An important factor for successful translational stroke research is study quality. Low-quality studies are at risk of biased results and effect overestimation, as has been intensely discussed for ...small animal stroke research. However, little is known about the methodological rigor and quality in large animal stroke models, which are becoming more frequently used in the field. Based on research in two databases, this systematic review surveys and analyses the methodological quality in large animal stroke research. Quality analysis was based on the Stroke Therapy Academic Industry Roundtable and the Animals in Research: Reporting In Vivo Experiments guidelines. Our analysis revealed that large animal models are utilized with similar shortcomings as small animal models. Moreover, translational benefits of large animal models may be limited due to lacking implementation of important quality criteria such as randomization, allocation concealment, and blinded assessment of outcome. On the other hand, an increase of study quality over time and a positive correlation between study quality and journal impact factor were identified. Based on the obtained findings, we derive recommendations for optimal study planning, conducting, and data analysis/reporting when using large animal stroke models to fully benefit from the translational advantages offered by these models.
Increased systemic oxidative stress, implicated in adverse pregnancy outcomes for both mothers and fetuses, has been associated with gestational exposure to air pollutants such as polycyclic aromatic ...hydrocarbons (PAHs), fine particulate matter (PM2.5), and nitrogen dioxide (NO2). However, it is unclear whether exposure to pollutants at levels below the current air quality standards can increase oxidative stress in pregnant women. In a cohort of 305 pregnant persons residing in western New York, we examined the association between exposure to PM2.5, NO2, and PAHs (measured as urinary 1-hydroxypyrene) and urinary biomarkers of oxidative stress (malondialdehyde MDA and 8-hydroxy-2′-deoxyguanosine 8-OHdG) measured in each trimester. After controlling for gestational stage, maternal age, lifestyles, and socioeconomic factors, each interquartile range (IQR) increase in 1-hydroxypyrene concentration (65.8 pg/ml) was associated with a 7.73% (95%CI: 3.18%,12.3%) higher in MDA levels throughout the pregnancy and in the first and second trimester. An IQR increase in PM2.5 concentration (3.20 μg/m3) was associated with increased MDA levels in the first trimester (8.19%, 95%CI: 0.28%,16.1%), but not the 2nd (−7.99%, 95% CI: 13.8%, −2.23%) or 3rd trimester (−2.81%, 95% CI: 10.0%, 4.38%). The average cumulative PM2.5 exposures in the 3–7 days before urine collection were associated with increased 8-OHdG levels during the second trimester, with the largest difference (22.6%; 95% CI: 3.46%, 41.7%) observed in relation to a one IQR increase in PM2.5 concentration in the previous 7 days. In contrast, neither oxidative stress biomarker was associated with NO2 exposure. Observed in pregnant women exposed to low-level air pollution, these findings expanded previously reported associations between systemic oxidative stress and high-level PM2.5 and PAH concentrations. Further, the first and second trimesters may be a susceptible window during pregnancy for oxidative stress responses to air pollution exposure.
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•Gestational PM2.5 and NO2 exposure are below national standards.•Short-term exposure to PM2.5 was associated with urinary oxidative biomarkers.•Urinary 1-hydroxypyrene was associated with lipid peroxidation biomarker.•Stronger associations were observed in early- and mid-pregnancy.
It has been well documented in the arthroplasty literature that lumbar degenerative disc disease (DDD) contributes to abnormal spinopelvic motion. However, the relationship between the severity or ...pattern of hip osteoarthritis (OA) as measured on an anteroposterior (AP) pelvic view and spinopelvic biomechanics has not been well investigated. Therefore, the aim of the study is to examine the association between the severity and pattern of hip OA and spinopelvic motion. A retrospective chart review was conducted to identify patients undergoing primary total hip arthroplasty (THA). Plain AP pelvic radiographs were reviewed to document the morphological characteristic of osteoarthritic hips. Lateral spine-pelvis-hip sitting and standing plain radiographs were used to measure sacral slope (SS) and pelvic femoral angle (PFA) in each position. Lumbar disc spaces were measured to determine the presence of DDD. The difference between sitting and standing SS and PFA were calculated to quantify spinopelvic motion (ΔSS) and hip motion (ΔPFA), respectively. Univariate analysis and Pearson correlation were used to identify morphological hip characteristics associated with changes in spinopelvic motion. In total, 139 patients were included. Increased spinopelvic motion was observed in patients with loss of femoral head contour, cam deformity, and acetabular bone loss (all p < 0.05). Loss of hip motion was observed in patients with loss of femoral head contour, cam deformity, and acetabular bone loss (all p < 0.001). A decreased joint space was associated with a decreased ΔPFA (p = 0.040). The presence of disc space narrowing, disc space narrowing > two levels, and disc narrowing involving the L5-S1 segment were associated with decreased spinopelvic motion (all p < 0.05). Preoperative hip OA as assessed on an AP pelvic radiograph predicts spinopelvic motion. These data suggest that specific hip osteoarthritic morphological characteristics listed above alter spinopelvic motion to a greater extent than others.
Poly- and perfluoroalkyl substances (PFAS) are ubiquitous and persistent environmental contaminants that may act as endocrine disruptors in utero, but the specific endocrine pathways are unknown.
We ...examined associations between maternal serum PFAS and sex steroid hormones at three time points during pregnancy.
Pregnant women participating in the Understanding Pregnancy Signals and Infant Development (UPSIDE) study contributed biospecimens, questionnaire, and medical record data in each trimester (n = 285). PFAS (including perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA)) were analyzed in second-trimester serum samples by high-performance liquid chromatography and tandem mass spectrometry (LC-MS/MS). Total testosterone TT, free testosterone fT, estrone E1, estradiol E2, and estriol E3) were measured by LC-MS/MS in serum samples from each trimester. Linear mixed models with random intercepts were used to examine associations between log-transformed PFAS concentrations and hormone levels, adjusting for covariates, and stratifying by fetal sex. Results are presented as the mean percentage difference (Δ%) in hormone levels per ln-unit increase in PFAS concentration.
In adjusted models, PFHxS was associated with higher TT (%Δ = 20.0, 95%CI: 1.7, 41.6), particularly among women carrying male fetuses (%Δ = 15.3, 95%CI: 1.2, 30.7); this association strengthened as the pregnancy progressed. PFNA (%Δ = 7.9, 95%CI: 3.4, 12.5) and PFDA (%Δ = 7.2, 95%CI: 4.9, 9.7) were associated with higher fT, with associations again observed only in women carrying male fetuses. PFHxS was associated with higher levels of E2 and E3 in women carrying female fetuses (%Δ = 13.2, 95%CI: 0.5, 29.1; %Δ = 17.9, 95%CI: 3.2, 34.8, respectively). No associations were observed for PFOS and PFOA.
PFHxS, PFNA, and PFDA may disrupt androgenic and estrogenic pathways in pregnancy in a sex-dependent manner.
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•Detectable levels were very low for shorter chain PFAS including PFBS and PFHpA.•PFOA and PFOS had minimal impact in maternal sex steroid hormones.•PFHxS, PFNA, and PFDA may exert androgenic effects.•Associations between PFAS and maternal sex steroid hormones differed by fetal sex.
Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear.
The purpose of this study was to evaluate ...sex-specific associations of CV risk factors and biomarkers with incident HF.
The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio.
Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p < 0.001), and the combined clinical model had good discrimination in men (C-statistic = 0.80) and in women (C-statistic = 0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic = 0.006; likelihood ratio chi-square = 146; p < 0.001), and after adding cardiac troponins in women (ΔC-statistic = 0.003; likelihood ratio chi-square = 73; p < 0.001).
CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in a clinical HF risk prediction model is limited in both sexes.
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The extent to which co-occurrence of cardiovascular disease (CVD) and cancer is due to shared risk factors or other mechanisms is unknown.
This study investigated the association of standard CVD risk ...factors, CVD biomarkers, pre-existing CVD, and ideal cardiovascular (CV) health metrics with the development of future cancer.
This study prospectively followed Framingham Heart Study and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants free of cancer at baseline and ascertained histology-proven cancer. This study assessed the association of baseline CV risk factors, 10-year atherosclerotic (ASCVD) risk score, established CVD biomarkers, prevalent CVD, and the American Heart Association (AHA) Life’s Simple 7 CV health score with incident cancer using multivariable Cox models. Analyses of interim CVD events with incident cancer used time-dependent covariates.
Among 20,305 participants (mean age 50 ± 14 years; 54% women), 2,548 incident cancer cases occurred over a median follow-up of 15.0 years (quartile 1 to 3: 13.3 to 15.0 years). Traditional CVD risk factors, including age, sex, and smoking status, were independently associated with cancer (p < 0.001 for all). Estimated 10-year ASCVD risk was also associated with future cancer (hazard ratio HR: 1.16 per 5% increase in risk; 95% confidence interval CI 1.14 to 1.17; p < 0.001). The study found that natriuretic peptides (tertile 3 vs. tertile 1; HR: 1.40; 95% CI: 1.03 to 1.91; p = 0.035) were associated with incident cancer but not high-sensitivity troponin (p = 0.47). Prevalent CVD and the development of interim CV events were not associated with higher risk of subsequent cancer. However, ideal CV health was associated with lower future cancer risk (HR: 0.95 per 1-point increase in the AHA health score; 95% CI: 0.92 to 0.99; p = 0.009).
CVD risk, as captured by traditional CVD risk factors, 10-year ASCVD risk score, and natriuretic peptide concentrations are associated with increased risk of future cancer. Conversely, a heart healthy lifestyle is associated with a lower risk of future cancer. These data suggest that the association between CVD and future cancer is attributable to shared risk factors.
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During pregnancy, estrogens and testosterone influence brain development, resulting in sex-typical behavioral phenotypes. Prenatal testosterone exposure is associated with more male-typical behaviors ...in rodents, monkeys, and humans; however, few studies have examined the relationship between maternal sex hormones within the normal range and sex-dimorphic behaviors. In this study, we examined associations between prenatal estrogens and testosterone and sex-typical play in The Infant Development and the Environment Study (TIDES), a multicenter pregnancy cohort. We collected prenatal serum during the first trimester (mean=11.1 ± 2.6 weeks) and assessed child play behavior using the maternally completed Pre-School Activities Inventory (PSAI) at a mean age of 4.5 ± 0.3 years. This analysis includes mother-child pairs with complete data on hormones, play behavior, and covariates (n = 192 boys and 207 girls). No associations were seen between testosterone and PSAI scores in boys or girls or between estrogens and PSAI scores in boys. In girls, we observed an inverse relationship between feminine PSAI scores and both estradiol (E2) and estriol (E3) in multivariable linear regression analyses (E2: −0.11 95% CI −0.20, −0.02; E3: −0.44 95% CI −0.83,−0.04). Because the relationship between sex hormones and PSAI scores appeared nonlinear, we fit piecewise regression models to better fit the data and identify inflection points (point at which there is a significant change in slope). Piecewise regression analyses yielded inverse associations between masculine PSAI scores and estrone (E1) at values of E1 > 1340 pg/mL and E2 at values of E2 > 2870 pg/mL in girls. Further studies are needed to better understand the role of prenatal sex steroids on sexually dimorphic behavior.
•The association between early prenatal sex hormones and child sex-stereotypical play at 4–5 years of age was investigated and a non-linear association between estradiol (E1) and estriol (E2) and less male-typed play was seen in girls.•No associations were seen between estrogen and play behavior in boys.•No associations were seen between testosterone and play behavior in girls or boys.•This suggests that maternal prenatal hormone effects on sex-typed play are hormone and sex-dependent.•This is the first study to show associations between prenatal estrogens and play behavior in childhood.
Coexpression of mRNAs under multiple conditions is commonly used to infer cofunctionality of their gene products despite well-known limitations of this “guilt-by-association” (GBA) approach. Recent ...advancements in mass spectrometry-based proteomic technologies have enabled global expression profiling at the protein level; however, whether proteome profiling data can outperform transcriptome profiling data for coexpression based gene function prediction has not been systematically investigated. Here, we address this question by constructing and analyzing mRNA and protein coexpression networks for three cancer types with matched mRNA and protein profiling data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Our analyses revealed a marked difference in wiring between the mRNA and protein coexpression networks. Whereas protein coexpression was driven primarily by functional similarity between coexpressed genes, mRNA coexpression was driven by both cofunction and chromosomal colocalization of the genes. Functionally coherent mRNA modules were more likely to have their edges preserved in corresponding protein networks than functionally incoherent mRNA modules. Proteomic data strengthened the link between gene expression and function for at least 75% of Gene Ontology (GO) biological processes and 90% of KEGG pathways. A web application Gene2Net (http://cptac.gene2net.org) developed based on the three protein coexpression networks revealed novel gene-function relationships, such as linking ERBB2 (HER2) to lipid biosynthetic process in breast cancer, identifying PLG as a new gene involved in complement activation, and identifying AEBP1 as a new epithelial-mesenchymal transition (EMT) marker. Our results demonstrate that proteome profiling outperforms transcriptome profiling for coexpression based gene function prediction. Proteomics should be integrated if not preferred in gene function and human disease studies.
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