Response to “Normothermic Machine Perfusion: A New World Deserving Careful Exploration”
Bibliographic record
Abstract
To the Editor: We thank Pezzati and colleagues for endorsing our innovative endeavors in ex vivo liver normothermic perfusion (NMP) (1Bral M Gala-Lopez B Bigam D et al.Preliminary single-center canadian experience of human normothermic ex vivo liver perfusion: Results of a clinical trial.Am J Transplant. 2016; (doi:10.1111/ajt.14049.)PubMed Google Scholar,2Pezzati D Liu Q Hassan A Diago Uso T Buccini L Quintini C Normothermic machine perfusion: A new world deserving careful exploration.Am J Transplant. 2017; (doi: 10.1111/ajt.14249.)Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). We take issue, however, with the surmise that we implicitly assumed the notion that NMP provides superior outcomes in this small 10-liver pilot trial. Our trial was designed with safety, not efficacy, as the primary outcome determinant. Only large-scale randomized controlled studies such as those currently being completed in Europe and in the United States by OrganOx will have the power to determine superiority. The seemingly high rate of donation after cardiac death (DCD; four livers) in our small consecutive series was not an intent on our part to push NMP limits. We acknowledge, however, that in the collective clinical NMP experience to date, there has been preferential use of DCD livers within experimental arms. We see that as positive because it has begun to generate important preliminary safety data that may justify application of NMP with marginal livers in future trials. We accept that the donor risk index has potential limitations and that alternative approaches could have been applied to generate a better control group. We acknowledge that our NMP group had a high proportion of outliers with long perfusion times and that we could have chosen to transplant some of those grafts in shorter time frames. In our opinion, total preservation time represents an overly cautious way to compare outcomes of cold stored versus NMP grafts, as it assumes that cumulative injury over time is similar with both modalities; this is hard for us to accept for metabolically functional livers actively producing bile ex vivo. Matching storage duration in both modalities would be difficult because livers require at least 4–6 h to stabilize during the NMP phase (3Angelico R Perera MT Ravikumar R et al.Normothermic machine perfusion of deceased donor liver grafts is associated with improved postreperfusion hemodynamics.Transplant Direct. 2016; 2: e97Crossref PubMed Scopus (46) Google Scholar, 4Ravikumar R Jassem W Mergental H et al.Liver transplantation after ex vivo normothermic machine preservation: A phase 1 (first-in-man) clinical trial.Am J Transplant. 2016; 16: 1779-1787Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, 5Selzner M Goldaracena N Echeverri J et al.Normothermic ex vivo liver perfusion using steen solution as perfusate for human liver transplantation: First North American results.Liver Transpl. 2016; 22: 1501-1508Crossref PubMed Scopus (134) Google Scholar). Although extended NMP duration should be monitored closely in ongoing safety trials, accrued porcine and limited pilot clinical experience suggests that NMP duration is not a critical variable, especially when kept ≤24 h (4Ravikumar R Jassem W Mergental H et al.Liver transplantation after ex vivo normothermic machine preservation: A phase 1 (first-in-man) clinical trial.Am J Transplant. 2016; 16: 1779-1787Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar). However, we recognize that little is known about metabolic substrate depletion or accumulation of toxic waste products on the NMP circuit, which could potentially become a critical issue when extreme time limits are reached. Perhaps we can all agree that safety is paramount, but the new NMP paradigm offers opportunities to explore potential beyond the limited confines of the ice box. The author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.005 | 0.035 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.003 | 0.003 |
| Scholarly communication | 0.004 | 0.005 |
| Open science | 0.004 | 0.001 |
| Research integrity | 0.035 | 0.045 |
| Insufficient payload (model declined to judge) | 0.008 | 0.007 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".