International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

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

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Opas 3–6-vuotiaan maahanmuuttajalapsen vanhemmille suun terveyden edistämiseen

Tässä opinnäytetyössä käsiteltiin 3–6-vuotiaiden maahanmuuttajalasten suun terveyttä. Toimintaympäristönä toimi Metropolian Ammattikorkeakoulun Suunhoidon opetusklinikka. Kohderyhmänä olivat 1–6-vuotiaat maahanmuuttajalapsen vanhemmat ja Suunhoidon opetusklinikan opiskelijat. Hyödynsaajina olivat 3–6-vuotiaat maahanmuuttajalapset sekä suunterveydenhuollon tutkinto-ohjelman opiskelijat. Opinnäytetyömme tarkoituksena oli antaa tietoa kattavasti sekä selkeästi kahden oppaan avulla 3–6-vuotiaille maahanmuuttajalapsille, heidän perheilleen sekä Metropolian Ammattikorkeakoulun suunhoidon opetusklinikalla opiskeleville. Tavoitteena oli lisätä maahanmuuttajaperheiden tietoutta lastensa suun terveydestä sekä edistää kotona tapahtuvaa omahoitoa. Opinnäytetyön kehittämistehtävät olivat: 1. Mitä asioita maahanmuuttajavanhemmat voivat oppia lastensa suun omahoidosta? 2. Mitä asioita maahanmuuttajalapsen on hyvä oppia suun omahoidosta? 3. Millä keinoilla suuhygienistiopiskelija edistää maahanmuuttajaperheen suun terveyttä? Opinnäytetyö toteutettiin toiminnallisena kehittämistyönä ja tietoperusta kerättiin luotettavista tietokannoista. Opinnäytetyömme tuloksena tuotimme kaksi opasta, joista ensimmäinen auttaa maahanmuuttajavanhempia heidän lastensa suun omahoidossa. Ensimmäinen opas on nimetty “Näin hoidat lapsesi hampaat kotona”. Tämä opas on käännetty myös englanniksi. Toinen opas on tarkoitettu Metropolian Ammattikorkeakoulun suunhoidon opetusklinikan suuhygienistiopiskelijoille ja se on nimetty “Opas suuhygienistiopiskelijoille maahanmuuttaja asiakkaiden hoitotyön tueksi”. Päädyimme tuottamaan kaksi opasta, sillä yhteistyötahomme on Metropolian Ammattikorkeakoulun suunhoidon opetusklinikka ja tulimme siihen tulokseen, että myös opiskelijat tarvitsevat apua maahanmuuttajaperheiden kohtaamisessa. Tarpeellisuus ohjemateriaalille kasvoi, kun opetusklinikkamme siirtyi Ruskeasuolta Myllypuroon. Se kuuluu Helsingin alueisiin, joissa on paljon ulkomaalaisia. Vieraskielisten asiakkaiden määrää kasvaa koko ajan suun terveydenhuollossa. Tämän vuoksi kommunikointi hoitohenkilökunnan ja asiakkaiden välillä on haastavaa, sillä yhteinen kieli voi puuttua. Jatkokehitysideana materiaalia voisi jakaa pääkaupungin sosiaali- ja terveyspalveluissa sähköisesti, sekä kehittää materiaalista sovelluksen ladattavaksi älypuhelimiin.The thesis processed with the oral health of 3-6-year-old immigrant children. An operating environment was the Metropolia University of Applied Sciences Department of Oral Care. The target group was the parents of an immigrant children aged 1-6 years and students from the Oral Care Teaching Clinic. The benefits were immigrant children aged 3-6 years and students in the Oral Health Degree program. The purpose of our thesis was to provide comprehensive and clear information through two guides to immigrant children aged 3-6 years, their families and those studying at Metropolia University of Applied Sciences Oral Care Teaching Clinic. The aim was to raise awareness of the oral health of immigrant families and to promote self-care at home. The thesis development tasks were: 1. What lessons can immigrant parents learn from their children's oral self-care? 2. What lessons should an immigrant child learn about oral self-care? 3. How a dental hygienist student promotes the oral health of an immigrant family? The thesis was implemented out as functional development work and the data base was collected from reliable databases. As a result of our thesis, we produced two guides, the first one helps immigrant parents with their children's oral self-care. The first guide is named "How to take care of your child's teeth at home". This guide has also been translated into English. The second guide is intended for oral hygienist students at Metropolia University of Applied Sciences Oral Care Teaching Clinic and is named "Guide for dental hygienist students to support the care of immigrant clients". We ended up producing two guides, as our partner is the Oral Care Teaching Clinic at Metropolia University of Applied Sciences, and we concluded that students also need help meeting immigrant families. Necessity for guidance material increased when our teaching clinic moved from Ruskeasuo to Myllypuro. It belongs to areas of Helsinki where there are many foreigners. The number of foreign-language speakers is constantly increasing in oral health care. This makes communication between nursing staff and clients challenging, as a common language can be lacking. As a further development idea, the material could be distributed electronically in the capital's social and health services and develop the material into an application to download to smartphones

Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score.

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

Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score.

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

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis.

BACKGROUND & AIMS: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version, accepted versio