Amyloid and Tau Prediction of Cognitive and Functional Decline in Unimpaired Older Individuals: Longitudinal Data from the A4 and LEARN Studies.

BACKGROUND: Converging evidence suggests that markers of Alzheimer's disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes. OBJECTIVES: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay. DESIGN: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aß+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aß-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks. SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia. PARTICIPANTS: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aß+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aß+ underwent tau PET imaging in A4 (n=350). Aß- were enrolled into the LEARN Study (n=553). MEASUREMENTS: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo). RESULTS: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aß- and A4 Aß+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models. CONCLUSIONS: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.

Longitudinal Phospho-tau217 Predicts Amyloid Positron Emission Tomography in Asymptomatic Alzheimer's Disease.

BACKGROUND: Blood-based AD biomarkers such as plasma P-tau217 are increasingly used in clinical trials as a screening tool. OBJECTIVES: To assess the utility of an electrochemiluminescence (ECL) immunoassay in predicting brain amyloid PET status in cognitively unimpaired individuals. SETTING: Plasma samples collected at baseline, week 12, and week 240 or endpoint originated from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. PARTICIPANTS: Both A4 and LEARN enrolled eligible cognitively unimpaired persons 65 to 85 years. Individuals with elevated brain amyloid PET levels were eligible for the A4 Study, while those without elevated brain amyloid PET levels were eligible for the LEARN Study. INTERVENTION: Participants in the A4 Study received intravenous solanezumab (up to 1600 mg) or placebo every 4 weeks. The LEARN Study is an observational study without intervention. MEASUREMENTS: Plasma P-tau217 concentration levels from A4 Study participants were measured using an ECL immunoassay. Receiver Operating Characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by ≥22 CL and ≥ 33 CL. RESULTS: Receiver operating characteristic curve (ROC) analysis indicates high diagnostic value of P-tau217 in individuals with amyloid PET ≥ 20 (Area under the ROC (AUROC): 0.87) and ≥ 33 CL (AUROC: 0.89). Repeated testing with the placebo group taken 12 weeks apart (range: 68 to 143 days) and the LEARN participants taken between 1.4 and 1.75 years resulted in a strong positive correlation (Corr. 0.91 (0.90 to 0.92)). CONCLUSION: An ECL immunoassay testing plasma P-tau217 accurately predicts amyloid PET positivity in cognitively unimpaired individuals. Our future analyses aim to determine if use of this assay may reduce the screening burden of preclinical individuals into anti-amyloid clinical trials.

Relationship between Plasma P-Tau217 and Amyloid PET in Racial and Ethnic Underrepresented Groups (RE-URG) Compared with Non RE-URG in LEARN and A4.

BACKGROUND: Individuals from diverse racial and ethnic groups are severely underrepresented in Alzheimer's disease trials in part due to disproportionate biomarker ineligibility. Evidence from recent studies support plasma phosphorylated tau 217 (P-tau217) as an early marker for brain Aß pathology and a reliable marker in predicting elevated brain amyloid PET in cognitively unimpaired adults. OBJECTIVES: To examine whether the relationship between P-tau217 and 18-F florbetapir PET standard uptake value ratios (SUVR) is influenced by race and ethnicity in the Anti-Amyloid treatment in Asymptomatic Alzheimer's disease (A4) preclinical AD studies. DESIGN: We conducted a retrospective analysis of A4 clinical trial and the LEARN natural history companion study data to evaluate the relationship between baseline P-tau217 and PET SUVR concentration levels by race and ethnicity. SETTING: The analysis was conducted on samples from participants enrolled across 65 study sites in the United States and Canada. PARTICIPANTS: Cognitively unimpaired adults aged 65-85 enrolled at North American sites in the A4 preclinical AD trial, pre-dose, (N=1018), and the LEARN (N=480) study. Participants were grouped into 2 categories, racial and ethnic underrepresented group (RE-URG) and non-RE-URG (nRE-URG) based on self-identification. MEASUREMENTS: A mixed-effects regression model was fit to determine differences in the relationship between P-tau217 and PET SUVR by race and ethnicity, adjusting for age, and APOE ε4 carrier status. RESULTS: Results from the linear mixed-effects model support that there was no statistically significant effect of race and ethnicity on the relationship between P-tau217 and PET SUVR. CONCLUSION: These findings suggest that the relationship between plasma P-tau217 and PET SUVR is the same across race and ethnicity. Future analyses should corroborate these findings in a larger sample and examine whether plasma P-tau217 reflects the differential amyloid prevalence previously reported for other biomarkers of amyloid.

A Geospatial Analysis of Social and Structural Determinants of Health and High HIV Prevalence in Alabama, USA.

OBJECTIVE: This study utilizes geospatial analytic techniques to examine HIV hotspots in Alabama leveraging Medicaid utilization data. METHODS: This cross-sectional study leveraged Medicaid utilization data from Alabama's 67 counties, averaging 9,861 Medicaid recipients aged > 18 years old per county. We used Alabama Medicaid administrative claims data from January 1, 2016, to December 31, 2020, to identify individuals with HIV. Using Microsoft SQL Server, we obtained the average annual count of HIV Medicaid claims in each of the 67 Alabama counties (numerator) and the number of adult Medicaid recipients in each county (denominator), and standardized with a multiplier of 100,000. We also examined several other area-level summary variables (e.g., non-high school completion, income greater than four times the federal poverty level, social associations, urbanicity/rurality) as social and structural determinants of health. County-boundary choropleth maps were created representing the geographic distribution of HIV rates per 100,000 adult Medicaid recipients in Alabama. Leveraging ESRI ArcGIS and local indicators of spatial association (LISA), results were examined using local Moran's I to identify geographic hotspots. RESULTS: Eleven counties had HIV rates higher than 100 per 100,000. Three were hotspots. Being an HIV hotspot was significantly associated with relatively low educational attainment and less severe poverty than other areas in the state. CONCLUSIONS: Findings suggesting that the HIV clusters in Alabama were categorized by significantly less severe poverty and lower educational attainment can aid ongoing efforts to strategically target resources and end the HIV epidemic in U.S.' Deep South.

Transcriptomic analyses of joint tissues during osteoarthritis development in a rat model reveal dysregulated mechanotransduction and extracellular matrix pathways.

OBJECTIVE: Transcriptomic changes in joint tissues during the development of osteoarthritis (OA) are of interest for the discovery of biomarkers and mechanisms of disease. The objective of this study was to use the rat medial meniscus transection (MMT) model to discover stage and tissue-specific transcriptomic changes. DESIGN: Sham or MMT surgeries were performed in mature rats. Cartilage, menisci and synovium were scored for histopathological changes at 2, 4 and 6 weeks post-surgery and processed for RNA-sequencing. Differentially expressed genes (DEG) were used to identify pathways and mechanisms. Published transcriptomic datasets from animal models and human OA were used to confirm and extend present findings. RESULTS: The total number of DEGs was already high at 2 weeks (723 in meniscus), followed by cartilage (259) and synovium (42) and declined to varying degrees in meniscus and synovium but increased in cartilage at 6 weeks. The most upregulated genes included tenascins. The 'response to mechanical stimulus' and extracellular matrix-related pathways were enriched in both cartilage and meniscus. Pathways that were enriched in synovium at 4 weeks indicate processes related to synovial hyperplasia and fibrosis. Synovium also showed upregulation of IL-11 and several MMPs. The mechanical stimulus pathway included upregulation of the mechanoreceptors PIEZO1, PIEZO2 and TRPV4 and nerve growth factor. Analysis of data from prior RNA-sequencing studies of animal models and human OA support these findings. CONCLUSION: These results indicate several shared pathways that are affected during OA in cartilage and meniscus and support the role of mechanotransduction and other pathways in OA pathogenesis.

Amyloid-Related Imaging Abnormalities and Other MRI Findings in a Cognitively Unimpaired Population With and Without Cerebral Amyloid.

BACKGROUND: Screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies provide a unique opportunity to compare magnetic resonance imaging (MRI) findings such as amyloid-related imaging abnormalities (ARIA) in cognitively unimpaired elderly with and without elevated cerebral amyloid. OBJECTIVES: To compare screening MRI findings, such as ARIA, in the cognitively unimpaired potential participants of a clinical trial with and without elevated cerebral amyloid. DESIGN: Cross-sectional analysis of structural MRI findings in screening data from the A4 and LEARN studies. SETTING: The A4 Study is a multi-center international clinical trial. The LEARN Study is a multi center observational study in the United States. PARTICIPANTS: Clinically normal older adults (65-85 years) with elevated cerebral amyloid (Aß+; n = 1250, A4) and without elevated cerebral amyloid (Aß-; n = 538, LEARN). MEASUREMENTS: Participants underwent florbetapir positron emission tomography for Aß+/- classification. A centrally read 3T MRI to assess for study eligibility was conducted on study qualified MRI scanners. RESULTS: No ARIA-effusions (ARIA-E) was detected on screening MRI in the Aß+ or Aß- cohorts. At least one ARIA-H (microhemorrhages [MCH] or superficial siderosis [SS]) was present in 18% of the Aß+ cohort compared with 8% in Aß- (P < 0.001). In the Aß+ cohort, approximately 2% of screening MRIs demonstrated MCH ≥4 compared with 0% in Aß-. The presence of two apolipoprotein E ε4 (APOEε4) alleles (vs no ε4 alleles) in the Aß+ cohort increased the odds for presence of MCH (odds ratio [OR] = 2.03; 95% CI, 1.23 to 3.27, P = 0.004). Cortical infarctions (4% vs 0%) and subcortical infarctions (10% vs 1%) were observed at statistically significantly higher prevalence in the Aß+ cohort compared with Aß- (P < 0.001). Females showed reduced odds of MCH in the Aß+ cohort by a factor of 0.63 (95% CI, 0.47 to 0.84, P = 0.002). CONCLUSIONS: ARIA-E is rare in cognitively unimpaired Aß+ and Aß- populations prior to anti-amyloid drug intervention. ARIA-H in Aß+ was greater than in Aß- populations.

Everyday Functioning and Entorhinal and Inferior Temporal Tau Burden in Cognitively Normal Older Adults.

BACKGROUND: Performance of cognitively complex "instrumental activities of daily living" (IADL) has previously been related to amyloid deposition in preclinical Alzheimer's disease. OBJECTIVES: We aimed to investigate the relationship between IADL performance and cerebral tau accumulation in cognitively normal older adults. DESIGN: Cross-sectional. SETTING: Data was collected in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. PARTICIPANTS: Participants (n = 447, age 71.9±4.9 years, 57.5% female) who underwent tau positron emission tomography were selected from the A4 and LEARN studies. MEASUREMENTS: IADL performance was measured using the self- and study partner-reported versions of the Alzheimer's Disease Cooperative Study Activities of Daily Living - Prevention Instrument (ADCS ADL-PI). We also investigated discordance between participants and their study partners. Cross-sectional associations between entorhinal and inferior temporal tau (independent variables) and ADCS ADL-PI total scores, item-level scores and discordance (dependent variables) were investigated in linear and logistic regressions. Analyses were adjusted for age, sex and education and a tau by amyloid interaction was also included. RESULTS: Participants and their study partners reported high levels of IADL performance. Entorhinal and inferior temporal tau were related to study partner but not to self-reported total ADCS ADL-PI scores. The association was not retained after adjustment for global cerebral amyloid burden. At the item level, greater entorhinal tau was associated with study partner-reported difficulties remembering important dates (odds ratio (OR) = 1.24, 95% confidence interval (95%CI) = [1.06, 1.45], p = 0.008) and difficulties remembering the details of TV programs and movies (OR = 1.32, 95%CI = [1.08, 1.61], p = 0.007). Greater inferior temporal tau was associated with self-reported difficulties managing to find personal belongings (OR = 1.23, 95%CI = [1.04, 1.46], p = 0.018) and study partner-reported difficulties remembering the details of TV programs and movies (OR = 1.39, 95%CI = [1.11, 1.75], p = 0.005). Discordance between participant and study partner-report was more likely with greater entorhinal (OR = 1.18, 95%CI = [1.05, 1.33], p = 0.005) and inferior temporal tau burden (OR = 1.29, 95%CI = [1.10, 1.51], p = 0.002). DISCUSSION: We found a cross-sectional relationship between study partner-reported everyday functioning and tau in cognitively normal older adults. Participants were more likely to self-report difficulties differently from their study partners when tau burden was higher. This may hint at an altered early-disease awareness of functional changes and underscores the importance of self-report of IADL functioning in addition to collateral report by a study partner.

Item-Level Investigation of Participant and Study Partner Report on the Cognitive Function Index from the A4 Study Screening Data.

BACKGROUND: Greater subjective cognitive changes on the Cognitive Function Index (CFI) was previously found to be associated with elevated amyloid (Aß) status in participants screening for the A4 Study, reported by study partners and the participants themselves. While the total score on the CFI related to amyloid for both sources respectively, potential differences in the specific types of cognitive changes reported by either participants or their study partners was not investigated. OBJECTIVES: To determine the specific types of subjective cognitive changes endorsed by participants and their study partners that are associated with amyloid status in individuals screening for an AD prevention trial. DESIGN, SETTING, PARTICIPANTS: Four thousand four hundred and eighty-six cognitively unimpaired (CDR=0; MMSE 25-30) participants (ages 65-85) screening for the A4 Study completed florbetapir (Aß) Positron Emission Tomography (PET) imaging. Participants were classified as elevated amyloid (Aß+; n=1323) or non-elevated amyloid (Aß-; n=3163). MEASUREMENTS: Prior to amyloid PET imaging, subjective report of changes in cognitive functioning were measured using the CFI (15 item questionnaire; Yes/Maybe/No response options) and administered separately to both participants and their study partners (i.e., a family member or friend in regular contact with the participant). The impact of demographic factors on CFI report was investigated. For each item of the CFI, the relationship between Aß and CFI response was investigated using an ordinal mixed effects model for participant and study partner report. RESULTS: Independent of Aß status, participants were more likely to report 'Yes' or 'Maybe' compared to the study partners for nearly all CFI items. Older age (r= 0.06, p<0.001) and lower education (r=-0.08, p<0.001) of the participant were associated with higher CFI. Highest coincident odds ratios related to Aß+ for both respondents included items assessing whether 'a substantial decline in memory' had occurred in the last year (ORsp= 1.35 [95% CI 1.11, 1.63]; ORp= 1.55 [95% CI 1.34, 1.79]) and whether the participant had 'seen a doctor about memory' (ORsp= 1.56 [95% CI 1.25, 1.95]; ORp =1.71 [95% CI 1.37, 2.12]). For two items, associations were significant for only study partner report; whether the participant 'Repeats questions' (ORsp = 1.30 [95% CI 1.07, 1.57]) and has 'trouble following the news' (ORsp= 1.46[95% CI 1.12, 1.91]). One question was significant only for participant report; 'trouble driving' (ORp= 1.25 [95% CI 1.04, 1.49]). CONCLUSIONS: Elevated Aß is associated with greater reporting of subjective cognitive changes as measured by the CFI in this cognitively unimpaired population. While participants were more likely than study partners to endorse change on most CFI items, unique CFI items were associated with elevated Aß for participants and their study partners, supporting the value of both sources of information in clinical trials.

Assessing attention orienting in mice: a novel touchscreen adaptation of the Posner-style cueing task.

Atypical attention orienting has been found to be impaired in many neuropsychological disorders, but the underlying neural mechanism remains unclear. Attention can be oriented exogenously (i.e., driven by salient stimuli) or endogenously (i.e., driven by one's goals or intentions). Genetic mouse models are useful tools to investigate the neurobiology of cognition, but a well-established assessment of attention orienting in mice is missing. This study aimed to adapt the Posner task, a widely used attention orienting task in humans, for use in mice using touchscreen technology and to test the effects of two attention-modulating drugs, methylphenidate (MPH) and atomoxetine (ATX), on the performance of mice during this task. In accordance with human performance, mice responded more quickly and more accurately to validly cued targets compared to invalidly cued targets, thus supporting mice as a valid animal model to study the neural mechanisms of attention orienting. This is the first evidence that mice can be trained to voluntarily maintain their nose-poke on a touchscreen and to complete attention orienting tasks using exogenous peripheral cues and endogenous symbolic cues. The results also showed no significant effects of MPH and ATX on attention orienting, although MPH improved overall response times in mice during the exogenous orienting task. In summary, the current study provides a critical translational task for assessing attention orienting in mice and to investigate the effects of attention-modulating drugs on attention orienting.

Neurofibroma of the ulnar nerve in the carpal canal in a dog: treatment by marginal neurectomy.

Peripheral nerve sheath tumours arising in the plexus or peripheral nerves can be treated by limb amputation. There are few reports of these tumours affecting peripheral nerves in the distal regions of the limbs. Here we describe a case of neurofibroma affecting the palmar branch of the ulnar nerve in an Irish setter. Surgical treatment in the region of the carpus by ulnar neurectomy resulted in resolution of chronic thoracic limb lameness. At 11 months following the surgery, clinical examination and MRI did not detect any evidence of recurrence. Neurectomy may be a feasible option for management of selected cases of distally located peripheral nerve sheath tumours.

Consistency of feed efficiency ranking and mechanisms associated with inter-animal variation among growing calves.

This study investigated the possible mechanisms for explaining interanimal variation in efficiency of feed utilization in intact male Holstein calves. Additionally, we examined whether the feed efficiency (FE) ranking of calves (n = 26) changed due to age and/or diet quality. Calves were evaluated during three periods (P1, P2, and P3) while fed a high-quality diet (calculated mobilizable energy [ME] of 11.8 MJ/kg DM) during P1 and P3, and a low-quality diet (calculated ME of 7.7 MJ/kg DM) during P2. The study periods were 84, 119, and 127 d, respectively. Initial ages of the calves in P1, P2, and P3 were 7, 11, and 15 mo, respectively, and initial body weight (BW) were 245, 367, and 458 kg, respectively. Individual dry matter intake (DMI), average daily gain (ADG), diet digestibility, and heat production (HP) were measured in all periods. The measured FE indexes were: residual feed intake (RFI), the gain-to-feed ratio (G:F), residual gain (RG), residual gain and intake (RIG), the ratio of HP-to-ME intake (HP/MEI), and residual heat production (RHP). For statistical analysis, animals' performance data in each period, were ranked by RFI, and categorized into high-, medium-, and low-RFI groups (H-RFI, M-RFI, and L-RFI). RFI was not correlated with in vivo digestibility, age, BW, BCS, or ADG in all three periods. The L-RFI group had lowest DMI, MEI, HP, retained energy (RE), and RE/ADG. Chemical analysis of the longissimus dorsi muscle shows that the L-RFI group had a higher percentage of protein and a lower percentage of fat compared to the H-RFI group. We suggested that the main mechanism separating L- from H-RFI calves is the protein-to-fat ratio in the deposited tissues. When efficiency was related to kg/day (DMI and ADG) and not to daily retained energy, the selected efficient L-RFI calves deposited more protein and less fat per daily gain than less efficient H-RFI calves. However, when the significant greater heat increment and maintenance energy requirement of protein compared to fat deposition in tissue were considered, we could not exclude the hypothesis that variation in efficiency is partly explained by efficient energy utilization. The ranking classification of calves to groups according to their RFI efficiency was independent of diet quality and age.

Identification of loci associated with susceptibility to subspecies () tissue infection in cattle.

Johne's disease is a contagious bacterial infection of cattle caused by ssp. (). A previous genome-wide association analysis (GWAA) in Holstein cattle identified QTL on BTA3 and BTA9 that were highly associated (P < 5 × 10) and on BTA1, BTA16, and BTA21 that were moderately associated (P < 5 × 10) with Map tissue infection. The objectives of this study were to validate previous GWAA results in Jersey cattle ( = 57), Holstein cattle from the Pacific Northwest (PNW, = 205) and a combined Holstein population from the PNW and the Northeast (PNW + NE, = 423), and also identify new loci associated with tissue infection. DNA was genotyped using the Illumina BovineSNP50 BeadChip, and the PNW + NE data was also imputed to whole genome sequence level using Run4 of the 1000 Bull Genomes project with Beagle v 4.1 and FImpute. Cases were ileocecal node positive and controls were negative for by quantitative PCR (qPCR). Individuals were removed for SNP call rate < 90%, and SNP were removed for genotype call rate < 90% or minor allele frequency < 1%. For the Jersey, PNW, and PNW + NE, GWAA were conducted using an allelic dosage model. For the PNW and the PNW + NE, an additional efficient mixed-model association eXpedited (EMMAX) analysis was performed using additive, dominance and recessive models. Seven QTL on BTA22 were identified in the Jersey population with the most significant ( = 4.45 × 10) located at 21.7 megabases (Mb). Six QTL were associated in the PNW and the PNW + NE analyses, including a QTL previously identified on BTA16 in the NE population. The most significant locus for the PNW was located on BTA21 at 61 Mb ( = 8.61 × 10) while the most significant locus for the PNW + NE was on BTA12 at 90 Mb ( = 2.33 × 10). No additional QTL were identified with the imputed GWAA. Putative positional candidate genes were identified within 50 kb 5' and 3' of each QTL. Two positional candidate genes were identified in Jersey cattle, 1 identified in the PNW and 8 in the PNW + NE populations. Many identified positional candidate genes are involved in signal transduction, have immunological functions, or have putative functional relevance in entry into host cells. This study supported 2 previously identified SNP within a QTL on BTA16 and identified 16 new QTL, including 2 found in the PNW and the PNW+NE, associated with tissue infection.

The haematoma and its role in bone healing.

Fracture treatment is an old endeavour intended to promote bone healing and to also enable early loading and regain of function in the injured limb. However, in today's clinical routine the healing potential of the initial fracture haematoma is still not fully recognized. The Arbeitsgemeinschaft für Osteosynthesefragen (AO) formed in Switzerland in 1956 formulated four AO principles of fracture treatment which are still valid today. Fracture treatment strategies have continued to evolve further, as for example the relatively new concept of minimally invasive plate osteosynthesis (MIPO). This MIPO treatment strategy harbours the benefit of an undisturbed original fracture haematoma that supports the healing process. The extent of the supportive effect of this haematoma for the bone healing process has not been considered in clinical practice so far. The rising importance of osteoimmunological aspects in bone healing supports the essential role of the initial haematoma as a source for inflammatory cells that release the cytokine pattern that directs cell recruitment towards the injured tissue. In reviewing the potential benefits of the fracture haematoma, the early development of angiogenic and osteogenic potentials within the haematoma are striking. Removing the haematoma during surgery could negatively influence the fracture healing process. In an ovine open tibial fracture model the haematoma was removed 4 or 7 days after injury and the bone that formed during the first two weeks of healing was significantly reduced in comparison with an undisturbed control. These findings indicate that whenever possible the original haematoma formed upon injury should be conserved during clinical fracture treatment to benefit from the inherent healing potential.

Stabilisation of periarticular fractures and osteotomies with a notched head locking T-plate.

OBJECTIVE: To report the clinical outcomes and complications of small animals that had articular or periarticular fractures or osteotomies stabilised with a notched head locking T-plate. METHODS: Medical records were searched retrospectively to identify animals that had a notched head locking T-plate used to stabilise a small articular or periarticular bone fragment. RESULTS: Nine dogs and two cats had an articular or periarticular bone fragment stabilised with a 2.0- or 2.4-mm notched head locking T-plate (12 procedures). The median body weight was 4.7 kg. The plate was modified by removing holes in 10/12 procedures and a combination of locking and non-locking screws were used in 7/12 procedures. All fractures or osteotomies progressed to clinical union. There were two intraoperative complications (intra-articular screw placement and overlong screw) and two postoperative complications (skin necrosis and stress protection) CONCLUSIONS: This study reports the successful use of a 2.0- or 2.4-mm notched head locking T-plate for articular or periarticular fractures or osteotomies in a variety of small-breed dogs and cats. Care must be taken to prevent inadvertent penetration of the articular surface, particularly in regions such as the proximal tibia. The ability to modify the plate dimensions intraoperatively proved beneficial in most cases.

Technical note: Relationship between infrared thermography and heat production in young bulls.

The traditional techniques to measure heat production (HP) are calorimetry (direct and indirect) and comparative slaughter. Both methods are expensive and require extensive amounts of time and infrastructure. Infrared thermography (IRT) could be a faster and less expensive alternative to estimate cattle HP. The objective of this project was to evaluate the use of the IRT technique as an indicator of HP in cattle. A total of 24 bulls (12 Nellore and 12 Black Angus) with initial BW of 380 ± 7 kg were used. Initially, 4 animals of each breed were harvested (baseline animals) and simple regressions were developed for each breed from these baseline animals to estimate the initial chemical composition of the remaining bulls. Eight animals of each breed were fed a silage/concentrate diet for ad libitum intake in individual stalls. On the 25th, 50th, and 75th experimental day, infrared thermal images (Fluke Ti 55ft; Fluke Corporation) were taken of each animal's face to access skin and ocular surface temperatures. A metabolism trial was conducted to estimate the ME intake (MEI). After 84 experimental days, the cattle were harvested and retained energy (RE) and HP were calculated. The data were analyzed using the MIXED and REG procedures of SAS adopting a significance level of 0.05. Angus cattle had a greater daily MEI, HP, and skin and eye temperatures than Nellore. We found significant correlations ( ≤ 0.005) between daily HP and maximum ( = 0.65) and average skin temperatures ( = 0.65) and maximum ( = 0.65) and average ocular surface ( = 0.69) temperatures recorded on d 50. Infrared thermography has potential to be used to evaluate HP in cattle.

Putamen-midbrain functional connectivity is related to striatal dopamine transporter availability in patients with Lewy body diseases.

Prior work has shown that functional connectivity between the midbrain and putamen is altered in patients with impairments in the dopamine system. This study examines whether individual differences in midbrain-striatal connectivity are proportional to the integrity of the dopamine system in patients with nigrostriatal dopamine loss (Parkinson's disease and dementia with Lewy bodies). We assessed functional connectivity of the putamen during resting state fMRI and dopamine transporter (DAT) availability in the striatum using 11C-Altropane PET in twenty patients. In line with the hypothesis that functional connectivity between the midbrain and the putamen reflects the integrity of the dopaminergic neurotransmitter system, putamen-midbrain functional connectivity was significantly correlated with striatal DAT availability even after stringent control for effects of head motion. DAT availability did not relate to functional connectivity between the caudate and thalamus/prefrontal areas. As such, resting state functional connectivity in the midbrain-striatal pathway may provide a useful indicator of underlying pathology in patients with nigrostriatal dopamine loss.

Cow-calf reproductive, genetic, and nutritional management to improve the sustainability of whole beef production systems.

Optimizing efficiency in the cow-calf sector is an important step toward improving beef sustainability. The objective of the study was to use a model to identify the relative roles of reproductive, genetic, and nutritional management in minimizing beef production systems' environmental impact in an economically viable, socially acceptable manner. An economic and environmental diet optimizer was used to identify ideal nutritional management of beef production systems varying in genetic and reproductive technology use. Eight management scenarios were compared to a least cost baseline: average U.S. production practices (CON), CON with variable nutritional management (NUT), twinning cattle (TWN), early weaning (EW), sire selection by EPD using either on-farm bulls (EPD-B) or AI (EPD-AI), decreasing the calving window (CW), or selecting bulls by EPD and reducing the calving window (EPD-CW). Diets to minimize land use, water use, and/or greenhouse gas (GHG) emissions were optimized under each scenario. Increases in diet cost attributable to reducing environmental impact were constrained to less than stakeholder willingness to pay for improved efficiency and reduced environmental impact. Baseline land use, water use, and GHG emissions were 188 m, 712 L, and 21.9 kg/kg HCW beef. The NUT scenario, which assessed opportunities to improve sustainability by altering nutritional management alone, resulted in a simultaneous 1.5% reduction in land use, water use, and GHG emissions. The CW scenario improved calf uniformity and simultaneously decreased land use, water use, and GHG emissions by 3.2%. Twinning resulted in a 9.2% reduction in the 3 environmental impact metrics. The EW scenario allowed for an 8.5% reduction in the 3 metrics. The EPD-AI scenario resulted in an 11.1% reduction, which was comparable to the 11.3% reduction achieved by EPD-B in the 3 metrics. Improving genetic selection by using AI or by purchasing on-farm bulls based on their superior EPD demonstrated clear opportunity to improve sustainability. When genetic and reproductive technologies were adopted, up to a 12.4% reduction in environmental impact was achievable. Given the modeling assumptions used in this study, optimizing nutritional management while concurrently improving genetic and reproductive efficiency may be promising avenues to improve productivity and sustainability of U.S. beef systems.

Suspected intramedullary bone infarct subsequent to tibial plateau levelling osteotomy in a dog.

BACKGROUND: Bone infarction is a syndrome associated with disruption to the medullary blood supply of a long bone and may present as either a cause of lameness or, more commonly, an incidental finding. Bone infarction is a known complication of total hip replacement in the dog and may be associated with several other systemic diseases. CASE REPORT: A 3-year-old female desexed Labrador Retriever presented for acute lameness 4 weeks following tibial plateau levelling osteotomy (TPLO). Subsequent radiographs revealed an increase in medullary bone opacity, radiographically consistent with a medullary bone infarction. The lesion was followed with serial radiographs and appeared to spontaneously resolve. CONCLUSION: This is the first reported case of bone infarction following TPLO in the dog. Bone infarction should be considered as an unlikely but potential complication of TPLO.