Ebola virus disease
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g7348 (Published 10 December 2014) Cite this as: BMJ 2014;349:g7348All rapid responses
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Under intense pressure to react, the World Health Organization (WHO) is set to fast-track phase II/III evaluation of candidates Ebola virus vaccines based on adenovirus vectors in Western and Central Africa. Notably though, adenovirus vectors have regularly shown encouraging preclinical results that were followed by disappointing clinical efficacy. Despite the immunogenicity shown in phase 1/2 studies, two proof-of-concept HIV vaccine trials (STEP and Phambili), using an adenovirus vector were interrupted due to lack of efficacy, and because vaccinees were more prone to HIV acquisition than those exposed to placebo [1]. Post-hoc analyses of these studies, which together enrolled ~3,800 at-risk men and women, showed that vaccinees had a statistically significant increased risk of HIV infection [2]. The most relevant data may be the Phambili study, where sexually active young adults were enrolled. Here, 9% of the placebo group, while 16% of the vaccinees acquired HIV (p=0.01) - predicting that up to 7% more of hundreds of thousands vaccinees would become HIV-infected as a consequence of the vaccine-induced susceptibility. While there are a handful of potential non-exclusive explanations for increased HIV acquisition in vaccinees, identifying one is difficult for obvious ethical reasons. Importantly though, increased HIV acquisition was recapitulated in vaccinated nonhuman primates [3], albeit the size of the cohort was too small to allow a robust analysis.
These results beg the question “Is there a risk of increased HIV acquisition when using adenovirus vectored vaccine?” This question is particularly urgent because the WHO could requisition hundreds of thousands of Ebola vaccine doses in a region with mostly concentrated HIV epidemics. Our intention is not to be anti-vaccine, predict a nosocomial catastrophe or to delay a protective treatment for the Ebola epidemic. We argue that incorporating HIV surveillance in the trial endpoints is sine qua non, and trial organizers need to provide the volunteers and target population with comprehensive information on HIV acquisition risk, HIV disease progression and therapy, as well as with educational and preventive tools against HIV acquisition. Success against the Ebola epidemic needs urgent short-term intervention, but also broad long-term vision.
References
1. Steinbrook R. One step forward, two steps back--will there ever be an AIDS vaccine? N Engl J Med 2007;357(26):2653-5
2. Gray GE, Moodie Z, Metch B, et al. Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: unblinded, long-term follow-up of the phase 2b HVTN 503/Phambili study. Lancet Infectious diseases 2014;14(5):388-96
3. Qureshi H, Ma ZM, Huang Y, et al. Low-dose penile SIVmac251 exposure of rhesus macaques infected with adenovirus type 5 (Ad5) and then immunized with a replication-defective Ad5-based SIV gag/pol/nef vaccine recapitulates the results of the phase IIb step trial of a similar HIV-1 vaccine. J Virol 2012;86(4):2239-50
Competing interests: No competing interests
Dear Editor,
We congratulate the BMJ for their broad and open-access coverage of the Ebola outbreak, and Beeching et al for this excellent review.
We are members of the second cohort of NHS volunteers that helped to set up an Ebola Treatment Centre (ETC), run by International Medical Corps in Bombali district, Sierra Leone. Here we present an overview of the outcomes of a new centre for the duration of our deployment (Dec 19th – Jan 17th).
We assessed seventy-five patients in total. Seventy (93%) were admitted – this included a mix of patients who met the case definition for Ebola or already had a positive test in the community. In total, thirty-four patients were confirmed positive.
Twenty-four (70%) of our Ebola patients were female. The most common symptoms were malaise, fever, myalgia and diarrhoea. We recorded 18 deaths (62% case fatality rate) and 11 survivors. The remaining four patients continued to convalesce as our deployment ended. Average length of stay for survivors was 10.6 days and 3 days for those who died.
Seventeen patients developed haemorrhagic symptoms – all but three of these died.
There were no instances of staff infection.
Treatment consisted of empirical antibiotics (oral cefixime or intravenous ceftriaxone) and anti-malarials (artemether/lumefantrine). We also routinely prescribed omeprazole, multivitamins, vitamin C and vitamin A. Paracetamol, ondansetron, loperamide, morphine sulphate, and diazepam were used as required. Oral rehydration solution was provided liberally.
We found that intravenous rehydration could be facilitated safely, resuscitating the sickest patients with 2-4 litres of IV fluid per day, and this appeared to result in clinical improvement. Most patients were cannulated at the time of their admission blood test and the cannula left in situ in case of deterioration.
Our case fatality rate (CFR) of 62% falls between the two, much larger, case series published, which showed CFRs of 74% (Shieffelin et al, NEJM ) and 31% (Ansumana et al, NEJM ), and similar to the CFR of 50-61% seen among all hospitalised patients in this outbreak.
We felt privileged to participate in this phase of the Ebola response as volunteers from the United Kingdom, and are re-assured to see case numbers starting to decrease, with only 128 new cases across all countries reported in the week to February 15th.
Disclaimer: the views in this letter are those of NHS volunteers, not International Medical Corps. The data has been independently verified by the International Medical Corps.
Acknowledgements: We would like to acknowledge the other NHS volunteers on our deployment. David Anderson; Dr Michael James Barstow; Dr Emily Bayne; Dr Daniel Cooper; Duncan Cushnie; Rachel Duncombe-Anderson; Caroline Gore; Professor Bill Irish; Dr Anna Martin; Hannah McReynolds; Dr Matthew Dominic Newport; Sarah Rippon; Stephen Saslav; and Christopher Wilson
Competing interests: No competing interests
Devnani and Guo bemoan the compulsory isolation of a gentleman who has Ebola virus in his semen. They claim it is unscientific and question the ethics of this practice.
Of course randomised controlled trials could help in establishing the scientific foundations or lack of foundations.
I doubt if such trials would be possible to mount.
As for telling the patient not to "mount" without a condom, excellent idea. But
Will the patient listen?
Will the condom stay in situ?
Will the condom remain intact?
Do Devnani and Guo believe that it is ethical to just advise the Seminal Carrier and hope for the best?
Have they not read or heard the reports of HIV infected persons who knowingly engaged in sex with previously uninfected persons, thereby infecting them?
Competing interests: No competing interests
Ebola disease is so virulent because the virus as a rule entered via a deep puncture wound: unsterile and contaminated non-disposable injections.
When one contracts natural infectious disease, the causative organism enters via normal portals of entry, nose and mouth. The natural and beneficial immunising process starts on that level.
When one injects bacteria and viruses and other foreign and toxic substances, one bypasses the normal portals of entry and enables the microorganisms and other substances entry into the blood stream with a direct access to vital organs. Proponents of vaccination argue that microorganisms in vaccines are not live. They are inactivated or attenuated, however they revert back to the original or even more virulent forms when injected (Fenner 1962. The reactivation of animal viruses. BMJ; July 21: 135-142).
The best illustration of this phenomenon is the classic tetanus disease.
It is a very serious condition because the causative organism, Clostridium tetani, is introduced into the body via a deep puncture wound, bypassing nose and mouth.
What is injection? A deep puncture wound.
When Clostridium tetani is breathed in or swallowed, it triggers natural immune response and results in minimal non-specific symptoms, such as a runny nose, cough, fever and mild diarrhoea. The final result is acquiring natural immunity to Clostridium tetani toxin and to tetanus disease.
Natural immunity to tetanus has been studied and demonstrated in such countries as India and Galapagos Islands by Veronesi et al. (1983. Naturally acquired antibodies to tetanus toxin in humans and animals from the Galapagos Island. J Infect Dis; 147(2): 308-311). They wrote, “Reports from India based in serologic surveys indicate that 40%-80% of the unvaccinated population have antibodies to tetanus toxin in their blood [7, 10, 14].” And, “All nine animals studied showed antibody to tetanus toxin.”
They also wrote, ”Before the discovery of tetanus toxoid, Tenbroeck and Bauer [1] reported that they were able to detect antibody to tetanus toxin in the blood of one third of a group of inhabitants of Peking (Beijing), China. Since then, there have been many similar reports concerning animals, mainly herbivores [2], and humans living under poor hygienic conditions [3-5]. Recently, similar reports have been reviewed by authors in many different countries [3, 5-14].”
Ehrengut et al (1983) found “naturally acquired tetanus antitoxin in the serum of children and adults in Mali” (Immun Infekt; 11(6): 229-232). They wrote, “Among 48 adults without a history of tetanus immunization, we found with the aid of indirect hemagglutination test 20 individuals with protective tetanus antibody titters, 23 with low levels of antitoxin (under 0,1 I.U./ml) and five devoid of tetanus antitoxin…The data suggest a silent oral immunization by tetanus bacilli thus boosting under unhygienic conditions the [natural] tetanus immunity with advancing age.”
On the other hand, De Moraes Pinto et al. (1995) reported on “Neonatal tetanus despite immunization and protective antitoxin antibody (J Infect Dis; 171: 1076-1077). They wrote, “neonatal tetanus (NNT) accounting for up to 50% of all neonatal deaths [1]. The World Health Organization, in an effort to eradicate NNT, has recommended the immunization of pregnant women against tetanus with two injections of tetanus toxoid vaccine together with sterile cord care...However, some reports of NNT occurring in babies of immunized women have demonstrated the necessity of more extensive studies on the subject.”
Many researchers defined immune response to tetanus vaccines as anaphylaxis (Jacobs et al. 1982. Adverse reactions to tetanus toxoid. JAMA; 247(1): 40-42).
The same applies to the introduction of other toxic and infectious substances together with Ebola virus into the blood stream via unsteriloe and contaminated injections and is quite obviously relevant to Ebola disease and Ebola vaccine. This is documented in a number of publications of WHO such as Anonymous (Report of an International Commission. (Bull WHO; 56(2): 271-293).
Indeed the effect of all injectable vaccines can best be described as anaphylaxis, i.e. sensitisation resulting in increased susceptibility to the targeted diseases and also to related and unrelated bacterial and viral infections. Product inserts for all vaccines recommend to keep appropriate resuscitation equipment and epinephrine ready for possible anaphylactic reaction.
It’s not just my opinion, that the best way to stop the Ebola virus outbreak is to administer adequate doses of sodium ascorbate, a non-acidic form of vitamin C, amply shown efficient in many infectious diseases and conditions (which are generally aggravated by the underlying scurvy, often subclinical), as demonstrated by Dr Thomas Levy in his book ”Vitamin C. Infectious diseases and toxins: curing the incurable”.
In summary, vitamin C is needed to stop the ongoing Ebola outbreak, rather than Ebola vaccine. Moreover, developing countries should stop playing the Russian roulette with re-used non-sterile, highly contaminated non-disposable syringes and needles.
Competing interests: No competing interests
Clinical judgement should trump protocols
That Dr Welsby is " talking sense" ought to be obvious to any one with clinical experience of infectious disease (including those public health doctors who practised communicable disease epidemiology).
Perhaps the passion for protocols produced by experts, followed slavishly by doctors, nurses and other "health care professionals" needs to cool down.
Could the doctors start using their clinical judgement and consign protocols to the bin? Could nurses use their professional judgement to refer to an experienced doctor, a patient who feels unwell? Clearly a history of recent exposure to an infectious disease ought to prompt referral to a proper doctor.
This will be important even when a vaccine becomes available.
Merely because somebody has been vaccinated does not mean that immunity is complete.
Competing interests: No competing interests
Dear BMJ Editor,
A nurse who had nursed Ebola patients arrived at Heathrow where she was screened, process described as “shambolic” by a doctor (1) and told officials she believed a fever might be developing. Her temperature was taken seven times and was normal each time, so, apparently consistent with guidelines, she was allowed to fly home to Scotland, potentially exposing others to Ebola infection.
I quote opinion that remains unchallenged since 1978. “Unfortunately there are no distinctive features in the early stages of viral haemorrhagic fevers to enable a firm diagnosis to be made on clinical grounds, so judgement rests mainly on epidemiological evidence… patients judged as high risk were those living or working in rural areas, medical and nursing staff from country hospitals; contacts of known cases; and laboratory workers handling dangerous material.”(2). We made no mention of fever because if a patient feels unwell “needs to have their temperature taken” and was in a high risk group they should be managed as high risk.”
What happened at Heathrow defied common sense and should cause all to recognise that guidelines are advice, not commands. All sensible clinicians will occasionally decide to ignore guidelines. I once ignored Guidelines on meningitis that I had organised and written. Historically obeying commands has not absolved individuals from personal responsibility.
The Heathrow enquiry will no doubt report that lessons have been learned. But is a there is a much wider message that should be stated now. Guidelines should always provide a preface “When your common sense contradicts these guidelines, pick up the phone and pass the buck to someone more knowledgable.”
Philip D Welsby
Consultant in Infectious Diseases,
Currently Teaching Fellow in General Medicine, Edinburgh University.
Edinburgh EH12 8UB
Philipwelsby@aol.com
1. SundayTimes 4th January 2015 p.19)
2. Emond RTD, Smith H, Welsby PD. Assessment of patients with viral haemorrhagic fever. BMJ 1978;1:966-967.
Competing interests: No competing interests
The case of the British nurse, Pauline Cafferkey who was diagnosed with Ebola hours after being given the “all clear” at Heathrow airport raises concerns about the criteria used to assess risk of Ebola infection used by Public Health England. 87% Ebola patients have a raised temperature (1). Although this is the most common symptom and the one that can be objectively assessed it should not be taken as the only criteria for suspecting Ebola in people returning from working with Ebola patients in West Africa.
Pauline Cafferkey felt unwell and told health staff at the airport but it took a call to 111 from her home to get the diagnostic test for Ebola. She could have had diarrhoea and vomiting on the way home and thereby put other passengers on the flight at risk.
In another scenario care staff who have early symptoms of Ebola may be in denial or choose to hide them until they have reached home territory where they are likely to receive better treatment than that available in West Africa.
Preferable to the reliance on temperature checks would be a confidential medical consultation with a doctor with specific questions about any symptoms and the use of antipyretics such as Paracetamol. Follow up travel by ambulance to the Royal Free Hospital, the test for Ebola and swift diagnosis would enable passengers to return home or receive treatment as needed.
Frances Taggart PhD
Warwick Medical School
Competing interests: No competing interests
As a 'matter of abundant caution' India recently isolated an asymptomatic male returning from Liberia after being treated for Ebola Virus Disease (EVD) because his semen was found positive for Ebola(1). Despite his blood, saliva and urine samples are negative for Ebola virus he is currently in isolation until his semen is tested negative which could take as long as three months(2). Till date there is no conclusive scientific evidence of sexual transmission of Ebola(3) and WHO does not recommend isolation of patients whose blood has been tested negative for Ebola. The current evidence-based practice is to trust and advise these individuals either to abstain from sex for three months or use condoms(4).
One might argue that although remote, hypothetical risk of sexual transmission exists and one person’s mistake could result in a catastrophic epidemic especially in a densely populated country like India where EVD has never been reported before. But on other hand, isolating a person in absence of scientific evidence is not only unscientific over-precaution but raises serious ethical and legal issues related to potential violation of individual rights. Further Indian health authorities have not taken enough efforts to communicate the decision making process to the public. The decision making process is obscure and there is no discourse about the alternative measures considered and found insufficient or ineffective (if any) before restrictive measures being imposed upon the individual.
During the times of public health emergencies, Governments have the right to take appropriate measures in transparent and ethical manner to protect its citizens. These measures should be guided by science and taken transparently after consultations among various stakeholders across culture, community, provider, and recipient groups so as to balance the interests of the community and the rights of the individual. The decisions should be adequately communicated to the public.
References
1 Press Information Bureau, Government of India, Ministry of Health and Family Welfare. Ebola Treated and Cured Person from Liberia Quarantined at Airport Health Organisation Quarantine Centre, Delhi. 18 November 2014. http://pib.nic.in/newsite/PrintRelease.aspx?relid=111541. Accessed on 22 December 2014.
2 Press Information Bureau, Government of India, Ministry of Health and Family Welfare. Press note on Ebola. 22 November 2014. http://pib.nic.in/newsite/PrintRelease.aspx?relid=111685. Accessed on 22 December 2014.
3 Mackay IM, Arden KE. Ebola virus in the semen of convalescent men. Lancet Infect Dis 2014; 19 November 2014(Article in Press DOI: 10.1016/S1473-3099(14)71033-3).
4 WHO. Ebola virus in semen of men who have recovered from Ebola virus disease. www.who.int/reproductivehealth/topics/rtis/ebola-virus-semen/en/. Accessed on 22 December 2014.
Competing interests: No competing interests
It is recommended that aspirin be avoided in the symptomatic management of Ebola. (1) However, the upregulation of heme oxygenase by cobalt protoporphyrin has been shown to have an attenuating effect on the viral replication and transcription rates of the Ebola virus. Aspirin also induces heme oxygenase. Therefore it may also slow Ebola replication.
Although there are a number of therapeutic agents under development, none have yet been approved for Ebola (EBOV), and at present treatment consists of IV fluids, maintenance of oxygen status and blood pressure and management of secondary infections. Once the disease is advanced prognosis is poor. If the progress of the disease could be slowed during early infection while arrangements to travel to hospital were being made, outcomes may be improved.
EBOV infection of macrophages and monocytes leads to hypercytokinaemia, which causes superoxide-mediated endothelial damage and the characteristic haemorrhaging, and activation of the coagulation cascade, which causes thrombosis.
Thus treatment of patients with EBOV depends not only on the inhibition of the virus but management of hypercytokinaemia. Heme oxygenase has been shown to have a mitigating effect in both these areas.
Heme oxygenase (HO-1) catalyses the degradation of heme to carbon monoxide, free iron and biliverdin. It can protect from septic shock and the oxidative injury experienced in hypercytokinaemia. (2). Upregulation of HO-1 with cobalt protoporphyrin has been shown to inhibit EBOV replication. This was shown to be an HO-1 dependent effect. Entry and budding were not affected, but viral replication and transcription were attenuated. (3) This may be due to the up-regulation of IFN-stimulated genes and the anti-oxidant effect of HO-1.
Other inducers of HO-1 include statins, rapamycin, paclitaxel, nitric oxide, probucol and aspirin.
Aspirin has been shown to produce significant dose-related increases in HO-1 in vivo (4), and in cultured human endothelial cells aspirin increased (HO-1) protein levels in a concentration-dependent fashion up to fivefold over basal levels. (5). Therefore viral replication and transcription of EBOV should be attenuated by aspirin.
Aspirin induces HO-1 by enhancing the production of 15-epi-lipoxin A4, (6), which stimulates NO production. This leads to an increase in HO-1 concentration. Other cyclooxygenase inhibitors such as indomethacin do not induce HO-1. (5). In vitro models show that aspirin is associated with an increase in O2 -scavenging, protecting endothelial cells from free radical-mediated toxicity. (5). Thus aspirin could mitigate the effects of hypercytokinaemia.
Conclusion
Although aspirin will not stop entry and budding of EBOV, it is likely to slow replication by the induction of HO-1, and could lessen cytokine-mediated endothelial damage by the scavenging of superoxide radicals. Therefore aspirin at the first onset of symptoms and in tandem with rehydration therapies may have a beneficial effect.
I declare no competing interests.
References
1. Beeching, N.J., Fenech, M, Houlihan, C.F., (2014) BMJ 2014;349:g7348. “Ebola virus disease.”
2. Pae HO ,Chung HT, (2009) Immune Network 9:12–19. “Heme oxygenase-1: its therapeutic roles in inflammatory diseases.”
3. Hill-Batorski, L, Halfmann, P, Neuman, G, Kawaoka, Y. (2013) doi: q10.1128/JVI.02422-13 J. Virol. December 2013 vol. 87 no. 24 13795-13802 “The Cytoprotective Enzyme Heme Oxygenase-1 Suppresses Ebola Virus Replication.”
4. Hennekens, CH, Schneider, WR, Pokov, A, Hetzel, S, David DeMets, D, Schröder, H, Victor Serebruany, V. (2009) Circulation 2009;120:S405.) “Usual Doses of Aspirin Markedly Increase Nitric Oxide Formation in Humans.”
5. Grosser, N, Abate, A, Oberle, S, Vreman, HJ, Dennery, PA, Becker, JC, Pohle, T, Seidman, DS, Schroeder, H. (2003) Biochemical and Biophysical Research Communications, Vol 308, 956-960. “Heme oxygenase-1 induction may explain the antioxidant profile of aspirin.”
6. Nascimento-Silva V, Arruda MA, Barja-Fidalgo C, Villela CG, Fierro IM. (2005) Am J Physiol Cell Physiol, 289(3):C557-63. “Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells.”
Competing interests: No competing interests
Ebola virus, HIV and vaccines
We thank Kremer and Van der Perre for their letter, which highlights important concerns. HIV incidence was increased predominantly in men in the long term follow-up (3.5 years post vaccination) of the Phambili HIV vaccine trial, which used adenovirus type 5 (Ad5)-vectored DNA vaccine encoding HIV-1 subtype B gag, pol, and nef proteins.1 The current candidate Ebola vaccine, Chimpanzee adenovirus 3 (ChAd3)–vectored vaccine is of a different adenovirus subtype.2,3 However, the postulated mechanism of increased HIV risk, ie an increase in adenovirus type-specific T cells, targets for HIV that could migrate to the gut and genitalia, may still apply.
The prevalence of HIV-1 in young adults in the three West African countries worst affected by Ebola is estimated at 1.1% in Liberia, 1.6% in Sierra Leone and 1.7% in Guinea (http://www.unaids.org/en/dataanalysis/datatools/aidsinfo), much lower than 19.1% in adults in South Africa, where the Phambili trial was conducted (http://www.unaids.org/en/dataanalysis/datatools/aidsinfo). Ebola vaccine trials, including those using adenovirus vectors, should not be delayed. However, long term follow-up of study participants should be planned, and should include voluntary HIV counselling and testing. Study participants should be made aware of the potential risk.1
Concern has been expressed about the effect the current Ebola outbreak will have on delivery of routine healthcare to people living with HIV in the affected countries.4 Parallels have been drawn between the stigma experienced by people living with HIV, survivors of Ebola virus disease and health care workers looking after people with either infection.4 Yet there are no current data on the clinical presentation or prognosis of Ebola in HIV-infected individuals, including in those taking antiretrovirals. A possible protective effect from protease inhibitors and less convincingly, lamivudine, has been highlighted.5,6 Of additional concern is the possibility that HIV-infected survivors might maintain Ebola virus in sanctuary sites, such as semen, for longer than currently described.7 Information is needed on dual infection with HIV and Ebola, and consideration should be given to this potential confounder in interventional studies and reports on outcomes from Ebola treatment centres in West Africa.
Catherine F Houlihan
Research Fellow, London School of Hygiene and Tropical Medicine, London
Manuel Fenech
Specialist Trainee in Infectious Diseases, Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP
Nicholas J Beeching
Senior Lecturer in Infectious Diseases, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA
Competing interests: No competing interests.
References
1. Gray GE, Moodie Z, Metch B, et al. Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: unblinded, long-term follow-up of the phase 2b HVTN 503/Phambili study. Lancet Infectious Diseases 2014;14(5):388-96
2. Ledgerwood JE, DeZure AD, Stanley DA, et al. Chimpanzee Adenovirus vector Ebola vaccine - preliminary report. N Engl J Med. 2014 Nov 26. [Epub ahead of print]
3. Rampling T, Ewer K, Bowyer G, et al. A monovalent chimpanzee Adenovirus Ebola vaccine - preliminary report. N Engl J Med. 2015 Jan 28. [Epub ahead of print]
4. Wainberg MA, Lever AM. How will the ebola crisis impact the HIV epidemic? Retrovirology. 2014 Nov 30;11(1):110. [Epub ahead of print]
5. Zhou Y, Vedantham P, Lu K, et al. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. 2015 Feb 7;116C:76-84. doi: 10.1016/j.antiviral.2015.01.011. [Epub ahead of print]
6. Hensley LE, Dyall J, Olinger Jr GG, Jahrling PB. Lack of effect of lamivudine on Ebola virus replication. Emerg Infect Dis. 2015 Mar; 21(3): 550–552. doi: 10.3201/eid2103.141862
7. Rogstad KE, Tunbridge A. Ebola virus as a sexually transmitted infection. Curr Opin Infect Dis. 2015 Feb;28(1):83-5.
Competing interests: No competing interests