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Tail biting is an abnormal behaviour that causes stress, injury and pain. Given the critical role of the gut-microbiota in the development of behavioural problems in humans and animals, the aim of this study was to determine whether pigs that are biters, victims of tail biting or controls (nine matched sets of pigs) have a different microbiota composition, diversity and microbial metabolite profile. We collected faecal and blood samples from each individual for analysis. The gut microbiota composition was most different between the biter and the control pigs, with a higher relative abundance of Firmicutes in tail biter pigs than the controls. Furthermore, we detected differences in faecal and plasma short chain fatty acids (SCFA) profiles between the biter and victim pigs, suggesting physiological differences even though they are kept in the same pen. Thus, in addition to supporting an association between the gut microbiota and tail biting in pigs, this study also provides the first evidence of an association between tail biting and SCFA. Therefore, further research is needed to confirm these associations, to determine causality and to study how the SCFA profiles of an individual play a role in the development of tail biting behaviour.
Despite decades of research, tail biting is still a major problem in intensive pig production. Tail biting has serious consequences for the animals involved because it leads to physical injury and pain as well as psychological stress1,2. Tail biting also has a negative impact on the economic performance of pig farms3. The EU Council directive 2008/120/EG bans routine tail docking, but allows exemptions to prevent individual animal damage. However, a total ban on tail docking currently exists in only three European countries (Norway, Sweden and Finland) and it is estimated that 80–99% of pigs are tail docked in other European countries3.
There is no single cause of tail biting, and there is an extensive amount of literature identifying different causes and risk factors as well as numerous investigations of different solutions (reviewed in4). A generally accepted theme is that tail biting is an abnormal behaviour, that is expressed under barren conditions, and results from the inability to fulfil the natural need for rooting, foraging and explorative behaviours5,6. In addition, domestic pigs are exposed to many stressful challenges throughout their lives, and several of these have been identified as risk factors for the development of tail biting. These factors can be environmental, such as temperature7, feeding method7, lack of appropriate enrichment8, and inappropriate pen design e.g., fully slatted floors7,9. Also several social factors such as insufficient space at the feeder leading to social competition9,10 and high stocking density9 are risk factors for tail biting, as are individual factors such as nutritional status11 and neurobiology12. However, it is currently not fully understood how all these different factors contribute to the development of tail biting.
One factor that could provide the link between food-related behaviours, different types of stressors and tail biting, is the gut microbiota11. The gut microbiota plays a major role in regulating homeostatic processes in the host, such as the immune system, the cardiovascular system, the digestive system and metabolic processes13. The gut microbiota also influences key brain processes, and this link between the gut and the brain is called the microbiota-gut-brain axis14. Rodents raised without a gut microbiota (germ-free) showed increased physiological stress responses to restraint15, and it is now recognized that the gut microbiota is a critical component in the regulation of the Hypothalamus–Pituitary–Adrenal (HPA)-axis16. Germ-free mice also showed socially impaired and repetitive behaviours17, suggesting that the gut microbiota is important for the development of normal social behaviour. On the other hand, stressful experiences (including social stress) alter gut microbiota structure18 and reduce diversity19. Providing faecal matter from healthy animals or supplementing with probiotics can reverse some of the abnormal social behaviours in animals with an unbalanced gut microbiota20,21. In humans, it is now thought that an unbalanced gut microbiota contributes to the development of a range of abnormal behaviours and can be a contributing factor to depression and anxiety disorders22,23,24.
Intensively reared pigs are kept under tightly controlled environmental conditions, fed a standardized diet to promote fast growth, and may be given antibiotics. They are also kept indoors under strict hygienic conditions, which compromises the normal development of the gut microbiota due to a lack of exposure to environmental microbes25,26. Furthermore, the multiple stressors experienced already from an early age (e.g., weaning and separation from the dam, castration, frequent mixing with unfamiliar animals) may pose an increased risk of developing an unbalanced gut microbiota. A first explorative study has shown that pigs involved in tail biting had a different microbiota composition compared to pigs not involved in tail biting, and this difference was primarily dependent on a reduced abundance of Lactobacillus in the animals involved in tail biting27.
One of the pathways for crosstalk between the gut and the brain is through the production of microbial metabolites that have neuroactive properties. Short-chain fatty acids (SCFA) are the main metabolites produced in the large intestine by anaerobic bacterial fermentation of dietary fibre28. Acetate, propionate, and butyrate are the main SCFA in the colon and are key components in gut-brain communication through a number of signalling pathways, including the stimulation of neuropeptides from enteroendocrine cells (e.g., glucagon-like peptide 1 (GLP-1), peptide YY, serotonin, and GABA) through which they can influence behaviour28. A reduction in SCFA producing bacteria has been identified as a key factor in dysbiosis of the gut microbiota and is linked to neuropsychiatric disorders in both humans and in animal models29. In humans30 and monkeys31, faecal SCFA concentrations were lower in individuals with depressive symptoms compared to healthy controls. SCFA concentrations were also lower in children diagnosed with autism spectrum disorder32, which is characterized by repetitive behaviours and impaired social interactions. Even though faecal SCFA are usually measured as a proxy of colon-derived SCFA, only approximately 5% is excreted in the faeces while 95% of colonic SCFA is readily absorbed in the colon in mammals28,33,34. SCFA from the periphery can also cross the blood–brain-barrier28. How the gut-microbiota and SCFA influence behaviour in pigs has so far received little attention. The novelty of this study is that we will investigate for the first time whether there is an association between faecal and plasma SCFA profiles and abnormal behaviour in pigs.
Given the critical role of the gut-microbiota in the development of behavioural problems in humans and animals, the aim of this study was to determine whether matched sets of pigs that are biters, victims of tail biting or controls, i.e., pigs not involved in a tail biting episode, have a different microbiota composition, diversity and SCFA profile. We expect differences between the biter and victim pigs compared to the control pigs, given the stress of being involved in tail biting, but differences between biters and victims might support the hypothesis that an unbalanced gut-microbiota and an altered SCFA profile plays a role in the development of tail biting.
All methods were carried out in accordance with relevant guidelines and regulations. The study was approved by Uppsala animal ethics committee (document numbers C105416/16) and complied with the ARRIVE guidelines35.
Animals and housing
In total, 29 pigs were included in the study, of which ten were biters, nine were victims and ten were controls. The pigs were selected to belong to nine matched sets, each set consisting of at least one biter, one victim and one control. Matching appropriate controls to the biter and victim pigs increases the efficiency of the study, and therefore increases the likelihood of finding consistent differences even with a relatively low number of tail biting episodes36. Our original aim was to include only pigs from an experimental farm, but after one year we had only identified a few episodes of tail biting. Therefore, we also included pigs from a commercial farm to increase the number of animals available. In total, seven episodes of tail biting on the experimental farm (23 animals) and two episodes of tail biting (six animals) on the commercial farm were identified over a 2-year period.
The experimental farm housed specific pathogen free crossbreed sows of Swedish Landrace, Yorkshire and Hampshire. All pigs had intact tails and were housed in groups no larger than ten finishing pigs, in pens with partially slatted floors (3.6 × 2.2 m). A small amount of straw was given as enrichment but no bedding was provided. The pigs were fed a standard commercial diet (Lantmännen Delta F4106) for finishing pigs, see also Table 1.
The pigs on the commercial farm were crossbreeds between Swedish Landrace, Yorkshire and Hampshire. All pigs had intact tails and were housed in groups of 10–11 pigs in pens with partially slatted floors (3.4 × 2.3 m). A small amount of straw was given as enrichment but no bedding was provided. The diet is indicated in Table 1.
Selection of pigs
The farm staff identified pens with tail biting problems by monitoring pigs for visible signs of tail injuries on a daily basis during routine cleaning of the pens. In case there was visible tail damage, the farm staff were instructed to conduct direct observations at the home pen for 15 min to identify the biter. For ethical reasons, all biter pigs were removed from the pen as soon as possible to prevent further damage and suffering. Tail biting was defined as one pig having the tail of a conspecific in its mouth resulting in a physical reaction (squealing, grunting, moving away) from the conspecific. A pig was considered a biter when it was clearly observed biting the tail of a pig with visible tail damage at least five times within the 15 min observation time, similar to previous studies37,38,39. In case the farm staff could not clearly identify the biter, the researchers would observe the pigs for 20 min sessions until a biter was identified (minimum of five bites to the tail of a pig with tail injuries). A victims was identified by the presence of tail injuries, and was selected from the same pen as the biter pig. The severity of the tail biting was scored for each victim according to the scoring system developed by Sutherland40, based on tail length (scored from 1 to 5), presence of injuries (scored from 1 to 4) and presence of blood (scored from 1 to 4). We then summed the scores for each individual pig, and victims with tail damage scores between 0 and 5 points were considered mild, 5–10 points moderate and more than 10 points severe. Because tail biting in pigs is often mutual, with 80–98% of pigs in the pen involved in tail biting37, we chose to select the control pigs randomly from a nearby pen with pigs of similar ages and the same sex as the biters and victims (matched controls) but without any animals with tail damage in the control pen. The pens from which the control pigs were selected had no pigs with tail injuries but were in the same room of the barn and therefore had the same management, diet and environment as the pen with the biter and victim pigs.
Sample collection and analysis
Faecal and blood samples (EDTA vacutainer) were collected between one (experimental farm) and five days (commercial farm) after victims and biters had been identified. Samples were placed on ice directly after collection and transported to the lab where blood was centrifuged (2000g for 10 min at 4 °C) and plasma and faecal matter stored at − 80 °C until analysis. The sample analysis was done by different experimenters than the ones collecting the samples, and the experimenters analysing the samples were blind to the treatments.
Analysis of the microbiota
DNA was extracted from faecal samples using QIAamp DNA Stool Minikit (Qiagen, Hilden, Germany). The DNA isolation followed the instructions of the manufacturer, but with an extra mechanical lysis step, using 0.1 mm Zirconium/Silica beads (Biospec products, Bartlesville, USA), 2 × 1 min at 6000 rpm with a Precellys evolution (Bertin Instruments, Montigny-le-Bretonneux, France). The isolated DNA was stored at − 20 °C until analysis. 16S rRNA gene amplicons were generated from the V3 and V4 region using the primers (341F 5′-CCTACGGGAGGCAGCAG-3′ and 806R 5′-GGACTACNNGGGTATCTAAT-3′). Sequencing libraries were generated using NEB Next® Ultra™ DNA Library Prep Kit for Illumina (NEB, USA) and the amplicon library was sequenced on an Illumina HiSeq 2500 platform at Novogene. The generated paired-end reads were merged with FLASH (V1.2.7, http://ccb.jhu.edu/software/FLASH/)41 and assigned to each sample according to the sample specific barcodes. Quality filtering of sequence data was performed with QIIME (V1.7.0)42 and UCHIME43 was used to detect and remove chimeric sequences44. The reads were clustered using Uparse software (Uparse v7.0.1001)45 and OTUs (Operational Taxonomic Units) were generated based on 97% sequence homology.
Analysis of short chain fatty acids
Faecal SCFA were analysed in 0.5 g faecal matter diluted in 1 mL water, as previously described46, using an HPLC system consisted of an Alliance 2795 separations module and 2414 RI Detector (Waters Corp. Milford, MA, USA). Column packet ReproGel H 9µ 300*8 mm was used as the separation column and a ReproGel H, 9µ 30*8 mm (Dr. A. Maisch, Ammerbuch, Germany) was used as a pre-column. SCFAs were analyzed in plasma by LC–MS according to a method described earlier, but with some minor modifications. For detailed description of the analytical procedure for the SCFA analysis, see Supplementary File 1.
The microbial alpha diversity within samples was assessed on OTU level data. Principal coordinate analysis (PCoA) with Bray Curtis distance metrics was used to assess the relationship in microbiota composition between samples. In addition, cluster analyses were done for the individual sets and were based on Bray Curtis distances and UPGMA algorithms. The multivariate analyses were executed on OTU level data using the software PAST (version 4.02)47.
The relative abundance of the different phyla, orders, genera and families, and alpha diversity index data were analysed by a non-parametric Friedman test fitting category of pig as a fixed effect and with set as a blocking factor in r (version 4.0.2.)48. Because there were two sets with four animals, one animal in the duplicated category was randomly excluded to form nine sets of three animals each (victim, control and biter). To reduce the number of tests, only taxa present in 50% of the samples and with an average abundance of more than 0.1% were included. Both unadjusted and Benjamini–Hochberg False Discovery Rate (FDR) adjusted p-values are presented. Posthoc testing was done when the unadjusted p-value was less than 0.05 using an asymptotic general symmetry test (coin49 and multcomp packages50), and p-values were Bonferroni corrected.
SCFA data were analysed in r (version 4.0.2.) and model assumptions of normality and homoscedasticity of the data were visually checked by QQ-plots (LMERConvenienceFunctions package51). SCFA were analysed by mixed models (packages lme452 and lmerTest53), with category of pig, farm, sex and age as fixed effects and the specific matched set that the animals belonged to and pen as random effects. If the data did not meet the normality assumptions, a data transformation was applied first (log-transformed variables: faecal acetate, iso-butyrate, valerate; faecal proportions of iso-butyrate; all plasma SCFA; and plasma proportions of acetate, butyrate, propionate, iso-valerate). Faecal acetate concentrations still did not meet normality assumptions, and one outlier with a residual larger than 2.5 units was excluded from the analysis. After data transformation and exclusion of the outlier, all variables met the normality assumptions. Non-significant terms were dropped from the model in the final analysis. Posthoc Tukey HSD tests were performed using the emmeans package54. The data presented in Figs. 1 and 2 were plotted in the software PAST, and Figs. 3, 4, 5, 6, 7 and 8 were plotted using the package ggplot2 in r55.
In total, we included nine sets of pigs matched for sex and age, with seven sets of three animals and two sets of four animals (Table 2). In set nine (pen 213, Table 2), we could not clearly identify the biter, even after multiple observation sessions. One pig in pen 213 was biting body parts other than the tail. Pigs that tail bite also perform more abnormal behaviours that involve biting other body parts38,39. No other pig in pen 213 was observed to perform any biting behaviour. Therefore, it is very likely that the suspected biter pig in set 9 was the actual tail biter pig.
Composition and diversity of the microbiota
The sequence analysis generated on average 83,510 (range 32,981–119,580) sequences/sample. The sequence data was dominated by Firmicutes (average relative abundance; 40.9%), Bacteroidetes (39.3%) and Proteobacteria (12.3%). The alpha-diversity using Shannon (p < 0.05) and Simpson (p < 0.05) diversity indexes were associated with tail biting category (Table 3).
The assessment of the Beta diversity using PCoA revealed a primary clustering of samples that was dependent on the set, although with some overlap between the sets within animals located on the same farm (Fig. 1). The samples from the commercial farm (set 2 and 3 in Fig. 1) clustered together with the samples collected from the experimental farm. The PCoA also revealed that the biters and controls were generally the samples with the largest distance within the sets. A cluster analysis was therefore performed for each set separately. When comparing the pattern of biters, victims and controls within each set, there was a larger distance between biters and controls compared with biters and victim for six of the nine matched sets, so confirming a different microbiota composition in animals involved in tail biting (Fig. 2).
Relative abundance of different phyla, orders, genera and families
Univariate statistical tests were applied in order to identify specific taxa that differed in relative abundance between animals involved in tail biting and controls. The relative abundance of the phylum Firmicutes was the only variable that was significant after applying the FDR adjustment, (Friedman χ2 = 11.55, adjusted p < 0.05 and unadjusted p < 0.01, Fig. 3a), with a higher relative abundance of Firmicutes in the biters than the controls (Bonferroni corrected posthoc test p < 0.01) while victims were not different from controls or biters. None of the other variables reached statistical significance after FDR adjustment, so we present only the non-adjusted p-values here. At the order level, the relative abundance of Clostridiales, which is a member of the Firmicutes phylum, was associated with tail biting status (Friedman χ2 = 9.55, p < 0.01, Fig. 3b), with a higher relative abundance in the biters than the controls (p < 0.05).
At the family level, three different families belonging to the Clostridiales order were associated with tail biting. The first was Lachnospiraceae (Friedman χ2 = 10.89, p < 0.01, Fig. 4a), with a higher relative abundance in the biter (p < 0.05), and a tendency for a greater abundance in the victims (p = 0.08) than the controls. Ruminococcaceae (Friedman χ2 = 9.56, p < 0.01, Fig. 4b) also had a greater abundance in the biters than the controls (p < 0.01). Clostridiales Family_XIII (Friedman χ2 = 6.89, p < 0.05, Fig. 4c) also had a greater abundance in the biters than controls (p < 0.1).
At the genus level, Prevotella_7 relative abundance was associated with category of pig (Friedman χ2 = 12.23, p < 0.01, Fig. 5a), with a lower relative abundance in the victims than the controls (p < 0.01). Ralstonia abundance (Friedman χ2 = 8.22, p < 0.05, Fig. 5b) tended to be lower in the victims compared to the controls (p = 0.08). Alloprevotella relative abundance (Friedman χ2 = 6.89, p < 0.05, Fig. 5c) tended to be higher in the victims than controls (p = 0.08). Solobacterium (Friedman χ2 = 6.22, p < 0.05, Fig. 5d) and Agathobacter (Friedman χ2 = 6.22, p < 0.05, Fig. 5h) were associated with category of pig, but no contrasts were significant after Bonferroni correction. The relative abundance of Butyrivibrio was associated with category of pig (Friedman χ2 = 8.22, p < 0.05, Fig. 5e) and tended to be higher in the victims compared to the controls (p = 0.08). Family_XIII_AD3011_group (Friedman χ2 = 7.6, p < 0.05, Fig. 5f) was higher in the biters than in the controls (p < 0.05). Ruminiclostridium_9 (Friedman χ2 = 6.89, p < 0.05, Fig. 5g) tended to be higher in the biters than in the control (p = 0.08).
Faecal short chain fatty acids
Faecal acetate concentrations were associated with category of pig (F(2,5.4) = 6.8, p < 0.05, Fig. 6a), with the biters having significantly lower concentrations than the victim pigs (p < 0.05). Acetate was also significantly higher on the commercial farm (65.8 ± 4.6 mmol/L) than on the experimental farm (41.8 ± 1.8 mmol/L, F(1,10.6) = 17.9, p < 0.01). Faecal propionate concentrations were associated with category of pig (F(2,12.1) = 6.4.0, p < 0.05, Fig. 6b), with lower propionate concentrations in the biters than the victims (p < 0.05) and to a lesser extent the control pigs (p < 0.1). Butyrate concentrations were associated with category of pig (F(2,5.6) = 12.2, p < 0.01, Fig. 6c), with lower concentrations in both biters (p < 0.05) and victims (p < 0.04) than controls. Iso-butyrate concentrations were associated with category of pig (F(2,19.2) = 4.0, p < 0.05, Fig. 6d), with biters tending to have lower concentrations than the controls (p < 0.1). There was also a main effect of sex, with females (1.0 ± 0.15 mmol/L) having higher iso-butyrate concentrations than males (0.5 ± 0.11 mmol/L, F(1,23.6) = 9.3, p < 0.01). Furthermore, iso-butyrate concentrations were higher on the commercial farm (1.0 ± 0.3 mmol/L) than on the experimental farm (0.5 ± 0.1, F(1,12.0) = 6.5, p < 0.05). Valerate concentrations were associated with category of pig (F(2,9.7) = 4.6, p < 0.05, Fig. 6e), with lower concentrations in the biters (p < 0.05) than in the controls.
The molar proportion of acetate was associated with tail biting (F(2,18.3) = 11.0, p < 0.001, Fig. 7a), with the biters having (p < 0.05) and victims (p = 0.09) tending to have a higher proportion than the controls. The molar proportions of acetate were higher on the commercial farm (0.59 ± 0.01) than on the experimental farm (0.53 ± 0.01, F(1,7.4) = 13.5, p < 0.01). The molar proportions of butyrate were also associated with category of pig (F(2,6.7) = 9.4, p < 0.01, Fig. 7b), with the proportion being higher in the control group than in the biters (p < 0.05) and tending to be higher than the victims (p < 0.1). The molar proportions of iso-butyrate tended to be affected by tail biting category (F(2,20.6) = 2.7, p = 0.05, Supplement Fig. 1a) and were higher in the females (0.011 ± 0.001) than the males (0.005 ± 0.009, F(1,22.7) = 9.0, p < 0.01). The molar proportion of valerate was also associated with category (F(2,18.6) = 3.8, p < 0.05, Supplement Fig. 1b), although we could not detect any differences between biter, victim or control pigs in the posthoc test.
Plasma short-chain fatty acids
Butyrate was associated with category of pig (F(2,11.6) = 4.7, p < 0.05, Fig. 8a), with the biters having higher concentrations than the victims (p < 0.05). Iso-butyrate concentrations were also associated with category (F(2,15.8) = 4.2, p < 0.05, Fig. 8b), with the control pigs having higher concentrations than the victims (p < 0.05). Valerate concentrations were also associated with category (F(2,10.5) = 5.5, p < 0.05, Fig. 8c), with the biters having higher concentrations than the victims (p < 0.05). Iso-valerate concentrations were associated with category (F(2,13.8) = 3.9, p < 0.05, Fig. 8d), with the controls tending to have higher concentrations than the victims (p = 0.051). The molar proportions of plasma SCFA were not associated with category of pig nor farm (data not shown).
The aim of this study was to determine whether matched sets of pigs that were tail biters, victims of tail biting, or control pigs that were not involved in tail biting had a different microbiota composition, diversity and SCFA profile. Our results showed that the gut microbiota of tail biter pigs was more diverse than the control pigs. Furthermore, the gut microbiota composition within each tail biting set was most different between the biter and the control pigs, with a higher relative abundance of Firmicutes in tail biter pigs than the controls. This study also provides the first evidence of an association between tail biting and faecal and plasma SCFA.
The higher relative abundance of Firmicutes in the tail biter pigs was primarily driven by the higher abundance of the families Lachnospiraceae, Ruminococcaceae and Clostridiales Family XIII. Our results are partly in line with the so far only published paper on gut microbiota composition and tail biting in pigs27. In line with their results, we also found the highest similarity in microbiota composition between the biters and the victims and the largest differences between biters and controls. By contrast, we found a higher microbial alpha diversity in the tail biting pigs, whereas the study by Rahbi et al. did not. A high microbial diversity is commonly interpreted as favourable as it enables the community to have a greater ability to respond to disturbances56. However, all pigs in our study had reasonably high alpha diversity values, and therefore, the higher diversity in the biters may not necessarily be beneficial57.
In agreement with the study by Rabhi et al.27, we identified taxa differences between biter pigs and controls. Rabhi et al., reported lower Lactobacillus in the biter pigs, and a similar reduction in the abundance of Lactobacillus has also been reported in feather pecking hens58. A lower abundance of Lactobacillus has been linked to high psychological stress in a number of species18,59,60. However, we did not find any effect of tail biting on Lactobacillus in our study. We did find a higher relative abundance of several families within the Clostridiales order in the biter pigs, which is in line with previous studies in laying hens involved in feather pecking58,61. Clostridiales regulate microbial gut-derived T-cell immune and serotonergic signals through which they can affect behavior62,58,64. Increases in the relative abundance of the Clostridiales order has also been linked to a number of behavioural disorders such as autism62, schizophrenia65 and as a consequence of social stress18,66. At family level, we found increased levels of Lachnospiraceae, Ruminococcaceae and Clostridiales Family XIII in the tail biter pigs. Members of the Clostridiales order and in particular within the Ruminococcaceae and Lachospiraceae families, have been associated with serotonin biosynthesis via production of 5-HT67. An increase in serotonin metabolism (increased 5-HIAA levels) has also been detected in the prefrontal cortex of biter pigs12. Ruminococcaceae and Lachnospiraceae families are also important for the production of SCFA and in particular butyrate68.
This study also provides the first evidence of an association between tail biting and faecal and plasma SCFA. Faecal SCFA concentrations were lowest in the biting pigs. In addition, there was a shift towards increased faecal molar proportions of acetate but reduced proportions of butyrate in the biter pigs, and to a lesser extend also in the victim pigs. The lower faecal concentrations of SCFA in biter pigs (and to a lesser extent victim pigs) could indicate an increased colonic absorption69, or an altered rate of passage of the digesta28,70. However, the lower concentrations of SCFA in the biter pigs seems contradictory to the higher abundance of SCFA producing microbial families. Other studies have also found altered SCFA in humans and animals with behavioural disorders. For example, lower faecal acetate32,71, propionate32,71 and butyrate71 concentrations have been observed in autistic children compared to healthy controls, although increased faecal SCFA in autism has also been reported72. Mice subjected to social stress had lower colonic concentrations of acetate and butyrate but increased concentrations of propionate73. However, hens that feather pecked had a higher concentrations of total caecal SCFA and a reduced proportion of acetate compared to low feather pecking birds74.
Most butyrate is used as an energy source by the colonic mucosa75, and acetate and propionate are metabolized by the liver as a substrate for lipogenesis and gluconeogenesis76,77. Therefore, only a minor fraction of colonic produced SCFA reaches the circulation, and plasma concentrations of SCFA are not necessarily a good reflection of faecal concentrations78. We found increased plasma concentrations of butyrate and valerate in biter pigs compared to the victims and increased iso-butyrate and iso-valerate in the control pigs compared to victim pigs, although we could not detect any major shifts in the molar proportion of plasma SCFA related to tail biting. The differences in plasma SCFA profiles between biter and victim pigs suggest that they may be physiologically different from each other, even though they are kept in the same pens, and it would be valuable to further look into how plasma SCFA profiles play a role in the development of tail biting.
The SCFA profiles were not consistent in relation to tail biting in blood and faeces, with lower faecal concentrations of SCFA in the biters, but lower plasma SCFA in victim pigs. It has been suggested that circulating concentrations of SCFA may be better indicators of metabolic health than faecal SCFA78,79, and therefore, the lower plasma concentrations of SCFA may suggest poorer metabolic health in the victim pigs. The circulating SCFA may influence the brain locally, but on the other hand, it has also been shown that colonic SCFA can impact the brain remotely via interaction with receptors GPR 43/41 in the colonic mucosa that release Glucagon-like Peptide 1 and Peptide YY which influence the signalling to the brain via the vagus nerve80.
The different SCFA can have varying impacts on behaviour. Butyrate administration has been shown to have anti-depressant effects in mice81,77,83. When SCFA in the colon were experimentally increased by feeding acylated starches in mice, it was shown that higher acetate concentrations, but not butyrate or propionate, led to a reduction in anxiety-like behaviours, suggesting that acetate may have a beneficial impact on host behaviour84. Chronically stressed mice orally supplemented with a mixture of acetate, propionate and butyrate showed normalized reward-seeking behaviour and increased stress responsiveness85. On the other hand, propionate administration directly into the brain impairs social behavior86,87 and peripheral administration increases anxiety and repetitive behaviours88. These studies suggest that faecal acetate and butyrate may be associated with reduced depression- and anxiety-like behaviours, but that propionate may be associated with abnormal social behaviours. However, the biter pigs in our study had lower faecal concentrations of acetate, butyrate and propionate. Studies assessing the effects of SCFA on behaviours vary widely in SCFA measurement location (i.e., colonic, cecal, faecal, circulating) as do studies administering SCFA (i.e., orally, intra-gastric, intra-colonic, intraperitoneal) and this is likely to affect the outcomes. It is also worth noting that the SCFA production in the colon and their absorption by the colonic epithelium is a dynamic process, and the measurements in stool or blood samples will display a snapshot of how the situation looks at a given time point. Despite this, our study is the first to suggest reduced faecal SCFA in biter pigs, and reduced circulating SCFA in victim pigs. Further research would be necessary to confirm any cause and effect relationships between circulating and faecal SCFA and tail biting behaviour.
To ensure that the control pig was not involved in tail biting, we chose a control pig from a different but nearby pen with the same diet and management. Thus, we cannot rule out that subtle differences between the pen environments or the stress of being housed in a pen with an ongoing episode of tail biting contributed to the observed differences. Tail biting and victim pigs, on the other hand, come from the same pen and so the differences between these two categories could be especially relevant. However, even here there are potential difficulties in interpretation, since in three sets, the biter pigs were also victims themselves. Neither can we rule out that more victim pigs would have been classified as biter pigs if we had observed them more often or had left the biters in the pen for a longer period of time. We removed the biter pigs from the pens at the first signs of tail damage for ethical reasons. We used the same criteria to identify biter pigs as in previous studies, e.g., when a pig was clearly observed biting another pig with visible tail damage at least five times (e.g.37). However, many tail biting relationships are mutual, with two pigs biting each other38. In some studies, as many as 98% of the pigs in a pen are involved in tail biting37, although other studies have found that some pigs will not engage in tail biting (e.g., a tail biting resistant phenotype89). In future studies, it may be valuable to create four categories of pigs instead (true’ biter without tail damage, biter/victim, ‘true’ victim never observed biting and ‘true’ control), but more pigs would be required for such a study. Finally, in one set it was difficult to identify the biter, and we suggest more extensive monitoring by video cameras as long as this can be done in an ethical way so that further damage can be prevented.
We collected data on two different farms, because the occurrence of tail biting was relatively low and it was difficult to get enough episodes. We speculate that the reason for the low occurrence was that several factors known to protect against the development of tail biting (e.g., low stocking densities9, environmental enrichment8 good environmental conditions7,9) were present on the farms from which we recruited our pigs.
While we observed differences between biter pigs and controls in microbiota composition within the matched sets, the farm environment and/or diet had a larger impact on the microbiota composition than tail biting category. We found some differences in SCFA profiles between the farms, and the differences between tail biting categories appeared to be larger—but in the same direction—on the commercial farm than on the experimental farm. The diet, such as the phosphorus content90 and the amount of fibre91,87,93 has an impact on SCFA and microbiota, and differences in the diet most likely explained the differences between farms. Despite the diet and other differences in environment and management, the results on both farms were in agreement with each other, which strengthens the findings of this study.
The pigs in our study were housed in mixed-sex pens with females and castrated males. The majority of the victim pigs were males, which is in agreement with previous studies5. However, previous studies have reported that females are more likely to be biters94. Females become more active when reaching sexual maturity and may re-direct their behaviour towards biting inactive male castrates because of lack of stimulation5. However, we observed that most biter pigs were also males. We also found some sex differences with higher levels of faecal (but not plasma) concentrations iso-butyrate in females, independent of tail biting category. The reasons for this is not clear, but could be due to the small number of females in the study, and would need further investigation.
In conclusion, we identified differences in microbiota composition and diversity as well as in faecal and plasma SCFA profiles between biter, victim and control pigs. Within each matched set, the gut microbiota composition was most different between the biter and the control pigs, with a higher relative abundance of Firmicutes in tail biter pigs and this difference was primarily driven by the higher abundance of the families Lachnospiraceae, Ruminococcaceae and Clostridiales Family XIII. However, other factors, such as the farm and diet, had a larger impact on the gut microbiota composition than the category of the pig. We also found reduced concentrations of SCFA in the faeces of biter pigs as well as reduced plasma SCFA concentrations in the victim pigs. This study provides further evidence for the role of the gut microbiota composition and diversity, and now also for the role of SCFA, in tail biting in pigs. Future studies need to confirm these associations and determine the potential causality.
The datasets generated and analysed for the current study are available in the Open Science Framework repository (https://osf.io/j5g9q/).
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The authors would like to thank Rikard Fristedt for assistance with the plasma SCFA analysis and Jorge André for assistance with the faecal SCFA analysis.
Open access funding provided by Swedish University of Agricultural Sciences. This study was funded by the Swedish research council FORMAS, project number: DNR 942-2015-630. The funders did not have any influence on the experimental design, data analysis, interpretation of the results and the decision to publish.
The authors declare no competing interests.
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Verbeek, E., Keeling, L., Landberg, R. et al. The gut microbiota and microbial metabolites are associated with tail biting in pigs. Sci Rep 11, 20547 (2021). https://doi.org/10.1038/s41598-021-99741-8
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Item: "Sarah's Mask", part of Focus on Women, 1977-1979
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Title: "Sarah's Mask", part of Focus on Women, 1977-1979
Description: Sarah's Mask *Steel *14", from ritual Tale Sarah and Hagar, sculpture and ritual by Suzanne Benton.
Physical Description: Photo print - Black and White
Keywords: focus on women, suzanne benton, sculpture,
Photograph ID: parc-001016

domain: artistic


text:
ATHENS — Greece became the latest European country on Thursday to impose further restrictions on unvaccinated citizens amid rising coronavirus cases and hospitalizations.
Starting Monday, those without a vaccine certificate will be barred from indoor venues such as cinemas, theaters and gyms. They were already not allowed inside restaurants, bars and cafes. Unvaccinated people will still be able to enter certain essential indoor stores, such as pharmacies and supermarkets, as well as attend church, despite the Church of Greece suggesting negative test results be required for entry.
Greek Prime Minister Kyriakos Mitsotakis said in a televised address announcing the new rules that his plan was for the country “to have a better Christmas this year than last year” and urged Greeks to “vaccinate, vaccinate, vaccinate.”

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Background: Andexanet alfa, a modified recombinant factor Xa (FXa), was FDA approved in 2018 for anticoagulant reversal in patients with life-threatening bleeding associated with FXa inhibitors (FXaI). The ANNEXA-4 investigators administered andexanet alfa to patients within an 18-h from last dose of oral FXaI. In practice, time from last dose is often unknown. Previous studies have shown that clearance of these agents may be impaired by renal and hepatic dysfunction, as well as drug-drug interactions. Decision for use of andexanet alfa is also complicated by its high cost, limited drug availability, and thrombotic risk. This study aimed to describe the utility of anti-Xa DOAC levels as a decision point to administer andexanet alfa. Methods: This is a case series of four patients with an anti-Xa DOAC level that received andexanet alfa for oral FXaI reversal in the setting of life-threatening bleeding or prior to procedure. Results: Four patients were included in the study. Two patients had a known time since last dose of oral FXaI. All patients had a detectable anti-Xa DOAC levels prior to administration of andexanet alfa. Two patients had levels within the peak range, one patient had a level below the peak range, and one patient had a level above the peak range. Andexanet alfa was administered after anti-Xa DOAC level return in all patients. Conclusion: In our case series, obtaining anti-Xa DOAC levels prior to administration of andexanet alfa was achievable and facilitated use of reversal agents in patients with major bleeding or emergent procedural need.
|Idioma original||English (US)|
|Número de páginas||5|
|Publicación||Journal of Thrombosis and Thrombolysis|
|Estado||Published - ene 2022|
|Publicado de forma externa||Sí|
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine

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Living the Post-Modern Hamlet
Written by Triptayan Chatterjee
[dropcap]L[/dropcap]ife is not a Shakespearian gathering of players on a stage. It’s actually a curvilinear activity of mind and body. It is the stream of consciousness. Momentary actions of the subconscious mind. And this sub-conscious mind can only narrate the definition of cinema.
To speak out for the universal life, there is the only way in cinema; traditionally we call it film language. But in the era of Postmodernism if we call it cinema language, then it gets an astounding height and covers the real meaning of cinematic creation. The world has seen so many historical phases and subphases of cinema.
Sometimes, to make a non-linear presentation, cinemas are ending with some isolated shots and images, which is not bringing any compact message at the end. Film language is thought with the theme, woven with the images and shots, framed with many abstract sentences and lastly, it makes a thing which is called a perfect universal cinema. Film language is the heartbeat of all good and creative cinemas irrespective of all definitions, all genres and all cultures. It is an inevitable tool for the postmodernism.
Just like a sentence formed with some words.
Lines are made with innumerable points. But in fact, no straight line can be drawn on earth, because any part of the world is an oblate spheroid. This is the shape of our earth, so any line drawn is always a curve and the idea of a straight line is imaginary. And the natural law in every sector of life, living or non-living is universal. Hence life is like a curve. Postmodern films have to develop a certain film language according to their needs.
A postmodernist film is formed with some shots and each shot contains some images. Every image has a micro-theme which leads to the greater theme manifested in the entire film. In some cases, a traditional postmodern creator takes the help of dialogues and those dialogues are compensated by subtitles for the viewers who have not any knowledge of the language of these dialogues. But the more dialogue there is, the more subtitle is needed, which compels viewers to use both their brain and eyes. One is for translating the subtitles and another one is for continuously running successive shots and images in the film. This can be horribly harmful for post-modern cinema. Sometimes the lack of maintaining variance of these two layers can confuse the viewer. Here comes the relevance of the film language which avoids dialogues as much as it can and speaks out with the shots and images only in abstract words and sentences. All these will come through appropriate pacing. Actually, making postmodern films is not the presentation of the stream of consciousness as it is, it is the presentation of this stream of consciousness in a routine manner which can actually make a good film.
There is no alternative for a postmodern creation in our times.
A particular shot of a postmodern film can be described by image sequence, by dialogues or by the film language. Actually, it can only narrate the events of the film without words or dialogues but can’t explain the critical issues. It can make the viewer realize the events to some extent. A linear or non-linear storyline can be expressed by simple image sequences. And even sometimes this storyline can be explained by dialogues. But our individual, social and other aspects of life are so critical which stands helpless before the image sequence only.
“Camera is ready to take a shot!
Let us go with a filming of William Wordsworth’s classical poem ‘Solitary Reaper.’ In the first stanza there is
‘Behold her single in the field
Yon solitary highland lass.
Reaping and singing by herself
Stop here or gently pass.”’
We can make it with image sequence simply by shooting a highland girl reaping and singing and a few dialogues between two characters, one asking another to be silent or to gently pass. It’s a simple image sequence which will explain the lines of the poem. But when we look at the last lines of the poem and when we see there is ‘The music in my heart I bore/Long after it was heard no more’, then what image sequence will we form there? Actually, no simple image sequence can explain this theme. Here we must swim across the film language. And the best way and only possible way of explaining this theme, this feeling is symbolization. Allegorical symbolization can make the theme succeed.
The complex moments, the inner conflicts of individual, conflicts among different theme flows of the storyline must be explained using the film language to make the cinema comprehensible. But unfortunately, in many cases, special effects and editing capabilities are being used to explain the abstract themes. Here, technology is being dominant over human creation. We can’t deny editing and special effects, but art is something created by human beings and we should keep it in mind when it comes to postmodern cinema.
We are now swimming across the postmodern era of cinema. Looking back to the modern era of cinema it comes before our eyes a term called ‘DETAIL’. In cinematic language, this ‘DETAIL’ is one part of the film language. The ‘DETAIL’ was used particularly in narrative films, especially in narrative features. In the postmodern era there are diversified ways of thoughts, expressions, themes and presentation. Sometimes other branches of art like painting, architecture, literature are also being entangled with the cinema. At the highest level, it is being defined as an experimental film. In this paradigm, the postmodern film is discovering and somehow inventing the different language. In today’s films, postmodern language can be theatrical lexicology, can be a trigonometric formula, can be an atomic structure and can also be the universe made with innumerable galaxies.
A postmodern film which has decided to abide by this formula will make, for instance, three characters basically balanced with each other and give an output of a certain totality. An incident will have to pass along the film where the characters will play. But when a particular character is loosened in the script, other two will have to balance it to maintain this totality which is represented by the triangle. A sense of this triangle, a flavor of this geometric formula will have to show in different situation of the film. The theme, plots, characters, events, shots and images will have to go according to the different steps of this geometrical formula. A postmodern film can succeed then.
TAKE will go on.
The earth is still moving around the sun. Global warming, tectonic plates, celestial bodies are taking new dimensions. All these are leaving strong impressions in our conscious and subconscious mind. New feelings are being born along with their complex theory of existence. In this arena, we have ‘miles to go before we sleep.’ We must make serious, meaningful and impressive postmodern cinema.
Triptayan is a filmmaker looking for a different horizon. Earlier a journalist Triptayan has done intensive research on film language and made different documentaries so far. He is now concentrating upon feature film in a vast landscape. Professionally a teacher, Triptayan has also passion for making films threaded with the international and universal thoughts.


[SOCCER ON THE AIR]
The NSCAA is providing high school soccer teams the opportunity to be featured on the NSCAA's digital channel, NSCAATV.
is teaming up with the National Federation of State High School Associations (NFHS) and branding the show "The NFHS Network Game of the Week on NSCAA." High schools that have a production crew in
place can submit an application
to have a featured game streamed live this spring on NSCAATV.
week, NSCAATV will feature one boys or girls game. Considerations for selection as the Game of the Week include compelling games (nationally ranked teams, big rivalries, unique athlete stories),
enthusiastic fan bases (especially for the home team) and special event games (homecoming, opening game, student promotion event).


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Twenty-five per cent of the crew members running Indian Railways are not picked according to rules, says official data, prompting the transport behemoth to direct railway zones to adhere to norms.
The zones have to choose their crew from the Crew Management System (CMS) of Railways, which has a database of 89,000 members and provides information about their status and availability for train operations, be it freight or passenger.
The Railway Board in a directive said that while on an average, 75 per cent of the crew are chosen by zones according to rule, it was still below satisfactory levels. In the letter, the board has "expressed concern" that train drivers, assistant drivers, guards who form the core team responsible for train operations are not selected by zones according to rules mandated by the public transporter.
The CMS system provides two options for choosing crew members — the 'fetch crew as per rule' option and the 'fetch all' option.
Under the 'as per rule' option, zones are expected to select crew who meet certain criteria — those who are not due for a periodical medical examination (PME), or due for transport refresher, are fit for the section, have competency to work loco and are rested.
For the 'fetch all' option, the crew needs to meet just two parameters — they should not be due for medical examination and should have completed a transport refresher.
"The board feels that any crew member who is part of Railway operations be it freight or coaching should be in optimum condition, both health wise and in expertise.
"So, he should tick all the boxes under the 'fetch as per rule' option. With safety of passengers being priority, the board feels that this cannot be compromised with," a senior official said.
While on an average 75 per cent of such crew members have been picked under the 'fetch crew as per rule' option in 2017 across zones, the average has fallen in certain zones like South Eastern Railway, which has chosen only 56 per cent under the rule, East Coast Railway, 61 per cent and Central Railways only 66 per cent.
This, the board has said, is 'below satisfactory'.
However, compared to last year, the zones have in fact shown improvement in choosing crew as per rule.
A report of CMS for the period 1 January 2016 to 30 June 2016 has shown that South Eastern Railway has picked a mere 4.49 per cent crew as per rule, in Eastern Railway it was 5.25 per cent and in Southern Railway it was only 7.45 per cent.
"Board desires that zonal railways shall make all efforts to book crew as per rule in the CMS," the letter sent out last month has said.
Introducing ElectionsHQ + 50 Ground Reports Project
The 2024 elections might seem easy to guess, but there are some important questions that shouldn't be missed.
Do freebies still sway voters? Do people prioritise infrastructure when voting? How will Punjab vote?
The answers to these questions provide great insights into where we, as a country, are headed in the years to come.
Swarajya is starting a project with an aim to do 50 solid ground stories and a smart commentary service on WhatsApp, a one-of-a-kind. We'd love your support during this election season.
Click below to contribute.


Request for Proposals: Branding and Marketing Project
March 15, 2024
REQUEST FOR PROPOSALS
BRANDING AND MARKETING PROJECT
The City of Ishpeming invites qualified branding and marketing firms to submit proposals for the development of a compelling and authentic community brand. This project aims to enhance the city’s visibility, credibility, and market presence through a comprehensive branding and marketing strategy.
Pre-Submission Conference & FAQS
The City will hold a virtual pre-submission conference for interested bidders on March 27, 2024 at 1PM. Attendance is highly encouraged, but not required. To receive a link to the meeting, RSVP at https://bit.ly/IshpemingRFP.
Written questions may be submitted at email@example.com using the Subject: “Marketing Proposal Questions” until March 30, 2024, 1PM. The City will provide written answers to all questions within 72 hours.
Final Proposals Due
Proposals must be received at Ishpeming City Hall not later than April 9, 2024 at 5PM
Click the link below to view the full Request for Proposals (RFP):


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Sure, you want to put up some of your harvest so you can enjoy it all winter long. But you don’t want to spend the last of the summer indoors, laboring in the kitchen. The solution? Freeze and dry your bounty. Both methods are easier (and cooler) than canning. Here’s the scoop, crop by crop.
Before freezing, remove the tomato skins. Immerse your fresh tomatoes in boiling water until the skins crack, then plunge the fruits into very cold water for another minute. Take them out, peel off the skin, and pack them whole or quartered in plastic freezer containers.
A faster method is to freeze whole, unpeeled tomatoes. When you’re ready to use them, put the frozen bag under hot water briefly, until you can remove the tomatoes. Then stick the tomatoes under the hot water for a few more seconds to loosen the skin, which will easily peel off.
Dehydration removes all that messy water and leaves you with pure tomato flavor. And almost any kind of tomato—even cherry types—dries into a sweet, chewy chip. Some people say that meaty paste tomatoes work best for drying, but others prefer to dry the big, sweet beefsteak types.
Cut slices about 1⁄2 inch thick (cut cherry tomatoes in half) and set the slices on the dehydrator trays. Don’t let the pieces touch. Most machines will dry them in about 4 hours, but many people let them go overnight (they’re done when the pieces are leathery and flat). You can store them in tightly lidded jars or put them in bags in the freezer. After drying, a bushel of tomatoes takes up very little space. (To keep the dehydrator from heating up your house, run it outdoors in a sheltered area.)
To get a taste of summer sweetness in the middle of winter, freeze some of your corn. First, blanch the ears by boiling them for 3 to 4 minutes. Plunge the blanched ears into cold water. After the ears have cooled, scrape the kernels off the cob. Put meal-size portions of the cut kernels into plastic freezer bags. You can eat the corn lightly steamed, right out of the freezer (don't defrost it before cooking it). If you prefer your winter corn on the cob, blanch the fresh ears for 6 minutes, then freeze the whole ears. When you're ready to serve them, just steam the frozen ears for another 6 minutes.

domain: hobby


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ROMAINE AND STRAWBERRY SALAD WITH POPPY SEED DRESSING
2 heads romaine lettuce, chopped
1 Red onion, julienned
2 pints strawberries, sliced
½ cup milk
1 cup mayonnaise
⅔ cup sugar
4 teaspoon Poppy seeds
4 teaspoon Cider vinegar
Optional – add grilled chicken breast for a main dish salad
Mix salad ingredients in a large bowl. Put all dressing ingredients into a large jar, cover, and shake until thoroughly mixed. Pour over salad and serve.
Also great with candied pecans or walnuts (just toast nuts with brown sugar in small frying pan until brown sugar melts on nuts).

domain: food


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by means of Lena | Literature Department
Last summer I read Nora, of brand Oslo brand! (not yet translated into English) by the Swedish first-time novelist Johanna Frid. The novel tells the story of a woman attempting to overcome pathological jealousy towards the ex-girlfriend of her lover and endometriosis, a painful condition that affects the pelvic organs. Frid devotes an entire chapter to Megan Nolan's essay Watch me in which she recognized herself in sentences such as: ‘I tried to be open to what love might feel like when I knew I was not the prettiest person he had touched’. Equally mesmerized by Nolan's candor as Frid was, I have been anticipating her debut ever since. Once it arrived, it came as no surprise that jealousy plays an equally important role as it did in its Swedish counterpart. But, as the plot progresses, Acts of Desperation also shows what happens when obsession is replaced by boredom and longing by restlessness in a long-term toxic relationship.
Some reviewers have placed Nolan in the so-called Irish Avant-Garde alongside Naoise Dolan (Exciting Times) and Sally Rooney (Normal People, Conversations with Friends and her upcoming novel Beautiful World, Where Are You). In my opinion, this grouping is a little too short-sighted. Whereas all these women write about millennial-love, Nolan distinguishes herself by not only taking into account the parts of early adulthood one wishes to remember but also examening those one longs to forget. Acts of Desperation is a book for the lovers of Karl Ove Knausgård (who highly recommends it!), the HBO series Girls and, (for the Dutch readers) it is akin to the novels of Jan Cremer with a (much needed) feminist touch.

domain: entertainment


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Despite a 20% drop in mortality since 2009, colorectal cancer accounted for 9.8% (881,000) of deaths worldwide in 2018 and represents 10.2% of all cancer cases worldwide. It is No. 3 on the list of most prevalent cancers worldwide—1.8 million new cases in 2018—behind only lung cancer and breast cancer.
Despite a 20% drop in mortality since 2009, colorectal cancer (CRC) accounted for 9.8% (881,000) of deaths worldwide in 2018 and represents 10.2% of all cancer cases worldwide. It is No. 3 on the list of most prevalent cancers worldwide—1.8 million new cases in 2018—behind only lung cancer and breast cancer.
CRC tumors are heterogeneous in both their inter- and intratumor characteristics due to chromosomal instability (CIN), microsatellite instability (MSI), aberrant DNA methylation, and DNA repair defects. These same things, however, dictate how patients respond to therapy. Therefore, using biomarkers for early detection, diagnosis, and staging make up the ideal clinical strategy that leads to disease recovery.
A group of researchers from the University of Naples Federico II, in a recent issue of the journal, Cancers, reviewed molecular biomarkers from tumor tissue and liquid biopsy currently being used in CRC, that help to decide on the appropriate therapy for patients. We discuss several of these below.
In confirmed cases of hereditary nonpolyposis CRC (also known as Lynch syndrome), mutations in the MMR gene are used to make treatment decisions. Tumors that are MSI high typically mean better outcomes and higher rates of survival compared with tumors that are MSI low or stable; however, this particular mutation also doesn’t respond as well to 5-Flurouracil (5-FU)-based chemotherapy compared with the same.
With familial adenomatous polyposis, tumors that feature the CIN phenotype and APC gene mutations are markers of a poor prognosis, but they do help to identify high-risk patients with stage II disease who could benefit from adjuvant chemotherapy.
Variants in the GREM1 and BRAF genes, meanwhile, predispose individuals to hereditary mixed polyposis, with tumors that feature BRAF and KRAS mutations along with MSI. KRAS mutations are markers of a poor prognosis, but they also help indicate patients who might not respond to anti-EGFR therapy.
Lastly, the 4 consensus molecular subtypes (CMS) of CRC identified by the CRC Subtyping Consortium—CMS1, CMS2, CMS3, and CMS4—are used to identify patients with poor progression-free survival (PFS) (CMS1 and CMS2), better PFS and overall survival (CMS4), and good response to 5-FU treatment (CMS1, CMS2, and CMS3).
“All of these mechanisms confer specific features to each tumor in terms of malignancy, aggressiveness, invasion, and response to therapy,” the study authors stated. “Consequently, the identification and standardization of cancer prognostic and predictive molecular biomarkers is becoming increasingly more relevant.”
Turano M, Delrio P, Rega D, et al. Promising colorectal cancer biomarkers for precision prevention and oncology. Cancers. 2019;11(12):1932-1951.


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Actor Amy Schumer is in negotiations to feature in the biopic of champion boxer Christy Martin.
The 36-year-old actor is in talks to star in the drama written and directed by Katherine Fugate, Deadline reported.
Based on the real-life story of the world champion boxer of the same name, the film will follow Martin who had to fight to achieve success in the man’s world and later ended up fighting for her life.
Martin, who now goes by the name Christy Salters, grew up in West Virginia earning the nickname in the boxing world of The Coalminer’s Daughter after she won a boxing competition.
By 1990, she was in the boxing ring pushing the glass ceiling for women to be allowed to box.
The film will be produced by Alix Madigan, Nicolas Chartier and Alissa Phillips. Jonathan Deckter will serve as executive producer.


And if something designs, don’t hesitate to ask, we love new challenges who make us better. Usage To add the ‘Add to Cart’ button on you theme’s template files, use . Replace PRODUCT-NAME and PRODUCT-PRICE with the actual name and price. To display the numbers of items in cart use . The string display are set in the plugin’s settings. To add the ‘Add to Cart’ button simply add the trigger text [wp_cart:PRODUCT-NAME:price:PRODUCT-PRICE:end] to a post or page next to the product. Replace PRODUCT-NAME and PRODUCT-PRICE with the actual name and price. To add the ‘Add to Cart’ button on the sidebar use the widget. To add the ‘Add to Cart’ button on you theme’s template files, use the following function: . Replace PRODUCT-NAME and PRODUCT-PRICE with the actual name and price. You can use price and shipping variation too.
s2Member's Stripe Pro-Forms integrate seamlessly with WordPress Shortcodes. This allows you to keep customers on your site at all times, and it consolidates registration/checkout into a single step. Since checkout occurs on your site, you can dress up the Post/Page containing your Pro-Form in ways that are most effective for your product/service. .
Is it possible that REQUIRING a shipping address is NOT possible with a “donate” button?
All products available on WPspring.com are purchased directly from the original developers and distributed without alteration.
You can access all your Plugin lists by going to your profile and clicking the "Lists" tab.
1. First Download "ui-for-wp-simple-paypal-shopping-cart.zip" Plugin to your Local Computer. (Click Download)
Yes! Thanks for getting back to me. I really hope this plugin will work for me.
The building of the tool takes place within the Elfsight website and you don’t need to code. Apply our active demo to personalize your personal widget, acquire the code and implement it in your site.
WooCommerce is undoubtedly the most popular choice to create an online shop on the WordPress platform. It is also the most widely used e-commerce plugin, and numerous themes support it.
For online shoppers, a handy and safe way to pay means a lot. Construct your button for PayPal using Elfsight and you will install a reliable and prompt payment procedure for your clients. No coding, no sweat.
Yes, I already enabled now the debug. Btw, do you have a testing paypal account? Because that was my boss paypal account. I don’t want to bother him that the first thing we test are not successful.
Regarding the button image, it sounds like a theme CSS issue. What happens if you temporarily switch to a default WordPress theme (e.g. Twenty Twenty)?
For selling digital goods and products, this plugin is definitely worth a go. It advertises a very streamlined experience with some very useful features, and it gets rid of all the unnecessary features that WooCommerce incorporates for selling digital goods. Plus, you can accept payments via Stripe with this plugin.
Be the first to get notified with all the latest updates of New Wordpress Themes and Plugins. Subscribe now for all Wordpress Updates
Catalin did a great job at recommending the right ecommerce platform and kickstarting our marketing.
Monetize your website with Jetpack ads to make money and sell products or accept donations with Jetpack Payments button. 7 Best WordPress shopping cart plugins to Build an eCommerce Website in 2020
Starting off our list, we have the WordPress Simple PayPal Shopping Cart plugin. The plugin will help you embed an “Add to Cart” button on your posts or pages using shortcodes. Inside the shopping cart, users will be able to see what items they have selected, and can also change the quantity or remove items altogether.


Yes, my fellow X79 friends, the day is finally upon us. As of yesterday, Intel released new RSTe drivers
that bring TRIM to RAID 0/1 SSD configs (let Win 7/8 TRIM commands pass through the Intel C600 chipset storage controller)! Best of all, no OROM update (and accompanying BIOS flashes) required! At least I didn't for my ASRock X79.
I verified with this TRIM check tool
. With the old RSTe drivers, the tool indicated that TRIM was not working on my RAID 0 array. After installing the new drivers and a reboot, it indicated that it was.
As they say, better late than never... Anyway, I bet the 3 other people that use SSD RAID on X79 that read TR will be interested in this.
Thanks to this forum post
for the heads up.


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|Best price found||£851||The best flight deal from Santiago to Bristol found on momondo in the last 72 hours is £851|
|Fastest flight time||19h 40m||The fastest flight from Santiago to Bristol takes 19h 40m|
|Direct flights||None||There are no direct flights from Santiago to Bristol. Popular non-direct route for this connection is Santiago Arturo Merino Benitez Airport - Bristol Airport.|
|Airports in Bristol||1 airport||There is 1 airport near Bristol: Bristol (BRS)|
The cheapest time of year to fly to Bristol from Santiago is June. The most expensive is January.
Santiago Arturo Merino Benitez - Bristol
Fly from Santiago Arturo Merino Benitez to Bristol for the best Santiago - Bristol flight prices
The straight-line distance from Santiago Arturo Merino Benitez to Bristol is 7159.9 mi. In terms of flight time, this usually takes a little over 18h 30m.

domain: travel


Wedding bells are ringing for this pair of puppies. This gift would be the perfect gift for any newly weds or as an anniversary present.
This lovely music box is powered by hand. Once turning the crank, you will hear the melodious music.
The tune is Wedding March.
Personalization is available (a short phrase, and/or name written on the back of the music box).
There is only 1 in stock; each music box is unique as they are hand crafted individually.
Please feel free to message me for further inquires or requests!
Approximately W95 mm x D95 mm x H130 mm. Dimensions may vary slightly as every item is uniquely made in the perspective of the artist.
Hand made in Canada
Wholesale and trade prices are available. Contact mailto:email@example.com for more information.
Custom dimensions are available. Please contact firstname.lastname@example.org for more information.


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It's your chance to dress-up the new sensational singer of the animal kingdom, Justin Beaver! Listen to his fantastic music while you dress him for his upcoming live performance!
There are dozens of clothes and accessories to dress him up in different outfits for his live performances!
Bonus items are unlocked if you purchase other dress up games!
4 - shades of fur for your desired complexion
4 - different expressions for each types of songs
20 - clothes, shoes and caps to mix-match and wear for performances
15 - accessories to magnify stage coolness
3 - colors of spotlights to bathe on


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A wind advisory is in place for portions of Oklahoma, Central Texas, and extends all the way out to the SE Texas coast for Saturday as winds are expected to gust as high as 45 mph. The western end of the state has been experiencing dry conditions, which will aid in a fire threat when gusty winds are added into the forecast.
Red Flag warnings and a Fire weather watch has been issued. Temperatures in locations such as midland and Odessa will climb to near 20 degrees above normal, with relative humidity as low as 12%. These conditions will quickly spread any wildfire that forms.
Closer to home we will have significant coastal impacts due to these strong winds. From Friday night – Saturday morning a Gale warning is issued to warn boaters on possible life threatening conditions if not careful. High seas and reduced visibility will be a result of the passing front. Winds will exceed 45 knots. These conditions will pose the threat for small vessels to capsize. Best to remain docked for the start of the weekend.
Temperatures will start to drop behind the passing of the cold front on Saturday morning. Winds will shift to out of the northwest near 40 mph in Houston Saturday morning. Our wind chill factor will become increasingly relevant throughout the evening and especially the start of Sunday… just in time for the Houston Marathon.
As runners are lacing up their shoes and prepping to hit the pavement, our feels-like temperatures will be dropping to below freezing! Mid-20s expected for the north side of town. You will need to bundle up for those first few miles. Winds calm down throughout Sunday morning, back to a comfortable 10 mph by lunch.


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Description & More Info
Houston, we have a problem…we're not sure we can handle just how cool this T-Shirt is! Two icons of intergalactic greatness come together on Chunk's out-of-this-world Star Wars tee. Perfect for those looking for a real unique parody tee.
- Men's Grey Marl We Have A Problem AT-AT Star Wars T-Shirt from Chunk
- Screen printed for a high quality finish
- Made from 100% cotton single jersey
- Carbon brushed and treated to a silicone wash for a super-soft, authentic vintage look and feel
- Please check our custom size guide for your perfect fit
Verified PurchaseJulie from West Midlands - 4th Jan 2020
Review: Great quality, washed well
Verified PurchaseAnonymous TruffleShuffle Purchaser - 1st Dec 2019
Review: Good quality. I'm sure brother in law will love it
Verified PurchaseAnonymous TruffleShuffle Purchaser - 23rd Oct 2019
Review: Perfect for the geek in my life!


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Melanoma, the most aggressive form of skin cancer, kills about 9,000 Americans every year. The five year survival of patients with melanoma is just 15%. In the United States, more than 70,000 people are diagnosed with the disease each year, and there are over 800,000 people living with the disease according to the American Cancer Society. The traditional treatment of melanoma is with the chemotherapeutic drug dacarbazine, which usually results in a median survival of 6-8 months. Two recent advances in the treatment of melanoma were announced in Chicago on June 5, 2011 at the annual meeting of the American Society of Clinical Oncology. The results were also published simultaneously online in the New England Journal of Medicine. Researchers have shown that two new drugs can significantly improve survival of patients with metastatic melanoma. In the first study, lead by Dr. Paul Chapman of Memorial Sloan Kettering Cancer Center in New York City, investigators conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma. About 50% of melanomas have a mutation in the BRAF protein kinase, which is known as BRAF V600E. Vemurafenib targets this mutation and inhibits its cancer causing potential. The study participants were randomly assigned to receive either vemurafenib or dacarbazine. At the six month time point, overall survival was 84% in the vemurafenib group compared to only 64% in the dacarbazine group. In addition, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine. The results were so remarkable that an independent data and safety monitoring board recommended stopping the study early and providing vemurafenib to the study participants taking dacarbazine. In the second study, lead by Dr. Jedd Wolchok of Memorial Sloan Kettering Cancer Center in New York City, investigators conducted a phase 3 randomized clinical trial of ipilimumab plus dacarbazine in patients with previously untreated metastatic melanoma. Ipilimumab (Yervoy) is a human antibody that binds to and blocks the activity of CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), and thus causes a sustained and active immune response against cancer cells. The investigators randomly assigned 502 patients with previously untreated metastatic melanoma to receive ipilimumab plus dacarbazine or dacarbazine plus placebo. The group receiving ipilimumab plus dacarbazine had significantly greater overall survival compared to the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months). These are very remarkable and exciting advances for the field of melanoma cancer treatment, which has not seen improvements in more than 30 years. Ipilimumab has already received approval from the Food and Drug Administration, and approval for vemurafenib is expected later this year. The pharmaceutical companies who manufacture vemurafenib and ipilimumab, Roche and Bristol-Myers Squibb respectively, have announced that they will be working on a collaborative study to evaluate the benefits of using both drugs together as a treatment for metastatic melanoma. These are truly exciting times for both melanoma patients and cancer researchers.
See the YouTube video entitled “Advances in the Treatment of Melanoma” released by mskcc.org below:


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30-day free trial
Let's play hangman or maybe even take a quiz! Just with a click of your mouse!
My Quia activities and quizzes
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Get Set Go!!!!: session get set go!!!
a cool study sight for everything!!
a fun place JUST for Girls
love those manatees then just click here!!
2008/09/28 10:20:09 PDT


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The nutrients that make up B complex are thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3) pantothenic corrosive (vitamin B5) pyridoxine vitamin B6, biotin, flic corrosive and the cobalamins (vitamin B12)
The vast majority of the B nutrients are found in a wide scope of food sources since they are so essential to cell work. Some similar to vitamin B12, are observed generally in meet and other created food sources.
Vitamin B Nutrients
The B nutrients assist chemicals in our bodies with going about their responsibilities and are significant for a wide scope of cell capacities, such as separating carbs and shipping supplements all through the body. Likewise, B complex can give medical advantages like. Solid Brain Function The B nutrients assume a between related part in keeping our cerebrums running appropriately.
Sufficient measures of B nutrients in the body are fundamental for ideal physiological and neurological working. Sums and Dosage The suggested day by stipend (RDA) of B Complex nutrients shifts by age. orientation, and condition. Really look at supplements plans with your PCP ensure the does in them are suitable for you.
You can likewise observe B complex nutrients in an assortment of food sources, including oat grains, meat, poultry, eggs, fish, milk, vegetables, and new vegetables.
Vitamin B Food Sources
Salmon This inside and out nutrients dish is high in a few B nutrients. A 3.5-ounce (100-gram) cooked serving of salmon contains (3):
Eggs One enormous egg contains 33% of the RDI for biotin conveyed between the yolk and white. Indeed, eggs are one of the top wellsprings of biotin – just liver contains more.
Chicken and Turkey are generally prominent for their nicen and pyridoxine content White meat – like the bosom – supplies a greater amount of these two nutrients than dull meat – like the thigh – as displayed in the table underneath.
Wholesome and Brewer’s Yeast Wholesome yeast and brewer’s yeast are inert, meaning you can’t utilize them to make bread. Rather, individuals use them to help flavor and supplements profile of shies. These yeasts normally contain B nutrients and are regularly strengthened with them also – especially healthful yeast. Assuming supplement’s are added, you’ll see them recorded in the fixings on the name.


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When educators are placed in challenging situations without the necessary supports (e.g., information, expectations, strategies, etc.), the experiences can be less than optimal for both the educator and the student. Individuals with autism spectrum disorder often require specific consideration in the classroom. This workshop is designed to familiarize educators and support staff with what these considerations might look like and how best to support these students.
This workshop covers the following areas:
- The AODA and its implications in the school environment;
- Autism spectrum disorder including characteristics, deficits, and strengths;
- Teaching implications of various characteristics of students with autism spectrum disorder;
- Approaches and strategies for working with students with autism spectrum disorder; and
- Applied behavioural analysis overview, components, and strategies.

domain: psychology