Dietary and Animal Strategies to Reduce the Environmental Impact of Pastoral Dairy Systems Result in Altered Nutraceutical Profiles in Milk.

The objective of this study was to evaluate and provide further insights into how dairy cows genetically divergent for milk urea N breeding values [MUNBV, high (2.21 ± 0.21) vs. low (−1.16 ± 0.21); µ ± SEM], consuming either fresh cut Plantain (Plantago lanceolata L., PL) or Ryegrass (Lolium perenne L., RG) herbage, impacted the nutraceutical profile of whole milk by investigating amino and fatty acid composition and applying metabolomic profiling techniques. Both diet and MUNBV, and their interaction term, were found to affect the relative abundance of alanine, glycine, histidine, and phenylalanine in the milk (p < 0.05), but their minor absolute differences (up to ~0.13%) would not be considered biologically relevant. Differences were also detected in the fatty acid profile based on MUNBV and diet (p < 0.05) with low MUNBV cows having a greater content of total unsaturated fatty acids (+16%) compared to high MUNBV cows and cows consuming PL having greater content of polyunsaturated fatty acids (+92%), omega 3 (+101%) and 6 (+113%) compared to RG. Differences in the metabolomic profile of the milk were also detected for both MUNBV and dietary treatments. Low MUNBV cows were found to have greater abundances of choline phosphate, phosphorylethanolamine, N-acetylglucosamine 1-phosphate, and 2-dimethylaminoethanol (p < 0.05). High MUNBV cows had a greater abundance of methionine sulfoxide, malate, 1,5-anhydroglucitol (1,5-AG), glycerate, arabitol/xylitol, 3-hydroxy-3-methylglutarate, 5-hydroxylysine and cystine (p < 0.05). Large differences (p < 0.05) were also detected as a result of diet with PL diets having greater abundances of the phytochemicals 4-acetylcatechol sulfate, 4-methylcatechol sulfate, and p-cresol glucuronide whilst RG diets had greater abundances of 2,6-dihydroxybenzoic acid, 2-acetamidophenol sulfate, and 2-hydroxyhippurate. The results of this study indicate the potential to alter the nutraceutical value of milk from dietary and genetic strategies that have been previously demonstrated to reduce environmental impact.

Differential COVID-19 case positivity in New York City neighborhoods: socioeconomic factors and mobility.

New York City has been one of the hotspots of the COVID-19 pandemic and during the first two months of the outbreak considerable variability in case positivity was observed across the city's ZIP codes. In this study, we examined: a) the extent to which the variability in ZIP code level cases can be explained by aggregate markers of socioeconomic status and daily change in mobility; and b) the extent to which daily change in mobility independently predicts case positivity. Our analysis indicates that the markers considered together explained 56% of the variability in case positivity through April 1 and their explanatory power decreased to 18% by April 30. Our analysis also indicates that changes in mobility during this time period are not likely to be acting as a mediator of the relationship between ZIP-level SES and case positivity. During the middle of April, increases in mobility were independently associated with decreased case positivity. Together, these findings present evidence that heterogeneity in COVID-19 case positivity in New York City is largely driven by neighborhood socioeconomic status.

Differential COVID-19 case positivity in New York City neighborhoods: socioeconomic factors and mobility

New York City has been one of the hotspots of the COVID-19 pandemic and during the first two months of the outbreak considerable variability in case positivity was observed across the citys ZIP codes. In this study, we examined: a) the extent to which the variability in ZIP code level cases can be explained by aggregate markers of socioeconomic status and daily change in mobility; and b) the extent to which daily change in mobility independently predicts case positivity. Our analysis indicates that the markers considered together explained 56% of the variability in case positivity through April 1 and their explanatory power decreased to 18% by April 30. Our analysis also indicates that changes in mobility during this time period are not likely to be acting as a mediator of the relationship between ZIP-level SES and case positivity. During the middle of April, increases in mobility were independently associated with decreased case positivity. Together, these findings present evidence that heterogeneity in COVID-19 case positivity during the New York City spring outbreak was largely driven by residents socioeconomic status.

Mucus, mucins, and cystic fibrosis.

Cystic fibrosis (CF) is both the most common and most lethal genetic disease in the Caucasian population. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is characterized by the accumulation of thick, adherent mucus plaques in multiple organs, of which the lungs, gastrointestinal tract and pancreatic ducts are the most commonly affected. A similar pathogenesis cascade is observed in all of these organs: loss of CFTR function leads to altered ion transport, consisting of decreased chloride and bicarbonate secretion via the CFTR channel and increased sodium absorption via epithelial sodium channel upregulation. Mucosa exposed to changes in ionic concentrations sustain severe pathophysiological consequences. Altered mucus biophysical properties and weakened innate defense mechanisms ensue, furthering the progression of the disease. Mucins, the high-molecular-weight glycoproteins responsible for the viscoelastic properties of the mucus, play a key role in the disease but the actual mechanism of mucus accumulation is still undetermined. Multiple hypotheses regarding the impact of CFTR malfunction on mucus have been proposed and are reviewed here. (a) Dehydration increases mucin monomer entanglement, (b) defective Ca2+ chelation compromises mucin expansion, (c) ionic changes alter mucin interactions, and (d) reactive oxygen species increase mucin crosslinking. Although one biochemical change may dominate, it is likely that all of these mechanisms play some role in the progression of CF disease. This article discusses recent findings on the initial cause(s) of aberrant mucus properties in CF and examines therapeutic approaches aimed at correcting mucus properties.

Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3.

PURPOSE: Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups. METHODS: An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations. RESULTS: PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials. CONCLUSION: PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval.

Two clinical isolates of Mycoplasma hyosynoviae showed differing pattern of lameness and pathogen detection in experimentally challenged pigs

Mycoplasma (M.) hyosynoviae is known to colonize and cause disease in growing-finishing pigs. In this study, two clinical isolates of M. hyosynoviae were compared by inoculating cesarean-derived colostrum-deprived and specific-pathogen-free growing pigs. After intranasal or intravenous inoculation, the proportion and distribution pattern of clinical cases was compared in addition to the severity of lameness. Tonsils were found to be the primary site of colonization, while bacteremia was rarely detected prior to the observation of clinical signs. Regardless of the clinical isolate, route of inoculation, or volume of inocula, histopathological alterations and tissue invasion were detected in multiple joints, indicating an apparent lack of specific joint tropism. Acute disease was primarily observed 7 to 10 days post-inoculation. The variability in the severity of synovial microscopic lesions and pathogen detection in joint cavities suggests that the duration of joint infection may influence the diagnostic accuracy. In summary, these findings demonstrate that diagnosis of M. hyosynoviae-associated arthritis can be influenced by the clinical isolate, and provides a study platform to investigate the colonization and virulence potential of field isolates. This approach can be particularly relevant to auxiliate in surveillance and testing of therapeutic and/or vaccine candidates.

Quantitative real-time polymerase chain reaction for detecting Mycoplasma hyosynoviae and Mycoplasma hyorhinis in pen-based oral, tonsillar, and nasal fluids

Mycoplasma (M.) hyorhinis and M. hyosynoviae are pathogens known to cause disease in pigs post-weaning. Due to their fastidious nature, there is increased need for culture-independent diagnostic platforms to detect these microorganisms. Therefore, this study was performed to develop and optimize quantitative real-time PCR (qPCR) assays to rapidly detect M. hyorhinis and M. hyosynoviae in pen-based oral fluids as well as nasal and tonsillar fluids as proxies for samples used in swine herd surveillance. Two methods of genomic DNA extraction, automated versus manual, were used to compare diagnostic test performance. A wean-to-finish longitudinal study was also carried out to demonstrate the reproducibility of using pen-based oral fluids. Overall, pen-based oral and tonsillar fluids were more likely to be positive for both types of bacteria whereas only M. hyorhinis was detected in nasal fluids. DNA extraction protocols were shown to significantly influence test result. Although the initial detection time somewhat differed, both organisms were repeatedly detected in the longitudinal study. Overall, this study evaluated two qPCR methods for rapid and specific detection of either mycoplasma. Results from the present investigation can serve as a foundation for future studies to determine the prevalence of the two microorganisms, environmental load, and effectiveness of veterinary interventions for infection control.

Estrogenic side effects of androgen deprivation therapy.

Androgen deprivation therapy (ADT) is part of standard therapy for locally advanced or metastatic prostate cancer and is frequently used in men with a rising prostate-specific antigen following radical prostatectomy or radiation therapy. In some men, ADT may be administered for years or even decades. The intended therapeutic effect of ADT is testosterone deficiency. Because estrogen is a normal metabolite of testosterone, ADT also results in estrogen deficiency. ADT has a variety of adverse effects, many of which are primarily related to estrogen deficiency. Bone mineral density may decrease by 4% to 13% per year in men receiving ADT. The fracture rate for patients on ADT averages 5% to 8% per year of therapy. Hot flashes, gynecomastia, and breast tenderness are common side effects associated with ADT. In the clinic, minimum baseline testing should include weight measurement, blood pressure reading, and fasting lipid panel and serum glucose tests. Currently, there are no large outcome trials in men on ADT testing the available therapies for adverse effects. No therapies are specifically approved for treatment of adverse effects in men on ADT. Although some therapies can be used for a single indication (based upon small studies), there is currently no agent to treat the multiple estrogenic side effects of ADT.