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Background: Myocarditis is more common after severe acute respiratory syndrome coronavirus 2 infection than after COVID-19 vaccination, but the risks in younger people and after sequential vaccine doses are less certain. Methods: A self-controlled case series study of people ages 13 years or older vaccinated for COVID-19 in England between December 1, 2020, and December 15, 2021, evaluated the association between vaccination and myocarditis, stratified by age and sex. The incidence rate ratio and excess number of hospital admissions or deaths from myocarditis per million people were estimated for the 1 to 28 days after sequential doses of adenovirus (ChAdOx1) or mRNA-based (BNT162b2, mRNA-1273) vaccines, or after a positive SARS-CoV-2 test. Results: In 42 842 345 people receiving at least 1 dose of vaccine, 21 242 629 received 3 doses, and 5 934 153 had SARS-CoV-2 infection before or after vaccination. Myocarditis occurred in 2861 (0.007%) people, with 617 events 1 to 28 days after vaccination. Risk of myocarditis was increased in the 1 to 28 days after a first dose of ChAdOx1 (incidence rate ratio, 1.33 [95% CI, 1.09–1.62]) and a first, second, and booster dose of BNT162b2 (1.52 [95% CI, 1.24–1.85]; 1.57 [95% CI, 1.28–1.92], and 1.72 [95% CI, 1.33–2.22], respectively) but was lower than the risks after a positive SARS-CoV-2 test before or after vaccination (11.14 [95% CI, 8.64–14.36] and 5.97 [95% CI, 4.54–7.87], respectively). The risk of myocarditis was higher 1 to 28 days after a second dose of mRNA-1273 (11.76 [95% CI, 7.25–19.08]) and persisted after a booster dose (2.64 [95% CI, 1.25–5.58]). Associations were stronger in men younger than 40 years for all vaccines. In men younger than 40 years old, the number of excess myocarditis events per million people was higher after a second dose of mRNA-1273 than after a positive SARS-CoV-2 test (97 [95% CI, 91–99] versus 16 [95% CI, 12–18]). In women younger than 40 years, the number of excess events per million was similar after a second dose of mRNA-1273 and a positive test (7 [95% CI, 1–9] versus 8 [95% CI, 6–8]). Conclusions: Overall, the risk of myocarditis is greater after SARS-CoV-2 infection than after COVID-19 vaccination and remains modest after sequential doses including a booster dose of BNT162b2 mRNA vaccine. However, the risk of myocarditis after vaccination is higher in younger men, particularly after a second dose of the mRNA-1273 vaccine.

AbstractBackground:Myocarditis is more common after severe acute respiratory syndrome coronavirus 2 infection than after COVID-19 vaccination, but the risks in younger people and after sequential vaccine doses are less certain.Methods:A self-controlled case series study of people ages 13 years or older vaccinated for COVID-19 in England between December 1, 2020, and December 15, 2021, evaluated the association between vaccination and myocarditis, stratified by age and sex. The incidence rate ratio and excess number of hospital admissions or deaths from myocarditis per million people were estimated for the 1 to 28 days after sequential doses of adenovirus (ChAdOx1) or mRNA-based (BNT162b2, mRNA-1273) vaccines, or after a positive SARS-CoV-2 test.Results:In 42 842 345 people receiving at least 1 dose of vaccine, 21 242 629 received 3 doses, and 5 934 153 had SARS-CoV-2 infection before or after vaccination. Myocarditis occurred in 2861 (0.007%) people, with 617 events 1 to 28 days after vaccination. Risk of myocarditis was increased in the 1 to 28 days after a first dose of ChAdOx1 (incidence rate ratio, 1.33 [95% CI, 1.09–1.62]) and a first, second, and booster dose of BNT162b2 (1.52 [95% CI, 1.24–1.85]; 1.57 [95% CI, 1.28–1.92], and 1.72 [95% CI, 1.33–2.22], respectively) but was lower than the risks after a positive SARS-CoV-2 test before or after vaccination (11.14 [95% CI, 8.64–14.36] and 5.97 [95% CI, 4.54–7.87], respectively). The risk of myocarditis was higher 1 to 28 days after a second dose of mRNA-1273 (11.76 [95% CI, 7.25–19.08]) and persisted after a booster dose (2.64 [95% CI, 1.25–5.58]). Associations were stronger in men younger than 40 years for all vaccines. In men younger than 40 years old, the number of excess myocarditis events per million people was higher after a second dose of mRNA-1273 than after a positive SARS-CoV-2 test (97 [95% CI, 91–99] versus 16 [95% CI, 12–18]). In women younger than 40 years, the number of excess events per million was similar after a second dose of mRNA-1273 and a positive test (7 [95% CI, 1–9] versus 8 [95% CI, 6–8]).Conclusions:Overall, the risk of myocarditis is greater after SARS-CoV-2 infection than after COVID-19 vaccination and remains modest after sequential doses including a booster dose of BNT162b2 mRNA vaccine. However, the risk of myocarditis after vaccination is higher in younger men, particularly after a second dose of the mRNA-1273 vaccine.Clinical PerspectiveWhat Is New?•We performed an evaluation of the risk of myocarditis after COVID-19 vaccine in >42 million vaccinated people 13 years or older, including 21 million people receiving a booster dose, stratified by age and sex.•We extend our previous findings demonstrating that the risk of hospitalization or death from myocarditis after SARS-CoV-2 infection is substantially higher than the risk associated with a first dose of ChAdOx1, and a first, second, or booster dose of BNT162b2 mRNA vaccine.•Associations were stronger in younger men <40 years for all vaccines and after a second dose of mRNA-1273 vaccine, where the risk of myocarditis was higher after vaccination than SARS-CoV-2 infection.What Are the Clinical Implications?•Our findings will inform recommendations on the type of vaccine offered to younger people and will help to shape public health policy on booster programs enabling an informed discussion of the risk of vaccine associated myocarditis when considering the net benefit of vaccination.We recently reported an association between the first and second dose of COVID-19 vaccination and myocarditis, which generated considerable scientific, policy, and public interest.1 It added to evidence emerging from multiple countries that has linked exposure to BNT162b2 mRNA vaccine with acute myocarditis.2–8 In the largest and most comprehensive analysis to date, we reported an increased risk of hospital admission or death from myocarditis after both adenoviral (ChAdOx1) vaccines and mRNA (BNT162b2 or mRNA-1273) vaccines. It is important that we also demonstrated across the entire vaccinated population in England that the risk of myocarditis after vaccination was small compared with the risk after a positive SARS-CoV-2 test.1However, myocarditis is more common in younger people younger than the age of 40 years and in men in particular.9,10 Additional analyses stratified by age and sex are important because vaccine campaigns are rapidly being extended to include children and young adults. Furthermore, given the consistent observation that the risk of myocarditis is higher after the second dose of vaccine compared with the first dose,1,11 there is an urgent need to evaluate the risk associated with a booster dose because booster programs are accelerated internationally to combat the omicron variant.12Because new data were available, we have extended our analysis to include people ages 13 years or older and those receiving a booster dose to further evaluate the association between COVID-19 vaccination or infection and risk of myocarditis, stratified by age and sex.MethodsTransparency and Openness PromotionThis analysis makes use of multiple routinely collected health care data sources that were linked, deidentified, and held in a trusted research environment that was accessible to approved individuals who had undertaken the necessary governance training. Because of the sensitive nature of the data collected for this study, requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to National Health Service Digital and the United Kingdom Health Security Agency. Simulated data and the analysis code are available publicly at https://github.com/qresearchcode/COVID-19-vaccine-safety. National Health Service Research Ethics Committee approval was obtained from the East Midlands–Derby Research Ethics Committee (Reference 18/EM/0400]. Anonymized data are analyzed, so there is no requirement for written informed consent.Data SourcesWe used the National Immunisation Database of COVID-19 vaccination to identify vaccine exposure. This includes vaccine type, date, and doses for all people vaccinated in England. We linked National Immunisation Database vaccination data, at the individual level, to national data for mortality (Office for National Statistics), hospital admissions (Hospital Episode Statistics and Secondary User’s service data), and SARS-CoV-2 infection data (Second Generation Surveillance System).Study Design and OversightWe undertook a self-controlled case series design, originally developed to examine vaccine safety.12 The analyses are conditional on each case, so any fixed characteristics during the study period, such as sex, ethnicity, or chronic conditions, are inherently controlled for. Age was considered as a fixed variable because the study period was short. Any time-varying factors, such as seasonal variation, need to be adjusted for in the analyses. Hospital admissions were likely to be influenced by the pressure on the health systems because of COVID-19, which was not uniform during the pandemic study period. To allow for these underlying seasonal effects, we split the study observation period into weeks and adjusted for week as a factor variable in the statistical models.Study Period and PopulationWe included all people ages 13 years or older who had received at least 1 dose of ChAdOx1 (AstraZeneca), BNT162b2 (Pfizer), and mRNA-1273 (Moderna) vaccine and were admitted to hospital or died from myocarditis between December 1, 2020, and December 15, 2021.OutcomeThe primary outcome of interest was the first hospital admission caused by the myocarditis, or death recorded on the death certificate with the International Classification of Diseases, Tenth Revision code (Table S1) related to myocarditis within the study period (December 1, 2020, to December 15, 2022). We used the earliest date of hospitalization or date of death as the event date.ExposuresThe exposure variables were a first, second, or booster dose of the ChAdOx1, BNT162b2, or mRNA-1273 vaccines, and SARS-CoV-2 infection, defined as the first SARS-CoV-2–positive test in the study period. All exposures were included in the same model. We defined the exposure risk intervals as the following prespecified time periods: 0, 1 to 7, 8 to 14, 15 to 21, and 22 to 28 days after each exposure date, under the assumption that the adverse events under consideration are unlikely to be related to exposure later than 28 days after exposure. A pre-risk interval of 1 to 28 days before each exposure date was included to account for potential bias that might arise if the occurrence of the outcome temporarily influenced the likelihood of exposure. The baseline period for the vaccination exposures was the remaining time from December 1, 2020, until 29 days before the first dose date and from 29 days after the first or second dose until 29 days before the second or booster dose (if applicable), and from 29 days after the booster dose until December 15, 2021, or the censored date if earlier. We assumed that the risks might be different after each vaccine dose, and hence we allowed for a dose effect, by defining a separate risk interval after each dose: 0, 1 to 7, 8 to 14, 15 to 21, or 22 to 28 days after the first, second, or booster dose. To avoid overlapping risk periods, we assumed that later exposures take precedence over earlier ones, except for the 1- to 28-day pre-risk period for the second or booster dose. A positive SARS-CoV-2 test was considered as a separate exposure in the models, which allowed overlapping risk windows with vaccination exposure.Statistical AnalysisWe described the characteristics of the whole study population by vaccine dose and type, and in those with myocarditis stratified by age and sex.In vaccinated people with myocarditis, the self-controlled case series models were fitted using a conditional Poisson regression model with an offset for the length of the exposure risk period. Incidence rate ratios (IRR), the relative rate of hospital admissions or deaths caused by myocarditis in exposure risk periods relative to baseline periods, and their 95% CIs were estimated by the self-controlled case series model adjusted for calendar time. We investigated if associations between vaccine exposure and the myocarditis outcome were sex- or age-dependent by performing subgroup analyses stratified by sex and age (men age <40 years, men age≥ 40 years, women age <40 years, and women age ≥40 years). We also conducted analyses stratified by vaccination history, restricted to those who had the same type of vaccine in the first and second dose and by lag in days between the first and second dose (≤65, 66 to 79, and ≥80 days).We conducted sensitivity analyses to assess the robustness of results to assumptions, such as that the occurrence of an outcome event did not influence the probability of subsequent exposures by (1) excluding those who died from the outcome and (2) restricting analysis to the period after the first dose and (3) after the second dose, without censoring at death; and to assess potential reporting delays in the data by (4) restricting the study to the period up to December 1, 2021.We also performed sensitivity analyses (5) removing patients who had outcomes in the 28 days after a first dose, but before a second dose, and (6) removing patients who had outcomes in the 28 days after a second dose, but before a booster dose, because they are less likely to have a second dose if they experienced an adverse event after the first. Last, we conducted a sensitivity analysis (7) restricted to those without a positive SARS-CoV-2 test during the observation period.We used Stata (version 17) for these analyses.ResultsBetween December 1, 2020, and December 15, 2021, there were 42 842 345 people vaccinated with at least 1 dose of ChAdOx1 (n=20 650 685), BNT162b2 (n=20 979 704), or mRNA-1273 (n=1 211 956) (Table 1). Of these, 39 118 282 received a second dose of ChAdOx1 (n=20 080 976), BNT162b2 (n=17 950 086), or mRNA-1273 (n=1 087 220), and 21 242 629 people received a third vaccine dose: ChAdOx1 (n=53 606), BNT162b2 (n=17 517 692), and mRNA-1273 (n=3 671 331).Table 1. Baseline Demographic Characteristics of People Receiving ChAdOx1, BNT162b2, or mRNA-1273 Vaccines or Testing Positive for SARS-CoV-2 Virus (in Those Vaccinated) in England Between December 1, 2020, and December 15, 2021 ChAdOx1BNT162b2mRNA-1273ChAdOx1BNT162b2mRNA-1273ChAdOx1BNT162b2mRNA-1273SARS- CoV-2 positive*One dose (n=42 842 345)Two doses (n=39 118 282)Booster doses (n=21 242 629)(n=5 934 153)% (n)% (n)% (n)% (n)% (n)% (n)% (n)% (n)% (n)% (n)Total no. of people20 650 68520 979 7041 211 95620 080 97617 950 0861 087 22053 60617 517 6923 671 3315 934 153Sex Women49.5 (10 215 079)49.1 (10 295 561)38.7 (469 114)49.5 (9 945 533)50.1 (9 000 748)39.5 (429 705)61.2 (32 792)54.2 (9 489 364)48.4 (1 778 317)52.3 (3 103 168) Men43.3 (8 933 572)40.4 (8 476 032)42.0 (508 416)43.3 (8 697 560)39.8 (7 148 539)42.1 (457 629)34.8 (18 674)41.4 (7 244 858)44.2 (1 623 230)40.5 (2 405 336) Not recorded7.3 (1 502 034)10.5 (2 208 110)19.3 (234 426)7.2 (1 437 882)10.0 (1 800 799)18.4 (199 886)4.0 (2140)4.5 (783 471)7.3 (269 784)7.2 (425 649)Age, y Mean age (SD)54.9 (14.8)43.0 (22.4)32.3 (9.7)55.0 (14.7)46.5 (21.7)32.7 (9.8)63.1 (17.0)61.8 (15.9)53.7 (12.4)41.4 (18.0) 13–17<0.1 (10 214)10.6 (2 219 006)0.1 (838)<0.1 (9105)2.6 (468 569)0.1 (623)0.1 (31)0.1 (23 826)0.1 (2961)8.3 (493 728) 18–295.2 (1 081 177)24.4 (5 127 151)43.1 (521 916)5.1 (1 022 847)24.9 (4 472 159)41.3 (449 436)3.7 (1964)3.6 (624 465)4.0 (146 688)21.6 (1 279 933) 30–397.9 (1 634 841)21.5 (4 517 781)35.6 (431 515)7.8 (1 556 785)23.1 (4 146 117)36.1 (392 581)5.8 (3102)6.1 (1 067 916)8.6 (315 936)18.3 (1 084 406) 40–4922.1 (4 564 393)8.5 (1 784 664)18.4 (222 849)22.0 (4 414 864)9.3 (1 665 983)19.5 (212 187)11.5 (6171)11.1 (1 949 092)19.2 (706 004)19.4 (1 152 196) 50–5927.5 (5 673 878)8.0 (1 684 013)1.8 (22 320)27.6 (5 549 187)9.1 (1 636 430)1.9 (20 463)19.9 (10 644)20.8 (3 635 337)35.3 (1 295 168)16.7 (989 499) 60–6919.8 (4 083 887)8.5 (1 777 370)0.7 (8330)20.0 (4 013 588)9.8 (1 753 552)0.7 (8145)19.3 (10 371)22.5 (3 938 515)24.8 (910 586)8.5 (505 389) 70–7913.4 (2 763 041)9.4 (1 979 901)0.3 (3241)13.5 (2 717 638)10.9 (1 959 318)0.3 (2789)22.6 (12 090)23.1 (4 049 042)6.5 (237 287)4.2 (248 415) 80–893.1 (630 457)7.7 (1 621 129)0.1 (842)3.0 (604 788)8.9 (1 591 216)0.1 (837)12.5 (6710)10.8 (1 888 973)1.3 (47 228)2.2 (132 459) 90+1.0 (208 753)1.3 (268 563)<0.1 (103)1.0 (192 162)1.4 (256 698)<0.1 (158)4.7 (2523)1.9 (340 498)0.3 (9473)0.8 (48 117) Not recorded<0.1 (44)<0.1 (125)<0.1 (2)<0.1 (11)<0.1 (44)<0.0 (1)0<0.1 (29)0<0.1 (11)Women age groups, y <4014.8 (1 510 119)51.7 (5 325 910)77.9 (365 443)14.4 (1 437 517)45.9 (4 131 123)76.4 (328 311)9.2 (3020)10.9 (1 032 366)14.2 (252 054)47.6 (1 477 776) ≥4085.2 (8 704 960)48.3 (4 969 651)22.1 (103 671)85.5 (8 508 009)54.1 (4 869 604)23.6 (101 394)90.8 (29 772)89.1 (8 456 981)85.8 (1 526 263)52.4 (1 625 385) Not recorded<0.1 (16)<0.1 (59)0<0.1 (7)<0.1 (21)0000<0.1 (7)Men age groups, y <4011.2 (998 025)56.2 (4 762 038)78.2 (397 521)10.9 (949 865)49.4 (3 533 806)76.7 (35 074)8.8 (1650)7.5 (541 432)10.5 (171 132)46.2 (1 110 723) ≥4088.8 (7 935 546)43.8 (3 712 994)21.8 (110 895)89.1 (7 747 692)50.8 (3 614 721)23.3 (106 834)91.2 (17 024)92.5 (6 703 416)89.5 (1 452 098)53.8 (1 294 609)Not recorded<0.1 (21)<0.1 (42)<0.1 (2)<0.1 (3)<0.1 (12)<0.1 (1)000<0.1 (4)Ethnicity/race White67.9 (14 012 353)63.6 (13 344 722)53.0 (642 168)68.0 (13 656 716)64.2 (11 530 182)54.0 (587 123)74.3 (39 827)73.6 (12 891 303)69.6 (2 553 453)66.9 (3 971 366) Indian2.0 (406 066)2.2 (469 302)1.1 (13 385)2.0 (395 171)2.2 (394 274)1.1 (11 902)2.1 (1141)2.0 (354 433)1.4 (51 193)2.6 (153 403) Pakistani1.2 (253 523)1.6 (335 100)1.0 (12 213)1.2 (239 511)1.4 (249 446)0.9 (9732)0.9 (477)0.6 (109 038)0.5 (19 186)2.0 (118 522) Bangladeshi0.5 (96 392)0.5 (111 314)0.5 (5966)0.5 (92 835)0.5 (83 524)0.5 (4902)0.4 (217)0.2 (43 360)0.3 (10 775)0.7 (40 093) Other Asian0.9 (177 629)1.1 (238 245)1.0 (11 859)0.9 (171 863)1.1 (191 996)1.0 (10 365)0.8 (436)0.7 (128 434)0.6 (23 284)1.1 (67 392) Caribbean0.6 (117 507)0.5 (96 994)0.4 (4265)0.6 (110 470)0.4 (80 146)0.3 (3296)1.3 (706)0.4 (77 095)0.3 (11 820)0.5 (28 327) Black African0.9 (185 852)1.0 (218 158)1.0 (12 121)0.9 (176 094)0.9 (164 260)0.9 (9258)1.1 (588)0.6 (98 216)0.5 (16 997)1.0 (57 157) Chinese0.3 (63 180)0.3 (70 206)0.4 (5176)0.3 (61 902)0.3 (58 438)0.5 (4902)0.3 (149)0.3 (47 390)0.3 (11 899)0.2 (11 732) Other‡1.8 (378 719)2.4 (502 815)2.6 (31 811)1.8 (363 257)2.2 (388 674)2.5 (27 107)1.7 (902)1.4 (245 301)1.4 (50 501)2.3 (138 024) Not recorded24.0 (4 959 464)26.7 (5 592 847)39.0 (472 992)24.0 (4 813 156)26.8 (4 809 146)38.5 (418 633)17.1 (9163)20.1 (3 523 123)25.1 (922 223)22.7 (1 348 137)History of myocarditis Previous myocarditis<0.1 (1837)<0.1 (1632)<0.1 (69)<0.1 (1778)<0.1 (1511)<0.1 (56)<0.1 (18)<0.1 (1885)<0.1 (272)<0.1 (687)COVID-19 status† No COVID-1986.3 (17 815 732)86.0 (18 052 842)85.8 (1 039 833)86.3 (17 334 448)87.3 (15 674 125)86.2 (937 147)88.4 (47 367)90.5 (15 846 583)88.0 (3 230 055)… COVID-19 previous vaccination5.9 (1 227 131)7.8 (1 629 334)8.4 (101 484)5.9 (1 183 882)6.5 (1 170 434)7.8 (85 166)6.3 (3398)4.7 (815 805)5.3 (194 056)49.8 (2 958 026) COVID-19 after first dose0.7 (143 526)2.8 (594 914)3.2 (38 200)0.5 (99 981)2.2 (401 516)3.0 (32 222)0.9 (456)0.6 (108 097)0.4 (15 316)13.1 (776 725) COVID-19 after second dose6.7 (1 383 490)3.0 (638 578)2.7 (32 215)6.9 (1 381 868)3.6 (639 976)3.0 (32 452)1.8 (969)3.5 (621 836)5.8 (213 627)34.6 (2 054 331) COVID-19 after booster dose0.4 (80 807)0.3 (64 035)<0.1 (224)0.4 (80 796)0.4 (64 035)<0.1 (233)2.6 (1416)0.7 (125 372)0.5 (18 277)2.4 (145 071)No. of doses One dose only2.3 (467 328)14.8 (3 114 034)11.9 (144 026)………………12.8 (761 515) Two doses only36.0 (7 430 747)45.1 (9 464 269)80.8 (979 495)36.5 (7 328 422)53.2 (9 550 989)91.7 (996 599)………51.5 (3 054 000) Two doses + booster61.8 (12 752 610)40.0 (8 401 400)7.3 (88 435)63.5 (12 752 553)46.8 (8 399 097)8.3 (90 621)100.0 (53 606)100.0 (17 517 692)100.0 (3 671 331)35.7 (2 118 638)Type of vaccines Two doses of ChAdOx197.0 (20 040 458)……99.8 (20 040 458)……83.0 (44 472)55.8 (9 780 549)79.1 (2 903 545)46.2 (2 741 419) Two doses of BNT162b2…84.9 (17 815 058)……99.2 (17 815 058)…5.1 (2760)43.7 (7 653 274)19.6 (720 535)38.0 (2 256 069) Two doses of mRNA-1273……87.5 (1 060 277)……97.5 (1 060 277)<0.1 (8)0.3 (45 269)1.2 (42 783)2.5 (146 385)*Among vaccinated individuals.†Determined by a SARS-CoV-2 test.‡Other indicates any other ethnic group not covered by the categories listed in the Table.Among people receiving at least 1 vaccine dose, 5 934 153 (13.9%) tested positive for SARS-CoV-2, including 2 958 026 (49.8%) before their first vaccination.Of the 42 842 345 people in the study population, 2861 (0.007%) were hospitalized or died from myocarditis during the study period; 345 (<0.001%) patients died within 28 days from a hospital admission with myocarditis or with myocarditis as cause of death recorded in the death certificate. A total of 617 (0.001%) of these events occurred 1 to 28 days after any dose of vaccine (Table 2). Of the 524 patients admitted to the hospital with myocarditis in the 1 to 28 days after any first or second vaccine dose, 151 (28.8%) had received a booster dose: 34.4% (79/230) of those who had ChAdOx1 in the first or second dose and 29.7% (72/243) of those who had BNT162b2 in the first or second dose (Table 2). Of the 5 934 153 patients with a SARS-CoV-2 infection, 195 (0.003%) were hospitalized or died with myocarditis in the 1 to 28 days after the positive test; 114 (58.5%) of these events occurred before vaccination (Table S2).Table 2. Demographic and Clinical Characteristics of Patients Who Were Admitted to the Hospital for Myocarditis in the 1 to 28 Days After a COVID-19 Vaccine First Dose, Second Dose

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Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex | Circulation