bluuebunny/crossref_metadata_2025 huggingface dataset:
Laboratory Investigation of Thrombophilia
Authors: Tripodi Armando , Mannucci Pier Mannuccio
Published: January 2020

Until recently, laboratory diagnosis of thrombophilia was based on investigation of the plasmatic anticoagulant pathways to detect antithrombin, protein C, and protein S deficiencies and on the search for dysfibrinogenemia and anti-phospholipid antibodies/lupus anticoagulants. More recently, laboratory investigations have been expanded to include activated protein C (APC) resistance, attributable or not to the presence of the factor V Leiden mutation; hyperprothrombinemia attributable to the presence of the prothrombin gene mutation G20210A; and hyperhomocysteinemia attributable to impairment of the relevant metabolic pathway because of enzymatic and/or vitamin deficiencies. All of the above are established congenital or acquired conditions associated with an increased risk of venous and, more rarely, arterial thrombosis.

Testing is recommended for patients who have a history of venous thrombosis and should be extended to their first-degree family members. Because most of the tests are not reliable during anticoagulation, it is preferable to postpone laboratory testing until after discontinuation of treatment.

Whenever possible, testing should be performed by means of functional assays. DNA analysis is required for the prothrombin gene mutation G20210A. Laboratory diagnosis for anti-phospholipid antibodies/lupus anticoagulant should be performed by a combination of tests, including phospholipid-dependent clotting assays and solid-phase anti-cardiolipin antibodies. Hyperhomocysteinemia can be diagnosed by HPLC methods or by fluorescence polarization immunoassays.
Instability of Lipoprotein(a) in Plasma Stored at −70 °C
Authors: Simó Josep M , Camps Jordi , Vilella Elisabet , Gómez Federico , Paul Antonio , Joven Jorge
Published: January 2020

Background: There is considerable evidence to suggest that plasma lipoprotein(a) [Lp(a)] concentration is a cardiovascular risk factor. Confusing results in epidemiologic studies, however, suggest that the effects of storage should be further investigated. The influence of the assay method, the initial plasma Lp(a) concentration, and the apolipoprotein(a) [apo(a)] genotype are all factors that should be considered.

Methods: Blood was obtained from 65 survivors of premature myocardial infarction and 95 age-matched controls. The plasma samples were stored in sterile conditions at −70 °C for 5 years in the presence of antioxidant and antiproteolytic substances. Plasma Lp(a) was measured by immunoturbidimetry, and apo(a) alleles were determined by pulsed-field gel electrophoresis and Southern blotting.

Results: Plasma Lp(a) was significantly higher in patients. The mean kringle number for the smallest isoform was also lower in patients than in controls, but no differences were found in the distribution of the largest isoform. All patients and controls were heterozygotes. During storage, mean Lp(a) decreased significantly in samples from patients (−23%; P <0.001) but not in samples from controls (−9%; P, not significant). This was not related to the kringle number and was limited to samples with initial plasma Lp(a) concentrations between 41 and 345 mg/L.

Conclusions: Plasma Lp(a) from patients is less stable than Lp(a) from controls, and the difference is not related to distribution of apo(a) genotypes but may be concentration-dependent. Differential sample stability may complicate the interpretation of several studies.
Whole-Blood Calcineurin Activity Is Not Predicted by Cyclosporine Blood Concentration in Renal Transplant Recipients
Authors: Caruso Raffaele , Perico Norberto , Cattaneo Dario , Piccinini Giampiero , Bonazzola Samantha , Remuzzi Giuseppe , Gaspari Flavio
Published: January 2020

Background: In transplant patients, current cyclosporine (CsA) dose monitoring with classic pharmacokinetics has demonstrated limitations. Evaluation of the activity of calcineurin (CN), the serine-threonine phosphatase enzyme target of CsA, has been proposed as a reliable way to optimize CsA dosing.

Methods: CN activity was measured in whole blood in an attempt to overcome the high variability of results obtained previously with peripheral blood mononuclear cells (PBMCs). We also explored, in vitro, a possible relationship between the CsA concentration and CN inhibition in whole blood. Finally, we assessed whether the CsA blood trough concentration correlates with whole-blood CN activity in kidney transplant recipients (n = 15) on maintenance immunosuppression with CsA.

Results: In 14 healthy individuals, less scattered CN activity values were documented in whole blood than in the PBMC fraction. Whole-blood CN activity was higher than the sum of the enzyme activity in each cell blood fraction. After ex vivo incubation of whole blood from healthy subjects (n = 5) with increasing concentrations of CsA (50–1000 μg/L for 1 h), a concentration-dependent inhibition of CN activity was found comparable to that in the PBMC fraction. Moreover, in 15 kidney transplant recipients, no relationship was found between CsA pharmacokinetic parameters and CN activity at time 0. However, a highly significant correlation was found between CN area under the CN activity-time curve, which represents the extent of the CN daily inhibition, and CN activity at time 0 (r = 0.79; P <0.01) and at 12 h postdosing (r = 0.96; P <0.01).

Conclusions: Measuring CN activity in whole-blood samples is a reproducible method. In kidney transplant recipients, CsA trough concentrations do not predict baseline CN activity. Moreover, a single CN activity monitoring at baseline or at time 12 h post-CsA dosing may be a useful surrogate for the inhibition of this enzyme by CsA during 12 h.
Direct Serum Total Iron-binding Capacity Assay Suitable for Automated Analyzers
Authors: Siek Gordon , Lawlor Joseph , Pelczar Donna , Sane Meena , Musto Joseph
Published: January 2020

Background: Present methods for measuring serum total iron-binding capacity (TIBC) involve manipulation of samples or performance of two assays on each sample. We developed a direct automated assay (DTIBC) for TIBC.

Methods: We added to serum a saturating amount of iron bound to an excess of chelating dye at a low pH, recorded a blank reading that represented the sum of the saturating amount of iron plus the serum iron, and then added a strong neutral pH buffer. The decrease in absorbance (as transferrin extracts iron from the iron-dye complex) is directly proportional to the TIBC. TIBC values for 125 patients were determined by DTIBC, alumina column TIBC (AC), magnetic particle TIBC (MTIBC), and the UIBC method (UIBC) on Roche COBAS FARA and Mira chemistry analyzers. In a separate study, TIBC values for 128 patients were determined on an Olympus AU400 by the DTIBC and the MTIBC methods.

Results: Methods comparisons on the COBAS analyzers yielded the following results: DTIBC = 1.05(MTIBC) − 1.0 μmol/L (r = 0.987; Sy|x = 2.6 μmol/L); DTIBC = 1.07(AC) − 1.0 μmol/L (r = 0.982; Sy|x = 3.0 μmol/L); and DTIBC = 1.14(UIBC) + 3.4 μmol/L (r = 0.982; Sy|x = 3.0 μmol/L). A similar correlation study using the Olympus AU400 yielded DTIBC = 1.00(MTIBC) − 0.1 μmol/L (r = 0.983; Sy|x = 2.7 μmol/L). The assay was linear from 12.5 to 125 μmol/L (70–700 μg/dL) TIBC on the COBAS FARA. Within- and between-run imprecision (CV) was ≤4.8% at two concentrations. Plasma samples were unsuitable for the method. No interference was seen with common interferants other than ascorbate, deferoxamine, and ferrous sulfate, and only at concentrations well above normal.

Conclusion: The new DTIBC assay is suitable for routine use in clinical laboratories and may improve the quality of iron metabolism studies.
Compliance of General Practitioners with a Guideline-based Decision Support System for Ordering Blood Tests
Authors: van Wijk Marc AM , van der Lei Johan , Mosseveld Mees , Bohnen Arthur M , van Bemmel Jan H
Published: January 2020

Background: Guidelines are viewed as a mechanism for disseminating a rapidly increasing body of knowledge. We determined the compliance of Dutch general practitioners with the recommendations for blood test ordering as defined in the guidelines of the Dutch College of General Practitioners.

Methods: We performed an audit of guideline compliance over a 12-month period (March 1996 through February 1997). In an observational study, a guideline-based decision support system for blood test ordering, BloodLink, was integrated with the electronic patient records of 31 general practitioners practicing in 23 practices (16 solo). BloodLink followed the guidelines of the Dutch College of General Practitioners. We determined compliance by comparing the recommendations for test ordering with the test(s) actually ordered. Compliance was expressed as the percentage of order forms that followed the recommendations for test ordering.

Results: Of 12 668 orders generated, 9091 (71%) used the decision-support software rather than the paper order forms. Twelve indications accounted for >80% of the 7346 order forms that selected a testing indication in BloodLink. The most frequently used indication for test ordering was “vague complaints” (2209 order forms; 30.1%). Of the 7346 order forms, 39% were compliant. The most frequent type of noncompliance was the addition of tests. Six of the 12 tests most frequently added to the order forms were supported by revisions of guidelines that occurred within 3 years after the intervention period.

Conclusions: In general practice, noncompliance with guidelines is predominantly caused by adding tests. We conclude that noncompliance with a guideline seems to be partly caused by practitioners applying new medical insight before it is incorporated in a revision of that guideline.
Hepatitis C Genotype Determination by Melting Curve Analysis with a Single Set of Fluorescence Resonance Energy Transfer Probes
Authors: Bullock Grant C , Bruns David E , Haverstick Doris M
Published: January 2020

Background: The genotype of hepatitis C virus (HCV) is a predictor of antiviral therapeutic response. We describe an approach for HCV genotype determination by real-time PCR and melting curve analysis.

Methods: After automated nucleic acid extraction, we used reverse transcription-PCR in a block cycler to amplify nucleotides 6–329 of the 5′-untranslated region of HCV. The product was further amplified by single-tube real-time seminested PCR in a LightCyclerTM instrument (Roche). The final product was analyzed by melting curves with the use of fluorescence resonance energy transfer (FRET) probes. The FRET sensor probe was directed at nucleotides 151–170 of type 1 HCV and was designed to distinguish types 1a/b, 2a/c, 2b, 3a, and 4, with melting temperatures (Tms) predicted to differ by 1 °C. Genotypes were compared in a blinded fashion with those of the INNO-LiPATM test (Bayer Diagnostics) on 111 serum samples.

Results: In preliminary experiments, the Mg2+ concentration was found to be critical in allowing clear separation of melting points, with the best separation at a Mg2+ concentration of 2 mmol/L. The results for 111 samples clustered at expected Tms for genotypes 1a/b (n = 78), 2a/c (n = 2), 2b (n = 11), 3a (n = 14), and 4 (n = 2). Of the 111 samples, results for 110 were concordant with the comparison method at the level of type 1, 2, 3, or 4. Subtyping results were discordant for two samples, both of type 2. For 108 samples concordant with INNO-LiPA at the genotype and subtype levels, the mean Tms were 64.1, 59.5, 54.2, 52.6, and 50.1 °C for types 1a/b, 2a/c, 4, 2b, and 3a, respectively, with SDs of 0.2, 0.3, 0.3, 0.2, and 0.3 °C. All 78 samples identified as type 1 were concordant with results of the comparison method.

Conclusions: Melting analysis with a single pair of FRET probes can rapidly provide information about HCV genotypes and identifies type 1 samples with high specificity.
Multiplex Minisequencing of the 21-Hydroxylase Gene as a Rapid Strategy to Confirm Congenital Adrenal Hyperplasia
Authors: Krone Nils , Braun Andreas , Weinert Stefanie , Peter Michael , Roscher Adelbert A , Partsch Carl-Joachim , Sippell Wolfgang G
Published: January 2020

Background: Congenital adrenal hyperplasia (CAH) is a frequent autosomal recessive disease, with a wide range of clinical manifestations, most commonly attributable to mutations in the 21-hydroxylase gene (CYP21). Large gene deletions, large gene conversions, a small 8-basepair deletion, and eight point mutations in CYP21 account for ∼95% of all enzyme deficiencies. We developed a new strategy for a rapid CYP21 analysis.

Methods: DNA samples from 40 CAH patients previously genotyped by direct DNA sequencing were reanalyzed by allele-specific amplification of the functional CYP21 gene followed by a multiplex minisequencing reaction using 13 primers. In addition, a second PCR that amplified a part of exon 3 was used to demonstrate the presence or absence of at least one functional gene.

Results: The assay detected the P453S mutation and nine of the most common mutations (P30L, intron 2 splice, Δ8bp, I172N, exon 6 cluster, V281L, F306+t, Q318X, and R356W) caused by microconversions from the CYP21P pseudogene. The concordance was 100% for detecting these mutations, including gene deletions and large gene conversions. The 40 patient DNA samples were analyzed in 1.5 working days by one technician (actual hands-on time, 3.5 h). The material cost for analyzing one sample was approximately €10.00 (US $9.00).

Conclusions: This novel mutation screening strategy rapidly detects 90–95% of all mutations associated with CAH and appears applicable as a tool for confirmation of increased 17-hydroxyprogesterone found in neonatal CAH screening.
Evaluation of a No-Pretreatment Cyclosporin A Assay on the Dade Behring Dimension RxL Clinical Chemistry Analyzer
Authors: Terrell Andrea R , Daly Thomas M , Hock Karl G , Kilgore Daniel C , Wei Tie Q , Hernandez Sharon , Weibe Don , Fields Leona , Shaw Leslie M , Scott Mitchell G
Published: January 2020

Background: Monitoring whole-blood concentrations of cyclosporin A (CsA) is common practice in the management of solid organ and bone marrow transplant recipients. In a multicenter study we evaluated a new, direct (no pretreatment) CsA assay on the Dade Behring Dimension RxLTM system and compared results with those from the Abbott TDx CsA immunoassay and a HPLC method.

Methods: Whole-blood samples from heart (n = 111; 35 patients), liver (n = 201; 44 patients), kidney (n = 279; 65 patients), and miscellaneous organ (n = 77; 12 lung, 12 bone marrow, 5 kidney/pancreas, and 1 pancreas patient) recipients were obtained from patient populations of the participating institutions. Routine clinical monitoring of CsA was performed using either the TDx method or HPLC.

Results: The minimum detectable concentration of CsA averaged 9.4 μg/L, and the lower limit of quantification was 30 μg/L. The method was linear from 30 to 500 μg/L. Cross-reactivity with seven different CsA metabolites ranged from 0.0% to 5.7% for the Dimension RxL assay compared with 0.4–15.9% for the TDx assay. Total imprecision (CV) averaged 6.2%, and within-run imprecision averaged 4.9%. Passing–Bablok linear regression analyses of all samples from two sites yielded the following: RxL = 0.81 × TDx − 16.8; and RxL = 1.12 × HPLC − 1.7.

Conclusions: The Dade Behring CsA assay for the random-access Dimension platform offers adequate performance characteristics for routine clinical use, does not require a manual pretreatment step, and demonstrates less cross-reactivity with CsA metabolites than another commonly used immunoassay.
Relationship of Serum HER-2/neu and Serum CA 15-3 in Patients with Metastatic Breast Cancer
Authors: Ali Suhail M , Leitzel Kim , Chinchilli Vernon M , Engle Linda , Demers Laurence , Harvey Harold A , Carney Walter , Allard Jeffrey W , Lipton Allan
Published: January 2020

Background: Serum HER-2/neu antigen concentrations have been reported to correlate with increased tumor volume in patients with breast cancer. We measured serum CA 15-3, a surrogate marker of disease burden, and correlated serum CA 15-3 with serum HER-2/neu and analyzed the association of both markers with clinical outcomes.

Methods: Pretreatment serum samples from 566 patients were retrospectively analyzed from 2 phase III clinical trials of estrogen receptor-positive (ER+), ER−/progesterone receptor-positive, or ER status unknown metastatic breast cancer patients randomized in two similar studies to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole). The extracellular domain of the HER-2/neu (c-erbB-2) oncogene and serum CA 15-3 were measured by ELISA on the Bayer Immuno 1.

Results: Serum HER-2/neu protein was increased in 168 patients (30%), and CA 15-3 was increased in 337 (60%) patients. Serum CA 15-3 and HER-2/neu were weakly correlated (r = 0.39; P <0.0001). The clinical benefit (complete responses plus partial responses plus stable disease) of endocrine therapy was significantly lower in patients with increased serum HER-2/neu. When adjusted for serum HER-2/neu, serum CA 15-3 was not predictive of response rates. The median time to progression was shorter in patients with increased serum HER-2/neu (89 days) compared with patients with normal serum HER-2/neu (176 days). Survival was significantly shorter in patients with increased serum HER-2/neu (513 vs 869 days; P <0.0001) or increased serum CA 15-3 (689 vs 939 days; P <0.0001). This observation was confirmed by multivariate analysis.

Conclusions: Serum HER-2/neu is a significant independent predictive and prognostic factor in hormone receptor-positive metastatic breast cancer, even when adjusted for tumor burden as measured by CA 15-3. The combination of increased serum HER-2/neu and increased serum CA 15-3 predicts a worse prognosis than does increased CA 15-3 alone.
Stromal Cells in the Pathogenesis of Inflammatory Bowel Disease
Authors: Barnhoorn M C , Hakuno S K , Bruckner R S , Rogler G , Hawinkels L J A C , Scharl M
Published: January 2020

Up till now, research on inflammatory bowel disease [IBD] has mainly been focused on the immune cells present in the gastrointestinal tract. However, recent insights indicate that stromal cells also play an important and significant role in IBD pathogenesis. Stromal cells in the intestines regulate both intestinal epithelial and immune cell homeostasis. Different subsets of stromal cells have been found to play a role in other inflammatory diseases [e.g. rheumatoid arthritis], and these various stromal subsets now appear to carry out also specific functions in the inflamed gut in IBD. Novel potential therapies for IBD utilize, as well as target, these pathogenic stromal cells. Injection of mesenchymal stromal cells [MSCs] into fistula tracts of Crohn’s disease patients is already approved and used in clinical settings. In this review we discuss the current knowledge of the role of stromal cells in IBD pathogenesis. We further outline recent attempts to modify the stromal compartment in IBD with agents that target or replace the pathogenic stroma.
Comparison of newer generation self-expandable vs. balloon-expandable valves in transcatheter aortic valve implantation: the randomized SOLVE-TAVI trial
Authors: Thiele Holger , Kurz Thomas , Feistritzer Hans-Josef , Stachel Georg , Hartung Philipp , Eitel Ingo , Marquetand Christoph , Nef Holger , Doerr Oliver , Lauten Alexander , Landmesser Ulf , Abdel-Wahab Mohamed , Sandri Marcus , Holzhey David , Borger Michael , Ince Hüseyin , Öner Alper , Meyer-Saraei Roza , Wienbergen Harm , Fach Andreas , Frey Norbert , König Inke R , Vonthein Reinhard , Rückert Yvonne , Funkat Anne-Kathrin , de Waha-Thiele Suzanne , Desch Steffen
Published: January 2020

Aims

Transcatheter aortic valve implantation (TAVI) has emerged as established treatment option in patients with symptomatic aortic stenosis. Technical developments in valve design have addressed previous limitations such as suboptimal deployment, conduction disturbances, and paravalvular leakage. However, there are only limited data available for the comparison of newer generation self-expandable valve (SEV) and balloon-expandable valve (BEV).

Methods and results

SOLVE-TAVI is a multicentre, open-label, 2 × 2 factorial, randomized trial of 447 patients with aortic stenosis undergoing transfemoral TAVI comparing SEV (Evolut R, Medtronic Inc., Minneapolis, MN, USA) with BEV (Sapien 3, Edwards Lifesciences, Irvine, CA, USA). The primary efficacy composite endpoint of all-cause mortality, stroke, moderate/severe prosthetic valve regurgitation, and permanent pacemaker implantation at 30 days was powered for equivalence (equivalence margin 10% with significance level 0.05). The primary composite endpoint occurred in 28.4% of SEV patients and 26.1% of BEV patients meeting the prespecified criteria of equivalence [rate difference −2.39 (90% confidence interval, CI −9.45 to 4.66); P  equivalence = 0.04]. Event rates for the individual components were as follows: all-cause mortality 3.2% vs. 2.3% [rate difference −0.93 (90% CI −4.78 to 2.92); P  equivalence < 0.001], stroke 0.5% vs. 4.7% [rate difference 4.20 (90% CI 0.12 to 8.27); P  equivalence = 0.003], moderate/severe paravalvular leak 3.4% vs. 1.5% [rate difference −1.89 (90% CI −5.86 to 2.08); P  equivalence = 0.0001], and permanent pacemaker implantation 23.0% vs. 19.2% [rate difference −3.85 (90% CI −10.41 to 2.72) in SEV vs. BEV patients; P  equivalence = 0.06].

Conclusion

In patients with aortic stenosis undergoing transfemoral TAVI, newer generation SEV and BEV are equivalent for the primary valve-related efficacy endpoint. These findings support the safe application of these newer generation percutaneous valves in the majority of patients with some specific preferences based on individual valve anatomy.
COMPARE: prospective, randomized, non-inferiority trial of high- vs. low-dose paclitaxel drug-coated balloons for femoropopliteal interventions
Authors: Steiner Sabine , Schmidt Andrej , Zeller Thomas , Tepe Gunnar , Thieme Marcus , Maiwald Lars , Schröder Henrik , Euringer Wulf , Ulrich Matthias , Brechtel Klaus , Brucks Steffen , Blessing Erwin , Schuster Johannes , Langhoff Ralf , Schellong Sebastian , Weiss Norbert , Scheinert Dierk
Published: January 2020

Aims

Drug-coated balloons (DCBs) for femoropopliteal interventions have not been tested against each other. We aimed to directly compare efficacy and safety of a high-dose (In.Pact™) vs. low-dose (Ranger™) DCB with nominal paclitaxel densities of 3.5 vs. 2.0 μg/mm2.

Methods and results

Within a prospective, multicentre, non-inferiority, clinical trial 414 patients with symptomatic femoropopliteal lesions (Rutherford classification 2–4) were randomly assigned in a 1:1 ratio to endovascular treatment with either high- or low-dose DCB after stratification for lesion length. Primary efficacy and safety endpoints comprised primary patency and freedom from major adverse events (i.e. device and procedure-related deaths through 1 month, major amputations, and clinically driven target lesion revascularization through 12 months). We set a non-inferiority margin of −10% at 12 months. Total occlusions were observed frequently (>40%) and provisional stenting was performed in every fourth intervention. Non-inferiority was determined for both primary efficacy and safety endpoints at 12 months. Primary patency was 81.5% in the high-dose and 83.0% in low-dose DCB group {difference: 1.5% [lower bound of the 90% two-sided confidence interval (CI) −5.2%]; P  non-inferiority < 0.01}. Freedom from major adverse events was determined in 92.6% in high-dose and in 91.0% in low-dose DCB group [difference −1.6% (lower bound of the 90% two-sided CI −6.5%); P  non-inferiority < 0.01]. Overall death rate was low (2.0%) and no major amputation occurred.

Conclusion

Two DCBs with different coating characteristics exhibited comparable results with excellent effectiveness and safety through 12 months for femoropopliteal interventions including a wide range of lesion lengths.

Clinical trial registration

The trial is registered with ClinicalTrials.gov (NCT02701543).
Integrated management of atrial fibrillation in primary care: results of the ALL-IN cluster randomized trial
Authors: van den Dries Carline J , van Doorn Sander , Rutten Frans H , Oudega Ruud , van de Leur Sjef J C M , Elvan Arif , Oude Grave Lisa , Bilo Henk J G , Moons Karel G M , Hoes Arno W , Geersing Geert-Jan
Published: January 2020

Aims

To evaluate whether integrated care for atrial fibrillation (AF) can be safely orchestrated in primary care.

Methods and results

The ALL-IN trial was a cluster randomized, open-label, pragmatic non-inferiority trial performed in primary care practices in the Netherlands. We randomized 26 practices: 15 to the integrated care intervention and 11 to usual care. The integrated care intervention consisted of (i) quarterly AF check-ups by trained nurses in primary care, also focusing on possibly interfering comorbidities, (ii) monitoring of anticoagulation therapy in primary care, and finally (iii) easy-access availability of consultations from cardiologists and anticoagulation clinics. The primary endpoint was all-cause mortality during 2 years of follow-up. In the intervention arm, 527 out of 941 eligible AF patients aged ≥65 years provided informed consent to undergo the intervention. These 527 patients were compared with 713 AF patients in the control arm receiving usual care. Median age was 77 (interquartile range 72–83) years. The all-cause mortality rate was 3.5 per 100 patient-years in the intervention arm vs. 6.7 per 100 patient-years in the control arm [adjusted hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.37–0.82]. For non-cardiovascular mortality, the adjusted HR was 0.47 (95% CI 0.27–0.82). For other adverse events, no statistically significant differences were observed.

Conclusion

In this cluster randomized trial, integrated care for elderly AF patients in primary care showed a 45% reduction in all-cause mortality when compared with usual care.
Peri-procedural management, implantation feasibility, and short-term outcomes in patients undergoing implantation of leadless pacemakers: European Snapshot Survey
Authors: Lenarczyk Radosław , Boveda Serge , Mansourati Jacques , Russo Vincenzo , Marijon Eloi , Lane Deirdre A , Dagres Nikolaos , Potpara Tatjana S
Published: January 2020

The aim of this European Heart Rhythm Association (EHRA) prospective snapshot survey is to assess procedural settings, safety measures, and short-term outcomes associated with implantation of leadless pacemakers (LLPM), across a broad range of tertiary European electrophysiology centres. An internet-based electronic questionnaire (30 questions) concerning implantation settings, peri-procedural routines, complications, and in-hospital patient outcomes was circulated to centres routinely implanting both LLPMs and transvenous pacemakers (TV-PM). The centres were requested to prospectively include consecutive patients implanted with either LLPMs or TV-PMs during the 10-week enrolment period. Overall, 21 centres from four countries enrolled 825 consecutive patients between November 2018 and January 2019, including 69 (9%) implanted with LLPMs. Leadless pacemakers were implanted mainly under local anaesthesia (69%), by an electrophysiologist (60%), in the electrophysiology laboratory (71%); 95% of patients received prophylactic antibiotics prior to implantation. Most patients on chronic oral anticoagulation were operated on-drug (35%), or during short-term (to 48 h) drug withdrawal (54%). Implantation was successful in 98% of patients and the only in-hospital procedure-related complication was groyne haematoma in one patient. This EHRA snapshot survey provides important insights into LLPM implantation routines and patient outcomes. These findings suggest that despite the unfavourable clinical profile of pacemaker recipients, LLPM implantation is associated with relatively low risk of complications and good short-term outcomes.
Incidence, mechanisms, and clinical impact of inappropriate shocks in patients with a subcutaneous defibrillator
Authors: Rudic Boris , Tülümen Erol , Fastenrath Fabian , Röger Susanne , Goranova Diana , Akin Ibrahim , Borggrefe Martin , Kuschyk Jürgen
Published: January 2020

Aims

Inappropriate shocks (IAS) remain a challenge for patients and physicians after implantation of the subcutaneous implantable cardioverter-defibrillator (S-ICD). The aims were to assess and characterize different patterns of IAS.

Methods and results

Two hundred and thirty-nine patients were implanted with an S-ICD between 2010 and 2018 for primary and secondary prevention. Follow-up data of at least 6 months were analysed. During a mean follow-up of 34.9 ± 16.0 months, a total of 73 shocks occurred in 38 patients (6%). Forty-three (59%) shocks were considered appropriate due to ventricular tachycardia/ventricular fibrillation, while 30 (41%) were inappropriate and occurred in 19 patients (8%). Myopotentials/noise was the most frequent cause of inappropriate shocks (n = 8), followed by T-wave oversensing (n = 6) and undersensing of the QRS, resulting in adaptation of the automatic gain control and inappropriate shock (n = 5). Seventy-four percent of all IAS occurred on the primary vector, while no IAS occurred on the alternate vector. In seven of eight patients (88%), IAS related to myopotentials have occurred on the primary sensing vector. Multivariate analysis identified taller patients, primary sensing vector and first-generation S-ICD device as predictors for IAS. SMART pass effectively reduced the occurrence of IAS in the second-generation S-ICD system.

Conclusion

Inappropriate therapies are less frequently observed on the alternate vector. The primary vector seems to be unfavourable with regard to oversensing caused by myopotentials. Inappropriate shocks were associated with an increased rate of rehospitalization but not mortality. These observations have implications for the prevention of inappropriate S-ICD shocks.
Motion, Contact and Profanity in Rutebeuf’s Tales of ‘Charlot Le Juif’: (Not) Going There, (Not) Touching That
Authors: Simpson James R
Published: January 2020

This article explores what we can learn about the context of thirteenth-century Paris from the relation between what is explicit and implicit in Rutebeuf’s tales of Charlot the Jew. Dated to the 1260s, these two texts – ‘La Disputaison de Charlot et du Barbier de Melun’ and ‘Charlot le juif qui chia dans la peau du lièvre’ – survive in Paris, BnF, MS fr. 1635. In themselves, in relation to one another and in their manuscript context, these tales reveal much about the function of hints and hidden jokes as soundings of intercommunal tensions and polemic in the period between the Paris Disputation of 1240 and the outbursts of violence later in the century. The discussion of the text focuses on the representation of cultural and religious provocation, and especially Rutebeuf ’s possible adumbrating of sensitive issues not always addressed in explicit fashion. Charlot’s seeming resistance to provocation in various regards may thus reflect a context in which Louis IX encouraged the lay population to take direct action in response to any perceived insults against Christianity from the Jewish population.
Developing a European Toolbox to manage potential invasion by emerald ash borer (Agrilus planipennis) and bronze birch borer (Agrilus anxius), important pests of ash and birch
Authors: Evans H F , Williams D , Hoch G , Loomans A , Marzano M
Published: January 2020

The threats posed by the buprestid beetles emerald ash borer (Agrilus planipennis Fairmaire) and bronze birch borer (Agrilus anxius Gory) have been the subject of considerable research, primarily to develop methods for detection and management of the pests. PREPSYS, a Euphresco project, has worked with collaborators globally to assess the ‘state of the art’ for the two insect pests and to identify those measures that would best prepare Europe for potential invasion by the pests, especially emerald ash borer which is now in the western part of Russia and in eastern Ukraine. Building on an excellent exchange of knowledge and discussion at the OECD-sponsored international conference held in Vienna in October 2018, the concept of a European Toolbox to increase preparedness for dealing with the pests has been developed. This includes key components including surveillance, direct intervention, use of natural enemies and increased awareness of the problems associated with the pests. Collaboration is essential in delivering and refining the European Toolbox.
Multisectoral approach and WHO ‘Bestbuys’ in Nigeria’s nutrition and physical activity policies
Authors: Oluwasanu Mojisola , Oladunni Opeyemi , Oladepo Oladimeji
Published: January 2020

Unhealthy diet and physical inactivity are modifiable risk factors for non-communicable diseases. Policies formulated in line with international guidelines are required for the implementation of population-level interventions to reduce the risks. This study describes the utilization of multisectoral approach (MSA) for the formulation of nutrition and physical activity policies and the extent to which they align with the WHO ‘Best Buy Interventions’. The research utilized a descriptive case study design and the theoretical model guiding the study was the Walt and Gilson framework for policy analysis. Data were obtained through the interview of 44 key informants using pre-tested guides and document review of 17 policies and articles obtained from government institutions or through the search of electronic databases. Data were integrated and analysed using thematic analysis. Between 2000 and 2016, Nigeria had formulated 10 nutrition-related policies and 5 guidelines with actions to promote physical activity. Only three nutrition and two physical activity policies adopted a high level of MSA. In line with the WHO best buy interventions, educational interventions for the general population are proposed to reduce sugar and salt intake and replace transfat with polyunsaturated fats but there are no legal regulatory acts to support these actions. Policy documents with actions to reduce physical inactivity do not include the WHO best buys. The country should adopt a wider range of actors to formulate and review policies, integrate all the WHO best buy interventions and develop effective legislation to regulate the salt and sugar content of processed foods.
Beyond an Anxiety Logic: A Critical Examination of Language Rights Cases before the European Court of Human Rights
Authors: Schmalz Dana
Published: January 2020

Language rights have traditionally been codified and discussed in the context of minority protection. The identification of language rights with questions of national minorities can, however, confound the analysis. This article explores the freedom of using a language and argues that the individual dimension of language rights must not be ignored beside the group dimension. The argument proceeds along a reading of three recent cases from the European Court of Human Rights, which concerned the use of Kurdish in Turkey. The Court’s reasoning illustrates the risk of an ‘anxiety logic’, which sees any language rights in connection with political claims of groups, thereby introducing additional conditions for the right and disregarding the significance a specific language can have for an individual, being more than a medium of conveying and receiving information. Conceptualising language use as an individual freedom is necessary also to account for situations other than national minorities, most importantly for the language rights of immigrants.
P096 DE NOVO COLITIS AFTER OCRELIZUMAB THERAPY
Authors: Akram Ali , Valasek Mark , Patel Derek
Published: January 2020

Introduction

Ocrelizumab is a humanized anti-CD20 monoclonal antibody approved for the treatment of adults with primary progressive or relapsing multiple sclerosis (MS). We report a case of de novo colitis in an MS patient who received a single dose of ocrelizumab.

Case report

A 62-year-old-male with primary progressive MS diagnosed in 2002, previously treated with corticosteroids, interferon beta-1a, and dimethyl fumarate, was admitted with 2 weeks of nonbloody diarrhea resulting in dehydration and weight loss. These symptoms began approximately 1 week after receiving a 300mg induction dose of ocrelizumab. Stool studies including culture, nucleic acid gastrointestinal pathogen panel and ova and parasite examination were negative. Stool fat stain was negative and fecal elastase was normal. Fecal calprotectin was markedly elevated, as were sedimentation rate (ESR) and c-reactive protein (CRP) (Table 1). CT of the abdomen and pelvis with intravenous contrast demonstrated pancolitis. Flexible sigmoidoscopy was performed and showed diffuse mucosal edema, loss of vascular pattern, granularity and multiple small ulcers to the proximal extent of the exam (Figure 1, Panel A). Biopsies confirmed moderately active colitis with mild architectural changes and mild plasmacytosis. Immunohistochemistry showed abundant CD3 cells with paucity of CD19 and CD 20 cells. The patient was treated with IV methylprednisolone with symptomatic improvement and was discharged on oral prednisone.

Two months after discharge (week 12 after ocrelizumab), diarrhea recurred during attempt to taper prednisone. Full colonoscopy at this time showed mild pancolitis with normal terminal ileum. Biopsies revealed minimally active colitis and new focal subepithelial collagen table thickening. Following multiple unsuccessful attempts to taper off of prednisone, extended release budesonide was started at week 41. This allowed for prednisone taper while maintaining symptomatic remission. Follow-up sigmoidoscopy at week 50 showed mucosal healing (Figure 1, Panel B); biopsies showed thickened subepithelial collagen layer typical of collagenous colitis.

The patient continues on budesonide at week 60; CD19 cell count remains undetectable (normal 6–23%).

Conclusion

To our knowledge, this is the first reported case of colitis associated with ocrelizumab therapy. Pertinent features include a) initial presentation with nonbloody diarrhea and endoscopic pancolitis with elevated ESR, CRP and fecal calprotectin, b) clinical response to prednisone and budesonide, and c) evolution into a collagenous colitis phenotype.
1 LOW RISK OF LYMPHOMA IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE TREATED USING ANTI-TUMOR NECROSIS FACTOR AGENTS
Authors: Egberg Matthew , Smitherman Andrew , Zhang Xian , Kappelman Michael
Published: January 2020

Background

Anti-Tumor Necrosis Factor (aTNF) agents are among the most effective medications used to treat pediatric inflammatory bowel diseases (pIBD). Despite their effectiveness, concerns regarding an association with lymphoma limit their use in everyday practice. We sought to determine the incidence rate and absolute risk of lymphoma in pIBD patients receiving aTNF treatment using a large, geographically diverse administrative insurance claims database.

Methods

We used the IQVIA Legacy PharMetrics Administrative Claims Database to identify pediatric (≤18 years) IBD patients (Crohn’s disease and ulcerative colitis) enrolled between 2007 and 2016. The IQVIA dataset contains enrollees’ clinical utilization, expenditures, and outpatient prescription information. We identified patient baseline data and medication exposure history over time to determine the incidence and absolute risk of lymphoma in our pIBD cohort.

Results

We identified 9,284 pIBD patients enrolled between 2007 and 2016, 62% with Crohn’s disease. The mean age of the cohort was 13.7 years (SD, 4.2) and comprised of 47% females. The median follow-up was 24 months (IQR, 33). Twenty-one percent of the cohort were treated with an aTNF agent during follow-up and 38% with an immune modulator (Thiopurine or Methotrexate). Nearly 8.5% were started on an aTNF agent while treated with an immune modulator, of which 90% were Thiopurines. We identified 3 cases of lymphoma occurring over 25,413 person-years of follow-up (Incidence rate, 11.8 cases/100,000 person-years). The absolute risk of lymphoma in our pIBD sample was 0.3 x 10–3. There were no cases of hepatosplenic T cell lymphoma observed. The medication exposure history for cases of lymphoma did not include treatment with an aTNF agent and/or an immune modulator.

Conclusion

Among our cohort of pIBD, the overall incidence and absolute risk of lymphoma were extremely low. Treatment with aTNF agents and/or immune modulators was not associated with an increased risk of malignancy. Our results would support prioritization of the clinical benefits of aTNF agents over the low risk for malignancy.
5 CREATION OF A CHRONIC PERIANAL CROHN’S FISTULA IN SWINE
Authors: Li Ling , Duraes Leonardo , Gearhart Susan , Zaheer Atif , Hu Haijie , Cheng Jiafei , Yao zhicheng , Donet Jean , Salem George , Mao Hai-quan , Selaru Florin , Parian Alyssa
Published: January 2020

Introduction

Perianal Crohn’s disease (PCD) is associated with worse outcomes including poor quality of life and higher medical costs. PCD is notoriously difficult to treat despite advancements in biologic therapies for luminal disease. In order to test innovative therapies for PCD, an animal model that closely mimics human perianal disease is warranted. Previous efforts were successful in creating perianal fistulas in swine, however, these closed after removal of the seton. A chronic model that maintains the fistula open and replicates the inflammatory component found in clinic is necessary.

Methods

Under general anesthesia, 4 female pigs underwent creation of surgical perianal fistulas using basic surgical technique with scalpel and hemostat. Size 24 French silicone foley catheter setons were placed to maintain patency of the fistula tract. Each pig had 3 fistulas created – 1 rectovaginal and 2 perianal. The setons were left in place for 4 weeks. After removal of the setons, Trinitrobenzenesulfonic acid (TNBS) was administered into the fistula tract twice a week to create local inflammation. After 2 weeks of TNBS, an MRI was obtained to assess the fistula tracts and the pigs were sacrificed to review histopathology.

Results

MRI showed successful creation of chronic fistula tracts, and maintenance of these tracts 2 weeks after removal of setons. We noted a transsphincteric fistula with supralevator component as well as an associated abscess 3.3 x 1.0 cm containing fluid and gas (Fig 1). Gross specimen revealed patent fistula tracts. Histopathology found significant chronic active inflammation on standard H&E staining (Fig 2).

Conclusions

A chronic perianal fistula model in pigs was successfully created using large bore rubber setons and TNBS stimulation that strongly resembles that seen in humans. Further studies are needed to standardize the conditions required to have a reproducible model with well-defined levels of inflammation, fistula patency, and other parameters.
P151 DISRUPTION OF ENDOGENOUS ITACONATE PRODUCTION EXACERBATES EXPERIMENTAL COLITIS
Authors: Frieler Ryan , Vigil Thomas , Mortensen Richard , Shah Yatrik
Published: January 2020

Background

Inflammation is a hallmark of inflammatory bowel disease and alterations in tricarboxylic acid cycle (TCA) metabolism have been identified as major regulators of immune cell phenotype during inflammation and hypoxia. The TCA cycle metabolite, itaconate, is produced by the enzyme aconitate decarboxylase 1 (Acod1) and is highly upregulated during classical macrophage activation and during experimental colitis. Itaconate and cell permeable derivatives have robust anti-inflammatory effects on macrophages, therefore we hypothesized that Acod1-produced itaconate has a protective, anti-inflammatory effect during experimental colitis.

Methods and Results

Wild type (WT) control and Acod1-/- mice were administered 3% Dextran Sulfate Sodium (DSS) in water for 7 days to induce experimental colitis. After DSS was discontinued, Acod1-/- mice had significantly reduced body weight recovery with increased macroscopic disease severity, and upon dissection had decreased colon length and more severe inflammation. To determine if myeloid cells are the critical Acod1/itaconate-producing cell types, we generated myeloid-specific Acod1 deficient mice, however no differences in weight loss, colon length or inflammatory gene expression were detected compared to WT controls. To test whether supplementation with exogenous itaconate could ameliorate colitis, WT mice were treated with the cell-permeable form of itaconate, dimethyl itaconate (DMI). Administration of DMI significantly improved recovery after 7 days of DSS treatment and significantly reduced inflammatory gene expression in the colon.

Conclusion

Our data suggest that Acod1-produced itaconate has an important role in the regulation of inflammation during experimental colitis. Although myeloid cells have been thought to be major producers of Acod1 and itaconate, our data indicate that other cell types are involved. These results highlight the importance of this immunometabolic pathway and suggest that preservation or enhancement of this pathway with natural metabolites or metabolite derivatives could have beneficial effects during colitis.
6 NOVEL BRD4 INHIBITORS BLOCK THE PATHOLOGICAL ACTIVATION OF BRD4-NFκB SIGNALING AND SUPPRESS COLONIC INFLAMMATION IN IBD MOUSE MODELS
Authors: Liu Zhiqing , Uribe Gabriela , Li Yi , Pingyuan Wang , Chen Haiying , Brasier Allan , Pinchuk Irina , Zhou Jia , Tian Bing
Published: January 2020

Ulcerative Colitis (UC) and Crohn’s Disease (CD) are two major types of inflammatory bowel disease (IBD), with recurrent symptoms and significant morbidity. Long-term persistence of chronic inflammation in IBD is among the major factors contributing to neoplastic transformation and development of colitis-associated colorectal cancer. There is a lack of efficient medications for IBD, due to either limited efficacy or side effects. Antibodies against TNFα are effective therapies; however, they are expensive, and up to 40% of patients are non-responders. Thus, improved therapy with higher efficacy, enhanced safety and better patient affordability is urgently needed.

The master regulator of innate immune response NFκB plays a critical role in the initiation and chronicity of IBD mucosal inflammation. We demonstrated that bromodomain-containing protein 4 (BRD4), an epigenetic reader, is required for stabilization of NFκB binding on the promoters of inflammatory genes, activation of RNA polymerase II, and histone H3 Lys122 acetylation (H3K122ac) to permit high levels of inflammatory gene expressions by sentinel epithelial cells and stromal fibroblasts. Our data using human IBD patient samples suggest that BRD4 activation is critical to the initiation of colonic inflammation.

We have successfully identified highly potent and specific BRD4 inhibitors, demonstrating that inhibition of BRD4 suppresses expression of inflammatory cytokines TNFα, IL-6, IL-17A, and IL-8. Administration of our lead inhibitors (ZL0454 & ZL0420) significantly reduces initiation of the mucosal inflammation in both dextran sulfate sodium (DSS)-induced and Cbir1 T cell transfer colitis models in vivo, but with low toxicity and much safer than the generic NFκB/IKK inhibitor BMS345541. The levels of NFkB and BRD4 activation were also compared using immunofluorescence staining of NFkB/RelA translocation, phospho-Ser276 RelA formation, and induction of the BRD4 marker H3K122Ac. The BRD4 inhibitors reduced DSS-induced NFkB-BRD4 activation in colon tissue, demonstrating the target specificity in vivo.

Our data suggest that BRD4 activation is critical to the initiation of the colonic inflammation during IBD. BRD4 inhibition disrupts its interactions with acetylated histone lysine residues, thereby blocking the pathological activation of the BRD4-NFκB signaling and suppressing colonic inflammation. Therefore, inhibition of the BRD4 activation is an attractive target for the development of novel IBD therapy and in prevention of CAC. Using our novel BRD4 inhibitors, we will further seek to evaluate the effect of long-term BRD4 inhibition on UC-induced neoplastic transformation and development of CAC.

Funding support: Crohn’s & Colitis Foundation Entrepreneurial Investing (EI) Initiative award and a research fellowship award from the Crohn’s & Colitis Foundation of America.