c337711036072b5a447c78853ff66820  300085.pdf
c68ec1e02cd92ad79b3f70dd19424abe0241b234  300085.pdf
6d0bd4780cffe319e3d9ddb0f3943d102381aad96e6860349d69f093ee79b9a5  300085.pdf

Title:           Remdesivir or Nirmatrelvir/Ritonavir Therapy for Omicron SARS-CoV-2 Infection in Hematological Patients and Cell Therapy Recipients
Subject:         Background: Scarce data exist that analyze the outcomes of hematological patients with SARS-CoV-2 infection during the Omicron variant period who received treatment with remdesivir or nirmatrelvir/ritonavir. Methods: This study aims to address this issue by using a retrospective observational registry, created by the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group, spanning from 27 December 2021 to 30 April 2023. Results: This study included 466 patients, 243 (52%) who were treated with remdesivir and 223 (48%) with nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir was primarily used for mild cases, resulting in a lower COVID-19-related mortality rate (1.3%), while remdesivir was preferred for moderate to severe cases (40%), exhibiting a higher mortality rate (9%). A multivariate analysis in the remdesivir cohort showed that male gender (odds ratio (OR) 0.35, p = 0.042) correlated with a lower mortality risk, while corticosteroid use (OR 9.4, p < 0.001) and co-infection (OR 2.8, p = 0.047) were linked to a higher mortality risk. Prolonged virus shedding was common, with 52% of patients shedding the virus for more than 25 days. In patients treated with remdesivir, factors associated with prolonged shedding included B-cell malignancy as well as underlying disease, severe disease, a later onset of and shorter duration of remdesivir treatment and a higher baseline viral load. Nirmatrelvir/ritonavir demonstrated a comparable safety profile to remdesivir, despite a higher risk of drug interactions. Conclusions: Nirmatrelvir/ritonavir proved to be a safe and effective option for treating mild cases in the outpatient setting, while remdesivir was preferred for severe cases, where corticosteroids and co-infection significantly predicted worse outcomes. Despite antiviral therapy, prolonged shedding remains a matter of concern.
Keywords:        remdesivir; nirmatrelvir/ritonavir; molnupiravir SARS-CoV-2 vaccines; Omicron;respiratory virus; hematological malignancies; allogeneic stem cell transplantation; autologous stem cell transplantation; COVID-19; mRNA vaccine; immunocompromised patients
Author:          José Luis Piñana, Inmaculada Heras, Tommaso Francesco Aiello, Irene García-Cadenas, Lourdes Vazquez, Javier Lopez-Jimenez, Pedro Chorão, Cristina Aroca, Carolina García-Vidal, Ignacio Arroyo, Eva Soler-Espejo, Lucia López-Corral, Alejandro Avendaño-Pita, Anna Arrufat, Valentín Garcia-Gutierrez, Elena Arellano, Lorena Hernández-Medina, Clara González-Santillana, Julia Morell, José Ángel Hernández-Rivas, Paula Rodriguez-Galvez, Mireia Mico-Cerdá, Manuel Guerreiro, Diana Campos, David Navarro, Ángel Cedillo, Rodrigo Martino and Carlos Solano
Creator:         LaTeX with hyperref
Producer:        pdfTeX-1.40.21
CreationDate:    Sun Oct  8 10:42:21 2023 CEST
ModDate:         Sun Oct  8 10:46:39 2023 CEST
Custom Metadata: no
Metadata Stream: no
Tagged:          no
UserProperties:  no
Suspects:        no
Form:            none
JavaScript:      no
Pages:           17
Encrypted:       no
Page size:       595.276 x 841.89 pts (A4)
Page rot:        0
File size:       938512 bytes
Optimized:       no
PDF version:     1.7


name                                 type              encoding         emb sub uni object ID
------------------------------------ ----------------- ---------------- --- --- --- ---------
XNLXUN+VnURWPalladioL                Type 1            Custom           yes yes no      10  0
DHNLGR+URWPalladioL-Bold             Type 1            Custom           yes yes no      15  0
XXOAEV+URWPalladioL-Roma             Type 1            Custom           yes yes no      20  0
YLPWUT+URWPalladioL-Ital             Type 1            Custom           yes yes no      24  0
NILCAS+VnURWPalladioL-Bold           Type 1            Custom           yes yes no      28  0
HOWKDX+TimesNewRomanPS-BoldItalicMT  Type 1C           WinAnsi          yes yes no      46  0
YSZATT+CMSY10                        Type 1            Builtin          yes yes no      71  0
BIJRVS+URWPalladioL-BoldItal         Type 1            Custom           yes yes no      78  0
XIGCQR+Dingbats                      Type 1            Builtin          yes yes no      88  0
EDEPJO+Symbol                        Type 1C           Custom           yes yes yes    102  0
EDEPIN+PalatinoLinotype,BoldItalic   TrueType          WinAnsi          yes yes no     107  0
EDEPJP+Arial                         CID TrueType      Identity-H       yes yes yes    110  0
EDFBAH+Wingdings                     CID TrueType      Identity-H       yes yes yes    116  0
EDENNA+PalatinoLinotype,Bold         TrueType          WinAnsi          yes yes no     122  0
EDENNC+PalatinoLinotype              TrueType          WinAnsi          yes yes no     125  0
EDENNE+PalatinoLinotype,Italic       TrueType          WinAnsi          yes yes no     128  0
VYCBDF+CMBSY10                       Type 1            Builtin          yes yes no     138  0
TSEGZF+PazoMath-Bold                 Type 1            Builtin          yes yes no     145  0
SPXLNH+PazoMath                      Type 1            Builtin          yes yes no     152  0
EDENNA+PalatinoLinotype,Bold         TrueType          WinAnsi          yes yes no     171  0
EDENNB+PalatinoLinotype              CID TrueType      Identity-H       yes yes yes    174  0
EDENNC+PalatinoLinotype              TrueType          WinAnsi          yes yes no     180  0
EDENND+PalatinoLinotype,Italic       CID TrueType      Identity-H       yes yes yes    183  0
EDENNE+PalatinoLinotype,Italic       TrueType          WinAnsi          yes yes no     189  0
EDEPAN+PalatinoLinotype              TrueType          MacRoman         yes yes no     192  0


Jhove (Rel. 1.28.0, 2023-05-18)
 Date: 2024-09-05 02:38:12 CEST
 RepresentationInformation: 300085.pdf
  ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16)
  LastModified: 2024-09-04 12:01:23 CEST
  Size: 938512
  Format: PDF
  Version: 1.7
  Status: Well-Formed and valid
  SignatureMatches:
   PDF-hul
  MIMEtype: application/pdf
  PDFMetadata: 
   Objects: 348
   FreeObjects: 1
   IncrementalUpdates: 0
   DocumentCatalog: 
    PageLayout: SinglePage
    PageMode: UseNone
    Outlines: 
     Item: 
      Title: Introduction 
      Destination: section.1
     Item: 
      Title: Patients and Methods 
      Destination: section.2
      Children: 
       Item: 
        Title: Study Population 
        Destination: subsection.2.1
       Item: 
        Title: Inclusion Criteria, Variables of Interest and Clinical and Virological Monitoring 
        Destination: subsection.2.2
       Item: 
        Title: Definitions 
        Destination: subsection.2.3
       Item: 
        Title: Endpoints and Statistical Analysis 
        Destination: subsection.2.4
     Item: 
      Title: Results 
      Destination: section.3
      Children: 
       Item: 
        Title: Patient Characteristics 
        Destination: subsection.3.1
       Item: 
        Title: Characteristics of SARS-CoV-2 Infection and Efficacy According to the Type of Antiviral Used 
        Destination: subsection.3.2
       Item: 
        Title: Univariate and Multivariate Analyses for Mortality 
        Destination: subsection.3.3
       Item: 
        Title: Cause of Death 
        Destination: subsection.3.4
       Item: 
        Title: Prolonged Shedding 
        Destination: subsection.3.5
       Item: 
        Title: Antiviral Effect According to the Antiviral Drug 
        Destination: subsection.3.6
       Item: 
        Title: Tolerability of Antiviral Drugs 
        Destination: subsection.3.7
     Item: 
      Title: Discussion 
      Destination: section.4
     Item: 
      Title: Conclusions 
      Destination: section.5
     Item: 
      Title: References
      Destination: section.6
   Info: 
    Title: Remdesivir or Nirmatrelvir/Ritonavir Therapy for Omicron SARS-CoV-2 Infection in Hematological Patients and Cell Therapy Recipients
    Author: José Luis Piñana, Inmaculada Heras, Tommaso Francesco Aiello, Irene García-Cadenas, Lourdes Vazquez, Javier Lopez-Jimenez, Pedro Chorão, Cristina Aroca, Carolina García-Vidal, Ignacio Arroyo, Eva Soler-Espejo, Lucia López-Corral, Alejandro Avendaño-Pita, Anna Arrufat, Valentín Garcia-Gutierrez, Elena Arellano, Lorena Hernández-Medina, Clara González-Santillana, Julia Morell, José Ángel Hernández-Rivas, Paula Rodriguez-Galvez, Mireia Mico-Cerdá, Manuel Guerreiro, Diana Campos, David Navarro, Ángel Cedillo, Rodrigo Martino and Carlos Solano
    Subject: Background: Scarce data exist that analyze the outcomes of hematological patients with SARS-CoV-2 infection during the Omicron variant period who received treatment with remdesivir or nirmatrelvir/ritonavir. Methods: This study aims to address this issue by using a retrospective observational registry, created by the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group, spanning from 27 December 2021 to 30 April 2023. Results: This study included 466 patients, 243 (52%) who were treated with remdesivir and 223 (48%) with nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir was primarily used for mild cases, resulting in a lower COVID-19-related mortality rate (1.3%), while remdesivir was preferred for moderate to severe cases (40%), exhibiting a higher mortality rate (9%). A multivariate analysis in the remdesivir cohort showed that male gender (odds ratio (OR) 0.35, p = 0.042) correlated with a lower mortality risk, while corticosteroid use (OR 9.4, p < 0.001) and co-infection (OR 2.8, p = 0.047) were linked to a higher mortality risk. Prolonged virus shedding was common, with 52% of patients shedding the virus for more than 25 days. In patients treated with remdesivir, factors associated with prolonged shedding included B-cell malignancy as well as underlying disease, severe disease, a later onset of and shorter duration of remdesivir treatment and a higher baseline viral load. Nirmatrelvir/ritonavir demonstrated a comparable safety profile to remdesivir, despite a higher risk of drug interactions. Conclusions: Nirmatrelvir/ritonavir proved to be a safe and effective option for treating mild cases in the outpatient setting, while remdesivir was preferred for severe cases, where corticosteroids and co-infection significantly predicted worse outcomes. Despite antiviral therapy, prolonged shedding remains a matter of concern.
    Keywords: remdesivir; nirmatrelvir/ritonavir; molnupiravir SARS-CoV-2 vaccines; Omicron;respiratory virus; hematological malignancies; allogeneic stem cell transplantation; autologous stem cell transplantation; COVID-19; mRNA vaccine; immunocompromised patients
    Creator: LaTeX with hyperref
    Producer: pdfTeX-1.40.21
    CreationDate: Sun Oct 08 10:42:21 CEST 2023
    ModDate: Sun Oct 08 10:46:39 CEST 2023
   ID: 0x30236f258fb8e0d8a24610fa23c3b9e9, 0x30236f258fb8e0d8a24610fa23c3b9e9
   Filters: 
    FilterPipeline: FlateDecode
   Fonts: 
    Type1: 
     Font: 
      BaseFont: TSEGZF+PazoMath-Bold
      FontSubset: true
      FirstChar: 87
      LastChar: 87
      FontDescriptor: 
       FontName: TSEGZF+PazoMath-Bold
       Flags: Symbolic
       FontBBox: -10, -266, 829, 695
       FontFile: true
     Font: 
      BaseFont: XXOAEV+URWPalladioL-Roma
      FontSubset: true
      FirstChar: 2
      LastChar: 252
      FontDescriptor: 
       FontName: XXOAEV+URWPalladioL-Roma
       Flags: Symbolic
       FontBBox: -166, -283, 1021, 943
       FontFile: true
      EncodingDictionary: 
       Differences: true
     Font: 
      BaseFont: YSZATT+CMSY10
      FontSubset: true
      FirstChar: 2
      LastChar: 58
      FontDescriptor: 
       FontName: YSZATT+CMSY10
       Flags: Symbolic
       FontBBox: -29, -960, 1116, 775
       FontFile: true
     Font: 
      BaseFont: YLPWUT+URWPalladioL-Ital
      FontSubset: true
      FirstChar: 2
      LastChar: 121
      FontDescriptor: 
       FontName: YLPWUT+URWPalladioL-Ital
       Flags: Symbolic
       FontBBox: -170, -305, 1010, 941
       FontFile: true
      EncodingDictionary: 
       Differences: true
     Font: 
      BaseFont: XIGCQR+Dingbats
      FontSubset: true
      FirstChar: 226
      LastChar: 226
      FontDescriptor: 
       FontName: XIGCQR+Dingbats
       Flags: Symbolic
       FontBBox: -1, -143, 981, 819
       FontFile: true
     Font: 
      BaseFont: SPXLNH+PazoMath
      FontSubset: true
      FirstChar: 87
      LastChar: 87
      FontDescriptor: 
       FontName: SPXLNH+PazoMath
       Flags: Symbolic
       FontBBox: -40, -283, 878, 946
       FontFile: true
     Font: 
      BaseFont: XNLXUN+VnURWPalladioL
      FontSubset: true
      FirstChar: 129
      LastChar: 226
      FontDescriptor: 
       FontName: XNLXUN+VnURWPalladioL
       Flags: Symbolic
       FontBBox: -166, -283, 1021, 943
       FontFile: true
      EncodingDictionary: 
       Differences: true
     Font: 
      BaseFont: VYCBDF+CMBSY10
      FontSubset: true
      FirstChar: 2
      LastChar: 21
      FontDescriptor: 
       FontName: VYCBDF+CMBSY10
       Flags: Symbolic
       FontBBox: -26, -940, 1332, 825
       FontFile: true
     Font: 
      BaseFont: NILCAS+VnURWPalladioL-Bold
      FontSubset: true
      FirstChar: 129
      LastChar: 226
      FontDescriptor: 
       FontName: NILCAS+VnURWPalladioL-Bold
       Flags: Symbolic
       FontBBox: -152, -301, 1000, 935
       FontFile: true
      EncodingDictionary: 
       Differences: true
     Font: 
      BaseFont: BIJRVS+URWPalladioL-BoldItal
      FontSubset: true
      FirstChar: 67
      LastChar: 116
      FontDescriptor: 
       FontName: BIJRVS+URWPalladioL-BoldItal
       Flags: Symbolic
       FontBBox: -170, -300, 1073, 935
       FontFile: true
      EncodingDictionary: 
       Differences: true
     Font: 
      BaseFont: DHNLGR+URWPalladioL-Bold
      FontSubset: true
      FirstChar: 2
      LastChar: 241
      FontDescriptor: 
       FontName: DHNLGR+URWPalladioL-Bold
       Flags: Symbolic
       FontBBox: -152, -301, 1000, 935
       FontFile: true
      EncodingDictionary: 
       Differences: true
   Pages: 
    Page: 
     Sequence: 1
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 54, 279, 152, 288
      Annotation: 
       Subtype: Link
       Rect: 34, 269, 68, 276
      Annotation: 
       Subtype: Link
       Rect: 34, 164, 96, 186
      Annotation: 
       Subtype: Link
       Rect: 126, 90, 154, 99
      Annotation: 
       Subtype: Link
       Rect: 34, 78, 147, 87
      Annotation: 
       Subtype: Link
       Rect: 34, 756, 147, 792
      Annotation: 
       Subtype: Link
       Rect: 515, 756, 560, 792
      Annotation: 
       Subtype: Link
       Rect: 357, 642, 368, 655
      Annotation: 
       Subtype: Link
       Rect: 302, 629, 313, 643
      Annotation: 
       Subtype: Link
       Rect: 500, 629, 511, 643
      Annotation: 
       Subtype: Link
       Rect: 303, 616, 314, 630
      Annotation: 
       Subtype: Link
       Rect: 159, 605, 170, 618
      Annotation: 
       Subtype: Link
       Rect: 249, 591, 260, 605
      Annotation: 
       Subtype: Link
       Rect: 482, 579, 493, 593
      Annotation: 
       Subtype: Link
       Rect: 141, 566, 152, 580
      Annotation: 
       Subtype: Link
       Rect: 112, 17, 241, 28
      Annotation: 
       Subtype: Link
       Rect: 411, 17, 560, 28
      Annotation: 
       Subtype: Link
       Rect: 34, 400, 87, 419
    Page: 
     Sequence: 2
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 250, 478, 257, 487
       ActionDest: 203
      Annotation: 
       Subtype: Link
       Rect: 257, 478, 264, 487
       ActionDest: 203
      Annotation: 
       Subtype: Link
       Rect: 360, 452, 367, 461
       ActionDest: 203
      Annotation: 
       Subtype: Link
       Rect: 367, 452, 374, 461
       ActionDest: 203
      Annotation: 
       Subtype: Link
       Rect: 229, 440, 236, 449
       ActionDest: 203
      Annotation: 
       Subtype: Link
       Rect: 239, 440, 246, 449
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 213, 415, 220, 424
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 404, 402, 411, 411
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 453, 402, 460, 411
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 511, 402, 523, 411
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 245, 390, 257, 399
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 435, 390, 447, 399
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 336, 352, 348, 361
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 239, 289, 251, 298
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 537, 264, 549, 273
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 491, 201, 503, 210
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 506, 201, 518, 210
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 280, 151, 292, 160
       ActionDest: 206
    Page: 
     Sequence: 3
    Page: 
     Sequence: 4
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 409, 493, 416, 505
       ActionDest: 75
    Page: 
     Sequence: 5
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 530, 172, 537, 182
       ActionDest: 85
      Annotation: 
       Subtype: Link
       Rect: 210, 145, 217, 157
       ActionDest: 92
    Page: 
     Sequence: 6
    Page: 
     Sequence: 7
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 214, 320, 221, 332
       ActionDest: 132
    Page: 
     Sequence: 8
    Page: 
     Sequence: 9
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 191, 192, 199, 204
       ActionDest: 142
    Page: 
     Sequence: 10
    Page: 
     Sequence: 11
    Page: 
     Sequence: 12
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 409, 733, 416, 745
       ActionDest: 157
      Annotation: 
       Subtype: Link
       Rect: 223, 309, 230, 321
       ActionDest: 157
    Page: 
     Sequence: 13
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 486, 494, 498, 503
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 395, 343, 407, 352
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 471, 331, 483, 340
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 269, 281, 276, 290
       ActionDest: 203
      Annotation: 
       Subtype: Link
       Rect: 279, 280, 286, 290
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 212, 218, 224, 227
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 227, 218, 239, 227
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 374, 193, 386, 202
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 465, 155, 477, 164
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 474, 130, 486, 139
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 486, 130, 498, 139
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 312, 80, 324, 89
       ActionDest: 209
      Annotation: 
       Subtype: Link
       Rect: 327, 80, 339, 89
       ActionDest: 209
      Annotation: 
       Subtype: Link
       Rect: 332, 67, 344, 76
       ActionDest: 209
    Page: 
     Sequence: 14
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 498, 723, 510, 732
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 337, 673, 349, 682
       ActionDest: 206
      Annotation: 
       Subtype: Link
       Rect: 272, 622, 284, 631
       ActionDest: 209
      Annotation: 
       Subtype: Link
       Rect: 201, 509, 213, 519
       ActionDest: 209
      Annotation: 
       Subtype: Link
       Rect: 384, 422, 396, 431
       ActionDest: 209
      Annotation: 
       Subtype: Link
       Rect: 471, 283, 483, 293
       ActionDest: 209
      Annotation: 
       Subtype: Link
       Rect: 287, 258, 299, 267
       ActionDest: 209
      Annotation: 
       Subtype: Link
       Rect: 382, 221, 394, 230
       ActionDest: 209
      Annotation: 
       Subtype: Link
       Rect: 397, 221, 409, 230
       ActionDest: 209
      Annotation: 
       Subtype: Link
       Rect: 492, 208, 504, 217
       ActionDest: 209
      Annotation: 
       Subtype: Link
       Rect: 495, 145, 507, 154
       ActionDest: 206
    Page: 
     Sequence: 15
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 176, 219, 214, 229
      Annotation: 
       Subtype: Link
       Rect: 82, 172, 119, 183
      Annotation: 
       Subtype: Link
       Rect: 179, 126, 217, 137
      Annotation: 
       Subtype: Link
       Rect: 373, 80, 411, 91
    Page: 
     Sequence: 16
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 59, 699, 96, 710
      Annotation: 
       Subtype: Link
       Rect: 194, 653, 232, 664
      Annotation: 
       Subtype: Link
       Rect: 483, 629, 521, 640
      Annotation: 
       Subtype: Link
       Rect: 108, 607, 146, 617
      Annotation: 
       Subtype: Link
       Rect: 476, 583, 514, 594
      Annotation: 
       Subtype: Link
       Rect: 104, 550, 141, 560
      Annotation: 
       Subtype: Link
       Rect: 341, 515, 378, 525
      Annotation: 
       Subtype: Link
       Rect: 149, 481, 186, 491
      Annotation: 
       Subtype: Link
       Rect: 192, 481, 228, 491
      Annotation: 
       Subtype: Link
       Rect: 176, 435, 214, 445
      Annotation: 
       Subtype: Link
       Rect: 220, 435, 256, 445
      Annotation: 
       Subtype: Link
       Rect: 426, 399, 464, 410
      Annotation: 
       Subtype: Link
       Rect: 470, 399, 506, 410
      Annotation: 
       Subtype: Link
       Rect: 224, 376, 262, 387
      Annotation: 
       Subtype: Link
       Rect: 268, 376, 304, 387
      Annotation: 
       Subtype: Link
       Rect: 371, 342, 409, 353
      Annotation: 
       Subtype: Link
       Rect: 353, 307, 390, 318
      Annotation: 
       Subtype: Link
       Rect: 396, 307, 432, 318
      Annotation: 
       Subtype: Link
       Rect: 157, 285, 194, 295
      Annotation: 
       Subtype: Link
       Rect: 324, 261, 361, 272
      Annotation: 
       Subtype: Link
       Rect: 59, 239, 96, 249
      Annotation: 
       Subtype: Link
       Rect: 102, 239, 138, 249
      Annotation: 
       Subtype: Link
       Rect: 59, 182, 95, 192
      Annotation: 
       Subtype: Link
       Rect: 178, 159, 216, 169
      Annotation: 
       Subtype: Link
       Rect: 222, 159, 258, 169
      Annotation: 
       Subtype: Link
       Rect: 100, 124, 137, 134
      Annotation: 
       Subtype: Link
       Rect: 86, 90, 123, 100
      Annotation: 
       Subtype: Link
       Rect: 269, 66, 307, 77
    Page: 
     Sequence: 17
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 162, 711, 200, 721
      Annotation: 
       Subtype: Link
       Rect: 231, 676, 269, 687
      Annotation: 
       Subtype: Link
       Rect: 465, 652, 503, 664
      Annotation: 
       Subtype: Link
       Rect: 241, 618, 279, 629
      Annotation: 
       Subtype: Link
       Rect: 59, 584, 96, 594
      Annotation: 
       Subtype: Link
       Rect: 270, 549, 307, 560
      Annotation: 
       Subtype: Link
       Rect: 414, 491, 560, 502
      Annotation: 
       Subtype: Link
       Rect: 187, 480, 225, 491
      Annotation: 
       Subtype: Link
       Rect: 59, 446, 96, 456
      Annotation: 
       Subtype: Link
       Rect: 278, 388, 315, 399
      Annotation: 
       Subtype: Link
       Rect: 95, 354, 132, 364
      Annotation: 
       Subtype: Link
       Rect: 86, 320, 123, 330
      Annotation: 
       Subtype: Link
       Rect: 261, 297, 298, 307
      Annotation: 
       Subtype: Link
       Rect: 342, 273, 378, 284
  Checksum: 687ecdd6
   Type: CRC32
  Checksum: c337711036072b5a447c78853ff66820
   Type: MD5
  Checksum: c68ec1e02cd92ad79b3f70dd19424abe0241b234
   Type: SHA-1
  Checksum: 6d0bd4780cffe319e3d9ddb0f3943d102381aad96e6860349d69f093ee79b9a5
   Type: SHA-256