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Background: A significant increased risk of complications and mortality in immunocompromised patients affected by COVID-19 has been described. However, the impact of COVID-19 in solid organ transplant (SOT) recipients is an issue still on debate, due to conflicting evidence emerged from different observational studies. Objective: We performed a systematic review with meta-analysis to assess the clinical outcome in SOT recipients with COVID-19 compared to general population. Data source: PubMed-MEDLINE and Scopus were independently searched until 13 October 2021. Study eligibility criteria: Prospective or retrospective observational studies comparing clinical outcome in SOT recipients versus general populations affected by COVID-19. Primary endpoint was 30-day mortality. Participants: Patients with confirmed COVID-19. Intervention: Solid organ transplant recipients. Assessment of risk of bias: Quality of included studies was independently assessed according to ROBINS-I tool for observational studies. Methods of data synthesis: Meta-analysis was performed by pooling odds ratio (OR) retrieved from studies providing adjustment for confounders using a random-effect model with inverse variance method. Multiple subgroup and sensitivity analyses were conducted to investigate source of heterogeneity. Results: 3,501 articles were screened, and thirty-one observational studies (N=590,375; 5,759 SOT recipients vs. 584,616 general population) were included in the meta-analyses. No difference in 30-day mortality rate was found in primary analysis including studies providing adjustment for confounders (N=17; 3,752 SOT recipients vs. 159,745 general population; OR 1.13, 95%CI 0.94-1.35; I2=33.9%). No evidence of publication bias was reported. Higher risk of ICU admission (OR 1.56, 95%CI 1.03-2.63) and occurrence of acute kidney injury (OR 2.50 95%CI 1.81-3.45) was found in SOT recipients. Conclusions: No increased risk in mortality was found in SOT recipients affected by COVID-19 compared to general population when adjusted for demographic and clinical features and COVID-19 severity.

Background. Intra-abdominal candidiasis (IAC) is burdened by high mortality rates. However, the correct management of a critically ill patient with suspected IAC is an issue still on debate. The aim of our study was to evaluate the safety of pulse high-dose of liposomal amphotericin B (L-AmB) in patients with suspected IAC managed with a Beta-D-Glucan (BDG)-guided strategy. Methods. Phase 2 prospective study enrolling adult patients with intra-abdominal sepsis following surgery. Patients received a single dose of L-AmB 5mg/kg on day 1. At day 3, L-AmB was discontinued in case of negativity of basal serum (1, 3)-Beta-D-Glucan (BDG) and was continued (3 mg/kg/daily) in case of positive basal BDG, or microbiologically confirmed IAC. The main endpoint was occurrence of adverse events according with common toxic criteria definition. Results. Overall, 40 patients were enrolled from January 2019 until August 2022. Of them 15 (37.5%) were male, median age was 65 (49–76) years. Urgent surgery accounted for 31 (77.5%) cases, principal indication was secondary/tertiary peritonitis (22, 55%), half of patients had a previous surgical operation within 30 days. Five (12.5%) patients had criteria for septic shock at enrolment. The median APACHE II score at ICU admission was 12 (10–15). In 33 (85%) cases IAC was excluded, whereas 5 (12.5%) and 2 (5%) patients had a probable and proven IAC, respectively. The single dose of L-AmB 5 mg/Kg was well tolerated in all patients, no early and late severe adverse events related to the drug were reported. L-AmB was discontinued in 65% of patients following a negative basal BDG result. All-cause 30-day mortality rate was 15%, in none case death was related to L-AmB administration or uncontrolled IAC. More specifically, mortality rates between patients with and without proven IAC was 0% vs. 15.8%, p = 0.99. Conclusions. The rate of proven IAC among critically ill high-risk patients was low, attesting at 5%. A single dose of L-AmB 5 mg/Kg following prompt withdrawal in case of basal negative BDG result seems to be a safe and effective approach in such population.

Background: Infections of cardiovascular implantable electronic devices (CIED) are mainly due to Gram-positive bacteria (GPB). Data about Gram-negative bacteria CIED (GNB-CIED) infections are limited. This study aimed to investigate risk factors, clinical and diagnostic characteristics, and outcome of patients with GNB-CIED. Methods: A multicentre, international, retrospective, case-control-control study was performed on patients undergoing CIED implantation from 2015 to 2019 in 17 centres across Europe. For each patient diagnosed with GNB-CIED, one matching control with GPB-CIED infection and two matching controls without infection were selected. Results: A total of 236 patients were enrolled: 59 with GNB-CIED infection, 59 with GPB-CIED infection and 118 without infection. No between-group differences were found regarding clinical presentation, diagnostic and therapeutic management. A trend toward a higher rate of fluorodeoxyglucose positron emission computed tomography (FDG PET/CT) positivity was observed among patients with GNB than in those with GPB-CIED infection (85.7% vs. 66.7%; P = 0.208). Risk factors for GNB-CIED infection were Charlson Comorbidity Index Score (relative risk reduction, RRR = 1.211; P = 0.011), obesity (RRR = 5.122; P = 0.008), ventricular-pacing ventricular-sensing inhibited-response pacemaker implantation (RRR = 3.027; P = 0.006) and right subclavian vein site of implantation (RRR = 5.014; P = 0.004). At 180-day survival analysis, GNB-CIED infection was associated with increased mortality risk (HR = 1.842; P = 0.067). Conclusions: Obesity, high number of comorbidities and right subclavian vein implantation site were associated with increased risk of GNB-CIED infection. A prompt therapeutic intervention that may be guided using FDG PET/CT is suggested in patients with GNB-CIED infection, considering the poorer outcome observed in this group.

Background The role of culturing the graft preservation fluid (PF) is controversial and its impact on graft arteritis development remains unclear. Methods Systematic literature search retrieving all-languages observational studies comparing SOT recipients with culture positive PF versus culture negative PF. Graft site arteritis within 180 days from transplant was selected as primary outcome. Data were independently extracted using a pre-specified form, and quality of included studies was independently assessed according to ROBINS-I tool for observational studies. Meta-analysis was performed using Mantel-Haenszel random-effect models. Results 2,492 articles were screened, and twenty-one observational studies (N=2,208 positive PF vs. 4,458 negative) were included in the meta-analyses. Among positive PF, 857 (38.8%) were classified as high-risk group pathogens (fungi, Gram negative, Enterococcus spp., beta-hemolytic streptococci and Staphylococcus aureus) and 1,351 (61.2%) as low-risk (mostly coagulase negative Staphylococci) pathogens. A significant higher risk of graft arteritis was found in SOT recipients with a PF yielding a high-risk pathogen (odds ratio [OR] 18.43, 95%CI 7.83-43.40), with low heterogeneity (I²=2.24%). Similar results were found considering separately high-risk bacteria (OR 12.02, 95%CI 4.88-29.60) and fungi (OR 71.00, 95%CI 28.07–179.56), with no heterogeneity (I²=0%), and in the subgroup analyses of liver (OR 16.78, 95%CI 2.95–95.47) and kidney (OR 19.90, 95%CI 4.78–82.79) recipients. However, data about diagnostic features of graft arteritis were very limited, indeed for only 11 of the 93 events histological or microbiological results were reported. Conclusion Our results may support the performance of PF culturing and a preemptive diagnostic or therapeutic management upon isolation of high-risk pathogen. Further studies based on reliable diagnosis of graft arteritis are needed to confirm our findings. Disclosures All Authors: No reported disclosures.

Background Solid organ transplant (SOT) recipients are at higher risk than general population for complicated COVID-19 course. Moreover COVID-19 vaccination in this setting is associated with a suboptimal immune response. However, the impact of this finding on the risk of breakthrough infection (BI) in SOT recipients has to be yet determined. Methods Single-center prospective longitudinal cohort of adult SOT recipients who received three doses of mRNA COVID-19 vaccine between February and December 2021 and were followed up to March 30 2022. Patients were tested for antibody response at several timepoints (1 st dose, 2 nd dose, 3±1 month after 1 st dose, and 1 month after 3 rd dose). Main endpoints were: i) BI defined as laboratory confirmed SARS-CoV2 infection diagnosed ≥14 day after 2 nd dose; ii) positive antibody response (AbR) defined as anti-rapid binding domain titer ≥5 U/ml determined by Elecsys Anti-SARS-CoV-2 ECLIA assay (Roche Diagnostics, CH), the last available determination before BI was considered. Results Study cohort consists of 642 SOT (277 kidney, 191 liver, 144 heart, 37 lung) recipients: 63.9% males, median age 54 ± 14.5 years. Of them, 111 (17.8%) developed BI, BI rates were 19.9%, 18.1%, 15.2% and 10.8% among liver, heart, kidney and lung transplant recipients, respectively. Positive-AbR was observed in 60% of all patients, but rates varied from 8.7% to 91.3% among patients with BI and without BI, respectively. Predictors of BI infection at multivariable analysis were liver (vs. other grafts) transplant (OR 2.98, 95%CI 1.47-6.03), mycophenolate (1.63, 0.92-2.88) and steroids (1.8, 1.05- 3.33), while positive-AbR (0.61, 0.35-1.04) and age (0.97, 0.95-0.99) were protective. On the other hand, liver transplant (1.94, 1.02-3.69), time from transplant (1.09, 1.05-1.21), and Moderna vaccine (2.32, 1.46-3.70) were associated with positive-AbR, while age (0.97, 0.95-0.98), heart transplant (0.56, 0.33-0.96), mycophenolate (0.65, 0.39-1.06) and steroids (0.39, 0.23-0.65) with lower probability of positive-AbR. Conclusion Although associated with positive-AbR, liver transplant and younger age were also BI predictors, suggesting the importance of social factors and the controversial role of immune monitoring. Disclosures All Authors: No reported disclosures.

The role of culturing the graft preservation fluid (PF) is controversial and its impact on graft arteritis development remains unclear.Systematic literature search retrieving observational studies comparing solid organ transplant (SOT) recipients with culture-positive PF versus culture-negative PF. The quality of included studies was independently assessed according to the ROBINS-I tool for observational studies. Meta-analysis was performed using Mantel-Haenszel random-effect models. Graft site arteritis within 180 days from transplant was selected as the primary outcome.Twenty-one observational studies (N = 2208 positive PF vs. 4458 negative) were included. Among positive PF, 857 (38.8%) were classified as high-risk group pathogens and 1351 (61.2%) as low-risk pathogens. Low-risk and negative PF showed similar odds ratios. A significant higher risk of graft arteritis was found in SOT recipients with a PF yielding a high-risk pathogen (odds ratio [OR] 18.43, 95% confidence interval [CI] 7.83-43.40) compared to low-risk and negative PF, with low heterogeneity (IOur results may support the performance of PF culturing and a preemptive diagnostic or therapeutic management upon isolation of high-risk pathogens. Further studies based on a reliable diagnosis of graft arteritis are needed.

Asbestos causes malignant transformation of primary human mesothelial cells (HM), leading to mesothelioma. The mechanisms of asbestos carcinogenesis remain enigmatic, as exposure to asbestos induces HM death. However, some asbestos-exposed HM escape cell death, accumulate DNA damage, and may become transformed. We previously demonstrated that, upon asbestos exposure, HM and reactive macrophages releases the high mobility group box 1 (HMGB1) protein that becomes detectable in the tissues near asbestos deposits where HMGB1 triggers chronic inflammation. HMGB1 is also detectable in the sera of asbestos-exposed individuals and mice. Searching for additional biomarkers, we found higher levels of the autophagy marker ATG5 in sera from asbestos-exposed individuals compared to unexposed controls. As we investigated the mechanisms underlying this finding, we discovered that the release of HMGB1 upon asbestos exposure promoted autophagy, allowing a higher fraction of HM to survive asbestos exposure. HMGB1 silencing inhibited autophagy and increased asbestos-induced HM death, thereby decreasing asbestos-induced HM transformation. We demonstrate that autophagy was induced by the cytoplasmic and extracellular fractions of HMGB1 via the engagement of the RAGE receptor and Beclin 1 pathway, while nuclear HMGB1 did not participate in this process. We validated our findings in a novel unique mesothelial conditional HMGB1-knockout (HMGB1-cKO) mouse model. Compared to HMGB1 wild-type mice, mesothelial cells from HMGB1-cKO mice showed significantly reduced autophagy and increased cell death. Autophagy inhibitors chloroquine and desmethylclomipramine increased cell death and reduced asbestos-driven foci formation. In summary, HMGB1 released upon asbestos exposure induces autophagy, promoting HM survival and malignant transformation.

Introduction Although echinocandins are recommended as first-line prophylaxis for high-risk orthotopic liver transplant (OLT) recipients, occurrence of breakthrough-invasive fungal infections (IFIs) remains a serious concern. We aim to assess the risk of breakthrough IFIs among OLT recipients exposed to prophylaxis with echinocandins compared to other antifungals. Materials and methods Two authors independently searched PubMed-MEDLINE, Embase, study registries and reference lists from inception to March 2021, to retrieve randomised controlled trials (RCTs) or observational studies comparing efficacy and safety of echinocandins vs other antifungals for prophylaxis in OLT recipients. Data were independently extracted from two authors, and the quality of included studies was independently assessed according to ROB 2.0 tool for RCTs and ROBINS-I tool for observational studies. The primary outcome was occurrence of breakthrough IFI at the end of prophylaxis (EOP). Results 698 articles were screened, and ten studies (3 RCTs and 7 observational) were included. No difference between echinocandins and other antifungals in terms of breakthrough IFIs at the EOP emerged both from RCTs (odds ratio [OR] 0.85, 95% CI 0.24-2.99) and observational studies (OR 1.43, 95% CI 0.28-7.40). No difference emerged also for secondary outcomes. In the subgroup comparison between echinocandins and polyenes, a trend for higher risk of breakthrough IFI at the EOP (OR 4.82, 95% CI 0.97-24.03) was noted. Conclusions Echinocandins do not seem to be associated with increased risk of breakthrough IFIs in OLT recipients. However, the large diversity in the comparator group hinders a definitive interpretation. Further studies exploring the relationship between echinocandin use and breakthrough IFIs according to specific comparators are warranted.

Mitochondria and endoplasmic reticulum (ER) are fundamental in the control of cell physiology regulating several signal transduction pathways. They continuously communicate exchanging messages in their contact sites called MAMs (mitochondria-associated membranes). MAMs are specific microdomains acting as a platform for the sorting of vital and dangerous signals. In recent years increasing evidence reported that multiple scaffold proteins and regulatory factors localize to this subcellular fraction suggesting MAMs as hotspot signaling domains. In this review we describe the current knowledge about MAMs' dynamics and processes, which provided new correlations between MAMs' dysfunctions and human diseases. In fact, MAMs machinery is strictly connected with several pathologies, like neurodegeneration, diabetes and mainly cancer. These pathological events are characterized by alterations in the normal communication between ER and mitochondria, leading to deep metabolic defects that contribute to the progression of the diseases.

Mitochondria and endoplasmic reticulum (ER) are fundamental in the control of cell physiology regulating several signal transduction pathways. They continuously communicate exchanging messages in their contact sites called MAMs (mitochondria-associated membranes). MAMs are specific microdomains acting as a platform for the sorting of vital and dangerous signals. In recent years increasing evidence reported that multiple scaffold proteins and regulatory factors localize to this subcellular fraction suggesting MAMs as hotspot signaling domains. In this review we describe the current knowledge about MAMs' dynamics and processes, which provided new correlations between MAMs' dysfunctions and human diseases. In fact, MAMs machinery is strictly connected with several pathologies, like neurodegeneration, diabetes and mainly cancer. These pathological events are characterized by alterations in the normal communication between ER and mitochondria, leading to deep metabolic defects that contribute to the progression of the diseases.

Recent cardiology research studies have reported the role, function, and structure of the mitochondrial permeability transition pore (mPTP) and have shown that its opening plays a key role in the progression of myocardial cell death secondary to reperfusion. In this manuscript, we validated a new pharmacological approach as an adjunct to reperfusion in myocardial infarction (MI) treatment and describe the discovery, optimization, and structure–activity relationship (SAR) studies of the first small-molecule mPTP opening inhibitors based on a 1,3,8-triazaspiro[4.5]decane scaffold that targets the c subunit of the F1/FO-ATP synthase complex. We identified three potential compounds with good mPTP inhibitory activity and beneficial effects in a model of MI, including a decreased apoptotic rate in the whole heart and overall improvement of cardiac function upon administration during reperfusion. The selected compounds did not show off-target effects at the cellular and mitochondrial levels. Moreover, the compou...

Melatonin, more commonly known as the sleep hormone, is mainly secreted by the pineal gland in dark conditions and regulates the circadian rhythm of the organism. Its intrinsic properties, including high cell permeability, the ability to easily cross both the blood–brain and placenta barriers, and its role as an endogenous reservoir of free radical scavengers (with indirect extra activities), confer it beneficial uses as an adjuvant in the biomedical field. Melatonin can exert its effects by acting through specific cellular receptors on the plasma membrane, similar to other hormones, or through receptor-independent mechanisms that involve complex molecular cross talk with other players. There is increasing evidence regarding the extraordinary beneficial effects of melatonin, also via exogenous administration. Here, we summarize molecular pathways in which melatonin is considered a master regulator, with attention to cell death and inflammation mechanisms from basic, translational and clinical points of view in the context of newborn care.

STAT3 is an oncogenic transcription factor exerting its functions both as a canonical transcriptional activator and as a non-canonical regulator of energy metabolism and mitochondrial functions. While both activities are required for cell transformation downstream of different oncogenic stimuli, they rely on different post-translational activating events, namely phosphorylation on either Y705 (nuclear activities) or S727 (mitochondrial functions). Here, we report the discovery of the unexpected STAT3 localization to the Endoplasmic Reticulum (ER), from where it modulates ER-mitochondria Ca2+ release by interacting with the Ca2+ channel IP3R3 and facilitating its degradation. The release of Ca2+ is of paramount importance for life/death cell decisions, as excessive Ca2+ causes mitochondrial Ca2+ overload, the opening of the mitochondrial permeability transition pore and the initiation of the intrinsic apoptotic program. Indeed, STAT3 silencing enhances ER Ca2+ release and sensitivity to apoptosis following oxidative stress in STAT3-dependent mammary tumor cells, correlating with increased IP3R3 levels. Accordingly, basal-like mammary tumors, which frequently display constitutively active STAT3, show an inverse correlation between IP3R3 and STAT3 protein levels. These results suggest that STAT3-mediated IP3R3 down-regulation in the ER crucially contributes to its anti-apoptotic functions via modulation of Ca2+ fluxes.

Recent cardiology research studies have reported the role, function, and structure of the mitochondrial permeability transition pore (mPTP) and have shown that its opening plays a key role in the progression of myocardial cell death secondary to reperfusion. In this manuscript, we validated a new pharmacological approach as an adjunct to reperfusion in myocardial infarction (MI) treatment and describe the discovery, optimization, and structure-activity relationship (SAR) studies of the first small-molecule mPTP opening inhibitors based on a 1,3,8-triazaspiro[4.5]decane scaffold that targets the c subunit of the F

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.

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.