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Este artículo analiza el papel del escándalo como mecanismo de crítica al poder político en la Argentina del cambio de siglo. De manera similar, a la sátira política en años anteriores, los escándalos sirvieron para denunciar públicamente las falencias del sistema político, poniendo en primer plano la ruptura de las normativas socialmente consensuadas. En el contexto de la segunda presidencia de Julio A. Roca, el debate público alentó éste tipo de crítica y posibilitó el éxito de este tipo de intervenciones que puso de manifiesto las polémicas existentes sobre distintos modos de entender y hacer política. Específicamente, se analiza la denuncia por corrupción realizada en junio de 1901 al ministro de Justicia e Instrucción Pública Osvaldo Magnasco. Este caso permite reflexionar sobre el rol jugado por la definición de las características morales de los políticos y los cuestionamientos públicos al funcionamiento del sistema de división de poderes, dando cuenta de las tensiones existentes en el debate publico sobre el lugar que el Congreso y el Presidente ocuparon en esas impugnaciones, y examinar los modos en que era percibida esta relación., Anuario de Historia de América Latina, Vol 56 (2019)

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.

International audience; Humans use whistled communications, the most elaborate of which are commonly called “whistled languages” or “whistled speech” because they consist of a natural type of speech. The principle of whistled speech is straightforward: people articulate words while whistling and thereby transform spoken utterances by simplifying them, syllable by syllable, into whistled melodies. One of the most striking aspects of this whistled transformation of words is that it remains intelligible to trained speakers, despite a reduced acoustic channel to convey meaning. It constitutes a natural traditional means of telecommunication that permits spoken communication at long distances in a large diversity of languages of the world. Historically, birdsong has been used as a model for vocal learning and language. But conversely, human whistled languages can serve as a model for elucidating how information may be encoded in dolphin whistle communication. In this paper, we elucidate the reasons why human whistled speech and dolphin whistles are interesting to compare. Both are characterized by similar acoustic parameters and serve a common purpose of long distance communication in natural surroundings in two large brained social species. Moreover, their differences – e.g., how they are produced, the dynamics of the whistles, and the types of information they convey – are not barriers to such a comparison. On the contrary, by exploring the structure and attributes found across human whistle languages, we highlight that they can provide an important model as to how complex information is and can be encoded in what appears at first sight to be simple whistled modulated signals. Observing details, such as processes of segmentation and coarticulation, in whistled speech can serve to advance and inform the development of new approaches for the analysis of whistle repertoires of dolphins, and eventually other species. Human whistled languages and dolphin whistles could serve as complementary test benches for the development of new methodologies and algorithms for decoding whistled communication signals by providing new perspectives on how information may be encoded structurally and organizationally.

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.

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.

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.

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.

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.

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.

In daily life, in the operating room and in the laboratory, the operational way to assess wakefulness and consciousness is through responsiveness. A number of studies suggest that the awake, conscious state is not the default behavior of an assembly of neurons, but rather a very special state of activity that has to be actively maintained and curated to support its functional properties. Thus responsiveness is a feature that requires active maintenance, such as a homeostatic mechanism to balance excitation and inhibition. In this work we developed a method for monitoring such maintenance processes, focusing on a specific signature of their behavior derived from the theory of dynamical systems: stability analysis of dynamical modes. When such mechanisms are at work, their modes of activity are at marginal stability, neither damped (stable) nor exponentially growing (unstable) but rather hovering in between. We have previously shown that, conversely, under induction of anesthesia those modes become more stable and thus less responsive, then reversed upon emergence to wakefulness. We take advantage of this effect to build a single-trial classifier which detects whether a subject is awake or unconscious achieving high performance. We show that our approach can be developed into a means for intra-operative monitoring of the depth of anesthesia, an application of fundamental importance to modern clinical practice.

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.

In the context of the rural electrification challenge, sharing-based nanogrids represent an innovative approach for affordable and sustainable electricity. The peer-to-peer topology of these nanogrids is targeted at organic growth and thus requires real time monitoring and optimization. A data analysis tool has been developed, aiming at achieving an efficient power flow and real time optimization of generation, storage, load and distribution capacities. This paper elaborates the core algorithms of the network topology optimization and provides first results based on data from a pilot nanogrid in Bangladesh.

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.

Alloantibody-mediated graft injury is a major cause of kidney dysfunction and loss. The complement-binding ability of de novo donor-specific antibodies (dnDSAs) has been suggested as a prognostic tool to stratify patients for clinical risk. In this study, we analyzed posttransplant kinetics of complement-fixing dnDSAs and their role in antibody-mediated rejection development and graft loss. A total of 114 pediatric nonsensitized recipients of first kidney allograft were periodically monitored for dnDSAs using flow bead assays, followed by C3d and C1q assay in case of positivity. Overall, 39 patients developed dnDSAs, which were C1q(+) and C3d(+) in 25 and nine patients, respectively. At follow-up, progressive acquisition over time of dnDSA C1q and C3d binding ability, within the same antigenic specificity, was observed, paralleled by an increase in mean fluorescence intensity that correlated with clinical outcome. C3d-fixing dnDSAs were better fit to stratify graft loss risk when the different dnDSA categories were evaluated in combined models because the 10-year graft survival probability was lower in patients with C3d-binding dnDSA than in those without dnDSAs or with C1q(+) /C3d(-) or non-complement-binding dnDSAs (40% vs. 94%, 100%, and 100%, respectively). Based on the kinetics profile, we favor dnDSA removal or modulation at first confirmed positivity, with treatment intensification guided by dnDSA biological characteristics.

Current research is focusing on identifying bioclinical parameters for risk stratification of renal allograft loss, largely due to antibody-mediated rejection (AMR). We retrospectively investigated graft outcome predictors in 24 unsensitized pediatric kidney recipients developing HLA de novo donor-specific antibodies (dnDSAs), and treated for late AMR with plasmapheresis + low-dose IVIG + Rituximab or high-dose IVIG + Rituximab. Renal function and DSA properties were assessed before and longitudinally post treatment. The estimated GFR (eGFR) decline after treatment was dependent on a negative % eGFR variation in the year preceding treatment (P = 0.021) but not on eGFR at treatment (P = 0.74). At a median follow-up of 36 months from AMR diagnosis, 10 patients lost their graft. Altered eGFR (P < 0.001) and presence of C3d-binding DSAs (P = 0.005) at treatment, and failure to remove DSAs (P = 0.01) were negatively associated with graft survival in the univariable analysis. Given the relevance of DSA removal for therapeutic success, we analyzed antibody properties dictating resistance to anti-humoral treatment. In the multivariable analysis, C3d-binding ability (P < 0.05), but not C1q-binding, and high mean fluorescence intensity (P < 0.05) were independent factors characterizing DSAs scarcely susceptible to removal. The poor prognosis of late AMR is related to deterioration of graft function prior to treatment and failure to remove C3d binding and/or high-MFI DSAs.

The emerging role of humoral immunity in the pathogenesis of chronic allograft damage has prompted research aimed at assessing the role of anti-HLA antibody (Ab) monitoring as a tool to predict allograft outcome. Data on the natural history of allografts in children developing de novo Ab after transplantation are limited. Utilizing sera collected pretransplant, and serially posttransplant, we retrospectively evaluated 82 consecutive primary pediatric kidney recipients, without pretransplant donor-specific antibodies (DSA), for de novo Ab occurrence, and compared results with clinical-pathologic data. At 4.3-year follow up, 19 patients (23%) developed de novo DSA whereas 24 had de novo non-DSA (NDSA, 29%). DSA appeared at a median time of 24 months after transplantation and were mostly directed to HLA-DQ antigens. Among the 82 patients, eight developed late/chronic active C4d+ antibody-mediated rejection (AMR), and four C4d-negative AMR. Late AMR correlated with DSA (p < 0.01), whose development preceded AMR by 1-year median time. Patients with DSA had a median serum creatinine of 1.44 mg/dL at follow up, significantly higher than NDSA and Ab-negative patients (p < 0.005). In our pediatric cohort, DSA identify patients at risk of renal dysfunction, AMR and graft loss; treatment started at Ab emergence might prevent AMR occurrence and/or progression to graft failure.

Summary Background and objectives Prednisone and calcineurin inhibitors are the mainstay therapy of idiopathic nephrotic syndrome (INS) in children. However, drug dependence and toxicity associated with protracted use are common. Case series suggest that the anti-CD20 monoclonal antibody rituximab (RTX) may maintain disease remission. Design, setting, participants, & measurements This open-label randomized controlled trial was powered to show that a strategy based on RTX and lower doses of prednisone and calcineurin inhibitors was noninferior to standard doses of these agents in maintaining 3-month proteinuria as low as baseline or up to 1 g/d greater (noninferiority margin). Participants were stratified by the presence of toxicity to prednisone/calcineurin inhibitors and centrally assigned to add RTX (Mabthera, 375 mg/m 2 intravenously) to lower doses of standard agents or to continue with current therapy alone. The risk of relapse was a secondary outcome. Results Fifty-four children (mean age 11 4 years) with INS dependent on prednisone and calcineurin inhibitors for 12 months were randomized. Three-month proteinuria was 70% lower in the RTX arm (95% confidence interval 35% to 86%) as compared with standard therapy arm (intention-to-treat); relapse rates were 18.5% (intervention) and 48.1% (standard arm) (P 0.029). Probabilities of being drug-free at 3 months were 62.9% and 3.7%, respectively (P 0.001); 50% of RTX cases were in stable remission without drugs after 9 months. Conclusions Rituximab and lower doses of prednisone and calcineurin inhibitors are noninferior to standard therapy in maintaining short-term remission in children with INS dependent on both drugs and allow their temporary withdrawal. Clin J Am Soc Nephrol 6: 1308–1315, 2011. doi: 10.2215/CJN.09421010

We report the diagnostic evaluation, management, and intermediate-term outcomes of a rare variant of bladder cancer and concomitant Abdominal Aortic Aneurysm. A 62 year old male with gross haematuria and Abdominal Aortic Aneurysm was admitted to our hospital. Cystoscopy revealed a large bulky mass occupying the posterior bladder wall. The tumor was transurethrally resected and its histology showed a Sarcomatoid Carcinoma of the urinary bladder. Due to the aggressive behavior of the tumor and the risk of aneurysm rupture, concomitant endovascular exclusion of Aneurysm, total cystectomy with urinary diversion was performed. 12 months after radical surgery the patient was alive without any local recurrence, distant metastasis, and thrombosis of iliac axis. To our knowledge this study is the first report to describe data on the diagnostic evaluation, Management, and intermediate-term outcomes in Sarcomatoid carcinoma and Concomitant Abdominal Aortic Aneurysm. Multi-institutional collaboration is important to perform clinical trials of adequate sample size to design more effective treatments for these aggressive cancers in the presence of Concomitant Abdominal Aortic Aneurysm.

The brain processes visual inputs having structure over a large range of spatial scales. The precise mechanisms or algorithms used by the brain to achieve this feat are largely unknown and an open problem in visual neuroscience. In particular, the spatial extent in visual space over which primary visual cortex (V1) performs evidence integration has been shown to change as a function of contrast and other visual parameters, thus adapting scale in visual space in an input-dependent manner. We demonstrate that a simple dynamical mechanism---dynamical criticality---can simultaneously account for the well-documented input-dependence characteristics of three properties of V1: scales of integration in visuotopic space, extents of lateral integration on the cortical surface, and response latencies.

We recently presented an estimate of the number of mutually discriminable olfactory stimuli at one trillion (1). Subjects were asked to sniff mixtures of molecules with increasing component overlap selected from a panel of 128 isointense structurally and perceptually diverse monomolecular odorants (2). We considered stimulus pairs discriminable when the majority of subjects could significantly discriminate them at p=0.05, a conventional statistical threshold given our sample size. From these empirical data, we estimated that human discriminative capacity exceeds one trillion olfactory stimuli. Several readers have pointed out that such extrapolations are sensitive to underlying assumptions about the chosen significance threshold (3) and the dimensionality of olfaction (4). It is important to note that any exponential function will be sensitive in this way, and the goal of our model was not to identify the exact number of discriminable olfactory stimuli, or even the exact mathematical bounds, but an estimate of the order of magnitude of human discriminatory power across a population of human subjects. This was not clearly stated in our paper, and we agree that contradictory references to a “lower limit” and an “upper bound” were confusing. The central argument in (4) is that our estimation method assumes that the dimensionality of olfactory space is large. We agree that the high-dimensional nature of olfaction is indeed an assumption, and we should have stated this explicitly in our paper (1). Even if we follow this logic of the models presented in (4), purely geometrical calculations show that our results hold if the dimensionality of olfactory representations is D≥25. The dimensionality of olfaction is a question of interest to everyone, and while we do not know for sure, all available evidence suggests that olfaction is a high-dimensional sense. The olfactory system is wired to keep information from the ~400 odorant receptors strictly separated, so it is plausible that olfaction operates at least in 400-dimensional space. This is an important topic of discussion in olfaction, and we welcome continued debate of the dimensionality of smell and how this impacts human olfactory perception.

Blood flow (Qa) measurements are an important step in the surveillance protocol of haemodialysis vascular access (VA). The glucose pump test (GPT) is a new test for Qa measurement based on the dilution of a constant glucose infusion. The aim of this study is to verify the clinical accuracy of GPT in a graft surveillance protocol with sequential Qa measurements.In 30 chronic haemodialysis patients with graft, we compared monthly sequential Qa measurements performed with GPT in pre-dialysis and the ultrasound dilution technique (HD01 device Transonic Systems Inc., USA) during dialysis. The colour Doppler ultrasonography study (CDU) was our reference standard for the diagnosis of stenosis. The endpoints were the graft thrombosis or PTA treatment.According to the K/DOQI guidelines we could identify the thrombosis high-risk grafts when Qa was600 ml/min or1000 ml/min with a decrease25% in serial Qa measurements. HD01 yielded 27 of 112 high-risk Qa measurements (21 Qa600 ml/min; mean 406+/-145 ml/min; 6 deltaQa25%; mean 43+/-7%). In 12 of 27 cases the CDU control did not show haemodynamically significant stenoses (false positive); 15 of 27 cases were confirmed high-risk accesses by CDU and did PTAs (HD01 specificity 86%). GPT yielded 14 of 112 high-risk Qa measurements (8 Qa600 ml/min; mean 404+/-135 ml/min; 6 deltaQa25%; mean 38+/-8%) and all had severe stenoses and underwent PTA treatments showing a GPT specificity of 100%. The CDU study allowed us to correctly assess the Qa negative cases. HD01 method had 10 false negative cases (treated or clotted grafts with a Qa600 ml/min and deltaQa25%) with a sensitivity of 60%, while GPT had 11 false negative cases with a sensitivity of 56%. The diagnostic accuracy tested with the ROC curves was similar with both tests (area under the curve was 0.762 and 0.752 with GPT and ultrasound dilution, respectively; P = 0.985). The diagnostic efficiency (percentage of grafts with agreement between test result and factual situation) was 90 and 80% (P = 0.056) for GPT and HD01, respectively.Compared with HD01, the GPT had a lower false positive rate and similar diagnostic accuracy and efficiency. The clinical implication is a smaller number of unnecessary, invasive procedures (angiographies or PTAs), without increasing the thrombosis risk. This study has shown that GPT is an accurate, quick and economic test for Qa monitoring.

Data on the different HLA-antibody (Ab) categories in pediatric kidney recipients developing de novo donor-specific Abs (DSA) after transplantation are scarce. We retrospectively evaluated 82 consecutive nonsensitized pediatric recipients of a first kidney graft for de novo HLA Ab occurrence and antigen specificity. At a median follow-up of 6 years, 29% of patients developed de novo DSA, while 45% had de novo non-DSA. DSA appeared at 25-month median time post-transplant and were mostly directed toward HLA-DQ antigens. Considering each HLA antigen, the estimated rate of DQ DSA (7.55 per 100 person-years) was much higher than the rates observed for non-DQ DSA. The HLA-DQ Ab recognized determinants of the DQβ chain in 70% of cases, α chain in 25% of cases, and both chains in one patient. Non-DSA peaked earlier than DSA, and were largely directed against HLA class I specificities that belonged to HLA-A- and HLA-B-related cross-reacting epitope groups (CREG) in 56% of cases. Our results indicate a need for evaluating HLA-DQ compatibilities in kidney allocation, in order to minimize post-transplant development of de novo DSA, known to be responsible for antibody-mediated rejection and graft loss.

To understand how the human visual system analyzes images, it is essential to know the structure of the visual environment. In particular, natural images display consistent statistical properties that distinguish them from random luminance distributions. We have studied the geometric regularities of oriented elements (edges or line segments) present in an ensemble of visual scenes, asking how much information the presence of a segment in a particular location of the visual scene carries about the presence of a second segment at different relative positions and orientations. We observed strong long-range correlations in the distribution of oriented segments that extend over the whole visual field. We further show that a very simple geometric rule, cocircularity, predicts the arrangement of segments in natural scenes, and that different geometrical arrangements show relevant differences in their scaling properties. Our results show similarities to geometric features of previous physiological and psychophysical studies. We discuss the implications of these findings for theories of early vision., Comment: 3 figures, 2 large figures not included

Glucose infusion test: A new screening test for vascular access recirculation. Background Vascular access recirculation is an important cause of diminished dialysis efficiency. We propose a new screening test based on glucose infusion as a tracer for recirculation. Methods The glucose infusion test (GIT) protocol comprises a basal blood sample (A) from the arterial port, a 5 mL bolus of 20% glucose into the venous chamber (time 0), followed by a second sample (B) in four seconds (from 13 to 17 s with Q B 300 mL/min) from the same port. The blood glucose level is determined at the bedside on A and B with a reflectance photometer (CV 1.8%). Interpretation of the test is straightforward: If B=A, there is no recirculation, whereas if B > A, recirculation can be calculated from the regression equation: 0.046 × (B - A) + 0.07, obtained from in vitro tests reproducing artificial recirculation at 0, 5, and 10%. To validate this new method in vivo, we compared GIT and the urea test on 39 hemodialysis patients, obtaining a good correlation ( r = 0.93). The two tests were considered positive (recirculation present) when the lower 95% confidence intervals were more than zero. Results Our patients were divided into two groups: those with (22 out of 39, mean recirculation 11.8%) or without recirculation (17 out of 39, mean 0.06%). The urea test did not recognize 7 out of 22 patients because they had a small recirculation below the urea test limit of detection. Conclusions GIT was more sensitive (detection limit 0.3%), simpler, and immediate in showing the results than the urea test. It is an accurate and low-cost technique for screening and follow-up of vascular access in a dialysis unit.

We show that presentation of individual canary song syllables results in distinct expression patterns of the immediate-early gene ZENK in the caudomedial neostriatum (NCM) of adult canaries. Information on the spatial distribution and labeling of stained cells provides for a classification of ZENK patterns that (1) accords to the organization of stimuli into families, (2) preserves the stimuli intrafamily relationships, and (3) confers salience to natural over artificial stimuli, resulting in a nonclassical tonotopic map. Moreover, complex syllable maps cannot be reduced to any linear combinations of simple syllable maps. These properties arise from the collective response of NCM neurons to auditory stimuli, rather than from the behavior of single neurons. The syllabic representation described here may constitute an important step toward deciphering the rules of birdsong auditory representation.

The objectives of this study were to assess the risk factors for metritis, its effects on milk yield and on reproductive performance, and the efficacy of ceftiofur therapy in Holstein dairy cows. Cows (n. =. 303) from a commercial dairy herd in Argentina were studied. Cows were scored for body condition, and blood samples were collected on d -14, 7, 21, 31, 41, and 50 relative to parturition. Cows having a watery, purulent, or brown, and fetid vaginal discharge (VD) and rectal temperature ≤39.2°C were diagnosed as having clinical metritis, and those having a similar VD and rectal temperature >39.2°C were diagnosed as having puerperal metritis. Both clinical and puerperal metritis cows were randomly assigned to control (no treatment) or ceftiofur group (2.2. mg/kg. ×. 3 consecutive days). Cure was declared if clear VD was observed at 21 d in milk (DIM). Blood samples were analyzed for nonesterified fatty acids, β-hydroxybutyrate, and blood urea nitrogen using commercial kits, and for insulin-like growth factor-1, insulin, and leptin by RIA. Data were analyzed with PROC MIXED, GENMOD, PHREG, and LIFETEST from SAS (SAS Institute Inc., Cary, NC). The risk for metritis increased with dystocia, retained fetal membranes, and dead calf [AOR (adjusted odds ratio). =. 2.58, 95% CI: 1.189-5.559], and as prepartum nonesterified fatty acids levels increased (AOR. =. 1.001, 95% CI: 0.999-1.002). Conversely, risk decreased as prepartum insulin-like growth factor-1 increased (AOR. =. 0.65, 95% CI: 0.349-1.219). Cows having either clinical or puerperal metritis produced less milk by 90 DIM than did healthy cows (2,236. ±. 172 vs. 2,367. ±. 77 vs. 2,647. ±. 82 kg, respectively). Cows with puerperal metritis had lower risk for pregnancy by 100 DIM (AOR. =. 0.189, 95% CI: 0.070-0.479) and a lower hazard rate for pregnancy by 150 DIM (hazard rate: 0.753, 95% CI: 0.621-0.911), and took longer to get pregnant (129 vs. 111 vs. 109 d, for puerperal metritis, clinical metritis, and healthy cows, respectively). Ceftiofur treatment was not associated with cure rate or milk yield but was related to increased risk for pregnancy at timed artificial insemination (AOR. =. 2.688, 95% CI: 0.687-10.832), and for lower risk of reproductive cull (AOR. =. 0.121, 95% CI: 0.014-1.066). In conclusion, abnormal calving and negative energy balance are associated with increased risk for metritis. Metritis, especially puerperal metritis, correlates with reduced milk production and poor reproductive performance. Finally, the likelihood for having a normal VD (indicative of cure) increased 2.6% for every day of increase in postpartum time and was 2 times higher for cows with clinical metritis than for those with puerperal metritis., Facultad de Ciencias Veterinarias

In children with idiopathic nephrotic syndrome, rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin inhibitors. Long-term effects including the number of repeated infusions to maintain remission are unknown. To test this, we treated 46 consecutive children with idiopathic nephrotic syndrome lasting for at least 1 year (mean 6.3 years), maintained in remission with oral prednisone and calcineurin inhibitors. They received 1–5 rituximab courses during a median follow-up of 3 years. Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and 2-year-remission probabilities were, respectively, 20 and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months, respectively, following the first and subsequent courses. The time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20, or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Thus, rituximab can be safely and repeatedly used as a prednisone and calcineurin inhibitor–sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further study is needed to identify patients who will benefit most from rituximab therapy.

The objectives of this study were to assess the clinical and metabolic risk factors for clinical endometritis, the likelihood for having a normal vaginal discharge during postpartum, and the effects of endometritis on milk yield, reproductive efficiency, and metabolic status in Holstein cows. The study was conducted in a commercial dairy herd (Cordoba, Argentina) where 303 Holstein cows were enrolled. Cows were body condition scored (1 to 5) and tail bled on -14, 7, 21, 31, 41, and 50. d relative to parturition. Cows having a vaginal discharge with presence of pus between 21 and 41. d postpartum (dpp) were diagnosed as having clinical endometritis. Plasma blood samples were analyzed for nonesterified fatty acids (NEFA), β-hydroxybutyrate (BHBA), and blood urea nitrogen using commercial kits and insulin-like growth factor 1, insulin, and leptin by RIA. Data were analyzed with PROC MIXED, PROC GENMOD, and PROC PHREG of SAS (SAS Institute Inc., Cary, NC). Abnormal calving and puerperal metritis increased the risk for endometritis [adjusted odds ratio (AOR)=2.21 for both]. High prepartum NEFA and high postpartum BHBA increased the risk for endometritis (AOR=1.003 and 1.001, respectively), whereas high prepartum blood urea nitrogen reduced it (AOR=0.853). Cut-offs of 456.6 μ M NEFA and 402.5 μM BHBA had sensitivities of 0.69 and 0.58, and specificities of 0.88 and 0.86, respectively. The likelihood for having normal vaginal discharge increased with time (∼1% × dpp) and with normal calving. Cows with endometritis had higher milk yield than normal herdmates (27.8±0.9 vs. 25.7±0.4. kg/d), lower risk for pregnancy by 100. dpp (AOR=0.10), higher nonpregnancy risk by 200. dpp (AOR=2.87), and higher risk for culling than normal cows (AOR=2.28). Cows with endometritis had a lower hazard rate (0.44) for pregnancy and had approximately 70. d longer calving-to-conception intervals. Finally, endometritis had no effect on metabolic hormones. In conclusion, the risk for clinical endometritis increases with abnormal calving and puerperal metritis, as prepartum NEFA and postpartum BHBA concentrations increase. Prepartum NEFA and postpartum BHBA could be useful for the prediction of endometritis. Last, clinical endometritis has detrimental effects on reproductive efficiency, as affected cows take longer to get pregnant and are at higher risk for culling., Facultad de Ciencias Veterinarias

Idiopathic nephrotic syndrome resistant to standard treatments remains a therapeutic dilemma in pediatric nephrology. To test whether the anti-CD20 monoclonal antibody rituximab may benefit these patients, we conducted an open-label, randomized, controlled trial in 31 children with idiopathic nephrotic syndrome unresponsive to the combination of calcineurin inhibitors and prednisone. All children continued prednisone and calcineurin inhibitors at the doses prescribed before enrollment, and one treatment group received two doses of rituximab (375 mg/m(2) intravenously) as add-on therapy. The mean age was 8 years (range, 2-16 years). Rituximab did not reduce proteinuria at 3 months (change, -12% [95% confidence interval, -73% to 110%]; P=0.77 in analysis of covariance model adjusted for baseline proteinuria). Additional adjustment for previous remission and interaction terms (treatment by baseline proteinuria and treatment by previous remission) did not change the results. In conclusion, these data do not support the addition of rituximab to prednisone and calcineurin inhibitors in children with resistant idiopathic nephrotic syndrome.

Summary The mechanism responsible for proteinuria in non-genetic idiopathic nephrotic syndrome (iNS) is unknown. Animal models suggest an effect of free radicals on podocytes, and indirect evidence in humans confirm this implication. We determined the oxidative burst by blood CD15+ polymorphonucleates (PMN) utilizing the 5-(and-6)-carboxy-2′,7′-dichlorofluorescin diacetate (DCF-DA) fluorescence assay in 38 children with iNS. Results were compared with PMN from normal subjects and patients with renal pathologies considered traditionally to be models of oxidative stress [six anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis, seven post-infectious glomerulonephritis]. Radicals of oxygen (ROS) production was finally determined in a patient with immunodeficiency, polyendocrinopathy, enteropathy X-linked (IPEX) and in seven iNS children after treatment with Rituximab. Results demonstrated a 10-fold increase of ROS production by resting PMN in iNS compared to normal PMN. When PMN were separated from other cells, ROS increased significantly in all conditions while a near-normal production was restored by adding autologous cells and/or supernatants in controls, vasculitis and post-infectious glomerulonephritis but not in iNS. Results indicated that the oxidative burst was regulated by soluble factors and that this regulatory circuit was altered in iNS. PMN obtained from a child with IPEX produced 100 times more ROS during exacerbation of clinical symptoms and restored to a near normal-level in remission. Rituximab decreased ROS production by 60%. In conclusion, our study shows that oxidant production is increased in iNS for an imbalance between PMN and other blood cells. Regulatory T cells (Tregs) and CD20 are probably involved in this regulation. Overall, our observations reinforce the concept that oxidants deriving from PMN are implicated in iNS.