Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients

Letter processing and font information during reading: beyond distinctiveness, where vision meets design

Letter identification is a critical front end of the reading process. In general, conceptualizations of the identification process have emphasized arbitrary sets of distinctive features. However, a richer view of letter processing incorporates principles from the field of type design, including an emphasis on uniformities across letters within a font. The importance of uniformities is supported by a small body of research indicating that consistency of font increases letter identification efficiency. We review design concepts and the relevant literature, with the goal of stimulating further thinking about letter processing during reading

Movement asymmetries in horses presented for prepurchase or lameness examination

Background The increasing popularity of objective gait analysis makes application in prepurchase examinations (PPE) a logical next step. Therefore, there is a need to have more understanding of asymmetry during a PPE in horses described on clinical evaluation as subtly lame.Objectives The objective of this study is to objectively compare asymmetry in horses raising minor vet concerns in a PPE and in horses raising major vet concerns with that found in horses presented with subtle single-limb lameness, and to investigate the effect of age/discipline on the clinicians' interpretation of asymmetry on the classification of minor vet concerns in a PPE.Study Design Clinical case-series.Methods Horses presented for PPE (n = 98) or subjectively evaluated as single limb low-grade (1-2/5) lame (n = 24, 13 forelimb lame, 11 hindlimb lame), from the patient population of a single clinic, were enrolled in the study provided that owners were willing to participate. Horses undergoing PPE were assigned a classification of having minor vet concerns (n = 84) or major vet concerns (n = 14) based on findings during the dynamic-orthopaedic part of the PPE. Lame horses were only included if pain-related lameness was confirmed by an objective improvement after diagnostic analgesia exceeding daily variation determined for equine symmetry parameters using optical motion capture. Clinical evaluation was performed by six different clinicians, each with >= 8 years of equine orthopaedic experience. Vertical movement symmetry was measured using optical motion capture, simultaneously with the orthopaedic examination. Data were analysed using previously described parameters and mixed model analysis and least squares means were used to calculate differences between groups.Results There was no effect of age or discipline on the levels of asymmetry within PPE horses raising minor vet concerns. MinDiff and RUD of the head discriminated between forelimb lame and PPE horses raising minor vet concerns; MinDiff, MaxDiff, RUD of the Pelvis, HHDswing and HHDstance did so for hindlimb lameness. Two lameness patterns differentiated both forelimb and hindlimb lame from PPE horses with minor vet concerns: RUD Poll + MinDiff Withers - RUD Pelvis and RUD Pelvis + RUD Poll - MinDiff Withers. Correcting for vertical range of motion enabled differentiation of PPE horses with minor vet concerns from PPE horses with major vet concerns.Main Limitations Objective data only based on trot on soft surface, limited number of PPE horses with major vet concerns.Conclusions Combinations of kinematic parameters discriminate between PPE horses with minor vet concerns and subtly lame horses, though overlap exists

Transforming growth factor-β and breast cancer: Lessons learned from genetically altered mouse models

Transforming growth factor (TGF)-βs are plausible candidate tumor suppressors in the breast. They also have oncogenic activities under certain circumstances, however. Genetically altered mouse models provide powerful tools to analyze the complexities of TGF-βaction in the context of the whole animal. Overexpression of TGF-β can suppress tumorigenesis in the mammary gland, raising the possibility that use of pharmacologic agents to enhance TGF-β function locally might be an effective method for the chemoprevention of breast cancer. Conversely, loss of TGF-β response increases spontaneous and induced tumorigenesis in the mammary gland. This confirms that endogenous TGF-βs have tumor suppressor activity in the mammary gland, and suggests that the loss of TGF-β receptors seen in some human breast hyperplasias may play a causal role in tumor development

Development and initial validation of the Influences on Patient Safety Behaviours Questionnaire

YesBackground: Understanding the factors that make it more or less likely that healthcare practitioners (HCPs) will perform certain patient safety behaviors is important in developing effective intervention strategies. A questionnaire to identify determinants of HCP patient safety behaviors does not currently exist. This study reports the development and initial validation of the Influences on Patient Safety Behaviors Questionnaire (IPSBQ) based on the Theoretical Domains Framework. Methods: Two hundred and thirty-three HCPs from three acute National Health Service Hospital Trusts in the United Kingdom completed the 34-item measure focusing on one specific patient safety behavior (using pH as the first line method for checking the position of a nasogastric tube). Confirmatory factor analysis (CFA) was undertaken to generate the model of best fit. Results: The final questionnaire consisted of 11 factors and 23 items, and CFA produced a reasonable fit: χ2 (175) = 345.7, p < 0.001; CMIN/DF = 1.98; GFI = 0.90 and RMSEA = 0.06, as well as adequate levels of discriminant validity, and internal consistency (r = 0.21 to 0.64). Conclusions: A reliable and valid theoretically underpinned measure of determinants of HCP patient safety behavior has been developed. The criterion validity of the measure is still unknown and further work is necessary to confirm the reliability and validity of this measure for other patient safety behaviors

Coexistence of K-ras mutations and HPV infection in colon cancer

BACKGROUND: Activation of the ras genes or association with human papillomavirus infection have been extensively studied in colorectal cancer. However, the correlation between K-ras mutations and HPV in colorectal cancer has not been investigated yet. In this study we aimed to investigate the presence of K-ras mutations and their correlation with HPV infection in colon cancer. METHODS: K-ras mutations were analyzed by a mutagenic PCR assay and digestion with specific restriction enzymes to distinguish the wild-type and mutant codons. HPV infection was analyzed by PCR amplification and hybridization with specific probes by Southern blotting. Stattistical analyses were performed by the chi-square and Fisher's exact tests RESULTS: HPV gene fragments were detected in 43 tumors and 17 normal tissue samples. HPV 18 was the prevalent type in the tumor tissue. A mutation at codon 12 of the K-ras gene was present in 31 patients. 56% of the HPV-positive tumors also harbored a K-ras mutation. Codon 13 mutations were not observed. These data indicate that infection with high risk HPV types and mutational activation of the K-ras gene are frequent events in colorectal carcinogenesis. CONCLUSION: Our findings suggest that mutational activation of the K-ras gene is a common event in colon carcinogenesis and that HPV infection may represent an important factor in the development of the premalignant lesions leading to the neoplastic phenotype

Xnrs and Activin Regulate Distinct Genes during Xenopus Development: Activin Regulates Cell Division

BACKGROUND: The mesoderm of the amphibian embryo is formed through an inductive interaction in which vegetal cells of the blastula-staged embryo act on overlying equatorial cells. Candidate mesoderm-inducing factors include members of the transforming growth factor type β family such as Vg1, activin B, the nodal-related proteins and derrière. METHODOLOGY AND PRINCIPLE FINDINGS: Microarray analysis reveals different functions for activin B and the nodal-related proteins during early Xenopus development. Inhibition of nodal-related protein function causes the down-regulation of regionally expressed genes such as chordin, dickkopf and XSox17α/β, while genes that are mis-regulated in the absence of activin B tend to be more widely expressed and, interestingly, include several that are involved in cell cycle regulation. Consistent with the latter observation, cells of the involuting dorsal axial mesoderm, which normally undergo cell cycle arrest, continue to proliferate when the function of activin B is inhibited. CONCLUSIONS/SIGNIFICANCE: These observations reveal distinct functions for these two classes of the TGF-β family during early Xenopus development, and in doing so identify a new role for activin B during gastrulation

A guide to using the Theoretical Domains Framework of behaviour change to investigate implementation problems

Background: Implementing new practices requires changes in the behaviour of relevant actors, and this is facilitated by understanding of the determinants of current and desired behaviours. The Theoretical Domains Framework (TDF) was developed by a collaboration of behavioural scientists and implementation researchers who identified theories relevant to implementation and grouped constructs from these theories into domains. The collaboration aimed to provide a comprehensive, theory-informed approach to identify determinants of behaviour. The first version was published in 2005, and a subsequent version following a validation exercise was published in 2012. This guide offers practical guidance for those who wish to apply the TDF to assess implementation problems and support intervention design. It presents a brief rationale for using a theoretical approach to investigate and address implementation problems, summarises the TDF and its development, and describes how to apply the TDF to achieve implementation objectives. Examples from the implementation research literature are presented to illustrate relevant methods and practical considerations. Methods: Researchers from Canada, the UK and Australia attended a 3-day meeting in December 2012 to build an international collaboration among researchers and decision-makers interested in the advancing use of the TDF. The participants were experienced in using the TDF to assess implementation problems, design interventions, and/or understand change processes. This guide is an output of the meeting and also draws on the a uthors' collective experience. Examples from the implementation research literature judged by authors to be representative of specific applications of the TDF are included in this guide. Results: We explain and illustrate methods, with a focus on qualitative approaches, for selecting and specifying target behaviours key to implementation, selecting the study design, deciding the sampling strategy, developing study materials, collecting and analysing data, and reporting findings of TDF-based studies. Areas for development include methods for triangulating data, e.g. from interviews, questionnaires and observation and methods for designing interventions based on TDF-based problem analysis. Conclusions: We offer this guide to the implementation community to assist in the application of the TDF to achieve implementation objectives. Benefits of using the TDF include the provision of a theoretical basis for implementation studies, good coverage of potential reasons for slow diffusion of evidence into practice and a method for progressing from theory-based investigation to intervention

High Affinity Antibodies to Plasmodium falciparum Merozoite Antigens Are Associated with Protection from Malaria

Malaria kills almost 1 million people every year, but the mechanisms behind protective immunity against the disease are still largely unknown. In this study, surface plasmon resonance technology was used to evaluate the affinity (measured as k(d)) of naturally acquired antibodies to the Plasmodium falciparum antigens MSP2 and AMA1. Antibodies in serum samples from residents in endemic areas bound with higher affinities to AMA1 than to MSP2, and with higher affinities to the 3D7 allele of MSP2-3D7 than to the FC27 allele. The affinities against AMA1 and MSP2-3D7 increased with age, and were usually within similar range as the affinities for the monoclonal antibodies also examined in this study. The finding of MSP2-3D7 type parasites in the blood was associated with a tendency for higher affinity antibodies to both forms of MSP2 and AMA1, but this was significant only when analyzing antibodies against MSP2-FC27, and individuals infected with both allelic forms of MSP2 at the same time showed the highest affinities. Individuals with the highest antibody affinities for MSP2-3D7 at baseline had a prolonged time to clinical malaria during 40 weeks of follow-up, and among individuals who were parasite positive at baseline higher antibody affinities to all antigens were seen in the individuals that did not experience febrile malaria during follow up. This study contributes important information for understanding how immunity against malaria arises. The findings suggest that antibody affinity plays an important role in protection against disease, and differs between antigens. In light of this information, antibody affinity measurements would be a key assessment in future evaluation of malaria vaccine formulations