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BackgroundFragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy.DesignCONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS.MethodsPatients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist-Community Edition FXS (ABC-CFXS) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the FMR1 methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely.ResultsA total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the FMR1 promoter and full mutation of FMR1. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of FMR1 (nominal P = 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression-Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal P-values: P = 0.038, P = 0.028, and P = 0.002). Similar results were seen in patients with 100% methylation of FMR1. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%).ConclusionsIn CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe.Trial registrationThe CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663).

This study was designed to determine whether exposure to low-dose endotoxin (lipopolysaccharide; LPS) during gestation can enhance immunity to a subsequent LPS challenge in piglets after weaning. Pregnant sows (parity: 2.6 ± 1.4) were assigned to prenatal immune stimulation (PIS; n = 7; administered 2.5 µg/kg BW LPS, i.m.) or saline treatment groups (CON; n = 7) administered at day 78 ± 1.8 of gestation. From the two prenatal treatment groups, barrows (n = 17 PIS, 17 CON) were identified at weaning (21 ± 1.3 day of age) to subsequently receive a postweaning LPS challenge. On day --1, the pigs were fitted with indwelling jugular catheters and subcutaneous temperature loggers. On day 0, the pigs were challenged i.v. with LPS (10 µg/kg BW), and blood samples were collected at --2, 0, 1, 2, 4, 6, 8, 12, and 24 h relative to LPS challenge. There was a treatment x time interaction for subcutaneous temperature (P < 0.01), where the temperature increased more quickly at 1 and 2 h post-challenge in PIS compared to CON pigs. There was a tendency (P = 0.08) for less change in white blood cells, relative to baseline values, in PIS compared to CON pigs. There was a treatment x time interaction (P = 0.01) for lymphocyte concentrations where the concentrations were reduced in PIS compared to CON pigs at 8 h post-challenge. There was also a treatment x time interaction (P = 0.01) for the change in eosinophil concentrations, where there was less change in eosinophil concentrations from 1 to 12 h in PIS compared to CON pigs. There was a tendency (P ≤ 0.06) for a treatment x time interaction for serum interleukin-6 (IL-6) and IL-8. Granulocyte-macrophage colony-stimulating factor tended to be greater, and tumor necrosis factor-a tended to be reduced in PIS compared to CON pigs (P ≤ 0.08). These data suggest that exposure to endotoxin in utero may influence the postnatal innate immune response to endotoxin. More research is necessary to further understand the mechanism behind the differences observed and the potential long-term influence of prenatal immune stimulation on pig offspring. [ABSTRACT FROM AUTHOR]

Previous research demonstrated that lowdose endotoxin (LPS) administered during gestation can attenuate the postnatal response to LPS in weaned piglets. The follow-up study was designed to determine whether exposure to low dose LPS or a commercial Escherichia coli vaccine during gestation can alter immunity to an LPS challenge in piglets after weaning. Pregnant gilts were assigned to prenatal immune stimulation (PIS; n = 4; administered 2.5 µg/kg body weight (BW) LPS i.m. at d 77 ± 2.3 of gestation), vaccine (VAX; n = 3; administered LitterGuard-LTC i.m. at d 77 and 94 ± 1.7 of gestation), or saline treatment groups (CON; n = 3). From the three prenatal treatment groups, barrows (n = 13 PIS, 13 VAX, 14 CON) were identified at weaning (21 ± 1.9 d of age) to subsequently receive a post-weaning LPS challenge. On d -5, barrows were transported and housed in individual, indoor pens with ad libitum access to water and a starter ration. On d -1, pigs were fitted with indwelling jugular catheters and subcutaneous temperature loggers. On d 0, pigs were administered LPS (10 µg/kg BW i.v.), and blood samples were collected at -2, 0, 1, 2, 4, 6, 8, and 24 h relative to LPS challenge. Data were analyzed using PROC MIXED in SAS, specific for repeated measures. There was a tendency (P = 0.10) for a treatment effect for sow vaginal temperature, measured using indwelling logger, where PIS sows had greater vaginal temperature than CON sows, with VAX being intermediate. There was a treatment × time interaction (P = 0.02) for the change in lymphocyte concentration relative to pre-challenge values, where PIS piglets had less change in lymphocyte concentrations at 2 and 4 h compared with CON, and 8 h compared with CON and VAX piglets. Additionally, there was a treatment effect (P = 0.01) for neutrophil: lymphocyte ratio, where PIS piglets had a greater ratio compared with CON and VAX piglets. There was a treatment × time interaction (P = 0.04) for piglet subcutaneous body temperature, where PIS piglets had reduced temperature from 3 to 5 h compared with CON, and at 2 and from 4 to 7 h compared with VAX piglets. There was a tendency (P = 0.09) for a treatment effect for spleen length measured 24 h post-LPS administration where length was shorter in PIS compared with CON piglets, with VAX being intermediate. While data analysis continues for this study, these initial data support previous data suggesting an attenuated immune response to postnatal LPS when pigs are exposed to LPS in utero. Further, pigs exposed to an E. coli vaccine during gestation appear to respond similarly to CON pigs. These data add to available information on the ability to alter immunity of pigs in utero in an effort to positively influence piglet health after birth. [ABSTRACT FROM AUTHOR]

In a three-round Delphi, secondary agriculture teachers and administrators, field staff and agriculture teacher educators (n=31, 33, 29) compiled a list of 102 tasks for early field experiences and student teaching experiences in agricultural education. The list is comprehensive enough for the three states where it was developed and flexible enough for local needs. (SK)

South Carolina agriculture teachers (n=78) ranked 50 teaching competencies. Top needs of beginning teachers (less than 5 years experience) were using advisory committees, developing adult education programs, fundraising, preparing contest teams, and developing supervised agricultural experience. Experienced teachers needed help using computers in teaching, using multimedia, and teaching recordkeeping. (Contains 17 references.) (SK)

Beef carcasses with non-normal color costs the United States industry billions of dollars annually. While dark cutters have long been attributed to long-term stress and glycogen depletion, few studies have aimed to understand other potential metabolomic markers of dark and light-colored beef. The objective of this study was to determine the metabolomic profile of carcasses possessing dark, intermediate, normal, and light lean according to RGB instrumental color evaluation. Over 9 consecutive months, 216 carcasses (n = 24/ mo) from 4 color categories were collected from 2 commercial abattoirs. Carcasses were identified using L* values from industry grading cameras. Carcasses were classified into categories based on the least L* value from either side: dark (L* ≤ 55; n = 53), intermediate (55 < L* < 60; n = 54), normal (60 ≤ L* < 80; n = 54), or light (L* ≥ 80; n = 54). A 5.08 cm steak was collected from the longissimus lumborum from both carcass sides. Steaks were aged until 5 d postmortem, snapfrozen and homogenized into a powder. Metabolites were extracted by weighing 50 mg of sample into a tube with 50 μL of ribitol and 1.5 mL of 80% methanol and homogenized using a bead beater. Sample extract was dried with nitrogen gas before being reconstituted with 50 μL of methoxyamine hydrochloride and 50 μL of N-methyl-N-trimethylsilyltrifluoroacetamide with 1% trimethylchlorosilane. Untargeted metabolomics was conducted via gas chromatography-mass spectrometry. Mass spectral data were deconvoluted, aligned, and annotated using MS-DIAL. Total ion counts were normalized by the internal standard and log10 transformed prior to analysis. Data were analyzed using MetaboAnalyst by analysis of variance. Pathway analyses were conducted using the KEGG Bos taurus pathway library. Significance for all analyses was declared at FDR P < 0.05. Metabolite analyses identified 137 total features with 74 identified by the reference library and 45 were differentially expressed between carcass color categories. Malic acid was greatest in dark carcasses and least in normal and light carcasses (FDR P < 0.05). 1-methylgalactose, beta-D-galactose, sorbose, and phosphohexonoic acid was greatest in light carcasses, second in normal, third in intermediate, and least in dark carcasses (FDR P < 0.05). [ABSTRACT FROM AUTHOR]