpatient neurology ward. We exploited a natural experiment created by potentially exogenous variation in boarding time across days of the week because of competition for the neurology floor beds. Using proportional hazard models adjusting for socio-demographic and clinical characteristics in a propensity score, we examined the time to delirium onset among 858 patients: 2/3 were admitted for stroke, with the remaining admitted for another acute neurologic event. Among all patients, 81.2% had at least one delirium risk factor in addition to age. All eligible patients received delirium prevention protocols upon admission to the floor and received at least one delirium screening event. While the clinical and social-demographic characteristics of admitted patients were comparable across days of the week, patients with ED arrival on Sunday or Tuesday were more likely to have had delayed floor admission (waiting time greater than 13 hours) and delirium (adjusted HR = 1.54, 95%CI:1.37–1.75). Delayed initiation of delirium prevention protocol appeared to be associated with greater risk of delirium within the initial 72 hours of a hospital admission.
To clarify the association of poor oral function with loss of independence (LOI) or death in functionally independent older adults in the community.
We conducted a secondary analysis of data from a prospective cohort study in two municipalities in Japan. We included participants who were older than 65 years of age and had no certification in long-term care at baseline. Poor oral function was evaluated by the Kihon Checklist. Among participants with poor oral function, they were further classified by the degree of quality of life (QOL) impairment due to dysphagia. Main outcome is LOI or death from all cause. The hazard ratio (HR) and 95% confidence of intervals (CIs) were estimated by Cox proportional hazard models adjusted for potential confounders.
Of 1,272 participants, 150 participants (11.8%) had poor oral function. The overall incidence of LOI or death was 10.0% in the participants with poor oral function, while 3.3% in the participants without. Participants with poor oral function were more likely to develop LOI or death than those without (crude HR = 3.17 [95% CIs 1.74–5.78], adjusted HR = 2.30 [95% CIs 1.22–4.36]). 10 participants (0.79%) were classified as poor oral function with QOL impairment, and were more likely to develop LOI or death than those without poor oral function (crude HR = 7.45 [95% CIs 1.80–30.91], adjusted HR = 8.49 [95% CIs 1.88–38.34]).
Poor oral function was associated with higher risk of LOI or death in functionally independent older adults in the community.
Limited research has examined the associations between different forms of school exclusion and offending, and variation in these associations according to age of first exclusionary event, among justice-involved youth. Using data from the Pathways to Desistance Study, the current study examined the associations between suspension, expulsion, and recidivism and the association between age at first suspension/expulsion and recidivism. According to Cox proportional hazard models, both expulsion and frequency of suspension increased risk of recidivism; age at first suspension was not associated with recidivism, and youth who were first expelled in childhood were significantly less likely to recidivate than youth first expelled in adolescence. Results suggest juvenile justice and educational systems should provide collaborative services to better support justice-involved youth.
Background and Objectives: Oral squamous cell carcinoma (OSCC) is a malignant disease with a particularly high incidence in Taiwan. Our objective in this study was to elucidate the involvement of sphingolipid transporter 2 (SPNS2) expression and SPNS2 protein expression in the clinicopathological indexes and the clinical outcomes of OSCC patients. Materials and Methods: Immunohistochemistry analysis was performed for SPNS2 protein expression in samples from 264 cases of OSCC. Correlations of SPNS2 expression with clinicopathological variables and patient survival were analyzed. Results: Our results revealed that the cytoplasmic protein expression of SPNS2 in OSCC tissue specimens was lower than in normal tissue specimens. Negative cytoplasmic protein expression of SPNS2 was significantly correlated with T status and stage. Kaplan–Meier survival curve analysis revealed that negative cytoplasmic SPNS2 expression was predictive of poorer overall survival of OSCC patients in stage III/IV. We also determined that low SPNS2 expression was an independent prognostic factor related to overall survival among OSCC patients in stage III/IV from univariate Cox proportional hazard models. Multivariate Cox proportional hazard models revealed that cytoplasmic SPNS2 expression, T status, lymph node metastasis, and histological grade were independent prognostic factors for survival. Conclusions: Overall, this study determined that SPNS2 protein may be a useful prognostic marker for OSCC patients and potential therapeutic target for OSCC treatment.
BackgroundIt is unclear whether the sandwich vertebra, is at higher risk of new symptomatic fractures (NSFs), and whether prophylactic augmentation might benefit patients with sandwich vertebrae.ObjectiveTo compare fracture-free probabilities of sandwich, ordinary-adjacent, and non-adjacent vertebrae, and identify predictors of NSFs.MethodsData were retrospectively analyzed for patients who had undergone vertebral augmentation resulting in sandwich vertebrae. NSF rates were determined and predictors were identified using Cox proportional hazard models.ResultsThe analysis included 1408 untreated vertebrae (147 sandwich, 307 ordinary-adjacent, 954 non-adjacent vertebrae) in 125 patients. NSFs involved 19 sandwich, 19 ordinary-adjacent, and 16 non-adjacent vertebrae. The NSF rate was significantly higher in the patients with sandwich vertebrae (27.2%) than among all patients (14.8%). At the vertebra-specific level, the NSFs rate was 12.9% for sandwich vertebrae, significantly higher than 6.2% for ordinary-adjacent and 1.7% for non-adjacent vertebrae. The corresponding fracture-free probabilities of sandwich, ordinary-adjacent, and non-adjacent vertebrae were 0.89, 0.95, and 0.99 at 1 year, and 0.85, 0.92, and 0.98 at 5 years (p<0.05). Cox modeling identified the following as predictors for occurrence of an NSF in a given vertebra: vertebra location, type of vertebrae, number of augmented vertebrae, and puncture method.ConclusionSandwich vertebrae are at higher risk of NSFs than ordinary-adjacent and non-adjacent vertebrae, and several NSF risk factors were identified. Since 85% of sandwich vertebrae are fracture-free for 5 years and NSF risk increases with the number of augmented vertebrae, prophylactic augmentation of every sandwich vertebra may be unnecessary.
This study explored the reciprocal association between otitis media and asthma in children.
The 2002–2013 Korean Health Insurance Review and Assessment Service-National Sample Cohort participants < 15 years old were used. In study I, 14,665 asthma patients from 2002 through 2005 were selected. The asthma patients were matched 1:1 with the control I group, and the occurrence of otitis media was followed until 2013. In study II, 27,043 otitis media patients from 2002 through 2005 were selected. The otitis media patients were matched 1:1 with the control II group, and the occurrence of asthma was followed until 2013. Stratified Cox proportional hazard models were used to analyze the hazard ratio (HRs) of asthma for otitis media (study I) and otitis media for asthma (study II).
The HR for otitis media was 1.46 in asthma patients (95% confidence interval [CI] = 1.40–1.52, P < 0.001). The HR for asthma was 1.43 in otitis media patients (95% confidence interval [CI] = 1.36–1.50, P < 0.001).
Asthma and otitis media have a bidirectional association in children.
Background and Objective: Gastric cancer (GC) is a common tumor malignancy with high incidence and poor prognosis. Laminin is an indispensable component of basement membrane and extracellular matrix, which is responsible for bridging the internal and external environment of cells and transmitting signals. This study mainly explored the association of the LAMB1 expression with clinicopathological characteristics and prognosis in gastric cancer. Methods: The expression data and clinical information of gastric cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG). And we analyzed the relationship between LAMB1 expression and clinical characteristics through R. CIBERSORTx was used to calculate the absolute score of immune cells in gastric tumor tissues. Then COX proportional hazard models and Kaplan-Meier curves were performed to evaluate the role of LAMB1 and its influence on prognosis in gastric cancer patients. Finally, GO and KEGG analysis were applied for LAMB1-related genes in gastric cancer, and PPI network was constructed in Cytoscape software. Results: In the TCGA cohort, patients with gastric cancer frequently generated LAMB1 gene copy number variation, but had little effect on mRNA expression. Both in the TCGA and ACRG cohorts, the mRNA expression of LAMB1 in gastric cancer tissues was higher than it in normal tissues. All patients were divided into high expression group and low expression group according to the median expression level of LAMB1. The elevated expression group obviously had more advanced cases and higher infiltration levels of M2 macrophages. COX proportional hazard models and Kaplan-Meier curves revealed that patients with enhanced expression of LAMB1 have a worse prognosis. GO/KEGG analysis showed that LAMB1-related genes were enriched in PI3K-Akt signaling pathway, focal adhesion, ECM-receptor interaction, etc. Conclusions: The high expression of LAMB1 in gastric cancer is related to the poor prognosis of patients, and it may be related to microenvironmental changes in tumors.