{"id":43,"date":"2022-09-16T19:31:38","date_gmt":"2022-09-16T19:31:38","guid":{"rendered":"https:\/\/pressbooks.palni.org\/prindlepost\/?post_type=chapter&p=43"},"modified":"2022-09-30T19:43:49","modified_gmt":"2022-09-30T19:43:49","slug":"medical-challenge-trials-time-to-embrace-the-challenge","status":"publish","type":"chapter","link":"https:\/\/pressbooks.palni.org\/prindlepost\/chapter\/medical-challenge-trials-time-to-embrace-the-challenge\/","title":{"raw":"Medical Challenge Trials: Time to Embrace the Challenge?","rendered":"Medical Challenge Trials: Time to Embrace the Challenge?"},"content":{"raw":"
\r\n
\r\n

Should we continue to turn away willing volunteers from experimental trials even in times of crisis?<\/p>\r\n\r\n<\/header>\r\n

\r\n
\r\n\r\nBefore reading: Should willing volunteers be barred from experimental treatments? Draw and label the scale below in your notes. Place yourself more toward the left side of the scale if you think consenting adults should be allowed to be intentionally infected. Place yourself more toward the right side of the scale if you think that even consenting adults shouldn\u2019t be intentionally harmed in the name of science.\r\n\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n\"\"\r\n\r\n<\/header><\/div>\r\n
\r\n\r\nStakeholder Map Prompt: Using the instructions from \"How to Create and Use a Stakeholder Map<\/a>,\" create a stakeholder map in your notes, either individually or with your class. Show the topic, the subjects affected, and possible outcomes based on the ideas introduced at the beginning of this article and your own background knowledge of the topic.\r\n\r\n<\/div>\r\nThe development of the COVID-19 vaccines is worthy of celebration. Never has a vaccine for a\u00a0 novel virus been so quickly developed, tested, and rolled out. Despite this success, we could have done much<\/a> better<\/a>. In particular, a recent study<\/a> estimates that by allowing \u201cchallenge trials\u201d in the early months of the pandemic, we would have completed the vaccine licensing process between one and eight months faster than we did using streamlined conventional trials. The study also provides a conservative estimate<\/a> of the years of life that an earlier vaccine rollout would have saved: between 720,000 and 5,760,000. However, whether we should have used challenge trials depends on a number of ethical considerations.\r\n\r\nHere is an extraordinary fact: we first genetically sequenced the virus in January 2020. Moderna then developed their RNA vaccine in just two days. But the F.D.A. could only grant the vaccine emergency authorization in late December \u2014 almost a year later. Over this period the virus killed approximately 320,000 U.S. citizens. The vast majority of the delay between development and approval was due to the time needed to run the necessary medical trials. Enough data needed to be collected to show the vaccines were effective and, even more importantly, safe.\r\n\r\nHere\u2019s how those trials worked. Volunteers from a large pool (for example, 30,420 volunteers in Moderna\u2019s phase three trial) were randomly provided either a vaccine or a placebo. They then went about their lives. Some caught the virus, others didn\u2019t. Researchers, meanwhile, were forced to wait until enough volunteers caught the illness for the results to be statistically valid. The fact that the virus spread so quickly was a blessing in this one respect; it sped up their research considerably.\r\n\r\nSo-called \u201cchallenge trials\u201d are an alternative way to run medical trials. The difference is that in a\u00a0 challenge trial healthy (and informed<\/a>) volunteers are intentionally infected with the pathogen responsible for the illness researchers want to study. The advantages are that statistically significant results can be found with far fewer volunteers far more quickly. If we vaccinate volunteers and then expose them to the virus, we\u2019ll have a good idea of the vaccine\u2019s effectiveness within days. This means faster licensing, faster deployment of the vaccine, and, therefore, thousands<\/a> of saved lives.\r\n\r\nChallenge trials are generally blocked from proceeding on ethical grounds. Infecting healthy people with a patho\u00adgen they might nev\u00ader oth\u00ader\u00adwise be ex\u00adposed to \u2014 a patho\u00adgen which might cause them ser\u00adi\u00adous or per\u00adman\u00adent harm or even death \u2014 might seem dif\u00adfi\u00adcult to jus\u00adti\u00adfy. Some med\u00adic\u00adal prac\u00adti\u00adtion\u00aders con\u00adsider it a vi\u00adol\u00ada\u00adtion of the Hip\u00adpo\u00adcrat\u00adic oath they have sworn to up\u00adhold \u2014 \u201cFirst, do no harm.\u201d Ad\u00advoc\u00adates of chal\u00adlenge tri\u00adals point out that slow, tra\u00addi\u00adtion\u00adal med\u00adic\u00adal tri\u00adals can cause even great\u00ader harm. Hun\u00addreds of thou\u00adsands of lives could likely have been saved had COV\u00adID-19 chal\u00adlenge tri\u00adals been per\u00admit\u00adted and the various vac\u00adcines\u2019 emer\u00adgency approv\u00adal occurred months earli\u00ader.\r\n\r\nAd\u00admit\u00adtedly, chal\u00adlenge tri\u00adals ef\u00adfect\u00adively shift some risk of harm from the pub\u00adlic at large to a small group of med\u00adic\u00adal vo\u00adlun\u00adteers. Can we really accept greater risk of harm and death in a small group in order to protect society as a whole? Or are there moral limits to what we can do for the \u2018greater good\u2019? Per\u00adhaps it is this unequal distribution of burdens and benefits that critics object to as un\u00adeth\u00adic\u00adal or un\u00adjust.\r\n\r\nAd\u00advocates of chal\u00adlenge tri\u00adals point out that vo\u00adlun\u00adteers con\u00adsent to these risks. Hence, per\u00admit\u00adting chal\u00adlenge tri\u00adals is, fun\u00adda\u00adment\u00adally, simply per\u00admitting fully con\u00adsent\u00ading adults to put them\u00adselves at risk to save oth\u00aders. We don\u2019t ban healthy adults from run\u00adning into dan\u00adger\u00adous wa\u00adter to save drowning swim\u00admers (even though these adults would be risk\u00ading harm or death). So, the reas\u00adon\u00ading goes, nor should we ban healthy adults from vo\u00adlun\u00adteer\u00ading in med\u00adic\u00adal tri\u00adals to save oth\u00aders\u2019 lives.\r\n\r\nOf course, if a volunteer is lied to or otherwise misinformed about the risks of a medical trial, their consent to the trial does not make participation ethically permissible. For consent to be ethically meaningful, it must be informed. Volunteers must understand the risks they face and judge them to be acceptable. But making sure that volunteers fully understand the risks involved (including the \u2018unknown\u2019 risks) can be difficult. For example, a well-replicated finding from psychology is that people are not very good<\/a> at understanding the likelihood of very low- (or high-) probability events occurring. We tend to \u201cround down\u201d low probability events to \u201cwon\u2019t happen\u201d and \u201cround up\u201d high probability events to \u201cwill happen\u201d. A 0.2% probability of death doesn\u2019t seem very different from a 0.1% probability to most of us, even though it\u2019s double the risk.\r\n\r\nInformed consent also cannot be obtained from children or those who are mentally incapable of providing it, perhaps due to extreme old age, disability, or illness. So members of these groups cannot participate in challenge trials. This limitation, combined with the fact that younger, healthier people may be more likely to volunteer for challenge trials than their more vulnerable elders, means that the insights we gain from the trial data may not translate well to the broader population. This could weaken the cost-benefit ratio of conducting challenge trials, at least in certain cases.\r\n\r\nA fur\u00adther eth\u00adic\u00adal worry about chal\u00adlenge tri\u00adals is that the poor and the dis\u00adad\u00advant\u00adaged, those with no oth\u00ader op\u00adtions, might be indirectly coerced to take part. If in\u00addividu\u00adals are des\u00adper\u00adate enough to ac\u00adcess fin\u00adan\u00adcial resources, for ex\u00adample for food or shel\u00adter they require, they might take on in\u00adcred\u00adible per\u00adson\u00adal risk to do so. This dy\u00adnam\u00adic is called \u201cdes\u00adper\u00adate ex\u00adchange,\u201d and it must be avoided if chal\u00adlenge tri\u00adals are to be eth\u00adically per\u00admiss\u00adible.\r\n\r\nOne way to pre\u00advent des\u00adper\u00adate ex\u00adchanges is to place lim\u00adits on the fin\u00adan\u00adcial com\u00adpens\u00ada\u00adtion provided to vo\u00adlun\u00adteers, for ex\u00adample merely cov\u00ader\u00ading travel and in\u00adcon\u00adveni\u00adence costs. But this solu\u00adtion might be thought to threaten to un\u00adder\u00admine the pos\u00adsib\u00adil\u00adity of run\u00adning chal\u00adlenge tri\u00adals at all. Who is go\u00ading to volun\u00adteer to put his life at risk for noth\u00ading?\r\n\r\nThere\u2019s some evid\u00adence that people would be will\u00ading to vo\u00adlun\u00adteer even without ser\u00adi\u00adous fisc\u00adal com\u00adpens\u00adation. In the case of blood dona\u00adtion, un\u00adpaid vol\u00aduntary sys\u00adtems see high dona\u00adtion rates and high\u00ader donor qual\u00adity<\/a> than mar\u00adket-based, paid-dona\u00adtion sys\u00adtems such as the U.S.\u2019s. As I write this 38,659 vo\u00adlun\u00adteers from 166 coun\u00adtries have already signed up to be Chal\u00adlenge Tri\u00adal volun\u00adteers with \u201c1 Day Soon\u00ader<\/a>,\u201d a pro-Chal\u00adlenge Tri\u00adal or\u00adgan\u00adiz\u00ada\u00adtion fo\u00adcus\u00ading on COV\u00adID-19 tri\u00adals. These vo\u00adlun\u00adteers ex\u00adpect no mon\u00adet\u00adary com\u00adpens\u00ada\u00adtion, and are primar\u00adily mo\u00adtiv\u00adated by eth\u00adic\u00adal con\u00adsid\u00ader\u00ada\u00adtions.\r\n\r\nThe ad\u00advoc\u00adates of chal\u00adlenge tri\u00adals sys\u00adtem\u00adat\u00adic\u00adally<\/a> failed to<\/a> win the ar\u00adgu\u00adment<\/a> as COV\u00adID-19 spread across the globe in 2020. Med\u00adic\u00adal reg\u00adu\u00adlat\u00adors deemed the eth\u00adic\u00adal con\u00adcerns too great. But the tide may now be chan\u00adging. This Feb\u00adru\u00adary, Brit\u00adish reg\u00adulat\u00adors ap\u00adproved<\/a> a COV\u00adID-19 chal\u00adlenge tri\u00adal. When time-in-tri\u00adal equates with lives lost, the prom\u00adise of chal\u00adlenge tri\u00adals may prove too strong to ig\u00adnore.\r\n
\r\n
Respond to the following questions in your notes and through classroom discussion.<\/h5>\r\n
    \r\n \t
  1. What moral considerations could possibly explain our hesitancy to allow willing volunteers to help with the process of finding an effective COVID-19 vaccine?<\/li>\r\n \t
  2. How can we safeguard against the possibility of \u201cdesperate exchange\u201d \u2013 that is, having vulnerable populations provide consent that is motivated by their precarious position?<\/li>\r\n \t
  3. The author asks whether we can \u201creally accept greater risk of harm and death in a small group in order to protect society as a whole,\u201d and also wonders whether there are \u201cmoral limits\u201d to what anyone can be tasked with doing in order to serve the \u201cgreater good.\u201d Should these worries concern us? Can we allow a small few to be harmed so that the rest of us might benefit? Why should arguments concerning sacrifice for the \u201cgreater good\u201d give us pause?<\/li>\r\n<\/ol>\r\n<\/div>\r\n ","rendered":"
    \n
    \n
    <\/div>\n<\/header>\n
    \n

    Should we continue to turn away willing volunteers from experimental trials even in times of crisis?<\/p>\n<\/header>\n

    \n
    \n

    Before reading: Should willing volunteers be barred from experimental treatments? Draw and label the scale below in your notes. Place yourself more toward the left side of the scale if you think consenting adults should be allowed to be intentionally infected. Place yourself more toward the right side of the scale if you think that even consenting adults shouldn\u2019t be intentionally harmed in the name of science.<\/p>\n<\/div>\n<\/div>\n<\/div>\n

    \"\"<\/div>\n
    \n

    Stakeholder Map Prompt: Using the instructions from “How to Create and Use a Stakeholder Map<\/a>,” create a stakeholder map in your notes, either individually or with your class. Show the topic, the subjects affected, and possible outcomes based on the ideas introduced at the beginning of this article and your own background knowledge of the topic.<\/p>\n<\/div>\n

    The development of the COVID-19 vaccines is worthy of celebration. Never has a vaccine for a\u00a0 novel virus been so quickly developed, tested, and rolled out. Despite this success, we could have done much<\/a> better<\/a>. In particular, a recent study<\/a> estimates that by allowing \u201cchallenge trials\u201d in the early months of the pandemic, we would have completed the vaccine licensing process between one and eight months faster than we did using streamlined conventional trials. The study also provides a conservative estimate<\/a> of the years of life that an earlier vaccine rollout would have saved: between 720,000 and 5,760,000. However, whether we should have used challenge trials depends on a number of ethical considerations.<\/p>\n

    Here is an extraordinary fact: we first genetically sequenced the virus in January 2020. Moderna then developed their RNA vaccine in just two days. But the F.D.A. could only grant the vaccine emergency authorization in late December \u2014 almost a year later. Over this period the virus killed approximately 320,000 U.S. citizens. The vast majority of the delay between development and approval was due to the time needed to run the necessary medical trials. Enough data needed to be collected to show the vaccines were effective and, even more importantly, safe.<\/p>\n

    Here\u2019s how those trials worked. Volunteers from a large pool (for example, 30,420 volunteers in Moderna\u2019s phase three trial) were randomly provided either a vaccine or a placebo. They then went about their lives. Some caught the virus, others didn\u2019t. Researchers, meanwhile, were forced to wait until enough volunteers caught the illness for the results to be statistically valid. The fact that the virus spread so quickly was a blessing in this one respect; it sped up their research considerably.<\/p>\n

    So-called \u201cchallenge trials\u201d are an alternative way to run medical trials. The difference is that in a\u00a0 challenge trial healthy (and informed<\/a>) volunteers are intentionally infected with the pathogen responsible for the illness researchers want to study. The advantages are that statistically significant results can be found with far fewer volunteers far more quickly. If we vaccinate volunteers and then expose them to the virus, we\u2019ll have a good idea of the vaccine\u2019s effectiveness within days. This means faster licensing, faster deployment of the vaccine, and, therefore, thousands<\/a> of saved lives.<\/p>\n

    Challenge trials are generally blocked from proceeding on ethical grounds. Infecting healthy people with a patho\u00adgen they might nev\u00ader oth\u00ader\u00adwise be ex\u00adposed to \u2014 a patho\u00adgen which might cause them ser\u00adi\u00adous or per\u00adman\u00adent harm or even death \u2014 might seem dif\u00adfi\u00adcult to jus\u00adti\u00adfy. Some med\u00adic\u00adal prac\u00adti\u00adtion\u00aders con\u00adsider it a vi\u00adol\u00ada\u00adtion of the Hip\u00adpo\u00adcrat\u00adic oath they have sworn to up\u00adhold \u2014 \u201cFirst, do no harm.\u201d Ad\u00advoc\u00adates of chal\u00adlenge tri\u00adals point out that slow, tra\u00addi\u00adtion\u00adal med\u00adic\u00adal tri\u00adals can cause even great\u00ader harm. Hun\u00addreds of thou\u00adsands of lives could likely have been saved had COV\u00adID-19 chal\u00adlenge tri\u00adals been per\u00admit\u00adted and the various vac\u00adcines\u2019 emer\u00adgency approv\u00adal occurred months earli\u00ader.<\/p>\n

    Ad\u00admit\u00adtedly, chal\u00adlenge tri\u00adals ef\u00adfect\u00adively shift some risk of harm from the pub\u00adlic at large to a small group of med\u00adic\u00adal vo\u00adlun\u00adteers. Can we really accept greater risk of harm and death in a small group in order to protect society as a whole? Or are there moral limits to what we can do for the \u2018greater good\u2019? Per\u00adhaps it is this unequal distribution of burdens and benefits that critics object to as un\u00adeth\u00adic\u00adal or un\u00adjust.<\/p>\n

    Ad\u00advocates of chal\u00adlenge tri\u00adals point out that vo\u00adlun\u00adteers con\u00adsent to these risks. Hence, per\u00admit\u00adting chal\u00adlenge tri\u00adals is, fun\u00adda\u00adment\u00adally, simply per\u00admitting fully con\u00adsent\u00ading adults to put them\u00adselves at risk to save oth\u00aders. We don\u2019t ban healthy adults from run\u00adning into dan\u00adger\u00adous wa\u00adter to save drowning swim\u00admers (even though these adults would be risk\u00ading harm or death). So, the reas\u00adon\u00ading goes, nor should we ban healthy adults from vo\u00adlun\u00adteer\u00ading in med\u00adic\u00adal tri\u00adals to save oth\u00aders\u2019 lives.<\/p>\n

    Of course, if a volunteer is lied to or otherwise misinformed about the risks of a medical trial, their consent to the trial does not make participation ethically permissible. For consent to be ethically meaningful, it must be informed. Volunteers must understand the risks they face and judge them to be acceptable. But making sure that volunteers fully understand the risks involved (including the \u2018unknown\u2019 risks) can be difficult. For example, a well-replicated finding from psychology is that people are not very good<\/a> at understanding the likelihood of very low- (or high-) probability events occurring. We tend to \u201cround down\u201d low probability events to \u201cwon\u2019t happen\u201d and \u201cround up\u201d high probability events to \u201cwill happen\u201d. A 0.2% probability of death doesn\u2019t seem very different from a 0.1% probability to most of us, even though it\u2019s double the risk.<\/p>\n

    Informed consent also cannot be obtained from children or those who are mentally incapable of providing it, perhaps due to extreme old age, disability, or illness. So members of these groups cannot participate in challenge trials. This limitation, combined with the fact that younger, healthier people may be more likely to volunteer for challenge trials than their more vulnerable elders, means that the insights we gain from the trial data may not translate well to the broader population. This could weaken the cost-benefit ratio of conducting challenge trials, at least in certain cases.<\/p>\n

    A fur\u00adther eth\u00adic\u00adal worry about chal\u00adlenge tri\u00adals is that the poor and the dis\u00adad\u00advant\u00adaged, those with no oth\u00ader op\u00adtions, might be indirectly coerced to take part. If in\u00addividu\u00adals are des\u00adper\u00adate enough to ac\u00adcess fin\u00adan\u00adcial resources, for ex\u00adample for food or shel\u00adter they require, they might take on in\u00adcred\u00adible per\u00adson\u00adal risk to do so. This dy\u00adnam\u00adic is called \u201cdes\u00adper\u00adate ex\u00adchange,\u201d and it must be avoided if chal\u00adlenge tri\u00adals are to be eth\u00adically per\u00admiss\u00adible.<\/p>\n

    One way to pre\u00advent des\u00adper\u00adate ex\u00adchanges is to place lim\u00adits on the fin\u00adan\u00adcial com\u00adpens\u00ada\u00adtion provided to vo\u00adlun\u00adteers, for ex\u00adample merely cov\u00ader\u00ading travel and in\u00adcon\u00adveni\u00adence costs. But this solu\u00adtion might be thought to threaten to un\u00adder\u00admine the pos\u00adsib\u00adil\u00adity of run\u00adning chal\u00adlenge tri\u00adals at all. Who is go\u00ading to volun\u00adteer to put his life at risk for noth\u00ading?<\/p>\n

    There\u2019s some evid\u00adence that people would be will\u00ading to vo\u00adlun\u00adteer even without ser\u00adi\u00adous fisc\u00adal com\u00adpens\u00adation. In the case of blood dona\u00adtion, un\u00adpaid vol\u00aduntary sys\u00adtems see high dona\u00adtion rates and high\u00ader donor qual\u00adity<\/a> than mar\u00adket-based, paid-dona\u00adtion sys\u00adtems such as the U.S.\u2019s. As I write this 38,659 vo\u00adlun\u00adteers from 166 coun\u00adtries have already signed up to be Chal\u00adlenge Tri\u00adal volun\u00adteers with \u201c1 Day Soon\u00ader<\/a>,\u201d a pro-Chal\u00adlenge Tri\u00adal or\u00adgan\u00adiz\u00ada\u00adtion fo\u00adcus\u00ading on COV\u00adID-19 tri\u00adals. These vo\u00adlun\u00adteers ex\u00adpect no mon\u00adet\u00adary com\u00adpens\u00ada\u00adtion, and are primar\u00adily mo\u00adtiv\u00adated by eth\u00adic\u00adal con\u00adsid\u00ader\u00ada\u00adtions.<\/p>\n

    The ad\u00advoc\u00adates of chal\u00adlenge tri\u00adals sys\u00adtem\u00adat\u00adic\u00adally<\/a> failed to<\/a> win the ar\u00adgu\u00adment<\/a> as COV\u00adID-19 spread across the globe in 2020. Med\u00adic\u00adal reg\u00adu\u00adlat\u00adors deemed the eth\u00adic\u00adal con\u00adcerns too great. But the tide may now be chan\u00adging. This Feb\u00adru\u00adary, Brit\u00adish reg\u00adulat\u00adors ap\u00adproved<\/a> a COV\u00adID-19 chal\u00adlenge tri\u00adal. When time-in-tri\u00adal equates with lives lost, the prom\u00adise of chal\u00adlenge tri\u00adals may prove too strong to ig\u00adnore.<\/p>\n

    \n
    Respond to the following questions in your notes and through classroom discussion.<\/h5>\n
      \n
    1. What moral considerations could possibly explain our hesitancy to allow willing volunteers to help with the process of finding an effective COVID-19 vaccine?<\/li>\n
    2. How can we safeguard against the possibility of \u201cdesperate exchange\u201d \u2013 that is, having vulnerable populations provide consent that is motivated by their precarious position?<\/li>\n
    3. The author asks whether we can \u201creally accept greater risk of harm and death in a small group in order to protect society as a whole,\u201d and also wonders whether there are \u201cmoral limits\u201d to what anyone can be tasked with doing in order to serve the \u201cgreater good.\u201d Should these worries concern us? Can we allow a small few to be harmed so that the rest of us might benefit? Why should arguments concerning sacrifice for the \u201cgreater good\u201d give us pause?<\/li>\n<\/ol>\n<\/div>\n

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