Replication and Meta-analysis of the Association between BDNF Val66Met Polymorphism and Cognitive Impairment in Patients Receiving Chemotherapy.

Cancer-related cognitive impairment (CRCI) adversely affects cancer patients. We had previously demonstrated that the BDNF Val66Met genetic polymorphism is associated with lower odds of subjective CRCI in the multitasking and verbal ability domains among breast cancer patients receiving chemotherapy. To further assess our previous findings, we evaluated the association of BDNF Val66Met polymorphism with subjective and objective CRCI in a temporally separate cohort of patients and pooled findings from both the original (n = 145) and current (n = 193) cohorts in a meta-analysis. Subjective CRCI was assessed using FACT-Cog. Objective CRCI was evaluated using computerized neuropsychological tests. Genotyping was carried out using Sanger sequencing. The association of BDNF Val66Met genotypes and CRCI was examined with logistic regression. A fixed-effect meta-analysis was conducted using the inverse variance method. In the meta-analysis (n = 338), significantly lower odds of CRCI were associated with Met allele carriers based on the global FACT-Cog score (OR = 0.52, 95% CI 0.29-0.94). Furthermore, Met allele carriers were at lower odds of developing impairment in the domains of memory (OR = 0.34, 95% CI: 0.17-0.70), multitasking (OR = 0.33, 95% CI: 0.18-0.59), and verbal ability (OR = 0.46, 95% CI: 0.24-0.88). Consistent with the previous study, lower odds of subjective CRCI among patients with the BDNF Met allele was observed after adjusting for potential confounders in the multitasking (OR = 0.30, 95% CI: 0.14-0.67) domain. In conclusion, carriers of the BDNF Met allele were protected against global subjective CRCI, particularly in the domains of memory, multitasking, and verbal ability. Our findings further contribute to the understanding of CRCI pathophysiology

Characterizing and Prognosticating Heart Failure with Improved Ejection Fraction Using NT-proBNP, Growth Differentiation Factor 15 and Global Longitudinal Strain

Background: Heart failure with improved ejection fraction (HFiEF) is a novel heart failure (HF) subgroup. There are sparse data on using NT-proBNP, growth differentiation factor 15 (GDF15) and global longitudinal strain (GLS) to characterize and prognosticate HFiEF patients. Objectives: (1) To determine the level and correlation between NT-proBNP, GDF-15 and GLS in HFiEF patients. (2) To examine the correlation of each marker with NYHA, MAGGIC prognostic score, HF etiologies, comorbidities status, degree of LVEF/ LV end-diastolic diameter change from baseline and diastolic dysfunction. (3) To look for association of each marker with follow-up LVEF change and 1-year composite mortality or HF events outcome. Materials & Methods: This was a cross-sectional observational study in Sarawak Heart Centre HF clinic. 53 HfiEF patients who had NT-proBNP and GDF15 tests performed were selected. This cohort had no HF events in the past 6 months during the blood tests. Clinical characteristics, echocardiography parameters, and 1-year composite clinical outcome were analyzed retrospectively. Results: The mean age of the cohort was 52 years old and 81% were male. The cohort was highly comorbid (hypertension 71%; diabetes 45.3%; AF 17.3%). Most of the patients (87%) were asymptomatic by NYHA (I) and low rate of composite outcome was observed, 5.7%. The mean NT-proBNP, GDF-15, GLS were 357 pg/ml, 1572 pg/ml, and -12.1% respectively. There were significant moderate correlation between GDF15 with NT-proBNP (r=0.414) and NT-proBNP with GLS (r=-0.351). Higher NT-proBNP and GDF15 levels were associated with poorer MAGGIC prognostic scores (r=0.549, 0.41 respectively). NT-proBNP was the only marker associated with a higher degree of LVEF improvement compare to baseline echocardiography. NT-proBNP was also related to severe diastolic echo parameters. Hypertension and diabetes were strongly associated with higher elevated GDF15 levels. The lower mean GLS level was significantly associated with the presence of composite outcome (-6.45% vs -12.47%, p=0.0). Patients with NT-proBNP levels below the median cutoff had favourable follow-up LVEF improvement (+9.73%, p=0.035). Conclusion: In our HFiEF study cohort, NT-proBNP best correlate and prognosticate future LV remodelling. GDF15 was closely related to systemic illnesses such as diabetes. The role of GLS in our HFiEF cohort remains uncertain

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

An Algorithm for the Determination of Buckling Load Using Vibratory Data

本論文提供一種簡易可靠的方法，可以求得結構組件之挫屈載重，其特點為不必理會 邊界條件情況及不必需要太多之構件材料性質。分析原理係利用能量等值觀念，將作 用結構組件導致挫屈可能之軸向力，等值為垂直結構組件之橫向力，並依序利用隨機 遞減法原理及亞伯拉罕時域法求得結構系統之振動參數、自然頻率及振型，再利用振 動參數求得影響函數，最後透過力法觀念解得一特微值式，解其最大特徵值即求得結 構組件之最小挫屈荷重。A Dynamic Method is developed for determining the buckling load of structural system. It is worth to mention that the proposed method requires no action of axial or in-plane loads throughout the whole process. It requires only the vibrational excitation of the structural system, from which the vibration parameters are acquired through the application of Random Decrement Technique followed by Ibrahim Time Domain Method to establish the Influence Function. Besides, the algorithm involves also the determination of the Deformation Function by utilizing Lagrange''s Interpolation Function. The two above- mentioned functions are then combined together to form up a eigenvalue problem by means of Force Method. Finally, the inverse of eigenvalues are the buckling loads required. The feasibility of the algorithm is verified by two simulated cases using a simply- supported beam and a simply- supported rectangular plate. The two simulated cases involve the action of random forces in the determination of buckling load

EVALUATING MODEL UNCERTAINTY OF AN SPT-BASED SIMPLIFIED METHOD FOR RELIABILITY ANALYSIS FOR PROBABILITY OF LIQUEFACTION

In this paper, an innovative procedure is developed for estimating the uncertainty of an empirical geotechnical model. Here, the Youd et al. (2001) method, a deterministic model for liquefaction triggering evaluation, is examined for its model uncertainty. The procedure for evaluating this model uncertainty involves two steps: 1) deriving a Bayesian mapping function based on a database of case histories, and 2) using the calibrated Bayesian mapping function as a reference to back-figure the uncertainty of the model. Details of the developed procedure within the framework of the first-order reliability method (FORM) are presented. Using FORM with the calibrated model uncertainty, the probability of liquefaction can be readily determined, and thus, the results presented in this paper extend the use of the Youd et al. (2001) method

Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer.

BackgroundBrain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment.MethodsOverall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy-Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates.ResultsOf the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08-0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12-0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15-0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism.ConclusionsThis is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings