Cryptic genomic imbalances in patients with de novo or familial apparently balanced translocations and abnormal phenotype

<p>Abstract</p> <p>Background</p> <p>Carriers of apparently balanced translocations are usually phenotypically normal; however in about 6% of <it>de novo </it>cases, an abnormal phenotype is present. In the current study we investigated 12 patients, six <it>de novo </it>and six familial, with apparently balanced translocations and mental retardation and/or congenital malformations by applying 1 Mb resolution array-CGH. In all <it>de novo </it>cases, only the patient was a carrier of the translocation and had abnormal phenotype. In five out of the six familial cases, the phenotype of the patient was abnormal, although the karyotype appeared identical to other phenotypically normal carriers of the family. In the sixth familial case, all carriers of the translocations had an abnormal phenotype.</p> <p>Results</p> <p>Chromosomal and FISH analyses suggested that the rearrangements were "truly balanced" in all patients. However, array-CGH, revealed cryptic imbalances in three cases (3/12, 25%), two <it>de novo </it>(2/12, 33.3%) and one familial (1/12, 16.6%). The nature and type of abnormalities differed among the cases. In the first case, what was identified as a <it>de novo </it>t(9;15)(q31;q26.1), a complex rearrangement was revealed involving a ~6.1 Mb duplication on the long arm of chromosome 9, an ~10 Mb deletion and an inversion both on the long arm of chromosome 15. These imbalances were located near the translocation breakpoints. In the second case of a <it>de novo </it>t(4;9)(q25;q21.2), an ~6.6 Mb deletion was identified on the short arm of chromosome 7 which is unrelated to the translocation. In the third case, of a familial, t(4;7)(q13.3;p15.3), two deletions of ~4.3 Mb and ~2.3 Mb were found, each at one of the two translocation breakpoints. In the remaining cases the translocations appeared balanced at 1 Mb resolution.</p> <p>Conclusion</p> <p>This study investigated both <it>de novo </it>and familial apparently balanced translocations unlike other relatively large studies which are mainly focused on <it>de novo </it>cases. This study provides additional evidence that cryptic genomic imbalances are common in patients with abnormal phenotype and "apparently balanced" translocations not only in <it>de novo </it>but can also occur in familial cases. The use of microarrays with higher resolution such as oligo-arrays may reveal that the frequency of cryptic genomic imbalances among these patients is higher.</p

Prognostic stratification of patients with advanced renal cell carcinoma treated with sunitinib: comparison with the Memorial Sloan-Kettering prognostic factors model

<p>Abstract</p> <p>Background</p> <p>The treatment paradigm in advanced renal cell carcinoma (RCC) has changed in the recent years. Sunitinib has been established as a new standard for first-line therapy. We studied the prognostic significance of baseline characteristics and we compared the risk stratification with the established Memorial Sloan Kettering Cancer Center (MSKCC) model.</p> <p>Methods</p> <p>This is a retrospective analysis of patients treated in six Greek Oncology Units of HECOG. Inclusion criteria were: advanced renal cell carcinoma not amenable to surgery and treatment with Sunitinib. Previous cytokine therapy but no targeted agents were allowed. Overall survival (OS) was the major end point. Significance of prognostic factors was evaluated with multivariate cox regression analysis. A model was developed to stratify patients according to risk.</p> <p>Results</p> <p>One hundred and nine patients were included. Median follow up has been 15.8 months and median OS 17.1 months (95% CI: 13.7-20.6). Time from diagnosis to the start of Sunitinib (<= 12 months vs. >12 months, p = 0.001), number of metastatic sites (1 vs. >1, p = 0.003) and performance status (PS) (<= 1 vs >1, p = 0.001) were independently associated with OS. Stratification in two risk groups ("low" risk: 0 or 1 risk factors; "high" risk: 2 or 3 risk factors) resulted in distinctly different OS (median not reached [NR] vs. 10.8 [95% confidence interval (CI): 8.3-13.3], p < 0.001). The application of the MSKCC risk criteria resulted in stratification into 3 groups (low and intermediate and poor risk) with distinctly different prognosis underlying its validity. Nevertheless, MSKCC model did not show an improved prognostic performance over the model developed by this analysis.</p> <p>Conclusions</p> <p>Studies on risk stratification of patients with advanced RCC treated with targeted therapies are warranted. Our results suggest that a simpler than the MSKCC model can be developed. Such models should be further validated.</p

THINK4JOBS TRAINING: Critical Thinking Training Packages for Higher Education Instructors and Labour Market Tutors

This Report presents the findings of the “Critical Thinking for Successful Jobs-Think4Jobs” Partnership regarding the development of Critical Thinking Training Packages for Higher Education Instructors and Labour Market Organisations Tutors, namely Intellectual Output II. Considering previous research findings, it is suggested that despite HE and LMO instructors’ willingness to promote CT, they both might lack conceptual as well as procedural knowledge regarding CT. In order to assume that a common understanding between HE and LMOs can be achieved to promote CT skills development effectively in future graduates, the aim of this project was to develop a training course for HE instructors as well as LMO tutors. More specifically, the project aims to strengthen University-Business Collaboration for the effective promotion, development, support and assessment of students’ CT through their transition into a professional context using apprenticeships as a privileged interface in order to “bridge the gap” between their skills and those needed by the labour market. The specific objective of the second Intellectual Output was to develop a training curriculum for Higher Education Instructors and Labour Market Organisations Tutors on how to promote, develop, support and assess students’ CT in apprenticeships curricula as well as on how to develop blended curricula using Moodle. The training aimed at reaching 30 participants from the Partnership (i.e., 15 from Higher Education and 15 from Labour Market Organisations). To reach the aforementioned objective for the delivery of the Output, five activities were originally designed: 1. Define the goals, outcomes and assessment criteria of the training packages. 2. Identify the training subjects and design the activities to be held. 3. Identify, select and/or create training resources, which will support the activities during the training packages. 4. Develop a transnational training course. 5. Delivery of the training course. University of Western Macedonia (UOWM) was the leading Organisation for the delivery of the second Intellectual Output. A Participatory Co-Design (PC-D Methodology was implemented to map the participants’ requirements and needs for the training. For the implementation of the training course, participants from both the Higher Education and the Labor Market Organisations from the five countries partake as Trainers providing various workshops focusing on experiential learning. More specifically, workshops concerned the deconstruction and reconstruction of previously held ideas regarding CT, the development of a working definition on CT for the Think4Jobs project, instructional approaches and teaching strategies that promote CT, blended learning and Moodle, the assessment of CT as well as the preparation of the Memorandum of Understanding (MoU) between HE and LMOs. Finally, a reflective session on the work carried out for the MoU and a session for the design and development of the CT blended apprenticeship curricula were scheduled. According to the registrations, on a daily basis, 35 participants engaged in the LTTA. Participants' knowledge on conceptual and procedural knowledge regarding CT, evaluation of CT, as well as blended learning, University-Business Collaboration and Moodle were evaluated in a pre-post measurement. In order to assess participants’ previous knowledge as well as the knowledge acquired during the LTTA, two online questionnaires were used. The first questionnaire (pre-measurement) was administered to participants at the beginning of the training course, while the second questionnaire (post-measurement) at the end of the LTTA (122 items for the pre-test, 130 items for the post-test, including questions about participants’ commitment during LTTA and their evaluation of the LTTA). The data collection tool consisted of seven distinct parts. The first part concerned demographic information, while the second part assessed participants’ level of perceived self-confidence in the issues addressed in the LTTA, the Moodle’s ease of use and perceived self-efficacy. Parts three to five of the tool explored participants’ conceptions regarding myths and facts about conceptual and procedural knowledge of CT, the evaluation of CT, blended learning and the University and Business Collaboration. Moreover, participants’ level of confidence about their answers was also assessed. Statistical analysis of data collected suggested that participants’ knowledge about CT, blended learning and the University and Business Collaboration increased after their participation in the LTTA. However, these results were not statistically significant. A statistically significant median increase elicited only in participants’ perceived self-confidence on the topics addressed during the LTTA, only for HE participants. Finally, the administrative and management of the implemented LTTA was evaluated highlighting that the event reached the predefined objectives and goals, met participants’ expectations and offered a high quality learning and training experience to the participants. Apart from the measurable data, a significant outcome of the LTTA was the development of a Memorandum of Understanding (MoU) between each pair of HEIs and LMOs partner per country. The MoU set a specific framework on the expected collaboration between HE and LMOs for the design-development (IO3), implementation and evaluation (IO4) of the CT blended apprenticeships curricula. The development of MoUs suggest that a common understanding on the design and delivery of CT blended apprenticeships curricula has been achieved and that UBC has been tailored to each pair of contributors. Overall, the CT training course presented in the current report has contributed to the existing research and literature in numerous ways. First, it presented a course designed to address the specific needs of its participants, by employing a PC-D approach. Second, it presented a training course that can also be applied in the future, as an intensive program aiming to enhance CT in educational and LMO settings. Third, it actively engaged HE Instructors and LMOs in a common training course, trying to reach a common understanding. Finally, the current report contributes to the literature with the exploitation of a multiple-choice instrument incorporating a Certainty Response Index identifying not only participants’ alternative concepts but also their level of confidence on aspects of CT, blended learning and UBC

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity &gt; 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

The future of road transport

A perfect storm of new technologies and new business models is transforming not only our vehicles, but everything about how we get around, and how we live our lives. The JRC report “The future of road transport - Implications of automated, connected, low-carbon and shared mobility” looks at some main enablers of the transformation of road transport, such as data governance, infrastructures, communication technologies and cybersecurity, and legislation. It discusses the potential impacts on the economy, employment and skills, energy use and emissions, the sustainability of raw materials, democracy, privacy and social fairness, as well as on the urban context. It shows how the massive changes on the horizon represent an opportunity to move towards a transport system that is more efficient, safer, less polluting and more accessible to larger parts of society than the current one centred on car ownership. However, new transport technologies, on their own, won't spontaneously make our lives better without upgrading our transport systems and policies to the 21st century. The improvement of governance and the development of innovative mobility solutions will be crucial to ensure that the future of transport is cleaner and more equitable than its car-centred present.JRC.C.4-Sustainable Transpor

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries