Andrew P. Woodward

While most cases of human muscle-invasive bladder cancer (MIBC) are diagnosed as conventional urothelial carcinoma (UC), there is growing recognition of histologic subtypes and divergent differentiation within conventional UC. In this study, 31 dogs with UC (33 slides) were evaluated for histologic subtypes and divergent differentiation, as specified by the recent World Health Organization update on the classification of urinary bladder cancers. Slides were reviewed by a medical uropathologist and 3 board-certified veterinary pathologists and assessed for expression of uroplakin III, vimentin, and E-cadherin. All tumors were classified as UC. Fifteen cases were identified as conventional UC. Among the remainder, 8 displayed glandular differentiation, 4 were classified as sarcomatoid UC, 2 showed squamous differentiation, 1 case was classified as a large nested subtype, and 1 case was classified as a tubular/microcystic subtype. This study found a higher frequency of certain histologic subtypes and divergent differentiation in canine UC, particularly sarcomatoid UC and UC with glandular differentiation, compared to previous reports of both canine UC and human MIBC. The relatively high prevalence of the sarcomatoid UC and UC with glandular differentiation in dogs observed in this study suggests that canine UC may serve as a valuable translational model for evaluating novel therapeutic agents, particularly for these rare and aggressive subtypes in humans.

Approximately 25% of human urothelial carcinoma (UC) cases progress to high-grade, muscle-invasive bladder cancer (MIBC), for which treatment response rema

Antimicrobial therapy is informed by quantitative models of drug disposition and action. These models utilize experimental and observational evidence, subject to uncertainties, to support drug selection and dosage regimen optimization, and interpret antimicrobial resistance data. The framework includes multiple components, which characterize mechanisms contributing to therapeutic outcome. The components must be combined in a logical sequence to generate predictions, so propagation of uncertainty is a critical consideration. Quantitative evaluation of this uncertainty has received apparently little attention. This essay argues for the importance of uncertainty quantification in antimicrobial pharmacology. The impact of parameter uncertainties and measurement errors on the validity of pharmacokinetic-pharmacodynamic modelling of antimicrobials is described. Major components of the modelling workflow are assessed, and uncertainties characterized. The influence of major design and statistical analysis decisions at each step is emphasized. Finally, using detailed simulations, the impact of these sources of uncertainty on outcomes including clinical breakpoints and dose individualization is illustrated. Measurement of antimicrobial potency as the minimum inhibitory concentration contributes approximately twofold error, which is important for individual dose determination. Interpretation of PK/PD parameters is generally conducted dichotomously as thresholds, which are empirically determined, and subject to error. Parameter uncertainties in the exposure-response relationship are potentially substantial, and contribute apparently major uncertainty to predictions at both population and individual levels. The importance of uncertainty in pharmacokinetics appears context-sensitive. Applications including dose optimization or susceptibility breakpoints appear overly confident, and point estimation from these models may be an unreliable basis for decision making. These observations highlight the importance of uncertainty quantification for rigorous antimicrobial pharmacology.

The integrative influence of heat acclimation (HA) protocol characteristics and approach on adaptation kinetics and exercise capacity/performance in the heat remains unclear. Bayesian multilevel regression models were used to estimate adaptations with the number of exposures, exposure duration, ambient temperature, water vapor pressure, and HA approach (e.g., constant workrate) as predictors. Data from 211 papers were included in meta‐analyses with results presented as posterior means and 90% credible intervals. Mean protocol characteristics were as follows: 8 ± 4 exposures, 90 ± 36 min/exposure, 39.1°C ± 4.8°C, and 2.78 ± 0.83 kPa. HA decreased resting (−5 beats·min⁻¹ [−7, −3]) and end‐exercise heart rate (−17 beats·min⁻¹ [−19, −14]), resting (−0.19°C [−0.23, −0.14]) and end‐exercise core temperature (−0.43°C [−0.48, −0.36]), and expanded plasma volume (5.6% [3.8, 7.0]). HA also lowered exercise metabolic rate (−87 mL·min⁻¹ [−126, −49]), increased whole‐body sweat rate (WBSR) (163 mL·h⁻¹ [94, 226]), time to exhaustion (49% [35, 61]) and incremental exercise time (14% [7, 24]), and improved time trial performance (3.1% [1.8, 4.5]). An additional HA exposure increased hemoglobin mass (1.9 g [0.6, 3.2]) and WBSR (9 mL·h⁻¹ [1, 17]), and an additional 15 min/exposure further lowered end‐exercise core temperature (−0.04°C [−0.05, −0.03]) and expanded plasma volume (0.4% [0.1, 0.7]). A 5°C increase in ambient temperature further lowered end‐exercise HR (−2 beats·min⁻¹ [−3, −1]) and a 1 kPa increase enhanced WBSR (37 mL·h⁻¹ [4, 72]). End‐exercise heart rate and core temperature decreased similarly following controlled hyperthermia (−16 beats·min⁻¹ [−18, −14]; −0.43°C [−0.48, −0.36]) and constant workrate HA (−17 beats·min⁻¹ [−18, −16]; −0.45°C [−0.49, −0.42]). HA protocol characteristics influence the adaptive response and may be manipulated to optimize adaptations. A predictor for estimating HA adaptations based on protocol characteristics is available at: https://www.canberra.edu.au/research/centres/uc‐rise/research/environmental‐physiology/exercise‐heat‐acclimation‐predictor.

The histologic and molecular heterogeneity of human muscle-invasive bladder cancer (MIBC) is a major contributor to poor treatment outcomes. While most cases of MIBC are diagnosed as conventional urothelial carcinoma (UC), there is growing recognition of histologic subtypes and divergent differentiation within conventional UC. This is clinically significant, as some require modification of therapy and some are associated with more aggressive behavior. Spontaneously occurring UC in dogs has been shown to exhibit histologic and molecular features that closely resemble those of human MIBC. In this study, we evaluated 31 canine UC tumor samples for histologic subtypes and divergent differentiation. Slides were reviewed by a human uropathologist and three board-certified veterinary pathologists and assessed for expression of uroplakin III and E-cadherin. All tumors were classified as high-grade UC. Fifteen cases were identified as conventional UC. Among the remainder, eight displayed glandular differentiation, four were classified as sarcomatoid UC, two showed squamous differentiation, and one case each was classified as large nested and tubular and microcystic subtypes. In summary, this study found a higher frequency of certain histologic subtypes and divergent differentiation in canine UC—particularly sarcomatoid UC and UC with glandular differentiation—compared to previous reports in both canine UC and human MIBC. Conclusion The relatively high prevalence of the sarcomatoid UC subtype in dogs observed in this study suggests that canine UC may serve as a valuable translational model for evaluating novel therapeutic agents, particularly for this rare and aggressive variant in humans.

Changes in bone metabolism occur to meet the varying demands for calcium during pregnancy and lactation. These changes are regulated locally and systemically by a variety of factors, including hormones, cytokines, chemokines, and growth factors. The goal of the present experiment was to document the dynamics of bone turnover and metabolic state during a complete lactation cycle in dairy cows and to monitor the plasma profile of 10 cytokines previously known to play roles in bone turnover during lactation. Blood samples were collected sequentially from Holstein-Friesian cows during late pregnancy (1-9 wk prepartum; n = 30), early lactation (4-8 wk postpartum [pp]; n = 30), mid lactation (18-22 wk pp; n = 26), and late lactation (35-39 wk pp; n = 21). Due to reproductive failures, 8 of the cows went through extended lactation and samples for these cows were collected at a fifth time point, extended lactation (51-71 wk pp; n = 8). Twelve nonpregnant, nonlactating cows were also sampled. These cows included 4 heifers and 8 nonpregnant (empty) cows. Samples were assayed for calcium, phosphate, the bone resorption marker CTX-I, the bone formation marker, osteocalcin, and 3 metabolic markers, nonesterified fatty acids (NEFA), BHB, and glucose. The plasma levels of IL-1β, IL-4, IL-6, IL-8, IL-10, IFN-γ, IL-17A, TNF-α, MIP-1α, and VEGF-A were also measured using a multiplex cytokine assay. Plasma calcium and phosphate concentrations were found to be within the normal range across all lactation stages. Plasma CTX-I and osteocalcin concentrations corresponded to the stage of production, showing higher levels of CTX-I in late pregnancy and early lactation, and higher levels of osteocalcin in mid lactation, than at other stages of the production cycle. Analysis of metabolic markers, NEFA, and BHB, indicated that fat metabolism was increased to meet high energy demands during specific reproductive stages. The results showed that although glucose concentrations and IL-10, TNF-α, and MIP-1α were not detectably different at any of the stages of production, IL-4, IL-6, IL-8, IFN-γ, and VEGF-A were affected by stage of production. Most of the changes observed in cytokine levels occurred during late pregnancy and late lactation. Plasma IL-6 levels were high during late pregnancy, whereas plasma levels of IFN-γ and IL-4 were elevated during late lactation. In conclusion, these data demonstrate that plasma concentrations of a biomarker bone resorption, but not bone formation, and the cytokines IL-4, IL-6, and IFN-g are related to the stage of production in dairy cattle. Furthermore, the timing of changes in plasma concentrations of cytokines differ, with plasma IL-6 concentration elevated in parallel with CTX-I concentrations and plasma IL-4 and IFN-g concentrations elevated later in lactation.