Why did European Radiology reject my radiomic biomarker paper? How to correctly evaluate imaging biomarkers in a clinical setting

This review explains in simple terms, accessible to the non-statistician, general principles regarding the correct research methods to develop and then evaluate imaging biomarkers in a clinical setting, including radiomic biomarkers. The distinction between diagnostic and prognostic biomarkers is made and emphasis placed on the need to assess clinical utility within the context of a multivariable model. Such models should not be restricted to imaging biomarkers and must include relevant disease and patient characteristics likely to be clinically useful. Biomarker utility is based on whether its addition to the basic clinical model improves diagnosis or prediction. Approaches to both model development and evaluation are explained and the need for adequate amounts of representative data stressed so as to avoid underpowering and overfitting. Advice is provided regarding how to report the research correctly

Prototype ATLAS IBL Modules using the FE-I4A Front-End Readout Chip

The ATLAS Collaboration will upgrade its semiconductor pixel tracking detector with a new Insertable B-layer (IBL) between the existing pixel detector and the vacuum pipe of the Large Hadron Collider. The extreme operating conditions at this location have necessitated the development of new radiation hard pixel sensor technologies and a new front-end readout chip, called the FE-I4. Planar pixel sensors and 3D pixel sensors have been investigated to equip this new pixel layer, and prototype modules using the FE-I4A have been fabricated and characterized using 120 GeV pions at the CERN SPS and 4 GeV positrons at DESY, before and after module irradiation. Beam test results are presented, including charge collection efficiency, tracking efficiency and charge sharing.Comment: 45 pages, 30 figures, submitted to JINS

Structural and Luminescence Properties of Silica-Based Hybrids Containing New Silylated-Diketonato Europium(III) Complex

A new betadiketonate ligand displaying a trimethoxysilyl group as grafting function and a diketone moiety as complexing site (TTA-Si = 4,4,4-trifluoro-2-(3-trimethoxysilyl)propyl)-1-3-butanedione (C4H3S)COCH[(CH2)3Si(OCH3)3]COCF3) and its highly luminescent europium(III) complex [Eu(TTA-Si)3] have been synthesized and fully characterized. Luminescent silica-based hybrids have been prepared as well with this new complex grafted on the surface of dense silica nanoparticles (28 (+/-3 nm) or on mesoporous silica particles. The covalent bonding of Eu(TTA-Si)3 inside the core of uniform silica nanoparticles (40 (+/- 5 nm) was also achieved. Luminescence properties are discussed in relation to the europium chemical environment involved in each of the three hybrids. The general methodology proposed allowed high grafting ratios and overcame chelate release and tendency to agglomeration, and it could be applied to any silica matrix (in the core or at the surface, nanosized or not, dense or mesoporous) and therefore numerous applications such as luminescent markers and luminophors could be foreseen

Chronic low back pain among French healthcare workers and prognostic factors of return to work (RTW): a non-randomized controlled trial

BACKGROUND: Many factors influence the return to work of workers with chronic low back pain (CLBP). They have been said to vary according to socio-professional group. This study first aimed to compare prognostic factors influencing the return to work of CLBP healthcare workers (HCWs) and other workers (non-HCWs) after rehabilitation coupled with an occupational intervention. The second objective was to improve the evolution of indicators such as clinical examination, psychosocial impact and pain impact. METHODS: Between 2007 and 2012, a cohort of 217 CLBP workers (54.8 %-women; mean age = 41.3 ± 9.5 years, 118 non-HCWs; 99 HCWs mainly from the public sector) was included in an ambulatory rehabilitation program (standard physiotherapy or intensive network physiotherapy) coupled with an occupational intervention. Workers completed a questionnaire and had a clinical examination at baseline and after 24 months\u27 follow up. Physical, social and occupational data was collected at the same time. Statistical analyses were performed to evaluate prognostic factors for return to work and compare the two worker populations. RESULTS: There was no difference between groups for the rate of OP (occupational physician) intervention or type of physiotherapy. 77.3 % of workers returned to work after 2 years following inclusion. To be an HCW (OR 0.1; 95 % CI [0.03-0.34]), to have less than 112 sick- leave days (OR 1.00; 95 % CI [0.93-1.00]), a small fingertip-floor distance (OR 0.96; 95 % CI [0.93-0.99]), a low anxiety/depression score (OR 0.97; 95 % CI [0.95-1.00]), a low impact of CLBP on daily life (OR 0.96; 95 % CI [0.93-1.00]), and on quality of life (OR 0.98; 95 % CI [0.95-1.00]) at baseline were statistically associated with return to work after 2 years of follow up. Only the profession (workplace) was statistically associated with return to work after 2 years of follow up using multivariate analysis. CONCLUSION: To our knowledge, this is the first cohort study concerning predictive factors of RTW among CLBP workers after 2 years of follow up. Interventions in the work environment did not seem to predict job retention significantly. But only 50 % of the employees in both groups (HCW and non-HCW) had one intervention at their workplace after 2 years. This study underlined the fact that the type of physiotherapy with a well-trained physiotherapist used to take care of CLBP could not impact on the RTW forecast. To develop these initial results, it might be interesting to study the comparison between private and public sectors and to randomize the physiotherapeutic intervention

Recommendations for accurate genotyping of SARS-CoV-2 using amplicon-based sequencing of clinical samples.

Genotyping of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been instrumental in monitoring viral evolution and transmission during the pandemic. The quality of the sequence data obtained from these genotyping efforts depends on several factors, including the quantity/integrity of the input material, the technology, and laboratory-specific implementation. The current lack of guidelines for SARS-CoV-2 genotyping leads to inclusion of error-containing genome sequences in genomic epidemiology studies. We aimed to establish clear and broadly applicable recommendations for reliable virus genotyping. We established and used a sequencing data analysis workflow that reliably identifies and removes technical artefacts; such artefacts can result in miscalls when using alternative pipelines to process clinical samples and synthetic viral genomes with an amplicon-based genotyping approach. We evaluated the impact of experimental factors, including viral load and sequencing depth, on correct sequence determination. We found that at least 1000 viral genomes are necessary to confidently detect variants in the SARS-CoV-2 genome at frequencies of ≥10%. The broad applicability of our recommendations was validated in over 200 clinical samples from six independent laboratories. The genotypes we determined for clinical isolates with sufficient quality cluster by sampling location and period. Our analysis also supports the rise in frequencies of 20A.EU1 and 20A.EU2, two recently reported European strains whose dissemination was facilitated by travel during the summer of 2020. We present much-needed recommendations for the reliable determination of SARS-CoV-2 genome sequences and demonstrate their broad applicability in a large cohort of clinical samples

A qualitative exploration of menstruation-related restrictive practices in Fiji, Solomon Islands and Papua New Guinea

Attitudes and beliefs about menstruation can place restrictions on menstruating women and girls, limiting their ability to fully participate in community life, education and employment. This paper presents evidence on menstruation-related beliefs contributing to restrictive practices in Papua New Guinea (PNG), Solomon Islands (SI) and Fiji. Focus group discussions and interviews were undertaken with 307 adolescent girls, women and men in a rural and urban site in each country. Data were analysed using an inductive thematic approach. Participants described a range of attitudes and beliefs that restrict the behaviour of menstruating women and girls. Themes include the belief that menstrual blood is ‘dirty’; that when menstruating, girls and women can bring ‘bad luck’ to men; secrecy and shame associated with menstruation; and beliefs about the impact of certain behaviours on menstruation and health. Restrictive practices were more frequently reported in PNG and SI than Fiji, and more common in rural compared with urban sites. Some restrictions, such as avoidance of household chores, were perceived as desirable or driven by women themselves. However participants identified other restrictions, such as not being able to attend church or hygienically wash menstrual hygiene materials, as unwanted, in some cases impacting on participation in school, work and community life. Education initiatives guided by women and girls, implemented by local stakeholders and grounded in a sound understanding of specific contexts are needed to address discriminatory attitudes and beliefs that contribute to unwanted restrictions, and to support enabling attitudes and beliefs regarding menstruation

BCR-ABL1-independent PI3Kinase activation causing imatinib-resistance

<p>Abstract</p> <p>Background</p> <p>The <it>BCR-ABL1 </it>translocation occurs in chronic myeloid leukemia (CML) and in 25% of cases with acute lymphoblastic leukemia (ALL). The advent of tyrosine kinase inhibitors (TKI) has fundamentally changed the treatment of CML. However, TKI are not equally effective for treating ALL. Furthermore, <it>de novo </it>or <it>secondary </it>TKI-resistance is a significant problem in CML. We screened a panel of <it>BCR-ABL1 </it>positive ALL and CML cell lines to find models for imatinib-resistance.</p> <p>Results</p> <p>Five of 19 <it>BCR-ABL1 </it>positive cell lines were resistant to imatinib-induced apoptosis (KCL-22, MHH-TALL1, NALM-1, SD-1, SUP-B15). None of the resistant cell lines carried mutations in the kinase domain of <it>BCR-ABL1 </it>and all showed resistance to second generation TKI, nilotinib or dasatinib. STAT5, ERK1/2 and the ribosomal S6 protein (RPS6) are <it>BCR-ABL1 </it>downstream effectors, and all three proteins are dephosphorylated by imatinib in sensitive cell lines. TKI-resistant phosphorylation of RPS6, but responsiveness as regards JAK/STAT5 and ERK1/2 signalling were characteristic for resistant cell lines. PI3K pathway inhibitors effected dephosphorylation of RPS6 in imatinib-resistant cell lines suggesting that an oncogene other than <it>BCR-ABL1 </it>might be responsible for activation of the PI3K/AKT1/mTOR pathway, which would explain the TKI resistance of these cells. We show that the TKI-resistant cell line KCL-22 carries a PI3Kα E545G mutation, a site critical for the constitutive activation of the PI3K/AKT1 pathway. Apoptosis in TKI-resistant cells could be induced by inhibition of AKT1, but not of mTOR.</p> <p>Conclusion</p> <p>We introduce five Philadelphia-chromosome positive cell lines as TKI-resistance models. None of these cell lines carries mutations in the kinase domain of <it>BCR-ABL1 </it>or other molecular aberrations previously indicted in the context of imatinib-resistance. These cell lines are unique as they dephosphorylate ERK1/2 and STAT5 after treatment with imatinib, while PI3K/AKT1/mTOR activity remains unaffected. Inhibition of AKT1 leads to apoptosis in the imatinib-resistant cell lines. In conclusion, Ph+ cell lines show a form of imatinib-resistance attributable to constitutive activation of the PI3K/AKT1 pathway. Mutations in <it>PIK3CA</it>, as observed in cell line KCL-22, or PI3K activating oncogenes may undelie TKI-resistance in these cell lines.</p

In Vitro and In Vivo Human Herpesvirus 8 Infection of Placenta

Herpesvirus infection of placenta may be harmful in pregnancy leading to disorders in fetal growth, premature delivery, miscarriage, or major congenital abnormalities. Although a correlation between human herpesvirus 8 (HHV-8) infection and abortion or low birth weight in children has been suggested, and rare cases of in utero or perinatal HHV-8 transmission have been documented, no direct evidence of HHV-8 infection of placenta has yet been reported. The aim of this study was to evaluate the in vitro and in vivo susceptibility of placental cells to HHV-8 infection. Short-term infection assays were performed on placental chorionic villi isolated from term placentae. Qualitative and quantitative HHV-8 detection were performed by PCR and real-time PCR, and HHV-8 proteins were analyzed by immunohistochemistry. Term placenta samples from HHV-8-seropositive women were analyzed for the presence of HHV-8 DNA and antigens. In vitro infected histocultures showed increasing amounts of HHV-8 DNA in tissues and supernatants; cyto- and syncitiotrophoblasts, as well as endothelial cells, expressed latent and lytic viral antigens. Increased apoptotic phenomena were visualized by the terminal deoxynucleotidyl transferase-mediated deoxyuridine nick end-labeling method in infected histocultures. Ex vivo, HHV-8 DNA and a latent viral antigen were detected in placenta samples from HHV-8-seropositive women. These findings demonstrate that HHV-8, like other human herpesviruses, may infect placental cells in vitro and in vivo, thus providing evidence that this phenomenon might influence vertical transmission and pregnancy outcome in HHV-8-infected women

Real time contrast enhanced ultrasonography in detection of liver metastases from gastrointestinal cancer

Background: Contrast enhanced ultrasound (CEUS) is an imaging technique which appeared on the market around the year 2000 and proposed for the detection of liver metastases in gastrointestinal cancer patients, a setting in which accurate staging plays a significant role in the choice of treatment. Methods: A total of 109 patients with colorectal (n = 92)or gastric cancer prospectively underwent computed tomography (CT) scan and conventional US evaluation followed by real time CEUS. A diagnosis of metastases was made by CT or, for lesions not visibile at CT, the diagnosis was achieved by histopathology or by a malignant behavior during follow-up. Results: Of 109 patients, 65 were found to have metastases at presentation. CEUS improved sensitivity in metastatic livers from 76.9% of patients (US) to 95.4% (p < 0.01), while CT scan reached 90.8% (p = n.s. vs CEUS, p < 0.01 vs US). CEUS and CT were more sensitive than US also for detection of single lesions (87 with US, 122 with CEUS, 113 with CT). In 15 patients (13.8%), CEUS revealed more metastases than CT, while CT revealed more metastases than CEUS in 9 patients (8.2%) (p = n.s.). Conclusion: CEUS is more sensitive than conventional US in the detection of liver metastases and could be usefully employed in the staging of patients with gastrointestinal cancer. Findings at CEUS and CT appear to be complementary in achieving maximum sensitivity. © 2007 Piscaglia et al; licensee BioMed Central Ltd