Enhanced surveillance for vaccine-associated adverse events: dTap catch-up of high school students in Yukon
Introduction
Yukon has pertussis (whooping cough) outbreaks every 2 to 4 years. Pertussis is most frequently reported in children aged < 10 years. However, in Yukon, youth aged 10 to 14 years had the highest rates of reported infection during outbreaks in 2000 and 2002-2003. The number of cases of pertussis among adolescents and adults continues to rise throughout the Yukon.
The increasing incidence of pertussis among older individuals has been observed in other jurisdictions(1-3) and is believed to be due to a combination of increased awareness, waning vaccine-induced immunity, and the low efficacy (50% to 60%) of the adsorbed whole-cell vaccine used from the early 1980s to the mid-1990s(1,4).
Historically, routine immunization in Yukon included tetanus/ diphtheria/inactivated polio (TdIPV) vaccination of Grade 9 students. To counter the upward trend in the age of pertussis cases, the Grade 9 TdIPV booster was replaced in the spring of 2004 with a new adolescent/adult vaccine for diphtheria/tetanus/ acellular pertussis (dTap), AdacelTM.
To increase the proportion of the young adult population protected against pertussis, the Territorial Advisory Committee on Immunization (TACI) recommended a 3-year catch-up program to provide Grade 12 students with one dose of acellular pertussis vaccine. Since no monovalent product was approved for sale in Canada, Grade 12 students were offered one dose of dTap in spring 2004, meaning that vaccinated Grade 12 students received a tetanus toxoid booster approximately 3 years after their Grade 9 TdIPV vaccination.
Studies suggest that rates of local reactions increase with the number of doses of tetanus toxoid received(4). Therefore, the National Advisory Committee on Immunization (NACI) recommends that tetanus toxoid “not be given routinely to a patient who has received a booster dose in the preceding five years”(5). TACI viewed the proposed 3-year dTap catch-up program not as “routine” but, rather, as a short-term rescue program whose benefits of enhanced pertussis protection would outweigh the risk of vaccine-associated adverse events (VAAEs).
As Yukon was the first Canadian jurisdiction to administer dTap to a cohort of students within < 5 years of their last tetanus toxoid, the territory implemented enhanced surveillance for VAAEs with the following intentions:
To monitor the rate and nature of adverse events following AdacelTM vaccination of Grade 9 and Grade 12 students;
To compare the rates and severity of VAAEs among students who had received their previous tetanus toxoid component within 3 to < 5 years with those of students who had received that component >= 5 years previously, to determine whether the former group was at increased risk of severe VAAEs.
Methods
Vaccination clinics were offered at Yukon high schools. Community health nurses administered vaccine to students who returned completed consent forms and for whom dTap was not contraindicated. Contraindications included a tetanus toxoid booster < 3 years previously, confirmed pertussis since 1996, fever on the day of vaccination, or a history of either severe oropharyngeal swelling that limited breathing or hives in response to any previous vaccine. All of the dTap vaccines had the same lot number.
Vaccinated students were asked to complete a self-administered adverse events questionnaire (AEQ). Students received small packages of OreoTM cookies with which to gauge the size of redness and swelling (OreoTM cookies are 46 mm in diameter).
Primary health care providers were sent information before the vaccination program, including details about the program and a request to report VAAEs to Yukon Communicable Disease Control.
Public Health conducted follow-up telephone interviews with students who reported indicators of severe VAAEs on their AEQ to determine whether the students truly experienced severe VAAEs. Key indicators were as follows:
- absence from school due to symptoms related to vaccination;
- one or more of the following: erythema or swelling >= Oreo™ cookie size (46 mm), fever > 38.3o C or marked limitation of arm movement; and/or,
- medical attention sought for symptoms related to vaccination.
Community health centres across Yukon adapted class lists and lists of home-schooled students provided by the Department of Education to include demographic and past vaccination information from the students’ vaccination records.
Each student was assigned a unique identification number. The AEQ and class list data were entered into EpiData(6) databases and linked non-nominally. Data were analyzed using EpiInfo(7) software. The proportion of respondents developing each adverse reaction was compared between those who had received the tetanus toxoid >= 5 years previously (Group F) and those who had received the tetanus toxoid between 3 and >= 5 years previously (Group T) using odds ratios and Fisher’s exact test. Symptom severity was compared between the two groups using Chi square analysis, odds ratios, and Fisher’s exact test. When the sample size was insufficient, symptom categories were collapsed to allow valid statistical analysis. Duration of symptoms and times between vaccination and symptom onset were compared using Kruskal-Wallis H test. The level of significance was set at 0.05, and 95% confidence intervals (CI) were calculated.
Results
The number of students in each grade, percentage vaccinated, and response rate to the AEQ are outlined in Table 1. Eighty- eight students in Group T and 172 students in Group F were vaccinated and completed the AEQ. Thirty-five students were excluded from our analysis either because they had received dTap < 3 years after their last tetanus booster or the date of their last tetanus booster was unknown
Table 1. Participation in vaccination and completion of the adverse events questionnaire (AEQ)
Grade 9 (n = 342) |
Grade 12 (n = 456) |
Other grade* | ||||
---|---|---|---|---|---|---|
No. | % | No. | % | No. | % | |
Ineligible for vaccine | 24 | 7.0 | 61 | 13.4 | 1 | |
Vaccinated | 239 | 69.9 | 178 | 39.0 | 15 | |
Completed AEQ | 185 | 77.4 | 97 | 54.5 | 13 | 86.7 |
*Grades 10, 11, or not specified |
Table 2 outlines respondent demographic features by time since last tetanus booster. The majority of Group T were in Grade 12, and the majority of Group F were in Grade 9 (p < 0.001). The school distributions of the two groups also varied significantly (p = 0.020).
Table 2. Demographic features of students by time since last tetanus toxoid
Group U1 (n = 31) |
Group L2 (n = 4) |
Group T3 (n = 88) |
Group F4 (n = 172) |
Statistical comparison of Group T versus Group F | |||||
---|---|---|---|---|---|---|---|---|---|
# | % | # | % | # | % | # | % | ||
Grade | Chi square = 230.91, p < 0.001* | ||||||||
9 | 27 | 87.1 | 1 | 25.0 | 0 | 0.0 | 157 | 91.3 | |
12 | 3 | 9.7 | 1 | 25.0 | 87 | 98.9 | 6 | 3.5 | |
Other | 1 | 3.2 | 2 | 50.0 | 1 | 1.1 | 9 | 5.2 | |
School | Chi square = 13.39, p = 0.020* | ||||||||
FHC | 6 | 19.4 | 0 | 0.0 | 23 | 26.1 | 43 | 25.0 | |
PCSS | 17 | 54.8 | 1 | 25.0 | 32 | 36.4 | 39 | 22.7 | |
RS | 0 | 0.0 | 1 | 25.0 | 9 | 10.2 | 18 | 10.5 | |
V | 7 | 22.6 | 1 | 25.0 | 12 | 13.6 | 55 | 32.0 | |
WL | 0 | 0.0 | 0 | 0.0 | 4 | 4.5 | 3 | 1.7 | |
Other | 1 | 3.2 | 1 | 25.0 | 8 | 9.1 | 14 | 8.1 | |
Sex | Chi square = 2.22, p = 0.330 | ||||||||
Male | 17 | 54.8 | 1 | 25.0 | 31 | 35.2 | 77 | 44.8 | |
Female | 13 | 42.9 | 1 | 25.0 | 41 | 46.6 | 67 | 39.0 | |
Unspecified | 1 | 3.2 | 2 | 50.0 | 16 | 18.2 | 28 | 16.3 | |
Age | |||||||||
Mean | 15.0 | 16.8 | 17.6 | 14.6 | H = 173.171, p < 0.001* | ||||
Mean Age, Grade 9 | 14.6 | 15.0 | n/a | 14.4 | n/a | ||||
Mean Age, Grade 12 | 17.7 | 17.0 | 17.6 | 17.5 | H = 0.839, p = 0.360 | ||||
1 Unknown time since last tetanus toxoid |
Symptoms reported by respondents are outlined in Table 3. Group T was more likely than Group F to report pain at the injection site (p = 0.049) and less likely to report swelling at the injection site (p = 0.010), limitations of arm movement (p = 0.002), headache (p = 0.034), body aches (p = 0.015), and sore joints (p = 0.008). There were no statistically significant differences in reports of redness at the injection site, decreased energy, fever, nausea/vomiting, diarrhea, symptom severity, or symptom duration.
Table 3. Symptoms reported by respondents by time since last tetanus toxoid
Group T: >= 3 to < 5 years since last tetanus toxoid (n = 88) | Group F: >= 5 years since last tetanus toxoid (n = 172) |
Statistical comparison of difference | |||||
---|---|---|---|---|---|---|---|
# Reporting symptom | # Responding | % | # Reporting symptom | # Responding | % | ||
Redness at injection site | |||||||
Any redness at injection site | 6 | 87 | 6.9 | 25 | 172 | 14.5 | OR = 0.44 (0.15-1.19), p = 0.074 |
Size of redness | 6 | 24 | p = 1.000 | ||||
Smaller than an OreoTM | 6 | 100.0 | 21 | 87.5 | |||
Larger than an OreoTM* | 0 | 0.0 | 2 | 8.3 | |||
Upper arm* | 0 | 0.0 | 1 | 4.2 | |||
Entire arm* | 0 | 0.0 | 0 | 0.0 | |||
Time to onset (hours) | Range = 2-48, median = 2.5 | Range = 0-48, median = 2 | H = 1.387, p = 0.239 | ||||
Duration (hours) | Range = 1.5-8, median = 5.5 | Range = 1 to ongoing, median = 4 | H = 0.113, p = 0.737 | ||||
Swelling | |||||||
Any swelling | 3 | 88 | 3.4 | 23 | 169 | 13.6 | OR = 0.22 (0.05-0.83), p = 0.010† |
Size of swelling | 3 | 23 | p = 0.238 | ||||
Smaller than an OreoTM | 3 | 100.0 | 12 | 52.2 | |||
Larger than an OreoTM* | 0 | 0.0 | 8 | 34.8 | |||
Upper arm* | 0 | 0.0 | 3 | 13.0 | |||
Entire arm* | 0 | 0.0 | 0 | 0.0 | |||
Time to onset (hours) | Range = 0-24, median = 3 | Range = 0-31, median = 3 | H = 0.031, p = 0.860 | ||||
Duration (hours) | Range = 72 to ongoing, median = 96 | Range = 1 to ongoing, median = 24 | H =1.248, p = 0.264 | ||||
Pain at injection site | |||||||
Any pain at injection site | 61 | 88 | 69.3 | 97 | 171 | 56.7 | OR = 1.72 (0.96-3.10), p = 0.049† |
Severity of pain | 60 | 94 | p = 0.108 | ||||
Mild | 41 | 68.3 | 52 | 55.3 | |||
Moderate* | 18 | 30.0 | 39 | 41.5 | |||
Marked* | 1 | 1.7 | 3 | 3.2 | |||
Time to onset (hours) | Range = 0-24, median = 1.5 | Range = 0-48, median = 1 | H = 2.053, p = 0.152 | ||||
Duration (hours) | Range = 0.5 to ongoing, median = 36 | Range = 0.1 to ongoing, median = 24 | H = 1.486, p = 0.223 | ||||
Limitation of arm movement | |||||||
Any limitation of arm movement | 24 | 88 | 27.3 | 81 | 171 | 47.4 | OR = 0.42 (0.23-0.76), p = 0.002 |
Severity of movement limitation | 23 | 76 | p = 0.629† | ||||
Mild | 11 | 47.8 | 32 | 42.1 | |||
Moderate* | 11 | 47.8 | 39 | 51.3 | |||
Marked* | 1 | 4.3 | 5 | 6.6 | |||
Time to onset (hours) | Range = 0-24, median = 1 | Range = 0-24, median = 2 | H = 1.448, p = 0.229 | ||||
Duration (hours) | Range = 2 to ongoing, median = 24 | Range = 0.1 to ongoing, median = 24 | H = 0.001, p = 0.973 | ||||
Decreased energy | |||||||
Any decreased energy | 5 | 87 | 5.7 | 21 | 171 | 12.3 | OR = 0.44 (0.14-1.29), p = 0.100 |
Affected usual activity level | 2 | 5 | 40.0 | 13 | 21 | 61.9 | OR = 0.41 (0.03-4.58), p = 0.619 |
Time to onset (hours) | Range = 0.1-12, median = 4 | Range = 0-48, median = 2 | H = 0.000, p = 1.000 | ||||
Duration (hours) | Range = 1-60, median = 4 | Range = 0.1 to ongoing, median = 24 | H = 1.098, p = 0.295 | ||||
Fever | |||||||
Any fever | 0 | 88 | 0.0 | 3 | 171 | 1.8 | OR = 0.00 (0.00-4.44), p = 0.553 |
Time to onset (hours) | Range = 3-72, median = 4.0 | ||||||
Duration (hours) | Range = 4.5-24, median = 6 | ||||||
Headache | |||||||
Any headache | 3 | 88 | 3.4 | 19 | 169 | 11.2 | OR = 0.28 (0.06-1.05), p = 0.034† |
Severity of headache | 3 | 18 | p = 0.553 | ||||
Mild | 1 | 33.3 | 11 | 61.1 | |||
Moderate* | 2 | 66.7 | 5 | 27.8 | |||
Severe* | 0 | 0.0 | 2 | 11.1 | |||
Medication for headache | 1 | 33.3 | 10 | 58.8 | OR = 0.35 (0.01-6.87), p = 0.566 | ||
Time to onset (hours) | Range = 6-72, median = 24 | Range = 0-72, median = 2 | H = 3.149, p = 0.076 | ||||
Duration (hours) | Range = 5-60, median = 24 | Range = 0.3 to ongoing, median = 5.5 | H = 1.271, p = 0.260 | ||||
Body aches | |||||||
Any body aches | 1 | 88 | 1.1 | 15 | 168 | 8.9 | OR = 0.12 (0.01-0.88), p = 0.015† |
Severity of body aches | 1 | 15 | OR = 0.00 (0.00-8.55), p = 0.313 | ||||
Mild | 0 | 0.0 | 11 | 73.3 | |||
Moderate | 1 | 100.0 | 4 | 26.7 | |||
Severe | 0 | 0.0 | 0 | 0.0 | |||
Time to onset (hours) | 24 | Range = 0-48, median = 3.0 | |||||
Duration (hours) | 24 | Range = 6 to ongoing, median = 48 | |||||
Sore joints | |||||||
Any sore joints | 3 | 88 | 3.4 | 24 | 169 | 14.2 | OR = 0.21 (0.05-0.78), p = 0.008† |
Severity of sore joints | 3 | 22 | p = 0.527 | ||||
Mild | 3 | 100.0 | 14 | 63.6 | |||
Moderate | 0 | 0.0 | 8 | 36.4 | |||
Severe | 0 | 0.0 | 0 | 0.0 | |||
Time to onset (hours) | Range = 1-24, median = 2 | Range = 0-48, median = 2 | H = 0.053, p = 0.818 | ||||
Duration (hours) | Range = 1-24, median = 12 | Range = 0.1 to ongoing, median = 24 | H = 0.699, p = 0.403 | ||||
Nausea/vomiting | |||||||
Nausea | 1 | 88 | 1.1 | 8 | 168 | 4.8 | OR = 0.23 (0.01-1.88), p = 0.171 |
Vomiting | 0 | 1 | 0.0 | 0 | 7 | 0.0 | Chi square = 0.00, p = 1.000 |
Time to onset (hours) | 0.5 | Range = 0-60, median = 0.25 | |||||
Duration (hours) | 0.3 | Range = 2-24, median = 4 | |||||
Diarrhea | |||||||
Diarrhea | 1 | 88 | 1.1 | 1 | 168 | 0.6 | OR = 1.92 (0.02-151.56), p = 1.000 |
Time to onset (hours) | 24 | ||||||
Duration (hours) | 12 | ||||||
Other symptoms | 5 | 88 | 5.7 | 15 | 158 | 9.5 | OR = 0.57 (0.17-1.79), p = 0.295 |
Severe VAAE | |||||||
Reported indicator | 2 | 88 | 2.3 | 22 | 172 | 12.8 | OR = 0.16 (0.02-0.73), p = 0.006† |
Experienced | 1 | 88 | 1.1 | 10 | 172 | 5.8 | OR = 0.19 (0.01-1.45), p = 0.105 |
*These categories were collapsed during statistical analyses comparing symptom severities between groups. †Statistically significant difference (p < 0.050) NOTE: When a participant indicated that a symptom was "ongoing", the value used to calculate mean duration was 120 hours (the average duration of those who indicated that symptoms were ongoing and who were followed up with a phone call because of markers of serious adverse events). |
Group T was more likely than Group F to complete the AEQ > 7 days after receiving the vaccine (63% versus 15%, Chi square = 106.06, p < 0.001). Those completing their questionnaires late were less likely than those completing it at 7 days to report limitations of arm movement (28% versus 43%, OR = 0.51, 95% CI = 0.27-0.96, p = 0.025), headache (0% versus 11%, OR = 0.00, 95% CI = 0.00-0.55, p = 0.002), and sore joints (4% versus 15%, OR = 0.22, 95% CI = 0.05-0.82, p = 0.010). Subanalyses demonstrated that the time lag between vaccine receipt and AEQ completion did not confound or interact with the relations between time since last tetanus toxoid and limitations of arm movement or headache; however, it did confound the relation with reports of sore joints. When the time lag between vaccination and AEQ completion was controlled for, reporting of sore joints was no longer associated with time since last tetanus toxoid (OR = 0.45, 95% CI = 0.09-2.37, p = 0.520).
A significantly smaller proportion of Group T members (2%) than Group F members (13%) reported indicators of severe reactions (p = 0.006) (Table 3). Public Health follow-up with these students found that some respondents misinterpreted measures of symptom severity on the AEQ, recording symptoms as being more severe then they actually were. Reports from five students (one in Group T, four in Group F) were likely not related to the vaccine. The reactions of seven students in Group F were re-coded as mild or moderate. One student in Group T and 10 in Group F experienced severe VAAEs. The rate of severe VAAEs did not differ between Group T and Group F (p = 0.105) (Table 3).
One student experiencing a severe VAAE reported fever; the other 10 reported marked limitation of arm movement and/or redness or erythema larger than an OreoTM cookie (Table 4). In all cases, symptoms resolved without further complication within 2 to 12 days.
There were no reports of dTap-associated VAAEs by health care professionals. One student reported visiting the emergency room for pain at the injection site; however, she left without being seen by a physician, and symptoms resolved within 24 hours.
Table 4. Reports of severe vaccine associated adverse events
Time* (years) | Symptoms | Missed school |
---|---|---|
3-5 | Marked limitation of arm movement, severe pain at injection site | No |
> 5 | Fever, moderate pain at injection site, decreased energy, headache | No |
> 5 | Marked limitation of arm movement, redness < 46 mm, swelling < 46 mm, mild pain at injection site, lump in armpit | No |
> 5 | Marked limitation of arm movement, redness < 46 mm, severe pain at injection site, moderately sore joints, nausea | No |
> 5 | Redness >= 46 mm, mild pain at injection site, mild soreness in joints | No |
> 5 | Redness >= 46 mm cookie, swelling >= 46 mm, moderate pain at injection site, decreased energy, moderate sore joints |
No |
> 5 | Entire upper arm red, moderate limitation of arm movement, decreased energy, moderate headache, mildly sore joints | No |
> 5 | Swelling >= 46 mm, redness < 46 mm, decreased energy | No |
> 5 | Swelling >= 46 mm, moderate pain at injection site, diarrhea | No |
> 5 | Entire upper arm swollen, marked limitation of arm movement, severe pain at injection site | Yes |
> 5 | Entire upper arm swollen, mild limitation of arm movement | No |
*Time since last tetanus toxoid |
Discussion
In enhanced surveillance for VAAEs it was found that Group T was more likely than Group F to report pain at the injection site. Surprisingly, this group was significantly less likely to report swelling at the injection site, limitations of arm movement, headache, or body aches. The rates of adverse events reported for both groups were either within or below the range of those observed elsewhere(8,9).
Reporting of VAAE symptoms was subjective. Public Health telephone follow-up with students reporting severe VAAEs indicators revealed that some questions were open to misinterpretation. When severity was assessed during follow-up questioning, many of the adverse events were found to be less severe than initially reported. Other reported indicators (i.e. missed school) were unrelated to the dTap vaccine. Once inappropriate reports had been excluded, there was no association between VAAEs and time since last tetanus toxoid.
Group T reported fewer VAAE indicators than Group F. Group T also reported a number of other symptoms less frequently than Group F. However, if any group experienced increased reactions, it would be expected to be the group with the shortened time interval between tetanus toxoid boosters (Group T). The decreased reporting by Group T when compared with Group F may reflect differences in reporting behaviour between the two groups. This may be attributable to age, as Group F was younger than Group T.
Because this was enhanced surveillance following a community-based vaccination program and not a controlled trial, variations in age and grade distribution with time since last tetanus toxoid booster were expected. In general, Grade 9 students had not received tetanus toxoid since school entry, and Grade 12 students had received it when they were in Grade 9. However, the observed differences in participation rates within each school between the two groups were not expected and may be attributable to other factors not assessed, such as socio-economic status.
The timing of the vaccination program limited the quality of the data collected. The AEQs were intended to be administered to all students during class time 1 week following vaccination. Unforeseen delays resulted in the vaccination program being carried out in the last few weeks of the school year. Because of the proximity to examinations and graduation ceremonies, a number of schools could not afford the class time for questionnaire completion by Grade 12 students. This resulted in the majority of Grade 12 students being given their AEQ and OreoTM cookies at the time of vaccination and being asked to complete the questionnaire in their own time. As Group T consisted mainly of Grade 12 students and Group F consisted mainly of Grade 9 students, this resulted in different treatment of the two comparison groups and may have introduced bias. Being presented with a list of potential reactions at the time of immunization might have resulted in the Grade 12 students being more aware of their symptoms and more likely to report them. Such bias was not evident, as the Grade 12 students did not consistently report more symptoms than the Grade 9 students.
As a result of this difference in data collection methods, many Grade 12 students (i.e. Group T) completed the AEQ late. This reporting delay may have contributed to the recall bias, as late responders may have had diminished recall or perceptions of the symptoms experienced. The time lag may partially explain why Group T was less likely to report symptoms than Group F. Stratifying by time between vaccine and AEQ completion demonstrated that the time lag confounded the relation between the time since last tetanus toxoid and reporting of sore joints. Once the time lag had been controlled for, however, there was no significant difference in the reports of sore joints between Group T and Group F.
The inopportune timing of the program may have contributed to the low vaccine uptake among Grade 12 students and low rate of response to the AEQ. The small sample may have led to less precise comparisons of symptom severity. However, the sample was large enough to detect differences in individual symptoms associated with the vaccine. No difference was detected in the incidence of severe adverse events between the two groups; however, the group we were concerned about was less likely to report severe reactions.
Conclusions
Enhanced surveillance of VAAEs provides evidence that the adverse events following dTap vaccination of high school students in Yukon were within the expected range.
Five lines of evidence support our conclusion that students who received dTap 3 to < 5 after their last tetanus toxoid booster did not experience increased risk of severe VAAEs:
While a larger proportion of students who received dTap 3 to < 5 years after their last tetanus toxoid booster reported pain at the injection site, they were less likely than students who received dTap >= 5 years after their last tetanus toxoid booster to report swelling at the injection site, limitations of arm movement, headache, and body aches.
There was no significant difference in the severity/duration of symptoms reported by the two groups.
There was no significant difference in the proportion of respondents in either group experiencing severe VAAEs.
None of the respondents who completed the AEQ reported obtaining medical attention for VAAEs.
No medical professionals reported seeing patients with VAAEs associated with dTap.
Catch-up dTap and routine VAAE monitoring will continue in Yukon in 2005. Further surveillance of VAAEs among larger numbers of vaccinated students is required to strengthen our findings.
Acknowledgements
B. Candow and J. O’Connor from the Yukon Centre for Disease Control; Dr. L. Panaro, Dr. W. Walop, E. Nadarajah da Silva, D. Ducharme from the Public Health Agency of Canada; Dr. M. Naus from the BC Centre for Disease Control; Y. Titley and Yukon public health nurses; Dr. G. de Serres, Quebec National Institute of Public Health and Laval University.
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Source: ST David, MHSc, Canadian Field Epidemiology Program, Public Health Agency of Canada and Epidemiology Services, British Columbia Centre for Disease Control; C Hemsley, RN, Yukon Health and Social Services; PE Pasquali, PhD, Yukon Health and Social Services; B Larke, MD, Yukon Health and Social Services; JA Buxton, MB, BS, British Columbia Centre for Disease Control; LY Lior, MD, MSc, Canadian Field Epidemiology Program, Public Health Agency of Canada.
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