Adjudicating Mild Cognitive Impairment Due to Alzheimer's Disease as a Novel Endpoint Event in the TOMMORROW Prevention Clinical Trial.

BACKGROUND: The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer's disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. METHODS: The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant's clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages - independent review, collaborative review, and full committee review - requiring a unanimous decision and ratification by the chair. RESULTS: Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators' clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80-90% for the remainder of the study. CONCLUSIONS: The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.

Late-gestation protein restriction negatively impacts muscle growth and glucose regulation in steer progeny.

The objective of this study was to determine whether the amount of protein provided to cows during late gestation would affect postnatal growth and lead to changes in glucose and insulin concentrations. At 129 d of gestation, 10 mature multiparous Angus cows were stratified by body weight (BW) and body condition score (BCS) and allotted to either low protein level (LP, 6% crude protein [CP]) or high protein level (HP, 12% CP) groups. After calving, cows were managed together on improved pastures, which provided forage in excess of requirements until weaning. Male calves were maintained as a group after weaning on native range until 23 mo of age when individual steers were placed in single pens and fed a finishing diet for 84 d. The 12th rib fat thickness and longissimus muscle area were measured during finishing phase by ultrasound. Twenty days before the end of the finishing phase, steers were subjected to an intravenous glucose tolerance test. Steers were harvested and carcass characteristics collected. Cows' BW and BCS were similar at the initiation of treatment. During treatment HP dams gained 21 kg, whereas LP dams lost 7 kg (P = 0.04). Protein nutrition during late gestation did not influence calf birth weight, BW at weaning, adjusted 205 d BW, or average daily gain during lactation (P > 0.10). Longissimus muscle area measure by ultrasound was greater (P = 0.02) in HP steers at the beginning and end of finishing phase. Fat thickness of the 12th rib was not different (P > 0.10) between treatments. Glucose concentration after intravenous administration decreased (P = 0.002) in LP compared with HP steers. Peak of serum insulin concentration was greater (P = 0.04) and serum insulin concentration tended to decrease (P = 0.08) more rapidly in LP compared with HP steers after glucose infusion. At harvest, hot carcass weight was similar between treatments, but dressing percentage was increased (P = 0.05) in HP compared with LP steers. These data demonstrate that a lower protein nutrition level of dams during late gestation affect carcass characteristics and alter glucose regulation enhancing insulin secretion in steer progeny.

Frequency of Neospora caninum infections in beef cow-calf operations under extensive management.

The aim of this study was to evaluate the frequencies of Neospora caninum horizontal and vertical transmissions in beef cow-calf operations under three different extensive management systems: group A: 0.75 head per hectare pasturing on natural grass; group B: 1.1 head per hectare on natural grass and improved cultured pastures; and group C: 2 head per hectare on natural grass, improved cultured pasture and whole corn silage. Serum samples from 72 multiparous cows assigned to each beef cow-calf operations were obtained every 3 months during 2 years. A group of 30 replacement heifers from each group were tested similarly since they were 10-21 months old. Twenty four, 20 and 34 calves from groups A, B and C respectively, were bled before colostrum intake and again 6 months later. The samples were analyzed by indirect fluorescence antibody test (IFAT) for detection of total IgG against N. caninum at a serological titre ≥ 200 for multiparous cows and replacement heifers, and a serological titre ≥ 25 for calves. Serum samples from seropositive cows were assessed by ELISA to evaluate the avidity of their specific antibodies. There were no differences in the proportion of seropositive cows from groups A, B and C at the beginning of the trial (p>0.05). Interestingly, the lowest serological titres in seropositive cows from all groups were observed during the first trimester (p<0.05). Although seropositive cows had medium to high avidity antibodies, suggesting chronic infection; seroconversion associated with low antibody avidity was found in 2, 3 and 3 seropositive cows from groups A, B and C. All replacement heifers remained seronegative. No abortions were recorded but 2, 1, and 2 calves from groups A, B and C were seropositive before colostrum intake, respectively. Seropositive calves born from cows having intermediate or high avidity remained with the same serostatus at 6 months of age. Even under varying extensive management conditions, both N. caninum horizontal and vertical transmission methods do occur in beef cow-calf operations.