_:b429699288 . _:b429699373 . . _:b429699120 "2"^^ . _:b429699081 . _:b429699291 . . _:b429699123 "2"^^ . _:b429699050 . _:b429699290 . _:b7410096 "lateral sclerosis, generally about a third or less of the studies reported random allocation to the treatment group, and even fewer studies reported concealment of treatment allocation or blinded outcome assessment [2],[16],[19],[>>24<<],[25]. Even when reported, the methods used for randomisation and blinding were rarely given." . _:b429699122 "2"^^ . . _:b429699301 . _:b429699133 "2"^^ . . _:b429699300 . _:b429699132 "2"^^ . _:b429699015 . _:b429699303 . . _:b429699135 "2"^^ . . _:b429699302 . _:b429699210 . _:b429699134 "2"^^ . _:b429699297 . _:b429699129 "2"^^ . _:b429699296 . _:b429699128 "2"^^ . _:b429699299 . _:b429699463 . _:b7410114 "It is difficult to believe that in every other study every single experiment went as smoothly as the investigators had planned [>>19<<]." . _:b429699131 "2"^^ . _:b429699298 . _:b429699130 "2"^^ . . _:b429699309 . _:b429699141 "2"^^ . . _:b429699308 . _:b429699140 "2"^^ . . _:b429699311 . . _:b429699143 "2"^^ . _:b429699310 . _:b429699417 . _:b429699142 "2"^^ . . _:b429699305 . . _:b429699137 "2"^^ . _:b429699304 . _:b429699136 "2"^^ . _:b429699307 . . . _:b429699139 "2"^^ . . _:b429699306 . _:b429699138 "2"^^ . _:b429699317 . _:b429699149 "2"^^ . _:b429699316 . _:b7410073 . . _:b429699148 "2"^^ . . . _:b429699319 . _:b429698589 . _:b429699151 "2"^^ . _:b429698628 . _:b429699318 . . _:b7410082 . _:b429698713 . _:b429699150 "2"^^ . _:b429699036 . _:b429699313 . . _:b429699145 "2"^^ . _:b429699270 . _:b429699312 . _:b7410084 . _:b429699144 "2"^^ . . _:b429699315 . _:b7410085 . _:b429699147 "2"^^ . . _:b429699314 . _:b7410086 . . _:b429699146 "2"^^ . _:b429699074 . _:b429699021 . _:b429699325 . _:b429699157 "2"^^ . _:b429699324 . _:b429698789 . _:b429699156 "2"^^ . _:b429699327 . _:b7410089 . _:b429699159 "2"^^ . _:b429699075 . _:b429699326 . _:b429699158 "2"^^ . _:b429699321 . _:b7410091 . _:b429699153 "2"^^ . _:b429699320 . _:b429698597 . _:b429699152 "2"^^ . . _:b429699323 . _:b429699155 "2"^^ . _:b429699350 . _:b429699322 . _:b429699154 "2"^^ . _:b429699256 . _:b429699165 "2"^^ . . _:b429699347 . _:b429699164 "2"^^ . _:b429698862 . _:b429699432 . . _:b429699167 "2"^^ . . . _:b429699166 "2"^^ . _:b429699161 "2"^^ . _:b429699160 "2"^^ . _:b429699163 "2"^^ . _:b429698663 . _:b429699459 . . _:b429699162 "2"^^ . _:b429699203 . _:b429698857 . _:b429698755 . _:b429699173 "2"^^ . . . _:b429699172 "2"^^ . . _:b429699175 "2"^^ . . _:b429698814 . _:b429699174 "2"^^ . . _:b429699169 "2"^^ . _:b429698931 . _:b429698669 . _:b429699168 "2"^^ . _:b429699202 . _:b429698905 . _:b429699171 "2"^^ . . _:b429699170 "2"^^ . _:b429699181 "2"^^ . . _:b429699180 "2"^^ . . _:b429699318 . _:b429699183 "2"^^ . _:b7410143 "Scott 2008 [>>40<<]: Elaborate study suggesting that the majority of published effects of treatments for amyotrophic lateral sclerosis are most likely measurements of noise in the distribution of survival means as opposed to actual drug effect." . . . _:b429699182 "2"^^ . _:b429698906 . _:b429699177 "2"^^ . . . _:b429699176 "2"^^ . _:b429699179 "2"^^ . _:b429699178 "2"^^ . . _:b429699189 "2"^^ . . _:b429699188 "2"^^ . _:b429699191 "2"^^ . . _:b429699190 "2"^^ . _:b429698818 . _:b429699185 "2"^^ . _:b429698842 . . _:b429699184 "2"^^ . . . _:b429699187 "2"^^ . . . _:b429699186 "2"^^ . _:b429699197 . _:b429699197 "2"^^ . . _:b429699017 . _:b429699196 "2"^^ . _:b429698892 . _:b429699140 . _:b429699199 "2"^^ . . . . _:b429699198 "2"^^ . . . _:b429699193 "2"^^ . _:b429698633 . _:b429699192 "2"^^ . _:b429699195 "2"^^ . _:b429698929 . _:b429699194 "2"^^ . _:b429698908 . _:b429699205 "2"^^ . . _:b429699204 "2"^^ . _:b429699207 "2"^^ . . . . _:b429699206 "2"^^ . . . _:b429699368 . _:b429699201 "2"^^ . . _:b429699032 . _:b429699200 "2"^^ . . _:b429699203 "2"^^ . _:b429699202 "2"^^ . _:b429698938 . _:b429699213 "2"^^ . _:b429698749 . _:b429699445 . _:b429699212 "2"^^ . _:b429698732 . _:b429698825 . _:b429699215 "2"^^ . _:b429699214 "2"^^ . . . _:b7410127 "Over 95% of the studies were performed in rats and mice, and animals that are perhaps biologically closer to humans are hardly ever used [16],[>>19<<]. Moreover, most animal studies have failed to acknowledge the inevitable delay between the onset of symptoms and the possibility to start treatment in patients. In a systematic review of animal studies of five different neuroprotective" . _:b429699209 "2"^^ . . _:b7410092 "Indeed, adopting a multicentre approach to animal studies has been proposed, as a way of securing transparent quality control [>>23<<]." . . _:b429699208 "2"^^ . . _:b429699211 "2"^^ . _:b429698867 . . _:b429698964 . _:b429698714 . _:b7410132 . _:b429699345 . _:b429699210 "2"^^ . _:b429699209 . . . . _:b429699221 "2"^^ . . . _:b429699220 "2"^^ . _:b429699163 . . . . _:b429699223 "2"^^ . _:b429698588 "34"^^ . . _:b429699222 "2"^^ . _:b429698589 "33"^^ . _:b429699217 "2"^^ . . _:b429698590 "33"^^ . . _:b7410142 . _:b429699216 "2"^^ . _:b7410135 . _:b429699219 "2"^^ . _:b7410130 "Several studies have suggested that in patients the relation between infarct volume and functional outcome is moderate at best [37],[>>38<<]. Finally, the usual time of outcome assessment of 1\u20133 days in animal models contrasts sharply with that of 3 months in patients [19]. For these reasons, it is not surprising that, except for thrombolysis, all treatment strategies proven" . _:b429699218 "2"^^ . _:b429698586 "45"^^ . _:b429698587 "34"^^ . _:b429699229 "2"^^ . . . _:b7410121 . . . _:b429699228 "2"^^ . . _:b429699231 "2"^^ . . _:b429699358 . . . _:b429699230 "2"^^ . _:b429699225 "2"^^ . _:b429698649 . _:b429699224 "2"^^ . _:b429699033 . _:b7410143 . _:b429699227 "2"^^ . _:b429699392 . . _:b429699226 "2"^^ . _:b429699399 . . _:b429698737 . _:b429699146 . _:b429699237 "2"^^ . _:b429699249 . . _:b7410112 "There is an overlap of 18 publications between references [16] and [>>19<<]." . _:b429699236 "2"^^ . _:b429698976 . _:b7410137 . _:b429699239 "2"^^ . . _:b429699238 "2"^^ . _:b429698951 . _:b429699233 "2"^^ . _:b429698914 . _:b429699232 "2"^^ . _:b429699323 . _:b429699235 "2"^^ . _:b429698861 . _:b429699302 . _:b7410075 "In a recent systematic review of studies testing the efficacy of interventions in animal models of human disease, only six reported testing for the presence of publication bias, and such bias was found in four [34],[42]\u2013[>>46<<]. No study gave quantitative estimates of the impact on effect size of publication bias [47]." . _:b429699234 "2"^^ . _:b429699245 "2"^^ . _:b429698706 . _:b429699244 "2"^^ . . . _:b429699247 "2"^^ . _:b429699246 "2"^^ . _:b429699223 . _:b429699241 "2"^^ . _:b429699026 . _:b429699240 "2"^^ . _:b429699257 . . . . _:b429699243 "2"^^ . _:b429699065 . . _:b7410115 "These checklists have included items relating first to the range of circumstances under which efficacy has been shown and second to the characteristics that might act as a source of bias in individual experiments [>>16<<]." . _:b429699242 "2"^^ . . _:b429699085 . _:b429698591 "25"^^ . _:b429699253 "2"^^ . . _:b429698640 . _:b429699396 . . _:b429699252 "2"^^ . _:b429699255 "2"^^ . . _:b429698593 "21"^^ . _:b429699254 "2"^^ . _:b429698592 "22"^^ . . _:b429699249 "2"^^ . _:b429698595 "19"^^ . . _:b429698854 . _:b429699248 "2"^^ . _:b429699093 . _:b429698594 "19"^^ . . . . . _:b429699251 "2"^^ . _:b429698596 "17"^^ . _:b7410089 "of the study with a formal sample size calculation, of which the fundamental elements of statistical significance (\u03B1), effect size (\u03B4), power (1\u2013\u03B2), and standard deviation of the measurements have been explained in numerous articles [>>13<<],[21]. Unfortunately, the assumptions on variation of the measurements are often based on incomplete data, and small errors can lead to a study that is either under- or overpowered." . _:b429699250 "2"^^ . _:b429698597 "17"^^ . _:b429699261 "2"^^ . _:b7410100 "of PublicationNumber of PublicationsRandomisation, n (%)Blinded Outcome Assessment, n (%)A Priori Sample Size Calculation, n (%)Heart failure [24] 200396 (67)9 (100)0 (0)Emergency medicine [33] 200329094 (32)31 (11)N/AIschemic stroke [>>19<<] 20054519 (42)18 (40)0 (0)Ischemic stroke [49] 20057317 (23)9 (12)N/AIschemic stroke [50] 2005258 (32)1 (4)N/AIschemic stroke [51] 2006272 (7)1 (4)N/ATraumatic brain injury [2] 2007172 (12)3 (18)N/AHemorrhage in surgery [2] 200783 (38)4" . _:b429698598 "17"^^ . . _:b429699260 "2"^^ . . _:b429698599 "16"^^ . _:b429698888 . _:b429698600 "15"^^ . _:b429699263 "2"^^ . . _:b429698607 "13"^^ . _:b429698601 "15"^^ . _:b429699262 "2"^^ . . _:b429698606 "13"^^ . _:b429698602 "15"^^ . _:b429699257 "2"^^ . _:b429698815 . _:b429698637 . _:b429698603 "15"^^ . _:b429699256 "2"^^ . _:b429699126 . _:b429699183 . _:b429698604 "14"^^ . _:b429699259 "2"^^ . _:b429698986 . _:b429698605 "14"^^ . _:b429699258 "2"^^ . _:b429699138 . _:b429699269 "2"^^ . . . _:b429699268 "2"^^ . _:b429698885 . . . . _:b429698615 "11"^^ . _:b429699271 "2"^^ . . . _:b429698614 "11"^^ . _:b429699270 "2"^^ . _:b429699484 . _:b429698613 "11"^^ . _:b429699265 "2"^^ . _:b429698720 . _:b429698612 "11"^^ . _:b429699264 "2"^^ . _:b429698611 "11"^^ . _:b429699267 "2"^^ . _:b429699266 "2"^^ . _:b429698610 "12"^^ . _:b429699277 "2"^^ . _:b429698609 "12"^^ . . _:b429699288 . _:b429699276 "2"^^ . _:b429698608 "12"^^ . _:b429699105 . _:b429698623 "10"^^ . . _:b429699279 "2"^^ . _:b429698803 . _:b429698622 "10"^^ . _:b429698802 . _:b429699278 "2"^^ . _:b429698621 "10"^^ . _:b429699273 "2"^^ . _:b429698620 "10"^^ . . _:b429699272 "2"^^ . . _:b429698619 "11"^^ . _:b429699275 "2"^^ . _:b429699115 . _:b429698916 . . _:b429698610 . _:b429698618 "11"^^ . _:b429699274 "2"^^ . . _:b429698617 "11"^^ . _:b429699285 "2"^^ . _:b429698660 . _:b429698616 "11"^^ . _:b429699284 "2"^^ . _:b429699287 "2"^^ . _:b429698630 "9"^^ . . _:b429699286 "2"^^ . _:b429698631 "8"^^ . _:b429699281 "2"^^ . _:b429698628 "9"^^ . . _:b429699280 "2"^^ . . . _:b429699346 . _:b429698629 "9"^^ . _:b429699283 "2"^^ . _:b429699490 . _:b429698626 "9"^^ . _:b429698852 . _:b429699282 "2"^^ . . _:b429698627 "9"^^ . _:b429699293 "2"^^ . _:b429699480 . _:b429698624 "10"^^ . _:b429699292 "2"^^ . _:b429698625 "9"^^ . . _:b429698638 "7"^^ . _:b429699295 "2"^^ . . _:b7410132 "between animal models and clinical trials similar to those mentioned above have been proposed as causes of the recurrent failure of a range of strategies to reduce lethal reperfusion injury in patients with acute myocardial infarction [>>6<<],[7]. The failure to acknowledge the presence of often severe comorbidities in patients, and short and clinically unattainable onset-to-treatment delays, have also limited the external validity of animal models of traumatic brain injury" . _:b429698917 . _:b429698639 "7"^^ . _:b429699294 "2"^^ . _:b429699289 "2"^^ . _:b429699394 . _:b429698636 "8"^^ . . . _:b429699288 "2"^^ . . _:b429698637 "8"^^ . _:b429698615 . _:b429698973 . . _:b429699291 "2"^^ . _:b429698634 "8"^^ . . _:b429699352 . _:b429699290 "2"^^ . _:b429698635 "8"^^ . . _:b429699118 . _:b429699301 "2"^^ . _:b429698632 "8"^^ . _:b429699468 . _:b429699000 . _:b429699300 "2"^^ . _:b429698633 "8"^^ . . _:b429698646 "7"^^ . _:b429699303 "2"^^ . _:b429699096 . _:b429698647 "7"^^ . _:b429699302 "2"^^ . . _:b429698644 "7"^^ . _:b429699297 "2"^^ . _:b429698895 . _:b429698645 "7"^^ . _:b429699296 "2"^^ . _:b7410102 "Priori Sample Size Calculation, n (%)Heart failure [24] 200396 (67)9 (100)0 (0)Emergency medicine [33] 200329094 (32)31 (11)N/AIschemic stroke [19] 20054519 (42)18 (40)0 (0)Ischemic stroke [49] 20057317 (23)9 (12)N/AIschemic stroke [>>50<<] 2005258 (32)1 (4)N/AIschemic stroke [51] 2006272 (7)1 (4)N/ATraumatic brain injury [2] 2007172 (12)3 (18)N/AHemorrhage in surgery [2] 200783 (38)4 (50)N/ANeonatal RDS [2] 20075614 (25)3 (5)N/AOsteoporosis [2] 2007165 (31)0 (0)N/AIschemic" . _:b429698893 . _:b429698642 "7"^^ . _:b429699299 "2"^^ . _:b429698704 . _:b429698643 "7"^^ . _:b429699298 "2"^^ . . . _:b429698640 "7"^^ . _:b429699309 "2"^^ . . _:b429698641 "7"^^ . _:b429699308 "2"^^ . _:b429699293 . _:b429698654 "6"^^ . . _:b429699311 "2"^^ . _:b429699028 . _:b429698655 "6"^^ . _:b429699310 "2"^^ . _:b429698652 "6"^^ . _:b429699305 "2"^^ . _:b429698653 "6"^^ . _:b429698653 . _:b429699304 "2"^^ . _:b429699254 . . _:b429698593 . _:b429698650 "6"^^ . _:b429699094 . _:b429699307 "2"^^ . . _:b429698651 "6"^^ . _:b429699306 "2"^^ . . _:b429698648 "7"^^ . _:b429699317 "2"^^ . _:b429698649 "7"^^ . _:b429699316 "2"^^ . . _:b429698662 "6"^^ . . _:b429699442 . _:b429699319 "2"^^ . _:b429698663 "6"^^ . _:b429698629 . _:b429698944 . _:b429699318 "2"^^ . . _:b429698660 "6"^^ . _:b429699313 "2"^^ . _:b429698661 "6"^^ . . _:b429699312 "2"^^ . _:b429698592 . _:b429698658 "6"^^ . _:b429699315 "2"^^ . _:b429698659 "6"^^ . . _:b429699314 "2"^^ . . _:b429698656 "6"^^ . _:b429699325 "2"^^ . . _:b429698657 "6"^^ . _:b429699324 "2"^^ . . . _:b429699327 "2"^^ . . _:b429698669 "5"^^ . . _:b429699326 "2"^^ . _:b429698668 "6"^^ . _:b429699321 "2"^^ . _:b429698671 "5"^^ . _:b429699263 . . _:b429699320 "2"^^ . _:b429698670 "5"^^ . _:b429698840 . _:b429698666 "6"^^ . . . _:b429699323 "2"^^ . . _:b429698667 "6"^^ . _:b429699322 "2"^^ . _:b429698664 "6"^^ . _:b429699048 . _:b429699333 "2"^^ . . _:b429698665 "6"^^ . _:b429699332 "2"^^ . . . _:b429699335 "2"^^ . _:b429698677 "5"^^ . _:b429698819 . _:b429698776 . _:b429699272 . _:b429699334 "2"^^ . . _:b429698676 "5"^^ . _:b429699329 "2"^^ . _:b429698591 . _:b429698679 "5"^^ . . _:b429699328 "2"^^ . . _:b429698678 "5"^^ . _:b429699171 . _:b429699331 "2"^^ . _:b429698673 "5"^^ . _:b429698827 . _:b429699330 "2"^^ . _:b429698774 . _:b429698672 "5"^^ . _:b429699341 "2"^^ . _:b429698675 "5"^^ . . _:b429699340 "2"^^ . _:b429698674 "5"^^ . _:b429699343 "2"^^ . _:b429698685 "5"^^ . _:b429699342 "2"^^ . . _:b429698684 "5"^^ . _:b429699340 . . _:b429699337 "2"^^ . _:b429699447 . _:b429698687 "5"^^ . . _:b429699336 "2"^^ . . _:b429698686 "5"^^ . _:b429699339 "2"^^ . . _:b429698681 "5"^^ . _:b429698925 . _:b429699338 "2"^^ . _:b429698680 "5"^^ . . _:b429699349 "2"^^ . _:b429698683 "5"^^ . . _:b429699348 "2"^^ . _:b429699450 . _:b429698682 "5"^^ . _:b429699042 . . _:b429699351 "2"^^ . _:b429699274 . _:b429698998 . _:b429698693 "5"^^ . _:b7410137 "Recommendations based on [>>13<<],[17]." . _:b429699350 "2"^^ . _:b429698692 "5"^^ . _:b429699345 "2"^^ . _:b429698695 "5"^^ . . _:b429699344 "2"^^ . . _:b429698694 "5"^^ . . _:b429699347 "2"^^ . _:b429698689 "5"^^ . _:b429699346 "2"^^ . _:b429698688 "5"^^ . _:b429698599 . . _:b429699357 "2"^^ . _:b429698691 "5"^^ . _:b429699356 "2"^^ . _:b429698690 "5"^^ . _:b429699089 . _:b429699359 "2"^^ . _:b429698701 "4"^^ . . _:b429699358 "2"^^ . _:b429698700 "5"^^ . . _:b429699353 "2"^^ . _:b429698703 "4"^^ . . _:b429699352 "2"^^ . _:b429698702 "4"^^ . _:b429698763 . _:b429699355 "2"^^ . . _:b429698697 "5"^^ . _:b429699354 "2"^^ . _:b429698696 "5"^^ . . _:b429699389 . _:b429699365 "2"^^ . _:b429698699 "5"^^ . _:b429699492 . _:b429699364 "2"^^ . _:b429698698 "5"^^ . _:b429699367 "2"^^ . _:b429698709 "4"^^ . _:b429699366 "2"^^ . _:b429698708 "4"^^ . _:b429699361 "2"^^ . _:b429698711 "4"^^ . . _:b429699360 "2"^^ . _:b429698710 "4"^^ . _:b429698778 . _:b429699363 "2"^^ . _:b429699337 . _:b429698705 "4"^^ . _:b429699362 "2"^^ . _:b429698704 "4"^^ . _:b429698639 . . _:b429699373 "2"^^ . _:b429698707 "4"^^ . . _:b429698806 . _:b429699372 "2"^^ . _:b429698706 "4"^^ . _:b429699375 "2"^^ . _:b429698717 "4"^^ . _:b429699208 . _:b429699374 "2"^^ . _:b429698716 "4"^^ . . _:b429699369 "2"^^ . _:b429698719 "4"^^ . _:b429699368 "2"^^ . _:b429698718 "4"^^ . _:b429699311 . _:b429699371 "2"^^ . _:b429698713 "4"^^ . _:b429699370 "2"^^ . _:b429698712 "4"^^ . . _:b429699434 . . _:b429699381 "2"^^ . _:b429698715 "4"^^ . . _:b429698703 . _:b429699380 "2"^^ . _:b429698714 "4"^^ . . . _:b429699383 "2"^^ . _:b429698725 "4"^^ . . _:b429699382 "2"^^ . _:b429698724 "4"^^ . _:b429699150 . _:b429698797 . _:b429699377 "2"^^ . _:b429698727 "4"^^ . . _:b429699376 "2"^^ . _:b429698726 "4"^^ . _:b429699239 . . . _:b429699379 "2"^^ . . _:b429698721 "4"^^ . . _:b429698617 . _:b429699378 "2"^^ . _:b429698720 "4"^^ . . _:b429699389 "2"^^ . _:b429698723 "4"^^ . _:b429698816 . . _:b429699388 "2"^^ . _:b429698722 "4"^^ . _:b429699276 . _:b429699154 . _:b429699391 "2"^^ . _:b429698733 "4"^^ . _:b429699390 "2"^^ . _:b429698732 "4"^^ . . _:b429699385 "2"^^ . _:b429698735 "4"^^ . _:b429699384 "2"^^ . _:b429698734 "4"^^ . . _:b429699387 "2"^^ . _:b429698729 "4"^^ . _:b7410103 "failure [24] 200396 (67)9 (100)0 (0)Emergency medicine [33] 200329094 (32)31 (11)N/AIschemic stroke [19] 20054519 (42)18 (40)0 (0)Ischemic stroke [49] 20057317 (23)9 (12)N/AIschemic stroke [50] 2005258 (32)1 (4)N/AIschemic stroke [>>51<<] 2006272 (7)1 (4)N/ATraumatic brain injury [2] 2007172 (12)3 (18)N/AHemorrhage in surgery [2] 200783 (38)4 (50)N/ANeonatal RDS [2] 20075614 (25)3 (5)N/AOsteoporosis [2] 2007165 (31)0 (0)N/AIschemic stroke [16] a 2007288103 (36)84 (29)8" . _:b429699386 "2"^^ . _:b429698728 "4"^^ . _:b7410088 "in some articles of animal studies \u201Cdouble blinding\u201D is reported raises questions about the authors' knowledge of blinding as well as about the review and editorial processes of the journals in which the studies were published [19],[>>20<<]." . _:b429699397 "2"^^ . _:b429698731 "4"^^ . . _:b429699396 "2"^^ . _:b429698730 "4"^^ . _:b429699058 . . _:b429699399 "2"^^ . _:b429698741 "4"^^ . _:b429698847 . _:b429699398 "2"^^ . _:b429698740 "4"^^ . . _:b429698782 . _:b429699393 "2"^^ . _:b429698743 "4"^^ . _:b7410105 "brain injury [2] 2007172 (12)3 (18)N/AHemorrhage in surgery [2] 200783 (38)4 (50)N/ANeonatal RDS [2] 20075614 (25)3 (5)N/AOsteoporosis [2] 2007165 (31)0 (0)N/AIschemic stroke [16] a 2007288103 (36)84 (29)8 (3)Parkinson's disease [>>16<<] 200711814 (12)18 (15)0 (0)Multiple sclerosis [16] 20071834 (2)20 (11)0 (0)ALS [45] 20078521 (25)21 (25)1 (1)Brain injury [52] 20081812 (67)7 (39)N/AIschemic stroke [25] 200893 (33)4 (44)2 (22)Ischemic stroke [53] 2009191 (5)5 (26)0" . _:b429699392 "2"^^ . _:b429698742 "4"^^ . . . _:b429699395 "2"^^ . _:b7410099 . _:b429698737 "4"^^ . _:b7410117 . . _:b429698913 . _:b429698635 . _:b429699394 "2"^^ . _:b429698736 "4"^^ . . _:b429699405 "2"^^ . _:b429698739 "4"^^ . _:b429698911 . _:b429699404 "2"^^ . _:b429698738 "4"^^ . _:b429699407 "2"^^ . _:b429698749 "4"^^ . _:b429699406 "2"^^ . _:b429698748 "4"^^ . _:b429699401 "2"^^ . _:b429698751 "4"^^ . . _:b429699400 "2"^^ . _:b429698750 "4"^^ . _:b429698992 . _:b429698948 . . _:b429699403 "2"^^ . _:b429698745 "4"^^ . . _:b429699402 "2"^^ . _:b429698744 "4"^^ . . _:b429699413 "2"^^ . _:b429698747 "4"^^ . . _:b429699412 "2"^^ . _:b429698746 "4"^^ . . _:b429699415 "2"^^ . _:b429698757 "4"^^ . _:b429698952 . _:b429699414 "2"^^ . _:b429698756 "4"^^ . _:b429699297 . _:b429698759 "3"^^ . _:b429699409 "2"^^ . _:b429698801 . _:b429699464 . . _:b429698758 "3"^^ . _:b429699408 "2"^^ . _:b429698739 . _:b429699411 "2"^^ . _:b429698753 "4"^^ . . _:b429699410 "2"^^ . _:b429698752 "4"^^ . . _:b429699421 "2"^^ . _:b429698755 "4"^^ . . . _:b429699003 . _:b429699336 . _:b429699420 "2"^^ . _:b429698754 "4"^^ . . _:b429698765 "3"^^ . _:b7410119 . _:b429699423 "2"^^ . _:b429699131 . _:b429698764 "3"^^ . _:b429699422 "2"^^ . . . _:b429698767 "3"^^ . _:b7410093 "The presence of bias in animal studies has been tested most extensively in studies of acute ischemic stroke, probably because in this field the gap between the laboratory and the clinic is both very large and well recognised [>>8<<]. In systematic reviews of different interventions tested in animal models of acute ischemic stroke, other emergencies, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis, generally about a third or less of the" . _:b429699417 "2"^^ . _:b429698766 "3"^^ . _:b429699416 "2"^^ . . . _:b429698761 "3"^^ . _:b429699419 "2"^^ . . _:b429698761 . _:b429699418 "2"^^ . _:b429698760 "3"^^ . _:b429699007 . _:b7410144 "Sena 2010 [>>47<<]: The first study to estimate the impact of publication bias on the efficacy reported in systematic reviews of animal studies." . _:b429698763 "3"^^ . _:b7410117 "trials in which authors did not report randomisation, adequately conceal treatment allocation, or use double blinding yielded larger estimates of treatment effects than trials in which these study quality issues were reported [12],[>>27<<]\u2013[32]." . _:b429699429 "2"^^ . . _:b429698753 . _:b429698762 "3"^^ . _:b7410109 "stroke [16] a 2007288103 (36)84 (29)8 (3)Parkinson's disease [16] 200711814 (12)18 (15)0 (0)Multiple sclerosis [16] 20071834 (2)20 (11)0 (0)ALS [45] 20078521 (25)21 (25)1 (1)Brain injury [52] 20081812 (67)7 (39)N/AIschemic stroke [>>25<<] 200893 (33)4 (44)2 (22)Ischemic stroke [53] 2009191 (5)5 (26)0" . _:b429699428 "2"^^ . _:b429699231 . . _:b429698773 "3"^^ . _:b429699431 "2"^^ . . . _:b429698772 "3"^^ . _:b429699430 "2"^^ . . . _:b429698775 "3"^^ . _:b429699425 "2"^^ . _:b429699309 . . _:b429698774 "3"^^ . _:b429699424 "2"^^ . _:b429699428 . _:b429698810 . . . _:b429699427 "2"^^ . _:b429698769 "3"^^ . . _:b429699198 . . _:b429698873 . . _:b429698768 "3"^^ . _:b429699426 "2"^^ . . _:b429698771 "3"^^ . _:b429699437 "2"^^ . _:b429698793 . . _:b429698770 "3"^^ . _:b429699436 "2"^^ . _:b429699169 . _:b429698781 "3"^^ . _:b429699439 "2"^^ . _:b429699284 . _:b429698646 . _:b429698780 "3"^^ . _:b429699438 "2"^^ . _:b429698728 . _:b429698865 . _:b429698923 . _:b429698783 "3"^^ . _:b429699433 "2"^^ . _:b429699421 . _:b429698782 "3"^^ . _:b429699432 "2"^^ . _:b429698777 "3"^^ . _:b429699435 "2"^^ . _:b429698776 "3"^^ . _:b429699434 "2"^^ . _:b429699360 . _:b429698779 "3"^^ . _:b429699445 "2"^^ . _:b7410097 "lateral sclerosis, generally about a third or less of the studies reported random allocation to the treatment group, and even fewer studies reported concealment of treatment allocation or blinded outcome assessment [2],[16],[19],[24],[>>25<<]. Even when reported, the methods used for randomisation and blinding were rarely given." . . _:b429698778 "3"^^ . _:b429699444 "2"^^ . _:b429698789 "3"^^ . _:b429699447 "2"^^ . . _:b429698612 . _:b429699343 . _:b429698788 "3"^^ . _:b429699446 "2"^^ . _:b429699110 . _:b429698791 "3"^^ . _:b429699441 "2"^^ . _:b429698790 "3"^^ . _:b429699440 "2"^^ . . _:b429698785 "3"^^ . _:b429699443 "2"^^ . . . _:b429698784 "3"^^ . _:b429699442 "2"^^ . _:b429698787 "3"^^ . _:b429699453 "2"^^ . . _:b429698786 "3"^^ . _:b429699452 "2"^^ . _:b429699439 . _:b429698841 . _:b429699199 . _:b429698797 "3"^^ . _:b429699455 "2"^^ . _:b429699044 . _:b429698796 "3"^^ . _:b429699454 "2"^^ . _:b429698799 "3"^^ . _:b429699449 "2"^^ . _:b429699278 . . _:b429698798 "3"^^ . _:b429699448 "2"^^ . _:b429698793 "3"^^ . _:b429699451 "2"^^ . . . _:b429699450 "2"^^ . _:b429698792 "3"^^ . _:b429698795 "3"^^ . _:b429699461 "2"^^ . _:b429699216 . _:b429698794 "3"^^ . _:b429699460 "2"^^ . _:b429698805 "3"^^ . _:b429699463 "2"^^ . _:b429698804 "3"^^ . _:b429699462 "2"^^ . _:b429699079 . . _:b429699457 "2"^^ . _:b429698807 "3"^^ . . _:b429698806 "3"^^ . _:b429699456 "2"^^ . _:b429699144 . _:b429698625 . _:b429699068 . _:b429698801 "3"^^ . _:b429699459 "2"^^ . . _:b429698800 "3"^^ . _:b429699458 "2"^^ . . _:b429698803 "3"^^ . _:b429699469 "2"^^ . . . _:b429699468 "2"^^ . _:b429698802 "3"^^ . . _:b429698813 "3"^^ . _:b429699471 "2"^^ . _:b429698812 "3"^^ . _:b429699470 "2"^^ . _:b429699084 . _:b429699123 . _:b429698815 "3"^^ . _:b429699465 "2"^^ . _:b429698771 . _:b429699149 . _:b429698814 "3"^^ . _:b429699464 "2"^^ . _:b429699395 . . _:b429698809 "3"^^ . _:b429699467 "2"^^ . . . . _:b429698808 "3"^^ . _:b429699466 "2"^^ . . . _:b429698811 "3"^^ . _:b429699477 "2"^^ . _:b429699313 . . _:b429698810 "3"^^ . _:b429699476 "2"^^ . . . . _:b429699122 . _:b429698821 "3"^^ . _:b429699479 "2"^^ . _:b429698643 . . _:b429698820 "3"^^ . _:b429699478 "2"^^ . _:b429698894 . . _:b429699473 "2"^^ . _:b429698823 "3"^^ . _:b429698822 "3"^^ . _:b7410087 "that in some articles of animal studies \u201Cdouble blinding\u201D is reported raises questions about the authors' knowledge of blinding as well as about the review and editorial processes of the journals in which the studies were published [>>19<<],[20]." . _:b429699472 "2"^^ . _:b429699251 . _:b429698817 "3"^^ . _:b429699475 "2"^^ . _:b429699165 . . _:b429698926 . _:b429698816 "3"^^ . _:b429699474 "2"^^ . _:b429699092 . . _:b429699093 . _:b429699094 . _:b429699095 . _:b429699485 "2"^^ . _:b429699329 . _:b429698819 "3"^^ . . _:b429699088 . _:b429699089 . _:b429699090 . _:b429699091 . _:b429699484 "2"^^ . _:b429698818 "3"^^ . _:b429699100 . _:b429699101 . _:b429699102 . _:b429699103 . _:b429699487 "2"^^ . _:b429698829 "3"^^ . _:b429699096 . . _:b429699097 . . _:b429699098 . _:b429699099 . _:b7410074 . _:b429699486 "2"^^ . _:b429699016 . _:b429698828 "3"^^ . _:b429699076 . _:b429699077 . _:b429699078 . _:b429699079 . _:b429699481 "2"^^ . . _:b429698831 "3"^^ . _:b429699072 . _:b429699314 . _:b429699073 . _:b429699074 . _:b429699075 . _:b429699480 "2"^^ . _:b429698830 "3"^^ . _:b429699084 . _:b429699085 . _:b429699086 . _:b429699060 . . _:b429699087 . _:b429699483 "2"^^ . _:b429698825 "3"^^ . _:b429699080 . _:b429699081 . _:b429699082 . . _:b429698746 . _:b429699083 . _:b429699482 "2"^^ . _:b429698824 "3"^^ . _:b429699124 . _:b429699125 . _:b429699161 . _:b429699126 . _:b429699127 . _:b429698827 "3"^^ . _:b429699120 . _:b429699121 . _:b7410139 . _:b429699122 . _:b429699087 . _:b429699055 . _:b429698978 . _:b429699123 . _:b429699492 "2"^^ . _:b429698826 "3"^^ . _:b429699132 . . . _:b429699133 . . _:b429699134 . _:b429699135 . _:b429698837 "3"^^ . _:b429699128 . _:b429699129 . _:b429699130 . _:b429699131 . _:b7410095 "lateral sclerosis, generally about a third or less of the studies reported random allocation to the treatment group, and even fewer studies reported concealment of treatment allocation or blinded outcome assessment [2],[16],[>>19<<],[24],[25]. Even when reported, the methods used for randomisation and blinding were rarely given." . _:b429698836 "3"^^ . _:b429699108 . _:b429699109 . _:b429699110 . _:b429699111 . _:b429699489 "2"^^ . _:b429698839 "3"^^ . _:b429699104 . . _:b429699105 . _:b429699106 . _:b429699107 . _:b429699488 "2"^^ . _:b429698838 "3"^^ . _:b429699116 . _:b429699117 . _:b429699118 . _:b429699119 . _:b429699491 "2"^^ . _:b429698833 "3"^^ . _:b429698807 . _:b429699112 . _:b429699113 . _:b429699114 . _:b429699115 . _:b429699490 "2"^^ . _:b429698832 "3"^^ . _:b429699156 . _:b429699157 . _:b429698855 . _:b429699158 . . _:b429699159 . _:b429699064 . _:b429698835 "3"^^ . _:b429699152 . _:b7410075 . _:b429699153 . _:b429699154 . _:b429699155 . _:b429698834 "3"^^ . _:b429699164 . _:b429699165 . _:b429699166 . . _:b429699167 . . _:b429698845 "3"^^ . _:b429699160 . _:b429699185 . _:b429699161 . _:b429699162 . _:b429699163 . _:b429698844 "3"^^ . _:b429699140 . . . _:b429699141 . _:b429699142 . . _:b429699143 . . _:b429698847 "3"^^ . . _:b429699136 . _:b429699137 . _:b429699138 . . _:b429699139 . _:b429698846 "3"^^ . _:b429699148 . _:b429699149 . _:b7410116 "For example, in the most frequently used CAMARADES checklist, \u201Cadequate allocation concealment\u201D may have a much larger impact on effect size than \u201Ccompliance with regulatory requirements\u201D [>>16<<]." . _:b429699150 . _:b429699151 . _:b429698841 "3"^^ . _:b429699144 . _:b429699145 . _:b429699146 . _:b429699147 . . _:b429698840 "3"^^ . _:b429699188 . _:b429699189 . _:b429698997 . _:b429699190 . _:b429699018 . . . _:b429699191 . _:b429698843 "3"^^ . . _:b429699184 . _:b429699185 . _:b429699186 . _:b429699006 . _:b429699187 . _:b429698842 "3"^^ . _:b429699196 . . . _:b429699197 . _:b429699198 . _:b429698634 . _:b429699199 . _:b429698959 . _:b429698853 "3"^^ . . _:b429699192 . _:b429699193 . _:b429699194 . . _:b429699195 . _:b429698852 "3"^^ . _:b429699172 . _:b429699173 . _:b429699174 . _:b429699175 . _:b429698855 "3"^^ . _:b429699168 . _:b429699169 . _:b429699170 . _:b429699171 . _:b429698854 "3"^^ . _:b429699180 . _:b429699181 . _:b429699482 . _:b429699419 . _:b429699182 . . _:b429699183 . . _:b429698849 "3"^^ . _:b429699176 . _:b429699177 . _:b429699178 . _:b429699179 . _:b429698848 "3"^^ . . _:b429699220 . _:b429699221 . _:b429699222 . _:b429699223 . _:b429698851 "3"^^ . _:b429699216 . _:b429699217 . _:b7410072 "Such publication bias will lead to overestimation of treatment effects and can make the readily available evidence unreliable for decision making [>>41<<]." . _:b429699218 . _:b429699487 . _:b429698738 . _:b429699219 . _:b429698850 "3"^^ . _:b429699228 . _:b429699462 . _:b429699229 . . _:b429699230 . . _:b429699231 . _:b429698861 "3"^^ . _:b429699224 . _:b429699225 . _:b429699226 . _:b429698824 . _:b429699227 . _:b7410070 . _:b429698860 "3"^^ . _:b429699204 . _:b429699205 . _:b429699212 . _:b429699206 . _:b7410071 . _:b429699207 . . _:b429698863 "3"^^ . _:b429699200 . _:b429699201 . _:b429698769 . _:b429699202 . _:b429699203 . _:b429698862 "3"^^ . _:b429699212 . _:b429699213 . _:b429699214 . _:b429699215 . . _:b429698857 "3"^^ . _:b429699208 . _:b429699209 . . _:b429698969 . _:b429699210 . _:b429699211 . _:b429698856 "3"^^ . _:b429699252 . _:b429699253 . _:b429699254 . _:b7410076 "No study gave quantitative estimates of the impact on effect size of publication bias [>>47<<]." . _:b429699255 . _:b429698859 "3"^^ . _:b429699248 . _:b429699249 . _:b429698903 . _:b429699250 . _:b7410076 . _:b429699251 . _:b429698858 "3"^^ . _:b429699260 . _:b429699261 . . _:b429699262 . _:b7410077 . _:b429699263 . _:b429698869 "3"^^ . _:b429699256 . _:b429699232 . _:b429699257 . . _:b429699258 . _:b7410078 . _:b429699259 . . _:b429698868 "3"^^ . _:b429699236 . _:b429699237 . _:b429699238 . _:b429699239 . _:b7410079 . _:b429698871 "3"^^ . _:b429699232 . _:b429699233 . _:b429699234 . _:b7410072 . _:b429699235 . _:b429698870 "3"^^ . _:b429699244 . _:b429699245 . _:b429698650 . _:b429699246 . _:b7410073 . _:b429698821 . _:b429699247 . _:b429698930 . _:b429698865 "3"^^ . _:b429699240 . _:b429699354 . _:b429699205 . . _:b429699241 . _:b429699242 . _:b7410074 . _:b429699167 . _:b429698820 . _:b429699243 . _:b429698864 "3"^^ . _:b429699284 . _:b429699285 . _:b429699286 . _:b7410075 . _:b429698823 . _:b429699287 . _:b429698867 "3"^^ . _:b429699280 . _:b429698849 . _:b429699281 . _:b429699010 . _:b429699282 . _:b7410084 . _:b429699285 . _:b429698822 . _:b429699283 . _:b429698866 "3"^^ . _:b429699292 . _:b429699293 . . _:b429699294 . _:b7410085 . _:b429698817 . _:b429699295 . _:b429698877 "3"^^ . _:b429699288 . _:b429698768 . _:b429699289 . _:b429699111 . . _:b7410086 . _:b429698816 . _:b429699290 . _:b429699291 . _:b429698876 "3"^^ . _:b429699268 . . _:b429699269 . _:b429699270 . _:b7410087 . _:b429698819 . _:b429699271 . _:b429698879 "3"^^ . _:b429699264 . _:b429699265 . _:b429698602 . _:b429699266 . _:b7410080 . _:b429698818 . _:b429699267 . _:b429698878 "3"^^ . _:b429699276 . _:b429699277 . _:b429699278 . _:b429698829 . _:b7410081 . _:b429698873 "3"^^ . _:b429699279 . _:b429699272 . _:b429699273 . _:b429699274 . _:b7410082 . _:b429698828 . _:b429699275 . _:b429698872 "3"^^ . _:b429699316 . . _:b429699317 . _:b429699318 . _:b7410142 "Dirksen 2007 [>>6<<]: Provides an overview of the various strategies that inhibit reperfusion injury after myocardial infarction and discusses potential mechanisms that may have contributed to the discrepancy between promising pre-clinical data and the" . _:b7410083 . _:b429698831 . _:b429699319 . _:b429698875 "3"^^ . _:b429699312 . . _:b429699313 . _:b429699314 . _:b7410092 . _:b429698830 . _:b429699315 . _:b429698881 . _:b429698874 "3"^^ . _:b429699324 . _:b429699325 . _:b429699326 . _:b7410093 . _:b429698825 . _:b429699327 . _:b429698885 "3"^^ . _:b429699320 . _:b429699211 . _:b429699321 . . _:b429699322 . _:b7410094 . _:b7410071 "Systematic review and meta-analysis are techniques developed for the analysis of data from clinical trials and may be helpful in the selection of the most promising strategies [>>16<<]. However, if studies are published selectively on the basis of their results, even a meta-analysis based on a rigorous systematic review will be misleading." . _:b429699143 . _:b429698824 . _:b429699323 . _:b429699488 . _:b429698799 . _:b429698884 "3"^^ . _:b429699300 . _:b429698719 . _:b429699301 . . _:b429699302 . _:b7410095 . _:b429698827 . _:b429699303 . . . _:b429698887 "3"^^ . _:b429699296 . . _:b429698672 . _:b429699297 . _:b429699298 . _:b7410088 . _:b429698712 . _:b429698826 . _:b429699299 . _:b429698886 "3"^^ . _:b429699308 . _:b429699309 . _:b429699310 . _:b7410089 . _:b429698837 . _:b429699311 . _:b429698881 "3"^^ . _:b429699304 . _:b429699305 . _:b429699306 . _:b7410090 . _:b429698836 . _:b429699307 . _:b429698880 "3"^^ . _:b429699348 . _:b429699349 . _:b429699253 . _:b429699350 . _:b7410091 . _:b429698839 . _:b429699351 . _:b429698883 "3"^^ . _:b429699344 . _:b429699052 . _:b429699345 . _:b429699346 . _:b7410100 . _:b429698838 . _:b429699347 . _:b429698882 "3"^^ . _:b429699356 . _:b429699357 . _:b429699358 . _:b7410101 . _:b429698833 . _:b429699359 . _:b429698893 "3"^^ . _:b429699352 . _:b429699353 . _:b429699354 . _:b7410102 . _:b429698832 . . _:b429699355 . _:b429698892 "3"^^ . _:b429699332 . _:b429698999 . _:b429699333 . _:b429699334 . _:b7410103 . _:b429698835 . _:b429698665 . _:b429699335 . _:b429698895 "3"^^ . _:b429699328 . _:b429699329 . . . _:b7410096 . _:b429698834 . _:b429699330 . _:b429699331 . _:b429698894 "3"^^ . _:b429699340 . _:b429699341 . . _:b429699342 . _:b7410097 . _:b429698845 . . _:b429699343 . _:b429698889 "3"^^ . _:b429699336 . _:b429699337 . _:b429699338 . _:b7410098 . _:b429698844 . _:b429699339 . _:b7410118 "in which authors did not report randomisation, adequately conceal treatment allocation, or use double blinding yielded larger estimates of treatment effects than trials in which these study quality issues were reported [12],[27]\u2013[>>32<<]." . _:b429699252 . _:b429698888 "3"^^ . _:b429699380 . _:b429699381 . _:b429699382 . _:b7410099 . _:b429698847 . _:b429699383 . . _:b429698891 "3"^^ . _:b429699376 . _:b429699377 . _:b429699378 . _:b7410108 . _:b429698846 . _:b429699379 . _:b429698890 "3"^^ . _:b429699388 . _:b429699295 . . _:b429699389 . . _:b429699390 . _:b7410109 . _:b429698841 . _:b429698901 "2"^^ . _:b429699391 . _:b429699384 . _:b429699385 . _:b429698919 . _:b429699386 . _:b7410110 . . _:b429698840 . _:b429698900 "2"^^ . _:b429699387 . _:b429699364 . . _:b429699334 . _:b429699365 . _:b429699366 . _:b7410111 . _:b429698843 . _:b429698903 "2"^^ . _:b429699367 . . _:b429699360 . _:b429699361 . _:b429699362 . _:b7410104 . _:b429698842 . _:b429698902 "2"^^ . _:b429699363 . _:b429699372 . _:b429699373 . _:b429699423 . . _:b429699374 . _:b7410105 . _:b429698853 . _:b429699375 . _:b429698897 "3"^^ . _:b429699368 . _:b429699369 . _:b429699370 . _:b7410106 . _:b429699038 . _:b429698852 . _:b429699371 . _:b429698896 "3"^^ . _:b429699412 . _:b429699413 . _:b429699414 . _:b7410107 . _:b429698855 . _:b429698899 "2"^^ . _:b429699415 . _:b429699408 . . _:b429699409 . _:b429699237 . _:b429699071 . _:b429699410 . _:b7410116 . _:b429698854 . _:b429698898 "2"^^ . _:b429699411 . _:b429699420 . _:b429699421 . . _:b429698676 . _:b429699422 . _:b7410117 . _:b429698849 . _:b429698909 "2"^^ . _:b429699423 . _:b7410090 . _:b429699416 . _:b429699307 . _:b429699417 . _:b429699407 . . _:b429699418 . _:b7410118 . _:b429698848 . _:b429698908 "2"^^ . _:b429699419 . _:b429699396 . _:b429699151 . _:b429699397 . _:b429699398 . _:b7410119 . _:b429698851 . _:b429698911 "2"^^ . _:b429699399 . _:b429699392 . _:b429699393 . _:b429699394 . _:b7410112 . _:b429699098 . _:b429698850 . _:b429698910 "2"^^ . _:b429699395 . _:b429698962 . _:b429699404 . . _:b429699405 . _:b429699406 . _:b7410113 . _:b429698861 . _:b429698905 "2"^^ . _:b429699407 . _:b429699400 . _:b429699401 . _:b429699402 . _:b7410114 . _:b429699037 . _:b429698860 . . _:b429698904 "2"^^ . _:b429699403 . _:b429699444 . _:b7410125 "Of patients with acute stroke, up to 75% and 68% have hypertension and hyperglycaemia, respectively [9],[>>36<<]. While it is important to know whether candidate stroke drugs retain efficacy in the face of these comorbidities, only about 10% of focal ischaemia studies have used animals with hypertension, and fewer than 1% have used animals with" . _:b429699445 . _:b429698956 . _:b429699446 . _:b7410115 . _:b429698863 . _:b429698907 "2"^^ . _:b429699447 . _:b429699440 . _:b429699441 . . _:b429699442 . _:b7410124 . _:b429698862 . _:b429698906 "2"^^ . _:b429699443 . _:b429699452 . _:b429699453 . _:b429699473 . _:b429699454 . _:b7410125 . _:b7410102 . _:b429698857 . _:b429698917 "2"^^ . _:b429699455 . _:b429699057 . _:b429698922 . _:b429699448 . _:b429698811 . _:b429699261 . _:b429699449 . _:b429699450 . _:b7410126 . _:b429698856 . _:b429698916 "2"^^ . _:b429699451 . _:b429699428 . _:b429698688 . . _:b429699429 . _:b429699430 . _:b7410127 . _:b429698859 . _:b429698919 "2"^^ . _:b429699431 . _:b429699424 . _:b429699425 . . _:b7410120 . _:b429698858 . _:b429698918 "2"^^ . _:b429699426 . _:b429699427 . _:b429699436 . _:b429699472 . _:b429699437 . _:b429699438 . _:b7410121 . _:b429699342 . _:b429698869 . _:b429698913 "2"^^ . _:b429699439 . _:b429699432 . _:b429699433 . _:b429699434 . _:b7410122 . _:b429698868 . _:b429698912 "2"^^ . _:b429699435 . _:b429699476 . _:b429699477 . . _:b429699478 . _:b429698871 . _:b429698915 "2"^^ . _:b7410123 . _:b429698673 . _:b429699479 . _:b429699472 . . _:b429699473 . . _:b429699474 . _:b7410132 . _:b429698870 . _:b429698914 "2"^^ . _:b429699475 . . _:b429699484 . _:b429699485 . _:b429699059 . _:b429699486 . _:b7410133 . _:b429698865 . _:b429698925 "2"^^ . _:b429699487 . . _:b429699480 . _:b429699481 . _:b429699363 . _:b429699482 . _:b7410134 . _:b429698864 . _:b429698924 "2"^^ . _:b429699483 . _:b429699460 . _:b429699461 . _:b429699462 . _:b7410135 . _:b429698867 . _:b429698927 "2"^^ . _:b429699463 . _:b429699456 . _:b429699457 . _:b429699458 . _:b7410133 "animal models and clinical trials similar to those mentioned above have been proposed as causes of the recurrent failure of a range of strategies to reduce lethal reperfusion injury in patients with acute myocardial infarction [6],[>>7<<]. The failure to acknowledge the presence of often severe comorbidities in patients, and short and clinically unattainable onset-to-treatment delays, have also limited the external validity of animal models of traumatic brain injury [2]." . _:b7410128 . _:b429698866 . _:b429698926 "2"^^ . _:b429699459 . _:b429699468 . _:b429699469 . _:b429699470 . _:b7410129 . _:b429698877 . _:b429698921 "2"^^ . _:b429699471 . _:b429699464 . _:b7410126 "Over 95% of the studies were performed in rats and mice, and animals that are perhaps biologically closer to humans are hardly ever used [>>16<<],[19]. Moreover, most animal studies have failed to acknowledge the inevitable delay between the onset of symptoms and the possibility to start treatment in patients. In a systematic review of animal studies of five different" . _:b429699465 . . _:b429699466 . _:b7410130 . _:b429698876 . _:b429698920 "2"^^ . _:b429699467 . _:b429698621 . _:b429699226 . . _:b429698923 "2"^^ . _:b7410131 . _:b429698879 . _:b7410134 . _:b429698922 "2"^^ . _:b7410140 . _:b7410121 "In systematic reviews of FK-506 or hypothermia for acute ischemic stroke, an inverse relation was found between effect size and study quality, as assessed by a ten-item study-quality checklist [20],[>>34<<]. The same review on hypothermia found large overstatements of the reduction in infarct volume in animal stroke studies without randomisation or blinded outcome assessment when they were compared with randomised or blinded studies, but a" . _:b429698878 . _:b429699120 . _:b7410124 . _:b429698873 . _:b7410141 . _:b429698933 "2"^^ . _:b429698872 . _:b7410142 . _:b429698932 "2"^^ . _:b429699492 . _:b429699436 . . _:b7410143 . _:b429698935 "2"^^ . _:b429698875 . . _:b429698880 . _:b429699488 . _:b429699489 . _:b429699490 . _:b429698934 "2"^^ . _:b429698874 . _:b7410136 . _:b429699491 . _:b429699022 . _:b429698929 "2"^^ . _:b7410137 . _:b429698885 . . . _:b429698928 "2"^^ . _:b7410138 . _:b429698884 . _:b429698587 . _:b429698915 . _:b429698887 . _:b7410139 . _:b429698931 "2"^^ . _:b429698886 . _:b429698930 "2"^^ . . _:b429698881 . _:b429698981 . _:b429698941 "2"^^ . _:b429698880 . _:b429698940 "2"^^ . _:b429698883 . _:b429698943 "2"^^ . _:b429698882 . _:b7410144 . _:b429698942 "2"^^ . _:b429698893 . _:b429698937 "2"^^ . . _:b429698892 . _:b429698936 "2"^^ . . . _:b429699481 . _:b429698939 "2"^^ . _:b429698895 . _:b429698603 . . . _:b429698894 . _:b429699364 . _:b429698938 "2"^^ . _:b429699385 . _:b429698889 . _:b429698949 "2"^^ . _:b429698888 . _:b429698948 "2"^^ . _:b429699112 . _:b429698671 . _:b429698891 . _:b429698951 "2"^^ . _:b429698890 . _:b429698950 "2"^^ . _:b429698748 . _:b429698921 . _:b429698901 . _:b429698945 "2"^^ . . _:b429698900 . _:b429698944 "2"^^ . _:b429698903 . _:b429698947 "2"^^ . _:b429698679 . _:b429698902 . _:b429698946 "2"^^ . _:b429698897 . _:b7410110 "disease [16] 200711814 (12)18 (15)0 (0)Multiple sclerosis [16] 20071834 (2)20 (11)0 (0)ALS [45] 20078521 (25)21 (25)1 (1)Brain injury [52] 20081812 (67)7 (39)N/AIschemic stroke [25] 200893 (33)4 (44)2 (22)Ischemic stroke [>>53<<] 2009191 (5)5 (26)0" . _:b429698957 "2"^^ . . . _:b429698896 . _:b429698956 "2"^^ . . _:b7410090 "The statistical analysis of the results of animal experiments has been given elaborate attention in review articles and books [>>22<<]. However, even when data appear simple and their analysis straightforward, inadequate techniques are often used." . _:b429698959 "2"^^ . _:b429698899 . _:b429698898 . _:b429699426 . _:b429698958 "2"^^ . . . _:b429698953 "2"^^ . _:b429698909 . _:b429698908 . _:b429698952 "2"^^ . . _:b429698784 . . _:b429698955 "2"^^ . _:b429698619 . _:b429698911 . . _:b429698910 . _:b429699435 . _:b429698954 "2"^^ . _:b7410124 "Of patients with acute stroke, up to 75% and 68% have hypertension and hyperglycaemia, respectively [>>9<<],[36]. While it is important to know whether candidate stroke drugs retain efficacy in the face of these comorbidities, only about 10% of focal ischaemia studies have used animals with hypertension, and fewer than 1% have used animals with" . _:b429698905 . _:b429698965 "2"^^ . . _:b429698904 . _:b429698964 "2"^^ . . _:b429699189 . _:b429698967 "2"^^ . _:b429698907 . . _:b429698906 . _:b7410103 . _:b429698966 "2"^^ . _:b429698808 . _:b429698716 . . . _:b429698917 . _:b429698961 "2"^^ . _:b429698853 . . _:b429698916 . _:b429698960 "2"^^ . _:b7410118 . _:b429699225 . _:b429698919 . _:b429698963 "2"^^ . _:b429698918 . _:b429699393 . _:b429698962 "2"^^ . _:b429698913 . _:b429698973 "2"^^ . _:b429698967 . . _:b429698912 . _:b429698972 "2"^^ . _:b429699400 . _:b429698915 . _:b429698975 "2"^^ . . _:b429699063 . _:b429698914 . _:b429699061 . _:b429698974 "2"^^ . _:b429698955 . _:b429698872 . _:b429699279 . _:b429698969 "2"^^ . _:b429698925 . . _:b429698698 . _:b429699177 . _:b429698924 . _:b429698968 "2"^^ . _:b429698927 . _:b429698971 "2"^^ . . _:b429699380 . _:b429698926 . _:b429698970 "2"^^ . _:b429699158 . _:b429698921 . _:b429698981 "2"^^ . _:b429698858 . _:b429698920 . _:b429698980 "2"^^ . _:b429699247 . _:b429698624 . _:b429698923 . _:b429698983 "2"^^ . . _:b429698982 "2"^^ . _:b429698922 . _:b429698933 . _:b429698977 "2"^^ . _:b429699062 . _:b7410134 "of time in the context of this slowly progressive disease, putative neuroprotective agents were administered before or at the same time as an acute Parkinson's disease-like lesion was induced in the typical underlying animal studies [>>39<<]." . . _:b429699035 . _:b429698976 "2"^^ . _:b429698932 . _:b429698689 . _:b429698979 "2"^^ . _:b429698935 . . _:b429698604 . . _:b429698900 . . _:b429699355 . _:b429698978 "2"^^ . _:b429698934 . _:b7410101 . . _:b429698929 . _:b429698989 "2"^^ . _:b429698928 . _:b429698988 "2"^^ . _:b429698931 . _:b429698991 "2"^^ . _:b429699091 . . _:b429699166 . _:b429698990 "2"^^ . _:b429698930 . . _:b429698941 . _:b429699218 . _:b429698985 "2"^^ . _:b429699196 . _:b429698940 . _:b429698984 "2"^^ . _:b7410128 "trials including a total of more than 12,000 patients with acute ischaemic stroke, the median time between the onset of ischaemia and start of treatment in the animal studies was just 10 minutes, which is infeasible in the clinic [>>19<<]. In the large majority of clinical trials, functional outcome is the primary measure of efficacy, whereas animal studies usually rely on infarct volume." . _:b429698943 . _:b429698987 "2"^^ . . _:b429698942 . _:b429698986 "2"^^ . _:b429699306 . _:b7410135 "Consistent with this hypothesis, several of the compounds reported as efficacious in SOD1G93A mice are broad-spectrum antibiotics and general anti-inflammatory agents [>>40<<]." . _:b429698937 . _:b429698997 "2"^^ . . . . _:b429698936 . _:b429698996 "2"^^ . _:b429698939 . _:b429698999 "2"^^ . . . _:b429698938 . _:b429698998 "2"^^ . . _:b429698993 "2"^^ . _:b429698949 . . . . . _:b429699245 . _:b429698992 "2"^^ . _:b429698948 . . _:b429698996 . . _:b7410072 . _:b429698989 . _:b429698951 . _:b429698995 "2"^^ . _:b429698993 . _:b429698907 . _:b429698994 "2"^^ . _:b429698950 . _:b429698945 . _:b429699005 "2"^^ . . . _:b429698944 . _:b429699004 "2"^^ . _:b7410085 "Foreknowledge of treatment group assignment may also lead to selective exclusion of animals based on prognostic factors [>>13<<]. These problems can arise with any method in which group allocation is known in advance or can be predicted. Such methods include both the use of predetermined rules (e.g., assignment in alternation or on the basis of the days of the" . . _:b429699007 "2"^^ . _:b429698947 . _:b429698946 . _:b429699006 "2"^^ . _:b429698957 . _:b429699001 "2"^^ . _:b429699069 . _:b429699332 . . _:b429699000 "2"^^ . _:b429698956 . . _:b429698959 . _:b429699003 "2"^^ . . _:b429698835 . . . _:b7410106 "in surgery [2] 200783 (38)4 (50)N/ANeonatal RDS [2] 20075614 (25)3 (5)N/AOsteoporosis [2] 2007165 (31)0 (0)N/AIschemic stroke [16] a 2007288103 (36)84 (29)8 (3)Parkinson's disease [16] 200711814 (12)18 (15)0 (0)Multiple sclerosis [>>16<<] 20071834 (2)20 (11)0 (0)ALS [45] 20078521 (25)21 (25)1 (1)Brain injury [52] 20081812 (67)7 (39)N/AIschemic stroke [25] 200893 (33)4 (44)2 (22)Ischemic stroke [53] 2009191 (5)5 (26)0" . . _:b429699002 "2"^^ . _:b429698958 . _:b429698759 . . . _:b429698953 . _:b429699013 "2"^^ . _:b429698687 . . . _:b429698952 . _:b429699012 "2"^^ . . _:b429699099 . _:b429698955 . _:b429699015 "2"^^ . . _:b7410096 . _:b429699014 "2"^^ . _:b429698954 . _:b429698735 . _:b429699217 . _:b429698941 . _:b429698833 . _:b429698965 . _:b429699009 "2"^^ . . _:b7410093 . _:b429698964 . _:b7410098 . _:b429699008 "2"^^ . . . _:b429698967 . _:b429699011 "2"^^ . . _:b429699010 "2"^^ . _:b429698966 . _:b429698638 . _:b429699021 "2"^^ . _:b429698961 . _:b429698812 . _:b429698960 . _:b429699020 "2"^^ . _:b429698963 . _:b429699023 "2"^^ . _:b429698937 . _:b429698962 . _:b429699449 . _:b429699022 "2"^^ . _:b429699303 . . _:b429699017 "2"^^ . _:b429698973 . _:b429698972 . _:b429699157 . _:b429699016 "2"^^ . . _:b429698975 . _:b429699019 "2"^^ . _:b429698974 . _:b429699018 "2"^^ . _:b429698627 . . _:b429698985 . _:b429698969 . _:b429699029 "2"^^ . _:b429698968 . _:b429699028 "2"^^ . . _:b429698740 . _:b429698971 . _:b429699031 "2"^^ . _:b429698970 . _:b429699030 "2"^^ . . . _:b429698981 . _:b429699025 "2"^^ . . _:b429698980 . _:b429699024 "2"^^ . . . _:b429698983 . _:b429699027 "2"^^ . _:b429698982 . _:b429699026 "2"^^ . _:b429698977 . _:b429699037 "2"^^ . . . _:b429698976 . _:b429699036 "2"^^ . _:b429698979 . _:b429699039 "2"^^ . _:b429698978 . _:b429699038 "2"^^ . _:b429699390 . _:b429698989 . _:b429699033 "2"^^ . _:b429698691 . . _:b429698988 . _:b429699032 "2"^^ . . . _:b429698991 . _:b429699035 "2"^^ . _:b429698990 . _:b429699034 "2"^^ . _:b429699277 . _:b429699299 . . _:b429699045 "2"^^ . _:b429698985 . . . _:b429699044 "2"^^ . _:b429698984 . _:b429698987 . _:b429699047 "2"^^ . _:b429699357 . . _:b429699046 "2"^^ . _:b429698986 . _:b429698648 . . . _:b429698997 . _:b429699041 "2"^^ . _:b429698996 . _:b429699040 "2"^^ . _:b429698999 . _:b429699051 . _:b429699043 "2"^^ . _:b429698998 . _:b429699042 "2"^^ . _:b429699184 . . _:b429699053 "2"^^ . _:b429698993 . . _:b429698992 . _:b429699052 "2"^^ . _:b429699441 . . . _:b429699055 "2"^^ . _:b429698995 . _:b429698994 . _:b429699054 "2"^^ . . _:b429699219 . _:b429699005 . _:b429699049 "2"^^ . _:b429699011 . . . _:b429699004 . _:b429699048 "2"^^ . . _:b429699007 . _:b429699051 "2"^^ . _:b429699479 . _:b429699006 . _:b429699050 "2"^^ . _:b429699001 . _:b429699061 "2"^^ . _:b429698817 . _:b429698693 . _:b429699060 "2"^^ . _:b429699000 . _:b429699003 . _:b429699063 "2"^^ . _:b429698946 . _:b429699002 . _:b429699062 "2"^^ . _:b429699013 . _:b429699057 "2"^^ . . _:b429698975 . _:b429699012 . _:b429699056 "2"^^ . _:b7410113 . . _:b429699009 . _:b429699059 "2"^^ . _:b429699015 . . _:b429698647 . _:b429699014 . _:b429699058 "2"^^ . . _:b429699009 . _:b429699069 "2"^^ . _:b429698940 . . _:b429698974 . _:b429699068 "2"^^ . _:b429699008 . _:b429698705 . _:b429699071 "2"^^ . _:b429699011 . . _:b429699023 . _:b429698860 . _:b429699070 "2"^^ . _:b429699010 . _:b429699021 . _:b429699065 "2"^^ . . _:b429699020 . _:b429699064 "2"^^ . _:b429699271 . _:b429699023 . _:b429699067 "2"^^ . . _:b7410120 . _:b429699022 . _:b429699066 "2"^^ . . _:b429699308 . _:b429699017 . . . _:b429699016 . . _:b429699019 . _:b429699018 . _:b429699286 . _:b429699294 . _:b429699014 . . _:b429699029 . . . _:b429699028 . _:b429699031 . _:b429699030 . . . _:b429699025 . . . _:b429698765 . _:b429699024 . . _:b429699027 . _:b429698770 . . _:b429699387 . _:b429699026 . _:b429699037 . . . _:b429698701 . _:b429698947 . _:b429699036 . _:b429699103 . . _:b429698859 . _:b429699039 . . _:b7410084 "Adapted from [12],[>>13<<]." . _:b429699038 . _:b429699033 . _:b429698651 . _:b429698928 . _:b429699045 . . _:b429699032 . _:b429699035 . . . _:b429699034 . _:b429699045 . . . _:b429699008 . _:b7410113 "All but one of these complications concerned premature death, and about 90% of these animals were excluded from the analyses [>>20<<]. In another review of several treatment strategies for acute ischemic stroke, only one of 45 studies mentioned predefined inclusion and exclusion criteria, and in just 12 articles (27%) exclusion of animals from analysis was mentioned and" . _:b429699044 . _:b429699310 . . _:b429699047 . _:b429698870 . . _:b429699046 . _:b429698887 . _:b429699041 . _:b429698904 . _:b429699040 . . . _:b429698708 . _:b429699043 . _:b429698618 . _:b429699453 . . _:b429699042 . _:b429699053 . . _:b429699052 . . . _:b429698936 . _:b429699461 . _:b429699055 . _:b429698851 . _:b7410088 . _:b429699367 . _:b429699054 . . _:b7410087 . _:b429699049 . . _:b429698883 . _:b429699048 . . _:b7410104 "(4)N/AIschemic stroke [51] 2006272 (7)1 (4)N/ATraumatic brain injury [2] 2007172 (12)3 (18)N/AHemorrhage in surgery [2] 200783 (38)4 (50)N/ANeonatal RDS [2] 20075614 (25)3 (5)N/AOsteoporosis [2] 2007165 (31)0 (0)N/AIschemic stroke [>>16<<] a 2007288103 (36)84 (29)8 (3)Parkinson's disease [16] 200711814 (12)18 (15)0 (0)Multiple sclerosis [16] 20071834 (2)20 (11)0 (0)ALS [45] 20078521 (25)21 (25)1 (1)Brain injury [52] 20081812 (67)7 (39)N/AIschemic stroke [25] 200893 (33)4" . _:b429698686 . _:b429699051 . _:b429698742 . _:b429699050 . _:b429699076 . _:b429699061 . _:b429699060 . _:b429699412 . _:b429699173 . _:b429699172 . _:b429699063 . . _:b429698987 . _:b429699062 . . _:b7410095 . _:b429698942 . _:b429699057 . _:b429699056 . . _:b429699059 . . . _:b429699058 . . _:b429699069 . _:b429699301 . _:b7410100 . _:b429699068 . _:b7410083 "based on the clinical CONsolidated Standards of Reporting Trials (CONSORT) statement, and to a smaller extent on published recommendations and guidelines for the conduct and reporting of animal studies of acute ischemic stroke [13]\u2013[>>17<<]." . _:b429699071 . _:b429699188 . . _:b429699291 . _:b429699054 . _:b429699070 . _:b7410080 . . _:b7410092 . _:b429699065 . _:b429699215 . . _:b429698700 . _:b429699064 . _:b429699242 . _:b429699067 . _:b429698622 . _:b429699113 . . _:b429699066 . . _:b429699072 . . . _:b429698891 . . . . _:b429699444 . . _:b429699121 . . _:b429699040 . _:b429698957 . _:b429698983 . . _:b7410080 "purposes, the designs of some clinical trials have also failed to acknowledge the limitations of efficacy observed in animal studies, for example by allowing therapy at later time points when the window of opportunity has passed [10],[>>11<<]. Secondly, the failure of apparently promising interventions to translate to the clinic may also be caused by inadequate animal data and overoptimistic conclusions about efficacy drawn from methodologically flawed animal studies." . . _:b429698626 . _:b429698664 . . _:b429698971 . _:b429699025 . _:b429698658 . . . _:b429698779 . . . _:b429699027 . . . . . _:b429699024 . _:b429699451 . _:b429699491 . _:b7410074 "In a recent systematic review of studies testing the efficacy of interventions in animal models of human disease, only six reported testing for the presence of publication bias, and such bias was found in four [34],[>>42<<]\u2013[46]. No study gave quantitative estimates of the impact on effect size of publication bias [47]." . . _:b429699371 . _:b429699213 . _:b429699229 . _:b429698961 . . _:b429698773 . _:b429698589 . _:b429698798 . _:b429699077 . . _:b429698588 . _:b429698591 . _:b429699243 . _:b429698590 . _:b429699135 . _:b429698809 . _:b429698587 . . _:b429699341 . _:b429698586 . _:b429698995 . _:b429699244 . _:b429698597 . _:b429698912 . . . . _:b429698596 . . _:b429698599 . _:b429699384 . _:b429698830 . _:b429699365 . _:b429698598 . _:b429698593 . . _:b429698592 . . . _:b7410110 . _:b429699148 . . . _:b429698595 . _:b429698869 . _:b429698667 . _:b429699043 . _:b429698594 . _:b429698783 . _:b429699104 . _:b429698950 . _:b429698605 . _:b429699388 . _:b429698604 . _:b429699086 . . _:b429698607 . _:b429698933 . . . _:b429698606 . . _:b429699238 . _:b429698601 . _:b429699005 . _:b429698600 . _:b429699153 . _:b429698603 . . . _:b429699230 . _:b429698766 . _:b429698602 . _:b429698866 . _:b429699437 . _:b429698613 . _:b429699056 . _:b429698612 . _:b429698615 . . _:b429698614 . _:b429698609 . _:b429698608 . _:b429698611 . _:b429699097 . _:b429698696 . _:b429698610 . _:b429698772 . _:b429699002 . _:b429698621 . _:b429699159 . _:b429698620 . _:b429698838 . _:b429699440 . _:b429698623 . _:b429698622 . . _:b429698617 . _:b429698594 . _:b429698616 . _:b429699369 . _:b429698619 . _:b429698668 . . _:b429698618 . _:b429699413 . _:b429698629 . _:b429699391 . _:b429699109 . _:b429699108 . _:b429698628 . _:b429699141 . . . . . . _:b429698631 . . _:b429698630 . _:b429698788 . . _:b429698625 . _:b429698963 . . . _:b7410112 . _:b429698624 . . _:b429699179 . _:b429698627 . _:b429699235 . _:b7410114 . _:b429698863 . _:b429698626 . . _:b429698637 . _:b429698965 . _:b429698636 . . _:b429698639 . _:b429699416 . _:b429698638 . _:b429698633 . _:b429698632 . _:b429698635 . _:b429699190 . _:b429698717 . _:b429698634 . _:b429698795 . _:b429698645 . _:b429699186 . _:b429698924 . _:b429698644 . _:b429698647 . . _:b429699124 . _:b429698646 . _:b429699377 . _:b7410127 . _:b429698641 . _:b7410128 . _:b429698640 . . . _:b429698643 . . . _:b429698642 . . _:b429698652 . _:b7410131 . _:b429698653 . _:b429699266 . . _:b429698877 . _:b429698652 . _:b429698655 . _:b429698654 . _:b429698649 . . _:b429698901 . _:b429699187 . _:b429698648 . _:b429698876 . _:b429698651 . _:b429698596 . _:b429698650 . _:b429698661 . _:b429699378 . _:b429698660 . _:b429698663 . . _:b429698662 . _:b429698657 . . _:b429699241 . _:b429698656 . _:b429698620 . . . _:b429698659 . _:b429699471 . . _:b429698658 . _:b429698669 . _:b429698623 . _:b429699136 . _:b429698668 . _:b429698671 . _:b429699275 . _:b429699031 . _:b429698670 . _:b429698736 . _:b429698831 . _:b429698636 . . _:b429698665 . _:b429698777 . . _:b429698664 . _:b429699333 . _:b429698820 . . _:b429699332 . _:b429698667 . . . . _:b429699335 . _:b429698832 . _:b429698666 . . . _:b429698677 . _:b429699334 . . _:b429698676 . _:b429699329 . _:b429698910 . . _:b429699328 . _:b429699080 . _:b429698679 . _:b429699130 . _:b7410078 "It is therefore probably more revealing that of the 525 publications, only ten (2%) did not report at least one significant effect on either infarct volume or neurobehavioural score [>>47<<]. Although unproven, it appears unlikely that the animal stroke literature is uniquely susceptible to publication bias." . . _:b429699331 . . _:b429698678 . _:b429698673 . _:b429699330 . _:b429699321 . _:b429698672 . _:b429699341 . _:b429698675 . _:b429699340 . . _:b429699119 . _:b429698674 . _:b429699343 . _:b429699312 . _:b429699178 . _:b429699362 . _:b429698685 . _:b7410091 "In clinical trials, an intention-to-treat analysis is generally favoured because it avoids bias associated with nonrandom loss of participants [>>13<<]. As explained above, the explanatory character of most studies justifies the use of an analysis restricted to data from animals that have fulfilled all eligibility criteria, provided that all animals excluded from the analysis are" . _:b429699342 . _:b429699082 . _:b429699383 . _:b7410130 . _:b429699476 . _:b429698684 . _:b429699337 . _:b429699156 . _:b429698687 . _:b429699336 . . . _:b429698692 . . _:b429699339 . _:b429698686 . _:b429699195 . . . _:b429699083 . _:b429698681 . _:b429699338 . _:b429698680 . _:b429699349 . _:b429698683 . _:b429699348 . . _:b429698682 . _:b429699351 . _:b429698693 . _:b429699350 . . _:b429699458 . _:b429698692 . _:b429699345 . _:b429698878 . . . _:b429699320 . _:b429698695 . _:b429699344 . _:b429698694 . _:b429699347 . _:b429699292 . . _:b429698689 . _:b429699346 . _:b429698726 . _:b429698644 . _:b429698688 . _:b429699357 . . _:b429699361 . _:b429698691 . _:b429699356 . _:b429699175 . . _:b429698690 . _:b429699359 . _:b429698701 . _:b429699358 . _:b429699356 . . _:b429698700 . _:b429699353 . _:b429699222 . _:b429698703 . _:b429699352 . _:b429698934 . . . _:b429698702 . _:b429699355 . . _:b429698697 . _:b429699354 . _:b429698696 . _:b429699365 . . . . _:b429698699 . _:b429699364 . _:b429698698 . _:b429699367 . _:b429698954 . _:b429698709 . _:b429699366 . _:b429698674 . . _:b429699106 . . _:b429699398 . _:b429699361 . _:b429698708 . . _:b7410138 "Recommendations based on [13],[>>17<<]." . _:b429699486 . _:b429698711 . _:b429699430 . _:b429699360 . _:b429698710 . _:b429699363 . . _:b429698670 . _:b429699362 . _:b429698705 . _:b429698882 . . _:b429698775 . _:b429698704 . _:b429699373 . _:b429698707 . _:b429699372 . . _:b429699375 . _:b429698706 . _:b7410070 "publication bias" . _:b429698717 . _:b429699374 . . _:b429698716 . _:b7410099 "Disease ModeledYear of PublicationNumber of PublicationsRandomisation, n (%)Blinded Outcome Assessment, n (%)A Priori Sample Size Calculation, n (%)Heart failure [24] 200396 (67)9 (100)0 (0)Emergency medicine [>>33<<] 200329094 (32)31 (11)N/AIschemic stroke [19] 20054519 (42)18 (40)0 (0)Ischemic stroke [49] 20057317 (23)9 (12)N/AIschemic stroke [50] 2005258 (32)1 (4)N/AIschemic stroke [51] 2006272 (7)1 (4)N/ATraumatic brain injury [2] 2007172 (12)3" . _:b429699369 . . _:b429699368 . _:b429698719 . . _:b429698598 . _:b429698718 . _:b429699371 . . _:b429698713 . _:b429699370 . _:b429699107 . _:b429698712 . _:b429699381 . _:b429698805 . . _:b429699380 . _:b429698715 . _:b429699049 . _:b429698714 . _:b429699383 . _:b429698725 . _:b429699382 . . . _:b429699327 . . _:b429698724 . _:b429699377 . _:b429699331 . _:b429698608 . _:b429698727 . _:b429699376 . . _:b429698751 . . _:b429699477 . . . _:b429699379 . . _:b429698726 . . . _:b429698721 . _:b429699378 . . _:b429698720 . _:b429699389 . _:b429698730 . . _:b429698710 . . _:b429699317 . _:b429698723 . _:b429699388 . _:b429699330 . _:b429698722 . _:b429699391 . . _:b429698733 . _:b429699390 . _:b7410133 . . _:b7410122 "In this meta-meta-analysis, only allocation concealment was associated with a larger effect size [>>35<<]." . _:b429698732 . _:b429699385 . _:b429698960 . . _:b429699384 . . _:b429698735 . _:b429698734 . _:b429699387 . . _:b429698984 . _:b429699376 . _:b429698729 . _:b429699386 . _:b429699255 . . _:b429698728 . _:b429699397 . . _:b429699396 . _:b429698731 . . _:b429699456 . _:b429698730 . _:b429699399 . . _:b7410108 . _:b429698741 . _:b429699398 . _:b429699201 . _:b429699269 . _:b429698740 . _:b429699393 . _:b429699134 . _:b429698743 . _:b429699392 . _:b429699420 . _:b429698742 . _:b429699395 . _:b429698737 . _:b429699394 . _:b429698792 . _:b429699438 . _:b429699133 . _:b429698736 . _:b429699405 . . . _:b429698739 . _:b429699404 . _:b429699454 . . . _:b429698656 . _:b429698738 . _:b7410082 "largely based on the clinical CONsolidated Standards of Reporting Trials (CONSORT) statement, and to a smaller extent on published recommendations and guidelines for the conduct and reporting of animal studies of acute ischemic stroke [>>13<<]\u2013[17]." . _:b429699407 . . _:b429698856 . . _:b429699137 . _:b429698749 . _:b429699406 . _:b429698748 . _:b429699401 . _:b429698864 . . _:b429698751 . _:b429699400 . _:b429698780 . _:b429699030 . _:b429698750 . _:b429699403 . _:b429699248 . _:b429698745 . _:b429699402 . _:b429698744 . _:b429699413 . . _:b429698794 . . _:b429698677 . _:b429698747 . _:b7410140 "Hackam 2006 [>>1<<]: Shows that about a third of highly cited animal research translates at the level of human randomised trials." . _:b429699412 . . _:b429698690 . _:b429698746 . _:b429699415 . . _:b429698757 . _:b429699414 . . _:b429698756 . _:b429699409 . _:b429699470 . . _:b429698759 . _:b429699408 . . . . _:b429698758 . _:b429699411 . _:b429698970 . _:b429698828 . _:b429698753 . _:b429699410 . . _:b429698752 . _:b429699421 . _:b429698755 . _:b429699420 . _:b429698754 . _:b429699423 . _:b429699333 . _:b429698765 . _:b429699422 . . _:b429698764 . _:b429699417 . . _:b429698767 . _:b429699416 . _:b429698766 . _:b429699419 . . _:b429699418 . _:b429698761 . . _:b429698977 . _:b429698760 . _:b429699429 . _:b429698767 . . _:b429698763 . _:b429699428 . . _:b429698762 . _:b429699431 . _:b429699415 . _:b429699012 . . _:b429698773 . _:b429699430 . . . _:b429699425 . _:b429698772 . _:b429698595 . _:b429698839 . . . _:b429699424 . _:b429698775 . . _:b429698774 . _:b429699427 . _:b429698769 . _:b429699485 . _:b429699426 . _:b429698768 . _:b429699437 . _:b429699339 . . . _:b429699436 . _:b429698771 . . _:b429698848 . _:b429698770 . _:b429699439 . _:b429699324 . . _:b429698781 . _:b429699438 . _:b429698780 . _:b7410141 "Sena 2007 [>>16<<]: Proposes minimum standards for the range and quality of pre-clinical animal data before these are taken to clinical trials." . _:b429699433 . . _:b429698783 . _:b429699432 . _:b429698782 . _:b429699435 . . _:b429698777 . _:b429699434 . _:b429699359 . _:b429699406 . _:b429698776 . _:b429699445 . . _:b429698779 . _:b429699444 . . _:b429698778 . _:b429699447 . . . _:b429698789 . _:b429699466 . _:b429699446 . _:b429698786 . _:b429698788 . _:b429699441 . . _:b429699234 . _:b429698791 . _:b429699440 . _:b429698790 . _:b429699443 . _:b429699090 . _:b429698785 . _:b429699442 . . _:b429698829 . _:b429698606 . _:b429698784 . _:b429699453 . _:b429698935 . _:b429698695 . _:b429698787 . _:b7410109 . _:b429699452 . _:b429698786 . _:b429699455 . _:b429699070 . _:b429699316 . . . . . _:b429699454 . _:b429698797 . _:b429699431 . _:b429698796 . _:b429699449 . . . . _:b429699433 . _:b429699427 . _:b429698799 . _:b429699448 . . _:b429698798 . _:b429699451 . _:b429698982 . _:b429698793 . _:b429699450 . _:b429699114 . _:b429699374 . _:b429698792 . _:b429699461 . _:b429698795 . _:b429699460 . _:b429698794 . _:b429699463 . _:b429698805 . _:b429699462 . . . _:b429698804 . _:b429699457 . _:b429698657 . _:b429698807 . _:b7410097 . _:b429699456 . _:b429698662 . _:b429698758 . _:b429698806 . _:b429699459 . . _:b429698801 . _:b429699458 . _:b429698800 . _:b429699469 . _:b429698803 . _:b429699468 . . _:b7410081 "internal validity" . _:b429698802 . _:b429699471 . _:b7410111 "There is an overlap of 18 publications between references [>>16<<] and [19]." . _:b429698966 . _:b7410131 "Finally, the usual time of outcome assessment of 1\u20133 days in animal models contrasts sharply with that of 3 months in patients [>>19<<]. For these reasons, it is not surprising that, except for thrombolysis, all treatment strategies proven effective in the laboratory have failed in the clinic." . _:b429698813 . _:b429699470 . . . _:b429698812 . _:b429699465 . _:b429699176 . _:b429698815 . _:b429699464 . . _:b429698814 . _:b429699467 . _:b429699282 . _:b429698631 . _:b429699206 . _:b429698809 . _:b429699466 . . _:b429699379 . _:b429698808 . _:b429699477 . . _:b429698725 . _:b429699476 . _:b429698811 . . . _:b429699335 . _:b429699287 . _:b429698810 . _:b429699479 . . . _:b429699478 . _:b429698609 . _:b429699296 . _:b429699473 . . _:b429698733 . _:b429699472 . _:b429699475 . _:b429698588 . . . _:b429699474 . . _:b429699020 . . . _:b429699485 . . _:b429699088 . _:b429699484 . _:b429699487 . _:b429699047 . _:b429699486 . _:b429699029 . . _:b429699481 . _:b429698927 . . _:b429699480 . _:b429699483 . _:b7410107 . _:b429698886 . _:b429699482 . . . . _:b429699492 . . . _:b429699478 . . _:b429699489 . _:b429698722 . _:b429699258 . _:b429699300 . _:b429699488 . . _:b7410098 "Disease ModeledYear of PublicationNumber of PublicationsRandomisation, n (%)Blinded Outcome Assessment, n (%)A Priori Sample Size Calculation, n (%)Heart failure [>>24<<] 200396 (67)9 (100)0 (0)Emergency medicine [33] 200329094 (32)31 (11)N/AIschemic stroke [19] 20054519 (42)18 (40)0 (0)Ischemic stroke [49] 20057317 (23)9 (12)N/AIschemic stroke [50] 2005258 (32)1 (4)N/AIschemic stroke [51] 2006272 (7)1" . _:b429699491 . _:b429699168 . _:b429699101 . _:b429699490 . _:b429699268 . . . . _:b429699164 . _:b429698871 . . _:b429699326 . . _:b429699180 . . . . . . _:b429699227 . _:b429698949 . _:b429698958 . _:b429698902 . _:b429698837 . . . _:b429698715 . . . . _:b429698822 . . . _:b429699142 . _:b429699280 . _:b429698845 . . _:b429698707 . . . _:b429699405 . . _:b429698968 . . . _:b429699240 . _:b429698920 . _:b429698899 . . _:b429699298 . . _:b429699281 . . . . . . . "PMC0" . _:b429698709 . _:b429698607 . _:b429698875 . . . . . . _:b429699139 . _:b429699162 . _:b7410123 _:b7410124 . . _:b7410123 _:b7410125 . . _:b7410123 _:b7410126 . _:b7410123 _:b7410127 . _:b429698980 . . . _:b429698972 . . _:b7410129 . _:b7410123 _:b7410128 . . _:b7410123 _:b7410129 . _:b7410123 _:b7410130 . . _:b7410123 _:b7410131 . _:b7410123 _:b7410132 . . _:b7410123 _:b7410133 . _:b7410123 _:b7410134 . _:b7410123 _:b7410135 . _:b429698785 . . . . _:b429699066 . _:b429699465 . _:b429698939 . _:b429699273 . . _:b429698953 . . _:b429698659 . _:b429698750 . . . . . _:b429699204 . . "10.1371%2Fjournal.pmed.1000245" . _:b429699128 . _:b429698787 . . _:b429698836 . _:b429698796 . . . _:b429699475 . _:b7410136 _:b7410140 . _:b7410136 _:b7410141 . _:b7410136 _:b7410142 . _:b7410136 _:b7410143 . . _:b7410136 _:b7410137 . _:b7410136 _:b7410138 . _:b7410136 _:b7410139 . _:b7410077 "In a subsequent meta-analysis of 525 publications [>>47<<] included in systematic reviews of 16 interventions tested in animal studies of acute ischaemic stroke, Egger regression and Trim and Fill analysis suggested that publication bias was widely prevalent." . _:b429698727 . _:b7410136 _:b7410144 . _:b429699224 . _:b429699102 . _:b429699182 . . _:b429699366 . . . . _:b429698682 . . . . _:b429699349 . _:b429698588 . _:b429698589 . _:b429698590 . _:b429698591 . _:b429698991 . _:b429698586 . _:b429698587 . _:b429699305 . _:b429698943 . . _:b429699034 . . . . _:b429698612 . _:b429698613 . _:b429699425 . _:b429698699 . _:b429698614 . . _:b429698615 . _:b429698850 . _:b429698608 . _:b429698609 . _:b429698610 . _:b429698611 . _:b429698762 . _:b429698620 . _:b429698621 . _:b429698622 . _:b429698623 . _:b429698616 . _:b429698617 . _:b429698618 . _:b429698619 . _:b429698596 . . _:b429698597 . _:b429699233 . _:b429698598 . _:b429698599 . _:b429699408 . . _:b429698844 . . _:b429698592 . _:b429698593 . _:b429698594 . _:b429698595 . _:b429699446 . _:b429698604 . _:b429699381 . . _:b429698605 . _:b429698606 . _:b429698898 . _:b429698607 . _:b429698600 . _:b429698601 . _:b429698602 . _:b429698603 . _:b429698644 . _:b429698702 . _:b429698645 . _:b429698646 . _:b429698647 . _:b429699429 . _:b429698640 . _:b429698641 . _:b7410076 . _:b429698642 . _:b429698643 . _:b429698652 . _:b429698653 . _:b7410077 . _:b429698654 . _:b429698655 . _:b429698648 . _:b429698649 . _:b7410078 . _:b429698650 . _:b429698651 . _:b429698697 . _:b429698628 . . _:b429698629 . _:b429698630 . _:b429698631 . _:b429699403 . _:b429698624 . _:b429698625 . _:b429699448 . _:b429698626 . _:b429698627 . _:b429698988 . _:b429698636 . _:b429698637 . _:b429698638 . _:b429698639 . _:b429698632 . _:b429698633 . _:b429698634 . _:b429698635 . _:b429698676 . _:b429699264 . _:b429698677 . _:b429698678 . _:b429698679 . _:b429698672 . _:b429698673 . _:b429698674 . . . _:b429698675 . _:b429698684 . _:b429698685 . _:b429698694 . _:b429698686 . _:b429698687 . _:b429698680 . _:b429698681 . _:b429698682 . _:b429699077 . _:b429698683 . _:b429698660 . _:b429699207 . _:b429698661 . _:b429699315 . . _:b429698662 . _:b429699181 . _:b429699076 . _:b429698663 . _:b429698656 . . _:b429698657 . _:b429698658 . _:b429699079 . _:b429698731 . _:b429698659 . _:b429698668 . _:b429698669 . _:b429698675 . _:b429698670 . _:b429699078 . _:b429698671 . _:b429698664 . _:b429698665 . _:b429698666 . _:b429699073 . _:b429699041 . _:b429698667 . . _:b429698708 . _:b429698709 . _:b429698710 . _:b429699072 . _:b429698711 . _:b429698704 . _:b429698705 . _:b429698706 . _:b429699170 . _:b429699075 . . _:b429698707 . _:b429698716 . _:b429698717 . _:b429698718 . _:b429699074 . _:b429698719 . . _:b429698712 . . _:b429698713 . _:b429698714 . _:b429699085 . . _:b429698800 . _:b429698879 . _:b429698715 . _:b429698692 . . _:b429698693 . _:b429698694 . _:b429699084 . _:b429698695 . _:b429698613 . _:b429698688 . _:b429699469 . _:b429698689 . _:b429698690 . _:b429699087 . _:b429698691 . _:b429698700 . _:b429698701 . _:b429698702 . _:b429699086 . _:b429698703 . _:b429698696 . _:b429698697 . _:b429698698 . _:b429699081 . _:b429698699 . . _:b429698740 . _:b429698741 . _:b429698846 . _:b429698742 . _:b429699080 . _:b429698743 . _:b7410070 _:b7410076 . _:b429698736 . _:b7410070 _:b7410077 . _:b429698737 . _:b429699152 . _:b7410070 _:b7410078 . _:b429698738 . _:b429699083 . _:b429698739 . _:b7410070 _:b7410072 . _:b429698748 . _:b7410070 _:b7410073 . _:b429698749 . _:b429699046 . . _:b7410070 _:b7410074 . _:b429698750 . _:b429699319 . _:b429699082 . _:b7410070 _:b7410075 . _:b429698751 . _:b429698744 . . _:b429698745 . . _:b429699093 . _:b7410070 _:b7410071 . _:b429698746 . _:b429698747 . . _:b429698724 . _:b429699290 . _:b429698725 . _:b429698726 . _:b429699092 . _:b429698727 . _:b429698645 . _:b429698720 . . _:b429698721 . _:b7410144 . _:b429698722 . _:b429699095 . . _:b429698723 . _:b429698732 . _:b429698733 . . _:b429698614 . _:b429698734 . _:b429699094 . _:b429698735 . _:b7410079 _:b7410080 . . _:b429699474 . _:b429698728 . _:b429698729 . . _:b429698730 . _:b429699089 . . _:b429698731 . _:b429698772 . _:b429698773 . _:b429698774 . _:b429699088 . _:b429698775 . _:b429698768 . _:b429698769 . _:b429698770 . _:b429699091 . _:b429698771 . _:b429698780 . _:b429698781 . _:b429698782 . _:b429699090 . _:b429698681 . _:b429698783 . _:b429698741 . . _:b429698776 . _:b429698777 . _:b429698778 . _:b429699101 . _:b429698779 . _:b429698756 . _:b429698757 . _:b429698758 . _:b429699100 . _:b429698759 . _:b429698752 . _:b429698753 . _:b429698754 . _:b429699103 . _:b429698755 . . _:b429698764 . _:b429698765 . _:b429698766 . _:b429699102 . _:b429698600 . . _:b429699404 . _:b429698767 . _:b429698760 . _:b429698761 . _:b429698762 . _:b7410111 . _:b429699097 . . _:b429698763 . _:b429698804 . _:b429698805 . _:b429698806 . _:b429699096 . _:b429698807 . _:b429698800 . _:b429698801 . _:b429698802 . _:b7410105 . _:b429699099 . _:b429698803 . _:b429698812 . . _:b429698813 . _:b429698814 . _:b7410104 . _:b429699098 . _:b429698815 . _:b429698808 . _:b429698809 . _:b429698810 . _:b429699109 . _:b429698811 . . _:b429698788 . . _:b429698789 . _:b429698790 . _:b7410106 . _:b429699108 . _:b429698791 . _:b429698784 . _:b429698785 . _:b429698786 . _:b429699250 . _:b429699214 . _:b429699111 . _:b429698787 . _:b429698796 . . _:b429698797 . _:b429698798 . _:b429699110 . _:b429698799 . _:b429699200 . _:b429698792 . _:b429698793 . _:b429698794 . _:b429699105 . _:b429698795 . _:b429698836 . . _:b429698837 . _:b429698838 . _:b429699104 . _:b429698839 . _:b429699192 . . _:b429698832 . _:b429698833 . _:b429698834 . _:b429699107 . . _:b429698835 . _:b429698844 . _:b429698845 . . _:b429699106 . _:b429698846 . _:b429698847 . . _:b429698840 . _:b429698841 . . _:b429698842 . _:b429699418 . _:b429699117 . _:b429698843 . _:b429698820 . _:b429698821 . _:b429698822 . _:b429699116 . _:b429698743 . _:b429698823 . _:b429698823 . _:b429698816 . _:b429698817 . _:b429698818 . _:b429699119 . _:b429698819 . _:b429698828 . _:b429698829 . . . _:b429699118 . _:b429698830 . _:b429698831 . _:b429698824 . _:b429698825 . _:b429698826 . _:b429699113 . . _:b429698827 . _:b429698868 . _:b429698869 . _:b429698870 . _:b7410094 . _:b429699112 . _:b429698871 . _:b7410081 _:b7410112 . _:b429698864 . _:b7410081 _:b7410113 . _:b429698865 . _:b429698781 . _:b7410081 _:b7410114 . _:b429698866 . _:b429699443 . _:b429699115 . _:b7410081 _:b7410115 . _:b429698867 . _:b7410081 _:b7410116 . _:b429698876 . . _:b7410081 _:b7410117 . _:b429698877 . _:b7410081 _:b7410118 . _:b429698878 . _:b429699114 . _:b7410081 _:b7410119 . _:b429698879 . _:b7410081 _:b7410120 . _:b429698872 . . . _:b7410081 _:b7410121 . . _:b7410081 _:b7410122 . _:b429698873 . _:b429698874 . _:b429699125 . . _:b7410101 "n (%)Blinded Outcome Assessment, n (%)A Priori Sample Size Calculation, n (%)Heart failure [24] 200396 (67)9 (100)0 (0)Emergency medicine [33] 200329094 (32)31 (11)N/AIschemic stroke [19] 20054519 (42)18 (40)0 (0)Ischemic stroke [>>49<<] 20057317 (23)9 (12)N/AIschemic stroke [50] 2005258 (32)1 (4)N/AIschemic stroke [51] 2006272 (7)1 (4)N/ATraumatic brain injury [2] 2007172 (12)3 (18)N/AHemorrhage in surgery [2] 200783 (38)4 (50)N/ANeonatal RDS [2] 20075614 (25)3" . . _:b429698875 . _:b429698852 . _:b429698853 . _:b429698896 . _:b429699124 . . _:b429698854 . _:b429698855 . _:b429698848 . _:b429698849 . _:b429698850 . _:b429699127 . _:b429698851 . . . _:b429698945 . _:b429698860 . _:b429698861 . _:b429698862 . _:b429699126 . . . _:b429698863 . _:b429698856 . _:b429698857 . _:b7410086 "Definitions adapted from [>>13<<] and from Wikipedia (http://www.wikipedia.org, accessed on 9 November 2009)." . _:b429698858 . _:b429699121 . _:b429698859 . _:b429698632 . _:b429698900 . . _:b429698901 . _:b429698902 . _:b429699120 . . _:b429698903 . _:b429698896 . _:b429698897 . _:b7410081 _:b7410082 . _:b429698898 . _:b429699123 . _:b7410081 _:b7410083 . _:b429698899 . _:b7410081 _:b7410084 . _:b429698908 . _:b7410081 _:b7410085 . _:b429698909 . _:b7410073 "In a recent systematic review of studies testing the efficacy of interventions in animal models of human disease, only six reported testing for the presence of publication bias, and such bias was found in four [>>34<<],[42]\u2013[46]." . _:b7410081 _:b7410086 . _:b429698910 . _:b429699122 . _:b7410081 _:b7410087 . _:b429698911 . _:b7410081 _:b7410088 . _:b429698904 . _:b7410081 _:b7410089 . _:b429698905 . _:b7410081 _:b7410090 . _:b429698906 . _:b429699133 . _:b7410081 _:b7410091 . _:b429698907 . _:b7410081 _:b7410092 . _:b429698745 . _:b429698884 . _:b7410081 _:b7410093 . _:b429698885 . _:b7410081 _:b7410094 . _:b429698886 . _:b429699260 . _:b429699132 . _:b7410081 _:b7410095 . _:b429698887 . _:b429698890 . _:b7410081 _:b7410096 . _:b429698880 . . _:b7410081 _:b7410097 . _:b429698881 . _:b7410081 _:b7410098 . _:b429698882 . _:b429699135 . _:b429698918 . _:b7410081 _:b7410099 . _:b429698883 . _:b429699092 . _:b7410081 _:b7410100 . _:b429698892 . _:b429699353 . _:b7410081 _:b7410101 . _:b429698893 . . _:b7410081 _:b7410102 . _:b429698894 . _:b429699134 . _:b7410081 _:b7410103 . _:b429698895 . . _:b7410081 _:b7410104 . . _:b7410081 _:b7410105 . _:b429698888 . _:b429698889 . . _:b7410081 _:b7410106 . _:b429698890 . _:b429699460 . _:b429699129 . _:b7410081 _:b7410107 . . _:b7410081 _:b7410108 . _:b429698891 . _:b429698932 . _:b7410081 _:b7410109 . _:b429698933 . _:b7410081 _:b7410110 . _:b429698934 . _:b429699128 . _:b7410081 _:b7410111 . _:b429698935 . . _:b429698928 . _:b429698929 . _:b429698930 . _:b429699455 . _:b429699147 . _:b429699131 . _:b429698931 . _:b429699325 . _:b429698940 . _:b429698941 . . . _:b429698942 . _:b429699130 . _:b429698943 . . _:b429698936 . . _:b429698937 . _:b429698938 . _:b429699141 . _:b429698939 . _:b429698990 . _:b429698916 . _:b429699267 . _:b429698917 . _:b429698918 . _:b429699140 . _:b429698919 . . _:b429698912 . . _:b429698913 . _:b429699100 . . _:b429698914 . _:b429699143 . _:b429698915 . _:b429698924 . . . _:b429698925 . _:b429698926 . _:b429699142 . _:b429698927 . _:b429698920 . _:b429698921 . _:b429698922 . _:b7410071 . _:b429699375 . _:b429699137 . . _:b429698923 . _:b429699401 . _:b429698964 . _:b429698826 . . _:b429698965 . _:b429698966 . _:b429699136 . _:b429698967 . _:b429698960 . _:b429698961 . _:b429698962 . _:b429699262 . _:b429699139 . _:b429698963 . _:b429699414 . _:b429698972 . _:b429698973 . _:b429698974 . _:b429699138 . . _:b429698975 . _:b429698968 . _:b429698969 . _:b429698970 . _:b429699149 . _:b429698971 . _:b429698948 . _:b429699132 . _:b429698949 . _:b429699457 . _:b429698950 . _:b429699148 . _:b429698951 . _:b429698944 . . _:b429698945 . _:b429698946 . _:b429699228 . _:b429699151 . _:b429698947 . _:b429698956 . _:b429698957 . _:b429698958 . _:b429699150 . _:b429698959 . _:b429698952 . _:b429699372 . _:b429698953 . _:b429698954 . _:b429699145 . _:b429698955 . _:b429698996 . _:b429698997 . _:b429698998 . _:b429699144 . _:b429698999 . _:b429698590 . _:b429698992 . _:b429698993 . _:b429698994 . _:b429699338 . _:b429699147 . . _:b429698995 . _:b429699004 . _:b429699005 . _:b429698747 . _:b429699006 . _:b429699146 . _:b429699007 . _:b429699000 . _:b429699001 . _:b429699001 . _:b429698721 . . _:b429699002 . _:b429699157 . _:b429699003 . _:b429698980 . _:b429698981 . . _:b429698982 . _:b429699156 . _:b429698641 . _:b429698983 . _:b429699424 . . _:b429698976 . _:b429698834 . _:b429698977 . _:b429698874 . _:b429698978 . _:b429699159 . _:b429698642 . _:b429698979 . _:b7410094 "or amyotrophic lateral sclerosis, generally about a third or less of the studies reported random allocation to the treatment group, and even fewer studies reported concealment of treatment allocation or blinded outcome assessment [2],[>>16<<],[19],[24],[25]. Even when reported, the methods used for randomisation and blinding were rarely given." . _:b429698988 . _:b7410120 "In systematic reviews of FK-506 or hypothermia for acute ischemic stroke, an inverse relation was found between effect size and study quality, as assessed by a ten-item study-quality checklist [>>20<<],[34]. The same review on hypothermia found large overstatements of the reduction in infarct volume in animal stroke studies without randomisation or blinded outcome assessment when they were compared with randomised or blinded studies," . _:b429698989 . _:b429699053 . . _:b429698990 . _:b429699158 . _:b429698991 . _:b429698984 . _:b429698985 . _:b429698986 . _:b429699153 . _:b429698987 . _:b429699028 . _:b429699029 . _:b429699030 . _:b429699152 . _:b429699031 . . _:b429699024 . _:b429699236 . _:b429699025 . . _:b429699026 . _:b429699155 . _:b7410123 . . _:b429699027 . _:b429699036 . _:b429699037 . _:b429699038 . _:b7410140 . _:b429699154 . _:b429699039 . _:b429698889 . _:b429699032 . _:b429699033 . _:b429699034 . _:b429699194 . _:b429699165 . _:b429698611 . _:b429699035 . _:b429699019 . _:b429699012 . _:b429699013 . _:b429699014 . _:b429699164 . _:b429698744 . _:b7410136 . _:b429699015 . _:b429699008 . _:b429699009 . _:b429699010 . _:b429699167 . . _:b429699011 . _:b429699020 . _:b429699021 . _:b429699022 . _:b429699351 . _:b429699289 . _:b429699166 . _:b429699023 . . _:b429699016 . _:b429699017 . . _:b429699018 . _:b429699161 . _:b429699019 . _:b429699060 . _:b429699489 . _:b429699061 . _:b429699062 . _:b429699160 . _:b429699063 . _:b429699056 . _:b429699057 . _:b429699304 . _:b429699058 . _:b429699163 . _:b429699059 . _:b429699068 . . _:b429699069 . _:b429699070 . _:b429699162 . _:b429699071 . _:b429699064 . _:b429699065 . _:b429699066 . _:b429699173 . _:b429699067 . . _:b429699044 . _:b429699045 . _:b429699046 . _:b429699172 . _:b429699047 . _:b429699040 . _:b429699041 . _:b429699042 . _:b429699175 . _:b429698804 . _:b429699043 . _:b429699052 . . _:b429699053 . _:b429699054 . _:b429699174 . _:b429699055 . _:b429699048 . _:b429699049 . _:b429699283 . . . _:b429699322 . _:b429699169 . _:b429699050 . _:b429699051 . . _:b429699168 . _:b429699193 . _:b429699171 . _:b7410070 . _:b429698764 . . _:b429699170 . _:b429698994 . _:b429699181 . _:b429698821 . . _:b429699344 . _:b7410079 . _:b429699180 . _:b429699125 . _:b429699183 . _:b7410129 "Several studies have suggested that in patients the relation between infarct volume and functional outcome is moderate at best [>>37<<],[38]. Finally, the usual time of outcome assessment of 1\u20133 days in animal models contrasts sharply with that of 3 months in patients [19]. For these reasons, it is not surprising that, except for thrombolysis, all treatment strategies" . _:b7410125 . _:b429698680 . _:b429699182 . . _:b7410081 . _:b429699177 . _:b429698756 . _:b429699483 . . _:b429699067 . _:b429699176 . _:b429699179 . . . _:b429699178 . _:b7410108 "[2] 2007165 (31)0 (0)N/AIschemic stroke [16] a 2007288103 (36)84 (29)8 (3)Parkinson's disease [16] 200711814 (12)18 (15)0 (0)Multiple sclerosis [16] 20071834 (2)20 (11)0 (0)ALS [45] 20078521 (25)21 (25)1 (1)Brain injury [>>52<<] 20081812 (67)7 (39)N/AIschemic stroke [25] 200893 (33)4 (44)2 (22)Ischemic stroke [53] 2009191 (5)5 (26)0" . _:b429699189 . _:b429698683 . _:b429699188 . . _:b429699191 . . _:b429699190 . _:b429699185 . . _:b429699184 . . _:b429698678 . _:b429698757 . _:b429699187 . _:b429699397 . _:b429699186 . . _:b429699095 . _:b429699197 . _:b429699467 . _:b429699196 . . . _:b429699199 . _:b7410141 . _:b7410138 . _:b429699198 . . _:b429698760 . _:b429699193 . _:b429699386 . _:b429698791 . _:b429699192 . _:b429699409 . . _:b429699195 . _:b429699194 . . . . _:b7410119 "testing interventions in emergency medicine, the odds of a positive result were more than three times as large if the publication did not report randomisation or blinding as compared with publications that did report these methods [>>33<<]. In systematic reviews of FK-506 or hypothermia for acute ischemic stroke, an inverse relation was found between effect size and study quality, as assessed by a ten-item study-quality checklist [20],[34]." . _:b429699205 . _:b429699204 . _:b429699207 . . _:b429699206 . . . _:b429699201 . _:b429699200 . _:b429698932 . _:b429699013 . _:b429699117 . _:b429699203 . _:b429699202 . . . _:b7410136 "practical improvement strategies" . _:b429699213 . . _:b429699212 . _:b429699215 . . _:b429699214 . . _:b429699209 . _:b429698729 . _:b7410126 . _:b429699208 . _:b429699211 . . _:b429699210 . . _:b429699221 . _:b429698724 . _:b429699145 . _:b429699220 . . _:b429698723 . _:b429698666 . _:b429698790 . _:b429699370 . _:b429699246 . _:b429699223 . _:b429699222 . _:b7410116 . . _:b429699116 . _:b429699217 . . _:b429699216 . . _:b429698752 . _:b429699160 . _:b429699219 . . _:b429698843 . _:b429699218 . _:b429699229 . _:b7410115 . . _:b429699228 . _:b429699402 . . . _:b429699231 . _:b429699230 . _:b429698654 . _:b429699225 . . _:b429698754 . _:b429699259 . _:b429699224 . _:b429699227 . . _:b429699226 . . . _:b429699237 . _:b429699236 . . . _:b429699265 . _:b429699239 . _:b429699422 . . _:b429699238 . _:b429699233 . _:b7410079 "causes of failed translation" . _:b429699004 . _:b429699232 . . . _:b7410122 . . _:b429699235 . _:b429699234 . _:b429699382 . _:b429698685 . _:b429699245 . _:b429699077 "2"^^ . _:b429698813 . _:b429699244 . . _:b429699348 . _:b429699076 "2"^^ . _:b429699247 . _:b429699079 "2"^^ . _:b429698897 . _:b429699246 . _:b429699078 "2"^^ . _:b429699241 . _:b429699073 "2"^^ . _:b429699240 . _:b429699072 "2"^^ . _:b429698684 . _:b429699243 . _:b429699075 "2"^^ . _:b429698909 . _:b429699242 . _:b429699074 "2"^^ . . _:b429699253 . _:b429699085 "2"^^ . _:b429698661 . _:b429699252 . _:b7410083 . _:b429699084 "2"^^ . . _:b429699255 . _:b429699087 "2"^^ . _:b429699254 . _:b429699086 "2"^^ . _:b429699249 . _:b429699081 "2"^^ . . _:b429699248 . _:b429699080 "2"^^ . _:b429699251 . . _:b429698586 . _:b429699083 "2"^^ . _:b429699250 . _:b429698630 . _:b429699129 . _:b429699082 "2"^^ . _:b429699261 . _:b7410123 "external validity" . _:b429699093 "2"^^ . . _:b429699260 . . _:b429699092 "2"^^ . _:b429699263 . _:b429699095 "2"^^ . _:b429699262 . _:b429698711 . _:b429699094 "2"^^ . _:b429699257 . . _:b429699089 "2"^^ . _:b429699256 . _:b429699220 . _:b429699088 "2"^^ . _:b429699259 . _:b429699091 "2"^^ . _:b429699258 . _:b429699090 "2"^^ . . _:b429699269 . _:b429699101 "2"^^ . _:b429699268 . _:b429698734 . _:b429699100 "2"^^ . . _:b429698979 . _:b429699271 . _:b7410107 "(50)N/ANeonatal RDS [2] 20075614 (25)3 (5)N/AOsteoporosis [2] 2007165 (31)0 (0)N/AIschemic stroke [16] a 2007288103 (36)84 (29)8 (3)Parkinson's disease [16] 200711814 (12)18 (15)0 (0)Multiple sclerosis [16] 20071834 (2)20 (11)0 (0)ALS [>>45<<] 20078521 (25)21 (25)1 (1)Brain injury [52] 20081812 (67)7 (39)N/AIschemic stroke [25] 200893 (33)4 (44)2 (22)Ischemic stroke [53] 2009191 (5)5 (26)0" . _:b429699103 "2"^^ . _:b429698601 . _:b429699270 . _:b429699102 "2"^^ . _:b429699265 . _:b429698616 . _:b429699097 "2"^^ . _:b429699264 . . . _:b429699096 "2"^^ . . _:b429699267 . _:b429698655 . _:b429699099 "2"^^ . . _:b429699221 . . _:b429699266 . _:b429699098 "2"^^ . _:b429699277 . _:b429699109 "2"^^ . _:b429698884 . _:b429699276 . _:b429699108 "2"^^ . _:b429698868 . _:b429699279 . . _:b429699111 "2"^^ . _:b429699073 . _:b429699278 . _:b429699110 "2"^^ . . _:b429699273 . . . _:b429699410 . _:b429699105 "2"^^ . _:b429698718 . . . . _:b429699272 . _:b429699104 "2"^^ . . _:b429699275 . _:b429699107 "2"^^ . _:b429699411 . _:b429699274 . _:b429699106 "2"^^ . _:b429699285 . _:b429699117 "2"^^ . _:b429699284 . _:b429699116 "2"^^ . _:b429699078 . _:b429699191 . _:b429699287 . . _:b429699119 "2"^^ . _:b429699286 . . _:b429699118 "2"^^ . . _:b429699281 . _:b429699174 . _:b429699113 "2"^^ . . _:b429699280 . _:b429699112 "2"^^ . . . _:b429699283 . . _:b429699452 . _:b429699115 "2"^^ . _:b429699282 . _:b429699114 "2"^^ . . _:b429699293 . . _:b429699125 "2"^^ . _:b7410139 "bias in the clinical literature has led to the introduction of clinical trial registration systems to ensure that those summarising research findings are at least aware of all relevant clinical trials that have been performed [>>48<<]. Given that a framework regulating animal experimentation already exists in many countries, we suggest that this might be exploited to allow the maintenance of a central register of experiments performed, and registration referenced in" . _:b429699127 . _:b429699292 . . _:b429699124 "2"^^ . _:b429699328 . . _:b429699295 . _:b429699127 "2"^^ . _:b429698605 . _:b429699294 . _:b429699155 . _:b429699126 "2"^^ . _:b429699289 . . _:b429699121 "2"^^ . _:b429699039 .