Restricted Maximum Likelihood Research Articles

Evaluation of Oseltamivir Used to Prevent Hospitalization in Outpatients With Influenza

Despite widespread use, summary evidence from prior meta-analyses has contradictory conclusions regarding whether oseltamivir decreases the risk of hospitalization when given to outpatients. Several large investigator-initiated randomized clinical trials have not yet been meta-analyzed. To assess the efficacy and safety of oseltamivir in preventing hospitalization among influenza-infected adult and adolescent outpatients. PubMed, Ovid MEDLINE, Embase, Europe PubMed Central, Web of Science, Cochrane Central, ClinicalTrials.gov, and WHO International Clinical Trials Registry were searched from inception to January 4, 2022. Included studies were randomized clinical trials comparing oseltamivir vs placebo or nonactive controls in outpatients with confirmed influenza infection. In this systematic review and meta-analysis, Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. Two independent reviewers (R.H. and É.B.C.) extracted data and assessed risk of bias using the Cochrane Risk of Bias Tool 2.0. Each effect size was pooled using a restricted maximum likelihood random effects model. The quality of evidence was graded using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Hospitalization was pooled as risk ratio (RR) and risk difference (RD) estimates with 95% CIs. Of 2352 studies identified, 15 were included. The intention-to-treat infected (ITTi) population was comprised of 6166 individuals with 54.7% prescribed oseltamivir. Across study populations, 53.9% (5610 of 10 471) were female and the mean age was 45.3 (14.5) years. Overall, oseltamivir was not associated with reduced risk of hospitalization within the ITTi population (RR, 0.79; 95% CI, 0.48 to 1.29; RD, -0.17%; 95% CI, -0.23% to 0.48%). Oseltamivir was also not associated with reduced hospitalization in older populations (mean age ≥65 years: RR, 1.01; 95% CI, 0.21 to 4.90) or in patients considered at greater risk of hospitalization (RR, 0.65; 0.33 to 1.28). Within the safety population, oseltamivir was associated with increased nausea (RR, 1.43; 95% CI, 1.13 to 1.82) and vomiting (RR, 1.83; 95% CI, 1.28 to 2.63) but not serious adverse events (RR, 0.71; 95% CI, 0.46 to1.08). In this systematic review and meta-analysis among influenza-infected outpatients, oseltamivir was not associated with a reduced risk of hospitalization but was associated with increased gastrointestinal adverse events. To justify continued use for this purpose, an adequately powered trial in a suitably high-risk population is justified.

Does vitamin D reduce the mortality rate of Plasmodium infection?: a systematic review and meta-analysis

BackgroundVitamin D supplementation is recommended as an effective adjunct to counteract malaria pathogenesis, but the evidence on this point is limited and controversial. This systematic review and meta-analysis aimed to investigate the effect of vitamin D administration on the survival rate of Plasmodium-infected animals in experimentally-induced malaria on days 6 and 10 post-infection.MethodsFive electronic databases were searched up to 20 December 2021. The pooled risks ratio (RR) and associated 95% confidence interval were estimated using the Restricted-maximum likelihood (REML) random-effects model. Heterogeneity was assessed by Cochran’s Q test and I2 value. Sub-group analyses were used to identify the sources of heterogeneity for several variables, such as type of vitamin D, type of intervention, and dose of vitamin D.ResultsOut of 248 articles found in the electronic database, six were eligible for inclusion in the meta-analysis. The current study found that the pooled random effect of risks ratio favored a statistically significant effect of vitamin D administration on survival rate in infected mice on day 6 post Plasmodium infection (RR = 1.08, 95%CI 1.03, 1.15, p < 0.99; I2 = 0%). It also found that vitamin D administration significantly affected the survival rate on day 10 post-infection (RR = 1.94, 95%CI 1.39, 2.71, p < 0.001; I2 = 69.02%). Subgroup analyses demonstrated a significant pooled RRs of the positive effect of vitamin D administration for cholecalciferol (RR = 3.11, 95%CI 2.41, 4.03, p < 0.001; I2 = 0%), doses higher than 50 µg/kg (RR = 3.37, 95%CI 2.55, 4.27, p < 0.001; I2 = 0%), and oral administration (RR = 3.01, 95%CI 2.37, 3.82, p < 0.001; I2 = 0%).ConclusionThis systematic review and meta-analysis showed that vitamin D administration positively affects the survival rate in Plasmodium-infected mice. Since, the mouse model may not accurately reproduce the clinical and pathological features of human malaria, future research should investigate the impact of vitamin D in human malaria.

Heritability and genetic association of social organization traits with feeding behavior, feed efficiency and growth in Bos indicus

Dominance relationships are important to maintain a stable social organization in group living animals and reduces conflicts between individuals. However, there is a lack of knowledge on the genetic components of social organization. The aim of this study was to estimate the heritability of social organization traits obtained using electronic feed bunk data and their genetic and phenotypic correlations with feeding behavior, feed efficiency and growth in Nellore cattle. Data were obtained from 970 young bulls evaluated in 12 feed efficiency tests. The method used to evaluate social organization was based on feeding event data to detect displacements at the feed bunks. Social organization was evaluated using two traits: dominance value (DV) and social hierarchy (SH). The (co)variance components were estimated by the restricted maximum likelihood method using an animal model in single- and two-traits analyses. The heritability estimates for DV and SH were 0.23 ± 0.07 and 0.25 ± 0.08, respectively. The genetic correlations of the social organization traits with dry matter intake per visit (DV: −0.37 ± 0.17; SH: −0.29 ± 0.17) and time spent at the feed bunk per visit (DV: −0.47 ± 0.16; SH: −0.46 ± 0.15) were negative and ranged from moderate to high, while the genetic correlations with the frequency of feed bunk visits were moderate and positive (DV: 0.34 ± 0.18; SH: 0.22 ± 0.19). On the other hand, the genetic correlations between social organization and growth traits were close to zero. The results indicate that the visits of dominant animals to the feed bunk are shorter but more frequent throughout the day; and these animals tend to consume less feed per visit than subordinate animals. Furthermore, the genetic correlations of DV and SH with growth traits close to zero suggest that selection for higher growth does not affect the social position that the animal occupies within the group. The social organization traits are inheritable and are genetically associated with feeding behavior traits. There is evidence that DV and SH are not genetically correlated with growth traits.

Johnson–Schumacher Split-Plot Design Modelling of Rice Yield

Summary In this research, an intrinsically nonlinear split-plot design model (INSPDM) is formulated and studied. It was formulated by fitting a Johnson–Schumacher (JS) function to the split-plot model mean function. The fitted model parameters are estimated using the estimated generalized least squares (EGLS) technique based on a Gauss–Newton procedure with Taylor series expansion, by minimizing the objective function of the model. The variance components for the whole plot and subplot random effects are estimated using restricted maximum likelihood estimation (REML) techniques. The adequacy of the fitted INSPDM was tested using four median adequacy measures: resistant coefficient of determination, resistant prediction coefficient of determination, the resistant modeling efficiency statistic, and the median square error prediction statistic based on the residuals of the fitted model. Akaike’s Information Criterion (AIC), Corrected Akaike’s Information Criterion (AICC) and Bayesian Information Criterion (BIC) statistics are used to select the best parameter estimation technique. The results obtained are compared with the techniques of ordinary least squares (OLS) and EGLS via maximum likelihood estimation (MLE). The results showed the model to be adequate, reliable, stable, and a good fit based on EGLS-REML when compared with OLS and EGLS-MLE fitted model parameter estimates.

Genome-wide Association Study of Birth Weight in Bali Cattle (Bos javanicus)

The genome-wide association study is popularly used to identify markers associated with high economic traits in cattle breeds worldwide. However, this method has never been applied to Bali cattle ( Bos javanicus ), which are indigenous to Indonesia. Therefore, this study aimed to determine whether the GWAS can also be employed to figure out genomic regions potentially affecting Bali cattle's birth weight trait. In this study, phenotypic and genotypic data of 48 Bali cattle were used to figure out genomic regions which are potentially affecting the birth weight trait of Bali cattle. Those samples were genotyped using an Illumina bead chip array with 53.218 single nucleotide polymorphisms (SNPs). The estimation of the variance proportion explained by each SNP was conducted by a restricted maximum likelihood (REML) approach. The result showed that the birth weight trait in Bali cattle was affected by multiple regions dispersed over the genome, especially chromosomes 20 and 21. This study demonstrated that GWAS can be used effectively and discovered two intriguing regions related to quantitative trait loci and genes, namely STXBP6 and TERT , which previously had been linked to cattle birth weight and growth. These findings are important for developing and refining genomic-based selection programs for Bali cattle in Indonesia.

The impact of music therapy on opioid use in cancer survivors with chronic pain.

e24124 Background: Chronic pain and persistent opioid use are significant problems for many cancer survivors. Opioid tapering comes with major challenges. It is therefore recommended that cancer survivors learn non-pharmacological techniques to support opioid tapering. Methods: The purpose of this pilot study ( N = 26) was to examine the benefits of interactive music therapy (IMT) for opioid tapering in cancer survivors with chronic pain who are persistent opioid users. Those with a history of polysubstance abuse/substance use disorder or who were receiving maintenance methadone or suboxone were excluded. Participants were randomized to 10 weekly, individual IMT ( n = 14) or social attention control ( n = 12) sessions. We measured daily opioid use and chronic pain outcomes (pain interference, pain-related self-efficacy, and pain intensity) at baseline, post-intervention (week 10) and 3-month follow-up (FU). We also conducted semi-structured interviews to gain understanding of participants’ perspectives on the usefulness of IMT for opioid tapering. We modeled the pattern of mean daily opioid dose change over time using multilevel models. The cross-level interaction between time and treatment was used to determine the effect of treatment condition on the pattern of change in the target outcomes. We used restricted maximum likelihood to estimate model parameters and to test the significance of random effects. Given the small sample size, we relied on effect sizes for interpretation. Interview transcripts were analyzed using thematic analysis. Results: Participants were 58±13 years old. Most participants identified as female (58%), not Hispanic or Latino (92%), and white (58%) or Black (38%), and reported to have had breast (23%), cervical (8%), lung (8%), or melanoma skin cancer (8%). A total of 85% of participants said that they were quite to very motivated to taper their opioid use. About one third had had prior opioid tapering attempts and 31% stated that they had concerns related to opioid tapering. We found a large effect of IMT on mean daily opioid use at week 10 ( η2p = 0.36) and at 3-month FU ( η2p = 0.27). There was a medium effect of IMT on pain interference at week 10 ( η2p = 0.18) and a large effect at 3-month FU ( η2p = 0.30). For pain-related self-efficacy, we found a medium effect at week 10 ( η2p = 0.21) and small effect at 3-month FU ( η2p = 0.09). IMT resulted in a small treatment effect for pain intensity at week 10 and at 3-month FU (week 10: η2p = 0.05; 3 month: η2p = 0.09). The quantitative results were congruent with the qualitative findings as many IMT participants reported feeling more “in control” of their pain and being able to apply the music-based self-management strategies outside of the sessions to help with pain management and improve their functioning. Conclusions: These promising findings warrant further research on the effects of IMT on opioid tapering and chronic pain management in cancer survivors. Clinical trial information: NCT03782506 .

Interleukin-1 beta treatment alters prostaglandin-related mRNA expression and cytokine abundance in equine endometrial culture

Interleukin-1β (IL-1β) is a proinflammatory cytokine that modulates the immunoinflammatory response and induces prostaglandin synthesis. IL-1β has a variety of roles in the endometrium during inflammation, decidualization, pregnancy, and post-partum. It can cause changes in endometrial gene expression and may affect cytokine, chemokine, and prostaglandin-related pathways. The relationship between IL-1β, prostaglandins, and downstream inflammatory responses in the equine uterine environment is not fully known. Our objective was to determine the effect that IL-1β has on prostaglandin-related gene expression, as well as cytokine and chemokine abundance, in endometrial cell culture. Light breed mares (n=8) were examined daily by transrectal ultrasound until ovulation. An endometrial biopsy was collected at day 11 post ovulation, and used for primary endometrial cell culture. Cells were cultured in DMEM with 10% FBS. At 80% confluence, cells were either not supplemented or supplemented with: 100 nM Progesterone (Prog); 1 nM Estradiol-17β (Est); or 100 nM Prog and 1 nM Est (P+E). After 24 hours, cells were treated with recombinant equine IL-1β at either 10 ng/mL (Low) or 1000 ng/mL (High), or 0.2% DMSO as an untreated control. Twenty-four hours post-treatment, supernatant was collected, and a bead-based multiplex assay was used to quantify concentration of twelve cytokines and chemokines. Total RNA was extracted from the cells and mRNA expression was evaluatedfor 10 prostaglandin-related genes, using the ΔCT method with ACTB as the reference gene. Data analysis was performed using JMP Pro 16, using a restricted maximum likelihood model with treatment and supplementation as factors, and mare as a random factor. Treatment with IL-1β High resulted in increased levels of CCL2, CCL5, and CCL11 (p<0.001) in cell culture supernatant, as well as increased mRNA expression of PTGS2 (p<0.02), regardless of supplementation. Cells supplemented with Prog or P+E and treated with IL-1β High had increased expression of IL1R1, IL1RAP, PTGS1, and PTGES compared to non-supplemented cells (p<0.05). IL-1β High treatment increased LiF expression in cells supplemented with Prog or P+E compared to untreated cells (p<0.05). IL-1β likely acts to modulate inflammatory pathways in the endometrium, altering chemokine levels and activating expression of PTGS2, leading to changes in downstream prostaglandin synthesis and other related pathways. Progesterone appears to increase expression of several target genes when compared to non-supplemented cells. Progesterone has been shown to be involved in the suppression of several inflammatory pathways, and investigation into the ovarian steroid regulation of genes and proteins in the equine endometrium is warranted. Further studies on the effect of IL-1β on molecular pathways and prostaglandin regulation could lead to a greater understanding of the uterine environment in the pregnant and non-pregnant mare.

Adverse events (AEs) of immune checkpoint therapy (ICT) combined with vascular endothelial growth factor inhibitors (VEGFi) vs. ICT alone: A pooled meta-analysis of 1735 patients.

e14667 Background: ICT combined with VEGFi are established as approved therapies for multiple malignancies. However, added toxicities remain unclear. We hypothesized that the combination of ICT + VEGFi has higher treatment-related AEs (TRAEs) and immune-related AEs (irAEs) compared with ICT alone. Methods: We performed a meta‐analysis to identify studies evaluating toxicity profile of ICT + VEGFi as compared to ICT. Systemic search was performed across all cancer types and major databases until August 10, 2022. Search structures, subject headings, and keywords were tailored to databases by medical research librarian. Screening of studies was done by two investigators. Inclusion criteria consisted of prospective phase II or III clinical studies which included at least one arm of patients treated with ICT + VEGFi and one arm treated with ICT alone. Restricted maximum likelihood fixed effects model was used to pool AEs data; I2 was used for heterogeneity. Results: From a total of 9366 studies found, seven met inclusion criteria. A total of 808 patients were treated with ICT while 927 were treated with ICT + VEGFi. Only one study reported irAEs. Therefore, we restricted our analysis to TRAEs. The total number of TRAEs (including grade 5) was significantly higher in ICT + VEGFi group with more frequent treatment withdrawals attributed to TRAEs. The list of TRAEs and specific effect sizes are summarized. The highest TRAE effect size increases with ICT + VEGFi were noted for rash (RR 6.50), hypertension (RR 6.07), hypothyroidism (RR 5.02), and diarrhea (RR 4.94). Conclusions: Combination therapy with ICT + VEGFi confers increased risk of specific TRAEs in comparison to ICT. Clinicians should be particularly mindful of the increased risk for rash, hypertension, hypothyroidism, diarrhea, nausea, anorexia, and proteinuria with ICT + VEGFi therapies. There are insufficient data on irAEs and future trials should provide more granular details on the AE cause. [Table: see text]

Characterization of interferons in the equine conceptus and endometrium

Interferons (IFN) are involved in the maintenance and establishment of pregnancy in a variety of species. There are three types of IFNs, which include type I (IFN-α, β, ε, τ, and δ), type II (IFN-γ), and type III (IFN-λ1, λ2 and λ3). In the horse, IFNA, IFND and IFNO are expressed in the equine trophoblast, and IFNE is expressed in higher abundance in equine endometrium during the luteal phase. However, investigation of IFNs and their receptors during early equine pregnancy is still lacking. Our objective was to investigate the expression of IFN types I and II and their receptors, and other IFN related genes in equine conceptuses and endometrium during early pregnancy. Mares were examined daily by transrectal ultrasound when in estrus until the day (D) of ovulation (OV). Pregnant (P) group mares were bred using artificial insemination by a single fertile stallion. Conceptuses were detected and measured via transrectal ultrasound and collected via uterine lavage using 0.9% NaCl through a transcervical bivona catheter. Following conceptus retrieval, an endometrial biopsy was collected. Endometrial samples from nonpregnant (NP) mares were collected at D11 (NP11; n=6) and D13 (NP13; n=7), while endometrium and conceptuses were collected from pregnant mares at D11 (P11; n=7), D13 (P13; n=8), and D16 (P16; n=6). As the majority of nonpregnantmares would have undergone luteolysis, a D16 sample was not included in this study. Total RNA was isolated and evaluated for expression of interferon-related genes using Real-time PCR. The mean threshold cycle was determined and then normalized to the mean of the reference genes (GAPDH and ACTB) (ΔCT). A restricted maximum likelihood model was performed in JMP Pro 16 (Cary, NC) with mare as a random factor with significance set at P<0.05. There was no amplification for IFNB and IFND in the endometrium, and no amplification of IFNG, IFNB and IFNAR2 in the conceptus. In the endometrium, IFNAR1 and IFNGR1 had higher expression in P11 compared to P13 (P<0.02). Expression of endometrial IFNG mRNA was higher in P11 and P16 compared to P13 (P<0.004). There was no difference in the mRNA relative abundance of endometrial ISG15 and IFITM1 between groups or days. In the conceptus, IFNA, IFNO, and IFNGR2 expression were higher in D16 compared to other ages (P<0.05). D11 and D16 conceptuses had higher expression of IFNAR1 compared to D13 (P<0.0002), while IFNGR1 was higher in D16 compared to D11 (P<0.004). The role of interferons during maternal recognition of pregnancy in the horse is unknown. Unlike the pig, the horse embryo does not seem to express IFNG. Further investigation is underway.

Differential gene expression in the equine endometrium and conceptus from Day 11 to 16 post-ovulation

Mobility of the equine conceptus is essential for maternal recognition of pregnancy (MRP) and is regulated by the conceptus's own derived prostaglandin secretion. Our objective was to compare prostaglandin-related genes and other genes of interest during the expected MRP time. Light breed mares were examined daily by transrectal ultrasound when in estrus until the day (D) of ovulation. Mares in the pregnant (P) group were bred by artificial insemination with >500 million progressively motile normal sperm from one fertile stallion until D0. Conceptuses were detected and measured via transrectal ultrasound and collected via uterine lavage using 0.9% NaCl through a transcervical bivona catheter. Endometrium was collected via a transcervical biopsy punch following conceptus retrieval. Endometrium of non-pregnant (NP) mares was collected at: D11 (NP11; n=6) and D13 (NP13; n=7), while endometrium from the pregnant horn and conceptuses was collected at D11 (P11; n=7), D13 (P13; n=8), and D16 (P16; n=6). Total RNA from trophoblast and endometrial samples was isolated and evaluated for expression of PTGS2, PTGES, mPGES2, PTGER4, PTGER2, PTGIS, PTGIR, HPGD, SLCO2A1, CRTC2, NR3C1, CBR1, CREB, NF-Kβ, SPP1, IGFBP1, ESR1 and DNTTIP2 using Real-time PCR. Mean threshold cycle was determined and normalized to the reference gene (GAPDH and ACTB) (ΔCT). Statistical analyses were performed using JMP Pro 16, and data was ranked, transformed if necessary, followed by a restricted maximum likelihood model with mare as arandom factor to test differences between Groups and Day. Regarding endometrial mRNA, NP11 had higher expression for NF-Kβ, PTGIS, PTGIR and CBR1 compared to NP13 (p<0.007). ESR1, mPGES2, PTGIS, and CBR1 mRNA were higher in P11 compared to P16 (p<0.05), while CRTC2 was higher in P16 compared to P11 (p<0.06). Lastly, NF-Kβ, PTGIR and CBR1 were higher in P11 compared to P13 (p<0.01), but NF-Kβ P13 was lower compared to P16 (p<0.04). Regarding the conceptuses, CREB and PTGFR expressions were higher in D16 compared to D11 (p<0.003), while CRTC2, NR3C1, NF-Kβ and SPP1 were higher in D16 compared to D11 and 13 (p<0.02). D13 conceptuses had lower expression of HPGD compared to D11 and 16 (p<0.02). Lastly, D11 conceptuses had higher expression of mPGES2, PTGIS and PTGER4 compared to D13 and D16 (p<0.03). Higher expression of D11 PTGIS from both tissues may increase nutrient and blood flow to the endometrium in support of the early conceptus. The upregulation of endometrial NF-Kβ at D11 may be a result of endometrial receptivity through the regulation of inflammation, and the up-regulation of HPGD may function to regulate PGE2 during early pregnancy. Understanding embryonic and endometrial prostaglandin regulation during MRP may help to develop future therapies to ameliorate pregnancy loss in the horse.

Investigation of cytokines in equine serum, conceptuses and endometrium in early pregnancy

Cytokines and their receptor systems are present at the fetomaternal interface of some species and regulate trophoblast biology. The cytokine and chemokine systems are key in the communication between fetal derived trophoblast cells and the maternal tissue. However, evidence for the presence of cytokines and their receptors during early equine pregnancy is lacking. Our objective was to investigate interleukins, chemokine ligands, dendritic cells and TNFα in equine serum, conceptuses and endometrium during early pregnancy. Daily transrectal ultrasound examinations of the mares were performed when in estrus until the day (D) of ovulation (OV). An endometrial biopsy was taken from non-pregnant (NP) mares at: D11 (NP11; n=6) or D13 (NP13; n=7). Mares in the pregnant (P) group were bred by artificial insemination from a single fertile stallion, and transrectal ultrasound was performed to detect and measure conceptuses. On the day of sample collection, conceptuses were collected through a transcervical bivona catheter and uterine lavage using 0.9% NaCl, and this was followed by an endometrial biopsy. Pregnant mares’ conceptuses and endometrial biopsies were retrieved at D11 (P11; n=7), D13 (P13; n=8), or D16 (P16; n=6). A D16 sample was not obtained for NP group. A Bradford assay was performed on extracted endometrium and conceptus tissue to determine total protein concentration,followed by a bead-based equine validated multiplex assay (Luminex Corp. Austin, TX) to quantify concentration of the following equine specific inflammatory markers: IL-4, IL-17, IL-10, IL-1β, CCL2, CCL3, CCL5, CCL11, sCD-14 and TNFα. A restricted maximum likelihood model was performed to compare the protein concentration between groups and days in JMP Pro 16 (Cary, NC) with the mare as a random factor and significance set at p<0.05. Cytokine and chemokine serum concentrations were similar between groups and days of collection. Regarding the endometrium, IL-17 U/mg was higher (p<0.05) in group NP13 [median (interquartile)] [11.4 (8.2, 21.7)] than NP11 [4.1 (2.6, 5.3)]. In pregnant mares, endometrial IL-17 was higher in P13 group [6.3 (3.4, 13.9)] compared to group P16 [2.5 (2.1, 4.8)] (p<0.05). In conceptuses, D11 had significantly higher concentrations of CCL2 [1350.2 (793, 1839.5); p<0.03], CCL3 [1990.9 (998.6, 3083.8); p<0.01], CCL5 [363.2 (149.6, 480.6); p<0.006] and CCL11[3143.7 (1764.2, 5221.9); p<0.01 compared to D16 [66.7 (38.8, 644.8); 67.8 (43, 572.30); 9.1 (6.6, 96.3); 196.2 (150.9, 1436.6)], respectively. Higher chemokine concentrations in the earlier embryos may reflect the recruitment of endometrial leukocytes. Further investigation into the role of cytokines and chemokines in early equine pregnancy is warranted.

Mesenchymal stromal cell conditioned media is immunomodulatory in the equine endometrium

Endometritis is a common and costly disorder in horses that results in poor reproductive performance. Current therapies are supportive, and the industry suffers from a paucity of immunomodulatory treatment modalities for this disease that is characterized by inflammatory dysregulation. Recently, mesenchymal stromal cell conditioned media (MSC-CM) is being explored as a treatment option for various inflammatory conditions due to its immunoregulatory, antimicrobial, biofilm disruption, and tissue repair properties. Our objective was to evaluate changes in the endometrial inflammatory response after treatment with MSC-CM in vitro. We hypothesized that endometrial cells in culture would have altered cytokine expression and production. Five estrous mares were biopsied to establish primary endometrial cell cultures. After cell dissociation, endometrial cells were cultured in DMEM supplemented with 10% FBS and 1% antibiotic antimycotic solution (Sigma Aldrich) at 37°C with 5% CO2. At 80% confluence, cultures were hormonally supplemented with 1nM Estradiol-17β, 100 nM Progesterone, or no supplementation; and 24 hours later, treated with MSC-CM or DMSO as control. Supernatants from the cell cultures were analyzed for cytokine expression using an equine cytokine Multiplex assay (Luminex Corp. Austin, TX) quantifying inflammatory biomarkers including IFN-α, IFN-γ, IL-4, IL-17, IL-10, IL1-β, CCL2, CCL3, CCL5, CCL11, TNF-α, and sCD14. In parallel, cells were lysed and RNA extracted for Real-time PCR using the ΔCT method with ACTB as the reference gene for geneexpression of IL-6, IL-8, PTGS2, PTGES, PTGIS, TNFα, TGFB, and NFKb. Data analysis was performed with JMP Pro 16 with level of significant p<0.05. A restricted maximum likelihood model with treatment, supplementation and their interaction and mare as a random factor was used. There was no effect of hormone supplementation on supernatant cytokine concentrations, but treatment with MSC-CM altered their concentration. MSC-CM treatment increased the concentration of CCL2 pg/ml [median (interquartile)] [1862554 (32482, 240080) (p≤0.02); and decreased CCL3 [66 (0.1, 99)] (p≤ 0.01) and IL-10 [6.5 (0.1, 9.5)] (p≤0.007) compared to DMSO control [3114 (2398.5, 7483); 109 (0.1, 154); and 13 (0.1, 17)], respectively. Gene expression analysis showed that MSC-CM-treated cells had increased expression of IL-6 (p≤0.001), IL-8 (p≤0.001), PTGS2 (p≤0.002), PTGES (p≤0.0012), and NFKb (p≤0.01). Additionally, gene expression analysis revealed an effect of hormone supplementation, with increased expression of IL-8 (p≤0.027) and PTGS2 (p≤0.0443) in estrogen or progesterone supplemented cultures compared to no supplementation. Taken together, treatment with MSC-CM resulted in increased inflammatory marker production and greater gene expression of inflammatory cytokines and prostaglandin-related genes. These results are supportive of the potential role of MSC-CM in equine endometrial immunomodulation. Further studies in vivo are warranted to investigate the clinical outcome of this immunomodulatory effect after intrauterine infusion.

Cardiac Computed Tomography for Quantification of Myocardial Extracellular Volume Fraction: A Systematic Review and Meta-Analysis

BackgroundExtracellular volume (ECV) is a quantitative measure of extracellular compartment expansion, and an increase in ECV is a marker of myocardial fibrosis. Although cardiac magnetic resonance (CMR) is considered the standard imaging tool for ECV quantification, cardiac computed tomography (CT) has also been used for ECV assessment. ObjectivesThe aim of this meta-analysis was to evaluate the correlation and agreement in the quantification of myocardial ECV by CT and CMR. MethodsPubMed and Web of Science were searched for relevant publications reporting on the use of CT for ECV quantification compared with CMR as the reference standard. The authors employed a meta-analysis using the restricted maximum-likelihood estimator with a random-effects method to estimate summary correlation and mean difference. A subgroup analysis was performed to compare the correlation and mean differences between single-energy CT (SECT) and dual-energy CT (DECT) techniques for the ECV quantification. ResultsOf 435 papers, 13 studies comprising 383 patients were identified. The mean age range was 57.3 to 82 years, and 65% of patients were male. Overall, there was an excellent correlation between CT-derived ECV and CMR-derived ECV (mean: 0.90 [95% CI: 0.86-0.95]). The pooled mean difference between CT and CMR was 0.96% (95% CI: 0.14%-1.78%). Seven studies reported correlation values using SECT, and 4 studies reported those using DECT. The pooled correlation from studies utilizing DECT for ECV quantification was significantly higher compared with those with SECT (mean: 0.94 [95% CI: 0.91-0.98] vs 0.87 [95% CI: 0.80-0.94], respectively; P = 0.01). There was no significant difference in pooled mean differences between SECT vs DECT (P = 0.85). ConclusionsCT-derived ECV showed an excellent correlation and mean difference of <1% with CMR-derived ECV. However, the overall quality of the included studies was low, and larger, prospective studies are needed to examine the accuracy and diagnostic and prognostic utility of CT-derived ECV.

GENETIC PARAMETERS AND CORRELATIONS OF EARLY WEIGHT TRAITS IN A NIGERIAN INDIGENOUS HEAVY X LIGHT ECOTYPES POPULATION OF CHICKENS

&lt;p&gt;&lt;strong&gt;Background&lt;/strong&gt;: Improvement of the Nigerian indigenous chickens is desirable because of its socioeconomic important. &lt;strong&gt;Objective&lt;/strong&gt;: To estimate the heritability, genetic and phenotypic correlations among body weight, body length, wing length and shank length of the mating of heavy ecotype cocks with light ecotype hens of Nigerian indigenous chickens. &lt;strong&gt;Methodology&lt;/strong&gt;: The mating design was such that one heavy ecotype cock mated with 10 light ecotype hens in twenty replicate pens. The mating produced 752 chicks from ten batches of hatch. The estimates of variance components were obtained from paternal half sib analysis using the average information restricted maximum likelihood of BLUPF90 family of programs. &lt;strong&gt;Results&lt;/strong&gt;: The heritability of body weight ranged from 0.20 to 0.44 from 6 to 12 weeks of age. Similarly, the heritability of body length, wing length and shank length ranged from 0.39 to 0.63, 0.51 to 0.71 and 0.31 to 0.54 respectively from 6 to 12 weeks of age. The genetic correlations among the early growth traits measured were negative to positive in magnitude and ranged from -0.99 to 0.66 while the phenotypic correlations ranged from -0.15 to 0.91. &lt;strong&gt;Implication&lt;/strong&gt;: The results imply that early growth traits of light and heavy ecotype Nigerian indigenous chicken could be improved through mass selection. &lt;strong&gt;Conclusion&lt;/strong&gt;: It is concluded from this study that the heritability of early growth traits were moderate to high in magnitude and the genetic and phenotypic correlations mostly positive.&lt;/p&gt;

Modelling Lactation Curve for Genetic Evaluation of Crossbred Cattle

The present study was conducted on first lactation 4415 monthly test-day milk yield records of 466 crossbred (CB) cattle sired by 89 bulls during 2000–2018 (19 years) maintained at Directorate of Livestock Farms, GADVASU, Ludhiana, Punjab, India. The crossbred cattle with lactation length of minimum 100 days were considered for the study. The aim was to develop the best lactation curve model and to compare the breeding values of sires based on actual and predicted first lactation 305-day milk yield (FL305DMY). The data were classified and coded according to different season and age at first calving groups for first lactation 305-day milk yield. Monthly test-day milk yields of first lactation were used to develop the best lactation curve model. The Polynomial Regression Function (PRF) model was the best model amongst all the models based on both R2 and RMSE values. The breeding values of 60 HF crossbred sires with two or more daughters were estimated from the actual and predicted FL305DMY using Polynomial Regression Function by applying two sire evaluation methods viz. least squares method (LSQ) and restricted maximum likelihood method (REML). The effectiveness of LSQ and REML methods of sire evaluation was compared on the basis of Spearman’s rank correlations, coefficients of determination (R2) and coefficients of variation (CV). LSQ was found most efficient and accurate method for sire evaluation using actual and predicted first lactation 305-day milk yield in HF crossbred cattle.

On asymptotic distributions of several test statistics for familial relatedness in linear mixed models.

In this study, the asymptotic distributions of the likelihood ratio test (LRT), the restricted likelihood ratio test (RLRT), the F and the sequence kernel association test (SKAT) statistics for testing an additive effect of the expected familial relatedness (FR) in a linear mixed model are examined based on an eigenvalue approach. First, the covariance structure for modeling the FR effect in a LMM is presented. Then, the multiplicity of eigenvalues for the log-likelihood and restricted log-likelihood is established under a replicate family setting and extended to a more general replicate family setting (GRFS) as well. After that, the asymptotic null distributions of LRT, RLRT, F and SKAT statistics under GRFS are derived. The asymptotic null distribution of SKAT for testing genetic rare variants is also constructed. In addition, a simple formula for sample size calculation is provided based on the restricted maximum likelihood estimate of the effect size for the expected FR. Finally, a power comparison of these test statistics on hypothesis test of the expected FR effect is made via simulation. The four test statistics are also applied to a data set from the UK Biobank.

Applying Regulatory Focus Theory to Encourage Weight Loss in a Self-directed Intervention.

Regulatory focus theory proposes two self-regulatory systems: promotion focus-related to fulfilling aspirations and maximizing positive outcomes-and prevention focus-related to fulfilling responsibilities and avoiding negative outcomes. Building on research demonstrating associations between regulatory focus and weight outcomes, a proof-of-concept weight control intervention framed intervention procedures in terms of promotion or prevention focus and descriptively examined whether the impact of the intervention conditions depended on dispositional regulatory focus. After random assignment to control (received pamphlet on diet and physical activity), promotion, or prevention conditions (1.5-hour baseline sessions; detailed manuals; 1-hour sessions at 3 months), community participants from a metropolitan area in the United States (N = 57; age M = 40; BMI M = 30.9) completed the Regulatory Focus Questionnaire and were weighed at baseline, 3 months, and 6 months. Longitudinal analysis was conducted with SAS Proc Mixed using restricted maximum likelihood estimation. Estimated weight change was -2.99 kg, 95% CI [-4.65, -1.32], in the promotion condition, -1.70 kg, 95% CI [-3.29, -0.12], in the prevention condition, and -0.18 kg, 95% CI [-1.42, 1.05], in the control condition. Exploratory analyses revealed that for relatively more promotion-focused participants, estimated weight change was -1.43 kg, 95% CI [-3.38, 0.51], in the promotion condition, +0.48 kg, 95% CI [-1.01, 1.97], in the prevention condition, and -1.09 kg, 95% CI [-2.32, 0.14], in the control condition. For relatively more prevention-focused participants, estimated weight change was -5.19 kg, 95% CI [-7.14, -3.25], in the promotion condition, -3.35 kg, 95% CI [-4.83, -1.86], in the prevention condition, and +0.42 kg, 95% CI [-0.81, 1.65], in the control condition. Results suggest that self-directed, promotion-focused interventions may be effective and that tailoring to self-regulatory dispositions may not be of additional benefit in initiating weight loss.

SNP-Based Heritability of Osteochondrosis Dissecans in Hanoverian Warmblood Horses.

Before the genomics era, heritability estimates were performed using pedigree data. Data collection for pedigree analysis is time consuming and holds the risk of incorrect or incomplete data. With the availability of SNP-based arrays, heritability can now be estimated based on genotyping data. We used SNP array and 1.6 million imputed genotype data with different minor allele frequency restrictions to estimate heritabilities for osteochondrosis dissecans in the fetlock, hock and stifle joints of 446 Hanoverian warmblood horses. SNP-based heritabilities were estimated using a genomic restricted maximum likelihood (GREML) method and accounting for patterns of regional linkage disequilibrium in the equine genome. In addition, we employed GREML for family data to account for different degrees of relatedness in the study population. Our results indicate that we were able to capture a larger proportion of additive genetic variance compared to pedigree-based estimates in the same population of Hanoverian horses. Heritability estimates on the linear scale for fetlock-, hock- and stifle-osteochondrosis dissecans were 0.41-0.43, 0.62-0.63, and 0.23-0.25, respectively, with standard errors of 0.11-0.14. Accounting for linkage disequilibrium patterns had an upward effect on the imputed data and a downward impact on the SNP array genotype data. GREML for family data resulted in higher heritability estimates for fetlock-osteochondrosis dissecans and slightly higher estimates for hock-osteochondrosis dissecans, but had no effect on stifle-osteochondrosis dissecans. The largest and most consistent heritability estimates were obtained when we employed GREML for family data with genomic relationship matrices weighted through patterns of regional linkage disequilibrium. Estimation of SNP-based heritability should be recommended for traits that can only be phenotyped in smaller samples or are cost-effective.

Home-based exercise improves quality of life in breast and prostate cancer survivors: A meta-analysis.

Breast (BCa) and prostate (PCa) cancer are two of the most common but survivable cancers. One important component of survivorship that is impacted by treatment long term is diminished quality of life (QoL). Supervised exercise improves QoL and subsequent outcomes but is not accessible for all survivors. Additionally, many factors influence QoL including physical activity (PA), cardiorespiratory fitness (CRF), physical function, and fatigue. However, the COVID-19 pandemic has highlighted the need to increase access to exercise beyond supervised exercise facilities. Home-based exercise may provide a feasible alternative for cancer survivors especially for those living in rural communities. The primary aim is to investigate the effects of home-based exercise training (Pre-training vs. Post-training) on QoL in BCa/PCa. A secondary aim is to investigate PA, CRF, physical function, and fatigue and potential moderators (age, cancer-type, intervention duration and type). Home-based exercise trials (randomized crossover or quasi-experimental design) with adults (aged 18 years and over) breast or prostate cancer survivors (not currently undergoing chemotherapy or radiation treatment) were eligible for inclusion. Electronic databases were searched (inception-December 2022) for studies which included adult BCa or PCa survivors (not currently on chemotherapy/radiation), at least measured QoL, and undergoing unsupervised, home-based exercise training. Initially, 819 studies were identified, from which 17 studies (20 effects) involving 692 participants were extracted. Effect sizes were calculated as standardized mean differences (SMD). Data were pooled using a 3-level model with restricted maximum likelihood estimation. Pooled SMD was used to assess the magnitude of effect, where <0.2, 0.2, 0.5, and 0.8 was defined as trivial, small, moderate, and large respectively. Home-based exercise resulted in small improvements in QoL (SMD = 0.30, 95% CI 0.01, 0.60, p = 0.042), PA (SMD = 0.49, 95% CI 0.26, 0.75, p<0.001) and CRF (SMD = 0.45, 95% CI -0.01, 0.91, p = 0.056). Physical function (SMD = 0.00, 95% CI -0.21, 0.21, p = 1.000) and fatigue (SMD = -0.61, 95%CI -1.53, 0.32, p = 0.198) did not change. Home-based exercise results in small improves QoL in BCa/PCa survivors, independent of cancer type, intervention duration and type, or age. Home-based exercise also improves PA and CRF enhancing survivorship. Therefore, home-based exercise is an efficacious alternative option to improve QoL for BCa and PCa survivors especially for those who live in rural communities or lack access to exercise facilities.

Genetic parameters and selection of mango genotypes using the FAI-BLUP multitrait index

Mango (Mangifera indica L.) presents phenotypic diversity in relation to fruit quality. Due to this diversity, studies on performance and evaluation of genotypes help in the selection of new cultivars. The aim of this study was to select superior mango genotypes for fruit quality using a mixed model selection index. The fruit quality of two hundred and forty six different hybrids and four commercial cultivars (Ataulfo, Kent, Palmer and Tommy Atkins) was evaluated in three consecutive harvests. Estimates of variance components and predictions of phenotypic and genotypic values were obtained, as well as principal component analysis, factor analysis and genotype-ideotype distance (FAI-BLUP). Permanent variance among plants represented the largest portion of phenotypic variance for most traits. Estimates of the repeatability coefficient ranged from 0.09 to 0.96, being high for most variables. The selective accuracy predicted by the restricted maximum likelihood model (REML) ranged from 0.48 to 0.99, revealing a good degree of confidence in the inferences. Eigenvalue estimates revealed five principal components responsible for 77.72% of the total genetic variability. The greatest positive genetic gains were for fruit weight (37.29%), soluble solids/titratable acidity ratio (35.02%), b* (23.02%), pulp firmness (20.99%), ventral diameter (12.18%), transverse diameter (11.80%), skin luminosity (8.08%), soluble solids content (6.97%), length (4.28%), c* (3.08%), pulp luminosity (2.18%) and h* (0.88%). Negative genetic gains were observed for titratable acidity (-26.04%) and a* (-12.82%). Twenty-five genotypes were selected as the most promising based on factor analysis and FAI-BLUP index, promoting improvement and genetic gain in several traits. Between commercial cultivars, Ataulfo was the highest ranked genotype (29th), followed by Kent (36th), Palmer (243th) and Tommy Atkins (247th). The genotypes selected should be included in the next stages of the mango breeding program for high-quality fruits under irrigated cultivation in the Brazilian semiarid region.