phenomenon · claim-type · cross-domain-transfer · mechanism · claim-relation · replication-status · limitation — grounded in the full text| phenomenon | a field that cannot replicate itself, writing down what it will count as rigour— “In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size” | |
| claim-type | method— “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | |
| method — evidence | — “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | |
| object of study — evidence | — “The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago [ 180 ]. Despite extension of the concept to ischemic postconditioning [ 460 ] and remote ischemic conditioning [ 202 , 344 ] and literally thousands of experimental studies in various species and models which identified a multitude… | |
| research question — evidence | — “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | |
| contribution — evidence | — “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | |
| mechanism | THE PAPER DEFINES ITS OWN TWO WORDS AND MAKES ONE DEPEND ON THE OTHER: `we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment.` Rigour is a property of the doing; reproducibility is a property of what happens next, somewhere else— “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | mechanisms[0] |
| mechanism | AND THE FAILURE THAT MOTIVATES IT IS COUNTED: `literally thousands of experimental studies in various species and models ... so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients`— “The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago [ 180 ]. Despite extension of the concept to ischemic postconditioning [ 460 ] and remote ischemic conditioning [ 202 , 344 ] and literally thousands of experimental studies in various species and models which identified a multitude… | mechanisms[1] |
| mechanism | AND A STANDARDISED MULTI-CENTRE REPLICATION FOUND ONE EFFECT OF THREE: `the CAESAR consortium ... in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size`— “In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size” | mechanisms[2] |
| mechanism | AND TWO IMPLEMENTATIONS OF ONE NAMED TEST GIVE DIFFERENT ANSWERS: `Caveat - different statistical software packages work with slightly different assumptions and can come to different outcomes, as demonstrated for the Wilcoxon-Mann-Whitney`. Third consecutive record in this corpus where one construct measured two ways gives two answers - zook2016's aligners, ainsworth2020's five assays, and now a statistical test that has a name and a citation— “Caveat—different statistical software packages work with slightly different assumptions and can come to different outcomes, as demonstrated for the Wilcoxon–Mann–Whitney” | mechanisms[3] |
| mechanism | AND THE SURROGATES DO NOT PREDICT THE THING THEY STAND IN FOR, with the real definition arriving in a parenthesis immediately afterwards: `None of the above-mentioned variable/surrogate endpoints is indeed predictive of clinical outcomes in patients with acute myocardial infarction, i.e. truly indicative of `cardioprotection` (which is primarily infarct size reduction)`— “None of the above-mentioned variable/surrogate endpoints is indeed predictive of clinical outcomes in patients with acute myocardial infarction, i.e. truly indicative of “cardioprotection” (which is primarily infarct size reduction).” | mechanisms[4] |
| mechanism | AND ONE DRUG IS THE COMMON DENOMINATOR OF THE FAILURES: `propofol specifically abrogates the protection by remote ischemic conditioning in patients undergoing elective coronary artery bypass graft surgery ... and seems to be a common denominator of all studies that failed to see protection`. A confounder that explains a literature's negative results, named— “Propofol seems no more cardioprotective than isoflurane per se, but in contrast to isoflurane and sevoflurane, propofol specifically abrogates the protection by remote ischemic conditioning in patients undergoing elective coronary artery bypass graft surgery [ 32 , 260 , 261 , 454 ], and seems to be a common denominator of all studies that… | mechanisms[5] |
| mechanism | the choice of statistical test follows the shape of the data, not the field: one endpoint at one time point takes a t test or one-way ANOVA, sequential measurements take a two-way repeated-measures ANOVA— “When comparing just a single endpoint at one single time point, a Student t test is appropriate for comparison of two groups; for more than two groups, a one-way ANOVA with subsequent tests for pairwise comparisons of mean values is appropriate.” | mechanisms[6] |
| mechanism | an improving standard of care raises the sample size a trial needs, because the event rate the intervention must beat keeps falling— “Current cardioprotection studies in patients undergoing reperfusion for STEMI are challenged by the excellent outcome with modern standard therapy.” | mechanisms[7] |
| mechanism | the assumed effect size is imported from proof-of-concept studies - a 25% reduction in events is rationalised by 30% reductions in infarct size reported earlier— “An effect size of 25% relative reduction in the event rate is rationalized by proof-of-concept clinical studies, in which remote ischemic conditioning was reported to induce 30% reductions in infarct size [ 185 ].” | mechanisms[8] |
| extends | the ARRIVE guidelines for reporting animal research and the ICH E9 and E6 guidelines for clinical trials, which this document adapts to cardioprotection— “According to the ICH E9 guideline [ 168 ], the primary variable “should be the variable capable of providing the most relevant and convincing evidence directly related to the primary objective of the trial”. This is also true for experimental studies, and ideally there is only one primary endpoint.” | claim_relations[0] |
| builds-on | the CAESAR consortium's standardised multi-centre preclinical replication, whose result is the evidence that the field's preclinical base does not replicate— “In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size” | claim_relations[1] |
| sense | `rigor` - DEFINED HERE AS A PROPERTY OF THE DOING: `standardized state-of-the-art design, conduct and reporting of a study`— “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | senses[0] |
| sense | `reproducibility` - DEFINED AS A PROPERTY OF WHAT HAPPENS ELSEWHERE: `replication of results by another laboratory when performing exactly the same experiment`, and rigour is named as its PREREQUISITE— “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | senses[1] |
| sense | `cardioprotection` - the operative sense arrives in a parenthesis at the moment the surrogates are disowned: `truly indicative of `cardioprotection` (which is primarily infarct size reduction)`— “None of the above-mentioned variable/surrogate endpoints is indeed predictive of clinical outcomes in patients with acute myocardial infarction, i.e. truly indicative of “cardioprotection” (which is primarily infarct size reduction).” | senses[2] |
| sense | `outlier` - operationalised by Tukey's fences rather than by judgement: data outside `first quartile - 1.5 inter-quartile range and third quartile + 1.5 inter-quartile range`— “The “whiskers” of the full box plot according to Tukey’s [ 428 ] original definition extend to the most extreme data within the inner fences, that is, first quartile—1.5 inter-quartile range and third quartile + 1.5 inter-quartile range. Data outside the inner fences, i.e. data points outside of the range depicted by the box and whiskers, are… | senses[3] |
| sense | `primary variable` - `the variable capable of providing the most relevant and convincing evidence directly related to the primary objective of the trial`, quoted from ICH E9, with `ideally there is only one primary endpoint`— “According to the ICH E9 guideline [ 168 ], the primary variable “should be the variable capable of providing the most relevant and convincing evidence directly related to the primary objective of the trial”. This is also true for experimental studies, and ideally there is only one primary endpoint.” | senses[4] |
| sense | `epitranscriptomics` - DEFINED ENTIRELY BY ITS PREFIX AND ITS SIBLING, IN ONE SENTENCE THAT DEFINES BOTH: `While transcriptomics refers to the characterization of gene expression at the ribonucleic acid (RNA) level, epitranscriptomics refers to post-transcriptional RNA modifications`. Neither term is given independently; the pair is introduced as a division of one territory.— “While transcriptomics refers to the characterization of gene expression at the ribonucleic acid (RNA) level, epitranscriptomics refers to post-transcriptional RNA modifications; the most frequent ones are pseudouridine (also called the “fifth nucleoside”) and N 6 -methyladenosine” | senses[5] |
| sense | `pseudouridine` / `the fifth nucleoside` - AN ALIAS THAT NAMES A POSITION IN A LIST, NOT A STRUCTURE. `pseudouridine (also called the “fifth nucleoside”)`. The paper reaches for the older name in passing; it is the kind of name that stops being true when the list it counts is extended.— “While transcriptomics refers to the characterization of gene expression at the ribonucleic acid (RNA) level, epitranscriptomics refers to post-transcriptional RNA modifications; the most frequent ones are pseudouridine (also called the “fifth nucleoside”) and N 6 -methyladenosine” | senses[6] |
| control | pre-specified inclusion and exclusion criteria, blinding, randomisation and a power calculation before the experiment starts — held— “The selection of the design (observational/exploratory vs. prospective) for a given project always represents a compromise of a most rigorous approach vs. limited resources and feasibility. Clearly, an exploratory study, while aiming for novelty, is associated with a greater risk of false-positive findings due to confounding factors, whereas… — rules out post-hoc adjustment of the study to its own result - stated as a prohibition: 'it is not permitted to change the sample size post hoc, to add a new randomized group, or to supplement additional experiments'— “When the analysis of the experiment results in no or only a borderline significance, it is not permitted to change the sample size post hoc, to add a new randomized group, or to supplement additional experiments.” | controls[0] |
| control | pretests for normality or homogeneity of variance before choosing a test — failed— “In some applications, pretests are performed to test data for normality or to test for homogeneity of variances. Those pretests cannot be recommended, since the failure to reject the null hypothesis does not imply that the null hypothesis holds, in particular since the power of the pretests is often low.” — rules out nothing, and the paper refuses the practice: 'Those pretests cannot be recommended, since the failure to reject the null hypothesis does not imply that the null hypothesis holds'— “In some applications, pretests are performed to test data for normality or to test for homogeneity of variances. Those pretests cannot be recommended, since the failure to reject the null hypothesis does not imply that the null hypothesis holds, in particular since the power of the pretests is often low.” | controls[1] |
| control | a consensus re-read when two human readers disagree about infarct size by more than 3% — held— “Infarct size is the gold standard primary endpoint; ventricular function or release of biomarkers during reperfusion may also be used as endpoints of cardioprotection. When infarct size is used as the primary endpoint, secondary endpoints can be hemodynamics such as coronary blood flow or ventricular function.” — rules out reader-dependent infarct size on the primary endpoint - a disagreement threshold that triggers a procedure rather than an argument— “If the difference in infarct size between the readers exceeds 3%, a consensus reading is recommended from the two or additional readers.” | controls[2] |
| control | a surrogate endpoint that predicts clinical outcome — absent-not-in-staged-text— “None of the above-mentioned variable/surrogate endpoints is indeed predictive of clinical outcomes in patients with acute myocardial infarction, i.e. truly indicative of “cardioprotection” (which is primarily infarct size reduction).” — rules out nothing - the paper says none exists: 'None of the above-mentioned variable/surrogate endpoints is indeed predictive of clinical outcomes'— “None of the above-mentioned variable/surrogate endpoints is indeed predictive of clinical outcomes in patients with acute myocardial infarction, i.e. truly indicative of “cardioprotection” (which is primarily infarct size reduction).” | controls[3] |
| weight | the ARRIVE guidelines for reporting animal research and the ICH E9 and E6 guidelines for clinical trials, which this document adapts to cardioprotection — 0.9— “According to the ICH E9 guideline [ 168 ], the primary variable “should be the variable capable of providing the most relevant and convincing evidence directly related to the primary objective of the trial”. This is also true for experimental studies, and ideally there is only one primary endpoint.” | claim_relations[0] |
| weight | the CAESAR consortium's standardised multi-centre preclinical replication, whose result is the evidence that the field's preclinical base does not replicate — 0.85— “In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size” | claim_relations[1] |
| note | exploratory —contrasted-with→ prospective — 'an EXPLORATORY…' - and the choice between them 'VS. LIMITED RESOURCES…'— “The selection of the design (observational/exploratory vs. prospective) for a given project always represents a compromise of a most rigorous approach vs. limited resources and feasibility. Clearly, an exploratory study, while aiming for novelty, is associated with a greater risk of false-positive findings due to confounding factors, whereas… | concept_edges[1] |
| weight | exploratory —contrasted-with→ prospective — 0.95— “The selection of the design (observational/exploratory vs. prospective) for a given project always represents a compromise of a most rigorous approach vs. limited resources and feasibility. Clearly, an exploratory study, while aiming for novelty, is associated with a greater risk of false-positive findings due to confounding factors, whereas… | concept_edges[1] |
| note | propofol —distinct-from→ isoflurane — 'Propofol seems…'. Equal on one axis, opposite on the one that decides the result— “Propofol seems no more cardioprotective than isoflurane per se, but in contrast to isoflurane and sevoflurane, propofol specifically abrogates the protection by remote ischemic conditioning in patients undergoing elective coronary artery bypass graft surgery [ 32 , 260 , 261 , 454 ], and seems to be a common denominator of all studies that… | concept_edges[2] |
| weight | propofol —distinct-from→ isoflurane — 0.95— “Propofol seems no more cardioprotective than isoflurane per se, but in contrast to isoflurane and sevoflurane, propofol specifically abrogates the protection by remote ischemic conditioning in patients undergoing elective coronary artery bypass graft surgery [ 32 , 260 , 261 , 454 ], and seems to be a common denominator of all studies that… | concept_edges[2] |
| audit | ischemic preconditioning —distinct-from→ nitrite — Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span reports nitrite failing where preconditioning worked; distinct-from is loose.— “In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size” | concept_edges[3] |
| note | ischemic preconditioning —distinct-from→ nitrite — 'identified ONLY…'. A standardised multi-centre replication separating one claimed effect from two that did not survive it— “In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size” | concept_edges[3] |
| weight | ischemic preconditioning —distinct-from→ nitrite — 0.95— “In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size” | concept_edges[3] |
| note | transcriptomics —distinct-from→ epitranscriptomics — 'While X refers to ..., Y refers to ...' - the paper asserts the division outright, so weight 1.0.— “While transcriptomics refers to the characterization of gene expression at the ribonucleic acid (RNA) level, epitranscriptomics refers to post-transcriptional RNA modifications; the most frequent ones are pseudouridine (also called the “fifth nucleoside”) and N 6 -methyladenosine” | concept_edges[4] |
| note | pseudouridine —same-as→ fifth nucleoside — 'also called' - an explicit alias, both names inside the one span.— “While transcriptomics refers to the characterization of gene expression at the ribonucleic acid (RNA) level, epitranscriptomics refers to post-transcriptional RNA modifications; the most frequent ones are pseudouridine (also called the “fifth nucleoside”) and N 6 -methyladenosine” | concept_edges[5] |
| note | HL-1 cells —distinct-from→ adult cardiomyocytes — 'they do not represent true adult cardiomyocytes' - a flat denial of the model relation, in a paper whose subject is whether preclinical models support their conclusions. Not hedged: weight 1.0.— “they do not represent true adult cardiomyocytes but rather a hybrid stage between embryonic and postmitotic cells. In contrast to adult cardiomyocytes, the energy metabolism of HL-1 cells relies on glycolytic activity” | concept_edges[6] |
| outcome | control — held— “When the analysis of the experiment results in no or only a borderline significance, it is not permitted to change the sample size post hoc, to add a new randomized group, or to supplement additional experiments.”— “The selection of the design (observational/exploratory vs. prospective) for a given project always represents a compromise of a most rigorous approach vs. limited resources and feasibility. Clearly, an exploratory study, while aiming for novelty, is associated with a greater risk of false-positive findings due to confounding factors, whereas… | controls[0] |
| outcome | control — failed— “In some applications, pretests are performed to test data for normality or to test for homogeneity of variances. Those pretests cannot be recommended, since the failure to reject the null hypothesis does not imply that the null hypothesis holds, in particular since the power of the pretests is often low.” | controls[1] |
| outcome | control — held— “If the difference in infarct size between the readers exceeds 3%, a consensus reading is recommended from the two or additional readers.”— “Infarct size is the gold standard primary endpoint; ventricular function or release of biomarkers during reperfusion may also be used as endpoints of cardioprotection. When infarct size is used as the primary endpoint, secondary endpoints can be hemodynamics such as coronary blood flow or ventricular function.” | controls[2] |
| outcome | control — absent-not-in-staged-text— “None of the above-mentioned variable/surrogate endpoints is indeed predictive of clinical outcomes in patients with acute myocardial infarction, i.e. truly indicative of “cardioprotection” (which is primarily infarct size reduction).” | controls[3] |
| limitation | THE INSTRUMENT DECIDES WHAT IS FOUND, STATED THREE TIMES IN THREE TECHNOLOGIES. RNA: `it is not recommended to use different kits in the same study, since some will favor the isolation of short RNAs while others will enrich the RNA fraction with long molecules`— “Due to the different kind of kits, it is not recommended to use different kits in the same study, since some will favor the isolation of short RNAs while others will enrich the RNA fraction with long molecules.” | limitations[0] |
| limitation | proteomics: `the large abundance proteins mask the changes of low-abundance proteins which also make a significant contribution to cellular signalling` - and the targeted alternative `loses the unbiased feature of proteomics`. Coverage and accuracy traded against each other, explicitly— “This results in the major limitation of unbiased proteomics analysis, i.e. the large abundance proteins mask the changes of low-abundance proteins which also make a significant contribution to cellular signalling.” | limitations[1] |
| limitation | and multiomics software: `their diversity in mathematical models and source data do not yet allow accurate comparison of different results`— “Analysis of multiomics data (target predictions, pathway analyses) needs excessive bioinformatic expertise. However, user-friendly software is rapidly emerging, but their diversity in mathematical models and source data do not yet allow accurate comparison of different results.” | limitations[2] |
| limitation | AND THERE IS NO ACCEPTED METHOD FOR MISSING VALUES, QUOTED FROM SOMEBODY ELSE RATHER THAN ASSERTED: `Unfortunately, there is `NO METHODOLOGICAL APPROACH FOR HANDLING MISSING VALUES THAT IS UNIVERSALLY ACCEPTED IN ALL SITUATIONS``— “Missing values can bias the results. In the presence of many missing values, the ability to draw valid conclusions is seriously compromised. Unfortunately, there is “no methodological approach for handling missing values that is universally accepted in all situations” | limitations[3] |
| limitation | AND A COMMON PRACTICE IS REFUSED FOR A REASON THAT IS A ZERO-CLAIM ABOUT AN INSTRUMENT: `pretests are performed to test data for normality ... Those pretests cannot be recommended, since the failure to reject the null hypothesis does not imply that the null hypothesis holds, in particular since the power of the pretests is often low`— “In some applications, pretests are performed to test data for normality or to test for homogeneity of variances. Those pretests cannot be recommended, since the failure to reject the null hypothesis does not imply that the null hypothesis holds, in particular since the power of the pretests is often low.” | limitations[4] |
| limitation | AND THE CHOICE OF DESIGN IS ADMITTED TO BE A COMPROMISE RATHER THAN A STANDARD: `The selection of the design ... always represents a compromise of a most rigorous approach vs. limited resources and feasibility. Clearly, an exploratory study, while aiming for novelty, is associated with a greater risk of false-positive findings ... whereas a prospective study aims for an existing specific hypothesis but provides more robust data`— “The selection of the design (observational/exploratory vs. prospective) for a given project always represents a compromise of a most rigorous approach vs. limited resources and feasibility. Clearly, an exploratory study, while aiming for novelty, is associated with a greater risk of false-positive findings due to confounding factors, whereas… | limitations[5] |
| limitation | and two authors of a rigour guideline hold commercial interests in the field, declared: shareholders in a company and a founder-CEO of a group of R&D companies. Not a defect - a disclosure, and it belongs next to the paper's subject the way hoste2006's `SOME MEMBERS OF OUR RESEARCH GROUP HAVE CONTRIBUTED TO THE CONSENSUS PROCESS BY WHICH RIFLE WAS DEVELOPED` does— “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | limitations[6] |
| limitation | cardiac mortality has fallen steadily for 25 years and is now very low, so the outcome a cardioprotection trial must improve on is already excellent— “Cardiac mortality at 12 months has decreased continuously over the last 25 years [ 368 ] and is now below 6% [ 126 ], while rehospitalisation for heart failure is 8% [ 126 ].” | limitations[7] |
| limitation | a clinical outcome trial on the composite endpoint needs patients in the thousands per arm, which the paper spells out rather than leaving implicit— “To demonstrate a 25% reduction in the primary composite endpoint in the intervention group (from 8.0 to 6.0%), with 80% power and at the 5% significance level, will require 2554 patients/treatment arm which equates to 5108 patients in total.” | limitations[8] |
| limitation | reduction of the biochemical marker by the intervention has ranged from no effect at all to a large reduction across previous studies— “The reduction of biochemical marker release by a cardioprotective intervention has varied from no effect to up to 43% reduction by remote ischemic conditioning in previous studies [ 202 ].” | limitations[9] |
| limitation | stratified analyses must carry their own power calculations, or the stratification is not valid— “Power calculations must be provided to ensure the validity of the stratified analyses.” | limitations[10] |
finding · quantity · variable · definition · key-term — grounded in the full text| finding | — “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | content_tags.findings[0] |
| finding | — “The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago [ 180 ]. Despite extension of the concept to ischemic postconditioning [ 460 ] and remote ischemic conditioning [ 202 , 344 ] and literally thousands of experimental studies in various species and models which identified a multitude… | content_tags.findings[1] |
| finding | — “In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size” | content_tags.findings[2] |
| finding | — “Caveat—different statistical software packages work with slightly different assumptions and can come to different outcomes, as demonstrated for the Wilcoxon–Mann–Whitney” | content_tags.findings[3] |
| finding | — “None of the above-mentioned variable/surrogate endpoints is indeed predictive of clinical outcomes in patients with acute myocardial infarction, i.e. truly indicative of “cardioprotection” (which is primarily infarct size reduction).” | content_tags.findings[4] |
| finding | — “Propofol seems no more cardioprotective than isoflurane per se, but in contrast to isoflurane and sevoflurane, propofol specifically abrogates the protection by remote ischemic conditioning in patients undergoing elective coronary artery bypass graft surgery [ 32 , 260 , 261 , 454 ], and seems to be a common denominator of all studies that… | content_tags.findings[5] |
| finding | — “Due to the different kind of kits, it is not recommended to use different kits in the same study, since some will favor the isolation of short RNAs while others will enrich the RNA fraction with long molecules.” | content_tags.findings[6] |
| finding | — “This results in the major limitation of unbiased proteomics analysis, i.e. the large abundance proteins mask the changes of low-abundance proteins which also make a significant contribution to cellular signalling.” | content_tags.findings[7] |
| finding | — “Analysis of multiomics data (target predictions, pathway analyses) needs excessive bioinformatic expertise. However, user-friendly software is rapidly emerging, but their diversity in mathematical models and source data do not yet allow accurate comparison of different results.” | content_tags.findings[8] |
| finding | — “Missing values can bias the results. In the presence of many missing values, the ability to draw valid conclusions is seriously compromised. Unfortunately, there is “no methodological approach for handling missing values that is universally accepted in all situations” | content_tags.findings[9] |
| finding | — “In some applications, pretests are performed to test data for normality or to test for homogeneity of variances. Those pretests cannot be recommended, since the failure to reject the null hypothesis does not imply that the null hypothesis holds, in particular since the power of the pretests is often low.” | content_tags.findings[10] |
| finding | — “If the difference in infarct size between the readers exceeds 3%, a consensus reading is recommended from the two or additional readers.” | content_tags.findings[11] |
| finding | with the outlier included, the test gives t = 4.82 (36 df) and P < 0.001— “When the analysis is performed with all data including the outlier, the test statistic is t = 4.82 (36 degrees of freedom) and the P value is given as P < 0.001.” | content_tags.findings[12] |
| finding | without the outlier, t = 6.08 (35 df), P < 0.001, and the group-mean difference is 20.06 (SD 10.03)— “When the analysis is performed without the outlier, the test statistic is t = 6.08 (35 degrees of freedom), the P value is given as P < 0.001, and the difference between the group means is 38.89–18.83 = 20.06 with a standard deviation of 10.03.” | content_tags.findings[13] |
| finding | detecting a 0.1 increase in salvage index needs 83 patients per group at 80% power and two-sided alpha 0.05— “Assuming a standard deviation of the salvage index of 0.23 [ 370 ] and that data conform with a parametric distribution, a demonstration of an increase in salvage index of 0.1 requires a sample size of 83 patients in each group with a power of 80% and a two-sided α value of 0.05.” | content_tags.findings[14] |
| finding | a biomarker reduction that was not powered for outcome nonetheless tracked increased survival and fewer events in an earlier study— “Although not powered for clinical outcome, a previous study demonstrated that a 17.3% reduction in the troponin-I (TnI) area under the curve by remote ischemic conditioning translated into a clinical benefit in terms of increased survival and lower numbers of MACCE [ 421 ].” | content_tags.findings[15] |
| quantity | 3 % infarct size — the disagreement between two human readers that triggers a consensus re-read— “If the difference in infarct size between the readers exceeds 3%, a consensus reading is recommended from the two or additional readers.” | content_tags.quantities[0] |
| quantity | 1.5 inter-quartile ranges — Tukey's inner fences - the operational boundary of 'outlier'— “The “whiskers” of the full box plot according to Tukey’s [ 428 ] original definition extend to the most extreme data within the inner fences, that is, first quartile—1.5 inter-quartile range and third quartile + 1.5 inter-quartile range. Data outside the inner fences, i.e. data points outside of the range depicted by the box and whiskers, are… | content_tags.quantities[1] |
| quantity | 1 study — the number of studies that had unequivocally translated cardioprotection to improved clinical outcome, against thousands of experimental ones— “The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago [ 180 ]. Despite extension of the concept to ischemic postconditioning [ 460 ] and remote ischemic conditioning [ 202 , 344 ] and literally thousands of experimental studies in various species and models which identified a multitude… | content_tags.quantities[2] |
| quantity | the infarct size target and the salvage index change it corresponds to— “A final infarct size of ≤ 12% of left ventricle is a rational target, because an infarct size of this magnitude is associated with very low mortality [ 63 , 306 ].” | content_tags.quantities[3] |
| quantity | current cardiac mortality, heart-failure rehospitalisation and composite endpoint incidence in the most recent cohort— “have demonstrated a further decrease with a cardiac mortality of 2.1%, rehospitalization for heart failure at 12 months of 6.4% and a composite endpoint incidence of 8.0%.” | content_tags.quantities[4] |
| variable | Infarct size— “Infarct size is the gold standard primary endpoint; ventricular function or release of biomarkers during reperfusion may also be used as endpoints of cardioprotection. When infarct size is used as the primary endpoint, secondary endpoints can be hemodynamics such as coronary blood flow or ventricular function.” | content_tags.variables[0] |
| definition | rigor— “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | content_tags.definitions[0] |
| definition | reproducibility— “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | content_tags.definitions[1] |
| definition | outlier— “The “whiskers” of the full box plot according to Tukey’s [ 428 ] original definition extend to the most extreme data within the inner fences, that is, first quartile—1.5 inter-quartile range and third quartile + 1.5 inter-quartile range. Data outside the inner fences, i.e. data points outside of the range depicted by the box and whiskers, are… | content_tags.definitions[2] |
| definition | primary variable— “According to the ICH E9 guideline [ 168 ], the primary variable “should be the variable capable of providing the most relevant and convincing evidence directly related to the primary objective of the trial”. This is also true for experimental studies, and ideally there is only one primary endpoint.” | content_tags.definitions[3] |
| concept | rigor — standardized state-of-the-art design, conduct and reporting of a study— “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | concepts[0] |
| concept | reproducibility — not defined in this paper's own words; replication of results by another laboratory performing exactly the same experiment— “We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [ 279 ], and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [ 279 ], we define rigor as standardized state-of-the-art design… | concepts[1] |
| concept | exploratory — not defined in this paper's own words; the design that aims for novelty and carries a greater risk of false positives— “The selection of the design (observational/exploratory vs. prospective) for a given project always represents a compromise of a most rigorous approach vs. limited resources and feasibility. Clearly, an exploratory study, while aiming for novelty, is associated with a greater risk of false-positive findings due to confounding factors, whereas… | concepts[2] |
| concept | prospective — not defined in this paper's own words; the design that tests an existing hypothesis and provides more robust data— “The selection of the design (observational/exploratory vs. prospective) for a given project always represents a compromise of a most rigorous approach vs. limited resources and feasibility. Clearly, an exploratory study, while aiming for novelty, is associated with a greater risk of false-positive findings due to confounding factors, whereas… | concepts[3] |
| concept | propofol — not defined in this paper's own words; the anaesthetic that abolishes remote ischemic conditioning's protection and is common to the studies that found none— “Propofol seems no more cardioprotective than isoflurane per se, but in contrast to isoflurane and sevoflurane, propofol specifically abrogates the protection by remote ischemic conditioning in patients undergoing elective coronary artery bypass graft surgery [ 32 , 260 , 261 , 454 ], and seems to be a common denominator of all studies that… | concepts[4] |
| concept | isoflurane — not defined in this paper's own words; the inhaled anaesthetic that does not abolish it— “Propofol seems no more cardioprotective than isoflurane per se, but in contrast to isoflurane and sevoflurane, propofol specifically abrogates the protection by remote ischemic conditioning in patients undergoing elective coronary artery… | concepts[5] |
| concept | ischemic preconditioning — not defined in this paper's own words; the one intervention CAESAR's standardised multi-centre replication confirmed | concepts[6] |
| concept | nitrite — not defined in this paper's own words; one of the two interventions the same replication did not confirm | concepts[7] |
| concept | salvage index — not defined in this paper's own words; the proportion of the area at risk rescued - the proof-of-concept endpoint, which converts an infarct-size change into the quantity trials are powered on | concepts[8] |
| concept | area at risk — not defined in this paper's own words; the denominator of the salvage index - how much myocardium was threatened, without which an infarct size means nothing | concepts[9] |
| concept | hazard ratio — not defined in this paper's own words; what a survival-endpoint power calculation is actually based on, illustrated here with the survival percentages that produce it | concepts[10] |
| concept | multiplicity — not defined in this paper's own words; the requirement that testing several pairs after an omnibus test be adjusted for, with the adjusted P values reported | concepts[11] |
| concept | effect size — not defined in this paper's own words; here the difference between group means with its confidence interval - reported alongside the P value rather than instead of it Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[12] |
| concept | transcriptomics — not defined in this paper's own words; characterization of gene expression at the RNA level - defined here only by the contrast with its own prefixed sibling Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[13] |
| concept | epitranscriptomics — not defined in this paper's own words; post-transcriptional RNA modification, i.e. the layer ABOVE the transcript rather than the transcript itself; the 'epi-' prefix does the whole definitional work Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[14] |
| concept | pseudouridine — not defined in this paper's own words; an RNA modification, carrying a second and much older name given by position in a list rather than by structure Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[15] |
| concept | fifth nucleoside — not defined in this paper's own words; the alias for pseudouridine - a name that says only WHERE IT COMES IN AN ENUMERATION, and so cannot survive the enumeration changing Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[16] |
| concept | HL-1 cells — not defined in this paper's own words; an immortalised cardiac line the paper declines to treat as a stand-in for adult tissue Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[17] |
| concept | adult cardiomyocytes — not defined in this paper's own words; the thing HL-1 cells are a model OF and, the paper says, are not Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[18] |
Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.statistics[0] | |
Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.statistics[1] |
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