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Why the FUSS (Fentanyl Urine Screen Study)? A cross-sectional survey to characterize an emerging threat… Amlani, Ashraf; McKee, Geoff; Khamis, Noren; Raghukumar, Geetha; Tsang, Erica; Buxton, Jane A Nov 14, 2015

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RESEARCH Open AccessWhy the FUSS (Fentanyl Urine ScreenStudy)? A cross-sectional survey tocharacterize an emerging threat to peoplewho use drugs in British Columbia, CanadaAshraf Amlani1* , Geoff McKee3, Noren Khamis2, Geetha Raghukumar2, Erica Tsang2 and Jane A. Buxton1,2AbstractBackground: Fentanyl-detected illicit drug overdose deaths in British Columbia (BC) recently increased dramaticallyfrom 13 deaths in 2012 to 90 deaths in 2014, signaling an emerging public health concern. Illicit fentanyl is sold aspills or powders, often mixed with other substances like heroin or oxycodone; reports from coroners suggested thatfentanyl was frequently taken unknowingly by people who use drugs. This study aimed to assess the prevalenceand characteristics of fentanyl use among clients accessing harm reduction (HR) services in BC.Methods: Participants attending HR services at 17 sites across BC were invited to complete an anonymousquestionnaire describing drugs they have used within the last 3 days and provide a urine sample to test forfentanyl. Data from eligible participants were analyzed using descriptive, bivariate, and multivariate statisticalmethods.Results: Surveys from 17 HR sites were received, resulting in analysis of responses from 242 eligible participants. Mostparticipants used multiple substances (median = 3), with crystal meth (59 %) and heroin (52 %) use most frequentlyreported. Seventy participants (29 %) tested positive for fentanyl, 73 % of whom did not report using fentanyl.Controlling for age, gender, and health authority, reported use of fentanyl (odds ratio (OR) = 6.13, 95 % confidenceinterval (CI) = [2.52, 15.78], p < 0.001) and crystal methamphetamine (OR = 3.82, 95 % CI = [1.79, 8.63], p < 0.001) usewere significantly associated with fentanyl detection.Conclusions: The proportion of those testing positive who did not report knowingly using fentanyl represents aconsiderable public health concern. The risk of overdose among this vulnerable population highlights the need fortargeted HR strategies, such as increased accessibility to naloxone, overdose education, and urine screens.Keywords: Survey, People who use drugs, Fentanyl, Overdose, OpioidsBackgroundUse of illicit fentanyl has emerged as a dangerous trendamong people who use drugs in British Columbia (BC).Fentanyl-detected, illicit drug overdose deaths in BC haveincreased dramatically between 2012 and 2015 [1].Reports from the BC Coroners Service suggest many ofthose testing positive for fentanyl were unknowingly usingthe substance [1]. The rapid increase in fentanyl-detectedoverdoses and risk of unintentional administrationpresents an emerging public health concern in BC.Fentanyl is a synthetic opioid, far more potent thanmorphine and heroin, clinically used in anesthesia, and formanagement of chronic pain, pharmaceutical fentanyl isonly available as transdermal patches in Canada [2].Recently in Canada, illicit fentanyl has been sold aspills or powders, often mixed with other substanceslike heroin or oxycodone and, on many occasions,ingested unintentionally by people who use drugs dueto undisclosured pill/powder contents [2]. Historically,nonpharmaceutical fentanyl and its analogs have been* Correspondence: ashraf.amlani@bccdc.ca1British Columbia Centre for Disease Control, 655 West 12th Avenue,Vancouver BC V5Z 4R4, CanadaFull list of author information is available at the end of the article© 2015 Amlani et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Amlani et al. Harm Reduction Journal  (2015) 12:54 DOI 10.1186/s12954-015-0088-4sold under various street names, while recent prepara-tions, called “green jellies” or “street oxy,” have becomeavailable across Canada [2, 3].Fentanyl overdose can lead to respiratory depression,followed by decreased mental status, brain damage, anddeath. The potency of fentanyl considerably increases therisk of overdose. This is particularly concerning with illicitfentanyl, as doses can be highly variable and people usingmay be opioid naïve. The pharmacodynamic properties offentanyl metabolites may also lead to prolonged physiologiceffects in the context of an overdose, similar to longer act-ing opioids [4]. This complicates the emergency responseand may increase the risk of complications, as patients canre-narcotize following reversal with naloxone [5].Several clusters of fentanyl-related overdose deaths havebeen reported in both Canada and the USA. Between2002 and 2004, 112 fentanyl-detected deaths werereported in Ontario [6]. These deaths were associated witha variety of fentanyl formulations and co-administeredsubstances; however, a particular pattern of illicit use wasnot reported. A large cluster of 1013 fentanyl-relateddeaths between 2005 and 2007 in six US states was foundto be associated with illicit fentanyl mixed with heroin andcocaine [7]. Another fentanyl-associated cluster of illicitdrug deaths was identified in 2013 in Rhode Island [8].Between 2009 and 2014 in Canada, fentanyl was deemeda cause or contributory cause in at least 655 deaths andwas detected in at least 1019 drug poisoning deaths [9]. InBC, fentanyl-detected overdose deaths increased sevenfoldfrom 13 deaths in 2012 to 90 in 2014 [9]. This representeda considerable increase in the proportion of total fentanyl-detected illicit drug overdose deaths, from 5 % in 2012 toover 25 % in 2014.In response to the emerging threat of fentanyl use andsubsequent overdose to people who use drugs in BC, thisstudy was developed to assess the prevalence and charac-teristics of fentanyl use among clients accessing harmreduction (HR) services in BC. Increased understanding ofthese patterns may lead to more effectively targeted harmreduction strategies, such as health promotion campaignstargeting unsafe drug use practices and take-home nalox-one programs.MethodsThe study used a cross-sectional design linking surveysof demographics and substance usage patterns withfentanyl urine tests. The Behavioural Ethics ReviewBoards at the University of BC and Interior HealthAuthority granted ethics approval.Study materialsThe survey used questions adapted from an annual surveyof clients at HR sites conducted by the BC Centre forDisease Control [10]. Study materials were reviewed witha group of five peers (people with experience using drugs)at the Vancouver Area Network of Drug Users (VANDU).Materials were also distributed to potential sites in orderto check for suitability and acceptability of study design,as there was potential for urine testing to be perceived asa threatening activity.Although renal clearance of fentanyl varies by ageand dosage, the urine levels of norfentanyl, a fentanylmetabolite, typically become negligible within 3 daysof administration [11]. The surveys collected informa-tion on substance use within 3 days prior to surveycompletion and urine collection, as this was deemedthe optimal window to link urine norfentanyl detec-tion with fentanyl use.After consultation with medical facilities already testingpatients’ urine for fentanyl, BNTX Rapid Response TMfentanyl urine strip tests at a detection level of 20 ng/mlnorfentanyl were chosen as the method for measuringurine norfentanyl levels [12].Recruitment and survey distributionIn BC, supplies for safer sex and drug use (e.g., needlesand condoms) are distributed by a network of over 200HR sites, including public health units and communityservice organizations [10]. We estimated a total samplesize of 385 respondents would allow us to report resultsat 95 % confidence level of +/− 5 % for an unknownpopulation. Based on general population density, 4–10sites in each of five regional health authorities were inviteddirectly by the British Columbia Centre for Disease Control(BCCDC) or the regional HR coordinator to participate inthe study. Questionnaires, participant refusal tracking sheet,urine test strips and instructions, and honorarium fundswere mailed to each participating site. Site staff wereresponsible for recruiting clients, getting informed consentfrom participants, administering the questionnaire, testingthe urine sample, and providing the $5 participant honorar-ium. Unique client ID labels were used to maintainanonymity and link the survey, urine sample, and urinestrip result. Data were collected from February throughMarch 2015.The sample population included individuals whoreported using substances within the preceding 3 days,were over 19 years of age, presented to a participating siteduring the study period, and were able to give verbal,informed consent.Data cleaning and analysisData was entered into a Microsoft Access database andimported into the R statistical software environment forcleaning and analysis. This was performed using R pack-age (version 3.1.1) & R Studio (version 0.98.1062) withfunctions from the MASS package (version 7.3-40).Amlani et al. Harm Reduction Journal  (2015) 12:54 Page 2 of 7Participants less than 19 years of age, who reported nosubstance use within the previous 3 days or whosefentanyl urine screen results were unlinked with theassociated surveys, were excluded from analysis.Substance use data was cleaned and recoded for analysis.For the substance use questions, blanks were assumed toindicate negative responses.Descriptive statistical techniques were applied todemographic and substance use variables. To maintainanonymity due to small cell sizes, location data wasaggregated to the health authority level.Odds ratios were calculated using logistic regressionfor number and type of substances used, health author-ity, gender, age group, and history of overdose. Analysisof variance (ANOVA) with the chi-square test was runon age and health authority variables to determine theirsignificance. Significant variables were then controlledfor age, gender, and health authority in a multivariateregression model.ResultsOverall, 294 surveys were received from 17 HR supplydistribution sites (Fig. 1). Only 28 individuals approachedto participate in the study declined, corresponding to aparticipation rate of 91.3 %. Fifty-two participants wereexcluded from analysis resulting in a final sample size of242:41 due to the absence of accurate linkage betweenurine test results and surveys, two were less than 19 yearsof age, five did not list their age, and four reported nosubstance use in the previous 3 days.Descriptive analysisDemographic and substance use information issummarized in Table 1. A higher proportion of males(58 %) participated in the study than females (40 %),and 40–49-year-olds had the highest representation(34 %), followed by 30–39-years-olds (28 %). Samplesizes varied among the province’s five health author-ities; Island Health was under-sampled and comprisedonly 6 % (n = 14) of total participants.As per Fig. 2, crystal methamphetamine was the mostfrequently reported substance used (58 %), followed byheroin (52 %). A total of 31 (13 %) individuals reportedusing fentanyl. Reported substance use varied signifi-cantly between health authorities (Fig. 3). The majorityof participants reported using more than one substance(88 %) in the previous 3 days (median = 3). A total of 24individuals (10 %) reported a history of overdose withinthe previous month and 5 (2 %) within the previousweek. Approximately 29 % (n = 70) of the participantstested positive for fentanyl, 73 % (n = 51) of whichreported no known fentanyl use within the previous3 days. All participants reporting an overdose within theprevious week (n = 5) tested positive for fentanyl, two ofwhich did not report knowingly using the substance.Bivariate analysisOdds ratios are summarized in Table 1. Among substanceuse patterns, those substances most significantly correlatedwith positive fentanyl urine screens were crystal metham-phetamine (odds ratio (OR) = 3.50, 95 % confidence interval(CI) = [1.88, 6.86], p < 0.001) and fentanyl (OR = 4.97, 95 %CI = [2.28, 11.20], p < 0.001). Health authority was signifi-cantly correlated with a positive fentanyl urine screen (p <0.01); in particular, Island Health was highly correlated(OR = 3.60, 95 % CI = [1.10, 13.08]). All other variables,including gender, age, history of overdose, and number ofsubstances used, were found not to be significantly corre-lated with fentanyl detection.Multivariate analysisA multivariate logistic regression model was created tocontrol for associations between variables (Table 2). Aftercontrolling for age, gender, location, and health authority,fentanyl (OR = 6.13, 95 % CI = [2.52, 15.78], p <0.001) andcrystal methamphetamine (OR = 3.82, 95 % CI = [1.79,8.63], p <0.001) use remained significantly associated withfentanyl detection.DiscussionThe patterns of substance use reported by participantsdiffered from those identified by a recent provincial survey[13]. The higher reported use of crystal meth in oursample corresponds to anecdotal reports of a trend amongexperienced users in BC toward crystal methamphetamineand away from heroin and crack [14]. Differences inreported pattern of use between this study and the annualprovincial survey may be due to smaller sample size(17 vs. 30+ sites) and time of year (winter vs. sum-mer). BC’s natural geographic features and winterFig. 1 Outline of exclusion criteria for data analysisAmlani et al. Harm Reduction Journal  (2015) 12:54 Page 3 of 7weather conditions may facilitate or restrict access tocertain substances in various urban, rural, and remotecommunities. The significant correlation betweenlocation and fentanyl detection may be related to thesefactors.The results of our study support the hypothesis that aconsiderable portion of fentanyl use in BC is uninten-tional, with 73 % of those testing positive for fentanyl,reporting no known fentanyl use within the previous3 days. This represents a substantial risk to people whouse drugs, as the dose of fentanyl in substances consumedmay vary and individuals may be opioid naïve, creating anoptimal scenario for overdose.Reported use of heroin or other opioids besidesfentanyl was not significantly correlated with fentanylpositivity, while crystal methamphetamine was signifi-cantly associated. The intentional inclusion of fentanylin crystal methamphetamine by distributors is counter-intuitive, as opioids tend to oppose many of theintended effects of stimulants, and this group of usersTable 1 Descriptive and bivariate analysis of demographics, substance use patterns, and associated fentanyl-detection as reportedby participantsVariable Total number (%) Number positive (%) OR [95 %CI] p valueSubstance useMethadone 73 (30 %) 18 (25 %) 0.74 [0.39, 1.36] 0.34Morphine 97 (40 %) 27 (28 %) 0.91 [0.51, 1.61] 0.76Dilaudid 55 (23 %) 13 (24 %) 0.71 [0.34, 1.39] 0.33Oxycodone 23 (10 %) 9 (39 %) 1.67 [0.66, 4.00] 0.26Fentanyl 31 (13 %) 19 (61 %) 4.97 [2.28, 11.20] <0.001Benzodiazapines 48 (20 %) 14 (29 %) 1.01 [0.49, 2.00] 0.97Stimulants NOSa 25 (10 %) 7 (28 %) 0.95 [0.35, 2.30] 0.91Heroin 126 (52 %) 42 (33 %) 1.57 [0.90, 2.78] 0.12Cocaine powder 65 (27 %) 16 (25 %) 0.74 [0.38, 1.40] 0.37Crack 78 (32 %) 21 (27 %) 0.86 [0.47, 1.56] 0.64Crystal meth 143 (59 %) 55 (38 %) 3.50 [1.88, 6.86] <0.001Marijuana 55 (23 %) 14 (25 %) 0.80 [0.39, 1.55] 0.52Number of substances used1 substanceb 30 (12 %) 5 (17 %) 1.0 0.12>1 substance 212 (88 %) 65 (31 %) 2.21 [0.87, 6.78] 0.12OverdoseOverdose within last month 24 (10 %) 7 (29 %) 0.98 [0.36, 2.39] 0.97Overdose within last week 5 (2 %) 5 (100 %) – –Health authorityFraser Health Authority 57 (24 %) 22 (39 %) 1.26 [0.59, 2.69] <0.001Interior Health Authority 54 (22 %) 9 (17 %) 0.40 [0.16, 0.96] <0.001Northern Health Authority 57 (24 %) 10 (18 %) 0.43 [0.17, 1.00] <0.001Vancouver Coastal Healthb 60 (25 %) 20 (33 %) - = 1.0 <0.001Island Health 14 (6 %) 9 (64 %) 3.60 [1.10, 13.08] <0.001Age group19–29 45 (19 %) 12 (27 %) 0.99 [0.41, 2.31] 0.8530–39b 67 (28 %) 18 (27 %) 1.0 0.8540–49 83 (34 %) 27 (33 %) 1.31 [0.65, 2.70] 0.8550+ 47 (19 %) 13 (28 %) 1.04 [0.44, 2.40] 0.85GenderFemale 98 (40 %) 32 (33 %) 1.31 [0.75, 2.31] 0.34Maleb 141 (58 %) 38 (27 %) 1.0 0.34aNot otherwise specifiedbVariable used as reference for OR calculationsAmlani et al. Harm Reduction Journal  (2015) 12:54 Page 4 of 7may be opioid naïve and more likely to overdose.Although this finding was unexpected, there have beenreports of individuals using opioid/stimulant combina-tions, such as “speedballs” combining heroin and cocaine,as well as individuals experiencing opioid overdose symp-toms following crystal methamphetamine use [15]. Thesecombinations rely on the variability in pharmacodynamicsbetween the opioid and stimulant, causing the transitionbetween depressant and stimulant effects. Another pos-sible explanation for the association may be unintentionalcontamination through handling and storage prior todistribution.Intentional fentanyl use was highly correlated withfentanyl detection in the urine; however, 12 out of 31participants reporting fentanyl use tested negative. It ispossible that, due to the rapid clearance of fentanyl bythe kidneys, fentanyl metabolites may be below thedetectable level when a small amount and/or full 3 daysbetween consumption and testing [12, 16]. Alternately,individuals reporting fentanyl use may actually be takingsomething entirely different.The risk of overdose from unknown presence of fentanylin street drugs highlights the need for strategies that focuson overdose prevention, recognition, and response. BCpublic health agencies have developed messagingcampaigns to increase awareness of fentanyl-relatedoverdoses and recommend precautionary strategiesbased on the unintentional fentanyl use identified bythis study [17]. Providing overdose response training andnaloxone, an opioid overdose antidote, is needed to reducethe harms of fentanyl overdose. Take-home naloxoneprograms implemented in BC and across North Americasupport early reversal for opioid overdoses, as subsequentrespiratory depression may lead to brain damage and death[18, 19]. While these programs traditionally target peoplewho use opioids, the unintentional use of fentanyl maysupport a need to broaden coverage to people who useother substances, as well as their friends and family.*NOS = Not otherwise specified0%10%20%30%40%50%60%70%020406080100120140160Percent PositiveNumber of ParticipantsNegativePositivePercent PositiveFig. 2 Prevalence of specific substance use and proportion of positive fentanyl test results among participants using these substances*NOS = Not otherwise specified0%10%20%30%40%50%60%70%80%90%100%Percent of Participants within Health AuthorityFHAIHANHAVCHIHFig. 3 Percent of participants reporting specific substance use by health authorityAmlani et al. Harm Reduction Journal  (2015) 12:54 Page 5 of 7Given that illicit fentanyl may be mixed into manystreet drugs, the availability of street drug checking forfentanyl could reduce the risk of accidental overdose.However, in the absence of a cheap rapid fentanyl detec-tion test that could be used on a drug sample, fentanylurine testing strips could be provided to people who usedrugs as an additional harm reduction service.The elevated prevalence of fentanyl use also has implica-tions on the use of naloxone by paramedics or in theemergency room (ER) to treat suspected opioid overdoses,and for the management of withdrawal for patients indetoxification centers. Given the pharmacodynamic prop-erties of fentanyl, overdoses may result in more prolongedrespiratory depression than other opioids and may requirehigher levels of naloxone for reversal [5]. Clinicians shouldconsider fentanyl urine testing when managing overdosesin ER. Although this may not change the clinical manage-ment of the overdose, test results can serve as an oppor-tunity to educate patients about their overdose andincrease uptake of take-home naloxone programs.In the time between the data collection phase and thepublication of this study, fentanyl has become a publichealth concern in many jurisdictions outside BC, includingother areas in Canada and the USA [9, 20, 21]. The recom-mendations stemming from our findings could reduceharms due to overdose in all regions affected by thepresence of illicit fentanyl in the street market.Several characteristics of this study limit the scope ofour conclusions. Those sampled from participating HRsites are a small subset of individuals accessing harmreduction sites and of all people who use drugs in BC.The exclusion of 48 participants, in part due to thesubmission of unlinked surveys and test results fromone site, also reduced the power of the study. Anothersite only sent samples and surveys of participants whotested positive for fentanyl, which may lead to an overestimate of fentanyl prevalence.Technical limitations include cross-reactivity of thefentanyl urine tests and fentanyl analogs, such as sufenta-nyl. The rapid clearance of fentanyl may also result innegative test results, even if it was used within the 3-daywindow. The study was also limited by the exclusion ofthose younger than 19 years of age due to ethics approval;however, only a few of fentanyl-detected illicit drug deathsin BC have occurred in people under 19 years. Other limi-tations include reliance on self-reported questionnaires,the assumption that nonresponses represented negativeanswers and other biases inherent in cross-sectional studydesigns.ConclusionsThe results of this study demonstrate that illicit fentanylis a considerable risk to people who use drugs in BC,particularly among those who consume it unknowingly.The widespread use of crystal methamphetamine and itsassociation with fentanyl detection suggests that eventhose using stimulants may be at risk of opioid overdose,thus emphasizing the importance of broadening overdoseeducation and prevention programs.Further research is required to verify the associationsmade in this report and may include investigation into drugdistribution patterns, as well as a review of coroners’ files toidentify substances implicated in illicit drug-associateddeaths.While the increase in fentanyl availability and fentanyl-detected deaths is alarming, support of harm reductionstrategies can help mitigate the risks. Public health agencieshave taken steps to combat this trend; however, furtherengagement is necessary to reduce the impact of illicitfentanyl on this vulnerable population.Competing interestsThe authors have no competing interests to declare.Authors’ contributionsAA, GR, ET, and JAB designed the study and associated materials. AArecruited the participating sites. AA, NK, and GM were involved in the datacollection, cleaning, and analysis. AA and JAB supervised all aspects of theproject from inception to completion. All authors read and approved thefinal manuscript.Authors’ informationJAB is a physician epidemiologist and harm reduction lead at the BC Centrefor Disease Control. In these roles, she championed the creation of aprovincial Take Home Naloxone program, which educates people on how toprevent, recognize, and respond to opioid overdoses using naloxone(restores breathing during an overdose). The appearance of fentanyl in BC’sillicit drug markets has led to an increased demand for naloxone.AcknowledgementsThe authors would like to thank the peers from the Vancouver Area Networkof Drug Users for their input on the study design, as well as the healthauthority regional harm reduction representatives and participating sites,including the staff and participants, for their assistance in the recruitmentand data collection. We acknowledge the contributions of Robert Balshaw,Senior Statistician, BCCDC, as well as medical students Jennifer Campbell andHugh Guan on their early work designing the study. Funding for this projectwas provided through BC Centre for Disease Control.Author details1British Columbia Centre for Disease Control, 655 West 12th Avenue,Vancouver BC V5Z 4R4, Canada. 2Faculty of Medicine, University of BritishColumbia, Vancouver, Canada. 3School of Public and Population Health,University of British Columbia, Vancouver, Canada.Received: 10 September 2015 Accepted: 8 November 2015Table 2 Multivariate, additive logistic regression models ofsignificant variables controlled for age, gender, location, andconcurrent opioid useVariable OR [95 % CI] p valueFentanyl 6.13 [2.52, 15.78] <0.001Crystal meth 3.82 [1.79, 8.63] <0.001Amlani et al. Harm Reduction Journal  (2015) 12:54 Page 6 of 7References1. British Columbia Coroners Service. Information bulletin: BC Coroners Servicewarns of deaths related to illicit fentanyl use. 2014. http://www.pssg.gov.bc.ca/coroners/reports/docs/2014JAG0150-000766.pdf. Accessed 27 Oct 2015.2. 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Community-based opioidoverdose prevention programs providing naloxone—United States, 2010.MMWR Morb Mortal Wkly Rep. 2012;61(6):101–5.19. Banjo O, Tzemis D, Al-Qutub D, Amlani A, Kesselring S, Buxton JA. Aquantitative and qualitative evaluation of the British Columbia Take HomeNaloxone program. Can Med Assoc. 2014;2(3):E153–61. http://www.cmajopen.ca/content/2/3/E153.full. Accessed 26 May 2015. CMAJ Open.20. A strategic plan for Rhode Island: RI Governor’s Overdose Prevention andIntervention Task Force . 2015 http://www.strategicplanri.org/. Accessed 3Nov 2015.21. CDC Health Alert Network (HAN): increases in fentanyl drug confiscationsand fentanyl-related overdose fatalities. Atlanta, GA; 2015 http://emergency.cdc.gov/han/han00384.asp . Accessed 3 Nov 2015.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitAmlani et al. Harm Reduction Journal  (2015) 12:54 Page 7 of 7

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