V O L 2 9 I S S U E 1 / 2 0 M a r c h / A p r i l 2 0 2 0 T H E E U R O P E A N F O R U M F O R T H O S E I N T H E B U S I N E S S O F M A K I N G H E A L T H C A R E W O R K 1-5 NEWS & RESEARCH • The effect of mask wearing is enormous • Taiwan – a model for hospital viral care • Where are the infectologists? 9-13 LABORATORY • Self-testing health in space – blood tests for astronauts • Breathomics – far more than hot air • Seeking an ideal lab life r o t c e v x e T / k c o t s r e t t u h S © The potential role of ACE2 As COVID-19 continues to jet and alight invisibly around the globe, scientists now report that the virus has mutated to become two strains: the older ‘S-type’ appears milder and less infectious, while the later-emerging ‘L-type’, is more aggressive, spreads more quickly, and currently accounts for about 70 percent of cases. Worldwide, medical researchers are exploring whether existing viral treatments just might work against the new strains as well as examining which current research should speed into trials. In Australia, researchers have reasoned that a well-known HIV drug could work against the new coronavirus, for example, whilst other reports indicate that Chinese scientists have seen success in delivering high intravenous doses of Vitamin C to seriously infected patients (The journal Caduceus also reports that large ship- ments of Vitamin C are now enroute to that country). Meanwhile, ACE2 raises hopes as a rational therapy against this devastating viral attack. Report: Mark Nicholls Scientific hopes are that the angioten- sin converting enzyme 2 (ACE2) will play a critical role in tackling the COVID-19 pandemic. During a live webcast lecture ‘ACE2 – a rational frontline therapy for COVID-19’, organised by the European Society of Radiology, the enzyme’s back- ground, development and potential role as a therapy was explored by one of the world’s leading geneti- cists and molecular immunologists. Professor Josef Penninger out- lined the relationship between ACE2 and the renin-angiotensin system (RAS) – responsible for systemic vascular resistance and for regulat- ing blood pressure and fluid-elec- trolyte balance in instances of lung injury – highlighting the predisposi- tion of ACE2 as a SARS-CoV and SARS-CoV-2 receptor and potential treatment approach. Starting more than two decades ago, the research led to the dis- covery of ACE2, initially in fly and mouse models and then indicat- ing a human link and, the expert explained, how more recently that has led his team to believe they are closer to testing a medicine for COVID-19. From a knockout mouse model, they found that, if ACE2 was lacking then heart function was impaired, www.healthcare-in-europe.com and was a negative regulator of the RAS. This also pointed to a possible gender bias in COVID-19 – with ACE2 on the X chromosome, meaning males have one copy and females two. ‘In simple terms,’ Penninger said, ‘ACE cleaves to amino acid from angiotensin 1 to make angiotensin 2, which acts on receptors 81 and 82. ACE2 is a catalytically active molecule on the surface of cells – though it can also be soluble in serum – and inactivates this path- way.’ From there, the research showed that ACE2 also affects kidney dis- ease and regulates liver and lung fibrosis. ‘If you knock out ACE2,’ he continued, ‘disease gets much worse and if you have ACE2 it gets much Professor Josef Penninger during the ESR live webcast on COVID-19 milder because it counterbalances the ACE function and, by doing so, regulates the system.’ With a lack of ACE2 in the lung leading to severe injury, research by other groups in the early 2000s had indicated that ACE2 might be a receptor for the SARS coronavirus of 2003. With the explanation of SARS binding to ACE2 and enhanc- ing disease severity, his team saw a new pathway to develop a medicine against acute lung injury. ‘Based on this,’ Pennington explained, ‘we decided to develop a human recom- binant angiotensin renin converting enzyme for the therapy of lung injury.’ He also highlighted the dif- ference between the SARS virus of 2003, which infected about 8000 people leading to 800 deaths, and COVID-19. For SARS to spread, a patient had to be very ill and in close contact with other individuals to transmit, whereas the new virus is easy to transmit. ‘That’s why there is fundamental difference between old outbreak and new outbreak. ‘What we believe is happening is that the virus comes in via this spike protein, binds to ACE2 and together with ACE2 gets into the cell, fuses to the membrane, the virus gets out from the endosome, and replicates. So, ACE2 is essential for binding to the virus and surface – of course this leads to viral release and rep- licates and then spread, leading to diseases we know as SARS and COVID-19,’ Penninger explained. Currently, Apeiron Biologics AG, a company founded by Penninger, is scheduled to start a pilot clinical trial for a newly-developed drug designed to decrease mortality in those affected by the virus. ‘This is where we believe our soluble ACE2 would come in,’ he explained, ‘Because ACE2 sits on the membrane and our molecule is sol- uble, it would soak up the virus like a neutralising antibody, so the virus cannot find its real receptor. With less virus coming, this would slow down viral infection and improve Hospital heroes STAY HOME – SAVE LIVES Around the globe, care staff and physi- cians are working beyond their limits to help COVID-19 patients. They are our modern heroes, risking their own health to save lives – faced with a highly con- tagious virus, sometimes without ade- quate protective equipment. Physicians and nurses at Raphaelsklinik in Münster, Germany, have a message for all of us: “We stay here for you, please stay home for us.” Only if we stay at home we will neither acquire the virus nor pass it on to other people. This is the only way to keep COVID-19 from spreading. Photo: Raphaelsklinik Münster/Michael Bührke As one of the world’s leading geneticists and molecular immunologists, Professor Josef Penninger has gained numerous awards for his work and research and he is also author of around 1100 publications. He established the Viennese Institute of Molecular Biotechnology and is the cur- rent Director of the Life Sciences Institute at the University of British Columbia in Canada. The main focus of his work has been autoimmune, bone, and heart and lung diseases, and cancers. disease because the virus cannot properly get in and infect the cells. ‘We believe, based on the discov- ery of ACE2 – and its function as a negative regulator of renin angio- tensin, protecting heart, kidneys, liver, protecting the lung – this would make sense as a therapeutic for COVID-19.’ This, he concluded, would have two functions – taking the virus away from its real receptor by work- ing as a neutralising antibody and, second, protecting tissues – as in the lung – from the disease. Penninger emphasised that care- fully designed placebo controlled trials in COVID patients are now needed to test the science. www.healthcare-in-europe.com CONTENTS NEWS & RESEARCH IT & TELEMEDICINE DIGITAL PATHOLOGY LABORATORY ROBOTICS RADIOLOGY 1-5 6 7-8 9-13 14-16 17-32

N E W S & R E S E A RC H 3 Nosocomial influenza The effect of mask wearing is enormous fronted with influenza every year. At the moment, everyone seems to forget how many deaths are caused by viral influenza each year.’ affected, as they usually have no immunity. By comparison, the mor- tality rate across the total population per season is less than 0.5%. Reason enough for him to study the influenza virus intensively. He presented his current findings at the 6th Joint Congress of the German Society of Hygiene and Microbiology and the Association for General and Applied Microbiology, held in Leipzig. Cancer patients are affected the most ‘When influenza occurs in a hos- pital, it’s particularly dangerous,’ Ambrosch stressed. ‘Up to 50% of influenza patients may die due to their underlying diseases.’ Patients on oncology wards are particularly The expert uses these numbers to confirm that prevention can indeed save lives: Ambrosch has been working on a study about the spread of the influenza virus at the 1,000 bed Hospital of the Brothers of Mercy in Regensburg since 2015. As a result, since 2017, as soon as more than three influenza patients are on a ward, all staff members have had to wear mouth and nose protection during their entire shift. The objective was to lower the high nosocomial infection rate for influenza known at the hospital and other German hospitals by 20-30%. ‘Eight hours – it sounds more dra- Interview: Katrin Schreiter The Coronavirus dominates everyday conversation as well as medical and scientific discussions, but in a Leipzig hygiene congress, other top- ics – such as nosocomial influenza – took a strong position. Dr Andreas Ambrosch, head of the Institute of Laboratory Medicine, Microbiology and Hospital Hygiene at the Brothers of Mercy Hospital in Regensburg, Germany, presented a new study on the spread of noso- comial influenza. But the question arises, whether this, in view of the new coronavirus, is this only an inci- dental topic. ‘Not at all,’ the hygiene expert exclaimed: ‘Nobody knows whether the coronavirus will still be around next year. But we are con- ecommendations might not be valid tomorrow © Shutterstock/Lightspring matic than it is. But the protection is not really much of a hindrance during work,’ the doctor confirms. ‘The effect is enormous!’ he adds, pointing out the numbers. The hospital in Regensburg sees an average of 150-380 influenza patients annually. The relatively small change of wearing protective clothing has helped to lower the rate of new nosocomial infection by 60% (from more than 20% to just under 10%), Ambrosch reports. The number of mortalities has even decreased by 85%. In 2015 and 2016 respectively, there were seven nosocomial influenza victims in the hospital; afterwards there was a maximum of only one patient a year. Consistent mouth and nose protection are also deci- sive in the fight against the coronavirus. Hand disinfection is always impor- tant ‘Obviously there are other important meas- ures to contain, or respectively pre- vent, influenza,’ A m b r o s c h adds. ‘Hand disinfection is always impor- tant.’ His hos- pital has been a member of the ASH – Action on Clean Hands – for six years and has been awarded the gold certificate. But, hand dis- infection alone has proven not to Dr Andreas Ambrosch is head of the Institute of Laboratory Medicine, Micro- biology and Hospital Hygiene at The Hospital of the Brothers of Mercy in Regensburg, Germany. A microbiologist and Anti biotic Stewardship (ABS) expert, Dr Ambrosch has been working on an effective action plan for the protection of patients against so-called nosocomial infections – i.e. infections which patients acquire in the hospital – for the last four years. be enough. ‘Vaccination is the most effective measure,’ Ambrosch is con- vinced. ‘However, there are many shortcomings here, as the German OkaPII Study (online survey on influenza vaccination amongst hos- pital staff) has shown. The last nationwide survey was carried out in spring 2019, when 171 hospitals with around 27,000 staff partici- pated. Result: only 76% of doctors have themselves vaccinated against influenza, and only 46% of nurses do. ‘To ensure effective protection more than 85% of hospital staff need to be vaccinated.’ Willingness to be vaccinated at The Hospital of the Brothers of Mercy in Regensburg also leaves a lot to be desired: ‘Only 57% of doc- tors are vaccinated, and only 34% of nurses. ‘We are banking on edu- cation – but only make very small steps forward.’ Ambrosch’s biggest wish regard- ing influenza: ‘Vaccination should be mandatory for medical staff. This would be a really big step in the right direction.’ Milagros Martí de Gracia is Vice President of the Spanish Society of Radiology (SERAM), President of the Spanish Society of Emergency Radiology (SERAU) and head of the department of emergency radiology at La Paz Hospital, a general tertiary hospital in Madrid. She was President of La Paz’s Catastrophe Committee from 2006 to 2019 and is now its Vice President. She is a founding mem- ber of the European Society of Emergency Radiology (ESER). A graduate from the Complutense University she gained her MD from the Autonomous University in Madrid, where she is Honorary Professor of Medicine. have been reached for its immediate acquisition of several digital port- able equipment for the radiology department and mechanical ventila- tion equipment for the ICUs.’ of the etiological test. But if the film shows pathological findings, patients are admitted to the hospital for observation. ‘Usually the absence or presence of pathological findings on chest X-ray is determining to send the patient home or keep him/her under observation ‘But if the clinical sus- picion is high and the PCR or/and chest X-ray is normal, a chest CT is indicated. ‘This is a fast-evolving issue and today’s recommendations might not be valid tomorrow. ‘The SERAM is developing and updating guidelines for radiologists that are available on our website. We have also created working groups to help not only diagnose the virus, but also to promote safe management among patients and healthcare staff.’ How important is radiology in diagnosing COVID-19 infection? ‘Radiology is fundamental in this process. The radiologist’s main con- tribution is to facilitate and expedite as much as possible the exploration, help design specific circuits and provide a fast and accurate report of the radiological findings that should indicate whether or not these are consistent with the COVID-19 coro- navirus infection.’ What are the typical radiological findings? ‘The findings that make us strongly suspect that we are dealing with a COVID-19 infection are the ground glass patterned areas, which, even in the initial stages, affect both lungs, in particular the lower lobes, and especially the posterior segments, with a fundamentally peripheral and subpleural distribution. These find- ings are present on chest CT in prac- tically 50% of patients in the first two days; For this, in China, CT is being used as a screening or diagnostic method. ‘These lesions progress in the fol- lowing days until they become more diffuse. If they associate with septal thickening, they will present with a crazy paving pattern. In general, they progress in extension and also towards the consolidation that is done concomitantly with the ground glass pattern, which can present a rounded morphology. It is very rare that it associates lymphadenopathy or capitation or pneumothorax, as the Middle East respiratory syn- drome coronavirus (MERS-CoV) did.’ Do you also use imaging to fol- low-up the disease? ‘We have had little time to discuss our experience in the follow-up of infected patients so far. But, for the time being, radiology is playing a crucial role in the diagnosis and identification of patients for obser- vation in the hospital admission or at home. ‘The most commonly used diag- nostic modality is chest radiography. At the moment, computed tomogra- phy (CT) plays a limited role and is carried out in cases of clinical mis- match and PCR, i.e. in patients with high suspicion of being infected but with negative or inconclusive PCR. ‘CT is also indicated for the recog- nition of possible complications that are not obvious on the chest radio- graph, or to diagnose very serious patients quickly, whose PCR results are not yet available, for placement in a specific coronavirus intensive surveillance unit. ‘In other countries like China, CT is being used as a diagnostic modal- ity because of its high sensitivity to show lung lesions before PCR. The WHO considers typical CT find- ings as a diagnostic criterion since February 17. ‘We have published our recommendations on our web- site (https://www.seram.es), and will update them soon.’ After a decade of healthcare budget cuts in Spain, do you have enough equipment to face the out- break? ‘Certainly the high number of infect- ed is a great challenge for public health in Madrid and Spain because we have suffered great cuts due to the crisis. In my department, a priori, we did not have enough equipment to face the crisis but agreements Infection with COVID-19 lymphopenia, elevation of transami- nases or lactate dehydrogenase aug- ment the degree of suspicion.’ What is the protocol? ‘Patients with respiratory symptoms must remain isolated and wear a mask. If clinical suspicion persists after the examination, a sample of nasopharyngeal exudate is taken to test reverse-transcription polymerase chain reaction (RT-PCR). ‘Then, we perform a chest X-ray. Getting the results of the PCR test may take several hours. The chest X-ray is a discriminating element; if the clinical situation and the chest X-ray film are normal, patients can go home and wait for the results www.healthcare-in-europe.com

N E W S & R E S E A RC H 5 est providers usually are awarded the contract without employees’ competence being checked. The good news: physicians, at least in Germany, tend to be more reluctant to prescribe antibiotics. In Germany, 25 percent of all patients receive antibiotics, in southern European countries the rate is twice that number – 55 percent in Greece, for example, Popp points out. With increasing migration, infection con- trol has become an international issue. While MRSA is retreating, the non-resistant variant of this bacteri- um causes thousands of deaths each year, according to a German Society for Infectiology report. In Germany, there are 400,000 to 600,000 treat- ment-associated infections each year, 10-15,000 of which are fatal. They are connected with hospital and non-hospital care as the Federal Ministry of Health has explained on its website since 2015. However, one third of these infections could be prevented with hygiene protocols, including measures such as appro- priate equipment sterilisation. Well-meant programmes from ABS to APS ‘Since the “Microbial Threat” confer- ence, held in Copenhagen in 1998, the 2001 EU report on “Prudent Use of Antimicrobial Agents in Human so-called Antibiotic Medicine”, Stewardship (ABS) Programmes are considered necessary to rein in antibiotic resistance by rational anti-infection protocols. ABS pro- grammes have proved to influence resistance, costs and use positively, and have become an important com- ponent of patient safety in modern healthcare,’ the ABS Initiative’s web- site states. Popp begs to differ. In his opin- ion, first there is no sufficient data pool on the administration of anti- biotics in hospitals. Secondly, he claims, ‘ABS doesn’t work, since the freshly certified ABS experts, once they do exist in a hospital, don’t have time for education and recom- mendations.’ Johanna Knüppel agrees. ‘The main task of hygiene experts in nursing is handling the hygiene plan – which is nothing but a fig leaf anyway.’ The Aktionsbündnis Patienten- sicherheit e.V. (APS), an initiative founded in 2005 to focus on patient safety, is optimistic, since its first international day of patient safety was held with WHO support: ‘APS will continue to point out the issues that obstruct safe patient care.’ To make a long story short: Improvements, or even solutions to the hygiene problem, are not in sight even though everyone is busy working on them. And politics? In the political arena, cynics would say, the motto ‘only a dead patient is a good patient’ appears to prevail. The ones still alive need to try to be well informed and prepare themselves for their hospital stay, for example when surgery is scheduled. The best way to begin: Ask your family doc- tor to screen you for multi-resistant bacteria, try to eradicate them and make your immune system fit for the hospital environment. If you do this, you enter the OR as a ‘healthy’ person, and your chance of leaving the OR and hospital in the same healthy state increases considerably. as routine as disinfection data, but also to changed or switched off product functionality. Unknown consequences for health, or even patient death, could result. The current version of the B3S is now being revised. ‘It is a document in progress, with continuous revi- sions,’ Holzbrecher-Morys explains. ‘We will have finished it in the third or fourth quarter of 2020 and be prepared for the next assessment in 2021. We have succeeded in writing a joint paper with all those involved in the process, which was approved by the BSI, which was not a given. We have made a successful start and now we can build on this.’ Under cyber attack What can happen when a cyber attack is successful was demonstrat- ed in July 2019. The entire network of the DRK hospitals in Rhineland- Palatinate and Saarland was hacked. The BSI knows of further cases in hospitals in Neuss, Giessen and Fürstenfeldbruck. ‘Most hospitals have numerous IT connections – 30,000 devices is not unusual. Add to this different IT and device sup- pliers and old systems, no longer supported, and cannot be integrated into modern IT security structures without great difficulty,’ which make access easier for hackers. At worst, this unauthorised access not only leads to theft of sensitive patient www.healthcare-in-europe.com Markus Holzbrecher-Morys is Deputy Managing Director of the Department for IT, Data Exchange and eHealth at the German Hospital Federation (DKG). After gaining his IT degree he initially carried out academic research, focusing on further developments of neuroinformatic proce- dures for bio signal analysis. Since 2008 he has been responsible for electronic data exchange procedures in hospitals and hos- pital IT at the DKG, particularly for techni- cal data protection, IT risk management and information security. Sharing concept works for stage IV lung cancer patients Improved cancer communication The Heidelberg Thorax Clinic is trialling a newly structured, longitudinal communication concept to meet proactively the complex needs of stage IV lung cancer patients and their relatives. The concept is aimed at enhancing prognostic understanding and building the basis for proactive care planning, early integra- tion of palliative care and shared decision-making, ultimately to improve improving overall care. First experiences look promising. Patients, and those treating them, talk about better patient-doctor relation- ships and also about the positive impact on the wellbeing of sufferers, along with a reduced psycho- logical impact on staff. Report: Cornelia Wels-Maug According to one study, more than 60% of medical errors occur due to lack of communication between doctors and patients. The German Federal Ministry of Health (BMG) acknowledged the importance of communication for treatment success when it listed ‘strengthening patient-centred care/ information for patients’ in its 2008 National Cancer Plan as one of the four fields of action to contribute towards improved care of cancer patients. At the Heidelberg Symposium ‘HeiMeKOM Heidelberg Milestone Communication’ held in the Thorax Clinic at the end of January, Dr Antonius Helou of the BMG explained that to enhance patient focus, the ministry is examining the relationship between doctors, nurses and patients. Given the importance the BMG places on communication, it also promotes the HeiMeKOM initiative. The symposium featured insights and experiences gathered in the context of this project so far. The ini- tiative is run by the Thorax Clinic at Heidelberg University Hospital, the Department for General Medicine & Health Services Research and by the Institute for Medical and Pharmaceutical Proficiency Assessment (IMPP). concept treatment A ground-breaking concept The choice of the title ‘Milestone Communication’ refers to a novel format of interactions with lung cancer patients who have a terminal prognosis (median survival < 12 months). It builds on the four cen- tral discussions, or milestones: the initial discussion discussion of the discussion of perspectives discussion around censensus With this new concept, a nurse is now always present alongside the doctor during these discussions, with the treatment team having received special communication training. Nurses also call patients a week after each milestone discus- sion and then monthly, to assess their understanding and progress of the illness and their needs for pallia- tive care, making the care process as seamless as possible. HeiMeKOM also aims to enhance interprofessional cooperation and assist all those involved in the treat- ment process in supporting one another during these challenging discussions. For the first time: recording patients’ preferences Keeping records that also integrate relatives is done to ensure patients are better listened to and that sensi- tive topics (the importance of thera- peutic measures with limited effect, proactive care planning and pal- liative care) are integrated into the care plan in time and in a more structured manner and then suc- cessfully implemented. The exchange with the patient during more stable phases of their illness is particularly important, especially as the target group con- sists of people with limited life expectancy. Great importance is attached to their wellbeing and to maintain, or respectively improve, the quality of their lives. Patients are now also asked about their preferences, with those being docu- mented. What has emerged is patients’ wish for continuity, for regular appointments, for reassurance that the treatment concept is the right one and for opportunities to talk about their end of life care. The HeiMeKOM concept also has been recognised outside the Thorax Clinic and was awarded the ‘Springer Medicine Innovation Prize 2019 – Inter-professional Projects the 7th Interprofessional Healthcare Congress. in Healthcare’, at HeiMeKOM in action Some advanced stage lung cancer patients at the Thorax Clinic have been cared for using this approach since May 2018. The key objective is to improve care helped by the new approach and to generate evidence for it. A range of qualitative and quantitative tools is available for evaluation, including assessments of patients’ needs for support and quality of life as well as health economic measures of captured via interviews, workshops and ques- tionnaires. The first (133) and second (172) milestone discussions along with follow-up conversations (total: 146) have been evaluated so far. The assessment of the other two mile- stone discussions, as well as the control group discussions, have not been concluded yet, so the final results of the project are not avail- able. e M y r r u l B / k c o t s r e t t u h S © The treatment team at the Thorax Clinic has received a lot of positive feedback from patients and col- leagues, confirming the high rate of acceptance for the project. Initial findings The evaluation of the milestone discussions indicates the following positive effects: Improved individual quality of Less distress amongst patients & Better orientation in the health- improved life for patients & relatives care system, cross-sector networking relatives incl. Enhanced informed decision- making: better adherence to treatment, higher prognostic awareness, more efficient use of healthcare resources (fewer A&E admissions at night and during weekends) petence Strengthening of patient com- Enhanced interprofessional cooperation and team processes Improved communicative com- petence within the treatment team. Compared to the quarterly costs incurred for a cancer patient’s pharmacological care, the cost of medical consultations carries hard- ly any weight. A staff member at the Thorax Clinic calculated that the quarterly cost of medication is around €20,000 while medical con- sultations amount to between €80 and €150. This is a good reason to continue with HeiMeKOM, to extend it to other conditions and to embed the milestone concept in standard care in the medium term, so that more patients can benefit from it. ‘HeiMeKOM should cover the entire medical landscape,’ says Professor Michael Thomas MD, who is the Senior Consultant for Medical Oncology in the Heidelberg Thorax Clinic. Undoubtedly, the professor will not be the only one to wish for this.

D I G I TA L PAT H O LO G Y 7 Transforming a raw histology image into a spatial roadmap Deep learning for small cohorts Exemplar: Automated Glomerulus Identification Model system: use of VIPR, Markov Models, and Gradient Descent Support Vector Machines with an ensemble of 68 Vectors Vector selectors were chosen to match ground truth maps (regions in red) provided by a subject matter expert, yielding the generation of a fully‐automated computational pipeline that can identify both intact and fractional sections of glomeruli (in green), from novel, cross‐validation images that were not previously used for training. Classification convergence was obtained with 41 fields of view from 12 cases, yielding an AUC of 0.9840. This trajectory of convergence exceeds performance typically encountered with the use of conventional DL‐based Convolutional Neural Networks alone, When so few training tiles are used. yielding a pixel-level heat map indi- cating all areas that are similar (from textural, luminance and colorimet- ric aspects) to the initial search predicate(s). ogy routinely encounters. ‘It’s effective for rare entities where only small cohorts of images or ROIs are available,’ he added. ‘It potentially allows pathologists to operate at their highest creden- Use of VIPR allows thousands of training images to be reduced to hundreds or even tens, and Balis suggests that, by use of VIPR-based heat maps as an intermediary syn- thetic image, satisfactory perfor- mance from DL-CNNs, including their exhibiting of more rapid algo- rithm convergence, can be realised on the small image sets that pathol- tialed level of practice, given the interactive, real-time nature of the tool, which operates in the spatial domain with an intuitive, exemplar- driven model.’ During his presentation ‘Augmented Deep-Learning Pipelines with Use of the VIPR Algorithm to Realise Histology Image Segmentation/ Classification in the Setting of last December, he advocates the use of VIPR (Validated Identification of Pre-screened Regions), a particu- lar type of spatial data augmenta- tion technique which transforms an image’s raw pixels into a local kernel figure-of-merit heat map. When used as a pre-processing step to subsequent use of DL-CNN approaches, his group has observed that the resulting ensemble-based algorithm can converge to a robust image classification and segmenta- tion solution with far fewer cases and images, than encountered with use of DL-CNNs alone. This combination can provide a workable approach matching the diagnostic cohort sizes as encoun- tered in histopathological entities. Balis explained how the VIPR- based data augmentation technique spatially prequalifies image regions with a supervised figure of merit, allowing for subsequent deep learn- ing pipeline stages to benefit from enhanced foreground delineation. This image augmentation approach uses an initial set of pro- totypic local image kernels as the starting point for their subsequent equivalence throughout the entire surface are of image sets under interrogation, ultimately testing Exemplar: Renal Tubule Vacuolization Classifier Exemplar: Renal Tubule Vacuolization Classifier • 16 distinct VIPR spatial pre‐filters • Each vector processed through a low‐pass • 16 distinct VIPR spatial pre‐filters • Each vector processed through a low‐pass Gaussian pipeline to increase spatial distribution of matching events Initial AUC of 0.906 / Final AUC of 0.936, maintained with cross‐validation Gaussian pipeline to increase spatial distribution of matching events Initial AUC of 0.906 / Final AUC of 0.936, maintained with cross‐validation • • VIPR vectors (positive and negative) as below: • VIPR vectors (positive and negative) as below: • ‐ ‐ ‐ ‐ ‐ + ‐ ‐ ‐ ‐ + ‐ ‐ + + ‐ ‐ ‐ ‐ + ‐ ‐ ‐ + ‐ + + ‐ To investigate rare diseases, applying image-based analytics approaches, including the use of deep learn- ing convolutional neural networks (DL-CNNs), can be a major challenge due to great difficulties in acquiring sufficient numbers of cases and associated digital image sets from the small cohorts typically available. To realise algorithms that are both effective and generalisable, conven- tional DL-CNN algorithms typically require hundreds to thousands of cases and larger yet numbers of image tile ensembles. In the case of uncommon or rare diagnostic entities, such as encountered in the routine practice of pathology, this data shortfall can be an obstacle. However, Professor Ulysses Balis believes that the use of a particular type of data augmentation tech- nique, as a pre-processing stage to subsequent DL-CNN use, could hold the key and offer a solution to the challenge posed by smaller cohort sizes. Speaking at the 6th Digital Pathology & AI Congress in London Nicolas Pages MD, a graduate from Bordeaux University, also specialised in emergency anaesthetics, intensive care recovery and paediatric anaesthetics. Currently he works as a medical resi- dent at the Bordeaux University Hospital Centre (CHU). He co-founded Satelia in 2017 and is actively involved in its evolu- tion and development. can make it more accessible and pertinent to their and their patients’ needs. Uptake of the system has been strongly aided by its prescription being 100% reimbursed by social security and by the fact that doctors are at the centre of its development. Today, Satelia has 21 employees; including two data scientists and four developers and is ready to expand. Expansion in France has been helped enormously by the reimbursement rate, but Pages also has his sights on Italy and Germany, where he is already working with existing digital platforms that are now licencing Satelia to distribute instead of their own brands, due to its better fit with medical profes- sionals and patients. Satelia, as a concept, can be adapted to remote healthcare anywhere and in any disease. Pages has plans to cover up to 20 different diseases within the next five to six years and is actively seeking partnerships to develop the system internationally. With such an auspicious start, the world of remote medicine does indeed appear to be Satelia’s oyster. www.healthcare-in-europe.com Ulysses Balis is Professor of Pathology and Director of the Division of Pathology Informatics at the University of Michigan. His long-standing interest lies in the inter- section of engineering, computational approaches and the practice of medicine. He has research interests in several areas of pathology and medical informatics including machine learning and the use of encoded data, image-based analytics, machine vision tools for histopathology and image-based search algorithms. Smaller Training Image Sets,’ Balis explained: ‘If you have a small cohort of cases, you have the chal- lenge of having the algorithm con- verge upon a generalised solution. ‘Many contemporary AI approach- es that address image classification make use of some variant of deep learning, but deep learning typically requires many images or image tiles to allow for convergence upon a robust and generalisable solution.’ With many diagnostic entities in pathology offering case cohort sizes that are too small in number to qual- ify for direct application of deep learning techniques alone, Balis believes the use of a pre-processing stage at the pixel level – with VIPR being one such example will help overcome that. He feels that image data augmen- tation techniques, in general, and VIPR specifically, can serve as the vehicle by which smaller numbers of images can be suitably magnified in their representational content of foreground subject matter of inter- est, as a means of extending the stochastic likelihood that a DL-CNN- based classifier will recognise the intended features of interest. VIPR’s role This approach effectively shifts deep learning’s unsupervised learn- ing mode to a supervised learning mode, but without the typically associated heavy burden of manu- ally generating hand-drawn ground truth segmentation maps. ‘That’s VIPR’s role,’ he said, adding: ‘We can transform a raw histology image into a spatial roadmap where indi- vidual pixels are transformed from merely conveying local luminance information, to their representing a local domain goodness-of-fit for one or more bespoke image features, thus realising a powerful image pre- processing step.’ ‐ ‐ + + In 97% of instances tested so far (over 850 predicates), he said VIPR will converge on a solution with AUC >0.90, with fewer than 10 vec- tors. ‘This overall approach appears to exhibit robust performance, even for novel and cognitively challeng- ing annotation exercises, and even in the setting of small cohorts of cases and image set sizes,’ Balis said. ‘Deep learning pipelines with pre-processing steps purposefully designed to operate within the con- straints of the known small cohort sizes of histopathology entities are compelling, in that they can offer the possibility of [algorithm] classifi- cation convergence in more instanc- es than with the use of deep learn- ing approaches alone.’ (mn) Ki67, ER, PR, CD3 Imaging•Fully automatic•For WSI or microscope camera•LIMS IntegratedDigital Pathology Solutionswww.vmscope.de

L A B O R AT O RY 9 Lab technology on a square centimetre Self-testing health in space Dr Susana Zanello has 25 years’ experi- ence in biomedical research and 12 years supporting human spaceflight research. Her investigations have focused on human health risks associated with space explo- ration and on the pursuit of solutions for space medicine needs. She recently joined Imec USA as R&D Manager for Space Health. are easy to use, however, only one specific pathogen is tested. The miDiagnostics device, on the other hand, is capable of detecting various pathogens, such as bacteria or viruses, with one drop of blood, and thus offers a syndromic panel test. The physician’s role remains The doctor retains the leading role in diagnostics. A patient who has to undergo a new chemotherapy course, and tests his blood count, does not decide for himself whether he is capable of doing so. The blood sampling is done with a separately supplied syringe because fitting it would make the device an invasive product, with the necessary regulatory consequenc- es: ‘Compare the test procedure with the way diabetes patients tests themselves,’ Vergauwe advises. ‘The device makes it possible to perform a full blood count, results of which can be read by a doctor on site within 15-20 minutes. The results can also be made available to doc- Dr Andrew Janowczyk is an Assistant Research Professor at the Centre of Computational Imaging and Personalised Diagnostics at Case Western Reserve University, and a senior research scien- tist in the Department of Personalised Oncology at CHUV (Switzerland). He is also a Senior Bioinformatician with the Swiss Institute of Bioinformatics. His research focuses on applying machine learning and computer visions algorithms to digital pathology images for disease detection, and the prediction of prognosis and therapy response. Nanoelectronics and digital technologies R&D and innovation hub Imec recently received NASA funding to test a new technology in a gravity-free environment. Eventually, this will enable astronauts to perform blood tests to monitor their health. We discussed the pro- ject and technology with Nicolas Vergauwe, CEO of miDiagnostics, the Leuven firm that developed the diagnostic device, and Susana B Zanello, Development Manager at Imec’s design centre in Kissimmee (Florida) and also the project’s principal investigator. r o t c e v x e T / k c o t s r e t t u h S © readily available. ‘I was in Sierra Leone during the Ebola outbreak. We had to build a whole infrastruc- ture with our Western instruments. If we could provide diagnostic tools of this kind there, people on the spot can take the initiative and start treatment themselves.’ Using a needle, a few drops of blood are applied to a test card, which will be inserted into a device. Many existing rapid tests are based on the detection of antigens of a specific virus or bacterium. They focused on and thorough validation will be needed with new generation tools, because concerns raised by the black-box nature of deep learning are warranted. Finally, he tools produced by the CCIPD to sup- port precision medicine advances. These open-source tools include the HistoQC, which addresses the unmet need for quality control by identifying and visualising slides of poor quality, thus enabling them to be recut and rescanned immediately before getting into a workflow to a pathologist. He added that HistoAnno, a tool which employs deep learning-based active learning for rapid annota- tion generation, is expected to be released in early 2020. Olivier Michaud is a chief resident for the Anatomic Pathology Training Program at Université Laval, in Quebec City, Canada. His main research focuses on digital pathology implementation in public fund- ed systems, as well as in breast pathology and the implementation of new targeted therapies in breast cancer treatment. fessional isolation and insecurity among pathologists reduced. However, Michaud acknowledged that challenges and barriers remain, with surgeons having to adjust to asking for the service, different work patterns, and the need for mutual confidence and trust between cen- tres and personnel. There was also the need to adapt workflow, archiv- ing, integration with local LIS, issues of prioritising telepathology over in-house cases and reimbursement and also legal issues to be resolved. Yet, there are now plans to expand to other regions in Quebec and fully digitise laboratories at selected sites. ‘We are looking at tele-autopsy for remote regions,’ he pointed out, ‘so the body does not have to be transported to Quebec – and we are already doing that for educational purposes.’ (mn) www.healthcare-in-europe.com Report: Madeleine van de Wouw Vergauwe: ‘The operating principle of the device is based on capillarity – the same force that sucks spilled coffee into a napkin or tissue. ‘This enables the technology to be fit in very small devices. The silicon chip is as big as the chip in a smart- phone. It is integrated in a test card the size of half a bank card and a device the size of a bank’s ID-card reader. An additional advantage is the low cost of the test card, which is for single use.’ Applications from chemo- therapy monitoring to coro- navirus screening ‘Usually, blood analysis takes at least a day because the blood must be examined in a laboratory. Since the information is not available dur- ing a consultation, doctors will often prescribe antibiotics to a patient with a possible viral or bacterial infection – this often turns out to be unjustified. Our device enables blood analysis during the consulta- tion, so infections can be distin- guished without delay and treat- ment adjusted accordingly. ‘It can also be used for patients undergoing chemotherapy. For each new cycle, it must first be assessed whether the body has recovered sufficiently. The actual therapy can often be done at home, but for the blood test, patients need to go to hospital. ‘With our device, the blood test can also be performed at home. We can roll it out even further and apply it at airports, for example. Look at the current situation with the coronavirus. ‘You can screen people by measuring temperature, but there can be many reasons for having a higher temperature. With our device, you could specifically check for the presence of the virus.’ Another application is use in countries where healthcare is not Bioscience engineer Nicolas Vergauwe joined molecular diagnostics firm Biocartis in 2012 after gaining his PhD at the Katholieke Universiteit Leuven, Belgium, in collaboration with the École Polytechnique Fédérale de Lausanne (EPFL) at Lausanne, Switzerland. He served as the company’s Vice President for Innovations, responsi- ble for bringing novel technologies and assay concepts to the market. In 2018, he became CEO of miDiagnostics. tors online. This will of course have to be done via a secure connection. ‘The future might bring even further applications, for example via a smartphone, or a reader via Bluetooth to the cloud,’ Vergauwe suggests. In space Because capillary forces overcome gravity, NASA sees enormous poten- tial for application in space. Imec received a grant from NASA to use miDiagnostics’ technology as a first test in a zero-gravity environment. During parabolic test flights, a team consisting of Imec and miDiagnostic will check the operation of the test cards combined with microgravity to evaluate the correct functioning and robustness of the subcompo- nents. Susana Zanello comments: ‘This technology demonstration is intended to meet NASA’s need for technologies that support human exploration and further commercial activities, both in orbit and beyond. Human exploration in deep space, such as travel to Mars, requires the development of medical devices and the diagnostics of small mass, volume and power requirements, designed for a more autonomous practice of medicine.’ What will the future probably deliver? miDiagnostics hopes to market the device for use within three to four years. Tests are carried out in collab- oration with universities, such as John Hopkins, to ensure sufficient sensitivity and specificity of the test. This process must then be adapt- ed for each coun- try, which have their own requirements, conditions, and guide- lines for approval. ‘The first tests were positive and now we are going to develop it further’, says Vergauwe. ‘We are very excited that our technology has been selected by Imec to demonstrate its operation during para- bolic flights.’ Zanello adds, with notable pride: ‘This is a very exciting process and a good example of how Imec and miDiagnostics work together to bring diagnostics to the most remote places, both on Earth and in space.’

L A B O R AT O RY 1 1 Breath analysis to aid diagnoses Breathomics: far more than hot air Exhaled air can give valuable insights into a patient’s health status. This diagnostic is known as breathomics In diagnostics, it sometimes makes sense to follow your nose. During the Labmed Forum at Medica 2019, Dr Beniam Ghebremedhin and Dr Simona Cristescu discussed the diagnostic potential of breath- omics – the analysis of a patient’s exhaled air for disease indicators. However, there are options beyond lab procedures: dogs can smell dia- betes and even lung cancer in the patient’s exhaled air. Unfortunately, as the expert points out, ‘Dogs require long and complex training, which makes this option hardly suitable for mass application.’ Extensive preparation, few common denominators The technical measurements are not straightforward either: the exhaled air samples must be prepared for l v o n u d o K / k c o t s r e t t u h S © the instruments to be able to detect VOCs. Several procedures are avail- able, inter alia solid phase microex- traction (SPME), thermal desorption or so-called needle-trap techniques, with each of these procedures com- ing with their own advantages and disadvantages. After the lengthy preparation and processing, the data are analysed to determine the pathology. Strengths and weaknesses The numerous procedures cover a wide range of possible diseas- es. Paradoxically, this strength of breathomics is at the same time one of its weaknesses since, as Ghebremedhin explains, there is currently no standardised approach to allow comparison of results: ‘We don’t even have an agreed-upon terminology; for example, there is no hard and fast definition for the basic elements such as the different phases of the exhaled air.’ A volatile fingerprint offers a wealth of information Simona Cristescu, expert member of the Exhaled Biomarkers Group at the Department of Molecular and Laser Physics at Radboud University in Nijmegen, Netherlands, stresses the benefits of a good nose: ‘Many diseases follow a specific meta- bolic schedule. Take a Pseudomonas aeroginosa infection, for example. In the course of the disease, hydro- gen cyanide (HCN) and ammonia (NH3) are produced. Both are vola- tile compounds of exhaled breath and can be detected. However, the two compounds are not produced at the same time. Thus, if we notice a decrease in the HCN concentration in the exhaled air, and an increase in the NH3 concentration, we conclude that the infection has entered a new stage and we can adjust the treat- ment correspondingly.’ In brief: the chemical VOC fin- gerprint not only provides informa- tion on the kind of disease present but also on the disease progres- sion. Even the interaction of sev- eral pathogens in a polymicrobial environment can be tracked in the exhaled air. For the experts, breathomics is an interesting diagnostic tool with promising approaches and signifi- cant potential. However, a number of obstacles have to be overcome before this potential can be fully leveraged in clinical routine Dr Simona Cristescu is Assistant Professor at Radboud University Nijmegen, Netherlands. As a member of the Exhaled Biomarkers Group she studies the compo- sition of organic compounds in breathing air and their significance with regard to diagnostics and treatment monitoring. She is a member of several professional socie- ties, inter alia, European Respiratory Society (ERS) and the International Association of Breath Research (IABR). Report: Wolfgang Behrends The idea that a patient’s breath can aid in the diagnosis of diseases is far from new: In ancient Greece, physicians considered sweet smell- ing breath an indicator of diabetes or a fishy smell suggesting a liver condition. While modern breath- omics is based on the same prin- ciple, it is much more sophisti- cated and offers a host of diagnostic insights. Exhaled air consists mainly of nitrogen, oxygen, argon and water. In addition, there are traces of hundreds and even thousands of so- called volatile organic compounds (VOC) – and ‘traces’ here does mean minute amounts, measured in parts PD Dr Beniam Ghebremedhin is a specialist in microbiology, virology and infection epidemiology, and a biochemist and specialist in laboratory medicine at Helios University Hospital in Wuppertal, Germany. He also teaches at the University Witten/Herdecke. His research focuses on molecular epidemiology of multi-resistant pathogens, particularly in the hospital, and the development/intro- duction of new tools for infection diag- nostics. His memberships of professional societies include the German Society for Hygiene and Microbiology (DGHM); German Society for Clinical Chemistry and Laboratory Medicine (DGKL); European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and the American Society of Microbiology (ASM). per million (ppm), or even parts per billion (ppb). Nevertheless, these VOCs reflect a person’s health status, in certain cases even long before other biomarkers indicate that something is off-kilter. Prognostic potential ‘Changes in the VOC profile of a per- son have enormous potential for the early diagnosis of diseases and can even be used for prognostic purpos- es,’ said Dr Beniam Ghebremedhin, microbiology expert at Helios University Hospital in Wuppertal, Germany. The major advantage: the method is non-invasive and is thus suited for neonates for whom draw- ing blood constitutes a risk. Today, there are several methods to determine VOCs based on mass spectrometry. Gas-chromatography (GC-MS), eNose and infrared spec- troscopy have their specific advan- tages and drawbacks and are suit- ed for different diagnostic profiles. www.healthcare-in-europe.com

L A B O R AT O RY 1 3 Challenges for laboratory technology The value of the human microbiome Report: Sandra Theison The human species maintains symbi- otic relationships with a multitude of microbial organisms that colonise the inside as well as the surface of the body. Scientists, for a long time, underestimated the significance of these organisms for humans. By far the most bacteria of the microbiome can be found in the gastrointestinal tract, particularly in the colon. The number of microbes in the body is estimated to exceed ten times the number of human cells; the body thus contains 100-fold more unique genes than the human genome. Only 10 to 30 percent of these microbial organisms are cultur- able. In humans, most bacteria of the gastrointestinal microbiome belong to the four phyla Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. In clinical care, the identifica- tion of bacteria is crucial to be able to distinguish between bac- teria that are colonisers or those that originally cause an infection. Today, this identification is achieved via sequencing of 16S rRNA, par- ticularly if phenotypic methods of bacterial identification are difficult. The bacterial 16S rRNA gene codes for the subunit 30S of the prokaryotic ribosome 70S and is thus present in the genome of all bacteria. Since it differs from its eukaryotic homologue 18S rRNA, precise identification of bacterial DNA versus human DNA is pos- sible. The gene sequence of this subunit is used in evolution biology as the instrument for phylogenetic analysis. The 16S rRNA gene consists of approx. 1,500 base pairs and can be separated into several conserved and Objectives of Human Microbiome Project phases HMP1 and HMP2 nine less conserved regions (V1-V9). Since the less conserved regions have little impact on the formation of the subunit 30S, they are hyper- variable and specific to particular bacterial species. These regions may thus be used as taxonomic markers. During a polymerase chain reaction (PCR), primers can dock onto the known conserved areas and selec- tively amplify the variable regions. Sequencing of these DNA sections is usually done by pyrosequencing. The Human Microbiome Project The Human Microbiome Project (HMP) is one of the largest bio- logical projects ever. It aims to iden- tify all microbes that colonise the human body and study their roles in health and disease states. HMP was launched in 2008 by the US National Institute of Health (NIH), focusing on five body sites of a healthy individual: skin, nose, mouth, gut and vagina. In 2013, HMP1 was completed after having collected 14 TB of data from the samples of 300 individuals. The second phase of HMP, also called Integrative HMP (HMP2/ iHMP), was launched in 2014. HMP2 was designed to explore host-micro- biome interplay and focused on three topics: pregnancy & pre-term birth, inflammatory bowel diseases (IBD) and onset of Type 2 diabetes (T2D). By way of example, the pro- cedure regarding pre-term birth is described in the figure above shown on this page. There are significant disparities in the frequency of pre-term birth. In the United States, for example, American women of African ances- try are at a much higher risk of pre-term birth than any other group of women. 16S rRNA analysis was performed and additional profiles from 45 pre- term births and 90 term births were established. Early on in the selection process, it became clear that the per- centage of pre-term birth is higher among women of African ancestry. The analyses showed that women who delivered pre-term exhibited significantly lower vaginal levels of Improved cap design for blood tubes Easier blood droplet collection The MiniCollect Capillary Blood Collection System launched by Greiner Bio-One in 2016, has an improved cap on all its blood col- lection tubes. The new version, designed for easier opening, has an increased number of ridges that are also deeper to improve grip and user comfort. The cap rim also overlaps the top of the tube to augment grip and ease opening. The capillary blood collection tubes offer a gentle way to collect small blood samples for a wide range of analyses, Greiner points out. ‘The MiniCollect tube includes an integrated scoop, allowing drop- lets of blood to be collected easily and hygienically. The wide open- ing of the tube ensures an effi- cient blood flow while the increased diameter minimises adhesion to the wall of the tube and facilitates the mixing of the sample. ‘The system is perfectly suited for young children, geriatric patients, as well as patients with fragile veins. MiniCollect is also recommended in situations where venous blood col- MiniCollect Capillary Blood Collection Tubes range. H b m G e n O - o B i r e n i e r G © www.healthcare-in-europe.com lection proves particularly difficult, such as for patients with extensive burns.’ MiniCollect Complete Version MiniCollect tubes can be thread- ed into a Premium carrier tube. This combination corresponds to the dimensions of a standard 13 x 75mm tube, the manufacturer adds. With the Complete version, which is already irreversibly assembled with the carrier tube, the advantages – particularly for automated analysis of the sample – are numerous, Greiner reports: Changing the settings of analy- sis instruments is not always necessary since, in many cases, both venous and capil- lary blood samples can be analysed in the same way. MiniCollect Complete tubes generally fit into 13 x 75mm racks, which can be directly inserted into the analyser. The carrier tubes also enable iden- tification with standard label formats. MiniCollect tubes are primary tubes. Blood collection and analysis can be carried out in the same tube. It is not abso- Functional principle of pyrosequencing PYROSEQUENCING As in Sanger sequencing, the DNA poly- merase originating in a primer elon- gates the complementary DNA strand. When DNA polymerase adds a comple- mentary nucleotide to the DNA strand to be synthesised, pyrophosphate is released. The enzyme ATP sulfurylase converts the pyrophosphate into aden- osintriphosphate, which triggers the luciferase reaction where luciferine is turned into oxyluciferine. The intensity of light emission during this process is proportional to the amount of adenos- intriphosphate used. Unincorporated nucleotides are degraded by apyrase. Since the individual nucleotides are sequentially added to the reaction, the temporal pattern of light emis- sion allows determination of the DNA sequences. Lactobacillus crispatus and higher levels of 13 other bacterial taxa. Pre-term-birth-associated taxa were correlated with proinflammatory cytokines in vaginal fluid. These findings highlight new opportuni- ties for assessment of the risk of pre-term birth. The way forward Future research might focus on identifying and characterising the microbiome with regard to itpro- teome and metabolome and their interaction with human proteins and metabolites. H b m G e n O - o B i r e n i e r G © MiniCollect Capillary Blood Collection Tube with newly designed cap. lutely necessary to transfer the sample material into a second- ary tube for analysis. The cap of the tube can be pierced with an analy- sis needle while still closed and remains leakproof. It is not necessary to remove the cap, thus ensuring increased hygiene. MiniCollect tubes combined with carrier tubes do not need a separate centrifuge. Due to the 13 x 75mm dimensions the tubes can be processed in a standard centrifuge. Full details: www.gbo.com.

R O B OT I C S 1 5 NEW: Fringe Field Navigation (FFN) transforms endovascular surgery Harmless penetration of tiny vessels field. A new technique could enable vascular surgeons to reach even the more difficult body regions. Instead of pushing catheters into minute veins, the system, devised in Canada by Professor Sylvain Martel and team at the Polytechnique Montréal Nanorobotics Laboratory, uses magnetic forces to pull a guidewire, or catheter, into remote physical locations, guiding medical instruments into narrow and complex vascular structures. ‘So,’ added Martel, who directs the NanoRobotics Laboratory at the University of Montréal, ‘when the medical specialist navigates the instrument in tortuous vessels, a computer calculates the optimal position for the patient, to exert the highest possible directional pulling force, and then send commands to a robotic table to position the patient accordingly, as the instrument is navigated through a narrow tortu- ous vessel.’ He believes this is the first time that an MRI fringe field has been used for a medical application. Movement on all axes The computerised robotic table, designed by his colleague Arash Azizi, a biomedical engineering PhD candidate, is positioned within the fringe field next to the scanner and can be programmed to move auto- matically on all axes, to position the patient according to the direction in which the instrument must be guided through their body, using a technique that Professor Martel has dubbed Fringe Field Navigation (FFN). ‘We were using the magnetic field inside the MRI scanner to navi- gate drug carriers for cancer therapy and no-one was using the external field, he said. ‘Through that, this fringe field had particularities that MRI and robotic table out. ‘For us, that fringe field rep- resents an excellent solution that is far superior to the best existing magnetic guidance approaches, and it is in a peripheral space conducive to human-scale interventions.’ However, the key is a computerised robotic table, he emphasised. This is used to move the patient around the fringe field to induce a high directional pulling force at the tip of the instrument, because the size and weight of the MRI scanner means the machinery cannot be moved to change the direction of the magnetic Vital: A computerised robotic table Scanner robotic table diagram Professor Sylvain Martel is Director of the NanoRobotics Laboratory, Department of Computer and Software Engineering, at the Institute of Biomedical Engineering, École Polytechnique de Montréal, Canada, and a Fellow of the Canadian Academy of Engineering. His main expertise lies in nanorobotics and the development of novel instrumented platforms and related support technologies targeted for biomedi- cal and bioengineering applications. He currently leads a multidisciplinary team involved in research and development of new instrumented platforms for the medi- cal field and in bioengineering. no other field has, so we were trying to see if we could use its super high gradient for medical applications. From there, I put together a team to prove that the concept works.’ Standard MRI scanners can be used for the technique – with a robotic table installed in the MRI room – and with no impact on image quality. The team has spent five years developing the concept and, Martel added, ‘So far it’s been very suc- cessful and showed in pig models that the instrument can go much deeper than when done manually with experts.’ An in-vivo study of Fringe Field Navigation with X-ray mapping has demonstrated the capacity of the system for efficient and minimally invasive steering of extremely small- diameter instruments deep within complex vascular structures which were hitherto inaccessible using known methods. The robotic solution has promise for diagnosis, imaging and local treatments and could assist surgeons in procedures requiring the least invasive methods, including deep access to the brain for treatment of brain damage such as an aneurysm or a stroke, those needing diagnos- tics in hard-to-reach vascular regions and in urology. (mn) The magnetised tip of the device har- nesses the fringe field generated by the superconducting magnet of a clinical MRI scanner – coupled with an innovative robotic table – to help overcome one major challenge in endovascular surgery. As Martel explained: ‘For very thin wire – guidewire or catheter – or tethered instruments that must be miniaturised further to navigate deeper through narrow and most often tortuous vessels, or other con- strained physiological spaces, the stiffness of the wire is decreasing so much that at some point pushing the instrument is no longer possible. “If such wire or instrument must be as thin as a hair to navigate deep- er through narrow vessels, the only way is to induce a pulling force.’ MRI Fringe field opportunities ‘A magnetic field is appropriate,’ he continued, ‘because it can penetrate the human body without harm and is not affected by various tissue density. ‘The most important characteristic for a magnetic field to exert a pull- ing force on a micromagnet, placed at the tip of the navigated instru- ment, is the gradient, defined as a change of the magnetic field magni- tude over distance.’ The highest magnitude of mag- netic field is achieved with a super- conducting magnet, such as found in clinical MRI scanner, he said; hence the use of the fringe field of an MRI for this project. Whilst the magnetic field inside the MRI scanner tunnel is uniform, the fringe field outside the machine – which is normally reduced to minimal levels – offered opportunities. ‘It’s a very-high-amplitude field that decays very rapidly,’ he pointed Simulating acetabulum preparation eality training to improve hip replacement the user acquires a better feel for the forces at work and the area that can be worked. The simulation is based on real data. To compute the forces and torques when milling the hip, the researchers conducted biomechani- cal tests with anatomical specimens. ‘We found out that we are dealing with up to 200 Newton. Force is needed when the surgeon applies pressure on the acetabulum. The forces applied on the surgeon’s wrists when the machine stops is between 20 and 50 Newton depending on the size of the wrist,’ Lorenz explains. With these measurement data, researchers at the University of Bremen, Germany, designed a mate- rial model that allows a surgeon to compute, within a millisecond, where the surgical milling instru- www.healthcare-in-europe.com ment meets the acetabulum and what forces are present. In a next step, a software mod- ule was developed that features a user interface integrated by FAKT Software GmbH. The result is an interactive application based on an anatomical model by CAT Production GmbH, which had created the ana- tomical 3-D models and the virtual operating room (OR). The team at the Technical Virtual milling on the surgical training simulator University Chemnitz developed the interface with the robot arm to ‘tell’ the robot the force it has to simulate. ‘Originally, the robot was certified for collaborative human-machine tasks on the shop floor. We managed to use the existing interface to provide the user with haptic feedback while maintaining the certification,’ Lorenz points out. Over the next few months, the researchers will conduct a small-scale study to have the system validated by assistant and senior physicians. Subject to approval of funding, the © Screenshot ‘Video report of project meeting’ kick-off for the follow-up project will take place in May. The aim is to further develop the system to include more surgical steps. ‘We will look at the way the tip of the femoral neck is cut off, the femur is scraped, the shaft is fitted in the femoral neck and the socket is fitted in the milled acetabu- lum,’ says Lorenz. The three-year HIPS project received €670,000 from the German Federal Ministry of Economics and Energy (BMWi). The project consorti- um consisted of the Chair of Machine Tools at the Technical University Chemnitz, the Institute of Computer Graphics and Virtual Reality at the University of Bremen, Leipzig-based FAKT Software GmbH in Leipzig and CAT Production GmbH in Munich. und Plastic The medical development partner was the Clinic for Orthopaedics, Trauma Surgery at University Hospital Leipzig, ZESBO (Centre for Research on the Musculoskeletal System), the research team Clinical Anatomy at the University of Otago, New After having completed his informat- ics program in 2010, at Westsächsische Hochschule Zwickau, Germany, Mario Lorenz was appointed assistant at the Chair of Machine Tools at the Technical University Chemnitz in the field of VR and Augmented Reality (AR). In 2016, he also became a guest scientist at the Clinic for Orthopaedics, Trauma and Plastic Surgery at University Hospital Leipzig. His research focuses on the use of VR and AR technolo- gies in production and medical training. Zealand, and the Department of Medical Technology at Fraunhofer Institute for Machine Tools and Forming Technology.

Radiologyin Europe S P E C I A L I S S U E O N L AT E S T D E V E L O P M E N T S I N D I AG N O S T I C I M AG I N G Gathering around a digital table Radiology, pathology, medical genetics and laboratory medicine under one roof: many hospitals are toying with the idea of ‘inte- grated diagnostics’ but it was the medical management at Geneva’s University Hospital that dared to take the first step and consoli- date all these diagnostic disciplines in a single organisational unit: The Diagnostic Department. Report: Daniela Zimmermann and Michael Krassnitzer ‘Our longterm vision is a “diagnostic board” within which radiologists, pathologists and geneticists collabo- rate to create a detailed and struc- tured diagnosis that goes far beyond mere imaging,’ underlines Christoph Becker, Emeritus Professor at the University of Geneva and, until 2019, Head of Radiology at the University Hospital Geneva. In Geneva, joining these disci- plines was above all an administra- tive-organisational procedure, the Swiss radiologist explains. This is not about radiologists doing the pathologists‘ work, or vice versa, he emphasises: ‘We aim to do away with the insular approach of the diagnostic disciplines and arrive at a closer cooperation of the diagnostic specialists.’ Integrate diagnostics – but how? Becker considers three aspects are crucial for diagnostics integration, first the organisational-administra- tive aspect. Since this is determined to a large extent by local factors – such as geography; the hospital’s organisational structure; distances between departments; budget – no general recommendations can be made. The second aspect is the digi- tal infrastructure where, as Becker points out, significant differences need to be taken into account: ‘Radiology launched the digitisa- tion project 20 years ago and thus is almost fully digitised. In the lab, digitisation has also progressed very well.’ Pathology, however, has only recently begun to digitise, one rea- son being the sheer complexity of the endeavour. ‘Whilst today, radiology images are digital from the beginning, a tissue sample is, obviously, analo- gous. ‘The analogous sample and all necessary analytical steps have to be digitised. This requires much more computer power, since col- our and high resolution are basic requirements,’ Becker points out. In Geneva, the first steps towards digi- tal pathology and a comprehensive digital infrastructure for the entire medical imaging complex are cur- www.healthcare-in-europe.com s d n e r h e B / E i H y b p u h s a M , ) 0 . 3 A S - Y B - C C ; s n o m m o C a i d e m i k i W ( n o r h p e N : e c r u o S rently being implemented. A cen- tral digital archive is planned in which all acquired image data in the University Hospital are stored – radiology images as well as images and videos created in other depart- ments, e.g. dermatology, or images from endoscopies. Successful workflow The third crucial aspect of inte- grated diagnostics is a workflow that allows to identify and remove discrepancies in diagnostic proce- dures: today it may well happen in complex clinical situations that dif- ferent diagnostic disciplines arrive at different conclusions in their assessment of findings. This should be avoided by intelligent diagnostic processes aiming at a synthesis of the diagnostic findings: Diagnostic specialists and their tools must be able to communicate more directly about discrepancies in their assess- ment. A first small step was made sev- eral years ago at the University Hospital of Geneva. ‘During an image guided biopsy in the radiol- ogy department, a pathologist is present and has access to the nec- essary technical infrastructure for staining and microscopic evaluation in order to assess the sample right away for its quality. If the sample is insufficient, or cannot be used for whatever reason, a second sample is taken immediately. ‘The pathologists like being on site because they appreciate the direct communication with col- leagues. The patients also benefit because they don’t have to come back for a second biopsy,’ Becker explains. Today, treatment strategies for individual patients are often decided jointly in multidisciplinary meet- ings including all necessary clinical specialists. Typical examples are the tumour boards in oncology. ‘These tumour boards are time-consuming and difficult to organise,’ the radi- ologist points out, ‘because to get the different specialists to meet at a certain time, at a certain place, is not easy. A specialist’s time is very valu- able, and the time spent to align the different complex diagnostic find- ings during the tumour board meet- ing reduces the number of patients who can benefit from common deci- sions,’ Becker underlines. Therefore, discrepancies between the findings of the individual diag- nostic disciplines should be identi- fied early on and resolved before the tumour board convenes. ‘Ideally, radiologists, pathologists and other diagnostic specialists should pro- vide a consensual integrated diag- nostic report, which is then the input for the tumour board,’ Becker explains. ‘While this might not be necessary in all cases, he adds, ‘it will be very useful in many special and complex cases, with a clear benefit to both treating physicians and patients’. Radiologists and pathologists should learn to communicate Communication: this is easier said than done because, in a way, radi- ologists and pathologists speak dif- ferent languages. While radiologists and macroscopic pathologists both assess morphology, they look at the issue at hand from very dif- ferent vantage points. Radiology strives to offer an overview of body regions or organs; pathology in turn offers insights that are anatomically less comprehensive but – with the help of a microscope – go deeper to the cell and immunology level. Evaluating the results of each of these methods in a separate or ‘insular’ way can be misleading, due to the heterogeneity of tumours. For a best possible diagnostic workup it is therefore imperative to look at the complementary data in a joint con- text. ‘Having said that, we must also point out that modern technology increasingly enables radiologists to look at deeper-lying features of tis- sue structures,’ Becker concedes, adding that functional imaging has now become routine. For instance, CT perfusion shows how fast tissue takes up blood; diffusion-weighted MRI offers insights into the cel- lular level of the tissues, and pos- itron-emissions tomography (PET) provides information on metabolic activities, such as glucose consump- tion. ‘MRI parameters, such as T1 or T2, enable us to interrogate tissue with different non-invasive param- eters,’ Becker points out, adding that all data ‘need to be merged to be able to understand a patient’s exact status’. Patient empowerment Speaking of the patient, Becker is deeply convinced that, in the Professor Christoph D Becker gained his medical doctorate and specialist radiology training at Berne University, Switzerland, followed by a two-year clini- cal fellowship in interventional radiol- ogy at the Univer sity of British Columbia, Vancouver, Canada. He returned to Berne University Hospital as a staff radiologist and also acquired his university teach- ing licence. In 1994, he joined Geneva University Hospital to become head of Interventional and abdominal radiology. In 2001, he was appointed as tenured pro- fessor and Vice Director of the hospital’s radiology clinic, followed by an appoint- ment as Director in 2004. As a full profes- sor he also chaired the clinical depart- ment of medical Imaging and the academ- ic department of radiology and medical informatics of the faculty of medicine. He was involved in setting up the new clini- cal diagnostics department. In 2019, fol- lowing the end of his tenure as professor and director of the clinical and univer- sity departments he became an Emeritus Professor at the University of Geneva. future, patients will be increas- ingly involved in decision-making. ‘Patients of the younger generations want to know what’s going on. Some want to be present when their case is discussed and when further steps are decided. They want to hear arguments; ask questions. In Geneva, even today some patients take part in the tumour board meet- ing on their case.’ This concept of ‘patient empowerment’ can be sum- marised with the modern slogan ‘nothing about me without me’. Studies have shown that patients, above all younger ones and women, with online access to their electronic patient records, call up their radiol- ogy findings more often than any other clinical documents. However, patient empowerment also raises questions: when find- ings become ever more detailed and complex, when parameters are included that only specialists can decode, how can patients under- stand the findings? ‘Enter artificial intelligence,’ Becker suggests, with a smile. Why not have algorithms translate the highly complex find- ings in layperson’s terms, he asks. This seems the only viable solution because, as he points out, ‘manu- ally translating these findings and integrating them in routine clinical workflow is so time-consuming that it can be done only with the help of computers.’

ADVANCING HEALTHCARE When you’re a company who has spent over 80 years striving to move the world forward, you never stop. We’ll never stop innovating in the medical areas of prevention, diagnosis and treatment. With technologies like AI powered imaging solutions that are Designed to help improve the accuracy of diagnoses and surgery. Applying our scientifi c expertise to advance regenerative medicine to meet unmet medical needs. Creating nano-particle based drug delivery technologies to help in the fi ght against cancer, or continuing to pioneer endoscopic and x-ray imaging technologies. We’ll never stop improving the future, creating value from innovation that will change the world of healthcare forever. FUJIFILM and Fujifi lm Value from Innovation are trademarks of FUJIFILM Corporation. ©2018 FUJIFILM Corporation. All rights reserved.

R A D I O LO G Y I N E U R O P E 2 1 olutionising medical Artificial Intelligence imaging and analysis with AI direct conversion flat panel detector with hexagonal pixels to produce clear images with a low X-ray dose. This system makes use of an intel- ligent AEC (i-AEC) combined with advanced image analysis technolo- gies to automatically optimise the X-ray dosage for each breast type. The Amulet uses dynamic image processing DV2m enhancing breast composition analysis, for optimised visualisation of structures. Moreover, thanks to advanced proprietary technologies such as ISR and FSC, Amulet Innovality is capable of a significant reduction in the dose to the patient per view. ‘S-View’ syn- thetic 2-D processing is also capable of reducing the number of expo- sures in the event of a screening examina- tion performed with tomosynthesis tech- nique (vertical and lateral approach) At Fujifilm’s booth at the European Congress of Radiology 2020 (ECR), it will be possible to see live demon- strations of AI delivering enhanced workflows. Fujifilm will also dem- onstrate how AI will be utilised in the future through the review of multiple cases in the same Synapse PACS technology that radiologists use today. At the booth it will be possible to see the FDR nano with AI CAD soft- ware Lunit insight CXR which pro- vides abnormality score by heatmap for 10 main chest abnormalities. In a hospital, a typical emergency room is crowded with equipment and staff. The extremely lightweight FDR nano delivers freedom of move- ment with its four-wheel caster and provides an advanced workflow and improved patient care pathway. Fujifilm announced that it will preview its new FDR D-EVO III DR detector, the world’s lightest flat panel detector. The innovative design of this device is a world first, because it removes the tra- ditional glass substrate from the capture layer, which allows a much lighter weight compared to previous models, improving durability, while still maintaining Fujifilm’s renowned image quality at a low dose. The next generation 14x17” detector retains all of the ground-breaking features of the FDR D-EVO II includ- ing its sleek design with smooth, tapered edges for easier position- ing, antibacterial coating, memory mode and is compatible with the same accessories. Thanks to the lighter weight, enhanced durability and streamlined design, this new detector will be ideal for demanding high-volume portable environments. Women’s health In the breast imaging segment, Fujiflm›s strong commitment to con- tinuous technology evolution and a clear commitment in providing inno- vative solutions in women’s health products has led to the release of the AMULET Innovality Full Field Digital Mammography system. With its state- of-the-art features in dose reduction, image quality and advanced clinical applications, Amulet Innovality rep- resents Fujifilm’s capability to con- vert pure technology insights into drastic care improvements. At ECR it will be possible see live demonstra- tions of the Amulet Innovality. This device utilises Fujifilm’s unique a-Se gies, storage of actual imaging data in a blockchain is unlikely. ‘Some of the concerns surround- ing AI algorithms are that a ‘black box’ could be alleviated by block- chain. All data that algorithms are trained on can be tracked and veri- fied, as can all outputs of the algo- rithms,’ he said. ‘Blockchain is definitely a viable solution for certain use cases, but it is far from a panacea and cannot solve all of our problems in health- care,’ McBee concluded. ‘I think the biggest impact of blockchain on healthcare can be data sharing.’ www.healthcare-in-europe.com You can discover these innovations during ECR tradeshow, booth 10 – Foyer D! Improving hospitals’ time efficiency via our Connected Radiology platform Thales’s expert knowledge in digital technology as well as in hardware and software systems has enabled the company to become a market leader in major innovation fields such as Cloud computing, Connectivity and Artificial Intelligence. Thales is proud to launch its unique Connected Radiology platform Additionally, with Thales’s strong competencies in cybersecurity, which will bring multiple benefits to the efficiency of hospitals the platform is fully cyber-secured, preventing it from any kind of through the non-stop use of radiology systems, meaning that the security threat. disruption of patient workflow will now be a problem of the past! This platform will allow equipment manufacturers to monitor their to discuss and share with you all our proud innovations complete fleet of systems in real time. Thanks to connectivity, at stand 10 – Foyer D. Join us at the 2020 ECR event where we will be pleased systems manufacturers as well as hospitals will now be constantly up-to-date with how their equipment and subsystems are func- tioning. Our monitors analyse data received from equipment and predict when the equipment might break down by looking at the average lifespan of machines and their daily usage in the field. Predicting this helps manufacturers renew the equipment or fix potential faults before they become an actual problem. This means hospitals will be more efficient and provide a higher quality service. Our Connected Radiology platform gives equip- ment manufacturers complete control of their systems all around the world, enabling them to update their system software in various countries simultaneously by just the click of a button! www.thalesgroup.com

R A D I O LO G Y I N E U R O P E 2 3 What is breast CT? And what are the benefits? With nu:view, their expert team of genius software engineers, design engineers, and medical physicists did not just develop another CT device, but a disruptive technol- Leveraging AI for the future of decision-making Our Al-powered solutions address major challenges that are facing the healthcare field. Right now, the demand for diagnostic services is outpacing the supply of experts in the workforce. Developing solutions for managing this ever-increasing workload is a crucial task for the healthcare sector. Moreover, as the workload is growing, diagnostics and treatment are also becoming more complex. Diagnostic experts and physicians need a new set of tools that can handle large volumes of medical data quickly and accurately, allowing you to make more objective treatment decisions based on quantitative data and tailored to the needs of the individual patient. To provide this new toolset, we will need to draw on the power of artificial intelligence (AI). siemens-healthineers.com/ai-rad These are two questions the experts at AB-CT, the team behind the world’s first spiral breast CT system, come across on a regular basis. In case you are asking the same questions – here are the answers. ogy designed to leverage clinical excellence and empower radiologists all over the world to diag- nose breast cancer at the earliest possible stage. A disruptive technology for clinical excellence Breast CT, more precisely spiral breast CT (commercialised under the brand name nu:view), is a dis- ruptive technology that is destined to change the breast imaging world. With excellent image resolution, suberb soft tissue differentiation and short scan times at low dose, it combines the benefits of conven- tional modalities in one system, pro- viding a valuable tool for diagnos- tic breast imaging. The CE-marked scanner that is made in Germany is already in use on patients in Europe. Enhanced patient comfort Developed with the highest level of patient comfort in mind, nu:view allows for the patient to lie prone on the scanner table during the exami- nation process, with the breast to be examined conveniently placed into the aperture. No compression is applied – making the entire pro- cess pain-free and helping that little extra for patients to feel reassured in a situation that may generally perceived as highly distressing. The scan parameters are adjust- able to accommodate various clini- cal requirements and patient types. There are no restrictions regarding age or gender. Even patients with dense breast tissue or patients with implants are able to experience the comfort, convenience, and peace of mind nu:view offers. The gentle examination proce- dure makes breast CT also suitable for post-op follow-ups. Advanced visualisation techniques such as 3D volume rendering make the 3D high isotropic resolution images also a vested option for surgery planning. As the acquisitions are made with the breast in its natural shape, the three-dimensional images can pro- vide information about the exact location of depicted lesions. Single photon counting detector Featuring state-of-the-art technol- ogy, nu:view provides images of the breast in true isotropic 3D resolu- tion. Unlike conventional scintilla- tion, nu:view uses a single photon counting detector based on cad- mium telluride (CdTe) that converts x-rays directly into electrical signals. In the course of one rotation around the breast, up to 2,000 projection images are created – with a full spiral scan taking as little as 7 to 12 seconds, keeping dose levels low. Efficient workflows Thanks to its RIS/PACS integration capabilities (DICOM), the cutting- edge breast CT also provides effi- cient support for seamless work- flows. And with no custom viewer required, radiologists can continue working in their familiar reading environment. About AB-CT – Advanced Breast-CT GmbH AB-CT is a pioneering medical tech- nology company in the field of quality diagnostic breast imaging. www.healthcare-in-europe.com

R A D I O LO G Y I N E U R O P E 2 5 there and it mainly relates to the way engineers and medical doctors communicate and, of course, how brain tumours biologically behave. Images are not biological entities. With glioblastomas, neurosurgeons can remove everything and two months later we have a new tumour lesion. Microscopic tumour invasion cannot be captured either by imag- ing or by AI. When we segment tumours, an active tumour, in the language of engineers, is regarded as an enhancing tumour - and that is just not true. Lower grade tumour parts in glioblastomas are often non-enhancing,’ she added. Clinical validation goes beyond the pure act of segmentation. The final aim is to adapt these algorithms to answer the current clinical and radiological challenges as stated, more reliably than current clinical practice. ‘If we think about segmen- tation,’ she said, ‘I think the targets are: stepping up to molecular diag- nostics, detailed treatment planning, volumetric therapy follow-up and more detailed evaluation and early prediction of overall survival.’ AI in medical data analysis and neuro-oncology is here to stay and from the technical point of view, results are getting quite reliable. But to be introduced in the clinical setting, future investment should be in interpretability, trust and safety. ‘Some algorithms are able to make Illustration of a complex tumoural lesion in the right frontal lobe. The technical segmen- tation entities (oedema, non-enhancing tumour or tumour core, enhancing tumour and necrosis) are difficult to distinguish in this example. Notice the irregular, ill-defined tumour borders (arrows – left image) and the faint contrast enhancement (dashed circles – right image). These are possible hurdles for automatic segmentation algorithms. extremely accurate predictions but, from a clinical point of view, how can we trust predictions of features we can’t understand? We need to invest more in biological and clini- cal validation of techniques.’ Dr Sofie Van Cauter is a neuroradiolo gist at Ziekenhuis Oost Limburg in Genk and University Hospitals Leuven, Belgium. To gain her PhD, she researched advanced MRI techniques in gliomas with an emphasis on diffusion kurtosis imaging, MR spectroscopy and perfusion techniques. This was done in collaboration with the department of Electrical Engineering of the Catholic University Leuven, where she researched deep learning techniques in diagnosis and follow-up of gliomas. in size, shape and location. Tumour boundaries are often unclear or irregular, with discontinuities. In addition, hospitals all have differ- ent scanners and image protocols, which complicates standardisation and data quality. Nonetheless, there has been some progress, especially with the Brain Tumour Segmentation Challenge (BraTS), an objective evaluation of the different state-of-the-art meth- ods that offers publicly available data sets and a community bench- mark. BraTS is a data set of more than 500 cases, from different scan- ners, centres and imaging protocols, and also provides additional clinical data on overall survival as well as an extra assessment of uncertainty in brain tumour segmentation. ‘This has been a tremendous evo- lution in the field of engineering to face the challenges of the technical validation, the first step of get- ting brain tumour segmentation into a validated clinical product,’ van Cauter said. Investing in interoperability, trust and safety The next step is biological vali- dation. ‘We still have a problem ease and subgroup. ‘Imaging is, in my opinion, quite a lot of param- eters that you can assess: atrophy, Continued on page 27 www.healthcare-in-europe.com

R A D I O LO G Y I N E U R O P E 2 7 Alzheimer‘s research: A lost century Continued from page 25 social integration, education, activity in daily life, nutrition etc. A complex situation ‘We should not simply assume that a case with, for example, moderate hippocampal atrophy will inevitably also have moderate clinical symp- toms of dementia. The situation is significantly more complex. Early diagnosis is key and pro- filing is an interesting strategy. Ongoing European trials run tests to assess risk factors, family his- tory and genetics for preselec- tion of high-risk people for drug trials, for example the European Prevention of Alzheimer’s Dementia Consortium (EPAD). Haller: ‘A lot of work remains to be done, but if efforts are put to good use and properly targeted, we could make big leaps in AD and dementia treat- ment in the near future.’ Sven Haller, visiting professor at the University of Uppsala, Sweden, and neuroradiologist at the Centre d’Imagerie Rive Droite (CIRD) in Geneva, Switzerland, follows a special interest in advanced neuro-imaging techniques, particularly advanced MR techniques including functional MRI, real-time functional MRI neurofeedback and arterial spin labelling (ASL), notably in the domain of neurodegenerative and neurovascular diseases. His scientific awards include the Lucien Appel Prize and many more. He is also section editor for advanced imaging in Neuroradiology, the official journal of most European Societies of Neuroradiology, and section editor for neurodegeneration in the new textbook of Neuroradiology from the European Society of Neuroradiology. which is a marker of neurodegen- eration; perfusion, a marker of brain function, and a different range of markers of vascular disease.’ Imaging is very useful to diag- nose patients with mild cogni- tive impairment (MCI) at an early stage. However, this is not enough. ‘Approximately half of unselected MCI will remain stable even with- out intervention,’ Haller explained. ‘In the MCI group, you must detect those who will likely deteriorate later on.’ The typical pharmaceutical trial including unselected MCI cases will include approximately 50% of stable MCI patients, half of whom will get placebo and the other half will receive treatment. ‘This means only 25% of MCI cases will progress and get the true medication, while 25% of MCI cases remain stable despite being in the placebo group. That’s one of the many reasons it’s so dif- ficult to detect a treatment effect. Appeal for a more faceted approach Most studies focus on hippocampal atrophy alone, the known imaging hallmark of dementia. However, hip- pocampal atrophy is not specific to AD – it also occurs in other types of dementia, e.g. frontal dementia. And not all cases with a mild degree of hippocampal atrophy will devel- op dementia. ‘We should therefore include the assessment of the entire pattern of atrophy of the whole- brain, which is much more specific than looking only at the hippocam- pus. Moreover,’ Haller added, ‘we should add into the equation mark- ers of vascular disease, brain func- tion etc., as discussed above.’ Radiologists should watch out for the obvious. Intuitively it is obvi- ous to assume a linear correla- tion between more atrophy and worse clinical symptoms. However, in reality it is much more complex.’ There is a cognitive reserve or brain reserve. The same amount of meas- urable atrophy may be associated with a very large variability of cog- nitive decline at the individual level, depending on the cognitive reserve, elling support system is always in the optimal position for the patient. This purely mechanical construction ensures easy handling and extended durability. www.healthcare-in-europe.com Ingenia Ambition 1.5TMR services. Helium-free. The Philips Ingenia Ambition offers cutting-edge MR imaging techniques to help you excel clinically every day. Based on its new, revolutionary fully sealed BlueSeal magnet, the solution lets you experience more productive1 helium-free MR operations.Get superb image quality even for challenging patients, and perform your MRI exams up to 50% faster with Compressed SENSE acceleration for all anatomies in both 2D- and 3D scanning2. Fast overall exam-time is achieved by simplifying patient handling at the bore with the touchless guided patient setup. There’s always a way to make life better.1. Compared to the Ingenia 1.5T ZBO magnet. 2. Compared to Philips scans without Compressed SENSE. Discover more about Ingenia Ambitionwww.philips.com/ambition

R A D I O LO G Y I N E U R O P E 2 9 On the way: specific AI apps to scan children The future of paediatric imaging A premature infant with sepsis and the tiniest veins receives precisely targeted, lifesaving medications intravenously. A teen cyclist collides with a car; his head is hit; minutes later attending medics know there is bleeding in the brain. Thanks to advances in medical imaging, paediatric patients are receiving faster, more accurate diagnoses, quicker treatments, and experiencing better outcomes, says Dr Diku Mandavia, chief medical officer for Fujifilm Medical Systems in the USA and Fujifilm SonoSite Inc. a children’s hospital – their imaging should be immediately accessible to the new clinical team. New advances in healthcare IT and enterprise imaging will drive better care and outcomes for paediatric patients. Sharing of imaging data needs to be seamless. This capability reduces the need for repeat exams in children and thereby minimises their exposure to excessive radiation. intelligence has the potential to revolutionise paediat- ric care. Boston Children’s Hospital helped develop and is using a deci- sion support platform to improve the accuracy of paediatric brain scans. Artificial viders seeing a While pro- con- tinue to adhere to safe, low-dose imaging proto- cols, we are also trend toward finding new care path- ways that use ionising-free modali- ties. For example, more clinicians are opting to use point-of-care ultra- sound over CT to diagnose appendi- citis in children because it’s safer and has a very high accuracy rate. Many paediatric emergency physicians are adopting an ultrasound-first philoso- phy because it delivers a speedier diagnosis. It’s also less costly, safer, painless, and because children typi- cally have low body fat, it’s easy to acquire very clear images with ultrasound. Neonatal and paediatric intensive care units are adopting dedicated imaging equipment, such as wire- Children’s brains change at a rapid rate, so accuracy is vital. The deep- learning tool that reviews thousands of previous scans is helping clini- cians to pinpoint the exact diagnosis. In the future, we will see many new AI applications specific to paediatric imaging. A profession in need of a boost One unfortunate trend is the lack of young residents seeking to pursue the paediatric radiology subspecialty. Moreover, a recent survey of mem- bers of the Society for Paediatric Radiology found that today’s pae- diatric radiologists suffer from sig- nificant burnout, with 66 percent of respondents reporting high levels of emotional exhaustion. While imaging technology will continue to evolve, it is imperative that the medical profession find ways to revive interest in the subspecialty, and recruit and retain the best and the brightest. High tech will never trump human touch. The future of paediatric imaging depends not only on technological advances, but most importantly, on the people who put those tools to use. less, portable DR and point-of-care ultrasound, so that children can be diagnosed more quickly and avoid being moved around the hospital, where they risk exposure to poten- tial nosocomial infections. New technologies are also aim- ing to reduce the need for sedation during paediatric imaging, making exams safer. In terms of design, reducing patient anxiety is a top priority. That means smaller, less noisy, more soothing equipment that acquires images faster and reduces the need for the patient to stay still. There are also important social factors for imaging children. Since paediatric patients are not always able to speak up for themselves, radiology is in a unique position to uncover adverse life events, such as physical abuse. Historically, hospitals sometimes use double density CR films to conduct skeleton surveys to detect abuse – requiring as much as 20 films on a 9-month-old. With new advances in digital radiography sys- tems, physicians can detect evidence of abuse in the bones with lower dose exposure. Healthcare IT and artificial intelligence While it is always important to have a comprehensive picture of the patient, it is particularly vital in paediatrics. First, young children lack the verbal skills to provide any kind of history. Moreover, many very sick children begin treatment at a community hos- pital, but need to be transferred to Ángel Alberich-Bayarri PhD is the CEO of QUIBIM, a company that applies AI and advances computational models to radiological images to measure changes produced by a lesion or pharmacological treatment, offering quantitative information to radiology. integrating all these elements for prostate applications. The main goal is to avoid work- flow interruption and to be pre- pared for massive analysis comput- ing performance. ‘Using these types of architecture,’ he said, ‘our main aim is to convert our radiology department into a quantitative radi- ology department, where all bio- markers are seamlessly extracted.’ Radiologists will not manage to integrate SR with quantitative imaging if SR is independent from the user and biomarker’s interface. ‘Radiologists,’ he concluded, ‘want the SR integrated with AI and bio- markers. So we have to think of changing our current paradigm.’ Neuroradiologist Dr Shah Islam, who runs the DIG and FPIA studies, is a clinical research fellow at Imperial College London. Having graduated from Barts and The London School of Medicine and Dentistry, he underwent combined clinical academic training at Barts and was an NIHR academic clinical fellow in Radiology at The Royal Marsden NHS Foundation Trust. His research focuses on developing novel imaging biomarkers to detect early treatment response in glioblastoma using advanced imaging techniques achieved through a number of clinical trials and advanced computational methods involving AI. ple to second- line therapies; if we can identify those that won’t do well on first-line treatment, we can change them to another treatment,’ he said. ‘The average life expectancy is approximately 18 months and we haven’t seen a positive trial result since the introduction of temozolo- mide 15 years ago; so we are failing these patients. ‘We hope a benefit will be to allow new drugs to be tested in clinical trials using the new bio- markers to appropriately validate the new drug.’ Preliminary results of the trials were presented at RSNA 19, but Islam confirmed that they are still a long way from clinical translation into routine imaging. * Baroness Tessa Jowell was a UK politician who died of GBM and worked to raise awareness of the condition. www.healthcare-in-europe.com NEWTOM 5G XLEXTRA.VISION www.newtom.itCUTTING EDGE PERFORMANCE FOR ADVANCED DIAGNOSTICS.Advanced diagnostics with 5G XL, the only CBCT device with lying down patient positioning that offers excellent stabilisation and a broad range of FOVs for very high quality 3D and 2D images. 5G XL is the first device with native FOV 21 x 19 cm for highly detailed investigations. The ideal device that produces clear, high definition images for orthopaedics, otorhinolaryngology, maxillofacial surgery and dentistry applications.SUPERIOR DIAGNOSTIC QUALITY Very high resolution 2D and 3D images with a broad range of FOV for an extensive selection of clinical applications.OPTIMAL LYING DOWN POSITION The only CBCT system with patient lying down positioning, a motor-driven patient table and an open gantry. Perfect patient stabilisation considerably reduces any movement-induced artifacts.LOW X-RAY DOSE The ECO Scan mode and SafeBeamTM technology offered by 5G XL further reduce the dose radiated to the patient, compared to examinations performed with CT technology.SPECIALIST SOFTWARE The adaptive user interface displays images and provides access to innovative 3D and 2D analysis functions for rapid and accurate diagnoses and optimal workflow.ECR 2020 · Vienna · AUSTRIA15-19 JULY EXPO X1 BOOTH N. 111AUSTRIA CENTER VIENNA (ACV)Bruno Kreisky-Platz 1, 1220 Vienna

R A D I O LO G Y I N E U R O P E 3 1 The ascent of computerisation in radiology AI for thorax-CT As a highly innovative medical specialisation, radiology increasingly takes advantage of the possibilities offered by artificial intelligence (AI). Yet, there is no risk for the future of the specialty. Demands on this discipline are too complex, too communicative. Thus, machines will not replace a radiologist any time soon – of that Uwe Joseph Schöpf, professor of radiology, cardiology and paediatrics, and director of the Cardiovascular Imaging department at the Medical University of South Carolina (USA), is convinced. Using a few impressive examples, he explains what AI has to offer the radiologists. It is true that the popularity of radiol- ogy declined in recent years among young medical graduates in the USA. There was just too much worry about entering a specialty that might just be made obsolete by progress in artificial intelligence. Meanwhile the trend has reversed again, simply because that is not expected to hap- pen. The reason? There are far too many indispensable interpersonal competencies needed for success in radiology: communication with a patient and referring physicians; interdisciplinary procedures and a holistic view of the patient’s cur- rent situation – not just of a specific image pattern. ‘These are capabili- ties that a computer still cannot assume, no matter how good it is,’ Schöpf points out. ‘For that we still need capable and well-educated specialists.’ AI undertakes the time-con- suming work For the professor, AI constitutes a highly potent capacity to seri- ously improve the diagnosis using a continuously perfected image evaluation. What does this really mean? First there is the enormous time-saving AI provides – above all for measurements in quantita- tive imaging. Thus, an appropriately trained computer can automatically and precisely generate the Agatson score for calcification of coronary arteries within seconds. The same measurement takes between 15 and 20 minutes for a radiology trainee or specialist depending on the degree of calcification. Another example is the automatic measurement of mitral valve dimen- sions. ‘This is difficult for the human observer, because it moves in a three-dimensional space; even four- dimensional if heartbeat is consid- ered. The 2-D image on the worksta- tion is not well-suited to this kind of precise measurement.’ The comput- er recognises no such restrictions. It measures automatically, fast and probably also better. Artificial intelligence recognises and classifies fine branching in the coronary vessels with a high degree of reliability. Genuine value added That is not all AI can do. It can enrich findings with additional results and thus enhance them. So-called opportunistic screening delivers important information which is not sought routinely but can decisively improve diagnosis. A good example is emphysema quantification. The computer recognises, on its own, whether or not there is a pulmonary emphysema and can even determine its extension simultaneously. Without any further effort, this measurement is taken automatically and precisely with every thoracic CT. The same applies to measur- ing bone density. Detailed infor- mation about bone substance can be highly relevant for diagnostic and therapeutic aspects. A human observer, concentrating on other thoracic structures, easily overlooks this irregularity. The measurement of the thoracic aorta to find an aortic aneurysm is a third example. Due to numerous curves in the course of the aorta, measurement is difficult for radiolo- gists – but no problem for the com- puter; here it also measures quickly and accurately. Two birds with one stone ‘On one hand, we are currently working on the discovery of pul- monary nodules and, on the other, the automatic detection of coronary vessels and plaques.’ Here, the long- term objective is to identify as many potential problem areas as possible with one and the same CT image. That means, with a lung CT, calcifi- cation of coronary vessels are auto- matically measured in parallel and, with a heart CT, there is simultane- ous detection of pulmonary nodes. ‘A very efficient procedure, impos- sible without AI,’ Schöpf observes. ‘We also work with AI especially in cardiovascular diagnosis to assess how serious a coronary stenosis is.’ The focus here is measurement of the flow reserve. Results to date indicate that this examination could become part of clinical routine very soon. In one fell swoop The digital twin of a human heart contains information from imaging, the medical file and other sources and permits simulation and prediction of the effect of influences and therapies Professor Uwe J Schöpf studied medicine in Munich and specialist training at the Institute for Clinical Radiology of the Ludwig-Maximilian-University. In 2001, with a keen interest in cardio-thoracic imaging, he left Bavaria for the USA where, he was to become a radiologist at the Brigham & Women’s Hospital, Massachusetts, until 2004, Today he is professor of radiology, cardiology and paediatrics and directs the cardiovascular imaging department at the Medical University of South Carolina in Charleston. The use of AI is very promising – even beyond image identification. Catchwords: structured reporting. Based on unstructured findings dic- tated by a physician, AI allows fil- tering of the relevant text elements and their transfer to a structured diagnosis. The advantage is obvious: more objective diagnosis, easier bill- ing, better use in studies and also easier to understand for a referring physician. ‘I see the value of struc- tured diagnosis, but,’ Schöpf points out, ‘also the problem of practical implementation. The preparation of a structured diagnosis takes longer than one freely dictated. The physi- cian has to click laboriously through web pages, in which all possible structures are queried, even the unobtrusive ones.’ From his experi- ence, he sees it as not particularly user-friendly for routine radiological operations. Hence the very promis- ing use of the computer is even more welcome here. Moreover, the procedure can be applied to all organ fields, once the computer has been appropriately trained. ast media injector radiologists and vascular surgeons are running imaging series or per- forming a 3-D angiographic proce- dure. An advantage for the patient is the possibility of direct interven- tion in the case of narrowing or aneurysmatic vascular changes and bleeding. For example, if it turns out during the imaging that there is a constriction that can be treated with a catheter procedure, the therapy can take place in the same session. Most importantly, by improv- ing the procedures in the above described way, the new Accutron HP-D offers enhanced safety for the patients. It can help to reduce the contrast dose impact on the patient without affecting image quality. is important A most reliable device Reliability in Sahlgrenska’s busy imaging and intervention centre. Magnus con- firms: ‘The Accutron HP-D is a very reliable device that always works. We don’t have any issues or problems with it. It just works.’ www.healthcare-in-europe.com