Predicting cytotoxicity of engineered nanoparticles using regularized regression models: an in silico approach.

The widespread application of engineered nanoparticles (NPs) in various industries has demonstrated their effectiveness over the years. However, modifications to NPs' physicochemical properties can lead to toxicological effects. Therefore, understanding the toxicity behaviour of NPs is crucial. In this paper, regularized regression models, such as ridge, LASSO, and elastic net, were constructed to predict the cytotoxicity of various engineered NPs. The dataset utilized in this study was compiled from several journals published between 2010 and 2022. Data exploration revealed missing values, which were addressed through listwise deletion and kNN imputation, resulting in two complete datasets. The ridge, LASSO, and elastic net models achieved F1 scores ranging from 91.81% to 92.65% during internal validation and 92.89% to 93.63% during external validation on Dataset 1. On Dataset 2, the models attained F1 scores between 92.16% and 92.43% during internal validation and 92% and 92.6% during external validation. These results indicate that the developed models effectively generalize to unseen data and demonstrate high accuracy in classifying cytotoxicity levels. Furthermore, the cell type, material, cell source, cell tissue, synthesis method, and coat or functional group were identified as the most important descriptors by the three models across both datasets.

The global soil community and its influence on biogeochemistry.

Soil organisms represent the most biologically diverse community on land and govern the turnover of the largest organic matter pool in the terrestrial biosphere. The highly complex nature of these communities at local scales has traditionally obscured efforts to identify unifying patterns in global soil biodiversity and biogeochemistry. As a result, environmental covariates have generally been used as a proxy to represent the variation in soil community activity in global biogeochemical models. Yet over the past decade, broad-scale studies have begun to see past this local heterogeneity to identify unifying patterns in the biomass, diversity, and composition of certain soil groups across the globe. These unifying patterns provide new insights into the fundamental distribution and dynamics of organic matter on land.

Genome-wide association study for response to vaccination in Angus calves1.

BACKGROUND: Bovine respiratory disease complex (BRDC) is one of the most important sources of loss within the beef cattle industry in the USA. Steps have been taken to reduce the incidence of BRDC through vaccination. Despite the effectiveness of vaccines, large proportions of cattle still experience morbidity and mortality. Identification of genomic regions that are associated with variation in response to vaccination would allow for the selection of individuals genetically predisposed to respond to vaccination based on specific markers, while heritability and accuracy estimates would help facilitate genomic selection. This in turn may lead to selection for beef cattle herds that may have lower incidence rate of BRDC after vaccination. This study utilizes an Angus herd of more than 2000 head of cattle to identify these regions of association. RESULTS: Genome wide association studies were performed for viral neutralization antibody level and response to vaccination traits against four different viruses associated with BRDC: bovine viral diarrhea virus 1 and 2 (BVDV1 and BVDV2), bovine respiratory syncytial virus (BRSV), and bovine herpesvirus (BHV1). A total of six 1-Mb windows were associated with greater than 1% of the genetic variance for the analyzed vaccination response traits. Heritabilities ranged from 0.08 to 0.21 and prediction accuracy ranged from 0.01 to 0.33 across 7 different vaccination traits. CONCLUSIONS: Although six 1-Mb windows were identified as associated with 1% or greater genetic variance for viral neutralization antibody level and response to vaccination traits, few genes around these windows could readily be considered candidates. This indicates the need for further functional genomic annotation, as these regions appear to be gene deserts. Traits ranged from lowly to moderately heritable, which indicated the potential for selection of individuals that are genetically pre-disposed to respond to vaccination. The relatively low amount of genetic variance accounted for by any 1-Mb window indicated that viral neutralization antibody level and response to vaccination traits are polygenic in nature. Selection for these traits is possible, but likely to be slow due to the low heritabilities and absence of markers with high genetic variation associated with them.

Change in practice: a qualitative exploration of midwives' and doctors' views about the introduction of STan monitoring in an Australian hospital.

BACKGROUND: The present study examines the introduction of an innovation in intrapartum foetal monitoring practice in Australia. ST-Analysis (STan) is a technology that adds information to conventional fetal monitoring (cardiotocography) during labour, with the aim of reducing unnecessary obstetric intervention. Adoption of this technology has been controversial amongst obstetricians and midwives, particularly as its use necessitates a more invasive means of monitoring (a scalp clip), compared to external monitoring from cardiotocography alone. If adoption of this technology is going to be successful, then understanding staff opinions about the implementation of STan in an Australian setting is an important issue for maternity care providers and policy makers. METHODS: Using a maximum variation purposive sampling method, 18 interviews were conducted with 10 midwives and 8 doctors from the Women's and Children's Hospital, South Australia to explore views about the introduction of the new technology. The data were analysed using Framework Analysis. RESULTS: Midwives and doctors indicated four important areas of consideration when introducing STan: 1) philosophy of care; 2) the implementation process including training and education; 3) the existence of research evidence; and 4) attitudes towards the new technology. Views were expressed about the management of change process, the fit of the new technology within the current models of care, the need for ongoing training and the importance of having local evidence. CONCLUSIONS: These findings, coupled with the general literature about introducing innovation and change, can be used by other centres looking to introduce STan technology.

Evaluation of responses to vaccination of Angus cattle for four viruses that contribute to bovine respiratory disease complex.

Although vaccination is an effective measure in reducing the risk of bovine respiratory disease complex (BRDC) in cattle, BRDC losses remain significant. Increasing the efficacy of vaccination depends on elucidating the protective immune response to different antigens included in vaccines, determining the best timing for vaccination, and understanding the impact of the age of the calf on vaccination. This study measured the serum antibodies present in calves following vaccination against 4 viruses commonly associated with BRDC: bovine viral diarrhea virus type 1 and 2 (BVDV1 and BVDV2), bovine respiratory syncytial virus (BRSV), and bovine herpesvirus 1 (BHV1). Serum antibody titers were measured in more than 1,600 calves at 3-wk intervals starting at the time of the first vaccination. This first vaccination occurred at weaning for approximately half of the individuals and 3 wk before weaning for the other half. Dam age (years), time of weaning (initial vaccination or booster vaccination), and age of calf within year-season (days within year-season) classification all were found to have a significant effect on measured traits such as the initial titer and overall response. An increased initial titer was negatively correlated with each response trait (initial, booster, and overall response). Calves that were weaned at initial vaccination had greater overall antibody response to BVDV1 and BVDV2 compared with calves weaned 3 wk before initial vaccination. In contrast, calves given their initial vaccination 3 wk before weaning had greater overall antibody response to BRSV and BHV1 compared with calves that were vaccinated at weaning. Furthermore, the circulating antibody titer at which each virus needed to be below for an individual calf to positively respond to vaccination was determined (log titer of 0.38 for BVDV1, 1.5 for BVDV2, 3.88 for BRSV, and 1.5 for BHV1). This information can be used to improve vaccination protocols to allow for a greater response rate of individuals to vaccination and, hopefully, improved protection.

Epistatic interactions associated with fatty acid concentrations of beef from angus sired beef cattle.

BACKGROUND: Consumers are becoming increasingly conscientious about the nutritional value of their food. Consumption of some fatty acids has been associated with human health traits such as blood pressure and cardiovascular disease. Therefore, it is important to investigate genetic variation in content of fatty acids present in meat. Previously publications reported regions of the cattle genome that are additively associated with variation in fatty acid content. This study evaluated epistatic interactions, which could account for additional genetic variation in fatty acid content. RESULTS: Epistatic interactions for 44 fatty acid traits in a population of Angus beef cattle were evaluated with EpiSNPmpi. False discovery rate (FDR) was controlled at 5 % and was limited to well-represented genotypic combinations. Epistatic interactions were detected for 37 triacylglyceride (TAG), 36 phospholipid (PL) fatty acid traits, and three weight traits. A total of 6,181, 7,168, and 0 significant epistatic interactions (FDR < 0.05, 50-animals per genotype combination) were associated with Triacylglyceride fatty acids, Phospholipid fatty acids, and weight traits respectively and most were additive-by-additive interactions. A large number of interactions occurred in potential regions of regulatory control along the chromosomes where genes related to fatty acid metabolism reside. CONCLUSIONS: Many fatty acids were associated with epistatic interactions. Despite a large number of significant interactions, there are a limited number of genomic locations that harbored these interactions. While larger population sizes are needed to accurately validate and quantify these epistatic interactions, the current findings point towards additional genetic variance that can be accounted for within these fatty acid traits.

Single-specificity anti-Ku antibodies in an international cohort of 2140 systemic sclerosis subjects: clinical associations.

Autoantibodies directed against the Ku autoantigen are present in systemic sclerosis (SSc) and have been associated with myositis overlap and interstitial lung disease (ILD). However, there is a paucity of data on the clinical correlates of anti-Ku antibodies in the absence of other SSc-specific antibodies. The aim of this study was to assess the clinical correlates of single-specificity anti-Ku in SSc.An international (Canada, Australia, USA, Mexico) cohort of 2140 SSc subjects was formed, demographic and clinical variables were harmonized, and sera were tested for anti-Ku using a line immunoassay. Associations between single-specificity anti-Ku antibodies (i.e., in isolation of other SSc-specific antibodies) and outcomes of interest, including myositis, ILD, and survival, were investigated.Twenty-four (1.1%) subjects had antibodies against Ku, and 13 (0.6%) had single-specificity anti-Ku antibodies. Subjects with single-specificity anti-Ku antibodies were more likely to have ILD (58% vs 34%), and to have increased creatine kinase levels (>3× normal) at baseline (11% vs 1%) and during follow-up (10% vs 2%). No difference in survival was noted in subjects with and without single-specificity anti-Ku antibodies.This is the largest cohort to date focusing on the prevalence and disease characteristics of single-specificity anti-Ku antibodies in subjects with SSc. These results need to be interpreted with caution in light of the small sample. International collaboration is key to understanding the clinical correlates of uncommon serological profiles in SSc.

Distribution and predictive factors of seizure types in 104 cases.

REASONS FOR PERFORMING THE STUDY: Although many studies have been performed to classify seizures by type in man and small animals, a similar study in horses is lacking. OBJECTIVES: The aims of this study were as follows: 1) to characterise the distribution of seizure types in 104 horses presented for seizure disorders to a referral veterinary hospital; and 2) to characterise the various types of seizures by identifying associated clinical factors. STUDY DESIGN: Retrospective analysis of clinical records. METHODS: Seizures were classified based on seizure type, according to the most recent accepted definitions in both human and small animal epileptology. History, clinical and neurological examinations, diagnostic investigations and post mortem examinations, when available, were recorded for univariable and multivariable logistic regression analyses. RESULTS: Seizures were categorised as primary generalised in 23% of horses, focal without secondary generalisation in 42% of cases and secondary generalised in 24% of cases. The type of seizure could not be classified in 11% of cases. Significant associations were found between seizure type and the following characteristics: 1) gender; 2) frequency of seizures; and 3) presence of seizures during hospitalisation. Seizure type was not significantly associated with aetiology. For a horse with recurrent seizures, the odds of having focal seizures was 3.7 times higher (P = 0.02) than in a similar horse with nonrecurring seizures in the final logistic regression model. CONCLUSIONS: The majority of the seizures described were focal seizures with or without secondary generalisation. The clinical presentation was independent of the underlying disease.

Evaluation of response to bovine viral diarrhea virus type 2 vaccination and timing of weaning on yearling ultrasound body composition, performance, and carcass quality traits in Angus calves.

There are concerns about antagonisms between immunity and animal productivity in livestock production. The objective of this study was to evaluate the effect of antibody levels through a response to vaccination protocol, weaning timing, and their interaction on performance and carcass quality traits in Angus beef cattle. Final antibody level and response to vaccination were based on neutralizing serum antibodies against bovine viral diarrhea virus type 2 (BVDV2). Calves were followed through development and the feedlot phase, with collection of yearling ultrasound (n=957), preharvest (n=762), and carcass (n=673) data. In this study, 48% of the animals were observed to have positively responded to the vaccine, as evidenced by higher final antibody levels compared to prevaccination antibody levels. Increased final antibody levels were significantly (P<0.05) associated with increased yearling weight and increased subcutaneous fat over the rump. An interaction between final antibody level and weaning time also was associated (P<0.05) with Warner-Bratzler shear force (WBSF) and meat pH, with a favorable, negative relationship between final antibody and WBSF in calves weaned at initial vaccination. Overall antibody response by wean time interaction had a significant (P<0.05) association with ADG and meat pH, with calves weaned at initial vaccination having a favorable, positive relationship between overall antibody response and ADG. Under both the final antibody and overall antibody response models, animals weaned at initial vaccination had significantly (P<0.05) lower intramuscular fat at yearling time and conversely higher harvest weight than animals weaned at the booster vaccination. When antibody response was grouped (none, low, high), a significant interaction (P<0.05) between antibody response group and weaning time was identified for ADG, harvest weight, and HCW. Animals weaned at the initial vaccination in the high antibody response group had the advantage for ADG, harvest weight, and HCW compared to animals in the high-response group that were weaned at booster vaccination. Linear increases in antibody response generally did not have negative effects on performance or carcass quality traits in finished cattle (P>0.05). Therefore, producers should not be concerned about decreased production or quality attributes as a result of developing a robust antibody response to vaccination for BVDV2 in beef cattle.

Association of HLA-DQB1*0501 with scleroderma and its clinical features in Chinese population.

Specific human leukocyte antigen (HLA) DQB1 alleles confer strong susceptibility to systemic sclerosis (SSc). However, the frequencies of specific DQB1 alleles and their associations with SSc vary according to ethnicity and clinical features of SSc. The aim of this study was to profile DQB1 alleles in a Chinese population and to identify specific DQB1 alleles in association with SSc of Han Chinese. A cohort containing 213 patients with SSc and 239 gender-matched and unrelated controls was examined in the study. The HLA-DQB1 genotyping was performed with sequence-based typing (SBT) method. Exact p-values were obtained (Fisher's test) from 2x2 tables of allele counts or allele carriers and disease status. Seventeen DQB1 alleles were found in the cohort. DQB1*03:03 was the most common allele in this cohort. DQB1*05:01 was significantly increased in SSc, and was strongly associated with anti-centromere autoantibodies (ACA). Compared with SSc in other ethnic populations, SSc patients of Han Chinese are distinct in association with DQB1*06:11, common in association with DQB1*05:01, but lack association with DQB1*03:01. In addition, DQB1*06:01 appeared more common in ATA-positive Chinese SSc, and marginally associated with pulmonary fibrosis, and an increased frequency of DQB1*03:03 was observed in anti-U1RNP-positive Chinese SSc patients.

An evaluation of circulating bovine viral diarrhea virus type 2 maternal antibody level and response to vaccination in Angus calves.

Vaccination against viruses has been shown to help prevent bovine respiratory disease in cattle. However, both passively acquired maternal antibody concentration and calf age have been shown to impact the ability of the immune system of a calf to respond to vaccination. The objectives of this study were to identify and evaluate environmental and management factors that affect 1) passively acquired bovine viral diarrhea virus (BVDV) type 2 antibody level, 2) decay rate of passively acquired BVDV type 2 antibody level, and 3) responses to BVDV type 2 vaccinations. A 2-shot modified live vaccine was administered to 1,004 Angus calves that were weaned at either the initial vaccination (n = 508) or the booster vaccination (n = 496). Calves weaned at the initial vaccination averaged 139 d whereas calves weaned at booster vaccination averaged 128 d of age. Bovine viral diarrhea virus type 2 antibodies were measured in 3 approximately 21-d intervals, serially collected serum samples to quantify antibody levels at initiation and end of vaccination protocol in addition to responses to initial, booster, and overall vaccination protocol. Amount of passively transferred antibody in the calf increased as dam age increased from 2 to 6 yr (P < 0.05) with no differences after dams reached 6 yr (P > 0.05). Calf age nested within birth year-season and dam age affected both initial and final antibody level, initial response, booster response, and overall antibody response to vaccination. The level of circulating, passively acquired maternal antibodies present at the time of vaccination had a significant (P < 0.05) negative effect on antibody responses to vaccination (initial response, booster response, and overall response). Calves that were weaned at the time of initial vaccination had significantly (P < 0.05) greater final antibody level, initial response, and overall response to vaccination than animals weaned at booster vaccination. In order for a calf to mount an overall antibody response to vaccination, maternal antibodies in circulation need to be less than 3.12 titers. However, the age at which a calf reached this antibody threshold was dependent on dam age. This information will help cattle managers and consultants design vaccination protocols to successfully mount an antibody response to vaccination.

Genome-wide association study of concentrations of iron and other minerals in longissimus muscle of Angus cattle.

The objective of this study was to characterize variation and identify SNP and chromosomal regions associated with mineral concentrations in LM of Angus beef cattle. Samples of LM from 2,285 Angus cattle were obtained, and concentrations of 7 minerals, including iron, magnesium, manganese, phosphorus, potassium, sodium, and zinc, were quantified. Genomic DNA extracted from the ground beef sample used for mineral composition was genotyped with the Bovine SNP50 Infinium II BeadChip, and effects of SNP on each trait were estimated using the Bayes-Cπ module of GenSel software. Pedigree-based estimates of heritabilities and corresponding genetic variances indicate iron was the only mineral concentration that could be considered a good candidate for manipulation by genomic selection. The amount of variation that could be accounted for by SNP genotypes was concordant with pedigree-based heritabilities and varied from very low for potassium and sodium (<0.09) to medium high (0.37) for iron. Although significant chromosomal regions were identified for all minerals analyzed in this study, further study focused on iron. Seven regions on 6 chromosomes (1, 2, 7, 10, 15, and 28) were identified to have a major effect on the iron content of LM in Angus cattle. The accuracy of direct genomic values (DGV) for iron concentration was estimated using a 5-fold cross-validation strategy. The accuracy of DGV estimated as the genetic correlation between DGV and the phenotype (iron concentration) adjusted for contemporary groups was 0.59. A bivariate animal model was used to estimate genetic correlations between iron concentrations and a reduced set of economically important carcass traits: HCW, rib eye area, calculated USDA yield grade, percent KPH, and marbling score. The genetic correlations between iron concentration and HCW, percentage KPH, marbling score, and rib eye area were small (-0.19 to 0.15) and nonsignificant. Although still weak (0.22), a positive significant genetic correlation was identified between iron content and USDA calculated yield grade. Beef is a major contributor of iron and zinc in the human diet, and this study found that iron content might be effectively manipulated through marker-assisted selection programs, without compromising other carcass and palatability traits.

STAT4 is a genetic risk factor for systemic sclerosis in a Chinese population.

Systemic sclerosis (SSc) is an immune-mediated and complex genetic disease. An association of single-nucleotide polymorphisms (SNPs) in the STAT4 gene with SSc has been reported in European Caucasians, North Americans and Japanese. We undertook the current study to examine whether the STAT4 SNPs are also associated with susceptibility to SSc and SSc subsets in a Han Chinese population. A total of 453 Han Chinese patients with SSc and 534 healthy controls were examined in the study. The SNPs rs7574865, rs10168266 and rs3821236 of the STAT4 gene were examined with SNP TaqMan assays. The T-allele carriers of rs7574865 and rs10168266 were strongly associated with the presence of anti-topoisomerase I (ATA) and pulmonary fibrosis in SSc patients, as well as with diffuse cutaneous SSc (dcSSc). The presence of anti-centromere (ACA) and limited cutaneous SSc (lcSSc) did not show significant association with any of the examined SNPs. The results were consistent with previous reports in other ethnic populations in supporting the notion that polymorphisms of STAT4 may play an important role in susceptibility to SSc. It also revealed different genetic aspects of SSc subsets in a Han Chinese population.

Genetic parameters for concentrations of minerals in longissimus muscle and their associations with palatability traits in Angus cattle.

The objective of this study was to estimate genetic parameters for concentrations of minerals in LM and to evaluate their associations with beef palatability traits. Samples of LM from 2,285 Angus cattle were obtained and fabricated into steaks for analysis of mineral concentrations and for trained sensory panel assessments. Nine minerals, including calcium, copper, iron, magnesium, manganese, phosphorus, potassium, sodium, and zinc, were quantified. Restricted maximum likelihood procedures were used to obtain estimates of variance and covariance components under a multiple-trait animal model. Estimates of heritability for mineral concentrations in LM varied from 0.01 to 0.54. Iron and sodium were highly and moderately heritable, respectively, whereas the other minerals were lowly heritable except for calcium, copper, and manganese, which exhibited no genetic variation. Strong positive genetic correlations existed between iron and zinc (0.49, P < 0.05), between magnesium and phosphorus (0.88, P < 0.05), between magnesium and sodium (0.68, P < 0.05), and between phosphorus and potassium (0.69, P < 0.05). Overall tenderness assessed by trained sensory panelists was positively associated with manganese, potassium, and sodium and negatively associated with phosphorus and zinc concentrations (P < 0.05). Juiciness assessed by trained sensory panelists was negatively associated with magnesium and positively associated with manganese and sodium concentrations (P < 0.05). Livery or metallic flavor was not associated with any of the minerals (P > 0.05). Beefy flavor was positively associated with calcium, iron, and zinc and negatively associated with sodium concentration, whereas a painty or fishy flavor was positively associated with sodium and negatively associated with calcium and potassium concentrations (P < 0.05). Beef is a major contributor of iron and zinc in the human diet, and these results demonstrate sufficient genetic variation for these traits to be improved through marker-assisted selection programs without compromising beef palatability.

Genetic parameters for carnitine, creatine, creatinine, carnosine, and anserine concentration in longissimus muscle and their association with palatability traits in Angus cattle.

The objective of this study was to estimate genetic parameters for carnitine, creatine, creatinine, carnosine, and anserine concentration in LM and to evaluate their associations with Warner-Bratzler shear force (WBSF) and beef palatability traits. Longissimus muscle samples from 2,285 Angus cattle were obtained and fabricated into steaks for analysis of carnitine, creatine, creatinine, carnosine, anserine, and other nutrients, and for trained sensory panel and WBSF assessments. Restricted maximum likelihood procedures were used to obtain estimates of variance and covariance components under a multiple-trait animal model. Estimates of heritability for carnitine, creatine, creatinine, carnosine, and anserine concentrations in LM from Angus cattle were 0.015, 0.434, 0.070, 0.383, and 0.531, respectively. Creatine, carnosine, and anserine were found to be moderately heritable, whereas almost no genetic variation was observed in carnitine and creatinine. Moderate positive genetic (0.25, P < 0.05) and phenotypic correlations (0.25, P < 0.05) were identified between carnosine and anserine. Medium negative genetic correlations were identified between creatine and both carnosine (-0.53, P < 0.05) and anserine (-0.46, P < 0.05). Beef and livery/metallic flavor were not associated with any of the 5 compounds analyzed (P > 0.10), and carnitine concentrations were not associated (P > 0.10) with any of the meat palatability traits analyzed. Carnosine was negatively associated with overall tenderness as assessed by trained sensory panelists. Similar negative associations with overall tenderness were identified for creatinine and anserine. Painty/fishy was the only flavor significantly and negatively associated with creatinine and carnosine. These results provide information regarding the concentration of these compounds, the amount of genetic variation, and evidence for negligible associations with beef palatability traits in LM of beef cattle.

Genetic polymorphisms in bovine transferrin receptor 2 (TFR2) and solute carrier family 40 (iron-regulated transporter), member 1 (SLC40A1) genes and their association with beef iron content.

Beef is considered to be an excellent source of dietary iron. However, little is known about the genetic control of beef iron content. We hypothesized that genetic polymorphisms in transferrin receptor 2 (TFR2) and solute carrier family 40 (iron-regulated transporter), member 1 (SLC40A1) could influence skeletal muscle iron content. The objective of this study was to use Angus cattle to identify single-nucleotide polymorphisms (SNPs) in the exons and flanking regions of the bovine TFR2 and SLC40A1 genes and to evaluate the extent to which genetic variation in them was associated with bovine longissimus dorsi muscle iron content. Ten novel SNPs were identified in TFR2, of which one SNP tended to be associated (P < 0.013) with skeletal muscle iron content. Nine novel SNPs in SLC40A1, NC007300: rs133108154, rs137140497, rs135205621, rs136600836, rs134388440, rs136347850, rs134186279, rs134621419 and rs137555693, were identified, of which SNPs rs134388440, rs136347850 and rs137555693 were significantly associated (P < 0.007) with skeletal muscle iron content. High linkage disequilibrium was observed among SLC40A1 SNPs rs134388440, rs136347850 and rs137555693 (R(2) > 0.99), from which two haplotypes, TGC and CAT, were defined. Beef from individuals that were homozygous for the TGC haplotype had significantly (P < 0.001) higher iron content than did beef from CAT homozygous or heterozygous individuals. The estimated size of effect of the identified haplotypes was 0.3% of the phenotypic variance. In conclusion, our study provides evidence for genetic control of beef iron concentration. Moreover, SNPs identified in SLC40A1, rs134388440, rs136347850 and rs137555693 might be useful markers for the selection of Angus cattle for altered iron content.

Patterns and predictors of change in outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine the range and responsiveness to change of clinical outcome measures and study predictors of clinical response in patients with diffuse cutaneous systemic sclerosis (dcSSc) in the context of clinical trials. METHODS: Data were combined from 629 patients with dcSSc who participated in 7 multicenter clinical therapeutic trials. Trials used common outcome measures: modified Rodnan skin thickness score (MRSS), Health Assessment Questionnaire disability index (HAQ DI), patient's global assessment of disease activity, pulmonary function tests (forced vital capacity, diffusing capacity for carbon monoxide), hand span, and oral aperture. RESULTS: The combined database included 629 patients (82% women, mean ± SD age 46.5 ± 11.8 years, mean ± SD disease duration 19.4 ± 15.9 months). Outcomes tended to improve during trials for patients with more severe disease at study entry and to worsen for patients with less severe disease at entry. Disease duration was mildly negatively predictive of change in MRSS at 6 months (r = -0.27, P < 0.001), and substantial bidirectional variation in change in MRSS and HAQ DI score was seen across the spectrum of disease duration. Sixty-three percent of patients with "early" disease (disease duration <18 months) had a decline in MRSS, and 37% had an increase in MRSS. Eighty-one percent of patients with "late" disease (disease duration ≥ 18 months) had a decline in MRSS, and 19% had an increase in MRSS. Multivariate mixed models did not demonstrate that any baseline variables were strongly predictive of subsequent outcome. CONCLUSION: Among patients with dcSSc enrolled in clinical trials, standard outcome measures tend to improve in those with more severe disease at study entry and to worsen in those with less severe disease at entry. Overall, the MRSS improves during trials, while HAQ DI scores and lung function are mostly static. None of these variables, including disease duration, reliably identifies groups of subjects whose MRSS will predictably increase or decrease in the course of a clinical trial. These findings have important implications for clinical trial design in scleroderma.

Epilepsy in horses: aetiological classification and predictive factors.

REASONS FOR PERFORMING THE STUDY: In contrast with reports in man and small animals, a systematic classification of seizures in horses is lacking. OBJECTIVES: The purpose of this study was to classify seizures based on their aetiology and to characterise epilepsy in 104 horses presented for seizures at the Ohio State University Veterinary Medical Center between 1988 and 2009. METHODS: In a retrospective observational study, seizures were classified by aetiology based on history, clinical observations, diagnostic investigations (e.g. electroencephalograms, cerebrospinal fluid and computed tomography imaging of the head) and post mortem examinations, when available. Univariate and multivariate logistic regression analyses were performed. RESULTS: Epilepsy (i.e. 2 or more recurrent seizures) was identified in 70% of cases, and further classified as symptomatic (i.e. structural brain pathology, 35.6% of cases), cryptogenic (i.e. unknown, 54.8% of cases) and idiopathic (i.e. suspected genetic predisposition, 2.7% of cases). Normal neurological examination on admission, the presence of seizures unprovoked by any identified factors and paroxysmal epileptiform activity on electroencephalogram recordings were all strongly (P<0.05) correlated with epilepsy on univariate analysis. For a horse with generalised seizures, the odds of having epilepsy was 7 times lower compared with a similar horse with partial seizures (P<0.05) in multivariate modelling. CONCLUSIONS: Seizure aetiology was symptomatic or cryptogenic in most horses, whereas reactive seizures and idiopathic epilepsy were less common. POTENTIAL RELEVANCE: This study is the first attempt to classify seizures and to characterise epilepsy in a referral-based equine population. Predictive factors of epilepsy in horses were similar to those reported in other species and may assist the clinician with the early diagnosis of epilepsy.

Mapping genetic loci that interact with myostatin to affect growth traits.

Myostatin, or GDF8, is an inhibitor of skeletal muscle growth. A non-functional myostatin mutation leads to a double muscling phenotype in some species, for example, mice, cattle and humans. Previous studies have indicated that there are loci in the genome that interact with myostatin to control backfat depth and other complex traits. We now report a quantitative trait loci (QTL) mapping study designed to identify loci that interact with myostatin to impact growth traits in mice. Body weight and average daily gain traits were collected on F2 progeny derived from a myostatin-null C57BL/6 strain by M16i cross. In all, 44 main effect QTL were detected above a 5% genome-wide significance threshold when an interval mapping method was used. An additional 37 QTL were identified to significantly interact with myostatin, sex or reciprocal cross. A total of 12 of these QTL interacted with myostatin genotype. These results provide a foundation for the further fine mapping of genome regions that harbor loci that interact with myostatin.

Identification of a novel HLA-DPB1 allele, DPB1*131:01, by sequence-based typing.

This report identifies a novel HLA-DPB1 allele, DPB1* 131:01.