998d0737d7ad1843f96dd40372c1872b pmc_34575280.pdf 59ef93a1d87d5b9f212e31623b14167cbbb4a999 pmc_34575280.pdf 1764874b04b8c1c3378b48329a856c0e944b4a7266b80de205b0d79eb532237e pmc_34575280.pdf Title: Complement Component C1q as a Potential Diagnostic Tool for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subtyping Subject: Background: Routine blood analytics are systematically used in the clinic to diagnose disease or confirm individuals’ healthy status. For myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disease relying exclusively on clinical symptoms for its diagnosis, blood analytics only serve to rule out underlying conditions leading to exerting fatigue. However, studies evaluating complete and large blood datasets by combinatorial approaches to evidence ME/CFS condition or detect/identify case subgroups are still scarce. Methods: This study used unbiased hierarchical cluster analysis of a large cohort of 250 carefully phenotyped female ME/CFS cases toward exploring this possibility. Results: The results show three symptom-based clusters, classified as severe, moderate, and mild, presenting significant differences (p < 0.05) in five blood parameters. Unexpectedly the study also revealed high levels of circulating complement factor C1q in 107/250 (43%) of the participants, placing C1q as a key molecule to identify an ME/CFS subtype/subgroup with more apparent pain symptoms. Conclusions: The results obtained have important implications for the research of ME/CFS etiology and, most likely, for the implementation of future diagnosis methods and treatments of ME/CFS in the clinic. Keywords: myalgic encephalomyelitis; chronic fatigue syndrome; C1q; complement system; blood analytics; diagnosis; symptoms; cluster analysis Author: Jesús Castro-Marrero, Mario Zacares, Eloy Almenar-Pérez, José Alegre-Martín and Elisa Oltra Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Sep 16 07:56:17 2021 CEST ModDate: Thu Sep 16 08:02:03 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1199916 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ACCAND+VnURWPalladioL Type 1 Custom yes yes no 10 0 NOFAPO+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 UBJXDU+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 FVECOU+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 WABLSD+SFRM1000 Type 1 Custom yes yes no 28 0 NBDQEL+VnURWPalladioL-Bold Type 1 Custom yes yes no 33 0 XPUSBJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 41 0 BSDWLC+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 44 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 66 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 70 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 74 0 NWYVYM+CMSY10 Type 1 Builtin yes yes no 89 0 QLBIEB+URWPalladioL-BoldItal Type 1 Custom yes yes no 96 0 LAEDPG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 109 0 LAEDPI+PalatinoLinotype TrueType WinAnsi yes yes no 112 0 LAEDPK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 115 0 LAEFDF+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 118 0 LAEDPG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 132 0 LAEDPI+PalatinoLinotype TrueType WinAnsi yes yes no 135 0 LAEDPK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 138 0 LAEDPG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 158 0 LAEDPI+PalatinoLinotype TrueType WinAnsi yes yes no 161 0 LAEDPK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 164 0 LWLIVD+EURM10 Type 1 Builtin yes yes no 178 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-03-22 02:45:01 CET RepresentationInformation: pmc_34575280.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2021-10-11 03:36:18 CEST Size: 1199916 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 362 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Children: Item: Title: Participants Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Measures Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Children: Item: Title: Fatigue Impact Scale Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Composite Autonomic Symptom Score Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Pittsburgh Sleep Quality Index Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Short-Form-36 Health Survey Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Blood Collection and Processing Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Blood Analytics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Cluster Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Statistical Analysis and Plotting Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Children: Item: Title: Demographics and Clinical Characteristics of the Participants Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Exploratory Case Cluster Analysis Based on Symptoms Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Cluster-Based Differential Analysis of Blood Parameters Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Stratified Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Children: Item: Title: Outstanding Blood Parameters with Abnormal Values Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Symptom Differences across C1q Case Clusters Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Blood analytic Differences across C1q Case Clusters Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Info: Title: Complement Component C1q as a Potential Diagnostic Tool for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subtyping Author: Jesús Castro-Marrero, Mario Zacares, Eloy Almenar-Pérez, José Alegre-Martín and Elisa Oltra Subject: Background: Routine blood analytics are systematically used in the clinic to diagnose disease or confirm individuals’ healthy status. For myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disease relying exclusively on clinical symptoms for its diagnosis, blood analytics only serve to rule out underlying conditions leading to exerting fatigue. However, studies evaluating complete and large blood datasets by combinatorial approaches to evidence ME/CFS condition or detect/identify case subgroups are still scarce. Methods: This study used unbiased hierarchical cluster analysis of a large cohort of 250 carefully phenotyped female ME/CFS cases toward exploring this possibility. Results: The results show three symptom-based clusters, classified as severe, moderate, and mild, presenting significant differences (p < 0.05) in five blood parameters. Unexpectedly the study also revealed high levels of circulating complement factor C1q in 107/250 (43%) of the participants, placing C1q as a key molecule to identify an ME/CFS subtype/subgroup with more apparent pain symptoms. Conclusions: The results obtained have important implications for the research of ME/CFS etiology and, most likely, for the implementation of future diagnosis methods and treatments of ME/CFS in the clinic. Keywords: myalgic encephalomyelitis; chronic fatigue syndrome; C1q; complement system; blood analytics; diagnosis; symptoms; cluster analysis Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Sep 16 07:56:17 CEST 2021 ModDate: Thu Sep 16 08:02:03 CEST 2021 ID: 0xaef3e5fb43332e15681a26a73a1b09b1, 0xaef3e5fb43332e15681a26a73a1b09b1 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: QLBIEB+URWPalladioL-BoldItal FontSubset: true FirstChar: 110 LastChar: 112 FontDescriptor: FontName: QLBIEB+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: NBDQEL+VnURWPalladioL-Bold FontSubset: true FirstChar: 178 LastChar: 243 FontDescriptor: FontName: NBDQEL+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: LWLIVD+EURM10 FontSubset: true FirstChar: 12 LastChar: 12 FontDescriptor: FontName: LWLIVD+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: UBJXDU+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: UBJXDU+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: FVECOU+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 246 FontDescriptor: FontName: FVECOU+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: NWYVYM+CMSY10 FontSubset: true FirstChar: 2 LastChar: 21 FontDescriptor: FontName: NWYVYM+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: ACCAND+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 243 FontDescriptor: FontName: ACCAND+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: WABLSD+SFRM1000 FontSubset: true FirstChar: 180 LastChar: 180 FontDescriptor: FontName: WABLSD+SFRM1000 Flags: Symbolic FontBBox: -189, -321, 1456, 937 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: NOFAPO+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 121 FontDescriptor: FontName: NOFAPO+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 35, 759, 176, 795 Annotation: Subtype: Link Rect: 515, 759, 560, 795 Annotation: Subtype: Link Rect: 144, 641, 155, 654 Annotation: Subtype: Link Rect: 430, 641, 441, 654 Annotation: Subtype: Link Rect: 530, 641, 541, 654 Annotation: Subtype: Link Rect: 99, 358, 154, 367 Annotation: Subtype: Link Rect: 35, 346, 102, 355 Annotation: Subtype: Link Rect: 35, 162, 97, 184 Annotation: Subtype: Link Rect: 153, 89, 154, 98 Annotation: Subtype: Link Rect: 35, 77, 147, 86 Annotation: Subtype: Link Rect: 199, 183, 206, 192 ActionDest: 169 Annotation: Subtype: Link Rect: 209, 183, 216, 192 ActionDest: 169 Annotation: Subtype: Link Rect: 231, 145, 238, 154 ActionDest: 169 Annotation: Subtype: Link Rect: 517, 145, 524, 154 ActionDest: 169 Annotation: Subtype: Link Rect: 527, 145, 534, 154 ActionDest: 169 Annotation: Subtype: Link Rect: 234, 95, 241, 104 ActionDest: 169 Annotation: Subtype: Link Rect: 502, 70, 509, 79 ActionDest: 172 Annotation: Subtype: Link Rect: 131, 17, 268, 28 Annotation: Subtype: Link Rect: 422, 17, 558, 28 Annotation: Subtype: Link Rect: 35, 446, 87, 465 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 334, 737, 346, 746 ActionDest: 172 Annotation: Subtype: Link Rect: 347, 737, 359, 746 ActionDest: 172 Annotation: Subtype: Link Rect: 295, 699, 307, 708 ActionDest: 172 Annotation: Subtype: Link Rect: 280, 459, 287, 468 ActionDest: 169 Annotation: Subtype: Link Rect: 527, 459, 534, 468 ActionDest: 169 Annotation: Subtype: Link Rect: 544, 132, 556, 141 ActionDest: 172 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 270, 685, 282, 694 ActionDest: 172 Annotation: Subtype: Link Rect: 377, 571, 389, 580 ActionDest: 172 Annotation: Subtype: Link Rect: 532, 483, 544, 492 ActionDest: 172 Annotation: Subtype: Link Rect: 532, 168, 544, 177 ActionDest: 172 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 523, 644, 535, 653 ActionDest: 172 Annotation: Subtype: Link Rect: 389, 631, 401, 640 ActionDest: 172 Annotation: Subtype: Link Rect: 382, 567, 389, 576 ActionDest: 169 Annotation: Subtype: Link Rect: 389, 567, 396, 576 ActionDest: 169 Annotation: Subtype: Link Rect: 324, 542, 336, 551 ActionDest: 172 Annotation: Subtype: Link Rect: 339, 542, 351, 551 ActionDest: 172 Annotation: Subtype: Link Rect: 468, 527, 475, 539 ActionDest: 100 Annotation: Subtype: Link Rect: 220, 492, 232, 501 ActionDest: 172 Annotation: Subtype: Link Rect: 389, 415, 396, 426 ActionDest: 100 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 454, 416, 461, 428 ActionDest: 83 Annotation: Subtype: Link Rect: 430, 391, 437, 403 ActionDest: 100 Annotation: Subtype: Link Rect: 549, 316, 556, 328 ActionDest: 103 Annotation: Subtype: Link Rect: 251, 228, 258, 240 ActionDest: 100 Annotation: Subtype: Link Rect: 292, 228, 299, 240 ActionDest: 103 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 201, 313, 208, 325 ActionDest: 83 Annotation: Subtype: Link Rect: 486, 275, 493, 287 ActionDest: 103 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 235, 644, 242, 656 ActionDest: 122 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 464, 679, 471, 691 ActionDest: 143 Annotation: Subtype: Link Rect: 531, 386, 543, 395 ActionDest: 172 Annotation: Subtype: Link Rect: 543, 386, 555, 395 ActionDest: 172 Annotation: Subtype: Link Rect: 408, 373, 420, 382 ActionDest: 172 Annotation: Subtype: Link Rect: 421, 373, 433, 382 ActionDest: 172 Annotation: Subtype: Link Rect: 483, 335, 495, 344 ActionDest: 172 Annotation: Subtype: Link Rect: 496, 335, 508, 344 ActionDest: 172 Annotation: Subtype: Link Rect: 376, 273, 388, 282 ActionDest: 172 Annotation: Subtype: Link Rect: 321, 157, 328, 169 ActionDest: 146 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 200, 522, 207, 534 ActionDest: 83 Annotation: Subtype: Link Rect: 247, 512, 254, 521 ActionDest: 146 Annotation: Subtype: Link Rect: 312, 190, 324, 199 ActionDest: 172 Annotation: Subtype: Link Rect: 485, 175, 492, 187 ActionDest: 122 Annotation: Subtype: Link Rect: 500, 149, 507, 161 ActionDest: 100 Annotation: Subtype: Link Rect: 527, 149, 534, 161 ActionDest: 103 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 188, 697, 200, 706 ActionDest: 172 Annotation: Subtype: Link Rect: 201, 697, 212, 706 ActionDest: 172 Annotation: Subtype: Link Rect: 376, 685, 388, 694 ActionDest: 172 Annotation: Subtype: Link Rect: 512, 672, 524, 681 ActionDest: 172 Annotation: Subtype: Link Rect: 524, 672, 536, 681 ActionDest: 172 Annotation: Subtype: Link Rect: 204, 609, 211, 618 ActionDest: 169 Annotation: Subtype: Link Rect: 214, 609, 221, 618 ActionDest: 169 Annotation: Subtype: Link Rect: 200, 559, 212, 568 ActionDest: 172 Annotation: Subtype: Link Rect: 212, 559, 224, 568 ActionDest: 172 Annotation: Subtype: Link Rect: 225, 559, 237, 568 ActionDest: 172 Annotation: Subtype: Link Rect: 237, 559, 249, 568 ActionDest: 172 Annotation: Subtype: Link Rect: 531, 559, 543, 568 ActionDest: 172 Annotation: Subtype: Link Rect: 544, 559, 556, 568 ActionDest: 172 Annotation: Subtype: Link Rect: 229, 494, 236, 506 ActionDest: 146 Annotation: Subtype: Link Rect: 311, 421, 323, 430 ActionDest: 172 Annotation: Subtype: Link Rect: 324, 421, 336, 430 ActionDest: 172 Annotation: Subtype: Link Rect: 545, 408, 556, 417 ActionDest: 172 Annotation: Subtype: Link Rect: 491, 396, 503, 405 ActionDest: 172 Annotation: Subtype: Link Rect: 503, 396, 515, 405 ActionDest: 175 Annotation: Subtype: Link Rect: 215, 371, 222, 380 ActionDest: 169 Annotation: Subtype: Link Rect: 225, 371, 232, 380 ActionDest: 169 Annotation: Subtype: Link Rect: 214, 346, 226, 355 ActionDest: 175 Annotation: Subtype: Link Rect: 229, 346, 241, 355 ActionDest: 175 Annotation: Subtype: Link Rect: 529, 283, 540, 292 ActionDest: 175 Annotation: Subtype: Link Rect: 543, 283, 555, 292 ActionDest: 175 Annotation: Subtype: Link Rect: 504, 255, 511, 267 ActionDest: 146 Annotation: Subtype: Link Rect: 519, 217, 526, 229 ActionDest: 103 Annotation: Subtype: Link Rect: 546, 217, 553, 229 ActionDest: 152 Annotation: Subtype: Link Rect: 268, 192, 275, 204 ActionDest: 100 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 450, 269, 462, 278 ActionDest: 175 Annotation: Subtype: Link Rect: 463, 268, 474, 278 ActionDest: 175 Annotation: Subtype: Link Rect: 494, 241, 501, 253 ActionDest: 143 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 424, 683, 560, 694 Annotation: Subtype: Link Rect: 166, 671, 267, 682 Annotation: Subtype: Link Rect: 338, 553, 430, 564 Annotation: Subtype: Link Rect: 199, 195, 237, 206 Annotation: Subtype: Link Rect: 243, 195, 279, 206 Annotation: Subtype: Link Rect: 122, 173, 160, 183 Annotation: Subtype: Link Rect: 166, 173, 202, 183 Annotation: Subtype: Link Rect: 95, 138, 133, 148 Annotation: Subtype: Link Rect: 139, 138, 175, 148 Annotation: Subtype: Link Rect: 296, 103, 334, 114 Annotation: Subtype: Link Rect: 59, 69, 97, 79 Annotation: Subtype: Link Rect: 491, 57, 529, 68 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 240, 709, 278, 720 Annotation: Subtype: Link Rect: 520, 686, 557, 697 Annotation: Subtype: Link Rect: 59, 653, 97, 663 Annotation: Subtype: Link Rect: 305, 629, 342, 640 Annotation: Subtype: Link Rect: 348, 629, 384, 640 Annotation: Subtype: Link Rect: 276, 606, 313, 617 Annotation: Subtype: Link Rect: 325, 583, 362, 594 Annotation: Subtype: Link Rect: 493, 548, 530, 559 Annotation: Subtype: Link Rect: 148, 525, 259, 536 Annotation: Subtype: Link Rect: 437, 502, 475, 513 Annotation: Subtype: Link Rect: 481, 502, 517, 513 Annotation: Subtype: Link Rect: 252, 480, 289, 490 Annotation: Subtype: Link Rect: 375, 457, 413, 467 Annotation: Subtype: Link Rect: 519, 433, 557, 444 Annotation: Subtype: Link Rect: 59, 423, 95, 433 Annotation: Subtype: Link Rect: 353, 399, 391, 410 Annotation: Subtype: Link Rect: 122, 377, 160, 387 Annotation: Subtype: Link Rect: 234, 341, 271, 352 Annotation: Subtype: Link Rect: 236, 318, 273, 329 Annotation: Subtype: Link Rect: 214, 295, 251, 306 Annotation: Subtype: Link Rect: 126, 262, 164, 272 Annotation: Subtype: Link Rect: 216, 238, 254, 249 Annotation: Subtype: Link Rect: 391, 215, 429, 226 Annotation: Subtype: Link Rect: 435, 215, 471, 226 Annotation: Subtype: Link Rect: 427, 192, 464, 203 Annotation: Subtype: Link Rect: 277, 169, 315, 180 Annotation: Subtype: Link Rect: 321, 169, 357, 180 Annotation: Subtype: Link Rect: 247, 134, 284, 145 Annotation: Subtype: Link Rect: 291, 134, 327, 145 Annotation: Subtype: Link Rect: 519, 111, 557, 122 Annotation: Subtype: Link Rect: 59, 100, 95, 111 Annotation: Subtype: Link Rect: 328, 88, 366, 99 Annotation: Subtype: Link Rect: 372, 88, 408, 99 Annotation: Subtype: Link Rect: 276, 65, 313, 76 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 477, 732, 514, 743 Annotation: Subtype: Link Rect: 521, 732, 557, 743 Annotation: Subtype: Link Rect: 178, 710, 215, 720 Annotation: Subtype: Link Rect: 221, 710, 257, 720 Annotation: Subtype: Link Rect: 458, 686, 496, 697 Annotation: Subtype: Link Rect: 502, 686, 538, 697 Annotation: Subtype: Link Rect: 95, 653, 133, 663 Annotation: Subtype: Link Rect: 131, 630, 167, 640 Annotation: Subtype: Link Rect: 218, 583, 256, 594 Annotation: Subtype: Link Rect: 168, 549, 206, 559 Annotation: Subtype: Link Rect: 322, 514, 359, 525 Annotation: Subtype: Link Rect: 365, 514, 401, 525 Checksum: ed0edf2a Type: CRC32 Checksum: 998d0737d7ad1843f96dd40372c1872b Type: MD5 Checksum: 59ef93a1d87d5b9f212e31623b14167cbbb4a999 Type: SHA-1