Effectiveness of COVID-19 vaccines against delta variant (B.1.617.2): A meta-analysis

Effectiveness of COVID-19 vaccines against delta variant (B.1.617.2): A meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Effectiveness of COVID-19 vaccines against delta variant (B.1.617.2): A meta-analysis Rashidul Alam Mahumud, Mohammad Afshar Ali, Satyajit Kundu, Md Ashfikur Rahman, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1130796/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Feb, 2022 Read the published version in Vaccines → Version 1 posted You are reading this latest preprint version Abstract Objectives The highly transmissible COVID-19 delta variant (DV) has contributed to the surge in cases and has now been exacerbated the worldwide public health crisis. Several COVID-19 vaccines play a significant role in a high degree of protection against DV. The primary purpose of this meta-analysis is to estimate the pooled effectiveness of the COVID-19 vaccines against DV in terms of risk ratio (RR) among fully vaccinated, compared to unvaccinated populations. Methods We carried out a systematic review with meta-analysis of original studies focused on COVID-19 vaccines effectiveness of COVID-19 vaccines against B.1.617.2 clinical perspective among fully COVID-19 vaccinated populations, compared to placebo (unvaccinated populations), published before September 30, 2021. Eleven studies containing data of 17.2 million participants were identified and included in our study. Pooled estimates of COVID-19 vaccines effectiveness (i.e., risk ratio, RR) against delta variant with 95% confidence intervals were assessed using random-effect models. Publication bias was assessed using Egger's regression test and funnel plot to investigate potential sources of heterogeneity and identify any differences in study design. Results A total population of 17.2 million (17,200,341 peoples) were screened for the COVID-19 vaccines' effectiveness against delta variant. We found 61.13% of study population were fully vaccinated with 2-dose of COVID-19 vaccines. Weighted pooled incidence of COVID-19 infection was more than double (20.07%) among unvaccinated populations, compared to the fully vaccinated population (8.16%). Overall, the effectiveness of COVID-19 vaccine against DV was 85% (RR = 0.15, 95% CI: 0.07-0.31). The effectiveness of COVID-19 vaccines varied slidably by study designs, 87% (RR = 0.13, 95% CI: 0.06-0.30) and 84% (RR = 0.16, 95% CI:0.02, 1.64) for cohort and case-control studies, respectively. Conclusion Effectiveness COVID-19 vaccines were noted to offer higher protection against delta variant among populations who received two vaccine doses compared with unvaccinated populations. This finding would help efforts to maximise vaccine coverage (i.e., at least 60 to 70% of the population) with two doses among vulnerable populations to have herd immunity to breat the chain of transmission and gain greater overall population protection more rapidly. Biostatistics Immunology Virology Population Biology Delta variant COVID-19 vaccines herd immunity vaccines effectiveness meta-analysis B 1.617.2 Figures Figure 1 Figure 2 Figure 3 Introduction On May 19, 2021, the delta variant (DV) of concern, formerly known as the Indian variant of concern (or B 1.617.2), became the most dominant strain of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) 1 . The SARS-CoV-2 DV has been demonstrated in 185 countries 2 , which is more contagious with higher number of R-naught (R 0 of 5-6), compared to other variants (e.g., Alpha, Beta, Gamma) 3 . A significant number of covid-19 new cases caused by the highly transmissible DV is exacerbating the worldwide public health crisis 4 , and 99% of sequenced, and genotyped cases being related to the DV. The burden of DV has led to considerable demand for herd immunity, and optimal timing of, booster doses for the vaccinated population 5 . COVID-19 vaccines have been identified as the most effective means of halting the spread of the disease over the world. Several vaccines are currently being administered to people of various ages all around the world. Although the COVID-19 vaccines two doses of vaccines played a significant role in a high degree of protection before delta variant than one dose of vaccination 6 . Performance of these vaccines are significant still to to have herd immunity to breat the chain of transmission of delta variant 7 . A recent study have examined the effectiveness of various COVID-19 immunisation programmes in the real world including the general public and health care settings such as among healthcare and among frontline workers and care home residents 8 . Emerging evidence suggests the BNT162b2 mRNA vaccine (Pfizer-BioNTech) and the Oxford AstraZeneca adenovirus-vector vaccine, ChAdOx1 nCoV-19 (ChAdOx1) exhibited great efficiency against the Alpha (B.1.1.7) and previous variants in studies before delta variant 9 – 11 . The continued appearance of novel SARS-CoV-2 variations could jeopardise the efficacy of immunisation efforts, especially since in vitro tests suggest that vaccine-elicited antibodies have lower neutralisation activity against emergent variants 12 , 13 . The delta variation (B.1.617.2) is of particular concern, as it has resulted in substantial increases in infections in many countries, including ones with excellent vaccination coverage, such as the United Kingdom (U.K.). In the U.K., after being recognised as a Variant of Concern (VOC) on April 28, 2021, it swiftly became dominant 13 . The rapid pace at which data is emerging, as well as heterogeneities in study protocol and design, different socioeconomic and demographic characteristics (i.e., age, sex, ethnicity, comorbidities etc.) and regions and implementation way, make interpreting and assessing the anticipated impact of vaccine campaigns on local epidemics difficult and challenging. Measuring the Effectiveness of COVID-19 vaccines against the most dominant variant (B.1.617.2) can be a basis for accentuating protection in patients with COVID-19 infection. In contrast, there is still a scarcity of real-world data on the effectiveness of vaccines against DV 14 . Therefore, using a systematic review and meta-analysis, we aimed to estimate the pooled COVID-19 vaccines efficacy and effectiveness against DV. This study is important and unlike previous systematic reviews and meta-analyses 15 – 17 , which focussed on risk assessment, immunogenicity, reactogenicity and efficacy across different vaccine platforms. We anticipated that our study findings will provide a comprehensive understanding of the effectiveness of COVID-19 vaccines and will inform strategies to promote protection against COVID-19, especially DV. Furthermore, the study provides real-time evidence to boost vaccine confidence. Globally, there has been unfounded concerns that have affected public confidence in vaccines and boosted vaccine hesitancy which could delay the fight against the pandemic if not urgently addressed 18 , 19 . Methods Search strategy We conducted a comprehensive search for academic research studies that reported the effectiveness of coronavirus disease-19 (COVID-19) vaccines against COVID-19 delta variant published May 1, 2021 and September 30, 2021 from the following electronic bibliographic databases: Scopus, EBSCOhost (CINAHL, Medline), PubMed, Web of Science, and the first 20 pages of Google Scholar. The following search terms were used with no language restrictions: [("Effectiveness" OR “Efficacy” OR “Security” OR “Safety” OR “Evaluation”) AND ("COVID-19 Vaccines" OR "Coronavirus-19 Vaccines" OR “mDNA COVID-19 vaccines” OR “Moderna” OR “mRAN-1273” OR “Pfizer/BioNTech” OR “BNT162b2” OR “Johnson & Johnson” OR “Ad26.COV2.S” OR “Oxford/AstraZeneca” OR “AZD1222” OR “BBIBP-CorV” OR “Vero Cells” OR “CoronaVac” OR “Vaccines”) AND ("Delta Variant" OR “B.1.617.2” OR “"Delta" OR "Alpha Variant" OR "Variant")] Study participants Our study scope comprises of vaccinated or unvaccinated populations that were infected with COVID-19 during delta variant. Inclusion and exclusion criteria Eligible studies were selected if they 1) were original articles; 2) published between May1, 2021 and September 30, 2021 (focuses on delta variant); focused on 3) effectiveness of COVID-19 vaccines against delta variant (B.1.617.2) clinical perspective, 4) effectiveness or efficacy of all COVID-19 vaccines, 5) effectiveness or efficacy on fully COVID-19 (i.e., 2-dose) vaccinated compared to placebo (unvaccinated), and 6) reported clinical characteristics of the COVID-19 among infected people. Editorials, letters, perspectives, commentaries, reports, opinion species, reviews, and studies with 'insufficient related data were excluded from our study. The reference lists of studies included were checked for eligible studies. We selected the starting date of date of May 1st 2021 because it marks a period when B.1.617.2 was escalated VOC having been earlier detected in April 2021 20,21 . Data extraction Data were independently extracted into EndNote libraries by three researchers who later compared their results. Emerging differences in the data were discussed and resolved by consensus and where the three researchers could not agree, the fourth and fifth researchers were consulted for adjudication. Extracted data captured author's name, year, settings, design or approach, the overall number of COVID-19 infections, number of vaccinated and unvaccinated participants, and number of participants. Study screening and selection The screening and selection of studies followed a three-stage screening procedure. The first stage involved screening studies by title to eliminate duplicates. The second stage required reading of abstracts to determine their relevance to our study. The third stage necessitated reading of full texts of the retained studies and those that met the set criteria were retained for our study as reflected in Fig. 1. RAM carried out and recorded the above process and shared the record with other two authors (RAM and MAR) for verification. Discrepancies were discussed and resolved by consensus. Quality assessment Quality assessment was independently conducted by two authors who applied four quality assessment tools due to the heterogeneity of included studies designs. Discrepancies in the two author's quality assessments were referred to the other authors for adjudication. The included studies designs were cohort, case series, and case controls. The three critical appraisal tools applied were from the Joanna Briggs Institute (JBI). The JBI tools have been used widely in academic studies 22 , 23 . The tools provide a subjective assessment of risk of bias (ranked as low, moderate, or high) 24 . Higher quality indicates greater confidence that future research is unlikely to change or contradict the results, while lower quality indicates higher likelihood that future research may not affirm the study results. The first JBI tool used was the checklist for cohort studies which we applied to four studies 25 – 28 included in this systematic review and meta-analysis. The checklist assesses critical areas of studies' methodologies for biasness in design, implementation, and analysis ( Appendix Table A1 ). The second tool of quality assessment used was the JBI checklist for analytical case control studies which we applied to six case control studies 6,29−33 included in this review. The checklist consists of ten items that enables the critical appraisal of studies for potential biasness ( Appendix Table A2 ). The third and last tool used was the JBI checklist for case series study and was applied to one study included 34 in our review ( Appendix Table A3 ). The checklist comprises of ten items measuring comparability of study groups, matching of cases and controls, identification criteria for cases and controls, reliability and validity of exposure measurement, similarities in exposure measurement for case and control, identification of confounding factors, addressing the confounding factors, assessment of outcomes, length of exposure period and statistical analysis. Data analysis Given the high heterogeneity between studies (I 2 >50%) 35 , we used random effects meta-analysis models to obtain pooled 2-dose COVID-19 vaccines effectiveness (VE) estimates against Delta variant (B.1.617.2) complemented with a sensitivity analysis to examine the effects of outliers. VE was calculated as 1 – risk ratio (RR). $$\text{V}\text{E}=\frac{\left(\text{R}\text{i}\text{s}\text{k} \text{a}\text{m}\text{o}\text{n}\text{g} \text{u}\text{n}\text{v}\text{a}\text{c}\text{c}\text{i}\text{n}\text{a}\text{t}\text{e}\text{d} \text{g}\text{r}\text{o}\text{u}\text{p}-\text{r}\text{i}\text{s}\text{k} \text{a}\text{m}\text{o}\text{n}\text{g} \text{v}\text{a}\text{c}\text{c}\text{i}\text{n}\text{a}\text{t}\text{e}\text{d} \text{g}\text{r}\text{o}\text{u}\text{p}\right)}{\text{R}\text{i}\text{s}\text{k} \text{a}\text{m}\text{o}\text{n}\text{g} \text{u}\text{n}\text{v}\text{a}\text{c}\text{c}\text{i}\text{n}\text{a}\text{t}\text{e}\text{d} \text{g}\text{r}\text{o}\text{u}\text{p}}$$ $$\text{A}\text{l}\text{t}\text{e}\text{r}\text{n}\text{a}\text{t}\text{i}\text{v}\text{e}\text{l}\text{y}, \text{V}\text{E}=1-\text{r}\text{i}\text{s}\text{k} \text{r}\text{a}\text{t}\text{i}\text{o} \left(\text{R}\text{R}\right)$$ For 2-dose VE, we calculated pooled estimate of VE against delta variant and by study design. We assessed residual heterogeneity between studies by calculating the I 2 statistic 35 . The I 2 statistic enabled us to determine whether the percentage of variance was attributable to the heterogeneity of the data in studies included using the random-effects model. We used forest plots to show the distribution of risk ratio of COVID-19 infection during the delta variant. Subgroup analysis based on the vaccine phases significantly decreased the heterogeneity in the high heterogeneity cases. The presence and effect of publication bias were assessed by using Egger's regression test 36 and funnel plot 37 , to investigate potential sources of heterogeneity and identify any differences study design. All analyses, two-tailed statistics and a significance level of less than 0.05 were considered. All statistical analyses were performed by STATA/SE version 15.0. Results Description of studies included A total of 17.2 million peoples were screened for the COVID-19 vaccines' effectiveness against delta variant. Our primary search of databases yielded 753 studies of which 11 met criteria (i.e., six studies were case-control 6,29−33 , four studies were cohort design 25 – 28 and one study was case-case design 34 which were included in this study (Fig. 1). The included studies had a total sample of ⁓17.2 million (N = 17,200,341) and of these, 61.13% of were fully vaccinated (n = 10,514,132) with 2–dose COVID-19 vaccines. The COVID-19 infection was more than double (21.61%, 95% CI:8.50%-34.72%) among unvaccinated population, compared to the fully population vaccinated (8.88%, 95% CI: 0.18%-17.95%) population. Table 1 Characteristics of selected studies Study Country Design Fully vaccinated group Unvaccinated group Number of infected persons, n (%) Total vaccinated population Number of infected persons, n (%) Total unvaccinated population Bernal et al. (2021) 31 United Kingdom Case–control 143 (0.60) 23,993 7,313 (7.59) 96371 Fowlkes et al. (2021) 25 USA Cohort study 34 (1.14) 2,976 194 (4.69) 4136 Grannis et al. (2021) 26 USA Cohort study 134 (2.94) 4,551 1,185 (20.76) 5708 Barlow et al. (2021) 6 USA Case-control 145 (29.00) 500 279 (55.80) 500 Hu et al. (2021) 30 China Case–control 187 (39.29) 476 184 (38.66) 476 Jara et al. (2021) 27 Chile Cohort study 12286 (0.29) 4,173,574 185,633 (3.39) 5471728 Kislaya et al. (2021) 34 Portugal Case-case study 162 (11.89) 1,363 777 (46.00) 1689 Li et al. (2021) 29 China Case–control 12 (12.37) 97 37 (34.58) 107 Nanduri et al. (2021) 28 USA Cohort study 2999 (0.06) 5,011,746 1,397 (0.15) 953861 Nasreen et al. (2021) 33 Canada Case–control 10 (0.12) 8,461 6,325 (22.03) 28705 Tang et al. (2021) 32 Qatar Case–control 249 (0.02) 1,286,395 4,993 (4.06) 122928 Total, n = 12 N = 16,361 (0.16) N = 10,514,132 N = 208,317 (3.12) N = 6,686,209 Weighted pooled incidence of COVID-19 infection. 8.88% (95% CI:0.18-17.95) 21.61% (95% CI: 8.50-34.72) Effectiveness of the COVID-19 vaccines against delta variant Figure 2 shows the effectiveness of the COVID-19 vaccines against delta variant after two doses. All four cohort studies showed vaccines played a significant role in reducing the risk of COVID-19 infections among fully vaccinated populations, compared to unvaccinated populations. The pooling of four cohort studies 25 – 28 showed vaccines significantly lowered the risk (RR = 0.20, 95% CI: 0.07-0.54) of exposure against delta variant (B.1.617.2) among fully vaccinated (i.e., 2 doses) populations by 80% compared to unvaccinated populations. Pooled estimates for six case-control studies, except one study, showed significantly lower risk of having COVID-19 infection (90%) [RR = 0.10, 95% CI:0.01-0.80] against delta variant among fully vaccinated populations than unvaccinated populations (Figure 2). Overall, the effectiveness of COVID-19 vaccine against delta variant was 86% (RR = 0.14, 95% CI: 0.07-0.54). The funnel plot shows some asymmetry (Figure 3); however, this is not significant for Begg's regression test (p = 481 for five case-control studies and p = 0.314 for five cohort studies) (Table 2 ), denoting absence of publication bias. Therefore, we included all 11 studies in the meta-analysis. There statistically significant heterogeneity (I 2 = 99.9%, p<0.001 for six case-control studies and I 2 = 99.8%, p<0.001 for four cohort studies, I 2 = 99.8%, p<0.001) (Figure 2). Table 2 Assessing publication bias Study design Number of studies Egger's regression test Small-study effect (p-value) RR, (95% CI) p-value Bias (RR), 95% CI p-value Case-control 6 0.61 (0.02, 5.53) 0.224 30.53 (0.89, 51.45) 0.481 p-value = 0.685 Cohort study 4 0.09 (0.04, 0.17) 0.015 13.32 (0.98, 45.47) 0.390 P-value = 0.390 Case-case study 1 - - - - - RR = risk ratio, p-value = probability value Quality of included studies Our findings suggest that five (n = 5) of the included studies 6 , 29 – 31 , 34 were of high quality implying that they were robust studies; six of the studies 25 , 26 , 28 , 30 , 32 , 33 were ranked as medium quality implying that their methods were of moderate quality based on the JBI quality assessment criteria. There was no study excluded based on poor scoring on the quality assessment scales. Notably, one (n = 1) cohort study 27 was assed as high on the JBI tools; the rest (n = 3) cohort studies were found to be of medium quality on the same scale 25 , 26 , 28 . Three out of six (n = 3/6) case-control studies included 6 , 29 , 31 , were found to be of high quality based on the JBI quality assessment scale for case-control studies; the rest (n = 3) of the studies 30 , 32 , 33 were found to be of medium quality on the same scale. Lastly, the only one case–series study 34 included in our review was found to be of high quality on the JBI quality assessment scale of case controls. Discussion In this catatrophic situation, several vaccines, including Pfizer-BioNTech, Moderna, AstraZeneca, protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These vaccines teach our cells how to make a protein (or even just a piece of a protein)—that triggers an immune response inside our bodies. Theoretical benefits of these vaccines are that those vaccinated gain protection without ever having to risk the serious consequences of getting sick and or die of COVID-19. Several studies found that these vaccines trigger an immune response against the virus 27 , 38 , 39 . These vaccines have been approved for clinical use by the World Health Organization based on comprehensive assessments of non-clinical, laboratory confirmation, clinical utility, and manufacturing data provided by manufacturers to respective regulatory bodies (i.e., U.S. Food and Drug Administration (FDA) and the Department of Health and Human Services or related institutes). Though these vaccines' efficacy and side effects have not yet been widely discussed, numerous claims have been made by popular media and politicians 40 , 41 . During this process, respective government bodies examine the quality and consistency of the vaccine so that the potential benefits offset the potential adverse effects of the vaccine. Despite unsubstantiated claims on the COVID-19 vaccines efficacy and associated side effects, there is a lack of accumulated evidence on the effectiveness of this vaccine 27 . However, among different variants of SARS-CoV-2, the delta variant has significantly increased virulence and transmission capacity 42 . In addition, recent evidence indicates that the vaccine's effectiveness declined with the emergence and promotion of the delta variant 6 . Therefore, this meta-analysis presents a piece of systematic and evidence-based information regarding the effectiveness of different COVID-19 vaccines against specific delta variant (B.1.617.2). The B.1.617.2 has seen a sharp rise in infections and mortality in 186 countries 2 , including those with relatively high vaccine coverage and increased hospitalization and mortality in the U.K. 20 , 43 . The high transmissibility of SARS-CoV-2 mainly of delta variant is a considerable socioeconomic global burden. Previous evidence on vaccine effectiveness reported reduced protection against the delta variant compared to the Alpha variant 1 , 31 . Even the efficacy of the 2-dose ChAdOX1 vaccine decreased by 59.8% after exposure to B.1.617.2 31 . Recent reports determined a higher vaccine breakthrough infection in terms of reduced prophylactic vaccine effectiveness against the SARS-CoV-2 delta variant (B.1.617.2) 1 , 31 . While more contributing factors may reduce immunity, a recent Israeli study has found higher infection rates even among the earliest vaccinated individuals 44 . Another study among nursing home residents found the effectiveness of the mRNA vaccine as 74.7% against infection, but the efficiency decreased significantly by 53.1% when the B.1.617.2 circulation predominated 28 . The interpretation of this report is complex due to the bias of the methodology, research population, care settings, immunisation timeline and the potential selection and case diagnosis 6 . Our study found that the effectiveness of COVID-19 vaccine was 80% more protective among those vaccinated with the delta variant (RR = 0.20, 95% CI: 0.07-0.54), compared to unvaccinated populations. A previous study also found a higher rate of vaccine infection breakthrough, indicating lower effectiveness of vaccines in protecting infection with the delta variant 34 . Another study also argued that infections with delta variant that are transmitted despite the vaccine carry a similar viral burden for people who have not been vaccinated 14 . Though the effectiveness of vaccines is lower among delta cases, completing the second dose of vaccines reduces the complication among those vaccinated 6 . In addition, a growing number of cases detected after one or two doses of vaccination are more likely to be infected with B.1.617.2 than other variants 12 . Since the efficacy of the vaccines against the B.1.617.2 is lower, several studies recommended an additional dose to curve the infection of the variant and optimise the immune response 12 , 28 . Single-dose vaccine recipients with high infection rates of B.1.617.2 or who have been infected before with another variant can risk vaccine-adapted forms of evolution 12 . We argues that the population should be vaccinated as much as possible since those who have not been vaccinated cannot be protected by a significant reduction in the number of vaccinated populations as seen by other infections, making herd immunity could be unachievable due emerging variants 14 . Our study is unique with several strengths. Firstly , this meta-analysis study that provides evidence-based data on vaccines' effectiveness against the B.1.617.2 variant. Secondly , we only considered the studies that provide symmetrical information of individuals vaccinated with two doses. Finally, a large population was considered in this study that yields a piece of adequate evidence on this topic. However, we acknowledge some limitations with our study design and selection of published studies. Effectiveness of vaccines (e.g., BNT162b2 or ChAdOx1 nCoV-19) after one dose was significantly lower among population with the B.1.617.2 variant (30.7%) than among those with the alpha variant (48.7%) 31 . Studies on single-dose vaccination and its efficacy were excluded in this meta-analysis due to lack of reported data, lower effectiveness with the delta variant, insufficient number of studies, and we did not employ any analysis considering the sub-groups of different types of vaccines due to insufficient number of studies and reported combined results with more than one vaccine. Nonetheless, our study provides valuable insights into the effectiveness of the vaccines against the delta variant since there is a dearth of information on this topic. Depending on the predominance of the delta variant, the findings of this study may help policy-makers take action or control measures, and coordinate vaccination effects. Recently, caution has been elevated that vaccine performance may diminish in the future, considering the possibility of a series of potential viral genetic drift 6 . These claims highlight the importance of both pharmaceutical and non-pharmaceutical interventions intandem to reduce SARS-CoV-2 infection. Future research can examine the combined efficacy of mass vaccination, contact tracing and social distancing measures in minimising the socioeconomic burden arising from COVID-19. Our study's practical implication is that taking the mounting evidence on the efficacy of pharmaceutical intervention into account, mass vaccination against should be continued in a planned manner to lessen the socioeconomic burden of COVID-19. To do so, COVID-19 vaccines should be categorised as a global humanitarian good emphasising the optimisation of production and equal distribution. On the other hand, the demand side should target reducing vaccine hesitancy so that more vulnerable populations are adequately covered. The effectiveness of COVID-19 vaccines was noted with the delta variant among populations after receiving two vaccine doses as compared with unvaccinated populations. This finding would help efforts to maximise vaccine coverage with two doses among vulnerable populations. Declarations Competing interests The authors declare that they have no competing interests. Funding No funding was received for conducting this study. Author contributions RAM conceptualised the systematic review and meta-analysis. RAM, MAA, SK and MAR conducted the search, data extraction, under the supervision of AMNR. RAM performed meta-analysis. All authors contributed to finalise the draft paper. RAM, MAA, SK, MAR, JKK and AMNR contributed to revision and approval for submission. References Sheikh A, McMenamin J, Taylor B, Robertson C. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet [Internet] 2021;397(10293):2461–2. Available from: http://dx.doi.org/10.1016/S0140-6736(21)01358-1 GISAID. Delta variant detected across 185 countries. Global Initiative on Sharing Avian Influenza Data (GIAID) [Internet]. Phylodynamics pandemic coronavirus Var. VOC Delta G/478K.V1 first Detect. India. 2021 [cited 2021 Sep 30];Available from: https://www.gisaid.org/hcov19-variants/ Gallagher J. COVID: Is there a limit to how much worse variants can get? How the R0 numbers of COVID-19 variants and other diseases compare [Internet]. 2021 [cited 2021 Sep 30];Available from: https://www.bbc.com/news/health-57431420 Krause PR, Fleming TR, Peto R, et al. Considerations in boosting COVID-19 vaccine immune responses. Lancet [Internet] 2021;6736(21):21–4. Available from: http://dx.doi.org/10.1016/S0140-6736(21)02046-8 Callaway E. COVID vaccine boosters: the most important questions. Nature 2021;596(7871):178–80. Barlow RS, Jian K, Larson L, Barlow RS. Effectiveness of COVID-19 Vaccines Against SARS-CoV-2 Infection During a Delta Variant Epidemic Surge in Multnomah County, Oregon, July 2021. MedRxiv Prepr 2021;(July). Public Health England. Effectiveness of covid-19 vaccines against hospital admission with the Delta (B.1.617.2) variant [Internet]. 2021. Available from: https://khub.net/web/phe-national/public-library/-/document_library/v2Ws-%0ARK3ZlEig/view/479607266 . Imai N, Hogan AB, Williams L, et al. Interpreting estimates of coronavirus disease 2019 (COVID-19) vaccine efficacy and effectiveness to inform simulation studies of vaccine impact: a systematic review. Wellcome Open Res 2021;6(185):185. Thompson MG, Burgess JL, Naleway AL, et al. Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers—eight US locations, December 2020–March 2021. Morb Mortal Wkly Rep 2021;70(13):495. Chemaitelly H, Yassine HM, Benslimane FM, et al. mRNA-1273 COVID-19 vaccine effectiveness against the B. 1.1. 7 and B. 1.351 variants and severe COVID-19 disease in Qatar. Nat Med 2021;1–8. Chung H, He S, Nasreen S, et al. Effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe COVID-19 outcomes in Ontario, Canada. 2021; Davis C, Logan N, Tyson G, et al. Reduced neutralisation of the Delta (B. 1.617. 2) SARS-CoV-2 variant of concern following vaccination. medRxiv 2021; Noori M, Nejadghaderi SA, Arshi S, et al. Potency of BNT162b2 and mRNA-1273 vaccine‐induced neutralizing antibodies against severe acute respiratory syndrome‐CoV‐2 variants of concern: A systematic review of in vitro studies. Rev Med Virol 2021;e2277. Pouwels KB, Pritchard E, Matthews P, et al. Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK. medRxiv 2021;2021.08.18.21262237. Chan BT, Mpa M, Bobos P, et al. Meta-Analysis of Risk of Vaccine-Induced Immune Thrombotic Thrombocytopenia Following ChAdOx1-S Recombinant Vaccine. medRxiv [Internet] 2021;2021.05.04.21256613. Available from: https://doi.org/10.1101/2021.05.04.21256613 McDonald I, Murray SM, Reynolds CJ, Altmann DM, Boyton RJ. Comparative systematic review and meta-analysis of reactogenicity, immunogenicity and efficacy of vaccines against SARS-CoV-2. npj Vaccines [Internet] 2021;6(1). Available from: http://dx.doi.org/10.1038/s41541-021-00336-1 Pormohammad A, Zarei M, Pormohammad A, et al. Efficacy and Safety of Mipomersen: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Vaccines 2019;79(7):751–66. Hou Z, Tong Y, Du F, et al. Assessing covid-19 vaccine hesitancy, confidence, and public engagement:a global social listening study. J Med Internet Res 2021;23(6):1–11. Afolabi AA, Ilesanmi OS. Dealing with vaccine hesitancy in Africa: The prospective COVID-19 vaccine context. Pan Afr Med J 2021;38(3):1–7. Public Health England. SARS-CoV-2 variants of concern and variants under investigation in England: Technical briefing 18 [Internet]. Public Health England, Wellington House, 133-155 Waterloo Road, London SE1 8UG: 2021. Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/990339/Variants_of_Concern_VOC_Technical_Briefing_13_England.pdf Noori M, Nejadghaderi SA, Arshi S, et al. Potency of BNT162b2 and mRNA-1273 vaccine-induced neutralizing antibodies against severe acute respiratory syndrome-CoV-2 variants of concern: A systematic review of in vitro studies. Rev Med Virol 2021;e2277:1–23. Mahumud RA, Kamara JK, Renzaho AMN. The epidemiological burden and overall distribution of chronic comorbidities in coronavirus disease-2019 among 202,005 infected patients: evidence from a systematic review and meta-analysis. Infection 2020;48(6):813–33. Munn Z, MClinSc SM, Lisy K, Riitano D, Tufanaru C. Methodological guidance for systematic reviews of observational epidemiological studies reporting prevalence and cumulative incidence data. Int J Evid Based Healthc 2015;13(3):147–53. Joanna Briggs Institute (JBI). JBI’s critical appraisal tools. Faculty of Health and Medical Sciences, The University of Adelaide SA 5006 Adelaide, Australia: Fowlkes A, Gaglani M, Groover K, Thiese MS, Tyner H, Ellingson K. Effectiveness of COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Frontline Workers Before and During B.1.617.2 (Delta) Variant Predominance — Eight U.S. Locations, December 2020–August 2021. MMWR Morb Mortal Wkly Rep 2021;70(34):1167–9. Grannis SJ, Rowley EA, Ong TC, et al. Interim Estimates of COVID-19 Vaccine Effectiveness Against COVID-19 – Associated Emergency Department or Urgent Care Clinic Encounters and Hospitalizations Among Adults During SARS-CoV-2 B. 1. 617. 2 (Delta) Variant Predominance — Nine States, June. Morb Mortal Wkly Rep 2021;70(37):1291–3. Jara A, Undurraga EA, González C, et al. Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile. N Engl J Med 2021;385(10):875–84. Nanduri S, Pilishvili T, Derado G, et al. Effectiveness of Pfizer-BioNTech and Moderna Vaccines in Preventing SARS-CoV-2 Infection Among Nursing Home Residents Before and During Widespread Circulation of the SARS-CoV-2 B.1.617.2 (Delta) Variant — National Healthcare Safety Network, March 1–August. MMWR Morb Mortal Wkly Rep 2021;70(34):1163–6. Li X-N, Huang Y, Wang W, et al. Effectiveness of inactivated SARS-CoV-2 vaccines against the Delta variant infection in Guangzhou: a test-negative case–control real-world study. Emerg Microbes Infect 2021;10(1):1751–9. Hu Z, Tao B, Li Z, et al. Effectiveness of inactive COVID-19 vaccines against severe illness in B.1.617.2 2 (Delta) variant-infected patients in Jiangsu, China. MedRxiv Prepr 2021; Bernal JL, Andrews N, Gower C, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med 2021;385(7):585–94. Tang P, Hasan MR, Chemaitelly H, et al. BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the Delta (B.1.617.2) variant in Qatar. medRxiv 2021;2021.08.11.21261885. Nasreen S, He S, Chung H, et al. Effectiveness of COVID-19 vaccines against variants of concern, Canada. medRxiv [Internet] 2021;2021.06.28.21259420. Available from: https://www.medrxiv.org/content/ 10.1101/2021.06.28.21259420v1 Kislaya I, Rodrigues EF, Borges V, et al. Delta variant and mRNA Covid-19 vaccines effectiveness: higher odds of vaccine infection breakthroughs. medRxiv 2021;2021.08.14.21262020. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21(11):1539–58. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34. Sterne JAC, Egger M. Funnel plots for detecting bias in meta-analysis: Guidelines on choice of axis. J Clin Epidemiol 2001;54:1046–1055. Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020;396(10249):467–78. Xia S, Zhang Y, Wang Y, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect Dis 2021;21(1):39–51. Ison MG, Wolfe C, Boucher HW. Emergency use authorization of remdesivir: the need for a transparent distribution process. JAMA 2020;323(23):2365–6. US Food and Drug Administration. Emergency use authorization. 2020; Burki TK. Lifting of COVID-19 restrictions in the UK and the Delta variant. Lancet Respir Med 2021;9(8):e85. Sander A-L, Yadouleton A, Moreira-Soto A, et al. An Observational Laboratory-Based Assessment of SARS-CoV-2 Molecular Diagnostics in Benin, Western Africa. MSphere 2021;6(1):e00979-20. Mizrahi B, Lotan R, Kalkstein N, et al. Correlation of SARS-CoV-2 breakthrough infections to time-from-vaccine; Preliminary study. MedRxiv 2021; Appendix Tables Appendix Table A1. Quality score assessment for cohort study # Quality assessment indicators Selected cohort studies Fowlkes et al. (2021) 25 Grannis et al. (2021) 26 Jara et al. (2021) 27 Nanduri et al. (2021) 28 Q1 Were the two groups similar and recruited from the same population? ✓ ✓ ✓ ✓ Q2 Were the exposures measured similarly to assign people to both exposed and unexposed groups? ✓ ✓ ✓ ✓ Q3 Was the exposure measured in a valid and reliable way? ✓ ✓ ✓ ✓ Q4 Were confounding factors identified? ✓ ✓ ✓ ✓ Q5 Were strategies to deal with confounding factors stated? ✓ ✓ ✓ ✓ Q6 Were the groups/participants free of the outcome at the start of the study (or at the moment of exposure)? ✓ ✓ ✓ ✓ Q7 Were the outcomes measured in a valid and reliable way? ✓ ✓ ✓ ✓ Q8 Was the follow-up time reported and sufficient to be long enough for outcomes to occur? ® ® ✓ ® Q9 Was follow-up complete, and if not, were the reasons to loss to follow-up described and explored? ✕ ✕ ® ✕ Q10 Were strategies to address incomplete follow-up utilized? ✕ ✕ ✕ ✕ Q11 Was appropriate statistical analysis used? ✓ ✓ ✓ ✓ Overall quality score 8.5 (medium) 8.5 (medium) 9.5 (high) 8.5 (medium) Overall appraisal Included Included Included Included Note ✓ = yes ( = 1), ✕ = no ( = 0), ® =unclear (=0.5); quality assessment decision rules for 11 scales [(i) poor if the overall score≤5, (ii) medium if overall scores is 6 to 9, and (iii) high if the overall score>9], Appendix Table A2. Quality score assessment for case-control # Quality assessment indicators Selected case-control studies Barlow et al. (2021) 6 Li et al. (2021) 29 Hu et al. (2021) 30 Bernal et al. (2021) 31 Tang et al. (2021) 32 Nasreen et al. (2021) 33 Q1 Were the groups comparable other than the presence of disease in cases or the absence of disease in controls? ✓ ✓ ✓ ✓ ✓ ✓ Q2 Were cases and controls matched appropriately? ✓ ✓ ✓ ✓ ✓ ✓ Q3 Were the same criteria used for identification of cases and controls? ✓ ✓ ✓ ✓ ✓ ✓ Q4 Was exposure measured in a standard, valid and reliable way? ✓ ✓ ✓ ✓ ✓ ✓ Q5 Was exposure measured in the same way for cases and controls? ✓ ✓ ✓ ✓ ✓ ✓ Q6 Were confounding factors identified? ✓ ✓ ✓ ✓ ✓ ✓ Q7 Were strategies to deal with confounding factors stated? ✓ ✕ ✕ ✓ ✕ ✕ Q8 Were outcomes assessed in a standard, valid and reliable way for cases and controls? ✓ ✓ ✓ ✓ ✓ ® Q9 Was the exposure period of interest long enough to be meaningful? ® ✕ ✕ ✕ ✕ ® Q10 Was appropriate statistical analysis used? ✓ ✓ ✓ ✓ ✓ ✓ Overall quality score 9.5 (high) 8 (high) 8 (medium ) 9 (high) 8 (medium) 8 (medium) Overall appraisal Included Included Included Included Included Included Note ✓ = yes ( = 1), ✕ = no (= 0), ® = unclear (= 0.5); quality assessment decision rules for 10 scales: (i) poor if the overall scores8 Appendix Table A3. Quality score assessment for case-series study # Quality assessment indicators for case-series study Kislaya et al. (2021) 34 Q1 Were there clear criteria for inclusion in the case series? ✓ Q2 Was the condition measured in a standard, reliable way for all participants included in the case series? ✓ Q3 Were valid methods used for identification of the condition for all participants included in the case series? ✓ Q4 Did the case series have consecutive inclusion of participants? ✓ Q5 Did the case series have complete inclusion of participants? ® Q6 Was there clear reporting of the demographics of the participants in the study? ✓ Q7 Was there clear reporting of clinical information of the participants? ✓ Q8 Were the outcomes or follow-up results of cases clearly reported? ✓ Q9 Was there clear reporting of the presenting site(s)/clinic(s) demographic information? ✓ Q10 Was statistical analysis appropriate? ✓ Overall quality score 9.5 (high) Overall appraisal Note ✓ = yes ( = 1), ✕ = no (= 0), ® = unclear (= 0.5); quality assessment decision rules for 10 scales: (i) poor if the overall scores8 Cite Share Download PDF Status: Published Journal Publication published 10 Feb, 2022 Read the published version in Vaccines → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1130796","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":67174354,"identity":"3c016d0b-05a2-4b6a-b839-d6cacc0ae8a9","order_by":0,"name":"Rashidul Alam Mahumud","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-9788-1868","institution":"NHMRC Clinical Trials Centre, The University of Sydney","correspondingAuthor":true,"prefix":"","firstName":"Rashidul","middleName":"Alam","lastName":"Mahumud","suffix":""},{"id":67174356,"identity":"c59da201-910d-45ae-bb34-5fe767b4c5fb","order_by":1,"name":"Mohammad Afshar Ali","email":"","orcid":"","institution":"University of South Australia","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"Afshar","lastName":"Ali","suffix":""},{"id":67174358,"identity":"6f5e2ab5-a168-4559-8b80-81e53672c887","order_by":2,"name":"Satyajit Kundu","email":"","orcid":"","institution":"Department of Biochemistry and food analysis, Patuakhali Science and Technology University, Patuakhali, Bangladesh","correspondingAuthor":false,"prefix":"","firstName":"Satyajit","middleName":"","lastName":"Kundu","suffix":""},{"id":67174360,"identity":"070ba60b-07d8-4e4f-b52f-5db23d719941","order_by":3,"name":"Md Ashfikur Rahman","email":"","orcid":"","institution":"Khulna University","correspondingAuthor":false,"prefix":"","firstName":"Md","middleName":"Ashfikur","lastName":"Rahman","suffix":""},{"id":67174362,"identity":"22f8bca1-3a22-43ab-8516-21f8707a2e52","order_by":4,"name":"Joseph Kihika Kamara","email":"","orcid":"","institution":"Regional Director, Humanitarian \u0026 Emergency Affairs, World Vision East Africa Regional Office, Karen, off Ngong Road, P.O.Box 133-00502, Karen, Nairobi","correspondingAuthor":false,"prefix":"","firstName":"Joseph","middleName":"Kihika","lastName":"Kamara","suffix":""},{"id":67174364,"identity":"c582e895-be28-447f-b9a2-5ddc368f32ee","order_by":5,"name":"Andre M.N. Renzaho","email":"","orcid":"","institution":"School of Medicine, Translational Health Research Institute, Western Sydney University, Campbelltown, NSW, Australia","correspondingAuthor":false,"prefix":"","firstName":"Andre","middleName":"M.N.","lastName":"Renzaho","suffix":""}],"badges":[],"createdAt":"2021-12-01 09:53:36","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":true,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":true,"coiExplicitlySet":false},"doi":"10.21203/rs.3.rs-1130796/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1130796/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.3390/vaccines10020277","type":"published","date":"2022-02-11T02:14:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":16148565,"identity":"bc9162d2-4b51-45a2-92d7-d9caae1f3648","added_by":"auto","created_at":"2021-12-03 15:43:05","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":75811,"visible":true,"origin":"","legend":"Steps of study selection procedures","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1130796/v1/b6849f565026dfeda8d892d6.jpg"},{"id":16148123,"identity":"91d51c34-de1a-44ee-b3c7-69bd94bfd01b","added_by":"auto","created_at":"2021-12-03 15:40:05","extension":"tif","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":82188,"visible":true,"origin":"","legend":"Effectiveness of COVID-19 vaccines against delta varient","description":"","filename":"Figure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-1130796/v1/585a78cb65af1370e647ba67.tif"},{"id":16148566,"identity":"3f0026fc-43e5-43ee-9a9b-26b41df65f6f","added_by":"auto","created_at":"2021-12-03 15:43:05","extension":"tif","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":50505,"visible":true,"origin":"","legend":"Funnel plot with pseudo 95% confidence intervals","description":"","filename":"Figure3.tif","url":"https://assets-eu.researchsquare.com/files/rs-1130796/v1/75b8dbbf242ca88eca8ecc1d.tif"},{"id":18181458,"identity":"4ab3442b-8bb2-4b13-8e2c-f3af5acc0c1b","added_by":"auto","created_at":"2022-02-14 02:14:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":524582,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1130796/v1/929cb89a-184d-4ddd-a47e-01646f6fa151.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEffectiveness of COVID-19 vaccines against delta variant (B.1.617.2): A meta-analysis\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOn May 19, 2021, the delta variant (DV) of concern, formerly known as the Indian variant of concern (or B 1.617.2), became the most dominant strain of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The SARS-CoV-2 DV has been demonstrated in 185 countries \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, which is more contagious with higher number of R-naught (R\u003csub\u003e0\u003c/sub\u003e of 5-6), compared to other variants (e.g., Alpha, Beta, Gamma) \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. A significant number of covid-19 new cases caused by the highly transmissible DV is exacerbating the worldwide public health crisis \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, and 99% of sequenced, and genotyped cases being related to the DV. The burden of DV has led to considerable demand for herd immunity, and optimal timing of, booster doses for the vaccinated population \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. COVID-19 vaccines have been identified as the most effective means of halting the spread of the disease over the world. Several vaccines are currently being administered to people of various ages all around the world. Although the COVID-19 vaccines two doses of vaccines played a significant role in a high degree of protection before delta variant than one dose of vaccination \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Performance of these vaccines are significant still to to have herd immunity to breat the chain of transmission of delta variant \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. A recent study have examined the effectiveness of various COVID-19 immunisation programmes in the real world including the general public and health care settings such as among healthcare and among frontline workers and care home residents \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Emerging evidence suggests the BNT162b2 mRNA vaccine (Pfizer-BioNTech) and the Oxford AstraZeneca adenovirus-vector vaccine, ChAdOx1 nCoV-19 (ChAdOx1) exhibited great efficiency against the Alpha (B.1.1.7) and previous variants in studies before delta variant \u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe continued appearance of novel SARS-CoV-2 variations could jeopardise the efficacy of immunisation efforts, especially since in vitro tests suggest that vaccine-elicited antibodies have lower neutralisation activity against emergent variants \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. The delta variation (B.1.617.2) is of particular concern, as it has resulted in substantial increases in infections in many countries, including ones with excellent vaccination coverage, such as the United Kingdom (U.K.). In the U.K., after being recognised as a Variant of Concern (VOC) on April 28, 2021, it swiftly became dominant \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe rapid pace at which data is emerging, as well as heterogeneities in study protocol and design, different socioeconomic and demographic characteristics (i.e., age, sex, ethnicity, comorbidities etc.) and regions and implementation way, make interpreting and assessing the anticipated impact of vaccine campaigns on local epidemics difficult and challenging. Measuring the Effectiveness of COVID-19 vaccines against the most dominant variant (B.1.617.2) can be a basis for accentuating protection in patients with COVID-19 infection. In contrast, there is still a scarcity of real-world data on the effectiveness of vaccines against DV \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Therefore, using a systematic review and meta-analysis, we aimed to estimate the pooled COVID-19 vaccines efficacy and effectiveness against DV. This study is important and unlike previous systematic reviews and meta-analyses \u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, which focussed on risk assessment, immunogenicity, reactogenicity and efficacy across different vaccine platforms.\u003c/p\u003e \u003cp\u003eWe anticipated that our study findings will provide a comprehensive understanding of the effectiveness of COVID-19 vaccines and will inform strategies to promote protection against COVID-19, especially DV. Furthermore, the study provides real-time evidence to boost vaccine confidence. Globally, there has been unfounded concerns that have affected public confidence in vaccines and boosted vaccine hesitancy which could delay the fight against the pandemic if not urgently addressed\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv class=\"Section2\" id=\"Sec7\"\u003e\n \u003ch2\u003eSearch strategy\u003c/h2\u003e\n \u003cp\u003eWe conducted a comprehensive search for academic research studies that reported the effectiveness of coronavirus disease-19 (COVID-19) vaccines against COVID-19 delta variant published May 1, 2021 and September 30, 2021 from the following electronic bibliographic databases: Scopus, EBSCOhost (CINAHL, Medline), PubMed, Web of Science, and the first 20 pages of Google Scholar. The following search terms were used with no language restrictions:\u003c/p\u003e\n \u003cp\u003e[(\u0026quot;Effectiveness\u0026quot; OR \u0026ldquo;Efficacy\u0026rdquo; OR \u0026ldquo;Security\u0026rdquo; OR \u0026ldquo;Safety\u0026rdquo; OR \u0026ldquo;Evaluation\u0026rdquo;) AND (\u0026quot;COVID-19 Vaccines\u0026quot; OR \u0026quot;Coronavirus-19 Vaccines\u0026quot; OR \u0026ldquo;mDNA COVID-19 vaccines\u0026rdquo; OR \u0026ldquo;Moderna\u0026rdquo; OR \u0026ldquo;mRAN-1273\u0026rdquo; OR \u0026ldquo;Pfizer/BioNTech\u0026rdquo; OR \u0026ldquo;BNT162b2\u0026rdquo; OR \u0026ldquo;Johnson \u0026amp; Johnson\u0026rdquo; OR \u0026ldquo;Ad26.COV2.S\u0026rdquo; OR \u0026ldquo;Oxford/AstraZeneca\u0026rdquo; OR \u0026ldquo;AZD1222\u0026rdquo; OR \u0026ldquo;BBIBP-CorV\u0026rdquo; OR \u0026ldquo;Vero Cells\u0026rdquo; OR \u0026ldquo;CoronaVac\u0026rdquo; OR \u0026ldquo;Vaccines\u0026rdquo;) AND (\u0026quot;Delta Variant\u0026quot; OR \u0026ldquo;B.1.617.2\u0026rdquo; OR \u0026ldquo;\u0026quot;Delta\u0026quot; OR \u0026quot;Alpha Variant\u0026quot; OR \u0026quot;Variant\u0026quot;)]\u003c/p\u003e\n \u003cdiv class=\"Section3\" id=\"Sec8\"\u003e\n \u003ch2\u003eStudy participants\u003c/h2\u003e\n \u003cp\u003eOur study scope comprises of vaccinated or unvaccinated populations that were infected with COVID-19 during delta variant.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec9\"\u003e\n \u003ch2\u003eInclusion and exclusion criteria\u003c/h2\u003e\n \u003cp\u003eEligible studies were selected if they 1) were original articles; 2) published between May1, 2021 and September 30, 2021 (focuses on delta variant); focused on 3) effectiveness of COVID-19 vaccines against delta variant (B.1.617.2) clinical perspective, 4) effectiveness or efficacy of all COVID-19 vaccines, 5) effectiveness or efficacy on fully COVID-19 (i.e., 2-dose) vaccinated compared to placebo (unvaccinated), and 6) reported clinical characteristics of the COVID-19 among infected people. Editorials, letters, perspectives, commentaries, reports, opinion species, reviews, and studies with \u0026apos;insufficient related data were excluded from our study. The reference lists of studies included were checked for eligible studies. We selected the starting date of date of May 1st 2021 because it marks a period when B.1.617.2 was escalated VOC having been earlier detected in April 2021 \u003csup\u003e20,21\u003c/sup\u003e.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec10\"\u003e\n \u003ch2\u003eData extraction\u003c/h2\u003e\n \u003cp\u003eData were independently extracted into EndNote libraries by three researchers who later compared their results. Emerging differences in the data were discussed and resolved by consensus and where the three researchers could not agree, the fourth and fifth researchers were consulted for adjudication. Extracted data captured author\u0026apos;s name, year, settings, design or approach, the overall number of COVID-19 infections, number of vaccinated and unvaccinated participants, and number of participants.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec11\"\u003e\n \u003ch2\u003eStudy screening and selection\u003c/h2\u003e\n \u003cp\u003eThe screening and selection of studies followed a three-stage screening procedure. The first stage involved screening studies by title to eliminate duplicates. The second stage required reading of abstracts to determine their relevance to our study. The third stage necessitated reading of full texts of the retained studies and those that met the set criteria were retained for our study as reflected in Fig.\u0026nbsp;1. RAM carried out and recorded the above process and shared the record with other two authors (RAM and MAR) for verification. Discrepancies were discussed and resolved by consensus.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec12\"\u003e\n \u003ch2\u003eQuality assessment\u003c/h2\u003e\n \u003cp\u003eQuality assessment was independently conducted by two authors who applied four quality assessment tools due to the heterogeneity of included studies designs. Discrepancies in the two author\u0026apos;s quality assessments were referred to the other authors for adjudication. The included studies designs were cohort, case series, and case controls. The three critical appraisal tools applied were from the Joanna Briggs Institute (JBI). The JBI tools have been used widely in academic studies \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. The tools provide a subjective assessment of risk of bias (ranked as low, moderate, or high)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Higher quality indicates greater confidence that future research is unlikely to change or contradict the results, while lower quality indicates higher likelihood that future research may not affirm the study results. The first JBI tool used was the checklist for cohort studies which we applied to four studies \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e included in this systematic review and meta-analysis. The checklist assesses critical areas of studies\u0026apos; methodologies for biasness in design, implementation, and analysis (\u003cem\u003eAppendix Table A1\u003c/em\u003e). The second tool of quality assessment used was the JBI checklist for analytical case control studies which we applied to six case control studies \u003csup\u003e6,29\u0026minus;33\u003c/sup\u003e included in this review. The checklist consists of ten items that enables the critical appraisal of studies for potential biasness (\u003cem\u003eAppendix Table A2\u003c/em\u003e). The third and last tool used was the JBI checklist for case series study and was applied to one study included \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e in our review (\u003cem\u003eAppendix Table A3\u003c/em\u003e). The checklist comprises of ten items measuring comparability of study groups, matching of cases and controls, identification criteria for cases and controls, reliability and validity of exposure measurement, similarities in exposure measurement for case and control, identification of confounding factors, addressing the confounding factors, assessment of outcomes, length of exposure period and statistical analysis.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec13\"\u003e\n \u003ch2\u003eData analysis\u003c/h2\u003e\n \u003cp\u003eGiven the high heterogeneity between studies (I\u003csup\u003e2\u003c/sup\u003e\u0026gt;50%) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e, we used random effects meta-analysis models to obtain pooled 2-dose COVID-19 vaccines effectiveness (VE) estimates against Delta variant (B.1.617.2) complemented with a sensitivity analysis to examine the effects of outliers. VE was calculated as 1 \u0026ndash; risk ratio (RR).\u003c/p\u003e\n \u003cdiv class=\"Equation\" id=\"Equa\"\u003e\n \u003cdiv class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e$$\\text{V}\\text{E}=\\frac{\\left(\\text{R}\\text{i}\\text{s}\\text{k} \\text{a}\\text{m}\\text{o}\\text{n}\\text{g} \\text{u}\\text{n}\\text{v}\\text{a}\\text{c}\\text{c}\\text{i}\\text{n}\\text{a}\\text{t}\\text{e}\\text{d} \\text{g}\\text{r}\\text{o}\\text{u}\\text{p}-\\text{r}\\text{i}\\text{s}\\text{k} \\text{a}\\text{m}\\text{o}\\text{n}\\text{g} \\text{v}\\text{a}\\text{c}\\text{c}\\text{i}\\text{n}\\text{a}\\text{t}\\text{e}\\text{d} \\text{g}\\text{r}\\text{o}\\text{u}\\text{p}\\right)}{\\text{R}\\text{i}\\text{s}\\text{k} \\text{a}\\text{m}\\text{o}\\text{n}\\text{g} \\text{u}\\text{n}\\text{v}\\text{a}\\text{c}\\text{c}\\text{i}\\text{n}\\text{a}\\text{t}\\text{e}\\text{d} \\text{g}\\text{r}\\text{o}\\text{u}\\text{p}}$$\u003c/div\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Equation\" id=\"Equb\"\u003e\n \u003cdiv class=\"mathdisplay\" id=\"FileID_Equb\" name=\"EquationSource\"\u003e$$\\text{A}\\text{l}\\text{t}\\text{e}\\text{r}\\text{n}\\text{a}\\text{t}\\text{i}\\text{v}\\text{e}\\text{l}\\text{y}, \\text{V}\\text{E}=1-\\text{r}\\text{i}\\text{s}\\text{k} \\text{r}\\text{a}\\text{t}\\text{i}\\text{o} \\left(\\text{R}\\text{R}\\right)$$\u003c/div\u003e\n \u003c/div\u003e\n \u003cp\u003eFor 2-dose VE, we calculated pooled estimate of VE against delta variant and by study design. We assessed residual heterogeneity between studies by calculating the I\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e statistic \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. The I\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e statistic enabled us to determine whether the percentage of variance was attributable to the heterogeneity of the data in studies included using the random-effects model. We used forest plots to show the distribution of risk ratio of COVID-19 infection during the delta variant. Subgroup analysis based on the vaccine phases significantly decreased the heterogeneity in the high heterogeneity cases. The presence and effect of publication bias were assessed by using Egger\u0026apos;s regression test \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e and funnel plot \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e, to investigate potential sources of heterogeneity and identify any differences study design. All analyses, two-tailed statistics and a significance level of less than 0.05 were considered. All statistical analyses were performed by STATA/SE version 15.0.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec15\"\u003e\n \u003ch2\u003eDescription of studies included\u003c/h2\u003e\n \u003cp\u003eA total of 17.2 million peoples were screened for the COVID-19 vaccines\u0026apos; effectiveness against delta variant. Our primary search of databases yielded 753 studies of which 11 met criteria (i.e., six studies were case-control \u003csup\u003e6,29\u0026minus;33\u003c/sup\u003e, four studies were cohort design \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e and one study was case-case design \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e which were included in this study (Fig. 1). The included studies had a total sample of ⁓17.2 million (N = 17,200,341) and of these, 61.13% of were fully vaccinated (n = 10,514,132) with 2\u0026ndash;dose COVID-19 vaccines. The COVID-19 infection was more than double (21.61%, 95% CI:8.50%-34.72%) among unvaccinated population, compared to the fully population vaccinated (8.88%, 95% CI: 0.18%-17.95%) population.\u003c/p\u003e\n \u003cp\u003e\u0026lt;Insert Fig. 1 here\u0026gt;\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristics of selected studies\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"7\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eStudy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eCountry\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eDesign\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eFully vaccinated group\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eUnvaccinated group\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNumber of infected persons, n (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003evaccinated\u003c/p\u003e\n \u003cp\u003epopulation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNumber of infected persons, n (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal unvaccinated population\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBernal et al. (2021) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnited Kingdom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCase\u0026ndash;control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e143 (0.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23,993\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7,313 (7.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96371\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFowlkes et al. (2021) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34 (1.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,976\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e194 (4.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4136\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrannis et al. (2021)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e134 (2.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4,551\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,185 (20.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5708\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBarlow et al. (2021) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCase-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e145 (29.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e279 (55.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e500\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHu et al. (2021) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCase\u0026ndash;control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e187 (39.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e476\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e184 (38.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e476\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJara et al. (2021) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12286 (0.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4,173,574\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e185,633 (3.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5471728\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKislaya et al. (2021) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePortugal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCase-case study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e162 (11.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,363\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e777 (46.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1689\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLi et al. (2021) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCase\u0026ndash;control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (12.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (34.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNanduri et al. (2021) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2999 (0.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5,011,746\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,397 (0.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e953861\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasreen et al. (2021) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCanada\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCase\u0026ndash;control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (0.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8,461\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6,325 (22.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28705\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTang et al. (2021)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQatar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCase\u0026ndash;control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e249 (0.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,286,395\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4,993 (4.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e122928\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal, n = 12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN = 16,361 (0.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN = 10,514,132\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN = 208,317 (3.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN = 6,686,209\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeighted pooled incidence of COVID-19 infection.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.88%\u003c/p\u003e\n \u003cp\u003e(95% CI:0.18-17.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.61%\u003c/p\u003e\n \u003cp\u003e(95% CI: 8.50-34.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec16\"\u003e\n \u003ch2\u003eEffectiveness of the COVID-19 vaccines against delta variant\u003c/h2\u003e\n \u003cp\u003eFigure 2 shows the effectiveness of the COVID-19 vaccines against delta variant after two doses. All four cohort studies showed vaccines played a significant role in reducing the risk of COVID-19 infections among fully vaccinated populations, compared to unvaccinated populations. The pooling of four cohort studies \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e showed vaccines significantly lowered the risk (RR = 0.20, 95% CI: 0.07-0.54) of exposure against delta variant (B.1.617.2) among fully vaccinated (i.e., 2 doses) populations by 80% compared to unvaccinated populations. Pooled estimates for six case-control studies, except one study, showed significantly lower risk of having COVID-19 infection (90%) [RR = 0.10, 95% CI:0.01-0.80] against delta variant among fully vaccinated populations than unvaccinated populations (Figure 2). Overall, the effectiveness of COVID-19 vaccine against delta variant was 86% (RR = 0.14, 95% CI: 0.07-0.54). The funnel plot shows some asymmetry (Figure 3); however, this is not significant for Begg\u0026apos;s regression test (p = 481 for five case-control studies and p = 0.314 for five cohort studies) (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), denoting absence of publication bias. Therefore, we included all 11 studies in the meta-analysis. There statistically significant heterogeneity (I\u003csup\u003e2\u003c/sup\u003e = 99.9%, \u003cem\u003ep\u0026lt;0.001\u003c/em\u003e for six case-control studies and I\u003csup\u003e2\u003c/sup\u003e = 99.8%, \u003cem\u003ep\u0026lt;0.001\u003c/em\u003e for four cohort studies, I\u003csup\u003e2\u003c/sup\u003e = 99.8%, p\u0026lt;0.001) (Figure 2).\u003c/p\u003e\n \u003cp\u003e\u0026lt;Insert Figure 2 and Figure 3 here\u0026gt;\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAssessing publication bias\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"7\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eStudy design\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNumber of studies\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eEgger\u0026apos;s regression test\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSmall-study effect (p-value)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRR, (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBias (RR), 95% CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCase-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.61 (0.02, 5.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.224\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.53 (0.89, 51.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.481\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep-value = 0.685\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09 (0.04, 0.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.32 (0.98, 45.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.390\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP-value = 0.390\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCase-case study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eRR = risk ratio, p-value = probability value\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cdiv class=\"Section3\" id=\"Sec17\"\u003e\n \u003ch2\u003eQuality of included studies\u003c/h2\u003e\n \u003cp\u003eOur findings suggest that five (n = 5) of the included studies \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e were of high quality implying that they were robust studies; six of the studies \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e were ranked as medium quality implying that their methods were of moderate quality based on the JBI quality assessment criteria. There was no study excluded based on poor scoring on the quality assessment scales. Notably, one (n = 1) cohort study \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e was assed as high on the JBI tools; the rest (n = 3) cohort studies were found to be of medium quality on the same scale \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Three out of six (n = 3/6) case-control studies included \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e, were found to be of high quality based on the JBI quality assessment scale for case-control studies; the rest (n = 3) of the studies \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e were found to be of medium quality on the same scale. Lastly, the only one case\u0026ndash;series study \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e included in our review was found to be of high quality on the JBI quality assessment scale of case controls.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this catatrophic situation, several vaccines, including Pfizer-BioNTech, Moderna, AstraZeneca, protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These vaccines teach our cells how to make a protein (or even just a piece of a protein)\u0026mdash;that triggers an immune response inside our bodies. Theoretical benefits of these vaccines are that those vaccinated gain protection without ever having to risk the serious consequences of getting sick and or die of COVID-19. Several studies found that these vaccines trigger an immune response against the virus \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. These vaccines have been approved for clinical use by the World Health Organization based on comprehensive assessments of non-clinical, laboratory confirmation, clinical utility, and manufacturing data provided by manufacturers to respective regulatory bodies (i.e., U.S. Food and Drug Administration (FDA) and the Department of Health and Human Services or related institutes). Though these vaccines' efficacy and side effects have not yet been widely discussed, numerous claims have been made by popular media and politicians \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. During this process, respective government bodies examine the quality and consistency of the vaccine so that the potential benefits offset the potential adverse effects of the vaccine. Despite unsubstantiated claims on the COVID-19 vaccines efficacy and associated side effects, there is a lack of accumulated evidence on the effectiveness of this vaccine \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. However, among different variants of SARS-CoV-2, the delta variant has significantly increased virulence and transmission capacity \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. In addition, recent evidence indicates that the vaccine's effectiveness declined with the emergence and promotion of the delta variant \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Therefore, this meta-analysis presents a piece of systematic and evidence-based information regarding the effectiveness of different COVID-19 vaccines against specific delta variant (B.1.617.2).\u003c/p\u003e \u003cp\u003eThe B.1.617.2 has seen a sharp rise in infections and mortality in 186 countries \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, including those with relatively high vaccine coverage and increased hospitalization and mortality in the U.K. \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. The high transmissibility of SARS-CoV-2 mainly of delta variant is a considerable socioeconomic global burden. Previous evidence on vaccine effectiveness reported reduced protection against the delta variant compared to the Alpha variant \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Even the efficacy of the 2-dose ChAdOX1 vaccine decreased by 59.8% after exposure to B.1.617.2 \u003csup\u003e31\u003c/sup\u003e. Recent reports determined a higher vaccine breakthrough infection in terms of reduced prophylactic vaccine effectiveness against the SARS-CoV-2 delta variant (B.1.617.2) \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. While more contributing factors may reduce immunity, a recent Israeli study has found higher infection rates even among the earliest vaccinated individuals \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Another study among nursing home residents found the effectiveness of the mRNA vaccine as 74.7% against infection, but the efficiency decreased significantly by 53.1% when the B.1.617.2 circulation predominated \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. The interpretation of this report is complex due to the bias of the methodology, research population, care settings, immunisation timeline and the potential selection and case diagnosis \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Our study found that the effectiveness of COVID-19 vaccine was 80% more protective among those vaccinated with the delta variant (RR = 0.20, 95% CI: 0.07-0.54), compared to unvaccinated populations. A previous study also found a higher rate of vaccine infection breakthrough, indicating lower effectiveness of vaccines in protecting infection with the delta variant \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Another study also argued that infections with delta variant that are transmitted despite the vaccine carry a similar viral burden for people who have not been vaccinated \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Though the effectiveness of vaccines is lower among delta cases, completing the second dose of vaccines reduces the complication among those vaccinated \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. In addition, a growing number of cases detected after one or two doses of vaccination are more likely to be infected with B.1.617.2 than other variants \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Since the efficacy of the vaccines against the B.1.617.2 is lower, several studies recommended an additional dose to curve the infection of the variant and optimise the immune response \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Single-dose vaccine recipients with high infection rates of B.1.617.2 or who have been infected before with another variant can risk vaccine-adapted forms of evolution \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. We argues that the population should be vaccinated as much as possible since those who have not been vaccinated cannot be protected by a significant reduction in the number of vaccinated populations as seen by other infections, making herd immunity could be unachievable due emerging variants \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur study is unique with several strengths. \u003cem\u003eFirstly\u003c/em\u003e, this meta-analysis study that provides evidence-based data on vaccines' effectiveness against the B.1.617.2 variant. \u003cem\u003eSecondly\u003c/em\u003e, we only considered the studies that provide symmetrical information of individuals vaccinated with two doses. Finally, a large population was considered in this study that yields a piece of adequate evidence on this topic. However, we acknowledge some limitations with our study design and selection of published studies. Effectiveness of vaccines (e.g., BNT162b2 or ChAdOx1 nCoV-19) after one dose was significantly lower among population with the B.1.617.2 variant (30.7%) than among those with the alpha variant (48.7%) \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Studies on single-dose vaccination and its efficacy were excluded in this meta-analysis due to lack of reported data, lower effectiveness with the delta variant, insufficient number of studies, and we did not employ any analysis considering the sub-groups of different types of vaccines due to insufficient number of studies and reported combined results with more than one vaccine.\u003c/p\u003e \u003cp\u003eNonetheless, our study provides valuable insights into the effectiveness of the vaccines against the delta variant since there is a dearth of information on this topic. Depending on the predominance of the delta variant, the findings of this study may help policy-makers take action or control measures, and coordinate vaccination effects. Recently, caution has been elevated that vaccine performance may diminish in the future, considering the possibility of a series of potential viral genetic drift \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. These claims highlight the importance of both pharmaceutical and non-pharmaceutical interventions intandem to reduce SARS-CoV-2 infection. Future research can examine the combined efficacy of mass vaccination, contact tracing and social distancing measures in minimising the socioeconomic burden arising from COVID-19. Our study's practical implication is that taking the mounting evidence on the efficacy of pharmaceutical intervention into account, mass vaccination against should be continued in a planned manner to lessen the socioeconomic burden of COVID-19. To do so, COVID-19 vaccines should be categorised as a global humanitarian good emphasising the optimisation of production and equal distribution.\u003c/p\u003e \u003cp\u003eOn the other hand, the demand side should target reducing vaccine hesitancy so that more vulnerable populations are adequately covered. The effectiveness of COVID-19 vaccines was noted with the delta variant among populations after receiving two vaccine doses as compared with unvaccinated populations. This finding would help efforts to maximise vaccine coverage with two doses among vulnerable populations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for conducting this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRAM conceptualised the systematic review and meta-analysis. RAM, MAA, SK and MAR conducted the search, data extraction, under the supervision of AMNR. RAM performed meta-analysis. All authors contributed \u0026nbsp;to finalise the draft paper. RAM, MAA, SK, MAR, JKK and AMNR contributed to revision and approval for submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSheikh A, McMenamin J, Taylor B, Robertson C. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet [Internet] 2021;397(10293):2461\u0026ndash;2. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/S0140-6736(21)01358-1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGISAID. Delta variant detected across 185 countries. Global Initiative on Sharing Avian Influenza Data (GIAID) [Internet]. Phylodynamics pandemic coronavirus Var. VOC Delta G/478K.V1 first Detect. India. 2021 [cited 2021 Sep 30];Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.gisaid.org/hcov19-variants/\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGallagher J. COVID: Is there a limit to how much worse variants can get? How the R0 numbers of COVID-19 variants and other diseases compare [Internet]. 2021 [cited 2021 Sep 30];Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.bbc.com/news/health-57431420\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKrause PR, Fleming TR, Peto R, et al. Considerations in boosting COVID-19 vaccine immune responses. Lancet [Internet] 2021;6736(21):21\u0026ndash;4. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/S0140-6736(21)02046-8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCallaway E. COVID vaccine boosters: the most important questions. Nature 2021;596(7871):178\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarlow RS, Jian K, Larson L, Barlow RS. Effectiveness of COVID-19 Vaccines Against SARS-CoV-2 Infection During a Delta Variant Epidemic Surge in Multnomah County, Oregon, July 2021. MedRxiv Prepr 2021;(July).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePublic Health England. Effectiveness of covid-19 vaccines against hospital admission with the Delta (B.1.617.2) variant [Internet]. 2021. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://khub.net/web/phe-national/public-library/-/document_library/v2Ws-%0ARK3ZlEig/view/479607266\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eImai N, Hogan AB, Williams L, et al. Interpreting estimates of coronavirus disease 2019 (COVID-19) vaccine efficacy and effectiveness to inform simulation studies of vaccine impact: a systematic review. Wellcome Open Res 2021;6(185):185.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThompson MG, Burgess JL, Naleway AL, et al. Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers\u0026mdash;eight US locations, December 2020\u0026ndash;March 2021. Morb Mortal Wkly Rep 2021;70(13):495.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChemaitelly H, Yassine HM, Benslimane FM, et al. mRNA-1273 COVID-19 vaccine effectiveness against the B. 1.1. 7 and B. 1.351 variants and severe COVID-19 disease in Qatar. Nat Med 2021;1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChung H, He S, Nasreen S, et al. Effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe COVID-19 outcomes in Ontario, Canada. 2021;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavis C, Logan N, Tyson G, et al. Reduced neutralisation of the Delta (B. 1.617. 2) SARS-CoV-2 variant of concern following vaccination. medRxiv 2021;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoori M, Nejadghaderi SA, Arshi S, et al. Potency of BNT162b2 and mRNA-1273 vaccine‐induced neutralizing antibodies against severe acute respiratory syndrome‐CoV‐2 variants of concern: A systematic review of in vitro studies. Rev Med Virol 2021;e2277.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePouwels KB, Pritchard E, Matthews P, et al. Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK. medRxiv 2021;2021.08.18.21262237.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan BT, Mpa M, Bobos P, et al. Meta-Analysis of Risk of Vaccine-Induced Immune Thrombotic Thrombocytopenia Following ChAdOx1-S Recombinant Vaccine. medRxiv [Internet] 2021;2021.05.04.21256613. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1101/2021.05.04.21256613\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcDonald I, Murray SM, Reynolds CJ, Altmann DM, Boyton RJ. Comparative systematic review and meta-analysis of reactogenicity, immunogenicity and efficacy of vaccines against SARS-CoV-2. npj Vaccines [Internet] 2021;6(1). Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1038/s41541-021-00336-1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePormohammad A, Zarei M, Pormohammad A, et al. Efficacy and Safety of Mipomersen: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Vaccines 2019;79(7):751\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHou Z, Tong Y, Du F, et al. Assessing covid-19 vaccine hesitancy, confidence, and public engagement:a global social listening study. J Med Internet Res 2021;23(6):1\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAfolabi AA, Ilesanmi OS. Dealing with vaccine hesitancy in Africa: The prospective COVID-19 vaccine context. Pan Afr Med J 2021;38(3):1\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePublic Health England. SARS-CoV-2 variants of concern and variants under investigation in England: Technical briefing 18 [Internet]. Public Health England, Wellington House, 133-155 Waterloo Road, London SE1 8UG: 2021. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/990339/Variants_of_Concern_VOC_Technical_Briefing_13_England.pdf\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoori M, Nejadghaderi SA, Arshi S, et al. Potency of BNT162b2 and mRNA-1273 vaccine-induced neutralizing antibodies against severe acute respiratory syndrome-CoV-2 variants of concern: A systematic review of in vitro studies. Rev Med Virol 2021;e2277:1\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahumud RA, Kamara JK, Renzaho AMN. The epidemiological burden and overall distribution of chronic comorbidities in coronavirus disease-2019 among 202,005 infected patients: evidence from a systematic review and meta-analysis. Infection 2020;48(6):813\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMunn Z, MClinSc SM, Lisy K, Riitano D, Tufanaru C. Methodological guidance for systematic reviews of observational epidemiological studies reporting prevalence and cumulative incidence data. Int J Evid Based Healthc 2015;13(3):147\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJoanna Briggs Institute (JBI). JBI\u0026rsquo;s critical appraisal tools. Faculty of Health and Medical Sciences, The University of Adelaide SA 5006 Adelaide, Australia:\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFowlkes A, Gaglani M, Groover K, Thiese MS, Tyner H, Ellingson K. Effectiveness of COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Frontline Workers Before and During B.1.617.2 (Delta) Variant Predominance \u0026mdash; Eight U.S. Locations, December 2020\u0026ndash;August 2021. MMWR Morb Mortal Wkly Rep 2021;70(34):1167\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrannis SJ, Rowley EA, Ong TC, et al. Interim Estimates of COVID-19 Vaccine Effectiveness Against COVID-19 \u0026ndash; Associated Emergency Department or Urgent Care Clinic Encounters and Hospitalizations Among Adults During SARS-CoV-2 B. 1. 617. 2 (Delta) Variant Predominance \u0026mdash; Nine States, June. Morb Mortal Wkly Rep 2021;70(37):1291\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJara A, Undurraga EA, Gonz\u0026aacute;lez C, et al. Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile. N Engl J Med 2021;385(10):875\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNanduri S, Pilishvili T, Derado G, et al. Effectiveness of Pfizer-BioNTech and Moderna Vaccines in Preventing SARS-CoV-2 Infection Among Nursing Home Residents Before and During Widespread Circulation of the SARS-CoV-2 B.1.617.2 (Delta) Variant \u0026mdash; National Healthcare Safety Network, March 1\u0026ndash;August. MMWR Morb Mortal Wkly Rep 2021;70(34):1163\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi X-N, Huang Y, Wang W, et al. Effectiveness of inactivated SARS-CoV-2 vaccines against the Delta variant infection in Guangzhou: a test-negative case\u0026ndash;control real-world study. Emerg Microbes Infect 2021;10(1):1751\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu Z, Tao B, Li Z, et al. Effectiveness of inactive COVID-19 vaccines against severe illness in B.1.617.2 2 (Delta) variant-infected patients in Jiangsu, China. MedRxiv Prepr 2021;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBernal JL, Andrews N, Gower C, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med 2021;385(7):585\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTang P, Hasan MR, Chemaitelly H, et al. BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the Delta (B.1.617.2) variant in Qatar. medRxiv 2021;2021.08.11.21261885.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNasreen S, He S, Chung H, et al. Effectiveness of COVID-19 vaccines against variants of concern, Canada. medRxiv [Internet] 2021;2021.06.28.21259420. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.medrxiv.org/content/\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1101/2021.06.28.21259420v1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKislaya I, Rodrigues EF, Borges V, et al. Delta variant and mRNA Covid-19 vaccines effectiveness: higher odds of vaccine infection breakthroughs. medRxiv 2021;2021.08.14.21262020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21(11):1539\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEgger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSterne JAC, Egger M. Funnel plots for detecting bias in meta-analysis: Guidelines on choice of axis. J Clin Epidemiol 2001;54:1046\u0026ndash;1055.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFolegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020;396(10249):467\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXia S, Zhang Y, Wang Y, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect Dis 2021;21(1):39\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIson MG, Wolfe C, Boucher HW. Emergency use authorization of remdesivir: the need for a transparent distribution process. JAMA 2020;323(23):2365\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUS Food and Drug Administration. Emergency use authorization. 2020;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurki TK. Lifting of COVID-19 restrictions in the UK and the Delta variant. Lancet Respir Med 2021;9(8):e85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSander A-L, Yadouleton A, Moreira-Soto A, et al. An Observational Laboratory-Based Assessment of SARS-CoV-2 Molecular Diagnostics in Benin, Western Africa. MSphere 2021;6(1):e00979-20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMizrahi B, Lotan R, Kalkstein N, et al. Correlation of SARS-CoV-2 breakthrough infections to time-from-vaccine; Preliminary study. MedRxiv 2021;\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Appendix Tables","content":"\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; line-height: 115%; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eAppendix Table A1. Quality score assessment for cohort study\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width:751.05pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 29.4pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 6.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e#\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 353.1pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 6.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQuality assessment indicators\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width:368.55pt;border:solid windowtext 1.0pt;border-left:none;padding:0in 5.4pt 0in 5.4pt;height:6.6pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eSelected cohort studies\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:95.6pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eFowlkes et al. (2021)\u0026nbsp;\u003csup\u003e25\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eGrannis et al. (2021)\u0026nbsp;\u003csup\u003e26\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.4pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eJara et al. (2021)\u0026nbsp;\u003csup\u003e27\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eNanduri et al. (2021)\u0026nbsp;\u003csup\u003e28\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29.4pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 353.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere the two groups similar and recruited from the same population?\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29.4pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 353.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere the exposures measured similarly to assign people to both exposed and unexposed groups?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29.4pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ3\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 353.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas the exposure measured in a valid and reliable way?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29.4pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ4\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 353.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere confounding factors identified?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29.4pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 353.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere strategies to deal with confounding factors stated?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29.4pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ6\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 353.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere the groups/participants free of the outcome at the start of the study (or at the moment of exposure)?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29.4pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ7\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 353.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere the outcomes measured in a valid and reliable way?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29.4pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 353.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas the follow-up time reported and sufficient to be long enough for outcomes to occur?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026reg;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026reg;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026reg;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29.4pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ9\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 353.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas follow-up complete, and if not, were the reasons to loss to follow-up described and explored?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026reg;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29.4pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ10\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 353.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere strategies to address incomplete follow-up utilized?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29.4pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ11 \u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 353.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas appropriate statistical analysis used?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 382.5pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 3pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eOverall quality score\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 3pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e8.5 (medium)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 3pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e8.5 (medium)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 3pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e9.5 (high)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 3pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e8.5 (medium)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width:382.5pt;border:solid windowtext 1.0pt;border-top:none;padding:0in 5.4pt 0in 5.4pt;height:3.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eOverall appraisal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.6pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:3.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eIncluded\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:3.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eIncluded\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.4pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:3.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eIncluded\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:3.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eIncluded\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:107%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eNote\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e= yes ( = 1),\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026nbsp;= no ( = 0), \u0026reg; =unclear (=0.5); quality assessment decision rules for 11 scales [(i) poor if the overall score\u0026le;5, (ii) medium if overall scores is 6 to 9, and (iii) high if the overall score\u0026gt;9],\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:107%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:107%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eAppendix Table A2. Quality score assessment for case-control\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width:732.75pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:28.1pt;border:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:20.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e#\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:206.15pt;border:solid windowtext 1.0pt;border-left:none;padding:0in 5.4pt 0in 5.4pt;height:20.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQuality assessment indicators\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"6\" style=\"width:498.5pt;border:solid windowtext 1.0pt;border-left:none;padding:0in 5.4pt 0in 5.4pt;height:20.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eSelected case-control studies\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:89.35pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:14.3pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eBarlow et al. (2021)\u0026nbsp;\u003csup\u003e6\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:75.8pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:14.3pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eLi et al. (2021)\u0026nbsp;\u003csup\u003e29\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:75.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:14.3pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eHu et al. (2021)\u0026nbsp;\u003csup\u003e30\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:82.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:14.3pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eBernal et al. (2021)\u0026nbsp;\u003csup\u003e31\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:82.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:14.3pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eTang et al. (2021)\u0026nbsp;\u003csup\u003e32\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:14.3pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eNasreen et al. (2021)\u0026nbsp;\u003csup\u003e33\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ1\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere the groups comparable other than the presence of disease in cases or the absence of disease in controls?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89.35pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere cases and controls matched appropriately?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89.35pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere the same criteria used for identification of cases and controls?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89.35pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas exposure measured in a standard, valid and reliable way?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89.35pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas exposure measured in the same way for cases and controls?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89.35pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere confounding factors identified?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89.35pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere strategies to deal with confounding factors stated?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89.35pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere outcomes assessed in a standard, valid and reliable way for cases and controls?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89.35pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026reg;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas the exposure period of interest long enough to be meaningful?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89.35pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026reg;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026reg;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ10\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas appropriate statistical analysis used?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89.35pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 10.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 234.25pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 4.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eOverall quality score\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89.35pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 4.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e9.5 (high)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 4.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e8 (high)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 4.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e8 (medium )\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 4.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e9 (high)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 4.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e8 (medium)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 4.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e8 (medium)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 234.25pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 8.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eOverall appraisal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89.35pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 8.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eIncluded\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 8.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eIncluded\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 8.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eIncluded\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 8.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eIncluded\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.7pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 8.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eIncluded\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 8.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eIncluded\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eNote\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026nbsp;= yes ( = 1),\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026nbsp;= no (= 0), \u0026reg; = unclear (= 0.5); quality assessment decision rules for 10 scales: (i) poor if the overall scores\u0026lt;6, (ii) medium if the overall scores is 6 to 8, and (iii) high if the overall scores\u0026gt;8\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:107%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:107%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eAppendix Table A3. Quality score assessment for case-series study\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width:467.55pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.6pt;border: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e#\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 365.4pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQuality assessment indicators\u0026nbsp;for case-series study\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eKislaya et al. (2021)\u0026nbsp;\u003csup\u003e34\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.6pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 365.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere there clear criteria for inclusion in the case series?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.6pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 365.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas the condition measured in a standard, reliable way for all participants included in the case series?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.6pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 365.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere valid methods used for identification of the condition for all participants included in the case series?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.6pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 365.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eDid the case series have consecutive inclusion of participants?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.6pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 365.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eDid the case series have complete inclusion of participants?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026reg;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.6pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 365.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas there clear reporting of the demographics of the participants in the study?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.6pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 365.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas there clear reporting of clinical information of the participants?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.6pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 365.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWere the outcomes or follow-up results of cases clearly reported?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.6pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 365.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas there clear reporting of the presenting site(s)/clinic(s) demographic information?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.6pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eQ10\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 365.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eWas statistical analysis appropriate?\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 390pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eOverall quality score\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e9.5 (high)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 390pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eOverall appraisal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:107%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eNote\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✓\u003c/span\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026nbsp;= yes ( = 1),\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Segoe UI Symbol\", sans-serif; color: rgb(0, 0, 0);'\u003e✕\u003c/span\u003e\u003cspan style='font-size: 13px; line-height: 107%; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003e\u0026nbsp;= no (= 0), \u0026reg; = unclear (= 0.5); quality assessment decision rules for 10 scales: (i) poor if the overall scores\u0026lt;6, ii) medium if the overall scores is 6 to 8, and (iii) high if the overall scores \u0026gt;8\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"University of Sydney","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Delta variant, COVID-19 vaccines, herd immunity, vaccines effectiveness, meta-analysis, B 1.617.2 ","lastPublishedDoi":"10.21203/rs.3.rs-1130796/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1130796/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe highly transmissible COVID-19 \u003cem\u003edelta variant\u003c/em\u003e (DV) has contributed to the surge in cases and has now been exacerbated the worldwide public health crisis. Several COVID-19 vaccines play a significant role in a high degree of protection against DV. The primary purpose of this meta-analysis is to estimate the pooled effectiveness of the COVID-19 vaccines against DV in terms of risk ratio (RR) among fully vaccinated, compared to unvaccinated populations.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eWe carried out a systematic review with meta-analysis of original studies focused on COVID-19 vaccines effectiveness of COVID-19 vaccines against B.1.617.2 clinical perspective among fully COVID-19 vaccinated populations, compared to placebo (unvaccinated populations), published before September 30, 2021. Eleven studies containing data of 17.2 million participants were identified and included in our study. Pooled estimates of COVID-19 vaccines effectiveness (i.e., risk ratio, RR) against delta variant with 95% confidence intervals were assessed using random-effect models. Publication bias was assessed using Egger's regression test and funnel plot to investigate potential sources of heterogeneity and identify any differences in study design.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eA total population of 17.2 million (17,200,341 peoples) were screened for the COVID-19 vaccines' effectiveness against delta variant. We found 61.13% of study population were fully vaccinated with 2-dose of COVID-19 vaccines. Weighted pooled incidence of COVID-19 infection was more than double (20.07%) among unvaccinated populations, compared to the fully vaccinated population (8.16%). Overall, the effectiveness of COVID-19 vaccine against DV was 85% (RR = 0.15, 95% CI: 0.07-0.31). The effectiveness of COVID-19 vaccines varied slidably by study designs, 87% (RR = 0.13, 95% CI: 0.06-0.30) and 84% (RR = 0.16, 95% CI:0.02, 1.64) for cohort and case-control studies, respectively. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eEffectiveness COVID-19 vaccines were noted to offer higher protection \u0026nbsp;against delta variant among populations who received two vaccine doses compared with unvaccinated populations. This finding would help efforts to maximise vaccine coverage (i.e., at least 60 to 70% of the population) with two doses among vulnerable populations to have herd immunity to breat the chain of transmission and gain greater overall population protection more rapidly.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","manuscriptTitle":"Effectiveness of COVID-19 vaccines against delta variant (B.1.617.2): A meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-12-03 15:40:03","doi":"10.21203/rs.3.rs-1130796/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"852b7548-a0f1-464c-8b06-52d1c6fd39c1","owner":[],"postedDate":"December 3rd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":8866639,"name":"Biostatistics"},{"id":8866640,"name":"Immunology"},{"id":8866641,"name":"Virology"},{"id":8866642,"name":"Population Biology"}],"tags":[],"updatedAt":"2022-02-14T02:14:06+00:00","versionOfRecord":{"articleIdentity":"rs-1130796","link":"https://doi.org/10.3390/vaccines10020277","journal":{"identity":"vaccines","isVorOnly":true,"title":"Vaccines"},"publishedOn":"2022-02-11 02:14:06","publishedOnDateReadable":"February 11th, 2022"},"versionCreatedAt":"2021-12-03 15:40:03","video":"","vorDoi":"10.3390/vaccines10020277","vorDoiUrl":"https://doi.org/10.3390/vaccines10020277","workflowStages":[]},"version":"v1","identity":"rs-1130796","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1130796","identity":"rs-1130796","version":["v1"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}