Search

Starch is often chemically modified to improve its emulsification properties for food processing applications. Amylose inclusion complexes prepared using single pure fatty acid salts have been shown to be effective emulsifiers but these salts could be prohibitively expensive for industrial production. Therefore, amylose inclusion complex were prepared by steam jet cooking using more economical fatty acid salt mixtures of differing compositions derived from different plant oils. Complexes were obtained in 92–96 % yield and had good surface active properties regardless of the fatty acid salt composition. The complexes exhibited Type I 61V helical crystalline structures. Fourier transform infrared and nuclear magnetic resonance spectroscopy confirmed complex formation. Aqueous suspensions of the complexes had Newtonian behavior with viscosities and surface tensions between 0.0020 to 0.0028 Pa s and 43 and 49 mN m−1, respectively. Complexes emulsified corn oil at a 1:3 ratio of corn oil to complex suspensions, giving emulsion activity and stability indices between 180–213 m2 g−1 and 33–41 min, respectively. These complexes prepared from an array of more economical fatty acid salt mixtures performed comparably to more costly complexes prepared from pure individual fatty acid salts. These starch-based emulsifiers are produced using industrially available equipment making them desirable for food and nonfood applications.

Summary: In humans, dietary patterns impact weight and metabolism differentially across individuals. To uncover genetic determinants for differential dietary effects, we subjected four genetically diverse mouse strains to humanized diets (American, Mediterranean, vegetarian, and vegan) with similar macronutrient composition, and performed body weight, metabolic parameter, and RNA-seq analysis. We observed pronounced diet- and strain-dependent effects on weight, and triglyceride and insulin levels. Differences in fat mass, adipose tissue, and skeletal muscle glucose uptake, and gene expression changes in most tissues were strain-dependent. In visceral adipose tissue, ∼400 genes responded to diet in a strain-dependent manner, many of them in metabolite transport and lipid metabolism pathways and several previously identified to modify diet effects in humans. Thus, genetic background profoundly impacts metabolism, though chosen dietary patterns modify the strong genetic effects. This study paves the way for future mechanistic investigations into strain-diet interactions in mice and translation to precision nutrition in humans.

The 2021 FSIS Stabilization Guidelines for Meat and Poultry Products (Appendix B) Option 1.2 limits Phase 1 cooling from 48.8 to 26.7 °C in uncured meats to 1 h. However, this time restriction is impractical to achieve in large−diameter whole−muscle products. The objective of this study was to compare the inhibitory effect of commercial dry vinegars (DVs) and cultured sugar-vinegar blends (CSVs) on Clostridium perfringens and Bacillus cereus in uncured beef and poultry products during extended cooling. Treatments (beef: 72–73% moisture, pH 6.2–6.3, 0.85–0.95% NaCl; turkey: 76–77% moisture, pH 6.5–6.7, 1.3–1.6% NaCl) included Controls without antimicrobials, and four DV and four CSV, each tested at 0.75 and 1.25%. Batches were inoculated with 2.5-log C. perfringens or B. cereus spores, vacuum-packaged, and cooked to 73 °C. Packages were cooled from 48.8 to 27 °C (Phase 1) in 3, 4, or 5 h; Phase 2 (27–12.8 °C) and Phase 3 (12.8–4 °C) were standardized for 5-h cooling each. Pathogens were enumerated on selective agar in triplicate samples assayed at precook, postcook, and at the end of Phase 1, 2, and 3 cooling. Experiments were conducted twice. B. cereus did not grow (4.5 log) in Control treatments when Phase 1 cooling was extended to ≥3 h. All 1.25% DV ingredients limited C. perfringens growth to ≤1-log when Phase 1 cooling was extended to 3 h but supported a >1-log increase when Phase 1 cooling was extended to 5 h. All 1.25% CSV inhibited growth under 3-h Phase 1 cooling; 1.25% CSV-A and ≥0.75% CSV-D inhibited growth in turkey during 5-h Phase 1 cooling, but inhibition with 1.25% CSV-C was inconsistent in beef. This study revealed that formulating uncured meats with 1.25% DV or certain CSV can extend Phase 1 cooling to 3 h. Although all ingredients inhibited growth when used at 0.75% or greater compared to a control, greater variability of inhibition was observed among CSV than for DV.

RASopathies cause nonsarcomeric hypertrophic cardiomyopathy via dysregulated signaling through RAS and upregulated mitogen-activated protein kinase activity. We provide the first report of the successful treatment of an adult with RAF1-associated hypertrophic cardiomyopathy using trametinib, a MEK inhibitor.

Objective: Metamorphosis is a transition from growth to reproduction, through which an animal adopts adult behavior and metabolism. Yet the neural mechanisms underlying the switch are unclear. Here we report that neuronal E93, a transcription factor essential for metamorphosis, regulates the adult metabolism, physiology, and behavior in Drosophila melanogaster. Methods: To find new neuronal regulators of metabolism, we performed a targeted RNAi-based screen of 70 Drosophila orthologs of the mammalian genes enriched in ventromedial hypothalamus (VMH). Once E93 was identified from the screen, we characterized changes in physiology and behavior when neuronal expression of E93 is knocked down. To identify the neurons where E93 acts, we performed an additional screen targeting subsets of neurons or endocrine cells. Results: E93 is required to control appetite, metabolism, exercise endurance, and circadian rhythms. The diverse phenotypes caused by pan-neuronal knockdown of E93, including obesity, exercise intolerance and circadian disruption, can all be phenocopied by knockdown of E93 specifically in either GABA or MIP neurons, suggesting these neurons are key sites of E93 action. Knockdown of the Ecdysone Receptor specifically in MIP neurons partially phenocopies the MIP neuron-specific knockdown of E93, suggesting the steroid signal coordinates adult metabolism via E93 and a neuropeptidergic signal. Finally, E93 expression in GABA and MIP neurons also serves as a key switch for the adaptation to adult behavior, as animals with reduced expression of E93 in the two subsets of neurons exhibit reduced reproductive activity. Conclusions: Our study reveals that E93 is a new monogenic factor essential for metabolic, physiological, and behavioral adaptation from larval behavior to adult behavior.

The co-occurrence of wind and rainfall extremes can yield larger impacts than when either hazard occurs in isolation. This study assesses compound extremes produced by Extra-tropical cyclones (ETCs) during winter from two perspectives. Firstly, we assess ETCs with extreme footprints of wind and rainfall; footprint severity is measured using the wind severity index (WSI) and rain severity index (RSI) which account for the intensity, duration, and area of either hazard. Secondly, we assess local co-occurrences of 6-hourly wind and rainfall extremes within ETCs. We quantify the likelihood of compound extremes in these two perspectives and characterise a number of their drivers (jet stream, cyclone tracks, and fronts) in control (1981–2000) and future (2060–2081, RCP8.5) climate simulations from a 12-member ensemble of local convection-permitting 2.2 km climate projections over the UK and Ireland. Simulations indicate an increased probability of ETCs producing extremely severe WSI and RSI in the same storm in the future, occurring 3.6 times more frequently (every 5 years compared to every 18 years in the control). This frequency increase is mainly driven by increased rainfall intensities, pointing to a predominantly thermodynamic driver. However, future winds also increase alongside a strengthened jet stream, while a southward displaced jet and cyclone track in these events leads to a dynamically-enhanced increase in temperature. This intensifies rainfall in line with Clausius-Clapeyron, and potentially wind speeds due to additional latent heat energy. Future simulations also indicate an increase in the land area experiencing locally co-occurring wind and rainfall extremes; largely explained by increased rainfall within warm and cold fronts, although the relative increase is highest near cold fronts suggesting increased convective activity. These locally co-occurring extremes are more likely in storms with severe WSI and RSI, but not exclusively so as local co-occurrence requires the coincidence of separate drivers within ETCs. Overall, our results reveal many contributing factors to compound wind and rainfall extremes and their future changes. Further work is needed to understand the uncertainty in the future response by sampling additional climate models.

Primary prostatic lymphoma is an exceedingly rare entity comprising less than 0.09% of all prostatic cancers with follicular lymphoma making up only 12% as a subset. To our knowledge, primary follicular lymphoma co-existing with high grade prostatic adenocarcinoma presenting as a PI-RADS lesion 4 on mpMRI has not been previously described. We report the case of a 73-year-old male who presented with mildly elevated PSA and lower urinary tract symptoms. Prostate needle biopsy revealed low grade follicular lymphoma juxtaposed with high grade prostatic adenocarcinoma. The patient has been treated with radiation therapy for adenocarcinoma and is under observation for lymphoma progression.

Background: Partial nephrectomy (PN) is preferred for a renal mass in a solitary kidney (RMSK), although tumors with high complexity can be challenging. Objective: To evaluate the evolution of RMSK management with a focus on achievement of PN. Design, setting, and participants: Patients with nonmetastatic RMSK (n = 499) were retrospectively reviewed; 133 had high tumor complexity, including 80 in the pre-tyrosine kinase inhibitor (TKI) era (1999–2008) and 53 in the TKI era (2009–2022). After 2009, 23/53 patients received neoadjuvant TKI and 30/53 had immediate-surgery. Outcome measurements and statistical analysis: Functional outcomes, adverse events and complications, dialysis-free survival, and recurrence-free survival (RFS) were the measures evaluated. Mann-Whitney and χ2 tests were used to compare cohorts, and the log-rank test was applied for survival analyses. Results and limitations: Overall, the median RENAL score was 10 and the median tumor diameter was 5.2 cm. Demographic characteristics, tumor diameter, and RENAL scores were similar between the pre-TKI-era and TKI-era groups. In the TKI era, 23/53 patients (43%) with clear-cell histology were selected for neoadjuvant TKI. These 23 patients had a greater median tumor diameter (7.1 vs 4.4 cm; p = 0.02) and RENAL score (11 vs 10; p = 0.07). After TKI treatment, the median tumor diameter decreased to 5.6 cm and the RENAL score to 9, and tumor volume was reduced by 59% (all p

Summary: Background: Medulloblastoma patients with a sub-total surgical resection (STR; >1.5 cm2 primary tumour residuum post-surgery) typically receive intensified treatment. However, the association of STR with poor outcomes has not been observed consistently, questioning the validity of STR as a high-risk disease feature. Methods: We collected extent of resection (EOR) data from 1110 patients (from UK CCLG centres (n = 416, collected between September 1990 and July 2014) and published (n = 694) cohorts), the largest cohort of molecularly and clinically annotated tumours assembled to specifically assess the significance of EOR. We performed association and univariable/multivariable survival analyses, assessing overall survival (OS) cohort-wide and with reference to the four consensus medulloblastoma molecular groups and clinical features. Findings: STR was reported in 20% (226/1110) of patients. Non-WNT (p = 0.047), children

Summary: Background: The malignant childhood brain tumour, medulloblastoma, is classified clinically into molecular groups which guide therapy. DNA-methylation profiling is the current classification ‘gold-standard’, typically delivered 3–4 weeks post-surgery. Pre-surgery non-invasive diagnostics thus offer significant potential to improve early diagnosis and clinical management. Here, we determine tumour metabolite profiles of the four medulloblastoma groups, assess their diagnostic utility using tumour tissue and potential for non-invasive diagnosis using in vivo magnetic resonance spectroscopy (MRS). Methods: Metabolite profiles were acquired by high-resolution magic-angle spinning NMR spectroscopy (MAS) from 86 medulloblastomas (from 59 male and 27 female patients), previously classified by DNA-methylation array (WNT (n = 9), SHH (n = 22), Group3 (n = 21), Group4 (n = 34)); RNA-seq data was available for sixty. Unsupervised class-discovery was performed and a support vector machine (SVM) constructed to assess diagnostic performance. The SVM classifier was adapted to use only metabolites (n = 10) routinely quantified from in vivo MRS data, and re-tested. Glutamate was assessed as a predictor of overall survival. Findings: Group-specific metabolite profiles were identified; tumours clustered with good concordance to their reference molecular group (93%). GABA was only detected in WNT, taurine was low in SHH and lipids were high in Group3. The tissue-based metabolite SVM classifier had a cross-validated accuracy of 89% (100% for WNT) and, adapted to use metabolites routinely quantified in vivo, gave a combined classification accuracy of 90% for SHH, Group3 and Group4. Glutamate predicted survival after incorporating known risk-factors (HR = 3.39, 95% CI 1.4–8.1, p = 0.025). Interpretation: Tissue metabolite profiles characterise medulloblastoma molecular groups. Their combination with machine learning can aid rapid diagnosis from tissue and potentially in vivo. Specific metabolites provide important information; GABA identifying WNT and glutamate conferring poor prognosis. Funding: Children with Cancer UK, Cancer Research UK, Children’s Cancer North and a Newcastle University PhD studentship.

The Multiphysics Object-Oriented Simulation Environment (MOOSE) electromagnetics module has been developed to increase MOOSE physics module capabilities, enabling standalone and coupled computational electromagnetics within the MOOSE multiphysics ecosystem. The module is actively being utilized in the areas of plasma physics and advanced manufacturing, and it currently provides initial demonstrated capability in multi-dimensional, complex-valued electromagnetic wave propagation, electrostatic contact, reflection and transmission, and electromagnetic eigenvalue problems. Two-dimensional wave propagation and one-dimensional wave reflection and transmission are showcased as examples in this work. The modularity, parallelism, and plug-in infrastructure for custom future development is inherited from MOOSE itself, and the module can be used with both MOOSE-based and external codes, giving great flexibility.

Population studies report elevated incidence of cardiovascular events in patients with chronic epilepsy. Multiple pathophysiologic processes have been implicated, including accelerated atherosclerosis, myocardial infarction, altered autonomic tone, heart failure, atrial and ventricular arrhythmias, and hyperlipidemia. These deleterious influences on the cardiovascular system have been attributed to seizure-induced surges in catecholamines and hypoxemic damage to the heart and coronary vasculature. Certain antiseizure medications can accelerate heart disease through enzyme-inducing increases in plasma lipids and/or increasing risk for life-threatening ventricular arrhythmias as a result of sodium channel blockade. In this review, we propose that this suite of pathophysiologic processes constitutes “The Epileptic Heart Syndrome.” We further propose that this condition can be diagnosed using standard electrocardiography, echocardiography, and lipid panels. The ultimate goal of this syndromic approach is to evaluate cardiac risk in patients with chronic epilepsy and to promote improved diagnostic strategies to reduce premature cardiac death.

Objective: The prevalence of postoperative cardiac arrest (CA) increases with cardiothoracic surgical case complexity and is associated with a 40% to 50% mortality. Despite having a low overall surgical mortality rate at our center, our postoperative CA rates were higher than expected, with an observed-to-expected ratio of 2.6. Utilizing quality improvement methodology, we evaluated the influence of proactive risk mitigation on postprocedure CA in a high-risk cohort of pediatric cardiac patients. Methods: This single-center study utilized the Institute for Healthcare Improvement model. We created and implemented our Proactive Mitigation to Decrease Serious Adverse Events program in July 2020, prospectively enrolling preidentified high-risk patients. Enrolled patients underwent scheduled multidisciplinary reviews via virtual platform at 2 periprocedural time points with discussion of patient-specific risks and the subsequent development of proactive risk mitigation plans. Primary outcome measures were derived from the Pediatric Cardiac Critical Care Consortium national registry and included rate of postprocedure CA within 7 days and an institution-specific observed-to-expected ratio for postoperative CA. Results: Our baseline median number of high-risk cases between postprocedure CAs was 3. Following project initiation, median high-risk cases between events increased to 7. Our observed-to-expected ratio for postoperative CA decreased from 2.56 during the 12 months before Proactive Mitigation to Decrease Serious Adverse Events program implementation to 1.01 during the 12 months after Proactive Mitigation to Decrease Serious Adverse Events program implementation, and hospital length of stay decreased by ∼10 days. Conclusions: Implementation of periprocedure-related proactive risk mitigation strategies in high-risk pediatric cardiac patients led to improvement in postprocedure CA with a 133% increase in high-risk cases between events.

Background: Unexpected adverse pathology is a major concern in surgical management of clinically localised renal cell carcinoma (RCC). Further studies are needed to improve preoperative risk stratification. Objective: To define and classify tumour shape irregularity (TSI) based on preoperative imaging, and to investigate its effect on pathological and oncological outcomes in clinically localised RCC. Design, setting, and participants: We retrospectively analysed 474 patients with cT1-2N0M0 RCC managed by partial or radical nephrectomy. Preoperative dynamic computed tomography was used to define and classify TSI, graded as 1 (completely elliptical shape), 2 (elliptical shape with minor and focal protrusions), or 3 (nonelliptical shape presenting with major and/or extensive protrusions). Intervention: Partial or radical nephrectomy. Outcome measurements and statistical analysis: A logistic regression analysis evaluated the risk factors for pT3a upstaging and Fuhrman grade 3–4. A Cox proportional hazard analysis assessed preoperative variables for recurrence-free survival (RFS). Results and limitations: The median tumour size was 3.5 cm, and 94 patients (20%) had (R)adius (tumour size as maximal diameter), (E)xophytic/endophytic properties of tumour, (N)earness of tumour deepest portion to collecting system or sinus, (A)nterior (a)/posterior (p) descriptor, and (L)ocation relative to polar lines (RENAL) score ≥10. TSI was graded as 1, 2, and 3 in 214 (45%), 151 (32%), and 109 (23%) patients, respectively. Higher TSI was significantly associated with a larger tumour size and a higher RENAL score. Overall, pT3a upstaging and Fuhrman grade 3–4 were observed in 45 (9.5%) and 116 patients (31% in 380 clear cell RCC cases), respectively. The incidence of pT3a upstaging and Fuhrman grade 3–4 was significantly higher in patients with higher TSI (0.5%, 8.6%, and 28% for pT3a upstaging and 12%, 33%, and 60% for Fuhrman grade 3–4 in TSI 1, 2, and 3 groups, respectively). In multivariable analyses, higher TSI was independently associated with adverse pathological outcomes. During the median follow-up of 6.0 yr, 49 patients (10%) developed recurrence. Multivariable analyses demonstrated that older age and higher TSI were independent risk factors for worse RFS. The limitations include the retrospective design. Conclusions: TSI may be a useful adjunct in preoperative risk stratification for adverse pathology and recurrence after surgery in clinically localised RCC. Patient summary: Tumour shape irregularity is significantly associated with unfavourable pathological outcomes, that is, locally advanced stage or high-grade cancer, and with a higher recurrence rate after surgery in patients with clinically localised renal cell carcinoma. Preoperative evaluation of the tumour shape may help in patient counselling and treatment decisions.

Updating predictions of the response of high-profile, at-risk species to climate change and anthropogenic stressors is vital for informing effective conservation action. Here, we review two prior generations of Bayesian network probability models predicting changes in global polar bear (Ursus maritimus) population status, and provide a contemporary update based on recent research findings and sea-ice projections by newer climate models. We compare predictions of polar bear population response from all 3 models among four circumpolar Arctic ecoregions, using sea ice projections based on three IPCC greenhouse gas emissions scenarios (SSP2.6, 4.5, 8.5). Consistent with the previous two model generations, polar bears will continue to experience increasing probability of declining or greatly declining populations throughout the 21st century, varying by emission scenario. Populations within the Polar Basin Divergent Ice Ecoregion have the highest predicted probability of declines, but predictions were slightly less dire relative to the previous model generation. Most of the influence, denoted by model sensitivity analysis, is from expected degradation and loss of sea ice and reduced access to marine prey. The lack of terrestrial prey adequate to substitute for loss of access to marine prey, as well as human-caused bear morality associated with hunting and defense of life and property encountered when polar bears are increasingly forced ashore also contributed to predicted declines. Although some tidewater glacial fjords and other localized onshore resources may provide local refugia, their benefit is transient. Our findings continue to inform priorities for inventory, monitoring, and research needs, and suggest that similar updates to models of other at-risk species can capitalize on the comparison framework we present here.

A 72-year-old man presented with breathlessness and a systolic murmur. Extensive diagnostic work-up revealed a rare pulmonary artery intimal sarcoma mimicking a right ventricular outflow tract thrombus and impacting a cardiac pacemaker lead. Surgical resection, pathology confirmation, and management strategies are discussed, highlighting the challenges of treating this rare malignancy.

ABSTRACT: Controlling Salmonella in poultry is an ongoing food safety measure and while significant progress has been made, there is a need to continue to evaluate different strategies that include understanding Salmonella-poultry interaction, Salmonella-microbiota interactions, Salmonella genetics and response to adverse conditions, and preharvest and postharvest parameters that enable persistence. The purpose of this symposium is to discuss different strategies to consider from feed milling to the farm to the processing environment. This Poultry Science Association symposium paper is divided into 5 different sections that covers 1) immunological aspects of Salmonella control, 2) application of Salmonella genetics for targeted control strategies in poultry production, 3) improving poultry feed hygienics: utilizing feed manufacture techniques and equipment to improve feed hygienics, 4) practical on farm interventions for controlling Salmonella—what works and what may not work, and 5) monitoring and mitigating Salmonella in poultry. These topics elucidate the critical need to establish control strategies that will improve poultry gut health and limit conditions that exposes Salmonella to stress causing alterations to virulence and pathogenicity both at preharvest and postharvest poultry production. This information is relevant to the poultry industry's continued efforts to ensure food safety poultry production.

Background: Exposures to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), environmentally persistent chemicals detectable in the blood of most Americans, have been associated with several health outcomes. To offer insight into their possible biologic effects, we evaluated the metabolomic correlates of circulating PFOS and PFOA among 3,647 participants in eight nested case-control serum metabolomic profiling studies from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Methods: Metabolomic profiling was conducted by Metabolon Inc., using ultra high-performance liquid chromatography/tandem accurate mass spectrometry. We conducted study-specific multivariable linear regression analyses estimating the associations of metabolite levels with levels of PFOS or PFOA. For metabolites measured in at least 3 of 8 nested case-control studies, random effects meta-analysis was used to summarize study-specific results (1,038 metabolites in PFOS analyses and 1,100 in PFOA analyses). Results: The meta-analysis identified 51 and 38 metabolites associated with PFOS and PFOA, respectively, at a Bonferroni-corrected significance level (4.8x10-5 and 4.6x10-5, respectively). For both PFOS and PFOA, the most common types of associated metabolites were lipids (sphingolipids, fatty acid metabolites) and xenobiotics (xanthine metabolites, chemicals). Positive associations were commonly observed with lipid metabolites sphingomyelin (d18:1/18:0) (P = 2.0x10-10 and 2.0x10-8, respectively), 3-carboxy-4-methyl-5-pentyl-2-furanpropionate (P = 2.7x10-15, 1.1x10-17), and lignoceroylcarnitine (C24) (P = 2.6x10-8, 6.2x10-6). The strongest positive associations were observed for chemicals 3,5-dichloro-2,6-dihydroxybenzoic acid (P = 3.0x10-112 and 6.8x10-13, respectively) and 3-bromo-5-chloro-2,6-dihydroxybenzoic acid (P = 1.6x10-14, 2.3x10-6). Other metabolites positively associated with PFOS included D-glucose (carbohydrate), carotene diol (vitamin A metabolism), and L-alpha-aminobutyric acid (glutathione metabolism), while uric acid (purine metabolite) was positively associated with PFOA. PFOS associations were consistent even after adjusting for PFOA as a covariate, while PFOA associations were greatly attenuated with PFOS adjustment. Conclusions: In this large metabolomic study, we observed robust positive associations with PFOS for several molecules. Further investigation of these metabolites may offer insight into PFOS-related biologic effects.

Summary: Here, we present a protocol for deriving a continuum score for group 3 and 4 medulloblastoma tumor samples analyzed via RNA-sequencing or DNA methylation microarray. We describe steps for utilizing NMF-defined group 3/group 4 metagenes to calculate a continuum score between 0 and 1 that can be projected onto new sample data analyzed via RNA-sequencing. We then detail procedures for reverse engineering a continuum score for samples analyzed via DNA methylation microarray using a random forest classifier. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, belong to the most prescribed analgesic medication after traumatic injuries. However, there is accumulating evidence that NSAIDs impair fracture healing. Because bone regeneration in aged patients is subject to significant changes in cell differentiation and proliferation as well as a markedly altered pharmacological action of drugs, we herein analyzed the effects of diclofenac on bone healing in aged mice using a stable closed femoral facture model. Thirty-three mice (male n = 14, female n = 19) received a daily intraperitoneal injection of diclofenac (5 mg/kg body weight). Vehicle-treated mice (n = 29; male n = 13, female n = 16) served as controls. Fractured mice femora were analyzed by means of X-ray, biomechanics, micro computed tomography (μCT), histology and Western blotting. Biomechanical analyses revealed a significantly reduced bending stiffness in diclofenac-treated animals at 5 weeks after fracture when compared to vehicle-treated controls. Moreover, the callus tissue in diclofenac-treated aged animals exhibited a significantly reduced amount of bone tissue and higher amounts of fibrous tissue. Further histological analyses demonstrated less lamellar bone after diclofenac treatment, indicating a delay in callus remodeling. This was associated with a decreased number of osteoclasts and an increased expression of osteoprotegerin (OPG) during the early phase of fracture healing. These findings indicate that diclofenac delays fracture healing in aged mice by affecting osteogenic growth factor expression and bone formation as well as osteoclast activity and callus remodeling.

Background: The impact of adjunctive anti-inflammatory treatment on outcomes for patients with Kawasaki disease (KD) and coronary artery aneurysms (CAAs) is unknown. Methods: Using data from the International KD Registry in patients with ≥ medium CAA we evaluate associations of treatment with outcomes and major adverse cardiac events (MACE). Results: Medium or large CAA was present in 527 (32%) patients. All were treated with intravenous immunoglobulin (IVIG), 70% were male, and the median age was 1.3 years (interquartile range: 0.4-4.0 years). The most common acute therapies included single IVIG alone in 243 (46%), multiple IVIG in 100 (19%), multiple IVIG + corticosteroids in 75 (14%), and multiple IVIG + infliximab + corticosteroids in 44 (8%) patients. Patients who received therapy beyond single IVIG had a larger CA z-score at baseline (P < 0.001) and a higher rate of bilateral CAA (P < 0.001). Compared with IVIG alone, early adjunctive treatments (within 3 days of initial IVIG) were not associated with time to CAA regression or MACE, whereas later adjunctive therapy was associated with MACE and longer time to CAA regression. Patients receiving IVIG plus steroids vs IVIG alone had a trend towards shorter time to CAA regression and lower risk of MACE (P = 0.07). A larger CAA z-score at baseline was the strongest predictor of an increase in the CAA z-score over follow-up, lower likelihood of CAA regression, and higher risk of MACE. Conclusions: Persistence of CAA and MACE are more strongly associated with baseline severity CAA than with acute adjuvant anti-inflammatory therapy. Patients who received late adjunctive therapy are at higher risk for worse outcomes. Résumé: Contexte: L’incidence d’un traitement anti-inflammatoire d’appoint chez les patients atteints de la maladie de Kawasaki (MK) compliquée d’anévrismes coronariens est inconnue. Méthodologie: À partir de données provenant du registre international de la maladie de Kawasaki portant sur les patients ayant subi des anévrismes coronariens modérés ou importants, nous avons évalué l’incidence des différents traitements sur les résultats cliniques et les événements cardiovasculaires indésirables majeurs (ECIM). Résultats: Des anévrismes coronariens modérés ou importants ont été relevés chez 527 patients (32 %). Tous les patients recevaient des immunoglobulines administrées par voie intraveineuse (IgIV); 70 % d’entre eux étaient de sexe masculin, et leur âge médian était de 1,3 an (écart interquartile : de 0,4 an à 4,0 ans). Les traitements d’urgence les plus fréquents comprenaient un seul traitement par IgIV chez 243 patients (46 %), plusieurs traitements par IgIV chez 100 patients (19 %), une association de plusieurs traitements IgIV et de corticostéroïdes chez 75 patients (14 %) et une association de plusieurs traitements IgIV, de corticostéroïdes et d’infliximab chez 44 patients (8 %). Les patients ayant reçu un traitement autre qu’un seul traitement IgIV présentaient des scores z initiaux plus élevés pour le diamètre des artères coronaires (P < 0,001) et un taux plus élevé d’anévrismes coronariens bilatéraux (P < 0,001). En comparaison d’un traitement par IgIV seulement, les traitements d’appoint précoces (administrés dans les trois jours suivant le début du traitement par IgIV) n’ont pas eu d’incidence sur la durée avant la régression des anévrismes coronariens ni sur la survenue d’ECIM, alors que les traitements d’appoint plus tardifs ont été associés à un risque plus élevé d’ECIM et à une régression plus tardive des anévrismes coronariens. Les patients ayant reçu une association d’IgIV et de corticostéroïdes avaient tendance à présenter une régression plus rapide des anévrismes coronariens et un plus faible risque d’ECIM que ceux recevant uniquement un traitement par IgIV (P = 0,07). Un score z initial plus élevé pour un anévrisme coronarien était le facteur prédictif le plus puissant d’une augmentation du score z pendant la période de suivi, d’une probabilité plus faible de régression de l’anévrisme et d’un risque plus élevé d’ECIM. Conclusions: La gravité initiale de l’anévrisme coronarien est plus fortement associée à la persistance de l’anévrisme et à la survenue d’ECIM que le recours à un traitement anti-inflammatoire d’urgence en appoint. Les patients recevant un traitement d’appoint tardif étaient par ailleurs plus susceptibles de présenter des résultats défavorables.

While partial nephrectomy (PN) is generally preferred for localized renal cell carcinoma (RCC), radical nephrectomy (RN) is occasionally required. A new-baseline glomerular filtration rate (NBGFR) >45 ml/min/1.73 m2 after kidney cancer surgery is associated with strong survival outcomes. If NBGFR after RN will be above this threshold and the tumor has increased oncologic potential, RN may be a relevant consideration. Predicting NBGFR, defined as the GFR at 3–12 mo after RN, has been challenging owing to omission of two important parameters: split renal function (SRF) and renal function compensation (RFC). Our objective was to evaluate a simple SRF-based model in comparison to five published non–SRF-based models using data from a retrospective cohort of 445 RN patients. SRF was obtained via readily available semiautomated software (FUJIFILM Medical Systems) that provides differential parenchymal volume analysis on the basis of preoperative imaging. Our conceptually simple and clinically implementable SRF-based model more accurately predicts NBGFR after RN than five published non–SRF-based models (all p 45 ml/min/1.73 m2 (all p

Climate services must provide robust estimates of future changes to precipitation extremes to inform flood risk management and to assess the resilience of existing urban drainage systems in a changing climate. We use an ensemble of convection-permitting UK climate projections, UKCP Local to estimate return levels of 1–24 h precipitation extremes, combining state-of-the-art climate and spatial statistical modelling. We produce low, central and high precipitation return level uplifts at 5 km resolution across the UK. On average across the UK, the 30y return level of 1 and 24 h precipitation is projected to increase by 30–45% and 20–40% respectively by 2070 under RCP8.5, for central-to-high estimates. Uplifts are consistently higher over the northern UK. For 1 h extremes, uplifts here are higher than the official guidance for some parts of the UK, where guidelines pre-date UKCP Local. These spatially-varying uplifts are given for durations out to 24 h with uplifts lower for longer duration extremes. We provide physical explanations for these spatial patterns and the variation with duration. The new uplifts improve on previous official guidance that used a single value for all durations and across most UK nations, and was based on climate models with poor representation of sub-daily precipitation extremes. The results translate the latest UK climate change projections into tailored climate adaptation information useful and suitable for the water industry and flood risk management stakeholders. This is critical for ensuring we benefit from the latest advances in climate modelling and build a society that is resilient to a changing climate.

Coronary artery calcium scores are derived from cardiac-gated noncontrast computed tomography scans that are used in cardiac risk stratification. However, an elevated calcium score does not always translate to coronary artery luminal obstruction. Our case demonstrates an extremely high coronary artery calcium score despite nonobstructive coronaries on angiogram.

An atomic-scale mechanism of T Cell Receptor (TCR) mechanosensing of peptides in the binding groove of the peptide-major histocompatibility complex (pMHC) may inform the design of novel TCRs for immunotherapies. Using steered molecular dynamics simulations, our study demonstrates that mutations to peptides in the binding groove of the pMHC – which are known to discretely alter the T cell response to an antigen – alter the MHC conformation at equilibrium. This subsequently impacts the overall strength (duration and length) of the TCR-pMHC bond under constant load. Moreover, physiochemical features of the TCR-pMHC dynamic bond strength, such as hydrogen bonds and Lennard-Jones contacts, correlate with the immunogenic response elicited by the specific peptide in the MHC groove. Thus, formation of transient TCR-pMHC bonds is characteristic of immunogenic peptides, and steered molecular dynamics simulations can be used in the overall design strategy of TCRs for immunotherapies.

The rational design of T Cell Receptors (TCRs) for immunotherapy has stagnated due to a limited understanding of the dynamic physiochemical features of the TCR that elicit an immunogenic response. The physiochemical features of the TCR-peptide major histocompatibility complex (pMHC) bond dictate bond lifetime which, in turn, correlates with immunogenicity. Here, we: i) characterize the force-dependent dissociation kinetics of the bond between a TCR and a set of pMHC ligands using Steered Molecular Dynamics (SMD); and ii) implement a machine learning algorithm to identify which physiochemical features of the TCR govern dissociation kinetics. Our results demonstrate that the total number of hydrogen bonds between the CDR2β-MHC⍺(β), CDR1α-Peptide, and CDR3β-Peptide are critical features that determine bond lifetime.

Myoepithelial carcinoma is a neoplasm that classically arises in the parotid glands, nasopharynx, paranasal sinus, and nasal cavity of the head and neck. It rarely arises in other organs or soft tissues and involvement of genitourinary organs is distinctly rare. We describe a case of a 21-year-old male, presenting with nausea, weight loss, and worsening suprapubic pain over 3 months, found to have a large mass at the dome of the bladder. Partial cystectomy was ultimately performed revealing myoepithelial carcinoma of the bladder. The patient is free of disease at four years without the need for systemic therapy.

Non-union formation represents a major complication in trauma surgery. Adequate vascularization has been recognized as vital for bone healing. However, the role of vascularization in the pathophysiology of non-union formation remains elusive. This is due to difficulties in studying bone microcirculation in vivo. Therefore, we herein studied in a murine osteotomy model whether photoacoustic imaging may be used to analyze vascularization in bone healing and non-union formation. We found that oxygen saturation within the callus tissue is significantly lower in non-unions compared to unions and further declines over time. Moreover, the amount of total hemoglobin (HbT) within the callus tissue was markedly reduced in non-unions. Correlation analyses showed a strong positive correlation between microvessel density and HbT, indicating that photoacoustically determined HbT is a valid parameter to assess vascularization during bone healing. In summary, photoacoustic imaging is a promising approach to study vascular function and tissue oxygenation in bone regeneration.

Background: Major League Baseball (MLB) was among the first professional team sports leagues to resume play in the United States after public health measures related to the appearance of coronavirus disease 2019 caused interruptions to preseason training and major alterations to regular season play. There was a high level of concern that these athletes were ill-prepared for competition and would experience an increased risk of injury under the restricted play rules. Methods: The data in our study were compiled using publicly accessible records of players placed on injured lists from 2015 to 2020. These records came from 4 open access websites: rotoworld.com, fangraphs.com, foxsports.com, and spotrac.com. All injuries were confirmed using the transaction database found on the official MLB website (mlb.com). Results: A greater proportion of pitchers were injured during the first 30 days of the 2020 season compared to the first 30 days of any of the 5 prior seasons (29.74% vs. 11.72%, n=2190, P

As more people receive coronavirus disease 2019 (COVID-19) vaccinations, the side effects of the vaccines will become more apparent. One reported side effect that has come to light is unilateral axillary lymphadenopathy ipsilateral to the vaccination site. In general, unilateral axillary lymphadenopathy has a broad differential including malignancy, infection, autoimmune disorder, and iatrogenic etiologies. We present a case of a previously healthy 38-year-old woman who received her first dose of Pfizer COVID-19 vaccination 3 days prior to presenting to the emergency department complaining of 2 weeks of abdominal pain and 20-pound unintentional weight loss. Unilateral axillary lymphadenopathy, ipsilateral to the vaccination site, was found on a contrast-enhanced computed tomography examination of the chest, abdomen, and pelvis. Subsequent diagnostic mammograms did not demonstrate evidence of malignancy; however, axillary ultrasound again revealed nonspecific lymphadenopathy. A short-term follow-up axillary ultrasound was recommended, rather than a lymph node biopsy, given the history of recent vaccination. At clinical follow-up, the patient's abdominal pain resolved and no further weight loss was noted. This case report discusses the key components and workup recommendation of unilateral axillary lymphadenopathy in the setting of COVID-19 vaccination.

Background: Common hurdles to pediatric cardiology research include the heterogeneity and relative rarity of specific cardiac malformations, the potential for effect of residual lesions occurring decades after repair, and the scarcity of objective and easily measurable outcomes such as death and transplantation. Methods: To help meet these challenges, the Canadian Pediatric Cardiology Research Network (CPCRN) was founded by the Canadian Pediatric Cardiology Association to link Canadian academic institutions to promote and facilitate multicollaborations for the benefit of pediatric and congenital cardiology research. The overarching goal of the CPCRN is to build a national framework that harnesses the strong desire for collaboration within the pediatric cardiology community and to identify solutions to barriers that impede multicentre partnerships. Results: In this report, the authors describe the approach and the components of the CPCRN. Specifically, we detail the rolling out of a pan-Canadian master agreement that covers current and future studies, the systematic banking of all project data, and the mechanisms developed to facilitate secondary use of data. Conclusions: This experience could help guide the formation of other national research groups, particularly those focused on congenital or rare diseases. Résumé: Contexte: Les obstacles courants dans le domaine de la recherche en cardiologie pédiatrique comprennent l’hétérogénéité et la rareté des malformations cardiaques, le fait que des lésions résiduelles aient des répercussions qui se manifesteront des décennies après une intervention, et la rareté des issues cliniques objectives et facilement mesurables comme les décès et les transplantations. Méthodologie: Pour remédier à ces obstacles, le Réseau canadien de recherche en cardiologie pédiatrique (CPCRN) a été fondé par la l'Association canadienne de cardiologie pédiatrique afin de mettre en relation les établissements universitaires canadiens et de promouvoir ainsi des collaborations multiples qui bénéficieront à la recherche en cardiologie pédiatrique et congénitale. L’objectif principal du CPCRN est de mettre sur pied une structure nationale qui tire profit de l’important désir de collaboration dans le domaine de la cardiologie pédiatrique et de trouver des solutions aux obstacles qui nuisent aux partenariats entre les différents établissements. Résultats: Dans cet article, les auteurs décrivent l’approche et les composantes du CPCRN. Ils passent en revue les détails du déploiement d’une entente-cadre pancanadienne concernant les études en cours et à venir, la mise en banque systématique de toutes les données de recherche et les mécanismes mis au point pour permettre l’utilisation secondaire de ces données. Conclusions: Cette expérience pourrait permettre de guider la formation d’autres groupes de recherche nationaux, plus particulièrement dans les domaines des maladies rares ou congénitales.

Clozapine has superior efficacy in the treatment of refractory schizophrenia; however, use of clozapine is limited due to severe side effects, including myocarditis. Using non-integrative Sendai virus, we generated induced pluripotent stem cell lines from peripheral blood mononuclear cells of two patients with refractory schizophrenia, one clozapine-tolerant and one clozapine-induced myocarditis. Both cell lines exhibited a normal karyotype and pluripotency was validated by flow cytometry, immunofluorescence and their ability to differentiate into the three germ layers. These lines can be used to generate 2D and 3D patient-specific human cellular models to identify the mechanism by which clozapine induces myocardial inflammation.

Summary: Background: Medulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of β-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis. Methods: Medulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between β-blockers and ionising radiations. Gene expression profiles of β-adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production. Findings: Low concentrations of β-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of β-adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages. Interpretation: These data provide the evidence of the efficacy of β-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours. Funding: This study was funded by institutional grants and charities.

We report a family with 2 neonatal deaths related to dilated cardiomyopathy (DCM) and compound heterozygous loss-of-function variants (c.1243_1244del, p.Leu415Valfs*108 and c.1537C > T, p.Arg513*) in Leiomodin 2 (LMOD2), a recently documented cause of early DCM. The phenotype in mice and humans consists of early, severe cardiac dilation and dysfunction related to decreased functional LMOD2, which results in abnormal actin filaments and abnormal myocardial contractility. Our cases confirm mutations in LMOD2 as a cause of DCM in humans and highlight the rapid changes occurring in cardiac genetics and the importance of reviewing previously negative genetic test results in the context of emerging literature. RÉSUMÉ: Notre compte rendu concerne une famille dont deux nouveau-nés sont décédés des suites d'une cardiomyopathie dilatée (CMD) et qui présentaient une perte hétérozygote composite de variants fonctionnels (c.1243_1244del, p.Leu415Valfs*108 et c.1537C > T, p.Arg513*) du gène Leiomodin 2 (LMOD2), une cause récemment avérée de CMD précoce. Chez la souris et l'humain, le phénotype de cette anomalie consiste en une dilatation et une dysfonction cardiaques sévères précoces liées à une diminution de la fonction du gène LMOD2 entraînant des anomalies dans les filaments d'actine et la contractilité du myocarde. Nos cas permettent de confirmer que les mutations du gène LMOD2 sont une cause de CMD chez l'humain. Ils mettent en évidence les modifications rapides se produisant dans la génétique cardiaque et l'importance de revoir les résultats négatifs d'anciens tests génétiques à la lumière des nouvelles données publiées.

Background: Extracorporeal cardiopulmonary resuscitation (ECPR) is a therapeutic option for refractory cardiac arrest. We sought to perform an environmental scan to describe ECPR utilization in Canada and perceived barriers for application to out-of-hospital cardiac arrest (OHCA). Methods: This was a national cross-sectional study. We identified all cardiovascular surgery- and extracorporeal membrane oxygenation (ECMO)-capable hospitals in Canada and emergency medical services (EMS) agencies delivering patients to those centres. We requested the medical lead from each hospital’s ECMO service and each EMS agency to submit data regarding ECMO and ECPR utilization, as well as perceived barriers to ECPR provision for OHCA. Results: We identified and received survey data from 39 of 39 Canadian hospital institutions and 21 of 22 EMS agencies. Of hospitals, 38 (97%) perform ECMO and 27 (69%) perform ECPR (74% of which perform ≤5 cases per year). Of the 18 (46%) sites offering ECPR for OHCA, 8 apply a formal protocol for eligibility and initiation procedures. EMS agencies demonstrate heterogeneity with intra-arrest transport practices. The primary rationale for nontransport of refractory OHCA is that hospital-based care offers no additional therapies. Perceived barriers to the use of ECPR for OHCA were primarily related to limited evidence supporting its use, rather than resources required. Conclusion: Many Canadian cardiovascular surgery- or ECMO-equipped hospitals use ECPR; roughly half employ ECPR for OHCAs. Low case volumes and few formal protocols indicate that this is not a standardized therapy option in most centres. Increased application may be dependent on a stronger evidence base including data from randomized clinical trials currently underway. Résumé: Contexte: La réanimation cardiorespiratoire (RCR) extracorporelle est une option thérapeutique en cas d'arrêt cardiaque réfractaire. Nous avons voulu faire une analyse contextuelle de l'utilisation de la RCR extracorporelle au Canada et des obstacles perçus quant à son emploi dans les cas d'arrêt cardiaque en dehors de l'hôpital. Méthodologie: Il s’agissait d’une étude nationale transversale. Nous avons repéré tous les hôpitaux en mesure d'effectuer des chirurgies cardiovasculaires et d'offrir l'oxygénation extracorporelle au Canada et les fournisseurs de services médicaux d'urgence (SMU) transportant les patients vers ces centres. Nous avons demandé au chef médical du service d'oxygénation extracorporelle de chacun des hôpitaux et de chacun des fournisseurs de SMU de présenter leurs données concernant l'utilisation de l'oxygénation extracorporelle et de la RCR extracorporelle, ainsi que les obstacles perçus quant à l'emploi de la RCR extracorporelle dans les cas d'arrêt cardiaque en dehors de l'hôpital. Résultats: Nous avons obtenu les données de 39 des 39 établissements hospitaliers canadiens ciblés, et de 21 des 22 fournisseurs de SMU. Parmi les hôpitaux, 38 (97%) utilisent l'oxygénation extracorporelle et 27 (69 %), la RCR extracorporelle (74 % ayant eu recours à celle-ci dans ≤ 5 cas par année). Parmi les 18 (46 %) centres offrant la RCR extracorporelle en cas d'arrêt cardiaque en dehors de l'hôpital, 8 appliquaient un protocole officiel pour l'admissibilité et les procédures de mise en place. Les fournisseurs de SMU ont montré des pratiques hétérogènes concernant la réanimation en déplacement. La principale raison justifiant de ne pas transporter les patients présentant un arrêt cardiaque réfractaire en dehors de l'hôpital est que les soins en milieu hospitalier n'offrent pas de traitements additionnels. Les obstacles perçus quant à l'emploi de la RCR extracorporelle dans les cas d'arrêt cardiaque en dehors de l'hôpital étaient principalement liés au peu de données appuyant son utilisation, plutôt qu'aux ressources nécessaires. Conclusion: De nombreux hôpitaux canadiens équipés pour la chirurgie cardiovasculaire et l'oxygénation extracorporelle utilisent la RCR extracorporelle; environ la moitié d'entre eux utilisent la RCR extracorporelle en cas d'arrêt cardiaque en dehors de l'hôpital. Le faible nombre de cas et le peu de protocoles officiels indiquent qu'il ne s'agit pas d'une option de traitement standardisée dans la plupart des centres. Une utilisation plus fréquente pourrait nécessiter davantage de données probantes, y compris les résultats des études cliniques à répartition aléatoire qui sont en cours.

Molecular interactions mediated by engagement of the Herpes virus entry mediator (HVEM) with members of TNF and Ig superfamily generate distinct signals in T cell activation pathways that modulate inflammatory and inhibitory responses. HVEM interacts with CD160 and B and T lymphocyte attenuator (BTLA), both members of the immunoglobulin (Ig) superfamily, which share a common binding site that is unique from that of LIGHT, a TNF ligand. BTLA or CD160 engagement with HVEM deliver inhibitory or stimulatory signals to the host immune response in a context dependent fashion, whereas HVEM engagement with LIGHT results in pro-inflammatory responses. We identified a mutation in human HVEM, G89F, which directly interferes with the human LIGHT interaction, but interestingly, also differentially modulates the binding of human BTLA and CD160 via an apparent allosteric mechanism involving recognition surfaces remote from the site of the mutation. Specifically, the G89F mutation enhances binding of CD160, while decreasing that of BTLA to HVEM in cell-based assays. Molecular dynamics simulations for wild-type and G89F mutant HVEM, bound to different sets of ligands, were performed to define the molecular basis of this unexpected allosteric effect. These results were leveraged to design additional human HVEM mutants with altered binding specificities.

The two oxylipins 7S,14S-dihydroxydocosahexaenoic acid (diHDHA) and 7S,17S-diHDHA [resolvin D5 (RvD5)] have been found in macrophages and infectious inflammatory exudates and are believed to function as specialized pro-resolving mediators (SPMs). Their biosynthesis is thought to proceed through sequential oxidations of DHA by lipoxygenase (LOX) enzymes, specifically, by human 5-LOX (h5-LOX) first to 7(S)-hydroxy-4Z,8E,10Z,13Z,16Z,19Z-DHA (7S-HDHA), followed by human platelet 12-LOX (h12-LOX) to form 7(S),14(S)-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-DHA (7S,14S-diHDHA) or human reticulocyte 15-LOX-1 (h15-LOX-1) to form RvD5. In this work, we determined that oxidation of 7(S)-hydroperoxy-4Z,8E,10Z,13Z,16Z,19Z-DHA to 7S,14S-diHDHA is performed with similar kinetics by either h12-LOX or h15-LOX-1. The oxidation at C14 of DHA by h12-LOX was expected, but the noncanonical reaction of h15-LOX-1 to make over 80% 7S,14S-diHDHA was larger than expected. Results of computer modeling suggested that the alcohol on C7 of 7S-HDHA hydrogen bonds with the backbone carbonyl of Ile399, forcing the hydrogen abstraction from C12 to oxygenate on C14 but not C17. This result raised questions regarding the synthesis of RvD5. Strikingly, we found that h15-LOX-2 oxygenates 7S-HDHA almost exclusively at C17, forming RvD5 with faster kinetics than does h15-LOX-1. The presence of h15-LOX-2 in neutrophils and macrophages suggests that it may have a greater role in biosynthesizing SPMs than previously thought. We also determined that the reactions of h5-LOX with 14(S)-hydroperoxy-4Z,7Z,10Z,12E,16Z,19Z-DHA and 17(S)-hydroperoxy-4Z,7Z,10Z,13Z,15E,19Z-DHA are kinetically slow compared with DHA, suggesting that these reactions may be minor biosynthetic routes in vivo. Additionally, we show that 7S,14S-diHDHA and RvD5 have anti-aggregation properties with platelets at low micromolar potencies, which could directly regulate clot resolution.

ABSTRACT: Poultry nutrition and feed manufacturing are interrelated for a variety of reasons. Diet formulation is essential for optimizing bird growth and feed conversion, but compositional differences and the presence of certain feed additives can alter the gastrointestinal microbial composition and functionality. Not only does dietary composition and digestibility influence poultry performance, but specific physical characteristics such as feed particle size and thermal treatments can impact the avian gastrointestinal tract (GIT) microbiota. Poultry feeds also have a characteristic microbial ecology consisting of pathogenic and nonpathogenic microorganisms. Some feed-borne pathogens such as Salmonella are well studied and linked with the colonization of birds consuming the feed. However, much less is known about the nonpathogenic feed microbiome and what impact that might have on the bird's GIT. This review discusses the potential interaction between poultry feed and the GIT microbiome, microbial ecology of feed, application of microbiome analyses to feed, and approaches for communicating these complex data sets to the poultry industry.

ABSTRACT: The use of “omics” has become widespread across poultry production, from breeding to management to bird health to food safety and everywhere in between. While the conventional poultry industry has become more exposed to the power and utility of “omic” technologies, smaller poultry flock producers typically do not have this same level of experience. Because smaller, nonconventional poultry production is a growing portion of the overall poultry market, it is important that they also have educational access to these research tools and the resultant data. While small flock producers are dedicated and knowledgeable farmers, their knowledge of these newer technologies may be limited at best, and it is the task of academic researchers to communicate the importance of these “omic” tools and how the omic data can improve a variety of different aspects of their operations. This review discusses ways to effectively communicate complex microbiota and microbial genome sequence data to small flock producers and transforming this data into meaningful and applicable information that they can utilize to inform beneficial management decisions.

ABSTRACT: Poultry processing is undergoing changes both in operations as well as microbial methodologies. Traditionally, microbial data has been gathered through a series of culturing methods using liquid media and plating for isolation and enumeration. Both foodborne pathogens and nonpathogenic bacterial populations are estimated to assess food safety risks as well as the potential for spoilage. Bacterial loads from carcasses are important for estimating processing control and the effectiveness of antimicrobial applications. However, these culture-based approaches may only provide part of the microbial ecology landscape associated with chicken carcasses and the subsequent changes that occur in these populations during processing. Newer molecular-based approaches, such as 16S sequencing of the microbiota, offer a means to retrieve a more comprehensive microbial compositional profile. However, such approaches also result in large data sets which must be analyzed and interpreted. As more data is generated, this will require not only bioinformatic programs to process the data but appropriate educational forums to present the processed data to a broad audience.

ABSTRACT: Optimal broiler performance is dependent on several factors such as bird genetics, environment management, and nutrition. The gastrointestinal tract microbial ecology and metabolic activities have long been considered factors contributing to broiler performance responses. However, until recently, it was difficult to define the impact of the gastrointestinal microorganisms on the broiler host. With advances in microbiome sequencing technology, there has been a rapid increase in data generated using both experimental and commercial broiler operations. As the gastrointestinal microbiome data becomes more in-depth, opportunities to link microbiota composition to broiler performance metrics such as broiler growth rate and feed conversion efficiency have emerged. In parallel, with the increased understanding of the microbiota, there has been a shift to modulate the microbiome in order to alter metabolic patterns such as fermentation products. In this review, fermentation pathways and metabolites and the relationship with the microbiome will be discussed. Additionally, this review will connect these patterns and interpretations with current broiler performance data and the potential future directions these relationships could take the broiler industry.

ABSTRACT: Management of laying hens has undergone considerable changes in the commercial egg industry. Shifting commercial production from cage-based systems to cage-free has impacted the housing environment and created issues not previously encountered. Sources of microorganisms that become established in the early stages of layer chick development may originate from the hen and depend on the microbial ecology of the reproductive tract. Development of the layer hen GIT microbiota appears to occur in stages as the bird matures. Several factors can impact the development of the layer hen GIT, including pathogens, environment, and feed additives such as antibiotics. In this review, the current status of the laying hen GIT microbial consortia and factors that impact the development and function of these respective microbial populations will be discussed, as well as future research directions.

Summary: Influenza is an important cause of illness and morbidity for infants. Seasonal influenza vaccination during pregnancy aims to provide protection to mothers, but it can also provide immunity to infants. The precise influence of maternal vaccination on immunity in infants and how vaccine-elicited antibodies provide protection in some but not all infants is incompletely understood. We comprehensively profiled the transfer of functional antibodies and defined humoral factors contributing to immunity against influenza in a clinical trial of maternal influenza vaccination. Influenza-specific antibody subclass levels, Fc ɣ receptor (FCGR) binding levels, and antibody-dependent innate immune functions were all profiled in the mothers during pregnancy and at birth, as well as in cord blood. Vaccination increased influenza-specific antibody levels, antibody binding to FCGR, and specific antibody-dependent innate immune functions in both maternal and cord blood, with FCGR binding most enhanced via vaccination. Influenza-specific FCGR binding levels were lower in cord blood of infants who subsequently developed influenza infection. Collectively these data suggest that in addition to increased antibody amounts, the selective transfer of FCGR-binding antibodies contributes to the protective immune response in infants against influenza.

As our climate continues to respond to anthropogenic forcing, the magnitude and frequency of individual weather events and the intensity of the weather extremes associated with these, remains highly uncertain. This is a particular concern for our infrastructure networks, as increasing storm-related damage to these vital lifelines has significant consequences for our communities. Effective first response is hence becoming an increasingly important part of the management of infrastructure systems. Here, we propose a novel and rational framework for ‘consequence forecasting’ that enables probabilistic, pre-event decision-making for first responders to effectively target resources prior to an extreme weather event and thus reduce the societal consequences. Our method is unique in that it minimises model bias by using the same numerical weather prediction model for both fault attribution and fault prediction. Our framework can predict failure rates that are within 50% of the true value for more than 50% of the events considered, some 24 h in advance, therefore demonstrating that it can be an important part of increasing societal climate resilience by reducing reinstatement times.