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Most neuroimaging studies linking regional brain volumes with cognition correct for total intracranial volume (ICV), but methods used for this correction differ across studies. It is unknown whether different ICV correction methods yield consistent results. Using a brain-wide association approach in the MRI substudy of UK Biobank (N = 41,964; mean age = 64.5 years), we used regression models to estimate the associations of 58 regional brain volumetric measures with eight cognitive outcomes, comparing no correction and four ICV correction approaches. Approaches evaluated included: no correction; dividing regional volumes by ICV (proportional approach); including ICV as a covariate in the regression (adjustment approach); and regressing the regional volumes against ICV in different normative samples and using calculated residuals to determine associations (residual approach). We used Spearman-rank correlations and two consistency measures to quantify the extent to which associations were inconsistent across ICV correction approaches for each possible brain region and cognitive outcome pair across 2320 regression models. When the association between brain volume and cognitive performance was close to null, all approaches produced similar estimates close to the null. When associations between a regional volume and cognitive test were not null, the adjustment and residual approaches typically produced similar estimates, but these estimates were inconsistent with results from the crude and proportional approaches. For example, when using the crude approach, an increase of 0.114 (95% confidence interval [CI]: 0.103-0.125) in fluid intelligence was associated with each unit increase in hippocampal volume. However, when using the adjustment approach, the increase was 0.055 (95% CI: 0.043-0.068), while the proportional approach showed a decrease of -0.025 (95% CI: -0.035 to -0.014). Different commonly used methods to correct for ICV yielded inconsistent results. The proportio

INTRODUCTION: We estimated the ages when associations between Alzheimers disease (AD) genes and brain volumes begin among middle-aged and older adults. METHODS: Among 45,616 dementia-free participants aged 45-80, linear regressions tested whether genetic risk score for AD (AD-GRS) had age-dependent associations with 38 regional brain magnetic resonance imaging volumes. Models were adjusted for sex, assessment center, genetic ancestry, and intracranial volume. RESULTS: AD-GRS modified the estimated effect of age (per decade) on the amygdala (-0.41 mm3 [-0.42, -0.40]); hippocampus (-0.45 mm3 [-0.45, -0.44]), nucleus accumbens (-0.55 mm3 [-0.56, -0.54]), thalamus (-0.38 mm3 [-0.39, -0.37]), and medial orbitofrontal cortex (-0.23 mm3 [-0.24, -0.22]). Trends began by age 45 for the nucleus accumbens and thalamus, 48 for the hippocampus, 51 for the amygdala, and 53 for the medial orbitofrontal cortex. An AD-GRS excluding apolipoprotein E (APOE) was additionally associated with entorhinal and middle temporal cortices. DISCUSSION: APOE and other genes that increase AD risk predict lower hippocampal and other brain volumes by middle age.

BACKGROUND: The objective of this study was to evaluate associations of diabetes overall, type 1 diabetes (T1D), and type 2 diabetes (T2D) with breast cancer (BCa) risk. METHODS: We included 250,312 women aged 40-69 years between 2006 and 2010 from the UK Biobank cohort. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated for associations of diabetes and its two major types with the time from enrollment to incident BCa. RESULTS: We identified 8182 BCa cases during a median follow-up of 11.1 years. We found no overall association between diabetes and BCa risk (aHR = 1.02, 95% CI = 0.92-1.14). When accounting for diabetes subtype, women with T1D had a higher risk of BCa than women without diabetes (aHR = 1.52, 95% CI = 1.03-2.23). T2D was not associated with BCa risk overall (aHR = 1.00, 95% CI = 0.90-1.12). However, there was a significantly increased risk of BCa in the short time window after T2D diagnosis. CONCLUSIONS: Though we did not find an association between diabetes and BCa risk overall, an increased risk of BCa was observed shortly after T2D diagnosis. In addition, our data suggest that women with T1D may have an increased risk of BCa.

ImportanceAdults with Alzheimer disease and related dementias (ADRD) are particularly vulnerable to the direct and indirect effects of the COVID-19 pandemic. Deaths associated with ADRD increased substantially in pandemic year 1. It is unclear whether mortality associated with ADRD declined when better prevention strategies, testing, and vaccines became widely available in year 2.ObjectiveTo compare pandemic-era excess deaths associated with ADRD between year 1 and year 2 overall and by age, sex, race and ethnicity, and place of death.Design, setting, and participantsThis time series analysis used all death certificates of US decedents 65 years and older with ADRD as an underlying or contributing cause of death from January 2014 through February 2022.ExposureCOVID-19 pandemic era.Main outcomes and measuresPandemic-era excess deaths associated with ADRD were defined as the difference between deaths with ADRD as an underlying or contributing cause observed from March 2020 to February 2021 (year 1) and March 2021 to February 2022 (year 2) compared with expected deaths during this period. Expected deaths were estimated using data from January 2014 to February 2020 fitted with autoregressive integrated moving average models.ResultsOverall, 2 334 101 death certificates were analyzed. A total of 94 688 (95% prediction interval [PI], 84 192-104 890) pandemic-era excess deaths with ADRD were estimated in year 1 and 21 586 (95% PI, 10 631-32 450) in year 2. Declines in ADRD-related deaths in year 2 were substantial for every age, sex, and racial and ethnic group evaluated. Pandemic-era ADRD-related excess deaths declined among nursing home/long-term care residents (from 34 259 [95% PI, 25 819-42 677] in year 1 to -22 050 [95% PI, -30 765 to -13 273] in year 2), but excess deaths at home remained high (from 34 487 [95% PI, 32 815-36 142] in year 1 to 28 804 [95% PI, 27 067-30 571] in year 2).Conclusions and relevanceThis study found that large increases in mortality with ADRD

INTRODUCTION: The challenge of accounting for practice effects (PEs) when modeling cognitive change was amplified by the COVID-19 pandemic, which introduced period and mode effects that may bias the estimation of cognitive trajectory. METHODS: In three Kaiser Permanente Northern California prospective cohorts, we compared predicted cognitive trajectories and the association of grip strength with cognitive decline using three approaches: (1) no acknowledgment of PE, (2) inclusion of a wave indicator, and (3) constraining PE based on a preliminary model (APM) fit using a subset of the data. RESULTS: APM-based correction for PEs based on balanced, pre-pandemic data, and with current age as the timescale produced the smallest discrepancy between within-person and between-person estimated age effects. Estimated associations between grip strength and cognitive decline were not sensitive to the approach used. DISCUSSION: Constraining PEs based on a preliminary model is a flexible, pragmatic approach allowing for meaningful interpretation of cognitive change. HIGHLIGHTS: The magnitude of practice effects (PEs) varied widely by study. When PEs were present, the three PE approaches resulted in divergent estimated age-related cognitive trajectories. Estimated age-related cognitive trajectories were sometimes implausible in models that did not account for PEs. The associations between grip strength and cognitive decline did not differ by the PE approach used. Constraining PEs based on estimates from a preliminary model allows for a meaningful interpretation of cognitive change.

The trichothecene toxin deoxynivalenol (DON) is a ribotoxic mycotoxin that contaminates cereal-based food. DON binds to ribosomes, thereby inhibiting protein translation and activating stress mitogen-activated protein kinases (MAPK). The activation of MAPK induces pro-inflammatory cytokine production. Emerging evidence showed that DON decreased bile acid reabsorption and apical sodium-dependent bile acid transporter (ASBT) expression in Caco-2 cell layers. We hypothesized that the effect of DON on decreased ASBT mRNA expression is regulated via pro-inflammatory cytokines. We observed that MAPK inhibitors prevented DON to induce IL-8 secretion and prevented the DON-induced downregulation of ASBT mRNA expression. However, DON-induced taurocholic acid (TCA) transport reduction was not prevent by the MAPK inhibitors. We next observed a similarity between the activity of the non-inflammatory ribotoxin cycloheximide and DON to decrease TCA transport, which is consistent with their common ability to inhibit protein synthesis. Together, our results suggest that DON-induced TCA malabsorption is regulated by MAPK activation-induced pro-inflammatory cytokine production and protein synthesis inhibition, both of which are initiated by DON binding to the ribosomes which therefore is the molecular initiating event for the adverse outcome of bile acid malabsorption. This study provides insights into the mechanism of ribotoxins-induced bile acid malabsorption in human intestine.

The fungal secondary metabolite deoxynivalenol (DON) that can contaminate cereal-based food products not only induces inflammation but also reduces bile acid absorption by a healthy human intestine. Bile acid malabsorption is commonly observed in individuals with an inflamed intestine. Here we studied the effects of DON on inflammation and primary bile acid transport using an in vitro model for an inflamed intestine. An inflamed intestinal in vitro model was established by co-culturing a Caco-2 cell-layer and LPS-pre-stimulated THP-1 macrophages in Transwells. We observed a decreased transport of 5 primary bile acids across inflamed co-cultures compared to healthy co-cultures but not of chenodeoxycholic acid. DON exposure further reduced the transport of the affected primary bile acids across the inflamed co-cultures. DON exposure also enhanced the secretion of pro-inflammatory cytokines in the inflamed co-cultures, while it did not increase the pro-inflammatory cytokines secretion from LPS-pre-stimulated THP-1 monocultures. Exposure of Caco-2 cell-layers to pro-inflammatory cytokines or THP-1 conditioned media partly mimicked the DON-induced effects of the co-culture model. Local activation of intestinal immune cells reinforces the direct pro-inflammatory effects of DON on intestinal epithelial cells. This affects the bile acid intestinal kinetics in an inflamed intestine.

Bile acid homeostasis plays an important role in many biological activities through the bile–liver–gut axis. In this study, two in vitro models were applied to further elucidate the mode of action underlying reported in vivo bile acid changes induced by antibiotics (colistin sulfate, tobramycin, meropenem trihydrate, and doripenem hydrate). 16S rRNA analysis of rat fecal samples anaerobically incubated with these antibiotics showed that especially tobramycin induced changes in the gut microbiota. Furthermore, tobramycin was shown to inhibit the microbial deconjugation of taurocholic acid (TCA) and the transport of TCA over an in vitro Caco-2 cell layer used as a model to mimic intestinal bile acid reuptake. The effects induced by the antibiotics in the in vitro model systems provide novel and complementary insight explaining the effects of the antibiotics on microbiota and fecal bile acid levels upon 28-day in vivo treatment of rats. In particular, our results provide insight in the mode(s) of action underlying the increased levels of TCA in the feces upon tobramycin exposure. Altogether, the results of the present study provide a proof-of-principle on how in vitro models can be used to elucidate in vivo effects on bile acid homeostasis, and to obtain insight in the mode(s) of action underlying the effect of an antibiotic, in this case tobramycin, on bile acid homeostasis via effects on intestinal bile acid metabolism and reuptake.

Earth-rock dam plays an important role in water conservancy project, but there were many damage cases caused by earthquakes, so it is necessary to investigate dynamic responses of earth-rock dams under combined action of earthquake and wave. Considering material nonlinearity, seepage, wave action, fluid-solid interaction, liquid sloshing, a numerical calculation model is established, and Arbitrary Lagrange Eulerian method is used to solve the nonlinear dynamic coupling problem. Dynamic responses under wave, earthquake and wave+earthquake are studied comparatively, and influences of near and far field earthquakes and PGA on dynamic responses are investigated. Results show that values and distributions of dynamic responses under wave and earthquake are quite different, and dynamic responses were further increased considering combination of earthquake and wave. Dynamic responses under far field long period earthquake is significantly larger than that under near field earthquake. With the increase of PGA, increase trends of horizontal displacement, vertical displacement and plastic strain are increased, while increase trend of maximum shear stress is slowed down. It can be obtained that when earthquake intensity is large, earth-rock dam will be easily damaged due to excessive deformation.

Concrete-filled steel tubular (CFST) column to steel beam joint with the ductility and energy dissipation components is a type of connection which is used in prefabricated structures, to improve the capacity of connections and construction efficiency. In this paper, two different type of steel beam to CFST column connections with the penetrated high-strength bolts and end-plate are investigated, i.e., steel beam to CFST column connection with end plate (CJ-1), and T-stub bolted (CJ-2) connections. The finite element model (FEM) of steel beam to CFST column connection with the penetrated high-strength bolts under cyclic loading are conducted based on the whole process of the nonlinear explicit analysis method using ABAQUS. The feasibility of FEM is verified by a set of experimental results performed by our research group, as well as available test results from other researchers. The failure modes, bearing capacity, energy dissipation capacity and ductility and rigidity degeneration were studied. As a result, the load-displacement hysteretic loop curve of CJ-2 connection is plump. However, the hysteresis curve of CJ-1 shows pinching phenomenon. The value of buckling load and ultimate load of CJ-2 increased by 28 % and 30 % respectively, compared with CJ-1. With respect of stress analysis, the plastic strain accumulation position distribution is relatively uniform duo to the T-stub connection, avoiding the penetrated high-strength bolt early yield or fracture. The results show that the steel beam to CFST column connection with penetrated bolts and T-stub connection has good seismic capacity.

My thesis focuses on the materials and structure of the first movements of three large-scale symphonic works by prominent minimalist and post-minimalist composers. I selected these composers and their works because each indicates a different side of both minimalism and symphonic composition. First, John Adams’ Harmonielehre features the repeated chords typical of the minimalist style as well as repetitive motor rhythms, but they do not follow a strict repetition scheme. In addition, the structure of Harmonielehre is more appropriate to the sonata-allegro format of the first movement of a symphony compared to the other two works. Next, Philip Glass re-interpreted Low by David Bowie and Brian Eno with his signature minimalist/repetitive treatment but in an orchestral arrangement. Symphony No. 1 (“Low”) features surprising polytonal complexities, long subtle rhythmic cycles, and his most basic minimalist technique: the additive process. As in many other minimalist pieces, this piece exploits one form of continuity by slowly growing from a sparse rhythmic framework to a structure that also includes contrasting sections. Finally, the “Continuous Wave,” the first movement of Symphony in Waves, by Aaron Jay Kernis, makes use of another continuous form through an uninterrupted rhythmic pattern flowing from the beginning to the end of the first movement. As the youngest of the three composers, the influence of his teacher, John Adams, brings variety and dynamic energy to his music.

My thesis focuses on the materials and structure of the first movements of three large-scale symphonic works by prominent minimalist and post-minimalist composers. I selected these composers and their works because each indicates a different side of both minimalism and symphonic composition. First, John Adams’ Harmonielehre features the repeated chords typical of the minimalist style as well as repetitive motor rhythms, but they do not follow a strict repetition scheme. In addition, the structure of Harmonielehre is more appropriate to the sonata-allegro format of the first movement of a symphony compared to the other two works. Next, Philip Glass re-interpreted Low by David Bowie and Brian Eno with his signature minimalist/repetitive treatment but in an orchestral arrangement. Symphony No. 1 (“Low”) features surprising polytonal complexities, long subtle rhythmic cycles, and his most basic minimalist technique: the additive process. As in many other minimalist pieces, this piece exploits one form of continuity by slowly growing from a sparse rhythmic framework to a structure that also includes contrasting sections. Finally, the “Continuous Wave,” the first movement of Symphony in Waves, by Aaron Jay Kernis, makes use of another continuous form through an uninterrupted rhythmic pattern flowing from the beginning to the end of the first movement. As the youngest of the three composers, the influence of his teacher, John Adams, brings variety and dynamic energy to his music.

One important characteristic of base-isolated liquid storage structure (LSS) is that the vibration periods of structure and liquid are different, namely, there are two kinds of periods in the system. As a result, structure or liquid resonance may occurs under external excitation. In order to reflect the nonlinear characteristics of liquid sloshing, subsonic potential-based element is used to simulate the liquid. The governing equations of liquid field and fluid-structure interaction (FSI) equations are established; the initial and boundary conditions of liquid sloshing in dynamic coordinate system are obtained. Harmonic functions used to conduct time history analysis are generated by the first order vibration frequencies of structure and liquid respectively. The dynamic responses of base-isolated rectangular liquid storage structure (RLSS) under two types of resonance are studied comparatively. Results show that when the external excitation frequency is equal to the first order vibration frequency of isolated structure or liquid sloshing, wall tensile stress, structure displacement, base shear force and liquid sloshing wave height will appear resonance amplification phenomenon. The dynamic responses of structure itself caused by structure resonance are greater than that of liquid resonance; while the liquid sloshing wave height caused by liquid resonance is greater than that of structure resonance. Under structure resonance, the wall is prone to be cracked; and under liquid resonance, the liquid velocity field will become unusually violent, and liquid overflow will be caused easily.

Background Gestational hypothyroidism (G-HypoT) is one of the most common thyroid diseases in pregnant women. Human milk, which closely links the mother with infant, is an important factor to the infant health. Here, we analyzed the colostrum whey proteome of women with or without G-HypoT. Methods and results Using high-mass accuracy and high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS), 1055 proteins were identified. Tandem Mass Tags (TMT) analysis identified differentially expressed proteins between G-HypoT and non-G-HypoT mothers. Of 44 proteins identified, 15 proteins were significantly increased in G-HypoT colostrum whey, while 29 were significantly decreased. Analysis revealed that enzymes involved in carbohydrate metabolism, and that reflect the metabolic activities in breastfeeding women, including fructose-1, 6-bisphosphatase 1, phosphoglycerate mutase 1 were down-regulated. Cell structural proteins, biomarkers of mammary integrity development, including Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and actin were lower in G-HypoT colostrum whey. However, immune protein fragments like Ig gamma-3 chain C region increased in G-HypoT colostrum whey. Conclusion These results implied that G-HypoT may changed human colostrum whey protein in composition level, decreasing levels of metabolic proteins and cell-structure proteins, while increasing levels of immune-related proteins, which may compromise or reflect mothers' and infants' health.

Background Gestational hypothyroidism (G-HypoT) is one of the most common thyroid diseases in pregnant women. Human milk, which closely links the mother with infant, is an important factor to the infant health. Here, we analyzed the colostrum whey proteome of women with or without G-HypoT. Methods and results Using high-mass accuracy and high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS), 1055 proteins were identified. Tandem Mass Tags (TMT) analysis identified differentially expressed proteins between G-HypoT and non-G-HypoT mothers. Of 44 proteins identified, 15 proteins were significantly increased in G-HypoT colostrum whey, while 29 were significantly decreased. Analysis revealed that enzymes involved in carbohydrate metabolism, and that reflect the metabolic activities in breastfeeding women, including fructose-1, 6-bisphosphatase 1, phosphoglycerate mutase 1 were down-regulated. Cell structural proteins, biomarkers of mammary integrity development, including Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and actin were lower in G-HypoT colostrum whey. However, immune protein fragments like Ig gamma-3 chain C region increased in G-HypoT colostrum whey. Conclusion These results implied that G-HypoT may changed human colostrum whey protein in composition level, decreasing levels of metabolic proteins and cell-structure proteins, while increasing levels of immune-related proteins, which may compromise or reflect mothers' and infants' health.

Jing Li,1 Wen Wen,2 Shu Zhao,1 Jingxuan Wang,1 Jingyu Chen,1 Yanrong Wang,3 Qingyuan Zhang11Department of Internal Medicine, 2Department of Anesthesia, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China; 3Key Laboratory of Fertility Maintenance, Ministry of Education, Ningxia Medical University, Xingqing, Yinchuan, Ningxia, People’s Republic of ChinaBackground: HOX transcript antisense intergenic RNA (HOTAIR), a long non-coding RNA transcribed from the antisense strand of the HOXC gene locus, has been shown to be overexpressed in various carcinomas and is thought to be an indicator of poor prognosis. Recently, HOTAIR was found to be an estrogen-responsive gene. We therefore conducted a meta-analysis to systematically summarize and clarify the association between HOTAIR expression and prognosis in the four main estrogen-dependent tumors.Methods: A systematic search of studies that examined the association and prognostic impact of HOTAIR in four of the main estrogen-dependent tumors was conducted in PubMed and Embase. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated to pool the effect size.Results: A total of 1,200 patients from eight eligible studies were included. The current study found an association between HOTAIR expression and overall survival (OS) in four estrogen-dependent tumor types (HR, 1.99; 95% CI: 1.02–3.90; PHeterogeneity=0.001). Subgroup analyses indicated that high HOTAIR expression appeared to be a potential prognostic biomarker in non-breast cancer patients (HR, 2.72; 95% CI: 1.65–4.48). There was also an increased risk in Asian populations (HR, 2.55; 95% CI: 1.62–4.00) compared with Caucasian populations (HR, 1.19; 95% CI: 0.16–8.83) and in patients without preoperative treatment (HR, 2.55; 95% CI: 1.62–4.00) compared with patients with preoperative treatment (HR, 1.19; 95% CI: 0.16&