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This study aimed to investigate the benefit of Bonebridge devices in patients with single-sided deafness.
Five patients with single-sided deafness who were implanted with Bonebridge devices were recruited in a single-centre study. Participants’ speech perception and horizontal sound localisation abilities were assessed at 6 and 12 months post-operatively. Speech intelligibility in noisy environments was measured in three different testing conditions (speech and noise presented from the front, speech and noise presented from the front and contralateral (normal ear) side separately, and speech presented from the ipsilateral (implanted Bonebridge) side and noise from the contralateral side). Sound localisation was evaluated in Bonebridge-aided and Bonebridge-unaided conditions at different stimuli levels (65, 70 and 75 dB SPL).
All participants showed a better capacity for speech intelligibility in quiet environments with the Bonebridge device. The speech recognition threshold with the Bonebridge device was significantly decreased at both short- and long-term follow up in the speech presented from the ipsilateral (implanted Bonebridge) side and noise from the contralateral side condition (p < 0.05). Additionally, participants maintained similar levels of sound localisation between the Bonebridge-aided and unaided conditions (p > 0.05). However, the accuracy of localisation showed some improvement at 70 dB SPL and 75 dB SPL post-operatively.
The Bonebridge device provides the benefit of improved speech perception performance in patients with single-sided deafness. Sound localisation abilities were neither improved nor worsened with Bonebridge implantation at the follow-up assessments.
Graphlet counting is a widely explored problem in network analysis and has been successfully applied to a variety of applications in many domains, most notatbly bioinformatics, social science, and infrastructure network studies. Efficiently computing graphlet counts remains challenging due to the combinatorial explosion, where a naive enumeration algorithm needs O(Nk) time for k-node graphlets in a network of size N. Recently, many works introduced carefully designed combinatorial and sampling methods with encouraging results. However, the existing methods ignore the fact that graphlet counts and the graph structural information are correlated. They always consider a graph as a new input and repeat the tedious counting procedure on a regular basis even if it is similar or exactly isomorphic to previously studied graphs. This provides an opportunity to speed up the graphlet count estimation procedure by exploiting this correlation via learning methods. In this paper, we raise a novel graphlet count learning (GCL) problem: given a set of historical graphs with known graphlet counts, how to learn to estimate/predict graphlet count for unseen graphs coming from the same (or similar) underlying distribution. We develop a deep learning framework which contains two convolutional neural network models and a series of data preprocessing techniques to solve the GCL problem. Extensive experiments are conducted on three types of synthetic random graphs and three types of real-world graphs for all 3-, 4-, and 5-node graphlets to demonstrate the accuracy, efficiency, and generalizability of our framework. Compared with state-of-the-art exact/sampling methods, our framework shows great potential, which can offer up to two orders of magnitude speedup on synthetic graphs and achieve on par speed on real-world graphs with competitive accuracy.
The Eating Assessment in Toddlers FFQ (EAT FFQ) has been shown to have good reliability and comparative validity for ranking nutrient intakes in young children. With the addition of food items (n 4), we aimed to re-assess the validity of the EAT FFQ and estimate calibration factors in a sub-sample of children (n 97) participating in the Growing Up Milk – Lite (GUMLi) randomised control trial (2015–2017). Participants completed the ninety-nine-item GUMLi EAT FFQ and record-assisted 24-h recalls (24HR) on two occasions. Energy and nutrient intakes were assessed at months 9 and 12 post-randomisation and calibration factors calculated to determine predicted estimates from the GUMLi EAT FFQ. Validity was assessed using Pearson correlation coefficients, weighted kappa (κ) and exact quartile categorisation. Calibration was calculated using linear regression models on 24HR, adjusted for sex and treatment group. Nutrient intakes were significantly correlated between the GUMLi EAT FFQ and 24HR at both time points. Energy-adjusted, de-attenuated Pearson correlations ranged from 0·3 (fibre) to 0·8 (Fe) at 9 months and from 0·3 (Ca) to 0·7 (Fe) at 12 months. Weighted κ for the quartiles ranged from 0·2 (Zn) to 0·6 (Fe) at 9 months and from 0·1 (total fat) to 0·5 (Fe) at 12 months. Exact agreement ranged from 30 to 74 %. Calibration factors predicted up to 56 % of the variation in the 24HR at 9 months and 44 % at 12 months. The GUMLi EAT FFQ remained a useful tool for ranking nutrient intakes with similar estimated validity compared with other FFQ used in children under 2 years.
Guanidinoacetic acid (GAA) can improve the growth performance of bulls. This study investigated the influences of GAA addition on growth, nutrient digestion, ruminal fermentation and serum metabolites in bulls. Forty-eight Angus bulls were randomly allocated to experimental treatments, that is, control, low-GAA (LGAA), medium-GAA (MGAA) and high-GAA (HGAA), with GAA supplementation at 0, 0.3, 0.6 and 0.9 g/kg DM, respectively. Bulls were fed a basal diet containing 500 g/kg DM concentrate and 500 g/kg DM roughage. The experimental period was 104 days, with 14 days for adaptation and 90 days for data collection. Bulls in the MGAA and HGAA groups had higher DM intake and average daily gain than bulls in the LGAA and control groups. The feed conversion ratio was lowest in MGAA and highest in the control. Bulls receiving 0.9 g/kg DM GAA addition had higher digestibility of DM, organic matter, NDF and ADF than bulls in other groups. The digestibility of CP was higher for HGAA than for LGAA and control. The ruminal pH was lower for MGAA, and the total volatile fatty acid concentration was greater for MGAA and HGAA than for the control. The acetate proportion and acetate-to-propionate ratio were lower for MGAA than for LGAA and control. The propionate proportion was higher for MGAA than for control. Bulls receiving GAA addition showed decreased ruminal ammonia N. Bulls in MGAA and HGAA had higher cellobiase, pectinase and protease activities and Butyrivibrio fibrisolvens, Prevotella ruminicola and Ruminobacter amylophilus populations than bulls in LGAA and control. However, the total protozoan population was lower for MGAA and HGAA than for LGAA and control. The total bacterial and Ruminococcus flavefaciens populations increased with GAA addition. The blood level of creatine was higher for HGAA, and the activity of l-arginine glycine amidine transferase was lower for MGAA and HGAA, than for control. The blood activity of guanidine acetate N-methyltransferase and the level of folate decreased in the GAA addition groups. The results indicated that dietary addition of 0.6 or 0.9 g/kg DM GAA improved growth performance, nutrient digestion and ruminal fermentation in bulls.
Ovarian follicle selection is a natural biological process in the pre-ovulatory hierarchy in birds that drives growing follicles to be selected within the ovulatory cycle. Follicle selection in birds is strictly regulated, involving signaling pathways mediated by dietary nutrients, gonadotrophic hormones and paracrine factors. This study aimed to test the hypothesis that dietary Ca may participate in regulating follicle selection in laying ducks through activating the signaling pathway of cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/extracellular signal-regulated kinase (ERK), possibly mediated by gonadotrophic hormones. Female ducks at 22 weeks of age were initially fed one of two Ca-deficient diets (containing 1.8% or 0.38% Ca) or a Ca-adequate control diet (containing 3.6% Ca) for 67 days (depletion period), then all birds were fed the Ca-adequate diet for an additional 67 days (repletion period). Compared with the Ca-adequate control, ducks fed 0.38% Ca during the depletion period had significantly decreased (P < 0.05) numbers of hierarchical follicles and total ovarian weight, which were accompanied by reduced egg production. Plasma concentration of FSH was decreased by the diet containing 1.8% Ca but not by that containing 0.38%. The ovarian content of cAMP was increased with the two Ca-deficient diets, and phosphorylation of PKA and ERK1/2 was increased with 0.38% dietary Ca. Transcripts of ovarian estradiol receptor 2 and luteinizing hormone receptor (LHR) were reduced in the ducks fed the two Ca-deficient diets (P < 0.05), while those of the ovarian follicle stimulating hormone receptor (FSHR) were decreased in the ducks fed 0.38% Ca. The transcript abundance of ovary gap junction proteins, A1 and A4, was reduced with the Ca-deficient diets (P < 0.05). The down-regulation of gene expression of gap junction proteins and hormone receptors, the increased cAMP content and the suppressed hierarchical follicle numbers were reversed by repletion of dietary Ca. These results indicate that dietary Ca deficiency negatively affects follicle selection of laying ducks, independent of FSH, but probably by activating cAMP/PKA/ERK1/2 signaling pathway.
The risk factors of criminal behavior in patients with schizophrenia are not well explored. This study is to explore the risk factors for criminal behavior in patients with schizophrenia in rural China.
We used data from a 14-year prospective follow-up study (1994-2008) of criminal behavior among a cohort (n=510) of patients with schizophrenia in Xinjin County, Chengdu, China.
There were 489 patients (95.9%) who were followed up from 1994 to 2008. The rate of criminal behavior was 13.5% among these patients with schizophrenia during the follow-up period. Compared with female subjects (6 cases, 20.0%), male patients had significantly higher rate of violent criminal behavior (e.g., arson, sexual assault, physical assault, and murder) (24 cases, 80.0%) (p< 0.001). Bivariate analyses showed that the risk of criminal behavior was significantly associated with being unmarried, of younger age, previous violent behavior, homelessness, lower family economic status, no family caregivers, and higher scores on measures (PANSS) of positive, negative, and total symptoms of illness. In multiple logistic regression analyses being unmarried and previous violent behavior were identified as independent predictors of increased criminal behavior in persons with schizophrenia.
The risk factors for criminal behavior among patients with schizophrenia should be understood within a particular social context. Criminal behavior may be predicted by specific characteristics of patients with schizophrenia in rural community. The findings of risk factors for criminal behavior should be considered in planning community mental health care and interventions for high-risk patients and their families.
To examine genetic influences the anatomy of the Corpus Callosum (CC) in Bipolar Disorder (BD) by examining first-degree relatives in addition to BD patients.
We compared CCl size and shape in 180 individuals: 70 with BD, 45 of their unaffected first-degree relatives, and 75 healthy controls. The CC was extracted from a mid-sagittal slice from T1-weighted magnetic resonance images; its total area, length and curvature were compared across groups. A non-parametric permutation method was used to examine for alterations in width of the callosum along 39 points.
Validating our previous findings, a significant global reduction in CC thickness was seen in BD patients, with a disproportionate thinning in the anterior body. First-degree relatives did not differ in CC size or shape from controls. Duration of illness was associated with thinning in the anterior body, whereas Lithium treatment associated with thicker anterior CC midbody.
Global and regional CC thinning is a disease related feature of BD and may not represent a marker of familial disposition.
Although the deviations of brain volume deficits in sporadic and familial first-episode schizophrenia patients (FEP) had been presented, the difference of brain asymmetries remained unidentified.
To assess the potential differences of volumetric asymmetries of gray matter (GM) and white matter (WM) between groups.
To find out the different injury alteration of sporadic FEP and familial FEP.
42 sporadic and 30 familiar drug-naïve FEP with and 72 matched normal controls (NC) were recruited. Participants were assessed with neuropsychological tests and scanned by a 3.0T MRI to obtain T1-weighted and DTI images. Lateralization distribution maps of GM and WM volume were generated by employing optimized voxel-based morphometry. The asymmetries were analyzed by comparing calculating Laterality Index (LI) voxel by voxel.
All three groups showed similar overall brain torque. Familiar FEP have more regional extensive GM asymmetry brain lesions compared to sporadic FEP. There was no shared regional lesion between two groups. LIGM and LIWM in right superior temporal were negatively correlated. Significant negative correlations were also found between LIGM of left superior parietal lobule and LIWM of right superior parietal lobule, and between LIGM of right inferior parietal lobule and LIWM of left inferior parietal lobule. The asymmetry in distinct brain regions were related to cognitive deficits especially in the domains of language and memory.
The two patient groups had different alteration in injuries of brain asymmetry. Familiar FEP has more GM extensive asymmetry brain region, which may correlate with their high genetic burdens.
Previously the GABA(A) receptor beta-2 subunit gene GABRB2 was found to be associated with schizophrenia (SCZ). for SNPs and haplotypes in GRBRB2, the associations with bipolar disorder (BPD), the functional consequences on GABRB2 expression and their relationship to demographic and clinical characteristics in BPD and SCZ remain to be elucidated.
Case-control analysis was performed for association study of GABRB2 with BPD, and its mRNA expression in postmortem BPD brains was examined using quantitative real-time PCR. Quantitative trait analysis was subsequently employed to assess the covariate effects of demographic and clinical characteristics on genotypic correlation of GABRB2 expression in SCZ and BPD.
Significant association of GABRB2 with BPD and reduction in GABRB2 mRNA expression in BPD brains were observed in the present study. Duration of illness (DOI) was found to be a significant covariate for the correlation of the disease-associated SNPs rs1816071, rs1816072 and rs187269 with GABRB2 expression in both SCZ and BPD. for individuals with homozygous major genotypes of these SNPs, while GABRB2 expression increased with age in the controls, it decreased with DOI and age in SCZ, and with DOI in BPD. with age of onset as covariate, these three SNPs were significantly correlated with antipsychotic dosage in SCZ.
These results have thus revealed correlations of GABRB2 SNPs and expression not only with the occurrence of SCZ and BPD, but also with the clinical characteristics of patients, therefore providing support for a shared etiological role played by the gene in both diseases.
Many family characteristics were reported to increase the risk of bipolar disorder (BPD). The development of BPD may be mediated through different pathways, involving diverse risk factor profiles. We evaluated the associations of family characteristics to build influential causal-pie models to estimate their contributions on the risk of developing BPD at the population level. We recruited 329 clinically diagnosed BPD patients and 202 healthy controls to collect information in parental psychopathology, parent-child relationship, and conflict within family. Other than logistic regression models, we applied causal-pie models to identify pathways involved with different family factors for BPD. The risk of BPD was significantly increased with parental depression, neurosis, anxiety, paternal substance use problems, and poor relationship with parents. Having a depressed mother further predicted early onset of BPD. Additionally, a greater risk for BPD was observed with higher numbers of paternal/maternal psychopathologies. Three significant risk profiles were identified for BPD, including paternal substance use problems (73.0%), maternal depression (17.6%), and through poor relationship with parents and conflict within the family (6.3%). Our findings demonstrate that different aspects of family characteristics elicit negative impacts on bipolar illness, which can be utilized to target specific factors to design and employ efficient intervention programs.
Patients with chronic kidney disease (CKD) have more cognitive impairments. However, the etiologies are not fully clear. Plasma homocysteine levels and vascular burden rise in CKD; meanwhile, high homocysteine levels and vascular factors are known risk factors of dementia in non-CKD patients. Thus, we aimed to investigate the association between homocysteine, vascular burden and cognitive impairment in CKD and to see if the effect of elevated homocysteine on cognitive impairment mediated by vascular factor.
146 patients with CKD and 69 normal comparisons were recruited. Cognitive function was evaluated by comprehensive neuropsychological tests assessing processing speed, executive function, language, visuospatial function, memory, and attention domains. Vascular burden was assessed by Framinghan cardiovascular risk scale (FCRS) which indicates risk of atherosclerotic diseases including stroke.
In controlled analysis, patients with CKD had lower scores in all cognitive domains, and had higher homocysteine levels (18.5±6.4 vs. 9.8±2.9, p< 0.0001) and FCRS(17.0±4.7 vs. 14.0±4.7, p< 0.0001). Among patients with CKD, higher homocysteine levels (p=0.026) were associated with lower score on digit symbol task which is related to processing speed and executive function with controlling for age, sex, education and stage of CKD. The association persisted (p=0.047) after controlling for vascular risks.
Patients with CKD had extensive cognitive impairments. Elevated homocysteine levels may be an risk factor, which is independent of vascular burden, of cognitive impairment on processing speed and executive function. Further studies to investigate if normalization of homocysteine can improve cognitive function will be suggested.
Bioinformatic investigations indicate that has-mir-206 (microRNA-206, miRNA-206) could regulate BDNF protein synthesis by interfering with BDNF mRNA translation, which is disrupted in bipolar disorder (BPD).
This study is to investigate whether miRNA-206 gene variants were associated with BPD susceptibility in a Han Chinese population.
342 patients who met DSM-IV criteria for bipolar disorder type I (BPD-I) or type II (BPD-II) and 386 matched health controls were enrolled into this study. the miRNA-206 gene and +/-500bp were selected for gene sequencing. for the case-control genetic comparisons, differences in the genotype and allele distributions between patients and controls were examined using Pearson's χ2 test.
Gene sequencing showed that there are two polymorphisms rs16882131(C/T) and rs62408583 (A/C) located at the upstream of miRNA-206 gene, which are complete linkage disequilibrium. the association analysis showed that there was no significant difference for genotype frequencies (χ2 = 2.075, df = 2, P = 0.354) or for allele frequencies (χ2 = 0.041, df = 1, P = 0.839) between BPD patients and controls. Similarly, no significant difference was found between BPD-I patients and controls (genotype χ2 = 1.411, df = 2, P = 0.494; allele χ2 = 0.380, df = 1, P = 0.538). However, there was significant difference between BPD-II patients and controls (genotype χ2 = 7.933, df = 2, P = 0.019; allele χ2 = 5.403, df = 1, P = 0.020).
Our findings do not support that BPD susceptibility was associated with miRNA-206 gene polymorphisms in the studied Han Chinese population. the association between miRNA-206 gene polymorphisms and bipolar disorder type II is needed to be carefully interpreted. Further studies are necessary to elucidate the involvement miRNA-206 in the pathophysiology of BPD.
Internet addiction is a newly emergent disorder. It has been found to be associated with a variety of psychiatric disorders. Information about such coexisting psychiatric disorders is essential to understand the mechanism of Internet addiction. In this review, we have recruited articles mentioning coexisting psychiatric disorders of Internet addiction from the PubMed database as at November 3, 2009. We describe the updated results for such disorders of Internet addiction, which include substance use disorder, attention-deficit hyperactivity disorder, depression, hostility, and social anxiety disorder. We also provide discussion for possible mechanisms accounting for the coexistence of psychiatric disorders and Internet addiction. The review might suggest that combined psychiatric disorders mentioned above should be evaluated and treated to prevent their deteriorating effect on the prognosis of Internet addiction. On the other hand, Internet addiction should be paid more attention to when treating people with these coexisting psychiatric disorders of Internet addiction. Additionally, we also suggest future necessary research directions that could provide further important information for the understanding of this issue.
The presence of comorbid anxiety disorders (AD) and bipolar II disorders (BP-II) compounds disability complicates treatment, worsens prognosis, and has been understudied. The genes involved in metabolizing dopamine and encoding dopamine receptors, such as aldehyde dehydrogenase 2 (ALDH2) and dopamine D2 receptor (DRD2) genes, may be important to the pathogenesis of BP-II comorbid with AD. We aimed to clarify ALDH2 and DRD2 genes for predisposition to BP-II comorbid with and without AD. The sample consisted of 335 subjects BP-II without AD, 127 subjects BP-II with AD and 348 healthy subjects as normal control. The genotypes of the ALDH2 and DRD2 Taq-IA polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Logistic regression analysis showed a statistically significant association between DRD2 Taq-I A1/A2 genotype and BP-II with AD (OR = 2.231, P = 0.021). Moreover, a significant interaction of the DRD2 Taq-I A1/A1 and the ALDH2*1*1 genotypes in BP-II without AD was revealed (OR = 5.623, P = 0.001) compared with normal control. Our findings support the hypothesis that a unique genetic distinction between BP-II with and without AD, and suggest a novel association between DRD2 Taq-I A1/A2 genotype and BP-II with AD. Our study also provides further evidence that the ALDH2 and DRD2 genes interact in BP-II, particularly BP-II without AD.
Studies have shown that mental health problems during pregnancy have adverse effects on fetal growth. The impact of depressive and anxiety symptoms during pregnancy on the fetus have not yet been examined in Singapore.
To examine the association between mental health problems during the second trimester of pregnancy on the quality of the pregnancy, reflected by birth weight and birth length of the newborn.
This study aims to understand the importance of mental health during pregnancy on the development of the child in an Asian population.
Preliminary data of a prospective cohort study of pregnant women (GUSTO), were followed from pregnancy onwards. At 26 weeks of the pregnancy, the Edinburgh Postnatal Depression Scale (EPDS), the Beck Depression Inventory (BDI) and the State Trait Anxiety Inventory (STAI) were administered. Data on birth parameters were collected from medical records.
Linear regression analyses of preliminary data show negative correlations between depressive symptoms measured with EPDS (n = 1025, P = 0.54), BDI (n = 1012, P = 0.001), and anxiety symptoms measured with STAI (n = 1023, P = 0.002) and birth length (corrected for gestational age and gender). No associations were found for birth weight.
There is an association between depressive and anxiety symptoms reported at the end of the second trimester of the pregnancy and birth length, but not birth weight, of the newborn. As it is known that fetal length increases mainly in the second trimester, it suggests that stress of the mother influences the development of the fetus during this trimester.
Persistent gaming, despite acknowledgment of its negative consequences, is a major criterion for individuals with Internet gaming disorder (IGD). This study evaluated the adaptive decision-making, risky decision, and decision-making style of individuals with IGD.
We recruited 87 individuals with IGD and 87 without IGD (matched controls). All participants underwent an interview based on the Diagnostic and Statistical Manual of Mental Disorders (5th Edition) diagnostic criteria for IGD and completed an adaptive decision-making task; the Preference for Intuition and Deliberation Scale, Chen Internet Addiction Scale, and Barratt Impulsivity Scale were also assessed on the basis of the information from the diagnostic interviews.
The results demonstrated that the participants in both groups tend to make more risky choices in advantage trials where their expected value (EV) was more favorable than those of the riskless choice. The tendency to make a risky choice in advantage trials was stronger among IGD group than that among controls. Participants of both groups made more risky choices in the loss domain, a risky option to loss more versus sure loss option, than they did in the gain domain, a risky option to gain more versus sure gain. Furthermore, the participants with IGD made more risky choices in the gain domain than did the controls. Participants with IGD showed higher and lower preferences for intuitive and deliberative decision-making styles, respectively, than controls and their preferences for intuition and deliberation were positively and negatively associated with IGD severity, respectively.
These results suggested that individuals with IGD have elevated EV sensitivity for decision-making. However, they demonstrated risky preferences in the gain domain and preferred an intuitive rather than deliberative decision-making style. This might explain why they continue Internet gaming despite negative consequences. Thus, therapists should focus more on decision-making styles and promote deliberative thinking processes to mitigate the long-term negative consequences of IGD.
Chlamydia trachomatis (CT) infection has been a major public health threat globally. Monitoring and prediction of CT epidemic status and trends are important for programme planning, allocating resources and assessing impact; however, such activities are limited in China. In this study, we aimed to apply a seasonal autoregressive integrated moving average (SARIMA) model to predict the incidence of CT infection in Shenzhen city, China. The monthly incidence of CT between January 2008 and June 2019 in Shenzhen was used to fit and validate the SARIMA model. A seasonal fluctuation and a slightly increasing pattern of a long-term trend were revealed in the time series of CT incidence. The monthly CT incidence ranged from 4.80/100 000 to 21.56/100 000. The mean absolute percentage error value of the optimal model was 8.08%. The SARIMA model could be applied to effectively predict the short-term CT incidence in Shenzhen and provide support for the development of interventions for disease control and prevention.
This study evaluated the effects of rumen-protected folic acid (RPFA) and betaine (BT) on growth performance, nutrient digestion and blood metabolites in bulls. Forty-eight Angus bulls were blocked by body weight and randomly assigned to four treatments in a 2 × 2 factorial design. BT of 0 or 0·6 g/kg DM was supplemented to diet without or with the addition of 6 mg/kg DM of folic acid from RPFA, respectively. Average daily gain increased by 25·2 and 6·29 % for addition of BT without RPFA and with RPFA, respectively. Digestibility and ruminal total volatile fatty acids of neutral-detergent fibre and acid-detergent fibre increased, feed conversion ratio and blood folate decreased with the addition of BT without RPFA, but these parameters were unchanged with BT addition in diet with RPFA. Digestibility of DM, organic matter and crude protein as well as acetate:propionate ratio increased with RPFA or BT addition. Ruminal ammonia-N decreased with RPFA addition. Activity of carboxymethyl cellulase, cellobiase, xylanase, pectinase and protease as well as population of total bacteria, protozoa, Fibrobacter succinogenes and Ruminobacter amylophilus increased with RPFA or BT addition. Laccase activity and total fungi, Ruminococcus flavefaciens and Prevotella ruminicola population increased with RPFA addition, whereas Ruminococcus albus population increased with BT addition. Blood glucose, total protein, albumin, growth hormone and insulin-like growth factor-1 increased with RPFA addition. Addition of RPFA or BT decreased blood homocysteine. The results indicated that addition of BT stimulated growth and nutrient digestion in bulls only when RPFA was not supplemented.