IMPACT OF REAL-LIFE ENVIRONMENTAL EXPOSURES ON REPRODUCTION: Biosolids and male reproduction.

Over the past 50 years, there has been a concerning decline in male reproductive health and an increase in male infertility which is now recognised as a major health concern globally. While male infertility can be linked to some genetic and lifestyle factors, these do not fully explain the rate of declining male reproductive health. Increasing evidence from human and animal studies suggests that exposure to chemicals found ubiquitously in the environment may in part play a role. Many studies on chemical exposure, however, have assessed the effects of exposure to individual environmental chemicals (ECs), usually at levels not relevant to everyday human exposure. There is a need for study models which reflect the 'real-life' nature of EC exposure. One such model is the biosolids-treated pasture (BTP) sheep model which utilises biosolids application to agricultural land to examine the effects of exposure to low-level mixtures of chemicals. Biosolids are the by-product of the treatment of wastewater from industrial and domestic sources and so their composition is reflective of the ECs to which humans are exposed. Over the last 20 years, the BTP sheep model has published multiple effects on offspring physiology including consistent effects on the male reproductive system in fetal, neonatal, juvenile, and adult offspring. This review focuses on the evidence from these studies which strongly suggests that low-level EC exposure during gestation can alter several components of the male reproductive system and highlights the BTP model as a more relevant model to study real-life EC exposure effects.

In vitro PK/PD modeling of tyrosine kinase inhibitors in non-small cell lung cancer cell lines.

Tyrosine kinase inhibitors (TKIs) are routinely prescribed for the treatment of non-small cell lung cancer (NSCLC). As with all medications, patients can experience adverse events due to TKIs. Unfortunately, the relationship between many TKIs and the occurrence of certain adverse events remains unclear. There are limited in vivo studies which focus on TKIs and their effects on different regulation pathways. Many in vitro studies, however, that investigate the effects of TKIs observe additional changes, such as changes in gene activations or protein expressions. These studies could potentially help to gain greater understanding of the mechanisms for TKI induced adverse events. However, in order to utilize these pathways in a pharmacokinetic/pharmacodynamic (PK/PD) framework, an in vitro PK/PD model needs to be developed, in order to characterize the effects of TKIs in NSCLC cell lines. Through the use of ordinary differential equations, cell viability data and nonlinear mixed effects modeling, an in vitro TKI PK/PD model was developed with estimated PK and PD parameter values for the TKIs alectinib, crizotinib, erlotinib, and gefitinib. The relative standard errors for the population parameters are all less than 25%. The inclusion of random effects enabled the model to predict individual parameter values which provided a closer fit to the observed response. It is hoped that this model can be extended to include in vitro data of certain pathways that may potentially be linked with adverse events and provide a better understanding of TKI-induced adverse events.

Reliability of isokinetic decay slope is superior to using fatigue indices for shoulder horizontal abduction.

INTRODUCTION: Reliable and valid measurements for shoulder muscular endurance should be available for clinical use. The posterior shoulder endurance test offers a potential clinical assessment, but its construct validity isn't available. Since a criterion measure of muscular endurance is not available, this study's purpose was to determine a reliable method for testing shoulder muscular endurance using an isokinetic dynamometer. METHODS: The test-retest reliability, standard error measurement, and minimal detectable change were calculated on four different paradigms to quantify muscular fatigue using two isokinetic speeds (60°sec-1,180°sec-1). Calculation paradigms included peak torque fatigue index (FI), average torque FI, area-under-the-curve FI, and peak torque decay slope. Testing occurred on two days. Repeated measures analysis of variance compared the two peak torque decay slopes across both testing days. RESULTS: Superior reliability was found within the decay slope measurements at both 60°sec-1 (ICC = 0.941) and 180°sec-1 (ICC = 0.764) speeds, with the 60°sec-1 decay slope being the highest reliability between the two angular velocities. There was a greater amount of fatigue in the 60°sec-1 decay slope compared to the 180°sec-1 decay slope. CONCLUSION: Using the decay slope of isokinetic shoulder horizontal abduction at 60°sec-1 is a reliable method to validate other muscular endurance clinical measures. Rehabilitation specialists should utilize the decay slope of the isokinetic dynamometry to monitor responsiveness.

Prolactin Mediates Long-Term, Seasonal Rheostatic Regulation of Body Mass in Female Mammals.

A series of well-described anabolic and catabolic neuropeptides are known to provide short-term, homeostatic control of energy balance. The mechanisms that govern long-term, rheostatic control of regulated changes in energy balance are less well characterized. Using the robust and repeatable seasonal changes in body mass observed in Siberian hamsters, this report examined the role of prolactin in providing long-term rheostatic control of body mass and photoinduced changes in organ mass (ie, kidney, brown adipose tissue, uterine, and spleen). Endogenous circannual interval timing was observed after 4 months in a short photoperiod, indicated by a significant increase in body mass and prolactin mRNA expression in the pituitary gland. There was an inverse relationship between body mass and the expression of somatostatin (Sst) and cocaine- and amphetamine-regulated transcript (Cart). Pharmacological inhibition of prolactin release (via bromocriptine injection), reduced body mass of animals maintained in long photoperiods to winter-short photoperiod levels and was associated with a significant increase in hypothalamic Cart expression. Administration of ovine prolactin significantly increased body mass 24 hours after a single injection and the effect persisted after 3 consecutive daily injections. The data indicate that prolactin has pleiotropic effects on homeostatic sensors of energy balance (ie, Cart) and physiological effectors (ie, kidney, BAT). We propose that prolactin release from the pituitary gland acts as an output signal of the hypothalamic rheostat controller to regulate adaptive changes in body mass.

A systematic review of the measurement properties of the Pennsylvania Shoulder Score.

BACKGROUND: Pennsylvania Shoulder Score (PSS) is a patient-reported outcome measure (PROM) that is gaining use when examining shoulder-specific outcomes. To date, a systematic review of the PSS measurement properties has not been published. PURPOSE: To systematically locate, appraise, and synthesize the evidence concerning the measurement properties of the PSS. STUDY DESIGN: Systematic literature review. METHODS: A pair of raters conducted a literature search using pre-defined keywords from 5 databases (PubMed, CINAHL, SPORTdiscus, PsychINFO, Scopus) during the week of October 23, 2022. Critical appraisal of study design for psychometric articles was used to assess methodological quality and risk of bias. Measurement property data were synthesized with pooled estimates for the indices of test-retest reliability (ICC), standard error of measurement (SEM), minimal detectable change (MDC), Cronbach α (CA), effect size (ES), and standardized response means (SRM) calculated from applicable studies. RESULTS: A total of 13 articles met the inclusion criteria for this review. Methodological quality was agreed upon between the 2 raters with a weighted kappa of 0.77, and 9/13 of the articles were rated above 70%. Test-retest reliability of the PSS total score ranged between 0.90 and 0.94, and construct validity was high when compared to other shoulder-specific PROMs (0.75 < r > 0.96). Responsiveness of the PSS was large across all studies with few PSS subscales dropping to moderate. Pooled MDC90 of the total PSS was 12.13 points, and the pooled ES of the total PSS was 0.85. CONCLUSIONS: The scope of this review demonstrates positive measurement properties of the PSS as a reliable, valid, and responsive measurement of shoulder-specific PROM. However, there are few studies examining the measurement properties of the PSS and more research is needed to assess cross-cultural appropriateness and factor analysis of the questions contained in the PSS.

Preconceptional and in utero exposure of sheep to a real-life environmental chemical mixture disrupts key markers of energy metabolism in male offspring.

Over recent decades, an extensive array of anthropogenic chemicals have entered the environment and have been implicated in the increased incidence of an array of diseases, including metabolic syndrome. The ubiquitous presence of these environmental chemicals (ECs) necessitates the use of real-life exposure models to the assess cumulative risk burden to metabolic health. Sheep that graze on biosolids-treated pastures are exposed to a real-life mixture of ECs such as phthalates, per- and polyfluoroalkyl substances, heavy metals, pharmaceuticals, pesticides, and metabolites thereof, and this EC exposure can result in metabolic disorders in their offspring. Using this model, we evaluated the effects of gestational exposure to a complex EC mixture on plasma triglyceride (TG) concentrations and metabolic and epigenetic regulatory genes in tissues key to energy regulation and storage, including the hypothalamus, liver, and adipose depots of 11-month-old male offspring. Our results demonstrated a binary effect of EC exposure on gene expression particularly in the hypothalamus. Principal component analysis revealed two subsets (B-S1 [n = 6] and B-S2 [n = 4]) within the biosolids group (B, n = 10), relative to the controls (C, n = 11). Changes in body weight, TG levels, and in gene expression in the hypothalamus, and visceral and subcutaneous fat were apparent between biosolid and control and the two subgroups of biosolids animals. These findings demonstrate that gestational exposure to an EC mixture results in differential regulation of metabolic processes in adult male offspring. Binary effects on hypothalamic gene expression and altered expression of lipid metabolism genes in visceral and subcutaneous fat, coupled with phenotypic outcomes, point to differences in individual susceptibility to EC exposure that could predispose vulnerable individuals to later metabolic dysfunction.

Reliability, accuracy, and minimal detectable difference of a mixed concept marker set for finger kinematic evaluation.

The study of finger biomechanics requires special tools for accurately recording finger joint data. A marker set to evaluate finger postures during activities of daily living is needed to understand finger biomechanics in order to improve prosthesis design and clinical interventions. The purpose of this study was to evaluate the reliability of a proposed hand marker set (the Warwick marker set) to capture finger kinematics using motion capture. The marker set consisted of the application of two and three marker clusters to the fingers of twelve participants who participated in the tests across two sessions. Calibration markers were applied using a custom palpation technique. Each participant performed a series of range of motion movements and held a set of objects. Intra and inter-session reliability was calculated as well as Standard Error of Measurement (SEM) and Minimal Detectable Difference (MDD). The findings showed varying levels of intra- and inter-session reliability, ranging from poor to excellent. The SEM and MDD values were lower for the intra-session range of motion and grasp evaluation. The reduced reliability can potentially be attributed to skin artifacts, differences in marker placement, and the inherent kinematic variability of finger motion. The proposed marker set shows potential to assess finger postures and analyse activities of daily living, primarily within the context of single session tests.

Coin-Shaped Opacities in the Stomach.

On day 7 after hospital admission, a patient with end-stage kidney disease prescribed sevelamer, hydrocodone-acetaminophen, hydromorphone, and chewable lanthanum tablets developed intermittent apneic episodes, bilateral rhonchi, and responsiveness to verbal commands only with deep painful stimulus; a chest radiograph showed 4 radio-opaque coin-shaped opacities in the stomach. What is the diagnosis and what would you do next?

Sexually dimorphic impact of preconceptional and gestational exposure to a real-life environmental chemical mixture (biosolids) on offspring growth dynamics and puberty in sheep.

Humans are ubiquitously exposed to complex mixtures of environmental chemicals (ECs). This study characterised changes in post-natal and peripubertal growth, and the activation of the reproductive axis, in male and female offspring of sheep exposed to a translationally relevant EC mixture (in biosolids), during pregnancy. Birthweight in both sexes was unaffected by gestational biosolids exposure. In contrast to females (unaffected), bodyweight in biosolids males was significantly lower than controls across the peripubertal period, however, they exhibited catch-up growth eventually surpassing controls. Despite weighing less, testosterone concentrations were elevated earlier, indicative of early puberty in the biosolids males. This contrasted with females in which the mean date of puberty (first progesterone cycle) was delayed. These results demonstrate that developmental EC-mixture exposure has sexually dimorphic effects on growth, puberty and the relationship between body size and puberty. Such programmed metabolic/reproductive effects could have significant impacts on human health and wellbeing.

Defining optimal thresholds for digital Brix refractometry to determine IgG concentration in ewe colostrum and lamb serum in Scottish lowland sheep flocks.

This research aimed to define thresholds for ewe colostrum and lamb serum Brix refractometer measurements in lowland Scottish sheep. This would facilitate the use of this convenient, sheep-side test, enabling quick and accurate identification of poor quality colostrum and prevention of failure of transfer of passive immunity (FTPI) in lambs. Secondary aims were to identify risk factors for poor colostrum quality and FTPI in lambs. Serum samples (n = 233) were collected from lambs between 24 and 48hrs after birth, from four lowland Scottish meat sheep farms. Pre-suckle colostrum samples (n = 112) were also collected from ewes on two of these farms. Farmers provided information on litter size, ewe body condition score, ewe breed and dystocia. Duplicate digital Brix refractometer measurements were compared with immunoglobulin G (IgG) radial immunodiffusion (RID) testing for all colostrum and serum samples. Receiver operating characteristic (ROC) curves were used to redefine thresholds for Brix testing in colostrum and serum. Linear regression models were constructed with colostrum and serum IgG concentration as the outcomes of interest. Colostrum and serum IgG concentrations were highly variable. The prevalence of inadequate colostrum quality (using <50 g/L IgG on RID) was 4.5% (95% CI = 1.5 - 10.1) and the prevalence of FTPI (using <15 g/L IgG in serum on RID) was 7.73% (95% CI = 4.64-11.93). A ewe's colostrum IgG concentration was significantly and positively associated with the serum IgG concentration of her lamb(s) (p = 0.02). ROC analysis defined a Brix threshold for adequate colostrum quality of > 22.10% (sensitivity 80% (95%CI=28.4-99.5), specificity 90% (95%CI=82.3-94.8)). ROC analysis defined a Brix threshold for serum of > 8.65% for adequate passive transfer of immunity in Scottish lambs (sensitivity 94% (95%CI=72.7-99.8), specificity 82% (95%CI=76.6-87.2)). To optimise passive transfer of immunity in lambs, we suggest that ewe colostrum Brix measurements be defined as 'poor' (<22%); 'fair' (22-26%) and 'good' (>26%); and lamb serum as 'poor' (<8%); 'fair' (8-9%) and 'good' (>9%). It is recommended that these tests are used as for flock screening, using samples from multiple animals.

Analysis of Protein Biomarkers From Hospitalized COVID-19 Patients Reveals Severity-Specific Signatures and Two Distinct Latent Profiles With Differential Responses to Corticosteroids.

OBJECTIVES: To identify and validate novel COVID-19 subphenotypes with potential heterogenous treatment effects (HTEs) using electronic health record (EHR) data and 33 unique biomarkers. DESIGN: Retrospective cohort study of adults presenting for acute care, with analysis of biomarkers from residual blood collected during routine clinical care. Latent profile analysis (LPA) of biomarker and EHR data identified subphenotypes of COVID-19 inpatients, which were validated using a separate cohort of patients. HTE for glucocorticoid use among subphenotypes was evaluated using both an adjusted logistic regression model and propensity matching analysis for in-hospital mortality. SETTING: Emergency departments from four medical centers. PATIENTS: Patients diagnosed with COVID-19 based on International Classification of Diseases , 10th Revision codes and laboratory test results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Biomarker levels generally paralleled illness severity, with higher levels among more severely ill patients. LPA of 522 COVID-19 inpatients from three sites identified two profiles: profile 1 ( n = 332), with higher levels of albumin and bicarbonate, and profile 2 ( n = 190), with higher inflammatory markers. Profile 2 patients had higher median length of stay (7.4 vs 4.1 d; p < 0.001) and in-hospital mortality compared with profile 1 patients (25.8% vs 4.8%; p < 0.001). These were validated in a separate, single-site cohort ( n = 192), which demonstrated similar outcome differences. HTE was observed ( p = 0.03), with glucocorticoid treatment associated with increased mortality for profile 1 patients (odds ratio = 4.54). CONCLUSIONS: In this multicenter study combining EHR data with research biomarker analysis of patients with COVID-19, we identified novel profiles with divergent clinical outcomes and differential treatment responses.

Developmental exposure to a real-life environmental chemical mixture alters testicular transcription factor expression in neonatal and pre-pubertal rams, with morphological changes persisting into adulthood.

Environmental chemical (EC) exposure may be impacting male reproductive health. The translationally relevant biosolids treated pasture (BTP) sheep model was used to investigate gestational low-level EC mixture exposure on the testes of F1 male offspring. Adult rams from ewes exposed to BTP 1 month before and throughout pregnancy had more seminiferous tubules with degeneration and depletion of elongating spermatids, indicating possible "recovery" from previously reported testicular dysgenesis syndrome-like phenotype in neonatal and pre-pubertal BTP lambs. Expression of transcription factors CREB1 (neonatal) and BCL11A and FOXP2 (pre-pubertal) were significantly higher in the BTP exposed testes, with no changes seen in adults. Increased CREB1, which is crucial for testes development and regulation of steroidogenic enzymes, could be an adaptive response to gestational EC exposure to facilitate the phenotypic recovery. Overall, this demonstrates that testicular effects from gestational exposure to low-level mixtures of ECs can last into adulthood, potentially impacting fertility and fecundity.

Body surface temperature of rats reveals both magnitude and sex differences in the acute stress response.

Understanding how biological markers of stress relate to stressor magnitude is much needed and can be used in welfare assessment. Changes in body surface temperature can be measured using infrared thermography (IRT) as a marker of a physiological response to acute stress. While an avian study has shown that changes in body surface temperature can reflect the intensity of acute stress, little is known about surface temperature responses to stressors of different magnitudes and its sex-specificity in mammals, and how they correlate with hormonal and behavioural responses. We used IRT to collect continuous surface temperature measurements of tail and eye of adult male and female rats (Rattus norvegicus), for 30 minutes after exposure to one of three stressors (small cage, encircling handling or rodent restraint cone) for one minute, and cross-validated the thermal response with plasma corticosterone (CORT) and behavioural assessment. To obtain individual baseline temperatures and thermal responses to stress, rats were imaged in a test arena (to which they were habituated) for 30 seconds before and 30 minutes after being exposed to the stressor. In response to the three stressors, tail temperature initially decreased and then recovered to, or overshot the baseline temperature. Tail temperature dynamics differed between stressors; being restrained in the small cage was associated with the smallest drop in temperature, in male rats, and the fastest thermal recovery, in both sexes. Increases in eye temperature only distinguished between stressors early in the response and only in females. The post stressor increase in eye temperature was greater in the right eye of males and the left eye of females. In both sexes encircling may have been associated with the fastest increase in CORT. These results were in line with observed behavioural changes, with greater movement in rats exposed to the small cage and higher immobility after encircling. The female tail and eye temperature, as well as the CORT concentrations did not return to pre-stressor levels in the observation period, in conjunction with the greater occurrence of escape-related behaviours in female rats. These results suggest that female rats are more vulnerable to acute restraint stress compared to male rats and emphasise the importance of using both sexes in future investigations of stressor magnitude. This study demonstrates that acute stress induced changes in mammalian surface temperature measured with IRT relate to the magnitude of restraint stress, indicate sex differences and correlate with hormonal and behavioural responses. Thus, IRT has the potential to become a non-invasive method of continuous welfare assessment in unrestrained mammals.

Human health risk surveillance of polychlorinated biphenyls in bovine milk from alluvial plain of Punjab, Pakistan.

Punjab is the leading province of Pakistan in the production of bovine milk and its consumption. Rapid industrialization, high energy demand, and the production of waste have increased the risk of polychlorinated biphenyls (PCBs) toxicity in the environment. This research work was designed to assess human dietary exposure of ∑PCBs17 congeners through ingestion of buffalo and cow's milk from eight main districts of Punjab, Pakistan. The average concentrations of ∑DL-PCBs (8.74 ng g-1 and 14.60 ng g-1) and ∑I-PCBs (11.54 ng g-1 and 18.68 ng g-1) in buffalo and cow milk samples were analyzed, respectively. The PCB-156 was predominantly high congener found in both buffalo (2.84 ng g-1) and cow milk (2.86 ng g-1). It was found that the highest PCBs in bovine milk samples were observed in close vicinities of urban and industrial areas. The estimated daily consumptions of DL-PCBs and I-PCBs, from buffalo and cow milk, were below the acceptable daily intake for both adults and children. Moreover, hazard quotients (HQ) of the ∑PCBs17 congener value were less than 1.0 in adults and greater in the case of children reflecting the high chances of cancer. Furthermore, comprehensive monitoring for childhood cancer is recommended to establish the relationship in future studies.

Associations between cow-level parameters and heart rate variability as a marker of the physiological stress response in dairy cows.

To maintain and enhance cow productivity and welfare, it is important that we can accurately assess and understand how cows respond to the physiological demands of gestation and lactation. Several methods have been developed for assessing the physiological responses to stressors and for detecting distress in cattle. Heart rate (HR) variability (HRV) is a non-invasive measure of autonomic nervous system activity and consequently a component of the physiological response to stress. In cattle, HRV has been successfully used to measure autonomic responses to a variety of health conditions and management procedures. The objectives of this study were to determine whether, among commercial Holstein Friesian cows and across farms, relationships exist between cow-level factors, HR and HRV. HRV parameters were compared with production records for 170 randomly selected, Holstein-Friesian-cows on 3 commercial dairy farms. Production data included parity, days in milk (DIM), milk yield, somatic cell count (SCC), % butterfat and protein, body condition score (BCS) and genetic indices. Fixed-effect, multivariable linear regression models were constructed to examine the association between cow-level variables and HRV parameters. Statistically significant relationships were found between HR and farm, temperature and BCS, and between HRV parameters and farm, rectal temperature, BCS, DIM, and percentage butterfat. Given the significant association between farms and several of the indices measured, it is recommended that care must be taken in the interpretation of HRV studies that are conducted on animals from a single farm. The current study indicated that within clinically normal dairy cattle HRV differed with the percentage of butterfat and BCS. Based on the relationships reported previously between HRV and stress in dairy cattle these results suggest that stress may be increased early in lactation, in cows with BCS <2.75 that are producing a high percentage of butterfat milk. Future work could focus on the physiological mechanisms through which these factors and their interactions alter HRV and how such physiological stress may be managed within a commercial farm setting.

Critical review and analysis of literature on low dose exposure to chemical mixtures in mammalian in vivo systems.

Anthropogenic chemicals are ubiquitous throughout the environment. Consequentially, humans are exposed to hundreds of anthropogenic chemicals daily. Current chemical risk assessments are primarily based on testing individual chemicals in rodents at doses that are orders of magnitude higher than that of human exposure. The potential risk from exposure to mixtures of chemicals is calculated using mathematical models of mixture toxicity based on these analyses. These calculations, however, do not account for synergistic or antagonistic interactions between co-exposed chemicals. While proven examples of chemical synergy in mixtures at low doses are rare, there is increasing evidence that, through non-conformance to current mixture toxicity models, suggests synergy. This review examined the published studies that have investigated exposure to mixtures of chemicals at low doses in mammalian in vivo systems. Only seven identified studies were sufficient in design to directly examine the appropriateness of current mixture toxicity models, of which three showed responses significantly greater than additivity model predictions. While the remaining identified studies were unable to provide evidence of synergistic toxicity, it became apparent that many results of such studies were not always explicable by current mixture toxicity models. Additionally, two data gaps were identified. Firstly, there is a lack of studies where individual chemical components of a complex mixture (>10 components) are tested in parallel to the chemical mixture. Secondly, there is a lack of dose-response data for mixtures of chemicals at low doses. Such data is essential to address the appropriateness and validity of future chemical mixture toxicity models.

Developmental exposure to real-life environmental chemical mixture programs a testicular dysgenesis syndrome-like phenotype in prepubertal lambs.

Current declines in male reproductive health may, in part, be driven by anthropogenic environmental chemical (EC) exposure. Using a biosolids treated pasture (BTP) sheep model, this study examined the effects of gestational exposure to a translationally relevant EC mixture. Testes of 8-week-old ram lambs from mothers exposed to BTP during pregnancy contained fewer germ cells and had a greater proportion of Sertoli-cell-only seminiferous tubules. This concurs with previous published data from fetuses and neonatal lambs from mothers exposed to BTP. Comparison between the testicular transcriptome of biosolids lambs and human testicular dysgenesis syndrome (TDS) patients indicated common changes in genes involved in apoptotic and mTOR signalling. Gene expression data and immunohistochemistry indicated increased HIF1α activation and nuclear localisation in Leydig cells of BTP exposed animals. As HIF1α is reported to disrupt testosterone synthesis, these results provide a potential mechanism for the pathogenesis of this testicular phenotype, and TDS in humans.

Urinary 11-dehydrothromboxane B2 concentrations in 20 dogs with primary immune-mediated hemolytic anemia.

BACKGROUND: Thromboembolic disease is a major cause of mortality in dogs with immune-mediated hemolytic anemia (IMHA). At present, no reliable biomarkers of individual patient thrombotic risk are available. In human medicine, increased urinary thromboxane concentrations have utility as markers of prothrombotic tendency in various situations. HYPOTHESIS/OBJECTIVES: First, to determine if urinary 11-dehydrothromboxane B2 (u11-dTXB) concentrations are increased in dogs with primary IMHA compared to normal dogs; second, to assess whether u11-dTXB concentration is associated with survival, known prognostic indicators, or frequency of thrombosis in dogs with IMHA. ANIMALS: Twenty client-owned dogs diagnosed with primary IMHA and 17 healthy dogs volunteered by hospital staff. METHODS: Prospective case-control study. A previously validated ELISA was used to measure urine 11-dTXB concentrations, which were normalized to urine creatinine concentration (u11-dTXB:Cr). Samples were obtained at presentation from patients with primary IMHA. Standard clincopathological data at baseline and survival data were collected. Urinary 11-dTXB:Cr was compared between outcome subgroups, and correlated with known markers of disease severity. RESULTS: Baseline u11-dTXB:Cr was significantly higher in dogs with IMHA than in healthy dogs (median, 3.75; range, 0.83-25.36 vs 0.65; 0.24-2.57; P = .003) but did not differ between dogs with IMHA that survived and did not survive to 30 days after presentation, nor between dogs with and without clinical suspicion of thrombotic disease. CONCLUSIONS AND CLINICAL IMPORTANCE: Urinary 11-dTXB:Cr is increased in dogs with IMHA compared to healthy controls, consistent with a prothrombotic state. However, in this IMHA population u11-dTXB:Cr was not associated with survival or suspected thrombosis.

Gonadotropin-releasing hormone (GnRH) measurements in pituitary portal blood: A history.

Much about the neuroendocrine control of reproduction is inferred from changes in the episodic release of luteinizing hormone (LH), as measured in samples of peripheral blood. This, however, assumes that LH precisely mirrors gonadotropin-releasing hormone (GnRH) release from the hypothalamus. Because GnRH is not measurable in peripheral blood, characterization of the relationship between these two hormones required the simultaneous measurement of GnRH and LH in pituitary portal and peripheral blood, respectively. Here, we review the history of why and how portal blood collection was developed, the aspects of the true output of the central component of the hypothalamic-pituitary-gonadal axis that this methodology helped clarify, and conditions under which the pituitary fails to serve as an adequate bioassay for the release pattern of GnRH.

Imputing Biomarker Status from RWE Datasets-A Comparative Study.

Missing data is a universal problem in analysing Real-World Evidence (RWE) datasets. In RWE datasets, there is a need to understand which features best correlate with clinical outcomes. In this context, the missing status of several biomarkers may appear as gaps in the dataset that hide meaningful values for analysis. Imputation methods are general strategies that replace missing values with plausible values. Using the Flatiron NSCLC dataset, including more than 35,000 subjects, we compare the imputation performance of six such methods on missing data: predictive mean matching, expectation-maximisation, factorial analysis, random forest, generative adversarial networks and multivariate imputations with tabular networks. We also conduct extensive synthetic data experiments with structural causal models. Statistical learning from incomplete datasets should select an appropriate imputation algorithm accounting for the nature of missingness, the impact of missing data, and the distribution shift induced by the imputation algorithm. For our synthetic data experiments, tabular networks had the best overall performance. Methods using neural networks are promising for complex datasets with non-linearities. However, conventional methods such as predictive mean matching work well for the Flatiron NSCLC biomarker dataset.