What Role Can Process Mining Play in Recurrent Clinical Guidelines Issues? A Position Paper

[EN] In the age of Evidence-Based Medicine, Clinical Guidelines (CGs) are recognized to be an indispensable tool to support physicians in their daily clinical practice. Medical Informatics is expected to play a relevant role in facilitating diffusion and adoption of CGs. However, the past pioneering approaches, often fragmented in many disciplines, did not lead to solutions that are actually exploited in hospitals. Process Mining for Healthcare (PM4HC) is an emerging discipline gaining the interest of healthcare experts, and seems able to deal with many important issues in representing CGs. In this position paper, we briefly describe the story and the state-of-the-art of CGs, and the efforts and results of the past approaches of medical informatics. Then, we describe PM4HC, and we answer questions like how can PM4HC cope with this challenge? Which role does PM4HC play and which rules should be employed for the PM4HC scientific community?Gatta, R.; Vallati, M.; Fernández Llatas, C.; Martinez-Millana, A.; Orini, S.; Sacchi, L.; Lenkowicz, J.... (2020). What Role Can Process Mining Play in Recurrent Clinical Guidelines Issues? A Position Paper. International Journal of Environmental research and Public Health (Online). 17(18):1-19. https://doi.org/10.3390/ijerph17186616S1191718Guyatt, G. (1992). Evidence-Based Medicine. JAMA, 268(17), 2420. doi:10.1001/jama.1992.03490170092032Hripcsak, G., Ludemann, P., Pryor, T. A., Wigertz, O. B., & Clayton, P. D. (1994). Rationale for the Arden Syntax. Computers and Biomedical Research, 27(4), 291-324. doi:10.1006/cbmr.1994.1023Peleg, M. (2013). Computer-interpretable clinical guidelines: A methodological review. Journal of Biomedical Informatics, 46(4), 744-763. doi:10.1016/j.jbi.2013.06.009Van de Velde, S., Heselmans, A., Delvaux, N., Brandt, L., Marco-Ruiz, L., Spitaels, D., … Flottorp, S. (2018). A systematic review of trials evaluating success factors of interventions with computerised clinical decision support. Implementation Science, 13(1). doi:10.1186/s13012-018-0790-1Rawson, T. M., Moore, L. S. P., Hernandez, B., Charani, E., Castro-Sanchez, E., Herrero, P., … Holmes, A. H. (2017). A systematic review of clinical decision support systems for antimicrobial management: are we failing to investigate these interventions appropriately? Clinical Microbiology and Infection, 23(8), 524-532. doi:10.1016/j.cmi.2017.02.028Greenes, R. A., Bates, D. W., Kawamoto, K., Middleton, B., Osheroff, J., & Shahar, Y. (2018). Clinical decision support models and frameworks: Seeking to address research issues underlying implementation successes and failures. Journal of Biomedical Informatics, 78, 134-143. doi:10.1016/j.jbi.2017.12.005Garcia, C. dos S., Meincheim, A., Faria Junior, E. R., Dallagassa, M. R., Sato, D. M. V., Carvalho, D. R., … Scalabrin, E. E. (2019). Process mining techniques and applications – A systematic mapping study. Expert Systems with Applications, 133, 260-295. doi:10.1016/j.eswa.2019.05.003Bhargava, A., Kim, T., Quine, D. B., & Hauser, R. G. (2019). A 20-Year Evaluation of LOINC in the United States’ Largest Integrated Health System. Archives of Pathology & Laboratory Medicine, 144(4), 478-484. doi:10.5858/arpa.2019-0055-oaLee, D., de Keizer, N., Lau, F., & Cornet, R. (2014). Literature review of SNOMED CT use. Journal of the American Medical Informatics Association, 21(e1), e11-e19. doi:10.1136/amiajnl-2013-001636TROTTI, A., COLEVAS, A., SETSER, A., RUSCH, V., JAQUES, D., BUDACH, V., … COLEMAN, C. (2003). CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Seminars in Radiation Oncology, 13(3), 176-181. doi:10.1016/s1053-4296(03)00031-6Daniel, C., & Kalra, D. (2019). Clinical Research Informatics: Contributions from 2018. Yearbook of Medical Informatics, 28(01), 203-205. doi:10.1055/s-0039-1677921Marco-Ruiz, L., Pedrinaci, C., Maldonado, J. A., Panziera, L., Chen, R., & Bellika, J. G. (2016). Publication, discovery and interoperability of Clinical Decision Support Systems: A Linked Data approach. Journal of Biomedical Informatics, 62, 243-264. doi:10.1016/j.jbi.2016.07.011Marcos, C., González-Ferrer, A., Peleg, M., & Cavero, C. (2015). Solving the interoperability challenge of a distributed complex patient guidance system: a data integrator based on HL7’s Virtual Medical Record standard. Journal of the American Medical Informatics Association, 22(3), 587-599. doi:10.1093/jamia/ocv003Wulff, A., Haarbrandt, B., Tute, E., Marschollek, M., Beerbaum, P., & Jack, T. (2018). An interoperable clinical decision-support system for early detection of SIRS in pediatric intensive care using openEHR. Artificial Intelligence in Medicine, 89, 10-23. doi:10.1016/j.artmed.2018.04.012Chen, C., Chen, K., Hsu, C.-Y., Chiu, W.-T., & Li, Y.-C. (Jack). (2010). A guideline-based decision support for pharmacological treatment can improve the quality of hyperlipidemia management. Computer Methods and Programs in Biomedicine, 97(3), 280-285. doi:10.1016/j.cmpb.2009.12.004Anani, N., Mazya, M. V., Chen, R., Prazeres Moreira, T., Bill, O., Ahmed, N., … Koch, S. (2017). Applying openEHR’s Guideline Definition Language to the SITS international stroke treatment registry: a European retrospective observational study. BMC Medical Informatics and Decision Making, 17(1). doi:10.1186/s12911-016-0401-5Eddy, D. M. (1982). Clinical Policies and the Quality of Clinical Practice. New England Journal of Medicine, 307(6), 343-347. doi:10.1056/nejm198208053070604Guyatt, G. H. (1990). Then-of-1 Randomized Controlled Trial: Clinical Usefulness. Annals of Internal Medicine, 112(4), 293. doi:10.7326/0003-4819-112-4-293CHALMERS, I. (1993). The Cochrane Collaboration: Preparing, Maintaining, and Disseminating Systematic Reviews of the Effects of Health Care. Annals of the New York Academy of Sciences, 703(1 Doing More Go), 156-165. doi:10.1111/j.1749-6632.1993.tb26345.xWoolf, S. H., Grol, R., Hutchinson, A., Eccles, M., & Grimshaw, J. (1999). Clinical guidelines: Potential benefits, limitations, and harms of clinical guidelines. BMJ, 318(7182), 527-530. doi:10.1136/bmj.318.7182.527Grading quality of evidence and strength of recommendations. (2004). BMJ, 328(7454), 1490. doi:10.1136/bmj.328.7454.1490Guyatt, G. H., Oxman, A. D., Vist, G. E., Kunz, R., Falck-Ytter, Y., Alonso-Coello, P., & Schünemann, H. J. (2008). GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ, 336(7650), 924-926. doi:10.1136/bmj.39489.470347.adHill, J., Bullock, I., & Alderson, P. (2011). A Summary of the Methods That the National Clinical Guideline Centre Uses to Produce Clinical Guidelines for the National Institute for Health and Clinical Excellence. Annals of Internal Medicine, 154(11), 752. doi:10.7326/0003-4819-154-11-201106070-00007Qaseem, A. (2012). Guidelines International Network: Toward International Standards for Clinical Practice Guidelines. Annals of Internal Medicine, 156(7), 525. doi:10.7326/0003-4819-156-7-201204030-00009Rosenfeld, R. M., Nnacheta, L. C., & Corrigan, M. D. (2015). Clinical Consensus Statement Development Manual. Otolaryngology–Head and Neck Surgery, 153(2_suppl), S1-S14. doi:10.1177/0194599815601394De Boeck, K., Castellani, C., & Elborn, J. S. (2014). Medical consensus, guidelines, and position papers: A policy for the ECFS. Journal of Cystic Fibrosis, 13(5), 495-498. doi:10.1016/j.jcf.2014.06.012Clinical Practical Guidelineshttp://www.openclinical.org/guidelines.htmlHaynes, A. B., Weiser, T. G., Berry, W. R., Lipsitz, S. R., Breizat, A.-H. S., Dellinger, E. P., … Gawande, A. A. (2009). A Surgical Safety Checklist to Reduce Morbidity and Mortality in a Global Population. New England Journal of Medicine, 360(5), 491-499. doi:10.1056/nejmsa0810119Grigg, E. (2015). Smarter Clinical Checklists. Anesthesia & Analgesia, 121(2), 570-573. doi:10.1213/ane.0000000000000352Hales, B., Terblanche, M., Fowler, R., & Sibbald, W. (2007). Development of medical checklists for improved quality of patient care. International Journal for Quality in Health Care, 20(1), 22-30. doi:10.1093/intqhc/mzm062Greenfield, S. (2017). Clinical Practice Guidelines. JAMA, 317(6), 594. doi:10.1001/jama.2016.19969Vegting, I. L., van Beneden, M., Kramer, M. H. H., Thijs, A., Kostense, P. J., & Nanayakkara, P. W. B. (2012). How to save costs by reducing unnecessary testing: Lean thinking in clinical practice. European Journal of Internal Medicine, 23(1), 70-75. doi:10.1016/j.ejim.2011.07.003Drummond, M. (2016). Clinical Guidelines: A NICE Way to Introduce Cost-Effectiveness Considerations? Value in Health, 19(5), 525-530. doi:10.1016/j.jval.2016.04.020Prior, M., Guerin, M., & Grimmer-Somers, K. (2008). The effectiveness of clinical guideline implementation strategies - a synthesis of systematic review findings. Journal of Evaluation in Clinical Practice, 14(5), 888-897. doi:10.1111/j.1365-2753.2008.01014.xWatts, C. G., Dieng, M., Morton, R. L., Mann, G. J., Menzies, S. W., & Cust, A. E. (2014). Clinical practice guidelines for identification, screening and follow-up of individuals at high risk of primary cutaneous melanoma: a systematic review. British Journal of Dermatology, 172(1), 33-47. doi:10.1111/bjd.13403Woolf, S., Schünemann, H. J., Eccles, M. P., Grimshaw, J. M., & Shekelle, P. (2012). Developing clinical practice guidelines: types of evidence and outcomes; values and economics, synthesis, grading, and presentation and deriving recommendations. Implementation Science, 7(1). doi:10.1186/1748-5908-7-61Legido-Quigley, H., Panteli, D., Brusamento, S., Knai, C., Saliba, V., Turk, E., … Busse, R. (2012). Clinical guidelines in the European Union: Mapping the regulatory basis, development, quality control, implementation and evaluation across member states. Health Policy, 107(2-3), 146-156. doi:10.1016/j.healthpol.2012.08.004Rashidian, A., Eccles, M. P., & Russell, I. (2008). Falling on stony ground? A qualitative study of implementation of clinical guidelines’ prescribing recommendations in primary care. Health Policy, 85(2), 148-161. doi:10.1016/j.healthpol.2007.07.011Yang, W.-S., & Hwang, S.-Y. (2006). A process-mining framework for the detection of healthcare fraud and abuse. Expert Systems with Applications, 31(1), 56-68. doi:10.1016/j.eswa.2005.09.003Kose, I., Gokturk, M., & Kilic, K. (2015). An interactive machine-learning-based electronic fraud and abuse detection system in healthcare insurance. Applied Soft Computing, 36, 283-299. doi:10.1016/j.asoc.2015.07.018Pryor, T. A., Gardner, R. M., Clayton, P. D., & Warner, H. R. (1983). The HELP system. Journal of Medical Systems, 7(2), 87-102. doi:10.1007/bf00995116Shahar, Y., Miksch, S., & Johnson, P. (1998). The Asgaard project: a task-specific framework for the application and critiquing of time-oriented clinical guidelines. Artificial Intelligence in Medicine, 14(1-2), 29-51. doi:10.1016/s0933-3657(98)00015-3Boxwala, A. A., Peleg, M., Tu, S., Ogunyemi, O., Zeng, Q. T., Wang, D., … Shortliffe, E. H. (2004). GLIF3: a representation format for sharable computer-interpretable clinical practice guidelines. Journal of Biomedical Informatics, 37(3), 147-161. doi:10.1016/j.jbi.2004.04.002Terenziani, P., Molino, G., & Torchio, M. (2001). A modular approach for representing and executing clinical guidelines. Artificial Intelligence in Medicine, 23(3), 249-276. doi:10.1016/s0933-3657(01)00087-2Sutton, D. R., & Fox, J. (2003). The Syntax and Semantics of the PROformaGuideline Modeling Language. Journal of the American Medical Informatics Association, 10(5), 433-443. doi:10.1197/jamia.m1264Musen, M. A., Tu, S. W., Das, A. K., & Shahar, Y. (1996). EON: A Component-Based Approach to Automation of Protocol-Directed Therapy. Journal of the American Medical Informatics Association, 3(6), 367-388. doi:10.1136/jamia.1996.97084511Ciccarese, P., Caffi, E., Quaglini, S., & Stefanelli, M. (2005). Architectures and tools for innovative Health Information Systems: The Guide Project. International Journal of Medical Informatics, 74(7-8), 553-562. doi:10.1016/j.ijmedinf.2005.02.001Shiffman, R. N., & Greenes, R. A. (1994). Improving Clinical Guidelines with Logic and Decision-table Techniques. Medical Decision Making, 14(3), 245-254. doi:10.1177/0272989x9401400306Peleg, M., Tu, S., Bury, J., Ciccarese, P., Fox, J., Greenes, R. A., … Stefanelli, M. (2003). Comparing Computer-interpretable Guideline Models: A Case-study Approach. Journal of the American Medical Informatics Association, 10(1), 52-68. doi:10.1197/jamia.m1135Karadimas, H., Ebrahiminia, V., & Lepage, E. (2018). User-defined functions in the Arden Syntax: An extension proposal. Artificial Intelligence in Medicine, 92, 103-110. doi:10.1016/j.artmed.2015.11.003Peleg, M., Keren, S., & Denekamp, Y. (2008). Mapping computerized clinical guidelines to electronic medical records: Knowledge-data ontological mapper (KDOM). Journal of Biomedical Informatics, 41(1), 180-201. doi:10.1016/j.jbi.2007.05.003German, E., Leibowitz, A., & Shahar, Y. (2009). An architecture for linking medical decision-support applications to clinical databases and its evaluation. Journal of Biomedical Informatics, 42(2), 203-218. doi:10.1016/j.jbi.2008.10.007Marcos, M., Maldonado, J. A., Martínez-Salvador, B., Boscá, D., & Robles, M. (2013). Interoperability of clinical decision-support systems and electronic health records using archetypes: A case study in clinical trial eligibility. Journal of Biomedical Informatics, 46(4), 676-689. doi:10.1016/j.jbi.2013.05.004Marco-Ruiz, L., Moner, D., Maldonado, J. A., Kolstrup, N., & Bellika, J. G. (2015). Archetype-based data warehouse environment to enable the reuse of electronic health record data. International Journal of Medical Informatics, 84(9), 702-714. doi:10.1016/j.ijmedinf.2015.05.016Gooch, P., & Roudsari, A. (2011). Computerization of workflows, guidelines, and care pathways: a review of implementation challenges for process-oriented health information systems. Journal of the American Medical Informatics Association, 18(6), 738-748. doi:10.1136/amiajnl-2010-000033Quaglini, S., Stefanelli, M., Cavallini, A., Micieli, G., Fassino, C., & Mossa, C. (2000). Guideline-based careflow systems. Artificial Intelligence in Medicine, 20(1), 5-22. doi:10.1016/s0933-3657(00)00050-6Schadow, G., Russler, D. C., & McDonald, C. J. (2001). Conceptual alignment of electronic health record data with guideline and workflow knowledge. International Journal of Medical Informatics, 64(2-3), 259-274. doi:10.1016/s1386-5056(01)00196-4González-Ferrer, A., ten Teije, A., Fdez-Olivares, J., & Milian, K. (2013). Automated generation of patient-tailored electronic care pathways by translating computer-interpretable guidelines into hierarchical task networks. Artificial Intelligence in Medicine, 57(2), 91-109. doi:10.1016/j.artmed.2012.08.008Shabo, A., Parimbelli, E., Quaglini, S., Napolitano, C., & Peleg, M. (2016). Interplay between Clinical Guidelines and Organizational Workflow Systems. Methods of Information in Medicine, 55(06), 488-494. doi:10.3414/me16-01-0006Mulyar, N., van der Aalst, W. M. P., & Peleg, M. (2007). A Pattern-based Analysis of Clinical Computer-interpretable Guideline Modeling Languages. Journal of the American Medical Informatics Association, 14(6), 781-787. doi:10.1197/jamia.m2389Grando, M. A., Glasspool, D., & Fox, J. (2012). A formal approach to the analysis of clinical computer-interpretable guideline modeling languages. Artificial Intelligence in Medicine, 54(1), 1-13. doi:10.1016/j.artmed.2011.07.001Kaiser, K., & Marcos, M. (2015). Leveraging workflow control patterns in the domain of clinical practice guidelines. BMC Medical Informatics and Decision Making, 16(1). doi:10.1186/s12911-016-0253-zMartínez-Salvador, B., & Marcos, M. (2016). Supporting the Refinement of Clinical Process Models to Computer-Interpretable Guideline Models. Business & Information Systems Engineering, 58(5), 355-366. doi:10.1007/s12599-016-0443-3Decision Model and Notation Version 1.0https://www.omg.org/spec/DMN/1.0Ghasemi, M., & Amyot, D. (2016). Process mining in healthcare: a systematised literature review. International Journal of Electronic Healthcare, 9(1), 60. doi:10.1504/ijeh.2016.078745Rebuge, Á., & Ferreira, D. R. (2012). Business process analysis in healthcare environments: A methodology based on process mining. Information Systems, 37(2), 99-116. doi:10.1016/j.is.2011.01.003Rovani, M., Maggi, F. M., de Leoni, M., & van der Aalst, W. M. P. (2015). Declarative process mining in healthcare. Expert Systems with Applications, 42(23), 9236-9251. doi:10.1016/j.eswa.2015.07.040Rojas, E., Munoz-Gama, J., Sepúlveda, M., & Capurro, D. (2016). Process mining in healthcare: A literature review. Journal of Biomedical Informatics, 61, 224-236. doi:10.1016/j.jbi.2016.04.007Lenkowicz, J., Gatta, R., Masciocchi, C., Casà, C., Cellini, F., Damiani, A., … Valentini, V. (2018). Assessing the conformity to clinical guidelines in oncology. Management Decision, 56(10), 2172-2186. doi:10.1108/md-09-2017-0906Fernández-Llatas, C., Benedi, J.-M., García-Gómez, J., & Traver, V. (2013). Process Mining for Individualized Behavior Modeling Using Wireless Tracking in Nursing Homes. Sensors, 13(11), 15434-15451. doi:10.3390/s131115434Qu, G., Liu, Z., Cui, S., & Tang, J. (2013). Study on Self-Adaptive Clinical Pathway Decision Support System Based on Case-Based Reasoning. Frontier and Future Development of Information Technology in Medicine and Education, 969-978. doi:10.1007/978-94-007-7618-0_95Van de Velde, S., Roshanov, P., Kortteisto, T., Kunnamo, I., Aertgeerts, B., Vandvik, P. O., & Flottorp, S. (2015). Tailoring implementation strategies for evidence-based recommendations using computerised clinical decision support systems: protocol for the development of the GUIDES tools. Implementation Science, 11(1). doi:10.1186/s13012-016-0393-

Comprehensive dissection of prevalence rates, sex differences, and blood level-dependencies of clozapine-associated adverse drug reactions

Clozapine is often underused due to concerns about adverse drug reactions (ADRs) but studies into their prevalences are inconclusive. We therefore comprehensively examined prevalences of clozapineassociated ADRs in individuals with schizophrenia and demographic and clinical factors associated with their occurrence. Data from a multi-center study (n=698 participants) were collected. The mean number of ADRs during clozapine treatment was 4.8, with 2.4% of participants reporting no ADRs. The most common ADRs were hypersalivation (74.6%), weight gain (69.3%), and increased sleep necessity (65.9%), all of which were more common in younger participants. Participants with lower BMI prior to treatment were more likely to experience significant weight gain (>10%). Constipation occurred more frequently with higher clozapine blood levels and doses. There were no differences in ADR prevalence rates between participants receiving clozapine monotherapy and polytherapy. These findings emphasize the high prevalence of clozapine-associated ADRs and highlight several demographic and clinical factors contributing to their occurrence. By understanding these factors, clinicians can better anticipate and manage clozapine-associated ADRs, leading to improved treatment outcomes and patient well-being

Plasmacytoid Dendritic Cells Sequester High Prion Titres at Early Stages of Prion Infection

In most transmissible spongiform encephalopathies prions accumulate in the lymphoreticular system (LRS) long before they are detectable in the central nervous system. While a considerable body of evidence showed that B lymphocytes and follicular dendritic cells play a major role in prion colonization of lymphoid organs, the contribution of various other cell types, including antigen-presenting cells, to the accumulation and the spread of prions in the LRS are not well understood. A comprehensive study to compare prion titers of candidate cell types has not been performed to date, mainly due to limitations in the scope of animal bioassays where prohibitively large numbers of mice would be required to obtain sufficiently accurate data. By taking advantage of quantitative in vitro prion determination and magnetic-activated cell sorting, we studied the kinetics of prion accumulation in various splenic cell types at early stages of prion infection. Robust estimates for infectious titers were obtained by statistical modelling using a generalized linear model. Whilst prions were detectable in B and T lymphocytes and in antigen-presenting cells like dendritic cells and macrophages, highest infectious titers were determined in two cell types that have previously not been associated with prion pathogenesis, plasmacytoid dendritic (pDC) and natural killer (NK) cells. At 30 days after infection, NK cells were more than twice, and pDCs about seven-fold, as infectious as lymphocytes respectively. This result was unexpected since, in accordance to previous reports prion protein, an obligate requirement for prion replication, was undetectable in pDCs. This underscores the importance of prion sequestration and dissemination by antigen-presenting cells which are among the first cells of the immune system to encounter pathogens. We furthermore report the first evidence for a release of prions from lymphocytes and DCs of scrapie-infected mice ex vivo, a process that is associated with a release of exosome-like membrane vesicles

Les droits disciplinaires des fonctions publiques : « unification », « harmonisation » ou « distanciation ». A propos de la loi du 26 avril 2016 relative à la déontologie et aux droits et obligations des fonctionnaires

The production of tt‾ , W+bb‾ and W+cc‾ is studied in the forward region of proton–proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98±0.02 fb−1 . The W bosons are reconstructed in the decays W→ℓν , where ℓ denotes muon or electron, while the b and c quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions.The production of $t\overline{t}$, $W+b\overline{b}$ and $W+c\overline{c}$ is studied in the forward region of proton-proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98 $\pm$ 0.02 \mbox{fb}^{-1}. The $W$ bosons are reconstructed in the decays $W\rightarrow\ell\nu$, where $\ell$ denotes muon or electron, while the $b$ and $c$ quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions

Physics case for an LHCb Upgrade II - Opportunities in flavour physics, and beyond, in the HL-LHC era

The LHCb Upgrade II will fully exploit the flavour-physics opportunities of the HL-LHC, and study additional physics topics that take advantage of the forward acceptance of the LHCb spectrometer. The LHCb Upgrade I will begin operation in 2020. Consolidation will occur, and modest enhancements of the Upgrade I detector will be installed, in Long Shutdown 3 of the LHC (2025) and these are discussed here. The main Upgrade II detector will be installed in long shutdown 4 of the LHC (2030) and will build on the strengths of the current LHCb experiment and the Upgrade I. It will operate at a luminosity up to 2×1034 cm−2s−1, ten times that of the Upgrade I detector. New detector components will improve the intrinsic performance of the experiment in certain key areas. An Expression Of Interest proposing Upgrade II was submitted in February 2017. The physics case for the Upgrade II is presented here in more depth. CP-violating phases will be measured with precisions unattainable at any other envisaged facility. The experiment will probe b → sl+l−and b → dl+l− transitions in both muon and electron decays in modes not accessible at Upgrade I. Minimal flavour violation will be tested with a precision measurement of the ratio of B(B0 → μ+μ−)/B(Bs → μ+μ−). Probing charm CP violation at the 10−5 level may result in its long sought discovery. Major advances in hadron spectroscopy will be possible, which will be powerful probes of low energy QCD. Upgrade II potentially will have the highest sensitivity of all the LHC experiments on the Higgs to charm-quark couplings. Generically, the new physics mass scale probed, for fixed couplings, will almost double compared with the pre-HL-LHC era; this extended reach for flavour physics is similar to that which would be achieved by the HE-LHC proposal for the energy frontier

LHCb upgrade software and computing : technical design report

This document reports the Research and Development activities that are carried out in the software and computing domains in view of the upgrade of the LHCb experiment. The implementation of a full software trigger implies major changes in the core software framework, in the event data model, and in the reconstruction algorithms. The increase of the data volumes for both real and simulated datasets requires a corresponding scaling of the distributed computing infrastructure. An implementation plan in both domains is presented, together with a risk assessment analysis

Joint Observation of the Galactic Center with MAGIC and CTA-LST-1

MAGIC is a system of two Imaging Atmospheric Cherenkov Telescopes (IACTs), designed to detect very-high-energy gamma rays, and is operating in stereoscopic mode since 2009 at the Observatorio del Roque de Los Muchachos in La Palma, Spain. In 2018, the prototype IACT of the Large-Sized Telescope (LST-1) for the Cherenkov Telescope Array, a next-generation ground-based gamma-ray observatory, was inaugurated at the same site, at a distance of approximately 100 meters from the MAGIC telescopes. Using joint observations between MAGIC and LST-1, we developed a dedicated analysis pipeline and established the threefold telescope system via software, achieving the highest sensitivity in the northern hemisphere. Based on this enhanced performance, MAGIC and LST-1 have been jointly and regularly observing the Galactic Center, a region of paramount importance and complexity for IACTs. In particular, the gamma-ray emission from the dynamical center of the Milky Way is under debate. Although previous measurements suggested that a supermassive black hole Sagittarius A* plays a primary role, its radiation mechanism remains unclear, mainly due to limited angular resolution and sensitivity. The enhanced sensitivity in our novel approach is thus expected to provide new insights into the question. We here present the current status of the data analysis for the Galactic Center joint MAGIC and LST-1 observations

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223