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This work examines the μ(I) relation that describes the effective friction coefficient μ of a dense granular flow as a function of flow inertial number I, at the center of a rotating drum from its flow onset to steady state using DEM. We want to see how the internal friction coefficient of an accelerating flow may be predicted so that the associated tangential stress can be estimated with the proper knowledge of the normal stress. Under the three investigated drum speeds (3, 4.5 and 6 rpm), the bulk normal stress, σn(y), is found to be a consistent linear depth profile throughout the flow development with a slope degraded from the hydrostatic value, Ph(y), due to lateral wall friction. With the discovery of a non-constant depth-decaying effective wall friction coefficient, we derive analytically a wall-degradation factor K(h) to give σn(y) = K(h)Ph(y). The depth profile of tangential stress, however, varies in time from a concave shape upon acceleration, τa(y), to a more linear trend at the steady state, τss(y). Hence, the μa-Ia profile (with μa=τa/σn) upon flow acceleration offsets from the steady μss(Iss) relation. A pseudo-steady acceleration modification number, ΔI, is proposed to shift the inertial number in the acceleration phase to I* = Ia + ΔI so that the μa-I* data converge to μss(Iss). This finding shall allow us to predict a transient tangential stress by τa(y) = μss(I*)K(y)Ph(y) using the well-accepted knowledge of steady flow rheology, hydrostatic pressure, and the currently developed wall-degradation factor.
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.
The present study investigated the association between fibre degradation and the concentration of dissolved molecular hydrogen (H2) in the rumen. Napier grass (NG) silage and corn stover (CS) silage were compared as forages with contrasting structures and degradation patterns. In the first experiment, CS silage had greater 48-h DM, neutral-detergent fibre (NDF) and acid-detergent fibre degradation, and total gas and methane (CH4) volumes, and lower 48-h H2 volume than NG silage in 48-h in vitro incubations. In the second experiment, twenty-four growing beef bulls were fed diets including 55 % (DM basis) NG or CS silages. Bulls fed the CS diet had greater DM intake (DMI), average daily gain, total-tract digestibility of OM and NDF, ruminal dissolved methane (dCH4) concentration and gene copies of protozoa, methanogens, Ruminococcus albus and R. flavefaciens, and had lower ruminal dH2 concentration, and molar proportions of valerate and isovalerate, in comparison with those fed the NG diet. There was a negative correlation between dH2 concentration and NDF digestibility in bulls fed the CS diet, and a lack of relationship between dH2 concentration and NDF digestibility with the NG diet. In summary, the fibre of CS silage was more easily degraded by rumen microorganisms than that of NG silage. Increased dCH4 concentration with the CS diet presumably led to the decreased ruminal dH2 concentration, which may be helpful for fibre degradation and growth of fibrolytic micro-organisms in the rumen.
Leg weakness (LW) issues are a great concern for pig breeding industry. And it also has a serious impact on animal welfare. To dissect the genetic architecture of limb-and-hoof firmness in commercial pigs, a genome-wide association study was conducted on bone mineral density (BMD) in three sow populations, including Duroc, Landrace and Yorkshire. The BMD data were obtained by ultrasound technology from 812 pigs (including Duroc 115, Landrace 243 and Yorkshire 454). In addition, all pigs were genotyped using genome-by-sequencing and a total of 224 162 single-nucleotide polymorphisms (SNPs) were obtained. After quality control, 218 141 SNPs were used for subsequent genome-wide association analysis. Nine significant associations were identified on chromosomes 3, 5, 6, 7, 9, 10, 12 and 18 that passed Bonferroni correction threshold of 0.05/(total SNP numbers). The most significant locus that associated with BMD (P value = 1.92e−14) was detected at approximately 41.7 Mb on SSC6 (SSC stands for Sus scrofa chromosome). CUL7, PTK7, SRF, VEGFA, RHEB, PRKAR1A and TPO that are located near the lead SNP of significant loci were highlighted as functionally plausible candidate genes for sow limb-and-hoof firmness. Moreover, we also applied a new method to measure the BMD data of pigs by ultrasound technology. The results provide an insight into the genetic architecture of LW and can also help to improve animal welfare in pigs.
We perform a numerical study of the heat transfer and flow structure of Rayleigh–Bénard (RB) convection in (in most cases regular) porous media, which are comprised of circular, solid obstacles located on a square lattice. This study is focused on the role of porosity
in the flow properties during the transition process from the traditional RB convection with
(so no obstacles included) to Darcy-type porous-media convection with
approaching 0. Simulations are carried out in a cell with unity aspect ratio, for Rayleigh number
and varying porosities
, at a fixed Prandtl number
, and we restrict ourselves to the two-dimensional case. For fixed
, the Nusselt number
is found to vary non-monotonically as a function of
; namely, with decreasing
, it first increases, before it decreases for
approaching 0. The non-monotonic behaviour of
originates from two competing effects of the porous structure on the heat transfer. On the one hand, the flow coherence is enhanced in the porous media, which is beneficial for the heat transfer. On the other hand, the convection is slowed down by the enhanced resistance due to the porous structure, leading to heat transfer reduction. For fixed
, depending on
, two different heat transfer regimes are identified, with different effective power-law behaviours of
, namely a steep one for low
when viscosity dominates, and the standard classical one for large
. The scaling crossover occurs when the thermal boundary layer thickness and the pore scale are comparable. The influences of the porous structure on the temperature and velocity fluctuations, convective heat flux and energy dissipation rates are analysed, further demonstrating the competing effects of the porous structure to enhance or reduce the heat transfer.
There seems to be geographical differences in decisions about breast conserving surgery (BCS) in breast cancer patients. This study was to evaluate patients’ attitude to BCS and to assess the factors affecting cancer practice in West China.
A structured questionnaire was distributed to 184 patients, eliciting information about the patients’ characteristics, occupation, education, family life, recognition of illness, knowledge about BCS, the main means of gaining surgery information, selecting surgery approaches, preferences to breast reservation.
In all, 163 patients completed the questionnaire. The results indicated that only 7.4% of patients received BCS and 23% of the remaining patients desired to have BCS and the affecting factors were significantly associated with their family life, recognition of illness and the main means of gaining surgery information (P < 0.05). No associations were between BCS selecting and the other variables studied. The most frequent reasons for selecting BCS were keeping the female shape and improving quality of life (71%), the second most were postoperative recovery, minimal influence of physical function (47%) and patients’ knowledge about BCS (42%). The most frequent reasons for not selecting BCS were uncertainty about BCS results and worry about recurrence (81%), the second most was the elderly age unnecessary for BCS (40%).
The findings indicate that breast cancer patients in West China do not take BCS as the first choice as the best treatment method. It is warranted that further study of more patients, attitude of patients’ partners and physicians to BCS.
White matter abnormalities have been repeatedly reported in both schizophrenia and bipolar disorder (BD) diseases from diffusion tensor imaging (DTI) studies respectively, while the empirical evidences about the diagnostic specificity of white matter abnormalities in these disorders are still limited.
25 patients with paranoid schizophrenia and 18 patients with bipolar mania were recruited from the in-patient unit of the Mental Health Centre, West China Hospital, China.
Patients were diagnosed according to the criteria of Diagnostic and Statistical Manual of Mental Disorders-Version IV (DSM- IV). 30 healthy controls were recruited from the community by means of leaflets distributed throughout Chengdu city.
This study sought to investigate the alterations in fractional anisotropy (FA) in white matter throughout the entire brain of patients from Chengdu, China with paranoid schizophrenia and bipolar mania.
Diffusion tensor imaging (DTI) was used to assess white matter integrity in patients with paranoid schizophrenia and bipolar mania, as well as in normal controls. The differences in FA were measured by use of voxel-based analysis.
Reduced FA was found in the left posterior corona radiate (PCR) in patients with bipolar mania and paranoid schizophrenia compared to the controls. Patients with bipolar mania also showed a significant reduction in FA in right posterior corona radiate and in right anterior thalamic radiation (ATR).
Common abnormalities in the left PCR might imply an overlap in white matter pathology of both diseases and might be related to the shared risk factors for both disorders.
This pooled analysis compared the efficacy of venlafaxine extended-release (XR) versus placebo in the treatment of social anxiety disorder (SAD).
Data were pooled from 5 randomized studies of patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) SAD (N=1459) who were treated with venlafaxine XR 75 mg/d to 225 mg/d or placebo for 12 weeks (4 studies) or 28 weeks (1 study). Response and remission rates were calculated for the overall sample, as well as stratified by gender and level of physical symptom severity at baseline. Response was defined as a score of 1 or 2 on the Clinical Global Impressions–Improvement (CGI-I) scale. Remission was defined as a total score of <30 on the Leibowitz Social Anxiety Scale (LSAS).
At baseline the mean LSAS score was 88.1 and 86.6 for the venlafaxine and placebo arms, respectively. Overall response rates at week 12 were 55% for venlafaxine XR and 33% for placebo (P<0.0001); remission rates were 25% and 12%, respectively (P<0.0001). Among patients with less severe physical symptoms, response rates were 52% and 32% for venlafaxine XR and placebo, respectively (P<0.0001); remission rates were 27% and 14%, respectively (P<0.0001). Response rates among patients with more severe physical symptoms were 56% for venlafaxine XR and 33% for placebo (P<0.0001); remission rates were 24% and 11%, respectively (P<0.0001).
Venlafaxine XR is effective in the treatment of SAD, regardless of gender or severity of physical symptoms.
To analyze baseline scores on individual items of the 17-item Hamilton Rating Scale for Depression (HAM-D17) in depressed outpatients by age groups approximating menopausal status.
This post-hoc, pooled analysis was conducted with populations from 7 double-blind, placebo-controlled desvenlafaxine succinate (DVS) trials in patients with major depressive disorder. The age groups, chosen as a proxy for pre-, peri-, and postmenopausal status, respectively, were 18-39, 40-55, and >55 years of age. Data from male patients were used to differentiate effects due to menopausal status from those related to age. Analysis of variance with Bonferroni adjustments was used to compare differences in baseline scores on individual HAM-D17 items.
A total of 1203 women (18-39 years [n=525]; 40-55 years [n=513]; >55 [n=165]) and 780 men (18-39 years [n=321]; 40-55 years [n=354]; >55 [n=105]) were included in this analysis. When analyzing these data by gender, women had significantly higher scores on HAM-D17 total (P=0.002), anxiety (P<0.001) and retardation subscales (P<0.001), and the somatic–anxiety (P<0.001), genital (P<0.001), and hypochondriasis (P=0.007) items. A significant age effect was observed for the HAM-D17 insomnia scale (P=0.004), and guilt (P<0.001), all insomnia items (P≤0.001), somatic–general (P<0.001), genital (P=0.019), and hypochondriasis (P≤0.001) individual items. An age effect among women was observed on the guilt (P=0.017), all insomnia items (P<0.05), somatic–general (P=0.022), and hypochondriasis (P=0.001) items.
Women in age groups approximating peri- and postmenopausal status had significantly higher baseline scores than younger women for the hypochondriasis, insomnia–middle and insomnia–late items of the HAM-D17.
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.
Previous studies have shown that the polymorphisms in COMT gene and environmental factors affect the risk of drug dependence, but there’s no research shown in relapse of heroin dependence, and the mechanism underlying remains uncertain.
Examine the interaction between allelic variants of the catechol-O- methlytransferase (COMT) gene and environmental factors (encountering drug-related environmental situations, social support) in contribution to relapse in heroin dependence.
Construct the gene-environment interaction model in order to understand the mechanism for relapse in heroin dependence.
The 249 heroin dependent subjects who followed up at one year after abstinent by using the natural history interview (NHI), social support rateing Scale (SSRS), and other questionnaires were genotyped for eight tagging single nucleotide polymorphisms (SNP) on the COMT gene. General Multifactor Dimensionality Reduction (GMDR) was used to construct the gene-environment interaction model which impacting relapse in heroin dependence.
The relapse group had higher frequencies of encountering drug-related environment (EDE) and G allele and GG genotype frequencies on COMT gene rs4680 locus and less Social Support Scale scores than that in the abstinence group. Logistic regression analysis showed that encountering more drug-related environment and GG genotype carriers were the risk factors for relapse in heroin dependence. GMDR analysis showed that the COMT gene was interact with the frequency of EDE and social support level to impact the relapse in heroin dependence.
Gene-environment interaction between COMT gene and the frequency of EDE and social support were related to heroin dependence relapse.
Many institutions are attempting to implement patient-reported outcome (PRO) measures. Because PROs often change clinical workflows significantly for patients and providers, implementation choices can have major impact. While various implementation guides exist, a stepwise list of decision points covering the full implementation process and drawing explicitly on a sociotechnical conceptual framework does not exist.
To facilitate real-world implementation of PROs in electronic health records (EHRs) for use in clinical practice, members of the EHR Access to Seamless Integration of Patient-Reported Outcomes Measurement Information System (PROMIS) Consortium developed structured PRO implementation planning tools. Each institution pilot tested the tools. Joint meetings led to the identification of critical sociotechnical success factors.
Three tools were developed and tested: (1) a PRO Planning Guide summarizes the empirical knowledge and guidance about PRO implementation in routine clinical care; (2) a Decision Log allows decision tracking; and (3) an Implementation Plan Template simplifies creation of a sharable implementation plan. Seven lessons learned during implementation underscore the iterative nature of planning and the importance of the clinician champion, as well as the need to understand aims, manage implementation barriers, minimize disruption, provide ample discussion time, and continuously engage key stakeholders.
Highly structured planning tools, informed by a sociotechnical perspective, enabled the construction of clear, clinic-specific plans. By developing and testing three reusable tools (freely available for immediate use), our project addressed the need for consolidated guidance and created new materials for PRO implementation planning. We identified seven important lessons that, while common to technology implementation, are especially critical in PRO implementation.
The fatty acid composition of chicken’s meat is largely influenced by dietary lipids, which are often used as supplements to increase dietary caloric density. The underlying key metabolites and pathways influenced by dietary oils remain poorly known in chickens. The objective of this study was to explore the underlying metabolic mechanisms of how diets supplemented with mixed or a single oil with distinct fatty acid composition influence the fatty acid profile in breast muscle of Qingyuan chickens. Birds were fed a corn-soybean meal diet supplemented with either soybean oil (control, CON) or equal amounts of mixed edible oils (MEO; soybean oil : lard : fish oil : coconut oil = 1 : 1 : 0.5 : 0.5) from 1 to 120 days of age. Growth performance and fatty acid composition of muscle lipids were analysed. LC-MS was applied to investigate the effects of CON v. MEO diets on lipid-related metabolites in the muscle of chickens at day 120. Compared with the CON diet, chickens fed the MEO diet had a lower feed conversion ratio (P < 0.05), higher proportions of lauric acid (C12:0), myristic acid (C14:0), palmitoleic acid (C16:1n-7), oleic acid (C18:1n-9), EPA (C20:5n-3) and DHA (C22:6n-3), and a lower linoleic acid (C18:2n-6) content in breast muscle (P < 0.05). Muscle metabolome profiling showed that the most differentially abundant metabolites are phospholipids, including phosphatidylcholines (PC) and phosphatidylethanolamines (PE), which enriched the glycerophospholipid metabolism (P < 0.05). These key differentially abundant metabolites – PC (14:0/20:4), PC (18:1/14:1), PC (18:0/14:1), PC (18:0/18:4), PC (20:0/18:4), PE (22:0/P-16:0), PE (24:0/20:5), PE (22:2/P-18:1), PE (24:0/18:4) – were closely associated with the contents of C12:0, C14:0, DHA and C18:2n-6 in muscle lipids (P < 0.05). The content of glutathione metabolite was higher with MEO than CON diet (P < 0.05). Based on these results, it can be concluded that the diet supplemented with MEO reduced the feed conversion ratio, enriched the content of n-3 fatty acids and modified the related metabolites (including PC, PE and glutathione) in breast muscle of chickens.
Three-dimensional printing is a revolutionary technology that is disrupting the status quo in surgery. It has been rapidly adopted by otolaryngology as a tool in surgical simulation for high-risk, low-frequency procedures. This systematic review comprehensively evaluates the contemporary usage of three-dimensional printed otolaryngology simulators.
A systematic review of the literature was performed with narrative synthesis.
Twenty-two articles were identified for inclusion, describing models that span a range of surgical tasks (temporal bone dissection, airway procedures, functional endoscopic sinus surgery and endoscopic ear surgery). Thirty-six per cent of articles assessed construct validity (objective measures); the other 64 per cent only assessed face and content validity (subjective measures). Most studies demonstrated positive feedback and high confidence in the models’ value as additions to the curriculum.
Whilst further studies supported with objective metrics are merited, the role of three-dimensional printed otolaryngology simulators is poised to expand in surgical training given the enthusiastic reception from trainees and experts alike.
Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample.
To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls.
The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression.
These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.
The effect of hot streaks from a gas turbine combustor on the thermodynamic load of internally air-cooled nozzle guide vanes (NGVs) and shrouds has been numerically investigated under flight conditions. The study follows two steps: one for the high-fidelity 60° combustor sector with simplified ten NGVs and three thermocouples attached; and the other for the NGV sectors where each sector consists of one high-fidelity NGV (probe NGV) and nine dummy NGVs. The first step identifies which NGV has the highest thermal load and provides the inlet flow boundary conditions for the second step. In the second step, the flow fields and thermal loads of the probe NGVs are resolved in detail.
With the systematically validated physical models, the two-phase flowfield of the combustor-NGVs sector has been successfully simulated. The predicted mean and maximum temperature at the combustor sector exit are in excellent agreement with the experimental data, which provides a solid basis for the hot-streak effect investigation. The results indicate that the second NGV, looking upstream from left, has the highest thermal load. Its maximum surface temperature is 8.4% higher than that for the same NGV but with the mean inlet boundary conditions, and 14.1% higher than the ninth NGV. The finding is consistent with the field-observed NGV damage pattern. To extend the service life of these vulnerable NGVs, some protection methods should be considered.
Single-crystalline gallium arsenide (GaAs) grown by various techniques can exhibit hillock defects on the surface when sub-optimal growth conditions are employed. The defects act as nonradiative recombination centers and limit solar cell performance. In this paper, we applied near-field transport imaging to study hillock defects in a GaAs thin film. On the same defects, we also performed near-field cathodoluminescence, standard cathodoluminescence, electron-backscattered diffraction, transmission electron microscopy, and energy-dispersive X-ray spectrometry. We found that the luminescence intensity around the hillock area is two orders of magnitude lower than on the area without hillock defects in the millimeter region, and the excess carrier diffusion length is degraded by at least a factor of five with significant local variation. The optical and transport properties are affected over a significantly larger region than the observed topography and crystallographic and chemical compositions associated with the defect.
The co-occurrence of hepatic cystic echinococcosis (CE) and alveolar echinococcosis (AE) is extremely rare. Here, we present the clinical manifestations and treatment outcomes of three cases with co-occurring CE and AE in the liver. Computed tomography (CT), magnetic resonance imaging and 18FFluorodeoxyglucose Positron Emission Tomography-CT were used for preoperative diagnosis. Specimens were taken intraoperatively and sent for pathological studies to confirm the coexistence of CE and AE by laminated membrane, daughter cysts or germinal layer and infiltration structure. Albendazole was prescribed after operation for 12 months. All patients were completely recovered and showed no recurrence at last follow-up. Therefore, surgical intervention and postoperative application of albendazole are recommended for patients with concurrence of hepatic AE and CE.
l-Carnitine is essential for mitochondrial β-oxidation and has been used as a lipid-lowering feed additive in humans and farmed animals. d-Carnitine is an optical isomer of l-carnitine and dl-carnitine has been widely used in animal feeds. However, the functional differences between l- and d-carnitine are difficult to study because of the endogenous l-carnitine background. In the present study, we developed a low-carnitine Nile tilapia model by treating fish with a carnitine synthesis inhibitor, and used this model to investigate the functional differences between l- and d-carnitine in nutrient metabolism in fish. l- or d-carnitine (0·4 g/kg diet) was fed to the low-carnitine tilapia for 6 weeks. l-Carnitine feeding increased the acyl-carnitine concentration from 3522 to 10 822 ng/g and alleviated the lipid deposition from 15·89 to 11·97 % in the liver of low-carnitine tilapia. However, as compared with l-carnitine group, d-carnitine feeding reduced the acyl-carnitine concentration from 10 822 to 5482 ng/g, and increased lipid deposition from 11·97 to 20·21 % and the mRNA expression of the genes involved in β-oxidation and detoxification in the liver. d-Carnitine feeding also induced hepatic inflammation, oxidative stress and apoptosis. A metabolomic investigation further showed that d-carnitine feeding increased glycolysis, protein metabolism and activity of the tricarboxylic acid cycle and oxidative phosphorylation. Thus, l-carnitine can be physiologically utilised in fish, whereas d-carnitine is metabolised as a xenobiotic and induces lipotoxicity. d-Carnitine-fed fish demonstrates increases in peroxisomal β-oxidation, glycolysis and amino acid degradation to maintain energy homeostasis. Therefore, d-carnitine is not recommended for use in farmed animals.