Mycobacterium leprae, the causative agent of leprosy, is an unculturable bacterium with a considerably reduced genome (3.27 Mb) compared to homologues mycobacteria from the same ancestry. In 2001,... Show moreMycobacterium leprae, the causative agent of leprosy, is an unculturable bacterium with a considerably reduced genome (3.27 Mb) compared to homologues mycobacteria from the same ancestry. In 2001, the genome ofM. lepraewas first described and subsequently four genotypes (1-4) and 16 subtypes (A-P) were identified providing means to study global transmission patterns for leprosy. In order to understand the role of asymptomatic carriers we investigatedM. lepraecarriage as well as infection in leprosy patients (n= 60) and healthy household contacts (HHC;n= 250) from Bangladesh using molecular detection of the bacterial element RLEP in nasal swabs (NS) and slit skin smears (SSS). In parallel, to studyM. lepraegenotype distribution in Bangladesh we explored strain diversity by whole genome sequencing (WGS) and Sanger sequencing. In the studied cohort in Bangladesh,M. lepraeDNA was detected in 33.3% of NS and 22.2% of SSS of patients with bacillary index of 0 whilst in HHC 18.0% of NS and 12.3% of SSS were positive. The majority of theM. lepraestrains detected in this study belonged to genotype 1D (55%), followed by 1A (31%). Importantly, WGS allowed the identification of a newM. lepraegenotype, designated 1B-Bangladesh (14%), which clustered separately between the 1A and 1B strains. Moreover, we established that the genotype previously designated 1C, is not an independent subtype but clusters within the 1D genotype. Intraindividual differences were present between theM. lepraestrains obtained including mutations in hypermutated genes, suggesting mixed colonization/infection or in-host evolution. In summary, we observed thatM. lepraeis present in asymptomatic contacts of leprosy patients fueling the concept that these individuals contribute to the current intensity of transmission. Our data therefore emphasize the importance of sensitive and specific tools allowing post-exposure prophylaxis targeted atM. leprae-infected or -colonized individuals. Show less
Davies, M.; Lalam, R.; Woertler, K.; Bloem, J.L.; Astrom, G. 2020
The diagnosis of tumors and tumorlike lesions of bone is a routine part of both general and specialist radiologic practices. The spectrum of disorders ranges from the small incidental lesion to the... Show moreThe diagnosis of tumors and tumorlike lesions of bone is a routine part of both general and specialist radiologic practices. The spectrum of disorders ranges from the small incidental lesion to the potentially life-limiting malignancies whether primary or secondary. In this review, authored by experts from several European orthopaedic oncology centers, we present a collection of pieces of advice in the form of 10 commandments. Adherence in daily practice to this guidance should help minimize adverse patient experiences and outcomes. Show less
Objective: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013.Participants: The Consensus... Show moreObjective: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013.Participants: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration.Evidence: This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities.Consensus Process: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system.Conclusions: Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality. Show less
Kalina, T.; Abraham, R.S.; Rizzi, M.; Burg, M. van der 2020
The EuroFlow PID consortium developed a set of flow cytometry tests for evaluation of patients with suspicion of primary immunodeficiency (PID). In this technical report we evaluate the performance... Show moreThe EuroFlow PID consortium developed a set of flow cytometry tests for evaluation of patients with suspicion of primary immunodeficiency (PID). In this technical report we evaluate the performance of the SCID-RTE tube that explores the presence of recent thymic emigrants (RTE) together with T-cell activation status and maturation stages and discuss its applicability in the context of the broader EuroFlow PID flow cytometry testing algorithm for diagnostic orientation of PID of the lymphoid system. We have analyzed peripheral blood cells of 26 patients diagnosed between birth and 2 years of age with a genetically defined primary immunodeficiency disorder: 15 severe combined immunodeficiency (SCID) patients had disease-causing mutations in RAG1 or RAG2 (n = 4, two of them presented with Omenn syndrome), IL2RG (n = 4, one of them with confirmed maternal engraftment), NHEJ1 (n = 1), CD3E (n = 1), ADA (n = 1), JAK3 (n = 3, two of them with maternal engraftment) and DCLRE1C (n = 1) and 11 other PID patients had diverse molecular defects [ZAP70 (n = 1), WAS (n = 2), PNP (n = 1), FOXP3 (n = 1), del22q11.2 (DiGeorge n = 4), CDC42 (n = 1) and FAS (n = 1)]. In addition, 44 healthy controls in the same age group were analyzed using the SCID-RTE tube in four EuroFlow laboratories using a standardized 8-color approach. RTE were defined as CD62L+CD45RO-HLA-DR-CD31+ and the activation status was assessed by the expression of HLA-DR+. Naive CD8+ T-lymphocytes and naive CD4+ T-lymphocytes were defined as CD62L+CD45RO-HLA-DR-. With the SCID-RTE tube, we identified patients with PID by low levels or absence of RTE in comparison to controls as well as low levels of naive CD4+ and naive CD8+ lymphocytes. These parameters yielded 100% sensitivity for SCID. All SCID patients had absence of RTE, including the patients with confirmed maternal engraftment or oligoclonally expanded T-cells characteristic for Omenn syndrome. Another dominant finding was the increased numbers of activated CD4+HLA-DR+ and CD8+HLA-DR+ lymphocytes. Therefore, the EuroFlow SCID-RTE tube together with the previously published PIDOT tube form a sensitive and complete cytometric diagnostic test suitable for patients suspected of severe PID (SCID or CID) as well as for children identified via newborn screening programs for SCID with low or absent T-cell receptor excision circles (TRECs). Show less
Hemophilia A and B are inherited X-linked disorders of hemostasis, associated with an increased bleeding tendency. Patients with severe hemophilia have undetectable clotting factor levels and... Show moreHemophilia A and B are inherited X-linked disorders of hemostasis, associated with an increased bleeding tendency. Patients with severe hemophilia have undetectable clotting factor levels and experience spontaneous bleeds. In patients with nonsevere hemophilia, the clotting factor levels are 2% to 40% of normal and bleeds predominantly occur after provocative events such as trauma and surgery. Despite this milder phenotype, patients with nonsevere hemophilia may suffer from considerable morbidity and have an increased mortality risk. However, many aspects of the course of disease and treatment remain unclear. Information on the factors influencing interindividual differences in bleeding phenotype is lacking, and misdiagnosis may occur due to assay discrepancies in the diagnostic workup. Desmopressin is the preferred treatment modality, but some patients and indications require treatment with clotting factor concentrates. This may elicit inhibitor formation, which is associated with an increased burden of disease and a higher mortality rate. It has been found that patients with nonsevere hemophilia A carry a lifelong risk for this serious complication. In this review, we provide an overview of the current knowledge of the diagnosis and management of nonsevere hemophilia. A report of science presented at the International Society on Thrombosis and Haemostasis 2019 Annual Congress is also provided. Show less
Purpose: It is suggested that tumour markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) could be used to predict the stage of pancreatic cancer. However, optimal cut-off... Show morePurpose: It is suggested that tumour markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) could be used to predict the stage of pancreatic cancer. However, optimal cut-off values for CEA and CA19-9 are disputable. This study aimed to assess the value of CEA and CA19-9 serum levels at diagnosis of pancreatic ductal adenocarcinoma (PDAC) as predictors for the advanced stage of PDAC in patients discussed at pancreatic multidisciplinary team (MDT) meetings. Methods: Patients with suspected PDAC discussed at MDT meetings from 2013 to 2017 were reviewed, in order to determine optimal cut-off values of both CEA and CA19-9. Results: In total, 375 patients were included. Optimal cut-off values for predicting advanced PDAC were 7.0 ng/ml for CEA and 305.0 U/ml for CA19-9, resulting in positive predictive values of 83.3%, 73.6%, and 91.4% for CEA, CA19-9 and combined, respectively. Both tumour markers were independent predictors of advanced PDAC, demonstrated by an odds ratio of 4.21 (95% CI:1.85-9.56; p = 0.001) for CEA and 2.58 for CA19-9 (95% CI:1.30-5.14; p = 0.007). Conclusions: CEA appears to be a more robust predictor of advanced PDAC than CA19-9. Implementing CEA and CA19-9 serum levels during MDT meetings as an additional tool for establishing tumour resectability is worthwhile for tailored diagnostics. Show less
Charidimou, A.; Frosch, M.P.; Salman, R.A.; Baron, J.C.; Cordonnier, C.; Hernandez-Guillamon, M.; ... ; Int CAA Assoc 2019
Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.Objective: To... Show moreBackground: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference.Setting: Online Delphi survey and consensus conference.Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as >= 70% agreement and <= 15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).Results and limitations: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease.Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach. Show less
Leiro-Fernandez, V.; Chiara, L. de; Rodriguez-Girondo, M.; Botana-Rial, M.; Valverde, D.; Nunez-Delgado, M.; Fernandez-Villar, A. 2019
Objectives. A positive family history (PFH) of spondyloarthritis, in particular a PFH of AS or acute anterior uveitis, is associated with HLA-B27 carriership in chronic back pain patients. As it is... Show moreObjectives. A positive family history (PFH) of spondyloarthritis, in particular a PFH of AS or acute anterior uveitis, is associated with HLA-B27 carriership in chronic back pain patients. As it is unknown, the study aimed to investigate if a PFH contributes to diagnosing axial spondyloarthritis (axSpA) once HLA-B27 status is known.Methods. In axSpA-suspected patients from the Assessment of SpondyloArthritis international Society (ASAS), DEvenir des Spondyloarthropathies Indifferenciees Recentes (DESIR) and SPondyloArthritis Caught Early (SPACE) cohorts, logistic regression analyses were performed with HLA-B27 status and PFH according to the ASAS definition (ASAS-PFH) as determinants and clinical axSpA diagnosis as outcome at baseline. Analyses were repeated with a PFH of AS or acute anterior uveitis.Results. In total, 1818 patients suspected of axSpA were analysed (ASAS n = 594, DESIR n = 647, and SPACE n = 577). In patients from the ASAS, DESIR and SPACE cohorts, respectively 23%, 39% and 38% had an ASAS-PFH, 52%, 58% and 43% were HLA-B27 positive, and 62%, 47% and 54% were diagnosed with axSpA. HLA-B27 was independently associated with an axSpA diagnosis in each cohort but an ASAS-PFH was not [ASAS cohort: HLA-B27 odds ratio (OR): 6.9 (95% CI: 4.7, 10.2), ASAS-PFH OR: 0.9 (95% CI: 0.6, 1.4); DESIR: HLA-B27 OR: 2.1 (95% CI: 1.5, 2.9), ASAS-PFH OR: 1.0 (95% CI 0.7, 1.3); SPACE: HLA-B27 OR: 10.4 (95% CI: 6.9, 15.7), ASAS-PFH OR: 1.0 (95% CI: 0.7, 1.5)]. Similar negative results were found for PFH of AS and acute anterior uveitis.Conclusion. In three independent cohorts with different ethnical backgrounds, ASAS, DESIR and SPACE, a PFH was not associated independently of HLA-B27 with a diagnosis of axSpA. This indicates that in the vast majority of patients presenting with back pain, a PFH does not contribute to the likelihood of an axSpA diagnosis if HLA-B27 status is known. Show less
Radiation-associated cardiac disease, a heterogeneous and complex disease, manifests years or even decades following radiation exposure to the chest. It is associated with a significantly higher... Show moreRadiation-associated cardiac disease, a heterogeneous and complex disease, manifests years or even decades following radiation exposure to the chest. It is associated with a significantly higher morbidity and mortality. Often, the presentation is vague and overlaps with many diseases, presenting unique diagnostic and management issues. As a result, a high index of suspicion followed by multimodality imaging is crucial, along with comprehensive screening to enable early detection. Timing of intervention should be carefully considered in these patients, because surgery is often complex with an emerging role of percutaneous interventions. (C) 2019 by the American College of Cardiology Foundation. Show less
BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is often diagnosed after a long delay, even though signs may already be present on the computed tomography pulmonary angiogram ... Show moreBACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is often diagnosed after a long delay, even though signs may already be present on the computed tomography pulmonary angiogram (CTPA) used to diagnose a preceding acute pulmonary embolism (PE). In this setting of suspected acute PE, we evaluated the diagnostic accuracy of dedicated CTPA reading for the diagnosis of already existing CTEPH.METHODS: Three blinded expert radiologists scored radiologic signs of CTEPH on initial CTPA scans with confirmed acute PE in 50 patients who were subsequently diagnosed with CTEPH during follow-up (cases), and in 50 patients in whom sequential echocardiograms performed >2 years after the acute PE diagnosis did not show any signs of pulmonary hypertension (controls). All 50 control index CTPA scans had signs of right ventricular (RV) overload. Sensitivity and specificity of expert CTPA reading was calculated, and best-predicting radiologic parameters were identified.RESULTS: The overall expert reading yielded a sensitivity of 72% (95% confidence interval [CI] 58%-84%) and a specificity of 94% (95% CI 83%-99%) for CTEPH diagnosis. Multivariate analysis identified 6 radiologic parameters as independent predictors: intravascular webs; pulmonary artery retraction or dilatation; bronchial artery dilatation; right ventricular (RV) hypertrophy; and interventricular septum flattening. The presence of 3 or more these parameters was associated with a sensitivity of 70% (95% CI 55%-82%), a specificity of 96% (95% CI 86%-100%), and a c-statistic of 0.92.CONCLUSIONS: Standardized reading of CTPA scans performed for acute PE can be useful for the diagnosis of CTEPH when structured identification of 6 characteristics is employed during interpretation. The use of this strategy may help reduce diagnostic delay of CTEPH. (C) 2019 International Society for Heart and Lung Transplantation. All rights reserved. Show less
Dongen, J.J.M. van; Burg, M. van der; Kalina, T.; Perez-Andres, M.; Mejstrikova, E.; Vlkova, M.; ... ; EuroFlow Consortium 2019
Purpose: The purpose of this study was to assess the clinical value of ultra-low-dose computed tomography (ULDCT) compared with chest x-ray radiography (CXR) for diagnosing chest pathology.... Show morePurpose: The purpose of this study was to assess the clinical value of ultra-low-dose computed tomography (ULDCT) compared with chest x-ray radiography (CXR) for diagnosing chest pathology. Materials and Methods: A total of 200 patients referred for CXR by outpatient clinics or general practitioners were enrolled prospectively. They underwent CXR (posteroanterior and lateral) and ULDCT (120 kV, 3 mAs) on the same day. In-room time and effective dose were recorded for each examination. Studies were categorized whether they were diagnostic or not, relevant radiologic diagnostic findings were reported, and confidence for diagnosis was recorded by a Likert scale. Differences in diagnostic confidence and effect on management decision were compared. Results: In-room time was <2 minutes for CXR and <3 minutes for ULDCT. Effective dose was 0.040 mSv for CXR and 0.071 mSv for ULDCT. CXR was considered diagnostic in 98% and ULDCT in 100%. The mean perceived confidence for diagnosis was 88 +/- 12% with CXR and 98 +/- 2% with ULDCT (P<0.0001), whereas discrepant findings between CXR and ULDCT were found in 101 of 200 patients. As compared with CXR, ULDCT had added value for management decisions in 40 of 200 patients. Conclusions: ULDCT provided added value to the radiologist by improved perceived confidence with a reduction in false-positive and false-negative CXR investigations that had management implications in 20% of patients. The effective dose of ULDCT will not be a limiting factor for introducing ULDCT of the chest on a broad scale in clinical practice. Show less
