Farm-level risk factors and treatment protocols for lameness in New Zealand dairy cattle.

AIMS: To identify farm-level risk factors for dairy cow lameness, and to describe lameness treatment protocols used on New Zealand dairy farms. METHODS: One hundred and nineteen farms from eight veterinary clinics within the major dairying regions of New Zealand were randomly enrolled into a cross-sectional lameness prevalence study. Each farmer completed a questionnaire on lameness risk factors and lameness treatment and management. Trained observers lameness scored cattle on two occasions, between October-December (spring, coinciding with peak lactation for most farms) and between January-March (summer, late lactation for most farms). A four-point (0-3) scoring system was used to assess lameness, with animals with a lameness score (LS) ≥2 defined as lame. At each visit, all lactating animals were scored including animals that had previously been identified lame by the farmer. Associations between the farmer-reported risk factors and lameness were determined using mixed logistic regression models in a Bayesian framework, with farm and score event as random effects. RESULTS: A lameness prevalence of 3.5% (2,113/59,631) was reported at the first LS event, and 3.3% (1,861/55,929) at the second LS event. There was a median prevalence of 2.8% (min 0, max 17.0%) from the 119 farms. Most farmers (90/117; 77%) relied on informal identification by farm staff to identify lame animals. On 65% (75/116) of farms, there was no external provider of lame cow treatments, with the farmer carrying out all lame cow treatments. Most farmers had no formal training (69/112; 62%). Animals from farms that used concrete stand-off pads during periods of inclement weather had 1.45 times the odds of lameness compared to animals on farms that did not use concrete stand-off pads (95% equal-tailed credible interval 1.07-1.88). Animals from farms that reported peak lameness incidence from January to June or all year-round, had 0.64 times odds of lameness compared to animals from farms that reported peak lameness incidence from July to December (95% equal-tailed credible interval 0.47-0.88). CONCLUSIONS: Lameness prevalence was low amongst the enrolled farms. Use of concrete stand-off pads and timing of peak lameness incidence were associated with odds of lameness. CLINICAL RELEVANCE: Veterinarians should be encouraging farmers to have formal lameness identification protocols and lameness management plans in place. There is ample opportunity to provide training to farmers for lame cow treatment. Management of cows on stand-off pads should consider the likely impact on lameness.

Associations between middle childhood executive control aspects and adolescent substance use and externalizing and internalizing problems.

This study examines the degree to which two middle childhood executive control aspects, working memory and combined inhibitory control/flexible shifting, predict adolescent substance use and externalizing and internalizing problems. Participants were 301 children (ages 3-6 years; 48.2% male) recruited from a Midwestern city in the United States and followed into adolescence (ages 14-18 years). Working memory had a statistically significant unadjusted association with externalizing problems (r = -.30, p = .003) in a confirmatory factor analysis. Neither factor significantly predicted any of the adolescent outcomes in a structural equation model that adjusted for each EC aspect, sociodemographic covariates, and middle childhood externalizing and internalizing problems. Stronger prediction of EC aspects might not emerge until they become more fully differentiated later in development.

The prevalence of damaged tails in New Zealand dairy cattle.

AIMS: To undertake a survey of the prevalence of tail deviations, trauma and shortening on a representative selection of New Zealand dairy farms, and to assess whether sampling based on milking order could be used instead of random sampling across the herd to estimate prevalence. METHODS: This was a cross-sectional observational study, with 200 randomly selected farms enrolled across nine regions of New Zealand via selected veterinary practices (one/region). Veterinary clinics enrolled 20-25 farms each depending on region, with 1-2 trained technicians scoring per region. All cows (n = 92,348) present at a milking or pregnancy testing event were tail scored using a modified version of the New Zealand Veterinary Association Industry Scoring System. Palpated lesions were recorded as deviated (i.e. non-linear deformity), shortened (tail shorter than normal) or traumatic (all other lesions). The location of lesions was defined by dividing the tail into three equal zones: upper, middle and lower. A cow could have more than one lesion type and location, and/or multiple lesions of the same type, but for the prevalence calculation, only the presence or absence of a particular lesion was assessed. Prevalence of tail damage calculated using whole herd scoring was compared to random sampling across the herd and sampling from the front and back of the milking order. Bootstrap sampling with replacement was used to generate the sampling distributions across seven sample sizes ranging from 40-435 cows. RESULTS: When scoring all cows, the median prevalence for deviation was 9.5 (min 0.9, max 40.3)%; trauma 0.9 (min 0, max 10.7)%, and shortening was 4.5 (min 1.3, max 10.8)%. Deviation and trauma prevalence varied between regions; the median prevalence of deviations ranged from 6% in the West Coast to 13% in Waikato, and the median prevalence of all tail damage from 7% in the West Coast to 29% in Southland. Sampling based on milking order was less precise than random sampling across the herd. With the latter and using 157 cows, 95% of prevalence estimates were within 5% of the whole herd estimate, but sampling based on milking order needed > 300 cows to achieve the same precision. CONCLUSIONS AND CLINICAL RELEVANCE: The proportion of cows identified as having damaged tails was consistent with recent reports from New Zealand and Ireland, but at 11.5%, the proportion of cows with trauma or deviation is below acceptable standards. An industry-wide programme is needed to reduce the proportion of affected cows.

Biosensor and machine learning-aided engineering of an amaryllidaceae enzyme.

A major challenge to achieving industry-scale biomanufacturing of therapeutic alkaloids is the slow process of biocatalyst engineering. Amaryllidaceae alkaloids, such as the Alzheimer's medication galantamine, are complex plant secondary metabolites with recognized therapeutic value. Due to their difficult synthesis they are regularly sourced by extraction and purification from the low-yielding daffodil Narcissus pseudonarcissus. Here, we propose an efficient biosensor-machine learning technology stack for biocatalyst development, which we apply to engineer an Amaryllidaceae enzyme in Escherichia coli. Directed evolution is used to develop a highly sensitive (EC50 = 20 µM) and specific biosensor for the key Amaryllidaceae alkaloid branchpoint 4'-O-methylnorbelladine. A structure-based residual neural network (MutComputeX) is subsequently developed and used to generate activity-enriched variants of a plant methyltransferase, which are rapidly screened with the biosensor. Functional enzyme variants are identified that yield a 60% improvement in product titer, 2-fold higher catalytic activity, and 3-fold lower off-product regioisomer formation. A solved crystal structure elucidates the mechanism behind key beneficial mutations.

Results from a Phase 1 Study Assessing the Pharmacokinetics of the Aldosterone Synthase Inhibitor Baxdrostat in Participants with Varying Degrees of Renal Function.

Baxdrostat is a selective small-molecule aldosterone synthase inhibitor in development for treatment of hypertension and chronic kidney disease. This phase 1, open-label, parallel-group study assessed the safety and pharmacokinetics (PK) of baxdrostat in participants with varying degrees of renal function. Participants were enrolled into control (estimated glomerular filtration rate [eGFR] ≥60 mL/min), moderate to severe renal impairment (eGFR 15-59 mL/min), or kidney failure (eGFR <15 mL/min) groups and received a single 10-mg baxdrostat dose followed by 7 days of inpatient PK blood and urine sampling. Safety was assessed by adverse events, clinical laboratory evaluations, vital signs, physical examinations, and electrocardiograms (ECGs). Thirty-2 participants completed the study. There were no deaths and only 1 mild drug-related adverse event (diarrhea). No clinically meaningful changes in laboratory values, vital signs, physical examinations, or ECGs occurred. Plasma concentration-time curves of baxdrostat were similar among all groups. Urine PK parameters were similar (approximately 12% excreted) in the moderate to severe renal impairment and control groups. Inadequate urine production in the kidney failure group resulted in minimal urinary baxdrostat excretion. Renal impairment had no significant impact on systemic exposure or clearance of baxdrostat, suggesting that dose adjustment due to PK differences in patients with kidney disease is unnecessary.

Can lameness prevalence in dairy herds be predicted from farmers' reports of their motivation to control lameness and barriers to doing so? An observational study from New Zealand.

Understanding what motivates and prevents behavioral change in farmers is a critical step in disease control in dairy cattle. A total of 101 New Zealand dairy farmers across 8 regions were randomly enrolled into a cross-sectional study to investigate farmer barriers and motivators to lameness control for cows managed 100% at pasture and the relationship between these responses and the true lameness status on farm. Trained technicians lameness scored all lactating cows on the enrolled farms on 2 occasions during one lactation. Farm-level prevalence proportions were calculated as the mean of the 2 lameness scores. Enrolled farmers were asked their perception of lameness in the current milking season and responded to 26 ordinal Likert-type items with 5 options ranging from not important at all to extremely important. The questions were grouped under 3 categories; barriers to lameness control (n = 9), impacts of lameness (n = 10), and motivators to control lameness (n = 7). The association between farmer perception of lameness and lameness prevalence was reported using linear regression. Multiple-factor analysis was conducted to identify latent variable themes within the responses. Linear discriminant analysis was used to assess whether barriers, impacts, and motivators could be used to predict farmer perception of lameness and lameness prevalence. Lameness prevalence was 0.8% greater on farms where farmers perceived lameness as a moderate or a major problem compared with farms where the farmer perceived lameness as a minor problem or not a problem. Farmers ranked all potential motivators to lameness control as important and declared few barriers to be important at preventing them from controlling lameness. Feeling sorry for lame cows and pride in a healthy herd were the most important motivators, with lack of time and skilled labor the most important barriers. The most important effects of lameness were cow-related factors such as pain and production, with farm and industry impacts of less importance. Farmers place different weightings of importance on barriers to lameness control compared with motivators for lameness control. The impacts and motivators were strongly correlated with the first dimension from the multiple-factor analysis, with only weak correlation between barriers and the first dimension. Linear discriminant analysis identified that the importance that farmers place on barriers, motivators, and impacts of lameness were poor predictors of farmers' belief in regard to their lameness problem or actual lameness prevalence (above or below the median lameness prevalence for the study cohort). Despite relatively low lameness prevalence, many New Zealand dairy farmers believe lameness is a problem on their farm, and they rank welfare effects of lameness of high importance. To investigate how farmer behavior change can be used to manage lameness, future studies should consider theoretical social science frameworks beyond the theory of planned behavior or involve prospective interventional studies investigating farmer actions instead of beliefs.

Exploring the Interaction Between Preschool Executive Control and Caregiver Emotion Socialization in Predicting Adolescent Weight Trajectories.

There is a critical need for research examining how neural vulnerabilities associated with obesity, including lower executive control, interact with family factors to impact weight trajectories across adolescence. Utilizing a longitudinal design, the present study investigated caregivers' emotion socialization practices as a moderator of the association between preschool executive control and adolescent body mass index (BMI) trajectories. Participants were 229 youth (Mage = 5.24, SD = 0.03; 47.2% assigned female at birth; 73.8% White, 3.9% Black, 0.4% Asian American, 21.8% multiracial; 12.7% Hispanic) enrolled in a longitudinal study. At preschool-age, participants completed performance-based executive control tasks, and their caregivers reported on their typical emotion-related socialization behaviors (i.e., supportive and nonsupportive responses to children's negative emotions). Participants returned for annual laboratory visits at ages 14 through 17, during which their height and weight were measured to calculate BMI. Although neither preschool executive control nor caregiver emotion-related socialization behaviors were directly associated with BMI growth in adolescence, supportive responses moderated the association between executive control and BMI trajectories. The expected negative association between lower preschool executive control and greater BMI growth was present at below average levels of supportive responses, suggesting that external regulation afforded by supportive responses might reduce risk for adolescent overweight and obesity among children with lower internal self-regulatory resources during preschool. Findings highlight the importance of efforts to bolster executive control early in development and targeted interventions to promote effective caregiver emotion socialization (i.e., more supportive responses) for youth with lower internal self-regulatory abilities to mitigate risk for overweight and obesity and promote health across childhood and adolescence.

Meta-analysis of risk of major adverse cardiovascular events in adults with type 2 diabetes treated with bexagliflozin.

AIM: To explore the risk of major adverse cardiovascular events (MACE) associated with exposure to bexagliflozin. METHODS: The analysis included 4090 participants with type 2 diabetes (T2D) enrolled in nine phase 2 and 3 double-blind randomized controlled trials. All potential MACE were adjudicated by a blinded committee. The primary endpoint for the meta-analysis was the hazard ratio (HR) for the time to first occurrence of non-fatal stroke, non-fatal myocardial infarction (MI), cardiovascular (CV) death or hospitalization for unstable angina (MACE+), tested for non-inferiority to a ratio of 1.8. The secondary endpoints were time to first occurrence of (i) non-fatal stroke, non-fatal MI or CV death (MACE), tested for non-inferiority to a ratio of 1.3; and (ii) CV death or hospitalization for heart failure, tested for superiority. RESULTS: The HR for the primary endpoint of MACE+ was 0.80 (95% confidence interval [CI] 0.58, 1.09), which fulfilled the non-inferiority objective with a P value of less than 0.0001. Non-inferiority for the first key secondary endpoint of MACE was also shown (HR = 0.82; 95% CI 0.59, 1.13; P = 0.0023). Superiority for time to CV death or first hospitalization for heart failure was not shown. CONCLUSIONS: Bexagliflozin did not increase the risk of MACE in participants with T2D when compared with placebo or active control. Both the preapproval and postapproval thresholds for CV safety were met and bexagliflozin has been approved by the US Food and Drug Administration.

Implant Surface Technologies to Promote Spinal Fusion: A Narrative Review.

The technology surrounding spinal fusion surgery has continuously evolved in tandem with advancements made in bioengineering. Over the past several decades, developments in biomechanics, surgical techniques, and materials science have expanded innovation in the spinal implant industry. This narrative review explores the current state of implant surface technologies utilized in spinal fusion surgery. This review covers various types of implant surface materials, focusing on interbody spacers composed of modified titanium, polyetheretherketone, hydroxyapatite, and other materials, as well as pedicle screw surface modifications. Advantages and disadvantages of the different surface materials are discussed, including their biocompatibility, mechanical properties, and radiographic visibility. In addition, this review examines the role of surface modifications in enhancing osseointegration and reducing implant-related complications and, hopefully, improving patient outcomes. The findings suggest that while each material has its potential advantages, further research is needed to determine the optimal surface properties for enhancing spinal fusion outcomes.

Development and psychometric validation of the Pandemic-Related Traumatic Stress Scale for children and adults.

To assess the public health impact of the COVID-19 pandemic on mental health, investigators from the National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) research program developed the Pandemic-Related Traumatic Stress Scale (PTSS). Based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) acute stress disorder symptom criteria, the PTSS is designed for adolescent (13-21 years) and adult self-report and caregiver-report on 3-12-year-olds. To evaluate psychometric properties, we used PTSS data collected between April 2020 and August 2021 from non-pregnant adult caregivers (n = 11,483), pregnant/postpartum individuals (n = 1,656), adolescents (n = 1,795), and caregivers reporting on 3-12-year-olds (n = 2,896). We used Mokken scale analysis to examine unidimensionality and reliability, Pearson correlations to evaluate relationships with other relevant variables, and analyses of variance to identify regional, age, and sex differences. Mokken analysis resulted in a moderately strong, unidimensional scale that retained nine of the original 10 items. We detected small to moderate positive associations with depression, anxiety, and general stress, and negative associations with life satisfaction. Adult caregivers had the highest PTSS scores, followed by adolescents, pregnant/postpartum individuals, and children. Caregivers of younger children, females, and older youth had higher PTSS scores compared to caregivers of older children, males, and younger youth, respectively. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Impact of Posterior Cervical Foraminotomy Before or After Cervical Disk Replacement: Current Evidence.

STUDY DESIGN: Narrative review. OBJECTIVES: The purpose of this study was to provide a review of the current evidence on the impact of posterior cervical foraminotomy (PCF) performed before or after cervical disk replacement (CDR). SUMMARY OF BACKGROUND DATA: The impact of PCF on outcomes in the setting of CDR is an evolving field, given the recent widespread adoption of CDR and the relative rarity of patients who have undergone both procedures. METHODS: A literature search was conducted using PubMed to determine current evidence regarding the indications, outcomes, and biomechanical effects of CDR and PCF when performed alone or in combination. RESULTS: When radicular symptoms persist following PCF, a CDR can be safely performed to provide further decompression. Conversely, a PCF can be safely performed following CDR for these same indications. The biomechanical effects of these procedures in combination demonstrate maintained stability when the facetectomy is less than 50% of the facet joint. Studies demonstrate that stability is not significantly decreased by the presence, amount, or level of posterior foraminotomies in the setting of CDR. CONCLUSIONS: A PCF can be safely performed before or after cervical disk arthroplasty for recurrent radicular symptoms. LEVEL OF EVIDENCE: Level V.

Prevalence of lameness on pasture-based New Zealand dairy farms: An observational study.

To understand the current impact of lameness on a system, it is important to define lameness prevalence across a range of dairy farms in that system. Prevalence estimates from dairy systems where cows are permanently managed at pasture are uncommon, although the limited data suggest that they have a lower lameness prevalence than housed cattle. One hundred and 20 farms from eight of the major dairying regions of New Zealand were randomly enrolled into a cross-sectional lameness prevalence study. On each of the farms, trained observers lameness scored cattle on two occasions, between October-December (spring, coinciding with peak lactation for most farms) and between January-March (summer, late lactation for most farms). At each visit, all lactating animals were scored using a four-point 0-3 scoring system, and included animals that had previously been identified as lame by the farmer. Animals with a lameness score (LS) ≥2 were defined as lame. Mixed logistic regression models assessed the interaction between region and season and island and season, respectively, and differences between the lameness prevalence within farm across the two seasons reported descriptively. A total of 116,317 locomotion scores over two events were conducted across the 120 farms. At the spring scoring event, 2128/60,007 (3.5 %) cows had a LS ≥2 and 1868/56,310 (3.3 %) cows had a LS ≥ 2 at the summer scoring event. At the farm level, across both scoring events, median lameness prevalence was 2.8 (interquartile range 1.5 - 4.5) %, with a range of 0.0-17.0 %. The median farm-level prevalence of LS = 3 was 0.5 % with a range of 0-4.6 %. The effect of timing of scoring was modified by region (p < 0.001), and island (p = 0.006) and at the individual farm level, differences between spring and summer farm level lameness prevalence were generally small (interquartile range: -1.8 to 1.0 %) but potentially large on individual farms (range from -12.3 % to 7.6 %). The median farm-level lameness prevalence estimate of 2.8 % across a random representative sample of New Zealand dairy farms give confidence that the overall prevalence of cattle lameness on New Zealand dairy farms is low. This adds to the growing evidence that pasture is a good management system with respect to hoof health. The evidence of strong seasonality of lameness was lacking. Instead of using lameness scoring to identify farms with large lameness problems, lameness scoring should be encouraged to farmers as a tool to improve the identification of lame animals.

Pathogenic Leptospira are widespread in the urban wildlife of southern California.

Leptospirosis, the most widespread zoonotic disease in the world, is broadly understudied in multi-host wildlife systems. Knowledge gaps regarding Leptospira circulation in wildlife, particularly in densely populated areas, contribute to frequent misdiagnoses in humans and domestic animals. We assessed Leptospira prevalence levels and risk factors in five target wildlife species across the greater Los Angeles region: striped skunks (Mephitis mephitis), raccoons (Procyon lotor), coyotes (Canis latrans), Virginia opossums (Didelphis virginiana), and fox squirrels (Sciurus niger). We sampled more than 960 individual animals, including over 700 from target species in the greater Los Angeles region, and an additional 266 sampled opportunistically from other California regions and species. In the five target species seroprevalences ranged from 5 to 60%, and infection prevalences ranged from 0.8 to 15.2% in all except fox squirrels (0%). Leptospira phylogenomics and patterns of serologic reactivity suggest that mainland terrestrial wildlife, particularly mesocarnivores, could be the source of repeated observed introductions of Leptospira into local marine and island ecosystems. Overall, we found evidence of widespread Leptospira exposure in wildlife across Los Angeles and surrounding regions. This indicates exposure risk for humans and domestic animals and highlights that this pathogen can circulate endemically in many wildlife species even in densely populated urban areas.

Randomized, noninferiority trial evaluating the efficacy of a novel teat sealant in pasture grazed dairy cows.

The intramammary infusion at the end of lactation of a bismuth subnitrate internal teat sealant (ITS), with no antibiotic component has been shown to be an effective means of reducing new intramammary infections over the dry period. There has, however, been very few comparative studies between different brands of ITS under grazed pasture conditions. The objectives of this study were, therefore, to determine if a new bismuth subnitrate internal teal sealant (ShutOut, MSD Animal Health) was noninferior to Teatseal (Zoetis) regarding end-points such as (a) detection of the ITS product after calving, (b) clinical mastitis during the dry period and early lactation, and (c) subclinical mastitis at 30 to 60 d in milk. A total of 1,105 mixed-age cattle were enrolled across 2 farms comparing 2 ITS products for detection of the ITS at calving and prevention of clinical and subclinical mastitis. Both ITS contained 65% (2.6 g) bismuth salts emulsified in ≤ 1.4 g of mineral oil (ShutOut as investigational product, IVP; Teatseal as control product, CPT). At dry-off, treatment was allocated to every second cow. All cows met industry best practice criteria for using ITS treatment without antibiotics. Outcomes included detection of ITS at first stripping of the udder by the farmer, clinical mastitis (CM) from dry-off to 30 d following calving and subclinical mastitis at 30 to 60 d following calving. For ITS detection, a generalized mixed linear regression model was used to model the data, with clustering of quarters within cow accounted for by including cow as a random intercept. Clinical mastitis was analyzed at the cow-level using a Fisher's exact test, and SCC was modeled using a negative binomial distribution. The IVP was noninferior to the CPT for ITS detection following calving. There were 1344/1800 (71.5%) of quarters with ITS detection in the IVP in comparison to 1076/1604 (67.1%) of quarters in the CPT treated group. The quarter-level CM incidence risk was low (45 cases out 4,324 quarters; 1.04%). The overall cow-level CM risk was 4.1% (44/1081), with 20/540 (3.7%) cases in animals in the IVP group and 24/541 (4.4%) cases in animals in the CPT group. The IVP was noninferior to the CPT for cow-level mastitis incidence. The median SCC for all animals was 23,000 cells/mL, with a mean of 92,000 cells/mL. The back-transformed estimated marginal mean estimated SCC was 84,800 (95% CI 75,200-95,600) cells/mL for animals in the IVP group, and 98,800 (95% CI 87,600-111,300) cells/mL for animals in the CPT group. The IVP was, therefore, noninferior for all outcomes measured.

The role of prenatal violence exposure in the development of disparities in children's adiposity from birth to middle childhood.

OBJECTIVE: This study examined whether women's exposure to multiple types of violence during childhood and pregnancy was associated with children's BMI trajectories and whether parenting quality moderated those associations. METHODS: A cohort of 1288 women who gave birth between 2006 and 2011 self-reported their exposure to childhood traumatic events, intimate partner violence (IPV), and residential address (linked to geocoded index of violent crime) during pregnancy. Children's length/height and weight at birth and at age 1, 2, 3, 4 to 6, and 8 years were converted to BMI z scores. Observed mother-child interactions were behaviorally coded during a dyadic teaching task. RESULTS: Covariate-adjusted growth mixture models identified three trajectories of children's BMI from birth to 8 years old: Low-Stable (17%), Moderate-Stable (59%), and High-Rising (22%). Children whose mothers experienced more types of IPV during pregnancy were more likely to be in the High-Rising than the Low-Stable (odds ratio [OR] = 2.62; 95% CI: 1.27-5.41) trajectory. Children whose mothers lived in higher crime neighborhoods were more likely to be in the High-Rising than the Low-Stable (OR = 1.11; 95% CI:1.03-1.17) or Moderate-Stable trajectories (OR = 1.08; CI: 1.03-1.13). Main effects of childhood traumatic events and moderation by parenting were not detected. CONCLUSIONS: Maternal experiences of violence during pregnancy increase children's risk for developing overweight, highlighting intergenerational transmission of social adversity in children's health.

Bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes in adults: A 24-week, randomized, double-blind, placebo-controlled trial.

AIM: To evaluate the relative safety and effectiveness of bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes mellitus. METHODS: In total, 317 participants were randomized to receive bexagliflozin or placebo plus metformin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24, with secondary endpoints for systolic blood pressure (SBP), fasting plasma glucose and weight loss. An open label arm enrolled participants with HbA1c >10.5% and was analysed separately. RESULTS: The mean change in HbA1c was -1.09% (95% CI -1.24%, -0.94%) in the bexagliflozin arm and -0.56% (-0.71%, -0.41%) in the placebo arm, a difference of -0.53% (-0.74%, -0.32%; p < .0001). Excluding observations after rescue medication, the intergroup difference was -0.70% (-0.92, -0.48; p < .0001). The open label group change in HbA1c was -2.82% (-3.23%, -2.41%). Placebo-adjusted changes from baseline SBP, fasting plasma glucose and body mass were -7.07 mmHg (-9.83, -4.32; p < .0001), -1.35 mmol/L (-1.83, -0.86; p < .0001) and -2.51 kg (-3.45, -1.57; p < .0001). Adverse events affected 42.4% and 47.2% of subjects in the bexagliflozin and placebo arms, respectively; fewer subjects in the bexagliflozin arm experienced serious adverse events. CONCLUSIONS: Bexagliflozin produced clinically meaningful improvement in glycaemic control, estimated glomerular filtration rate and SBP when added to metformin in a population of adults with diabetes.

Chasing the fitness optimum: temporal variation in the genetic and environmental expression of life-history traits for a perennial plant.

BACKGROUND AND AIMS: The ability of plants to track shifting fitness optima is crucial within the context of global change, where increasing environmental extremes may have dramatic consequences for life history, fitness, and ultimately population persistence. However, tracking changing conditions relies on the relationship between genetic and environmental variance, where selection may favour plasticity, the evolution of genetic differences, or both depending on the spatial and temporal scale of environmental heterogeneity. METHODS: Over three years, we compared the genetic and environmental components of phenological and life-history variation in a common environment for the spring perennial Geum triflorum. Populations were sourced from alvar habitats that exhibit extreme but predictable annual flood-desiccation cycles and prairie habitats that exhibit similar but less predictable variation in water availability. KEY RESULTS: Heritability was generally higher for early life-history (emergence probability) relative to later life-history traits (total seed mass), indicating that traits associated with establishment are under stronger genetic control relative to later life-history fitness expressions, where plasticity may play a larger role. This pattern was particularly notable in seeds sourced from environmentally extreme but predictable alvar habitats relative to less predictable prairie environments. Fitness landscapes based on seed source origin, largely characterized by varying water availability and flower production, described selection as the degree of maladaptation of seed source environment relative to the prairie common garden environment. Plants from alvar populations were consistently closer to the fitness optimum across all years. Annually, the breadth of the fitness optimum expanded primarily along a moisture gradient, with inclusion of more populations onto the expanding optimum. CONCLUSIONS: These results highlight the importance of temporally and spatially varying selection in life-history evolution, indicating plasticity may become a primary mechanism needed to track fitness for later life-history events within perennial systems.

Protective factors in the relationship between perceived discrimination and risky drinking among American Indian adolescents.

INTRODUCTION: The relationship between perceived discrimination and risky drinking among American Indian (AI) youth is understudied, and the potential protective factors that may buffer this association are unknown. Therefore, the objective of this study was to examine protective factors across individual, family, school, peer, and cultural domains of the social ecology that might attenuate the relationship between perceived discrimination and risky drinking among AI adolescents. METHOD: Data were from the Substance Use Among American Indian Youth Study (Swaim and Stanley, 2018, 2021). AI youth who have used alcohol in their lifetime (n = 2516 within 62 schools) had an average age of 15.16 years (SD = 1.75) and 55.5% were female. Five sets of linear regressions were conducted. Risky drinking was regressed on demographic variables, alcohol use frequency, perceived discrimination, one protective factor (religiosity, parental monitoring, peer disapproval of alcohol use, school engagement, and ethnic identity), and one two-way interaction between perceived discrimination and the protective factor. RESULTS: Prevalence of risky drinking among lifetime drinkers was 40.1%. There were positive associations between perceived discrimination and risky drinking in all models (Bs range from.20 to.23; p <.001). Parental monitoring had a negative association with risky drinking (B = -0.255, p <.001). Religiosity was the only statistically significant moderator (B = -0.08, p = 0.01), indicating that religiosity weakened the relation between perceived discrimination and risky drinking. CONCLUSIONS: Religiosity may represent an important protective factor that could help guide efforts to prevent risky drinking in the face of discrimination among AI adolescents.

Investigating the use of local nerve blocks and general anaesthesia in reducing pain during and after disbudding procedure in goat kids.

The aim of this study was to compare the pain responses (as measured by noise and movement) during administration of local anaesthetic and during and after disbudding in goat kids. Eighty, seven- to ten-day-old, Saanen goat kids from one farm were enrolled and randomly assigned to one of four different methods of pain relief. Twenty kids had local anaesthetic (LA) applied at two sites per horn bud (LA group), 20 kids had LA applied to the two locations using a jet injector (JI group) and 20 kids were given a general anaesthetic (GA) using a combination of 0.02 mg/kg medetomidine and 2 mg/kg ketamine followed by a horn bud block applied as per the LA group (GA group). The remaining 20 kids had no treatment other than meloxicam (control group). Although responses between goat kids and at different time periods were variable, in comparison to the control group, GA eliminated the responses associated with injection of lignocaine and the responses during the period of disbudding, and provided a reduction in head scratches and shakes across multiple time periods.