The new definition of dominant stricture in primary sclerosing cholangitis: Prevalence and clinical significance.

BACKGROUND AND AIMS: A new definition of dominant stricture (NDS) has recently been defined for patients with primary sclerosing cholangitis (PSC). Prevalence and clinical features of this, compared to traditional dominant stricture (TDS), have not been reported. METHODS: In this single-centre longitudinal prospective cohort study, all PSC patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) between October 2021 and 2022 were recruited. Symptoms of cholestasis, laboratory values (P-alkaline phosphatase, P-Bilirubin), Helsinki PSC-score, brush cytology findings and need for endoscopic therapy (i.e. dilation, stenting) were prospectively collected. RESULTS: Overall, 228 patients with PSC underwent 248 ERCPs. NDS was detected in 43 (17%; 36 patients) and TDS without NDS (TDS group) was detected in 62 (25%; 58 patients) ERCPs, respectively; in the remaining 143 ERCPs, neither TDS nor NDS was seen (no dominant stricture [NoDS] group). PSC duration (median 8 years) and patient's age did not differ between the three groups; males presented more often with NDS. Patients with NDS were more often symptomatic, had higher cholestatic liver enzymes, advanced bile duct disease and markers of biliary inflammation (p < .001). Patients with NDS needed dilation (81%) and stenting (21%) more often than the TDS group (60% and 5%, respectively). Dysplasia in brush cytology was more common in TDS (5%) and NDS (9%) than in NoDS (3%) groups (p = .04), but did not differ between TDS and NDS groups. CONCLUSIONS: Dominant stricture according to the new definition developed in 17% of PSC patients in our cohort and identifies patients with more advanced disease, biliary inflammation and need of endo-therapy.

The role of serology, liver function tests and imaging in screening of primary sclerosing cholangitis: the HelPSCreen score.

OBJECIVES: At present, no sensitive or specific screening test exists for primary sclerosing cholangitis (PSC). PSC screening is mainly based on elevated alkaline phosphatase (ALP) in patients with inflammatory bowel disease (IBD). We aimed to produce a screening score based on laboratory tests to predict the likelihood of PSC. Moreover, we evaluated the additional roles of liver histology and magnetic resonance cholangiopancreatography (MRCP) in the diagnosis of PSC. MATERIALS AND METHODS: The data of 385 patients who came for their first endoscopic retrograde cholangiography (ERC) to confirm PSC diagnosis were retrieved from the PSC registry of the Helsinki University Hospital. Overall, 69 patients referred for ERC with suspected PSC, in whom PSC was excluded by ERC or liver biopsy and MRCP, served as controls. We included patients' demographics and 13 laboratory test results in the analysis. Variables with significant odds ratios were selected for multivariate logistic regression, which was used to create a novel scoring system for PSC. The presence of IBD, serum perinuclear anti-neutrophil cytoplasmic antibodies, and ALP levels demonstrated the highest predictive value for PSC. A score was assigned for each statistically significant predictor. RESULTS: The optimal cut-off point for the score was ≥3, with an AUC of 0.83 (95%CI: 0.78-0.88). The addition of liver histology or MRCP findings to the score did not add a predictive value. CONCUSIONS: In conclusion, we created a novel, simple scoring system to screen the probability of PSC. The HelPSCreen-score may help to assess the disease prevalence and to target further investigations in patients suspected of PSC.

Occupational radiation dose from gastrointestinal endoscopy procedures with special emphasis on eye lens doses in endoscopic retrograde cholangiopancreatography.

Background and study aims Endoscopic retrograde cholangiopancreatography (ERCP) procedures may result in remarkable radiation doses to patients and staff. The aim of this prospective study was to determine occupational exposures in gastrointestinal endoscopy procedures, with a special emphasis on eye lens dose in ERCP. Methods Altogether 604 fluoroscopy-guided procedures, of which 560 were ERCPs belonging to four American Society for Gastrointestinal Endoscopy procedural complexity levels, were performed using two fluoroscopy systems. Personal deep-dose equivalent H p (10), shallow-dose equivalent H p (0.07), and eye lens dose equivalent H p (3) of eight interventionists and H p (3) for two nurse dosimeters were measured. Thereafter, conversion coefficients from kerma-area product (KAP) for H p (10), H p (0.07), and H p (3) were determined and dose equivalents per procedure to an operator and assisting staff were estimated. Further, mean conversion factors from H p (10) and H p (0.07) to H p (3) were calculated. Results The median KAP in ERCP was 1.0 Gy·cm 2 , with mobile c-arm yielding higher doses than a floor-mounted device ( P  < 0.001). The median H p (3) per ERCP was estimated to be 0.6 µSv (max. 12.5 µSv) and 0.4 µSv (max. 12.2 µSv) for operators and assisting staff, respectively. The median H p (10) and H p (0.07) per procedure ranged from 0.6 to 1.8 µSv. ERCP procedural complexity level ( P  ≤ 0.002) and interventionist ( P  < 0.001) affected dose equivalents. Conclusions Occupational dose limits are unlikely to be exceeded in gastrointestinal endoscopy practice when following radiation-hygienic working methods and focusing on dose optimization. The eye lens dose equivalent H p (3) may be estimated with sufficient agreement from the H p (10) and H p (0.07).

Preoperative prescriptions and polypharmacy in elective total hip and knee arthroplasty from 2010 to 2017, a descriptive cohort study.

BACKGROUND: Evaluation of regular medication is an essential part of the preanesthetic consultation. However, even in elective surgical patients, such as those scheduled for total hip (THA) and knee arthroplasty (TKA), this task may be increasingly complex due to increasing age and number of pharmacologically treated comorbidities. Nevertheless, data on prescribed drugs and polypharmacy in elective surgical patients is sparse. METHODS: Descriptive study in elective unilateral fast-track THA and TKA between 2010 and 2017 based on data from the Centre for fast-track Hip and Knee Replacement Database. Nationwide information on dispensed prescriptions up to 3 months preoperatively was acquired from the Danish National Database of Reimbursed Prescriptions. Drugs were divided into individual subgroups according to the fourth Anatomical Therapeutic Chemical level (ATC4). Primary outcome was changes in the median number of prescribed drugs/year. Secondarily, we investigated the fraction of patients with polypharmacy (≥5 individual ATC4-subgroups), severe polypharmacy (≥10) and specific drugs of relevance at the preanesthetic evaluation. RESULTS: Of 36,934 procedures in 32,515 patients with a median age of 69 years, we found a median of 3 ATC4-subgroups with no time-related changes regardless of year of surgery but increasing in patients ≥65 years (median: 3 [IQR: 2-4]) versus < 65 years (2 [IQR 1-3]; p < .001). In total, 35.1% and 4.2% had polypharmacy or severe polypharmacy. There was a significant declining trend in severe polypharmacy from 2010 to 2017 (p = .003). Drugs of anesthetic relevance were used by 41.1% of all patients, most often ANG-II or ACE inhibitors and betablockers, which were used by 28.0% and 15.7%. Oral antihyperglycemics was used by 7.8% and 2.0% used insulin. Only 4.0% and 2.1% of patients used vitamin-K antagonists and direct oral anticoagulants, respectively. MAO-inhibitors/Lithium salts were used by 0.3%. The combination of ANG-II/ACE inhibitors, a diuretic and NSAID ("triple whammy") was present in 4.3% of all patients. CONCLUSION: Patients scheduled for elective THA and TKA used a median of 3 prescribed drugs. However, 1/3 of patients qualified as having polypharmacy and 41% used drugs requiring anesthetic consideration when planning for surgery.

Risk factors, epidemiology and prognosis of cholangiocarcinoma in Finland.

BACKGROUND: Cholangiocarcinoma (CCA) is a cancer arising from the intra- and extrahepatic bile ducts. The early stages are often asymptomatic, CCA is frequently diagnosed in an advanced stage and the prognosis of CCA is often dismal. OBJECTIVE: Our objective was to estimate the incidence of CCA in Finland and to identify risk factors for CCA, with a special interest in primary sclerosing cholangitis (PSC). METHODS: We identified all CCA cases during 1974-2018 from the Finnish Cancer Registry and calculated age-standardised incidence rates. Five controls for each case were extracted from the Population Registry, matched by age, gender and municipality of residence at the time of diagnosis. Odds ratios (ORs) for risk factors were estimated with conditional logistic regression and survival estimates with the Kaplan-Meier method. RESULTS: Incidence of CCA remained stable in both genders; the age-standardised rate (World Standard) in 2013-2017 in males and females was 1.7 per 100,000 person years and 1.3 per 100,000 person years, respectively. Primary sclerosing cholangitis carried a 30-fold risk of intrahepatic cholangiocarcinoma (iCCA) and 25-fold risk of extrahepatic cholangiocarcinoma (eCCA). Diabetes, inflammatory bowel disease and liver cirrhosis were associated with iCCA, whereas cholelithiasis and viral hepatitis C were associated with eCCA. The cumulative 5-year survival was 4.6%. CONCLUSIONS: The incidence of CCA has been stable. Known risk factors for CCA were confirmed, with PSC having the highest OR. Survival remains poor.

Epidemiology, risk of malignancy and patient survival in primary sclerosing cholangitis: a population-based study in Finland.

Background: There are only a few and mostly small population-based epidemiological studies of primary sclerosing cholangitis (PSC).Objective: We aimed to estimate prevalence and incidence rates of PSC, and survival and malignancy risk for PSC patients in a large population-based study.Methods: We retrieved 632 PSC patients from 1990 to 2015 in the Hospital District of Helsinki and Uusimaa (HUS), comprising 29% of the Finnish population. Mortality information of the PSC patients was obtained from the national Population Registry, malignancy information from the Finnish Cancer Registry and the causes of death from the Statistics Finland. Standardized incidence ratio and standardized mortality ratio (SMR) were calculated for predefined malignancy types.Results: The crude incidence of PSC in the HUS area was 1.58/100,000 person-years, and the point prevalence in 2015 was 31.7/100,000 inhabitants. The mean time from diagnosis to death was 21.9 years. The risk for any malignancy was three-fold and the risk for colorectal carcinoma was five-fold when comparing with the general population. During the first year after diagnosis of PSC, the risk for cholangiocarcinoma is 900-fold compared to the general population and after that 150-fold. SMR for all malignant neoplasms was 5.9 (95% CI 4.2-8.1).Conclusion: We found that the incidence of PSC in the HUS area in Finland is similar or higher than previously reported from other countries. The prevalence is markedly higher than reported elsewhere, probably due to the active search of the disease, suggesting that the disease is underdiagnosed.

Incidence, prevalence, and causes of death of patients with autoimmune hepatitis: A nationwide register-based cohort study in Finland.

BACKGROUND: Epidemiological studies of autoimmune hepatitis are scarce and often based on single centre registries. AIMS: We conducted a nationwide register study of incidence, prevalence, survival, and causes of death of autoimmune hepatitis patients in Finland. METHODS: Autoimmune hepatitis cases 1995-2015 were retrieved from the national database of special reimbursements for drugs costs. Data on causes of death were retrieved from Statistics Finland. RESULTS: After incomplete registration of AIH during the first years, the incidence of autoimmune hepatitis stabilised to 1.1/100,000 person-years (1.6 in women and 0.52 in men) in 2008-2015. The prevalence of autoimmune hepatitis at the end of 2015 was 14.3/100,000, 23.0/100,000 in women and 6.6/100,000 in men. The all-cause standardized mortality ratio (SMR) of autoimmune hepatitis patients was 1.81 (95% confidence interval (CI) 1.47-2.20). The SMR was increased in all age groups and in both sexes. The SMR for hepatocellular carcinoma was 20.6 (95% CI 10.3-36.8), and for digestive diseases in overall 13.5 (95% CI 8.2-20.8), constituting mainly from autoimmune hepatitis and liver cirrhosis. CONCLUSION: Incidence of autoimmune hepatitis has remained stable, with clear female predominance. Autoimmune hepatitis is associated with a markedly increased risk of death with hepatocellular cancer forming the greatest risk.

Health-related quality of life among patients with primary sclerosing cholangitis.

BACKGROUND & AIMS: To assess health-related quality of life (HRQoL) of patients with primary sclerosing cholangitis (PSC), and to compare it with that of the general population. Also, to examine changes in HRQoL in newly diagnosed PSC patients at a follow-up 1-2 years later, and to compare their HRQoL with HRQoL of newly diagnosed inflammatory bowel disease (IBD) patients. Furthermore, sources of and need for disease-related information among PSC patients were surveyed. METHODS: Primary sclerosing cholangitis patients filled in the survey questionnaire when attending an endoscopic retrograde cholangiography examination. The 15D served as a general HRQoL instrument. The follow-up questionnaire was mailed to the newly diagnosed patients 1-2 years later. RESULTS: No significant difference was seen in 15D scores between PSC patients and general population, but the dimensions of excretion (P < 0.001), depression (P = 0.003), distress (P = 0.003) and vitality (P = 0.005) were significantly lower in PSC. Age and symptoms affected HRQoL but severity of biliary changes did not. Those with newly diagnosed IBD had lower 15D scores than those with PSC. No significant changes were observed in 15D scores of new PSC patients in the follow-up. Many patients were dissatisfied with information received. CONCLUSION: Newly diagnosed PSC patients have better HRQoL than do IBD patients, and no significant HRQoL changes were observed in the mean follow-up of 1.58 years after PSC diagnosis. ERC findings did not correlate with HRQoL or symptoms. HRQoL of PSC patients was mostly comparable with that of general population, but special attention should be paid to patients' psychological well-being.

Can phylogeny predict chemical diversity and potential medicinal activity of plants? A case study of Amaryllidaceae.

BACKGROUND: During evolution, plants and other organisms have developed a diversity of chemical defences, leading to the evolution of various groups of specialized metabolites selected for their endogenous biological function. A correlation between phylogeny and biosynthetic pathways could offer a predictive approach enabling more efficient selection of plants for the development of traditional medicine and lead discovery. However, this relationship has rarely been rigorously tested and the potential predictive power is consequently unknown. RESULTS: We produced a phylogenetic hypothesis for the medicinally important plant subfamily Amaryllidoideae (Amaryllidaceae) based on parsimony and Bayesian analysis of nuclear, plastid, and mitochondrial DNA sequences of over 100 species. We tested if alkaloid diversity and activity in bioassays related to the central nervous system are significantly correlated with phylogeny and found evidence for a significant phylogenetic signal in these traits, although the effect is not strong. CONCLUSIONS: Several genera are non-monophyletic emphasizing the importance of using phylogeny for interpretation of character distribution. Alkaloid diversity and in vitro inhibition of acetylcholinesterase (AChE) and binding to the serotonin reuptake transporter (SERT) are significantly correlated with phylogeny. This has implications for the use of phylogenies to interpret chemical evolution and biosynthetic pathways, to select candidate taxa for lead discovery, and to make recommendations for policies regarding traditional use and conservation priorities.

Two conserved modules of Schizosaccharomyces pombe Mediator regulate distinct cellular pathways.

Mediator is an evolutionary conserved coregulator complex required for transcription of almost all RNA polymerase II-dependent genes. The Schizosaccharomyces pombe Mediator consists of two dissociable components-a core complex organized into a head and middle domain as well as the Cdk8 regulatory subcomplex. In this work we describe a functional characterization of the S. pombe Mediator. We report the identification of the S. pombe Med20 head subunit and the isolation of ts alleles of the core head subunit encoding med17+. Biochemical analysis of med8(ts), med17(ts), Deltamed18, Deltamed20 and Deltamed27 alleles revealed a stepwise head domain molecular architecture. Phenotypical analysis of Cdk8 and head module alleles including expression profiling classified the Mediator mutant alleles into one of two groups. Cdk8 module mutants flocculate due to overexpression of adhesive cell-surface proteins. Head domain-associated mutants display a hyphal growth phenotype due to defective expression of factors required for cell separation regulated by transcription factor Ace2. Comparison with Saccharomyces cerevisiae Mediator expression data reveals that these functionally distinct modules are conserved between S. pombe and S. cerevisiae.

Genome-wide occupancy profile of mediator and the Srb8-11 module reveals interactions with coding regions.

Mediator exists in a free form containing the Med12, Med13, CDK8, and CycC subunits (the Srb8-11 module) and a smaller form, which lacks these four subunits and associates with RNA polymerase II (Pol II), forming a holoenzyme. We use chromatin immunoprecipitation (ChIP) and DNA microarrays to investigate genome-wide localization of Mediator and the Srb8-11 module in fission yeast. Mediator and the Srb8-11 module display similar binding patterns, and interactions with promoters and upstream activating sequences correlate with increased transcription activity. Unexpectedly, Mediator also interacts with the downstream coding region of many genes. These interactions display a negative bias for positions closer to the 5' ends of open reading frames (ORFs) and appear functionally important, because downregulation of transcription in a temperature-sensitive med17 mutant strain correlates with increased Mediator occupancy in the coding region. We propose that Mediator coordinates transcription initiation with transcriptional events in the coding region of eukaryotic genes.