%PDF-1.4
%
24 0 obj
<>
endobj
20 0 obj
[/CalGray<>]
endobj
21 0 obj
[/CalRGB<>]
endobj
74 0 obj
<>stream
Acrobat PDFWriter 4.05 for Power Macintosh
2003-06-02T10:40:16Z
2024-03-28T22:17:04-07:00
2024-03-28T22:17:04-07:00
QuarkXPress™ 4.11
application/pdf
Heather
uuid:73847fc1-1dd2-11b2-0a00-5309277d8900
uuid:73847fc4-1dd2-11b2-0a00-d30000000000
endstream
endobj
19 0 obj
<>
endobj
25 0 obj
<>/ProcSet[/PDF/Text/ImageB]/XObject<>>>/Rotate 0/Type/Page>>
endobj
1 0 obj
<>/ProcSet[/PDF/Text/ImageB]/XObject<>>>/Rotate 0/Type/Page>>
endobj
9 0 obj
<>/ProcSet[/PDF/Text/ImageB]/XObject<>>>/Rotate 0/Type/Page>>
endobj
80 0 obj
[82 0 R]
endobj
81 0 obj
<>stream
BT
/TT0 10 Tf
2.192 Tw 53.275 714 Td
(\(i.e., HIV)Tj
2.10899 Tw 45.012 0 Td
(infected\) may be anergic; however, studies of)Tj
2.39999 Tw -44.921 -12 Td
(anergy testing in HIV)Tj
2.483 Tw 99.124 0 Td
(positive individuals to aid in the)Tj
0 Tw -99.234 -12 Td
(prevention of TB have failed to show a benefit)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 239.987 693.25 Tm
(20)Tj
/TT0 10 Tf
1 0 0 1 246.487 690 Tm
(. Given that)Tj
-0.27699 Tw -193.035 -12 Td
(the relative risk of developing active TB is highest with HIV)Tj
1.457 Tw -0.047 -12 Td
(coinfection, it is reasonable to assume that anergy testing)Tj
0.841 Tw -0.052 -12 Td
(would also fail to provide benefit in RA)Tj
0 Tw 168.331 0 Td
(patients receiving)Tj
-168.353 -12 Td
(TNF-)Tj
/TT1 10 Tf
[-0.2 (a)]TJ
/TT0 10 Tf
1.19701 Tw 32.281 0 Td
(inhibitors. Recommendations for the interpretation)Tj
-0.239 Tw -32.203 -12 Td
(of Mantoux skin tests in patients receiving TNF-)Tj
/TT1 10 Tf
193.018 0 Td
(a)Tj
/TT0 10 Tf
0 Tw 8.809 0 Td
(inhibitors)Tj
-201.915 -12 Td
(have recently been published)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 169.968 621.25 Tm
(10)Tj
/TT0 10 Tf
1 0 0 1 176.468 618 Tm
[(.)-175 (As the probability of anergy)]TJ
0.159 Tc -123.175 -12 Td
(increases, )Tj
0 Tc 47.146 0 Td
(the )Tj
0.13901 Tc 18.967 0 Td
(decision )Tj
0 Tc 40.825 0 Td
(to )Tj
0.15601 Tc 14.028 0 Td
(provide )Tj
0.136 Tc 38.047 0 Td
(preventive )Tj
0.179 Tc 49.952 0 Td
(therapy)Tj
0 Tc 2.15601 Tw -208.765 -12 Td
(becomes more reliant on epidemiologic risk factors, and)Tj
0.25 Tw -0.23 -12 Td
(should be made in consultation with a TB specialist.)Tj
3.01601 Tw 12.131 -12 Td
(As long as a global TB epidemic exists and potent)Tj
0.19099 Tw -12.06 -12 Td
(immunosuppressive therapies are used to treat RAand other)Tj
1.793 Tw 0.135 -12 Td
(autoimmune diseases, the threat of TB will not fade. By)Tj
2.978 Tw -0.055 -12 Td
(considering TB prevention early in the management of)Tj
0.592 Tw -0.06 -12 Td
(patients with RA, active disease can be avoided in the vast)Tj
0 Tw 0.015 -12 Td
(majority of cases.)Tj
/TT2 10 Tf
0.15401 Tc 76.061 -24 Td
(MICHAELGARDAM)Tj
/TT0 10 Tf
97.245 0 Td
(,)Tj
/TT0 6 Tf
0 Tc 5.25 0 Td
(MSc, MD, CM, FRCPC,)Tj
/TT0 8 Tf
-102.53 -10 Td
(Division of Infectious Disease;)Tj
/TT2 10 Tf
-0.087 -12 Td
(KAREN IVERSON)Tj
/TT0 10 Tf
84.68 0 Td
(,)Tj
/TT0 6 Tf
5.25 0 Td
(BSc, MHSc, MSc,)Tj
/TT0 8 Tf
-89.945 -10 Td
(Infection Prevention and Control,)Tj
0.131 -10 Td
(University Health Network,)Tj
0.783 Tw -0.01 -10 Td
(200 Elizabeth Street, NUW13-117,)Tj
-0.013 -10 Td
(T)Tj
0 Tw 4.137 0 Td
(oronto, Ontario M5G 2C4, Canada.)Tj
/TT3 8 Tf
-0.175 Tw -80.161 -20 Td
(Address reprint requests to Dr. Gardam. )Tj
0 Tw -0.105 -10 Td
(E-mail: michael.gardam@uhn.on.ca )Tj
/TT2 10 Tf
0.213 -24 Td
(REFERENCES)Tj
/TT0 8 Tf
6.986 -10 Td
[(1.)-875 (Dye C, Scheele S, Dolin P, Pathania )-17.625 (V)124.875 (, Raviglione MC. Global)]TJ
0.2 Tw 13.312 -10 Td
(burden of tuberculosis. Estimated incidence, prevalence and)Tj
0.533 Tw 0.071 -10 Td
(mortality by country. JAMA1999;282:677-86.)Tj
0 Tw -13.494 -10 Td
(2.)Tj
0.2 Tw 13 0 Td
(Njoo H, Long R. The epidemiology of tuberculosis in Canada. In:)Tj
0 Tw 0.602 -10 Td
(Long R, editor. Canadian tuberculosis standards. Ottawa:)Tj
-0.007 -10 Td
(Government of Canada. Canadian Lung Association; 2000:3-14.)Tj
-13.679 -10 Td
[(3.)-875 (Keane J, Gershon S, )-100.25 (W)31.375 (ise RP, et al. )25.625 (T)62.625 (uberculosis associated with)]TJ
0.2 Tw 13.54 -10 Td
(infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl)Tj
0 Tw 0.112 -10 Td
(J Med 2001;345:1098-104.)Tj
-13.463 -10 Td
[(4.)-875 (Bouza E, Moya JG, Munoz P. Infections in systemic lupus)]TJ
0.138 Tw 13.335 -10 Td
(erythematosus and rheumatoid arthritis. Infect Dis Clin North Am)Tj
0 Tw 0.139 -10 Td
(2001;25:1900-7.)Tj
-13.641 -10 Td
(5.)Tj
0.2 Tw 13 0 Td
(Menzies D, Pourier L. Diagnosis of tuberculosis infection and)Tj
0 Tw 0.475 -10 Td
(disease, In: Long R, editor. Canadian tuberculosis standards.)Tj
0.107 -10 Td
(Ottawa: Government of Canada. Canadian Lung Association; 2000.)Tj
250.459 495.25 Td
(6.)Tj
0.2 Tw 13 0 Td
(Smith JD, Knox JM. Mycobacterium tuberculosis infection in)Tj
0.627 -10 Td
(patients with systemic rheumatic disease. Rheumatology Oxford)Tj
0 Tw -0.151 -10 Td
(1971;40:341-2.)Tj
-13.391 -10 Td
(7.)Tj
0.2 Tw 13 0 Td
(Binymin K, Cooper RG. Late reactivation of spinal tuberculosis by)Tj
0.398 -10 Td
(low-dose methotrexate therapy in a patient with rheumatoid)Tj
0 Tw 0.174 -10 Td
(arthritis. Rheumatology Oxford 2001;40:341-2.)Tj
-13.697 -10 Td
[(8.)-875 (Kim HA, )-50.125 (Y)]TJ
0.2 Tw 49.704 0 Td
(oo CD, Baek HJ, et al. Mycobacterium tuberculosis)Tj
-36.053 -10 Td
(infection in a corticosteroid-treated rheumatic disease patient)Tj
0 Tw -0.077 -10 Td
(population. Clin Exp Rheumatol 1998;16:9-13.)Tj
-13.598 -10 Td
[(9.)-875 (T)]TJ
0.2 Tw 17.387 0 Td
(argeted tuberculin testing and treatment of latent tuberculosis)Tj
0 Tw -3.694 -10 Td
(infection. American Thoracic Society. MMWR Recomm Rep 2000)Tj
-0.073 -10 Td
(Jun 9;49 RR-6:1-51.)Tj
-17.541 -10 Td
(10.)Tj
0.144 Tw 17 0 Td
(Gardam MA, Keystone EC, Menzies R, et al. Anti-tumour necrosis)Tj
0.2 Tw 0.589 -10 Td
(factor agents and tuberculosis risk: mechanisms of action and)Tj
-0.068 -10 Td
(clinical management. Lancet Infect Dis 2003;3:148-55.)Tj
-17.199 -10 Td
(1)Tj
0 Tw 3.75 0 Td
(1.)Tj
0.10899 Tw 13 0 Td
(Ehlers S, Benini J, Kutsch S, Endres R, Rietschel ET, Pfeffer K.)Tj
0.2 Tw 0.474 -10 Td
(Fatal granuloma necrosis without exacerbated mycobacterial)Tj
-0.133 -10 Td
(growth in tumor necrosis factor receptor p55 gene-deficient mice)Tj
0.213 -10 Td
(intravenously infected with Mycobacterium avium. Infect Immun)Tj
0 Tw -0.112 -10 Td
(1999;67:3571-9.)Tj
-17.391 -10 Td
[(12.)-875 (Mohan VP, Scanga CA, )87.25 (Y)]TJ
0.16901 Tw 100.433 0 Td
(u K, et al. Effects of tumor necrosis factor)Tj
0.2 Tw -83.033 -10 Td
(alpha on host immune response in chronic persistent tuberculosis:)Tj
0 Tw -0.025 -10 Td
(possible role for limiting pathology. Immunol 2001;102:248-53.)Tj
-17.538 -10 Td
(13.)Tj
0.2 Tw 17 0 Td
[(Flynn JL, Goldstein MM, Chan J, et al. )0.625 (T)]TJ
0 Tw 133.542 0 Td
(umor necrosis factor-alpha)Tj
0.2 Tw -132.858 -10 Td
(is required in the protective immune response against)Tj
-0.01 -10 Td
(Mycobacterium tuberculosis in mice. Immunity 1995;2:561-72.)Tj
0 Tw -17.508 -10 Td
(14.)Tj
0.125 Tw 17 0 Td
(Scallon B, Cai A, Solowski N, et al. Binding and functional)Tj
0.2 Tw 0.344 -10 Td
(comparisons of two types of tumor necrosis factor antagonists. )Tj
0 Tw 0.175 -10 Td
(J Pharmacol Exp Ther 2002;301:418-26.)Tj
-17.528 -10 Td
(15.)Tj
0.144 Tw 17 0 Td
(Lugering A, Schmidt M, Lugering N, Pauels HG, Domschke )Tj
0 Tw 197.691 0 Td
(W,)Tj
-197.199 -10 Td
[(Kucharzik )6.75 (T)]TJ
0.2 Tw 39.403 0 Td
(. Infliximab induces apoptosis in monocytes from)Tj
0.117 Tw -39.437 -10 Td
(patients with chronic active Crohn\325s disease by using a caspase-)Tj
0 Tw -0.149 -10 Td
(dependent pathway. Gastroenterology 2001;121:1145-57.)Tj
-17.525 -10 Td
(16.)Tj
0.117 Tw 17 0 Td
[(Manadan AM, Mohan AK, Cote TR, Siegel JN, Sequeira )32.375 (W)]TJ
0 Tw 192.683 0 Td
(, Block)Tj
-191.941 -10 Td
[(JA. )37.125 (T)0.125 (uberculosis and etanercept treatment [abstract]. Arthritis)]TJ
-0.151 -10 Td
(Rheum 2002;46 Suppl:S166.)Tj
-17.424 -10 Td
[(17.)-875 (Carmona L, Hern\207ndez-Garc\222a C, )-67.25 (V)93.625 (adillo C. Increased risk of)]TJ
0.2 Tw 17.412 -10 Td
(tuberculosis in patients with rheumatoid arthritis. J Rheumatol)Tj
0 Tw -0.076 -10 Td
(2003;30:xxxx.)Tj
-17.305 -10 Td
[(18.)-875 (W)93.875 (olfe F, Flowers N, Anderson J, Urbansky K. )-44.625 (T)31.375 (uberculosis rates)]TJ
0.138 Tw 17.32 -10 Td
(are not increased in rhematoid arthritis [abstract]. Arthritis Rheum)Tj
0 Tw 0.002 -10 Td
(2001;44 Suppl:S105.)Tj
-17.484 -10 Td
[(19.)-875 (Hoeppner )6.375 (V)]TJ
0.2 Tw 55.27 0 Td
[(, Marciniuk D, Hershfield E. )0.75 (T)]TJ
0 Tw 99.391 0 Td
(reatment of tuberculosis)Tj
0.138 Tw -137.041 -10 Td
(disease and infection. In: Long R, editor. Canadian tuberculosis)Tj
0.2 Tw 0.077 -10 Td
(standards. Ottawa: Government of Canada. Canadian Lung)Tj
0 Tw -0.023 -10 Td
(Association; 2000:3-14.)Tj
-17.667 -10 Td
(20.)Tj
0.164 Tw 17 0 Td
(Anergy skin testing and tuberculosis [corrected] preventive therapy)Tj
0 Tw 0.603 -10 Td
(for HIV-infected persons: revised recommendations. Centers for)Tj
0.2 Tw 0.075 -10 Td
(Disease Control and Prevention. MMWR Recomm Rep 1997;46)Tj
0 Tw -0.209 -10 Td
(RR-15:1-10.)Tj
ET
1 g
424.25 745.75 133 15.25 re
f
q
30 31 552 730 re
W n
0 g
53.25 54.25 504 1 re
f
BT
/TT3 8 Tf
53.975 36.75 Td
(Gardam and Iverson: Editorial)Tj
487.315 -0.25 Td
(1399)Tj
ET
1 g
108.25 48.75 397 11.25 re
f
108.75 49.25 396 10.25 re
f
q
0 g
397 0 0 11.25 108.25 48.75 cm
/Im0 Do
Q
Q
q
0 0 612 792 re
W n
BT
0 0 0 rg
/T1_0 8 Tf
117.48 51 Td
(Personal, non-commercial use only. The Journal of Rheumatology Copyrig\
ht \251 2003. All rights reserved.)Tj
ET
Q
BT
0 g
/T1_1 1 Tf
10 0 0 10 540 17 Tm
( )Tj
0 0.48627 0.77255 rg
-7.22298 0 Td
(www.jrheum.org)Tj
0 g
-16.72996 0 Td
(Downloaded on March 28, 2024 from )Tj
ET
endstream
endobj
16 0 obj
<>/Filter/CCITTFaxDecode/Height 45/ImageMask true/Length 24/Name/I5/Subtype/Image/Type/XObject/Width 1588>>stream
ˁh?
endstream
endobj
58 0 obj
<>
endobj
77 0 obj
<>
endobj
29 0 obj
<>
endobj
39 0 obj
<>
endobj
17 0 obj
<>
endobj
27 0 obj
<>
endobj
82 0 obj
<>
endobj
83 0 obj
<>
endobj
78 0 obj
[84 0 R]
endobj
79 0 obj
<>stream
BT
/TT0 10 Tf
1.457 Tw 65.388 713.75 Td
(Of the 2 agents, the data associating TNF-)Tj
/TT1 10 Tf
178.791 0 Td
(a)Tj
/TT0 10 Tf
0 Tw 10.309 0 Td
(inhibition)Tj
1.549 Tw -201.108 -12 Td
(and active TB are greater for infliximab. On a molecular)Tj
2.94501 Tw -0.052 -12 Td
(level, infliximab binds more avidly to both membrane-)Tj
2.377 Tw 0.012 -12 Td
(bound and free forms of TNF-)Tj
/TT1 10 Tf
[0.4 (a)]TJ
/TT0 10 Tf
2.427 Tw 144.55 0 Td
(than does etanercept)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 284.368 681 Tm
(14)Tj
/TT0 10 Tf
1 0 0 1 290.868 677.75 Tm
(.)Tj
2.51199 Tw -237.5 -12 Td
(Infliximab has also been shown to cause drug-mediated)Tj
1.32201 Tw 0.022 -12 Td
(apoptosis of macrophages and monocytes)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 225.303 657 Tm
(15)Tj
/TT0 10 Tf
1 0 0 1 231.803 653.75 Tm
(.)Tj
1.32201 Tw 6 0 Td
(The available)Tj
0.356 Tw -184.542 -12 Td
[(epidemiologic data also suggest that infliximab use is asso)-21.4 (-)]TJ
0.69501 Tw 0.022 -12 Td
(ciated with an increased risk of active TB compared to the)Tj
3.147 Tw 0.195 -12 Td
[(general population and that the proportion of extrapul)3.4 (-)]TJ
0.311 Tw 0.015 -12 Td
(monary cases is perhaps higher than predicted)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 239.74 609 Tm
(3)Tj
/TT0 10 Tf
0 Tw 1 0 0 1 242.865 605.75 Tm
(. Finally, the)Tj
1.075 Tw -189.576 -12 Td
(development of TB typically occurred within the first few)Tj
1.345 Tw 0.2 -12 Td
(months of infliximab therapy)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 174.448 585 Tm
(3)Tj
/TT0 10 Tf
1 0 0 1 177.573 581.75 Tm
[(. Recent abstracts, however)51.3 (,)]TJ
3.69099 Tw -124.288 -12 Td
(suggest that etanercept use is also associated with an)Tj
1.912 Tw 0.022 -12 Td
[(increased TB risk, with a similar proportion of extrapul)-22.1 (-)]TJ
0 Tw -0.043 -12 Td
(monary cases)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 107.91 549 Tm
(16)Tj
/TT0 10 Tf
1 0 0 1 114.41 545.75 Tm
(.)Tj
0.735 Tw -49 -12 Td
(What remains unclear is the magnitude of the increased)Tj
2.03999 Tw -11.983 -12 Td
(TB risk associated with either of these agents. The case)Tj
0.255 Tw -0.047 -12 Td
(series published to date have relied on passive surveillance,)Tj
0.771 Tw 0.022 -12 Td
(and hence likely under-represent the true magnitude of the)Tj
0 Tw -0.035 -12 Td
(association. Further, the underlying TB)Tj
-0.23399 Tc 158.832 0 Td
(risk factors of )Tj
0 Tc -2.75 Tw 53.787 0 Td
(T N F -)Tj
/TT1 10 Tf
21.222 0 Td
(a)Tj
/TT0 10 Tf
2.632 Tw -233.941 -12 Td
(exposed and comparator populations, such as receipt of)Tj
0 Tw 0.02 -12 Td
[(other )-399.7 (immunosuppressive )-424.5 (therapy )-399.5 (\(i.e., )-399.7 (corticosteroids\),)]TJ
1.677 Tw 0.026 -12 Td
(world region of origin, age, sex, comorbid illness, recent)Tj
0.466 Tw 0.024 -12 Td
[(contact with an active case, and the presence of TB-associ)3.4 (-)]TJ
0.60201 Tw -0.05 -12 Td
(ated abnormalities on chest radiograph, have not been well)Tj
0.741 Tw 0.015 -12 Td
(defined. Given that corticosteroids and patient age and sex)Tj
1.315 Tw 0.017 -12 Td
(will confound the relationship between RA)Tj
1.19 Tw 182.286 0 Td
(and TB, these)Tj
0.25 Tw -182.106 -12 Td
(factors should be controlled in any comparison.)Tj
1.584 Tw 11.98 -12 Td
(In this issue of )Tj
/TT2 10 Tf
[0.1 (The Journal)]TJ
/TT0 10 Tf
117.388 0 Td
(, Carmona, )Tj
/TT2 10 Tf
50.074 0 Td
(et al )Tj
/TT0 10 Tf
22.913 0 Td
(report an)Tj
1.907 Tw -202.6 -12 Td
(increased incidence of active TB in Spanish RA)Tj
0 Tw 209.234 0 Td
(patients)Tj
0.51199 Tw -209.146 -12 Td
(compared to an age and sex-matched Spanish population)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 284.352 357 Tm
(17)Tj
/TT0 10 Tf
1 0 0 1 290.852 353.75 Tm
(.)Tj
0.576 Tw -237.5 -12 Td
(These researchers surveyed 788 randomly selected patients)Tj
-0.103 Tw 0.027 -12 Td
[(from a large cohort of Spanish patients with RAfor the pres)2.3 (-)]TJ
1.64101 Tw 0.017 -12 Td
(ence of active TB over a one year study period. Patients)Tj
0.931 Tw -0.055 -12 Td
(were interviewed and their medical and laboratory records)Tj
1.446 Tw 0.024 -12 Td
(reviewed. The incidence of TB in the Spanish population)Tj
0 Tw 0.119 -12 Td
[(was )-375.2 (determined )-424 (from )-424.8 (the )-374.7 (Spanish )-425 (Network )-400 (of )-400 (Epide-)]TJ
0.18201 Tc -0.168 -12 Td
(miological )Tj
0.192 Tc 52.269 0 Td
(Surveillance )Tj
0.175 Tc 59.98 0 Td
(database, )Tj
0 Tc 46.174 0 Td
(which )Tj
0.15601 Tc 32.938 0 Td
(records )Tj
0 Tc 38.179 0 Td
(all)Tj
0.892 Tw -229.505 -12 Td
[(pulmonary and meningeal cases of TB in the country)52.8 (.)]TJ
0 Tw 224.548 0 Td
(The)Tj
0.478 Tw -224.453 -12 Td
(mean TB incidence in the RA)Tj
0.528 Tw 124.019 0 Td
(cohort was calculated over a)Tj
1.00999 Tw -124.057 -12 Td
(10 year period and standardized for age and sex using the)Tj
0.37199 Tw 0.02 -12 Td
(Spanish population over age 16. The incidence risk ratio of)Tj
0 Tw -0.055 -12 Td
(developing TB at any site in the RAcohort was calculated at)Tj
0.534 Tw -0.056 -12 Td
(4.13 \(95% CI 2.59\3206.83\), while the incidence risk ratio for)Tj
1.472 Tw 0.025 -12 Td
(pulmonary disease was 3.68 \(95% CI 2.36\3205.92\). As this)Tj
0.808 Tw 0.079 -12 Td
[(cohort was assembled in 1998\32099, this represents the inci)1.7 (-)]TJ
0.392 Tw 0.027 -12 Td
(dence of disease prior to the widespread use of anti-TNF-)Tj
/TT1 10 Tf
233.725 0 Td
(a)Tj
/TT0 10 Tf
2.97701 Tw -233.691 -12 Td
(inhibitors. Seventy-two percent of the selected patients,)Tj
-2.3 Tw -0.228 -12 Td
(h o w e v e r)Tj
0 Tw [0.1 (, )-425 (had )]TJ
0.194 Tc 66.567 0 Td
(received )Tj
0 Tc 42.362 0 Td
(other )Tj
0.181 Tc 28.297 0 Td
(disease-modifying )Tj
0 Tc 83.872 0 Td
(anti-)Tj
-220.925 -12 Td
(rheumatic drugs.)Tj
0.438 Tw 11.952 -12 Td
(These findings are more precise than those reported in a)Tj
1.286 Tw -11.976 -12 Td
[(recent American study)51.2 (.)-375 (W)]TJ
1.536 Tw 107.528 0 Td
(olfe, )Tj
/TT2 10 Tf
21.833 0 Td
(et al)Tj
/TT0 10 Tf
23.031 0 Td
(calculated the annual)Tj
0.662 Tw -152.528 -12 Td
(incidence of TB in 10,782 American RA)Tj
0.746 Tw 169.486 0 Td
(patients to be 6.2)Tj
1.69 Tw -169.443 -12 Td
(per 100,000 per year, similar to the 6.8 per 100,000 rate)Tj
-0.265 Tw 264.165 635.25 Td
(reported for the general US population)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 470.577 716.25 Tm
(18)Tj
/TT0 10 Tf
-0.34801 Tw 1 0 0 1 477.077 713 Tm
(. However, only one)Tj
0 Tw -159.677 -12 Td
[(case )-399.7 (was )-400.2 (identified )-474 (over )-424.9 (the )-399.7 (18 )-375 (month )-399.7 (study )-450 (period,)]TJ
0.534 Tw 0.089 -12 Td
(resulting in wide 95% confidence intervals \(0.2 to 34.4 per)Tj
0.48801 Tw -0.228 -12 Td
(100,000\), making it difficult to accurately estimate the true)Tj
0 Tw 0.193 -12 Td
(incidence risk ratio.)Tj
0.674 Tw 11.886 -12 Td
(By actively seeking out TB cases rather than relying on)Tj
0.56599 Tw -12.057 -12 Td
(passive surveillance, the error due to missed cases is likely)Tj
3.132 Tw 0.029 -12 Td
(less significant in the Carmona study than in previous)Tj
0.28799 Tw 0.02 -12 Td
(studies. Also, the large sample size and relatively increased)Tj
2.668 Tw 0.002 -12 Td
(tuberculosis rate in the Spanish population versus other)Tj
0.91901 Tw 0.025 -12 Td
[(developed countries also allowed for a more accurate esti)3.8 (-)]TJ
0 Tw 0.024 -12 Td
[(mation of risk. By not using a case-control design, however)115.8 (,)]TJ
1.19701 Tw -0.078 -12 Td
(the researchers recognize that they were unable to control)Tj
0.395 Tw 0.022 -12 Td
(for known TB risk factors other than age and sex. It is thus)Tj
1.978 Tw -0.04 -12 Td
(impossible to determine the relative risk afforded by the)Tj
0 Tw 0.2 -12 Td
[(disease itself versus immunosuppressive therapy \(i.e., corti)-90.7 (-)]TJ
-0.33099 Tw -0.213 -12 Td
(costeroids\). Further, their calculated rate may over-represent)Tj
2.194 Tw 0.13 -12 Td
(the true TB incidence rate in patients with RA, as only)Tj
0.186 Tw -0.057 -12 Td
(pulmonary and meningeal cases are reportable in Spain, yet)Tj
2.627 Tw 0.017 -12 Td
(all types of TB were recorded in the RA)Tj
2.377 Tw 186.02 0 Td
(patients. The)Tj
0.657 Tw -185.972 -12 Td
(authors attempted to correct for this by assuming that 20%)Tj
0 Tw 0.024 -12 Td
(of total TB cases are extrapulmonary. Using this correction,)Tj
1.44701 Tw -0.146 -12 Td
(the incidence risk rate decreased somewhat, yet remained)Tj
0.25 Tw 0.02 -12 Td
(more than 4-fold higher than the general population.)Tj
0.15601 Tc 0 Tw 12.13 -12 Td
(Despite )Tj
0 Tc 38.047 0 Td
(these )Tj
0.15401 Tc 27.547 0 Td
(limitations, )Tj
0 Tc 53.528 0 Td
(the )Tj
0.15601 Tc 18.967 0 Td
(results )Tj
0.14999 Tc 33.608 0 Td
(presented )Tj
0 Tc 46.065 0 Td
(by)Tj
-229.75 -12 Td
(Carmona, )Tj
/TT2 10 Tf
42.156 0 Td
(et al)Tj
/TT0 10 Tf
0.50101 Tw 20.996 0 Td
(suggest that a typical population of patients)Tj
3.37601 Tw -63.141 -12 Td
[(with RA)-500 (receiving standard therapy involving different)]TJ
0.332 Tw -0.127 -12 Td
(immunosuppressive drugs, yet excluding TNF-)Tj
/TT1 10 Tf
189.917 0 Td
(a)Tj
/TT0 10 Tf
0 Tw 9.309 0 Td
(inhibitors,)Tj
1.31 Tw -199.165 -12 Td
[(are at increased risk for developing active TB. It is inter)3.5 (-)]TJ
0.179 Tc 0 Tw -0.045 -12 Td
(esting )Tj
0 Tc 31.387 0 Td
[(that )-449.5 (the )-424.7 (4-fold )]TJ
0.175 Tc 72.65 0 Td
(increased )Tj
0 Tc 45.754 0 Td
[(risk )-425 (found )-475 (by )-425 (these)]TJ
2.166 Tw -149.873 -12 Td
(researchers is of similar magnitude to the increased risk)Tj
-0.179 Tw 0.032 -12 Td
(attributed to infliximab and possibly etanercept in American)Tj
0 Tw 0.066 -12 Td
(patients)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 348.471 332.25 Tm
(3,16)Tj
/TT0 10 Tf
-0.198 Tw 1 0 0 1 359.909 329 Tm
[(. However, as stated, these studies likely underes)1.5 (-)]TJ
0.20799 Tw -42.551 -12 Td
(timate the risk afforded by these therapies.)Tj
1.14 Tw 11.965 -12 Td
[(The results of this study suggest that the risk of devel)2.1 (-)]TJ
1.69299 Tw -11.971 -12 Td
(oping TB in patients with RA)Tj
1.743 Tw 130.825 0 Td
(is high enough to warrant)Tj
1.006 Tw -130.824 -12 Td
(consideration of screening and possible therapy to prevent)Tj
0.317 Tw 0.022 -12 Td
(TB. While it is difficult to recommend TB screening for all)Tj
0 Tw 0.054 -12 Td
(RA)Tj
1.519 Tw 17.142 0 Td
(patients, the evidence suggests that patients receiving)Tj
2.183 Tw -17.094 -12 Td
(prolonged corticosteroids with epidemiologic risk factors)Tj
3.48599 Tw -0.223 -12 Td
(for TB are at increased risk. Such patients should be)Tj
-0.127 Tw 0.203 -12 Td
[(screened for latent infection by Mantoux testing and consid)3.2 (-)]TJ
1.207 Tw 0.022 -12 Td
(ered for preventive therapy if positive. Preventive therapy)Tj
2.591 Tw -0.226 -12 Td
(has been a key component of TB control programs for)Tj
2.049 Tw 0.198 -12 Td
[(almost half a century)51.4 (.)]TJ
1.98599 Tw 96.533 0 Td
(The effectiveness of isoniazid has)Tj
2.31599 Tw -96.551 -12 Td
(been confirmed in randomized controlled trials, and can)Tj
0.66701 Tw 0.015 -12 Td
(afford up to 93% protection if complied with for 9 months)Tj
0 Tw -0.047 -12 Td
(or more)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 348.466 152.25 Tm
(19)Tj
/TT0 10 Tf
-0.31 Tw 1 0 0 1 354.966 149 Tm
[(. Other preventive therapies are available, and clin)3.5 (-)]TJ
0.179 Tc 0 Tw -37.545 -12 Td
(icians )Tj
0 Tc 31.075 0 Td
(are )Tj
0.16701 Tc 19.207 0 Td
(referred )Tj
0 Tc 39.636 0 Td
(to )Tj
0.16701 Tc 14.778 0 Td
(existing )Tj
0.18201 Tc 39.665 0 Td
(guidelines )Tj
0 Tc 49.604 0 Td
[(for )-450 (details)]TJ
-193.986 -12 Td
(regarding regimens, monitoring, and possible complications)Tj
0.019 -12 Td
(of therapy)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 358.485 116.25 Tm
(9,19)Tj
/TT0 10 Tf
1 0 0 1 369.922 113 Tm
(.)Tj
1.86 Tw -40.5 -12 Td
(Patients receiving TNF-)Tj
/TT1 10 Tf
99.808 0 Td
(a)Tj
/TT0 10 Tf
1.985 Tw 10.809 0 Td
(inhibitors are likely at even)Tj
1.26601 Tw -122.652 -12 Td
[(greater risk of developing TB. )51.5 (A)]TJ
1.31599 Tw 139.597 0 Td
(significant proportion of)Tj
0.37801 Tw -139.609 -12 Td
(patients in this and other immunocompromised populations)Tj
ET
1 g
433.25 750.75 123 10.25 re
f
q
30 31 552 730 re
W n
0 g
53.25 54.25 504 1 re
f
BT
/TT2 8 Tf
0.2 Tw 423.626 36.75 Td
(The Journal of Rheumatology 2003; 30:7)Tj
0 Tw -370.352 -0.25 Td
(1398)Tj
ET
1 g
108.25 48.75 397 11.25 re
f
108.75 49.25 396 10.25 re
f
q
0 g
397 0 0 11.25 108.25 48.75 cm
/Im0 Do
Q
Q
q
0 0 612 792 re
W n
BT
0 0 0 rg
/T1_0 8 Tf
0 Tw 117.48 51 Td
(Personal, non-commercial use only. The Journal of Rheumatology Copyrig\
ht \251 2003. All rights reserved.)Tj
ET
Q
BT
0 g
/T1_1 1 Tf
0 Tw 10 0 0 10 540 17 Tm
( )Tj
0 0.48627 0.77255 rg
-7.22298 0 Td
(www.jrheum.org)Tj
0 g
-16.72996 0 Td
(Downloaded on March 28, 2024 from )Tj
ET
endstream
endobj
8 0 obj
<>/Filter/CCITTFaxDecode/Height 45/ImageMask true/Length 24/Name/I4/Subtype/Image/Type/XObject/Width 1588>>stream
ˁh?
endstream
endobj
84 0 obj
<>
endobj
85 0 obj
<>
endobj
75 0 obj
[86 0 R]
endobj
76 0 obj
<>stream
BT
/TT0 8 Tf
53.875 36.75 Td
(Gardam and Iverson: Editorial)Tj
487.565 -0.25 Td
(1397)Tj
ET
1 g
436.25 745.75 121 15.25 re
f
q
30 31 552 730 re
W n
0 g
53.25 54.25 504 1 re
f
BT
/TT0 10 Tf
53.426 573 Td
[(Mycobacterium )-424.4 (tuberculosis )]TJ
/TT1 10 Tf
124.391 0 Td
[(remains )-399.5 (one )-374.8 (of )-400 (the )-374.7 (major)]TJ
0.646 Tw -124.535 -12 Td
(pathogens affecting humans, infecting roughly one-third of)Tj
1.326 Tw 0.2 -12 Td
(the population and being responsible for almost 2 million)Tj
0 Tw 0.015 -12 Td
(deaths annually)Tj
/TT1 6.25 Tf
1.04 0 0 1.04 116.329 540.25 Tm
(1)Tj
/TT1 10 Tf
1 0 0 1 119.704 537 Tm
(.)Tj
0.601 Tw 5.5 0 Td
(The continued presence of the disease, in)Tj
1.261 Tw -71.738 -12 Td
(association with a global increase in drug resistant strains)Tj
2.513 Tw 0.029 -12 Td
[(and increasing coinfection with the human immunodefi)3.3 (-)]TJ
0.179 Tc 0 Tw -0.235 -12 Td
(ciency )Tj
0 Tc 35.344 0 Td
(virus )Tj
0.179 Tc 29 0 Td
(\(HIV\), )Tj
0.194 Tc 36.184 0 Td
(resulted )Tj
0 Tc 41.405 0 Td
[(in )-599.8 (the )-574.7 (World )-574.7 (Health)]TJ
2.506 Tw -141.803 -12 Td
[(Organization declaring tuberculosis \(TB\) a global emer)3.3 (-)]TJ
0.25 Tw -0.047 -12 Td
[(gency one decade ago, a situation that continues today)78.3 (.)]TJ
2.71201 Tw 11.927 -12 Td
(Developed countries, in sharp contrast to the rest of)Tj
0.754 Tw -11.976 -12 Td
(world, have seen a remarkable decline in TB over the past)Tj
1.08099 Tw 0.195 -12 Td
(century: the Canadian TB incidence rate, which peaked at)Tj
3.00301 Tw -0.064 -12 Td
(over 120 cases per 100,000 sixty years ago, has since)Tj
-0.237 Tw 0.022 -12 Td
(decreased to roughly 6 cases per 100,000)Tj
/TT1 6.25 Tf
1.04 0 0 1.04 216.689 420.25 Tm
(2)Tj
/TT1 10 Tf
1 0 0 1 219.814 417 Tm
(.)Tj
0 Tw 4.5 0 Td
(While the overall)Tj
1.76401 Tw -171.061 -12 Td
(incidence has decreased, the relative proportion of active)Tj
3.41 Tw 0.017 -12 Td
(disease occurring in foreign-born versus Canadian-born)Tj
1.04601 Tw 0.032 -12 Td
(non-aboriginals has increased substantially, illustrating the)Tj
0.25 Tw 0.174 -12 Td
(impact of the global epidemic on industrialized nations)Tj
/TT1 6.25 Tf
1.04 0 0 1.04 275.446 372.25 Tm
(2)Tj
/TT1 10 Tf
1 0 0 1 278.571 369 Tm
(.)Tj
1.30901 Tw -213.25 -12 Td
(This decline in developed countries has resulted in TB)Tj
-0.261 Tw -12.057 -12 Td
(becoming a medical rarity. Frequently, the diagnosis may be)Tj
0 Tw 0.063 -12 Td
[(missed by healthcare providers who have little to no experi)-34.2 (-)]TJ
2.938 Tw 0.022 -12 Td
(ence with the disease. Opportunities for preventing TB)Tj
2.302 Tw -0.05 -12 Td
(through the treatment of latent infection may be missed)Tj
0.729 Tw 0.015 -12 Td
[(because of unfamiliarity with screening tests, at-risk popu)3.1 (-)]TJ
0 Tw 0.032 -12 Td
(lations, and preventive regimens. This lack of awareness, in)Tj
2.623 Tw -0.047 -12 Td
(association with the development of immunosuppressive)Tj
0.381 Tw 0.02 -12 Td
(therapies to treat a host of autoimmune disorders, may lead)Tj
1.16901 Tw 0.022 -12 Td
(to the development of TB in patients with latent infection)Tj
1.265 Tw -0.062 -12 Td
(that may otherwise have been prevented. Indeed, cases of)Tj
1.321 Tw 0.02 -12 Td
(active TB in patients with rheumatoid arthritis \(RA\) have)Tj
-0.358 Tw 0.2 -12 Td
(recently been reported, and this has brought about a renewed)Tj
0.25 Tw -0.231 -12 Td
(interest in the relationship between the 2 diseases)Tj
/TT1 6.25 Tf
1.04 0 0 1.04 252.708 204.25 Tm
(3)Tj
/TT1 10 Tf
1 0 0 1 255.833 201 Tm
(.)Tj
0.40199 Tw -190.5 -12 Td
(It is generally believed that rheumatologic diseases such)Tj
1.186 Tw -11.98 -12 Td
[(as systemic lupus erythematosus and possibly RA)-324 (may be)]TJ
-0.291 Tw 0.137 -12 Td
(associated with an increased risk of TB)Tj
/TT1 6.25 Tf
1.04 0 0 1.04 208.919 168.25 Tm
(4)Tj
/TT1 10 Tf
1 0 0 1 212.044 165 Tm
(.)Tj
0 Tw 4.5 0 Td
(What proportion of)Tj
2.66901 Tw -163.046 -12 Td
(this increased risk stems from the immunologic disease)Tj
0 Tw -0.223 -12 Td
[(itself, )-399.5 (rather )-424.5 (than )-374.7 (immunosuppressive )-449.5 (therapy, )-349.5 (remains)]TJ
-0.338 Tw 264.162 432 Td
(largely unknown. While profound immune suppression such)Tj
1.009 Tw -0.122 -12 Td
[(as that required for organ transplantation is clearly associ)3.2 (-)]TJ
0 Tw -0.04 -12 Td
(ated with an increased risk of developing active TB, the risk)Tj
1.877 Tw 0.198 -12 Td
(afforded by lesser degrees of immune suppression is not)Tj
0 Tw -0.038 -12 Td
[(well )-274.7 (defined)]TJ
/TT1 6.25 Tf
1.04 0 0 1.04 369.638 528.25 Tm
(5)Tj
/TT1 10 Tf
1 0 0 1 372.513 525 Tm
[(. )-300 (Cases )-300 (of )-300 (active )-224.2 (TB )-299.8 (occurring )-249.5 (in )-299.8 (patients)]TJ
-0.07899 Tc -55.243 -12 Td
(receiving methotrexate have been reported)Tj
/TT1 6.25 Tf
0 Tc -1.59399 Tw 1.04 0 0 1.04 484.49 516.25 Tm
(6 , 7)Tj
/TT1 10 Tf
-0.125 Tc 0 Tw 1 0 0 1 492.489 513 Tm
(; however, given)Tj
-0.078 Tc -175.076 -12 Td
(the paucity of such reports it is likely that methotrexate alone)Tj
0.04401 Tc -0.073 -12 Td
(is not a significant risk factor for the development of active)Tj
0.14999 Tc 0.144 -12 Td
(TB. There )Tj
0 Tc 47.344 0 Td
(is )Tj
0.125 Tc 11.42 0 Td
(no evidence )Tj
0 Tc 54.282 0 Td
[(that )-199.5 (other )-199.7 (immune )-199.3 (modulating)]TJ
0.052 Tc -113.133 -12 Td
(drugs such as penicillamine and leflunomide are associated)Tj
-0.08501 Tc -0.135 -12 Td
(with TB. Receiving intermittent or low-dose prednisone does)Tj
0 Tc 0.201 -12 Td
[(not )-224.8 (appear )-174.6 (to )-224.8 (increase )-199.4 (the )-199.7 (risk )-200 (of )-250 (developing )-149.4 (active )]TJ
-2.55 Tw 224.309 0 Td
(T B ;)Tj
-224.293 -12 Td
(h o w e v e r)Tj
0 Tw 33.629 0 Td
(, receiving a minimum of 15 mg of prednisone over)Tj
-33.634 -12 Td
[(2\3204 )-400 (weeks )-425 (will )-399.7 (suppress )-475.3 (the )-399.7 (tuberculin )-474.2 (reaction, )-449.2 (and)]TJ
0.10699 Tc -0.111 -12 Td
(receiving a mean prednisone dose of 15 to 20 mg/day/year)Tj
-0.071 Tc 0.092 -12 Td
(has been shown to markedly increase the risk of active TB in)Tj
0.09801 Tc -0.158 -12 Td
(a high-prevalence population)Tj
/TT1 6.25 Tf
1.04 0 0 1.04 436.417 384.25 Tm
(8)Tj
/TT1 10 Tf
0.355 Tc 1 0 0 1 439.542 381 Tm
(. This has led the )Tj
0 Tc -2.55 Tw 78.792 0 Td
(A m e r i c a n)Tj
0.121 Tc 0 Tw -200.926 -12 Td
(Thoracic Society to state that the TB risk is \322increased\323 in)Tj
0 Tc -0.05 -12 Td
[(patients )-274.4 (receiving )-224.2 (at )-299.7 (least )-274.5 (this )-249.8 (amount )-274.5 (of )-300 (prednisone )-224.7 (or)]TJ
0.078 -12 Td
(equivalent for one month or greater)Tj
/TT1 6.25 Tf
1.04 0 0 1.04 458.826 348.25 Tm
(9)Tj
/TT1 10 Tf
1 0 0 1 461.951 345 Tm
(.)Tj
2.86 Tw -132.5 -12 Td
(Recently the treatment options available for RA)Tj
0 Tw 213.513 0 Td
(and)Tj
1.034 Tw -225.562 -12 Td
(certain other autoimmune diseases have been substantially)Tj
1.54201 Tw 0.017 -12 Td
[(broadened with the arrival of the tumor necrosis factor)52.81 (-)]TJ
/TT2 10 Tf
233.668 0 Td
(a)Tj
/TT1 10 Tf
0 Tw -233.691 -12 Td
(\(TNF-)Tj
/TT2 10 Tf
[-0.2 (a)]TJ
/TT1 10 Tf
1.631 Tw 31.611 0 Td
(\) inhibitors etanercept and infliximab. While both)Tj
2.106 Tw -31.66 -12 Td
(drugs have been shown in large trials to be effective in)Tj
0.646 Tw 0.128 -12 Td
(treating RA, a growing body of data suggests that both are)Tj
2.10899 Tw 0.022 -12 Td
(associated with the development of active TB. That this)Tj
0.653 Tw -0.131 -12 Td
(should occur is perhaps not surprising given that TNF-)Tj
/TT2 10 Tf
223.829 0 Td
(a)Tj
/TT1 10 Tf
0 Tw 9.309 0 Td
(is)Tj
2.034 Tw -233.08 -12 Td
(central to the host\325s ability to control TB infection. The)Tj
2.06799 Tw -0.08 -12 Td
(production of TNF-)Tj
/TT2 10 Tf
[0.3 (a)]TJ
/TT1 10 Tf
2.19299 Tw 94.072 0 Td
(by alveolar macrophages has been)Tj
1.201 Tw -94.065 -12 Td
(shown to be essential in granuloma formation, chemokine)Tj
0.925 Tw 0.017 -12 Td
[(production, leukocyte recruitment, and the killing of intra)4 (-)]TJ
3.22099 Tw 0.015 -12 Td
(cellular pathogens such as )Tj
/TT0 10 Tf
2.72099 Tw 120.073 0 Td
(M. tuberculosis)Tj
/TT1 6.25 Tf
0 Tw 1.04 0 0 1.04 502.395 192.25 Tm
(10)Tj
/TT1 10 Tf
3.22099 Tw 1 0 0 1 508.895 189 Tm
(. In mouse)Tj
2.758 Tw -191.619 -12 Td
(models of TB infection, blocking TNF-)Tj
/TT2 10 Tf
171.545 0 Td
(a)Tj
/TT1 10 Tf
2.808 Tw 11.559 0 Td
(production or)Tj
0.35201 Tw -183.036 -12 Td
(inhibiting binding of TNF-)Tj
/TT2 10 Tf
108.306 0 Td
(a)Tj
/TT1 10 Tf
9.309 0 Td
(to its receptor typically results)Tj
1.35201 Tw -117.513 -12 Td
(in an increased burden of organisms, impaired granuloma)Tj
0 Tw -0.05 -12 Td
(formation, and host death)Tj
/TT1 6.25 Tf
1.04 0 0 1.04 420.342 144.25 Tm
[(1)57.44 (1-13)]TJ
/TT1 10 Tf
1 0 0 1 435.173 141 Tm
(.)Tj
ET
53.25 706 46.25 0.5 re
f
BT
/TT3 12 Tf
53.423 712 Td
(Editorial)Tj
/TT3 21 Tf
0.97 0 0 1 53.265 664 Tm
(Rheumatoid Arthritis and)Tj
0.087 -24 Td
[(T)79.42857 (uberculosis: Time T)134.66667 (o Take Notice)]TJ
/TT0 12 Tf
1 0 0 1 108.451 107 Tm
(See )Tj
/TT1 12 Tf
0.3 Tw 19.952 0 Td
(Increased risk of tuberculosis in patients with rheumatoid arthritis, )Tj
/TT0 12 Tf
0 Tw 324.37 0 Td
(page 1436)Tj
-334.374 -12 Td
(See)Tj
/TT1 12 Tf
0.3 Tw 19.902 0 Td
(Development of tuberculosis in a patient treated with infliximab who had\
)Tj
31.708 -12 Td
(received prophylactic therapy with isoniazid, )Tj
/TT0 12 Tf
0 Tw 220.752 0 Td
(page 1657)Tj
ET
53.25 129.5 503 0.5 re
f
53.25 72.5 504 0.5 re
f
Q
q
468.25 611.75 89 108 re
W n
q
126 0 0 149 449.25 586.75 cm
/Im0 Do
Q
Q
q
375.25 612.75 89 108 re
W n
q
126 0 0 156 360.25 585.75 cm
/Im1 Do
Q
Q
108.25 48.75 397 11.25 re
f
108.75 49.25 396 10.25 re
f
q
0 g
397 0 0 11.25 108.25 48.75 cm
/Im2 Do
Q
q
0 0 612 792 re
W n
BT
0 0 0 rg
/T1_0 8 Tf
117.48 51 Td
(Personal, non-commercial use only. The Journal of Rheumatology Copyrig\
ht \251 2003. All rights reserved.)Tj
ET
Q
BT
0 g
/T1_1 1 Tf
10 0 0 10 540 17 Tm
( )Tj
0 0.48627 0.77255 rg
-7.22298 0 Td
(www.jrheum.org)Tj
0 g
-16.72996 0 Td
(Downloaded on March 28, 2024 from )Tj
ET
endstream
endobj
49 0 obj
<>stream
Adobe d C
"#()%$%%!'+,,-/4443.4444444444 ~
a !1AQa"q2B#$Rb34rC%Scs5&DTdE£t6UeuF'Vfv7GWgw(8HXhx )9IYiy
*:JZjz ? NBRH/XNHO J4_R
@SH!I
@8NN
+Rfo=3]l˞}Pփ'ѿ*ZE@bWFdd_@Ө^*ͤYS~![ӯARܟr}탗+GLGy?ŏ漳+:sQ1+l~w+Tdݏr%ee]#1,a>|~kȒwrNJR>zQ?hq
β̇I/[OʵS\B'?q~.;u2?DŲC{tnX"|B[0~}`n;[齵Q|'_%DMԥHkHo+Ǧ=`W-n~q4ej˪qZSfW0갾fΓyо4+LkEԱ!'NˊO
i3~1Cz>-_Q~NFe
O ]=oTok`W:O{ǥ{]>cl 3~a?elg}VP$A
a0b~9'ӣ*\X77:- Z!H'_'WVv}q3 Vs$|%w?S(MwTi
T[(魺?n