Impact Of Low-Frequency HIV-1 Drug Resistance Mutations On Antiretroviral Therapy Outcomes.

BACKGROUND: The association between low-frequency HIV-1 drug resistance mutations (DRMs) and treatment failure (TF) is controversial. We explore this association using NGS methods that accurately sample low-frequency DRMs. METHODS: We enrolled women with HIV-1 in Malawi who were either ART naïve (A), had ART failure (B), or had discontinued ART (C). At entry, A and C began an NNRTI-based regimen and B started a PI-based regimen. We used Primer ID MiSeq to identify regimen-relevant DRMs in entry and TF plasma samples, and a Cox proportional hazards model to calculate hazard ratios (HRs) for entry DRMs. Low-frequency DRMs were defined as ≤ 20%. RESULTS: We sequenced 360 participants. Cohort B and C participants were more likely to have TF than Cohort A participants. The presence of K103N at entry significantly increased TF risk among A and C participants at both high and low frequency, with HR of 3.12 [1.58-6.18, 95% CI] and 2.38 [1.00-5.67, 95% CI] respectively. At TF, 45% of participants showed selection of DRMs while in the remaining participants there was an apparent lack of selective pressure from ART. CONCLUSIONS: Using accurate NGS for DRM detection may benefit an additional 10% of the patients by identifying low-frequency K103N mutations.

Evaluating the Rumen Degradation of Novel Protected Gelatin Capsules Containing Fish Oil Fed to Lactating Dairy Cows.

The objective of this study was to assess the effects of feeding gelatin capsules containing fish oil, treated with alcoholic solutions of flavoring agents followed by drying, on lactation performance, rumen fatty acids content and milk enrichment of fatty acids. In Trial 1, four multiparous ruminally fistulated Holstein cows were randomly assigned to one of four dietary treatments sequences in a 4 × 4 Latin square design. Treatments consisted of (1) Control with no capsules, (2) Control plus 200 untreated capsules per cow/day, mixed with the TMR, (3) Control plus 200 treated capsules per cow/day placed directly into the rumen, (4) Control plus 200 treated capsules per cow/day, mixed with the TMR. In Trial 2, three fistulated Holstein and three fistulated Jersey multiparous cows were randomly assigned to three dietary treatments sequences in a replicated 3 × 3 Latin square design. Treatments consisted of (1) Control with no capsules fed to the cows, (2) Control plus 180 untreated capsules per cow/day, (3) Control plus 180 treated capsules per cow/day. Compared to control, feeding fish oil capsules significantly (Trial 1) or numerically (Trial 2) reduced milk fat concentration and yield. Furthermore, in both trials, the feeding of untreated or treated capsules had no effect on animal performance or milk composition. In both trials, compared to controls, supplementing the diet with fish oil capsules consistently increased total trans C18:1 isomers and DHA concentration in the rumen and milk fat. However, for both trials, capsule protection treatment had a minimal effect on the concentration of any of the reported rumen and milk fatty acids. When assessed under laboratory control conditions, due to water absorption, the treated capsule weight was increased by 40% while resistance to pressure decreased by 84% after 2 h of incubation in water. The results of this study suggest that due to a reduction in the capsule shell's resistance to abrasion, treated capsules marginally prevented the release of fish oil in the rumen.

Assessing the Differential Abundance of Maternal Circulating MicroRNAs or Interferon-Stimulated Genes with Early Pregnancy.

Interferon-stimulated genes (ISG) and microRNA (miRNA) present in maternal circulation have been reported to be diagnostic of pregnancy in cattle prior to day (d)30 of gestation. The objective of this study was to assess specific ISG and miRNA abundance on d 18 of gestation. Cattle were subjected to estrous synchronization and artificially inseminated to a single Angus sire. At time of insemination (d 0) and d 18 post-insemination, blood was collected and total RNA isolated. Differential abundance (DA) in specific ISG and miRNA between d 0 and d 18 samples in pregnant (n = 10) and open (n = 10) cows were assessed via RT-qPCR. The relative Ct values were normalized using abundance of cyclophilin or the geometric mean of specific miRNA for the ISG and miRNA genes of interest, respectively. The DA of the ISG were increased due to pregnancy (p < 0.05); however, there was no expected day of gestation by pregnancy interaction. Relative abundance of Bta-miR-16 increased on d18 regardless of pregnancy status (p < 0.05). None of the miRNA evaluated in this study were associated with pregnancy status. These data indicate that certain ISG may serve as early indicators of pregnancy in cattle, but abundance of the miRNA does not.

Antibimicrobial Susceptibility of Trimethoprim-Sulfamethoxazole and 3rd-Generation Cephalosporin-Resistant Escherichia coli Isolates Enumerated Longitudinally from Feedlot Arrival to Harvest in High-Risk Beef Cattle Administered Common Metaphylactic Antimicrobials.

Multidrug resistant (MDR) Escherichia coli threaten the preservation of antimicrobials to treat infections in humans and livestock. Thus, it is important to understand where antimicrobial-resistant E. coli persist and factors that contribute to its their development. Crossbred cattle (n = 249; body weight = 244 kg ±25 kg standard deviation) were blocked by arrival date and assigned metaphylactic antimicrobial treatments of sterile saline control, tulathromycin (TUL), ceftiofur, or florfenicol at random. Trimethoprim-sulfamethoxazole (COTR) and third-generation cephalosporin (CTXR)-resistant E. coli were isolated from fecal samples on days 0, 28, 56, 112, 182, and study END (day 252 for block 1 and day 242 for block 2). Then, susceptibility testing was conducted on all confirmed isolates. MDR was detected in both COTR and CTXR E. coli isolates. In COTR isolates, the number of antimicrobials each isolate was resistant to and the minimum inhibitory concentration (MIC) for amoxicillin-clavulanic acid, ceftriaxone, and gentamicin was greatest on day 28 compared with all other days (p ≤ 0.04). Similarly, chloramphenicol MIC was greater on day 28 than on day 0 (p < 0.01). Overall, sulfisoxazole MIC was less for TUL than all other treatments (p ≤ 0.02), and trimethoprim-sulfamethoxazole MIC was greater for TUL than all other treatments (p ≤ 0.03). Finally, there was no effect of treatment, day, or treatment × day for tetracycline or meropenem MIC (p ≥ 0.07). In CTXR isolates, there was an effect of day for all antimicrobials tested except ampicillin and meropenem (p ≤ 0.06). In conclusion, administering a metaphylactic antimicrobial at feedlot arrival did influence the susceptibility of COTR and CTXR E. coli. However, MDR E. coli are widely distributed, and the MIC for most antimicrobials was not different from the initial value upon completion of the feeding period.

Use of Next-Generation Sequencing in a State-Wide Strategy of HIV-1 Surveillance: Impact of the SARS-COV-2 Pandemic on HIV-1 Diagnosis and Transmission.

BACKGROUND: The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic posed an unpreceded threat to the management of other pandemics such as human immunodeficiency virus-1 (HIV-1) in the United States. The full impact of the SARS-CoV-2 pandemic on the HIV-1 pandemic needs to be evaluated. METHODS: All individuals with newly reported HIV-1 diagnoses from NC State Laboratory of Public Health were enrolled in this prospective observational study, 2018-2021. We used a sequencing-based recency assay to identify recent HIV-1 infections and to determine the days postinfection (DPI) for each person at the time of diagnosis. RESULTS: Sequencing used diagnostic serum samples from 814 individuals with new HIV-1 diagnoses spanning this 4-year period. Characteristics of individuals diagnosed in 2020 differed from those in other years. People of color diagnosed in 2021 were on average 6 months delayed in their diagnosis compared to those diagnosed in 2020. There was a trend that genetic networks were more known for individuals diagnosed in 2021. We observed no major integrase resistance mutations over the course of the study. CONCLUSIONS: SARS-CoV-2 pandemic may contribute to the spread of HIV-1. Public health resources need to focus on restoring HIV-1 testing and interrupting active, ongoing, transmission.

Effects of Exogenous Glucocorticoid Infusion on Appetitic Center Development in Postnatal Dairy Bull Calves.

The objective of this study was to determine the effects of exogenous glucocorticoid administration on leptin concentrations and brain development markers, such as protein and hypothalamic gene expression, in dairy bull calves. Within 4 h of parturition, Holstein bulls were intravenously infused with either a low cortisol dose (LC; n = 9, 3.5 µg/kg of body weight (BW)), high cortisol dose (HC; n = 9, 7.0 µg/kg BW), or control (CON; n = 9, saline) dose, with a 2nd infusion 24 h postpartum. Jugular blood was collected prior to infusion and daily until the calves were euthanized (day 5). Cerebrospinal fluid (CSF) from the third ventricle and adipose (omental, perirenal, and mesenteric) and hypothalamic tissue were collected. The blood and CSF samples were analyzed for leptin concentrations. The data were analyzed using SAS. Serum (p = 0.013) and CSF (p = 0.005) leptin concentrations in HC- and LC-treated calves were decreased compared with CON-treated calves. Leptin protein expression was decreased (p < 0.044) in perirenal and omental adipose tissue of LC-treated calves compared with CON-treated calves. Gene abundance of brain-derived neurotrophic factor and fibroblast growth factors 1 and 2 were decreased (p < 0.006) in HC- and LC-treated calves compared with CON-treated calves. In summary, cortisol administered to dairy bull calves reduced leptin concentrations, decreased leptin protein expression in perirenal and omental adipose tissue, and altered gene expression in hypothalamic tissue.

Comparison of the 7-day CO-Synch and 8-day estradiol-based protocols for estrus synchronization and timed artificial insemination in suckled Bos taurus cows.

Two experiments were conducted to compare, follicle diameter (FD) on Day -1, corpus luteum (CL) area on Day 7, progesterone (P4) concentration on Day 7 and 18, pregnancy per timed artificial insemination (TAI) on Day 30, and pregnancy loss (PL) between Days 30 and 60 after TAI (TAI, Day 0) using two different synchronization protocols. In Experiment 1, Angus cows (n = 1148) were randomly assigned to either 7-d progesterone CO-Synch (7-d CO-Synch) or 8-d progesterone + estradiol (8-d P + ES) synchronization protocols for TAI. On Day -10, cows in the 7-d CO-Synch treatment group (n = 574) received a progesterone-releasing intravaginal device (PIVD; 0.5 g P4) and GnRH (0.105 mg), on Day -3 the PIVD was removed and cows received cloprostenol (0.150 mg), then, on Day 0 (64 h after PIVD removal), cows received GnRH (0.105 mg) and were TAI. On Day -10, cows in the 8-d P + ES treatment group (n = 574) received a PIVD (0.5 g P4) and estradiol benzoate (2.0 mg), on Day -2 the PIVD was removed, and cows received cloprostenol (0.150 mg) and estradiol cypionate (0.5 mg), then, on Day 0 (48 h after PIVD removal), cows were TAI. Pregnancy per TAI was determined on Days 30 and 60. In a subset of cows (7-d CO-Synch, n = 41; 8-d P + ES, n = 40), serum P4 concentration was evaluated on Day 18. In Experiment 2, anestrus (n = 34) and cyclic (n = 34) suckled beef cows were selected and submitted at random on Day -10, to either 7-d CO-Synch or 8-d P + ES treatment groups. Follicle diameter on Day -1, CL area, and serum P4 concentration on Day 7 were determined. In Experiment 1, pregnancy per TAI on Day 30 did not differ (7-d CO-Synch = 48.9%; 8-d P + ES = 45.6%) between treatments but it was greater for cows with BCS ≥5 (P < 0.01). Pregnancy loss between Days 30 and 60 did not differ between treatment groups but tended to be greater in cows with BCS <5.0 (P < 0.1). In a subset of cows, serum P4 concentration on Day 18 did not differ between treatment groups but tended to be lower (P < 0.1) in cows that had PL between Days 30 and 60 compared to cows that had no PL. In Experiment 2, FD tended to be greater (P < 0.1) and CL area was greater (P = 0.05) in anestrus cows from 7-d CO-Synch treatment. In cyclic cows, the treatment did not affect the FD or CL area. In conclusion, there was no difference in pregnancy per TAI on Day 30 and PL between Days 30 and 60 between cows using 7-d CO-Synch + PIVD or 8-d estradiol-based + PIVD protocols for estrus synchronization and TAI.

Evolution Driven By A Varying Host Environment Selects For Distinct HIV-1 Entry Phenotypes and Other Informative Variants.

HIV-1 generates remarkable intra- and inter-host viral diversity during infection. In response to dynamic selective pressures of the host environment, HIV-1 will evolve distinct phenotypes - biological features that provide fitness advantages. The transmitted form of HIV-1 has been shown to require a high density of CD4 on the target cell surface (as found on CD4+ T cells) and typically uses CCR5 as a co-receptor during entry. This phenotype is referred to as R5 T cell-tropic (or R5 T-tropic); however, HIV-1 can switch to a secondary co-receptor, CXCR4, resulting in a X4 T cell-tropic phenotype. Macrophage-tropic (or M-tropic) HIV-1 can evolve to efficiently enter cells expressing low densities of CD4 on their surface (such as macrophages/microglia). So far only CCR5-using M-tropic viruses have been found. M-tropic HIV-1 is most frequently found within the central nervous system, and infection of the CNS has been associated with neurological impairment. It has been shown that interferon resistance phenotypes have a selective advantage during transmission, but the underlying mechanism of this is still unclear. During untreated infection, HIV-1 evolves under selective pressure from both the humoral/antibody response and CD8+ T cell killing. Sufficiently potent antiviral therapy will suppress viral replication, but if the antiviral drugs are not sufficiently potent to stop replication then the replicating virus will evolve drug resistance. HIV-1 phenotypes are highly relevant to treatment efforts, clinical outcomes, vaccine studies, and cure strategies. Therefore, it is critical to understand the dynamics of the host environment that drive these phenotypes and how they affect HIV-1 pathogenesis. This review will provide a comprehensive discussion of HIV-1 entry, transmission, and drug resistance phenotypes. Finally, we will assess the methods used in previous and current research to characterize these phenotypes.

The effects of administering different metaphylactic antimicrobials on growth performance and health outcomes of high-risk, newly received feedlot steers.

Bovine respiratory disease (BRD) is the primary animal health concern facing feedlot producers. Many antimicrobial mitigation strategies are available, but few studies have compared feedlot performance during both the receiving and finishing periods following application of different antimicrobials used as metaphylaxis at arrival. The objective of this study was to compare antimicrobial metaphylaxis methods on clinical health and growth performance across both the receiving and finishing periods. A total of 238 multiple-sourced steers in two source blocks were used in a generalized complete block design. The four treatments included: 1) a negative control, 5 mL of sterile saline injected subcutaneously (CON); 2) subcutaneous administration of florfenicol at 40 mg/kg of BW (NUF); 3) subcutaneous administration of ceftiofur in the posterior aspect of the ear at 6.6 mg/kg of BW (EXC); and 4) subcutaneous administration of tulathromycin at 2.5 mg/kg of BW (DRA). The morbidity rate for the first treatment of BRD was decreased for the DRA and EXC treatments compared to CON and NUF (P < 0.01). Additionally, average daily gain (ADG), dry matter intake (DMI), and gain-to-feed (G:F) were greater (P ≤ 0.02) in the DRA treatment during the receiving period compared to all other treatments. The ADG was also greater (P < 0.05) for EXC than the CON treatment throughout the finishing period. Nonetheless, other growth performance variables did not differ among metaphylactic treatments during the finishing period (P ≥ 0.14). Likewise, no differences in carcass characteristics or liver abscess score were observed (P ≥ 0.18). All complete blood count (CBC) variables were affected by day (P ≤ 0.01) except mean corpuscular hemoglobin concentration (P = 0.29). Treatment × time interactions were observed for platelet count, white blood cell (WBC) count, monocyte count and percentage, and lymphocyte percentage (P ≤ 0.03). However, there were no observed hematological variables that differed among treatment (P ≥ 0.10). The results indicate that some commercially available antimicrobials labeled for metaphylactic use are more efficacious than others in decreasing morbidity rate.

Metaphylactic antimicrobial effects on occurrences of antimicrobial resistance in Salmonella enterica, Escherichia coli and Enterococcus spp. measured longitudinally from feedlot arrival to harvest in high-risk beef cattle.

AIMS: Our objective was to determine how injectable antimicrobials affected populations of Salmonella enterica, Escherichia coli and Enterococcus spp. in feedlot cattle. METHODS AND RESULTS: Two arrival date blocks of high-risk crossbred beef cattle (n = 249; mean BW = 244 kg) were randomly assigned one of four antimicrobial treatments administered on day 0: sterile saline control (CON), tulathromycin (TUL), ceftiofur (CEF) or florfenicol (FLR). Faecal samples were collected on days 0, 28, 56, 112, 182 and study end (day 252 for block 1 and day 242 for block 2). Hide swabs and subiliac lymph nodes were collected the day before and the day of harvest. Samples were cultured for antimicrobial-resistant Salmonella, Escherichia coli and Enterococcus spp. The effect of treatment varied by day across all targeted bacterial populations (p ≤ 0.01) except total E. coli. Total E. coli counts were greatest on days 112, 182 and study end (p ≤ 0.01). Tulathromycin resulted in greater counts and prevalence of Salmonella from faeces than CON at study end (p ≤ 0.01). Tulathromycin and CEF yielded greater Salmonella hide prevalence and greater counts of 128ERYR E. coli at study end than CON (p ≤ 0.01). No faecal Salmonella resistant to tetracyclines or third-generation cephalosporins were detected. Ceftiofur was associated with greater counts of 8ERYR Enterococcus spp. at study end (p ≤ 0.03). By the day before harvest, antimicrobial use did not increase prevalence or counts for all other bacterial populations compared with CON (p ≥ 0.13). CONCLUSIONS: Antimicrobial resistance (AMR) in feedlot cattle is not caused solely by using a metaphylactic antimicrobial on arrival, but more likely a multitude of environmental and management factors.

Effects of physical activity and feed and water restriction at reimplanting time on feed intake patterns, growth performance, and carcass characteristics of finishing beef steers.

In the feedlot, there can be a decrease in dry matter intake (DMI) associated with reimplanting cattle that negatively affects growth performance. This study was conducted to determine the mechanisms causing a decrease in DMI after reimplanting and identify a strategy to mitigate the decrease. Crossbred steers (n = 200; 10 pens/treatment; initial bodyweight [BW] = 386 ±â€…4.9 kg) were used in a randomized complete block design experiment. Cattle were implanted with Revalor-IS on day 0. Treatments included a Revalor-200 implant on day 90 before feeding with the following management practices imposed: 1) steers were returned to their home pen immediately after reimplant (PCON); 2) steers were placed in pens and restricted from feed and water for 4 h (RES); 3) steers were walked an additional 805 m after reimplant and then returned home (LOC); 4) steers were restricted from feed and water for 4 h and walked an additional 805 m (RES + LOC); 5) steers were given an oral bolus of Megasphaera elsdenii (Lactipro; MS Biotec, Wamego, KS) and were restricted from feed and water for 4 h, and then walked an additional 805 m (LACT). One hundred steers were given an ear tag to record minutes of activity (ESense Flex Tags, Allflex Livestock Intelligence, Madison, WI). As a percentage of BW, DMI was 5% greater (P = 0.01) from reimplant to end for PCON vs. RES, LOC, and RES + LOC treatments. Likewise, as a percentage of BW, DMI was 6.6% greater (P = 0.03) from reimplant to end and 4.0% greater (P = 0.05) overall for the PCON treatment vs. the LOC treatment. Overall, DMI as a percentage of BW was 3.3% greater (P = 0.02) for PCON vs. RES, LOC, and RES + LOC treatments. There was an increase in G:F from reimplant to end (P = 0.05) for RES + LOC vs. the LACT treatment. From these data, we conclude that restricting cattle from feed and water for 4 h after reimplanting did not alter subsequent DMI. Increasing locomotion had the greatest negative effect on DMI and growth performance. Management strategies to decrease locomotion associated with reimplanting would be beneficial to DMI and overall growth performance of finishing beef steers.

Effects of postweaning supplementation of immunomodulatory feed ingredient on circulating cytokines and microbial populations in programmed fed beef heifers.

The objective was to determine the effects of an immunomodulatory feed ingredient following weaning on cytokine expression and fecal microbial populations of heifers. Commercial Angus heifers (n = 72) were weaned (227 ± 7 d of age), blocked by BW (n = 9 blocks), and randomly assigned to one of two pens per block. Pens within weight block (four heifers per pen) were then randomly assigned to treatments. Heifers were fed twice daily from days 0 to 60 (to gain 0.75 kg/d) and top dressed with either 18 g/heifer/d of the immunomodulatory feed ingredient (Celmanax; Arm and Hammer Animal Nutrition, Princeton, NJ; CEL) or corn-germ meal (CON). Blood samples were collected on days 0, 15, 30, 45, 60 and fecal grab samples on day 0 of the feeding trial. After day 60, two heifers per pen (n = 32) were randomly selected for a transportation challenge. Serum samples were collected at hours 0, 4, 8, 12 and fecal grab samples at hours -24, 0, 24 and 7 d postchallenge. Blood samples were analyzed for interferonγ (IFNγ), interleukin-8 (IL-8), and haptoglobin (HP) using commercially available ELISA kits and qRT-PCR for genes of interest associated with cytokine expression. Fecal samples were enumerated for Clostridia and E. coli using selective media (≤5 isolates from each media/sample), tested to determine whether they were Clostridium perfringens or pathogenic E. coli, and then enriched for detection of Salmonella. Data were analyzed via ANOVA. During the feeding trial, HP was reduced (P = 0.018) in CEL compared with CON at days 15, 45, and 60, whereas IFNγ and IL-8 did not differ (P > 0.080) between treatments. All cytokines were decreased (P < 0.001) in CEL compared with CON during the challenge. During the feeding trial, HP mRNA was increased (P = 0.045) in CEL compared with CON at days 30 and 60. Similarly, IFNγ mRNA was increased (P = 0.040) in CEL compared with CON; however, other genes of interest did not differ (P > 0.172). Both C. perfringens and total E. coli counts were decreased (P = 0.036) in CEL compared with CON at 24 h after the start of the transportation challenge. Clostridia and pathogenic E. coli counts did not differ (P = 0.941) between treatments. Total Clostridia and E. coli counts were increased (P < 0.014) 24 h postchallenge. All microbial populations, except pathogenic E. coli, observed decreased (P ≤ 0.009) counts from 24 h to 7 d postchallenge. Overall, Celmanax supplementation decreased circulating cytokines, and altered microbial populations and gene expression, thus, may serve a role in preparing animals to better cope with immunological challenges.

With consumers wanting less antibiotic usage in cattle production, the need for natural feed ingredients that have positive effects on animal health are needed. The feeding of a yeast-based feed product decreased cytokines in the blood and their mRNA expression in white blood cells that act on stimulating an inflammatory response. When an animal has an inflammatory response, their immune system is working harder than necessary. This means they are using energy that could otherwise be used for growth, which decreases efficiency and performance. The feeding of this yeast-based feed ingredient also reduced the amount of harmful bacteria in the feces of the heifers. Having lower amounts of harmful bacteria (such as Salmonella) in the feces decreases the chance of carcass contamination. For consumers, this means less instances of food-borne illnesses.

Age at First Gestation in Beef Heifers Affects Fetal and Postnatal Growth, Glucose Metabolism and IGF1 Concentration.

This study aimed to determine the effects of age at first gestation on offspring growth performance, glucose metabolism, and IGF1 concentration. Heifers impregnated by AI from a single bull at 15 months of age (15 M, n = 20), or 27 months of age (27 M, n = 20), and multiparous cows (adult, n = 20) were used. Dams from all groups were managed in a single group during gestation and lactation. Gestational length was longer in the 15 M and 27 M than in adult dams (p = 0.009). Bodyweight at birth, at weaning and ADG during lactation were higher in calves from adult dams than in those from 27 M dams, and higher in calves from the latter than in 15 M calves (p < 0.001). Calves from 15 M dams had an increased head circumference/BW ratio compared to calves from 27 M dams, while calves from this latter group had an increased ratio compared to calves from adults (p = 0.005). Body mass index was greater in calves from adults than in those from 15 M and 27 M dams (p = 0.002). Milk production from 15 M and 27 M dams was similar but lower than that from adults (p = 0.03). Calves born from adult dams had greater blood glucose concentrations than those from 15 M and 27 M dams (p < 0.05). Serum IGF1 concentrations were higher in calves from adults than in calves from 15 M and 27 M dams (p = 0.01). This study showed that age at first gestation affects offspring postnatal growth performance, glucose metabolism and IGF1 concentration.

Thiazolidinediones: An In-Depth Study of Their Synthesis and Application to Medicinal Chemistry in the Treatment of Diabetes Mellitus.

2,4-Thiazolidinedione (TZD) is a privileged and highly utilised scaffold for the development of pharmaceutically active compounds. This sulfur-containing heterocycle is a versatile pharmacophore that confers a diverse range of pharmacological activities. TZD has been shown to exhibit biological action towards a vast range of targets interesting to medicinal chemists. In this review, we attempt to provide insight into both the historical conventional and the use of novel methodologies to synthesise the TZD core framework. Further to this, synthetic procedures utilised to substitute the TZD molecule at the activated methylene C5 and N3 position are reviewed. Finally, research into developing clinical agents, which act as modulators of peroxisome proliferator-activated receptors gamma (PPARγ), protein tyrosine phosphatase 1B (PTP1B) and aldose reductase 2 (ALR2), are discussed. These are the three most targeted receptors for the treatment of diabetes mellitus (DM).

The Effects of Age at Weaning and Length of Lipid Supplementation on Growth, Metabolites, and Marbling of Young Steers.

The objective of this study was to determine how weaning age, days on supplements, and lipid supplementation affected the growth and marbling deposition of steers. Steers from a single sire were early weaned (n = 24) at 150 ± 11 days of age or traditionally weaned (n = 24) at 210 ± 11 days of age. Steers were assigned to control (n = 12/weaning group) or an isocaloric, isonitrogenous rumen by-pass lipid (RBL, n = 12/weaning group) for either 45 (n = 6/treatment) or 90 (n=6/treatment) days then harvested. Steer body weight (BW) was recorded on days -14 and -7, then BW and blood samples were collected on days 0, 22, 45, 66, and 90. The right rib section of each animal was collected for proximate analysis. Longissimus dorsi from RBL steers had increased lipids compared with control steers (3.6 ± 0.2 vs. 2.4 ± 0.2% on a wet basis; p < 0.0001). Steers fed for 90 days had greater (p = 0.02) concentrations of Longissimus dorsi lipid (3.3 ± 0.2%) than those fed for 45 days (2.7 ± 0.2%). There was a weaning age by treatment by days on feed interaction for intramuscular adipocyte diameter (p = 0.02) in which early weaned RBL fed for 90 days steers had an increased adipocyte diameter compared to the early weaned control fed for 90 and early weaned fed for 45 days steers with all other treatment groups as intermediates. Supplementation of RBL increased concentrations of C18:2, C20:4, and total fatty acids on days 45 and 90 (p ≤ 0.05). Data show that RBL supplementation increased the marbling content of the Longissimus dorsi. Furthermore, a longer period of supplementation resulted in increased adipose diameter.

Eclipse stemless shoulder prosthesis vs. Univers II shoulder prosthesis: a multicenter, prospective randomized controlled trial.

BACKGROUND: Total shoulder arthroplasty is an accepted treatment for glenohumeral osteoarthritis. The Arthrex Eclipse shoulder prosthesis is a stemless, canal-sparing humeral prosthesis with bone ingrowth capacity on the trunnion, as well as through the fenestrated hollow screw, that provides both diaphyseal and metaphyseal load sharing and fixation. METHODS: Between 2013 and 2018, 16 sites in the United States enrolled 327 patients (Eclipse in 237 and Arthrex Univers II in 90). All patients had glenohumeral arthritis refractory to nonsurgical care. Strict exclusion criteria were applied to avoid confounding factors such as severe patient comorbidities, arthritis not consistent with osteoarthritis, and medical or prior surgical treatments that may have affected outcomes. Patients were randomized to the Eclipse or Univers II group via block randomization. RESULTS: In total, 149 Eclipse and 76 Univers II patients reached 2-year follow-up (139 Eclipse patients [93.3%] and 68 Univers II patients [89.5%] had complete data). The success rate using the Composite Clinical Success score was 95% in the Eclipse group vs. 89.7% in the Univers II group. No patient exhibited radiographic evidence of substantial humeral radiolucency, humeral migration, or subsidence at any point. Reoperations were performed in 7 patients (3.2%) in the Eclipse group and 3 (3.8%) in the Univers II group. CONCLUSION: The Arthrex Eclipse shoulder prosthesis is a safe and effective humeral implant for patients with glenohumeral arthritis at 2-year follow-up, with no differences in outcomes compared with the Univers II shoulder prosthesis.

Maternal energy status during late gestation: Effects on growth performance, carcass characteristics and meat quality of steers progeny.

The objetive of the current study was to determine the effect of maternal energy status during late gestation on growth performance, carcass characteristics and meat quality of steer progeny. At 180 ±â€¯4 d of gestation 56 multiparous Angus cows were blocked by BW and expected calving date and asigned to three levels of nutrition energy: SR (severe restricted; 50% of NRC requirement), MR (moderate restricted; 75% of requirement) and NR (no restricted; 100% of requirement). After parturition, all cows were managed in a single group during lactation. A total of 25 male calves (SR = 8 calves; MR = 9 calves; NR = 8 calves) were born from pregnant cows and all pens had at least one male calf. After weaning, male calves were separated of female calves and were stockered on native range until 24 ±â€¯0.1 months of age then placed into a feedlot for 104 d before harvest. Cow BW and BCS decreased linearly (P < .01) as nutritional energy restriction increased. Calves from SR dams were lighter (P = .04) than calves from MR and NR dams at parturition, however, at weaning and harvest BW was similar for SR and NR steers and decreased in MR steers. Steers from SR dams demonstrated catch-up growth with a tendecy to increased ADG from birth to harvest compared to MR and NR steers (P = .06). Hot carcass weigth was similar in SR and NR steers and increased in MR steers (P = .01). Longissimus muscle area was not affected (P > .10) by maternal energy status, however, 12 rib fat thickness was greater in SR and MR compared to NR steers (P < .01). Tenderness of Longissimus muscle was decreased in MR compared to SR and NR steers after 3d of aging. No treatment differences (P > .10) were observed in sarchomere length or collagen content. Adipocyte diameter was similar (P > .10) between treatments suggesting that decreased 12th rib fat thicness in MR steers could be due to decreased fat tissue hyperplasia. These results indicate that level of energy restriction during late gestation does no have linear response on growth performance and carcass quality of steers progeny.

The influence of protein restriction during mid- to late gestation on beef offspring growth, carcass characteristic and meat quality.

The objective of this study was to determine whether crude protein intake during the last three months of gestation affects growth performance, carcass characteristics and meat quality of steer progeny. At 134 ±â€¯14 d of gestation, 68 multiparous Angus cows were blocked by BW and expected calving date and randomly assigned to diets that contained either low or high dietary crude protein concentrations and were allotted in 12 pens per treatment. After calving, cows were managed together on improved pastures during lactation. After weaning at 219 ±â€¯13 d of age, steers calves were stockered on natural pastures until 687 ±â€¯13 d of age then placed into a feedlot for 83d before slaughter. Maternal dietary protein concentration had no influence on offspring body weight and growth rate during rearing or finishing phases (P > .10). Rib fat thickness of steers was not affected (P = .38) by maternal nutrition treatments, however, LM area was greater in HP steers than LP steers at entrance into the feedlot (P = .01) and end of finishing phase (P = .04). Hot carcass weight was similar between treatments (P = .69), however dressing percentage was increased in HP relative to LP steers (P = .01). Tenderness of Longissimus muscle was increased in HP compared to LP steers after 3 and 14d (P < .001) of aging. No treatment differences in troponin-t degradation (P = .77) and collagen content (P = .58) were observed. Muscle fiber diameter was similar in LP and HP steers (P = .20), suggesting that increase of LM area in HP steers could be due to muscle hyperplasia. These data indicated that level of protein during mid to late gestation does not affect offspring growth but has impacts on carcass composition and meat quality of steer progeny.

Ergot alkaloid exposure during gestation alters. I. Maternal characteristics and placental development of pregnant ewes1.

Tall fescue [Lolium arundinaceum (Scheyreb.) Darbysh] is the primary cool season forage grass in the Southeastern United States. Most tall fescue contains an endophytic fungus (Epichloë coenophiala) that produces ergot alkaloids and upon ingestion induces fescue toxicosis. The objective of this study was to assess how exposure to endophyte-infected (E+; 1.77 mg hd-1 d-1 ergovaline and ergovalinine) or endophyte-free (E-; 0 mg hd-1 d-1 ergovaline and ergovalinine) tall fescue seed fed during 2 stages of gestation (MID, days 35-85/LATE, days 86-133) alters placental development. Thirty-six, fescue naïve Suffolk ewes were randomly assigned to 1 of 4 fescue treatments: E-/E-, E-/E+, E+/E-, or E+/E+. Ewes were individually fed the same amount of E+ or E- seed mixed into total mixed ration during MID and LATE gestation. Terminal surgeries were conducted on day 133 of gestation. Ewes fed E+ fescue seed had elevated (P < 0.001) ergot alkaloid excretion and reduced (P < 0.001) prolactin levels during the periods when fed E+ seed. Ewes switched on day 86 from E- to E+ seed had a 4% reduction (P = 0.005) in DMI during LATE gestation, which translated to a 2% reduction (P = 0.07) in DMI overall. Average daily gain was also reduced (P = 0.049) by 64% for E-/E+ ewes during LATE gestation and tended to be reduced (P = 0.06) by 33% overall. Ewes fed E+ seed during LATE gestation exhibited a 14% and 23% reduction in uterine (P = 0.03) and placentome (P = 0.004) weights, respectively. Caruncle weights were also reduced by 28% (P = 0.003) for E-/E+ ewes compared with E-/E- and E+/E-. Ewes fed E+ seed during both MID and LATE gestation exhibited a 32% reduction in cotyledon (P = 0.01) weights, whereas ewes fed E+ seed only during MID gestation (E+/E-) had improved (P = 0.01) cotyledon weights. The percentage of type A placentomes tended to be greater (P = 0.08) for E+/E+ ewes compared with other treatments. Other placentome types (B, C, or D) did not differ (P > 0.05). Total fetal weight per ewe was reduced (P = 0.01) for ewes fed E+ seed during LATE gestation compared with E-; however, feeding E+ seed during MID gestation did not alter (P = 0.70) total fetal weight per ewe. These results suggest that exposure to ergot alkaloids during LATE (days 86-133) gestation has the greatest impact on placental development by reducing uterine and placentome weights. This, in turn, reduced total fetal weight per ewe by 15% in ewes fed E+ seed during LATE gestation (E-/E+ and E+/E+).

Impact of slick hair trait on physiological and reproductive performance in beef heifers consuming ergot alkaloids from endophyte-infected tall fescue1.

Fescue toxicosis is a multifaceted syndrome common in cattle grazing endophyte-infected tall fescue. The objective of this study was to evaluate the impact of the slick hair trait on physiological and reproductive parameters in heifers experiencing fescue toxicosis. Angus × Senepol heifers (n = 31) were blocked by weight (393.5 ± 17.3 kg) and phenotype relative to hair coat at birth, and randomly fed novel endophyte fescue (EN) or endophyte-infected fescue (EI) haylage in a total mixed ration for 91 d. Weekly measurements were collected to monitor heifer growth and response during ergot alkaloids exposure. Following 28 d of treatment, estrus was synchronized and heifers were inseminated. Ovary mapping and AI pregnancy rate were examined via transrectal ultrasonography. Blood samples were taken for genotyping: slick (S) or wildtype (W). Data were analyzed using repeated measures in PROC MIXED of SAS including fescue treatment (EN vs. EI), genotype (S vs. W), and sample collection time as main effects. Body condition scores were decreased for W heifers compared with S heifers (5.48 vs. 5.66, respectively; P < 0.0001). Surface temperature was greater for EI-W heifers (37.2 °C) compared with other groups (36.4, 36.6, 36.7 °C for EN-S, EN-W, EI-S, respectively; P < 0.05). Serum PRL concentrations were reduced for EI heifers compared with EN heifers (133.5 vs. 163.1 ng/mL, respectively; P < 0.05). The average number of 2 to 4 mm follicles were greater in EI-W heifers (13.8 follicles) compared with other groups (12.2, 10.6, and 11.1 for EN-S, EN-W, and EI-S, respectively; P < 0.0001). However, the average number of preovulatory follicles (≥9 mm) were reduced in EI-W heifers (0.52 follicles) compared with other heifer groups (0.94, 0.88, and 0.85 ± 0.04 for EN-S, EN-W, and EI-S, respectively; P < 0.05). Ovulatory follicle size was smaller in EI-W heifers compared with EN-W heifers (9.14 vs. 11.57 mm, respectively; P = 0.05). Corpus luteum area was reduced in EI-W heifers (235.1 mm2) compared with other heifer groups (297.2, 272.7, and 276.8 mm2 for EN-S, EN-W, and EI-S, respectively; P < 0.05). Concentrations of P4 were greater for EN heifers compared with EI heifers (2.7 vs. 1.8 ng/mL, respectively; P < 0.05). Pregnancy was not established in EI-W heifers (0%) compared with other heifer groups (37.5%, 57.1%, and 62.5% for EN-S, EN-W, and EI-S, respectively; P < 0.05). Overall, the slick hair mutation appears to aid in offsetting the physiological symptoms associated with fescue toxicosis and helps to improve reproductive performance.