Personalized Dynamic Treatment Regimes in Continuous Time: A Bayesian Approach for Optimizing Clinical Decisions with Timing

Accurate models of clinical actions and their impacts on disease progression are critical for estimating personalized optimal dynamic treatment regimes (DTRs) in medical/health research, especially in managing chronic conditions. Traditional statistical methods for DTRs usually focus on estimating the optimal treatment or dosage at each given medical intervention, but overlook the important question of "when this intervention should happen." We fill this gap by developing a two-step Bayesian approach to optimize clinical decisions with timing. In the first step, we build a generative model for a sequence of medical interventions-which are discrete events in continuous time-with a marked temporal point process (MTPP) where the mark is the assigned treatment or dosage. Then this clinical action model is embedded into a Bayesian joint framework where the other components model clinical observations including longitudinal medical measurements and time-to-event data conditional on treatment histories. In the second step, we propose a policy gradient method to learn the personalized optimal clinical decision that maximizes the patient survival by interacting the MTPP with the model on clinical observations while accounting for uncertainties in clinical observations learned from the posterior inference of the Bayesian joint model in the first step. A signature application of the proposed approach is to schedule follow-up visitations and assign a dosage at each visitation for patients after kidney transplantation. We evaluate our approach with comparison to alternative methods on both simulated and real-world datasets. In our experiments, the personalized decisions made by the proposed method are clinically useful: they are interpretable and successfully help improve patient survival

Kidney allograft rejection is associated with an imbalance of B cells, regulatory T cells and differentiated CD28-CD8+ T cells: analysis of a cohort of 1095 graft biopsies

IntroductionThe human immune system contains cells with either effector/memory or regulatory functions. Besides the well-established CD4+CD25hiCD127lo regulatory T cells (Tregs), we and others have shown that B cells can also have regulatory functions since their frequency and number are increased in kidney graft tolerance and B cell depletion as induction therapy may lead to acute rejection. On the other hand, we have shown that CD28-CD8+ T cells represent a subpopulation with potent effector/memory functions. In the current study, we tested the hypothesis that kidney allograft rejection may be linked to an imbalance of effector/memory and regulatory immune cells.MethodsBased on a large cohort of more than 1000 kidney graft biopsies with concomitant peripheral blood lymphocyte phenotyping, we investigated the association between kidney graft rejection and the percentage and absolute number of circulating B cells, Tregs, as well as the ratio of B cells to CD28-CD8+ T cells and the ratio of CD28-CD8+ T cells to Tregs. Kidney graft biopsies were interpreted according to the Banff classification and divided into 5 biopsies groups: 1) normal/subnormal, 2) interstitial fibrosis and tubular atrophy grade 2/3 (IFTA), 3) antibody-mediated rejection (ABMR), 4) T cell mediated-rejection (TCMR), and 5) borderline rejection. We compared group 1 with the other groups as well as with a combined group 3, 4, and 5 (rejection of all types) using multivariable linear mixed models.Results and discussionWe found that compared to normal/subnormal biopsies, rejection of all types was marginally associated with a decrease in the percentage of circulating B cells (p=0.06) and significantly associated with an increase in the ratio of CD28-CD8+ T cells to Tregs (p=0.01). Moreover, ABMR, TCMR (p=0.007), and rejection of all types (p=0.0003) were significantly associated with a decrease in the ratio of B cells to CD28-CD8+ T cells compared to normal/subnormal biopsies. Taken together, our results show that kidney allograft rejection is associated with an imbalance between immune cells with effector/memory functions and those with regulatory properties

On the clinical relevance of using complete high-resolution HLA typing for an accurate interpretation of posttransplant immune-mediated graft outcomes

Complete and high-resolution (HR) HLA typing improves the accurate assessment of donor-recipient compatibility and pre-transplant donor-specific antibodies (DSA). However, the value of this information to identify de novo immune-mediated graft events and its impact on outcomes has not been assessed. In 241 donor/recipient kidney transplant pairs, DNA samples were re-evaluated for six-locus (A/B/C/DRB1/DQB1+A1/DPB1) HR HLA typing. De novo anti-HLA antibodies were assessed using solid-phase assays, and dnDSA were classified either (1) as per current clinical practice according to three-locus (A/B/DRB1) low-resolution (LR) typing, estimating donor HLA-C/DQ typing with frequency tables, or (2) according to complete six-locus HR typing. The impact on graft outcomes was compared between groups. According to LR HLA typing, 36 (15%) patients developed dnDSA (LR_dnDSA+). Twenty-nine out of 36 (80%) were confirmed to have dnDSA by HR typing (LR_dnDSA+/HR_dnDSA+), whereas 7 (20%) did not (LR_dnDSA+/HR_dnDSA-). Out of 49 LR_dnDSA specificities, 34 (69%) were confirmed by HR typing whereas 15 (31%) LR specificities were not confirmed. LR_dnDSA+/HR_dnDSA+ patients were at higher risk of ABMR as compared to dnDSA- and LR_dnDSA+/HR_dnDSA- (logRank < 0.001), and higher risk of death-censored graft loss (logRank = 0.001). Both LR_dnDSA+ (HR: 3.51, 95% CI = 1.25-9.85) and LR_dnDSA+/HR_dnDSA+ (HR: 4.09, 95% CI = 1.45-11.54), but not LR_dnDSA+/HR_dnDSA- independently predicted graft loss. The implementation of HR HLA typing improves the characterization of biologically relevant de novo anti-HLA DSA and discriminates patients with poorer graft outcomes

Abordagem por Competências no Currículo Escolar em Cabo Verde: Desfazendo Equívocos para uma Mudança Significativa nas Políticas e Práxis Educacionais

A abordagem curricular por competências, enquanto fenómeno recente no discurso educativo em Cabo Verde, corre o risco de não passar de mero modismo, sem se traduzir numa inovação efectiva ao nível das práxis educacionais, se não for correctamente compreendida pelos diversos actores envolvidos na obra educativa e, em particular, nos processos de deliberação, gestão e realização dos currículos escolares. O presente artigo procura esclarecer alguns equívocos que em Cabo Verde, como em outras latitudes, acompanham a defesa da pedagogia por competências. Assim, importa elucidar que a abordagem curricular por competências vem aprofundar, entre outras, as abordagens por conteúdos e por objectivos e não, pura e simplesmente, substituí-las, por serem, alegadamente, tradicionais. Outrossim, no contexto da educação escolar, as competências não devem ser encaradas numa perspectiva redutora, focalizada na transferibilidade de conhecimentos para o mercado de trabalho, mas, fundamentalmente, no sentido da mobilização do conhecimento escolar para a resolução dos problemas nos diversos contextos ou situações da vida, que não se esgota no mercado

Human granzyme B regulatory B cells prevent effector CD4+CD25- T cell proliferation through a mechanism dependent from lymphotoxin alpha

IntroductionHuman Granzyme B (GZMB) regulatory B cells (Bregs) have suppressive properties on CD4+ effector T cells by a mechanism partially dependent on GZMB. Moreover, these cells may be easily induced in vitro making them interesting for cell therapy.MethodsWe characterized this population of in vitro induced GZMB+Bregs using single cell transcriptomics. To investigate their regulatory properties, Bregs or total B cells were also co-cultured with T cells and scRNAseq was used to identify receptor ligand interactions and to reveal gene expression changes in the T cells.ResultsWe find that Bregs exhibit a unique set of 149 genes differentially expressed and which are implicated in proliferation, apoptosis, metabolism, and altered antigen presentation capacity consistent with their differentiated B cells profile. Notably, Bregs induced a strong inhibition of T cell genes associated to proliferation, activation, inflammation and apoptosis compared to total B cells. We identified and validated 5 receptor/ligand interactions between Bregs and T cells. Functional analysis using specific inhibitors was used to test their suppressive properties and we identified Lymphotoxin alpha (LTA) as a new and potent Breg ligand implicated in Breg suppressive properties.DiscussionWe report for the first time for a role of LTA in GZMB+Bregs as an enhancer of GZMB expression, and involved in the suppressive properties of GZMB+Bregs in human. The exact mechanism of LTA/GZMB function in this specific subset of Bregs remains to be determined

Immunosuppressant drugs and quality-of-life outcomes in kidney transplant recipients: An international cohort study (EU-TRAIN)

Introduction: Patient-Reported Outcomes (PRO) integrate a wide range of holistic dimensions that arenot captured within clinical outcomes. Particularly, from induction treatment to maintenance therapy, patient quality-of-life (QoL) of kidney transplant recipients have been sparsely investigated in international settings.Methods: In a prospective, multi-centric cohort study, including nine transplant centers in four countries, we explored the QoL during the year following transplantation using validated elicitation instruments (EQ-5D-3L index with VAS) in a population of kidney transplant patients receiving immunosuppressive therapies. Calcineurin inhibitors (tacrolimus and ciclosporin), IMPD inhibitor (mycophenolate mofetil), and mTOR inhibitors (everolimus and sirolimus) were the standard-of-care (SOC) medications, together with tapering glucocorticoid therapy. We used EQ-5D and VAS data as QoL measures alongside descriptive statistics at inclusion, per country and hospital center. We computed the proportions of patients with different immunosuppressive therapy patterns, and using bivariate and multivariate analyses, assessed the variations of EQ-5D and VAS between baseline (i.e., inclusion Month 0) and follow up visits (Month 12).Results: Among 542 kidney transplant patients included and followed from November 2018 to June 2021, 491 filled at least one QoL questionnaire at least at baseline (Month 0). The majority of patients in all countries received tacrolimus and mycophenolate mofetil, ranging from 90.0% in Switzerland and Spain to 95.8% in Germany. At M12, a significant proportion of patients switched immunosuppressive drugs, with proportion varying from 20% in Germany to 40% in Spain and Switzerland. At visit M12, patients who kept SOC therapy had higher EQ-5D (by 8 percentage points, p &lt; 0.05) and VAS (by 4 percentage points, p &lt; 0.1) scores than switchers. VAS scores were generally lower than EQ-5D (mean 0.68 [0.5–0.8] vs. 0.85 [0.8–1]).Discussion: Although overall a positive trend in QoL was observed, the formal analyses did not show any significant improvements in EQ-5D scores or VAS. Only when the effect of a therapy use was separated from the effect of switching, the VAS score was significantly worse for switchers during the follow up period, irrespective of the therapy type. If adjusted for patient characteristics and medical history (e.g., gender, BMI, eGRF, history of diabetes), VAS and EQ-5D delivered sound PRO measures for QoL assessments during the year following renal transplantation

The Involvement of SMILE/TMTC3 in Endoplasmic Reticulum Stress Response

The state of operational tolerance has been detected sporadically in some renal transplanted patients that stopped immunosuppressive drugs, demonstrating that allograft tolerance might exist in humans. Several years ago, a study by Brouard et al. identified a molecular signature of several genes that were significantly differentially expressed in the blood of such patients compared with patients with other clinical situations. The aim of the present study is to analyze the role of one of these molecules over-expressed in the blood of operationally tolerant patients, SMILE or TMTC3, a protein whose function is still unknown.We first confirmed that SMILE mRNA is differentially expressed in the blood of operationally tolerant patients with drug-free long term graft function compared to stable and rejecting patients. Using a yeast two-hybrid approach and a colocalization study by confocal microscopy we furthermore report an interaction of SMILE with PDIA3, a molecule resident in the endoplasmic reticulum (ER). In accordance with this observation, SMILE silencing in HeLa cells correlated with the modulation of several transcripts involved in proteolysis and a decrease in proteasome activity. Finally, SMILE silencing increased HeLa cell sensitivity to the proteasome inhibitor Bortezomib, a drug that induces ER stress via protein overload, and increased transcript expression of a stress response protein, XBP-1, in HeLa cells and keratinocytes.In this study we showed that SMILE is involved in the endoplasmic reticulum stress response, by modulating proteasome activity and XBP-1 transcript expression. This function of SMILE may influence immune cell behavior in the context of transplantation, and the analysis of endoplasmic reticulum stress in transplantation may reveal new pathways of regulation in long-term graft acceptance thereby increasing our understanding of tolerance

Early acute microvascular kidney transplant rejection in the absence of anti-HLA antibodies is associated with preformed IgG antibodies against diverse glomerular endothelial cell antigens

International audienceBACKGROUND: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.METHODS: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.RESULTS: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.CONCLUSIONS: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that cell-based assays are needed to improve risk assessments before transplant

Donneurs à critères élargis en transplantation rénale (revue systématique de la littérature)

Introduction : La transplantation est la stratégie de prise en charge de l'insuffisance rénale chronique terminale (IRCt) la plus efficace et la moins coûteuse. Mais son développement est contraint par le manque de greffons, et celui-ci s'accentue avec l'augmentation constante de la prévalence de l'IRCt. Cette pénurie a incité à l'utilisation de greffons auparavant négligés, issus de donneurs à critères élargis (ECD pour Expanded Criteria Donor). Selon la définition de l'UNOS, un ECD est un donneur de plus de 60 ans ou entre 50 et 59 ans avec au moins deux des critères suivants : mort par Accident Vasculaire Cérébral (AVC), antécédent d'HyperTension Artérielle (HTA), créatininémie supérieure à 1,5 mg/l au moment du prélèvement. Notre objectif principal était d'étudier si les patients transplantés de greffons issus d'ECD, potentiellement de moins bonne qualité, avaient un moins bon pronostic que les patients bénéficiant de greffons standards (issus de SCD=Standard Criteria Donor). Un objectif secondaire envisagé est d'estimer les différentes survies chez les patients transplantés de greffons issus d'ECD. Matériel et Méthodes : Nous avons effectué une revue systématique de la littérature des études publiées ayant suivi des patients transplantés rénaux avec des greffons issus d'ECD. Nous avons réalisé une méta-analyse comparant la survie patient, la survie greffon (en censurant les décès) et la survie patient-greffon de patients transplantés de greffons issus d'ECD comparés à des patients transplantés de greffons issus de SCD. Les études retenues pour calculer un Hazard Ratio (HR) combiné étaient celles présentant un HR ajusté dont les facteurs d'ajustement n'incluaient pas les critères définissant un ECD. Résultats : 42 articles ont été retenus, parmi lesquels 22 étaient des études réalisées aux Etats-Unis et 15 étaient issus du même registre (UNOS United Network for Organ Sharing). Seuls 5 articles présentaient des données de survie utilisables, et pour chacune des trois survies étudiées le HR combiné reposait uniquement sur 2 études. Ces études étaient toutes américaines. La survie patient n'était pas significativement différente entre les patients greffés d'un ECD et ceux greffés d'un SCD (HR combiné [IC95%]=1,38 [0,96 ; 1,98]). Les survies greffon et patient-greffon étaient significativement inférieures chez les ECD (HR combinés=1,81 [1,60 ; 2,06] et 1,68 [1,32 ; 2,12] respectivement). Conclusion : Les patients transplantés rénaux d'ECD semblent avoir un moins bon pronostic pour la survie greffon et patient-greffon que ceux issus de patients transplantés de SCD. Mais ces résultats ne reposent que sur 2 études à chaque fois, et toutes réalisées aux Etats-Unis. Ailleurs dans le monde les données manquent pour savoir s'il est légitime d'appliquer cette même définition d'ECD.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF