SUPPLEMENT ARTICLE

doi:10.1111/add.12904

Death matters: understanding heroin/opiate overdose risk and testing potential to prevent deaths John Strang National Addiction Centre (Institute of Psychiatry/The Maudsley), London, UK

ABSTRACT

Aims To describe work undertaken over a 20-year period, investigating overdose characteristics among survivors, effects of acute heroin administration, clustering of risk of overdose fatality and potential interventions to reduce this fatal outcome. Methods Privileged-access interviewers obtained data from non-treatment as well as treatment samples; experimental study of drop in oxygen saturation following heroin/opiate injection; investigation of clusterings of death following prison release and treatment termination; and study of target populations as intervention work-force, including family as well as peers, and action research built into pilot implementation. Results Overdose has been experienced by about half of heroin/opiate misusers, with even higher proportions having witnessed an overdose, and with high levels of willingness to intervene. Heroin/opiates are associated with the majority of drug-related deaths, despite relative scarcity of use. Heroin injection causes a rapid drop in oxygen saturation, recovering only slowly over the next half hour. Deaths from drug overdose are greatly more likely on prison release and post-discharge from detoxification and other in-patient or residential settings. High levels of declared willingness to intervene are matched by active interventions. Both drug-using peers and family members show ability to improve knowledge and gain confidence from training. Audit study of take-home schemes finds approximately 10% of dispensed naloxone is used in real-life emergency situations. Conclusions Overdose is experienced by most users, with heroin/opiates contributing disproportionately to drug overdose deaths. High-risk times (e.g. after prison release) are now clearly identified. Peers and family are a willing potential intervention work-force, but are rarely trained or given pre-supply of naloxone. Large-scale naloxone provision (e.g. national across Scotland and Wales) is now being delivered, while large-scale randomized trials (e.g. N-ALIVE prison-release trial) are finally under way. Better naloxone products and better-organized provision are needed. The area does not need more debate; it now needs proper implementation alongside good scientific study. Keywords

Death, emergency, heroin, naloxone, opiate, policy, prevention, take-home.

Correspondence to: John Strang, National Addiction Centre (Institute of Psychiatry/The Maudsley), Denmark Hill, London SE5 8BB, UK. E-mail: john.strang@ kcl.ac.uk

WORKING WITH GRIFFITH EDWARDS I did not work with Griffith until my mid-career. I had trained in addictions at the Maudsley from the late 1970s, but on the drug unit with Philip Connell, and hence did not work with Griffith at this stage. I moved to Manchester for my first National Health Service (NHS) consultant post, and then back to the Maudsley in the mid1980s. It was from this point onwards that my increasingly close association with Griffith and the Addiction Research Unit (ARU) began. During the following years I worked closely with Griffith, who was extraordinarily generous, supportive and challenging in equal parts, and Griffith supported my move across to a full academic position in the early 1990s as Senior Lecturer and then Deputy Director © 2015 Society for the Study of Addiction

of the new National Addiction Centre (NAC). In 1994, I was appointed as Director of the NAC, and Griffith continued to give wise counsel from his (very active) retirement. DEATH MATTERS: IN SEARCH OF BETTER UNDERSTANDING Death matters. Alongside addiction, drug-related deaths are a source of loss and suffering—not only for the individual, of course, but also for family and community. During the course of the last 20 years, we have studied patterns of drug overdose deaths and have sought points of potential influence—interventions that may stem this waste of life and opportunity. In this work we were following a strong ARU tradition, with earlier work having been Addiction, 110, 27–35

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Table 1 Drug use prevalence (British Crime Survey) and drugrelated deaths (Office of National Statistics): England and Wales 2011/12.

Drug Cannabis Cocaine Amphetamine Ecstasy Opiates (inc heroin and methadone)

Prevalence in general population (use in last year, age 16–59 years)

No. of deaths in 2011

6.9% 2.2% 0.8% 1.4% 0.3%

7 112 62 13 1,082

© 2015 Society for the Study of Addiction

IM IV

96

94

SpO2 (%)

conducted by Hamid Ghodse, an active member of the ARU in the 1970s, who sadly also died in 2012. Much of this thinking is captured in the major report into ’Drug-Related Deaths’ [1] which Griffith Edwards chaired, which gave improved understanding, but always with an eye to how this might identify opportunity to intervene more effectively. Supported by a grant from the Department of Health in the early 1990s, and working closely with colleagues Mike Gossop and Paul Griffiths, we began a body of work looking specifically at overdose deaths from heroin and other opiates. The focus on opiates was because opiates loom large in the picture of drug overdose deaths, to a far greater extent than the prevalence of their abuse. For example, Table 1 shows (left-hand column) prevalence data from the Home Office British Crime Survey on the use of different illicit drugs in England, where heroin and the opiates are relatively rarely used: far less than the other illicit drugs. However, when the mortality data (Office of National Statistics: ONS) are examined (right-hand column), the prominence of heroin and the opiates in drug overdose deaths is striking. Despite their much lower prevalence of use, 85% of national drug overdose deaths report that opiates are one of the drugs reported, and 88% where opiates are the only drug reported. The particular contribution of deaths with opiates is perhaps not surprising. The opiates are respiratory depressants, and an intravenous bolus of a potent opiate (for example a shot of heroin) would be expected to stunt breathing. That is precisely what occurs, as shown with pulse oximetry monitoring of blood oxygen levels after intravenous injection of heroin (see Fig. 1). Captured in this figure is the sharp reduction in oxygen saturation following intravenous injection of heroin, severe within the first 10 minutes, in contrast to the slower and shallower reduction with intramuscular injection. However, what if the heroin was not given as a bolus? We had already been charting the diffusion of ’chasing the dragon’ (using heroin by heating it on tinfoil and inhaling the fumes) [2–5], and we were already using a

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Figure 1 Oxygen saturation after intravenous (IV) and intramuscular (IM) injection of heroin

’privileged access’ method of community penetration to study heroin chasers and injectors [6]. We initiated a new study of overdose events (both experienced and witnessed) among the community and treatment samples of heroin users: a sort of socio-psychological autopsy of the overdose situation. Did the slower onset of drug effect with ’chasing’ also have this fatal association? We found not [7]: of heroin ’chasers’ whom we interviewed, only 2% had ever suffered an overdose whereas, of those who had injected their heroin, 31% had already experienced an overdose. There was something else striking about the data: there was localization in time and context which had surprisingly been overlooked by the big data-capturing machines. In the transit zone between time in prison and post-release return to the community, there was a horrific concentration of deaths. Early work had been undertaken with Scottish data by Sheila Bird [8,9], and my colleagues Michael Farrell and John Marsden [10,11], working with Nicola Singleton and other colleagues at the Home Office and utilizing a larger data set from England and Wales, then confirmed the extraordinary concentration of excess mortality post-release as occurring particularly during the first fortnight post-release (Fig. 2).

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Figure 2 Excess mortality among former heroin users following release from prison (as reported in [10]) Addiction, 110, 27–35

Drug overdose deaths: understanding and prevention 10 Mortality rate ratio compared to not on treatment

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Figure 3 Risk of death during and after OST (opiate substitution treatment) (as reported in [16]). Linear-scale Y-axis on the left; log-scale Y-axis on the right.

DEATH MATTERS: INTERVENTION POSSIBILITIES It is important not simply to study the phenomenon, but also to look for possible means of intervening to prevent these deaths. With this improved understanding, we explored whether it might be possible to identify treatment or policy actions that might prevent these deaths. We have explored three areas which we continue to study. Medications Which Heal But Also Harm—A Complex Relationship The use of medications must be valued but must also be handled with respect and caution; as we observed, ’Methadone heals and methadone kills: the challenge is to achieve the former without incurring the latter’ [12]. We also identified other localizations of mortality in time and context. In addition to the clustering after prison release, we identified preliminary evidence of a similar clustering at the end of in-patient detoxification [13], an observation subsequently confirmed in larger studies [14,15]. With colleagues Matt Hickman and Rosie Cornish from Bristol, we also analysed data from the large General Practice Research Database (GPRD), looking over a 15-year period at the extent to which mortality data had a relationship to the initiation, continuation or termination of methadone or buprenorphine prescription. A clear increased mortality rate was evident during the first few weeks of maintenance treatment of individuals with heroin/opiate addiction problems, before patients reached the substantially reduced mortality rate during maintenance treatment [16] see Fig. 3. This confirmed the increased mortality during the first few weeks of maintenance treatment, as had been reported by colleagues in Australia [17,18]. Furthermore, just as there had been clustering in time of deaths after prison release, we observed a similar rebound increased mortality rate in the weeks following the conclusion of maintenance treatment, before © 2015 Society for the Study of Addiction

reaching the lower mortality rate beyond this transitional period. This confirmed the observation from the Italian VEdeTTE study [19]. However, note that both the observed post-maintenance spike and the subsequent lower mortality rate are both higher than during the maintenance treatment phase [16,19]. There is thus a complex picture with the prescribed treatment, methadone, itself contributing to overdose deaths. However, as Neeleman & Farrell observed [20], the reported increased deaths involving methadone appeared to be merely tracking the increased extent of the heroin problem in society as measured by increase in deaths from heroin itself [20]. Furthermore, evidence was emerging that many of these methadone deaths were as a result of diverted supplies of prescribed methadone, with the deaths being of individuals who were not the index patients to whom the drug had been prescribed. In the mid-1990s, we had the opportunity to contribute to a major government review of drug treatment [21,22]. The Task Force identified the markedly higher level (compared with other countries) of methadone as the drug reported in drug overdose deaths, as later reported by Hall, Lynskey & Degenhardt [23], and also commissioned work by Janie Sheridan and myself which established the lack of supervision of consumption of methadone in England [24]. As a direct result, through new national guidelines on the management of drug dependence [21], we were able to recommend widespread introduction of supervised dosing of prescribed methadone during the early months of maintenance treatment. Did this national recommendation result in any significant reduction in the extent to which methadone contributed to overdose deaths? We now wanted to test whether there had been any impact from these new guidelines. First, it was important to measure whether supervised dosing had actually been introduced, as recommended. It was only sensible to study impact of the policy change if we first established that the necessary dispensing behaviour had changed. We had already conducted a national Addiction, 110, 27–35

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survey of community pharmacists in 1995 [24] and had measured their attitudes and practices, thereby establishing their willingness to be involved in future provision of supervised dosing [25,26]. By repeating this national survey a decade later, we were able to chart the considerably increased provision of supervised dosing, which had increased from zero in 1995 to 36% in 2005 [27]. The next challenge was to test whether this change had actually resulted in a lower involvement of methadone in drug overdose deaths. Against a shifting baseline of increased provision of methadone (measured as amounts of methadone dispensed nationally), we calculated the number of overdose deaths per million daily dispensed doses of methadone (OD4-methadone). We then compared the time–course of the reduction in methadone overdose deaths (OD4) in Scotland versus England. This was of particular interest because it represented a natural experiment, as supervised dosing had been introduced a few years earlier in Scotland than in England (and more rapidly

and extensively). As displayed in Fig. 4, there was indeed a profound reduction in deaths per million prescriptions. A similar reduction in methadone deaths was then also seen in England, but later and more slowly, thus matching the later, slower English introduction of supervised dosing [28]. As statistician colleague Sheila Bird observed, the introduction of supervised dosing of methadone had saved more than 2500 lives during the 10-year study period [29]. Tackling Opiate Overdose Deaths at Prison Release Let us return to the clustering of deaths in the first few weeks following release from prison. What might we be able to do to reduce this waste of life? If we had a relevant intervention that might reduce overdose deaths, then the obvious area on which to concentrate would be the first few weeks following prison release. My colleagues Michael Farrell and John Marsden have been working with the prison health service to introduce

OD4-methadone, Scotland, 1993-2008 70.0 60.0

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Figure 4 Analysis of reduction in overdose deaths involving methadone over the period of introduction of supervised dosing (earliest in Scotland; later in England), measured as OD4 (overdose deaths per million daily dispensed doses) (as reported in [28]) Addiction, 110, 27–35

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effective maintenance treatment for incarcerated heroin addicts and are well advanced, with a large-scale observational study of 20 000 heroin-addicted prisoners who, for reasons which appear somewhat arbitrary and variable between institutions, are assigned either to maintenance or to abstinence. Their findings will shed light on the benefit obtained and on ways to improve prison health care and, crucially, on continuity of care on release from prison and return to the community. Additionally, with my colleague John Marsden, in early 2015 we commenced a clinical trial of naltrexone implants —a double-blind double-dummy randomized controlled trial (NEAT RCT) of naltrexone implants versus oral naltrexone versus placebo among recently detoxified heroin addicts (n = 300), and we anticipate that a substantial proportion of our recruited patient population may be individuals recently released from prison. Exploring the Life-Saving Potential of Overdose Training and Pre-Provision of Emergency Naloxone In the hospital setting, the life-threatening overdose situation is regularly reversed by emergency injection of the opiate antagonist naloxone: long-established as practice in the Accident and Emergency (A&E) department and increasingly also by ambulance crews. We then realized that this might be an example of overlooked important technology transfer—simply taking an established technology for the hospital setting and placing it in the location of potential emergency—as with wide-scale provision of adrenaline injections (EpiPen) to individuals with life-threatening allergies, and also the placement of emergency defibrillators in public areas and on aircraft, etc. Might drug users themselves, and also their families, be an untapped intervention work-force? The equivalent application would be to train drug users themselves, and their families, in the

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identification of the emergency situation, and in the emergency management, including giving a naloxone injection, while awaiting the arrival of an ambulance. In discussions, questions were then raised about whether it was really feasible to train these target populations and whether knowledge and skills would be properly retained. The possibility of pre-provision of emergency supplies of naloxone, alongside training in overdose management, began in the early/mid-1990s, and its first proper public presentation was as an editorial for debate in the BMJ [30]. Naloxone is unquestionably a highly effective antidote for heroin (and other opiates), rapidly displacing the heroin from receptors where it is suppressing respiratory drive. For several decades it has been the emergency medication of choice for A&E departments and ambulance personnel. In other areas of medicine we see progressive technology transfer, taking potentially life-saving interventions out of the hospital and into the community; and so the challenge is to establish whether the same can be carried out with interim emergency management of heroin overdose. For this to work, drug users themselves would need to be in the presence of others at the time of their overdose, and preferably in a home situation (where it would be more likely that an emergency supply of naloxone would be located). A necessary first study was thus to establish the extent to which opportunities existed for emergency resuscitation measures (as the provision of training and naloxone supplies would be pointless if, for example, most deaths occurred when alone). We surveyed not only those who are already involved in treatment programmes but also, crucially, the wider population of heroin users (among whom the risk of drug overdose death was greater). We investigated the circumstances of previous overdose events which our study subjects had either personally experienced or had witnessed [31], and found that approximately half of our study sample had already experienced an overdose,

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Figure 5 Impact of training on knowledge to detect and to intervene with overdose (addictions treatment patients/clients and addiction staff) (as reported in [36]) © 2015 Society for the Study of Addiction

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Figure 6 Impact of training on knowledge and attitudes and robustness over medium-term (3/12) (trained carers versus waiting-list control) (as reported in [40])

and more than two-thirds had already witnessed an overdose: levels far higher than realized previously. We also examined the circumstances of these overdoses, and found that more than three-quarters of overdoses occurred in a home situation and in the company of others (see Table 2) [31,32], hence apparently suitable for the training and naloxone provision that we were considering. We also conducted ’market research’—pre-launch testing of the acceptability of the proposed intervention with the target population of drug users themselves—and found high levels of approval and interest [32,33] and also high levels of previous active intervention, even though the interventions were often wrong [33–35]. Our next task was to establish whether our opiate addict patients would acquire and retain knowledge and confidence as a result of overdose training. We found that their improvements during training were broadly comparable to the improvements seen with the same training delivered to staff in addiction treatment services, and that they also showed comparable retention of knowledge and confidence over time [36] (see Fig. 5). Table 2 Personal experience of overdose of community and treatment samples (as reported in [32]). Community sample (n = 312)

Treatment sample (n = 142)

Ever overdosed?

118/312 (38%)

78/142 (55%)

Last personal overdose: Involved opiates at own or friend’s home own home friend’s home In company of others sexual partner close friends

102/118 (86%) 84/118 (80%) 52 42 95/118 (81%) 32 57

72/78 (92%) 61/78 (78%) 43 18 66/78 (85%) 33 27

© 2015 Society for the Study of Addiction

This was accompanied by observational reports of the first implementations of provision of take-home naloxone by statutory drug treatment services and non-governmental street agencies [37]. We then extended our thinking to another strangely overlooked potential intervention work-force: the family [38]. With the benefit of hindsight, it is surprising how long it took us to realize the intervention opportunity and the strategic importance of engaging the family (at the time of writing, they are still rarely considered in plans for wider provision of take-home naloxone). We identified high levels of concern about the possibility of heroin overdose alongside very low levels of knowledge about essential interim management while awaiting an ambulance. We also found very high levels of interest and wish to receive training in overdose management and pre-provision of an emergency naloxone supply. The next step was to test the impact of training on knowledge and attitudes. With work coordinated by Anna Williams, we have undertaken a randomized trial testing the immediate- and medium-term gains in knowledge and increased confidence in overdose management, using new measures to assess gains in knowledge and attitude [39] and demonstrating the extent of gain of knowledge and confidence and its robustness over time [40] (see Fig. 6). The final trial to mention is, in some ways, our boldest trial to date: the Medical Research Council (MRC)-funded N-ALIVE randomized trial of provision of emergency naloxone to prevent heroin overdose deaths after prison release [41]. Because we are measuring reduction of a rare event over a short period of time, we need an enormous sample size. Hence, the full randomized trial was calculated to need 30 000 prisoners, allocated 50/50 to either standard care (without naloxone provision) or alternatively to provision of a take-home supply of emergency naloxone (and training DVD, etc.), provided to the prisoner Addiction, 110, 27–35

Drug overdose deaths: understanding and prevention

on release. Then, by merging the release date with national mortality data, the primary outcome is the number of deaths in each of the two randomised groups to test the extent to which we have stunted this post-release mortality. The policy and political importance of the N-ALIVE RCT warrants special consideration, as the logistics, the challenge and the effort required are so considerable. The proposal for provision of overdose training and pre-provision of emergency naloxone is unquestionably bold and challenging. Without a clear signal one way or the other (and from a strongly designed and adequately powered study), there is a danger that professional or public opinion will not grasp the intervention sufficiently, and also unlikely that policymakers and funders will properly embrace and implement its novel preventive potential. LOOKING TO THE FUTURE More attention needs to be paid to at least five areas: 1 Observational studies of naloxone implementation need better scientific rigour in order to be definitive. Of course, there are major challenges (sometimes insuperable) to the use of randomized trial designs for this topic, but there is still a need (perhaps even more so) for attention to good scientific design and method in observational studies. Published reports are very reassuring, but they often have follow-up of only a small proportion of the individuals to whom naloxone had originally been distributed—this limits, in a major way, the robustness of any scientific conclusions and the generalizability of any findings. Wherever possible, good study design, adequate sample size, robust procedures, etc. should be implemented. 2 Greater awareness of times and situations of overdose risk is required. Naloxone pre-provision will not replace this need. Training in emergency overdose management for the public, as well as for user groups and patient populations, needs to be universal and include awareness of risk situations (after prison release, during induction and after termination of opioid substitution treatment), as well as training in emergency overdose management, including how to administer emergency interim naloxone. 3 Better naloxone formulations must surely be possible and should be products with acceptable pharmacokinetic profiles and proven efficacy. Existing injectable formulations could be made more user-friendly for the non-clinician, such as a pre-filled syringe with stake needle at the correct dose, and include simple instructions. Unlicensed adaptations are of real potential, perhaps such as nasal spray, but it is essential for there to be proper regulatory scrutiny of these alternative routes which are currently still unlicensed and untested. Other possibilities should also be explored © 2015 Society for the Study of Addiction

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(as we ourselves are currently doing), as the nasal route is not the only possible non-injectable route of administration. 4 There is real potential for healthy impact from training of different possible ’first responders’. There is a much wider work-force who need to know how to detect overdose crisis, and then how to manage the situation in the interim, while awaiting emergency response units— staff in hostels for the homeless, in-patient wards and residential rehabilitation units (notwithstanding the drug-free rules), as well as police, fire fighters and bus drivers—as is being considered and sometimes implemented in cities around the world. 5 There is a major problem concerning the legislative and organisational challenge of pre-placement of naloxone. If a parent or peer or hostel worker correctly identifies a heroin overdose crisis, then they need to call an ambulance (or similar emergency medical services) immediately. However, interim management of the overdose can be improved, with attention to clearing the airway, assisted breathing, the ’recovery position’ and intramuscular injection of the heroin antagonist naloxone. Nevertheless, it is often still unnecessarily difficult for the potential life-savers to obtain and hold such emergency supplies. We regularly provide families with such emergency injectable medicines for other conditions (severe allergies, diabetes, epilepsy, etc), but the extent of pre-provision of emergency naloxone has been painfully patchy and unacceptably slow. This needs to change. CONCLUSION Strategies to prevent opiate overdose deaths have been only minimally explored. It is as if there is nervousness to acknowledge that the unsanctioned behaviours occur, for fear of being seen as condoning the behaviour. This then obstructs proper study of the potential new interventions and also stands in the way of their subsequent implementation. Our studies, and the studies of others, clearly identify specific dangerous patterns of drug use, specific times and locations of increased risk and interventions which could potentially prevent the fatal outcomes. For the time being these remain, all too often, uncharted territories which are yet to be investigated. However, unless progress is made, the large excess mortality will continue unchecked. As intervention-interested researchers we can make a real difference, and it is our scientific and public responsibility to do so. Declaration of interests J.S. is directly employed by and leads the Addictions academic activity of the Institute of Psychiatry, Kings College Addiction, 110, 27–35

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London and also holds an honorary appointment at, and is in a leadership position for, the Addictions clinical activity of the South London & Maudsley (SLaM) NHS Foundation Trust, which provides treatments in the drug, alcohol and smoking cessation fields. J.S. has received project grant support and/or honoraria and/or consultancy payments from government agencies including Department of Health, NTA (National Treatment Agency), PHE (Public Health England), Home Office and NICE (National Institute for Health and Clinical Excellence), and has worked with the World Health Organization (WHO) and with the United Nations Office on Drugs and Crime (UNODC) and European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and other international government agencies. He has also received research grant support and/or payment in the form of honoraria, consultancy payments and/or travelling and/or accommodation and/or conference expenses from pharmaceutical companies who produce, or have been considering producing, new medicines for use in the addiction treatment field, including (past 3 years) Viropharma, Martindale/Catalent, Reckitt-Benkiser, ScheringPlough, Lundbeck, UCB, MundiPharma, Alkermes, Teva and also discussions with Lightlake, Lanacher, Rusan/iGen and Indivior; this includes companies who are considering development of naloxone products, including at least one which has a patent registration which includes declaration of contribution from JS. JS’s employer (King’s College London) has also recently submitted a patent application for a medication formulation to address heroin overdose. JS works closely with the charity Action on Addiction, and also with the Pilgrim Trust, and has received grant support from them. JS works (or has worked) with various drug policy organizations and advisory bodies, including the UK Drug Policy Commission (UKDPC) and the Society for the Study of Addiction (SSA). JS is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London.

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opiate overdose risk and testing potential to prevent deaths.

To describe work undertaken over a 20-year period, investigating overdose characteristics among survivors, effects of acute heroin administration, clu...
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