bbdf0baf803e9e787e6f095d04fc450a 271912.pdf 10adc89b84861ba94b4c2ecfc18bb33e7dc23f90 271912.pdf 25e3c2c7bab5f8b307422843560e9b91fa5ac2710cc8a076094703eef7ed2125 271912.pdf Title: Predictors of Global Non-Motor Symptoms Burden Progression in Parkinson’s Disease. Results from the COPPADIS Cohort at 2-Year Follow-Up Subject: Background and Objective: Non-motor symptoms (NMS) progress in different ways between Parkinson’s disease (PD) patients. The aim of the present study was to (1) analyze the change in global NMS burden in a PD cohort after a 2-year follow-up, (2) to compare the changes with a control group, and (3) to identify predictors of global NMS burden progression in the PD group. Material and Methods: PD patients and controls, recruited from 35 centers of Spain from the COPPADIS cohort from January 2016 to November 2017, were followed-up with after 2 years. The Non-Motor Symptoms Scale (NMSS) was administered at baseline (V0) and at 24 months 1 month (V2). Linear regression models were used for determining predictive factors of global NMS burden progression (NMSS total score change from V0 to V2 as dependent variable). Results: After the 2-year follow-up, the mean NMS burden (NMSS total score) significantly increased in PD patients by 18.8% (from 45.08 37.62 to 53.55 42.28; p < 0.0001; N = 501; 60.2% males, mean age 62.59 8.91) compared to no change observed in controls (from 14.74 18.72 to 14.65 21.82; p = 0.428; N = 122; 49.5% males, mean age 60.99 8.32) (p < 0.0001). NMSS total score at baseline ( = -0.52), change from V0 to V2 in PDSS (Parkinson’s Disease Sleep Scale) ( = -0.34), and change from V0 to V2 in NPI (Neuropsychiatric Inventory) ( = 0.25) provided the highest contributions to the model (adjusted R-squared 0.41; Durbin-Watson test = 1.865). Conclusions: Global NMS burden demonstrates short-term progression in PD patients but not in controls and identifies worsening sleep problems and neuropsychiatric symptoms as significant independent predictors of this NMS progression. Keywords: mood; non-motor symptoms; Parkinson’s disease; progression; quality of life Author: Diego Santos-García, Teresa de Deus, Carlos Cores, Hector Canfield, Jose M Paz González, Cristina Martínez Miró, Lorena Valdés Aymerich, Ester Suárez, Silvia Jesús, Miquel Aguilar, Pau Pastor, LLuis Planellas, Marina Cosgaya, Juan García Caldentey, Nuria Caballol, Ines Legarda, Jorge Hernández-Vara, Iria Cabo, Lydia López Manzanares, Isabel González Aramburu, Maria A Ávila Rivera, Maria J Catalán, Victor Nogueira, Victor Puente, Julio Dotor, Carmen Borrué, Berta Solano, Maria Álvarez Sauco, Lydia Vela, Sonia Escalante, Esther Cubo, Francisco Carrillo, Juan C Martínez Castrillo, Pilar Sánchez Alonso, Gemma Alonso, Nuria López Ariztegui, Itziar Gastón, Jaime Kulisevsky, Marta Blázquez, Manuel Seijo, Javier Rúiz Martínez, Caridad Valero, Monica Kurtis, Oriol de Fábregues, Jessica Ardura, Ruben Alonso, Carlos Ordás, Luis M López Díaz, Darrian McAfee, Pablo Martinez-Martin, Pablo Mir and COPPADIS Study Group Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Jul 1 03:36:39 2021 CEST ModDate: Thu Jul 1 05:09:54 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 25 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1176443 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- KWUCKX+VnURWPalladioL Type 1 Custom yes yes no 10 0 SZTFOX+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 PITHKT+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 RJDWBX+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 WIRPUU+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 UIJACC+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 36 0 BSDWLC+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 39 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 61 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 65 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 69 0 LWLIVD+EURM10 Type 1 Builtin yes yes no 81 0 CZMDWU+CMSY10 Type 1 Builtin yes yes no 85 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes no 101 0 OPGDDI+TimesNewRoman,Bold CID TrueType Identity-H yes yes yes 111 0 OPGDPM+PalatinoLinotype CID TrueType Identity-H yes yes yes 117 0 OPGDPN+PalatinoLinotype TrueType WinAnsi yes yes no 123 0 OPGDDJ+TimesNewRoman CID TrueType Identity-H yes yes yes 126 0 OPGDEK+TimesNewRoman,Italic TrueType WinAnsi yes yes no 132 0 OPGDNJ+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 135 0 OPGDNL+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 138 0 ZYYJXI+EURB10 Type 1 Builtin yes yes no 156 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 03:03:56 CEST RepresentationInformation: 271912.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 12:05:12 CEST Size: 1176443 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 394 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Data Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Standard Protocol Approvals, Registrations, and Patient Consents Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Info: Title: Predictors of Global Non-Motor Symptoms Burden Progression in Parkinson’s Disease. Results from the COPPADIS Cohort at 2-Year Follow-Up Author: Diego Santos-García, Teresa de Deus, Carlos Cores, Hector Canfield, Jose M Paz González, Cristina Martínez Miró, Lorena Valdés Aymerich, Ester Suárez, Silvia Jesús, Miquel Aguilar, Pau Pastor, LLuis Planellas, Marina Cosgaya, Juan García Caldentey, Nuria Caballol, Ines Legarda, Jorge Hernández-Vara, Iria Cabo, Lydia López Manzanares, Isabel González Aramburu, Maria A Ávila Rivera, Maria J Catalán, Victor Nogueira, Victor Puente, Julio Dotor, Carmen Borrué, Berta Solano, Maria Álvarez Sauco, Lydia Vela, Sonia Escalante, Esther Cubo, Francisco Carrillo, Juan C Martínez Castrillo, Pilar Sánchez Alonso, Gemma Alonso, Nuria López Ariztegui, Itziar Gastón, Jaime Kulisevsky, Marta Blázquez, Manuel Seijo, Javier Rúiz Martínez, Caridad Valero, Monica Kurtis, Oriol de Fábregues, Jessica Ardura, Ruben Alonso, Carlos Ordás, Luis M López Díaz, Darrian McAfee, Pablo Martinez-Martin, Pablo Mir and COPPADIS Study Group Subject: Background and Objective: Non-motor symptoms (NMS) progress in different ways between Parkinson’s disease (PD) patients. The aim of the present study was to (1) analyze the change in global NMS burden in a PD cohort after a 2-year follow-up, (2) to compare the changes with a control group, and (3) to identify predictors of global NMS burden progression in the PD group. Material and Methods: PD patients and controls, recruited from 35 centers of Spain from the COPPADIS cohort from January 2016 to November 2017, were followed-up with after 2 years. The Non-Motor Symptoms Scale (NMSS) was administered at baseline (V0) and at 24 months 1 month (V2). Linear regression models were used for determining predictive factors of global NMS burden progression (NMSS total score change from V0 to V2 as dependent variable). Results: After the 2-year follow-up, the mean NMS burden (NMSS total score) significantly increased in PD patients by 18.8% (from 45.08 37.62 to 53.55 42.28; p < 0.0001; N = 501; 60.2% males, mean age 62.59 8.91) compared to no change observed in controls (from 14.74 18.72 to 14.65 21.82; p = 0.428; N = 122; 49.5% males, mean age 60.99 8.32) (p < 0.0001). NMSS total score at baseline ( = -0.52), change from V0 to V2 in PDSS (Parkinson’s Disease Sleep Scale) ( = -0.34), and change from V0 to V2 in NPI (Neuropsychiatric Inventory) ( = 0.25) provided the highest contributions to the model (adjusted R-squared 0.41; Durbin-Watson test = 1.865). Conclusions: Global NMS burden demonstrates short-term progression in PD patients but not in controls and identifies worsening sleep problems and neuropsychiatric symptoms as significant independent predictors of this NMS progression. Keywords: mood; non-motor symptoms; Parkinson’s disease; progression; quality of life Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Jul 01 03:36:39 CEST 2021 ModDate: Thu Jul 01 05:09:54 CEST 2021 ID: 0xace753dfb48db439c5e7f062cb3ae6de, 0xace753dfb48db439c5e7f062cb3ae6de Filters: FilterPipeline: FlateDecode Fonts: Type1: 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: PITHKT+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 134 FontDescriptor: FontName: PITHKT+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: CZMDWU+CMSY10 FontSubset: true FirstChar: 0 LastChar: 21 FontDescriptor: FontName: CZMDWU+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: WBVKDJ+URWPalladioL-BoldItal FontSubset: true FirstChar: 112 LastChar: 112 FontDescriptor: FontName: WBVKDJ+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: RJDWBX+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 250 FontDescriptor: FontName: RJDWBX+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: KWUCKX+VnURWPalladioL FontSubset: true FirstChar: 129 LastChar: 243 FontDescriptor: FontName: KWUCKX+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: WIRPUU+VnURWPalladioL-Bold FontSubset: true FirstChar: 129 LastChar: 243 FontDescriptor: FontName: WIRPUU+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: ZYYJXI+EURB10 FontSubset: true FirstChar: 12 LastChar: 12 FontDescriptor: FontName: ZYYJXI+EURB10 Flags: Symbolic FontBBox: -30, -247, 1178, 723 FontFile: true Font: BaseFont: SZTFOX+URWPalladioL-Ital FontSubset: true FirstChar: 44 LastChar: 121 FontDescriptor: FontName: SZTFOX+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: 142, 641, 153, 654 Annotation: Subtype: Link Rect: 301, 641, 312, 654 Annotation: Subtype: Link Rect: 147, 628, 158, 642 Annotation: Subtype: Link Rect: 145, 603, 156, 617 Annotation: Subtype: Link Rect: 212, 603, 223, 617 Annotation: Subtype: Link Rect: 496, 603, 507, 617 Annotation: Subtype: Link Rect: 161, 566, 172, 579 Annotation: Subtype: Link Rect: 487, 565, 498, 579 Annotation: Subtype: Link Rect: 294, 553, 305, 566 Annotation: Subtype: Link Rect: 338, 528, 349, 541 Annotation: Subtype: Link Rect: 79, 358, 154, 367 Annotation: Subtype: Link Rect: 35, 346, 103, 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: 127, 17, 265, 28 Annotation: Subtype: Link Rect: 421, 17, 558, 28 Annotation: Subtype: Link Rect: 35, 482, 87, 501 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 435, 552, 443, 562 ActionDest: 173 Annotation: Subtype: Link Rect: 203, 179, 210, 188 ActionDest: 198 Annotation: Subtype: Link Rect: 549, 167, 556, 176 ActionDest: 198 Annotation: Subtype: Link Rect: 437, 141, 444, 151 ActionDest: 198 Annotation: Subtype: Link Rect: 305, 117, 312, 125 ActionDest: 198 Annotation: Subtype: Link Rect: 340, 104, 347, 113 ActionDest: 198 Annotation: Subtype: Link Rect: 350, 104, 357, 113 ActionDest: 198 Annotation: Subtype: Link Rect: 534, 91, 541, 100 ActionDest: 198 Annotation: Subtype: Link Rect: 544, 91, 556, 100 ActionDest: 198 Annotation: Subtype: Link Rect: 222, 66, 234, 75 ActionDest: 198 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 275, 722, 287, 731 ActionDest: 201 Annotation: Subtype: Link Rect: 393, 571, 405, 580 ActionDest: 201 Annotation: Subtype: Link Rect: 222, 544, 560, 556 Annotation: Subtype: Link Rect: 256, 534, 268, 543 ActionDest: 201 Annotation: Subtype: Link Rect: 490, 295, 502, 304 ActionDest: 201 Annotation: Subtype: Link Rect: 530, 220, 542, 229 ActionDest: 201 Annotation: Subtype: Link Rect: 240, 207, 252, 216 ActionDest: 201 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 344, 685, 356, 694 ActionDest: 201 Annotation: Subtype: Link Rect: 424, 383, 436, 392 ActionDest: 198 Annotation: Subtype: Link Rect: 292, 345, 304, 354 ActionDest: 201 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 553, 667, 560, 678 ActionDest: 98 Annotation: Subtype: Link Rect: 217, 654, 224, 666 ActionDest: 105 Annotation: Subtype: Link Rect: 405, 641, 412, 653 ActionDest: 105 Annotation: Subtype: Link Rect: 393, 616, 400, 628 ActionDest: 98 Annotation: Subtype: Link Rect: 541, 591, 548, 603 ActionDest: 105 Annotation: Subtype: Link Rect: 394, 541, 401, 553 ActionDest: 98 Annotation: Subtype: Link Rect: 542, 478, 549, 490 ActionDest: 144 Annotation: Subtype: Link Rect: 200, 428, 207, 440 ActionDest: 144 Page: Sequence: 6 Page: Sequence: 7 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 195, 399, 202, 411 ActionDest: 150 Annotation: Subtype: Link Rect: 195, 337, 202, 348 ActionDest: 150 Annotation: Subtype: Link Rect: 412, 198, 419, 210 ActionDest: 160 Annotation: Subtype: Link Rect: 322, 161, 329, 172 ActionDest: 160 Page: Sequence: 9 Page: Sequence: 10 Page: Sequence: 11 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 334, 418, 346, 427 ActionDest: 201 Annotation: Subtype: Link Rect: 191, 405, 197, 414 ActionDest: 198 Annotation: Subtype: Link Rect: 350, 405, 362, 414 ActionDest: 201 Annotation: Subtype: Link Rect: 221, 368, 233, 377 ActionDest: 201 Annotation: Subtype: Link Rect: 367, 355, 379, 364 ActionDest: 198 Annotation: Subtype: Link Rect: 435, 305, 442, 314 ActionDest: 198 Annotation: Subtype: Link Rect: 445, 305, 457, 314 ActionDest: 198 Annotation: Subtype: Link Rect: 519, 255, 526, 264 ActionDest: 198 Annotation: Subtype: Link Rect: 527, 255, 539, 264 ActionDest: 198 Annotation: Subtype: Link Rect: 273, 179, 285, 188 ActionDest: 201 Annotation: Subtype: Link Rect: 288, 179, 300, 188 ActionDest: 201 Annotation: Subtype: Link Rect: 191, 167, 203, 176 ActionDest: 201 Annotation: Subtype: Link Rect: 311, 129, 323, 138 ActionDest: 198 Annotation: Subtype: Link Rect: 544, 104, 556, 113 ActionDest: 198 Annotation: Subtype: Link Rect: 276, 79, 288, 88 ActionDest: 201 Annotation: Subtype: Link Rect: 544, 79, 556, 88 ActionDest: 201 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 387, 660, 399, 669 ActionDest: 201 Annotation: Subtype: Link Rect: 402, 659, 414, 669 ActionDest: 201 Annotation: Subtype: Link Rect: 523, 659, 535, 669 ActionDest: 201 Annotation: Subtype: Link Rect: 220, 647, 232, 656 ActionDest: 201 Annotation: Subtype: Link Rect: 206, 609, 218, 618 ActionDest: 201 Annotation: Subtype: Link Rect: 383, 572, 395, 581 ActionDest: 201 Annotation: Subtype: Link Rect: 545, 572, 557, 581 ActionDest: 201 Annotation: Subtype: Link Rect: 285, 496, 297, 505 ActionDest: 201 Annotation: Subtype: Link Rect: 298, 496, 310, 505 ActionDest: 201 Annotation: Subtype: Link Rect: 544, 433, 556, 443 ActionDest: 201 Annotation: Subtype: Link Rect: 461, 408, 473, 417 ActionDest: 201 Annotation: Subtype: Link Rect: 190, 371, 202, 380 ActionDest: 201 Annotation: Subtype: Link Rect: 488, 358, 500, 367 ActionDest: 201 Annotation: Subtype: Link Rect: 276, 333, 288, 342 ActionDest: 201 Annotation: Subtype: Link Rect: 525, 283, 537, 292 ActionDest: 204 Annotation: Subtype: Link Rect: 249, 233, 261, 242 ActionDest: 198 Annotation: Subtype: Link Rect: 204, 208, 216, 217 ActionDest: 201 Annotation: Subtype: Link Rect: 217, 208, 229, 217 ActionDest: 204 Annotation: Subtype: Link Rect: 229, 208, 241, 217 ActionDest: 204 Annotation: Subtype: Link Rect: 510, 208, 522, 217 ActionDest: 204 Annotation: Subtype: Link Rect: 523, 208, 535, 217 ActionDest: 204 Annotation: Subtype: Link Rect: 203, 120, 215, 129 ActionDest: 204 Annotation: Subtype: Link Rect: 449, 107, 461, 116 ActionDest: 204 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 544, 710, 556, 719 ActionDest: 204 Annotation: Subtype: Link Rect: 299, 685, 311, 694 ActionDest: 204 Annotation: Subtype: Link Rect: 311, 685, 323, 694 ActionDest: 204 Annotation: Subtype: Link Rect: 257, 659, 269, 669 ActionDest: 204 Annotation: Subtype: Link Rect: 269, 660, 281, 669 ActionDest: 204 Annotation: Subtype: Link Rect: 544, 609, 556, 618 ActionDest: 204 Annotation: Subtype: Link Rect: 391, 559, 403, 568 ActionDest: 204 Annotation: Subtype: Link Rect: 421, 534, 433, 543 ActionDest: 204 Annotation: Subtype: Link Rect: 477, 459, 489, 468 ActionDest: 204 Annotation: Subtype: Link Rect: 509, 383, 521, 392 ActionDest: 201 Annotation: Subtype: Link Rect: 334, 358, 346, 367 ActionDest: 198 Annotation: Subtype: Link Rect: 429, 358, 441, 367 ActionDest: 201 Annotation: Subtype: Link Rect: 544, 358, 556, 367 ActionDest: 201 Annotation: Subtype: Link Rect: 257, 320, 269, 330 ActionDest: 201 Annotation: Subtype: Link Rect: 196, 270, 203, 279 ActionDest: 198 Annotation: Subtype: Link Rect: 408, 233, 420, 242 ActionDest: 201 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 434, 551, 556, 562 Annotation: Subtype: Link Rect: 405, 410, 527, 421 Annotation: Subtype: Link Rect: 217, 398, 329, 409 Page: Sequence: 16 Page: Sequence: 17 Page: Sequence: 18 Page: Sequence: 19 Page: Sequence: 20 Page: Sequence: 21 Page: Sequence: 22 Page: Sequence: 23 Annotations: Annotation: Subtype: Link Rect: 519, 387, 557, 398 Annotation: Subtype: Link Rect: 59, 376, 95, 386 Annotation: Subtype: Link Rect: 143, 352, 181, 363 Annotation: Subtype: Link Rect: 96, 330, 133, 340 Annotation: Subtype: Link Rect: 333, 306, 370, 317 Annotation: Subtype: Link Rect: 183, 284, 220, 294 Annotation: Subtype: Link Rect: 226, 284, 262, 294 Annotation: Subtype: Link Rect: 156, 261, 194, 271 Annotation: Subtype: Link Rect: 219, 238, 256, 248 Annotation: Subtype: Link Rect: 263, 238, 299, 248 Annotation: Subtype: Link Rect: 237, 192, 274, 202 Annotation: Subtype: Link Rect: 208, 157, 245, 168 Annotation: Subtype: Link Rect: 140, 123, 178, 133 Annotation: Subtype: Link Rect: 391, 99, 428, 110 Annotation: Subtype: Link Rect: 300, 65, 338, 76 Page: Sequence: 24 Annotations: Annotation: Subtype: Link Rect: 243, 676, 281, 686 Annotation: Subtype: Link Rect: 287, 676, 323, 686 Annotation: Subtype: Link Rect: 218, 594, 256, 605 Annotation: Subtype: Link Rect: 262, 594, 298, 605 Annotation: Subtype: Link Rect: 218, 561, 255, 571 Annotation: Subtype: Link Rect: 261, 561, 298, 571 Annotation: Subtype: Link Rect: 358, 525, 395, 536 Annotation: Subtype: Link Rect: 165, 480, 202, 490 Annotation: Subtype: Link Rect: 242, 456, 280, 467 Annotation: Subtype: Link Rect: 357, 422, 394, 433 Annotation: Subtype: Link Rect: 147, 377, 185, 387 Annotation: Subtype: Link Rect: 191, 377, 227, 387 Annotation: Subtype: Link Rect: 91, 342, 128, 352 Annotation: Subtype: Link Rect: 135, 342, 171, 352 Annotation: Subtype: Link Rect: 259, 319, 297, 329 Annotation: Subtype: Link Rect: 303, 319, 339, 329 Annotation: Subtype: Link Rect: 244, 284, 281, 295 Annotation: Subtype: Link Rect: 182, 250, 220, 260 Annotation: Subtype: Link Rect: 226, 250, 262, 260 Annotation: Subtype: Link Rect: 260, 227, 297, 237 Annotation: Subtype: Link Rect: 510, 203, 548, 214 Annotation: Subtype: Link Rect: 453, 180, 491, 191 Annotation: Subtype: Link Rect: 410, 169, 448, 180 Annotation: Subtype: Link Rect: 95, 146, 132, 157 Annotation: Subtype: Link Rect: 169, 123, 207, 134 Annotation: Subtype: Link Rect: 213, 123, 249, 134 Annotation: Subtype: Link Rect: 469, 111, 506, 122 Annotation: Subtype: Link Rect: 237, 89, 274, 99 Annotation: Subtype: Link Rect: 190, 66, 228, 76 Page: Sequence: 25 Annotations: Annotation: Subtype: Link Rect: 513, 732, 551, 743 Annotation: Subtype: Link Rect: 59, 699, 97, 709 Annotation: Subtype: Link Rect: 170, 676, 207, 686 Annotation: Subtype: Link Rect: 214, 676, 250, 686 Annotation: Subtype: Link Rect: 131, 641, 169, 651 Annotation: Subtype: Link Rect: 367, 606, 404, 617 Annotation: Subtype: Link Rect: 411, 606, 447, 617 Annotation: Subtype: Link Rect: 410, 594, 447, 605 Annotation: Subtype: Link Rect: 454, 594, 490, 605 Annotation: Subtype: Link Rect: 109, 561, 146, 571 Annotation: Subtype: Link Rect: 153, 561, 189, 571 Annotation: Subtype: Link Rect: 272, 537, 310, 548 Annotation: Subtype: Link Rect: 316, 537, 352, 548 Annotation: Subtype: Link Rect: 230, 503, 268, 513 Annotation: Subtype: Link Rect: 274, 503, 310, 513 Annotation: Subtype: Link Rect: 190, 480, 227, 490 Annotation: Subtype: Link Rect: 219, 446, 257, 456 Annotation: Subtype: Link Rect: 370, 422, 408, 433 Annotation: Subtype: Link Rect: 520, 387, 557, 398 Annotation: Subtype: Link Rect: 180, 353, 217, 364 Checksum: 6c326e77 Type: CRC32 Checksum: bbdf0baf803e9e787e6f095d04fc450a Type: MD5 Checksum: 10adc89b84861ba94b4c2ecfc18bb33e7dc23f90 Type: SHA-1