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Letters to the Editor Issue 252
listed in letters to the editor, originally published in issue 252 - February 2019
Artificial Joint Restores Wrist-Like Movements to Forearm Amputees
A new artificial joint restores important wrist-like movements to forearm amputees, something which could dramatically improve their quality of life. A group of researchers led by Max Ortiz Catalan, Associate Professor at Chalmers University of Technology, Sweden, have published their research in the journal IEEE Transactions on Neural Systems & Rehabilitation Engineering.
osseointegrated artificial wrist joint
For patients missing a hand, one of the biggest challenges to regaining a high level of function is the inability to rotate one’s wrist, or to ‘pronate’ and ‘supinate’. When you lay your hand flat on a table, palm down, it is fully pronated. Turn your wrist 180 degrees, so the hand is palm up, and it is fully supinated. Most of us probably take it for granted, but this is an essential movement that we use every day. Consider using a door handle, a screwdriver, a knob on a cooker, or simply turning over a piece of paper. For those missing their hand, these are much more awkward and uncomfortable tasks, and current prosthetic technologies offer only limited relief to this problem.
“A person with forearm amputation can use a motorised wrist rotator controlled by electric signals from the remaining muscles. However, those same signals are also used to control the prosthetic hand,” explains Max Ortiz Catalan, Associate Professor at the Department for Electrical Engineering at Chalmers. “This results in a very cumbersome and unnatural control scheme, in which patients can only activate either the prosthetic wrist or the hand at one time and have to switch back and forth. Furthermore, patients get no sensory feedback, so they have no sensation of the hand’s position or movement.”
The new artificial joint works instead with an osseointegrated implant system developed by the Sweden-based company, Integrum AB – one of the partners in this project. An implant is placed into each of the two bones of the forearm – the ulna and radius – and then a wrist-like artificial joint acts as an interface between these two implants and the prosthetic hand. Together, this allows for much more naturalistic movements, with intuitive natural control and sensory feedback.
See a video of the joint in action here
https://www.youtube.com/watch?v=yV7vgIpQXLo&feature=youtu.be
Patients who have lost their hand and wrist often still preserve enough musculature to allow them to rotate the radius over the ulna – the crucial movement in wrist rotation. A conventional socket prosthesis, which is attached to the body by compressing the stump, locks the bones in place, preventing any potential wrist rotation, and thus wastes this useful movement.
“Depending on the level of amputation, you could still have most of the biological actuators and sensors left for wrist rotation. These allow you to feel, for example, when you are turning a key to start a car. You don’t look behind the wheel to see how far to turn – you just feel it. Our new innovation means you don’t have to sacrifice this useful movement because of a poor technological solution, such as a socket prosthesis. You can continue to do it in a natural way,” says Max Ortiz Catalan.
Read the paper ‘Restoring Natural Forearm Rotation in Transradial Osseointegrated Amputees’ published in the journal IEEE Transactions on Neural Systems & Rehabilitation Engineering Volume: 26 Issue: 12. 2018. https://ieeexplore.ieee.org/document/8533434
Further Information
Max Ortiz Catalan, Department of Electrical Engineering, Chalmers University of Technology, Sweden Tel: +46 70 846 10 65, maxo@chalmers.se
Acknowledgement Citation
Online version mynewsdesk.com
Heart Cell Defect Identified as Possible Cause of Heart Failure in Pregnancy: Tel Aviv University research has diagnostic and therapeutic implications
Peripartum cardiomyopathy (PPCM) is a rare form of heart failure that affects women in their last month of pregnancy and up to five months after giving birth. PPCM can be difficult to detect because its symptoms - swelling in the feet and legs and shortness of breath - mimic many of those of third trimester pregnancy. The disease, which can be fatal, manifests itself as heart muscle dysfunction and heart failure, but its underlying cause has eluded researchers.
Now, a new Tel Aviv University study reveals that one of the possible primary causes of PPCM is a functional heart cell defect. The findings may have diagnostic and therapeutic implications.
The research was led jointly by Prof. Jonathan Leor and Dr. Nili Naftali-Shani, both of the Cardiovascular Research Institute at TAU's Sackler School of Medicine and Sheba Medical Center, in collaboration with Dr Natali Molotski, Dr Uri Amit, Li-at Zeltzer and Alina Levich, all of TAU and Sheba; Prof. Michael Arad and Dr Rafael Kuperstein, Dr Yael Nevo-Caspi, Haya Abbas and Prof. Gidi Paret of Sheba Medical Center; Dr Irit Huber of the Technion–Israel Institute of Technology; and Dr Lorenzo Monserrat of Coruña, Spain. It was published in the journal Circulation on December 3, 2018.[1]
"It was previously suggested that levels of STAT3, an essential protective protein involved in cellular response to stress, were abnormally low in the heart cells of PPCM patients. This triggered a biological process that ultimately sliced the lactation hormone prolactin, creating toxic products that cause the disease," Prof. Leor says. "But we found that levels of the STAT3 protein were in fact higher in the heart cells of women with PPCM than in those of healthy women.
"We then discovered that a functional defect in the heart cells of patients with PPCM, characterized by an impaired release of growth factors that regulate blood vessel formation or factors that activate the immune system, was the underlying mechanism involved in the disease."
The researchers say their discovery calls into question the medical justification for treating women with PPCM with bromocriptine, a drug used to treat symptoms of hyperprolactinemia (high levels of prolactin), which has serious adverse effects.
Dr Naftali-Shani harnessed a cutting-edge genetic engineering technique, which won the Nobel Prize for medicine and physiology in 2012, to produce stem cells and beating heart cells from the skin cells of PPCM patients and healthy controls.
"This is the first time that this technique was used to study the mechanism of PPCM," Dr. Naftali-Shani says. "Using these heart cells, we were able to find that the accepted theory was incorrect. The myocardial cells produced from the stem cells of the patients had functional defects that caused them to secrete inflammatory proteins and a protein that inhibits the formation of blood vessels in the muscle, even without stress. We hope that this discovery will pave the way for early diagnoses and new, effective prevention and treatments."
Prof. Leor says, "Our future challenge will be to explore the exact molecular defect in heart cells of women with PPCM and to determine a new target for prevention and therapy."
Reference
1. Nili Naftali-Shani et al. Modeling Peripartum Cardiomyopathy With Human Induced Pluripotent Stem Cells Reveals Distinctive Abnormal Function of Cardiomyocytes. Circulation;138:2721–2723. 3 Dec 2018. DOI: 10.1161/CIRCULATIONAHA.118.035950
Further Information and Contact; Online Press Release
Source: George Hunka, American Friends of Tel Aviv University ghunka@aftau.org
Contact: Jordan Isenstadt Marino jisenstadt@marinopr.com Tel: +1 212.402.3510
Scientific Breakthrough could explain how Superbugs Rapidly Evolve
A scientific breakthrough has revealed a new way that bacteria evolves, thought to be at least 1,000 times more efficient than any currently known mechanism. The insights will help scientists to better understand how superbugs can rapidly evolve and become increasingly antibiotic resistant.
The research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC), the National Medical Research Council (NMRC) and the Singapore Ministry of Education (MOE) was led by the University of Glasgow and the National University of Singapore and published in Science[1] and has found a previously unknown method of genetic transduction - the process through which bacteria begins to evolve into potentially deadly superbugs. The new process has been named Lateral Transduction, and now joins the two known methods of transduction: Generalised and Specialised Transduction, both discovered by the American scientist Joshua Lederberg, who won the Nobel Prize in Physiology or Medicine for his work with bacteria. Working with the bacteria Staphylococcus aureus, scientists were able to demonstrate that this new naturally occurring method of transduction was at least one thousand times more efficient than generalised transduction, the best currently known method. Due to the efficiency of lateral transduction, scientists speculate it is likely to be the most impactful type of transduction to occur in bacteria during its evolutionary process.
Professor José R Penadés, from the University of Glasgow, said:
“This is an incredibly exciting and significant discovery. We have been able to show a new way that bacteria evolve. With the rise of superbugs that are increasingly antibiotic resistant, the importance of understanding the mechanisms for bacterial evolution has never been so important.
“Lateral transduction is an entirely natural process and we believe it also occurs in bacteria other than Staphylococcus aureus. This is a game-changer in terms of the way we understand bacterial evolution.”
Bacterial transduction is a process that involves viruses infecting bacteria. As a consequence of this mechanism, bacterial DNA moves from one to another bacteria, thereby causing mutation and evolution, often producing increasingly deadly and antibiotic resistant bugs.
Lateral transduction is unique in its efficiency. The process involves so many genes being transferred, that scientists have theorised whole sections of bacterial chromosome are being mobilised to other bacteria at the same time. This could help to explain the rapid pace at which superbugs are able to evolve.
This research also challenges current scientific thinking in this area, which assumes that only mobile genetic elements, but not the bacterial chromosomes, can be transferred at high frequencies. Now scientists believe lateral transduction has the power to move whole sections of bacterial chromosome including particularly deadly sections called pathogenic islands responsible for virulence and antibiotic resistance.
Assistant Professor John Chen, from the National University of Singapore, said:
“Phages are by far the most abundant biological entities on the planet, and the importance of genetic transduction as one of the principle drivers of microbial evolution has never been more apparent than with the discovery of lateral transduction.”
Reference
1. Genome hypermobility by lateral transduction is published in Science Vol. 362, Issue 6411, pp. 207-212. 12 Oct 2018. DOI: 10.1126/science.aat5867.
Further Information
For more information please contact Elizabeth McMeekin or Ali Howard in the University of Glasgow Communications and Public Affairs Office on Tel: 0141 330 4831 or Tel: 0141 330 6557; or email Elizabeth.mcmeekin@glasgow.ac.uk or ali.howard@glasgow.ac.uk
The National Food Agency’s (Sweden) Instructions Contravene Swedish and EU Law
The Supreme Administrative Court of Sweden has affirmed in its judgment of 13 November 2018: Swedish municipalities that imposed a sales ban on food supplements acted in contravention of applicable Swedish and EU law. In 2015, the National Food Agency issued a handbook to Sweden’s municipalities comprising instructions on how to implement controls of such items as food supplements. The agency handbook addressed the so-called recommended ULs (Upper Limits) levels from EFSA* (2006) on vitamins and minerals, although ULs are not officially prescribed as legally binding maximum permitted levels (MPL´s) threshold values – neither in Sweden nor the rest of the EU.
Consequently, Swedish municipalities banned companies and retail stores from selling completely safe and legal products. This has entailed Swedish consumers missing out on products and caused companies to suffer considerable economic losses.
In accordance with the Supreme Administrative Court’s judgment of case number 3160-17, Swedish municipalities are not entitled to institute local sales bans on food supplements deemed to be safe in accordance with the Food Supplement Directive (FSD). Therefore, municipalities that have imposed a sales ban on a food supplement in reference to its quantity (levels) of vitamins or minerals have done so entirely without statutory support.
The National Food Agency’s handbook, Kontrollwiki, contains gross errors
“There are no official, legally binding maximum permitted levels (MPL´s) threshold values for vitamins or minerals, neither under Swedish law nor within the regulatory framework of the European Commission. On the other hand, food supplement contents are regulated by the Food Supplement Directive 2002/46/EC, issued by the EU Commission with the aim of harmonising the trade of food supplements, and which is incorporated into Swedish law,”
explains Rolf Forslund of Kenkou Selfcare AB, one of the companies seriously impacted by the National Food Agency’s erroneous information to municipalities.
Protests by both business owners and lawyers against the erroneous information in the National Food Agency’s control handbook were lodged with municipalities, government agencies and the minister responsible. However, no amendments have been made to the misleading information. Municipalities are still being encouraged to impose sales bans and to submit reports to the EU’s safety-alert system for hazardous substances in foodstuffs, the Rapid Alert System for Food and Feed (RASFF), if food supplements are found to exceed the so-called UL values.
“This means that Swedish municipalities are being encouraged to act arbitrarily, without any legal basis and that the crucial RASFF system is being abused,” Rolf Forslund continued. “This is very dangerous, as it undermines the system’s vital functions. RASFF is meant to warn of the presence of hazardous substances like poisons, heavy metals and bacteria (i.e. Salmonella) in food, not for vitamins in completely safe doses.”
A Judgment by the Supreme Administrative Court is Precedent-Setting
“Now that this is a judgment by the Supreme Administrative Court, precedent has been set. “ Marcus Angström, attorney at 7Wise Law firm explains.
“It is completely unacceptable for companies and consumers to be subjected to such arbitrary treatment by Swedish government agencies. As business owners, we already apply the principles referred to in the Food Supplement Directive by means of clear labelling and the stipulated control procedures,” explains Patrick Wahlberg of Greatlife Group AB, which recently received an amendment to the previous ruling against its product with a daily dose of vitamin D 125 μg.
Government Agencies must now Conform to the Court Judgment
"I have great sympathy for the affected companies suffering from the National Food Agency’s and many municipalities erroneous actions. I now presume that the National Food Agency will immediately align its instructions according to this judgment so that correct information from now on will go out to all the Swedish municipalities.” says Marcus Angström, attorney at 7WISE Law Firm.
“If and when maximum permitted levels (MPL´s) threshold values for vitamins or minerals are imposed within the EU or at a national level in Sweden, the Court of Justice of the European Union (CJEU) has already in related verdicts clearly stated that the most recent research has to be taken into account. The balance between risk and benefit must also be given more careful consideration, according to the European Commission and risk assessment institutions like TNO.” Rolf Forslund says.
“However, maximum permitted levels (MPL´s) threshold values are not really needed, neither nationally or within the EU. Again, the Court of Justice of the European Union (CJEU) has already clearly established that food supplement labelling that gives the consumer clear information is the most proportionate measure that allows free trade between the Member States to continue whilst at the same time provides adequate protection to the consumers. Many EU countries already practice this. Västerås Municipality in Sweden has also recently begun to apply this principle since several administrative court verdicts have confirmed the validity of this practice. " concludes Rolf Forslund.
The Judgment of case no. 3160-17 can be read in its entirety here:
http://www.hogstaforvaltningsdomstolen.se/Templates/Pages/DV News.aspx?id=60310
Facts about the Supreme Administrative Court of Sweden: The Supreme Administrative Court of Sweden is the highest authority among Sweden’s administrative courts. Its primary function is to set precedents. The court tries the appeals of judgments and verdicts announced by the country’s four administrative courts of appeal. Out of the 9000+ applicants for rights to appeal in this court only about 2% (approx. 200 cases per year) gets approval to be looked at, when/if precendent-setting verdicts are needed.
About the Nordic Food Supplement Alliance:
In 2015, when erroneous instructions from the National Food Agency began to be applied, 12 of the companies impacted by the sales bans decided to jointly examine the decisions by legal means. The companies in the alliance comprise: Alpha Plus AB, Bättre Hälsa AB, Edura AB (Thorne Research), Egenvårdspoolen AB, Great Earth AB, Greatlife Group AB (Innate Response), Holistic Sweden AB, Hälsokraft (chain store), Kenkou Selfcare AB (Lamberts), Nordic Premium Group AB (Solgar, Terranova, Nordiq), RevivaBio AB, Au Naturel Inc (Solaray). The legal and scientific coordinators comprised of Rolf Forslund and Lennart Holmgren, as well as Marcus Angström of 7WISE Law Firm.
*History: Sweden is divided into 290 municipalities, each being independently governing control authorities. The control handbook issued by the Swedish National Food Administration is presently known as Kontrollwiki. It is the means by which municipalities are informed that they can impose sales bans on food supplements exceeding so-called Upper Limit values derived from the informal preparatory work report for the discussion paper presented in 2006 by the European Food Safety Authority, EFSA. The contents of food supplements are regulated by the Food Supplement Directive 2002/46/EC, issued with the aim of simplifying trade in food supplements and increasing consumer protection. This directive is incorporated into Swedish law.
Further Information
Marcus Angström 7WISE Advokatbyrå. T: +46 70-8664726 E: marcus.angstrom@7wise.se
Rolf Forslund, Kenkou Selfcare AB T: +46 76-2673325 E: rolf.forslund@lamberts.se
Lennart Holmgren, Scientific Adviser T: +46 76-1182665 E: lennart@lhhc.se
Self-Assessing Back Pain by App as Effective as Traditional Methods
Patients can assess their own back pain using an app on their phone or tablet as effectively as current paper methods, a new study from the University of Warwick has shown.
The study, published in the open access Journal of Medical Internet Research[1] demonstrates that digital versions of established measurements for assessing back pain are just as reliable and responsive, opening the possibility for their use by patients for routine measurements and clinical trials.
The researchers see this study as a necessary first step in the greater use of digital media in clinical settings, in light of recent calls for greater use of such technology by healthcare providers.
- Study lends weight to argument for using mobile apps for routine measurements and clinical trials
- Digital versions of existing assessments would be cheaper, greener and improve patient experience
- Validating the effectiveness of health apps could be first step to a learning health service
- Study by University of Warwick supports call by the Royal College of Physicians for greater use of already available technology in healthcare
For health issues that can’t be readily measured, such as pain and depression, clinicians will often use self-assessment to monitor change. In most cases, this will take the form of a paper-based assessment. These go through very thorough validation exercises to ensure that they measure what they intend to robustly and accurately.
The researchers created mobile app versions of the most commonly-used measures in back pain trials: the Roland Morris Disability Questionnaire (RMDQ), visual analogue scale (VAS) of pain intensity, and numerical rating scale (NRS). These were developed with support from the University of Warwick Higher Education Innovation Fund with the aim of being used in clinical trials and for routine clinical measurements.
Back pain is the number one cause of disability globally, affecting up to 84% of people at some point in their lives. It is estimated that it costs the UK economy billions of pounds each year.
Lead author Dr Robert Froud from the University of Warwick Clinical Trials Unit said:
“We have taken existing outcome measures and shown that they can be migrated to digital media and used in that format just as effectively as their paper-based versions. Our intention is to develop technology that allows people to securely complete these kinds of assessments on their own phones and tablets in a way that is safe, secure and accurate.
“If you can accurately monitor in clinical practice what’s happening to patients’ health, then analytically there is a lot that could be done with the data that will benefit patients. For example, we may be able to detect that particular treatment approaches are working better for certain types of people. We hear a lot about machine learning, but a learning healthcare system is perhaps next.
“The implications are quite big because we can aim to scale up. It opens up potential for the development of new instruments and dynamic instruments that adapt to the answers that a user gives. The potential of using digital technology in healthcare settings is quite extraordinary but you can’t do any of that without first having assessments that work robustly and well.”
Reliability and responsiveness were used as factors to determine whether their apps were measuring in the way that they should be. Reliability refers to the result of the measure not changing when nothing has changed, while responsiveness refers to a change in the result when a measurable factor has changed.
The researchers divided participants in the study into groups depending on whether they had recorded a change in their pain. People who had received treatment for their condition and improved tested the responsiveness of the apps. Those with chronic pain, and less likely to improve, tested the apps for reliability.
Digital tests have a number of advantages over paper-based versions, including their low cost, lower carbon footprint, better information security and improving the participant’s experience.
Earlier this month, a new report from the Royal College of Physicians, Outpatients: The future - Adding value through sustainability, called for greater use of already available technology in healthcare.
Reference
1. Froud R, Fawkes C, Foss J, Underwood M, Carnes D. Responsiveness, Reliability, and Minimally Important and Minimal Detectable Changes of 3 Electronic Patient-Reported Outcome Measures for Low Back Pain: Validation Study. J Med Internet Res;20(10):e272. 2018. doi:10.2196/jmir.5692
Further Information and Contact
Peter Thorley Media Relations Manager (Warwick Medical School and Department of Physics) | Press & Media Relations | University of Warwick peter.thorley@warwick.ac.uk Tel: +44 (0)24 761 50868 | Mob: +44 (0) 7824 540863 |
Handful of Pharmaceutical Companies Developing the Bulk of Urgently Needed Medicines for the Poor According to The Access to Medicine Index
The development of new medical products that are considered the highest priority for people in developing countries is highly concentrated – among five pharmaceutical companies and on five diseases.
The 2018 Access to Medicine Index, published 20 Nov 2018, is an independent ranking of 20 of the leading pharmaceutical companies on their efforts to improve access to medicine in low- and middle-income countries. Takeda rises furthest in 2018, jumping ten places to fifth. GSK retains its position at the top of the Index. Novartis moves into second, ahead of Johnson & Johnson and Merck KGaA, which complete the group of leaders in 2018.
The four leaders, together with Sanofi (in 6th), account for 63% of the priority research and development (R&D) being undertaken.
“The fact that a handful of companies are carrying the bulk of the priority R&D load shows how fragile the situation is. A retreat by even one of these players would have a significant impact,” said Jayasree K. Iyer, Executive Director of the Access to Medicine Foundation. “If more companies joined this group, that would bring much needed resilience.”
The Index found that the industry’s engagement in such R&D is focused on five diseases, with half of all such activity targeting malaria, HIV/AIDS, tuberculosis, Chagas disease and leishmaniasis. All five diseases are the target of global health initiatives and have international donors behind them. In total, 45 diseases have been identified as a priority for R&D by the WHO and others.
The analysis indicates that the majority of the priority R&D projects are being carried out with public sector research organisations. However, some companies are developing priority products without such facilitation. One example is Merck KGaA developing tests and treatments for schistosomiasis, a water-borne parasitic disease that affects around 252 million people.
“This is evidence that, when society agrees on the priorities, this clearly works in focusing the industry’s efforts,” said Danny Edwards, research lead for the Index. “Our analysis found evidence of this not only in R&D but also in the actions companies take to make medicines accessible after they reach the market. In short, where there is a call to action or donor funding, more companies will get involved, particularly in areas with low commercial potential.”
The concentration in companies and diseases is also seen in other activities important for access to medicine: for example, small groups of companies account for the increases in fairer pricing strategies, and in access planning while products are still in the pipeline.
Progress over the Last Two Years
The Index measures companies in seven areas of corporate behaviour that are important for increasing access to medicine.
Overall, the industry continues to mature in its approach to access to medicine. Three companies have set new or strengthened access strategies since the 2016 Index. Five companies are scaling up commercial models that explicitly view people living in underserved communities as customers. Companies are also more transparent about where they have patents in force, which is valuable information for international medicines procurers. Also, strategies that set different prices for different segments of a country’s population continue to become more sensitive to what people can afford.
However, performance continues to lag in some areas. For example, while companies are refining their pricing strategies to improve the affordability of more products, they are applying them in few countries, mostly emerging markets. Also, while licensing has enabled the manufacture and distribution of generic versions of all recommended treatments for people living with HIV/AIDS, its use remains confined to that disease and to hepatitis C but could be extended to other diseases.
The companies have more projects in the pipeline that target global health priorities than they did two years ago. Since the 2016 Index, at least 66 products have moved through the pipeline to reach the market. They are for 14 diseases that the Index covers, with half of them targeting cancers. Other examples include:
- Three new pills that each can cure all six major genotypes of hepatitis C. Gilead has voluntary licensing agreements in place with 11 India-based generic pharmaceutical manufacturers which enable the manufacture and distribution of two of these products in 105 developing countries. (Gilead and AbbVie)
- A child-friendly chewable form of a tablet for roundworm and whipworm, which currently infects an estimated 795 million people. The company has pledged a donation programme of 200 million doses per year until 2020. (Johnson & Johnson)
65% of Cancer Deaths Globally in Developing Countries
Cancer is taking an increasing toll in low- and middle-income countries, where approximately 65% of cancer deaths now occur. The Index examined company efforts to increase access to cancer products for the first time this year, focusing on those that are included on the World Health Organization (WHO) list of medicines it considers essential for all healthcare systems. It identified 72 such products. Novartis markets the largest proportion of these, including half of the cancer products that have an access initiative attached to them.
Efforts during the R&D phase to plan access initiatives for cancer products lag far behind those for communicable diseases. Plans are in place for 5% of candidate cancer products by the time they reach the later stages of development, compared with 54% for communicable disease pipeline products.
“There have been massive improvements in global health in the past decades, with all major pharmaceutical companies taking action. To close the gaps that remain, a greater diversity of companies must get involved and stay engaged for the long haul.” Jayasree K. Iyer, Executive Director.
About the Access to Medicine Index
The Access to Medicine Index analyses 20 of the largest research-based pharmaceutical companies with products for high-burden diseases in low- and middle-income countries. It ranks them on their efforts to improve access to medicine in seven areas of corporate behaviour and identifies best practices, highlights where progress is being made and uncovers where critical action is still required. The Index is endorsed by more than 80 investors, collectively managing assets worth more than USD 10 trillion. It is published every two years by the Access to Medicine Foundation, an independent non-profit organisation funded by the UK Government (UK AID), the Dutch Ministry of Foreign Affairs, and the Dutch Ministry of Health, Welfare and Sport and the Bill & Melinda Gates Foundation.
Further Information
Suzanne Wolf <swolf@accesstomedicinefoundation.org>
Tel: + 31 6 29 40 40 90 or +31 20 215 3535
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