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Red clover produces isoflavones, including biochanin A, which have been shown to have microbiological effects on the rumen while also promoting growth in beef cattle. The objective was to determine if supplementation of biochanin A via red clover hay would produce similar effects on the rumen microbiota and improve growth performance of lambs. Twenty-four individually-housed Polypay ram lambs (initial age: 114 ± 1 d; initial weight: 38.1 ± 0.59 kg) were randomly assigned to one of three experimental diets (85:15 concentrate:roughage ratio; N = 8 rams/treatment): CON—control diet in which the roughage component (15.0%, w/w, of the total diet) consisted of orchardgrass hay; 7.5-RC—red clover hay substituted for half (7.5%, w/w, of the total diet) of the roughage component; and 15-RC—the entire roughage component (15.0%, w/w, of the total diet) consisted of red clover hay. Feed intake and weight gain were measured at 14-d intervals for the duration of the 56-d trial, and rumen microbiological measures were assessed on days 0, 28, and 56. Red clover supplementation impacted growth performance of ram lambs. Average daily gains (ADG) were greater in ram lambs supplemented with red clover hay (7.5-RC and 15-RC) than for those fed the CON diet (P < 0.05). Conversely, dry matter intake (DMI) was lower in 7.5-RC and 15-RC than for CON lambs (P = 0.03). Differences in ADG and DMI resulted in greater feed efficiency in ram lambs supplemented with red clover hay (both 7.5-RC and 15-RC) compared to CON (P < 0.01). Rumen microbiota were also altered by red clover supplementation. The total viable number of hyper-ammonia-producing bacteria in 7.5-RC and 15-RC decreased over the course of the experiment and were lower than CON by day 28 (P ≤ 0.04). Amylolytic bacteria were also lower in 15-RC than in CON (P = 0.03), with a trend for lower amylolytic bacteria in 7.5-RC (P = 0.08). In contrast, there was tendency for greater cellulolytic bacteria in red clover supplemented lambs than in CON (P = 0.06). Red clover supplementation also increased fiber utilization, with greater ex vivo dry matter digestibility of hay for both 7.5-RC and 15-RC compared to CON by day 28 (P < 0.03). Results of this study indicate that low levels of red clover hay can elicit production benefits in high-concentrate lamb finishing systems through alteration of the rumen microbiota.

Background Gastric adenocarcinoma is common and consequent mortality high. Presentation and mortality are increased in obese individuals, many of whom have elevated circulating insulin concentrations. High plasma insulin concentrations may promote, and increase mortality from, gastric adenocarcinoma. Tumour promotion activities of insulin and its receptor are untested in gastric cancer cells. Methods Tumour gene amplification and expression were computed from sequencing and microarray data. Associations with patient survival were assessed. Insulin-dependent signal transduction, growth, apoptosis and anoikis were analysed in metastatic cells from gastric adenocarcinoma patients and in cell lines. Receptor involvement was tested by pharmacological inhibition and genetic knockdown. RNA was analysed by RT-PCR and proteins by western transfer and immunofluorescence. Results INSR expression was higher in tumour than in normal gastric tissue. High tumour expression was associated with worse patient survival. Insulin receptor was detected readily in metastatic gastric adenocarcinoma cells and cell lines. Isoforms B and A were expressed. Pharmacological inhibition prevented cell growth and division, and induced caspase-dependent cell death. Rare tumour INS expression indicated tumours would be responsive to pancreatic or therapeutic insulins. Insulin stimulated gastric adenocarcinoma cell PI3-kinase/Akt signal transduction, proliferation, and survival. Insulin receptor knockdown inhibited proliferation and induced programmed cell death. Type I IGF receptor knockdown did not induce cell death. Conclusions The insulin and IGF signal transduction pathway is dominant in gastric adenocarcinoma. Gastric adenocarcinoma cell survival depends upon insulin receptor. That insulin has direct cancer-promoting effects on tumour cells has implications for clinical management of obese and diabetic cancer patients.

Summary: Volatile short-chain fatty acids such as butyric and acetic acid have been supplemented in poultry rations as a feed ingredient and nutritive supplement. A novel Clostridium fermentation solubles broth (MiruTyton), containing short-chain fatty acids, minerals, and amino acids, was supplemented in a standard corn/soybean meal–based ration at a rate of 750, 1,500, 3,000, and 6,000 mg/kg to achieve approximately 277, 554, 1,108, and 2,216 mg/kg of ammonium butyrate in the diet. After 6 wk, supplementation at all levels did not cause significant changes in the blood parameters or any live performance metric of mixed-sex Cobb-500 broilers (N = 1,920). In addition, administering 6,000 mg/kg of MiruTyton caused no significant lesions in any of the tissue examined except for an increase (P

Dietary fiber has varying effects on nursery pig performance, which is a period when medications are supplemented to support disease challenges. An experiment was conducted to determine the effects of gentamicin sulfate (GS) water medication, dietary structural fiber, and their interaction on growth performance of nursery pigs. In total, 900 weanling pigs (initial body weight = 5.71 ± 0.04 kg) were randomly allotted to a 2 × 2 factorial arrangement of treatments (10 pens/treatment, 22 pigs/pen). Dietary treatments consisted of nursery diets with no additional fiber (CON) or nursery diets with 8% wheat middlings (STR) as a source of structural fiber. Phase 1 and 2 diets were fed from day 0-12 and day 12-21, respectively. Water medication treatments consisted of no GS or GS delivered through the drinking water from day 0-7 post-weaning (5 g GS per gallon stock solution at a 1:126 dilution of stock solution to drinking water). Data were analyzed using a general linear model in R. Contrasts tested the main effects of structural fiber, GS supplementation, and their interaction. Phase 1 average daily gain (ADG) and average daily feed intake (ADFI) did not differ, but gain:feed (G:F) was greater (P < 0.05) with GS (Table 1). Interactions (P < 0.05) were observed for day 21 body weight, ADG, and ADFI in phase 2, where additional structural fiber increased performance variables in absence of, but not in conjunction with, GS supplementation. A tendency for an interaction (P < 0.10) was observed for phase 2 G:F, where additional structural fiber increased G:F when no GS was administered but reduced G:F when GS was supplemented. In conclusion, the use of water medication impacted the performance response to dietary structural fiber, as pigs responded beneficially to additional fiber when GS was not administered, potentially due to modifications to the microbiome.

Beginning in March 2020, New York City began the fight against coronavirus disease 2019. Health care workers were faced with a disease that led to significant morbidity and mortality with no proven therapies. As hospitals became inundated with patients and underwent rapid expansion of capacity, resources such as drugs, protective and medical equipment, and hospital staff became limited. Pharmacists played a critical role in the management of clinical care and drug delivery during the pandemic. As members of the department of pharmacy within NewYork‐Presbyterian Hospital, we describe our experiences and processes to overcome challenges faced during the pandemic. Strict inventory management through the use of daily usage reports, frequent communication, and minimization of waste was critical for the management of drug shortages. The creation of guidelines, protocols, and restrictions were not only used to mitigate drug shortages, but also helped educate health care providers and guided medication use. Managing technology through setting up new automatic dispensing cabinets to address hospital expansions and modifying the electronic order entry system to include new protocols and drug shortage information were also vital. Additional key pharmacist functions included provision of investigational drug service support and training of pharmacists, prescribers, nurses, and respiratory therapists to educate and standardize medication use. Through implementation of operational and clinical processes, pharmacists managed critical drug inventory and guided patient treatment. As the pandemic continues, pharmacists will remain vital members of the multidisciplinary team dedicated to the fight against the virus. This article is protected by copyright. All rights reserved.

Arrestins demonstrate strong preference for phosphorylated over unphosphorylated receptors, but how arrestins “sense” receptor phosphorylation is unclear. A conserved lysine in the lariat loop of arrestins directly binds the phosphate in crystal structures of activated arrestin-1, −2, and −3. The lariat loop supplies two negative charges to the central polar core, which must be disrupted for arrestin activation and high-affinity receptor binding. Therefore, we hypothesized that receptor-attached phosphates pull the lariat loop via this lysine, thus removing the negative charges and destabilizing the polar core. We tested the role of this lysine by introducing charge elimination (Lys->Ala) and reversal (Lys->Glu) mutations in arrestin-1, −2, and −3. These mutations in arrestin-1 only moderately reduced phospho-rhodopsin binding and had no detectable effect on arrestin-2 and −3 binding to cognate non-visual receptors in cells. The mutations of Lys300 in bovine and homologous Lys301 in mouse arrestin-1 on the background of pre-activated mutants had variable effects on the binding to light-activated phosphorylated rhodopsin, while affecting the binding to unphosphorylated rhodopsin to a greater extent. Thus, conserved lysine in the lariat loop participates in receptor binding, but does not play a critical role in phosphate-induced arrestin activation.

PF-06881894 is a proposed biosimilar to pegfilgrastim (Neulasta®). This study evaluated the pharmacodynamic/pharmacokinetic (PD/PK) equivalence, immunogenicity, and safety of PF-06881894 vs pegfilgrastim reference products (US- and EU-Neulasta®) in healthy volunteers. A phase 1, open-label, randomized, crossover study was conducted to assess the pharmacologic equivalence and safety of a single 6-mg dose of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU. The primary PD endpoints were area under the effect-versus-time curve for absolute neutrophil count (ANC) from dose administration to 288 h postdose, and maximum observed ANC value among subjects confirmed negative for anti-pegfilgrastim antibodies. Primary PK variables included area under the serum pegfilgrastim-versus-time curve from the time of dose administration to time infinity and maximum observed serum pegfilgrastim concentration. A second phase 1, open-label, randomized (1:1), parallel-group, non-inferiority study was conducted to assess the immunogenicity and safety of multiple 6-mg doses of PF-06881894 versus pegfilgrastim-US. The primary endpoint for the immunogenicity study was the proportion of subjects with both negative baseline and confirmed positive postdose anti-pegfilgrastim antibodies at any time during the study. Across the single- and multiple-dose studies (N = 153 and N = 420 treated subjects, respectively), demographics for age (18–65 years), male gender (n = 264/573), and white race (n = 423/573) were similar. Three-way PD/PK equivalence of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU was demonstrated with the primary PD endpoints and primary PK variables being completely contained within the predefined 90% confidence interval acceptance limits (80–125%). The non-inferiority of PF-06881894 versus pegfilgrastim-US in terms of immunogenicity was established according to the prespecified non-inferiority margin (≤10%). Overall, there were no clinically meaningful differences in safety profiles among or between study groups. Single-dose PF-06881894 demonstrated PD/PK equivalence and comparable safety with US- and EU-pegfilgrastim reference products. Multiple-dose PF-06881894 demonstrated immunogenicity non-inferiority to pegfilgrastim-US with comparable safety. Both studies contributed to the totality of evidence supporting biosimilarity. ClinicalTrials.gov identifiers: NCT02629289 (C1221001); NCT03273842 (C1221005).

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants =67 years old and cases with disease duration =7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power. © 2022 - IOS Press. All rights reserved.

Irrigation water sources have been shown to harbor foodborne pathogens and could contribute to the outbreak of foodborne illness related to consumption of contaminated produce. Determining the probability of and the degree to which these irrigation water sources contain these pathogens is paramount. The purpose of this study was to determine the prevalence of Salmonella enterica and Listeria monocytogenes in alternative irrigation water sources. Water samples (n = 188) were collected over 2 years (2016 to 2018) from 2 reclaimed water plants, 3 nontidal freshwater rivers, and 1 tidal brackish river on Maryland’s Eastern Shore (ESM). Samples were collected by filtration using modified Moore swabs (MMS) and analyzed by culture methods. Pathogen levels were quantified using a modified most probable number (MPN) procedure with three different volumes (10 liters, 1 liter, and 0.1 liter). Overall, 65% (122/188) and 40% (76/188) of water samples were positive for S. enterica and L. monocytogenes, respectively. For both pathogens, MPN values ranged from 0.015 to 11 MPN/liter. Pathogen levels (MPN/liter) were significantly (P

Metastatic spread of invasive lobular breast carcinoma to stomach is rare especially before diagnosis of primary breast cancer. Incorrect diagnosis might result in delay of appropriate treatment for breast cancer. Recognition of this possibility enables better clinical management. A 62-year-old female presented with upper gastrointestinal symptoms and weight loss and was referred to a gastroenterologist for investigation. At the time of initial diagnosis of stomach cancer, patient was asymptomatic for breast cancer. Multiple gastric biopsies taken showed features suspicious of metastatic breast cancer. Consequently, the initial provisional diagnosis of stomach cancer changed into metastatic invasive lobular breast carcinoma. These findings were corroborated radiologically. The patient was treated with letrozole and zoledronic acid as first-line therapy for one year. Residual metastatic breast cancer was present in the gastric mucosa. The patient was treated with endocrine therapy containing ribociclib and treatment was ineffective confirmed by PET-CT scan. But her symptoms have resolved completely despite her presentation with stage IV. We present rare case of initial presentation of gastric metastasis before diagnosis of a primary invasive lobular breast carcinoma. Correct diagnosis and appropriate treatment were accomplished through initial clinical suspicion, accurate histological examination, and endoscopy together with analysis of disease-specific biomarkers.

Background: Studies have shown conflicting results on the efficacy of tocilizumab (TCZ) for patients with COVID-19, with many confounders of clinical status and limited duration of the observation. Here, we evaluate the real-world long-term efficacy of TCZ in COVID-19 patients. Methods: We conducted a retrospective study of hospitalized adult patients with COVID-19 using a large US-based multicenter COVID-19 database (Cerner Real-World Data; updated in September, 2020). The TCZ group was defined as patients who received at least one dose of the drug. Matching weight (MW) and a propensity score weighting method were used to balance confounding factors. Results: A total of 20,399 patients were identified. 1,510 and 18,899 were in the TCZ and control groups, respectively. After MW adjustment, no statistically significant differences in all-cause mortality were found for the TCZ vs. control group (Hazard Ratio [HR]:0.76, p=0.06). Survival curves suggested a better trend in short-term observation, driven from a subgroup of patients requiring oxygen masks, BIPAP or CPAP. Conclusion: We observed a temporal (early) benefit of TCZ, especially in patients on non-invasive high-flow supplemental oxygen. However, the benefit effects faded with longer observation. The long-term benefits and risks of TCZ should be carefully evaluated with follow-up studies.

Dietary fiber can provide functional benefits to nursery pigs, thereby improving gut health and growth performance. However, effects vary depending on the type and amount of fiber supplemented. The objective of this experiment was to determine the effects of dietary fermentable fiber (FRM), structural fiber (STR), and their interaction on growth performance of nursery pigs. In total, 3,014 weanling pigs (body weight = 5.71 ± 0.11 kg, 15 replicate pens/treatment, 21 – 23 pigs/pen) were allotted by pen in a randomized complete block design to treatments in a 3 × 3 factorial arrangement with 2 factors: FRM (12, 13, or 14%) and STR (3, 4, or 5%). Diets were formulated to maintain similar dietary protein and metabolizable energy, and rice hulls or beet pulp were added to achieve different levels of STR and FRM, respectively. Fiber concentrations were estimated using in vitro fermentation methods. Phase 1 and 2 diets were fed from day 0 – 11 and 11 – 21 post-weaning, respectively. A common diet was fed from d 21 – 43. Data were analyzed by general linear model in R with random effect of location block. Orthogonal contrasts tested for linear and quadratic effects of STR and FRM, and their interaction. Overall (d 0 – 43), increasing FRM increased average daily gain (ADG; linear, P < 0.05). As STR increased, overall ADG increased and then decreased (quadratic, P < 0.05), with 4% STR resulting in the greatest ADG. Interactions between fiber type were observed (P < 0.05) for final body weight, overall average daily feed intake, and overall gain:feed. Pigs fed 14% FRM and 5% STR had the numerically greatest final body weight and ADG. In summary, increasing STR up to 4% improved performance, and greater levels of FRM can further improve performance when higher levels of STR are provided in the diet.

Background Endoscopic submucosal dissection (ESD) is a novel endoscopic treatment for early esophageal adenocarcinoma (EAC). The western pathologists’ experience with ESD specimens remains limited. This study aimed to correlate histopathologic features of Barrett’s esophagus (BE)-associated adenocarcinoma in ESD resections with clinical outcomes to determine whether they aid future management decisions. Methods We retrospectively evaluated 49 consecutive ESD resection specimens from 42 patients with BE-associated adenocarcinoma (24 intramucosal and 18 submucosal EAC) at a single tertiary referral center. Pathologic evaluation included presence of dysplasia, invasive adenocarcinoma, peritumoral inflammation, desmoplasia, lymphovascular and perineural invasion; tumor differentiation, depth of invasion, morphology, and budding; and margin status for dysplasia or carcinoma. Follow up data included endoscopic biopsies in 35 patients and pathology reports of esophagectomies in 11 patients. Poor outcomes were defined as recurrence or residual invasive adenocarcinoma at esophagectomy, metastasis on imaging, or R1 resection in patients undergoing ESD for tumor debulking. Results Two patients (8%) with intramucosal adenocarcinoma and 9 patients (50%) with submucosal adenocarcinoma had poor outcomes. Histopathologic features associated with poor outcomes included poor differentiation, lymphovascular invasion, submucosal invasion > 500 μm, tumor budding, and tubuloinfiltrative histologic pattern. Four patients had positive deep margin away from the deepest tumor invasion and did not show residual tumor on follow up. Conclusions Our results validated European Society of Gastroenterology (ESGE) guidelines of high-risk pathologic features for additional therapy in esophageal adenocarcinoma and identified tumor budding frequently in association with other high-risk features. Positive deep margin distant from deepest tumor invasion could be procedural and warrants endoscopic correlation for management.

Background Acute odontogenic infections are a common surgical emergency managed by public hospitals in Australia which cause considerable patient morbidity and occasionally, mortality. Despite posing a significant public health burden, Australian data evaluating the cost of the management of these patients are lacking. This study assessed the patient and treatment variables associated with inpatient management of deep odontogenic infections, and their respective financial impact, at a statewide Oral & Maxillofacial service. Methods A retrospective audit was carried out of patients with deep odontogenic infections at our institution, over a 7-year period. The primary outcome was the total cost of admission. Secondary outcomes included treatment received, operating room time, return-to-theatre, length of admission (LOS), and intensive care unit (ICU) use. Cost variables were assessed against the total LOS and ICU use to determine clinical predictors affecting outcome. Results Four hundred and sixty two patients met the inclusion criteria. The average cost per patient was $12 228 Australian Dollars. After multivariate analysis, variables most significantly associated with increased cost of care and LOS were high-risk infections with airway compromise, high admission white cell count and age. Conclusion Hospital-based management of deep-space odontogenic infections engender significant costs compared to early primary care intervention such as a dental extraction ($181/extraction).

Background Little is known about the perceptions of older adults with end-stage kidney disease (ESKD) on chronic hemodialysis (HD) even though this could potentially influence how treatment is received. This study explores the perceptions of older adults with ESKD on HD, specifically their decision to initiate HD, preconceptions and expectations of HD, perceived difficulties with HD, and coping strategies. Design: Cross–sectional Setting: Outpatient chronic dialysis units Participants: Older adults with ESKD on HD Intervention: Open-ended interviews were conducted with 15 participants. Inclusion criteria were age 60 years and older, HD duration of at least three months, and ability to consent and participate in the interview process. Results: We report on four identified domains: decision to initiate HD; preconceptions and expectations of HD; drawback of HD; and coping strategies. All participants were reluctant to initiate HD, but made the decision on advice from their physicians for varying reasons. Trust in physicians’ opinions also played a role for some. Some participants had positive preconceptions of HD, while a few had negative preconceptions or unrealistic expectations. Even though the majority of participants identified several difficulties with being on HD, they also had positive coping strategies, and the majority indicated that they would make the same decision to initiate HD. Conclusion: As clinicians are turning more to patient-centered medicine, understanding patients’ perceptions of HD is of crucial importance. Our study highlights the importance of improving pre-hemodialysis education to ensure that patients’ expectations are realistic, as well as identifying individualized coping strategies by patients.

A quenching agent is commonly added to chlorinated, reclaimed water during sample collection to prevent chlorine-mediated die-off of viable microbiota. However, the effect of quenching on downstream 16S rRNA-based bacterial community analyses is unclear. We conducted a side-by-side comparison of 16S rRNA sequencing data from reclaimed water samples quenched with sodium thiosulfate and non-quenched samples. Our data showed that 16 S rRNA processing and sequencing methods, and resulting bacterial profiles, were not negatively impacted by quenching.

The microbial quality of irrigation water has increasingly become a concern as a source of contamination for fruits and vegetables. Non-traditional sources of water are being used by more and more growers in smaller, highly diversified farms in the Mid-Atlantic region of the U.S. Shiga-toxigenic E. coli (STEC) have been responsible for several outbreaks of infections associated with the consumption of leafy greens. Our study evaluated the prevalence of the “big seven” STEC serogroups and the associated enterohemorrhagic E. coli (EHEC) virulence factors (VF) genes in conventional and nontraditional irrigation waters in the Mid-Atlantic region of the U.S. Water samples (n = 510) from 170 sampling events were collected from eight untreated surface water sites, two wastewater reclamation facilities, and one vegetable processing plant, over a 12-month period. Ten liters of water were filtered through Modified Moore swabs (MMS); swabs were then enriched into Universal Pre-enrichment Broth (UPB), followed by enrichment into non-O157 STEC R&F broth and isolation on R & F non-O157 STEC chromogenic plating medium. Isolates (n = 2489) from enriched MMS from water samples were screened for frequently reported STEC serogroups that cause foodborne illness: O26, O45, O103, O111, O121, O145, and O157, along with VF genes stx1, stx2, eae, and ehxA. Through this screening process, STEC isolates were found in 2.35% (12/510) of water samples, while 9.0% (46/510) contained an atypical enteropathogenic E. coli (aEPEC) isolate. The eae gene (n = 88 isolates) was the most frequently detected EHEC VF of the isolates screened. The majority of STEC isolates (stx1 or stx2) genes mainly came from either a pond or reclamation pond water site on two specific dates, potentially indicating that these isolates were not spatially or temporally distributed among the sampling sites. STEC isolates at reclaimed water sites may have been introduced after wastewater treatment. None of the isolates containing eae were determined to be Escherichia albertii. Our work showed that STEC prevalence in Mid-Atlantic untreated surface waters over a 12-month period was lower than the prevalence of atypical EPEC.

This study was designed to determine the response of Escherichia coli to three different nutrient sources. In this study, E. coli was exposed to concentrations of ammonia as ammonium chloride and nitrate as sodium nitrate at 0.5, 1.0 and 2.0 mg/L; and reagent grade urea at 10, 20 and 30 µg/L using bacterial concentrations of 10−1, 10−2 and 10−3 per ml. Cultures were incubated for 24 h at 37 °C. Samples were analyzed using a LACHET™ (800 Series) for ammonia-N, Nitrate-N and Urea-N which was converted to molar concentrations. Growth rates for E. coli were determined using serial dilutions, incubated on 3 M™ Petrifilm™ for 24 h at 37 °C with colony counts taken. The results showed that E. coli was able to utilize both ammonia and nitrate, with ammonium utilization significantly greater than nitrate. Ammonium utilization was directly proportional to concentration of ammonium chloride added and to some degree, the initial number of bacteria exposed. Nitrate utilization occurred at all concentrations and dilutions when compared with control concentrations and corresponded with concentrations of nitrate, but there was very little difference between bacterial dilutions. Urea production did occur but was unaffected by either concentration of urea or bacteria dilution. Positive growth rates were seen with ammonium with increasing growth rates as ammonium chloride concentrations were increased. Urea appeared to cause a slight decrease in growth, but nitrate was inconclusive with regard to growth.

Three comparative clinical studies assessed the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and safety of PF-06881893 (filgrastim-aafi; Nivestym™), a filgrastim biosimilar, versus US-licensed reference product (filgrastim; US-Neupogen®) in healthy volunteers (HVs). Two separate open-label, crossover-design PK/PD studies were conducted: a single-dose study (n = 24) and a multiple-dose study (n = 60). In each study, HVs were randomized to Nivestym followed by US-Neupogen, or vice versa. Study drug (5 μg/kg) was administered subcutaneously as a single injection or as five consecutive daily injections. Primary PK and PD endpoints were area under the filgrastim serum concentration–time curve, maximum observed concentration, area under the effect curve (AUEC) for absolute neutrophil count (ANC), maximum observed ANC, AUEC for cluster of differentiation (CD)-34+ count, and maximum observed CD34+ count. In an open-label, parallel-design, non-inferiority, comparative immunogenicity study, HVs were randomized (n = 128/treatment) to Nivestym or US-Neupogen. The primary endpoint was the proportion of subjects with a negative baseline antidrug antibody (ADA) test result and one or more confirmed post-dose positive ADA result. Overall demographics were as follows: female (n = 162/340); White (n = 274/340), Black (n = 58/340), and other (n = 8/340); age (18–65 years); and weight (50.8–96.5 kg). All primary PK and PD endpoints met the pre-specified criteria for PK and PD equivalence. The primary endpoint in the comparative immunogenicity study met pre-specified criteria for non-inferiority. Nivestym demonstrated PK and PD equivalence in single and multiple subcutaneous-dose settings and non-inferiority for immunogenicity to US-Neupogen, with a comparable safety profile, supporting the demonstration of biosimilarity. ClinicalTrials.gov C1121002 (NCT02766647); C1121003 (NCT02766634); C1121012 (NCT02923791).

Large trees are often seen as a means of offsetting negative consequences of growing urban densification. To increase the tree canopy cover of dense urban landscapes, developers, planners and urban tree managers are often forced to plant into damaged and compacted sites. Compacted urban soils can hinder the establishment and growth of deep rooted, woody plants by: 1) impeding root exploration and development which is critical for water and nutrient acquisition; 2) reducing infiltration of water into the soil and the availability of water to plants; and 3) reducing gas exchange and the balance between anaerobic and aerobic conditions. At three sites in Melbourne, Australia with compacted and damaged soils, we established four soil remediation treatments: 1 & 2) tillage to 0.25 m with and without 50% (v/v) municipal green waste compost (MGWC) additions, and 3 & 4) tillage to 0.5 m with and without 50% MGWC addition, plus a non-remediated control. Each treatment was replicated (n = 3), and one Corymbia maculata (spotted gum) tree was planted into the centre of each 2 × 2 m treatment plot (n = 15), at all three sites (n = 45). Bulk density and field-saturated hydraulic conductivity were improved by tillage, at least in the short-term. The use of MGWC may maintain these changes for longer. Depending on site soil conditions tree growth may be improved by tillage alone. At one site, we found that additions of MGWC lead to nitrogen immobilisation due to site soil conditions. At another site, deep tillage (with or without MGWC) led to significantly improved tree growth. Compacted and degraded urban soils may be improved through simple tillage and/or organic amendment strategies for the successful establishment of deep rooted woody plants. However, site soil conditions will dictate whether the addition of MGWC is beneficial or not, as one site showed no positive response to any tillage or MGWC. This research has examined a technique that can be used by landscape managers to improve soil physical characteristics and, in certain circumstances, can improve deep-rooted woody plant establishment and growth in challenging compacted urban soil conditions.

BACKGROUND Identification of people with HIV from electronic health record (EHR) data is an essential first step in the study of important HIV outcomes, such as risk assessment. This task has been historically performed via manual chart review, but the increased availability of large clinical data sets has led to the emergence of phenotyping algorithms to automate this process. Existing algorithms for identifying people with HIV rely on a combination of International Classification of Disease codes and laboratory tests or closely mimic clinical testing guidelines for HIV diagnosis. However, we found that existing algorithms in the literature missed a significant proportion of people with HIV in our data. OBJECTIVE The aim of this study is to develop and evaluate HIV-Phen, an updated criteria-based HIV phenotyping algorithm. METHODS We developed an algorithm using HIV-specific laboratory tests and medications and compared it with previously published algorithms in national and local data sets to identify cohorts of people with HIV. Cohort demographics were compared with those reported in the national and local surveillance data. Chart reviews were performed on a subsample of patients from the local database to calculate the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the algorithm. RESULTS Our new algorithm identified substantially more people with HIV in both national (up to an 85.75% increase) and local (up to an 83.20% increase) EHR databases than the previously published algorithms. The demographic characteristics of people with HIV identified using our algorithm were similar to those reported in national and local HIV surveillance data. Our algorithm demonstrated improved sensitivity over existing algorithms (98% vs 56%-92%) while maintaining a similar overall accuracy (96% vs 80%-96%). CONCLUSIONS We developed and evaluated an updated criteria-based phenotyping algorithm for identifying people with HIV in EHR data that demonstrates improved sensitivity over existing algorithms.

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Background: Gestating ewes consuming ergot alkaloids, from endophyte-infected (E+) tall fescue seed, produce smaller lambs suffering from intrauterine growth restriction. Arginine (Arg) supplementation has been shown to increase birth weight and oral citrulline (Cit) administration is reported to increase arginine concentrations. Two experiments were conducted to: 1) evaluate if oral supplementation with Cit or water, to ewes consuming E+ fescue seed, increases lamb birth weight and 2) determine the effectiveness of Cit and citrulline:malate as an oral drench in elevating circulating levels of Cit to determine dosing levels and frequency of dose. In Experiment 1, gestating Suffolk ewes (n = 10) were assigned to one of two treatments [oral drench of citrulline-malate 2:1 (CITM; 81 mg/kg/d of citrulline) or water (TOX)] to start on d 86 of gestation. In Experiment 2, non-pregnant Suffolk ewes (n = 3) were assigned to either oral citrulline (CIT; 81 mg/kg/d), citrulline-malate 2:1 (CITM; 81 mg/kg/d of citrulline), or water (CON) drench in a Latin Square design for a treatment period of 4 d with a washout period of 3 d. On d 4, blood samples were collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 18 h post drench.Results:Expt 1: Ewes on CITM treatment had decreased (P < 0.05) plasma Arg and Cit concentrations during gestation. At birth, lambs from CITM ewes had reduced (P < 0.05) crude fat and total fat but did not differ (P > 0.05) in birth weight from lambs born to TOX ewes. Expt 2: Oral drenching of CIT and CITM increased (P < 0.0001) Cit concentrations within 2 h and levels remained elevated for 8 h. Apparent half-life of elimination for CIT and CITM were 8.484 h and 10.392 h respectively.Conclusions: Our results show that lamb birth weight was not altered with a single oral drench of citrulline-malate; however, lamb body composition was altered. The level and frequency of citrulline dosing may need to be greater in order to observe consistent elevation of Cit/Arg concentrations to determine its effectiveness in mitigating fescue toxicosis.

Urea-nitrogen (N) is commonly applied to crop fields, yet it is not routinely monitored despite its association with reduced water quality and its ability to increase toxicity of certain phytoplankton species. The purpose of this work was to characterize temporal fluctuations in urea-N concentrations and associated environmental conditions to infer sources of urea-N in agricultural drainage ditches. Physicochemical properties and N forms in ditch waters were measured weekly during the growing seasons of 2015-2018. Fertilizer application was only associated with spring peaks of urea-N concentrations in ditches next to cornfields, whereas summer peaks in ditches adjacent to corn (Zea mays L.) and soybean [Glycine max (L.) Merr.] fields were not associated with fertilizer applications. Environmental conditions of warmer temperatures, lower dissolved oxygen concentrations, and lower redox potentials were correlated with higher urea-N concentrations. In 2018, peaks of urea-N and ammonium-N during the summer co-occurred with peaks of dissolved organic N and total dissolved N, suggesting they might be associated with the breakdown of organic matter and with the turnover of the organic N pool. Although the highest urea-N concentrations occurred when ditch surface waters were hydrologically disconnected from nearby streams, heavy rainfalls can potentially flush accumulated urea-N into coastal waters, where it may affect algal bloom toxicity. Therefore, implementation of available drainage ditch management practices is recommended, but these strategies need to be optimized for targeting periods with high rainfall that coincide with fertilizer additions as well as for periods with low rainfall that promote stagnant water conditions.