VasCog 2023: 20 years of research on vascular behavioural and cognitive disorders.

This Commentary describes the 20th Anniversary of VasCog 2023, held in Gothenburg, Sweden.

Frailty-Related Factors among Women Living with and without HIV Aged 40 Years and Older. The Women's Interagency HIV Study.

BACKGROUND: Frailty is a clinical, geriatric syndrome linked to disability and mortality; and may be associated with a variety of factors among underrepresented and underserved women living with HIV (WLWH) and without HIV (WLWOH) transitioning through the adult life course. OBJECTIVES: Determine whether a published set of factors associated cross-sectionally with frailty in WLWH and similar WLWOH at average age 39 years in 2005/2006 were associated with frailty in 2018/2019 among women who initiated frailty assessments at age ≥40 years, or whether a new set of factors were associated with frailty. DESIGN: Cross-sectional analyses within a longitudinal cohort study. SETTING: The multi-center Women's Interagency HIV Study (WIHS). PARTICIPANTS: 1285 participants (951 WLWH, 334 WLWOH), median age 53 years (interquartile range 47-58 years). MEASUREMENTS: The Fried Frailty Phenotype (FFP) in association with 23 factors representing HIV serostatus, other infections, sociodemographic factors, health behaviors, and chronic diseases. RESULTS: Frailty prevalence was 11.1% in 2018/2019 (12.6% among WLWOH, 9.6% among WLWH, p=0.121). The published 2005/2006 final multivariable stepwise regression model contained 9 predictors of frailty. When refit to women in 2018/2019, only age ≥50 years and annual income ≤$12,000 were independently positively associated with frailty; other significant 2005/2006 factors, HIV serostatus, CD4+ count <500 cells/mL among WLWH, smoking, drinking, FIB-4 and eGFR, were not. A newly-derived stepwise model considering all 23 predictors measured in 2018/2019, showed independent positive associations between frailty and age ≥50 years, annual income ≤$12,000, obesity (body mass index (BMI) ≥30kg/m2), and history of tuberculosis and cancer. CONCLUSION: Different chronic and infectious disease factors were associated with frailty among WLWH and WLWOH over the adult life course. Understanding factors associated with frailty by adult life stage, allows identification and implementation of novel, temporal interventions to alleviate frailty-associated outcomes and enhance quality of life among WLWH and WLWOH.

Knowledge about infections is associated with antibiotic use: cross-sectional evidence from the health survey Northern Ireland.

BACKGROUND: Antibiotic overuse is the main modifiable driver of antibiotic resistance. Factors associated with overuse have been inconsistently reported and vary across populations. Given the burgeoning occurrence of infectious diseases around the world, there remains a great need to identify barriers and solutions to the control of infections. We examined whether knowledge about infections and antibiotic resistance is associated with antibiotic use in a northern European population sample. METHODS: The Health Survey Northern Ireland 2014/15 was completed by a cross-sectional sample of 4135 participants aged > 16 years. Participants were asked whether they had taken an antibiotic in the past 12 months; and six questions were asked concerning knowledge about infections and antibiotic resistance. Correct answers to the six knowledge questions defined a knowledge score (score range 0-6 correct answers). We used multivariable logistic regression to estimate odds of self-reported antibiotic use during the last 12 months in association with knowledge score (lowest score, 0/6, as referent), and response to each knowledge question. Covariates included sex, age group, smoking, alcohol drinking, deprivation index, self-rated health, and satisfaction with life. Results were outputted as Odds Ratios (OR) and 95% Confidence Intervals (CI). RESULTS: Antibiotic use in the past 12 months was reported by 39.0% (1614/4135); and 84.2% (3482/4135) scored < 6/6 correct on knowledge statements. Compared to the lowest knowledge score (0/6 correct), the highest knowledge score (6/6 correct) was associated with higher odds of antibiotic use (adjusted OR 2.03, 95% CI [1.46, 2.81], p < 0.001), with a P-value < 0.001 for trend with increasing knowledge score. Female sex, age, high deprivation, and poor general health, were independently associated with higher odds of antibiotic use. Stratified analyses showed sex and age group differences. CONCLUSION: Knowledge, and other modifiable and non-modifiable risk factors, were positively associated with antibiotic use in the past 12 months. While the causal direction of these associations could not be determined, given the high prevalence of lesser knowledge, as well as independent contributions of other factors including socioeconomic characteristics, health literacy campaigns to raise awareness of antibiotic resistance should take a multi-pronged approach.

Kidney tubule health scores and their associations with incident CKD in women living with HIV.

OBJECTIVES: Individual kidney tubule biomarkers are associated with chronic kidney disease (CKD) risk in people living with HIV (PLWH). Whether a combination of kidney biomarkers can be integrated into informative summary scores for PLWH is unknown. METHODS: We measured eight urine biomarkers of kidney tubule health at two visits over a 3-year period in 647 women living with HIV in the Women's Interagency Health Study. We integrated biomarkers into factor scores using exploratory factor analysis. We evaluated associations between CKD risk factors and factor scores, and used generalized estimating equations to determine associations between factor scores and risk of incident CKD. RESULTS: Factor analysis identified two unique factor scores: a tubule reabsorption score comprising alpha-1-microglobulin, beta-2-microglobulin and trefoil factor-3; and a tubule injury score comprising interleukin-18 and kidney injury molecule-1. We modelled the two factor scores in combination with urine epidermal growth factor (EGF) and urine albumin. Predominantly HIV-related CKD risk factors were independently associated with worsening tubule reabsorption scores and tubule injury scores. During a median follow-up of 7 years, 9.7% (63/647) developed CKD. In multivariable time-updated models that adjusted for other factor scores and biomarkers simultaneously, higher tubule reabsorption scores [risk ratio (RR) = 1.27, 95% confidence interval (CI): 1.01-1.59 per 1 SD higher time-updated score], higher tubule injury scores (RR = 1.36, 95% CI: 1.05-1.76), lower urine EGF (RR = 0.75, 95% CI: 0.64-0.87), and higher urine albumin (RR = 1.20, 95% CI: 1.02-1.40) were jointly associated with risk of incident CKD. CONCLUSIONS: We identified two novel and distinct dimensions of kidney tubule health that appear to quantify informative metrics of CKD risk in PLWH.

Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections.

Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. About 1538 participants with active HIV and/or HCV infection in three ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with log IL-18 including HCV and HIV infection status, and HIV RNA in each ancestry group and then meta-analyzed. Eleven highly correlated single-nucleotide polymorphisms (r2=0.98-1) in the IL-18-BCO2 region were significantly associated with log IL-18; each T allele of rs80011693 confers a decrease of 0.06 log pg ml-1 of IL-18 after adjusting for covariates (rs80011693; rs111311302 ß=-0.06, P-value=2.7 × 10-4). In conclusion, genetic variation in IL-18 is associated with IL-18 production in response to HIV and HCV infection, and may explain variability in the inflammatory outcomes of chronic viral infections.

Expression of Phosphorylated KIT in Canine Mast Cell Tumor.

Canine cutaneous mast cell tumor (MCT) is the most common canine skin tumor and exhibits variable biologic behavior. Signaling through the KIT receptor tyrosine kinase promotes cellular proliferation and survival and has been shown to play a role in MCT progression. Despite investigations into numerous biomarkers and the proposal of several grading schemas, no single marker or grading system can accurately predict outcome in canine MCT. The first aim of this study was to develop an immunohistochemical assay to measure phosphorylated KIT (pKIT) to investigate its association with 2 commonly used grading systems and other established prognostic markers for canine MCT. Thirty-four archived MCTs were evaluated for expression of pKIT and Ki-67, KIT localization, mitotic count, mutations in exons 8 and 11 in c-kit, and grading by the Patnaik and 2-tier systems. Expression of pKIT was significantly ( P < .05) correlated with the 2-tier grading scheme and c-kit mutation. Correlation approached significance ( P = .06) with Mitotic Index (MI) and Ki-67. An additional aim was to determine whether pKIT labeling provides a pharmacodynamic marker for predicting response to the receptor tyrosine kinase inhibitor toceranib (TOC). MCTs from 4 of 7 patients demonstrated a partial response to TOC. pKIT expression was assessed by immunohistochemistry in biopsies obtained before and 6 hours after the patients were treated with TOC. Reduced pKIT expression after TOC treatment was demonstrated in 3 of the 4 patients with a partial response compared to 1 of the 3 nonresponders. Collectively, these results demonstrate that immunohistochemical detection of pKIT may be a clinically relevant assay to evaluate the activation status of the major oncogenic pathway in canine MCT.

The Flint Animal Cancer Center (FACC) Canine Tumour Cell Line Panel: a resource for veterinary drug discovery, comparative oncology and translational medicine.

Mammalian cell tissue culture has been a critical tool leading to our current understanding of cancer including many aspects of cellular transformation, growth and response to therapies. The current use of large panels of cell lines with associated phenotypic and genotypic information now allows for informatics approaches and in silico screens to rapidly test hypotheses based on simple as well as complex relationships. Current cell line panels with large amounts of associated drug sensitivity and genomics data are comprised of human cancer cell lines (i.e. NCI60 and GDSC). There is increased recognition of the contribution of canine cancer to comparative cancer research as a spontaneous large animal model with application in basic and translational studies. We have assembled a panel of canine cancer cell lines to facilitate studies in canine cancer and report here phenotypic and genotypic data associated with these cells.

Topoisomerase IIα mediates TCF-dependent epithelial-mesenchymal transition in colon cancer.

Aberrant T-cell factor (TCF) transcription is implicated in the majority of colorectal cancers (CRCs). TCF transcription induces epithelial-mesenchymal transition (EMT), promoting a tumor-initiating cell (TIC) phenotype characterized by increased proliferation, multidrug resistance (MDR), invasion and metastasis. The data presented herein characterize topoisomerase IIα (TopoIIα) as a required component of TCF transcription promoting EMT. Using chromatin immunoprecipitation (ChIP) and protein co-immunoprecipitation (co-IP) studies, we show that TopoIIα forms protein-protein interactions with ß-catentin and TCF4 and interacts with Wnt response elements (WREs) and promoters of direct target genes of TCF transcription, including: MYC, vimentin, AXIN2 and LEF1. Moreover, both TopoIIα and TCF4 ChIP with the N-cadherin promoter, which is a new discovery indicating that TCF transcription may directly regulate N-cadherin expression. TopoIIα N-terminal ATP-competitive inhibitors, exemplified by the marine alkaloid neoamphimedine (neo), block TCF activity in vitro and in vivo. Neo effectively inhibits TopoIIα and TCF4 from binding WREs/promoter sites, whereas protein-protein interactions remain intact. Neo inhibition of TopoIIα-dependent TCF transcription also correlates with significant antitumor effects in vitro and in vivo, including the reversion of EMT, the loss of TIC-mediated clonogenic colony formation, and the loss of cell motility and invasion. Interestingly, non-ATP-competitive inhibitors of TopoIIα, etoposide and merbarone, were ineffective at preventing TopoIIα-dependent TCF transcription. Thus, we propose that TopoIIα participation in TCF transcription may convey a mechanism of MDR to conventional TopoIIα inhibitors. However, our results indicate that TopoIIα N-terminal ATP-binding sites remain conserved and available for drug targeting. This article defines a new strategy for targeted inhibition of TCF transcription that may lead to effective therapies for the treatment of CRC and potentially other Wnt-dependent cancers.

Frailty and Constellations of Factors in Aging HIV-infected and Uninfected Women--The Women's Interagency HIV Study.

BACKGROUND: Biological similarities are noted between aging and HIV infection. Middle-aged adults with HIV infection may present as elderly due to accelerated aging or having more severe aging phenotypes occurring at younger ages. OBJECTIVES: We explored age-adjusted prevalence of frailty, a geriatric condition, among HIV+ and at risk HIV- women. DESIGN: Cross-sectional. SETTING: The Women's Interagency HIV Study (WIHS). PARTICIPANTS: 2028 middle-aged (average age 39 years) female participants (1449 HIV+; 579 HIV-). MEASUREMENTS: The Fried Frailty Index (FFI), HIV status variables, and constellations of variables representing Demographic/health behaviors and Aging-related chronic diseases. Associations between the FFI and other variables were estimated, followed by stepwise regression models. RESULTS: Overall frailty prevalence was 15.2% (HIV+, 17%; HIV-, 10%). A multivariable model suggested that HIV infection with CD4 count<200; age>40 years; current or former smoking; income ≤$12,000; moderate vs low fibrinogen-4 (FIB-4) levels; and moderate vs high estimated glomerular filtration rate (eGFR) were positively associated with frailty. Low or moderate drinking was protective. CONCLUSIONS: Frailty is a multidimensional aging phenotype observed in mid-life among women with HIV infection. Prevalence of frailty in this sample of HIV-infected women exceeds that for usual elderly populations. This highlights the need for geriatricians and gerontologists to interact with younger 'at risk' populations, and assists in the formulation of best recommendations for frailty interventions to prevent early aging, excess morbidities and early death.

Limited sampling pharmacokinetics of subcutaneous ondansetron in healthy geriatric cats, cats with chronic kidney disease, and cats with liver disease.

Ondansetron, a 5-HT3 receptor antagonist, is an effective anti-emetic in cats. The purpose of this study was to compare pharmacokinetics of subcutaneous (SQ) ondansetron in healthy geriatric cats to cats with chronic kidney disease (CKD) or liver disease using a limited sampling strategy. 60 cats participated; 20 per group. Blood was drawn 30 and 120 min following one 2 mg (mean 0.49 mg/kg, range 0.27-1.05 mg/kg) SQ dose of ondansetron. Ondansetron concentrations were measured by liquid chromatography coupled to tandem mass spectrometry. Drug exposure represented as area under the curve (AUC) was predicted using a limited sampling approach based on multiple linear regression analysis from previous full sampling studies, and clearance (CL/F) estimated using noncompartmental methods. Kruskal-Wallis anova was used to compare parameters between groups. Mean AUC (ng/mL·h) of subcutaneous ondansetron was 301.4 (geriatric), 415.2 (CKD), and 587.0 (liver). CL/F (L/h/kg) of SQ ondansetron was 1.157 (geriatric), 0.967 (CKD), and 0.795 (liver). AUC was significantly higher in liver and CKD cats when compared to geriatric cats (P < 0.05). CL/F in liver cats was significantly decreased (P < 0.05) compared to geriatric cats. In age-matched subset analysis, AUC and CL/F in liver cats remained significantly different from geriatric cats.

Longitudinal associations between physical activity and depression scores in Swedish women followed 32 years.

OBJECTIVE: Physical activity is negatively associated with depressive symptoms. However, few studies consider dynamic associations of changes in physical activity and reciprocal relationships. This study aimed to perform comprehensive evaluations of relationships between physical activity and depression scores in women followed from mid- to late life. METHOD: The Prospective Population Study of Women in Gothenburg, Sweden, provided repeated measures of self-reported physical activity and depressive symptoms between 1974 and 2005 (baseline N = 676, 84.5% response rate). Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale, and physical activity was evaluated by the Saltin-Grimby Physical Activity Level Scale. Latent growth curve analyses were used to evaluate associations of change, and cross-lagged models were used to study the reciprocal relationship between physical activity and depression scores. RESULTS: At baseline, lower levels of physical activity were related to higher depression scores. Individuals with decreasing physical activity over time evidenced higher depression scores at 32-year follow-up. Higher average baseline depression score was related to declining levels of physical activity at subsequent examinations. CONCLUSION: Reduced physical activity may be a long-term consequence of depression. It is important to address individual changes in physical activity and not merely absolute levels of physical activity in relationship to depression.

Single- and multiple dose pharmacokinetics and multiple dose pharmacodynamics of oral ABT-116 (a TRPV1 antagonist) in dogs.

Six dogs were used to determine single and multiple oral dose pharmacokinetics of ABT-116. Blood was collected for subsequent analysis prior to and at 15, 30 min and 1, 2, 4, 6, 12, 18, and 24 h after administration of a single 30 mg/kg dose of ABT-116. Results showed a half-life of 6.9 h, k(el) of 0.1/h, AUC of 56.5 µg·h/mL, T(max) of 3.7 h, and C(max) of 3.8 µg/mL. Based on data from this initial phase, a dose of 10 mg/kg of ABT-116 (no placebo control) was selected and administered to the same six dogs once daily for five consecutive days. Behavioral observations, heart rate, respiratory rate, temperature, thermal and mechanical (proximal and distal limb) nociceptive thresholds, and blood collection were performed prior to and 4, 8, and 16 h after drug administration each day. The majority of plasma concentrations were above the efficacious concentration (0.23 µg/mL previously determined for rodents) for analgesia during the 24-h sampling period. Thermal and distal limb mechanical thresholds were increased at 4 and 8 h, and at 4, 8, and 16 h respectively, postdosing. Body temperature increased on the first day of dosing. Results suggest adequate exposure and antinociceptive effects of 10 mg/kg ABT-116 following oral delivery in dogs.

Comparative analysis of MAPK and PI3K/AKT pathway activation and inhibition in human and canine melanoma.

The lack of advanced animal models of human cancers is considered a barrier to developing effective therapeutics. Canine and human melanomas are histologically disparate but show similar disease progression and response to therapies. The purpose of these studies was to compare human and canine melanoma tumours and cell lines regarding MAPK and PI3K/AKT signalling dysregulation, and response to select molecularly targeted agents. Pathway activation was investigated via microarray and mutational analysis. Growth inhibition and cell cycle effects were assessed for pathway inhibitors AZD6244 (MAPK) and rapamycin (PI3K/AKT) in human and canine melanoma cells. Human and canine melanoma share similar differential gene expression patterns within the MAPK and PI3K/AKT pathways. Constitutive pathway activation and similar sensitivity to AZD6244 and rapamycin was observed in human and canine cells. These results show that human and canine melanoma share activation and sensitivity to inhibition of cancer-related signalling pathways despite differences in activating mutations.

Development of a limited-sampling model for prediction of doxorubicin exposure in dogs.

Understanding the relationship between drug dose and exposure (pharmacokinetics, PK) and the relationship between exposure and effect (pharmacodynamics) is an important component of pharmacology when attempting to predict clinical effects of anticancer drugs. PK studies can provide a better understanding of these relationships; however, they often involve intensive sampling over an extended period of time, resulting in increased cost and decreased compliance. Doxorubicin (DOX), one of the most widely used antineoplastic agents in veterinary cancer therapy, is characterized by large interpatient variability in overall drug exposure and the development and degree of myelosuppression following equivalent dosages. We have developed and validated a limited-sampling strategy for DOX, in which three blood samples are obtained over 1 h post-treatment, that accurately predicts patient exposure. This strategy could allow for refining of dosing variables and utilization of therapeutic drug monitoring to ensure optimized dosing.

Oral, subcutaneous, and intravenous pharmacokinetics of ondansetron in healthy cats.

Ondansetron is a 5-HT3 receptor antagonist that is an effective anti-emetic in cats. The purpose of this study was to evaluate the pharmacokinetics of ondansetron in healthy cats. Six cats with normal complete blood count, serum biochemistry, and urinalysis received 2 mg oral (mean 0.43 mg/kg), subcutaneous (mean 0.4 mg/kg), and intravenous (mean 0.4 mg/kg) ondansetron in a cross-over manner with a 5-day wash out. Serum was collected prior to, and at 0.25, 0.5, 1, 2, 4, 8, 12, 18, and 24 h after administration of ondansetron. Ondansetron concentrations were measured using liquid chromatography coupled to tandem mass spectrometry. Noncompartmental pharmacokinetic modeling and dose interval modeling were performed. Repeated measures anova was used to compare parameters between administration routes. Bioavailability of ondansetron was 32% (oral) and 75% (subcutaneous). Calculated elimination half-life of ondansetron was 1.84 ± 0.58 h (intravenous), 1.18 ± 0.27 h (oral) and 3.17 ± 0.53 h (subcutaneous). The calculated elimination half-life of subcutaneous ondansetron was significantly longer (P < 0.05) than oral or intravenous administration. Subcutaneous administration of ondansetron to healthy cats is more bioavailable and results in a more prolonged exposure than oral administration. This information will aid management of emesis in feline patients.

Cholesterol in mild cognitive impairment and Alzheimer's disease in a birth cohort over 14 years.

Animal epidemiological and clinical studies suggest that cholesterol is a risk factor for Alzheimer's disease (AD). Nevertheless, the relation of cholesterol to mild cognitive impairment (MCI), influence of APOE genotype and its changes in lifespan is controversial. We investigated the potential impact of plasma total cholesterol (TC) on development of MCI and AD in the interdisciplinary longitudinal study on adult development and aging, a representative birth cohort (born 1930-1932), examined in 1993/1994 (VT1), 1997/1998 (VT2), and 2005/2007 (VT3). Of 500 participants at baseline, 381 survived and were examined at VT3. After exclusion of participants with lifetime prevalence of major psychiatric diseases or mild cognitive disorder due to a medical condition, 222 participants were included in the analysis. At VT3, 82 participants had MCI, 22 participants had AD, and 118 were in good health. Participants with MCI and AD at VT3 evidenced higher TC levels at VT1 than those who were healthy. Higher TC levels at baseline were associated with an increased risk for cognitive disorders at VT3 (highest vs. lowest quartile: OR 2.64, 95 % CI 1.12-6.23, p < 0.05). Over the 14 year follow-up, TC levels declined in those with MCI and AD, but remained stable in those who remained healthy. These findings were not modified by APOE genotype or use of cholesterol-lowering medications. Our findings demonstrate that higher TC levels are observed long before the clinical manifestation of MCI and AD in patients without psychiatric or somatic comorbidities and are independent of APOE genotype.

Endometrial tissue and blood plasma concentration of ceftiofur and metabolites following intramuscular administration of ceftiofur crystalline free acid to mares.

REASONS FOR PERFORMING STUDY: Systemic administration of ceftiofur crystalline free acid (CCFA) may be a potential treatment for infectious endometritis caused by Streptococcus equi ssp. zooepidemicus (S. zooepidemicus) and other susceptible bacterial organisms in the mare. OBJECTIVE: To determine if i.m. administration of CCFA at the label dose will exceed the minimum inhibitory concentration (MIC) of S. zooepidemicus in the endometrium following single administration and multiple administration protocols. STUDY DESIGN: Experimental pharmacokinetic study. METHODS: Three mares (Group 1) were administered a single i.m. dose of CCFA (6.6 mg/kg bwt) and blood and endometrial biopsies were collected at selected intervals for 144 h. Six additional mares (Groups 2 and 3) received CCFA at times 0, 4, 11 and 18 days, and were sampled at predetermined times for 25 or 49 days, respectively. Plasma and tissue samples were analysed by high-pressure liquid chromatography with tandem mass spectrometry for desfuroylceftiofur acetamide concentration, which is a direct measure of all ceftofur and ceftiofur metabolites in the sample. RESULTS: A mean plasma desfuroylceftiofur acetamide concentration of 0.367 ± 0.0162 µg/ml (mean ± s.e.) was detected at 96 h following administration. Mean endometrial tissue concentration was 0.510 ± 0.0418 µg/g at 96 h and exceeded the MIC for S. zooepidemicus (0.25 µg/ml) throughout the 144 h monitoring period for Group 1. Mares in Groups 2 and 3, given multiple doses of CCFA, maintained plasma concentrations above the MIC for S. zooepidemicus for 25 days. Endometrial tissue levels remained above the MIC at most data collection points for 25 days. CONCLUSIONS: Ceftiofur crystalline free acid reaches appropriate endometrial tissue values to exceed the MIC of S. zooepidemicus, a common cause of bacterial endometritis. Therefore, CCFA should be effective in the treatment of equine bacterial endometritis caused by S. zooepidemicus and other susceptible bacterial pathogens in the mare.

Squeezed quadrature fluctuations in a gravitational wave detector using squeezed light.

Squeezed states of light are an important tool for optical measurements below the shot noise limit and for optical realizations of quantum information systems. Recently, squeezed vacuum states were deployed to enhance the shot noise limited performance of gravitational wave detectors. In most practical implementations of squeezing enhancement, relative fluctuations between the squeezed quadrature angle and the measured quadrature (sometimes called squeezing angle jitter or phase noise) are one limit to the noise reduction that can be achieved. We present calculations of several effects that lead to quadrature fluctuations, and use these estimates to account for the observed quadrature fluctuations in a LIGO gravitational wave detector. We discuss the implications of this work for quantum enhanced advanced detectors and even more sensitive third generation detectors.

Integrating expert judgment in veterinary epidemiology: example guidance for disease freedom surveillance.

Expert opinions supplement empirical data in many epidemiologic assessments. For veterinary disease freedom surveillance, where the geographic scope of concern is often broad, populations subject to change, decisions eminent and empirical data, expert opinion can be a critical component of the decision making process. However, opinion is by definition subjective and the manner in which opinion is sought can impact the quality and reliability of estimates. Group interaction can hinder or improve the estimation process, depending on its facilitation. Further, whether and how validation is conducted can limit or increase acceptance of the resulting model. While the utility of expert opinion is widely recognized in many fields, and the impact of its use or misuse implicit, standards for application to veterinary assessments are not readily available. This paper aims to foster discussion on this influential component of epidemiology, with disease freedom application as a focus. Benefits and concerns attributed to expert judgment and guidelines for its structured elicitation are described, borrowing insights from its long history of use in decision science fields and examples from recent veterinary assessments.

Milk thistle and its derivative compounds: a review of opportunities for treatment of liver disease.

Milk thistle extracts have been used as a "liver tonic" for centuries. In recent years, silibinin, the active ingredient in milk thistle extracts, has been studied both in vitro and in vivo to evaluate the beneficial effects in hepatic disease. Silibinin increases antioxidant concentrations and improves outcomes in hepatic diseases resulting from oxidant injury. Silibinin treatment has been associated with protection against hepatic toxins, and also has resulted in decreased hepatic inflammation and fibrosis. Limited information currently is available regarding silibinin use in veterinary medicine. Future study is justified to evaluate dose, kinetics, and treatment effects in domestic animals.