Lipid Trolling to Optimize A3 Adenosine Receptor-Positive Allosteric Modulators (PAMs).

A3 adenosine receptor (A3AR) positive allosteric modulators (PAMs) (2,4-disubstituted-1H-imidazo[4,5-c]quinolin-4-amines) allosterically increase the Emax of A3AR agonists, but not potency, due to concurrent orthosteric antagonism. Following mutagenesis/homology modeling of the proposed lipid-exposed allosteric binding site on the cytosolic side, we functionalized the scaffold, including heteroatom substitutions and exocyclic phenylamine extensions, to increase allosteric binding. Strategically appended linear alkyl-alkynyl chains with terminal amino/guanidino groups improved allosteric effects at both human and mouse A3ARs. The chain length, functionality, and attachment position were varied to modulate A3AR PAM activity. For example, 26 (MRS8247, p-alkyne-linked 8 methylenes) and homologues increased agonist Cl-IB-MECA's Emax and potency ([35S]GTPγS binding). The putative mechanism involves a flexible, terminally cationic chain penetrating the lipid environment for stable electrostatic anchoring to cytosolic phospholipid head groups, suggesting "lipid trolling", supported by molecular dynamic simulation of the active-state model. Thus, we have improved A3AR PAM activity through rational design based on an extrahelical, lipidic binding site.

Can profiles of behaviors occurring within 48 h of a suicide attempt predict future severity of suicidal thoughts and reattempt?: An examination of hospitalized patients 12 Months post-discharge.

Behavioral warning signs (WS) are near-term changes within individuals, which aid in determining imminent risk for suicide attempts. However, those who attempt suicide differ in their engagement of WS, and it is unclear if these differences relate to future risk of suicidal behavior. Using a sample of 132 adults presenting to a hospital following a suicide attempt, the current study sought to determine if differences in engagement in WS for the index attempt prospectively predicted suicide attempt, frequency of ideation, and intensity of suicide ideation 12 months post discharge. Latent class analyses (LCAs) conducted on 6 behaviors (i.e., alcohol use, nightmares, interpersonal negative life events, suicide communication, risky behavior, low sleep, and high sleep) found a 5-class solution optimally fit the data. One identified class, characterized by engagement in risky behaviors the hours before an attempt differed from other identified classes in terms of risk for future suicidal ideation and behaviors. More specifically, participants in "High Risky Behavior" class had higher rates of 12-month suicide reattempt, significantly more frequent suicide ideation, and significantly worse intensity of suicide ideation during the 12 months following their index attempt compared to participants endorsing typical patterns of WS. These results held when adjusting for various traditional baseline covariates (e.g., depressive symptoms). The current study demonstrates that patterns of behavioral WS may be utilized as their own prognostic indicator of future suicidal ideation and behaviors among high-risk individuals reporting a recent suicide attempt, which can inform post-discharge clinical intervention and prevention efforts.

Measuring the Interprofessional Health of the Pediatric Cardiovascular Operating Room Work Environment.

Introduction: Pediatric cardiac surgery is complex and has significant risk, requiring interprofessional teamwork for optimal outcomes. Unhealthy work environments have been linked to poor patient outcomes, staff dissatisfaction, and intention to leave. We describe the interprofessional health of pediatric cardiovascular operating room (CVOR) work environments in the United States and the establishment of a healthy work environment (HWE) benchmark score. Methods: Utilizing the American Association of Critical Care Nurses Healthy Work Environments Assessment Tool (HWEAT), interprofessional staff from 11 pediatric CVORs were surveyed. Responses were aggregated, summarized, and stratified by role to examine differences. The following phase used an e-Delphi approach to obtain expert consensus on a benchmark target. Results: Across 11 centers, 179 (60%) completed surveys were reviewed. The interprofessional mean HWEAT score was 3.55 (2.65-4.34). Mean scores for each standard were within the "good" range. Participants reported the highest scores for effective decision-making, with a mean of 3.69 (3.00-4.20). Meaningful recognition scored lowest, mean 3.26 (2.33-4.07). When stratified, surgeons reported higher overall HWE scores (M = 3.79, SD = 0.13) than nurses (M = 3.41, SD = 0.19; P = 0.02, two-tailed). The proposed benchmark was 3.50. Conclusions: This is the first time the American Association of Critical Care Nurses HWEAT has been used to describe the interprofessional health of work environments in pediatric CVORs in the United States. The targeted benchmark can support pediatric CVOR improvement strategies. Creating and sustaining an HWE is an interprofessional opportunity to support high-quality patient outcomes and clinical excellence.

Infectious Extensor Tenosynovitis of the Hallucis Longus Tendon: A Case Report.

Infectious tenosynovitis can involve both flexor and extensor tendons of the extremities. If left untreated, it can lead to high morbidity and mortality. Most emergency providers recognize the signs and symptoms of flexor and extensor tenosynovitis of the hand. However, extensor tenosynovitis of the hallucis longus tendon is a rare condition with a risk of complications similar to infectious tenosynovitis of the hand. This case report describes a presentation of extensor tenosynovitis of the hallucis longus tendon. Clinical suspicion is essential to help the provider not miss this rare condition, which can lead to significant morbidity if not treated promptly or appropriately.

Nimodipine-associated standard dose reductions and neurologic outcomes after aneurysmal subarachnoid hemorrhage: the era of pharmacogenomics.

Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.

Phosphorylation of the nuclear poly(A) binding protein (PABPN1) during mitosis protects mRNA from hyperadenylation and maintains transcriptome dynamics.

Polyadenylation controls mRNA biogenesis, nucleo-cytoplasmic export, translation and decay. These processes are interdependent and coordinately regulated by poly(A)-binding proteins (PABPs), yet how PABPs are themselves regulated is not fully understood. Here, we report the discovery that human nuclear PABPN1 is phosphorylated by mitotic kinases at four specific sites during mitosis, a time when nucleoplasm and cytoplasm mix. To understand the functional consequences of phosphorylation, we generated a panel of stable cell lines inducibly over-expressing PABPN1 with point mutations at these sites. Phospho-inhibitory mutations decreased cell proliferation, highlighting the importance of PABPN1 phosphorylation in cycling cells. Dynamic regulation of poly(A) tail length and RNA stability have emerged as important modes of gene regulation. We therefore employed long-read sequencing to determine how PABPN1 phospho-site mutants affected poly(A) tails lengths and TimeLapse-seq to monitor mRNA synthesis and decay. Widespread poly(A) tail lengthening was observed for phospho-inhibitory PABPN1 mutants. In contrast, expression of phospho-mimetic PABPN1 resulted in shorter poly(A) tails with increased non-A nucleotides, in addition to increased transcription and reduced stability of a distinct cohort of mRNAs. Taken together, PABPN1 phosphorylation remodels poly(A) tails and increases mRNA turnover, supporting the model that enhanced transcriptome dynamics reset gene expression programs across the cell cycle.

How can we achieve more accurate reporting of average dog lifespan?

Despite major advances in our understanding of dogs as a biological system (including genetics/epigenetics, physiology, cognition, and behavior), the veterinary field lacks consensus around a critical piece of information: namely, the average lifespan/life expectancy of a domestic dog. This deficiency is due in part to unavailable and/or inconsistent collection of dog mortality data. In an effort to review historical and current reports of dog lifespan to determine whether the domestic dog's lifespan has changed over time, we found that incongruous data were prohibitive to conducting a formal meta-analysis of dog lifespan reports. However, in examining several different kinds of dog aging and mortality studies covering a span of about 40 years (1981 to 2023), it seems apparent that the median lifespan of domesticated dogs has not recently decreased, as has been reported in the popular press, but rather has increased steadily over that time frame. Still, assessing the validity of these numbers is a challenge, as methodology, cohort, and covariates (such as weight, breed, etc) vary from study to study. We therefore recommend the adoption of a comprehensive, standardized method for reporting and recording dog mortality so that a more accurate understanding of dogs' average lifespan can be obtained in the future.

Direct photocatalytic C-H functionalization mediated by a molybdenum dioxo complex.

Direct photocatalytic C-H activation mediated by MoO2Cl2(bpy-tBu), a unique photoactive metal OXO, is presented. The limiting step, reoxidation to the Mo dioxo, is evaluated and proposed to occur via a key Cl- loss event. Photocatalyst degradation occurs upon substitution of bpy-tBu with H2O generated during catalysis.

Severe Pediatric Neurological Manifestations With SARS-CoV-2 or MIS-C Hospitalization and New Morbidity.

Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition. Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.

Soluble Glycoprotein VI Predicts Abdominal Aortic Aneurysm Growth Rate and is a Novel Therapeutic Target.

A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (JAQ1) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist.

School-Based Intervention for Adolescents With ADHD: Predictors of Effects on Academic, Behavioral, and Social Functioning.

Adolescents with attention-deficit/hyperactivity disorder (ADHD) experience significant academic, behavioral, and social skill difficulties including underachievement, risk for school dropout, poor peer relations, and emotion dysregulation. Although stimulant medication reduces ADHD symptoms, psychosocial and educational interventions are necessary to address functional impairments. We examined the nature and predictors of academic, behavioral, and social skills trajectories in response to multicomponent organizational and interpersonal skills training in 92 high school students with ADHD. Latent trajectory class analyses revealed positive treatment response ranging from 61.5% (report card grades) to 100% (inattention symptoms, organizational skills, social skills). Organizational skill and academic grade treatment response trajectories were predicted by assigned sex, pretreatment anxiety, and treatment dosage, while improvement in behavioral and social functioning was associated with better emotion regulation and family relations prior to treatment along with stronger working alliance with treatment coach at midtreatment. Multicomponent organizational and interpersonal skills training appears effective for most high school students with ADHD and the degree treatment-induced change is associated with multiple malleable factors can be leveraged to enhance intervention response.

Corrigendum: The effect of low-abundance OTU filtering methods on the reliability and variability of microbial composition assessed by 16S rRNA amplicon sequencing.

[This corrects the article DOI: 10.3389/fcimb.2023.1165295.].

Impact of Surgeon Workload on Pregnancy Outcomes in Surgical Trainees and Faculty.

OBJECTIVE: To investigate the association between workload and pregnancy outcomes among US surgical faculty and trainees. SUMMARY BACKGROUND DATA: Despite the increased risk of pregnancy associated complications among surgeons, most US institutions do not have formalized support to help sustain a healthy pregnancy in surgeons. METHODS: An anonymous self-administered Qualtrics survey was distributed electronically to US surgeons across all surgical specialties. Female surgical trainees/faculty with current or previous pregnancy were invited to participate. Data pertaining to demographics, workload, and pregnancy outcomes were collected for each individual pregnancy resulting in live birth. Multivariate analysis was used to assess for workload and outcomes, controlling for age, race, gravidity, and use of assisted reproductive technology. A significance level of 0.0056 was used for each outcome (Bonferroni multiple-testing adjustment 0.05/9). RESULTS: 817 surgeons experiencing 1348 pregnancies resulting in live birth were included. The mean (SD) age at first live birth was 32(4). The most prevalent major and neonatal complications included preeclampsia/gestational hypertension (n=196, 14.5%) and preterm delivery (n=179, 12.8%), respectively. Most institutions did not have a policy regarding workload modification (n=1189, 88.5%). Most surgeons did not modify their workload (n=862, 63.9%). When looking at individual workload metrics, feeling overworked during the last week of pregnancy correlated with risk of major complication (P=0.0001), preeclampsia/gestational hypertension (P=0.0003), and intra/post-partum complication (P=0.0001). Association with unplanned cesarean section (P=0.0096) and preterm delivery (P=0.0036) reached nominal significance. CONCLUSIONS: Most surgeons do not modify their workload during pregnancy, potentially contributing to feeling overworked and peri-partum complications. There is an urgent need for a cultural shift and institutional policies to safeguard the health and wellbeing of pregnant surgeons.

Human Milk Cannabinoid Concentrations and Associations with Maternal Factors: The Lactation and Cannabis (LAC) Study.

Background and Objectives: As cannabis use increases among reproductive-aged women, there is a growing need to better understand the presence of cannabinoids in milk produced by women using cannabis. It is unclear how concentrations of cannabinoids such as delta-9-tetrahydrocannabinol (Δ9-THC) persist in milk after cannabis use and what factors contribute to variation in milk Δ9-THC concentrations. Our objectives were to measure cannabinoids in human milk following cannabis abstention, after single and repeated instances of cannabis use, and identify factors contributing to concentration variation. Methods: The Lactation and Cannabis (LAC) Study prospectively observed 20 breastfeeding participants who frequently used cannabis (≥1/week), had enrolled <6 months postpartum, were feeding their infant their milk ≥5 times/day, and were not using any illicit drugs. Participants collected a baseline milk sample after ≥12 hours of abstaining from cannabis and five milk samples at set intervals over 8-12 hours after initial cannabis use. Participants completed surveys and recorded self-directed cannabis use during the study period. Results: Δ9-THC peaked 120 minutes after a single instance of cannabis use (median, n = 9). More instances of cannabis use during the study period were associated with greater Δ9-THC area-under-the-curve concentrations (ρ = 0.65, p = 0.002), indicating Δ9-THC bioaccumulation in most participants. Baseline Δ9-THC logged concentration was positively associated with self-reported frequency of cannabis use (b = 0.57, p = 0.01). Conclusions: Cannabinoids are measurable in human milk following cannabis use, and concentrations remain elevated with repeated cannabis use over a day. Substantial variation in Δ9-THC milk concentrations reflects individual differences in characteristics and behavior, including average postpartum frequency of cannabis use.

Levels of engagement among office-based opioid treatment (OBOT) patients with concurrent methamphetamine use.

BACKGROUND AND OBJECTIVES: Recent increases in methamphetamine use among people seeking treatment for opioid use disorder (OUD) has created significant demand for effective approaches to support this clinical population. This study assessed the extent to which office-based opioid treatment (OBOT) patients, who were diagnosed with methamphetamine use disorder (MUD), engaged with providers. METHODS: A retrospective analysis was conducted of adult patients (n = 470) seeking treatment for OUD who attended at least one visit between March 2020 and March 2023 at a rural regional OBOT provider. Approximately one quarter (28.7%) of patients were diagnosed with MUD in addition to receiving an OUD diagnosis. Bivariate methods and multivariate negative binomial regression models were estimated to examine the associations between clinical measures and the numbers of office visits, peer visits, and telehealth visits. RESULTS: Regression results indicated patients who met criteria for MUD in addition to OUD attended a higher rate of peer visits (incidence rate ratio [IRR] = 2.63, p = .036) when compared to patients who did not meet criteria for MUD. In contrast, patients with MUD and OUD diagnoses displayed significantly lower (IRR = 0.68, p < .001) engagement rates through fewer office visits relative to those who did not meet MUD criteria. DISCUSSION AND CONCLUSIONS: Patients seeking treatment for OUD who meet criteria for MUD are more likely to engage through peer support specialists rather than office visits. SCIENTIFIC SIGNIFICANCE: This study demonstrates the ways patients who meet criteria for OUD and MUD engage with providers to receive treatment.

Evaluating the Educational Experience of Physiotherapy Students Using the Fitness and Mobility Exercise (FAME) Programme to Learn about Neurological Conditions: An Exploratory Study.

Purpose: Group exercise has the potential to be a cost-effective way to improve functional outcomes for those living with neurological injury. Leading group exercise is a foundational competency for entry-to-practice for physiotherapy students. The overall objective of this study was to examine the student experience of using the Fitness and Mobility Exercise (FAME) programme to learn about neurological conditions in a group setting. Methods: Sixteen physiotherapy students filled out a single point in time survey at the end of their placement during which they had the opportunity to use FAME with their clients twice a week. The survey had Likert and open-ended questions and demographic information. Likert responses were calculated as means. Open-ended questions were analyzed using thematic analysis. Results: The Likert questions were answered with almost entirely positive results. The main themes from the open-ended questions were how to personalize the class, characteristics of individual clients shape the class experience and factors that make the class successful. Conclusions: Overall, the physiotherapy students found using FAME to be a positive experience. From the student perspective, using FAME during placement was an effective way to learn about neurological conditions as well as to develop skills to manage a group exercise class.

Objectif: les exercices de groupe ont le potentiel d'être un moyen rentable d'améliorer les résultats fonctionnels des personnes qui vivent avec une atteinte neurologique. La direction d'exercices de groupe est une compétence fondamentale d'accès à la pratique chez les étudiants en physiothérapie. L'objectif global de cette étude consistait à examiner l'expérience des étudiants à l'égard de l'utilisation du programme d'exercices pour la forme physique et la mobilité (FAME, d'après l'acronyme anglais Fitness and Mobility Exercise) et à en apprendre davantage sur les atteintes neurologiques dans un contexte de groupe. Méthodologie: au total, seize étudiants en physiothérapie ont rempli un seul sondage à la fin de leur stage, au cours duquel ils avaient pu utiliser le programme FAME deux fois par semaine avec leurs clients. Le sondage contenait des questions de type échelle de Likert, des questions ouvertes et des renseignements démographiques. Les chercheuses ont analysé les réponses de type échelle de Likert sous forme de moyennes et les questions ouvertes, sous forme d'analyse thématique. Résultats: les réponses aux questions de type échelle de Likert étaient presque toujours positives. Les principaux thèmes des questions ouvertes étaient comment personnaliser le cours, les caractéristiques des clients individuels façonnent l'expérience du cours et les facteurs qui font du cours une réussite. Conclusions: dans l'ensemble, les étudiants en physiothérapie ont trouvé que l'utilisation du programme FAME était une expérience positive. De l'avis des étudiants, l'utilisation du programme FAME pendant le stage était un moyen efficace d'en apprendre davantage au sujet des maladies neurologiques et d'acquérir des compétences pour gérer un cours d'exercice de groupe.

Effects of a moderate exercise regimen on development and puberty attainment of beef heifers reared in drylots at a high stocking density.

This experiment evaluated growth, physiological responses, and puberty attainment in beef heifers reared in drylots with a high stocking density, and provided or not with a moderate exercise regimen. A total of 180 heifers (75% Angus × 25% Brahman) were used in this experiment replicated over 2 yr. Each year, 90 heifers were ranked by age (264 ±â€…1 d) and body weight (BW on day -3; 200 ±â€…2 kg) on day 0, and assigned to a) one of six drylot pens (10 × 14 m pens; 10 heifers per pen) with a stocking density of 14 m2/heifer (DENS), or b) one of three pastures (2-ha pastures; 10 heifers per pasture) with a stocking density of 2,000 m2/heifer (CON). Beginning on day 15, three DENS pens were given access to an exercise area (DENS-EX) 3 times/wk (1 h). Negligible forage was available for CON, whereas heifers from all treatments received the same limit-fed diet (~13 kg/heifer daily). Shrunk BW was recorded after 16 h of feed and water withdrawal on days -3 and 225 to calculate BW gain. Temperament was evaluated on days 0, 128, and 224. Heifers were fitted with a pedometer behind their shoulder on day 0 to record physical activity. Pedometer results and blood samples were collected weekly for progesterone analysis. Hair samples from the tail switch were collected every 28 d. Data were analyzed with pen or pasture as an experimental unit, via ANOVA using the MIXED or GLIMMIX procedures of SAS (SAS Inst. Inc., Cary, NC). Heifers from CON had more (P < 0.01) steps per week compared with DENS and DENS-EX (23,973, 6,706, and 12,354 steps/wk, respectively; SEM = 1,247), and DENS-EX heifers had more (P < 0.01) steps per week compared with DENS. No treatment effects (P ≥ 0.91) were detected for heifer BW gain (~0.820 kg/d). Hair cortisol concentrations were greater (P ≤ 0.05) in DENS and DENS-EX compared with CON beginning on day 56. Exit velocity and temperament score were greater (P ≤ 0.05) in DENS compared with DENS-EX and CON on day 224. Puberty attainment was delayed (treatment × day; P < 0.01) in DENS compared with DENS-EX and CON. A greater (P ≤ 0.05) proportion of CON were pubertal by day 105 compared with DENS and DENS-EX (30.0%, 11.6%, and 15.0%, respectively; SEM = 6.5), while a greater (P < 0.05) proportion of CON and DENS-EX were pubertal by day 154 compared to DENS (61.7%, 66.7%, and 43.3%, respectively; SEM = 6.5). Rearing replacement heifers in drylots with high stocking density has detrimental effects on their puberty attainment, and the moderate exercise regimen partially alleviated this negative outcome.

Replacement beef heifers are often reared in drylots with high stocking density to facilitate feeding and management, or to intensify beef production as availability of grazing areas becomes limited. Studies from our group, however, demonstrated that drylot heifers experience delayed puberty attainment compared with heifers reared on pastures. This negative outcome was associated with chronic stress caused by confinement and restricted physical activity; the latter being a key animal welfare factor with direct effects on reproductive development. Based on this rationale, this experiment evaluated growth, stress-related physiological responses, and puberty attainment heifers reared in drylots and exposed or not to a moderate exercise regimen. Moreover, drylot heifers were compared to contemporary cohorts being reared on pasture. As expected, heifers reared in drylots experienced heightened stress-related physiological responses and delayed puberty attainment compared to pasture heifers. Exposing drylot heifers to the moderate exercise regimen did not alleviate the physiological consequences of chronic stress, but lessened the delay in puberty attainment compared with non-exercised drylot cohorts. Therefore, stocking density and exercise opportunities should be considered to improve heifer welfare and reproductive development in intensive drylot systems, as lack of exercise directly contributes to delayed reproductive development of drylot heifers.

Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort.

INTRODUCTION: We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. METHODS: We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aß] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aß-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N = 299), mild cognitive impairment (MCI; N = 192), or dementia (DEM; N = 65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). RESULTS: Plasma biomarkers differed across diagnostic groups (DEM > MCI > CU), were altered in Aß-PET-positive individuals, and were associated with poorer brain health and kidney function. DISCUSSION: eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. HIGHLIGHTS: Plasma biomarkers differ across diagnostic groups (DEM > MCI > CU) and are altered in Aß-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.

A dose-response meta-analysis on the relationship between average amount of alcohol consumed and death by suicide.

BACKGROUND: To determine whether sub-clinical levels of drinking may contribute to suicide risk, and whether the risk differs by sex, we aimed to evaluate the relationship between average amount of alcohol consumed per day and death by suicide. METHODS: A systematic literature search was performed in Embase, Medline, PsycINFO, PubMed, and Web of Science from database inception up to April 27, 2022. The search strategies incorporated a combination of medical subject headings and keywords for "alcohol use" and "suicide". One-stage dose-response meta-analyses using a restricted maximum likelihood random-effect estimator were conducted to explore the relationship between average alcohol volume consumed and suicide, by sex. Three different shapes of the dose-response relationship-linear (on the log-scale), quadratic, and restrictive cubic splines-were tested. RESULTS: A total of eight studies were included (three studies for females (n=781,205), and eight studies for males (n=1,215,772)). A linear dose-response relationship between average alcohol volume consumed and the log-risk of suicide was identified for both males and females. For males and females, a relative risk (RR) of 1.11 (95% CI: 1.05, 1.18) and 1.64 (95% CI: 1.07, 2.51) for suicide when consuming an average of 10 g of pure alcohol per day compared to lifetime abstention, 1.38 (95% CI: 1.14, 1.66) and 4.39 (95% CI: 1.21, 15.88) for 30g/day, and 1.71 (95% CI: 1.25, 2.33) and 11.75 (95% CI: 1.38, 100.33) for 50g/day, respectively. CONCLUSIONS: As consumption increases, the risk of suicide increases proportionally. The risk of suicide associated with average daily alcohol consumption may be elevated for females, compared with males. Albeit, more research is needed, particularly among females.

Frequency of Agreement Between Structural and Functional Glaucoma Testing: A Longitudinal Study of 3D OCT and Current Clinical Tests.

PURPOSE: To evaluate how often tests of structure and function detect glaucoma progression at the same study visit. Tests include current glaucoma clinical tests and a new 3-dimensional (3D) optical coherence tomography (OCT) rim measurement. DESIGN: Prospective cohort study. METHODS: For 124 open-angle glaucoma patients at a single institution, one eye was randomly selected for each patient. Patients were included if they had open-angle glaucoma and if they had at least 4 yearly study visits. Study visits included a full dilated eye exam, disc photography (DP), Humphrey visual field (HVF 24-2) testing, 2D OCT retinal nerve fibre layer (RNFL) thickness measurements, and 3D OCT neuroretinal rim measurements (i.e., minimum distance band or MDB). For each test at each study visit, eyes were classified as progressors or non-progressors using event-based analysis. Agreement occurred if tests progressed in the same eye at the same study visit. Agreements between all compared tests were calculated as percentages of agreement. RESULTS: The study included 124 open-angle glaucoma eyes, which had an average follow-up period of 66.9 ± 16.4 months. Structural tests (i.e., DP, global RNFL thickness, and global MDB rim thickness) progressed at the same visit as the functional test (i.e., HVF testing) in only 5.0% (3/60) to 16.0% (13/81) of eyes. Global MDB thickness and global RNFL thickness showed similar agreement with functional HVF testing (i.e., 16.0% [13/81] and 8.3% [7/84], respectively), and global MDB thickness showed better structure-function agreement with HVF testing than between DP and HVF testing (i.e., 5.0% [3/60], P = 0.04). For all paired comparisons between testing methods, eyes with moderate glaucoma showed similar or better agreement than eyes with mild or severe glaucoma. CONCLUSIONS: Clinical tests of structure and function do not usually progress at the same clinic visit. Most of the time, glaucoma progression is only detected by one or two tests.