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Editorial. Discusses trends in ecologically sound architecture and urban environmental planning. Rejection of modernism in architecture for ecological reasons; Functions of the urban planner at a time of environmental change; Automobile as an ecological disaster; Factors behind the global atmospheric problems; Rise of the postmodernist movement and the pressure for urban change.

Improvement of outcome in patients with pancreatic ductal adenocarcinoma (PDAC) requires exploration of novel therapeutic targets. Thus far, most studies of PDAC therapies, including those inhibiting small ubiquitin-like modifications (SUMOylation), have focused on PDAC epithelial cell biology, yet SUMOylation occurs in a variety of cell types. The mechanisms by which SUMOylation impacts PDAC in the context of its tumor microenvironment are poorly understood. We used clinically relevant orthotopic PDAC mouse models to investigate the effect of SUMOylation inhibition using a specific, clinical-stage compound, TAK-981. In contrast to its inhibition of PDAC cell proliferation in vitro, the survival benefit conferred by TAK-981 in vivo is dependent on the presence of T cells, suggesting that induction of adaptive antitumor immunity is an important antitumor effect of SUMOylation inhibition in vivo. To understand how this adaptive antitumor immunity is promoted, we investigated how SUMOylation inhibition in vivo alters major cell types/subtypes and their communications in the PDAC tumor microenvironment by performing transcriptomic analyses at single-cell resolution, which allowed mapping of cells in our orthotopic mouse model to cells in human PDAC tumors based on gene expression profiles. Findings are further validated by flow cytometry, immunofluorescence, IHC, western blots, and qPCR. The single-cell transcriptome dataset provided here suggests several combination strategies to augment adaptive immune responses that are necessary for durable disease control in patients with PDAC., (©2024 American Association for Cancer Research.)

Background and Objectives: The SARS-COVID-19 pandemic significantly limited healthcare access. We sought to evaluate whether California's lockdown in March 2020 affected staging and time to treatment of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that patients diagnosed after the lockdown would have longer time to treatment and higher stage at presentation., Methods: We retrospectively identified and categorized 1294 patients presenting to five University of California healthcare systems with a new diagnosis of PDAC into "pre-lockdown" and "post-lockdown" groups based on timing of pathologic diagnosis., Results: In the 12 months pre-lockdown, 835 patients were diagnosed with PDAC, and 459 patients in the 6 months post-lockdown. Demographics, staging, and treatment type were similar between eras. There was a decreased male:female ratio post- versus pre-lockdown (0.97 vs. 1.25; p = 0.03). Time from symptom onset to first treatment was significantly increased among females post-lockdown (p = 0.001). However, overall time from diagnosis to first treatment was shorter in the post-lockdown era (median 23 vs. 26 days, p < 0.001)., Conclusions: The COVID-19 lockdown did not significantly delay initial presentation, diagnosis, or treatment of newly diagnosed PDAC patients. Time from diagnosis to first treatment was shorter post-lockdown. Reduced healthcare utilization for minor complaints and increased telehealth utilization may have contributed., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Breastfeeding is recognized as the gold standard of infant feeding and nutrition. The World Health Organization recommends exclusive breastfeeding (EBF) of infants for the first 6 months of life. A variety of factors may impact breastfeeding practices in-hospital which may continue after hospital discharge, such as the use of breastmilk substitutes (BMS). The Baby-Friendly Initiative (BFI), which aims to promote and support breastfeeding practices, established a target rate of 75% for EBF from birth to hospital discharge. Currently, this target is not being met at The Ottawa Hospital (TOH), indicating there is room for improvement in EBF rates. The purpose of this study is to explore health care professionals (HCP) decision-making around use of BMS and identify factors that drive the use of BMS with and without medical indications., Methods: In this qualitative study, semi-structured interviews were conducted with HCPs within TOH from January to June 2022. All participants had experience in maternity or postpartum care and were probed on factors influencing use of BMS at this institution. Interview transcripts were coded using an inductive approach., Results: A total of 18 HCPs were interviewed including physicians, midwives, lactation consultants, and registered nurses. Multilevel barriers influencing the use of BMS were categorized into patient, HCP, and institution-level factors. Subthemes that emerged ranged from parental preferences, training differences amongst HCPs, to budget and staffing issues. Over half of HCPs were prepared to answer questions on EBF and were familiar with the BFI. Although most were supportive of this institution receiving BFI designation, a few providers raised concerns of its impact on parents who would like to supplement., Conclusions: Several modifiable factors influencing decision-making for use of BMS were identified. These findings will be used to inform unit leads, help identify effective strategies to address modifiable barriers, and develop tailored breastfeeding supports to improve EBF rates., (© 2024. The Author(s).)

Adequate prediction of postruminal outflows of essential AA (EAA) is the starting point of balancing rations for EAA in dairy cows. The objective of this meta-analysis was to compare the performance of 3 dairy feed evaluation systems (National Research Council [NRC], Cornell Net Protein and Carbohydrate System version 6.5.5 [CNCPS], and National Academies of Sciences, Engineering and Medicine [NASEM]) to predict EAA outflows (Trp was not tested). The data set included a total of 354 treatment means from 70 duodenal and 24 omasal studies. To avoid Type I error, mean and linear biases were considered of concern if statistically significant and representing >5.0% of the observed mean. Analyses were conducted on raw observed values and on observations adjusted for the random effect of study. The analysis on raw data indicates the ability of the feed evaluation system to predict absolute values whereas the analysis on adjusted values indicates its ability to predict responses of EAA outflows to dietary changes. For the prediction of absolute values (based on raw data), NRC underpredicted outflows of all EAA, from 5.3% to 8.6% of the observed mean (% obs.mean ) except for Leu, Lys, and Val; NASEM overpredicted Lys (10.8% obs.mean ); and CNCPS overpredicted Arg, His, Lys, Met, and Val (5.2 to 26.0% obs.mean ). No EAA had a linear bias of concern with NASEM, followed by NRC for His (6.8% obs.mean ), and CNCPS for all EAA (5.6 to 12.2% obs.mean ) except Leu, Phe, and Thr. In contrast, for the prediction of responses to dietary changes (based on adjusted data), NRC had 2 EAA presenting a linear bias of concern, followed by NASEM and CNCPS with 4 and 6 EAA, respectively. Predictions of His showed a linear bias of concern (5.3 to 9.6% obs.mean ) with the 3 feed evaluation systems. Measured chemistry of crude protein and EAA were reported for 1 or more feed ingredients of the ration in 36% of the studies, and resulted in decreased linear biases in the 3 feed evaluation systems. The difference in mean biases of Met outflows was systematically positive when comparing omasal versus duodenal studies. Predictions of Met outflows with NRC had a higher concordance correlation coefficient in duodenal (used to develop NRC equations) versus omasal studies, whereas the opposite was observed with CNCPS, the latter showing the lowest mean bias for Met in omasal sampling studies. The 30% difference in Met mean biases between sampling sites appeared related to a similar difference found for observed Met versus nonammonia nitrogen outflows between duodenal and omasal studies, which is independent of predictions. In conclusion, NRC and NASEM yielded accurate predictions of EAA outflows, with a small superiority of NASEM to predict absolute values, and slight superiority of NRC to predict the responses to dietary changes. In comparison, CNCPS may present mean and linear biases of concern for many EAA. Moreover, it remains to determine which sampling site is more representative of the true supply of EAA to the cows., (Copyright © 2024 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Competing Interests: RRW is a site Principal Investigator for the DIRECT Registry Study of NanoKnife IRE (NCT03899649). ZTB declares no competing interests.

Background: Maternal obesity is associated with stillbirth, but uncertainty persists around the effects of higher obesity classes. We sought to compare the risk of stillbirth associated with maternal obesity alone versus maternal obesity and additional or undiagnosed factors contributing to high-risk pregnancy., Methods: We conducted a retrospective cohort study using the Better Outcomes Registry and Network (BORN) for singleton hospital births in Ontario between 2012 and 2018. We used multivariable Cox proportional hazard regression and logistic regression to evaluate the relationship between prepregnancy maternal body mass index (BMI) class and stillbirth (reference was normal BMI). We treated maternal characteristics and obstetrical complications as independent covariates. We performed mediator analyses to measure the direct and indirect effects of BMI on stillbirth through major common-pathway complications. We used fully adjusted and partially adjusted models, representing the impact of maternal obesity alone and maternal obesity with other risk factors on stillbirth, respectively., Results: We analyzed data on 681 178 births between 2012 and 2018, of which 1956 were stillbirths. Class I obesity was associated with an increased incidence of stillbirth (adjusted hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.35-1.78). This association was stronger for class III obesity (adjusted HR 1.80, 95% CI 1.44-2.24), and strongest for class II obesity (adjusted HR 2.17, 95% CI 1.83-2.57). Plotting point estimates for odds ratios, stratified by gestational age, showed a marked increase in the relative odds for stillbirth beyond 37 weeks' gestation for those with obesity with and without other risk factors, compared with those with normal BMI. The impact of potential mediators was minimal., Interpretation: Maternal obesity alone and obesity with other risk factors are associated with an increased risk of stillbirth. This risk increases with gestational age, especially at term., Competing Interests: Competing interests:: Qun Miao reports funding from the Canadian Institutes of Health Research (CIHR) and the Heart and Stroke Foundation. Yanfang Guo reports funding from the CIHR and the Dalhousie University Advancement Funding Grant. Mark Walker sits on the board of the CHEO Research Institute. Laura Gaudet reports consulting fees from the Canadian Medical Protective Association. No other competing interests were declared., (© 2024 CMA Impact Inc. or its licensors.)

Alternative methods to alleviate coccidiosis in broilers are of interest to producers, including dietary strategies to minimize disruptions in growth rate and efficiency when faced with health challenges. Our objective was to determine optimal combinations of dietary starch, amino acids (AA), and oil to benefit productivity of broilers experiencing Eimeria-induced immune activation. Two trials were conducted using 1,536 male Ross 308 broiler chicks in floor pens randomly assigned to 1 of 17 experimental treatments. All birds received common starter (d 0-10) and finisher (d 24-35) diets, and only differed based on their assigned experimental grower diet (d 10-24). Trial 1 experimental grower diets ranged from 2,700 to 3,300 kcal/kg AME. Trial 2 included 10 experimental grower diets following a simplex lattice design consisting of 3 basal lots formulated to have the highest starch (45.4%), oil (10.2%), or AA density (120, 1.33% digestible Lys) and mixed in 4 equally spaced levels for each component (0, 0.33, 0.67, 1). These mixtures enabled varying densities of AA (80-120% of recommendation), starch:oil (4:1-20:1), and AME (2,940-3,450 kcal/kg). Bird and feeder weights were collected on d 0, 10, 24, and 35, and birds were exposed to an Eimeria challenge on d 11 or 12. In trial 2, excreta samples were collected for AME determination and carcasses were processed on d 36. Data were analyzed using ANOVA, t test, or regression. In Trial 1, BW gain and feed conversion were improved (P < 0.05) by increasing dietary AME. In Trial 2, birds receiving diets containing AA at 93 to 107% of recommendations and higher oil exhibited improved (P < 0.05) performance, but increased starch at the expense of oil reduced performance (P < 0.05). Relative breast and fat pad weights were not influenced by diet in Trial 2. We determined that broilers mildly challenged with Eimeria would exhibit highest BW gain when receiving diets containing 35.8% starch, 8.9% oil, and 101.3% of AA recommendations, which can be utilized by producers to maintain productivity under health-challenged conditions., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The concentration of volatile fatty acid (VFA) provides an imprecise view of VFA dynamics due to the confounding effects of fluid pool size and dynamics. Determination of VFA flux using isotope is expensive and a complex methodology. Therefore, a rapid and affordable approach to explore VFA dynamics may allow comprehensive characterization of VFA availability. The objective of this study was to explore the use of VFA dynamics generated by meal feeding to derive time-series rates of VFA apparent appearance and disappearance driven by different protein and fiber sources. Six ruminally cannulated wethers were fed diets containing timothy hay or beet pulp (TH and BP) and soybean meal (SBM) or heated soybean meal (HSBM). Diets were, TH + HSBM; TH + SBM; BP + HSBM; and BP + SBM and the experimental design was a partially replicated 4 × 4 Latin Square. Concentrations of VFA and polyethylene glycol (PEG) in rumen fluid samples were estimated. Concentrations of PEG were used to estimate fluid passage and volume to calculate VFA mass, and fluid-mediated exit. Maximum apparent appearance rate (mmol/h), the rate of apparent appearance decline (mmol/mmol/h), mean apparent appearance flux (mmol/h), mean apparent disappearance (mmol/h), and apparent disappearance rate (mmol/mmol/h) were estimated by deriving a 1 pool model for each VFA on a mass basis where appearance was assumed to follow an exponential decay pattern and disappearance followed mass-action kinetics. Statistical analyses were conducted using a linear mixed effect regression with fixed effects for fiber source, protein source, and their interaction, as well as random effects for animal and period. Rumen fluid volume (L) was greater in HSBM diets (P = 0.033) and fluid passage (%/h) was greater in SBM diets (P = 0.048). Concentrations (higher acetate and butyrate, P = 0.002 and 0.004, respectively) and molar proportions (higher valerate, P = 0.035) of VFA were affected only by fiber source; however, protein source and fiber source interacted to significantly influence apparent appearance rates and absorption rates of many major VFA. On a flux basis, HSBM supported significantly elevated mean disappearance of propionate (P = 0.033). This data demonstrates that time-series evaluation of fermentation dynamics, including fluid dynamics and VFA concentrations can be used to estimate apparent appearance and disappearance of VFA. Although further work is needed to confirm the alignment of these estimates with measurements of VFA supplies to the animal, this modeling approach may provide a simpler way to better understand the kinetics of rumen., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Optical tweezers have been used to trap and micro-manipulate several biological specimens ranging from DNA, macromolecules, organelles, to single-celled organisms. Using a combination of the refraction and scattering of laser light from a focused laser beam, refractile objects are physically captured and can be moved within the surrounding media. The technique is routinely used to determine biophysical properties such as the forces exerted by motor proteins. Here, we describe how optical tweezers combined with total internal reflection fluorescence microscopy (TIRF) can be used to assess physical interactions between organelles, more specifically the ER and Golgi bodies in plant cells., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, projected to rank as the second most prevalent cause of cancer-related mortality by 2030. Despite significant progress in advances in surgical techniques and chemotherapy protocols, the overall survival (OS) remains to be less than 10 % for all stages combined. In recent years, local ablative techniques have been introduced and utilized as additional therapeutic approaches for locally advanced pancreatic cancer (LAPC), with promising results with respect to local tumor control and OS. In addition to successful cytoreduction, there is emerging evidence that local ablation induces antitumor immune activity that could prevent or even treat distant metastatic tumors. The enhancement of antitumor immune responses could potentially make ablative therapy a therapeutic option for the treatment of metastatic PDAC. In this review, we summarize current ablative techniques used in the management of LAPC and their impact on systemic immune responses., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

Adequate prediction of postruminal outflow of protein fractions is the starting point for the determination of metabolizable protein supply in dairy cows. The objective of this meta-analysis was to compare the performance of 3 dairy feed evaluation systems (National Research Council [NRC], Cornell Net Protein and Carbohydrate System [CNCPS], and National Academies of Sciences, Engineering and Medicine [NASEM]) to predict outflows (g/d) of nonammonia nitrogren (NAN), microbial N (MiN), and nonammonia nonmicrobial N (NANMN). Predictions of rumen degradabilities (% of nutrient) of protein (RDP), NDF, and starch were also evaluated. The data set included 1,294 treatment means from 312 digesta flow studies. The 3 feed evaluation systems were compared using the concordance correlation coefficient (CCC), the ratio of root mean square prediction error (RMSPE) on standard deviation of observed values (RSR), and the slope between observed and predicted values. Mean and linear biases were deemed biologically relevant and are discussed if higher than a threshold of 5% of the mean of observed values. The comparisons were done on observed values adjusted or not for the study effect; the adjustment had a small effect on the mean bias but the linear bias reflected a response to a dietary change rather than absolute predictions. For the absolute predictions of NAN and MiN, CNCPS had the best-fit statistics (8% greater CCC; 6% lower RMSPE) without any bias; NRC and NASEM underpredicted NAN and MiN, and NASEM had an additional linear bias indicating that the underprediction of MiN increased at increased predictions. For NANMN, fit statistics were similar among the 3 feed evaluation systems with no mean bias; however, the linear bias with NRC and CNCPS indicated underprediction at low predictions and overprediction at elevated predictions. On average, the CCC were smaller and RSR ratios were greater for MiN versus NAN indicating increased prediction errors for MiN. For NAN responses to a dietary change, CNCPS also had the best predictions, although the mean bias with NASEM was not biologically relevant and the 3 feed evaluation systems did not present a linear bias. However, CNCPS, but not the 2 other feed evaluation systems, presented a linear bias for MiN, with responses being overpredicted at increased predictions. For NANMN, responses were overpredicted at increased predictions for the 3 feed evaluation systems, but to a lesser extent with NASEM. The site of sampling had an effect on the mean bias of MiN and NANMN in the 3 feed evaluation systems. The mean bias of MiN was higher in omasal than duodenal studies in the 3 feed evaluation systems (from 55 to 61 g/d) and this mean bias was twice as large when 15 N labeling was used as a microbial marker compared with purines. Such a difference was not observed for duodenal studies. The reasons underlying these systematic differences are not clear as the type of measurements used in the current meta-analysis does not allow to delineate if one site or one microbial marker is yielding the "true" postruminal N outflows. Rumen degradabilities of protein was underpredicted with CNCPS, and RDP responses to a dietary change was underpredicted by the 3 feed evaluation systems with increased RDP predictions. Rumen degradability of NDF was underpredicted and had poor fit statistics for NASEM compared with CNCPS. Fit statistics were similar between CNCPS and NASEM for rumen degradability of starch, but with an underprediction of the response with NASEM and absolute values being overpredicted with CNCPS. Multivariate regression analyses showed that diet characteristics were correlated with prediction errors of N outflows in each feed evaluation system. Globally, compared with NAN and NANMN, residuals of MiN were correlated with several moderators in the 3 feed evaluation systems reflecting the complexity to measure and model this outflow. In addition, residuals of NANMN were correlated positively with RDP suggesting an overestimation of this parameter. In conclusion, although progress is still to be made to improve equations predicting postruminal N outflows, the current feed evaluation systems provide sufficient precision and accuracy to predict postruminal outflows of N fractions., (Crown Copyright © 2023. Published by Elsevier B.V. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the Open Government Licence (https://www.nationalarchives.gov.uk/doc/open-government-licence/version/3/).)

The purpose of this study was to investigate the potential of using ruminal pH measurements to track time-series ruminal volatile fatty acid (VFA) concentrations occurring in response to short-term dietary disruption. Four ruminally cannulated dry Holstein dairy cows were individually housed and assigned to 4 treatments in a Latin square design. Treatments differing in forage-to-concentrate (F:C) ratio (100:0 to 55:45) were used because they were expected to result in large differences in VFA concentration, over which the relationships between pH and VFA could be robustly evaluated. Each sampling period lasted 36 h. Animals were removed from pasture and fasted for 24 h, after which time they were fed their treatment ration for 2 h and sampled for rumen fluid hourly for 12 h. Rumen fluid samples were analyzed immediately for pH, frozen, and subsequently analyzed for VFA concentrations using gas chromatography. Animals were returned to pasture for 7 d between sampling periods. To confirm that the short-term dietary disruptions resulted in expected variation in VFA concentrations, mean VFA concentrations during each animal period (n = 16) were analyzed using a linear mixed effects model with fixed (linear and quadratic) effects for F:C ratio and random effects for animal and period. Results indicated significant changes in VFA concentration across F:C ratio, but no significant shifts in VFA molar proportions, perhaps due to the short-term nature of the feeding protocol. To explore opportunity to use pH measurements to explain variability in VFA concentrations in real time across dietary conditions, a linear mixed-effect model was used to link the time-series measurements (n = 207). The VFA concentrations were analyzed with linear mixed effect models using linear and quadratic terms for pH, and random effects for animal and period. These models had poor accuracy, with residual error variance ranging from 21% to 38%, and residuals patterning significantly with F:C ratio. The data suggest that pH may lack reliability for VFA prediction in short-term feeding scenarios differing considerably in F:C ratio., (© 2023.)

Introduction: Failure to properly prepare the equine athlete for exercise and support post-exercise recovery is a contributing factor to physical breakdown and lameness. Equine physiotherapy was not introduced until the early twentieth century and has since evolved to allow for wearable therapies such as therapeutic boots to be accessible to a broad spectrum of equestrians. The purpose of this study was to evaluate the effects of ceramic boots, boots combining vibration and cryotherapy, and boots containing tourmaline on the performance of sport horses during jumping as well as to examine changes in vital signs in response to treatment., Methods: Eight healthy horses received the 3 therapeutic boot treatments or a control (no boot) in a Latin square experiment for a period of 5 days each. Horses performed approximately 10 min of exercise through a jump chute for the 5 consecutive days and jump performance parameters were recorded during each exercise session. Therapeutics were applied in the morning prior to exercise per the manufacturer's recommendation and were removed only for exercise., Results and Discussion: In a Bayesian network analysis, changes in vital signs (heart rate, respiration, and temperature) were driven by individual animal, rather than boot treatment. Jump performance was influenced by boot treatment, physiological measurements, and individual animal. Therapeutic boots were associated with changes in conditional probabilities of numerous performance outcomes. This study indicates the use of wearable therapies may result in improved performance outcomes of sport horses in jumping exercises., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schmidt, Gleason, Samaniego and White.)

Background: Pregnancy is a vulnerable time where the physical and social stress of the COVID-19 pandemic affects psychological health, including postpartum depression (PPD). This study is designed to estimate the prevalence and correlates of PPD and risk of suicidality among individuals who gave birth during the COVID-19 pandemic., Methods: We surveyed individuals who gave birth at The Ottawa Hospital and were ≥ 20 days postpartum, between March 17 and June 16, 2020. A PPD screen consisted of a score ≥ 13 using the Edinburgh Postnatal Depression Scale. A score of 1, 2, or 3 on item 10 ("The thought of harming myself has occurred to me") indicates risk of suicidality. If a participant scores greater than ≥ 13 or ≥ 1 on item 10 they were flagged for PPD, the Principal Investigator (DEC) was notified within 24 h of survey completion for a chart review and to assure follow-up. Modified Poisson multivariable regression models were used to identify factors associated with PPD and risk of suicidality using adjusted risk ratios (aRR) and 95% confidence intervals (CI)., Results: Of the 216 respondents, 64 (30%) screened positive for PPD and 17 (8%) screened positive for risk of suicidality. The maternal median age of the total sample was 33 years (IQR: 30-36) and the infant median age at the time of the survey was 76 days (IQR: 66-90). Most participants reported some form of positive coping strategies during the pandemic (97%) (e.g. connecting with friends and family, exercising, getting professional help) and 139 (64%) reported negative coping patterns (e.g. over/under eating, sleep problems). In total, 47 (22%) had pre-pregnancy anxiety and/or depression. Negative coping (aRR:2.90, 95% CI: 1.56-5.37) and pre-existing anxiety/depression (aRR:2.03, 95% CI:1.32-3.11) were associated with PPD. Pre-existing anxiety/depression (aRR:3.16, 95% CI:1.28-7.81) was associated with risk of suicidality., Conclusions: Almost a third of participants in this study screened positive for PPD and 8% for risk of suicidality. Mental health screening and techniques to foster positive coping skills/strategies are important areas to optimize postpartum mental health., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Systemic immunotherapy has had limited clinical benefit in pancreatic ductal adenocarcinoma. This is thought to be due to its desmoplastic immunosuppressive tumor microenvironment in addition to high intratumoral pressures that limit drug delivery. Recent preclinical cancer models and early-phase clinical trials have demonstrated the potential of toll-like receptor 9 agonists, including the synthetic CpG oligonucleotide SD-101, to stimulate a wide range of immune cells and eliminate suppressive myeloid cells. We hypothesized that Pressure-Enabled Drug Delivery via Pancreatic Retrograde Venous Infusion of toll-like receptor 9 agonist would improve responsiveness to systemic anti-programmed death receptor-1 checkpoint inhibitor therapy in a murine orthotopic pancreatic ductal adenocarcinoma model., Methods: Murine pancreatic ductal adenocarcinoma (KPC4580P) tumors were implanted into the pancreatic tails of C57BL/6J mice and treated 8 days after implantation. Mice were assigned to one of the following treatment groups: Pancreatic Retrograde Venous Infusion delivery of saline, Pancreatic Retrograde Venous Infusion delivery of toll-like receptor 9 agonist, systemic anti-programmed death receptor-1, systemic toll-like receptor 9 agonist, or the combination of Pancreatic Retrograde Venous Infusion delivery of toll-like receptor 9 agonist and systemic anti-programmed death receptor-1 (Combo). Fluorescently labeled toll-like receptor 9 agonist (radiant efficiency) was used to measure uptake of the drug on day 1. Changes in tumor burden were evaluated by necropsy at 2 different time points, 7 and 10 days after toll-like receptor 9 agonist treatment. Blood and tumors were collected at necropsy 10 days after toll-like receptor 9 agonist treatment for flow cytometric analysis of tumor-infiltrating leukocytes and plasma cytokines., Results: All mice analyzed survived to necropsy. Site of tumor fluorescence measurements revealed 3-fold higher intensity fluorescence in Pancreatic Retrograde Venous Infusion delivery of toll-like receptor 9 agonist compared to systemic toll-like receptor 9 agonist mice. Tumor weights were significantly lower in the Combo group compared to Pancreatic Retrograde Venous Infusion delivery of saline. Flow cytometry of the Combo group demonstrated significantly increased overall T-cell number, specifically CD4+ T-cells, and a trend toward increased CD8+ T-cells. Cytokine analysis showed significantly decreased IL-6 and CXCL1., Conclusion: Pressure-Enabled Drug Delivery of toll-like receptor 9 agonist by Pancreatic Retrograde Venous Infusion with systemic anti-programmed death receptor-1 demonstrated improved pancreatic ductal adenocarcinoma tumor control in a murine pancreatic ductal adenocarcinoma model. These results support study of this combination therapy in pancreatic ductal adenocarcinoma patients and expansion of ongoing Pressure-Enabled Drug Delivery clinical trials., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Globally, ruminant production systems used to synthesize meat and milk differ tremendously in terms of their efficiency, productivity, and environmental impacts. Regardless of this variability, milk has been repeatedly identified as an essential source of nutrients for humans. The objective of this work was to characterize global contributions of fluid milk to human food and nutrient supplies, greenhouse gas emissions, and water withdrawal. Data were leveraged from the United Nations Food and Agriculture Organization to estimate global supplies of agricultural products. Trade of agricultural products and waste of those products, along with use of human food for livestock feed were accounted for before estimating human nutrient supplies. The contributions of milk to human-edible nutrient supplies were then enumerated in terms of their proportion of total nutrients supplied by the agricultural system and in terms of the human population's requirement for that nutrient. We identified that fluid milk provides over 10% of consumable supplies of vitamin B 12 , vitamin A, riboflavin, and calcium available for humans globally. In terms of human nutrient requirements, milk provides sufficient vitamin B 12 to meet the needs of over 60% of the global population, riboflavin to satisfy 50% of the population, and calcium and phosphorus for over 35% of the population. Compared with other foods, milk ranked among the highest in terms of nutrient-to-calorie ratio for numerous amino acids, phosphorus, calcium, and riboflavin. Conditional dependencies were identified between greenhouse gas emissions and ruminant milk and meat, but not between water withdrawal and milk production. When evaluating the trade-offs in nutrient use versus nutrient provision for producing milk or producing all ruminant products, the production of ruminants worldwide was associated with both net increases and net decreases of several key nutrients. Continued work focusing on strategies to reduce the environmental impact of milk production will improve the utility of milk for feeding the growing global population., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

The objective of the present study was to investigate the interaction of plane of nutrition and naturally occurring coccidiosis on finisher lamb growth performance, FAMACHA score, and rumen volatile fatty acid profile. The study included 30 Suffolk, Dorset or Suffolk x Dorset lambs and were divided into 2 groups based on their initial body weight and assigned to 2 feeding groups differing in dietary energy intake to create lambs representing divergent growth curves due to differing nutritional management. Lambs with naturally occurring coccidiosis and healthy lambs were present in both feeding groups making a 2 × 2 factorial arrangement of treatments, (a) high plane of nutrition (HPN) lambs with no clinical coccidiosis diagnosis (HPNH), (b) HPN lambs with clinical coccidiosis (HPNC), (c) low plane of nutrition (LPN) lambs with no clinical coccidiosis diagnosis (LPNH), (d) LPN lambs with clinical coccidiosis (LPNC). Body weight and FAMACHA scores were recorded once every 2 weeks. On d 65 of feeding, lambs were slaughtered, and rumen fluid samples were collected and analyzed for volatile fatty acid concentrations. All response variables were analyzed statistically using a linear mixed effects model with fixed effects for plane of nutrition, health status, and a random effect for initial body weight nested within the pen. The total and average weight gain were not associated with planes of nutrition, health status, or the interaction. Health status had an impact on FAMACHA© score ( P = 0.047) and concentration of isobutyrate ( P = 0.037) and tended to affect total VFA ( P = 0.085) and acetate ( P = 0.071) concentrations. The interaction between the plane of nutrition and the health status tended to affect butyrate concentration ( P = 0.058). These data support the conclusion that coccidiosis infection impacted on rumen fermentation in a manner independent of the plane of nutrition; however, the translation of these rumen level impacts did not translate to the production responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sujani, dos Reis, Ellett, Schramm, Helm and White.)

Precision livestock farming (PLF) offers a strategic solution to enhance the management capacity of large animal groups, while simultaneously improving profitability, efficiency, and minimizing environmental impacts associated with livestock production systems. Additionally, PLF contributes to optimizing the ability to manage and monitor animal welfare while providing solutions to global grand challenges posed by the growing demand for animal products and ensuring global food security. By enabling a return to the "per animal" approach by harnessing technological advancements, PLF enables cost-effective, individualized care for animals through enhanced monitoring and control capabilities within complex farming systems. Meeting the nutritional requirements of a global population exponentially approaching ten billion people will likely require the density of animal proteins for decades to come. The development and application of digital technologies are critical to facilitate the responsible and sustainable intensification of livestock production over the next several decades to maximize the potential benefits of PLF. Real-time continuous monitoring of each animal is expected to enable more precise and accurate tracking and management of health and well-being. Importantly, the digitalization of agriculture is expected to provide collateral benefits of ensuring auditability in value chains while assuaging concerns associated with labor shortages. Despite notable advances in PLF technology adoption, a number of critical concerns currently limit the viability of these state-of-the-art technologies. The potential benefits of PLF for livestock management systems which are enabled by autonomous continuous monitoring and environmental control can be rapidly enhanced through an Internet of Things approach to monitoring and (where appropriate) closed-loop management. In this paper, we analyze the multilayered network of sensors, actuators, communication, networking, and analytics currently used in PLF, focusing on dairy farming as an illustrative example. We explore the current state-of-the-art, identify key shortcomings, and propose potential solutions to bridge the gap between technology and animal agriculture. Additionally, we examine the potential implications of advancements in communication, robotics, and artificial intelligence on the health, security, and welfare of animals., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The objective of this study was to leverage a frequentist (ELN) and Bayesian learning (BLN) network analyses to summarize quantitative associations among variables measured in 4 previously published dual-flow continuous culture fermentation experiments. Experiments were originally designed to evaluate effects of nitrate, defaunation, yeast, and/or physiological shifts associated with pH or solids passage rates on rumen conditions. Measurements from these experiments that were used as nodes within the networks included concentrations of individual volatile fatty acids, mM and nitrate, NO3-,%; outflows of non-ammonia nitrogen (NAN, g/d), bacterial N (BN, g/d), residual N (RN, g/d), and ammonia N (NH3-N, mg/dL); degradability of neutral detergent fiber (NDFd, %) and degradability of organic matter (OMd, %); dry matter intake (DMI, kg/d); urea in buffer (%); fluid passage rate (FF, L/d); total protozoa count (PZ, cells/mL); and methane production (CH4, mmol/d). A frequentist network (ELN) derived using a graphical LASSO (least absolute shrinkage and selection operator) technique with tuning parameters selected by Extended Bayesian Information Criteria (EBIC) and a BLN were constructed from these data. The illustrated associations in the ELN were unidirectional yet assisted in identifying prominent relationships within the rumen that were largely consistent with current understanding of fermentation mechanisms. Another advantage of the ELN approach was that it focused on understanding the role of individual nodes within the network. Such understanding may be critical in exploring candidates for biomarkers, indicator variables, model targets, or other measurement-focused explorations. As an example, acetate was highly central in the network suggesting it may be a strong candidate as a rumen biomarker. Alternatively, the major advantage of the BLN was its unique ability to imply causal directionality in relationships. Because the BLN identified directional, cascading relationships, this analytics approach was uniquely suited to exploring the edges within the network as a strategy to direct future work researching mechanisms of fermentation. For example, in the BLN acetate responded to treatment conditions such as the source of N used and the quantity of substrate provided, while acetate drove changes in the protozoal populations, non-NH3-N and residual N flows. In conclusion, the analyses exhibit complementary strengths in supporting inference on the connectedness and directionality of quantitative associations among fermentation variables that may be useful in driving future studies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dairy cows are predisposed to diseases during the postpartum period. Dystocia has been associated with increased risk for disease, which is likely the result of increased tissue trauma and stress during the prolonged parturition. To attenuate the inflammatory response seen in dystocic animals and improve well-being, we assessed the effects of a glucocorticoid, dexamethasone administered within 12 h after calving. Dystocia was defined as a difficult birth resulting in a prolonged calving (≥70 min after the amniotic sac appears) and was monitored through 3 video cameras in the close-up dry-cow pen. Cows meeting the dystocia definition were randomly assigned to receive a single intramuscular injection of either dexamethasone (DEX; 0.1 mg/kg of body weight; n = 43) or saline (CON, n = 44) within 12 h following a dystocic calving. Serum haptoglobin, blood β-hydroxybutyrate (BHB) concentrations, body temperature, and several behaviors were measured for the first 7 d postpartum. Additionally, milk production and components for the first 120 d were recorded. Using a mixed model, the fixed effects of treatment, parity, calving assistance, and time, along with 2- and 3-way interactions, were analyzed with cow as a random effect. We observed that primiparous DEX cows had greater serum haptoglobin concentrations on d 3 and d 7 postpartum compared with primiparous CON cows. There was no difference between treatment groups for blood BHB concentrations and body temperature. Behavior was altered between treatments, with DEX cows having reduced activity for the first week postpartum, as well as less restlessness and increased lying times on some of the days following calving. Treatment interacted with time for milk yield, such that DEX cows produced 2.7 kg/d less milk than CON cows for the first month following calving. The administration of dexamethasone resulted in changes in behavioral measurements, which could suggest a reduction in discomfort; however, due to the reduction in milk yield for the first month following calving, DEX administration may not be applicable for typical farm use. Additional research is needed to investigate treatments for cows experiencing dystocia without detrimental effects on milk yield., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)