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Background: In recent years, many aspects of the physiological role of PCSK9 have been elucidated, in particular regarding its role in lipid metabolism, cardiovascular risk but also its role in innate immunity. Increasing evidence is available on the involvement of PCSK9 in the pathogenesis of viral infections, mainly HCV, as well as in the regulation of host response to bacterial infections, mainly sepsis and septic shock. Moreover, the action of PCSK9 has been investigated as a crucial step in the pathogenesis of malaria infection and disease severity. Objective: Aim of this paper is to review available published literature on the role of PCSK9 in a wide array of infectious diseases. Conclusion: Besides the ongoing investigation on PCSK9 inhibition among HIV-infected patients for the treatment of HIV- and ART-related hyperlipidemia, preclinical studies indicate how PCSK9 is involved in reducing the replication of HCV. Moreover, a protective role of PCSK9 inhibition has also been proposed against dengue and SARS-CoV-2 viral infections. Interestingly, high plasmatic PCSK9 levels have been described in patients with sepsis. Finally, a loss of function in the PCSK9-encoding gene has been reported to possibly reduce mortality in malaria infection.

Background Critically ill COVID-19 patients have pathophysiological lung features characterized by perfusion abnormalities. However, to date no study has evaluated whether the changes in the distribution of pulmonary gas and blood volume are associated with the severity of gas-exchange impairment and the type of respiratory support (non-invasive versus invasive) in patients with severe COVID-19 pneumonia. Methods This was a single-center, retrospective cohort study conducted in a tertiary care hospital in Northern Italy during the first pandemic wave. Pulmonary gas and blood distribution was assessed using a technique for quantitative analysis of dual-energy computed tomography. Lung aeration loss (reflected by percentage of normally aerated lung tissue) and the extent of gas:blood volume mismatch (percentage of non-aerated, perfused lung tissue—shunt; aerated, non-perfused dead space; and non-aerated/non-perfused regions) were evaluated in critically ill COVID-19 patients with different clinical severity as reflected by the need for non-invasive or invasive respiratory support. Results Thirty-five patients admitted to the intensive care unit between February 29th and May 30th, 2020 were included. Patients requiring invasive versus non-invasive mechanical ventilation had both a lower percentage of normally aerated lung tissue (median [interquartile range] 33% [24–49%] vs. 63% [44–68%], p p = 0.001), due to higher shunt (23% [15–32%] vs. 5% [2–16%], p = 0.001) and non-aerated/non perfused regions (5% [3–10%] vs. 1% [0–2%], p = 0.001). The PaO2/FiO2 ratio correlated positively with normally aerated tissue (ρ = 0.730, p ρ = − 0.633, p Conclusions In critically ill patients with severe COVID-19 pneumonia, the need for invasive mechanical ventilation and oxygenation impairment were associated with loss of aeration and the extent of gas:blood volume mismatch. Graphic abstract

BackgroundThe primary objective of the study is to describe the cellular characteristics of bronchoalveolar lavage fluid (BALF) of COVID-19 patients requiring invasive mechanical ventilation; the secondary outcome is to describe BALF findings between survivors vs non-survivors.Materials and methodsPatients positive for SARS-CoV-2 RT PCR, admitted to ICU between March and April 2020 were enrolled. At ICU admission, BALF were analyzed by flow cytometry. Univariate, multivariate and Spearman correlation analyses were performed.ResultsSixty-four patients were enrolled, median age of 64 years (IQR 58–69). The majority cells in the BALF were neutrophils (70%, IQR 37.5–90.5) and macrophages (27%, IQR 7–49) while a minority were lymphocytes, 1%, TCD3+ 92% (IQR 82–95). The ICU mortality was 32.8%. Non-survivors had a significantly older age (p = 0.033) and peripheral lymphocytes (p = 0.012) were lower compared to the survivors. At multivariate analysis the percentage of macrophages in the BALF correlated with poor outcome (OR 1.336, CI95% 1.014–1.759,p = 0.039).ConclusionsIn critically ill patients, BALF cellularity is mainly composed of neutrophils and macrophages. The macrophages percentage in the BALF at ICU admittance correlated with higher ICU mortality. The lack of lymphocytes in BALF could partly explain a reduced anti-viral response.

Background There is a paucity of data concerning the optimal ventilator management in patients with COVID-19 pneumonia; particularly, the optimal levels of positive-end expiratory pressure (PEEP) are unknown. We aimed to investigate the effects of two levels of PEEP on alveolar recruitment in critically ill patients with severe COVID-19 pneumonia. Methods A single-center cohort study was conducted in a 39-bed intensive care unit at a university-affiliated hospital in Genoa, Italy. Chest computed tomography (CT) was performed to quantify aeration at 8 and 16 cmH2O PEEP. The primary endpoint was the amount of alveolar recruitment, defined as the change in the non-aerated compartment at the two PEEP levels on CT scan. Results Forty-two patients were included in this analysis. Alveolar recruitment was median [interquartile range] 2.7 [0.7–4.5] % of lung weight and was not associated with excess lung weight, PaO2/FiO2 ratio, respiratory system compliance, inflammatory and thrombophilia markers. Patients in the upper quartile of recruitment (recruiters), compared to non-recruiters, had comparable clinical characteristics, lung weight and gas volume. Alveolar recruitment was not different in patients with lower versus higher respiratory system compliance. In a subgroup of 20 patients with available gas exchange data, increasing PEEP decreased respiratory system compliance (median difference, MD − 9 ml/cmH2O, 95% CI from − 12 to − 6 ml/cmH2O, p p = 0.003), increased PaO2 with FiO2 = 0.5 (MD 24 mmHg, 95% CI from 12 to 51 mmHg, p 2 with FiO2 = 1.0 (MD 7 mmHg, 95% CI from − 12 to 49 mmHg, p = 0.313). Moreover, alveolar recruitment was not correlated with improvement of oxygenation or venous admixture. Conclusions In patients with severe COVID-19 pneumonia, higher PEEP resulted in limited alveolar recruitment. These findings suggest limiting PEEP strictly to the values necessary to maintain oxygenation, thus avoiding the use of higher PEEP levels.

Background The goal of this study was to investigate the prevalence and factors associated with persistent viral shedding (PVS) in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods This was a prospective observational study including all consecutive adults hospitalized with SARS-CoV-2 infection. When the first nasopharyngeal swab was positive for SARS-CoV-2 RNA (day 0), additional samples were obtained on days + 3, + 5, + 7 and then once every 7 days until virus detection was negative. PVS was defined as the duration of shedding of at least 21 days after diagnosis. The primary endpoint of this study was the prevalence of PVS. Results Data were obtained regarding 121 consecutive hospitalized patients with SARS-CoV-2 infection (median age 66 years, male sex 65.3%). Overall, the prevalence of PVS was 38% (46/121 patients). According to univariate analysis, factors associated with PVS were immunosuppression (6.7% vs 21.7%, p = 0.02), increased interleukin-6 (IL-6) levels (≥ 35 ng/ml) at the time of diagnosis (43.4% vs 67.3%, p = 0.02), time from onset of symptoms to diagnosis (median days 7.0 vs 3.5, p = 0.001), intensive care unit admission (22.7% vs 43.5%, p = 0.02), and need for invasive mechanical ventilation (20.0% vs 41.3%, p = 0.01). The multivariate analysis indicated that immunosuppression, increased IL-6 levels at the time of diagnosis, time from onset of symptoms to diagnosis, and need for mechanical ventilation were independent factors associated with PVS. Conclusions PVS was detected in up to 38% of hospitalized patients with SARS-CoV-2 infection and was strongly associated with immunosuppression, increased IL-6 levels, and the need for mechanical ventilation. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-020-00381-8.

Background The prevalence of kidney involvement during SARS-CoV-2 infection has been reported to be high. Nevertheless, data are lacking about the determinants of acute kidney injury (AKI) and the combined effect of chronic kidney disease (CKD) and AKI in COVID-19 patients. Methods We collected data on patient demographics, comorbidities, chronic medications, vital signs, baseline laboratory test results and in-hospital treatment in patients with COVID-19 consecutively admitted to our Institution. Chronic kidney disease was defined as eGFR 2 or proteinuria at urinalysis within 180 days prior to hospital admission. AKI was defined according to KDIGO criteria. The primary and secondary outcomes were the development of AKI and death. Results Of 777 patients eligible for the study, acute kidney injury developed in 176 (22.6%). Of these, 79 (45%) showed an acute worsening of a preexisting CKD, and 21 (12%) required kidney replacement therapy. Independent associates of AKI were chronic kidney disease, C-reactive protein (CRP) and ventilation support. Among patients with acute kidney injury, 111 died (63%) and its occurrence increased the risk of death by 60% (HR 1.60 [95% IC 1.21–2.49] p = 0.002) independently of potential confounding factors including hypertension, preexisting kidney damage, and comorbidities. Patients with AKI showed a significantly higher rate of deaths attributed to bleeding compared to CKD and the whole population (7.5 vs 1.5 vs 3.5%, respectively). Conclusion Awareness of kidney function, both preexisting CKD and development of acute kidney injury, may help to identify those patients at increased risk of death.

The primary objective of this multicenter, observational, retrospective study was to assess the incidence rate of ventilator-associated pneumonia (VAP) in coronavirus disease 2019 (COVID-19) patients in intensive care units (ICU). The secondary objective was to assess predictors of 30-day case-fatality of VAP. From 15 February to 15 May 2020, 586 COVID-19 patients were admitted to the participating ICU. Of them, 171 developed VAP (29%) and were included in the study. The incidence rate of VAP was of 18 events per 1000 ventilator days (95% confidence intervals [CI] 16–21). Deep respiratory cultures were available and positive in 77/171 patients (45%). The most frequent organisms were Pseudomonas aeruginosa (27/77, 35%) and Staphylococcus aureus (18/77, 23%). The 30-day case-fatality of VAP was 46% (78/171). In multivariable analysis, septic shock at VAP onset (odds ratio [OR] 3.30, 95% CI 1.43–7.61, p = 0.005) and acute respiratory distress syndrome at VAP onset (OR 13.21, 95% CI 3.05–57.26, p &lt, 0.001) were associated with fatality. In conclusion, VAP is frequent in critically ill COVID-19 patients. The related high fatality is likely the sum of the unfavorable prognostic impacts of the underlying viral and the superimposed bacterial diseases.

The role of therapeutic drug monitoring (TDM) of valaciclovir (VA)/aciclovir (A) and valganciclovir/ganciclovir (VG/G) in critically ill patients is still a matter of debate. More data on the dose–concentration relationship might therefore be useful, especially in pediatrics where clinical practice is not adequately supported by robust PK studies. We developed and validated a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) micro-method to simultaneously quantify A and G from plasma and dried plasma spots (DPS). The method was based on rapid organic extraction from DPS and separation on a reversed-phase C-18 UHPLC column after addition of deuterated internal standards. Accurate analyte quantification using SRM detection was then obtained using a Thermo Fisher Quantiva triple-quadrupole MS coupled to an Ultimate 3000 UHPLC. It was validated following international (EMA) guidelines for bioanalytical method validation and was tested on samples from pediatric patients treated with A, VG, or G for cytomegalovirus infection following solid organ or hematopoietic stem cell transplantation. Concentrations obtained from plasma and DPS were compared using Passing–Bablok and Bland–Altman statistical tests. The assay was linear over wide concentration ranges (0.01–20 mg/L) in both plasma and DPS for A and G, suitable for the expected therapeutic ranges for both Cmin and Cmax, accurate, and reproducible in the absence of matrix effects. The results obtained from plasma and DPS were comparable. Using an LC-MS/MS method allowed us to obtain a very specific, sensitive, and rapid quantification of these antiviral drugs starting from very low volumes (50 μL) of plasma samples and DPS. The stability of analytes for at least 30 days allows for cost-effective shipment and storage at room temperature. Our method is suitable for TDM and could be helpful for improving knowledge on PK/PD targets of antivirals in critically ill pediatric patients.

No abstract present.

The IRONIC study group: Cuervo, Guillermo; Escrihuela-Vidal, Francesc; Tubau, Fe; Rodriguez Arias, Marisol; Merve Ayaz, Caglayan; Munita, Jose; Gasch, Oriol; Capilla, Silvia; Bochud, Pierre-Yves; Manuel, Oriol; Torre-Cisneros, Julian; Tabares, Salvador; Serrano Lopez, Josefina; Maschmeyer, Georg; Torres, Diego; Abdala, Edson; Bittencourt, Driele Peixoto; El Zein, Saeed; Jabbour, Jean-Francois; Bertz, Hartmut; Peyerl-Hoffmann, Gabriele; Lizasoain, Manuel; Maria Aguado, Jose; Clemencia Correa, Lina; Palop, Begona; Fortun, Jesus; Magnasco, Laura; Cespedes, Roberto; Lopez-Soria, Leire; Pablo Horcajada, Juan; Montaguti, Mia Hold; de Cueto, Marina; Rodriguez-Bano, Jesus; Greco, Raffaella; Cichero, Paola; Bassetti, Matteo; Castaldo, Nadia; Sangro del Alcazar, Paloma; Cardozo, Celia; Garcia-Vidal, Carolina; Aguilar-Company, Juan; Larrosa, Nieves; Uyan-Onal, Ayse; Nazli-Zeka, Arzu; Vasconcelos de Freitas, Wania; da Silva Machado, Amanda Aparecida, [Introduction]: Pseudomonas aeruginosa (PA) has historically been one of the major causes of severe sepsis and death among neutropenic cancer patients. There has been a recent increase of multidrug-resistant PA (MDRPA) isolates that may determine a worse prognosis, particularly in immunosuppressed patients. The aim of this study is to establish the impact of antibiotic resistance on the outcome of neutropenic onco-haematological patients with PA bacteraemia, and to identify the risk factors for MDRPA bacteraemia and mortality., [Methods and analysis]: This is a retrospective, observational, multicentre, international study. All episodes of PA bacteraemia occurring in neutropenic oncohaematological patients followed up at the participating centres from 1 January 2006 to 31 May 2018 will be retrospectively reviewed. The primary end point will be overall case-fatality rate within 30 days of onset of PA bacteraemia. The secondary end points will be to describe the following: the incidence and risk factors for multidrugresistant and extremely drug-resistant PA bacteraemia (by comparing the episodes due to susceptible PA with those produced by MDRPA), the efficacy of ceftolozane/tazobactam, the rates of persistent bacteraemia and bacteraemia relapse and the risk factors for very early (48 hours), early (7 days) and overall (30 days) case-fatality rates., [Ethics and dissemination]: The Clinical Research Ethics Committee of Bellvitge University Hospital approved the protocol of the study at the primary site. To protect personal privacy, identifying information of each patient in the electronic database will be encrypted. The processing of the patients’ personal data collected in the study will comply with the Spanish Data Protection Act of 1998 and with the European Directive on the privacy of data. All data collected, stored and processed will be anonymised. Results will be reported at conferences and in peerreviewed publications., This study was supported by Plan Nacional de I+D+i 2013‐2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001) and co-financed by European Development Regional Fund “A way to achieve Europe”, Operative Programme Intelligent Growth 2014‐2020.

We aimed to assess the prevalence of and factors associated with anti- severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positivity in a large population of adult volunteers from five administrative departments of the Liguria and Lombardia regions. A total of 3609 individuals were included in this analysis. Participants were tested for anti-SARS-CoV-2 antibodies [Immunoglobulin G (IgG) and M (IgM) class antibodies] at three private laboratories (Istituto Diganostico Varelli, Medical Center, and Casa della Salute di Genova). Demographic data, occupational or private exposure to SARS-CoV-2-infected patients, and prior medical history consistent with SARS-CoV-2 infection were collected according to a preplanned analysis. The overall seroprevalence of anti-SARS-CoV-2 antibodies (IgG and/or IgM) was 11.0% [398/3609; confidence interval (CI) 10.0%–12.1%]. Seroprevalence was higher in female inmates than in male inmates (12.5% vs. 9.2%, respectively, p = 0.002), with the highest rate observed among adults aged >55 years (13.2%). A generalized estimating equations model showed that the main risk factors associated with SARS-CoV-2 seroprevalence were the following: an occupational exposure to the virus [Odd ratio (OR) = 2.36; 95% CI 1.59–3.50, p = 0.001], being a long-term care facility resident (OR = 4.53; 95% CI 3.19–6.45, p = 0.001), and reporting previous symptoms of influenza-like illness (OR = 4.86; 95% CI 3.75–6.30, p = 0.001) or loss of sense of smell or taste (OR = 41.00; 95% CI 18.94–88.71, p = 0.001). In conclusion, we found a high prevalence (11.0%) of SARS-CoV-2 infection that is significantly associated with residing in long-term care facilities or occupational exposure to the virus. These findings warrant further investigation into SARS-CoV-2 antibody prevalence among the Italian population.

The SARS-CoV-2 infection causes severe respiratory involvement (COVID-19) in 5–20% of patients through initial immune derangement, followed by intense cytokine production and vascular leakage. Evidence of immune involvement point to the participation of T, B, and NK cells in the lack of control of virus replication leading to COVID-19. NK cells contribute to early phases of virus control and to the regulation of adaptive responses. The precise mechanism of NK cell dysregulation is poorly understood, with little information on tissue margination or turnover. We investigated these aspects by multiparameter flow cytometry in a cohort of 28 patients hospitalized with early COVID-19. Relevant decreases in CD56brightCD16+/- NK subsets were detected, with a shift of circulating NK cells toward more mature CD56dimCD16+KIR+NKG2A+ and “memory” KIR+CD57+CD85j+ cells with increased inhibitory NKG2A and KIR molecules. Impaired cytotoxicity and IFN-γ production were associated with conserved expression of natural cytotoxicity receptors and perforin. Moreover, intense NK cell activation with increased HLA-DR and CD69 expression was associated with the circulation of CD69+CD103+ CXCR6+ tissue-resident NK cells and of CD34+DNAM-1brightCXCR4+ inflammatory precursors to mature functional NK cells. Severe disease trajectories were directly associated with the proportion of CD34+DNAM-1brightCXCR4+ precursors and inversely associated with the proportion of NKG2D+ and of CD103+ NK cells. Intense NK cell activation and trafficking to and from tissues occurs early in COVID-19, and is associated with subsequent disease progression, providing an insight into the mechanism of clinical deterioration. Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches., Author summary This is a detailed study of activating and inhibitory receptors in NK cells of COVID-19 patients when first admitted to the hospital for respiratory insufficiency. NK cells are known to be the first line of defense against invading viruses, and regulate downstream B and T cell responses, including antibody production. We observed intense NK cell activation with decreased functional activity, as well as intense circulation of putative tissue resident CD69+CD103+CXCR6+ NK cells, with a related surge in inflammatory CD34+ precursors from the bone marrow. The findings suggest that there is unprecedented trafficking of NK cells from peripheral tissues, their increased death with recruitment of emergency precursors from the bone marrow, and a relationship with the subsequent course of the disease of the patients. This in turn suggests possible areas of treatment and prevention.

Objectives: The hypothesis of this study is that tocilizumab should affect common signs of infection due to its immunosuppressive properties. Primary aim of the study was to investigate whether the administration of tocilizumab to critically ill patients with COVID-19, led to a different clinical presentation of infectious complications compared to patients who did not receive tocilizumab. Secondary aim was investigating differences in laboratory parameters between groups. Methods: Single-centre retrospective study, enrolling COVID-19 patients who developed a microbiologically confirmed infectious complication [ventilator associated pneumonia or bloodstream infection] after intensive care unit [ICU] admission and either treated with tocilizumab or not [controls]. Results: A total of 58 patients were included, 25 treated with tocilizumab and 33 controls. Median time from tocilizumab administration to infection onset was 10 days [range 2-26]. Patients were 78% male, with median age 65 years [range 45-79]. At first clinical presentation of the infectious event, the frequency of hypotension [11/25, 44% vs. 11/33, 33%], fever [8/25, 32% vs. 10/33, 30%] or hypothermia [0/25,0%, vs. 2/33, 6%], and oxygen desaturation [6/25, 28% vs 4/33, 12%], as well as the frequency of SOFA score increase of ≥ 2 points [4/25, 16%,vs. 4/33, 12%] was similar in tocilizumab treated patients and controls [p>0.1 for all comparisons]. Among laboratory parameters, C-Reactive Protein elevation was reduced in tocilizumab treated patients compared to controls [8/25, 32% vs. 22/33, 67%, p=0.009]. Conclusion: The clinical features of infectious complications in critically ill patients with COVID-19 admitted to ICU were not affected by tocilizumab.

During the COVID-19 pandemic, the scientific community developed predictive models to evaluate potential governmental interventions. However, the analysis of the effects these interventions had is less advanced. Here, we propose a data-driven framework to assess these effects retrospectively. We use a regularized regression to find a parsimonious model that fits the data with the least changes in the $$R_t$$ R t parameter. Then, we postulate each jump in $$R_t$$ R t as the effect of an intervention. Following the do-operator prescriptions, we simulate the counterfactual case by forcing $$R_t$$ R t to stay at the pre-jump value. We then attribute a value to the intervention from the difference between true evolution and simulated counterfactual. We show that the recommendation to use facemasks for all activities would reduce the number of cases by 200,000 ($$95\%$$ 95 % CI 190,000–210,000) in Connecticut, Massachusetts, and New York State. The framework presented here might be used in any case where cause and effects are sparse in time.

Candida auris is an emerging MDR pathogen raising major concerns worldwide. In Italy, it was first and only identified in July 2019 in our hospital (San Martino Hospital, Genoa), where infection or colonization cases have been increasingly recognized during the following months. To gain insights into the introduction, transmission dynamics, and resistance traits of this fungal pathogen, consecutive C. auris isolates collected from July 2019 to May 2020 (n = 10) were subjected to whole-genome sequencing (WGS) and antifungal susceptibility testing (AST), patients’ clinical and trace data were also collected. WGS resolved all isolates within the genetic clade I (South Asian) and showed that all but one were part of a cluster likely stemming from the index case. Phylogenetic molecular clock analyses predicted a recent introduction (May 2019) in the hospital setting and suggested that most transmissions were associated with a ward converted to a COVID-19-dedicated ICU during the pandemic. All isolates were resistant to amphotericin B, voriconazole, and fluconazole at high-level, owing to mutations in ERG11(K143R) and TACB1(A640V). Present data demonstrated that the introduction of MDR C. auris in Italy was a recent event and suggested that its spread could have been facilitated by the COVID-19 pandemic. Continued efforts to implement stringent infection prevention and control strategies are warranted to limit the spread of this emerging pathogen within the healthcare system.

Background An unexpected high prevalence of enterococcal bloodstream infection (BSI) has been observed in critically ill patients with COVID-19 in the intensive care unit (ICU). Materials and methods The primary objective was to describe the characteristics of ICU-acquired enterococcal BSI in critically ill patients with COVID-19. A secondary objective was to exploratorily assess the predictors of 30-day mortality in critically ill COVID-19 patients with ICU-acquired enterococcal BSI. Results During the study period, 223 patients with COVID-19 were admitted to COVID-19-dedicated ICUs in our centre. Overall, 51 episodes of enterococcal BSI, occurring in 43 patients, were registered. 29 (56.9%) and 22 (43.1%) BSI were caused by Enterococcus faecalis and Enterococcus faecium, respectively. The cumulative incidence of ICU-acquired enterococcal BSI was of 229 episodes per 1000 ICU admissions (95% mid-p confidence interval [CI] 172–298). Most patients received an empirical therapy with at least one agent showing in vitro activity against the blood isolate (38/43, 88%). The crude 30-day mortality was 42% (18/43) and 57% (4/7) in the entire series and in patients with vancomycin-resistant E. faecium BSI, respectively. The sequential organ failure assessment (SOFA) score showed an independent association with increased mortality (odds ratio 1.32 per one-point increase, with 95% confidence interval 1.04–1.66, p = .021). Conclusions The cumulative incidence of enterococcal BSI is high in critically ill patients with COVID-19. Our results suggest a crucial role of the severity of the acute clinical conditions, to which both the underlying viral pneumonia and the enterococcal BSI may contribute, in majorly influencing the outcome.KEY MESSAGESThe cumulative incidence of enterococcal BSI is high in critically ill patients with COVID-19.The crude 30-day mortality of enterococcal BSI in critically ill patients with COVID-19 may be higher than 40%.There could be a crucial role of the severity of the acute clinical conditions, to which both the underlying viral pneumonia and the enterococcal BSI may contribute, in majorly influencing the outcome.

BackgroundIn COVID-19 patients with acute respiratory distress syndrome (ARDS), the effectiveness of ventilatory rescue strategies remains uncertain, with controversial efficacy on systemic oxygenation and no data available regarding cerebral oxygenation and hemodynamics.MethodsThis is a prospective observational study conducted at San Martino Policlinico Hospital, Genoa, Italy. We included adult COVID-19 patients who underwent at least one of the following rescue therapies: recruitment maneuvers (RMs), prone positioning (PP), inhaled nitric oxide (iNO), and extracorporeal carbon dioxide (CO2) removal (ECCO2R). Arterial blood gas values (oxygen saturation [SpO2], partial pressure of oxygen [PaO2] and of carbon dioxide [PaCO2]) and cerebral oxygenation (rSO2) were analyzed before (T0) and after (T1) the use of any of the aforementioned rescue therapies. The primary aim was to assess the early effects of different ventilatory rescue therapies on systemic and cerebral oxygenation. The secondary aim was to evaluate the correlation between systemic and cerebral oxygenation in COVID-19 patients.ResultsForty-five rescue therapies were performed in 22 patients. The median [interquartile range] age of the population was 62 [57–69] years, and 18/22 [82%] were male. After RMs, no significant changes were observed in systemic PaO2and PaCO2values, but cerebral oxygenation decreased significantly (52 [51–54]% vs. 49 [47–50]%,p 2(from 62 [56–71] to 82 [76–87] mmHg,p = 0.005) and rSO2(from 53 [52–54]% to 60 [59–64]%,p = 0.005). The use of iNO increased PaO2(from 65 [67–73] to 72 [67–73] mmHg,p = 0.015) and rSO2(from 53 [51–56]% to 57 [55–59]%,p = 0.007). The use of ECCO2R decreased PaO2(from 75 [75–79] to 64 [60–70] mmHg,p = 0.009), with reduction of rSO2values (59 [56–65]% vs. 56 [53–62]%,p = 0.002). In the whole population, a significant relationship was found between SpO2and rSO2(R = 0.62,p 2and rSO2(R0 0.54,p ConclusionsRescue therapies exert specific pathophysiological mechanisms, resulting in different effects on systemic and cerebral oxygenation in critically ill COVID-19 patients with ARDS. Cerebral and systemic oxygenation are correlated. The choice of rescue strategy to be adopted should take into account both lung and brain needs.RegistrationThe study protocol was approved by the ethics review board (Comitato Etico Regione Liguria, protocol n. CER Liguria: 23/2020).

The possible negative impact of severe adult respiratory distress caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (COVID-19) on antimicrobial stewardship and infection control has been postulated, but few real-life data are available. The aim of this study was to report our experience with colonization/infection of carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Klebsiella pneumoniae (CR-Kp) and Candida auris among critically ill COVID-19 patients admitted to the intensive care unit (ICU). All COVID-19 patients admitted to the ICUs at San Martino Policlinico Hospital&ndash, IRCCS in Genoa, Italy, were screened from 28 February to 31 May 2020. One-hundred and eighteen patients admitted to COVID-19 ICUs were included in the study. Among them, 12 (10.2%) became colonized/infected with CRPA, 6 (5.1%) with C. auris and 2 (1.6%) with CR-Kp. All patients with CRPA received prior treatment with meropenem, and in 11 (91.7%) infection was not preceded by colonization. Four patients (66.7%) developed C. auris candidemia. A significant spread of resistant pathogens was observed among critically ill COVID-19 patients. Dedicated strategies are warranted to prevent horizontal spread and maintain effective antimicrobial stewardship programs in the setting of COVID-19 care.

The aim of the present study is to evaluate if an independent association exists between liver enzyme elevations (LEE) and the risk of mortality or intensive care unit (ICU) admissions in patients with COVID-19. This was a single-center observational study, recruiting all consecutive adults with COVID-19. The elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) to the highest level between COVID-19 diagnosis and hospital discharge was categorized according to a standardized toxicity grade scale. In total, 799 patients were included in this study, 39% of which were female, with a mean age of 69.9 (±16.0) years. Of these patients, 225 (28.1%) developed LEE of grade ≥2 after a median of three days (interquartile range (IQR): 0–8 days) from the diagnosis of COVID-19, and they were estimated to have a higher hazard of death or ICU admission (adjusted hazard ratio (aHR): 1.46, 95% confidence interval (CI): 1.14–1.88). The clinical and laboratory variables associated with the development of LEE were male sex, higher respiratory rate, higher gamma glutamyl transpeptidase (GGT) and lower albumin levels at baseline. Among the analyzed treatments, steroids, tocilizumab and darunavir/ritonavir correlated with LEE. In conclusion, LEE were associated with mortality and ICU admission among COVID-19 patients. While the origin of LEE is probably multifactorial, LEE evaluation could add information to the clinical and laboratory variables that are commonly evaluated during the course of COVID-19.

The objectives of this study were to assess the association of a 4-point scale of vaginal discharge score (VDS) with time to pregnancy to define criteria for a practical case of purulent vaginal discharge (PVD) in dairy cows, to test the risk factors for PVD, and, finally, the effect of a dose of PGF2α on cure and reproductive performance. In experiment 1, grazing Holstein cows (n = 2,414) had their vaginal discharge scored at ∼32 d in milk (DIM) on a 4-point scale, the effect of VDS on the hazard of pregnancy by 300 DIM was then assessed to derive a case definition of PVD. Risk factors for PVD and self-cure were also assessed. In experiment 2, grazing Holstein cows (n = 6,326) from 5 herds were checked for PVD at ∼30 DIM. Cows with PVD were assigned to receive one dose of 500 μg of PGF2α analog (Cloprostenol; Ciclase, Syntex SA, Buenos Aires, Argentina) per cow (odd ear tag number) or to remain untreated (even tag number). Cure was declared if cows presented clear normal vaginal discharge (VDS-0) at visit 2 (∼62 DIM). Data were analyzed with Cox's regression and mixed logistic models. In experiment 1, cows with VDS ≥1 had lower hazard of pregnancy and longer calving to pregnancy interval than cows with VDS-0. This finding was not affected by the time at which the diagnosis was performed. Therefore, a cow ≥21 DIM and having VDS ≥1 was used to define a case of PVD. The odds of PVD were greater in primiparous cows compared with multiparous, in cows with abnormal calving compared with those with normal calving, and in those losing BCS peripartum. In experiment 2, PGF2α treatment tended to slightly increase the hazard of pregnancy (adjusted hazard ratio = 1.13). Conversely, PGF2α had no effect on the odds of cure of PVD [adjusted odds ratio (AOR) = 1.19], pregnancy at first service (AOR = 1.03), or pregnancy by 100 DIM (AOR = 0.89) or 200 DIM (AOR = 1.27). In conclusion, cows with VDS ≥1 can be considered to have PVD because of their lower hazard of pregnancy and longer calving to pregnancy interval (up to 48 d). Important risk factors are parity, calving, and body condition score loss peripartum. Optimal time of diagnosis is ≥28 to 35 DIM because cows experience a high self-cure rate. Self-cure is also affected by parity, prepartum BCS, and VDS. Finally, as treatment with one dose of PGF2α had a small effect on the hazard of pregnancy and no effect on clinical cure, its therapeutic use in grazing dairy cows with PVD is not recommended., Facultad de Ciencias Veterinarias

IntroductionCoronavirus disease 2019 (COVID-19) can lead to respiratory failure due to severe immune response. Treatment targeting this immune response might be beneficial but there is limited evidence on its efficacy.The aim of this study was to determine if early treatment of patients with COVID-19 pneumonia with tocilizumab and/or steroids was associated with better outcome.MethodsThis observational single-center study included patients with COVID-19 pneumonia who were not intubated and received either standard of care (SOC, controls) or SOC plus early (within 3 days from hospital admission) anti-inflammatory treatment. SOC consisted of hydroxychloroquine 400mg bid plus, in those admitted before March 24th, also darunavir/ritonavir. Anti-inflammatory treatment consisted of either tocilizumab (8mg/kg intravenously or 162mg subcutaneously) or methylprednisolone 1 mg/kg for 5 days or both. Failure was defined as intubation or death, and the endpoints were failure-free survival (primary endpoint) and overall survival (secondary) at day 30. Difference between the groups was estimated as Hazard Ratio by a propensity score weighted Cox regression analysis (HROW).ResultsOverall, 196 adults were included in the analyses. They were mainly male (67.4%), with comorbidities (78.1%) and severe COVID-19 pneumonia (83.7%). Median age was 67.9 years (range, 30-100) and median PaO2/FiO2200 mmHg (IQR 133-289). Among them, 130 received early anti-inflammatory treatment with: tocilizumab (n=29, 22.3%), methylprednisolone (n=45, 34.6%), or both (n=56, 43.1%). The adjusted failure-free survival among tocilizumab/methylprednisolone/SOC treated patients vs. SOC was 80.8% (95%CI, 72.8-86.7) vs. 64.1% (95%CI, 51.3-74.0), HROW0.48, 95%CI, 0.23-0.99; p=0.049. The overall survival among tocilizumab/methylprednisolone/SOC patients vs. SOC was 85.9% (95%CI, 80.7-92.6) vs. 71.9% (95%CI, 46-73), HROW0.41, 95%CI: 0.19-0.89, p=0.025.ConclusionEarly adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in non-intubated patients with COVID-19 pneumonia.

Among people with perinatal HIV infection (PHIV), non-communicable diseases, such as chronic kidney disease, are increasing. Both HIV replication and antiretroviral therapy are recognised causes of renal impairment. Objective of the study is to describe the impact of viremia copy-years (VCY) and antiretroviral therapy on trend of estimated glomerular filtration rate (eGFR) in a cohort of adults with perinatal HIV infection. We conducted a multicentre observational study in sixty adults living with PHIV across a 9-year period, from January 2010 to December 2018. The mean values of eGFR were analysed at the first (T0) and last year of observation (T1). VCY was defined as the area under HIV-RNA curve during the study period. We analysed data according to antiretroviral therapy: tenofovir disoproxil (TDF), non-nucleoside reverse transcriptase inhibitors (NNRTI), boosted protease inhibitors (PI/b), integrase inhibitors (INI). We observed a mean overall eGFR reduction from 126.6 mL/min (95%CI: 119.6-133.5) to 105.0 mL/min (95%CI: 99.55-110.6) (p2 log10. Our study outlines a progressive eGFR reduction in young adults with PHIV, related to the lower control on HIV-RNA VCY and related to aging.

We aimed to assess the rate and predictive factors of bloodstream infection (BSI) due to multidrug-resistant (MDR) Pseudomonas aeruginosa in neutropenic cancer patients. We performed a multicenter, retrospective cohort study including oncohematological neutropenic patients with BSI due to P. aeruginosa conducted across 34 centers in 12 countries from January 2006 to May 2018. A mixed logistic regression model was used to estimate a model to predict the multidrug resistance of the causative pathogens. of a total of 1,217 episodes of BSI due to P. aeruginosa, 309 episodes (25.4%) were caused by MDR strains. the rate of multidrug resistance increased significantly over the study period (P = 0.033). Predictors of MDR P. aeruginosa BSI were prior therapy with piperacillin-tazobactam (odds ratio [OR), 3.48; 95% confidence interval [CI], 2.29 to 5.30), prior antipseudomonal carbapenem use (OR, 2.53; 95% CI, 1.65 to 3.87), fluoroquinolone prophylaxis (OR, 2.99; 95% CI, 1.92 to 4.64), underlying hematological disease (OR, 2.09; 95% CI, 1.26 to 3.44), and the presence of a urinary catheter (OR, 2.54; 95% CI, 1.65 to 3.91), whereas older age (OR, 0.98; 95% CI, 0.97 to 0.99) was found to be protective. Our prediction model achieves good discrimination and calibration, thereby identifying neutropenic patients at higher risk of BSI due to MDR P. aeruginosa. the application of this model using a web-based calculator may be a simple strategy to identify high-risk patients who may benefit from the early administration of broad-spectrum antibiotic coverage against MDR strains according to the local susceptibility patterns, thus avoiding the use of broad-spectrum antibiotics in patients at a low risk of resistance development., ESGBIES study group; ESGICH study group; Spanish Plan Nacional de I+D+i 2013-2016; Instituto de Salud Carlos III, Subdireccion General de Redes y Centros de Investigacion Cooperativa, Ministerio de Economia, Industria y Competitividad, Spanish Network for Research in Infectious Diseases [REIPI RD16/0016/0001]; European Development Regional Fund A Way To Achieve Europe, Operative Program Intelligent Growth 2014-2020; Promex Stiftung fur die Forschung (Carigest SA); GileadGilead Sciences; PfizerPfizer, We thank the ESGBIES and the ESGICH study groups for supporting the study.; This study was supported by the Spanish Plan Nacional de I+D+i 2013-2016 and the Instituto de Salud Carlos III, Subdireccion General de Redes y Centros de Investigacion Cooperativa, Ministerio de Economia, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (grant REIPI RD16/0016/0001), cofinanced by the European Development Regional Fund A Way To Achieve Europe, Operative Program Intelligent Growth 2014-2020.; A.-S.B. received a grant from Promex Stiftung fur die Forschung (via Carigest SA) and funding from Gilead to attend the ECCMID Congress (2018). O.R.S. received speaker honoraria from MSD, Astellas, Novartis, and Pfizer. S.S.K. received speaker honoraria from Pfizer, MSD, Astellas. F.H. received speaker honoraria from MSD, and Pfizer and a research and educational grant from Pfizer. the rest of the authors declare no conflicts of interest.

Tracking the origin of propagating wave signals in an environment with complex reflective surfaces is, in its full generality, a nearly intractable problem which has engendered multiple domain-specific literatures. We posit that, if the environment and sensor geometries are fixed, machine learning algorithms can "learn" the acoustical geometry of the environment and accurately track signal origin. In this paper, we propose the first machine-learning-based approach to identifying the source locations of semi-stationary, tonal, dolphin-whistle-like sounds in a highly reverberant space, specifically a half-cylindrical dolphin pool. Our algorithm works by supplying a learning network with an overabundance of location "clues", which are then selected under supervised training for their ability to discriminate source location in this particular environment. More specifically, we deliver estimated time-difference-of-arrivals (TDOA's) and normalized cross-correlation values computed from pairs of hydrophone signals to a random forest model for high-feature-volume classification and feature selection, and subsequently deliver the selected features into linear discriminant analysis, linear and quadratic Support Vector Machine (SVM), and Gaussian process models. Based on data from 14 sound source locations and 16 hydrophones, our classification models yielded perfect accuracy at predicting novel sound source locations. Our regression models yielded better accuracy than the established Steered-Response Power (SRP) method when all training data were used, and comparable accuracy along the pool surface when deprived of training data at testing sites; our methods additionally boast improved computation time and the potential for superior localization accuracy in all dimensions with more training data. Because of the generality of our method we argue it may be useful in a much wider variety of contexts.

International audience; Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset and anti-dsDNA reactivity. In this study, we found that human patients with DNASE1L3 disease-associated gene variations showed aberrations in size and a reduction of a ''CC'' end motif of plasma DNA. Furthermore, we demonstrated that DNA from DNASE1L3-digested cell nuclei showed a median length of 153 bp with CC motif frequencies resembling plasma DNA from healthy individuals. Adeno-associated virus-based transduction of Dnase1l3 into Dnase1l3-deficient mice restored the end motif profiles to those seen in the plasma DNA of wild-type mice. Our findings demonstrate that DNASE1L3 is an important player in the fragmentation of plasma DNA, which appears to act in a cell-extrinsic manner to regulate plasma DNA size and motif frequency.

Background Little is known about the incidence and risk of intensive care unit (ICU)-acquired bloodstream infections (BSI) in critically ill patients with coronavirus disease 2019 (COVID-19). Materials and methods This retrospective, single-centre study was conducted in Northern Italy. The primary study objectives were as follows: (a) to assess the incidence rate of ICU-acquired BSI and (b) to assess the cumulative risk of developing ICU-acquired BSI. Results Overall, 78 critically ill patients with COVID-19 were included in the study. Forty-five episodes of ICU-acquired BSI were registered in 31 patients, with an incidence rate of 47 episodes (95% confidence interval [CI] 35-63) per 1000 patient-days at risk. The estimated cumulative risk of developing at least one BSI episode was of almost 25% after 15 days at risk and possibly surpassing 50% after 30 days at risk. In multivariable analysis, anti-inflammatory treatment was independently associated with the development of BSI (cause-specific hazard ratio [csHR] 1.07 with 95% CI 0.38-3.04 for tocilizumab, csHR 3.95 with 95% CI 1.20-13.03 for methylprednisolone and csHR 10.69 with 95% CI 2.71-42.17 for methylprednisolone plus tocilizumab, with no anti-inflammatory treatment as the reference group; overall P for the dummy variable = 0.003). Conclusions The incidence rate of BSI was high, and the cumulative risk of developing BSI increased with ICU stay. Further study will clarify if the increased risk of BSI we detected in COVID-19 patients treated with anti-inflammatory drugs is outweighed by the benefits of reducing any possible pro-inflammatory dysregulation induced by SARS-CoV-2.

Objectives To describe clinical characteristics, management and outcome of individuals with coronavirus disease 2019 (COVID-19); and to evaluate risk factors for all-cause in-hospital mortality. Methods This retrospective study from a University tertiary care hospital in northern Italy, included hospitalized adult patients with a diagnosis of COVID-19 between 25 February 2020 and 25 March 2020. Results Overall, 317 individuals were enrolled. Their median age was 71 years and 67.2% were male (213/317). The most common underlying diseases were hypertension (149/317; 47.0%), cardiovascular disease (63/317; 19.9%) and diabetes (49/317; 15.5%). Common symptoms at the time of COVID-19 diagnosis included fever (285/317; 89.9%), shortness of breath (167/317; 52.7%) and dry cough (156/317; 49.2%). An ‘atypical' presentation including at least one among mental confusion, diarrhoea or nausea and vomiting was observed in 53/317 patients (16.7%). Hypokalaemia occurred in 25.8% (78/302) and 18.5% (56/303) had acute kidney injury. During hospitalization, 111/317 patients (35.0%) received non-invasive respiratory support, 65/317 (20.5%) were admitted to the intensive care unit (ICU) and 60/317 (18.5%) required invasive mechanical ventilation. All-cause in-hospital mortality, assessed in 275 patients, was 43.6% (120/275). On multivariable analysis, age (per-year increase OR 1.07; 95% CI 1.04–1.10; p Conclusions COVID-19 mainly affected elderly patients with predisposing conditions and caused severe illness, frequently requiring non-invasive respiratory support or ICU admission. Despite supportive care, COVID-19 remains associated with a substantial risk of all-cause in-hospital mortality.

De novo posttransplant donor-specific HLA-antibody (dnDSA) detection is now recognized as a tool to identify patients at risk for antibody-mediated rejection (AMR) and graft loss. It is still unclear whether the time interval from transplant to DSA occurrence influences graft damage. Utilizing sera collected longitudinally, we evaluated 114 consecutive primary pediatric kidney recipients grafted between 2002 and 2013 for dnDSA occurrence by Luminex platform. dnDSAs occurred in 39 patients at a median time of 24.6 months. In 15 patients, dnDSAs developed within 1 year (early-onset group), while the other 24 seroconverted after the first posttransplant year (late-onset group). The two groups were comparable when considering patient- and transplant-related factors, as well as DSA biological properties, including C1q and C3d complement-binding ability. Only recipient age at transplant significantly differed in the two cohorts, with younger patients showing earlier dnDSA development. Late AMR was diagnosed in 47% of the early group and in 58% of the late group. Graft loss occurred in 3/15 (20%) and 4/24 (17%) patients in early- and late-onset groups, respectively (p = ns). In our pediatric kidney recipients, dnDSAs predict AMR and graft loss irrespective of the time elapsed between transplantation and antibody occurrence.

Systemic lupus erythematosus (SLE) is an autoimmune disease with variable clinical expression. It is a potentially devastating condition affecting mostly women and leading to clinically unpredictable outcomes. Remission and flares may, in fact, alternate over time and a mild involvement limited to few articular sites may be followed by severe and widespread organ damage. SLE is the prototype of any autoimmune condition and has, for this reason, attracted the interest of basic immunologists. Therapies have evolved over time and clinical prognosis has, in parallel, been improved. What clinicians still lack is the possibility to use biomarkers of the disease as predictors of outcome and, in this area, several studies are trying to find solutions. Circulating autoantibodies are clearly a milestone of clinical research and the concrete possibility is to integrate, in the future, classical markers of activation (like C3) with target organ autoantibodies. Anti-dsDNA antibodies represent a basic point in any predictive attempt in SLE and should be considered the benchmark for any innovative proposal in the wide field of target organ pathologies related to SLE. DNA is part of the nucleosome that is the basic unit of chromatin. It consists of DNA wrapped around a histone octamer made of 2 copies each of Histone 2A, 2B, 3, and 4. The nucleosome has a plastic organization that varies over time and has the potential to stimulate the formation of antibodies directed to the whole structure (anti-nucleosome) or its parts (anti-dsDNA and anti-Histones). Here, we present an updated review of the literature on antibodies directed to the nucleosome and the nucleosome constituents, i.e., DNA and Histones. Wetriedto merge the data first published more than twenty years ago with more recent results to create a balanced bridge between old dogma and more recent research that could serve as a stimulus to reconsider mechanisms for SLE. The formation of large networks would provide the chance of studying large cohorts of patients and confirm what already presented in small sample size during the last years.

Prevalence and clinical impact of viral respiratory tract infections (VRTIs) on community-acquired pneumonia (CAP) has not been well defined so far. The aims of this study were to investigate the prevalence and the clinical impact of VRTIs in patients with CAP. Prospective study involving adult patients consecutively admitted at medical wards for CAP and tested for VRTIs by real-time PCR on pharyngeal swab. Patients’ features were evaluated with regard to the presence of VRTI and aetiology of CAP. Clinical failure was a composite endpoint defined by worsening of signs and symptoms requiring escalation of antibiotic treatment or ICU admission or death within 30 days. 91 patients were enrolled, mean age 65.7 ± 10.6 years, 50.5% female. 62 patients (68.2%) had no viral co-infection while in 29 patients (31.8%) a VRTI was detected; influenza virus was the most frequently identified (41.9%). The two groups were similar in terms of baseline features. In presence of a VRTI, pneumonia severity index (PSI) was more frequently higher than 91 and patients had received less frequently pre-admission antibiotic therapy (adjusted OR 2.689, 95% CI 1.017–7.111, p = 0.046; adjusted OR 0.143, 95% CI 0.030–0.670, p = 0.014). Clinical failure and antibiotic therapy duration were similar with regards to the presence of VRTI and the aetiology of CAP. VRTIs can be detected in almost a third of adults with CAP; influenza virus is the most relevant one. VRTI was associated with higher PSI at admission, but it does not affect patients’ outcome.

Membranoproliferative GN (MPGN) was recently reclassified as alternative pathway complement–mediated C3 glomerulopathy (C3G) and immune complex–mediated membranoproliferative GN (IC-MPGN). However, genetic and acquired alternative pathway abnormalities are also observed in IC-MPGN. Here, we explored the presence of distinct disease entities characterized by specific pathophysiologic mechanisms. We performed unsupervised hierarchical clustering, a data-driven statistical approach, on histologic, genetic, and clinical data and data regarding serum/plasma complement parameters from 173 patients with C3G/IC-MPGN. This approach divided patients into four clusters, indicating the existence of four different pathogenetic patterns. Specifically, this analysis separated patients with fluid-phase complement activation (clusters 1–3) who had low serum C3 levels and a high prevalence of genetic and acquired alternative pathway abnormalities from patients with solid-phase complement activation (cluster 4) who had normal or mildly altered serum C3, late disease onset, and poor renal survival. In patients with fluid-phase complement activation, those in clusters 1 and 2 had massive activation of the alternative pathway, including activation of the terminal pathway, and the highest prevalence of subendothelial deposits, but those in cluster 2 had additional activation of the classic pathway and the highest prevalence of nephrotic syndrome at disease onset. Patients in cluster 3 had prevalent activation of C3 convertase and highly electron-dense intramembranous deposits. In addition, we provide a simple algorithm to assign patients with C3G/IC-MPGN to specific clusters. These distinct clusters may facilitate clarification of disease etiology, improve risk assessment for ESRD, and pave the way for personalized treatment.