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Background Cystic fibrosis (CF) lung disease is characterised by recurrent Pseudomonas aeruginosa (Pa) infections, leading to structural lung damage and decreased survival. The epidemiology of Pa infection and its impact on lung function in people with CF (pwCF), especially in recent birth cohorts, remain uncertain. Methods We included 1,231 French pwCF under 18 years of age. Age at initial acquisition (Pa-IA), chronic colonisation (Pa-CC), and duration from Pa-IA to Pa-CC were estimated using the Kaplan-Meier method. Demographic, clinical, and genetic characteristics were analysed as risk factors for Pa infection using Cox regression models. Lung function decline was assessed by modelling percent-predicted forced expiratory volume in 1 s (ppFEV1) before Pa infection, after Pa-IA, and after Pa-CC. Results Among the 1,231 pwCF, 50% had Pa-IA by the age of 5.1 years [95% confidence interval (CI) 3.8-6.2] and 25% had Pa-CC by the age of 14.7 years (95% CI 12.1 to ∞). We observed that CF-related diabetes and liver disease were risk factors for Pa, while gender, CFTR variants, and CF centre size were not. Genetic variants of TNF, DCTN4, SLC9A3, and CAV2 were confirmed to be associated with Pa. The annual rate of ppFEV1 decline before Pa was -0.38% predicted/year (95% CI -0.59 to -0.18), which decreased significantly after Pa-IA to -0.93% predicted/year (95% CI -1.14 to -0.71) and after Pa-CC to -1.51% predicted/year (95% CI -1.86 to -1.16). Conclusions We identified and replicated several risk factors associated with Pa infection and showed its deleterious impact on lung function in young pwCF. This large-scale study confirmed that Pa airway infection is a major determinant of lung disease severity.

Background & Aims Primary sclerosing cholangitis (PSC) has a variable, often progressive, course. Magnetic resonance cholangiography (MRC) is used in the diagnosis of PSC. Magnetic resonance risk scoring systems, called Anali without and with gadolinium, are used to predict disease progression, determined by radiologic factors. We aimed to assess the prognostic value of Anali scores in patients with PSC and validate our findings in a separate cohort. Methods We performed a retrospective study of patients with large-duct PSC (internal cohort, 119 patients in France; external cohort, 119 patients in Canada, Italy, and the United Kingdom). All the first-available MRC results were reviewed by 2 radiologists and the Anali scores were calculated as follows: Anali without gadolinium = (1× dilatation of intrahepatic bile ducts) + (2× dysmorphy) + (1× portal hypertension); Anali with gadolinium = (1× dysmorphy) + (1× parenchymal enhancement heterogeneity). The primary end point was survival without liver transplantation or cirrhosis decompensation. The prognostic value of Anali scores was assessed by Cox regression modeling. Results During a total of 549 patient-years for the internal cohort and 497 patient-years for the external cohort, we recorded 2 and 8 liver transplantations, 4 and 3 liver-related deaths, and 26 and 25 cirrhosis decompensations, respectively. In the univariate analysis, factors associated with survival without liver transplantation or cirrhosis decompensation in the internal cohort were as follows: serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, alkaline phosphatase, albumin, and Anali scores. Anali scores without and with gadolinium identified patients' survival without liver transplantation or cirrhosis decompensation with a c-statistic of 0.89 (95% CI, 0.84–0.95) and 0.75 (95% CI, 0.64–0.87), respectively. Independent prognostic factors identified by multivariate analysis were Anali scores and bilirubinemia. The prognostic value of Anali scores was confirmed in the external cohort. Conclusions In internal and external cohorts, we found that Anali scores, determined from MRC, were associated with outcomes of patients with PSC. These scores might be used as prognostic factors.

Magnetic resonance (MR) risk scores and liver stiffness (LS) have individually been shown to predict clinical outcomes in primary sclerosing cholangitis (PSC). The aim of this study was to assess their complementary prognostic value.Patients with PSC from 3 European centers with a 3-dimensional MR cholangiography available for central reviewing and a valid LS measurement assessed by vibration-controlled transient elastography by FibroScan performed within a 6-month interval were included in a longitudinal retrospective study. The MR score (Anali) without gadolinium (Gd) was calculated according to the formula: (1 × dilatation of intrahepatic bile ducts) + (2 × dysmorphy) + (1 × portal hypertension). The primary end point was survival without liver transplantation or cirrhosis decompensation. The prognostic values of LS and Anali score without Gd were assessed using Cox proportional hazard models.One hundred sixty-two patients were included. Over a total follow-up of 753 patient-years, 40 patients experienced an adverse outcome (4 liver transplantations, 6 liver-related deaths, and 30 cirrhosis decompensations). LS and Anali score without Gd were significantly correlated (ρ = 0.51, P0.001) and were independently associated with the occurrence of an adverse outcome. Optimal prognostic thresholds were 10.5 kPa for LS and 2 for the Anali score without Gd. Hazard ratios (95% confidence interval) were 2.07 (1.06-4.06) and 3.78 (1.67-8.59), respectively. The use in combination of these 2 thresholds allowed us to separate patients into low-, medium-, and high-risk groups for developing adverse outcomes. The 5-year cumulative rates of adverse outcome in these 3 groups were 8%, 16%, and 38% (P0.001), respectively.The combined use of MRI and vibration-controlled transient elastography permits easy risk stratification of patients with PSC.

To assess liver steatosis, the controlled attenuation parameter (CAP; giving an estimate of ultrasound attenuation ∼3.5 MHz) is available with the M probe of the FibroScan. We report on the adaptation of the CAP for the FibroScan XL probe (center frequency 2.5 MHz) without modifying the range of values (100-400 dB/m). CAP validation was successfully performed on Field II simulations and on tissue-mimicking phantoms. In vivo performance was assessed in a cohort of 59 patients spanning the range of steatosis. In vivo reproducibility was good and similar with both probes. The area under receiver operative characteristic curve was equal to 0.83/0.84 and 0.92/0.91 for the M/XL probes to detect >2% and >16% liver fat, respectively, as assessed by magnetic resonance imaging. Patients can now be assessed simultaneously for steatosis and fibrosis using the FibroScan, regardless of their morphology.

Viral infections are known to lead to serious respiratory complications in cystic fibrosis (CF) patients. Hypothesizing that CF patients were a population at high risk for severe respiratory complications from SARS-CoV-2 infection, we conducted a national study to describe the clinical expression of COVID-19 in French CF patients. This prospective observational study involves all 47 French CF centers caring for approximately 7500 CF patients. Between March 1st and June 30th 2020, 31 patients were diagnosed with COVID-19: 19 had positive SARS-CoV-2 RT-PCR in nasopharyngeal swabs, 1 had negative RT-PCR but typical COVID-19 signs on a CT scan, and 11 had positive SARS-CoV-2 serology. Fifteen were males, median (range) age was 31 (9&ndash, 60) years, and 12 patients were living with a lung transplant. The majority of the patients had CF-related diabetes (n = 19, 61.3%), and a mild lung disease (n = 19, 65%, with percent-predicted forced expiratory volume in 1 s (ppFEV1) &gt, 70). Three (10%) patients remained asymptomatic. For the 28 (90%) patients who displayed symptoms, most common symptoms at admission were fever (n = 22, 78.6%), fatigue (n = 14, 50%), and increased cough (n = 14, 50%). Nineteen were hospitalized (including 11 out of the 12 post-lung transplant patients), seven required oxygen therapy, and four (3 post-lung transplant patients) were admitted to an Intensive Care Unit (ICU). Ten developed complications (including acute respiratory distress syndrome in two post-lung transplant patients), but all recovered and were discharged home without noticeable short-term sequelae. Overall, French CF patients were rarely diagnosed with COVID-19. Further research should establish whether they were not infected or remained asymptomatic upon infection. In diagnosed cases, the short-term evolution was favorable with rare acute respiratory distress syndrome and no death. Post-lung transplant patients had more severe outcomes and should be monitored more closely.

Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement. The prognostic value of clinical, biochemical, and all three histologic scoring systems on predicting composite endpoints 1 (PSC-related death and liver transplantation), 2 (liver transplantation), and 3 (liver-related events), was assessed using univariable and multivariable Cox proportional hazards modeling. A total of 119 PSC patients were identified, and the median follow-up was 142 months. During follow-up, 31 patients died (20 PSC-related deaths), 31 patients underwent liver transplantation, and 35 patients experienced one or more liver-related events. All three staging systems were independent predictors of endpoints 2 and 3 (Nakanuma system: hazard ratio [HR], 3.16 [95% confidence interval (CI), 1.49-6.68] for endpoint 2 and HR, 2.05 [95% CI, 1.17-3.57] for endpoint 3; Ishak system: HR, 1.55 [95% CI, 1.10-2.18] for endpoint 2 and HR, 1.43 [95% CI, 1.10-1.85] for endpoint 3; Ludwig system: HR, 2.62 [95% CI, 1.19-5.80] for endpoint 2 and HR, 2.06 [95% CI, 1.09-3.89] for endpoint 3). Only the Nakanuma staging system was independently associated with endpoint 1: HR, 2.14 (95% CI, 1.22-3.77). Interobserver agreement was moderate for Nakanuma stage (κ = 0.56) and substantial for Nakanuma component fibrosis (κ = 0.67), Ishak stage (κ = 0.64), and Ludwig stage (κ = 0.62). Conclusion: We confirm the independent prognostic value and demonstrate for the first time the reproducibility of staging disease progression in PSC using the Nakanuma, Ishak, and Ludwig staging systems. The Nakanuma staging system—incorporating features of chronic biliary disease—again showed the strongest predictive value. (Hepatology 2017;65:907-919).

Introduction The diverted use of synthetic opioid buprenorphine by drug addicts can be responsible for serious ischemic and infectious complications, particularly in the case of intravenous injection. Aim We present a case of serious glans ischemia after buprenorphine injection directly into the deep dorsal vein of the penis. Analysis using new medical imaging techniques and treatments is detailed below. Methods A 26‐year‐old male drug addict presented with glans pain 4 days after self‐injection of buprenorphine into the deep dorsal vein of the penis. The patient was apyretic and presented a urethral discharge. His glans was blue without discoloration on digital pressure. Additionally, his biologic and serologic tests were normal while bacteriology showed the presence of Enterobacter cloacae urethritis. Results After 48 hours of intravenous antibiotic treatment without improvement, a specific medical treatment using enoxaparin and ilomedin was initiated, with the assumption that there was an ischemic complication. Laser speckle contrast imaging allowed confirmation of the presence of distal penis ischemia and provided an accurate mapping of the ischemic zone. A 28‐day treatment combining antibiotics, subcutaneous heparin at curative dose, antiplatelet drug, ilomedin, and hyperbaric oxygen therapy resulted in clinical improvement of the lesions with no functional complications. Conclusions To date, no consensus exists on the proper diagnostic and treatment approach to severe glans ischemia due to buprenorphine injection into the deep dorsal vein of the penis. The results of laser speckle contrast imaging were of real interest during the process of diagnosis. In addition, the combination of ilomedin with hyperbaric oxygen therapy and anticoagulant and antiplatelet drugs appeared to be an effective therapy. Brecheteau F, Grison P, Abraham P, Lebdai S, Kemgang S, Souday V, Nedelcu C, Culty T, Larre S, Azzouzi AR, and Bigot P. Successful medical treatment of glans ischemia after voluntary buprenorphine injection. J Sex Med 2013;10:2866–2870.

Epidemiological and intervention studies show that milk consumption in childhood and during adolescence is related to higher bone mineral density. Milk and milk products prevent the bone loss in pre- and postmenopausal women. Apart from calcium, there are other biologically active compounds in milk such as bioactive peptides which may play a role in promoting bone health. Casein is the major protein in milk which has also been reported to have numerous biological active peptides within it. The hypothesis of the present study was to identify the key peptides behind osteoanabolic nature of the milk protein, which further can be used to prepare functional foods to alleviate bone diseases like osteoporosis. Hence, this study was carried out to investigate osteogenic nature of four novel bioactive peptides [PEP1 (EDVPSER), PEP2 (NAVPITPTL), PEP3 (VLPVPQK) and PEP4 (HPHPHLSF)] derived from buffalo casein by in vitro osteoblast differentiation model. Calvaria cells were isolated from 3-day-old rat pups, cultured under in vitro conditions till confluence and further used for experiments. Calvarial osteoblast cells were cultured in the presence or absence of peptides including positive controls up to 21 days. Effect of peptides was checked at regular intervals by quantifying osteoblast differentiation marker genes (ALP, OCN and COL-1) expression, alkaline phosphatase activity, osteocalcin level in culture supernatants, mineral deposition by alizarin red staining and caspase-3 and 9 assays. The osteoblast differentiation marker genes (ALP, OCN and COL-1) expression was significantly [(p

BACKGROUND & AIMS: Dominant strictures occur in approximately 50% of patients with primary sclerosing cholangitis (PSC). Short-term stents have been reported to produce longer resolution of dominant strictures than single-balloon dilatation. We performed a prospective study to compare the efficacy and safety of balloon dilatation vs short-term stents in patients with non-end-stage PSC. METHODS: We performed an open-label trial of patients with PSC undergoing therapeutic endoscopic retrograde cholangiopancreatography (ERCP) at 9 tertiary-care centers in Europe, from July 2011 through April 2016. Patients found to have a dominant stricture during ERCP were randomly assigned to groups that underwent balloon dilatation (n = 31) or stent placement for a maximum of 2 weeks (n = 34); patients were followed for 24 months. The primary outcome was the cumulative recurrence-free patency of the primary dominant strictures. RESULTS: Study recruitment was terminated after a planned interim analysis because of futility and differences in treatment-related serious adverse events (SAEs) between groups. The cumulative recurrence-free rate did not differ significantly between groups (0.34 for the stent group and 0.30 for the balloon dilatation group at 24 months; P = 1.0). Most patients in both groups had reductions in symptoms at 3 months after the procedure. There were 17 treatment-related SAEs: post-ERCP pancreatitis in 9 patients and bacterial cholangitis in 4 patients. SAEs occurred in 15 patients in the stent group (45%) and in only 2 patients in the balloon dilatation group (6.7%) (odds ratio, 11.7; 95% confidence interval, 2.4-57.2; P = .001). CONCLUSIONS: In a multicenter randomized trial of patients with PSC and a dominant stricture, short-term stents were not superior to balloon dilatation and were associated with a significantly higher occurrence of treatment-related SAEs. Balloon dilatation should be the initial treatment of choice for dominant strictures in patients with PSC. This may be particularly relevant to patients with an intact papilla. ClinicalTrials.gov no. NCT01398917. ispartof: GASTROENTEROLOGY vol:155 issue:3 pages:752-+ ispartof: location:United States status: published

Food and fluid intake (FI) data are usually collected during one day with the assumption that this is representative of the daily intake of an individual. However, this assumption has never been validated. The aim of this analysis was to identify FI patterns of German adults using data of a Fluid Intake (FI) survey performed in spring 2012. FI of a national representative sample of German adults (N=1606; 18-65 years; mean FI 2,5 ± 0,9 L/d) was recorded with a 24h fluid specific diary over 7 consecutive days. To identify FI pattern across the week an AMMI (additive main effect and multiplicative interactions) model was created and to cluster subjects with similar patterns a principle component analysis was performed. The results indicated 3 FI patterns, regardless of the mean weekly FI of an individual. The largest cluster of subjects (45% of total sample) consumed less fluid during the weekdays compared to the other clusters, however they increased their FI during the weekend. The 2nd cluster (31% of tota...

Background & Aims Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease that leads to extensive liver fibrosis and cirrhosis, which are associated with poor outcome. However, there are no validated noninvasive markers of liver fibrosis in patients with PSC. We assessed the diagnostic performance, reproducibility, longitudinal changes, and prognostic value of liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE). Methods In a prospective study, we analyzed percutaneous liver biopsy specimens from 73 consecutive patients with PSC from January 2005 to December 2010. Patients underwent VCTE no more than 6 months after the biopsy specimens were collected. The biopsy specimens were analyzed by a pathologist blinded to the results of VCTE for the stage of fibrosis, and LSM was associated with the stage of fibrosis and other variables using the Kruskal–Wallis and Spearman correlation tests. The cutoff values of LSM were selected based on the accuracy with which they identified the stage of fibrosis on receiver-operating characteristic analysis. The rates of LSM progression were assessed using a linear mixed model, and the association between LSM values and clinical outcomes were evaluated using Cox regression analysis in 168 patients with PSC treated with ursodeoxycholic acid and followed up from November 2004 to July 2013 (mean follow-up period, 4 years). Results LSM was independently linked to the stage of fibrosis. Cutoff values for fibrosis stages ≥F1, ≥F2, ≥F3, and F4 were 7.4 kPa, 8.6 kPa, 9.6 kPa, and 14.4 kPa, respectively. The adjusted diagnostic accuracy values for severe fibrosis and cirrhosis were 0.83 and 0.88, respectively. The diagnostic performance of LSM was comparable to that of hyaluronic acid measurement but superior to the aspartate aminotransferase/platelet ratio index, FIB-4 score, and Mayo risk score in differentiating patients with significant or severe fibrosis from those without. LSM had a high level of reproducibility between operators for the same measurement site and for the same operator between 2 adjacent sites. LSM increased significantly and exponentially over time. Baseline measurements and rate of LSM progression were strongly and independently linked with patients' outcomes. Conclusions VCTE is able to differentiate severe from nonsevere liver fibrosis with high levels of confidence in patients with PSC. Baseline measurements of LSM and longitudinal changes are prognostic factors for PSC.

Summary Background & aims In patients with primary sclerosing cholangitis (PSC), ursodeoxycholic acid (UDCA) treatment improves serum liver tests and surrogate markers of prognosis but has no proven effect on survival. Additional therapies are obviously needed. Fibrates, PPAR agonists with anti-cholestatic properties, have a beneficial effect in primary biliary cholangitis. The aim of this study was to evaluate the safety and efficacy of fibrates in PSC patients. Methods Retrospectively, we investigated PSC patients treated with fibrates (fenofibrate 200 mg/day or bezafibrate 400 mg/day) for at least 6 months in addition to UDCA, after an incomplete biochemical response (alkaline phosphatase [ALP] ≥ 1.5 × upper limit of normal) to UDCA. Changes in biochemical parameters and clinical features were assessed. Results Twenty patients were included (fourteen from Paris and six from Barcelona): median age 43.8 years, median liver stiffness 11 kPa (≥ F3). Upon treatment with fibrates (median duration of 1.56 years), liver tests significantly improved, including a reduction of ALP levels by 41% and pruritus significantly decreased. No serious adverse event attributable to fibrates occurred. Discontinuation of fibrates was followed by a clear rebound of ALP. Despite biochemical improvement, liver stiffness significantly increased. Conclusions Combining UDCA with fibrates results in a significant biochemical improvement and pruritus decrease in PSC patients with incomplete response to UDCA. These results provide a rationale for larger and prospectively designed studies to establish the efficacy and safety of fibrates in PSC.