 Well, I'd just like to add to what Nick and Philip have already said about the late Malcolm Molyneux who sadly died on Tuesday night. He was a marvellous friend of 40 years, an incredible clinician and investigator and a really marvellous and outstanding person. We're so sorry to have lost him. So my title is from the words of the former Secretary General of the United Nations, Kofi Annan, and I'd certainly never heard of this particular crisis of public health before I began to work in West Africa. I went from Hammersmith Hospital to a new medical school at Amadou University in Zaria in Northern Nigeria in 1970 to study Epidemic Meningococcal meningitis. This was the dry Guinea savanna of Northern Nigeria. After being there for about 18 months, I had a really life-changing experience. I was on take midnight in December 1971 when a 50-year-old house of farmer was transferred from our country branch in Malanfashi about 55 miles away. The story was that three days earlier he'd been bitten by a snake which he called gajira while farming. He noticed a medium pain in the bitten part with some swelling. He'd treated himself at home using a tried and trusted herbal remedy, but after two hours the swelling had spread up his leg and after 12 hours he had pain in the lower back and abdomen and he was passing blood per urethra. He spent a miserable next two to three days at home feeling increasingly awful. He was faint and sweaty when he tried to sit up and he finally decided to seek medical help. When I examined him on admission, he appeared virtually moribund. He had a swollen tender ankle, he was very pale, he was globin only 2.5 grams per litre, low blood pressure with a rapid pulse and he fainted on sitting up. He had a distended and tender abdomen and sure enough there was a drop of blood at his urethral meatus. Well I resuscitated him by putting him head down feet up and starting intravenous fluid and as one would with an unfamiliar medical problem I tried to get help from my medical colleagues but was most surprised that none of them seemed to know anything about snakebite which raised the question was snakebite really so rare in this area? I made then a rather naive observation. I'd taken blood for cross-matching into a glass vessel and after 30 minutes I thought funny it hasn't plotted yet so how am I going to get some serum? I knew that there was an antidote to envenoming called anti-venom but our pharmacy only had one vial from the pasta anti-venom I think from their museum it was desiccated and long expired. Well tragically this poor man died seven hours after admission before blood was available for transfusion it's an awful experience to sit with a patient and preside over a death from hemorrhagic shock and the autopsy revealed really extensive bleeding in every part of the body so this tragic case raised a whole lot of questions first of all what on earth was gajira the snake how important was snakebite in Nigeria was this just a rare one off and what could be the pathophysiology the mechanism of such disastrous envenoming which venom toxins might be involved and were there specific antidotes or anti-venoms available in Nigeria if so how effective and safe were they? Well I quickly found out which snake this was this gajira was the one of the West African carpet vipers now called ecus romani it's not a particularly impressive looking snake it's really more than about 30 or 40 centimeters in total length and it's sort of earth colored it's certainly not dramatic I then did a sort of anecdotal epidemiology survey I asked absolutely everyone I met about snakes and snakebites you can imagine what a bore I became and I discovered that in many rural areas of the north of Nigeria people had lost close relatives to snakebite in recent years it was clear that snakebite victims didn't bother to go to hospitals or dispensaries unless they could expect to get some effective treatment there such as anti-venom and this probably explains why there no one in our hospital seemed to know anything about snakebite the patients just didn't come because they quite sensibly realized that there was nothing there for them I did discover from my sort of anecdotal survey that there was a hospital a former Sudan interior mission hospital up in the northeast in Kaltungo where it was reported that half a dozen or so snakebite patients turned up most evenings very appetizing for someone looking for a suitable site to do clinical studies of snakebite this was this very attractive area of Kaltungo the village is seen by Tangali Peak there and this is the hospital a fairly simple African district hospital well on the clinical side over the next few years working for periods in Kaltungo hospital I saw a lot of patients and I learned a lot about the effects of invenoming in patients most of the victims seem to be have been bitten by carpet vipers and certainly most of the deaths reported from the area were attributable to carpet vipers so you here see here some of the clinical effects of invenoming from the local swelling and blistering to bleeding spontaneous bleeding from the gums the local effects which can end up with necrosis requiring surgical intervention debridement this boy has got a subarachnoid hemorrhage and you'll see what a predominance of children a preponderance of children there are among among these patients well with the help of laboratory colleagues in in Liverpool school of tropical medicine and elsewhere we were able to develop some idea about how the venom of the carpet viper could cause such an appalling hemorrhagic diathesis as in the fatal case that introduced me to this topic first of all the venom contains some procoagulant serine proteases which stimulate the clotting cascade eventually leading to production of fibring which is instantly broken down by the body's fibrolytic system a second antihemostatic effect are these hemorrhagin or zinc metalloprotonases which damage the endothelial lining of blood vessels so this electron microscope microscope picture this is the lumen of a small blood vessel and here is an erythrocyte spurting through the junction of two adjacent endothelial cells opened up under the effect of a snake venom hemorrhagin and this shows the composition of these metalloprotonases which I'll come back to later and the third very important antihemostatic effect of carpet viper venom is on platelets the c-type lectins activate and inhibit blood platelets so all these three mechanisms acting in concert could produce fatal hemorrhage well more recent techniques such as the application of proteomics to toxinology has revealed a much more complex structure of well all snake venoms including carpet viper venom see that on reverse phase HPLC separation there are at least 43 identifiable peaks and in this schema of the proteome or venome of carpet viper venom you see that the bulk of the venom toxins are zinc and zinc metalloprotonases of four different classes and the known effects of these metalloprotonases include damage to capillary basement membranes causing local and systemic bleeding they also damage muscle locally and systemically and they cause blistering and edema they inhibit platelet aggregation and they also have a pro-coagulant activation of factor 10 contributing to the coagulopathy well it was quite clear from our studies in kaltunga that there was something of an anti-venom crisis certainly in Nigeria and through correspondence through the west of Africa our small observational studies showed that at least one anti-venom that could be obtained on the market this one was made in South Africa the South African Institute of Medical Research was highly effective in neutralizing and reversing effects of carpet viper venom but unfortunately it was too expensive and not widely available in those days in the 70s the import of South African products was complicated by the apartheid business a new anti-venom was needed but how did one go about this well a colleague of mine at the Liverpool School of Tropical Medicine David Thiekson and I decided that we would go public on this so we wrote a letter to the Lancet entitled a crisis in snake anti-venom supply for Africa and I'm glad to say that this was seemed to be widely read and we also approached many international anti-venom manufacturers different countries Europe and so on to consider developing a new carpet viper anti-venom so how do you go about producing an anti-venom well first of all you need to catch some snakes of the right sort so this was our team of snake catchers in northern Nigeria looking for carpet vipers then you need to milk venom from the snakes and then you hyper immunize some cooperative horses with increasing doses and from their plasma you refine immunoglobulin and then it's ready for intravenous preparing the drug which is given by intravenous injection to the snake bite victim we were extremely lucky to fight to get support in Nigeria from a very sympathetic um minister of health professor Oleg Koyuransakuti who was a former professor of pediatrics extremely helpful and a senior member of the federal ministry of health Dr. Absolami Nasidi and crucially we attracted the support of two very good anti-venom producers one in the United Kingdom Microfarm who raised their anti-venoms in Welsh sheep and another in Costa Rica and with their help we designed a new anti-venom we tested it pre-clinically in the laboratory and we carried out a large non-inferiority comparative trial phase one and two to three and we then encouraged the manufacturer and distribution of two new carpet viper anti-venoms west Africa and this shows the sort of team very important to get local support this is the chief of Tangali the traditional chief Islamic chief of this area with Tangali peak in the background and colleagues from from Liverpool David Theekston and from from Nigeria and professor now professor Abdul Razak Habib who helped coordinate the trial in Nigeria well after Nigeria I went back to Oxford for a while and was then given the opportunity to start a new unit in Thailand as you've heard from Nick Day this was the Welcome Mahidong University Oxford Tropical Medicine Research Unit so I moved from snowy Oxford one winter to to Bangkok and became very interested in the occupational problems of snake bite amongst particularly rice workers in the central rice growing area of Thailand I was working in eastern Thailand actually it was the site we'd discovered to work on cerebral malaria that was the main subject of my research in in Thailand at that stage in Jantaburi when I admitted a 13 year old boy who'd been bitten while he was asleep on the floor of his house in a rural area near Jantaburi and the snake was killed and I could identify it it was a Malayan crate quite a large snake over a meter long here are the marks made by the upper and lower jaw teeth on his thigh these are the marks made by the venom fangs within three hours he was showing early signs of neurotoxicity of interruption of neuromuscular transmission caused by pre and postsynaptic neurotoxins in the venom see he's been in to go a bit dusky and cyanosed as his respiratory muscles are involved after a further hour these symptoms are worse he's clearly got facial paralysis now there's descending paralysis of muscles innervated by the cranial nerves and at this stage he's unable to open his mouth and protrude his tongue and we've intubated him when he was unable to breathe and this is at nine hours and here he is being manually ventilated he was manually ventilated for 49 hours before he could be weaned off this assisted ventilation I'm glad to say the outcome was very good here he is leaving hospital after six days but this was a tremendous surprise because no one seemed to know about this snake we decided to undertake a national survey of this to find out what sorts of snakes were biting people in different parts of Thailand and we were just using the dead snakes brought in by patients that had been bitten by these snakes at these 80 different district and provincial hospitals we collected the dead snakes over a period of about two or three years to our surprise we found that 13 out of 46 fatal cases where we had the dead snake as evidence of causation were caused by this pretty well unknown snake the Malayan crepe the same one who'd been who'd bitten that 13 year old boy the snake seemed to be virtually unknown possibly because it's an exclusively nocturnal snake and there was no antivenom available because as I said it hadn't been recognised as the important cause of snake bite the survey brought to light another problem in the central rice growing part of Thailand shown here dashed in red there were three different snakes green pit vipers rustles viper and Malayan pit viper that all caused the same clinical syndrome of combination of local swelling with bleeding and carigulopathy third and if the patient as in the majority of cases the patient wasn't able to identify the snake that had bitten them it was very difficult for the clinician to know what to do because the antivenoms available at that stage back in the 1980s were only mono specific mono specific for each of these species these antivenoms did not have cross neutralization of other viper venoms so you can see the difficulties a matter of guesswork based on inadequate evidence fortunately the results of our research became known to the excellent national manufacturer of antivenom the Tyre cross society based in the beautiful Queen Sarah Palmer Memorial Institute in Bangkok and they were encouraged to produce a polyvalent to cover the three different viper venom so rustles green pit viper and Malayan pit viper the clinician no longer had to guess he or she could use this polyvalent to cover all three and in the case of the Malayan crate they not only produced a mono specific antivenom to cover this newly recognized major cause of snake bite death in Thailand but they also combined its venom in production of a neuro polyvalent antivenom that covered other neurotoxic species such as the common cobra and the king cobra well I was very keen to go to Burma because I knew that from pre-independence days from the 1930s Burma was notorious for its very high rates of snake bite mortality do you see here in these black areas at 16 or more deaths per 100 000 inhabitants per year caused by snake bite and I got the opportunity in the early 1980s to collaborate with the Department of Medical Research in Yangon which was a short flight from Bangkok and to start a research unit combining work on snake bite and malaria in this township medical hospital Thayawadi north of Yangon so here's a fairly simple colonial hospital serving a paddy growing area see the the rice farmers highly exposed to snake bite as they particularly when they gather the crop the paddy crop bare footed and bare handed and I was supported by a very strong team from the Department of Medical Research led by its brilliant director Dr Antan Bhattu the main problem here was Russell's Viper which was believed to be responsible for almost all the bites and deaths in the central area of Burma and this is a typical patient of ours during the work we did in Thayawadi this rice farmer bitten while he bitten on the foot while he was working in the rice fields and he collapses he's brought in unconscious hypotensive and the research team here gathered around giving him anti-venom and taking baseline blood samples and here is the the worried neighbour of his giving helping us with the clinical history well some of the effects the devastating effects of Russell's Viper in venoming are illustrated now fatal cerebral hemorrhage disseminate intravascular coagulation involving deposition of fibrin in the lungs also in the anterior pituitary this is the a section of the adenobituatory causing acute and chronic panhyper pituitaryism most important development of acute kidney injury by various mechanisms including ischemia by the deposition of fibrin stayed red here in the peritubular vessels and finally a late development of the syndrome of generalized increase in capillary permeability revealed clinically by this sign of chemosis or conjunctival edema followed by hemorrhage in subsequent years I was able to pursue my interest in snake bite by working in Sri Lanka in Papua New Guinea Bangladesh and in various countries in in Latin America and I certainly confirmed the idea that snake bite is an utterly fascinating and clinically challenging problem but how important was it was it really as Kofi Annan had suggested the biggest public health crisis you've never heard heard of the problem is that estimates of snake bite morbidity and mortality tended to be based largely on hospital records and as we know in rural areas of low middle income countries snake bite deaths often occur at home and uncertified undocumented so what was urgently needed was a community based survey to try and make a stronger case that snake bite was worth taking notice of and worth considering as a disease of public health importance I was very fortunate in Oxford I've been talking to Richard Pito about my interest in in snake bite and he introduced me to Dr Prabhak Jha of the University of Toronto who had helped to develop the registrar general of India's million death study which ran from 1998 to 2014 this was this was reckoned to be the largest epidemiological survey based on community studies ever attempted and it wasn't designed for snake bite of course it was designed to look at the health burden of tobacco related diseases and malaria and various other diseases but I managed to persuade Prabhak Jha to include some questions in his in his analysis dealing with snake bite and the cause of death in this study was based on verbal autopsy which is a potentially a controversial technique this involves questioning relatives and neighbours of the deceased to identify the cause of death and it involved nearly seven thousand randomly chosen sample areas throughout the whole of India each one about a thousand people each and this covered the whole country it was independent of hospital under reporting here are the people questioning relatives and the results were really quite extraordinary deaths attributable to snake bite in India and by the way I think this attribution is likely to be reliable in the case of snake bite because snake bite is such a dramatic and memorable for mode of death that it's highly likely that relatives and neighbours will remember anyway the estimate was of 46 000 snake bite deaths in India in the year 2005 these are the 99 percent confidence intervals so snake bite caused one death for every maternal death in India and for every two HIV AIDS deaths a lot were in children and the this estimate was more than 20 times the official government of India's figure based on unrepresentative hospital data and because it was a nationwide study it was possible to see the relative burden of snake bite in different states of India and therefore deploy scarce research resources more appropriately these data helped to persuade WHO to recognise snake bite as a priority neglected tropical disease and subsequently to persuade the welcome trust and other international funding agencies to make generous provision for snake bite research the update of the million death study which was published last year suggests that the number of snake bite deaths in India is has been as high as 58 000 a year during this period amounting to 1.2 million snake bite deaths and was increasing so I believe that these data have vindicated Kofi Annan's suggestion that snake bite was the biggest public health crisis you've never heard of thank you for your attention