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A study was conducted to determine the response to feeding diets containing canola meal (CM) as a protein supplement in place of all or portions of dried distillers grains with solubles (DDGS). Twelve lactating Holstein cows (4 primiparous and 8 multiparous) were fed in a 4 × 4 Latin square design over 4-wk periods. Data were collected wk 3 and 4 of each period. Diets were formulated in which CM was 100, 66, 33, and 0% of the supplemental protein replacing the protein from DDGS. All diets (averaged 15.1% crude protein and 4.5% ether extract) contained 55% forage and 45% concentrate, with the forage being 50% corn silage and 50% alfalfa hay. Dry matter intake (25.4 kg/d) was similar for all diets. Milk production (35.2, 35.8, 34.5, and 34.3 kg/d, respectively, for 100, 66, 33, and 0% CM) was similar for all diets, but tended to be greater with higher proportions of CM. Milk protein concentration (3.04%), fat concentration (3.92%), and fat yield (1.37 kg/d) were similar for all diets, whereas protein yield (1.08, 1.10, 1.05, and 1.03 kg/d, respectively, for 100, 66, 33, and 0% CM) tended to be greater with increasing amounts of CM in the diet. Feed efficiency (1.46 kg of energy-corrected milk/kg of dry matter intake) was similar for all diets. Lysine was the first limiting amino acid for milk protein synthesis when CM or DDGS were fed, whereas methionine was first limiting when the combination diets were fed. Concentrations of ammonia and volatile fatty acids in ruminal contents were similar for all diets. Canola meal is a suitable replacement for DDGS in dairy cow diets. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine if exposure to high temperatures in water affects the viability of various silage inoculants. Inoculants were enumerated on De Man, Rogosa, Sharpe agar to standardize a final count (colony-forming units) in water such that about 500 mL added to 1 tonne of wet forage would achieve a recommended application rate of about 100,000 cfu of lactic acid bacteria (LAB) per gram of wet forage. Testing was done in 4 sequences (SEQ). For each SEQ, inoculants were mixed in deionized water for 45 min at 30°C followed by incubation for 6 h at 30°C (SEQ 1), 35°C (SEQ 2), 40° C (SEQ 3), or 45° C (SEQ 4) in duplicate 125-mL flasks rotating at 125 rpm. After 6 h, rotation was stopped and the temperature was lowered to 30° C for the next 18 h for all SEQ. Numbers of LAB were enumerated at 0, 3, 6, and 24 h. Each sequence was repeated twice. Incubation at a moderate temperature (SEQ 1) did not affect the viability of the microbial inoculants. The viability of the inoculants declined with increasing temperature (SEQ 2 to 4) but the effect varied by inoculant. For some inoculants exposure to 35°C resulted in substantial decreases in viable cells (loss of 0.5 to 1 log cfu/ mL). Incubation at higher temperatures resulted in even greater losses in viability for some inoculants. Losses of more than 0.5 log cfu/mL would most likely make the application of these inoculants ineffective in the field. LactobaciUus plantarum MTD/1 was the most thermotolerant organism tested, because it was unaffected by all temperatures (30 to 45°C) after 3 h of incubation. Lactobacillus plantarum MTD/1 and Lactobacillus buchneri 40788 also appeared to have better thermotolerance as their numbers substantially increased between 6 and 24 h in SEQ 4. These data show that some silage inoculants are more thermotolerant than others and that precautions should be taken to ensure that microbial inoculants that are applied to forage do not reach elevated temperatures during use. [ABSTRACT FROM AUTHOR]

Microbial inoculants used to improve the fermentation of silages are often mixed in water and stored in containers that may be exposed to heat from high ambient temperatures and mechanical equipment. The objective of this research was to determine if exposure to high temperatures affects the viability of various inoculants. Inoculants (A-F) were enumerated on Mann Rogosa Sharpe agar to standardize a final count of colony forming units (CFU) in water such that about 473 ml added to a tonne of wet forage would achieve the recommended application rates of lactic acid bacteria (LAB) for each inoculant. Testing was done in four sequences (SEQ). For each SEQ, inoculants were rehydrated in deionized water for 45 min at 30°C followed by incubation for 6 h at 30°C (SEQ 1), 35°C (SEQ 2), 40°C (SEQ 3) or 45°C (SEQ 4) in duplicate 125 ml flasks rotating at 125 rpm. Rotation was stopped and the incubator temperature was lowered to 30°C for the next 18 h. Numbers of LAB were enumerated at 0, 3, 6, and 24 h. Each sequence was repeated twice. Data were analyzed using the MIXED procedure of SAS with repeated measures (time). Data after the first 3 h of incubation for each SEQ is shown below (LAB, log cfu/ml). Incubation at a moderate temperature (SEQ 1) did not affect the viability of the microbial inoculants. However, as temperature of incubation increased, the stability of some inoculants declined varying by inoculant, especially in SEQ 4. Only inoculant A was unaffected by any high temperature after 3 h of incubation. Precautions should be taken to ensure that rehydrated microbial inoculants do not reach elevated temperatures during use and storage. [ABSTRACT FROM AUTHOR]

A normal corn silage hybrid (Mycogen FQ7511) was cut at a normal height (leaving 10-15 cm of stalk) or a high height (leaving 46-51 cm of stalk) and a BMR hybrid (F2F797) was harvested at a normal-cut height (leaving 10-15 cm of stalk). High cutting of FQ7511 increased the concentrations of DM (+4%), CP (+5%), NEL (+3%) and starch (+7%) but decreased the concentrations of ADF (-9%), NDF (-8%) and ADL (-13%) compared to normal-cut FQ7511. The 30 h NDF-D of normal-cut FQ7511, high-cut FQ7511 and normal-cut BMR corn silage was 51.7, 51.4, and 63.5%, respectively. Corn silages were fed to cows and comprised 45% of the TMR ration DM. Diets were isonitrogenous and isocaloric. Thirty Holstein cows (average 81 ± 48 DIM) were blocked by production and DIM and randomly assigned to ten simultaneous 3 × 3 Latin squares. Each period consisted of a 3-wk period and the data from last 10 d of each period was used for statistical analysis. Mean separation was performed using the Least Significant Difference procedure when the treatment effect was significant. Milk production, milk protein production and milk lactose % were greater (P < 0.05) for cows fed normal-cut BMR (48.8 kg/d, 1.40 kg/d, 4.88%) than for those fed normal-cut FQ7511 (46.8 kg/d, 1.34 kg/d, 4.82%) or high cut 7511 (47.7 kg/d, 1.36 kg/d, 4.83%). Cows fed high-cut FQ7511 had milk with less fat (3.48%) than cows fed high-cut silage (3.60%). Cows fed BMR corn silage tended to produce more (P < 0.12) 3.5% FCM than cows fed the other silages. Dry matter intake was not affected by treatment. Feed efficiency (kg of 3.5% FCM milk/kg of DMI) was greater (1.83, P < 0.05) for cows fed normal-cut BMR than those fed normal-cut 7511 (1.77) or high cut 7511 (1.75) corn silages. Cows fed normal-cut BMR had milk with a lower (P < 0.05) MUN (14.8 mg/dl) than did other treatments (average of 16.2 ml/dl). Harvesting a normal corn hybrid at a high-cut height improved its nutritive value but the improvement in feeding value to lactating cows was not equivalent to that found when cows were fed BMR corn silage harvested at a normal-cut height. [ABSTRACT FROM AUTHOR]

A brown midrib (BMR) hybrid and a silage-specific non-BMR (7511FQ) hybrid were harvested at a normal cut height leaving 10 to 15 cm of stalk in the field. The non-BMR hybrid was also cut at a greater height leaving 45 to 50 cm of stalk. Cutting high increased the concentrations of dry matter (+4%), crude protein (+5%), net energy for lactation (+3%), and starch (+7%), but decreased the concentrations of acid detergent fiber (-9%), neutral detergent fiber (-8%), and acid detergent lignin (-13%) for 7511FQ. As expected, the BMR corn silage was 30% lower in lignin concentration than 7511FQ. After 30 h of in vitro ruminal fermentation, the digestibility of neutral detergent fiber for normal cut 7511FQ, the same hybrid cut high, and the normal cut BMR hybrid were 51.7, 51.4, and 63.5%, respectively. Twenty-seven multiparous lactating cows were fed a total mixed ration composed of the respective silages (45% of dry matter) with alfalfa haylage (5%), alfalfa hay (5%), and concentrate (45%) (to make the TMR isocaloric and isonitrogenous) in a study with a 3 x 3 Latin square design with 21-d periods. Milk production was greater for cows fed the BMR hybrid (48.8 kg/d) compared with those fed the normal cut 7511FQ (46.8 kg/d) or cut high (47.7 kg/d). Dry matter intake was not affected by treatment. Feed efficiency for cows fed the BMR silage (1.83) was greater than for those fed high-cut 7511FQ (1.75), but was not different from cows fed the normal cut 7511FQ (1.77). Cows fed the BMR silage had milk with greater concentrations of lactose but lower milk urea nitrogen than cows on other treatments. Harvesting a silage-specific, non-BMR corn hybrid at a high harvest height improved its nutritive content, but the improvement in feeding value was not equivalent to that found when cows were fed BMR corn silage. [ABSTRACT FROM AUTHOR]

The major determinant of blood culture (BC) diagnostic performance is blood volume, and pediatric sample volumes are frequently low. We aimed to assess BC volumes in our institution, design an intervention to increase volumes, and assess its impact. All pediatric BCs submitted over a 7-month period to the microbiology laboratory in a university hospital (including emergency department, pediatric ward, and neonatal unit) were included. A pre-intervention period assessed current practice. A multi-faceted intervention (education, guideline introduction, active feedback strategies) was collaboratively designed by all stakeholders. Impact was assessed in a post-intervention period. The main outcome measures included the percentage of samples adequately filled using three measures of sample adequacy (1) manufacturer-recommended minimum validated volume-> 0.5 ml, (2) manufacturer-recommended optimal minimum volume-> 1.0 ml, (3) newly introduced age-specific recommendations. Three hundred ninety-eight pre-intervention and 388 post-intervention samples were included. Initial volumes were low but increased significantly post-intervention (median 0.77 ml vs. 1.52 ml), with multivariable regression analysis estimating volumes increased 89% post-intervention. There were significant increases in all measures of volume adequacy, including an increase in age-appropriate filling (20.4-53.1%), with less improvement in those aged > 3 years. Overall, 68.4% of pathogens were from adequately filled cultures, while 76% of contaminants were from inadequately filled cultures. A pathogen was detected in a higher proportion of adequately filled than inadequately filled cultures (9.4% vs. 2.2%, p < 0.001).  Conclusion: Blood volume impacts BC sensitivity, with lower volumes yielding fewer pathogens and more contaminants. Focused intervention can significantly improve volumes to improve diagnostic performance. What is Known: • Blood volume is the major determinant of blood culture positivity, and yet pediatric blood culture volumes are frequently low, resulting in missed pathogens and increased contamination. What is New: • Adequately filled (for age) blood cultures have a pathogen detection rate three times higher than inadequately filled blood cultures. • This interventional study shows that collaboratively designed multi-modal interventions including focus on accurate volume measurement can lead to significant increases in blood volumes and improve blood culture diagnostic performance., (© 2024. The Author(s).)

Toxoplasma gondii is an obligate intracellular parasite capable of causing severe disease due to congenital infection and in patients with compromised immune systems. Control of infection is dependent on a robust Th1 type immune response including production of interferon gamma (IFN-γ), which is essential for control. IFN-γ activates a variety of antimicrobial mechanisms in host cells, which are then able to control intracellular parasites such as T. gondii. Despite the effectiveness of these pathways in controlling acute infection, the immune system is unable to eradicate chronic infections that can persist for life. Similarly, while antibiotic treatment can control acute infection, it is unable to eliminate chronic infection. To identify compounds that would act synergistically with IFN-γ, we performed a high-throughput screen of diverse small molecule libraries to identify inhibitors of T. gondii. We identified a number of compounds that inhibited parasite growth in vitro at low μM concentrations and that demonstrated enhanced potency in the presence of a low level of IFN-γ. A subset of these compounds act by enhancing the recruitment of light chain 3 (LC3) to the parasite-containing vacuole, suggesting they work by an autophagy-related process, while others were independent of this pathway. The pattern of IFN-γ dependence was shared among the majority of analogs from 6 priority scaffolds, and analysis of structure activity relationships for one such class revealed specific stereochemistry associated with this feature. Identification of these IFN-γ-dependent leads may lead to development of improved therapeutics due to their synergistic interactions with immune responses.

Background: The emergence and spread of drug resistance to current antimalarial therapies remains a pressing concern, escalating the need for compounds that demonstrate novel modes of action. Diversity-Oriented Synthesis (DOS) libraries bridge the gap between conventional small molecule and natural product libraries, allowing the interrogation of more diverse chemical space in efforts to identify probes of novel parasite pathways., Methods: We screened and optimized a probe from a DOS library using whole-cell phenotypic assays. Resistance selection and whole-genome sequencing approaches were employed to identify the cellular target of the compounds., Results: We identified a novel macrocyclic inhibitor of Plasmodium falciparum with nanomolar potency and identified the reduction site of cytochrome b as its cellular target. Combination experiments with reduction and oxidation site inhibitors showed synergistic inhibition of the parasite., Conclusions: The cytochrome b oxidation center is a validated antimalarial target. We show that the reduction site of cytochrome b is also a druggable target. Our results demonstrating a synergistic relationship between oxidation and reduction site inhibitors suggests a future strategy for new combination therapies in the treatment of malaria., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.

Here, we describe the discovery of a novel antimalarial agent using phenotypic screening of Plasmodium falciparum asexual blood-stage parasites. Screening a novel compound collection created using diversity-oriented synthesis (DOS) led to the initial hit. Structure-activity relationships guided the synthesis of compounds having improved potency and water solubility, yielding a subnanomolar inhibitor of parasite asexual blood-stage growth. Optimized compound 27 has an excellent off-target activity profile in erythrocyte lysis and HepG2 assays and is stable in human plasma. This compound is available via the molecular libraries probe production centers network (MLPCN) and is designated ML238.