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Determining eligibility for antiretroviral therapy in resource-limited settings using total lymphocyte… Moore, David M; Awor, Anna; Downing, Robert S; Were, Willy; Solberg, Peter; Tu, David; Chan, Keith; Hogg, Robert S; Mermin, Jonathan Jan 18, 2007

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ralssBioMed CentAIDS Research and TherapyOpen AcceResearchDetermining eligibility for antiretroviral therapy in resource-limited settings using total lymphocyte counts, hemoglobin and body mass indexDavid M Moore*1,2,3, Anna Awor1, Robert S Downing1, Willy Were1, Peter Solberg1,4, David Tu5, Keith Chan2, Robert S Hogg2,3 and Jonathan Mermin1Address: 1Global AIDS Program, US Centers for Disease Control and Prevention, Entebbe, Uganda, 2British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada, 3Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada, 4Institute for Global Health, University of California, San Francisco, San Francisco, California and 5Medicins Sans Frontieres – Holland, Amsterdam, The NetherlandsEmail: David M Moore* - dmoore@cfenet.ubc.ca; Anna Awor - ara2@ug.cdc.gov; Robert S Downing - rqd6@ug.cdc.gov; Willy Were - wgw7@ug.cdc.gov; Peter Solberg - lisapetermax@hotmail.com; David Tu - davidtu@telus.net; Keith Chan - kchan@cfenet.ubc.ca; Robert S Hogg - dr_bob_hogg@yahoo.com; Jonathan Mermin - jmermin@ke.cdc.gov* Corresponding author    AbstractBackground: CD4+ T lymphocyte (CD4) cell count testing is the standard method fordetermining eligibility for antiretroviral therapy (ART), but is not widely available in sub-SaharanAfrica. Total lymphocyte counts (TLCs) have not proven sufficiently accurate in identifying subjectswith low CD4 counts. We developed clinical algorithms using TLCs, hemoglobin (Hb), and bodymass index (BMI) to identify patients who require ART.Methods: We conducted a cross-sectional study of HIV-infected adults in Uganda, who presentedfor assessment for ART-eligibility with WHO clinical stages I, II or III. Two by two tables wereconstructed to examine TLC thresholds, which maximized sensitivity for CD4 cell counts ≤ 200cells µL, while minimizing the number offered ART with counts > 350 cells µL. Hb and BMI valueswere then examined to try to improve model performance.Results: 1787 subjects were available for analysis. Median CD4 cell counts and TLCs, were 239cells/µL and 1830 cells/µL, respectively. Offering ART to all subjects with a TLCs ≤ 2250 cells/µLproduced a sensitivity of 0.88 and a false positive ratio of 0.21. Algorithms that treated all patientswith a TLC <2000 cells/µL, excluded all patients with a TLC >3000 cells/µL, and used Hb and/orBMI values to determine eligibility for those with TLC values between 2000 and 3000 cells/µL,marginally improved accuracy.Conclusion: TLCs appear useful in predicting who would be eligible for ART based on CD4 cellcount criteria. Hb and BMI values may be useful in prioritizing patients for ART, but did not improvemodel accuracy.Published: 18 January 2007AIDS Research and Therapy 2007, 4:1 doi:10.1186/1742-6405-4-1Received: 27 September 2006Accepted: 18 January 2007This article is available from: http://www.aidsrestherapy.com/content/4/1/1© 2007 Moore et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 7(page number not for citation purposes)AIDS Research and Therapy 2007, 4:1 http://www.aidsrestherapy.com/content/4/1/1BackgroundGuidelines developed by the World Health Organization(WHO) for the use of antiretroviral therapy (ART) in low-income countries state that HIV-infected individualsshould commence ART if they have WHO stage IV disease,stage III disease and a CD4+ T lymphocyte (CD4) cellcount of ≤350 cells/µL, or stage I or II disease with CD4cell counts ≤200 cells/µL [1]. Recently WHO has recom-mended to increase this threshold for stage I and II indi-viduals to 350 cells/µL [2].If CD4 cell counting is not available, as is the case in mostof sub-Saharan Africa, the WHO guidelines recommendusing clinical staging alone, or in combination with totallymphocyte counts (TLCs) of < 1200/µL in order to deter-mine ART eligibility[1]. However, many studies havefound both clinical stages III/IV and this TLC threshold tohave poor sensitivity for low CD4 cell counts, leadingresearchers attempt to define other TLC thresholds whichbetter correspond to CD4 cell counts ≤ 200 or 350 cells/µL [3-5]. Studies which have incorporated hemoglobin(Hb) or hematocrit into clinical algorithms have shownimproved performance of TLC in predicting low CD4 cellcounts[6-8]. However, such studies have treated the CD4cell count threshold as an absolute standard, where initi-ating treatment in patients with cell counts above 200cells/µL is undesirable. As delaying ART until CD4 cellcounts fall below 200 cells/µL results in increased mortal-ity[9] and most studies from sub-Saharan African settingshave shown high mortality rates in the first year on ther-apy [10-12], it seems reasonable to adopt the more liberalART eligibility criteria of <350 cells/µL.We designed an analysis among HIV-infected adults inrural Uganda being screened for ART eligibility. We exam-ined the clinical utility of TLCs, Hb, and body mass index(BMI) to maximize the sensitivity to detect individualswith CD4 cell counts below 200 cells/µL, and limit theproportion of individuals who would be offered ART withCD4 cell counts above 350 cells/µL.MethodsThe Home-Based AIDS Care Program (HBAC) is a clinicaltrial of three different monitoring strategies for patientsreceiving ART in rural Eastern Uganda. Registered clientsof The AIDS Support Organization (TASO), a local HIV/AIDS care and support organization in Tororo and Busiadistricts, were invited to be screened for ART eligibility.The study includes participants from a prior diarrhea pre-vention and cotrimoxazole study described elsewhere[13], as well as newly recruited clients. Aggregated datafrom screening at baseline were used for this analysis. Thestudies were approved by the Science and Ethics Commit-and Prevention and the University of California, San Fran-cisco.All subjects in this analysis were HIV-infected adults aged≥ 18 years. Clinical and laboratory assessments at baselineincluded a complete blood counts (CBC), viral load, andCD4 cell counts. Those who had a CD4 count ≤250 or hadWHO stage III (excluding pulmonary TB) or IV wereoffered ART. Blood samples for TLC and CD4 testing werecollected in the same vacutainer tube containing EDTA atthe study clinic and transported to the CDC laboratory inEntebbe. CD4 cell counts were measured by a dual-plat-form protocol using a FACScan instrument and Tritest rea-gents (Beckson-Dickenson, San Carlos, CA). TLCs weremeasured both using a hematology analyzer (Beckman-Coulter, Fullerton, CA) and the FACScan instrument. Wehave previously found that delays in transport of up to 5days do not affect the accuracy of the FACScan results forCD4 cell counts (R. Downing, unpublished data) andtherefore used the TLC results obtained on the FACScan inorder to determine if transport time to the lab significantlyaffected the difference between the two methods. TLCsresults from the hematology analyzer were used for theanalysis. Clinical information during screening was col-lected using standardized instruments completed by studyphysicians. Subjects with WHO stage IV disease wereexcluded for this analysis.Bivariate correlations between TLC results obtained onthe FACscan and hematology analyzer were conducted.Differences between the two results were calculated andcompared with results stratified by time between blooddraw to testing of ≤ 1 day and > 1 day, using the WilcoxanRank Sum test. Distributions of TLCs, Hb and BMI acrossCD4 cell count strata were compared in a pair-wise fash-ion using the Wilcoxan Rank Sum test. Two by two tableswere constructed to examine the association between dif-ferent strata of TLCs, Hb and BMI with CD4 cell counts ≤200/µL or ≤350/µL. Sensitivity, specificity, positive andnegative predictive values and accuracy (true positives +true negatives/all subjects) of the models were then calcu-lated. We examined different TLC thresholds in terms oftheir ability to maximize sensitivity in detecting subjectswith CD4 cell counts ≤ 200 cells/µL and minimize theproportion of subjects offered ART with cell counts > 350cells/µL (false positives). Hb and BMI thresholds, aloneand in combination, were then used to classify subjectswith intermediate TLCs as qualifying for therapy. 95%confidence intervals for sensitivity and false positive ratioswere calculated for the final models according to the Waldmethod [14]. Final models were then run under the sce-nario where all subjects with WHO stage III disease wereoffered ART and the algorithm was used to determine ARTPage 2 of 7(page number not for citation purposes)tee of the Uganda Virus Research Institute and the Institu-tional Review Boards of the Centers for Disease Controleligibility for those with stages I and II only. Final modelswere also examined separately for men and women.AIDS Research and Therapy 2007, 4:1 http://www.aidsrestherapy.com/content/4/1/1The effects of tuberculosis, malaria parasitemia, ordiarrhea at the time of screening were examined by con-ducting sub-group analyses which excluded subjects withthese illnesses. All statistical analyses were conducted inSAS version 9.0 (SAS Institute, Cary, NC)ResultsBetween May 2003 and June 2005, 1944 HIV-infectedadults presented for assessment of ART eligibility. Ofthese, 104 (5.2%) were excluded from this analysis as theywere found to have WHO clinical stage IV disease.Another 53 individuals were excluded because of missingTLC or CD4 cell count values leaving 1787 subjects avail-able for analysis. 75.2% were women and 27.8% weremen. Median baseline CD4 cell counts and total lym-phocyte counts, were 239 (inter-quartile range [IQR] =119–411) and 1830 (IQR = 1420–2360) cells/µL, respec-tively. The mean time between blood sample collectionand TLC and CD4 testing was 1.4 days; 56% of subjectshad blood tested on the same day or one day after blooddraw and 43% were tested 2 days after blood draw. Onepatient had blood tested 8 days after blood draw and wasexcluded from the analysis. TLC results between thehematology analyzer and the FACScan instrument werehighly correlated (Pearson's r2 = 0.85, p < 0.001) with theanalyzer consistently giving greater values (median differ-ence 383 cells/µL; IQR = 253 – 560). Differences wereslightly greater for subjects whose blood samples weretested 2 days after blood draw in comparison with thosewhose blood was tested ≤ 1 day after draw (399 cells/µLvs. 360 cells/µL, p = 0.003).In total, 763 (42.7%) subjects had baseline CD4 cellcounts ≤ 200 cells/µL, 459(25.7%) had cell counts of201–350 cells/µL and 565 (31.6%) had CD4 counts > 350cells/µL (Table 1). Median baseline hemoglobin was 11.6g/Dl (IQR = 10.3–12.8) and median baseline body massindex was 20.0 kg/m2 (IQR = 18.-21.9). TLCs, Hb and BMIwere distributed differently between the CD4 cell countstrata (p < 0.01, for pair-wise comparisons for all parame-ters), with higher values for all parameters measured inthe higher CD4 cell count strata.A TLC threshold of 2250 cells/µL was the most accurate(0.73) predictor of CD4 cell counts ≤ 350 cells/µL, yield-ing a sensitivity of 0.81 and a specificity of 0.54 (Table 2).This corresponded to a sensitivity of 0.88 (95% confi-dence interval [CI] 0.86 – 0.90) for CD4 cell counts ≤ 200cells/µL and would result in 21% (95% CI 0.18 – 0.24) ofsubjects being offered ART with CD4 cell counts > 350cells/µL (false positives). Incorporating Hb and/or BMIinto algorithms produced two models with accuracy levelsof 0.75. Both methods would offer ART to all subjectsbetween 2000 and 3000 cells/µL, the first model used Hb≤ 11 g/Dl alone and had a sensitivity of 0.88 (95% CI 0.86– 0.90) for CD4 cell counts ≤ 200 cells/µL and a false pos-itive ratio of 0.18 (95% CI 0.15 – 0.21). The second modelused Hb values ≤ 11 g/Dl or a BMI ≤ 18 kg/m2 to classifyintermediate TLCs and resulted in a sensitivity of 0.90(95% CI 0.88 – 0.92) and a false positive ratio of 0.20(95% CI 0.17 – 0.23). Figure 1 describes the flow ofpatients through the second algorithm. The use of thesealgorithms would have resulted in treatment beingoffered to 1212 and 1268 subjects, respectively, in com-parison to 1230 subjects, if all subjects with CD4 cellcounts ≤ 350 cells/µL were offered treatment.Results for women were unchanged from that of thewhole group (data not shown). Both algorithms from thewhole group analysis performed well for men separately,with accuracies of 0.72 and 0.73 for the models includingTLC and Hb; and TLC, Hb and BMI, respectively (Table2E). However, the highest accuracy was found using analgorithm with TLC thresholds of 2000 and 3000, tofirstly include and exclude subjects for treatment; and Hbvalues of 12 g/dL and BMI of 18 kg/m2 to assign treatmentto those with intermediate TLCs. This model had an accu-racy of 0.75, a sensitivity for CD4 cell counts ≤ 200 cells/µL of 0.87 and a false positive ratio of 0.14.Offering ART to all subjects with WHO stage III diseaseand using the algorithms to determine ART-eligibility forthose with stage I or II disease would have resulted intreatment being offered to 1282 or 1328 subjects withsimilar levels of sensitivity and false positives. A total of19 subjects had malaria parasitemia, 60 subjects were onTB treatment or diagnosed with TB at screening and 96subjects had diarrhea at screening. However, excludingany of these subjects did not improve the predictive valueof the final models.DiscussionWe have demonstrated that using a TLC of 2250 cells/µLto determine ART eligibility in subjects with WHO clinicalstages I, II or III, could identify 88% of subjects with CD4cell counts ≤ 200 cells/µL, while 21% of subjects offeredART would have CD4 cell counts > 350 cells/µL. Using aTLC threshold of 2000 cells/µL to offer ART and an upperthreshold of 3000 cells/µL to exclude subjects from treat-ment with Hb and BMI thresholds to determine ART eligi-bility for those with intermediate TLCs only marginallyimproved the accuracy of TLCs alone.Despite the failure to improve accuracy of TLCs in predict-ing CD4 cell counts, using Hb and BMI may still be ofvalue in determining who should initiate ART in resource-Page 3 of 7(page number not for citation purposes)with TLCs ≤ 2000 cells/µL and defer treatment for thosewith TLCs > 3000 cells/µL. To evaluate subjects with TLCslimited settings. Recent studies have shown that low Hbvalues and low BMI are independent risk factors for earlyAIDS Research and Therapy 2007, 4:1 http://www.aidsrestherapy.com/content/4/1/1Table 1: Distribution of total lymphocyte counts, hemoglobin and body mass index values by CD4 strata for 1787 HIV – infected subjects in Tororo, Uganda.CD4 cell count ≤ 200 cells/µL(column 1)P value (column 1 to 2)CD4 cell count 200 – 350 cells/µL(column 2)P value(column 2 to 3)CD4 cell count > 350 cells/µL(column 3)Number of subjects (%) 763 (42.7) 459 (25.7) 565(31.6)TLC – cells/µL median (interquartile range)1460 (1120 – 1910)<0.001 1880 (1570 – 2330) <0.001 2330 (1910 – 2860)Hb in g/dL median (IQR) 11.3 (10.0 – 12.4) <0.001 11.8 (10.6 – 12.9) <0.001 12.3 (11.4 – 13.2)BMI in kg/m2 median (IQR) 19.7 (18.0 – 21.5) <0.001 20.4 (18.9 – 21.9) 0.009 20.8 (19.2 – 22.8)Table 2: Performance of algorithms using TLCs alone or in combination with Hb and BMI in predicting CD4 cell counts ≤ 350 cells/µL in the Home-Based AIDS Care project, Tororo, UgandaTLC Lower thresholdTLC Upper thresholdHb thresholdBMI thresholdSensitivity for CD4 <350Specificity for CD4 <350accuracy sensitivity for CD4<200False PositivesN Qualifying For ARTA) CD4 alone 1.00 1.00 1.00 1.00 0 1230B) TLC alone1500 0.40 0.95 0.67 5191750 0.59 0.85 0.67 0.69 0.11 8012000 0.71 0.69 0.71 0.80 0.17 1043*2250 0.81 0.54 0.73 0.88 0.21 12502500 0.88 0.41 0.73 0.93 0.24 14042750 0.92 0.28 0.72 0.96 0.27 15233000 0.95 0.21 0.71 0.97 0.28 1601C) TLC combined with Hb and/or BMI1750 2750 11 0.71 0.75 0.68 0.81 0.14 10171750 2750 12 0.78 0.62 0.73 0.86 0.18 11801750 2750 18 0.64 0.77 0.68 0.75 0.14 9171750 2750 11 18 0.74 0.69 0.73 0.84 0.16 1087*2000 3000 11 0.81 0.62 0.75 0.88 0.18 12122000 3000 12 0.85 0.51 0.74 0.94 0.21 13352000 3000 18 0.75 0.63 0.72 0.84 0.19 1138**2000 3000 11 18 0.83 0.57 0.75 0.90 0.20 12681750 2500 11 0.69 0.76 0.72 0.79 0.14 9891750 2500 12 0.79 0.61 0.73 0.84 0.20 11691750 2500 11 18 0.72 0.72 0.72 0.82 0.15 10452000 2750 11 0.79 0.62 0.74 0.86 0.18 11902000 2750 18 0.75 0.64 0.71 0.83 0.19 11282000 2750 11 18 0.81 0.57 0.74 0.89 0.20 1242D) TLC combined with Hb and/or BMI for WHO stages I and II only**2000 3000 11 0.80 0.62 0.74 0.93 0.19 1282‡2000 3000 11 18 0.83 0.57 0.73 0.90 0.20 1328‡E) TLC combined with Hb and/or BMI for men only2000 3000 11 0.58 0.71 0.72 0.80 0.122000 3000 12 0.76 0.63 0.73 0.84 0.142000 3000 11 18 0.77 0.60 0.73 0.87 0.14**2000 3000 12 18 0.80 0.57 0.75 0.89 0.15Models with the highest accuracy using TLC alone (*) and TLC and Hb +/- BMI (**)Page 4 of 7(page number not for citation purposes)mortality on ART in African settings [15,16]. Therefore‡ Includes offering ART to 333 subjects with WHO stage III disease of whom 46 had CD4 cell counts > 350 cells/µL.AIDS Research and Therapy 2007, 4:1 http://www.aidsrestherapy.com/content/4/1/1Page 5 of 7(page number not for citation purposes)Algorithm for determining ART eligibility for 1787 HIV infected individuals using TLCs, Hb and BMIFi u e 1Algorithm for determining ART eligibility for 1787 HIV infected individuals using TLCs, Hb and BMI.1944 adults  (≥ 18 yrs) present for assessment of ART eligibility 184 with TLCs > 3000 cells/ µL 1787 subjects available for analysis 53 subjects (2.7%) excluded b/c missing TLC or CD4 results 109 (5.2%) excluded b/c WHO clinical stage IV disease 558 subjects with TLCs 2001 - 3000 cells/ µL 1043 with TLCs ≤ 2000 cells/ µL ART offered to all TLC resultART decision unclear ART deferred for all Hb and BMI assessment 341 with  Hb > 11 g/dL and BMI > 18  kg/m2 216 with  Hb ≤ 11 g/dL or BMI ≤ 18   kg/m2  ART offered  ART deferred 868 True positive CD4s ≤ 350 cells/ µL 175 False positive CD4s > 350 cells/ µL 161 True negative CD4s > 200 cells/ µL 23  False negative CD4s ≤ 200 cells/ µL 144 True positive CD4s ≤ 350 cells/ µL 72  False positive CD4s > 350 cells/ µL 51  False negative CD4s ≤ 200 cells/ µL 290 True negative CD4s > 200 cells/ µL AIDS Research and Therapy 2007, 4:1 http://www.aidsrestherapy.com/content/4/1/1incorporating Hb and BMI into ART eligibility criteriamay help to prioritize treatment for those who are atincreased risk of death if ART is delayed until CD4 cellcounts drop further. ART guidelines in use in industrial-ized countries recommend treatment for individuals withCD4 cell counts in the range of 200 – 350 cells/µL prima-rily for those with factors which may limit the effective-ness of ART if treatment is much delayed [17]. The strategyproposed here adopts a similar approach but one which islikely more relevant to HIV-infected individuals living insub-Saharan Africa.The number of patients offered therapy under our TLC/Hb/BMI criteria were similar to the number offered treat-ment had ART been offered to all patients with CD4 cellcounts ≤ 350 cells/µL, however, the same patients wouldnot be treated under both scenarios. Between 17 and 19%of subjects with CD4 cell counts ≤350 cells/µL would notbe offered ART using the TLC/Hb/BMI algorithms, how-ever, as they would not have low BMIs or low Hb values,unless they also had TLCs >3000 cells/µL, it is unlikelythat they would be at risk for early mortality without treat-ment.More than 75% of the participants in this study werewomen. While the proportion of women aged 15 – 59with HIV in Uganda is about 28% greater than men (7.3versus 5.2%)[18], it is likely that differences in healthseeking behavior are a more likely explanation for thelarge differences in the numbers of men and women seenin our study. When models were run excluding womenfrom the analysis, we found that using a Hb threshold of12 g/dL was a more accurate threshold for distinguishingwhich men had low CD4 cell counts.If TLCs are to prove to be a viable alternative to using CD4cell counting in managing HIV-infected individuals inresource-limited settings, they will need to be shown to beuseful not only in determining when individuals shouldinitiate ART, but also in monitoring patients on ART.There have been few studies on the use of TLCs in moni-toring individuals on ART, but all have concluded thatTLCs correlate well with changes in CD4 cell counts onART[19,20]. However, the most recent ART guidelinesfrom WHO state that "TLC is not suitable for monitoringtherapy as a change in the TLC value does not reliably pre-dict treatment success."[2] It is unclear from where thisrecommendation derives as no reference is provided.The proportion of subjects in our study with CD4 cellcounts ≤ 200 cells/µL and ≤ 350 cells/µL was very high(42.7% and 68.4%, respectively), resulting in a largenumber of subjects being ART-eligible. It is likely that ourever, uptake of voluntary counseling and testing is quitelow in Uganda in that only 13% of women and 11% ofmen have ever been tested for HIV[18] and is also likelyvery low in other sub-Saharan African countries. Thereforeit is reasonable to expect that many people presenting forassessment of ART-eligibility will have been tested for HIVbecause of ill health and a large proportion will likelymeet eligibility criteria.This study has two potential limitations. Firstly, TLCs andCD4 cell counts were not conducted at the site of blooddrawing, but were transported to the CDC laboratory inEntebbe, which may have resulted in some deteriorationof the blood samples. However, we had previously shownthat CD4 cell count results from the FACScan instrumentare stable up to 5 days after blood draw and the variabilitybetween the TLC values obtained on the FACScan wereonly a median of 40 cells/µL less for subjects whose bloodwas tested 2 days after draw compared to those whosesamples were tested after ≤ 1 day delay between blood col-lection and testing. These observations suggest that trans-port time may not have caused significant inaccuracy inour laboratory test results. Secondly, the gold standard fordetermining inclusion or exclusion criteria for ART usedin this study, that of CD4+ T lymphocyte counts, are alsonot perfect predictors of morbidity and mortality amongpeople with HIV. While CD4 cell counting has provenuseful in allowing stratification of risk for disease progres-sion on ART individual variation of disease progressionwithin CD4 cell count strata is large [9]. TLCs have beenshown to be comparable predictors of mortality for HIV-infected populations receiving [21] and not receivingART[22].Thus, while TLCs may not correlate perfectly with CD4cell counts, they may be as useful in predicting diseaseprogression and therefore can be equally useful in deter-mining when ART should be initiated. While evaluatinghow well ART-eligibility criteria based on TLCs perform incomparison to CD4 cell count – based criteria can only beanswered by conducting clinical trials, this study has againdemonstrated that TLCs are useful proxy measures forCD4 cell counts in determining ART eligibility.AcknowledgementsThe authors would like to thank the HBAC participants, the HBAC staff who care for them and CDC-Uganda staff who compiled the data for anal-ysis. In particular we would like to thank Paul Ekwaru for his help with cal-culating confidence intervals. We would also like to acknowledge the support of the Ugandan Ministry of Health and The AIDS Support Organi-zation. The Home-based AIDS Care project is funded through the Presi-dents Emergency Plan for AIDS Relief. The authors have no known conflicts of interest.Page 6 of 7(page number not for citation purposes)algorithm may not function as well in settings where theproportion of ART eligible subjects is not so high. 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