Search Results (442)

Trimethylamine N-oxide (TMAO) and homocysteine are key biomarkers linked to cardiovascular and chronic kidney disease (CKD). Although they originate from distinct metabolic pathways, their circulating levels are jointly shaped by renal clearance, systemic metabolic status, and nutrient availability, complicating their biological interpretation. TMAO derives from gut microbiota–dependent metabolism of dietary precursors followed by hepatic oxidation of trimethylamine, whereas homocysteine is a central intermediate of one-carbon metabolism governed by remethylation and transsulfuration. Choline and betaine provide a nutritional interface between these pathways because choline can contribute to microbial TMA production and betaine acts as a methyl donor for homocysteine remethylation via betaine–homocysteine methyltransferase (BHMT). However, this interface does not establish direct metabolic interdependence between circulating TMAO and homocysteine. Declining renal function promotes the accumulation of both TMAO and homocysteine, although their renal handling and the mechanisms underlying their increase in CKD are not identical. Experimental and clinical evidence also links both metabolites to partially overlapping downstream processes, including oxidative stress, inflammation, endothelial dysfunction, and fibrotic remodeling. These shared pathophysiological responses should be distinguished from convergence of their biosynthetic pathways. This narrative review examines how renal function, metabolic regulation, and nutritional factors influence TMAO and homocysteine biology, emphasizing renal handling, analytical variability, shared downstream mechanisms, and the limitations of isolated measurements. A shift toward context-aware, multiparametric assessment may enhance their interpretation in cardiorenal research, although neither biomarker currently replaces established measures of kidney function. Full article

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide, driven by complex interactions among dyslipidemia, chronic inflammation, insulin resistance, endothelial dysfunction, and gut microbiome-derived metabolites. This review synthesizes mechanistic and clinical evidence on non-pharmacological strategies that modulate these pathways and contribute to ASCVD risk reduction. Dietary patterns such as Mediterranean, DASH, and plant-based diets improve lipid metabolism, attenuate inflammation, and enhance endothelial function. Chrononutrition approaches, including time-restricted feeding and structured fasting protocols, influence circadian regulation of glucose and lipid homeostasis. Circadian misalignment—including irregular sleep timing, shift work, and disrupted feeding–fasting cycles—independently contributes to ASCVD through impaired glucose tolerance, dyslipidemia, endothelial dysfunction, and systemic inflammation. Modulation of the gut microbiome, particularly through increased short-chain fatty acid production and reduced TMAO formation, provides additional cardiometabolic benefits. Key nutraceuticals—phytosterols, omega-3 fatty acids, and berberine—demonstrate clinically meaningful effects through micellar competition, inflammation-resolving lipid mediators, and AMPK activation, respectively. When combined with evidence-based pharmacotherapy, these interventions exert synergistic effects on cardiometabolic risk factors. This integrative biomedical framework highlights the importance of combining lifestyle, metabolic, microbiome-targeted, and nutraceutical strategies for comprehensive ASCVD prevention. Full article

Objective: This study aimed to investigate the combined associations of food insecurity and Mediterranean diet adherence with glycemic control and to determine whether gut-derived metabolites differ according to food insecurity and macrovascular complication status in adults with type 2 diabetes mellitus (T2DM). Methods: In this cross-sectional study, food insecurity was assessed using the Food Insecurity Experience Scale, and Mediterranean diet adherence was evaluated with the 14-item Mediterranean Diet Adherence (MDA) Scale. Serum trimethylamine N-oxide (TMAO) and L-carnitine concentrations were quantified using enzyme-linked immunosorbent assay (ELISA). Multinomial logistic regression was used as the primary analysis of data-derived HbA1c tertiles, and separate binary logistic regression models were performed as sensitivity analyses. ANCOVA was used for adjusted comparisons of continuous outcomes. Results: In the primary multinomial analysis, none of the combined food insecurity–MDA patterns were significantly associated with the intermediate or highest HbA1c tertiles after multivariable adjustment. However, point estimates suggested higher odds of the intermediate HbA1c tertile among participants with food insecurity and high MDA adherence (AOR = 3.41, 95% CI: 0.76–15.25) and of the highest HbA1c tertile among those with food insecurity and low MDA adherence (AOR = 4.74, 95% CI: 0.66–34.16); these estimates were imprecise. Sensitivity analyses using separate binary logistic regression models yielded stronger associations, but these findings should also be interpreted cautiously. Participants with macrovascular complications exhibited significantly higher serum TMAO and L-carnitine concentrations (p = 0.026 and p = 0.039, respectively), whereas food-insecure participants had significantly lower concentrations of both metabolites (p = 0.009 and p = 0.018, respectively). Higher dietary fiber and plant protein intakes were cross-sectionally associated with lower TMAO concentrations, while L-carnitine concentrations were positively associated with dietary fiber intake and inversely associated with plant protein intake. Conclusions: Combined food insecurity–MDA patterns showed suggestive but imprecise differences in HbA1c category membership that require confirmation in larger prospective studies. Serum TMAO and L-carnitine concentrations differed according to food insecurity and macrovascular complication status and were associated with selected dietary components. These findings should be interpreted as exploratory cross-sectional associations rather than evidence of causal or mechanistic effects. Full article

Cardiac senescence is not an isolated organ decline but a systemic consequence driven by pathological crosstalk between the heart and its peripheral metabolic organs. In this review, we discard the traditional organ–centric perspective and construct an integrated framework around multi-organ crosstalk axes, including the epicardial adipose tissue–heart axis, the skeletal muscle–heart axis, the gut–heart axis, and the kidney–heart axis. For each axis, we dissect the local molecular mediators—inflammatory cytokines, lipotoxic metabolites, microbiota-derived compounds such as trimethylamine N-oxide (TMAO), renin-angiotensin-aldosterone system (RAAS) effectors, and extracellular vesicle (EV) cargoes—and illustrate how they converge onto common pathways of oxidative stress, impaired autophagy, and cellular senescence. Importantly, we emphasize that these signals do not operate in isolation; they act synergistically through the circulation, converting local organ dysfunction into systemic cardiac aging via convergence onto shared senescence pathways. By redefining aging as a potentially modifiable multi-organ crosstalk, we propose emerging nodal points—senolytics, myokine mimetics, gut microbiota modulation, RAAS/sodium–glucose cotransporter 2 (SGLT2) inhibitors, and integrated lifestyle strategies—to block pathological crosstalk and delay cardiovascular aging. This framework shifts the research focus from isolated organs to systemic multi-organ crosstalk, providing new insights into cardiometabolic aging. Full article

Myocarditis is a clinically challenging form of inflammatory heart disease with heterogeneous etiologies, limited diagnostic tools, no targeted therapies, and a substantial risk of progression to heart failure or sudden cardiac death, particularly in young adults. Emerging evidence has increasingly associated myocarditis with gut microbiota dysbiosis. This review explores the gut–myocarditis axis, highlighting key mechanisms and therapeutic strategies. Significant alterations in gut microbial composition are observed in myocarditis patients and animal models. Gut microbiota influences disease development through multiple pathways: compromised intestinal barrier integrity leading to bacterial translocation and systemic inflammation via MAMP/PRR signaling (e.g., TLRs, NLRs); production of metabolites—including pro-inflammatory trimethylamine N-oxide (TMAO), anti-inflammatory short-chain fatty acids (SCFAs), and immunomodulatory bile acids—that regulate host inflammatory responses, immune cell differentiation, oxidative stress, and fibrotic remodeling; and molecular mimicry, where microbial peptides (e.g., from Bacteroides thetaiotaomicron) trigger cross-reactive autoimmune responses against cardiac proteins. Regarding therapeutic strategies, this review discusses fecal microbiota transplantation (FMT), probiotics, prebiotics, dietary modulation, and emerging approaches including engineered bacteria and oral nanomedicines. Although these strategies hold promise, their efficacy and safety remain to be validated in large-scale clinical trials, and further investigation is warranted. Full article

The gut microbiome has emerged as a critical determinant of health and disease across virtually all organ systems. In the context of chronic kidney disease (CKD) and renal transplantation, mounting evidence reveals a complex bidirectional relationship between the intestinal microbiota and kidney function—commonly referred to as the gut–kidney axis. Patients with CKD harbor a profoundly altered gut microbial ecosystem characterized by reduced diversity, depletion of beneficial commensal organisms, and expansion of pathobiont taxa capable of generating uremic toxins and pro-inflammatory mediators. These perturbations are further compounded by the uremic milieu itself, dietary restrictions, frequent antibiotic exposure, and the use of immunosuppressive agents following transplantation. The gut–liver–kidney axis adds an additional layer of complexity, linking hepatic metabolism, bile acid signaling, endotoxemia, and systemic immune activation to the progression of renal disease. Gut-derived metabolites—including short-chain fatty acids (SCFAs), bile acids, trimethylamine N-oxide (TMAO), and tryptophan-derived uremic solutes such as indoxyl sulfate and p-cresyl sulfate—serve as molecular mediators of inter-organ crosstalk and have been identified as both biomarkers and therapeutic targets. A growing body of literature supports the diagnostic and prognostic utility of microbiome composition and its metabolic signatures in patients with CKD and those undergoing renal replacement therapy. Therapeutic strategies aimed at restoring microbial homeostasis—encompassing dietary interventions, prebiotics, probiotics, synbiotics, fecal microbiota transplantation (FMT), bile acid–based therapies, and novel pharmacological approaches—hold considerable promise for improving outcomes in CKD and transplant recipients. Importantly, the bidirectional relationship between immunosuppressive drugs and the gut microbiota has emerged as a clinically significant determinant of both microbial ecology and drug pharmacokinetics: each major immunosuppressive agent class—corticosteroids, calcineurin inhibitors, mycophenolate mofetil, and mTOR inhibitors—induces characteristic dysbiotic patterns, while in turn, the microbiota modulates drug bioavailability through enzymatic biotransformation (notably bacterial beta-glucuronidase activity affecting mycophenolic acid enterohepatic recirculation) and modulation of host drug-metabolizing enzymes. This narrative review provides a comprehensive overview of the current understanding of microbiome dysbiosis in the setting of renal disease and transplantation, examines the mechanistic underpinnings of the gut–liver–kidney axis, details the multifaceted impact of dysbiosis on transplant outcomes—including allograft function and rejection, infection, post-transplant diabetes, and cardiovascular complications—and critically appraises the translational potential of microbiome-targeted interventions. We conclude by highlighting ongoing challenges and future directions toward personalized, microbiome-informed clinical care. Full article

To elucidate the synergistic effects of storage temperature and packaging on N-nitrosodimethylamine (NDMA) and its precursors dimethylamine (DMA) and trimethylamine N-oxide (TMAO) in roasted Alaska pollock fillets, two storage experiments were conducted. In Experiment I, commercially packaged fillets were stored at −20, 4, 10, 20, and 30 °C for 310 d. A two-way factorial ANOVA revealed a significant temperature × time interaction (F(24, 70) = 39.386, p < 0.001, partial η² = 0.931). NDMA formation was delayed until day 172 at −20 °C; however, the 4, 10, and 20 °C groups exceeded the 4 μg/kg limit by day 263, with the 20 °C group peaking at day 263 (4.26 μg/kg) before declining to 3.73 μg/kg by day 310. In Experiment II, a three-way factorial ANOVA was applied to samples stored under oxygen-absorber or vacuum packaging at refrigerated (4 °C) or ambient (22 °C) temperature for 270 days. The temperature × packaging × time interaction was significant for NDMA, DMA, and TMAO (p < 0.001). The partial η² for NDMA (0.933) was markedly larger than for DMA (0.540) and TMAO (0.607), indicating stronger combined effects on NDMA. The main effect of temperature on DMA was dominant (partial η² = 0.994), whereas NDMA formation depended strongly on both temperature and packaging. During the 270-day storage, all refrigerated groups remained below the 4 μg/kg limit throughout; however, the ambient vacuum-packaged (BCZ) group transiently exceeded the limit (reaching 4.21 μg/kg on day 60) and subsequently fluctuated near the limit. These findings provide a scientific basis for designing safer storage and packaging strategies for such dried aquatic products. Full article

Background: This study aimed to evaluate the phenotype-specific profiles of serum Isthmin-1 (ISM-1), Trimethylamine N-Oxide (TMAO) and Nitric Oxide (NO) levels in women diagnosed with Polyendocrine Metabolic Ovarian Syndrome (PMOS, formerly known as Polycystic Ovary Syndrome—PCOS) according to the Rotterdam criteria. Methods: This cross-sectional study enrolled 90 reproductive-aged women, divided equally into five groups (n = 18 per group) with similar baseline metabolic parameters: healthy controls and PMOS Phenotypes A, B, C, and D. To minimize confounding effects, individuals with recent use of specific medications were excluded, and 24 h dietary recalls were obtained. Fasting blood samples were collected during the early follicular phase. Serum ISM-1, TMAO, and NO levels were quantified via ELISA, and insulin resistance was determined using the HOMA-IR index. Data were adjusted for potential confounders, including age, BMI, and smoking status, using multivariate linear regression models. Results: No statistically significant differences were observed between the groups in key parameters such as BMI and HOMA-IR. Serum ISM-1 levels did not show a significant difference between the groups (p = 0.501). In contrast, NO levels were found to be significantly lower in all PMOS phenotypes compared to the control group (p < 0.001), and this reduction remained independent in regression models. TMAO levels, however, exhibited a phenotype-specific distribution; in the non-hyperandrogenic Phenotype D, they were found to be significantly lower than in the control group and hyperandrogenic phenotypes A and B. In the multivariate regression analysis, it was confirmed that Phenotype D was independently associated with low TMAO levels (B = −0.131, p = 0.027). Conclusions: Although PMOS patients share a similar profile of obesity and insulin resistance, they exhibit marked biochemical heterogeneity. Whilst the reduction in NO levels may indicate a generalised vascular change affecting all phenotypes, the observation of low TMAO levels specifically in the non-hyperandrogenic Phenotype D highlights a distinct biochemical signature associated with this subgroup, observed in the absence of hyperandrogenism. Our findings support the notion that adopting phenotype-specific, individualised approaches in the management of PMOS may be beneficial. Full article

In recent years, gut microbiota has emerged as a central modulator of cardiovascular health and disease. This has led to a transition from the old understanding of cardiovascular pathology as a largely cardiac-centric problem to a systemic, multi-organ process. A growing body of evidence demonstrates that changes in the makeup of gut microbes, generally called dysbiosis, are significant in the development and progression of cardiovascular illnesses, including heart failure. Moreover, there are bidirectional interactions between the failing heart and the gut. In heart failure, impaired hemodynamics and venous congestion further worsen intestinal hypoperfusion and barrier dysfunction in a self-perpetuating cycle that exacerbates dysbiosis and systemic inflammation. The gut–heart axis offers a fresh paradigm for illness progression beyond classical neurohormonal and hemodynamic processes. The gut microbiota acts as an endocrine organ by producing bioactive metabolites such as TMAO (trimethylamine N-oxide), SCFA (short-chain fatty acids) and bile acids, which, via several routes, have a serious impact on host health and disease. This narrative review aims to summarize the current evidence for the gut microbiota as a new cardiovascular risk factor, focusing on biological mechanisms and clinical and epidemiological evidence. Full article

Background/Objectives: The aim of this study is to evaluate the relationship between adherence to the Mediterranean diet and intestinal microbiota metabolite trimethylamine N-oxide (TMAO) levels, systemic inflammation markers, and oxidative stress parameters in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: MASLD patients whose fatty liver and fibrosis severity were determined with FibroScan and a healthy control group were included in the study. In addition to the routine biochemical parameters, serum TMAO levels, inflammatory cytokines (IL-6, IL-10, TNF-α), and oxidative stress indicators (malondialdehyde, glutathione, and MDA/GSH ratio) of all participants were measured. In comparing these parameters between fibrosis groups, adjustment for potential confounding variables (age, BMI, sex, comorbidity, relevant medication use, MEDAS score, and physical activity) was performed. Following anthropometric evaluations, the adherence levels of the participants to the Mediterranean diet were determined by the Mediterranean Diet Adherence Screening Scale (MEDAS), and their physical activity levels were determined through the International Physical Activity Questionnaire-Short Form (IPAQ-SF). Results: Individuals diagnosed with MASLD had significantly lower adherence to the Mediterranean diet and lower physical activity levels compared with healthy controls. Among the inflammatory parameters, IL-6 levels were significantly higher in the advanced fibrosis group than in the early-stage and significant fibrosis groups, while TNF-α levels were significantly higher in the advanced fibrosis group than in the early fibrosis group. No significant differences were observed among the groups in TMAO, IL-10, GSH levels, or the MDA/GSH ratio; however, among the oxidative stress markers, MDA levels were significantly higher in the early fibrosis group than in the significant fibrosis group. Conclusions: In MASLD patients, fibrosis severity was associated with alterations in TMAO, inflammatory, and oxidative stress markers, with increased TNF-α and IL-6 levels reflecting a high inflammatory burden as fibrosis progressed. Lower TMAO levels in fibrosis groups likely reflect reduced hepatic FMO3 activity, lower fish intake, and medication use, while elevated MDA levels in early-stage fibrosis suggest that lipid peroxidation may be more prominent in the initial phases of disease. Mediterranean diet adherence and physical activity were inversely associated with pro-inflammatory markers and MASLD severity, being highest in the control group, suggesting a potential protective role for these lifestyle factors in MASLD progression. Full article

Male infertility refers to the inability of a male partner to contribute to pregnancy after 12 months or more of regular unprotected intercourse. It is frequently associated with impaired spermatogenesis, and many cases cannot be completely explained by genetic, inflammatory, endocrine, or environmental factors. Trimethylamine N-oxide (TMAO) is generated when gut bacteria convert dietary choline, L-carnitine, and betaine into trimethylamine (TMA), which is oxidized in the liver mainly by flavin-containing monooxygenase 3 (FMO3). This focused review evaluates current evidence on TMAO and impaired spermatogenesis within the gut–testis axis. The rationale is biologically plausible because sperm motility depends on coordinated glycolytic and mitochondrial energy metabolism, whereas Leydig cell steroidogenesis depends on mitochondrial cholesterol transport and redox balance. Human observational studies associate TMAO with asthenozoospermia and Leydig cell-related markers, particularly insulin-like peptide 3 (INSL3), while mouse studies suggest testicular injury and reduced spermatogenesis after TMAO-related exposure. The Hippo/Yes-associated protein (YAP)–mitochondria–steroidogenic acute regulatory protein (StAR) axis has been proposed as one possible mechanism, but direct reproductive tract exposure, blood–testis barrier kinetics, and human validation remain unresolved. Overall, TMAO should be considered as a candidate metabolic mediator and not a proven causal factor or therapeutic target in male infertility. Full article

Alterations of gut microbiota are common in chronic kidney disease (CKD) and contribute to increased uremic toxins including indoxyl sulfate (IS), p-cresyl sulfate (pCS) and trimethylamine N-oxide (TMAO), which are linked to cerebrovascular disease risk. This study examined the kidney–gut–brain axis in CKD mice and in dialysis patients. Male and female mice with adenine-induced CKD were fed a high-amino-acid (HAA) diet to increase precursors of gut-derived uremic toxins. A subgroup of mice received antibiotics in drinking water to suppress gut microbiota and evaluate its role in toxin generation. Behavior tests, gut microbiome composition and brain histology for cerebral microhemorrhages were analyzed. CKD mice had higher serum levels of creatinine, cystatin C and gut-derived toxins, a 2.5-fold increase in brain microhemorrhages, and decreased locomotor activity. The HAA diet significantly increased serum TMAO but not IS and pCS, and all three toxins were reduced by antibiotic therapy. Sex differences were observed; in male animals, higher TMAO was associated with increased brain microhemorrhages, whereas in female mice, pCS was associated with brain microhemorrhage burden. The suppression of toxins with antibiotics improved working memory in male animals. Gut microbiota analysis revealed the expansion of Lactobacillus and Ileibacterium in CKD mice. The HAA diet and antibiotics altered gut microbiota composition without changing alpha diversity. The human study utilized biobanked serum samples and a retrospective review of brain imaging scans in a hemodialysis patient cohort; TMAO levels were associated with increased lobar microbleeds. Our study supports a role for bacterial-derived uremic toxins in the kidney–gut–brain axis and cerebral microhemorrhage formation in CKD. Full article

Atherosclerosis is a chronic multifactorial inflammatory vascular disease and the major risk factor for cardiovascular diseases (CVDs), characterized by arterial wall thickening, loss of arterial elasticity and the progressive accumulation of lipids and immune cells, ultimately leading to plaque formation and the development of unstable, rupture-prone plaques. Several studies suggest that gut microbiota might contribute to atherosclerosis, mainly by converting dietary and endogenous molecules into bioactive metabolites, such as trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), and the Gram-negative cell-wall component lipopolysaccharide (LPS). Such metabolites can promote key mechanisms involved in the development and progression of atherosclerotic plaque, and, importantly, plaque vulnerability. Specifically, they can worsen endothelial dysfunction, induce macrophage-driven inflammatory responses, and cause oxidative stress and extracellular matrix degradation. These processes are crucial for thinning of the fibrous cap and destabilization of atherosclerotic plaques. As a result, the risk of plaque rupture and related cardiovascular events increases. In this review, we summarize potential mechanisms by which the gut microbiota and their compounds induce the formation of vulnerable atherosclerotic plaques and discuss findings from experimental models and clinical studies that reveal the crucial role of microbiota–host dynamics in atherosclerosis. In contrast to previous reviews that primarily focused on atherosclerosis development, we specifically highlight the cellular and molecular mechanisms linking gut microbiota to plaque vulnerability and destabilization. We also address future research priorities to define microbiota-driven pathways better and develop targeted therapeutic interventions to reduce plaque vulnerability and cardiovascular risk. Full article

High circulating levels of trimethylamine-N-oxide (TMAO), largely produced by hepatic oxidation of gut-microbiota-derived trimethylamine (TMA), are associated with increased risk of cardiometabolic and neurodegenerative diseases. In contrast, the diet-derived compound ergothioneine (ET) possesses cytoprotective and neuroprotective properties, and higher circulating ET levels have been linked to a lower risk of cardiovascular, neurodegenerative, and other age-related disorders. However, concerns have been raised that microbial degradation of ET may also contribute to the TMAO pool. In this study, we examined the relationship between ET and TMAO. Bioinformatic analyses indicated that ergothionase, the enzyme responsible for ET degradation to trimethylamine (TMA), is restricted to a limited number of bacterial genera and is far less prevalent than choline trimethylamine lyase, which generates TMA from choline. In a randomised, placebo-controlled human study, ET supplementation (25 mg/day for 7 days) significantly increased plasma ET levels but did not increase TMAO concentrations. Similarly, in a heart failure cohort, plasma ET showed no correlation with TMA or TMAO levels, whereas TMAO was clearly correlated with TMA. Collectively, these findings suggest that ET is unlikely to contribute significantly to systemic TMAO levels. Full article

Background: Kidney transplantation is the preferred treatment for end-stage kidney disease (ESKD), but long-term outcomes remain limited by chronic allograft injury, infections, metabolic complications, and cardiovascular risk. Gut microbiota alterations and microbiota-derived metabolites may influence immune regulation, inflammation, drug metabolism, and graft outcomes through the gut–kidney axis. This review summarizes evidence on the gut microbiota in kidney transplantation, emphasizing immune tolerance, complications, cardiovascular risk, graft function, and perspectives. Methods: A structured search was conducted in PubMed, Scopus, and Web of Science to May 2026. Eligible publications included studies involving kidney transplant recipients (KTR), kidney disease or solid organ transplant populations, and mechanistic models. Evidence was synthesized narratively. Results: Gut microbiota alterations in KTR reflect pre-transplant dysbiosis and post-transplant exposures, including antibiotics, immunosuppression, infection, diet, hospitalization, and graft function. Dietary factors and nutrient-derived substrates may modulate microbial composition and production of relevant metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), tryptophan-derived compounds, bile acid derivatives, and uremic toxins. Microbiota-related pathways may involve barrier dysfunction, microbial translocation, innate immune activation, altered regulatory T cell/T helper 17 (Treg/Th17) balance, metabolite signaling, uremic toxin generation, and endothelial stress. Clinical studies associate dysbiosis and microbial metabolites with diarrhea, infections, delayed graft function (DGF), rejection-related shifts, tacrolimus variability, cardiovascular risk, graft dysfunction, graft failure, and mortality. Most findings need validation. Conclusions: Gut microbiota signatures and microbial metabolites are promising markers of transplant-related risk, but not established causal determinants or therapeutic targets. Clinical translation requires standardized methods, multi-omics integration, and prospective patient- and graft-centered trials. Full article