Xenotransplantation has entered a phase of accelerated clinical translation, necessitating renewed international consensus on governance, ethics, safety, and regulatory oversight. In September 2025, the International Xenotransplantation Association (IXA), in partnership with The Transplantation Society (TTS) and with engagement from the World Health Organization (WHO), convened a Global Consultation in Geneva to review, update, and harmonise international guidance for clinical xenotransplantation. This IXA consultation marked the twentieth anniversary of the first WHO Xenotransplantation Advisory Consultation in 2005 and built upon the foundational principles established through the Changsha Communiqué (2008, 2011 and 2018) and subsequent IXA and WHO-led initiatives. Responding to rapid scientific advances, including some defined donor genetic standards, improved immunosuppression, enhanced biosecurity, and strengthened infectious disease surveillance, the IXA undertook an 18‑month, structured, evidence‑based revision process. Seven expert working groups, comprising approximately forty internationally recognised specialists from fourteen countries, reviewed developments across source animal standards and biosecurity, clinical trial design and oversight, immunosuppression and patient management, infectious disease risk and surveillance, ethical and legal frameworks, international governance, and emerging technologies. Draft recommendations were further refined through iterative consultation and plenary deliberation at the in‑person meeting held in Geneva, September 2025. The consultation proposed updated Principles and Recommendations directed to WHO, national regulators, investigators and sponsors, and the IXA/TTS communities. Key elements include proportionate risk benefit assessments, robust donor and recipient surveillance, long‑term biobanking and monitoring, transparency and public engagement, harmonised regulatory oversight consistent with existing allotransplantation frameworks, and equitable access to future clinical applications. The revised guidance aligns with contemporary regulatory expectations of major international jurisdictions regulatory authorities including (AEMPS, ANMAT, CONABIA, CONFEPRIS, EMA, FDA, GTAC, HC, IEC, INCUCAI, Medsafe, MFDS, MHRA, MHLW, NMPA, NZGTAC, MFDS, MHRA, TGA); and consolidates international consensus at a critical juncture for the field. This IXA Global Consultation provides an authoritative, forward‑looking framework to support safe, ethical, and globally coordinated clinical xenotransplantation as it transitions from experimental innovation to regulated clinical practice.
Acute graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after haploidentical haematopoietic stem-cell transplantation (HSCT). Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor with established activity in steroid-refractory GVHD, has shown promise for prophylaxis in early studies, but there is little evidence from randomised trials in the haploidentical HSCT setting. We investigated whether, within a backbone of antithymocyte globulin, calcineurin inhibitor, and short-course methotrexate, replacing mycophenolate mofetil with low-dose ruxolitinib could reduce acute GVHD after haploidentical HSCT. In this multicentre, open-label, randomised, controlled, phase 3 trial conducted at five centres in China, eligible patients were aged 12-70 years, had haematological malignancies for which allogeneic HSCT was indicated, had a Karnofsky performance status of at least 70 or a Lansky score of at least 70 for patients younger than 16 years, and were undergoing their first myeloablative haploidentical HSCT. Patients were randomly assigned (1:1) to receive antithymocyte globulin, a calcineurin inhibitor, short-course methotrexate, and low-dose ruxolitinib, or standard prophylaxis with antithymocyte globulin, a calcineurin inhibitor, short-course methotrexate, and mycophenolate mofetil. Randomisation was stratified by centre and patient age (<40 years vs ≥40 years) using computer-generated permuted blocks with random block sizes. Oral ruxolitinib was started on day 1 at 5 mg twice daily for patients weighing at least 50 kg and 5 mg once daily for those weighing less than 50 kg, continued up to day 60, and then tapered to day 90 in the absence of grade II-IV acute GVHD. The primary endpoint was the cumulative incidence of grade II-IV acute GVHD by day 100. Efficacy and safety were analysed in the modified intention-to-treat population, which included all randomly assigned patients who received at least one dose of the assigned prophylaxis, excluding those with major protocol deviations. This trial is registered with ClinicalTrials.gov, NCT04838704, and is complete. Between April 1, 2021, and Dec 28, 2023, 215 patients were randomly assigned, of whom 206 were included in the modified intention-to-treat population (103 in the ruxolitinib prophylaxis group and 103 in the standard prophylaxis group). The median recipient age was 40 years (IQR 24-48), 98 (48%) patients were female and 108 (52%) were male, and all participants were Chinese. Among surviving patients, the median follow-up was 26·4 months (IQR 20·0-33·3). By day 100, grade II-IV acute GVHD occurred in seven (cumulative incidence of 6·8% [95% CI 1·9-11·7]) of 103 patients in the ruxolitinib prophylaxis group and 38 (36·9% [27·5-46·3]) of 103 patients in the standard prophylaxis group (subdistribution hazard ratio 0·15, 95% CI 0·07-0·34; p<0·0001). The most common grade 3-4 adverse events in the ruxolitinib prophylaxis group and the standard prophylaxis group were thrombocytopenia (17 [17%] vs 11 [11%]), neutropenia (14 [14%] vs 9 [9%]), anaemia (12 [12%] vs 9 [9%]), and cystitis (7 [7%] vs 10 [10%]). Serious adverse events occurred in 31 (30%) patients in the ruxolitinib prophylaxis group and 36 (35%) patients in the standard prophylaxis group. No fatal adverse events occurred in the ruxolitinib prophylaxis group. Three deaths occurred in the standard prophylaxis group: pulmonary infection (n=1), sepsis, bacteraemia, or fungaemia (n=1) and transplant-associated thrombotic microangiopathy (n=1). No deaths were considered related to the assigned study drug. Low-dose ruxolitinib, used in place of mycophenolate mofetil within a backbone of prophylactic antithymocyte globulin, calcineurin inhibitor, and short-course methotrexate, reduced grade II-IV acute GVHD by day 100 after haploidentical HSCT and had manageable toxicity. These findings support further evaluation of targeted JAK1/2 inhibition as part of GVHD prophylaxis. National Natural Science Foundation of China.
The pharmaco-epidemiological research program in kidney transplantation (PERP-KT) aims to evaluate, for the principal maintenance immunosuppressive drugs (MISDs): the influence of model-informed precision dosing on graft and patient survival; long-term exposure-effects relationships; and the benefit-harm balance of their combinations and time sequences in patient groups or clinical settings not adequately evaluated in comparative randomized clinical trials. It also aims to develop a hybrid, dynamic, deep learning model capable of predicting the rate of renal graft function decline, thereby providing a platform for individualized prediction of the benefits and risks associated with MISDs. After obtaining all regulatory andd ethical approvals, de-identified extracts of three national databases were linked to create the nationwide PERP-KT dataset, which is hosted within the highly secure environment of the French Health Data Hub. CRISTAL (the exhaustive registry of the French Agence de la Biomédecine) comprises data from 49 886 kidney donors and the corresponding 47 842 transplant recipients between 2005 and 2020. Following iterative deterministic matching and extensive quality control procedures, CRISTAL data were successfully linked to: the French national Health Data System (SNDS), which records reimbursed healthcare utilization, for 30 782 kidney transplant recipients; and to ISBA, a web-based platform for Bayesian dose adjustment of MISDs that contains pharmacological data, for 17 700 kidney grafts and 17 576 recipients. More than 20 pharmaco-epidemiological studies will leverage the database's extensive follow-up, large population size and richness of clinical, healtcare-utilization, and pharmacological data. This research program on kidney transplantation (PERP‐KT) intends to evaluate: the efficacy of fine‐tuned, individual dose adjustment of the main maintenance immunosuppressive drugs (MISDs) on the longevity of the graft and on patient survival; the long term effects of different blood levels of the main MISDs; the efficacy and adverse effects of the different combinations and time sequences of MISDs in patient groups or clinical conditions not previously evaluated; and to develop an artificial intelligence tool able to predict the speed at which each kidney graft will deteriorate after transplantation. PERP‐KT leverages the CRISTAL registry (managed by the French Agence de la Biomédecine) exhaustively listing kidney transplant procedures in France (49 886 donors and 47 842 recipients between 2005 and 2020), combined with the SNDS (Système National des Données de Santé) that contains all drugs delivered and healthcare activities for 30 782 of them, and ISBA (ImmunoSuppressive Bayesian dose Adjustment website) a database about the dose and blood levels of the main MISDs for 17 700 kidney grafts and 17 576 patients. This unprecedented database will support more than 20 studies on the efficacy and adverse events of MISDs and will foster personalized medicine in kidney transplantation.
Multiple myeloma (MM) has experienced rapid therapeutic innovation over the past two decades, leading to a substantial increase in clinical trial activity. However, the geographic distribution of these trials and the representation of different economic regions remain poorly characterized. We evaluated the global distribution, growth patterns, and phase-specific trends of MM clinical trials and trial sites across different economic settings. We conducted a retrospective registry-based analysis interventional MM clinical trials registered on ClinicalTrials.gov between January 2006 and January 2026. Trials were categorized based on the economic classification of participating countries using World Bank income groups and Economic Co-operation and Development (OECD) status. Trial characteristics including phase, geographic distribution, number of participating sites, and site-years were analyzed. Population-adjusted trial density and compound annual growth rates (CAGR) were calculated to assess temporal trends and geographic representation. A total of 845 interventional MM clinical trials were identified during the study period. Trial activity was highest in the United States (337 trials, 39.9%), followed by international trials (271, 32.1%), high-income-OECD countries (129, 15.3%), and upper-middle-income countries (103, 12.2%), while high-income non-OECD countries contributed only a small fraction of trials. Trial activity increased substantially over time across all regions with the highest growth observed in upper-middle-income countries (CAGR 18.5%). The US demonstrated the highest population-adjusted trial density (0.99 per million population) and accounted for the largest number of trial sites and site-years. Phase-specific analyses revealed distinct geographic patterns. Phase 1 trials were predominantly conducted in the US and in international collaborative trials. Phase 3 trials were largely international, although the majority of participating sites remained located in the US and High-income countries that are members of the OECD (HIC-OECD). Over the past two decades, MM clinical trial activity has expanded globally but remains highly concentrated in the United States and high income-OECD countries, particularly with respect to trial sites and population-adjusted trial density. Although upper-middle-income countries have shown the fastest growth in trial activity expanding clinical trial infrastructure and strengthening international collaboration will be essential to promote a more equitable global distribution of MM research.
Antimicrobial resistance and inadequate sanitation, particularly in developing nations such as Pakistan, exacerbate the impact of Salmonella, a leading cause of foodborne and clinical infections worldwide. Effective surveillance and source tracking are hindered by a lack of comprehensive analyses linking clinical and environmental strains, despite increasing reports of resistant variants. This study uses disk diffusion, conventional PCR, and ERIC-PCR to compare clinical and environmental Salmonella strains from Karachi, with an emphasis on antibiotic resistance, virulence factors, and genetic relatedness. Multidrug resistance is highly prevalent, with 63% of clinical strains (41/65) (MARi: 0.3-0.8) and 34.5% of environmental strains (22/55) (MARi: 0.4-0.7) exhibiting resistance to multiple antibiotics. All strains were capable of forming biofilms, and the correlation between MARi and biofilm formation in both sources was weak and non-significant (p > 0.05). All strains from both sources harbored core virulence genes; however, three genes, fimA, spvR, and acrA, were significantly more prevalent in clinical than in environmental strains (p < 0.001 and p = 0.023). ERIC-PCR showed low to moderate DI (0.45 to 0.75) across different clinical Salmonella serovars and moderate DI across different environmental serovars, indicating heterogeneous and homogeneous genetic relatedness. These results suggest a crucial and underexplored connection between environmental and clinical Salmonella reservoirs, implying potential environmental contamination from clinical sources. The coexistence of multidrug resistance and virulence highlights the critical need for integrated surveillance strategies to minimize the risk of widespread outbreaks.
Invasive mold diseases (IMDs) are rare, life-threatening infections that primarily affect persons with immunocompromising conditions. The most common molds associated with IMDs are Aspergillus spp., Mucorales (e.g., Mucor spp., Rhizomucor spp., and Rhizopus spp.), Fusarium spp., and Scedosporium spp. IMDs can affect the lungs, sinuses, skin, central nervous system, or multiple body sites. 2020-2024. IMD is not a nationally notifiable condition. CDC conducts active, laboratory-based IMD surveillance through the Georgia Emerging Infections Program at three laboratories that serve four Atlanta, Georgia, hospitals: two academic hospitals and their associated outpatient clinics, one federal hospital, and one community hospital. Identifying and classifying IMD cases is challenging because 1) symptoms often are nonspecific and 2) the presence of mold growth in clinical cultures might indicate infection, colonization, or laboratory contamination.Potential IMD cases were identified through a review of records from laboratories serving the hospitals included in this surveillance system to identify patients who received positive results from mold cultures or Aspergillus galactomannan tests, which detect the presence of galactomannan, a compound found in Aspergillus fungi, in serum or bronchoalveolar lavage fluid specimens. Potential cases in these patients were classified as proven or probable cases using established National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) criteria that consider laboratory findings (e.g., histopathologic evidence of angioinvasive mold infection or a fungal culture from a normally sterile body site), clinical or radiologic features supporting IMD classification (e.g., chest computed tomography or bronchoscopy results suggestive of fungal disease, sinonasal signs, or central nervous system imaging results), and host factors that predispose patients to IMD (e.g., recent history of neutropenia, hematologic malignancy, transplantation receipt, and use of certain immunosuppressive medications). Potential cases that did not meet the laboratory, clinical, and host-factor criteria for MSG-proven or MSG-probable cases could be categorized as surveillance cases if treating clinicians diagnosed IMD in a patient and initiated treatment with antifungal therapy effective against mold or if the patient died within 3 days of specimen collection. During 2020-2024, a total of 968 unique patients with potential IMD were identified across four Atlanta hospitals and their associated outpatient clinics. Of those, 449 (46%) were classified as having IMD, including 89 (20%) MSG-proven, 142 (32%) MSG-probable, and 218 (49%) surveillance cases. Among patients with IMD, 58 (13%) had a current or recent COVID-19 diagnosis. Information on bed count was available for three of the four hospitals. At the two academic hospitals, the pooled average annual IMD incidence was 4.8 inpatient cases per 100 inpatient beds and 14.0 intensive care unit (ICU) cases per 100 ICU beds. At the community hospital, the average annual incidence was 2.8 inpatient cases per 100 inpatient beds and 10.2 ICU cases per 100 ICU beds.Among 449 patients with IMD, the largest percentage were aged 45-64 years (43%), followed by ≥65 years (39%), 19-44 years (18%). Patients aged 1-18 years and <1 year each accounted for <1% of IMD cases. Pulmonary infections were most common (68%), followed by cutaneous or deep tissue (nonfacial) infections (11%), sinus or nasal infections (10%), and central nervous system infections (excluding eyes) (9%); less frequent sites of infection included soft tissue (2%), blood (1%), bone (1%), and eye (1%). The most common fungal species identified among IMD cases were Aspergillus spp. (n = 319 [71%]), most commonly Aspergillus fumigatus (n = 94 [21%]). Fusarium spp. were the second most common (n = 20 [4%]), followed by Mucorales (n = 17 [4%]), and Scedosporium spp. (n = 12 [3%]). Aspergillus spp., Scedosporium spp., and Curvularia spp. were most commonly associated with pulmonary infections. Mucorales genera were more commonly associated with sinus, nasal, or facial infections and Fusarium spp. with cutaneous or deep tissue infections. Among patients with IMD, 65% (n = 292) had at least one MSG host factor that predisposes patients to IMD, and 53% (n = 238) had at least one MSG clinical criterion supporting IMD classification, suggesting that surveillance based only on classic host risk factors or typical clinical findings might miss a substantial proportion of IMD cases.A total of 363 (81%) of 449 patients with IMD received antifungal treatment effective against molds, most commonly isavuconazole (n = 178 [40%]), followed by voriconazole (n = 142 [32%]) and amphotericin B (n = 93 [21%]). Overall, 43% of patients with IMD were admitted to an ICU during the 2 weeks preceding specimen collection, and 50% of patients with IMD required intubation and mechanical ventilation; the 90-day all-cause mortality rate, excluding 2024 cases, was 45% (157 of 349). Indicators of severe illness were more common among IMD patients with a current or recent COVID-19 diagnosis than among those without COVID-19, including higher frequency of ICU admission during the 2 weeks preceding specimen collection (66% [38 of 58] versus 39% [154 of 391]; p<0.001) and increased 90-day all-cause mortality (66% [35 of 53] versus 41% [122 of 296]; p<0.001). IMDs are severe infections associated with frequent ICU admission and high mortality rates, especially among patients with a current or recent COVID-19 diagnosis. The findings from this report could serve as benchmark data in establishing baseline IMD rates for future surveillance to detect outbreaks in health care settings. More than one third of IMD cases (35%) occurred in patients without MSG host factors, underscoring the need for clinicians and surveillance efforts to consider the possibility of IMDs among patients without classic host risk factors for infection. Health care providers should be vigilant for IMDs as a life-threatening complication among persons with immunocompromising conditions or critical illness. Continued surveillance could help identify emerging populations at risk for IMD, facilitate earlier recognition and treatment, and support detection of health care-associated outbreaks.
Anterior cruciate ligament reconstruction (ACLR) is complicated by high failure rates in young, active individuals, which is associated with worse outcomes and higher rates of osteoarthritis (OA). Failure of ACLR limits activity, reduces quality of life and substantially increases socio-economic costs. Thus, strategies to reduce ACLR failure are imperative. In the STABILITY 1 trial, we showed that adding a lateral extra-articular tenodesis (LET) to ACLR with a hamstring tendon (HT) graft provided greater stability than HT alone (Relative Risk Reduction (RRR)=0.38; 95% CI 0.21 to 0.52; p<0001). Recent meta-analyses suggest patellar tendon (bone patellar tendon bone (BPTB)) grafts provide better stability than HT although with greater donor site morbidity. Recently, the quadriceps tendon (QT) graft has become popular, claiming similar stability to BPTB without donor site morbidity. However, no high-quality studies have shown it to be better and no study has determined if the reduced rate of ACLR failure seen with the addition of a LET to a HT graft is still present when using stronger, stiffer BPTB or QT grafts. Therefore, this study will evaluate whether in patients at high risk of rerupture, graft type (QT, BPTB, HT) with or without a LET offers a greater reduction in rate of clinical failure, better performance-based function and patient-reported symptoms, function and quality of life or higher rates of return to sport 2 years after ACLR. And does graft type±LET affect muscle strength recovery or increase the risk of donor site morbidity or lateral compartment articular cartilage degeneration? Do females, who are more often quadriceps dominant in their landing biomechanics, experience better outcomes if their ACLR uses a BPTB and/or QT autograft compared with a HT+LET autograft? Finally, is a particular graft type±LET a more cost-effective approach to ACLR? Across 31 centres (9 Canadian, 8 European, 14 USA), we will randomly assign 1292 patients with an ACL rupture who are at high risk of failure to either QT (±LET) or BPTB (±LET). Eligible participants will be 14-25 years of age, with at least two of the following: (1) Grade 2 pivot shift or greater; (2) returning to high-risk pivoting sport; (3) generalised ligamentous laxity; or (4) knee recurvatum of 10 degrees or more. Surgeons with similar expertise and no preference for either graft type will use traditional randomisation; two centres will use an expertise-based approach. Outcomes include ACLR clinical failure, patient-reported outcomes that assess symptoms, activity, participation and quality of life, measures of impaired range of motion and muscle function (quadriceps and hamstring strength), performance-based measures of physical function (hop tests, drop vertical jump), return to preinjury sports, adverse outcomes, intervention-related donor site morbidity and complications. Clinical failure and performance-based outcomes will be assessed by blinded evaluators over 2 years following ACLR. Analyses will combine STABILITY 2 and STABILITY 1 data in a mixed effects model where fixed effects include study, graft type, meniscal repair status and sex, while time, patient and surgeon are random effects variables. Ethics approval was granted for each centre prior to beginning recruitment. If successful, the results of this study will inform the optimal treatment of ACL rupture in young athletes, and women specifically, who are at risk for persistent rotational laxity/instability and graft rerupture. Reducing the risk of ACLR clinical failure will reduce the need for revision ACLR and the associated decreased quality of life and socio-economic burden that occurs because of ongoing knee instability and the increased risk for OA. https://clinicaltrials.gov/study/NCT03935750.
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway have revolutionized cancer immunotherapy, yet their clinical benefit is constrained by variable response rates and immune-related adverse events. This review systematically analyzes the molecular mechanisms by which key gut microbiota-derived metabolites-including short-chain fatty acids (SCFAs), tryptophan metabolites, and bile acids-modulate the PD-1/PD-L1 axis. We synthesized and evaluated peer-reviewed preclinical and clinical studies published over the past decade, focusing on metabolite-immune interactions, biomarker validation, and combinatorial intervention strategies. The summarized evidence demonstrates that these metabolites exert significant influences on the tumor microenvironment, enhance T-cell effector functions, and reshape immune tolerance, thereby affecting ICI responsiveness. We critically assess the predictive value of microbiota metabolites as potential biomarkers and review current progress in probiotic supplementation, fecal microbiota transplantation, and metabolite-based combination therapies. Despite promising translational prospects, several challenges-including inter-individual variability, lack of standardized protocols, and mechanistic gaps-remain to be addressed. Future directions should prioritize large-scale longitudinal studies and refined intervention designs to facilitate the clinical integration of microbiota-guided strategies, ultimately improving the precision and efficacy of cancer immunotherapy.
Invasive fungal infections (IFIs) cause significant morbidity and mortality in immunocompromised pediatric patients; systematic data comparing mold- and yeast-related infections remain limited. To evaluate epidemiology, clinical features, antifungal treatment, and outcomes of proven infectious fungal infections (IFIs) in immunocompromised children, comparing mold and yeast infections. This single-center retrospective study included 65 immunocompromised patients aged ≤ 18 years with proven IFIs diagnosed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) criteria. Of 65 patients (75.4% male; median age 62 months), mold infections occurred in 21 (32.3%) and yeast infections in 44 (67.7%). Aspergillus spp. (n = 6) and Mucor spp. (n = 3) were common molds; Candida parapsilosis (n = 15) predominated among yeasts. ALL was more prevalent in the mold group (38.1% vs. 11.4%; p = 0.019), while other oncological malignancies predominated in the yeast group (50.0% vs. 19.0%; p = 0.017). Combination therapy (66.7% vs. 9.1%; p < 0.001), salvage therapy (52.4% vs. 27.3%; p = 0.048), and treatment duration (median 56 vs. 21 days; p < 0.001) were higher in the mold group. Mold infections showed higher rates of nodules, cavitation, and air-crescent sign on thoracic CT (p < 0.05) and greater pulmonary progression (23.8% vs. 2.3%; p = 0.011). The overall pediatric intensive care unit (PICU) admission rate was 40.0%; mechanical ventilation was more frequent in the mold group (47.6% vs. 15.9%; p = 0.007) and was identified as the sole independent predictor of IFI-attributable mortality (OR 14.5; 95% CI 3.47-60.41; p < 0.001).Overall mortality was 36.9% with no between-group difference (p = 0.892); IFI-attributable mortality was higher in the mold group (28.6% vs. 18.2%; p = 0.081). Mold and yeast infections show distinct clinical, radiological, and therapeutic profiles in immunocompromised children, with mold infections showing greater treatment burden and higher IFI-attributable mortality.
Genetic variations impact drug response, driving the need for personalised medicine through pre-emptive pharmacogenetic testing. However, the adoption of pre-emptive pharmacogenetic testing for commonly prescribed drugs, such as tacrolimus, outside of tertiary hospitals is limited due to a lack of pharmacoeconomic evidence to support widespread implementation by healthcare policymakers. The iPHARMGx Consortium addresses this by developing the TRANSPGx clinical trial to assess the hypothesis that widespread adoption of a pre-emptive genotyping scheme in populations susceptible to receiving tacrolimus as immunosuppressive therapy following a kidney transplant is effective, cost-effective and feasible within the Spanish National Health System (SNHS) when compared to the standard of care tacrolimus dosing. The TRANSPGx trial is a multicentre, adaptive, randomised, controlled, pragmatic phase IV clinical trial nested within the iPHARMGx master protocol, with two parallel arms, aiming for superiority. Randomisation will be conducted on an individual basis with a centralised approach, with stratification by centre. After inclusion in the trial and completion of genotyping, subjects will be randomly allocated to either the experimental group (pharmacogenetic genotype-guided tacrolimus prescription) or the standard of care tacrolimus prescription (as deemed by the attending physician). The primary objective is to assess the effectiveness of a tacrolimus pre-emptive genotyping strategy in reaching tacrolimus target plasma concentrations after renal transplant. A total of 114 subjects will be recruited among the different participating centres, provided that no futility/efficacy boundary is reached in the prespecified interim analyses. Recruitment will be carried out during a 12-month period, and subjects will be followed for a 6-month period. The TRANSPGx trial received ethical approval on 16 January 2025 (La Paz University Hospital 2024.740). Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences. Trial results will be submitted for publication in an open access peer-reviewed medical speciality-specific publication. Trial registration of this study can be located at both the EU Clinical Trials Register, available from https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en and https://clinicaltrials.gov. Registration on both websites was done before the enrolment of the first patient complying with European regulations. The EU Clinical Trials Register is a primary registry according to the WHO. EU CT number: 2024-5 16 596-32-00/Clinical trial Identifier (ClinicalTrials.gov): NCT06701825. Protocol V. 1.2, 8 January 2025.
The persistent disparity between organ supply and demand remains the principal limitation to kidney transplantation worldwide. ABO-incompatible kidney transplant has progressively evolved from an experimental procedure to an established strategy for expanding the living donor pool. This review critically evaluated whether ABO-incompatible kidney transplant represents a justified, effective, and feasible solution in low- and middle-income countries. We conducted a structured review of international registry data, meta-analyses, and major cohort studies to assess epidemiology, historical evolution, immunologic principles, clinical outcomes, desensitization protocols, economic implications, and complication profiles associated with ABO-incompatible kidney transplant. Our results showed that global transplant activity fulfills <10% of estimated needs. ABO-incompatible kidney transplant procedures have increased living donor availability by approximately 25% to 33% in countries adopting this strategy. Contemporary data showed that graft and patient survival rates approached rates of compatible transplant, although early risks of antibody-mediated rejection, infection, and bleeding remain higher. Advances in B-cell depletion therapy, immunoadsorption techniques, and modern immunosuppressive regimens have markedly improved outcomes. The primary limitation in low- and middle-income settings is financial cost, particularly related to antibody removal technologies; however, validated cost-reduction strategies exist. ABO-incompatible kidney transplantation is no longer experimental and should be considered a mature, evidence-supported strategy. When implemented in experienced centers with appropriate protocols and cost-adaptation measures, this method constitutes a reasonable and potentially transformative approach to mitigating organ shortages in selected low- and middle-income countries.
Neoadjuvant cisplatin-based chemotherapy is a standard therapy for muscle-invasive bladder cancer. The efficacy and safety of neoadjuvant and adjuvant (perioperative) enfortumab vedotin-pembrolizumab as compared with neoadjuvant cisplatin-based chemotherapy in persons with this cancer are unclear. We conducted a phase 3, open-label, randomized trial involving adults with muscle-invasive bladder cancer eligible for cisplatin-based chemotherapy and radical cystectomy with pelvic lymph-node dissection (cystectomy). Participants were assigned to receive neoadjuvant enfortumab vedotin-pembrolizumab (4 cycles; enfortumab vedotin [1.25 mg per kilogram of body weight on days 1 and 8] and pembrolizumab [200 mg on day 1] every 3 weeks), cystectomy, and 5 cycles of enfortumab vedotin and 13 cycles of pembrolizumab as adjuvant therapy or to receive neoadjuvant cisplatin-gemcitabine (4 cycles; cisplatin [70 mg per square meter of body-surface area on day 1] plus gemcitabine [1000 mg per square meter on days 1 and 8] every 3 weeks) and cystectomy. The primary end point was event-free survival; key secondary end points were overall survival and pathological complete response. Safety was assessed. A total of 405 participants were assigned to receive enfortumab vedotin-pembrolizumab and 403 to receive cisplatin-gemcitabine. The median time from randomization to the data-cutoff date was 33.6 months (range, 22.5 to 53.6). A total of 86.7% of the participants in the enfortumab vedotin-pembrolizumab group and 89.6% of those in the cisplatin-gemcitabine group underwent cystectomy. At 2 years, estimated event-free survival was 79.4% with enfortumab vedotin-pembrolizumab and 66.2% with cisplatin-gemcitabine (hazard ratio for an event or death, 0.53; 95% confidence interval [CI], 0.41 to 0.70; P<0.001); estimated overall survival was 86.9% and 81.3%, respectively (hazard ratio for death, 0.65; 95% CI, 0.48 to 0.89; two-sided P = 0.006). A pathological complete response occurred in 55.8% and 32.5% of the participants (P<0.001). The incidence of grade 3 or higher adverse events of any cause was 75.7% with enfortumab vedotin-pembrolizumab and 67.2% with cisplatin-gemcitabine. Among participants with muscle-invasive bladder cancer eligible for cisplatin-based chemotherapy, perioperative enfortumab vedotin-pembrolizumab led to significantly better event-free and overall survival outcomes and a significantly higher incidence of pathological complete response than neoadjuvant cisplatin-gemcitabine, but with more adverse events of grade 3 or higher. (Funded by Merck Sharp and Dohme and others; KEYNOTE-B15/EV-304 ClinicalTrials.gov number, NCT04700124.).
Metabolic complications are a major challenge after solid organ transplantation (SOT), impacting graft and patient survival. Understanding staff's knowledge, attitude, and practice (KAP) is crucial to optimize management. Utilizing data from a nationwide convenience sample (February-April 2025) of SOT clinicians and clinical pharmacists on the post-transplant metabolic complications management, this study analyzed 43-item KAP responses from 277 participants. Analyses included descriptive statistics, Spearman's correlation, and multinomial logistic regression to assess KAP levels and identify influencing factors. Among 277 participants, the high-level rate for overall KAP was 67.5%, with high-level rates of 62.8, 88.1, and 56.3% for the knowledge, attitude, and practice dimensions, respectively. All three KAP dimensions were significantly positively correlated (r = 0.372-0.462, all p < 0.05). Multinomial logistic regression identified variables associated with high level of KAP. Significant positive factors included: female gender, a master's degree, and 10-19 years of work time for high-level knowledge; both 10-19 and ≥20 years of work time for high-level attitude; being a clinical physician for high-level practice; and age 36-44 years, a master's degree and vice senior or chief senior titles for a high-level overall KAP score. Age 45-60 years was negatively associated with high-level attitude. Chinese SOT care providers demonstrate positive attitudes but suboptimal knowledge and practice in post-transplant metabolic complications management. Our study identifies self-reported educational needs and perceived practice gaps that may inform future training or quality-improvement initiatives.
Personalized vaccines provide the advantage of patient-specific antigen selection to optimize immune responses, a strategy extensively explored in oncology through neoantigen-targeted peptide, mRNA, and dendritic cell platforms. Peptide vaccines provide simplicity and stability though often elicit limited cytotoxic T-cell responses. What is more, mRNA vaccines lead to rapid, multiplexed neoantigen delivery, endogenous antigen processing and eventually improved immunogenic coverage. Dendritic cell-based vaccines have the potency to prime potent T-cells although this technology requires labor-intensive manufacturing and extensive production timelines. Integration with immune checkpoint inhibitors, adoptive cell therapies, and oncolytic viruses further enhances efficacy, suggesting that rational combinations may be more effective than single modalities. Recent advances in sequencing, computational epitope prediction, and bioinformatics pipelines have facilitated neoantigen prioritization and DC vaccine design, enabling more rapid and precise personalization. Hybrid vaccination strategies, such as ex-vivo mRNA-electroporated dendritic cells and in-vivo DC-targeted platforms, bridge the gap between manufacturing feasibility and potent immune activation. Emerging technologies, including AI-driven neoepitope prediction, receptor-targeted antigen delivery, biomaterial-based modulation, and distributed mRNA manufacturing, seem to be promising approaches to accelerate personalized vaccine development in future. From another point of view, lessons learned from the COVID-19 pandemic accelerated the development, large-scale deployment, and validation of mRNA vaccine platforms for infectious diseases. Host HLA diversity, prior immune history, and viral evolution create heterogeneity in immune responses, highlighting opportunities for semi-personalized or adaptive strategies. In this review, we provide a landscape of personalized vaccines, with a focus on DC-based platforms, and explore translational lessons for viral pathogens. A conceptual framework linking cancer immunotherapy and infectious disease preparedness is proposed, emphasizing hybrid personalization approaches, rapid manufacturing, and AI-enabled epitope selection. This perspective highlights how convergence of immunology, computational biology, and advanced vaccine technologies could expand the scope of personalized vaccination, from oncology to future epidemic and pandemic scenarios as well as the current challenges.
Aim: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of metabolic dysfunction-associated steatotic liver disease, linked to hepatic and extra-hepatic complications and substantial healthcare costs. Despite its clinical and economic impact, real-world evidence on disease progression and costs in Germany is limited. Materials & methods: We conducted a retrospective cohort study using statutory health insurance claims from the InGef database (2016-2023), covering 4.7% of the German population. Patients with MASH were identified using ICD-10-GM code K75.8, in absence of the more specific code in the German coding system. Baseline characteristics and comorbidities were assessed over 2 years prior to index diagnosis. Progression was defined by transitions through end-stage liver disease (ESLD) stages: compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver transplantation. Healthcare costs were analyzed descriptively and via regression models. Results: Among 4710 patients with MASH (prevalence: 0.15%), 39.4% had documented ESLD during follow-up (mean follow-up in days 1530). Disease progression to ESLD occurred in 26.0% of patients without baseline ESLD (n = 922/3490), whereas 4.0% of patients with baseline ESLD (n = 48/1188) progressed to a more severe ESLD stage during follow-up, with a mean time to first progression of approximately 25.3 months. Patients with ESLD incurred annual costs of €12,737 versus €4928 for those without ESLD. Progression to hepatocellular carcinoma and liver transplantation resulted in predicted costs of €12,948 and €75,719 per patient-year, respectively. Mortality was significantly higher among patients with ESLD (incidence rate ratio: 4.65; 95% CI: 3.76-5.79). Discussion: Over a quarter of identified patients with MASH already had advanced liver disease at baseline, suggesting potential underdiagnosis or late recognition in routine clinical practice. Early detection, proactive management and targeted therapies are essential to reduce progression and economic burden. What is this article about? This article looks at how metabolic dysfunction-associated steatohepatitis (MASH), a serious form of fatty liver disease, affects people in Germany. Using German health insurance claims data from 2016 to 2023, the study examined how often people with MASH developed advanced liver disease, what other health problems they had, and how much their healthcare cost. What were the results? Among 4710 identified patients with MASH, many already had advanced liver disease or developed it during follow-up. Patients with end-stage liver disease had much higher healthcare costs than those without it. Costs increased further in more severe stages such as liver cancer or liver transplantation. Patients with advanced liver disease also had a much higher risk of death and major cardiovascular events. What do the results mean? The findings show that MASH places a substantial burden on patients and the healthcare system in Germany, especially when the disease progresses to advanced liver stages. Earlier detection and better management may help reduce complications, improve outcomes and lower costs. The results also suggest that MASH may often be diagnosed late in routine care.
Alzheimer's disease(AD) is a highly prevalent neurodegenerative disorder with complex pathogenesis. Currently available mainstream drugs offer limited efficacy and often cause significant side effects. The herb pair of Astragali Radix and Acori Tatarinowii Rhizoma, known for its Qi-tonifying and orifice-opening properties in TCM, has demonstrated advantages in multi-target and holistic regulation in anti-AD research. This review systematically summarizes the synergistic mechanisms of active ingredients such as astragaloside Ⅳ, calycosin, and β-asarone against AD through multiple pathways, including peroxisome proliferator-activated receptor γ(PPARγ)/brain-derived neurotrophic factor(BDNF) pathway, phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) pathway, and gut-brain axis. It also points out that current studies remain largely confined to in vitro and animal experiments, with insufficient evidence for clinical translation. Building on this, the review further proposes innovative research directions, such as constructing astragaloside Ⅳ-β-asarone co-delivery nanosystems, optimizing the compatibility ratio of the herb pair, and combining with fecal microbiota transplantation to validate causal mechanisms via microbiota-gut-brain axis. These proposals aim to provide a systematic theoretical framework and experimental pathway for the in-depth development and clinical translation of the herb pair of Astragali Radix and Acori Tatarinowii Rhizoma.
It remains unclear whether different factors influence 30- and 90-day readmission rates. We identified predictors of 90-day mortality in a global cohort of hospitalised patients with cirrhosis. Variables associated with 30- and 90-day post-discharge readmission, liver transplantation (LT), and mortality were compared in prospectively enrolled, non-electively hospitalised adult patients with cirrhosis. We enrolled 4208 patients from 125 centres across 37 countries. Alcohol-related liver disease was the most common aetiology of cirrhosis (40%), followed by hepatitis B virus infection (21%); 47% were readmitted, 8% received liver transplantation (LT), and 23% died within 90 days post-discharge. In multivariable analysis, country income was significantly associated with both 30- and 90-day readmission rates, the receipt of LT, and mortality within 30 and 90 days post-discharge (all p-values < 0.001). Independent predictors of higher rates of 30- and 90-day readmissions, respectively, were disease severity (p < 0.001, p = 0.003), prior ascites (p = 0.025, p = 0.016), prior hospitalisation (p < 0.001), hyponatremia (p < 0.001, p = 0.008), and in-hospital vasopressor use (p = 0.002, p = 0.011). Prior variceal bleeding independently predicted higher 90-day readmission rates, whereas age, disease severity, mechanical ventilation, and in-hospital vasopressor use (all, p < 0.001) increased odds of 30- and 90-day post-discharge death. Additionally, admission (p = 0.011) and nosocomial (p = 0.022) infections increased the odds of 90-day post-discharge death. In a global cohort of hospitalised patients with cirrhosis, patients in high-income countries exhibited the highest rates of 30- and 90-day readmission, alongside lower mortality rates and a higher incidence of LT. Variables that predict 30-day readmission also predicted 90-day readmission. Understanding these disparities is essential for achieving health equity. Healthcare disparities in the prevention, diagnosis, and management of cirrhosis may substantially influence patient outcomes. In a prospectively enrolled global cohort study comprising 4,208 inpatients with cirrhosis, nearly half of the patients required readmissions, fewer than one‐tenth underwent liver transplantation, and one‐quarter died within 90 days after hospital discharge. Notably, major outcome differences appear to be independent of disease etiology and instead are more strongly associated with country income.
The microbial imbalance in head and neck cancer (HNC) is a promising area of research for developing targeted therapies. Maintenance of microbial diversity and balance through prebiotics, probiotics and faecal microbial transplantation (FMT) holds a potential approach in reestablishing the gut health. Preclinical studies and early clinical trials have shown positive results in restoring the favourable microbial environment, thereby minimizing the inflammation and maximizing the positive immune response. However, the link between microbial flora associated with oral dysbiosis, the associated biomarkers and HNC tumorigenesis needs to be further explored. Future research focusses on developing standardised strategies for maintaining the microbial environment, to serve as an adjunct to the standard treatment protocols for HNC. Biomarkers predicting immune response, synthetic genetically engineered beneficial bacteria, integration of metagenomics, metabolomics and meta transcriptomics for intra-tumoral microbial evaluation are the focus areas of emerging research.
Hematological malignancies remain one of the leading causes of morbidity and mortality despite advances in targeted therapies, immunotherapy, and stem cell transplantation. Emerging evidence indicates that treatment efficacy and toxicity depend not only on the choice of therapy but also on its timing relative to the patient's internal circadian rhythm. The circadian clock orchestrates fundamental processes in hematopoiesis and immunity, such as stem-cell proliferation, leukocyte trafficking, DNA repair, and drug metabolism, while its disruption promotes malignant transformation, therapeutic resistance, and systemic toxicity. This narrative review synthesizes current understanding of circadian regulation in hematopoietic and immune systems, the mechanistic and preclinical foundations of chronotherapy in blood cancers, and the limited but growing body of clinical evidence linking treatment timing with outcome in leukemia, lymphoma, and transplantation. The review also examines practical challenges, including inter-individual variability, disease-induced circadian disruption, and hospital workflow constraints, while highlighting emerging technologies, such as transcriptomic clocks, wearable biosensors, and AI-driven scheduling algorithms, that are poised to enable personalized, time-aware therapy. By integrating temporal precision into existing therapeutic frameworks, chronotherapy may represent a promising investigational dimension of precision medicine in hematological oncology. However, its clinical value remains to be defined through prospective studies that incorporate validated circadian biomarkers, predefined timing windows, and clinically meaningful efficacy and toxicity endpoints.
Nanotechnology has rapidly evolved into a transformative platform in transplant medicine, offering sophisticated tools for targeted drug delivery, organ preservation, precision diagnostics, and tolerance induction. Engineered nanoparticles enable localized and sustained delivery of immunosuppressive agents while minimizing systemic toxicity, thus allowing long-standing limitations of conventional immunosuppression to be addressed. Diverse nanomedicine platforms, including liposomes, polymeric nanoparticles, dendrimers, magnetic nanoparticles, and inorganic systems, enhance drug bioavailability, reduce off-target effects, and allow integration of imaging and therapeutic functions. This review synthesized current progress in nanoparticle-enabled therapeutics, diagnostics, machine-perfusion-based delivery, gene editing, and personalized nano-immunotherapy, highlighting their potential to reduce rejection, ischemia-reperfusion injury, and chronic graft dysfunction. Insights from recent advances.