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Background: Uncertainty exists about how best to identify primary biliary cholangitis (PBC) patients who would benefit from second-line therapy. Existing, purely clinical, ursodeoxycholic acid (UDCA) response criteria accept degrees of liver biochemistry abnormality in responding patients, emerging data, however, suggest that any degree of ongoing abnormality may, in fact, be associated with an increased risk of adverse outcomes. This cohort study explores the link between response status, the biology of high-risk disease and its implications for clinical practice., Methods: Proteomics, exploring 19 markers previously identified as remaining elevated in PBC following UDCA therapy, were performed on 400 serum samples, from participants previously recruited to the UK-PBC Nested Cohort between 2014 and 2019. All participants had an established diagnosis of PBC and were taking therapeutic doses of UDCA for greater than 12 months. UDCA response status was assessed using Paris 1, Paris 2 and the POISE criteria, with additional analyses using normal liver blood tests stratified by bilirubin level. Statistical analysis using parametric t tests and 1-way ANOVA., Findings: Disease markers were statistically significantly higher in UDCA non-responders than in responders for all the UDCA response criteria, suggesting a meaningful link between biochemical disease status and disease mechanism. For each of the criteria, however, marker levels were also statistically significantly higher in responders with ongoing liver function test abnormality compared to those who had normalised their liver biochemistry. IL-4RA, IL-18-R1, CXCL11, 9 and 10, CD163 and ACE2 were consistently elevated across all responder groups with ongoing LFT abnormality. No statistically significant differences occurred between markers in normal LFT groups stratified by bilirubin level., Interpretation: This study provides evidence that any ongoing elevation in alkaline phosphatase levels in PBC after UDCA therapy is associated with some degree of ongoing disease activity. There was no difference in activity between patients with normal LFT when stratified by bilirubin. These findings suggest that if our goal is to completely control disease activity in PBC, then normalisation of alkaline phosphatase and bilirubin should be the treatment target. This would also simplify messaging around goals of therapy in PBC, benefiting both patients and clinicians., Funding: Funding by the UK Medical Research Council (Stratified Medicine Programme) and an independent research grant by Pfizer. The study funders played no role in the study design, data collection, data analyses, data interpretation or manuscript writing., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Stratified therapy has entered clinical practice in primary biliary cholangitis (PBC), with routine use of second-line therapy in nonresponders to first-line therapy with ursodeoxycholic acid (UDCA). The mechanism for nonresponse to UDCA remains, however, unclear and we lack mechanistic serum markers. The UK-PBC study was established to explore the biological basis of UDCA nonresponse in PBC and identify markers to enhance treatment., Approach and Results: Discovery serum proteomics (Olink) with targeted multiplex validation were carried out in 526 subjects from the UK-PBC cohort and 97 healthy controls. In the discovery phase, untreated PBC patients (n = 68) exhibited an inflammatory proteome that is typically reduced in scale, but not resolved, with UDCA therapy (n = 416 treated patients). Nineteen proteins remained at a significant expression level (defined using stringent criteria) in UDCA-treated patients, six of them representing a tightly linked profile of chemokines (including CCL20, known to be released by biliary epithelial cells (BECs) undergoing senescence in PBC). All showed significant differential expression between UDCA responders and nonresponders in both the discovery and validation cohorts. A linear discriminant analysis, using serum levels of C-X-C motif chemokine ligand 11 and C-C motif chemokine ligand 20 as markers of responder status, indicated a high level of discrimination with an AUC of 0.91 (CI, 0.83-0.91)., Conclusions: UDCA under-response in PBC is characterized by elevation of serum chemokines potentially related to cellular senescence and was previously shown to be released by BECs in PBC, suggesting a potential role in the pathogenesis of high-risk disease. These also have potential for development as biomarkers for identification of high-risk disease, and their clinical utility as biomarkers should be evaluated further in prospective studies., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Backgrounds & Aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening., Methods: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts., Results: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57 th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (T H )1 and T H 17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders., Conclusions: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders., Lay Summary: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., Competing Interests: Conflicts of interest GMH has consulted and/or been a speaker for Intercept, Genfit, Cymabay, GSK, and Falk. RNS and GFM have each received research funding from Intercept Pharmaceuticals. HJC, JJF, KU, RD, YA, YH, MK, NN, S-SK, OG, YK, MN, KT, RT, YS, ZL, BDJ, EJA, AG, MC, RA, AC, MdA, AB, JH, MARF, DS, DEJ, SF, AS, VLM, KNL, CIA, MFS, PI, KAS, XM and MN report no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021. Published by Elsevier B.V.)

Background & Aims: There have been few high-quality studies of the costs, preference-based health-related quality of life (HRQoL) and cost effectiveness of treatments for primary biliary cholangitis (PBC). We aimed to estimate the marginal effects of PBC complications and symptoms, accounting for treatment, on HRQoL and the annual cost of health care in the United Kingdom (UK). These are essential components for evaluation of cost effectiveness and this information will aid in evaluation of new treatments., Methods: Questionnaires were mailed to 4583 participants in the UK-PBC research cohort and data were collected on HRQoL and use of the National Health Service (NHS) in the UK from 2015 through 2016. HRQoL was measured using the EQ-5D-5L instrument. The annual cost of resource use was calculated using unit costs obtained from NHS sources. We performed econometric analyses to determine the effects of treatment, symptoms, complications, liver transplantation status, and patient characteristics on HRQoL and annual costs., Results: In an analysis of data from 2240 participants (over 10% of all UK PBC patients), we found that PBC symptoms have a considerable effect on HRQoL. Ursodeoxycholic acid therapy was associated with significantly higher HRQoL regardless of response status. Having had a liver transplant and ascites were also independently associated with reduced HRQoL. Having had a liver transplant (US$4294) and esophageal varices (US$3401) were the factors with the two greatest mean annual costs to the NHS. Symptoms were not independently associated with cost but were associated with reduction in HRQoL for patients, indicating the lack of effective treatments for PBC symptoms., Conclusions: In an analysis of data from 2240 participants in the UK PBC, we found that HRQoL and cost estimates provide greater insight into the relative importance of PBC-related symptoms and complications. These findings provide estimates for health technology assessments of new treatments for PBC., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Given that variation exists in health care utilization, expenditure, and medical practice, there is a paucity of data on variation within the practice of anesthesia. The Pediatric Regional Anesthesia Network (PRAN) data lend itself to explore whether different medical practice patterns exist and if there are nerve blocks with more local anesthetic dosing variation than others. The primary aim of this study was to quantify variation in single injection caudal block dosing, and the secondary aim was to explore possible causes for variation (eg, number of blocks performed versus geographic location)., Methods: We queried the PRAN database for single injection caudal blocks in children <1 year of age. Data were analyzed for local anesthetic dose, variation within and across institutions, and possible causes., Results: Mean dose of bupivacaine equivalents per kilogram (BE·kg) among sites ranged from 1.39 to 2.22 with an interdecile range (IDR) containing the mid 80% of all doses ranging from 0.21 to 1.48. Mean dose (BE·kg) was associated with site, age, weight, and local anesthetic used (all P < .0001). Cohen's F effect size estimate was 10 times higher for site (0.65) than for age (0.05) or weight (0.02). Variation (IDR) was not related to number of blocks done at each site (P = .23). Mean volume per kilogram was 0.9± ± 0.2 (mean ± ±standard deviation) and was more strongly associated with site (Cohen's F 0.3) than age (0.04) or weight (0.07)., Conclusions: Wide variation in caudal local anesthetic dosing and administered volume exists. This variation is independent of the number of cases performed at each center but rather is determined by study site (ie, variation between centers) with considerable additional variation within study centers, suggesting additional variability dependent on individual practitioners. While there are legitimate reasons to vary dosing, the current approach is inconsistent and not supported by strong evidence over giving a standardized dose.

Background: Current guidelines in primary biliary cholangitis ( PBC) recommend routine screening for symptoms. However, at present there are no validated practical tools suitable for screening use in practice., Aim: To develop a short quality of life questionnaire for PBC METHODS: The short PBC HRQL questionnaire was derived and validated by analysing the PBC-40 questionnaires from the UK-PBC Research Cohort. Construct validity was assessed using the European Quality of Life Five Dimensions (EQ5D) questionnaire. Test-retest analysis was done by asking a subgroup of patients to complete the questionnaire twice within 2-4 weeks., Results: A total of 2219 patients completed PBC-40 questionnaire in 2013. Stepwise regression identified 10 questions that contributed to more than 95% of the PBC-40 score variance and covered the main domains of PBC. The short HRQL questionnaire, PBC-10, had good internal consistency (Cronbach's α 0.905) and item-total correlations. PBC-10 demonstrated no ceiling effects but a floor effect was noted. Further validation on 2502 patients who completed the PBC questionnaire in 2017 confirmed the psychometric properties of PBC-10. Further analysis on 186 patients showed that PBC-10 demonstrated good internal consistency (Cronbach's α = 0.936), had good reproducibility (intra-class correlation coefficient = 0.945), good correlation with the EQ5D (r = .736), and was responsive to change. A change of 4 points in the PBC-10 score would be considered clinically important., Conclusion: PBC-10 is a short and valid questionnaire for assessing the HRQL in patients with PBC in clinical practice., (© 2019 John Wiley & Sons Ltd.)

Background: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters., Methods: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples., Findings: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present)., Interpretation: We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis., Funding: UK Medical Research Council and University of Milan-Bicocca., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Unlabelled: The biochemical response to ursodeoxycholic acid (UDCA)--so-called "treatment response"--strongly predicts long-term outcome in primary biliary cholangitis (PBC). Several long-term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long-term prognostic models of PBC using data from the UK-PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA-treated participants. We used nonautomatic backward selection to derive the best-fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA-treated participants. The best-fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5-, 10-, and 15-year risk scores were highly accurate (areas under the curve: >0.90)., Conclusions: The prognosis of PBC patients can be accurately evaluated using the UK-PBC risk scores. They may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed up in primary care., (© 2015 by the American Association for the Study of Liver Diseases.)

This is a case of systemic ropivacaine toxicity from a sciatic nerve catheter. A 20-year-old patient after heart transplant with poor systemic perfusion on hemodialysis and multiple medications experienced local anesthetic systemic toxicity 72 hours after placement of a peripheral nerve catheter. The case demonstrates the potentially significant impact of medical comorbidities on system absorption of local anesthetics and reinforces that existing dose guidelines are not evidence based, and literature to guide local anesthetic bolus supplementation of continuous infusions is scant., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Workers experience large interindividual variability in exposure and biological response following exposure to chemicals. Quantitative methods to investigate occupational exposures and their relationship with biomarker levels, toxicokinetics of chemicals, and gene-environment interactions in disease development can be performed to unlock the black-box paradigm in exposure-disease associations. Exposure to a chemical at work is generally greater than that experienced in the wider environment. While inhalation exposure has traditionally been the main focus in exposure assessment, there is growing awareness of the significance of contact and uptake of chemicals through dermal and ingestion routes. Biological monitoring can provide information on exposure and uptake of a chemical, biological response to exposure, early subclinical changes, and susceptibility for disease. Thus, biomarkers can provide an important link between exposure and disease and may be an important tool for risk assessment. Integration of toxicology with exposure assessment, dose-response, and toxicogenomics can be used to improve one's understanding of exposure-disease relationships and shape risk assessment strategies to protect worker health., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Children with seizure disorders unresponsive to medical management may undergo surgical disconnection of a cerebral hemisphere, or hemispherectomy, in order to reduce or eliminate seizures. Because early cessation of seizures is thought to improve developmental outcomes, infants and young children with intractable seizures are undergoing hemispherectomies with increasing frequency. Previously, these procedures have been noted to be accompanied by severe cardiovascular, pulmonary, neurologic and coagulopathic complications. Newer surgical techniques (i.e. 'functional' rather than 'anatomic' hemispherectomy) and improved anesthetic management may reduce the perioperative complication rate of this procedure. The aim of this case series was to determine the incidence of major complication of functional hemispherectomy in our institution., Methods: A retrospective chart review was conducted of all children <3 years of age undergoing functional hemispherectomies for intractable seizures over a 4-year period at our institution., Results: Seven children were identified. No serious cardiovascular, pulmonary, neurologic or coagulopathic adverse events occurred. Perioperative blood loss and its sequelae were the most common complication. Postoperative management was generally uncomplicated, although one patient required readmission to the ICU for treatment of diabetes insipidus. All children survived and, at latest follow-up, all but one remained seizure-free., Conclusion: This small case series suggests that improvements in anesthetic and surgical techniques may be associated with a decreased complication rate for infants and small children undergoing seizure surgery than previously reported.

Quantitative methods to measure dermal and inhalation exposure to the fungicide propiconazole were developed in the laboratory and applied in the occupational exposure setting for monitoring five farm workers' exposure during pesticide preparation and application to peach crops. Dermal exposure was measured with tape-strips applied to the skin, and the amount of propiconazole was normalized to keratin content in the tape-strip. Inhalation exposure was measured with an OVS tube placed in the worker's breathing-zone during pesticide handling. Samples were analyzed by GC-MS in EI+ mode (limit of detection 6 pg microl(-1)). Dermal exposure ranged from non-detectable to 32.1 +/- 22.6 ng per microg keratin while breathing-zone concentrations varied from 0.2 to 2.2 microg m(-3). A positive correlation was observed between breathing-zone concentrations and ambient air temperature (r2 = 0.87, p < 0.01). Breathing-zone concentrations did not correlate with dermal exposure levels (r2 = 0.11, p = 0.52). Propiconazole levels were below limit of detection when rubber gloves, coveralls, and full-face mask were used. The total-body propiconazole dose, determined for each worker by summing the estimated dermal dose and inhalation dose, ranged from 0.01 to 12 microg per kg body weight per day. Our results show that tape-stripping of the skin and the OVS can be effectively utilized to measure dermal and inhalation exposure to propiconazole, respectively, and that the dermal route of exposure contributed substantially more to the total dose than the inhalation route.

Background and Objectives: The administration of therapeutic plasma protein concentrates has been associated with the real risk of transmitting viral diseases and the theoretical risks of prion transmission. Our objective was to determine if gamma-irradiation can inactivate viral or prion infectivity without damaging a protein biotherapeutically., Materials and Methods: Human albumin 25% solution, spiked with four model viruses (including porcine parvovirus) or with brain homogenate from scrapie-infected hamsters, was gamma-irradiated at constant low-dose rates and assayed for viral and prion infectivity or for albumin integrity., Results: At a radiation dose of 50 kGy, viruses were inactivated by >/= 3.2 to >/= 6.4 log10 and scrapie by an estimated 1.5 log10, whereas albumin was only moderately aggregated and fragmented., Conclusions: gamma-Irradiation can preferentially inactivate viral and prion pathogens without excessive damage to albumin structure.

Sedation for fibreoptic bronchoscopy should produce optimal conditions for the operator, patient comfort and rapid recovery allowing early discharge home. We have compared a regimen producing 'light' sedation with a more traditional regimen producing 'deep' sedation. Seventy-six patients undergoing fibreoptic bronchoscopy under topical anaesthesia were randomized to receive either light sedation with the short acting opiate, alfentanil (median dose 1.1 mg, range 0.5-2.6 mg) or deep sedation with a combination of papaveretum (median dose 10 mg, range 5-15 mg) and diazepam (median dose 8 mg, range 0-20 mg). Both techniques gave equally good operating conditions, although patients given alfentanil coughed less than those given papaveretum and diazepam (U = 2.814 P less than 0.01). Patients recorded their degree of apprehension on a visual analogue scale prior to sedation and the actual degree of comfort experienced after recovery. There was no significant difference between apprehension or comfort between the groups. This was despite a higher degree of amnesia for an irrelevant object shown during the bronchoscopy in the deeply sedated group (chi 2 = 21.084 P less than 0.001). Patients given alfentanil performed significantly better in a modified Romberg test (chi 2 = 4.357 P less than 0.05) and a visualisation test (t = 3.035 P less than 0.01) two hours after the bronchoscopy. Alfentanil produced good operating conditions, patient comfort, less cough and a more rapid recovery, compared to the deep sedation regimen, and is an ideal sedative for fibreoptic bronchoscopy.