Compound Symmetry Covariance Research Articles

Effects of Zinc Supplementation on Metabolomic Profiles in Tanzanian Infants: A Randomized Trial

BackgroundProvision of zinc supplementation to young children has been associated with reduced infectious morbidity and better growth outcomes. However, the metabolic pathways underlying these outcomes are unclear, and metabolomic data from humans undergoing zinc supplementation, particularly infants, are generally lacking. ObjectivesThis study aimed to examine the effect of zinc supplementation on metabolic profiles in Tanzanian infants aged 6 wk and 6 mo. MethodsBlood samples were collected at age 6 wk and 6 mo from 50 Tanzanian infants who were enrolled in a randomized placebo-controlled trial of zinc supplementation (5 mg oral daily). Metabolomic analysis using an ultrahigh-performance liquid chromatography/tandem mass spectroscopy platform was performed to identify potential metabolomic profiles and biomarkers associated with zinc supplementation. Principal component analysis (PCA) was used to summarize metabolomic data from all samples. Two-way repeated measures analysis of variance with compound symmetry covariance structures were used to compare metabolome levels over time between infants in the 2 treatment arms. ResultsIn PCA, the samples tended to be more separated by child age (6 wk compared with 6 mo) than by zinc supplementation status. We found that zinc supplementation affected a variety of metabolites associated with amino acid, lipid, nucleotide, and xenobiotic metabolism, including indoleacetate in the tryptophan metabolism pathway; 3-methoxytrosine and 4-hydrxoyphenylphruvate in the tyrosine pathway; eicosanedioate, 2-aminooctanoate, and N-acetyl-2-aminooctanoate in the fatty acid pathway; and N6-succinyladenosine in the purine metabolism pathway. Compared to the relatively small number of metabolites associated with zinc supplements, many infant metabolites changed significantly from age 6 wk to 6 mo. ConclusionsZinc supplementation, despite having overall clinical benefits, appears to induce limited metabolomic changes in blood metabolites in young infants. Future larger studies may be warranted to further examine metabolic pathways associated with zinc supplementation.The parent trial was registered at clinicaltrials.gov as NCT00421668.

Longitudinal Trends in Physical Functioning Patient-Reported Outcome Domains for Children with Sickle Cell Disease

Background: Children with sickle cell disease (SCD) often experience pain and have impaired physical functioning. Patient Reported Outcomes Measurement Information System (PROMIS) tools have previously been shown to be valid and responsive to varied states of health for children with SCD. However, there is limited understanding of the trend of patient-reported outcomes (PROs) over time and the factors associated with this trend and time-dependent changes. The objective of this study was to determine the longitudinal trends in physical functioning domains in children with SCD over a three-year time period and identify factors associated with worse PROs. Methods: Our study included a convenience sample of children with SCD recruited from a tertiary care facility during 2017 - 2020. Eligible children with SCD to self-report PROs were 8 years and older and cognitively capable. Validated PROMIS measures were used to assess fatigue, physical stress experience, strength impact and functioning/mobility over time. The PRO questionnaires were administered every 6 months (with time windows to facilitate completeness of data) for three years to obtain longitudinal data. In addition, we collected clinical data including disease management strategy (hydroxyurea use, chronic transfusion), pain medication, prior acute care use for pain (3 years at baseline and 6 months at follow-up) disease complications (overt stroke, acute chest syndrome, priapism) and other comorbidities. Generalized Estimating Equations with patients as clusters were used to determine changes in PROs over time. This model used compound symmetry covariance structure to account for correlations over time and was adjusted for age and other clinical data. Stepwise regression model was used to identify the significant variables associated with PROs. Results: We recruited 170 children with SCD into our study. Of these, 145 (85.3%) had self-report PRO data for more than one time point. The mean age of the cohort was 10.6 (SD 3.3) years, 53.1% were female. Table 1 shows the demographic and clinical characteristics of our study population. The average T-score for fatigue, physical functioning/mobility, stress experience and strength impact were 47.9, 49.1, 57.2 and 41.5 respectively. Figure 1 shows the unadjusted T-scores over time for each of the listed domains. The regression models showed there were no significant changes in scores for fatigue and physical function mobility over time. However, the stress experience [β (time in months) = -0.13 (95% CI = -0.20 - - 0.07), p-value <0.0001] and strength impact B estimate [β (time in months) = 0.13 (95% CI = 0.08 - 0.18), p-value <0.0001] improved over time. Age at enrollment was significantly associated with strength impact where older kids had a higher strength impact [β (age) = 0.49 (95% CI = 0.15 - 0.83), p = 0.005]. However, age was not associated with any of the other physical functioning domains. Disease severity at baseline, as determined by acute care use in the past three years, was significantly associated with stress experience [β (3 or more acute care visits for pain vs none) = 6.32 (95% CI = 1.71 - 10.93), p-value =.007] and fatigue [β (3 or more acute care visits for pain vs none) = 5.31 (95% CI = 0.95 - 9.66), p-value =.03]. The extent of acute care use within 6 months at follow-up time points was significantly associated with worse fatigue [β (acute care for pain within past 6 months) = 2.19 (95% CI = 0.19 - 4.20), p-value = 0.03] and physical functioning/mobility [β (acute care for pain within past 6 months)=-1.76 (95% CI = -3.24 - - 0.28), p-value = 0.02]. Conclusions: Fatigue and functioning/mobility did not change over time in children with SCD. There were slight improvements in stress experience and strength impact, but the clinical significance of these improvements is unknown. Disease severity, as measured by acute care use at baseline, was significantly associated with worse physical health across all domains.

Asparaginase-Associated Toxicities and Hypersensitivity Reactions in Pediatric and Adolescent Down Syndrome Patients with Acute Lymphoblastic Leukemia or Lymphoma

Children with Down syndrome acute lymphoblastic leukemia (DS-ALL) have worse prognosis compared to those with non-DS-ALL, largely due to higher treatment related mortality. Pegaspargase (PEG) is integral in protocols for the treatment of pediatric ALL and lymphoblastic lymphoma (LBL), and full exposure to all doses of PEG can be limited by toxicities, including hypersensitivity reactions (HSR) due to the production of anti-asparaginase antibodies rendering PEG therapy ineffective. To date, minimal data has been reported on the use of PEG in children with DS-ALL/LBL. We conducted a prospective, multicenter study to evaluate the efficacy of premedicating pediatric and adolescent ALL/LBL patients receiving PEG with antihistamines-H1 and -H2 blockers with subsequent therapeutic drug monitoring (TDM) to better identify patients with true HSR versus those with non-antibody mediated infusion reactions. Here, we report on the incidence of HSRs and PEG-associated toxicities in the cohort of children with DS-ALL/LBL. Eligible patients from six centers received PEG, as per a Children's Oncology Group protocol, beginning in induction therapy. An H1 blocker (diphenhydramine) and H2 blocker (ranitidine, famotidine or cimetidine) were administered prior to PEG administration in consolidation and subsequent cycles. TDM was performed at 7 and 14 days post each PEG. PEG was administered at 2500 International units/m 2/dose that was capped for obesity or age > 22 years. Patients were monitored for HSR and other PEG-related toxicities using CTCAE version 5 criteria. Therapeutic asparaginase activity (AA) was defined as ≥ 0.1 IU/mL (≥100 IU/L) at 7 days post infusion and greater than the lower level of quantification at 14 days. We observed for silent inactivation (subtherapeutic levels without symptoms) and accelerated clearance (levels below quantification at 14 days without symptoms). Descriptive statistics summarized patient characteristics and mixed effects modeling procedure assessed mean AA levels at 7 and 14 days with specification of repeat measures and compound symmetry covariance structure. Out of 148 patients, 9 DS (8 B-ALL, 1 B-LBL) were enrolled between 10/2019 - 3/2022. The median age at diagnosis was 5.0 years [IQR: 4.3, 14.9], 4 were National Cancer Institute (NCI) High Risk (HR) at diagnosis, 4 were Hispanic and none were obese. ALL 9 DS patients received a total of 26 doses of PEG at the standard dose without dose capping required. The mean unadjusted AA levels at 7 and 14 days post PEG were 0.76 IU/ml (SE=0.11) and 0.54 IU/ml (SE=0.11), respectively, p<.001. None of the DS patients experienced HSR or silent inactivation. Accelerated clearance was observed in 1 patient. Nineteen episodes of grade >3 PEG-associated toxicity were observed in 5 DS-ALL patients (5/9; 55.6%). PEG-associated toxicity was observed more frequently in older patients whose mean age was 13 years (SD=6.2) versus 4.3 years in those without toxicity (SDE=0.9), p=.028. Four of the DS-ALL who experienced toxicities were NCI HR at diagnosis and > 10 years of age. For the 19 episodes of toxicities: 6 occurred during induction, 9 during consolidation, and 4 during delayed intensification. The most common toxicity observed was hepatoxicity (increased alanine transaminase) which was experienced by 3 DS-ALL patients. There were no grade > 3 hyperbilirubinemia. All 4 DS-ALL patients who experienced PEG toxicity during induction also had toxicity with subsequent cycles. One DS-ALL patient had a dose limiting toxicity (grade 3 pancreatic pseudocyst), requiring discontinuation of subsequent PEG therapy. There were no grade 4 or 5 toxicities observed. All 4 DS patients who did not experience toxicities were NCI Standard Risk patients. All DS patients had undetectable minimal residual disease (MRD) that was < 0.01 at the end of induction therapy. We noted that in this small DS-ALL/LBL cohort, none of the patients experienced HSR, and all achieved therapeutic AA at both time points of 7 and 10 days post PEG. Five (55.6%) of the DS-ALL patients experienced at least one grade > 3 asparaginase toxicity, and they were older than those without toxicity. Most toxicity occurred during the consolidation phase and no grade 4 or 5 toxicities were observed. Given the PEG-associated toxicity observed in DS ALL/LBL, we are conducting pharmacokinetic analysis to propose a lower dose of PEG which may minimize toxicity while maintaining therapeutic efficacy.

The impact of daily mean air temperature on the proportion of time in hypoglycemia in 2,582 children and adolescents with type 1 diabetes – Is this association clinically relevant?

ObjectivesTo study the potential association between increases in daily mean air temperature and time below range (TBR <54 mg/dl) and time above range (TAR >250 mg/dl) in children and adolescents with type 1 diabetes. Research design and methodsIndividuals with type 1 diabetes <21 years with information on daily glucose profiles from the diabetes prospective follow-up study (DPV) were included (n = 2582). Further inclusion criteria were age at least 6 months at diabetes onset, diabetes duration for at least one year and treatment years 2020–2021. Mean daily air temperature and other meteorological parameters from 78 measurement stations in Germany were linked to the individual glucose sensor profile via the five-digit postcode areas of residency. We used multivariable repeated measures fractional logistic regression models with a compound symmetry covariance structure to study the association between a 1 °C increase in daily mean temperature and time in specific glucose ranges. ResultsA 1 °C increase in daily mean temperature was associated with an acute (Odds Ratio (OR) 1.009 (95%-CI 1.007, 1.011)) and up to 7 days delayed (OR 1.003 (1.001, 1.005)) increase in TBR <54 mg/dl. Moreover, an acute decrease in TAR >250 mg/dl (OR 0.997 (0.996, 0.997)) was found. ConclusionsResults of the DPV registry showed small, but statistically significant changes in TBR and TAR in association with a short-term temperature increase. Higher blood flow and faster insulin absorption might be one possible mechanism. In times of increasing temperature fluctuations meteorological impacts on time in range could become even more relevant.

Linear Mixed Model Analysis of Polygenic Hazard Score on Verbal Memory Decline in Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic, progressive, degenerative disease characterized by cognitive dysfunction, including verbal memory loss. Studies were lacking in examining the longitudinal effect of polygenic hazard score on the Rey Auditory Verbal Learning Test-Delayed Total (AVDELTOT) score (a common measure of verbal memory). A key step in analyzing longitudinal changes in cognitive measures using a linear mixed model (LMM) is choosing a suitable covariance structure. The study aims to determine the association between the polygenic hazard score and the AVDELTOT score accounting for repeated measures (the covariance structure). The AVDELTOT scores were collected at baseline, 12 months, 24 months, 36 months, and 48 months from 283 participants with AD, 347 with cognitive normal, and 846 with mild cognitive impairment in the Alzheimer's Disease Neuroimaging Initiative. The Bayesian information criterion statistic was used to select the best covariance structure from 10 covariance structures in longitudinal analysis of AVDELTOT scores. The multivariable LMM was used to investigate the effect of polygenic hazard score status (low vs. medium vs. high) on changes in AVDELTOT scores while adjusted for age, gender, education, APOE-ε4 genotype, and baseline Mini-Mental State Examination score. One-way analysis of variance revealed significant differences in AVDELTOT scores, Mini-Mental State Examination scores, and polygenic hazard scores among AD diagnoses at baseline. Bayesian information criterion favored the compound symmetry covariance structure in the LMM analysis. Using the multivariate LMM, the APOE-ε4 allele and high polygenic hazard score value was significantly associated with AVDELTOT declines. Significant polygenic hazard score status by follow-up visit interactions was discovered. Our findings provide the first evidence of the effect of polygenic hazard score status and APOE-ε4 allele on declines in verbal memory in people with AD.

Testing independence under a block compound symmetry covariance structure

Testing independence under a block compound symmetry covariance structure

A comparison of country-level data from the VISIONARY study examining treatment outcomes with preservative-free tafluprost/timolol fixed-dose combination therapy

Objective Analysis and comparison of country-level data from the VISIONARY study, examining treatment outcomes with the topical fixed-dose combination of preservative-free tafluprost (0.0015%) and timolol (0.5%) (PF tafluprost/timolol FC) in adults with open-angle glaucoma (OAG) and ocular hypertension (OHT) who were insufficiently treated with or unable to tolerate either beta-blocker or prostaglandin analogue (PGA) topical monotherapy. Methods A European, prospective, observational study was conducted in 11 countries. Adults with OAG/OHT were switched to the PF tafluprost/timolol FC from either PGA or beta-blocker topical monotherapy. Statistical analysis examined changes in mean standard deviation (SD) intraocular pressure (IOP) from baseline at Week 4, Week 12 and Month 6. Data were documented for each eye separately at baseline and during follow up visits, with the eye reported to have the higher IOP (mmHg), as measured using Goldmann applanation tonometry, being selected for analysis (study eye). Country-level subanalysis examined outcomes by prior monotherapy, diagnosis and timing of dosing for those countries recruiting ≥20 patients (Country-level Subanalysis Population). Two-sided paired t-test was used to assess significance regarding mean IOP reduction from baseline and a compound symmetry covariance model was used in cross-country comparisons regarding variation in IOP change from baseline. Treatment-related adverse events (AEs) were evaluated. Results Mean (SD) age among patients recruited to the VISIONARY study ranged between 63.9 (11.8) and 72.4 (10.6) years across all countries. The majority of participants (>50%) were female in each country. The Country-level Subanalysis Population included 551 eyes. Mean (SD) IOP was significantly reduced from baseline in each country at Week 4, Week 12 and Month 6 (p < .0001). Mean IOP reduction at Month 6 ranged from 5.0 mmHg (22.6%, Hungary) to 7.8 mmHg (31.8%, Latvia) and varied significantly between countries (p < .001). The greatest reductions were in Latvia and Russia, where baseline IOP was highest. Country-level IOP reductions were significant irrespective of prior monotherapy, diagnosis or dosing time (p < .0001). Most treatment-related AEs occurred in the UK (26 events, 73% mild). One serious AE was reported (Russia, status asthmaticus). Tolerability with PF tafluprost/timolol FC therapy was rated as good/very good by most patients (85.7–100%) in all countries. Conclusion Subanalysis of VISIONARY study data revealed significant IOP reductions following a switch to the PF tafluprost/timolol FC from either PGA or beta-blocker topical monotherapy. Cross-country variation was likely due to baseline IOP differences. Within country, outcomes were consistent regardless of diagnosis, dosing or prior monotherapy. Treatment was generally well tolerated.

Longitudinal changes in financial burden in patients with colorectal cancer treated with curative intent: Primary results of EAQ162CD.

6597 Background: We prospectively assessed financial burden (FB) due to treatment costs among patients with colorectal cancer (CRC) recruited by NCI Community Oncology Research Program (NCORP) sites. Methods: Patients with newly diagnosed CRC treated with curative intent enrolled through NCORP sites and completed the FACIT Comprehensive Score for Financial Toxicity (COST) instrument at 0-, 3, 6, and 12 months. Higher COST score (range 0-44) indicates greater financial well-being. Effects of demographic, clinical, self-efficacy and safety net affiliation on FB were assessed using linear mixed modeling with compound symmetry covariance structure to account for measurement correlation from the same subject. Results: In 450 patients (mean age 61, 47% female, 84% white, 64% colon, 31% rectal) attrition was comparable across demographics, clinical variables and baseline FB. Higher COST score was linearly correlated with time. Increasing age, income less than $60,000 (vs. less than $29,999), higher self-efficacy, and higher neighborhood socioeconomic status (nSES) predicted a higher COST score; these effects were not moderated by time. Chemotherapy receipt, insurance type, and treatment at a safety net hospital did not predict COST score. Conclusions: Among those with CRC treated with curative intent in community settings, FB improves over the 12 months post diagnosis. Individual and neighborhood level social determinants of health are protective from financial fragility.[Table: see text]

Mean Equality Tests for High-Dimensional and Higher-Order Data with k-Self Similar Compound Symmetry Covariance Structure

An extension of the D2 test statistic to test the equality of mean for high-dimensional and k-th order array-variate data using k-self similar compound symmetry (k-SSCS) covariance structure is derived. The k-th order data appear in many scientific fields including agriculture, medical, environmental and engineering applications. We discuss the property of this k-SSCS covariance structure, namely, the property of Jordan algebra. We formally show that our D2 test statistic for k-th order data is an extension or the generalization of the D2 test statistic for second-order data and for third-order data, respectively. We also derive the D2 test statistic for third-order data and illustrate its application using a medical dataset from a clinical trial study of the eye disease glaucoma. The new test statistic is very efficient for high-dimensional data where the estimation of unstructured variance-covariance matrix is not feasible due to small sample size.

Correlation of Quality of Life between Treatment Outcomes in the Majic Study Which Compared Ruxolitinib to Best Available Therapy in Polycythemia Vera

Correlation of Quality of Life between Treatment Outcomes in the Majic Study Which Compared Ruxolitinib to Best Available Therapy in Polycythemia Vera

Association of Pitch Timing and Throwing Arm Kinetics in High School and Professional Pitchers

Background: Understanding the relationship between the temporal phases of the baseball pitch and subsequent joint loading may improve our understanding of optimal pitching mechanics and contribute to injury prevention in baseball pitchers. Purpose: To investigate the temporal phases of the pitching motion and their associations with ball velocity and throwing arm kinetics in high school (HS) and professional (PRO) baseball pitchers. Study Design: Descriptive laboratory study. Methods: PRO (n = 317) and HS (n = 54) baseball pitchers were evaluated throwing 8 to 12 fastball pitches using 3-dimensional motion capture (480 Hz). Four distinct phases of the pitching motion were evaluated based on timing of angular velocities: (1) Foot-Pelvis, (2) Pelvis-Torso, (3) Torso-Elbow, and (4) Elbow-Ball. Peak elbow varus torque, shoulder internal rotation torque, and shoulder distraction force were also calculated and compared between playing levels using 2-sample t tests. Linear mixed-effect models with compound symmetry covariance structures were used to correlate pitch velocity and throwing arm kinetics with the distinct temporal phases of the pitching motion. Results: PRO pitchers had greater weight and height, and faster ball velocities than HS pitchers (P < .001). There was no difference in total pitch time between groups (P = .670). PRO pitchers spent less time in the Foot-Pelvis (P = .010) and more time in the Pelvis-Torso (P < .001) phase comparatively. Shorter time spent in the earlier phases of the pitching motion was significantly associated with greater ball velocity for both PRO and HS pitchers (Foot-Pelvis: B = −6.4 and B = −11.06, respectively; Pelvis-Torso: B = −6.4 and B = −11.4, respectively), while also associated with increased shoulder proximal force (Pelvis-Torso: B = −76.4 and B = −77.5, respectively). Decreased time in the Elbow-Ball phase correlated with greater shoulder proximal force for both cohorts (B = −1150 and B = −645, respectively) with no significant correlation found for ball velocity. Conclusion: Significant differences in temporal phases exist between PRO and HS pitchers. For all pitchers, increased time spent in the final phase of the pitching motion has the potential to decrease shoulder distraction force with no significant loss in ball velocity. Clinical Relevance: Identifying risk factors for increased shoulder and elbow kinetics, acting as a surrogate for loading at the respective joints, has potential implications in injury prevention.

Self Similar Compound Symmetry Covariance Structure

Self Similar Compound Symmetry Covariance Structure

Prevalence of Thromboembolic Complications in COVID-19 Infection: A Systematic Review and Meta-Analysis

Introduction: The coronavirus disease (COVID-19) infection is proved to be involved in the onset of thromboembolism episodes. This study aims to evaluate the prevalence of thromboembolic complications in patients with COVID-19 from March until May 2020. Methods: A literature review was conducted in MEDLINE (via PubMed), Scopus, Embase, Cochrane, and CINHAL without any language and date of publication restriction (Prospero registration number CRD42020186925). The inclusion criteria were as following: 1) patients with diagnosis of COVID-19; 2) occurrence of thromboembolic event, and 3) patients older than 18 years of age. A multi-variable random effects model was computed accounting for correlations among outcomes by considering a heterogeneous compound symmetry covariance matrix. Results: Observational studies included 2,442 participants from 268 to 7,999 participants per study, 1,014 (41.52%) were male and 825 (33.78%) were female. The multi-variable pooled event rate of acute myocardial infarction was rare, estimated to be 0.03 (95% confidence interval [CI]: 0.00–0.07; p=0.23); this is also true for the meta-analytical estimate of disseminated intravascular disease which was 0.04 (95% CI: 0.00–0.08; p=0.03). Conversely, other events were found to be more frequent. Indeed, the pooled proportion of pulmonary embolism was 0.14 (95% CI: 0.08–0.20; p&lt;0.001), while the venous thromboembolic event rate is 0.15 (95% CI: 0.09-0.30; p=0.04). The pooled intrahospital mortality rate was equal to 0.12 (95% CI: 0.08–0.16; p&lt;0.001). Conclusions: Thromboembolic events, particularly venous thromboembolic event rate and pulmonary embolism, are a frequent complication in patients hospitalised with COVID-19. These findings suggest that the threshold for clinical suspicion should be low to trigger prompt diagnostic testing and that evaluation of therapeutic treatment should be considered in patients in intensive care units with COVID-19.

Evaluation of a novel threonine source for nursery pig diets.

Four hundred and eighty (PIC 337 X 1050, PIC Genus, Hendersonville, TN) pigs were used to evaluate a novel threonine source (ThrPro, CJ America Bio, Fort Dodge, IA) for nursery pigs from approximately 7 to 20 kg body weight (BW). After weaning, pigs were sorted by sex and fed a common diet for 1 wk. Upon completion of the first week, pigs were sorted into randomized complete blocks, equalized by weight, within 16 replications. Pigs were allocated to one of three dietary treatments: positive control (POS)—standard ileal digestible threonine-to-lysine ratio (SID; Thr:Lys) 0.60, negative control (NEG)—SID Thr:Lys ≤0.46, and alternative Thr source (TEST)—SID Thr:Lys 0.60. The alternative Thr source included fermentative biomass and was assumed to contain 75% Thr and a digestibility coefficient of 100% based on the manufacturer’s specifications. All other nutrients met or exceeded the NRC recommendations. Growth and intake data were analyzed as repeated measures with a compound symmetry covariance structure using the MIXED procedure in SAS 9.4 (SAS Institute Inc., Cary, NC) with pen as the experimental unit. Treatment, phase, the interaction between treatment and phase, and block were included as fixed effects in the model. Differences in total removals were tested using Fisher’s Exact Test of PROC FREQ. Results were considered significant at P ≤ 0.05 and considered a trend at P > 0.05 and P ≤ 0.10. During the first 14 d, pigs fed TEST had decreased gain-to-feed ratio (G:F; 0.77 vs. 0.80, P = 0.022) compared to POS and increased G:F (0.77 vs. 0.73, P < 0.001) compared to NEG. Over days 14–28, pigs fed TEST had similar G:F (0.71 vs. 0.70, P = 0.112) compared to POS and increased G:F (0.71 vs. 0.63, P < 0.001) compared to NEG. Overall (days 0–28), pigs fed TEST had similar average daily gain (ADG; 0.47 vs. 0.47 kg/d, P = 0.982) and G:F (0.76 vs. 0.74, P = 0.395) compared to POS and increased ADG (0.47 vs. 0.43 kg/d, P < 0.001) and G:F (0.76 vs. 0.67, P < 0.001) compared to NEG. The average daily feed intake was not significantly different across treatments for the entirety of the study. In conclusion, the replacement of crystalline L-Thr with a novel Thr source resulted in similar growth performance in nursery pigs from approximately 7 to 20 kg.

Mild hypercapnia improves brain tissue oxygen tension but not diffusion limitation in asphyxial cardiac arrest: an experimental study in pigs

BackgroundWe sought to evaluate the effect of mild hypercapnia on brain tissue oxygen tension (Pbto2) and diffusion limitation (impaired ability of oxygen extraction) in a porcine post asphyxial cardiac arrest model.MethodsIn 16 Bama pigs, asphyxial cardiac arrest was induced by endotracheal tube clamping and remained untreated for another 4 min. After return of spontaneous circulation (ROSC), animals were randomly assigned to mild hypercapnia (end-tidal carbon dioxide (EtCO2): 45 ~ 50 mmHg) and normocapnia (EtCO2: 35 ~ 40 mmHg) groups for 12 h. Intracranial pressure (ICP), Pbto2, and brain tissue temperature were invasively measured by multimodality monitors. Blood gas analysis, neuron specific enolase (NSE), and S100β were tested at baseline, ROSC 1 h, 6 h, and 12 h. Generalized mixed model with a compound symmetry covariance matrix was used to compare the time-variables of the two groups.ResultsTwelve (75%) pigs had ROSC and 11 pigs survived for the study period, with 6 pigs in mild hypercapnia group and 5 in the normocapnia group. The mean EtCO2 in the mild hypercapnia was significantly higher than normocapnia group (48 vs 38 mmHg, p < 0.001). Compared with normocapnia, mild hypercapnia group had higher Pbto2 (p < 0.001), slightly higher mean arterial pressure (p = 0.012) and ICP (p = 0.009). There were no differences in cerebral perfusion pressure (p = 0.106), gradient of partial pressure of jugular venous bulb oxygen (Pjvo2) and Pbto2 (p = 0.262), difference of partial pressure of jugular venous CO2 and arterial CO2 (p = 0.546), cardiac output (p = 0.712), NSE (p = 0.822), and S100β (p = 0.759) between the two groups.ConclusionsShort term mild hypercapnia post-resuscitation could improve Pbto2. However, no corresponding improvements in the gradient of Pjvo2 to Pbto2 and biomarkers of neurological recovery were observed in the porcine asphyxial cardiac arrest model.

Asymptotic normality and moderate deviation principle for high-dimensional likelihood ratio statistic on block compound symmetry covariance structure

ABSTRACTThe paper considers a high-dimensional likelihood ratio (LR) test on the block compound symmetric (BCS) covariance structure of a multivariate Gaussian population. When the dimension of each block p, the number of blocks u and the sample size n satisfy that and pu<n−1 as , the asymptotic normality and the moderate deviation principle of the logarithmic LR statistic are obtained. Some numerical simulations demonstrate that the proposed method in high-dimensional BCS test outperforms the traditional Chi-square approximation method, and it is as efficient as the Edgeworth expansion method by Mitsui et al. [Likelihood ratio test statistic for block compound symmetry covariance structure and its asymptoic expansion. Technical Report No.15-03, Statistical Research Group, Hiroshima University, Japan; 2015]. In addition, the proposed method is more applicable because the asymptotic distribution of the test statistic is more concise and the restriction on parameters p, u is milder.

The influence of heat load on Merino sheep. 2. Body temperature, wool surface temperature and respiratory dynamics

Context Australia exports ~2 million sheep annually. On these voyages, sheep can be exposed to rapidly changing ambient conditions within a short time, and sheep may be exposed to periods of excessive heat load. Aims The aim of this study was to define the responses of sheep exposed to incremental heat load under simulated live export conditions. The study herein describes the influence of heat load on wool surface temperature, body temperature (rumen temperature (TRUM), °C; and rectal temperature (TREC), °C) and respiratory dynamics (respiration rate, breaths/min; and panting score (PS)) of sheep under live export conditions. In addition, the relationship between body temperature and respiratory dynamics was investigated. Methods A total of 144 Merino wethers (44.02 ± 0.32 kg) were used in a 29-day climate controlled study using two cohorts of 72 sheep (n = 2), exposed to two treatments: (1) thermoneutral (TN; ambient temperature was maintained between 18°C and 20°C), and (2) hot (HOT; ambient temperature minimum and maximum were 22.5°C and 38.5°C respectively). Sheep in the HOT treatment were exposed to heat load simulated from live export voyages from Australia to the Middle East. Respiration rate, PS and wool surface temperature (°C) data were collected four times daily, at 3-h intervals between 0800 hours and 1700 hours. Rectal temperatures were collected on five occasions at 7-day intervals. These data were evaluated using a repeated measures model, assuming a compound symmetry covariance structure. Individual TRUM were obtained via rumen boluses at 10-min intervals between Days 23 and 29 of Cohort 2. Individual TRUM data were collated and converted to an hourly mean TRUM for each sheep, these data were then used to determine the hourly mean TRUM for TN and HOT, then analysed using a first order autoregressive repeated measures model. Additionally, the relationship between respiratory dynamics and TRUM were investigated using a Pearson’s correlation coefficient, a partial correlation coefficient and a multivariate analysis of variance. Key results The respiration rate of the HOT sheep (140 ± 3.55 breaths/min) was greater (P &amp;lt; 0.01) than that of the TN sheep (75 ± 3.55 breaths/min). Similarly, the PS of the HOT (1.5 ± 0.02) sheep was greater (P = 0.009) compared with the TN sheep (1.2 ± 0.02). Wool surface temperatures and TREC were greater (P &amp;lt; 0.05) for the HOT sheep than for the TN sheep. There were treatment (P &amp;lt; 0.0001), hour (P &amp;lt; 0.0001), day (P = 0.038) and treatment × hour (P &amp;lt; 0.0001) effects on the TRUM of TN and HOT sheep. Conclusions The climatic conditions imposed within the HOT treatment were sufficient to disrupt the thermal equilibrium of these sheep, resulting in increased respiration rate, PS, TREC and TRUM. Implications These results suggest that the sheep were unable to completely compensate for the imposed heat load via respiration, thus resulting in an increase in TREC and TRUM.

The influence of heat load on Merino sheep. 3. Cytokine and biochemistry profiles

Context Approximately 2 million sheep are exported from Australia on live export voyages annually. As voyages travel from a southern hemisphere winter to a northern hemisphere summer, production and welfare issues associated with excessive heat load may arise. Aims The aim of this study was to evaluate the responses of sheep to incremental heat load under simulated live export conditions, specifically the influence of heat load on the metabolic and inflammatory status of sheep. Methods A total of 144 Merino wethers (44.02 ± 0.32 kg) were used in a 29-day climate controlled study using two cohorts of 72 sheep (n = 2), exposed to two treatments: (1) thermoneutral, and (2) hot. Sheep in the hot treatment were exposed to heat load simulated from live export voyages from Australia to the Middle East. Blood samples were collected from all sheep (n = 144) on Day 1, then at 7-day intervals (n = 5) for the duration of each 29-day period. Blood samples were analysed to determine the cytokine, biochemistry and haematology (data not presented here) profiles. Cytokine and biochemical profiles were analysed using a repeated measures model assuming a compound symmetry covariance. The model fitted included terms for cohort and treatment (hot, thermoneutral), and a term for sample collection day (day) and a treatment × day interaction. The subject factor corresponded to the cohort × treatment combinations. Key results There were no consistent trends in plasma cytokine and biochemical profiles. Bicarbonate was the only parameter that was influenced by cohort (P = 0.0035), treatment (P = 0.0025), collection (P = 0.0001) and treatment × collection (P = 0.0025). Furthermore, interleukin-6 and glutamate dehydrogenase were the only parameters that were not influenced by cohort (P &amp;gt; 0.295), treatment (P = 0.2567), collection (P &amp;gt; 0.06) or treatment × collection (P = 0.34). Conclusions Overall, these data highlight that the metabolic and inflammatory status of sheep exposed to incremental heat load, during a simulated live export voyage from a southern hemisphere winter to a northern hemisphere summer, were not markedly altered. Implications These results provide a preliminary evaluation of the inflammatory and metabolic status of sheep on arrival in the Middle East.

The influence of heat load on Merino sheep. 1. Growth, performance, behaviour and climate

Context Annually, millions of sheep are exported from Australia to the Middle East, typically during the southern hemisphere winter to the northern hemisphere summer. During these voyages, sheep can be exposed to relatively rapid changes in ambient conditions within a short period of time (≤29 days); therefore, excessive heat load concerns can arise. Aims The aim of this study was to define the responses of sheep to incremental heat load under simulated live export conditions. The study herein describes (1) the heat load imposed, and (2) the effect of this heat load on the growth, performance and behavioural responses of sheep during periods of incremental heat load. Methods A total of 144 Merino wethers (44.02 ± 0.32 kg) were included in a 29-day climate controlled study using two cohorts of 72 sheep (n = 2), exposed to two treatments: (1) thermoneutral and (2) hot (HOT). Ambient temperature (°C) and relative humidity (%) for the HOT treatment were modelled from live export voyages from Australia to the Middle East in July. Climatic conditions within the climate control chambers were recorded at 10-min intervals, then used to calculate a temperature humidity index. Sheep posture, rumination, eating, drinking and demeanour (calm, agitated or depressed) were observed four times daily at 3-h intervals between 0800 hours and 1700 hours. Feed intake was recorded daily and water intake was measured using an automated meter. Sheep were weighed on Day 0 and then at 7-day intervals. Sheep were weighed at slaughter and carcass weights were obtained, these data were used to determine carcass dressing percentage. Data were analysed using a repeated measures model, with a compound symmetry covariance structure. Key results Climatic conditions in the HOT treatment increased incrementally between Day 1 (temperature humidity index ≥19) and Day 29 (temperature humidity index ≤34.7). Behaviour, feed intake, average daily gain (g/day), carcass weight (kg) and dressing percentage were not influenced by treatment (P &amp;gt; 0.05). Sheep in the HOT treatment group showed a 137% increase in water intake (P &amp;lt; 0.01) and on average consumed 2.15 L/sheep.day, whereas the thermoneutral group consumed 1.67 L/sheep.day. Conclusions These results suggest that these sheep were capable of maintaining feed intake and growth despite exposure to heat load, albeit with a 137% increase in water intake. Implications These results highlight the resilience of the Australian Merino genotype, as these sheep were capable of maintaining feed intake and growth during exposure to heat load. As the climatic conditions in this study were modelled based on typical live export vessel conditions, these results may suggest that the climatic conditions experienced by sheep during voyages may not be as critical as previously thought.

On the estimation of correlation in a binary sequence model

We consider a binary sequence generated by thresholding a hidden continuous sequence. The hidden variables are assumed to have a compound symmetry covariance structure with a single parameter characterizing the common correlation. We study the parameter estimation problem under such one-parameter models. We demonstrate that maximizing the likelihood function does not yield consistent estimates for the correlation. We then formally prove the nonestimability of the parameter by deriving a non-vanishing minimax lower bound. This counter-intuitive phenomenon provides an interesting insight that one-bit information of each latent variable is not sufficient to consistently recover their common correlation. On the other hand, we further show that trinary data generated from the hidden variables can consistently estimate the correlation with parametric convergence rate. Thus we reveal a phase transition phenomenon regarding the discretization of latent continuous variables while preserving the estimability of the correlation. Numerical experiments are performed to validate the conclusions.