Modifiable risk factors, APOE and risk of Alzheimer disease: one size does not fit all.

Introduction: Evaluating the generalizability of dementia risk scores, primarily developed in non-Latinx White (NLW) participants, and interactions with genetic risk factors in diverse populations is crucial for addressing health disparities. Methods: We analyzed the association of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) and modified CAIDE (mCAIDE) scores with dementia risk using logistic regression models stratified by race/ethnicity in NACC and ADNI, and assessed their interaction with APOE . Results: Higher CAIDE scores were associated with an increased risk of dementia in Asian, Latinx, and NLW participants but not in Black participants. In contrast, higher mCAIDE scores were also associated with an increased risk of dementia in Black participants. Unfavorable mCAIDE risk profiles exacerbated the APOE *ε4 risk effect and attenuated the APOE *ε2 protective effect. Discussion: Our findings underscore the importance of evaluating the validity of dementia risk scores in diverse populations for their use in personalized medicine approaches to promote brain health.

Administering the maternal appeasing substance before slaughter to improve carcass characteristics of finishing cattle.

Two experiments evaluated carcass characteristics of finishing steers administered the maternal bovine appeasing substance (mBAS) prior to slaughter. In Exp. 1, 954 Angus-influenced finishing steers housed in 6 original pens were used. Each original pen was split into a pair of experimental pens 14.3 d ±â€…3 d prior to slaughter, in a manner that number of steers and average pen body weight (BW; 636 ±â€…4 kg) were similar. An oiler containing mBAS (Ferappease Finish Cattle 5%; FERA Diagnostics and Biologicals; College Station, TX) was added to one of the experimental pens 7 d prior to slaughter (n = 6), whereas the other pen did not contain an oiler (CON; n = 6). The oiler delivered 120 mL of mBAS/steer during a 7-d period. Steer BW was recorded 7 d prior to and during loading (final BW) to the packing plant. No treatment effects were detected (P ≥ 0.51) for BW gain, final BW, and proportion of carcasses that graded Choice or Prime. Carcass dressing percentage was greater (P = 0.02) in mBAS compared with CON steers (65.9% vs. 64.2%; SEM = 0.5), which was not sufficient to impact hot carcass weight (HCW; P = 0.29). Incidence of dark-cutting carcasses did not differ between treatments (P = 0.23). In Exp. 2, 80 Angus-influenced finishing steers housed in 16 pens (5 steers/pen; 600 ±â€…4 kg of BW) were used. Pens were arranged in 4 rows of 4 pens/row, and rows were alternately assigned to receive an oiler containing mBAS (n = 8) or mineral oil (CON+; n = 8) 7 d prior to slaughter. Oilers were designed to deliver 120 mL/steer of mBAS or mineral oil during the 7-d period. Steer BW was recorded as in Exp. 1, and a blood sample was collected during exsanguination. No treatment effects were detected (P ≥ 0.20) for BW parameters, carcass marbling score, backfat thickness, Longissimus muscle area, yield grade, and proportion of carcasses that graded Choice or Prime. Carcass dressing was greater (P = 0.02) in mBAS steers compared with CON + (60.6 vs. 59.6%; SEM = 0.3) but HCW did not differ (P = 0.47) between treatments. Plasma cortisol concentration was less (P < 0.01) in mBAS steers compared with CON + (11.7 vs. 20.8 ng/mL; SEM = 1.6). Incidence of dark-cutting carcasses did not differ (P = 0.53) between treatments. In summary, mBAS administration to finishing cattle using oilers during the last 7 d on feed alleviated the adrenocortical stress response elicited by the process of slaughter, which likely resulted in increased carcass dressing.

Causal Associations of Sleep Apnea with Alzheimer's Disease and Cardiovascular Disease: a Bidirectional Mendelian Randomization Analysis.

Background: Sleep apnea (SA) has been linked to an increased risk of dementia in numerous observational studies; whether this is driven by neurodegenerative, vascular or other mechanisms is not clear. We sought to examine the bidirectional causal relationships between SA, Alzheimer's disease (AD), coronary artery disease (CAD), and ischemic stroke using Mendelian randomization (MR). Methods: Using summary statistics from four recent, large genome-wide association studies of SA (n=523,366), AD (n=64,437), CAD (n=1,165,690), and stroke (n=1,308,460), we conducted bidirectional two-sample MR analyses. Our primary analytic method was fixed-effects inverse variance weighted MR; diagnostics tests and sensitivity analyses were conducted to verify the robustness of the results. Results: We identified a significant causal effect of SA on the risk of CAD (odds ratio (OR IVW ) =1.35 per log-odds increase in SA liability, 95% confidence interval (CI) =1.25-1.47) and stroke (OR IVW =1.13, 95% CI =1.01-1.25). These associations were somewhat attenuated after excluding single-nucleotide polymorphisms associated with body mass index (BMI) (OR IVW =1.26, 95% CI =1.15-1.39 for CAD risk; OR IVW =1.08, 95% CI =0.96-1.22 for stroke risk). SA was not causally associated with a higher risk of AD (OR IVW =1.14, 95% CI =0.91-1.43). We did not find causal effects of AD, CAD, or stroke on risk of SA. Conclusions: These results suggest that SA increased the risk of CAD, and the identified causal association with stroke risk may be confounded by BMI. Moreover, no causal effect of SA on AD risk was found. Future studies are warranted to investigate cardiovascular pathways between sleep disorders, including SA, and dementia.

The development and acceptability of an educational and training intervention for recruiters to neonatal trials: the TRAIN project.

BACKGROUND: Suboptimal or slow recruitment affects 30-50% of trials. Education and training of trial recruiters has been identified as one strategy for potentially boosting recruitment to randomised controlled trials (hereafter referred to as trials). The Training tRial recruiters, An educational INtervention (TRAIN) project was established to develop and assess the acceptability of an education and training intervention for recruiters to neonatal trials. In this paper, we report the development and acceptability of TRAIN. METHODS: TRAIN involved three sequential phases, with each phase contributing information to the subsequent phase(s). These phases were 1) evidence synthesis (systematic review of the effectiveness of training interventions and a content analysis of the format, content, and delivery of identified interventions), 2) intervention development using a Partnership (co-design/co-creation) approach, and 3) intervention acceptability assessments with recruiters to neonatal trials. RESULTS: TRAIN, accompanied by a comprehensive intervention manual, has been designed for online or in-person delivery. TRAIN can be offered to recruiters before trial recruitment begins or as refresher sessions during a trial. The intervention consists of five core learning outcomes which are addressed across three core training units. These units are the trial protocol (Unit 1, 50 min, trial-specific), understanding randomisation (Unit 2, 5 min, trial-generic) and approaching and engaging with parents (Unit 3, 70 min, trial-generic). Eleven recruiters to neonatal trials registered to attend the acceptability assessment training workshops, although only four took part. All four positively valued the training Units and resources for increasing recruiter preparedness, knowledge, and confidence. More flexibility in how the training is facilitated, however, was noted (e.g., training divided across two workshops of shorter duration). Units 2 and 3 were considered beneficial to incorporate into Good Clinical Practice Training or as part of induction training for new staff joining neonatal units. CONCLUSION: TRAIN offers a comprehensive co-produced training and education intervention for recruiters to neonatal trials. TRAIN was deemed acceptable, with minor modification, to neonatal trial recruiters. The small number of recruiters taking part in the acceptability assessment is a limitation. Scale-up of TRAIN with formal piloting and testing for effectiveness in a large cluster randomised trial is required.

APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry.

Importance: Apolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, common genetic variants for late-onset Alzheimer disease (AD), making APOE status highly relevant toward clinical trial design and AD research broadly. The associations of APOE genotypes with AD are modulated by age, sex, race and ethnicity, and ancestry, but these associations remain unclear, particularly among racial and ethnic groups understudied in the AD and genetics research fields. Objective: To assess the stratified associations of APOE genotypes with AD risk across sex, age, race and ethnicity, and global population ancestry. Design, Setting, Participants: This genetic association study included case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Data were analyzed between March 2022 and April 2023. Genetic data were available from high-density, single-nucleotide variant microarrays, exome microarrays, and whole-exome and whole-genome sequencing. Summary statistics were ascertained from published AD genetic studies. Main Outcomes and Measures: The main outcomes were risk for AD (odds ratios [ORs]) and risk of conversion to AD (hazard ratios [HRs]), with 95% CIs. Risk for AD was evaluated through case-control logistic regression analyses. Risk of conversion to AD was evaluated through Cox proportional hazards regression survival analyses. Results: Among 68 756 unique individuals, analyses included 21 852 East Asian (demographic data not available), 5738 Hispanic (68.2% female; mean [SD] age, 75.4 [8.8] years), 7145 non-Hispanic Black (hereafter referred to as Black) (70.8% female; mean [SD] age, 78.4 [8.2] years), and 34 021 non-Hispanic White (hereafter referred to as White) (59.3% female; mean [SD] age, 77.0 [9.1] years) individuals. There was a general, stepwise pattern of ORs for APOE*4 genotypes and AD risk across race and ethnicity groups. Odds ratios for APOE*34 and AD risk attenuated following East Asian (OR, 4.54; 95% CI, 3.99-5.17),White (OR, 3.46; 95% CI, 3.27-3.65), Black (OR, 2.18; 95% CI, 1.90-2.49) and Hispanic (OR, 1.90; 95% CI, 1.65-2.18) individuals. Similarly, ORs for APOE*22+23 and AD risk attenuated following White (OR, 0.53, 95% CI, 0.48-0.58), Black (OR, 0.69, 95% CI, 0.57-0.84), and Hispanic (OR, 0.89; 95% CI, 0.72-1.10) individuals, with no association for Hispanic individuals. Deviating from the global pattern of ORs, APOE*22+23 was not associated with AD risk in East Asian individuals (OR, 0.97; 95% CI, 0.77-1.23). Global population ancestry could not explain why Hispanic individuals showed APOE associations with less pronounced AD risk compared with Black and White individuals. Within Black individuals, decreased global African ancestry or increased global European ancestry showed a pattern of APOE*4 dosage associated with increasing AD risk, but no such pattern was apparent for APOE*2 dosage with AD risk. The sex-by-age-specific interaction effect of APOE*34 among White individuals (higher risk in women) was reproduced but shifted to ages 60 to 70 years (OR, 1.48; 95% CI, 1.10-2.01) and was additionally replicated in a meta-analysis of Black individuals and Hispanic individuals (OR, 1.72; 95% CI, 1.01-2.94). Conclusion and Relevance: Through recent advances in AD-related genetic cohorts, this study provided the largest-to-date overview of the association of APOE with AD risk across age, sex, race and ethnicity, and population ancestry. These novel insights are critical to guide AD clinical trial design and research.

Blood-Based Transcriptomic Biomarkers Are Predictive of Neurodegeneration Rather Than Alzheimer's Disease.

Alzheimer's disease (AD) is a growing global health crisis affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses being prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis as well as early detection of AD. In the present study, we used an unbiased combination of machine learning and functional network analyses to identify blood gene biomarker candidates in AD. Using supervised machine learning, we also determined whether these candidates were indeed unique to AD or whether they were indicative of other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Our analyses showed that genes involved in spliceosome assembly, RNA binding, transcription, protein synthesis, mitoribosomes, and NADH dehydrogenase were the best-performing genes for identifying AD patients relative to cognitively healthy controls. This transcriptomic signature, however, was not unique to AD, and subsequent machine learning showed that this signature could also predict PD and ALS relative to controls without neurodegenerative disease. Combined, our results suggest that mRNA from whole blood can indeed be used to screen for patients with neurodegeneration but may be less effective in diagnosing the specific neurodegenerative disease.

Inclusion of Yucca schidigera extract into finishing diets: impacts on ruminal, physiological, and productive responses of feedlot cattle.

This experiment compared ruminal, physiological, and productive responses of feedlot cattle receiving Yucca schidigera extract to replace or fed in conjunction with monensin + tylosin. Angus-influenced steers (n = 120) were ranked by body weight (BW; 315 ± 3 kg) and allocated to 4 groups of 30 steers each. Groups were housed in 1 of 4 drylot pens (30 × 12 m) equipped with GrowSafe feeding systems (4 bunks/pen) during the experiment (day -14 to slaughter). On day 0, groups were randomly assigned to receive a diet containing (2 × 2 factorial): 1) no inclusion or inclusion of monensin + tylosin (360 mg and 90 mg/steer daily, respectively) and 2) no inclusion or inclusion of Y. schidigera extract (4 g/steer daily). Steers were slaughtered in 3 groups balanced by treatment combination (36 steers on day 114, 36 steers on day 142, and 48 steers on day 169). Blood was sampled on days 0, 28, 56, and 84, and the day before shipping to slaughter. On day 41, eight rumen-cannulated heifers (BW = 590 ± 15 kg) were housed with steers (1 pair/pen). Pairs rotated among groups every 21 d, resulting in a replicated 4 × 4 Latin square (n = 8/treatment combination) with 14-d washout intervals. Heifers were sampled for blood and rumen fluid at the beginning and end of each 21-d period. Monensin + tylosin inclusion decreased (P < 0.01) feed intake and improved (P = 0.02) feed efficiency of steers, but did not alter (P ≥ 0.17) steer BW gain or carcass merit traits. Inclusion of Y. schidigera extract did not impact (P ≥ 0.30) steer performance and carcass characteristics. Plasma glucose, insulin, insulin-like growth factor-I, and urea-N concentrations were not affected (P ≥ 0.16) by monensin + tylosin, nor by Y. schidigera extract inclusion in steers and heifers. Ruminal pH in heifers was increased (P = 0.04) by monensin + tylosin, and also by (P = 0.03) Y. schidigera extract inclusion. Rumen fluid viscosity was reduced (P = 0.04) by Y. schidigera extract, and rumen protozoa count was increased (P < 0.01) by monensin + tylosin inclusion. The proportion of propionate in the ruminal fluid was increased (P = 0.04) by monensin + tylosin, and tended (P = 0.07) to be increased by Y. schidigera extract inclusion. Hence, Y. schidigera extract yielded similar improvements in rumen fermentation compared with monensin + tylosin, but without increasing performance and carcass quality of finishing cattle. No complimentary effects were observed when combining all these additives into the finishing diet.

Intravitreal injection of FGF and TGF-ß inhibitors disrupts cranial cartilage development.

Cartilage development is a tightly regulated process that requires the interaction of epithelial and mesenchymal tissues layers to initiate the aggregation of mesenchyme in a condensation. Several signaling molecules have been implicated in cartilage formation including FGFs, WNTs, and members of the TGF-ß super family. However, little is known about the earliest signals involved in these initial phases of development. Here we aimed to investigate whether direct intravitreal injection of pharmaceutical inhibitors for FGF and TGF-ß signaling would perturb cranial cartilages in zebrafish. Via wholemount bone and cartilage staining, we found effects on multiple cranial cartilage elements. We found no effect on scleral cartilage development, however, the epiphyseal bar, basihyal, and basicapsular cartilages were disrupted. Interestingly, the epiphyseal bar arises from the same progenitor pool as the scleral cartilage, namely, the periocular ectomesenchyme. This study adds to the foundational knowledge about condensation induction of cranial cartilage development and provides insight into the timing and signaling involved in the early development of several craniofacial cartilage elements in zebrafish.

Shared genetic risk loci between Alzheimer's disease and related dementias, Parkinson's disease, and amyotrophic lateral sclerosis.

BACKGROUND: Genome-wide association studies (GWAS) have indicated moderate genetic overlap between Alzheimer's disease (AD) and related dementias (ADRD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), neurodegenerative disorders traditionally considered etiologically distinct. However, the specific genetic variants and loci underlying this overlap remain almost entirely unknown. METHODS: We leveraged state-of-the-art GWAS for ADRD, PD, and ALS. For each pair of disorders, we examined each of the GWAS hits for one disorder and tested whether they were also significant for the other disorder, applying Bonferroni correction for the number of variants tested. This approach rigorously controls the family-wise error rate for both disorders, analogously to genome-wide significance. RESULTS: Eleven loci with GWAS hits for one disorder were also associated with one or both of the other disorders: one with all three disorders (the MAPT/KANSL1 locus), five with ADRD and PD (near LCORL, CLU, SETD1A/KAT8, WWOX, and GRN), three with ADRD and ALS (near GPX3, HS3ST5/HDAC2/MARCKS, and TSPOAP1), and two with PD and ALS (near GAK/TMEM175 and NEK1). Two of these loci (LCORL and NEK1) were associated with an increased risk of one disorder but decreased risk of another. Colocalization analysis supported a shared causal variant between ADRD and PD at the CLU, WWOX, and LCORL loci, between ADRD and ALS at the TSPOAP1 locus, and between PD and ALS at the NEK1 and GAK/TMEM175 loci. To address the concern that ADRD is an imperfect proxy for AD and that the ADRD and PD GWAS have overlapping participants (nearly all of which are from the UK Biobank), we confirmed that all our ADRD associations had nearly identical odds ratios in an AD GWAS that excluded the UK Biobank, and all but one remained nominally significant (p < 0.05) for AD. CONCLUSIONS: In one of the most comprehensive investigations to date of pleiotropy between neurodegenerative disorders, we identify eleven genetic risk loci shared among ADRD, PD, and ALS. These loci support lysosomal/autophagic dysfunction (GAK/TMEM175, GRN, KANSL1), neuroinflammation/immunity (TSPOAP1), oxidative stress (GPX3, KANSL1), and the DNA damage response (NEK1) as transdiagnostic processes underlying multiple neurodegenerative disorders.

Perspectives on quality of life among disability-related organization leaders serving individuals with paralysis.

Understanding how the Christopher & Dana Reeve Foundation Quality of Life grant recipients define quality of life has value in helping to further develop and refine the literature on this topic for individuals with spinal cord injury and/or organizations working to serve and/or support individuals with spinal cord injury. The purpose of this organizational evaluation project's evaluation activities was to engage with Quality of Life (QOL) Grant recipients, namely leaders at disability-related organizations across the United States, to better understand their definitions and operationalization of the term, "quality of life". To do so systematically, researchers compiled a list of all QOL grant recipients from two 2016 grant cycles and divided them into three categories based on the award amount. From these categories, we randomly selected organizations to invite to provide input. Phone interviews were completed with 19 grant recipients. A thematic content analysis was completed across the resulting transcripts using MAXQDA software. The sub-themes identified by researchers included: community connection, independence, self-determination, caregiver communication, and including caregivers in programs. Our analysis demonstrates the importance of both community and caregiver relationships to organizations that focus on QOL for people with SCI. Novel findings suggest the importance of community and connection as well as a reframing of both the constructs of independence and control within QOL. Lessons for evaluators are also provided.

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred.

INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

The complex genetic architecture of Alzheimer's disease: novel insights and future directions.

BACKGROUND: Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder and the most common form of dementia. AD is highly heritable, with heritability estimates of ∼70% from twin studies. Progressively larger genome-wide association studies (GWAS) have continued to expand our knowledge of AD/dementia genetic architecture. Until recently these efforts had identified 39 disease susceptibility loci in European ancestry populations. RECENT DEVELOPMENTS: Two new AD/dementia GWAS have dramatically expanded the sample sizes and the number of disease susceptibility loci. The first increased total sample size to 1,126,563-with an effective sample size of 332,376-by predominantly including new biobank and population-based dementia datasets. The second, expands on an earlier GWAS from the International Genomics of Alzheimer's Project (IGAP) by increasing the number of clinically-defined AD cases/controls in addition to incorporating biobank dementia datasets, resulting in a total sample size to 788,989 and an effective sample size of 382,472. Collectively both GWAS identified 90 independent variants across 75 AD/dementia susceptibility loci, including 42 novel loci. Pathway analyses indicate the susceptibility loci are enriched for genes involved in amyloid plaque and neurofibrillary tangle formation, cholesterol metabolism, endocytosis/phagocytosis, and the innate immune system. Gene prioritization efforts for the novel loci identified 62 candidate causal genes. Many of the candidate genes from known and newly discovered loci play key roles in macrophages and highlight phagocytic clearance of cholesterol-rich brain tissue debris by microglia (efferocytosis) as a core pathogenetic hub and putative therapeutic target for AD. WHERE NEXT?: While GWAS in European ancestry populations have substantially enhanced our understanding of AD genetic architecture, heritability estimates from population based GWAS cohorts are markedly smaller than those from twin studies. While this missing heritability is likely due to a combination of factors, it highlights that our understanding of AD genetic architecture and genetic risk mechanisms remains incomplete. These knowledge gaps result from several underexplored areas in AD research. First, rare variants remain understudied due to methodological issues in identifying them and the cost of generating sufficiently powered whole exome/genome sequencing datasets. Second, sample sizes of non-European ancestry populations in AD GWAS remain small. Third, GWAS of AD neuroimaging and cerebrospinal fluid endophenotypes remains limited due to low compliance and high costs associated with measuring amyloid-ß and tau levels and other disease-relevant biomarkers. Studies generating sequencing data, including diverse populations, and incorporating blood-based AD biomarkers are set to substantially improve our knowledge of AD genetic architecture.

Productive and physiological responses of feedlot cattle receiving different sources of Ca salts of fatty acids in the finishing diet.

This study evaluated productive and physiological responses in feedlot cattle receiving a finishing diet that included Ca salts of palm oil (CSPALM), or a blend of Ca salts of palm, cottonseed, and soybean oils (CSMIX). Ninety yearling steers were housed in 15 pens equipped with Calan-gate feeders (6 steers/pen). Steers within each pen were stratified by shrunk body weight (BW; 410 ±â€…3.3 kg across pens) on d 0 and assigned to receive a total-mixed ration (TMR) containing (dry matter basis) 2.2% of CSPALM (n = 30), 2.2% of CSMIX (n = 30), or no supplemental fat (CON; n = 30). Individual TMR intake was evaluated weekly. Blood samples were collected on d 0, 28, 56, 91, 119, and 147. Samples of the Longissimus muscle (LM) were collected on d 84 via biopsy. Upon slaughter on d 148, hot carcass weight (HCW) was recorded to estimate final BW (63% dressing), and one LM steak sample (2.54 cm thickness) was removed from the right side of each carcass. Steer ADG was greater (P = 0.02) for CSMIX compared with CSPALM and tended to be greater (P = 0.09) for CSMIX compared with CON. The gain:feed ratio was greater (P ≤ 0.05) for CSMIX compared with CSPALM and CON, and carcass LM area was less (P = 0.01) for CSPALM compared with CSMIX and CON. No treatment effects were detected (P ≥ 0.21) for TMR intake, final BW, and other carcass merit traits including marbling. Mean plasma cholesterol concentrations were greater (P < 0.01) in CSMIX and CSPALM compared with CON, and mRNA expression of adipocyte fatty acid binding protein in the LM on d 84 was greater (P ≤ 0.04) in CSPALM compared with CSMIX and CON. No treatment effects were detected (P ≥ 0.15) for plasma concentrations of glucose, insulin, insulin-like growth factor I, and leptin, nor for other LM genes associated with marbling and muscle growth. Concentrations of total fatty acids (FA) in plasma and LM steak samples were greater (P < 0.01) in CSMIX compared with CSPALM and CON, and greater (P < 0.01) in the LM samples of CSPALM compared with CON. Steers receiving CSMIX had greater (P < 0.01) concentrations of polyunsaturated and ω-6 FA in plasma and LM steak samples compared with CSPALM and CON. Supplementing CSMIX improved gain efficiency and FA profile in the LM of feedlot steers compared with the CON diet, but the same responses were not observed when CSPALM was offered. Perhaps the advantages from CSMIX supplementation resulted from increasing the supply of polyunsaturated and ω-6 FA to the finishing diet.

Supplemental fat has been provided to feedlot cattle to increase energy density of their diets, and may yield nutraceutical advantages if includes polyunsaturated fatty acids (FA). Alternatively, carcass quality can be improved when the fat supplement is based on saturated and monounsaturated FA. Hence, this experiment evaluated a blend of saturated, monounsaturated, and polyunsaturated FA to improve both performance and carcass merit in feedlot cattle. Steers received a finishing diet that included this blend (CSMIX), a source of saturated and monounsaturated FA (CSPALM), or no supplemental fat (CON). Growth rate and gain efficiency were improved in steers that received CSMIX compared with CSPALM and CON, and these traits did not differ between the latter treatments. Inclusion of CSMIX increased FA concentrations in the circulation of steers throughout the 147-day study and in Longissimus muscle (LM) samples collected after slaughter. This increase in FA concentrations was associated with greater accumulation of polyunsaturated and ω-6 FA, suggesting that CSMIX resulted in LM with FA profile deemed more beneficial for human consumption. Collectively, supplementing CSMIX to feedlot steers improved gain efficiency and FA composition in the LM, and these advantages may be associated with increased supply of polyunsaturated ω-6 FA to the finishing diet.

The role of mitochondrial genome abundance in Alzheimer's disease.

Mitochondrial dysfunction is an early and prominent feature of Alzheimer's disease (AD), with impaired energy metabolism preceding the onset of clinical symptoms. Here we propose an update to the mitochondrial dysfunction hypothesis of AD based on recent results examining the role of mitochondrial genome abundance in AD. In a large post mortem study, we show that lower brain mitochondrial genome abundance is associated with a greater odds of AD neuropathological change and worse cognitive performance. We hypothesize that lower mitochondrial genome abundance impairs mitochondrial function by reducing mitochondrial bioenergetics, thereby impacting neuronal and glial cell function. However, it remains to be determined if mitochondrial dysfunction causes, mediates, or is a by-product of AD pathogenesis. Additional support for this hypothesis will be generated by linking peripheral blood mitochondrial genome abundance to AD and establishing clinical trials of compounds that upregulate total mitochondrial genome abundance or boost mitochondrial mass.

Microglial efferocytosis: Diving into the Alzheimer's disease gene pool.

Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer's disease (AD) risk. In particular, AD risk alleles primarily affect the abundance or structure, and thus the activity, of genes expressed in macrophages, strongly implicating microglia (the brain-resident macrophages) in the etiology of AD. These genes converge on pathways (endocytosis/phagocytosis, cholesterol metabolism, and immune response) with critical roles in core macrophage functions such as efferocytosis. Here, we review these pathways, highlighting relevant genes identified in the latest AD genetics and genomics studies, and describe how they may contribute to AD pathogenesis. Investigating the functional impact of AD-associated variants and genes in microglia is essential for elucidating disease risk mechanisms and developing effective therapeutic approaches.

Shifts in bacterial communities in the rumen, vagina, and uterus of beef heifers receiving different levels of concentrate.

This experiment investigated the effects of diet composition on rumen, vaginal, and uterine microbiota of beef heifers. Fifteen rumen-cannulated, pubertal Angus-influenced heifers were used in a replicated 3 × 3 Latin square design (28-d periods and 21-d washout intervals). Dietary treatments included diets based on (as-fed) 100% grass hay (HF), 60% grass hay + 40% corn-based concentrate (INT), or 25% grass hay + 75% corn-based concentrate (HG). Treatments were offered individually to heifers once daily at 2% body weight. Rumen, vaginal, and uterine samples were collected on days 0 and 28 of each period. Data were analyzed using orthogonal contrasts (linear and quadratic), using results from day 0 as independent covariates and heifer as the experimental unit. Ruminal pH on day 28 decreased linearly (P < 0.01) as concentrate inclusion increased. Uterine and vaginal pH on day 28 were not affected by treatments (P ≥ 0.35). Within the rumen samples, Bacteriodetes was the most abundant phylum and its relative abundance linearly decreased (P ≤ 0.01) with the inclusion of concentrate. Prevotella was the most abundant genus within the rumen but was not affected by treatments (P ≥ 0.44). Genera with relative abundance ≥1% (average across treatments) in the rumen that were impacted by treatments (P ≤ 0.01) included Bacteroides, Pedobacter, Dysgonomonas, Caloramator, and Ruminococcus. Firmicutes was the most abundant phylum in the vagina and uterus, but it was unaffected by treatments (P ≥ 0.16). Prevotella was the most abundant genus in the vagina, and its relative abundance increased (P < 0.01) with the inclusion of concentrate. Other genera with relative abundance ≥1% that were significantly affected (P ≤ 0.05) by treatments were Clostridium, Pedobacter, Roseburia, Oscillospira, Faecalibacterium, Caloramator, Paludibacter, Rhodothermus, and Porphyromonas. In uterine samples, Prevotella was the most abundant genus but was unaffected by treatments (P ≥ 0.29). Genera with relative abundance ≥1% in the uterus that were significantly affected (P < 0.01) by treatments were Caloramator, Paludibacter, and Thalassospira. Collectively, inclusion of concentrate in the diet altered the bacterial composition within the rumen as well as shifting bacterial populations within the vagina and uterus. Research is warranted to further understand the impacts of these diet-induced microbiota changes on reproductive function and performance of beef heifers.

According to the United Nations, worldwide beef production must increase by 120% by 2050 to feed an additional 2.3-billion people. With a growing population and a reduction in available resources, the overall efficiency of beef production needs to advance to meet the increasing demand. Cow­calf operations serve as the foundation of the beef industry and supply all calves for beef production; however, poor reproductive performance limits the productivity in this system. Hence, management strategies to promote reproductive success are warranted for optimal reproductive and overall efficiency in cow­calf operations. Bacterial communities in the reproductive system of cattle have been shown to contribute to fertility and can be affected by several factors such as dietary changes. The objective of this experiment was to evaluate the impact of different diets on the reproductive bacterial communities. Overall, it was concluded that the reproductive tract can shift the abundance of bacteria due to changes in the diet, and more research is needed to better understand the impact of these changes and their consequences to beef production systems.

A Mitochondrial DNA Haplogroup Defines Patterns of Five-Year Cognitive Change.

BACKGROUND: Mitochondrial DNA (mtDNA) may play a role in Alzheimer's disease (AD) and cognitive decline. A particular haplogroup of mtDNA, haplogroup J, has been observed more commonly in patients with AD than in cognitively normal controls. OBJECTIVE: We used two mtDNA haplogroups, H and J, to predict change in cognitive performance over five years. We hypothesized that haplogroup J carriers would show less cognitive resilience. METHODS: We analyzed data from 140 cognitively normal older adults who participated in the University of Kansas Alzheimer's Disease Research Center clinical cohort between 2011 and 2020. We used factor analysis to create three composite scores (verbal memory, attention, and executive function) from 11 individual cognitive tests. We performed latent growth curve modeling to describe trajectories of cognitive performance and change adjusting for age, sex, years of education, and APOE ɛ4 allele carrier status. We compared haplogroup H, the most common group, to haplogroup J, the potential risk group. RESULTS: Haplogroup J carriers had significantly lower baseline performance and slower rates of improvement on tests of verbal memory compared to haplogroup H carriers. We did not observe differences in executive function or attention. CONCLUSION: Our results reinforce the role of mtDNA in changes to cognitive function in a domain associated with risk for dementia, verbal memory, but not with other cognitive domains. Future research should investigate the distinct mechanisms by which mtDNA might affect performance on verbal memory as compared to other cognitive domains across haplogroups.

Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, ß (females) = 0.08, P (females) = 5.76 × 10-09, ß (males) = -0.01, P(males) = 0.70, ß (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context.

An Interactive, Multimodal Curriculum to Teach Pediatric Cardiology to House Staff.

Pediatricians must be able to diagnose, triage, and manage infants and children with congenital heart disease. The pediatric cardiology division at the Medical University of South Carolina updated their curriculum for pediatric residents to a format supported by constructivist learning theory. The purpose of this study is to determine if shorter, interactive learning with fellow and faculty involvement improved pediatric cardiology knowledge demonstrated through test scores and resident satisfaction. A curriculum of short lectures and interactive workshops was delivered over 6 weeks in August and September 2018. Residents answered a 10-question pretest prior to the curriculum, followed by a post-test immediately after the last session and a delayed post-test 8 months later. Residents also provided summative feedback on the educational sessions. Sixty-six residents were eligible to participate in the curriculum with 44 (67%) completing the pretest, 40 (61%) completing the post-test, and 33 (50%) completing the delayed post-test. The mean score increased significantly from 56 to 68% between the pretest and post-test (p = 0.0018). The delayed post-test mean score remained high at 71% without significant change (p = 0.46). Overall feedback was positive highlighting the interactive nature of lectures and the participation of cardiology fellows. Using an interactive, multimodal educational series, pediatric residents had a significant increase in pediatric cardiology test scores and demonstrated good retention.

Genome-wide association study and functional validation implicates JADE1 in tauopathy.

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-ß (Aß) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aß toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.