Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide ...association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.
Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution ...to PBC, a sexually dimorphic complex autoimmune disease.
We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals).
Single-marker association analyses found approximately 100 loci displaying P < 5 × 10–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10–6; odds ratio OR, 1.39; 95% confidence interval CI, 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively).
This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.
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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.
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.
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).
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.
UK Medical Research Council and University of Milan-Bicocca.
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. (Hepatology 2016;63:930–950)
Private Sector Amendment to the Privacy Act - intended to strike a balance between the desire for protection of personal information and businesses request for flexible guidelines that would not be ...an expensive regulatory burden - Amendment hoped to strike a politically acceptable "middle course" between the EU and US approaches - offers inconsistent and ineffective privacy protection - should be strengthened to provide consistent and fair application of its substantive provisions - major shortcomings include the small business exemption - more extensive enforcement and harsher penalties are needed to ensure the law is followed - changes that would address the shortcomings and provide better uniformity in application and enforcement of the law.
Several vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine ...modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1
CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.
The CTC1-STN1-TEN1 (CST) complex is essential for telomere maintenance and resolution of stalled replication forks genome-wide. Here, we report the 3.0-angstrom cryo-electron microscopy structure of ...human CST bound to telomeric single-stranded DNA (ssDNA), which assembles as a decameric supercomplex. The atomic model of the 134-kilodalton CTC1 subunit, built almost entirely de novo, reveals the overall architecture of CST and the DNA-binding anchor site. The carboxyl-terminal domain of STN1 interacts with CTC1 at two separate docking sites, allowing allosteric mediation of CST decamer assembly. Furthermore, ssDNA appears to staple two monomers to nucleate decamer assembly. CTC1 has stronger structural similarity to Replication Protein A than the expected similarity to yeast Cdc13. The decameric structure suggests that CST can organize ssDNA analogously to the nucleosome's organization of double-stranded DNA.
Phospholane-phosphites are known to show highly unusual selectivity towards branched aldehydes in the hydroformylation of terminal alkenes. This paper describes the synthesis of hitherto unknown ...unsaturated phospholene borane precursors and their conversion to the corresponding phospholene-phosphites. The relative stereochemistry of one of these ligands and its Pd complex was assigned with the aid of X-ray crystal structure determinations. These ligands were able to approach the level of selectivity observed for phospholane-phosphites in the rhodium-catalysed hydroformylation of propene. High-pressure infra-red (HPIR) spectroscopic monitoring of the catalyst formation revealed that whilst the catalysts showed good thermal stability with respect to fragmentation, the C=C bond in the phospholene moiety was slowly hydrogenated in the presence of rhodium and syngas. The ability of this spectroscopic tool to detect even subtle changes in structure, remotely from the carbonyl ligands, underlines the usefulness of HPIR spectroscopy in hydroformylation catalyst development.
Reduction or elimination of inappropriate, ineffective, or potentially harmful healthcare services and public health programs can help to ensure limited resources are used effectively. Frameworks and ...models (FM) are valuable tools in conceptualizing and guiding the study of de-implementation. This scoping review sought to identify and characterize FM that can be used to study de-implementation as a phenomenon and identify gaps in the literature to inform future model development and application for research.
We searched nine databases and eleven journals from a broad array of disciplines (e.g., healthcare, public health, public policy) for de-implementation studies published between 1990 and June 2020. Two raters independently screened titles and abstracts, and then a pair of raters screened all full text records. We extracted information related to setting, discipline, study design, methodology, and FM characteristics from included studies.
The final search yielded 1860 records, from which we screened 126 full text records. We extracted data from 27 articles containing 27 unique FM. Most FM (n = 21) were applicable to two or more levels of the Socio-Ecological Framework, and most commonly assessed constructs were at the organization level (n = 18). Most FM (n = 18) depicted a linear relationship between constructs, few depicted a more complex structure, such as a nested or cyclical relationship. Thirteen studies applied FM in empirical investigations of de-implementation, while 14 articles were commentary or review papers that included FM.
De-implementation is a process studied in a broad array of disciplines, yet implementation science has thus far been limited in the integration of learnings from other fields. This review offers an overview of visual representations of FM that implementation researchers and practitioners can use to inform their work. Additional work is needed to test and refine existing FM and to determine the extent to which FM developed in one setting or for a particular topic can be applied to other contexts. Given the extensive availability of FM in implementation science, we suggest researchers build from existing FM rather than recreating novel FM.
Not registered.
Highlights
Thinking through when to let go: theory for identifying interventions that may not add value.
Examples of interventions ideal for discontinuation in public health and social service ...settings.
De‐implementation of interventions in the context of dissemination and implementation science.
The discontinuation of interventions that should be stopped, or de‐implementation, has emerged as a novel line of inquiry within dissemination and implementation science. As this area grows in human services research, like public health and social work, theory is needed to help guide scientific endeavors. Given the infancy of de‐implementation, this conceptual narrative provides a definition and criteria for determining if an intervention should be de‐implemented. We identify three criteria for identifying interventions appropriate for de‐implementation: (a) interventions that are not effective or harmful, (b) interventions that are not the most effective or efficient to provide, and (c) interventions that are no longer necessary. Detailed, well‐documented examples illustrate each of the criteria. We describe de‐implementation frameworks, but also demonstrate how other existing implementation frameworks might be applied to de‐implementation research as a supplement. Finally, we conclude with a discussion of de‐implementation in the context of other stages of implementation, like sustainability and adoption; next steps for de‐implementation research, especially identifying interventions appropriate for de‐implementation in a systematic manner; and highlight special ethical considerations to advance the field of de‐implementation research.
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