Background, & Aims Studies of primary biliary cirrhosis (PBC) phenotypes largely have been performed using small and selected populations. Study size has precluded investigation of important disease ...subgroups, such as men and young patients. We used a national patient cohort to obtain a better picture of PBC phenotypes. Methods We performed a cross-sectional study using the United Kingdom-PBC, patient cohort. Comprehensive data were collected for 2353 patients on diagnosis reports, response to therapy with ursodeoxycholic acid (UDCA), laboratory results, and symptom impact (assessed using the PBC-40 and other related measures). Results Seventy-nine percent of the patients reported current UDCA, therapy, with 80% meeting Paris response criteria. Men were significantly less likely to have responded to UDCA than women (72% vs 80% response rate; P < .05); male sex was an independent predictor of nonresponse on multivariate analysis. Age at diagnosis was associated strongly and independently with response to UDCA; response rates ranged from 90% among patients who presented with PBC when they were older than age 70, to less than 50% for those younger than age 30 ( P < .0001). Patients who presented at younger ages also were significantly more likely not to respond to UDCA therapy, based on alanine aminotransferase and aspartate aminotransferase response criteria, and more likely to report fatigue and pruritus. Women had mean fatigue scores 32% higher than men's ( P < .0001). The increase in fatigue severity in women was related strongly (r = 0.58; P < .0001) to higher levels of autonomic symptoms ( P < .0001). Conclusions Among patients with PBC, response to UDCA, treatment and symptoms are related to sex and age at presentation, with the lowest response rates and highest levels of symptoms in women presenting at younger than age 50. Increased severity of fatigue in women is related to increased autonomic symptoms, making dysautonomia a plausible therapeutic target.
Primary biliary cirrhosis (PBC) has a complex clinical phenotype, with debate about the extent and specificity of frequently described systemic symptoms such as fatigue. The aim of this study was to ...use a national patient cohort of 2,353 patients recruited from all clinical centers in the UK to explore the impact of disease on perceived life quality. Clinical data regarding diagnosis, therapy, and biochemical status were collected and have been reported previously. Detailed symptom phenotyping using recognized and validated symptom assessment tools including the PBC‐40 was also undertaken and is reported here. Perception of poor quality of life and impaired health status was common in PBC patients (35% and 46%, respectively) and more common than in an age‐matched and sex‐matched community control group (6% and 15%, P < 0.0001 for both). Fatigue and symptoms of social dysfunction were associated with impaired perceived quality of life using multivariate analysis. Fatigue was the symptom with the greatest impact. Depression was a significant factor, but appeared to be a manifestation of complex symptom burden rather than a primary event. Fatigue had its greatest impact on perceived quality of life when accompanied by symptoms of social dysfunction, suggesting that maintenance of social networks is critical for minimizing the impact of fatigue. Conclusion: The symptom burden in PBC, which is unrelated to disease severity or ursodeoxycholic acid response, is significant and complex and results in significant quality of life deficit. The complexity of symptom burden, and its lack of relation to disease severity and treatment response, suggest that specific approaches to symptom management are warranted that address both symptom biology and social impact. (Hepatology 2013;58:‐)
In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we ...carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10⁻⁸) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.
We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 ...loci newly associated with PBC (at P<5×10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r2>0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2>0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.
Purpose
To describe a surgical technique for posterior cerebral revascularization in pediatric patients with moyamoya arteriopathy. Here, we describe the clinical characteristics, surgical ...indications, operative techniques, and clinical and radiographic outcomes in a series of pediatric patients with moyamoya disease affecting the posterior cerebral artery (PCA) territory.
Methods
A retrospective single-center series of all pediatric patients with moyamoya disease who presented to our institute between July 2009 through August 2019 were reviewed. The clinical characteristics, surgical indications, operative techniques, and long-term clinical and radiographic outcomes of pediatric moyamoya patients with PCA territory ischemia were collected and analyzed.
Results
A total of 10 PCA revascularization procedures were performed in 9 patients, 5 female, ages 1 to 11.1 years (average 5.2 years). Complications included 1 stroke, with no infections, hemorrhages, seizures, or deaths. One patient had less than 1 year of radiographic and clinical follow-up. In 8 of 9 patients with at least 1 year of radiographic follow-up, there was engraftment of surgical vessels present in all cases. No new strokes were identified on long-term follow-up despite the radiographic progression of the disease. In the 8 cases available for analysis, the average follow-up was 50.8 months with a range of 12 to 117 months.
Conclusions
PCA territory ischemia in patients with progressive moyamoya disease can be surgically treated with indirect revascularization. Here, we describe our experience with PCA revascularization procedures for moyamoya disease, including pial pericranial dural (PiPeD) revascularization and pial synangiosis utilizing the occipital artery. These surgical options may be useful for decreasing the risk of stroke in pediatric moyamoya patients with severe posterior circulation disease.
Background & Aims Liver transplantation improves survival in end-stage primary biliary cirrhosis (PBC), but the benefit for systemic symptoms including fatigue is less clear. The aim of this study ...was to utilise the comprehensive UK-PBC Research Cohort, including 380 post-transplant patients and 2300 non-transplanted patients, to answer key questions regarding transplantation for PBC. Methods Cross-sectional study of post-transplant PBC patients and case-matched non-transplanted patients. Detailed clinical information was collected, together with patient systemic symptom impact data using validated assessment tools. Results Over 25% of patients in the transplant cohort were grafted within 2 years of PBC diagnosis suggesting advanced disease at presentation. Transplanted patients were significantly younger at presentation than non-transplanted (mean 7 years) and >35% of all patients in the UK-PBC cohort who presented under 50 years had already undergone liver transplantation at the study censor point (>50% were treatment failures (post-transplant or unresponsive to UDCA)). Systemic symptom severity (fatigue and cognitive symptoms) was identical in female post-transplant patients and matched non-transplanted controls and unrelated to disease recurrence or immunosuppression type. In males, symptoms were worse in transplanted than in non-transplanted patients. Conclusions Age at presentation is a major risk factor for progression to transplant (as well as UDCA non-response) in PBC. Although both confirmatory longitudinal studies, and studies utilising objective as well as subjective measures of function, are needed if we are to address the question definitively, we found no evidence of improved systemic symptoms after liver transplantation in PBC and patients should be advised accordingly. Consideration needs to be given to enhancing rehabilitation approaches to improve function and life quality after liver transplant for PBC.
Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these ...patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit.
The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations.
The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.
Objectives. Colorectal cancer (CRC) is a leading cause of cancer death worldwide, although effective uptake of bowel cancer screening is below 60% in England. This trial investigated the influence of ...volitional and motivational interventions and their combination on increasing guaiac fecal occult blood testing (gFOBT) screening uptake. Method. In total, 34,633 participants were recruited (via North-East of England bowel cancer screening hub) into a 2×2 factorial cluster randomized controlled trial. Social norm-based motivational intervention (SNA); Implementation intention-based Volitional Help Sheet (VHS); Combined intervention (SNA+VHS); Treatment as usual control. Screening rate (gFOBT kit return rate within 8 weeks of invitation) was the primary outcome. Results. Screening kits were returned by 60% of participants (N=20,847/34,633). A substantial imbalance was observed in participant characteristics, participants in the combined intervention group were younger and more likely to be first time invitees. Adjusted analyses found insufficient evidence that any of the interventions were different to control (Combined: OR = 1.18, 95% CI 0.97-1.44; SNA alone: OR=0.93; 95% CI: 0.76-1.15; VHS alone OR= 0.88; 95% CI: 0.75-1.03). Subgroup analyses demonstrated a significant beneficial effect of the combined intervention in the youngest age group compared to control (OR = 1.27; 95% CI: 1.05-1.54). Conclusions. The study did not support any benefit of either VHS or SNA interventions alone on bowel cancer screening uptake. The combined SNA+VHS intervention was significantly different from control only in the youngest age group in adjusted analyses. However, the magnitude of effect in the youngest age group suggests that further testing of VHS plus SNA interventions in carefully targeted populations may be warranted.
•Two brief behaviour change interventions were tested on bowel screening uptake.•Screening kits were returned by 60% of participants in the study.•A social norm-based motivational intervention had no effect on uptake.•An implementation intention-based volitional intervention had no effect on uptake.•The combined effect of both interventions did not increase uptake.
INTRODUCTION
The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention ...Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans.
METHODS
U.S. POINTER was planned as a 2‐year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well‐established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER.
RESULTS
U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide network of similar trials for harmonization of methods and data sharing.
DISCUSSION
U.S. POINTER is testing a potentially sustainable intervention to support brain health and Alzheimer's prevention for Americans. Impact is strengthened by the targeted participant diversity and expanded scientific scope through ancillary studies.
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