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COVID-19-related medical research: a meta-research and critical appraisal

1/12/2021

 
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As with many fields, science has been put to the test by the coronavirus pandemic. An international team of researchers, led by French scientists, has demonstrated novel scientific practices around Covid-19. Under the pressure of the number of cases and the urgent need to understand the virus, many research groups have shared results, sometimes to the expense of high scientific standards.

During the first wave of the Covid-19 epidemic, medical research saw a historic number of studies on the coronavirus published in a short period of time. An international consortium of experts in medical methodology undertook the major challenge of evaluating the Covid-19 research during this first wave.

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Assessment of the Utility of Kidney Histology as a Basis for Discarding Organs in the US

12/15/2020

 
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New research indicates that analyses of kidney biopsies from deceased donors don’t provide meaningful information beyond standard assessments of donor and recipient characteristics. In addition, the study revealed that relying on these analyses has prompted the discard of many potentially suitable organs for transplantation in the United States. The findings appear in JASN.

Despite a critical scarcity of organs available for transplantation, thousands of deceased donor kidneys are discarded each year in the United States. 


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Identification and characterization of trajectories of cardiac allograft vasculopathy after heart transplantation

5/4/2020

 
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Every year, tens of thousands of deaths are due to end-stage heart failure in Europe and in the US combined. Heart transplantation is the ultimate treatment, but its number is dramatically limited due to the shortage of organs in those countries. 
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​In the same time, the chances of survival beyond one year after transplantation have remained unchanged in recent years, despite significant progress in immunosuppressive therapy and patient care.
One of the most common reasons for long-term graft failure and patient death is an accelerated form of coronary artery disease called cardiac allograft vasculopathy. It is a frequent complication that affects up to half of patients within 10 years following heart transplantation. Yet, until now, little has been known about the different evolutive profiles of cardiac allograft vasculopathy and their risk factors.

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Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study

3/3/2020

 
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The first universal algorithm for predicting the risk of kidney transplant loss, named iBox, has been developed, validated and just made public by teams from Europe and the US.

​The iBox is designed for clinicians to personalize and improve patient follow-up. The iBox could also accelerate the development of new immunosuppressive treatments by reducing the duration of clinical trials and defining a valid surrogate endpoint.
Chronic kidney disease affects 1 out of 10 people worldwide and is steadily increasing. When it reaches end-stage renal disease and endangers the lives of patients, dialysis or transplantation is required. ​

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Disparities in Acceptance of Deceased Donor Kidneys Between the United States and France and Estimated Effects of Increased US Acceptance

8/26/2019

 
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New publication in JAMA Internal Medicine: The first international analysis of renal transplant patient data shows that a change in allocation criteria in the United States could benefit patients on the waiting list. Thousands more kidneys could be transplanted each year if the United States used, as France does, kidneys from older donors.
Nearly 5,000 people in the United States and 3,500 in Europe die each year waiting for a kidney transplant. Yet, over the same period, in the United States, more than 3,500 available kidneys were discarded. The Journal of the American Medical Association (JAMA) Internal Medicine today published our results, obtained with the help of an international team, that compared the use of kidneys available in the United States and France between 2004 and 2014. ​
Using a new approach based on validated analytical methods and computer simulations, this work revealed that French transplant centres are much more likely to transplant kidneys from older donors than their American counterparts, and that this effectively increases the number of patients transplanted. 

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Archetype Analysis Identifies Distinct Profiles in Renal Transplant Recipients with Transplant Glomerulopathy Associated with Allograft Survival

3/14/2019

 
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New research conducted by the Paris Translational Research Center for Organ Transplantation team could help clinicians determine which patients will have a disease that usually occurs after a kidney transplant and which are at high risk of transplant failure. The results are published today in the prestigious Journal of the American Society of Nephrology (JASN).

Transplant glomerulopathy was first described and characterized 50 years ago. It is a disease associated with the loss of a kidney transplant and common after a transplant. It affects the functional units (i. e. glomeruli) of the transplanted kidney. There is currently no treatment for this heterogeneous disease.

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Building a tissue-based molecular diagnostic system in heart transplant rejection: The heart Molecular Microscope Diagnostic (MMDx) System.

11/9/2017

 
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Abstract
Halloran PF, Potena L, Van Huyen JD, Bruneval P, Leone O, Kim DH, Jouven X, Reeve J, Loupy A.

The emergence of molecular systems offers opportunities for improving the assessment of rejection in heart transplant biopsy specimens. The present study developed a microarray-based system for assessing heart transplant endomyocardial biopsy (EMB) specimens.
We analyzed 331 protocol or for-cause EMB specimens from 221 subjects in 3 centers (Edmonton, Bologna, and Paris). Unsupervised principal component analysis (PCA) and archetype analysis used rejection-associated transcripts (RATs) shown in kidney transplants to be associated with antibody-mediated rejection (ABMR) or T cell-mediated rejection (TCMR), or both. To compare EMB specimens to kidney biopsy specimens, rejection status in both was simplified to TCMR, ABMR, or no rejection.
The pattern of RAT expression was similar in EMB and kidney specimens, permitting use of RATs to assign scores and group ("cluster") membership to each EMB, independent of histology. Three clusters emerged in EMB specimens, similar to kidney specimens: TCMR, ABMR, and no rejection. This permitted each EMB specimen to be given 3 scores and assigned to 1 cluster by its highest score. There was significant agreement between molecular phenotype-archetype scores or clusters-and both histologic diagnoses and donor-specific antibody. Area under curve estimates for predicting histologic TCMR, ABMR, and no rejection by molecular assessment were lower in EMB specimens than in kidney specimens, reflecting more uncertainty in EMB specimens, particularly in histologic diagnosis of TCMR.
Rejection-associated transcripts can be used to estimate the probability of TCMR and ABMR in heart transplant specimens, providing a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines.
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J Heart Lung Transplant. 2017 Nov;36(11):1192-1200
PMID:28662985

European Society of Organ Transplantation (ESOT) Congress 2017 - Our abstracts

9/24/2017

 
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​Sunday September 24, 2017

1/ MOLECULAR CORRELATES OF ENDOTHELIAL MTOR ACTIVATION IN HEART TRANSPLANT RECIPIENTS
Session: “ Basic and translational immunology” (17:45 to 18:45)
Location: Room 118 + 119 – 18:29 

M Racapé, A Loupy, J Reeve, J Venner , R Guillemain, L Hidalgo, C Lefaucher, X Jouven, P Bruneval, J Duaong Van Huyen, P Halloran 
Background
The detection of phosphorylated effectors of the mTOR pathway such as phosphorylated-S6RP in endothelial cells by immunohistochemistry (IHC) has been associated with Antibody-Mediated allograft Rejection (AMR). The aim of this study was to evaluate the molecular phenotype related to the endothelial detection of pS6RP in heart transplant recipients.
Methods
This case-control study included 41 heart transplant patients from four French referral centers with biopsy proven antibody-mediated rejection (pAMR+) and a matched control group of 30 patients without rejection (pAMR0) based on the updated ISHLT classification. From these patients, 94 endomyocardial biopsies (EMB) had adequate material for microarray analysis and endothelial expression analysis of pS6RP by IHC. We also determined the allograft gene expression profile using the ABMR molecular score in addition to pathogenesis-based transcripts reflecting endothelial activation (DSAST and ENDAT), macrophage burden (QCMAT), gamma-interferon response (GRIT) and NK-cell burden (NKB) (http://atagc.med.ualberta.ca).
Results
Among the 94 EMBs included in the main analyses, 50 were pAMR+ (53.2%) and 44 (46.8%) were pAMR0 normal EMBs. Endothelial expression of pS6RP was observed in 27/50 (54%) of pAMR+ biopsies and 12 out of 44 normal biopsies (27.3%, Fischer's exact: p=0.012). As compared with biopsies without pS6RP labeling, biopsies with pS6RP staining showed increased expression of DSAST (Mann-Whitney: p<0.0001), ENDAT (p=0.0009), QCMAT (p=0.0046), NKB (p=0.0001), GRIT (p=0.0008) and increased ABMR molecular score reflecting AMR injury (p=0.0001).
Conclusion
Endothelial activation of mTOR pathway is associated with AMR and increased expression in transcripts reflecting endothelial activation, macrophage burden, microcirculation and NK burden. Our results suggest the importance of the mTOR pathway activation in AMR injury and the potential interest of using mTOR inhibitors in this setting.

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ISHLT 2016 Annual Meeting & Scientific Sessions

4/30/2016

 
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Plenary session - Saturday April 30, 2016 - 10:55
Pushing New Scientific Frontiers: It’s In Our Heritage

Precision Medicine in Organ Transplantation: Moving from Off the Rack to Bespoke, Alexandre Loupy, MD, PhD, Necker Hospital, Paris, France

Abstracts -Thursday April 28, 2016 - 11:45
Molecular Correlates of Endothelial mTOR Activation in Heart Transplant Recipients

Authors
M. Racapé, A. Loupy, J. Reeve, J. Venner, R. Guillemain, L. Hidalgo, C. Lefaucheur, X. Jouven, P. Bruneval, J. Duong Van Huyen, P. Halloran. 

Abstract
  • Purpose: The detection of phosphorylated effectors of the mTOR pathway in endothelial cells by immunohistochemistry (IHC) has been associated with allograft rejection. The aim of this study was to evaluate in heart transplant recipients the molecular phenotype related to the endothelial detection of the phosphorylated effectors of the mTOR pathway, pS6RP.
  • Methods: This case-control study included 41 heart transplant patients from four French referral centers with biopsy proven antibody-mediated rejection (pAMR+) and a matched control group of 32 patients without rejection (pAMR0) based on the updated ISHLT classification. From these patients, 93 endomyocardial biopsies (EMB) had adequate material for microarray analysis and IHC. We studied in all EMB the endothelial expression of pS6RP by IHC. We also determined the allograft gene expression profile using the ABMR molecular score in addition to pathogenesis-based transcripts reflecting endothelial activation (DSAST and ENDAT), macrophage burden (QCMAT), gamma-interferon response (GRIT) and NK-cell burden (NKB) (http://atagc.med.ualberta.ca).
  • Results: Among the 93 EMBs included in main analyses, 49 were pAMR+ (52.7%) and 44 (47.3%) were pAMR0 normal EMBs. Endothelial expression of pS6RP was observed in 27/49 (55.1%) of pAMR+ biopsies and 12 out of 44 normal biopsies (27.3%, Fischer's exact: p=0.011). As compared with biopsies without endothelial pS6RP labeling, biopsies with positive endothelial pS6RP staining showed increased expression in DSAST (Mann-Whitney: p<0.0001), ENDAT (p=0.0008), QCMAT (p=0.0052), NKB (p=0.0001) and increased ABMR molecular score reflecting interferon-effects, microcirculation stress and NK burden (p=0.0001).
  • Conclusion: Endothelial activation of mTOR pathway is associated with antibody-mediated allograft rejection and increased expression in transcripts reflecting endothelial activation, macrophage burden, microcirculation and NK burden. Our results suggest the importance of the mTOR pathway activation in antibody-mediated heart allograft injury and the potential interest of using mTOR inhibitors in this setting.

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