Efficacy of ferric carboxymaltose on haemoglobin response among older patients with gastrointestinal bleeding: a randomised clinical trial.

BACKGROUND: Acute gastrointestinal bleeding (AGIB) is common in older patients but the use of iron in this context remains understudied. AIMS: This study aimed to evaluate prospectively the efficacy of ferric carboxymaltose to treat anaemia in older patients after AGIB. METHODS: This randomised double-blinded placebo-controlled clinical trial was conducted in 10 French centres. Eligible patients were 65 years or more, had controlled upper or lower gastrointestinal bleeding and a haemoglobin level of 9-11 g/dl. Patients were randomly assigned, in a 1:1 ratio, to receive either one intravenous iron injection of ferric carboxymaltose or one injection of saline solution. The primary endpoint was the difference in haemoglobin level between day 0 and day 42. Secondary endpoints were treatment-emergent adverse events, serious adverse events, rehospitalisation and improvement of quality of life (QOL) at day 180. RESULTS: From January 2013 to January 2017, 59 patients were included. The median age of patients was 81.9 [75.8, 87.3] years. At day 42, a significant difference in haemoglobin level increase was observed (2.49 g/dl in the ferric carboxymaltose group vs. 1.56 g/dl in the placebo group, P = 0.02). At day 180, QOL, measured on European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, improved by 10.5 points in the ferric carboxymaltose group and by 8.2 points in the placebo group (P = 0.56). Rates of adverse events and rehospitalisation were similar in the two groups. CONCLUSIONS: Intravenous iron seems safe and effective to treat anaemia in older patients after AGIB and should be considered as a standard-of-care treatment. ClinicalTrials.gov (NCT01690585).

Factors associated with decreased ovarian reserve in Crohn's disease: A systematic review and meta-analysis.

INTRODUCTION: It is still unclear whether Crohn's disease (CD) might be associated with diminished ovarian reserve (OvR) and factors influencing anti-Mullerian hormone (AMH) levels in CD are poorly known. MATERIAL AND METHODS: We conducted a comprehensive literature search of multiple electronic databases from inception to June 2022 to identify all studies reporting AMH levels or factors associated with diminished OvR in patients with CD. RESULTS: Of the 48 studies identified in our search, eight (including 418 patients with CD) were finally included. The mean difference (95% confidence interval [CI]) in the AMH level between pooled CD patients and controls was -0.56 (-1.14 to 0.03) (p = 0.06). A history of CD-related surgery was not associated with a lower OvR (odds ratio, OR [95% CI] 1.34, [0.66-2.7]; p = 0.4). While disease activity and perianal disease seems associated with a low OvR, disease location (L2 vs. L1, OR [95% CI] = 95% CI [0.47-7.4]; p = 0.4) and L3 vs. L1 (OR [95% CI] = 1.44 [0.67-3.12]; p = 0.3), CD medication, and disease behavior were not. CONCLUSIONS: Our systematic review and meta-analysis did not identify a significantly low OvR in patients with CD. Contrary to CD-related surgery risk factor, active disease was associated lower AMH levels.

Selecting Machine Learning Models to Support the Design of Al/CuO Nanothermites.

Novel properties associated with nanothermites have attracted great interest for several applications, including lead-free primers and igniters. However, the prediction of quantitative structure-energetic performance relationships is still challenging. This study investigates machine learning methods as tools to surrogate complex physical models to design novel nanothermites with optimized burning rates chosen for energetic performance. The study focuses on Al/CuO nanolaminates, for which nine supervised regressors commonly used in ML applied to materials science are investigated. For each, an ML model is built using a database containing a set of 2700 Al/CuO nanolaminate systems, specifically generated for this study. We demonstrate the superiority of the multilayer perceptron algorithm to surrogate conventional physical-based models and predict the Al/CuO nanolaminate microstructure-burn rate relationship with good efficiency: the burn rate is estimated with less than 1% error (0.07 m·s-1), which is very good for designing nano-engineered energetic materials, knowing that it typically varies from approximately 8-20 m·s-1. In addition, the optimization of the Al/CuO nanolaminate structure for burn rate maximization through machine learning takes a few milliseconds, against several days to achieve this task using a physical model, and months experimentally.

First Biologic Drug Persistence in Patients With Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis: A Real-World Canadian Physicians' Experience.

METHODS: Data were obtained from persons enrolled in the SpondyloArthritis Research Consortium of Canada registry between 2003 and 2018. Kaplan-Meier curves were constructed from the time of biologic initiation until discontinuation and compared using the log-rank test. Subanalyses were performed according to calendar year and disease activity. Cox proportional hazards models were used to identify factors associated with discontinuation. RESULTS: We identified 385 biologic-naive persons. Overall, the 349 AS participants had longer persistence to their first biologic than the 36 nr-axSpA subjects (p < 0.01). The Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index decreased by 2.3 points (95% confidence interval [CI], 1.9-2.7) and 3.2 points (95% CI, 2.6-3.7), respectively, in the first year and were stable thereafter. Adjusting for sex, human leukocyte antigen B27, and smoking status, nr-axSpA patients were more likely to discontinue their biologic than AS patients (hazards ratio, 1.65; 95% CI, 1.03-2.62). CONCLUSIONS: In this real-world study, AS patients had longer persistence to their first biologic compared with nr-axSpA, with disease subtype being the most significant predictor of treatment persistence. Future studies should be targeted at assessing long-term clinical outcome of axSpA in the real-world setting.

Immunosuppression does not prevent severe gastrointestinal tract involvement in systemic sclerosis.

OBJECTIVES: We aimed to test the hypothesis that exposure to immunosuppression in early systemic sclerosis (SSc) could modify the risk of developing new onset severe gastrointestinal (GIT) involvement. METHODS: A total of 762 subjects with <3 years of disease duration and without severe GIT disease at baseline study visit were identified from combined longitudinal cohort data from the Canadian Scleroderma Research Group (CSRG) and Australian Scleroderma Interest Group (ASIG). The primary exposure was ever use of methotrexate, cyclophosphamide, mycophenolate mofetil and/or azathioprine during the study period. Severe GIT disease was defined as: 1-malabsorption, 2-hyperalimentation, 3-pseudo-obstruction, and/or 4-≥10% weight loss in association with the use of antibiotics for bacterial overgrowth or oesophageal stricture. The change in the hazard of severe GIT disease due to exposure was estimated using a marginal structural Cox proportional hazards model fit by inverse probability of treatment weights (IPTW) to address potential confounding. RESULTS: Study subjects were 81.5% female, had a mean age of 53.7±13.0 years and mean disease duration at baseline of 1.4±0.8 years. During a mean follow-up of 4.0±2.6 years, severe GIT involvement developed in 11.6% of the 319 subjects exposed to immunosuppression and in 6.8% of the 443 unexposed subjects. In an IPTW-adjusted analysis, exposure to immunosuppression was not associated with severe GIT disease (weighted hazard ratio 0.91, 95% confidence interval 0.52-1.58). CONCLUSIONS: In this large inception SSc cohort, the risk of severe GIT involvement was not modified by exposure to immunosuppression.

Hordeum murinum aspiration revealed by a pneumopleurocutaneous fistula in a 15-month-old infant.

BACKGROUND: Hordeum murinum is a specie of grass rarely reported among the aspirated foreign body. It has high tissue penetration power and may cause lung damages. CASE PRESENTATION: We report the case of a 15-month-old girl who choke while playing in the grass without any evident cause. This episode was immediately followed by vomiting and coughing with traces of blood. While she was fine during the following week, she relapsed at day (D) 7 with fever. At D10, she was finally hospitalized for signs of respiratory distress. The chest CT-scan revealed a voluminous right sub pleural empyema with an aerial component, responsible for the collapse of the right lower lobe, and complicated by a pneumopleurocutaneous fistula to the right paravertebral muscles. Intravenous antibiotics were prescribed, but no invasive procedure was performed. At D18, the spikelet of a false barley spontaneously externalized through the fistula. Evolution was favorable thereafter with disappearance of the fever and progressive decrease of the biological inflammatory syndrome. The follow-up at 4 months was reassuring, with normal clinical evaluation, and complete regression of the empyema on the chest X-rays. CONCLUSIONS: Hordeum murinum is a rare type of foreign body, and the aspiration often goes unnoticed. In these peculiar cases, CT-scans can be as informative as bronchoscopies, and the evolution is usually favorable after fistulization.

Use of ruxolitinib in COPA syndrome manifesting as life-threatening alveolar haemorrhage.

COPA (coatomer subunit α) syndrome is a newly recognised cause of interstitial lung disease in children and adults, frequently associated with arthritis and renal dysfunction. We report a 11-year-old girl with disease limited to major pulmonary haemosiderosis manifesting at the age of 2 years, due to a heterozygous p.(Arg233His) mutation in COPA Her interferon (IFN) signature was elevated (10.312 and 12.429, healthy <2.466), as was the level of serum IFNα (211 fg/mL, healthy <10 fg/mL). STAT1 phosphorylation in T lymphocytes and monocytes was increased as compared with healthy controls. Based on these results she was treated with the JAK1/2 inhibitor ruxolitinib, which resulted in reduction in IFN signalling and appeared to be associated with partial though incomplete decrease in the severity of her pulmonary disease. Patients with alveolar haemorrhage of unknown origin should be considered for COPA screening. Functional tests can help to personalise patient therapy.

Severe gastrointestinal disease in very early systemic sclerosis is associated with early mortality.

OBJECTIVES: To examine the incidence, predictors and outcomes associated with severe gastrointestinal (GI) disease in a large inception SSc cohort. METHODS: SSc subjects with <2 years of disease duration were identified from two multicentre cohorts. Severe GI disease was defined as: malabsorption, hyperalimentation, pseudo-obstruction and/or ⩾10% weight loss in association with the use of antibiotics for bacterial overgrowth or oesophageal stricture. Kaplan-Meier, multivariate logistic regression and Cox proportional hazard analyses were performed to determine the cumulative incidence rate, independent clinical correlates and mortality rate associated with severe GI disease. A longitudinal mixed model was used to assess the impact of severe GI disease on the Short Form Health Survey. RESULTS: In this inception SSc cohort, the probability of developing severe GI disease was estimated at 9.1% at 2 years and 16.0% at 4 years. In multivariate analysis, severe GI disease was associated with inflammatory myositis (odds ratio 4.68, 95% CI 1.65, 13.24), telangiectasias (odds ratio 2.45, 95% CI 1.19, 5.04) and modified Rodnan skin score (odds ratio 1.03, 95% CI 1.01, 1.07). Severe GI disease was associated with a >2-fold increase in the risk of death (hazard ratio 2.27, 95% CI 1.27, 4.09) and worse health-related quality of life [Short Form Health Survey physical (ß = -2.37, P = 0.02) and mental (ß = -2.86, P = 0.01) component summary scores]. CONCLUSION: Severe GI disease is common in early SSc and is associated with significant morbidity and increased mortality. More research is needed to understand, prevent and mitigate severe GI disease in SSc.

Clinical correlates of faecal incontinence in systemic sclerosis: identifying therapeutic avenues.

Objectives: The aim was to establish the prevalence and severity of faecal incontinence (FI) in SSc, its association with other intestinal manifestations and potential predictors of FI, and its impact on quality of life. Methods: A multicentre, cross-sectional study of 298 SSc subjects followed in the Canadian Scleroderma Research Group cohort was performed using validated questionnaires: Jorge-Wexner score (an FI severity scale), Bristol stool scale (a visual scale of stool consistency) and FI Quality-of-Life scale. Constipation was defined by the Rome III criteria. Associations between the Jorge-Wexner score and other clinical variables were determined using multivariate regression analyses. Results: Eighty-one (27.2%) subjects had FI, which was mild in 37 (12.4%) and moderate to severe in 44 (14.8%). Most patients had well-formed stools, 111 (38.8%) reported constipation and 38 (13.4%) had been previously treated for small intestinal bacterial overgrowth (SIBO). Variables independently associated with FI were: loose vs well-formed stools [odds ratio (OR) = 7.01, 95% CI: 2.09, 23.51)], constipation (OR = 3.64, 95% CI: 1.61, 8.27, P = 0.002), history of SIBO (OR = 2.97, 95% CI: 1.06, 8.27) and urinary incontinence (OR = 2.45, 95% CI: 1.14, 5.27). Quality of life measured with the FI Quality-of-Life scale was inversely correlated with FI severity (correlation coefficients between -0.602 and -0.702, P < 0.001). Conclusion: FI was common and often severe in SSc. Loose stools, SIBO, constipation and urinary incontinence were strongly associated with FI. Other than targeting anorectal dysfunction, concomitant treatment of clinical correlates could lead to improvement in FI and quality of life in SSc.

Which magnetic resonance imaging feature is associated with treatment response in perianal fistulizing Crohn's disease?

PURPOSE: Perianal fistulae are disabling complications of Crohn's Disease. Magnetic resonance imaging features could predict treatment response. This study aimed to determine which magnetic resonance imaging features were predictive of long-term clinical outcome in real life. METHODS: Consecutive patients with magnetic resonance imaging performed in a tertiary center were retrospectively analyzed. Clinical outcome was defined as a need for surgical drainage of perianal fistulae or hospitalization. Clinical data and magnetic resonance imaging features (MAGNIFI-CD and Van Assche indices, degree of fibrosis) were studied. RESULTS: Fifty-two patients were included between 2016 and 2019 with a mean follow-up of 38 months [29;48]. A higher MAGNIFI-CD index (17/25 versus 11/25; p < 0.01) was associated with an unfavorable long-term clinical outcome. The MAGNIFI-CD index showed an area under the curve of 0.74 (p = 0.006) to predict the clinical outcome of perianal Crohn's disease, compared to 0.67 (p < 0.05) for the Van Assche index. At a threshold of 13 for the MAGNIFI-CD index, sensitivity was 75% (CI95% [59%; 86%]) and specificity was 69% (CI95% [44%; 86%]). No association was found between the degree of fibrosis and clinical outcome, but the association of a high degree of fibrosis (≥ 80%) and of a low MAGNIFI-CD index (≤ 13) was predictive of clinical outcome (p < 0.01). CONCLUSION: The MAGNIFI-CD index could be used to predict clinical outcome in perianal Crohn's disease. In combination with a high degree of fibrosis, a low MAGNIFI-CD index, may help to identify patients with the best prognosis.

Non-invasive evaluation of mucosal healing by intestinal ultrasound or fecal calprotectin is efficient in Crohn's disease: A cross-sectional study.

INTRODUCTION: Endoscopy is still the gold, standard for assessing disease activity in Crohn's disease (CD). Its invasiveness, poor acceptability, and cost limit its use in the era of tight control and treat-to-target management. Fecal calprotectin (FC) and intestinal ultrasound (IUS) are non-invasive alternatives to colonoscopy to assess disease activity. We aimed to evaluate the performance of IUS and FC to assess mucosal healing in CD. METHODS: All consecutive CD patients who underwent colonoscopy for mucosal healing assessment and IUS and/or FC within four weeks between September 2019 and April 2022 were included in a prospective cohort. The bowel-wall thickness (BWT) and color Doppler signal (CDS) were assessed for each segment. Endoscopic remission was defined by a CDEIS score < 3. RESULTS: In total, 153 patients were included, of whom 122 showed endoscopic mucosal healing. Eighty-two (53.6 %) were female, the median was age 36 years (IQR, 28-46), and the median disease duration was 10 years (IQR, 4-19). The sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) of a BWT < 3 mm to predict endoscopic mucosal healing were 56 %, 88 %, 95 %, and 36 %, respectively (patients misclassified as mucosal healing, 2.5 %). The best FC threshold (< 92.9 µg/g) provided similar results: 77 %, 89 %, 96 %, and 67 %, respectively (patients misclassified, 2.2 %). The association of an FC < 250 µg/g with a BWT < 3 mm and the absence of CDS increased the Sp and PPV: Se 58 %, Sp 95 %, PPV 97 %, VPN 43 %; patients misclassified, 1.3 %. CONCLUSION: Noninvasive evaluation of mucosal healing by IUS or calprotectin efficiently identifies patients with CD who have achieved endoscopic mucosal healing.

Real-World Effectiveness of Upadacitinib for Treatment of Rheumatoid Arthritis in Canadian Patients: Interim Results from the Prospective Observational CLOSE-UP Study.

INTRODUCTION: Upadacitinib (UPA), a selective, reversible, oral Janus kinase (JAK)-1 inhibitor, was approved in 2019 in Canada for the treatment of adults with moderately to severely active rheumatoid arthritis (RA). This phase 4 prospective study aimed to characterise the effectiveness of UPA in the real-world population of patients with RA. METHODS: Adults with RA who initiated treatment with once daily UPA (15 mg) and enrolled in the Canadian Real-Life post-marketing Observational Study assessing the Effectiveness of UPadacitinib for treating rheumatoid arthritis (CLOSE-UP) and who completed a 6-month assessment as of 28 February 2023 were included. The primary endpoint of the CLOSE-UP study is the proportion of patients achieving a Disease Activity Score-28 Joint Count C-reactive protein (DAS28-CRP) < 2.6 at 6 months. Data was collected at routine visits. Data analysed and summarised descriptively for the overall interim population and for subgroups based on prior therapy included remission or low disease activity, patient-reported outcomes (PROs), and adverse events. RESULTS: A total of 392 patients were included in the interim analysis. Overall, 63.5% (191/301) of patients achieved a DAS28-CRP score < 2.6 at month 6, with similar rates observed for all subgroups analysed according to prior therapy including those with prior JAK inhibitor exposure (range 57.4-71.0%), and in patients who received UPA monotherapy (71.6% [48/67]). Early (month 3) and sustained improvements up to 6 months were observed for all PROs. The safety profile was consistent with previous reports. CONCLUSION: Real-world improvements in disease activity and PROs in response to UPA treatment were consistent with clinical trial data across a range of Canadian patients with prior therapy exposure and with UPA monotherapy, with an overall favourable benefit-risk profile. TRIAL REGISTRATION: NCT04574492.

Intrapericardial Ectopic Hepatic Tissue Masquerading as a Fetal Pericardial Tumor.

Prenatal diagnosis of pericardial mass, with associated large pericardial effusion, resected postnatally and diagnosed to be ectopic hepatic tissue on pathology.

De novo 15q13.3 microdeletion with cryptogenic West syndrome.

West syndrome is a well-recognized form of epilepsy, defined by a triad of infantile spasms, hypsarrhythmia and developmental arrest. West syndrome is heterogenous, caused by mutations of genes ARX, STXBP1, KCNT1 among others; 16p13.11 and 17q21.31 microdeletions are less frequent, usually associated with intellectual disability and facial dysmorphism. So-called "idiopathic" West syndrome is of better prognostic, without prior intellectual deficiency and usually responsive to anti-epileptic treatment. We report on a boy falling within the scope of idiopathic West syndrome, with no dysmorphic features and normal development before the beginning of West syndrome, with a good resolution after treatment, bearing a de novo 15q13.3 microdeletion. Six genes are located in the deleted region, including CHRNA7, which encodes a subunit of a nicotinic acetylcholine receptor, and is frequently associated with epilepsy. Exploration of the 15q13.3 region should be proposed in idiopathic West syndrome.

Deep Levels and Electron Paramagnetic Resonance Parameters of Substitutional Nitrogen in Silicon from First Principles.

Nitrogen is commonly implanted in silicon to suppress the diffusion of self-interstitials and the formation of voids through the creation of nitrogen-vacancy complexes and nitrogen-nitrogen pairs. Yet, identifying a specific N-related defect via spectroscopic means has proven to be non-trivial. Activation energies obtained from deep-level transient spectroscopy are often assigned to a subset of possible defects that include non-equivalent atomic structures, such as the substitutional nitrogen and the nitrogen-vacancy complex. Paramagnetic N-related defects were the object of several electron paramagnetic spectroscopy investigations which assigned the so-called SL5 signal to the presence of substitutional nitrogen (NSi). Nevertheless, its behaviour at finite temperatures has been imprecisely linked to the metastability of the NSi center. In this work, we build upon the robust identification of the SL5 signature and we establish a theoretical picture of the substitutional nitrogen. Through an understanding of its symmetry-breaking mechanism, we provide a model of its fundamental physical properties (e.g., its energy landscape) based on ab initio calculations. Moreover by including more refined density functional theory-based approaches, we calculate EPR parameters (↔g and ↔A tensors), elucidating the debate on the metastability of NSi. Finally, by computing thermodynamic charge transition levels within the GW method, we present reference values for the donor and acceptor levels of NSi.

Crohn's disease: Why the ileum?

Crohn's disease (CD) is an inflammatory bowel disease characterized by immune-mediated flares affecting any region of the intestine alternating with remission periods. In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type. Moreover, the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes. Most of these genes are associated with Paneth cell dysfunction, a cell type found in the intestinal crypts of the ileum. Besides, a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota, which in turn modulates the susceptibility of the ileum to inflammation. Thus, the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis. Indeed, both immune response and cellular healing processes harbour differences between ileal and non-ileal CD. Taken together, these findings advocate for a dedicated therapeutic approach to managing ileal CD. Currently, interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site. However, the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.

Next generation sequencing for personalized therapy: About a class III BRAF N581K mutation associated to NRAS Q61L mutation in malignant melanoma: Case report.

In metastatic stage, therapeutic approach for malignant melanoma is particularly based on performance status, metastatic sites, and BRAF V600 status (BRAF V600E/V600K or V600R (class I BRAF mutations). In most cases, BRAF mutations and NRAS mutations are mutually exclusive to each other. However, some rare BRAF mutations class III are preferentially associated with a NRAS mutation, leading to the MAP Kinase pathway activation and subsequent cell proliferation. Melanomas with this double mutation are rare and difficult to treat because of the lack of codified therapeutic options. We report a patient with metastatic melanoma, harboring class III BRAF mutation (N581K) associated to NRAS mutation (Q61L) with treatment failure. He was treated in second line, after immunotherapy, by monotherapy of MEK inhibitor (MEKi), which underline the interest of NGS (Next Generation Sequencing) to early identify all mutations and enabling onco-dermatologist to discuss a treatment. Rare BRAF non V600 mutations represent 3 to 14% of melanoma mutants and the aim of this communication is to promote the next generation sequencing to extend the paradigm of individually therapeutic approach with target therapy into different spectrum of melanoma patients.