Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.</p

The JWS online simulation database

Summary: JWS Online is a web-based platform for construction, simulation and exchange of models in standard formats. We have extended the platform with a database for curated simulation experiments that can be accessed directly via a URL, allowing one-click reproduction of published results. Users can modify the simulation experiments and export them in standard formats. The Simulation database thus lowers the bar on exploring computational models, helps users create valid simulation descriptions and improves the reproducibility of published simulation experiments. Availability and Implementation: The Simulation Database is available on line at https://jjj.bio.vu. nl/models/experiments/

Growth and Reproductive Development of Male Piglets Are More Vulnerable to Midgestation Maternal Stress Than That of Female Piglets

In many mammalian species, prenatal stress masculinizes female and feminizes male offspring impairing their reproductive capacity. Regrouping gestating sows is a common, stressful production practice, but its impact on the developing pigs of the sow is not fully known. This study examined the effects of regrouping gestating sows and the administration of exogenous glucocorticoids on the growth and external reproductive morphology of pigs. At 37.2 ± 0.26 d of gestation, 6 cohorts of 18 sows (N = 108) were placed in 1 of 3 treatments: socially stable (Stable), hydrocortisone acetate (HCA), or mixed (Mixed). The HCA sows were administered 70 mg HCA, a synthetic glucocorticoid, twice daily during the 21 d experimental period. Each Mixed sow was penned with 2 companion sows (Companion) and regrouped on d 7 and 14 with 2 different Companion sows in a new pen. Stable and HCA sows were penned in treatment groups of 3 sows. Sow social rank was assessed weekly during feeding. After the 21 d experimental period, all sows were housed in gestation stalls for the duration of pregnancy. During the 21 d, Companion sows gained more weight than HCA and Mixed sows (P \u3c 0.05) with Stable sows intermediate. High ranked sows gained more weight than middle and low ranked sows (P \u3c 0.05). Mixed sows had greater head lesion scores than Stable and HCA sows (P \u3c 0.05) with Companion sows intermediate. Head lesions increased with lower social rank (P \u3c 0.001). Sow treatment did not affect farrowing rate, litter size, or sex ratio (P \u3e 0.10). Social rank also had no effect on farrowing rate (P \u3e 0.10), but affected total litter size (P = 0.03). High ranked sows bore and weaned more live females than low ranked sows (P \u3c 0.05), in part due to differential preweaning mortality among female pigs (P = 0.01). Only male pigs were affected by sow treatment. Preweaning mortality was higher among male pigs from HCA than from Mixed sows (P = 0.04) with other treatments intermediate. Despite no weight differences in the preweaning period, at 160 d of age males from HCA sows weighed more than males from Stable sows (P = 0.01) with other treatments intermediate. Males born to Companion sows had longer relative anogenital distances, a marker of fetal testosterone exposure, than males from Mixed sows (P = 0.03) with other treatments intermediate. The prenatal environment affected the pigs in a sex-specific manner altering the growth and reproductive morphology of the males more than that of the females

Leukocyte function and health status of calves supplemented with vitamins A and E

Forty-four Holstein calves were fed milk replacers with varied concentrations of vitamins A and E from 3 to 45 d of age to determine their effects on concentrations of plasma vitamin A (retinol and retinyl palmitate) and vitamin E (a- tocopherol), lymphocyte and neutrophil functions, and health of calves. Plasma a-tocopherol was unaffected by increased vitamin A supplementation. Fecal scores, and eye and nose membrane responses were improved with increased vitamin A and lower vitamin E concentration, whereas the same treatment tended to reduce neutrophil cytotoxic and bactericidal activity by 6 wk of age. Increased supplemental vitamin E tended to enhance neutrophil functions. However, age appeared to have an effect on response to both vitamins

Patient-reported outcome instruments used in immune-checkpoint inhibitor clinical trials in oncology: a systematic review.

Immune-checkpoint inhibitors (ICI) have shown significant benefits for overall survival across various cancer types. Patient-reported outcomes (PROs) are assessed in clinical trials as a measure of efficacy. However, it remains unclear to what extent current PRO instruments capture symptoms specific to ICI toxicities. We conducted a systematic review to identify the use and content validity of PRO instruments in ICI clinical trials in oncology. Literature was retrieved from PubMed, Embase, PsycINFO, Medline and CINAHL databases. Articles presenting ICI clinical trials' PRO results, clinical trial study protocols, and conference abstracts stating the use of PRO measures were assessed. We evaluated the validity of identified instruments by comparing their symptom-related content with the adverse events reported in each ICI clinical trial. From database inception until January 2020, we identified 191 ICI clinical trials stating the use of PRO measures of which 26 published PRO results. The cancer-specific EORTC QLQ-C30 and the generic EQ-5D questionnaires were the most widely used instruments, often in combination with disease-specific PROs. Instruments used to report PRO symptom-related toxicities covered 45% of the most frequently reported AEs, whereas 23% of AEs were partially covered and 29% were not covered at all. Of non-covered AEs, 59% referred to the dermatologic system. Partially covered AEs related to endocrine and specific types of pain. Despite the high frequency of symptom-related toxicities related to ICI, these events are only partially covered (or not addressed) by current PRO instruments, even when combined. Further research is needed to develop new strategies to tailor PRO instruments to specific ICI toxicities

Dyslexia and language impairment associated genetic markers influence cortical thickness and white matter in typically developing children

Dyslexia and language impairment (LI) are complex traits with substantial genetic components. We recently completed an association scan of the DYX2 locus, where we observed associations of markers in DCDC2, KIAA0319, ACOT13, and FAM65B with reading-, language-, and IQ-related traits. Additionally, the effects of reading-associated DYX3 markers were recently characterized using structural neuroimaging techniques. Here, we assessed the neuroimaging implications of associated DYX2 and DYX3 markers, using cortical volume, cortical thickness, and fractional anisotropy. To accomplish this, we examined eight DYX2 and three DYX3 markers in 332 subjects in the Pediatrics Imaging Neurocognition Genetics study. Imaging-genetic associations were examined by multiple linear regression, testing for influence of genotype on neuroimaging. Markers in DYX2 genes KIAA0319 and FAM65B were associated with cortical thickness in the left orbitofrontal region and global fractional anisotropy, respectively. KIAA0319 and ACOT13 were suggestively associated with overall fractional anisotropy and left pars opercularis cortical thickness, respectively. DYX3 markers showed suggestive associations with cortical thickness and volume measures in temporal regions. Notably, we did not replicate association of DYX3 markers with hippocampal measures. In summary, we performed a neuroimaging follow-up of reading-, language-, and IQ-associated DYX2 and DYX3 markers. DYX2 associations with cortical thickness may reflect variations in their role in neuronal migration. Furthermore, our findings complement gene expression and imaging studies implicating DYX3 markers in temporal regions. These studies offer insight into where and how DYX2 and DYX3 risk variants may influence neuroimaging traits. Future studies should further connect the pathways to risk variants associated with neuroimaging/neurocognitive outcomes

Effect of feed withdrawal and transportation on Salmonella enterica infection in market-weight pigs

A study was conducted to determine if two common pre-slaughter stressors, feed withdrawal and transportation, affect the levels of Salmonella in infected market pigs. A total of 60 market-weight pigs (220- 240 lbs.) were individually inoculated (intranasally; 105 cfu/mL) with Salmonella enterica serovar Typhimurium. The experiment was replicated 3 times with 20 pigs per replicate. Individual fecal samples were collected to confirm establishment of the infection (3 samples per pig) prior to treatment assignment

Experimental Salmonella enterica infection in market-weight pigs

Market pigs infected with Salmonella pose significant food safety risk by carrying the pathogen into abattoirs. A study was conducted to determine the dynamic of Salmonella infection in market-weight pigs (220-240 lbs.). Pigs (n=24) were individually inoculated (intranasally; 108 cfu/mL) with Salmonella enterica serovar Typhimurium. Fecal samples were collected from each pig, and 3 pigs were randomly selected and euthanized to collect additional samples (spleen, liver, mesenteric lymph node, ileal and cecal contents) on days 1, 2, 7, 14, 21, 28, 35, and 42 post-inoculation (p.i.)

Validation of the newly developed Advanced Practice Nurse Task Questionnaire: A national survey.

To describe psychometric validation of the newly developed Advanced Practice Nurse Task Questionnaire. Cross-sectional quantitative study. The development of the questionnaire followed an adapted version of the seven steps described in the guide by the Association for Medical Education in Europe. A nationwide online survey tested the construct and structural validity and internal consistency using an exploratory factor analysis, Cronbach's alpha coefficient and a Kruskal-Wallis test to compare the hypotheses. We received 222 questionnaires between January and September 2020. The factor analysis produced a seven-factor solution as suggested in Hamric's model. However, not all item loadings aligned with the framework's competencies. Cronbach's alpha of factors ranged between .795 and .879. The analysis confirmed the construct validity of the Advanced Practice Nurse Task Questionnaire. The tool was able to discriminate the competencies of guidance and coaching, direct clinical practice and leadership across the three advanced practice nurse roles clinical nurse specialist, nurse practitioner or blended role. A precise assessment of advanced practice nurse tasks is crucial in clinical practice and in research as it may be a basis for further refinement, implementation and evaluation of roles. The Advanced Practice Nurse Task Questionnaire is the first valid tool to assess tasks according to Hamric's model of competencies independently of the role or the setting. Additionally, it distinguishes the most common advanced practice nurse roles according to the degree of tasks in direct clinical practice and leadership. The tool may be applied in various countries, independent of the degree of implementation and understanding of advanced nursing practice. The STARD 2015 guideline was used to report the study. No patient or public contribution

The M33 Variable Star Population Revealed by Spitzer

We analyze five epochs of Spitzer Space Telescope/Infrared Array Camera (IRAC) observations of the nearby spiral galaxy M33. Each epoch covered nearly a square degree at 3.6, 4.5, and 8.0 microns. The point source catalog from the full dataset contains 37,650 stars. The stars have luminosities characteristic of the asymptotic giant branch and can be separated into oxygen-rich and carbon-rich populations by their [3.6] - [4.5] colors. The [3.6] - [8.0] colors indicate that over 80% of the stars detected at 8.0 microns have dust shells. Photometric comparison of epochs using conservative criteria yields a catalog of 2,923 variable stars. These variables are most likely long-period variables amidst an evolved stellar population. At least one-third of the identified carbon stars are variable.Comment: Accepted for publication in ApJ. See published article for full resolution figures and electronic table