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Made available in DSpace on 2022-04-29T08:30:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Background and aims: The role of thiopurines in therapeutic algorithms of Crohn's disease (CD) and Ulcerative colitis (UC) is being questioned. This work aimed to investigate current practice and future perspectives of Inflammatory Bowel Disease (IBD) physicians regarding the efficacy, safety, and role of precision medicine with thiopurines in IBD. Methods: A 29-questions web-based survey was developed and distributed to IBD physicians worldwide. Results: We collected the complete answers of 408 physicians from 50 countries. Most participants were experienced physicians in IBD; 26.0% met our definition of “IBD expert”. Four physicians reported to not use thiopurines in clinical practice. Most respondents used thiopurines in monotherapy and in combination therapy, both in CD and UC. Respondents tended to consider thiopurines as drugs with a good safety profile, with the agreement of 61.5% of the overall cohort. A minority of physicians (~6%) considered that thiopurines will not be used in the future in IBD patients, while 57.8% believed that these drugs will still be used, in mono and combination therapy. Conclusion: Despite the many emerging treatments in IBD, according to the beliefs of most physicians surveyed, thiopurines will still be an important part of the treatment algorithm of both CD and UC. Department of Gastroenterology Viseu Unit Tondela-Viseu Hospital Centre IBD Center Fondazione Policlinico Universitario A. Gemelli IRCCS Universita Cattolica Department of Medicine I Agaplesion Markus Hospital Goethe-University Department of Gastroenterology Oslo University Hospital IBD Unit Department of Gastroenterology Hospital Clínico Universitario de Santiago de Compostela Division of Gastroenterology and Hepatology University Hospital Department of Internal Medicine São Paulo State University (Unesp) Medical School Colorectal Surgery Unit IBD outpatient clinics Catholic University of Paraná (PUCPR) Department of Gastroenterology and Inserm NGERE U1256 University Hospital of Nancy University of Lorraine Department of Biomedicine Unit of Pharmacology and Therapeutics University of Porto Department of Gastroenterology São João University Hospital MedInUP Centre for Drug Discovery and Innovative Medicines Department of Internal Medicine São Paulo State University (Unesp) Medical School

Skin fibrosis is a complex biological remodeling process occurring in disease like systemic sclerosis, morphea, or eosinophilic fasciitis. Since the knowledge about the underlying pathomechanisms is still incomplete, there is currently no therapy, which prevents or reverses skin fibrosis sufficiently. The present study investigates the role of polo-like kinase 2 (PLK2) and the pro-fibrotic cytokine osteopontin (OPN) in the pathogenesis of cutaneous fibrosis and demonstrates the antifibrotic effects of systemic mesalazine treatment in vivo. Isolated primary dermal fibroblasts of PLK2 wild-type (WT) and knockout (KO) mice were characterized invitro. Skin thickness and histoarchitecture were studied in paraffin-embedded skin sections. The effects of mesalazine treatment were examined in isolated fibroblasts and PLK2 KO mice, which were fed 100 µg/g mesalazine for 6 months via the drinking water. Compared to WT, PLK2 KO fibroblasts displayed higher spontaneous myofibroblast differentiation, reduced proliferation rates, and overexpression of the fibrotic cytokine OPN. Invitro, 72 h of treatment with 10 mmol/L mesalazine induced phenotype conversion in PLK2 KO fibroblasts and attenuated OPN expression by inhibiting ERK1/2. In vivo, dermal myofibroblast differentiation, collagen accumulation, and skin thickening were prevented by mesalazine in PLK2 KO. Plasma creatinine levels indicated good tolerability of systemic long-term mesalazine treatment. The current study reveals a spontaneous fibrotic skin phenotype and ERK1/2-dependent OPN overexpression in PLK2 KO mice. We provide experimental evidence for the antifibrotic effectiveness of systemic mesalazine treatment to prevent fibrosis of the skin, suggesting further investigation in experimental and clinical settings.

AIM Tumour necrosis factor inhibitors (TNFi) have revolutionized the management of moderate to severe ulcerative colitis (UC) since their approval for UC in 2005. However, many patients ultimately require surgery with ileal pouch-anal anastomosis (IPAA). Development of de novo Crohn's disease (CD) following IPAA is an increasingly common and devastating complication, sometimes progressing to pouch failure. The aim of this study was to evaluate the association of preoperative TNFi exposure and the development of de novo CD after IPAA. METHOD A prospective single-centre inflammatory bowel disease (IBD) registry was searched for consecutive patients with UC undergoing IPAA during a 25-year period ending July 2018. Patients with preoperative CD or IBD-unclassified were excluded. De novo CD was diagnosed upon endoscopic evidence of five or more mucosal ulcers proximal to the ileal pouch any time after surgery and/or pouch fistula occurring more than three months after ileostomy closure. RESULTS The study cohort consisted of 400 patients with a median follow-up of 44.0 (IQR 11-113) months. Sixty-two (16%) patients developed de novo CD 28.0 (IQR 6-67) months following ileostomy closure. Survival analysis of TNFi era patients revealed a significant increase in de novo CD risk in those with preoperative TNFi exposure. Multivariable proportional hazards modelling revealed two independent predictors for de novo CD development: older age was protective (HR 0.89 per 5-year increase; P = 0.009) and preoperative TNFi exposure was hazardous (HR 2.10; P = 0.011). CONCLUSION This prospective study is the first to suggest an association between preoperative TNFi exposure and the development of de novo CD.

Background and Aims. Recent evidences reveal that epithelial to mesenchymal transition (EMT) exacerbates the process of intestinal fibrosis. Tumor necrosis factor-like ligand 1A (TL1A) is a member of the tumor necrosis family (TNF), which can take part in the development of colonic inflammation and fibrosis by regulating immune response or inflammatory factors. The purpose of this study was to elucidate the possible contribution of TL1A in onset and progression of intestinal inflammation and fibrosis through EMT. Methods. Colonic specimens were obtained from patients with inflammatory bowel disease (IBD) and control individuals. The expression levels of TL1A and EMT-related markers in intestinal tissues were evaluated. Furthermore, the human colorectal adenocarcinoma cell line, HT-29, was stimulated with TL1A, anti-TL1A antibody, or BMP-7 to assess EMT process. In addition, transgenic mice expressing high levels of TL1A in lymphoid cells were used to further investigate the mechanism of TL1A in intestinal fibrosis. Results. High levels of TL1A expression were detected in the intestinal specimens of patients with ulcerative colitis and Crohn’s disease and were negatively associated with the expression of an epithelial marker (E-cadherin), while it was positively associated with the expression of interstitial markers (FSP1 and α-SMA). Transgenic mice with high expression of TL1A were more sensitive to dextran sodium sulfate and exhibited severe intestinal inflammation and fibrosis. Additionally, the TGF-β1/Smad3 pathway may be involved in TL1A-induced EMT, and the expression of IL-13 and EMT-related transcriptional molecules (e.g., ZEB1 and Snail1) was increased in the intestinal specimens of the transgenic mice. Furthermore, TL1A-induced EMT can be influenced by anti-TL1A antibody or BMP-7 in vitro. Conclusions. TL1A participates in the formation and process of EMT in intestinal fibrosis. This new knowledge enables us to better understand the pathogenesis of intestinal fibrosis and identify new therapeutic targets for its treatment.

PURPOSE: The long-term effect of low and moderate doses of ionizing radiation on the lens is still a matter of debate and needs to be evaluated in more detail. MATERIAL AND METHODS: We conducted a detailed histological analysis of eyes from B6C3F1 mice cohorts after acute gamma irradiation (60Co source; 0.063 Gy/min) at young adult age of 10 weeks with doses of 0.063, 0.125 and 0.5 Gy. Sham irradiated (0 Gy) mice were used as controls. To test for genetic susceptibility heterozygous Ercc2 mutant mice were used and compared to wild type mice of the same strain background. Mice of both sexes were included in all cohorts. Eyes were collected 4 hours, 12, 18 and 24 months after irradiation. For a better understanding of the underlying mechanisms, metabolomics analyses were performed in lenses and plasma samples of the same mouse cohorts at 4 and 12 hours as well as 12, 18 and 24 months after irradiation. For this purpose, a targeted analysis was chosen. RESULTS: This analysis revealed histological changes particularly in the posterior part of the lens that rarely can be observed by using Scheimpflug imaging, as we reported previously. We detected a significant increase of posterior subcapsular cataracts 18 and 24 months after irradiation with 0.5 Gy (odds ratio 9.3; 95%-confidence interval 2.1 - 41.3) independent of sex and genotype. Doses below 0.5 Gy (i.e. 0.063 and 0.125 Gy) did not significantly increase the frequency of posterior subcapsular cataracts at any time point. In lenses, we observed a clear effect of sex and aging but not of irradiation or genotype. While metabolomics analyses of plasma from the same mice showed only a sex effect. CONCLUSIONS: This paper demonstrates a significant radiation-induced increase in the incidence of posterior subcapsular cataracts, which could not be identified using Scheimpflug imaging as the only diagnostic tool.

ispartof: JOURNAL OF CROHNS & COLITIS vol:13 issue:2 pages:144-+ ispartof: location:England status: published

Background Crohn disease (CD) affects the small bowel in 80% of patients. Double balloon endoscopy (DBE) provides the potential for direct and extensive mucosal visualization with the potential for diagnostic monitoring and therapeutic intervention. This study aimed to investigate the safety and effectiveness of DBE in small-bowel CD. Methods From our DBE database, patients with CD at the time of index DBE (January 2004-January 2013) were identified. Data collection included demographics, CD phenotype (age at diagnosis, disease location, disease activity), procedural information, adverse events (perforation, pancreatitis, death), therapeutic intervention (stricture dilation), and outcome (escalation or maintenance of existing therapy, referral to surgery). Results A total of 184 DBEs were performed in patients with inflammatory bowel disease over 162 endoscopic sessions. In this cohort, 115 patients had previously diagnosed CD. A diagnosis of CD was made in 22 patients. Of those with known CD, 140 DBEs were performed in 82 patients; DBE findings led to escalation of medical therapy in 26% of patients, maintenance of therapy in 26% of patients, and surgery in 18% of patients. We considered DBE to have failed in 11% (n = 18) of patients. During 46 endoscopic sessions, in 29 patients, 103 strictures were dilated via balloon dilation. Of patients undergoing dilation with clinical follow-up, 19 of 24 (79%) patients were surgery-free during the study period. Overall, there were 2 perforations. Conclusions We found that DBE is a safe and effective procedure in patients with suspected or established CD. Furthermore, patients undergoing dilation of strictures via DBE had an 80% surgery-free rate within the follow-up period.

INTRODUCTION Iron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD) and can result in reduced quality of life and increased healthcare costs. IDA is treated with iron supplementation, either with oral iron therapy (OI) or intravenous iron formulations, including ferric carboxymaltose (FCM), iron isomaltoside 1000 (IIM), and iron sucrose (IS). This analysis compared the cost-effectiveness of FCM versus IIM, IS, and OI in terms of additional cost per additional responder in Switzerland. METHODS A health economic model was developed to assess the additional cost per additional responder, defined as normalization or an increase of at least 2 g/dL in hemoglobin levels, for FCM versus IIM, IS, and OI. To date, no single head-to-head trial comparing all therapies is available, and therefore relative efficacy data were taken from a published network meta-analysis. Costs of treatment were calculated in 2020 Swiss francs (CHF) using a microcosting approach, and included the costs of iron, healthcare professional time, and consumables. Costs are also presented in euros (EUR) based on an exchange rate of CHF 1 = EUR 0.94. RESULTS Response rates with FCM, IIM, IS, and OI were 81%, 74%, 75%, and 69%, respectively, with FCM projected to be the most effective treatment. FCM was associated with cost savings of CHF 24 (EUR 23) versus IIM and of CHF 147 (EUR 138) versus IS, and increased costs by CHF 345 (EUR 324) versus OI. Therefore FCM was considered dominant versus both IIM and IS, improving clinical outcomes with cost savings. FCM was associated with an incremental cost-effectiveness ratio of CHF 2970 (EUR 2792) per additional responder versus OI. CONCLUSIONS FCM was projected to be the most cost-effective intravenous iron therapy in Switzerland, increasing the number of responders and leading to cost savings for healthcare payers.

Background Postoperative morbidity after laparoscopic bariatric surgery is considered higher for patients undergoing revisional versus primary procedures. The objective of this retrospective cohort study was to compare outcomes between patients undergoing primary versus revisional robotically assisted laparoscopic (RAL) Roux-en-Y gastric bypass (RYGB). Methods Data of all patients who underwent RAL primary and revisional RYGB between 2009 and 2019 at two accredited, high-volume bariatric surgery centers—the Memorial Hermann – Texas Medical Center, Houston, TX, and the Tower Health, Reading Hospital, Reading, PA, were analyzed. Primary outcomes were early ( Results Data of 1072 patients were analyzed, including 806 primary and 266 revisional RAL RYGB procedures. Longer operative times (203 versus 154 min, P P = 0.101). Early (P = 0.318). There were no statistically significant differences between groups in overall and severe complication rates. Conclusion Patients undergoing RAL primary and revisional RYGB had comparable overall outcomes, with a non-significant higher early complication rate in the revisional group. Despite the study being underpowered to detect differences in specific complication rates, the morbidity seen in the revisional RYGB group remains markedly below literature reports of revisional laparoscopic RYGB and might suggest a benefit of robotic assistance. Further prospective studies are needed to confirm these results.

After developing a magnetically actuated microshutter array sub-system, which acts as a field object selector for the James Webb Space Telescope (JWST), our team at the NASA Goddard Space Flight Center (GSFC) focused on the development of electrostatically actuated microshutter arrays – the Next Generation Microshutter Arrays (NGMSA). This letter describes the first NGMSA array that performed shutter operations for telescope imaging and spectroscopy in space. The carrier telescope, the Next-Generation Far-UV Off Rowland-circle Telescope for Imaging and Spectroscopy (NG-FORTIS) was produced by Prof. Stephan McCandliss and his team at Johns Hopkins University and launched into space successfully. [2020-0226]

Rationale: Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown. Objective: To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery. Methods and Results: Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca 2+ ] i -recordings in atrial cardiomyocytes, along with protein-expression levels in tissue homogenates or cardiomyocytes, were assessed in 265 atrial samples from patients without or with POAF. No indices of electrical, profibrotic, or connexin remodeling were noted in POAF, but Ca 2+ -transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca 2+ -release events and L-type Ca 2+ -current alternans occurred more frequently. CaMKII (Ca 2+ /calmodulin-dependent protein kinase-II) protein-expression, CaMKII-dependent phosphorylation of the cardiac RyR2 (ryanodine-receptor channel type-2), and RyR2 single-channel open-probability were significantly increased in POAF. SR Ca 2+ -content was unchanged in POAF despite greater SR Ca 2+ -leak, with a trend towards increased SR Ca 2+ -ATPase activity. Patients with POAF also showed stronger expression of activated components of the NLRP3 (NACHT, LRR, and PYD domains-containing protein-3)-inflammasome system in atrial whole-tissue homogenates and cardiomyocytes. Acute application of interleukin-1β caused NLRP3-signaling activation and CaMKII-dependent RyR2/phospholamban hyperphosphorylation in an immortalized mouse atrial cardiomyocyte cell-line (HL-1-cardiomyocytes) and enhanced spontaneous SR Ca 2+ -release events in both POAF cardiomyocytes and HL-1-cardiomyocytes. Computational modeling showed that RyR2 dysfunction and increased SR Ca 2+ -uptake are sufficient to reproduce the Ca 2+ -handling phenotype and indicated an increased risk of proarrhythmic delayed afterdepolarizations in POAF subjects in response to interleukin-1β. Conclusions: Preexisting Ca 2+ -handling abnormalities and activation of NLRP3-inflammasome/CaMKII signaling are evident in atrial cardiomyocytes from patients who subsequently develop POAF. These molecular substrates sensitize cardiomyocytes to spontaneous Ca 2+ -releases and arrhythmogenic afterdepolarizations, particularly upon exposure to inflammatory mediators. Our data reveal a potential cellular and molecular substrate for this important clinical problem.

Ferritin ist der fur die Entgiftung und Speicherung von Eisen entscheidende Proteinkomplex. Es zahlt zu den Akut-Phase-Proteinen und wird bei Entzundungen und hohem Eisenspiegel induziert. Bei Eisenmangel wird die Synthese unterdruckt. Zur Differenzialdiagnose der Hyperferritinamie mussen laborchemisch Anamien und Entzundungen gesucht werden. Ausserdem ist nach einer Eisenuberladung (Transferrinsattigung, HFE-Genetik und ggf. loslicher Transferrinrezeptor, Ferritinindex) und chronischen Lebererkrankungen (Hepatitis- und Autoimmunserologie, Sonographie, Elastographie) zu suchen. In 90 % ist eine Krankheit ohne Eisenuberladung Ursache der Hyperferritinamie. Eine Eisenuberladung kann bei Hamolyse oder Lebererkrankungen, die zu einem Mangel des „Eisenhormons“ Hepcidin fuhren, auftreten. Eine Leberbiopsie zur Bestimmung des hepatischen Eisenindex ist bei Erkrankungen ohne Eisenuberladung wie dem Hyperferritinamie-Katarakt-Syndrom kontraindiziert. Die genetische Hamochromatose ist eine seltene Ursache fur eine Hyperferritinamie mit primarer Eisenuberladung. Zur Vermeidung von Organschaden erfolgen Phlebotomien, die beim Hyperferritinamie-Katarakt-Syndrom hingegen kontraindiziert sind.

Infliximab rescue therapy is effective in patients with corticosteroid refractory acute severe ulcerative colitis, but predictors of response remain poorly understood. We aimed to identify predictors of colectomy in this high-risk patient population. Patients hospitalized with acute severe ulcerative colitis who received infliximab after failing intravenous corticosteroid therapy between July 2012 and June 2017 were retrospectively identified. Stepwise regression with backward elimination was used to identify predictors of colectomy at 90 days and 1 year. Ninety-day and 1-year colectomy rates were compared between the patients who received 5 mg/kg and 10 mg/kg IFX rescue dose. Sixty-three patients met the eligibility criteria. Twenty-nine patients received 5 mg/kg, and 34 received 10 mg/kg infliximab dose. Serum albumin on admission (OR 0.10; p = 0.04) and band neutrophil percentage at the time of infliximab administration (OR 1.21; p = 0.02) were independent predictors of 90-day colectomy. A combination of serum albumin ≤ 2.5 g/dl and band neutrophil count ≥ 13% had a 100% positive predictive value for 90-day colectomy. Unadjusted 90-day and 1-year colectomy rates were similar in the 5 mg/kg and 10 mg/kg infliximab groups. After adjusting for confounding factors, 10 mg/kg infliximab dose was potentially protective for 90-day (OR 0.07; p = 0.06) but not for 1-year colectomy (OR 0.19; p = 0.16). Bandemia and low serum albumin are independent predictors of failure of infliximab rescue therapy in acute severe ulcerative colitis. Serum albumin ≤ 2.5 g/dl and band neutrophil count ≥ 13% had a 100% positive predictive value for 90-day colectomy.

BACKGROUND AND AIMS Given the lack of data, we aimed to systematically analyze therapeutic patterns and health resource utilization in the year before inflammatory bowel disease (IBD)-related hospitalization. METHODS Based on claims data of the Helsana health insurance group, therapy patterns and health resource utilization were assessed, and costs reimbursed by mandatory basic health insurance were calculated during a one-year period before an index hospitalization between 1 January 2013 to 31 December 2015. RESULTS We analyzed 344 IBD patients (140 ulcerative colitis [40.7%], 204 Crohn's disease [59.3%]). Drug regimens applied in the year before index hospitalization were as follows: no IBD drugs (43.6% ulcerative colitis, 43.1% Crohn's disease); 5-ASA (45.7% ulcerative colitis, 19.1% Crohn's disease); local steroids (17.9% ulcerative colitis, 17.6% Crohn's disease); systemic steroids (38.6% ulcerative colitis, 29.4% Crohn's disease); immunomodulators (10.7% ulcerative colitis, 18.1% Crohn's disease); biologics (10% ulcerative colitis, 24% Crohn's disease); and calcineurin inhibitors (2.1% ulcerative colitis, 1.5% Crohn's disease). Forty-five percent of ulcerative colitis patients and 31.4% of Crohn's disease patients had no diagnostic procedures [computed tomography (CT), MRI, radiograph, sonography, colonoscopy, and calprotectin] in the year before hospitalization. Total annual health care costs before index hospitalization was EUR 4060 (interquartile range (IQR) 2360-7390) for ulcerative colitis and EUR 4900 (IQR 1520-14 880) for Crohn's disease patients, respectively. CONCLUSIONS Over 40% of ulcerative colitis and Crohn's disease patients did not receive any treatment in the year before index hospitalization. Efforts should be launched to timely diagnose and adequately treat IBD outpatients.

Early postoperative small bowel obstruction (ESBO) is a challenging problem. Although it is usually amenable to non-operative management, a significant proportion of patients will require re-operation. Certain causes of ESBO and types of index procedures should prompt consideration for early re-operation. A laparoscopic approach during the index operation, certain barrier agents and closure of mesenteric defects in bariatric surgery may reduce the risk of ESBO. There is no consensus regarding an acceptable length of time for initial non-operative management of ESBO but re-operation beyond two weeks may be associated with increased complications.

Radiochemotherapy is the standard treatment for anal carcinoma (ACa). Intensity-modulated radiotherapy (IMRT) has been introduced, allowing focused irradiation of the tumor area. Whether physical benefits of IMRT translate to clinical benefits has not been sufficiently demonstrated. We retrospectively reviewed data from 82 patients with newly diagnosed ACa. Patients treated with IMRT were compared with previous patients treated with conventional three-dimensional computational radiotherapy (3D-CRT). The influence of IMRT on complete remission and acute and chronic side effects was analyzed in univariate and multivariate analyses. 39/40 patients treated with IMRT were in complete remission after 1 year compared to 31/39 patients treated with 3D-CRT (p = 0.014). Multivariate analysis confirmed tumor T stage as well as lack of IMRT treatment as risk factors for persistent tumor at 6 months. No significant benefits of IMRT were apparent at later timepoints (median follow up 52 months, IQR: 31.5–71.8 months). Patients treated with IMRT had a significantly lower degree of skin toxicity (median 2 vs. 3 in a scale ranging from 0 to 3, p = 0.00092). Rates of hematological toxicity/proctitis were not reduced and rates of acute diarrhea increased (p = 0.034). Median length of hospitalization tended to be shorter in patients treated with IMRT (n. s.). We present a real-world experience of shifting radiation technique from conventional 3D-CRT to IMRT. IMRT patients had better tumor control at 1 year and lower degrees of skin toxicity. Our data indicate that IMRT can enable therapies with lower side effects with equal or better oncological results for patients with ACa.

Patient characteristics associated with difficult tracheal intubation using a flexible bronchoscope (FB) under general anesthesia have not been prospectively evaluated. This observational study aimed to identify demographic and morphologic factors associated with difficult FB intubation.We recruited 420 adult elective surgery patients undergoing tracheal intubation during general anesthesia. Patients characteristics were recorded including age, sex, weight, height, body mass index, American Society of Anesthesiologists physical status, history of snoring, obstructive sleep apnea, Mallampati score, upper lip bite test score, neck circumference and skinfold thickness, maximal neck flexion and extension angles, absence of teeth, Cormack and Lehane grade, presence of blood or secretions during intubation, as well as the inter-incisor, thyromental, sternothyroid, and manubriomental distances. The time (duration) needed to complete intubation (primary endpoint) and the number of attempts needed were correlated with these patient characteristics in a multivariable analysis.Intubation was successful on the first attempt in 409/420 patients (97%). Seven patients (1.7%) needed more than one attempt. Failure to intubate with the FB occurred in four patients (1%). A correlation was found between intubation duration and visibility impaired by secretions or blood (P0.001), higher neck skinfold thickness (P0.001), and larger endotracheal tube diameter (relative to a constant 5.5 mm FB; P0.001).The presence of secretions or blood that impair FB glottic visualization, a larger diameter endotracheal tube on the same size FB, as well as higher neck skinfold thickness may prolong the duration of FB intubation under general anesthesia.www.clinicaltrials.gov (NCT02769819); registered 5 May, 2016.RéSUMé: OBJECTIF: Les caractéristiques des patients associées à une intubation trachéale difficile avec un bronchoscope flexible sous anesthésie générale n’ont pas été évaluées de façon prospective. Cette étude observationnelle avait pour but d’identifier les facteurs démographiques et morphologiques associés aux intubations difficiles avec un bronchoscope flexible. MéTHODES: Nous avons recruté 420 patients adultes devant subir une intubation trachéale au cours d’une anesthésie générale pour une chirurgie élective. Les caractéristiques suivantes des patients ont été consignées : âge, sexe, poids, taille, indice de masse corporelle, score de l’American Society of Anesthesiologists, antécédents de ronflements et de syndrome d’apnée-hypopnée du sommeil, score de Mallampati, score du test de morsure de la lèvre supérieure, circonférence du cou et épaisseur du pli cutané cervical, angles maximums de flexion et extension du cou, absence de dents, grade de la classification de Cormack et Lehane, présence de sang ou de sécrétions pendant l’intubation, ainsi que les distances inter-incisives, menton-cartilage thyroïde, sterno-thyroïdienne et menton-manubrium. Le temps nécessaire pour compléter l’intubation (critère d’évaluation principal) et le nombre de tentatives nécessaires ont été corrélés aux caractéristiques des patients dans une analyse multifactorielle. RéSULTATS: L’intubation a été réussie dès la première tentative chez 409 patients sur 420 (97 %). Pour 7 patients (1,7 %, il a fallu plus d’une tentative. Un échec de l’intubation avec bronchoscope flexible est survenu chez 4 patients (1 %). Une corrélation a été trouvée entre la durée de l’intubation et une mauvaise visualisation due à des sécrétions ou du sang (P 0,001), un pli cutané cervical plus épais (P 0,001), et un plus grand diamètre du tube endotrachéal (par rapport à un fibroscope souple constant de 5,5 mm; P 0,001). CONCLUSIONS: La présence de sang ou de sécrétions gênant la visualisation de la glotte, un diamètre du tube endotrachéal augmenté par rapport à celui du fibroscope flexible ainsi qu’une plus grande épaisseur du pli cutané cervical peuvent prolonger le temps d’intubation avec endoscope flexible sous anesthésie générale. ENREGISTREMENT DE L’ESSAI CLINIQUE: www.clinicaltrials.gov (NCT02769819); enregistré le 5 mai 2016.

The purpose of this study was to investigate the impact of obesity on disease activity and disease outcome in patients with inflammatory bowel disease.The impact of obesity on inflammatory bowel disease disease activity and outcome was retrospectively assessed in 3075 patients enrolled in the prospective nation-wide Swiss inflammatory bowel disease cohort between July 2006 and September 2018. Baseline characteristics, disease activity and disease course in 325 obese inflammatory bowel disease patients (body mass index ≥30 kg/mAmong 3075 patients in the prospective Swiss inflammatory bowel disease cohort, 325 patients (10.6%) were obese, namely, 194 Crohn's disease patients, 131 ulcerative colitis, and inflammatory bowel disease-unclassified patients. Disease activity scores were elevated in obese Crohn's disease (Crohn's Disease Activity Index 33 vs 20,Obesity is associated with decreased rates of disease remission and increased risk of complicated disease course in Crohn's disease over a six-year follow-up period. No effects were seen on disease progression and index treatment failure neither in Crohn's disease nor ulcerative colitis.

Background Interstitial lung [ILD] disease and granulomatous lung disease [GLD] are rare respiratory disorders that have been associated with inflammatory bowel disease [IBD]. Clinical presentation is polymorphic and aetiology is unclear. Methods This was an ECCO-CONFER project. Cases of concomitant ILD or GLD and IBD, or drug-induced ILD/GLD, were collected. The criteria for diagnosing ILD and GLD were based on definitions from the American Thoracic Society and the European Respiratory Society and on the discretion of reporting clinician. Results We identified 31 patients with ILD. The majority had ulcerative colitis [UC] [n = 22]. Drug-related ILD was found in 64% of these patients, 25 patients [80.6%] required hospitalisation, and one required non-invasive ventilation. The causative drug was stopped in all drug-related ILD, and 87% of patients received systemic steroids. At follow-up, 16% of patients had no respiratory symptoms, 16% had partial improvement, 55% had ongoing symptoms, and there were no data in 13%. One patient was referred for lung transplantation, and one death from lung fibrosis was reported. We also identified 22 GLD patients: most had Crohn’s disease [CD] [n = 17]. Drug-related GLD was found in 36% of patients and 10 patients [45.4%] required hospitalisation. The causative drug was stopped in all drug-related GLD, and 81% of patients received systemic steroids. Remission of both conditions was achieved in almost all patients. Conclusions ILD and GLD, although rare, can cause significant morbidity. In our series, over half of cases were drug-related and therefore focused pharmacovigilance is needed to identify and manage these cases.

Background: Westernization, above all associated changes in diet, has been postulated to be one of the most important factors contributing to the increasing incidence in inflammatory bowel disease (IBD), consisting mainly of Crohn’s disease and ulcerative colitis. Summary: Diet represents a crucially important and intuitively relevant topic for IBD patients. Although a substantial number of patients are prone to follow dietary advice from a variety of sources, including the lay press, there is intriguingly little scientific evidence for such an incitement. This may result in physicians being insufficiently informed about various aspects of nutrition, precluding adequate guidance of their patients with IBD. Importantly, IBD patients are at risk to develop deficiencies in iron, vitamin B12, folic acid, and several micronutrients, which may even be more pronounced in patients with active disease and those following a restrictive diet. This review aims to summarize the latest data from clinical and epidemiological studies investigating diet and its effect on the course of the disease and to outline the most important nutrient deficiencies in IBD patients. Key Messages: A western diet with an imbalance between omega-6 (n-6)/omega-3 (n-3) polyunsaturated fatty acids (PUFAs), in favor of n-6 PUFAs, may increase the risk of IBD, whereas a diet high in fruits and vegetables may decrease the risk of IBD. Many approaches to influence the course of IBD with dietary intervention exist. However, to induce or maintain remission in IBD with a change of diet is still in its infancy, and more dietary research is needed before we can apply it in daily practice. Patients with IBD, even in remission, have to be screened regularly for malnutrition.

The parameterised description of subgrid-scale processes in the clear and cloudy boundary layer has a strong impact on the performance skill in any numerical weather prediction (NWP) or climate model and is still a prime source of uncertainty. Yet, improvement of this parameterised description is hard because operational models are highly optimised and contain numerous compensating errors. Therefore, improvement of a single parameterised aspect of the boundary layer often results in an overall deterioration of the model as a whole. In this paper, we will describe a comprehensive integral revision of three parameterisation schemes in the High Resolution Local Area Modelling – Aire Limitée Adaptation dynamique Développement InterNational (HIRLAM-ALADIN) Research on Mesoscale Operational NWP In Europe – Applications of Research to Operations at Mesoscale (HARMONIE-AROME) model that together parameterise the boundary layer processes: the cloud scheme, the turbulence scheme, and the shallow cumulus convection scheme. One of the major motivations for this revision is the poor representation of low clouds in the current model cycle. The newly revised parametric descriptions provide an improved prediction not only of low clouds but also of precipitation. Both improvements can be related to a stronger accumulation of moisture under the atmospheric inversion. The three improved parameterisation schemes are included in a recent update of the HARMONIE-AROME configuration, but its description and the insights in the underlying physical processes are of more general interest as the schemes are based on commonly applied frameworks. Moreover, this work offers an interesting look behind the scenes of how parameterisation development requires an integral approach and a delicate balance between physical realism and pragmatism.

Background and Aims: The treatment options for eosinophilic esophagitis (EoE) patients include drugs (proton pump inhibitors [PPIs], swallowed topical corticosteroids [STCs]), elimination diets, and dilation. Given the lack of data, we aimed to assess adult EoE patients’ satisfaction with different EoE-specific treatment modalities. Patients and Methods: We evaluated therapy satisfaction recalled over a 12-month period using the validated Treatment Satisfaction Questionnaire for Medication that assesses effectiveness, side effects, convenience, and overall satisfaction. The score for each scale ranges from 0 (dissatisfied) to 100 (satisfied). To evaluate satisfaction with nonpharmacologic therapies, the questionnaire was modified and debriefed into three focus groups. The final questionnaire was sent to 147 patients. Results: The patient response rate was 74%. In the last 12 months, 24, 75, 19, and 9% were treated with PPIs, STCs, elimination diet, and dilation, respectively. Patients identified the following considerations as important for therapy choice: effect on symptoms (89%), effect on esophageal inflammation (76%), side effects (69%), and ease of use (58%). Patients found STCs to be effective (83 points), convenient (83 points), and experienced no side effects when using this therapy. When using STCs alone (43%), overall patient satisfaction was high (86 points). Patients judged PPIs to be most convenient (89 points), STCs to be a bit less convenient (83 points), and diet to be most inconvenient (46 points) of the three therapies examined. Conclusions: Adult EoE patients consider both therapy effect on symptoms and esophageal inflammation as important criteria when choosing EoE therapy and appear to be satisfied with STC use.

Background Vedolizumab is an α4β7 integrin monoclonal antibody indicated for moderately to severely active Crohn’s disease (CD) and ulcerative colitis (UC). There are limited data on how vedolizumab impacts extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD). The aim of the study was to analyse the effect of vedolizumab on EIM in a real-world cohort of IBD patients. Methods A multicentre retrospective study was conducted in Belgium, Denmark, Israel, the Netherlands and Switzerland. Adult patients with moderately to severely active IBD and concurrent active EIM with at least 6 months follow-up after vedolizumab initiation (index date) were enrolled. Improvement of EIM was defined as absence of symptoms (resolution) or partial response (reduction of symptoms). Results 99 patients were included (UC: 44, CD: 55); the majority of active EIM at index were musculoskeletal (Table 1). Median disease duration at index was 9 (IQR: 3-19) years and 77% of patients had been exposed to 1+ biologic. Overall, after 6 and 12 months of vedolizumab, 37% and 50% of EIM respectively were reported as improved, 22%, 25% as stable (no change) and 1% and 3% as worsened (Table 2), missing values were 5% and 4%, respectively. Median time since first EIM improvement was 0.5 months (Figure 1). At 6 and 12 months, 48% (10/21) and 33% (6/18) of patients experienced clinical response/remission of their IBD, respectively. Vedolizumab treatment persistence at 12 months was 83% overall (Figure 2). Adverse Events were reported for 18% patients; 96% of them non-serious. Conclusion Vedolizumab treatment was associated with an improvement in 37% and 50% of EIM at 6 and 12 months, respectively, in a real-world IBD cohort.

Background The α4β7 integrin monoclonal antibody vedolizumab (VDZ) has been shown to be efficacious for patients with moderate-to-severe Crohn’s disease (CD). This study aimed to analyse the added value of budesonide in combination with VDZ as an induction treatment for this indication. Methods A multicentre, retrospective chart review study was conducted in Belgium, Israel, and Switzerland. Adult patients with moderately to severely active CD (defined as an abdominal pain [AP] score of ≥2 and/or a mean daily loose stool frequency [LSF] score of ≥4 for the previous 7 days) who initiated induction therapy with either VDZ monotherapy (mono) or a combination therapy (combo) of VDZ with budesonide (index date) between 1 January 2015 and 31 January 2019 were included. Patients who received VDZ by IV infusion at weeks 0, 2, 6, 10 (only some patients received VDZ during week 10), and 8 weeks thereafter were assessed for time to patient-reported outcome (PRO) clinical remission (Kaplan-Meier curves), defined as an average daily composite score of AP ≤1 and LSF ≤31 within 14 weeks. Regression models were used to assess differences and associations. Results Overall, 123 patients were included (mono, n=73; combo, n=50). Patients initiating combo presented with more severe disease at index date than patients initiating mono. PRO clinical remission rates were estimated at 71.4% (50/70) in the mono and 68.0% (34/50) in the combo groups, with a similar median time to PRO remission of 91 days (95% CI: 70–98) and 95 days (95% CI: 70–98), respectively (Figure 1). Figure 2 shows the mean % change in AP and LSF from baseline to week 14, which was comparable for mono and combo. The variables associated with mean % change were moderate and severe AP scores for AP and being a current smoker for LSF. One patient in each group discontinued VDZ before week 14 (due to lack of effectiveness [mono] and adverse event [AE; combo]); 68.0% of patients in the combo group discontinued budesonide by the end of the follow up period. The reasons for discontinuation were routine treatment regimen (8 weeks 9 mg/day+subsequent tapering-off) in 85.3% of the patients, lack of effectiveness in 5.9% and AEs in 2.9% (5.8% other reasons). Safety event rates were similar among the groups for overall AEs (mono, 23.3%; combo, 26.0%), with the majority designated as mild to moderate in severity, and 83.3% resolved within the follow-up period. Conclusion Comparable effectiveness and safety outcomes were observed with mono and combo therapy in patients with CD; however, disease state among patients receiving combo was more refractory/severe at baseline. Further evidence is needed to corroborate these findings. Reference

Zusammenfassung: Bei Patienten mit einer Proktitis - mit den Symptomen Tenesmen, anorektale Schmerzen, Diarrhö, Stuhldrang, Schleim- oder Blutabgang und Schmerzen im linken Unterbauch - sollte neben chronisch-entzündlichen Darmkrankheiten immer auch an die Möglichkeit einer infektiösen Ursache gedacht werden. Die Sexualanamnese, insbesondere der rezeptive anale Verkehr (dies muss auch bei heterosexuellen Frauen und auch bei Männern erhoben werden), spielt hier eine entscheidende Rolle. Patienten müssen über mögliche Risiken informiert und ggf. frühzeitig behandelt werden. Bei Nachweis einer Geschlechtskrankheit sollte dem Patienten ein weiterführendes Screening auf sexuell übertragbare Infektionen ("sexually transmitted diseases", STD) unter Einschluss eines HIV-Tests angeboten werden, da häufig mehrere Geschlechtskrankheiten gleichzeitig vorliegen können. Einer adäquaten und unverzüglichen Diagnostik sowie Therapie inklusive einer intensivierten Partnerbenachrichtigung und ggf. -therapie kommt hier eine besondere Bedeutung zu.

Background Patients with Crohn’s disease (CD) are at risk of complications. Performance characteristics of a decision support tool assessing the risk of CD complications were evaluated. Methods CDPATH (formerly called the Personalized Risk and Outcome Prediction Tool [PROSPECT]) was calibrated and validated in 2 cohorts. Tool prediction of disease characteristics was assessed using Cox regression and Harrell’s C-statistic. Results All associations of CD complications and CDPATH components were significant except perianal location. There was a significant association between individualized risk assessment scores and CD complications in both cohorts. Conclusion CDPATH is validated as a clinical decision support tool for assessing the risk of CD complications.

Vedolizumab has been proposed to lead to fewer postoperative complications because of its gut specificity. Studies, however, suggest an increased risk of surgical site infections, yet the data are conflicting.This study aimed to assess the effect of vedolizumab drug levels on postoperative outcomes in patients undergoing major abdominal surgery for IBD.This was a retrospective study of a prospectively maintained database.Patients were operated on by a single surgeon at an academic medical center.A total of 72 patients with IBD undergoing major abdominal surgery were included.Patients were exposed preoperatively to vedolizumab.The primary outcome measured was the postoperative morbidity in patients who had IBD with detectable vs undetectable vedolizumab levels.A total of 72 patients were included in the study. Thirty-eight patients had detectable vedolizumab levels (1.6 μg/mL), and 34 had undetectable vedolizumab levels. The overall rate of complications was 39%, and ileus was the most common complication. There were no significant differences in clinical variables between the detectable and undetectable vedolizumab level patient groups except for the time between the last dose and surgery (p0.01). There were 42 patients in the ulcerative colitis cohort; 48% had an undetectable vedolizumab level and 52% had a detectable vedolizumab level. There were no differences in any postoperative morbidity between ulcerative colitis groups. The Crohn's cohort had 27 patients; 48% had an undetectable vedolizumab levels and 52% had a detectable vedolizumab level. There was a significantly lower incidence of postoperative ileus in patients who had Crohn's disease with detectable vedolizumab levels compared with patients with an undetectable vedolizumab level (p0.04).Limitations include a low overall patient population and a high rate of stoma formation.Serum vedolizumab levels do not influence postoperative morbidity in IBD. Vedolizumab may reduce the incidence of postoperative ileus in patients with Crohn's disease. See Video Abstract at http://links.lww.com/DCR/B574.ANTECEDENTES:Se ha propuesto que el vedolizumab presenta menos complicaciones postoperatorias debido a su especificidad intestinal. Sin embargo, estudios sugieren un mayor riesgo de infecciones en el sitio quirúrgico, aunque los datos son contradictorios.OBJETIVO:Evaluar el efecto en los niveles del fármaco vedolizumab, en resultados postoperatorios de pacientes sometidos a cirugía mayor abdominal, por enfermedad inflamatoria intestinal.DISEÑO:Estudio retrospectivo de una base de datos mantenida prospectivamente.ENTORNO CLÍNICO:Pacientes intervenidos por un solo cirujano en un centro médico académico.PACIENTES:Un total de 72 pacientes con enfermedad inflamatoria intestinal sometidos a cirugía mayor abdominal.INTERVENCIONES:Exposición preoperatoria a vedolizumab.PRINCIPALES MEDIDAS DE VALORACIÓN:Morbilidad postoperatoria en pacientes con enfermedad inflamatoria intestinal, con niveles detectables versus no detectables de vedolizumab.RESULTADOS:Se incluyó en el estudio a un total de 72 pacientes. Treinta y ocho pacientes tuvieron niveles detectables de vedolizumab (1,6 mcg / ml) y 34 con niveles no detectables de vedolizumab. La tasa global de complicaciones fue del 39% y el íleo fue la complicación más común. No hubo diferencias significativas en las variables clínicas entre los grupos de pacientes con niveles detectables y no detectables de vedolizumab, excepto por el intervalo de tiempo entre la última dosis y la cirugía (p.01). La cohorte de colitis ulcerosa tuvo 42 pacientes, el 48% con un nivel no detectable de vedolizumab y el 52% un nivel detectable de vedolizumab. No hubo diferencias en ninguna morbilidad postoperatoria entre los grupos de colitis ulcerosa. La cohorte de Crohn tuvo 27 pacientes, 48% con niveles no detectables de vedolizumab y el 52% con niveles detectables de vedolizumab. Hubo una incidencia significativamente menor de íleo postoperatorio en pacientes de Crohn con niveles detectables de vedolizumab, comparados con los pacientes con un nivel no detectable de vedolizumab (p0,04).LIMITACIONES:Las limitaciones incluyen una baja población general de pacientes y una alta tasa de formación de estomas.CONCLUSIONES:Los niveles séricos de vedolizumab no influyen en la morbilidad postoperatoria de la enfermedad inflamatoria intestinal. Vedolizumab puede reducir la incidencia de íleo postoperatorio en pacientes de Crohn. Consulte Video Resumen en http://links.lww.com/DCR/B574.

Background: Due to the increased incidence of colorectal cancer in inflammatory bowel diseases (IBDs), the value of chemoprevention for this patient group has been repeatedly debated in the past decade. This review describes available evidence and the current recommendations for chemoprevention in national and international guidelines IBD guidelines. Summary: 5-Aminosalicylic acid (5-ASA) compounds are the preferred therapeutic option for mild to moderate ulcerative colitis (UC). Aside from the known anti-inflammatory effects, their chemopreventive abilities have been described in vitro and in vivo. Pooling the increasing number of retrospective and population-based clinical studies over the last 15 years, 7 consecutive meta-analyses revealed partially conflicting results for the chemopreventive efficacy of 5-ASA, and thus, not all IBD guidelines currently recommend chemoprevention with mesalamine compounds. Accumulating evidence for decreasing the colorectal cancer (CRC) risk in support of thiopurines more recently shows a protective effect. This effect seems solely mediated by control of intestinal inflammation since, for this drug class, another mechanistic interference in IBD-associated CRC pathogenesis is not known. The results regarding chemopreventive efficacy for ursodeoxycholic acid or folic acid are equivocal, and the use of these medications to prevent CRC is not firmly established. Like UC, the risk of CRC is also significantly increased in patients with Crohn’s disease (CD), especially Crohn’s colitis. However, no published studies exclusively assess the effects of surveillance on the early detection of cancer or CRC chemoprevention in CD patients. In meta-analyses, which predominantly included UC patients, 5-ASA or thiopurines were not beneficial in small CD subgroups. The level of evidence for anti-TNFα agents, anti-integrin (e.g., vedolizumab), or anti-IL-12/IL-23 agents (e.g., ustekinumab) and Janus kinase inhibitors is currently too low or nonexistent to use them solely for chemoprevention in UC or CD patients. Key Message: Intestinal inflammation is one of the main risk factors for developing CRC in IBD, and all drugs that induce and maintain mucosal healing most likely also decrease the IBD-associated CRC risk. Thus, a therapeutic strategy of adding a 5-ASA therapy to a successfully mucosal healing-inducing therapy, for example, with a biologic or a small molecule merely to prevent CRC appears to be obsolete.

International audience; Extraintestinal manifestations (EIMs) are frequently observed in IBDs and contribute considerably to morbidity and mortality. They have long been considered a difficult to treat entity due to limited therapy options, but the increasing use of anti-tumour necrosis factors has dramatically changed the therapeutic approach to EIM in recent years. Newly emerging therapies such as JAK inhibitors and anti-interleukin 12/23 will further shape the available armamentarium. Clinicians dealing with EIMs in everyday IBD practice may be puzzled by the numerous available biological agents and small molecules, their efficacy for EIMs and their potential off-label indications. Current guidelines on EIMs in IBD do not include treatment algorithms to help practitioners in the treatment decision-making process. Herein, we summarise knowledge on emerging biological treatment options and small molecules for EIMs, highlight current research gaps, provide therapeutic algorithms for EIM management and shed light on future strategies in the context of IBD-related EIMs.

Current guidelines state that systemic inflammation, together with endothelial dysfunction, calcification, and hypercoagulability, predispose to premature atherosclerosis in patients with inflammatory bowel disease (IBD). We assessed whether IBD can affect aortic stiffness, a well-recognized vascular biomarker and an independent risk factor for cardiovascular (CV) disease (CVD) in several populations. Recent studies reported that aortic stiffness is increased in adults with IBD compared with matched controls. This association is dependent on inflammatory burden and disease duration, and is reduced by antitumor necrosis factor therapy. Considered together, current findings suggest that increased aortic stiffness is an extraintestinal manifestation of IBD. This is clinically relevant since measuring aortic stiffness in patients with IBD could improve risk assessment, especially in those without established CVD. Moreover, effective control of inflammation could lower CV risk in patients with IBD by reducing aortic stiffness. Further longitudinal studies are needed to better clarify (i) the relationship between disease duration and irreversible changes of the arterial wall, (ii) the clinical characteristics of patients with IBD that have an increased arterial stiffness at least in part reversible, and (iii) whether arterial stiffness is useful to evaluate the efficacy of immunosuppressive therapy.

The Far-UV Off Rowland-circle Telescope for Imaging and Spectroscopy (FORTIS) has been successful in maturing technologies for carrying out multi-object spectroscopy in the far-UV, including: the successful implementation of the Next Generation of Microshutter Arrays; large-area microchannel plate detectors; and an aspheric "dual-order" holographically ruled diffraction grating with curved, variably-spaced grooves with a laminar (rectangular) profile. These optical elements were used to construct an efficient and minimalist "two-bounce" spectro-telescope in a Gregorian configuration. However, the susceptibility to Lyman alpha (Ly$\alpha$) scatter inherent to the dual order design has been found to be intractably problematic, motivating our move to an "Off-Axis" design. OAxFORTIS will mitigate its susceptibility to Ly$\alpha$ by enclosing the optical path, so the detector only receives light from the grating. The new design reduces the collecting area by a factor of 2, but the overall effective area can be regained and improved through the use of new high efficiency reflective coatings, and with the use of a blazed diffraction grating. This latter key technology has been enabled by recent advancements in creating very high efficiency blazed gratings with impressive smoothness using electron beam lithography and chemical etching to create grooves in crystalline silicon. Here we discuss the derivation for the OAxFORTIS grating solution as well as methods used to transform the FORTIS holographic grating recording parameters (following the formalism of Noda et al.1974a,b), into curved and variably-spaced rulings required to drive the electron beam lithography write-head in three dimensions. We will also discuss the process for selecting silicon wafers with the proper orientation of the crystalline planes and give an update on our fabrication preparations., Comment: 10 pages, 6 figures, to appear in Proc. of SPIE Vol. 11821, UV, X-Ray, and Gamma-Ray Space Instrumentation for Astronomy XXII

Neuromuscular monitoring is essential for optimal management of neuromuscular blocking drugs. Postoperative residual neuromuscular blockade continues to occur with an unacceptably high incidence and is associated with adverse patient outcomes. Use of a peripheral nerve stimulator and subjective tactile or visual assessment is useful for intraoperative management of neuromuscular blockade, especially when the patient's hand is accessible. Quantitative monitoring is necessary for confirmation of adequate reversal and for identification of patients who have recovered spontaneously and therefore should not receive pharmacologic reversal agents. Guidelines, as well as more user-friendly monitoring equipment, have created momentum toward improving routine perioperative neuromuscular monitoring.

We are presenting the result of the microshutter arrays for multi-object spectroscopy. Microshutter arrays are MEMS technology devices that are 2D programmable field masks for object selection in the sparsely populated fields. This next generation microshutters are based on the first generation of the microshutter arrays developed for the James Webb Space Telescope Near-Infrared Spectrometer (JWST NIRSpec) we developed new fabrication process that allowed to build fully electrostatic microshutter arrays. The microshutter arrays based on this new development have been successfully demonstrated in the FORTIS project sounding rocket flight. We are currently in the process of expanding the fabrication process to large format microshutter arrays designed for the use on the future NASA flagship missions such as HabEx and LUVOIR.

Microshutter arrays are powerful tools enabling simultaneous spectroscopy of multiple objects within a single, crowded field-of-view. This technology is currently employed on the James Webb Space Telescope, and next-generation arrays are being proposed for future flagship missions such as LUVOIR and HabEx. For these future large missions, it is important to fully characterize the performance of the next-generation microshutter arrays in the lab, particularly in the ultraviolet range not probed with JWST. To this end, we have developed a laboratory testbed to measure the contrast between opened and closed shutters achievable with these devices.

Patients with hematological malignancies undergoing intensive chemotherapy or due to their underlying disease often suffer from serious infections during neutropenia. One possibility of bridging ne...

Zusammenfassung. Bei chronisch entzündlichen Darmerkrankungen (Inflammatory Bowel Diseases, IBD) können nicht-entzündliche Gelenkschmerzen und entzündliche Gelenkmanifestationen auftreten. Letztere gehören zur Gruppe der Spondyloarthritiden. Sie werden am Achsenskelett als entzündlicher Rückenschmerz mit nächtlichen Schmerzen, Morgensteifigkeit und Besserung unter Aktivität manifest. Einschränkungen der Gelenkfunktion sind ebenfalls möglich. Bei anderen Patienten stehen periphere Gelenkbeschwerden im Vordergrund. Als Schmerzmedikamente werden COX-2-selektive, nicht-steroidale Antirheumatika (NSAR) empfohlen, da unselektive NSAR die zugrundeliegende IBD verschlimmern können. Am Achsenskelett werden Physiotherapie und Tumornekrosefaktor(TNF)-Inhibitoren eingesetzt, während bei peripherem Gelenkbefall Steroidinjektionen, Sulfasalazin und TNF-Inhibitoren wirksam sind. Entzündung, Malabsorption und Steroide führen bei IBD-Patienten zu Osteopenie und Osteoporose. Bei langdauernder Krankheitsaktivität bzw. langer Steroidgabe ist ein Screening mit DXA-Scan indiziert. Therapeutisch sollten ausreichend Kalzium und Vitamin D sowie gegebenenfalls Bisphosphonate gegeben werden.

Background Cardiac accessory β-subunits are part of macromolecular Nav1.5 channel complexes modulating biophysical properties and contributing to arrhythmias. Recent studies demonstrated the structural interaction between β-subunits of Na+ (Nav1.5) and K+ (Kv4.3) channels. Here, we identified the dipeptidyl peptidase-like protein-10 (DPP10), which is known to modulate Kv4.3-current kinetics, as a new regulator of Nav1.5 channels. Methods We assessed DPP10 expression in the healthy and diseased human heart and we studied the functional effects of DPP10 on the Na+ current in isolated rat cardiomyocytes expressing DPP10 after adenoviral gene-transfer (DPP10ad). Results DPP10 mRNA and proteins were detected in human ventricle, with higher levels in patients with heart failure. In rat cardiomyocytes, DPP10ad significantly reduced upstroke velocity of action potentials indicating reduction in Na+-current density. DPP10 significantly shifted the voltage-dependent Na+ channel activation and inactivation curve to more positive potentials, resulting in greater availability of Na+ channels for activation, along with increasing window Na+ current. In addition, time-to-peak Na+ current was reduced, whereas time course of recovery from inactivation was significantly accelerated by DPP10ad. DPP10 co-immunoprecipitated with Nav1.5 channels in human ventricles, confirming their physical interaction. Conclusion We provide first evidence that DPP10 interacts with Nav1.5 channels, linking Na+- and K+-channel complexes in the heart. Our data suggest that increased ventricular DPP10 expression in heart failure might promote arrhythmias by decreasing peak Na+ current, while increasing window Na+ current and channel re-openings due to accelerated recovery from inactivation.

Mechanical circulatory support (MCS) is an increasingly frequent treatment option for managing end-stage heart failure. Devices are implanted either as destination therapy or as bridge to transplant. Patients undergoing this treatment can experience significant symptoms of depression in addition to stresses associated with chronic illness. After implantation, some patients may decide that the burdens of an MCS device outweigh the benefits. Physician asked to assist in deactivating MCS devices in the face of depression must ensure appropriate assessment, informed consent, and multidisciplinary involvement to minimize suffering and maximize patient quality of life.

Der monoklonale Antikorper Dupilumab (Dupixent® ) ist seit September 2017 in der EU als neue systemische Therapie bei mittelschwerem bis schwerem atopischem Ekzem zugelassen. Eine Unterdruckung der IL-4- und IL-13-Signalwege durch die Anwendung von Dupilumab fuhrt zu einer Verbesserung objektiver und subjektiver Komponenten der Erkrankung. Die Blockade der IL-4Rα-Untereinheit fuhrt zu einer Reduktion der Th2-vermittelten Entzundung und zu einer Verbesserung der Hautbarriere. Die Nebenwirkungsrate unter Dupilumab ist gering. Allerdings entwickelten bis zu 28 % der Patienten unter Behandlung mit Dupilumab (gegenuber bis zu 11 % unter Placebo) eine bilaterale, milde bis moderate Konjunktivitis mit Rotung, Brennen und Fremdkorpergefuhl der Augen. Mit topischen Steroiden und topischen Calcineurininhibitoren stehen verschiedene Therapieoptionen der Dupilumab-assoziierten Konjunktivitis zur Verfugung. Dieser Artikel berichtet uber die klinische Prasentation sowie die medikamentosen und nichtmedikamentosen Therapieoptionen der klinisch hochrelevanten Dupilumab-assoziierten Konjunktivitis.

Background and Aims The optimal timing of treatment escalation in Crohn’s disease [CD] remains a challenging issue, and very little is known about its long-term development following early versus late administration of anti-TNF antibodies. The long-term outcome of Swiss CD patients was comparatively assessed in an up to 10-year follow-up, using patients participating in the Swiss Inflammatory Bowel Disease Cohort Study [SIBDCS]. Methods Prospectively collected SIBDCS patient data, including disease history, baseline characteristics at enrolment, and course of disease, were analysed in patients with early versus late [ Results A reduced risk of developing bowel stenosis was found in patients who received early anti-TNF treatment. This association was seen in patients overall and also in the subgroups of CD patients without pre-existing complications [Log-rank test: p < 0.001]. Furthermore, osteoporosis and anaemia were observed significantly less frequently in patients who received early anti-TNF treatment, compared with either patients who received treatment late [p < 0.001 and p = 0.046, respectively] or were never [p < 0.001 for both] treated with anti-TNF antibodies. Patients with early anti-TNF administration sought medical consultations significantly less often, including gastroenterologists in private practice [p = 0.017], ambulatory [outpatient] hospital visits [p = 0.038], and a composite of any medical visits [p = 0.001]. The percentage of patients unable to work was lowest for early-anti-TNF–treated patients, in comparison with patients who were treated late or never [3.6% vs 8.8% vs 3.7%, p = 0.016]. Conclusions In CD patients within the SIBDCS, early anti-TNF administration was found to be associated with several indicators of a more favourable long-term outcome.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide and the need for novel biomarkers and therapeutic strategies to improve diagnosis and surveillance is obvious. This study aims to identify β6 -integrin (ITGB6) as a novel serum tumor marker for diagnosis, prognosis, and surveillance of CRC. ITGB6 serum levels were validated in retro- and prospective CRC patient cohorts. ITGB6 serum levels were analyzed by ELISA. Using an initial cohort of 60 CRC patients, we found that ITGB6 is present in the serum of CRC, but not in non-CRC control patients. A cut-off of ≥2 ng/mL ITGB6 reveals 100% specificity for the presence of metastatic CRC. In an enlarged study cohort of 269 CRC patients, ITGB6 predicted the onset of metastatic disease and was associated with poor prognosis. Those data were confirmed in an independent, prospective cohort consisting of 40 CRC patients. To investigate whether ITGB6 can also be used for tumor surveillance, serum ITGB6-levels were assessed in 26 CRC patients, pre- and post-surgery, as well as during follow-up visits. After complete tumor resection, ITGB6 serum levels declined completely. During follow-up, a new rise in ITGB6 serum levels indicated tumor recurrence or the onset of new metastasis as confirmed by CT scan. ITGB6 was more accurate for prognosis of advanced CRC and for tumor surveillance as the established marker carcinoembryonic antigen (CEA). Our findings identify ITGB6 as a novel serum marker for diagnosis, prognosis, and surveillance of advanced CRC. This might essentially contribute to an optimized patient care.

The number of fixed oil and gas platforms are declining in the Gulf of Mexico, there were ∼3674 platforms installed the since 1942 and today there are ∼1320. Eventually, ∼30,000 jobs will be lost in related industries because of platform removals. Retired oil and gas platforms could be redeployed for alternate uses such as CO2 capture and storage, renewable wind energy, and sustainable fisheries and employ citizens in coastal areas. Elsewhere around the world, offshore platforms are used for purposes other than producing oil and gas. U.S. Federal legislation (Energy Policy Act 2005 Section 388 of Public Law [PL] 109-58); 30 CFR 285.1000 Subpart J) authorizes the use of retired oil and gas platforms for alternate uses. If the retired oil and gas structures are preserved, the infrastructure could also be used to recover stranded petroleum using CO2 enhanced oil recovery (CO2-EOR). We examined the socio-economic incentives, environmental impacts, and regulatory issues associated with the alternate uses. We suggest that CO2-EOR is the most economically efficient way to store CO2 offshore and that offshore wind turbines may assist with the energy requirements for oil and gas production and CO2-EOR. Data suggest that in our study area offshore platforms are more successful at producing fish and invertebrates if they are left standing instead of toppled over. The greatest regulatory issue facing the use of retired platforms is the transfer of liability. If the structures are redeployed, the previous oil and gas owner/operators are still responsible for eventual removal and catastrophic events. A variety of future economic activity in the Gulf of Mexico could take advantage of this infrastructure, if it remains in place.

Mills’ syndrome is an idiopathic, slowly progressive, spastic hemiparesis. We describe three cases that have been under review for a minimum of 11 years (range 11–19). In all patients, symptoms started in a leg, with a mean age of onset of 59 years (range 53–63). The only abnormality on laboratory investigations was a mildly elevated CSF protein in one case. MRI demonstrated focal T2 hyper-intensity located eccentrically in the cervical cord ipsilateral to the symptomatic side. No cerebral abnormality was demonstrated. Whilst visual and somatosensory evoked potentials were unremarkable, motor evoked potentials were abnormal in all patients: central motor conduction times were significantly prolonged unilaterally in two patients and bilaterally but asymmetrically in the third. Beta-band (15–30 Hz) intermuscular coherence, a potentially more sensitive method of assessing upper motor neuron integrity, was absent unilaterally in one patient and bilaterally in the other two. One patient developed amyotrophy and thus a picture of amyotrophic lateral sclerosis after 16 years, suggesting that Mills’ syndrome is part of the motor neuron disease spectrum. Both amyotrophy and subclinical contralateral upper motor neuron disease can therefore be features of Mills’ syndrome. However, even with the most sensitive electrodiagnostic techniques, unilateral upper motor neuron disease can remain the only abnormality for as long as 10 years. We conclude that whilst Mills’ syndrome should be classified as a motor neuron disorder, it is a distinct nosological entity which can be distinguished from amyotrophic lateral sclerosis, upper motor neuron-dominant amyotrophic lateral sclerosis and primary lateral sclerosis. We propose diagnostic criteria for Mills’ syndrome, and estimate a point prevalence of at least 1.2:1,000,000 based on our well-defined referral population in the North of England.