The impact of preservation fluid culture on graft site arteritis: a systematic review and metanalysis

The role of culturing the graft preservation fluid (PF) is controversial and its impact on graft arteritis development remains unclear

Evaluation of the Kinetics of Antibody Response to COVID-19 Vaccine in Solid Organ Transplant Recipients: The Prospective Multicenter ORCHESTRA Cohort

Previous studies assessing the antibody response (AbR) to mRNA COVID-19 vaccines in solid organ transplant (SOT) recipients are limited by short follow-up, hampering the analysis of AbR kinetics. We present the ORCHESTRA SOT recipients cohort assessed for AbR at first dose (t0), second dose (t1), and within 3 ± 1 month (t2) after the first dose. We analyzed 1062 SOT patients (kidney, 63.7%; liver, 17.4%; heart, 16.7%; and lung, 2.5%) and 5045 health care workers (HCWs). The AbR rates in the SOTs and HCWs were 52.3% and 99.4%. The antibody levels were significantly higher in the HCWs than in the SOTs (p < 0.001). The kinetics showed an increase (p < 0.001) in antibody levels up to 76 days and a non-significant decrease after 118 days in the SOT recipients versus a decrease up to 76 days (p = 0.02) and a less pronounced decrease between 76 and 118 days (p = 0.04) in the HCWs. Upon multivariable analysis, liver transplant, ≥3 years from SOT, mRNA-1273, azathioprine, and longer time from t0 were associated with a positive AbR at t2. Older age, other comorbidities, mycophenolate, steroids, and impaired graft function were associated with lower AbR probability. Our results may be useful to optimize strategies of immune monitoring after COVID-19 vaccination and indications regarding timing for booster dosages calibrated on SOT patients’ characteristics.The ORCHESTRA project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 101016167Peer reviewe

Relationship between immune response to SARS-CoV2 vaccines and development of breakthrough infection in solid organ transplant recipients: the CONTRAST cohort

Background: SARS-CoV-2 vaccination in solid organ transplant (SOT) is associated with poorer antibody response (AbR) compared to non-SOT recipients. However, its impact on the risk of breakthrough infection (BI) should yet be assessed. Methods: Single-center prospective longitudinal cohort study enrolling adult SOT recipients who received SARS-CoV2 vaccination during 1-year period from February 2021, and followed-up to April 30th 2022. Patients were tested for AbR at multiple timepoints. Primary endpoint was BI (laboratory confirmed SARS-CoV2 infection ≥14 days after 2nd dose). Immunization (positive AbR) was considered an intermediate state between vaccination and BI. Probabilities of being in vaccination, immunization and BI states were obtained for each type of graft and vaccination sequence with multistate survival analysis, then multivariable logistic regression was performed to analyse the risk of BI in AbR levels. Results: 614 SOT (275 kidney, 163 liver, 137 heart, 39 lung) recipients were included. Most patients (84.7%) received three vaccine doses, the first two consisted of BNT162b2 and mRNA-1273 in 73.5% and 26.5% of cases, respectively; while at the third dose mRNA-1273 was administered in 59.8% of patients. Overall, 75.4% of patients reached immunization and 18.4% developed BI. Heart transplant recipients showed lowest probability of immunization (0.418) and highest of BI (0.323), all-mRNA-1273 vaccine-sequence showed higher probability of immunization (0.732) and lowest of BI (0.098). Risk of BI was higher for non-high-level AbR, younger age and shorter time from transplant. Conclusions: SOT patients with non-high-level AbR, shorter time from transplantation, and heart recipients are at highest risk of BI

Antidepressants targeting the ubiquitin-proteasome-autophagy pathway increase mesothelioma response to chemotherapy

Malignant mesothelioma (MM) is a highly aggressive neoplasm with poor prognosis and survival averaging 6-12 months after diagnosis. The efficacy of the first-line treatment (pemetrexed plus cis-platinum) improves the overall survival of only 2-3 months because the marked resistance of MM cells to chemo-induced apoptosis limits response to the therapy. Recently, we demonstrated that the release of calcium (Ca2+) from the endoplasmic reticulum (ER) to mitochondria, a crucial event in apoptotic cell death, is deregulated in MM cells. Similarly, different studies highlighted a pivotal role of the autophagic process in MM, wherein enhanced autophagy allows cells to survive cytotoxic stimuli, thus conferring cell death resistance. Here, we found that some antidepressants (ADs), DCMI and sertraline, and antipsychotics (APs), clozapine and haloperidol, presented anti-autophagic effects that increased apoptosis in MM cells treated with pemetrexed and cis-platinum, alone or in combination. Furthermore, we showed that in MM cells, autophagy induced the degradation of type III inositol 1,4,5-trisphosphate receptor (IP3R3), the main player in Ca2+ release from ER to the cytosol and mitochondria, reducing apoptosis. By the other hand, ADs by inhibiting the autophagic-UPS (ubiquitin-proteasome system) degradation increased IP3R3 levels, an effect that led to increased Ca2+ transfer from the ER to mitochondria and promoted apoptosis. In conclusion, our results suggest that the chemo-resistance in MM is largely related to reduced levels or activity of the IP3R3 and consequent lower mitochondrial Ca2+ concentrations, which render cancer cells incapable to execute apoptosis. Thus, inhibiting the autophagic-UPS degradation of IP3R3 in MM cells could stabilize the receptor and it could restore susceptibility to chemo-induced apoptosis. In this light, we propose that ADs and APs, in combination with chemotherapy drugs, could represent an interesting novel therapeutic strategy for MM.Il mesotelioma maligno (MM) è una neoplasia molto aggressiva con una prognosi sfavorevole e una sopravvivenza media di 6-12 mesi dopo la diagnosi. L'efficacia del trattamento di prima linea (pemetrexed e cis-platino) aumenta la sopravvivenza di soli 2-3 mesi poiché la marcata resistenza delle cellule del MM all'apoptosi, indotta da chemioterapici, limita la risposta alla terapia. Recentemente, abbiamo dimostrato che il rilascio di calcio (Ca2+) dal reticolo endoplasmatico (ER) ai mitocondri, un evento cruciale nel processo di morte apoptotica delle cellule, è alterato nelle cellule del MM. Allo stesso modo, diversi studi hanno messo in evidenza un ruolo chiave del processo autofagico nel MM, nel quale un’autofagia potenziata consente alle cellule di sopravvivere a stimoli citotossici, conferendogli così resistenza alla morte cellulare. In questo lavoro, abbiamo mostrato che alcuni antidepressivi (AD), DCMI e sertralina, e antipsicotici (AP), clozapina e aloperidolo, presentano effetti anti-autofagici che aumentano l'apoptosi nelle cellule del MM trattate con pemetrexed e cis-platino, da solo o in combinazione. Inoltre, abbiamo dimostrato che nelle cellule del MM l'autofagia induce la degradazione del recettore inositolo 1,4,5-trisfosfato di tipo III (IP3R3), il principale protagonista nel rilascio di Ca2+ dall’ER al citosol e ai mitocondri, riducendo l'apoptosi. D'altra parte, abbiamo visto che gli AD, inibendo la degradazione mediata dall’autofagia e dal sistema ubiquitina-proteasoma (UPS), aumentano i livelli di IP3R3, un effetto che porta ad un aumento del trasferimento di Ca2+ dall'ER ai mitocondri e che favorisce l'apoptosi. In conclusione, i nostri risultati suggeriscono che la chemio-resistenza nel MM sia principalmente correlata a livelli ridotti, o ad un’attività ridotta, dell'IP3R3 e alla conseguente diminuzione delle concentrazioni di Ca2+ mitocondriale, che rendono le cellule tumorali incapaci di eseguire l'apoptosi. Pertanto, l'inibizione della degradazione dell’IP3R3, mediata dal sistema autofagia-UPS, nelle cellule del MM potrebbe stabilizzare il recettore e ripristinare la suscettibilità all'apoptosi indotta dalla chemioterapia. Dunque, proponiamo che gli AD e gli AP, in combinazione con i farmaci chemioterapici, possano rappresentare un'interessante nuova strategia terapeutica per il MM

Mitochondria-associated membranes (MAMs) and inflammation

The endoplasmic reticulum (ER) and mitochondria are tightly associated with very dynamic platforms termed mitochondria-associated membranes (MAMs). MAMs provide an excellent scaffold for crosstalk between the ER and mitochondria and play a pivotal role in different signaling pathways that allow rapid exchange of biological molecules to maintain cellular health. However, dysfunctions in the ER-mitochondria architecture are associated with pathological conditions and human diseases. Inflammation has emerged as one of the various pathways that MAMs control. Inflammasome components and other inflammatory factors promote the release of pro-inflammatory cytokines that sustain pathological conditions. In this review, we summarize the critical role of MAMs in initiating inflammation in the cellular defense against pathogenic infections and the association of MAMs with inflammation-mediated diseases

Functions and dys-functions of promyelocytic leukemia protein PML

The promyelocytic leukemia protein PML has been previously recognized as a critical and essential regulator of a broad number of cellular functions. At nuclear level PML forms the PML-nuclear bodies, where it can sequester and influence the post-translational modification of a wide number of proteins, ultimately affecting their regulative role in DNA transcription. In such a way, PML acts as a key player in strategic cellular activities like as the antiviral defense, in the regulation of the cell cycle, in senescence and programmed cell death. In addition, PML can redistribute also at cytoplasmic level, where it associates to the endoplasmic reticulum or is recruited to mitochondrial-associated membranes. Here it can interact with key cellular proteins like as p53 and influence cell metabolism, mitochondrial calcium upload and autophagy. Altogether, all these findings depict PML as a protein able to exert a widespread action mainly focused on pro-apoptotic and cytostatic activities. Anyway, presence of “Janus-like” pro-tumoral behaviors have been reported, prompting for further investigation to better dissect and highlight all the possible roles that PML can assume in the different physiological or pathological environments. In this review, we discuss the role of PML in multiple cellular functions and pathologic scenarios and summarize the players that control PML protein both at nuclear and at cytoplasmic level

Evaluation of the kinetics of antibody response to COVID-19 vaccine in solid organ transplant recipients: the prospective multicenter orchestra cohort

Previous studies assessing the antibody response (AbR) to mRNA COVID-19 vaccines in solid organ transplant (SOT) recipients are limited by short follow-up, hampering the analysis of AbR kinetics. We present the ORCHESTRA SOT recipients cohort assessed for AbR at first dose (t0), second dose (t1), and within 3 ± 1 month (t2) after the first dose. We analyzed 1062 SOT patients (kidney, 63.7%; liver, 17.4%; heart, 16.7%; and lung, 2.5%) and 5045 health care workers (HCWs). The AbR rates in the SOTs and HCWs were 52.3% and 99.4%. The antibody levels were significantly higher in the HCWs than in the SOTs (p < 0.001). The kinetics showed an increase (p < 0.001) in antibody levels up to 76 days and a non-significant decrease after 118 days in the SOT recipients versus a decrease up to 76 days (p = 0.02) and a less pronounced decrease between 76 and 118 days (p = 0.04) in the HCWs. Upon multivariable analysis, liver transplant, ≥3 years from SOT, mRNA-1273, azathioprine, and longer time from t0 were associated with a positive AbR at t2. Older age, other comorbidities, mycophenolate, steroids, and impaired graft function were associated with lower AbR probability. Our results may be useful to optimize strategies of immune monitoring after COVID-19 vaccination and indications regarding timing for booster dosages calibrated on SOT patients’ characteristics

Association of Patients’ Epidemiological Characteristics and Comorbidities with Severity and Related Mortality Risk of SARS-CoV-2 Infection Results of an Umbrella Systematic Review and Meta-Analysis

The objective of this study was to assess the association between patients’ epidemiological characteristics and comorbidities with SARS-CoV-2 infection severity and related mortality risk. An umbrella systematic review, including a meta-analysis examining the association between patients’ underlying conditions and severity (defined as need for hospitalization) and mortality of COVID-19, was performed. Studies were included if they reported pooled risk estimates of at least three underlying determinants for hospitalization, critical disease (ICU admission, mechanical ventilation), and hospital mortality in patients diagnosed with SARS-CoV-2 infection. Evidence was summarized as pooled odds ratios (pOR) for disease outcomes with 95% confidence intervals (95% CI). Sixteen systematic reviews investigating the possible associations of comorbidities with severity or death from COVID-19 disease were included. Hospitalization was associated with age > 60 years (pOR 3.50; 95% CI 2.97–4.36), smoking habit (pOR 3.50; 95% CI 2.97–4.36), and chronic pulmonary disease (pOR 2.94; 95% CI 2.14–4.04). Chronic pulmonary disease (pOR 2.82; 95% CI 1.92–4.14), cerebrovascular disease (pOR 2.74; 95% CI 1.59–4.74), and cardiovascular disease (pOR 2.44; 95% CI 1.97–3.01) were likely to be associated with increased risk of critical COVID-19. The highest risk of mortality was associated with cardiovascular disease (pOR 3.59; 95% CI 2.83–4.56), cerebrovascular disease (pOR 3.11; 95% CI 2.35–4.11), and chronic renal disease (pOR 3.02; 95% CI 2.61–3.49). In conclusion, this umbrella systematic review provides a comprehensive summary of meta-analyses examining the impact of patients’ characteristics on COVID-19 outcomes. Elderly patients and those cardiovascular, cerebrovascular, and chronic renal disease should be prioritized for pre-exposure and post-exposure prophylaxis and early treatment

Harmonization and standardization of data for a pan-European cohort on SARS- CoV-2 pandemic

The European project ORCHESTRA intends to create a new pan-European cohort to rapidly advance the knowledge of the effects and treatment of COVID-19. Establishing processes that facilitate the merging of heterogeneous clusters of retrospective data was an essential challenge. In addition, data from new ORCHESTRA prospective studies have to be compatible with earlier collected information to be efficiently combined. In this article, we describe how we utilized and contributed to existing standard terminologies to create consistent semantic representation of over 2500 COVID-19-related variables taken from three ORCHESTRA studies. The goal is to enable the semantic interoperability of data within the existing project studies and to create a common basis of standardized elements available for the design of new COVID-19 studies. We also identified 743 variables that were commonly used in two of the three prospective ORCHESTRA studies and can therefore be directly combined for analysis purposes. Additionally, we actively contributed to global interoperability by submitting new concept requests to the terminology Standards Development Organizations

Association of Patients' Epidemiological Characteristics and Comorbidities with Severity and Related Mortality Risk of SARS-CoV-2 Infection: Results of an Umbrella Systematic Review and Meta-Analysis

The objective of this study was to assess the association between patients' epidemiological characteristics and comorbidities with SARS-CoV-2 infection severity and related mortality risk. An umbrella systematic review, including a meta-analysis examining the association between patients' underlying conditions and severity (defined as need for hospitalization) and mortality of COVID-19, was performed. Studies were included if they reported pooled risk estimates of at least three underlying determinants for hospitalization, critical disease (ICU admission, mechanical ventilation), and hospital mortality in patients diagnosed with SARS-CoV-2 infection. Evidence was summarized as pooled odds ratios (pOR) for disease outcomes with 95% confidence intervals (95% CI). Sixteen systematic reviews investigating the possible associations of comorbidities with severity or death from COVID-19 disease were included. Hospitalization was associated with age &gt; 60 years (pOR 3.50; 95% CI 2.97-4.36), smoking habit (pOR 3.50; 95% CI 2.97-4.36), and chronic pulmonary disease (pOR 2.94; 95% CI 2.14-4.04). Chronic pulmonary disease (pOR 2.82; 95% CI 1.92-4.14), cerebrovascular disease (pOR 2.74; 95% CI 1.59-4.74), and cardiovascular disease (pOR 2.44; 95% CI 1.97-3.01) were likely to be associated with increased risk of critical COVID-19. The highest risk of mortality was associated with cardiovascular disease (pOR 3.59; 95% CI 2.83-4.56), cerebrovascular disease (pOR 3.11; 95% CI 2.35-4.11), and chronic renal disease (pOR 3.02; 95% CI 2.61-3.49). In conclusion, this umbrella systematic review provides a comprehensive summary of meta-analyses examining the impact of patients' characteristics on COVID-19 outcomes. Elderly patients and those cardiovascular, cerebrovascular, and chronic renal disease should be prioritized for pre-exposure and post-exposure prophylaxis and early treatment