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Smoking is a remarkable risk factor for inflammatory bowel disease (IBD), aggravating Crohn's disease (CD) while having beneficial effects on ulcerative colitis (UC). We studied the effects of active and passive smoking in Dutch IBD patients.MethodsA questionnaire focusing on cigarette smoke exposure was sent to 820 IBD patients. Returned questionnaires were incorporated into a retrospective chart review, containing details about disease behavior and received therapy.ResultsIn all, 675 IBD patients (380 [56%] CD and 295 [44%] UC) responded. At diagnosis there were 52% smokers in CD, 41% in the general population, and 28% in UC. The number of present smokers in CD is lower than in the general population (26% versus 35%). No detrimental effects of active smoking on CD were observed, but passive smokers needed immunosuppressants and infliximab more frequently than nonpassive smokers. Active smoking had beneficial effects on UC, indicated by reduced rates of colectomy, primary sclerosing cholangitis, and backwash-ileitis in active smokers compared to never smokers, and higher daily cigarette dose correlated with less extensive colitis and a lower need for therapy. Furthermore, smoking cessation after diagnosis was detrimental for UC patients, indicated by increased needs for steroids and hospitalizations for patients that stopped smoking after compared to before the diagnosis.ConclusionsActive smoking is a risk factor for CD, but does not affect the outcome; passive smoking is detrimental for the outcome of CD patients. In UC, active smoking shows dose-dependent beneficial effects. Our data suggest that passive smoking is a novel risk factor for CD.

Background Acute cholangitis is an infection of the biliary tract that is managed with adequate biliary drainage combined with antibiotic treatment. The international Tokyo Guidelines 2018 recommend 4 to 7 days of antibiotic treatment after adequate biliary drainage, but observational data suggest shorter treatment may be sufficient. We assessed whether 1 day of antibiotic treatment is non-inferior to 4–7 days of antibiotic treatment for acute cholangitis after adequate biliary drainage. Methods The COBRA-trial is a multicentre, open-label, parallel group randomized controlled non-inferiority trial with blinded outcome assessment. A total of 416 patients with acute cholangitis will be randomly assigned in a 1:1 ratio to the intervention group (1 day of antibiotic treatment after adequate biliary drainage) or to the control group (4–7 days of antibiotic treatment after adequate biliary drainage). Patients with acute cholangitis due to common bile duct stones, benign or malignant distal biliary obstruction, or distal biliary stent dysfunction are eligible. Randomization will take place once adequate biliary drainage is achieved by ERCP. Main exclusion criteria are concomitant pancreatitis, liver abscess, cholecystitis, and another infectious diagnosis at the time of randomization, use of systemic maintenance antibiotics, and specific immunosuppressants. Patients will be stratified for blood culture results at the time of randomization and aetiology of cholangitis. The primary endpoint is clinical cure, defined as the patient being symptom-free by day 14, with no relapse or death occurring by day 30. Secondary endpoints include 30-day and 90-day all-cause mortality, relapse of cholangitis by day 90, time from ERCP to first relapse, any other subsequent infection requiring antibiotic treatment within 90 days, duration of initial hospital stay, number of days treated with antibiotics by day 30, subsequent infections with multidrug resistant (MDR) bacteria, quality of life, and cost-effectiveness. Discussion This trial assesses whether a short course of antibiotic treatment for acute cholangitis is as safe and effective compared to a longer course of antibiotic treatment. If confirmed, the results could substantially reduce antibiotic exposure and healthcare resource utilization, thereby contributing to global efforts to minimize unnecessary antibiotic treatment. Trial registration ClinicalTrials.gov NCT05750966, registered on March 2nd, 2023.

IntroductionExtended criteria donor (ECD) livers are increasingly accepted for transplantation in an attempt to reduce the gap between the number of patients on the waiting list and the available number of donor livers. ECD livers; however, carry an increased risk of developing primary non-function (PNF), early allograft dysfunction (EAD) or post-transplant cholangiopathy. Ischaemia-reperfusion injury (IRI) plays an important role in the development of these complications. Machine perfusion reduces IRI and allows for reconditioning and subsequent evaluation of liver grafts. Single or dual hypothermic oxygenated machine perfusion (DHOPE) (4°C–12°C) decreases IRI by resuscitation of mitochondria. Controlled oxygenated rewarming (COR) may further reduce IRI by preventing sudden temperature shifts. Subsequent normothermic machine perfusion (NMP) (37°C) allows for ex situ viability assessment to facilitate the selection of ECD livers with a low risk of PNF, EAD or post-transplant cholangiopathy.Methods and analysisThis prospective, single-arm study is designed to resuscitate and evaluate initially nationwide declined ECD livers. End-ischaemic DHOPE will be performed for the initial mitochondrial and graft resuscitation, followed by COR of the donor liver to a normothermic temperature. Subsequently, NMP will be continued to assess viability of the liver. Transplantation into eligible recipients will proceed if all predetermined viability criteria are met within the first 150 min of NMP. To facilitate machine perfusion at different temperatures, a perfusion solution containing a haemoglobin-based oxygen carrier will be used. With this protocol, we aim to transplant extra livers. The primary endpoint is graft survival at 3 months after transplantation.Ethics and disseminationThis protocol was approved by the medical ethical committee of Groningen, METc2016.281 in August 2016 and registered in the Dutch Trial registration numberTrial registration numberNTR5972, NCT02584283.

Background Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide with a grim prognosis. Current treatment options for advanced HCC are limited, and a large proportion of patients is not amenable to any form of treatment, with best supportive care as the only remaining option. Meanwhile, the use of cannabis-derived products is rising in oncological patients who are seeking symptom relief. Cannabinoids, similar to endogenous endocannabinoids, have shown promise in recent preclinical cancer research due to their ability to interact with various signaling pathways and molecular mechanisms of interest. Case presentation In this report, we present two patients (A aged 82 and B 77, respectively) with advanced HCC with a high tumor burden who demonstrated durable and complete regression after use of cannabis oil (A 10% delta-9-tetrahydrocannabinol (THC) and 5% cannabidiol (CBD), two droplets sublingually three times daily and B 15% THC and 2% CBD, 5 droplets sublingually two times daily) for symptom relief. The observations in this report build on previous (pre)clinical research highlighting the potential anti-tumor qualities of cannabinoids and stress the need for clinical trials investigating the anti-tumor effects of cannabinoids in cancer patients. Conclusion Based on the two cases presented here, we call for further research into the potential beneficial effect of cannabinoids in patients with advanced HCC.

Background and Aim Direct cholangioscopy and pancreatoscopy have become widely implemented techniques in the diagnostic and therapeutic algorithms of several pancreaticobiliary disorders. This study aimed to generate general and indication‐specific European consensus recommendations on cholangioscopy and pancreatoscopy. Methods Supported by the available literature, statements were formulated and grouped into the following categories: (1) pre‐procedural considerations, (2) general technical aspects, (3) biliopancreatic stones, (4) biliary strictures, and (5) other indications. The evidence level of each statement was determined using the GRADE methodology. Cholangioscopy experts were invited to participate in a modified Delphi process. When 80% consensus was not reached, the statement was modified based on expert feedback and subjected to an additional Delphi round. Statements were rejected if they failed to reach consensus after three Delphi rounds. Results Thirty cholangioscopy experts completed the Delphi process. Forty‐two (97.6%) generated statements were accepted, of which 39 (92.9%) in the first Delphi round. 12 statements on preprocedural and periprocedural settings, 8 statements on biliopancreatic stones, 13 statements on biliary strictures, and 9 statements on other indications were accepted. Conclusion Using a modified Delphi process, we developed general and indication‐specific consensus recommendations for cholangioscopy to guide clinical practice.

Smoking behavior and genetic variations are important factors for the development of Crohn's disease (CD), but studies investigating the interaction between smoking and genetic background are scarce. We studied allelic associations of 19 confirmed variants located in 14 CD-associated genes or loci, in CD patients stratified for active smoking at diagnosis and passive smoking in childhood. Genotyping data of 19 CD-associated single-nucleotide polymorphisms (SNPs) were available for 310 CD patients and 976 controls. Data on active smoking at diagnosis and passive smoking in childhood were obtained through a written questionnaire and a review of medical charts. The loci associated in smoking, but not in non-smoking, CD patients were 5p13.1 (rs17234657), DLG5 (rs2165047), NKX2-3 (rs10883365), and NOD2 (R702W). The loci associated in non-smoking, but not in smoking, CD patients were IL23R (rs7517847), 5p13.1 (rs9292777), IRGM (rs13361189 and rs4958847), IL12B (rs6887695), and CCNY (rs3936503). PTPN2 (rs2542151) was only associated in the smoking CD cohort (P=0.041), and not in the entire cohort (P=0.23) or in the non-smoking CD cohort (P=0.80). In passively smoking CD patients, associations with 13 SNPs in 9 loci were found, including PTPN2. In non-passive smoking CD patients, only associations with NOD2 (1007fsinsC and G908R) were found. The difference in associated genes between smoking and non-smoking CD patients implies a complex gene-environment interaction. Therefore, genetic studies of CD should be stratified for smoking behavior, as otherwise moderately associated genes such as PTPN2 can be missed.

Combination therapy of thiopurines and anti–tumor necrosis factor alpha (TNF-α) antibodies is the most effective medical treatment of Crohn's disease (CD). Data on thiopurines and anti-TNF-α antibodies in preventing surgical recurrence (need for re-resection) of CD are scarce. Therefore, we analyzed which factors were involved in surgical recurrence of CD in a large cohort of patients with CD operated in a regional and a university hospital.MethodsThis is a retrospective cohort study of 567 patients who underwent surgery for CD. Clinical data and risk factors for surgical recurrence were analyzed, focusing on medical therapy and hospital type.ResultsOverall, 237 (41.8%) patients developed a surgical recurrence, after a median of 70 (2–482) months. Before surgical recurrence, 235 patients (41.4%) and 116 patients (20.5%) used thiopurines and anti-TNF-α antibodies, respectively. Multivariate analysis identified 3 independent risk factors associated with surgical recurrence of CD. A higher risk was seen in patients with colonic disease compared with patients with ileal disease (hazard ratio, 1.56; 95% confidence interval, 1.10–2.21; P = 0.012) and in patients using multiple types of medication (hazard ratio, 1.38; 95% confidence interval, 1.25–1.54; P < 0.001). However, a lower risk was seen in patients using thiopurines (hazard ratio, 0.51; 95% confidence interval, 0.34–0.77; P = 0.001).ConclusionsThiopurines are effective in preventing surgical recurrence of CD. The role of anti-TNF-α antibodies seems promising as well. Combination therapy of thiopurines and anti-TNF-α antibodies for prevention of surgical recurrence of CD should be studied in a randomized trial.

Combination therapy of thiopurines and anti-tumor necrosis factor alpha (TNF-α) antibodies is the most effective medical treatment of Crohn's disease (CD). Data on thiopurines and anti-TNF-α antibodies in preventing surgical recurrence (need for re-resection) of CD are scarce. Therefore, we analyzed which factors were involved in surgical recurrence of CD in a large cohort of patients with CD operated in a regional and a university hospital. This is a retrospective cohort study of 567 patients who underwent surgery for CD. Clinical data and risk factors for surgical recurrence were analyzed, focusing on medical therapy and hospital type. Overall, 237 (41.8%) patients developed a surgical recurrence, after a median of 70 (2-482) months. Before surgical recurrence, 235 patients (41.4%) and 116 patients (20.5%) used thiopurines and anti-TNF-α antibodies, respectively. Multivariate analysis identified 3 independent risk factors associated with surgical recurrence of CD. A higher risk was seen in patients with colonic disease compared with patients with ileal disease (hazard ratio, 1.56; 95% confidence interval, 1.10-2.21; P = 0.012) and in patients using multiple types of medication (hazard ratio, 1.38; 95% confidence interval, 1.25-1.54; P < 0.001). However, a lower risk was seen in patients using thiopurines (hazard ratio, 0.51; 95% confidence interval, 0.34-0.77; P = 0.001). Thiopurines are effective in preventing surgical recurrence of CD. The role of anti-TNF-α antibodies seems promising as well. Combination therapy of thiopurines and anti-TNF-α antibodies for prevention of surgical recurrence of CD should be studied in a randomized trial.

Background RaTexT®, an innovative rapid tick exposure test, was recently developed to provide farmers with quick, on-site results to improve their acaricide resistance management. This was achieved by exposing partially engorged adult ticks to a specially designed acaricide-impregnated matrix fitted inside a transparent polypropylene box. Each RaTexT® box contains six strips of four small, interconnected compartments, in which ticks are exposed immediately after removal from cattle in the field. In this study, we assessed whether a single strip of four interconnected compartments, instead of six strips, was sufficient to accurately detect resistance to deltamethrin and to a combination of cypermethrin, chlorpyrifos and piperonyl butoxide (PBO). We also statistically analysed the optimal number of ticks per compartment (ranging between 5 and 8). Moreover, the test reproducibility was checked by two independent observers who counted dead and live ticks in each compartment. Finally, a comparative analysis was undertaken between adult ticks exposed in RaTexT® and in the adult immersion test (AIT), and also with larvae in the resistance intensity test (RIT) and in the larval packet test (LPT). The novelty of this study lies in comparing adult ticks exposed in RaTexT and in the AIT Test, thereby overcoming limitations of previous studies, in which adults in RaTexT were compared with larvae in the LPT. Methods The internal coefficient of variation (CV) was calculated for each dose, box and acaricidal product to assess within-box consistency. The effect of the number of ticks per compartment ( n  = 5–8) was examined using Monte Carlo simulations. Inter-observer reliability of reading RaTexT® was statistically measured using Cohen’s kappa coefficient ( κ ). The comparative performance analysis of the bioassays was conducted using generalised linear models (GLMs) with laboratory and field strains of Rhipicephalus microplus ticks in Brazil. Results Overall agreement between individual strips and their corresponding box classification was 91.3%, indicating high consistency between replicates. The predefined threshold of  ≥  90% accuracy was met by a single strip, supporting the test's robustness even with minimal replication. The internal coefficient of variation within each RaTexT® box was high for deltamethrin (1.285 at 1× dose, 1.109 at 5× dose and 1.268 at 10× dose), but lower for cypermethrin/chlorpyriphos/PBO (0.648 at 1, 0.305 at 5× dose and 0.194 at 10× dose). Variability in the controls was relatively high (CV 1.776). Monte Carlo simulations showed that diagnostic accuracy gradually increased from 81.2% with five ticks to 86.1% with eight ticks per compartment. Furthermore, there was substantial agreement between the mortality of ticks assessed by two independent observers ( κ = 0.664). Finally, the comparative test analysis revealed that the deltamethrin resistance level in RaTexT® matched that observed in the AIT. Resistance to deltamethrin was also confirmed by the LPT, with resistance ratios (RR) of 33.8 and 39.5 for two different field strains (Biotech and UFRRJ, respectively). For cypermethrin/chlorpyriphos/PBO, RaTexT® exhibited significantly lower mortality than the AIT. Resistance was also confirmed by LPT, with RR of 5.2 for Biotech strain and 7.2 for the UFRRJ strain. Conclusions Overall, these findings demonstrate that RaTexT® is accurate and reproducible with a single test strip, making it a practical and cost-effective test that complements traditional laboratory bioassays. Graphical Abstract

Narcolepsy with cataplexy is a sleep disorder caused by the loss of hypocretin-producing neurons in the hypothalamus. It is tightly associated with a specific human leukocyte antigen (HLA)-allele: HLA - DQB1 * 06 : 02 . Based on this, an autoimmune process has been hypothesized. A functional HLA - DQ molecule consists of a DQ α and a DQ β chain. HLA - DQB1 * 06 : 02 ( DQ β) has a strong preference for binding to HLA - DQA1 * 01 : 02 ( DQ α), and together they form the functional DQ0602 dimer. A dosage effect would be expected if the HLA - DQ0602 dimer itself is directly involved in the aetiology. An increased expression of the HLA - DQ0602 dimer is expected in individuals homozygous for HLA - DQB1 * 06 : 02 - DQA1 * 01 : 02 , but is also hypothesized in individuals heterozygous for HLA - DQB1 * 06 : 02 and homozygous for HLA - DQA1 * 01 : 02 . To study the impact of the expression of the HLA - DQ0602 dimer on narcolepsy susceptibility, 248 Dutch narcolepsy patients and 1272 Dutch control subjects, all of them positive for DQB1 * 06 : 02 (heterozygous and homozygous), were HLA-genotyped with attention not only to DQB1 but also to DQA1 * 01 : 02. DQB1 * 06 : 02 - DQA1 * 01 : 02 homozygosity was significantly more often seen in patients compared to controls (O.R. 2.29) confirming previous observations. More importantly, a significantly higher prevalence of homozygosity for DQA1 * 01 : 02 was found in HLA - DQB1 * 06 : 02 heterozygous patients compared to controls (O.R. 2.37, p  < 0.001). The latter finding clearly supports a direct role of the HLA - DQ molecule in the development of disease.