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Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections represent a leading cause of purulent skin and soft tissue infections in some geographical regions. Traditionally, ‘old antibiotics’ such as trimethoprim-sulfamethoxazole, tetracyclines, clindamycin, chloramphenicol,vancomycin, and teicoplanin have been used to treat these infections, but these were often associated with low efficacy and excessive side effects and toxicity, especially nephrotoxicity. Along with the development of new compounds, the last decade has seen substantial improvements in the management of CA-MRSA infections. In this review, the authors discuss the current and emerging drug treatment strategies to tackle invasive CA-MRSA infections. Articles reported in this review were selected from through literature searches using the PubMed database. The availability of new drugs showing a potent in vitro activity against CA-MRSA represents a unique opportunity to face the threat of resistance while potentially reducing toxicity. All these compounds represent promising options to enhance our antibiotic armamentarium. However, data regarding the use of these new drugs in real-life studies are limited and their best placement in therapy and in terms of optimization of medical resources and balance of cost-effectiveness requires further investigation.

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.

Aim of this study was to assess the predictors of virological failure (VF) among patients living with HIV (PLWHIV) switching from an effective first-line antiretroviral therapy (ART) regimen, and to evaluate the emergence of resistance-associated mutations. All adult patients enrolled in the Antiviral Response Cohort Analysis cohort who started ART after 2010, with at least 6 months of virological suppression (VS) before ART switch and with an available genotypic resistance test (GRT) at baseline were included. Thirty-two patients out of the 607 PLWHIV included (5.3%) experienced VF after a median of 11 months from ART switch. Younger age (adjusted Hazard Ratio [aHR] 0.96, 95% confidence interval [CI] 0.92-0.99

This paper presents some unusual behaviors observed in one single specimen ofO. insularis. While nothing can be concluded rigorously from such data, we share the data and our analysis with the community, in the hope that others will be on the lookout for such rare events. Sleep is a fundamental biological function that is present in all tested vertebrates and most invertebrates.Cephalopods, such as octopuses, are cognitively complex animals that display active and inactive sleep states similar to those of vertebrates. In particular, octopuses have active sleep states during which they display sequences of camouflage patterns and modulation of basal rhythms, while remaining relatively unresponsive to outside stimuli. Some scientists have speculated that these states could be analogous to dreaming in mammals, involving episodic recall with a narrative structure. The convergent evolution of sleep in neurologically complex animals is a striking possibility, but its demonstration requires overcoming significant challenges. Towards this end, capturing abnormal sleep-associated episodes and other parasomnias in cephalopods can provide further insight into the biology of their sleep. This study reports abnormal behavioral episodes associated with transitions between activity states and sleep states observed in a maleOctopus insularis. The study used continuous video monitoring to characterize the animal’s activity patterns and detect rare behavioral episodes. Over the course of a month, four brief episodes (duration range: 44-290 seconds) were identified during which the octopus abruptly emerged from quiescent or active sleep, detached itself from its sleep position, and engaged in antipredator and predatory behaviors (with no predator present). The longest of these episodes resembled the species-typical response to a predatory attack, suggesting that the animal may have been responding to a negative episodic memory or exhibiting a form of parasomnia. These findings, in conjunction with recent evidence for sleep in octopuses, highlight the complexity of possible sleep-associated behavioral episodes. Investigating sleep in invertebrates is crucial to understanding the evolution of sleep across distantly related species.

A difficult-to-control outbreak of Candida auris is ongoing in a large tertiary care hospital in Liguria, Italy, where it first emerged in 2019. In a retrospective analysis, 503 cases of C. auris carriage or infection were observed between July 2019 and December 2022. Genomic surveillance identified putative cases that no longer occurred as part of one defined outbreak and the emergence of echinocandin (pandrug) resistance following independent selection of FKS1 S639F and FKS1 F635Y mutants upon prolonged exposure to caspofungin and/or anidulafungin.

Background Severely immunocompromised patients are at risk for prolonged or relapsed Coronavirus Disease 2019 (COVID-19), leading to increased morbidity and mortality. We aimed to evaluate efficacy and safety of combination treatment in immunocompromised COVID-19 patients. Methods We included all immunocompromised patients with prolonged/relapsed COVID-19 treated with combination therapy with 2 antivirals (remdesivir plus nirmatrelvir/ritonavir, or molnupiravir in case of renal failure) plus, if available, anti-spike monoclonal antibodies (mAbs), between February and October 2022. The main outcomes were virological response at day 14 (negative Severe Acute Respiratory Syndrome Coronavirus 2 [SARS-CoV-2] swab) and virological and clinical response (alive, asymptomatic, with negative SARS-CoV-2 swab) at day 30 and the last follow-up. Results Overall, 22 patients (Omicron variant in 17/18) were included: 18 received full combination of 2 antivirals and mAbs and 4 received 2 antivirals only; in 20 of 22 (91%) patients, 2 antivirals were nirmatrelvir/ritonavir plus remdesivir. Nineteen (86%) patients had hematological malignancy, and 15 (68%) had received anti-CD20 therapy. All were symptomatic; 8 (36%) required oxygen. Four patients received a second course of combination treatment. The response rate at day 14, day 30, and last follow-up was 75% (15/20 evaluable), 73% (16/22), and 82% (18/22), respectively. Day 14 and 30 response rates were significantly higher when combination therapy included mAbs. Higher number of vaccine doses was associated with better final outcome. Two patients (9%) developed severe side effects (bradycardia leading to remdesivir discontinuation and myocardial infarction). Conclusions Combination therapy including 2 antivirals (mainly remdesivir and nirmatrelvir/ritonavir) and mAbs was associated with high rate of virological and clinical response in immunocompromised patients with prolonged/relapsed COVID-19.

Schizophrenia (SZ) is hypothesised to represent a costly trade-off in the evolution of the neurodevelopmental ontogenetic mechanisms associated with human-specific cognitive capacities. Human Accelerated Regions (HARs) are evolutionary conserved genomic regions that have accumulated human-specific sequence changes. These evolutionary markers function as neurodevelopmental transcription enhancers and have been associated with the brain’s cortical expansion and connectivity, the processing of neural information, and the risk for SZ. We sought to investigate whether HARs’ polygenic load influenced neuroanatomical measures.Our sample consisted of 128 patients with SZ and 115 healthy controls with high-resolution structural T1 MRI and genome-wide genotyping data. We extracted the cortical thickness (CT) and surface area (SA) for the 34 Desikan-Killiany regions per hemisphere. We calculated four polygenic risk scores (PRS): SZ genetic load (Global PRSSZ), HARs’ specific variability (HARs PRSSZ), HARs’ variability associated with transcriptional regulatory elements uniquely active in the foetal brain (FB-HARs PRSSZ) and in the adult brain (AB-HARs PRSSZ). Through linear regression analyses, we explored whether these four PRSs modulated CT and SA within diagnostic groups and the PRSs and diagnostic interaction on the cortical measures.Results indicate that FB-HARs PRSSZinfluenced patients’ right SA on the lateral orbitofrontal cortex, the superior temporal cortex, the pars triangularis and the paracentral lobule and that a higher SZ risk load in FB-HARs is associated with lower SA values.These findings evidence the involvement of the HARs-foetal gene regulatory activity in SA architecture and the evolutionary component of this regulation in SZ. These data emphasise the importance of HARs in the transcriptional regulatory machinery from early neurodevelopment and their role as the bridging point between the neurodevelopmental and evolutionary hypotheses in SZ.

The diagnosis of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is challenging, and the role of Aspergillus-PCR in bronchoalveolar lavage (BAL) is unknown.This study evaluated diagnostic accuracy of Aspergillus-PCR in BAL in IPA in three different cohorts: ICU-admitted patients with COVID-19, ICU-admitted patients without COVID-19 and immunocompromised patients.All stored available BAL samples collected from three patient groups were tested with Aspergillus-PCR (AsperGeniusWe included 111 BAL samples from 101 patients: 52 (51%) patients admitted to ICU for COVID-19, 24 (24%) admitted to ICU for other reasons and 25 (25%) immunocompromised. There were 31 cases of IPA (28%). Aspergillus-PCR sensitivity was 64% (95% CI 47-79) and specificity 99% (95% CI 93-100). Aspergillus-PCR sensitivity was 40% (95%CI 19-64) in ICU COVID-19, 67% (95% CI 21-93) in non-COVID-19 ICU patients and 92% (95%CI 67-98) in the immunocompromised. The concordance between positive BAL-GM and BAL-PCR in patients with and without IPA was significantly lower in ICU patients (32%; 43% in COVID-19, 18% in non-COVID-19) than in the immunocompromised (92%), p .001.Aspergillus-PCR in BAL improves the diagnostic accuracy of BAL-GM in ICU patients.

Recurrent neural networks are extremely powerful yet hard to train. One of their issues is the vanishing gradient problem, whereby propagation of training signals may be exponentially attenuated, freezing training. Use of orthogonal or unitary matrices, whose powers neither explode nor decay, has been proposed to mitigate this issue, but their computational expense has hindered their use. Here we show that in the specific case of convolutional RNNs, we can define a convolutional exponential and that this operation transforms antisymmetric or anti-Hermitian convolution kernels into orthogonal or unitary convolution kernels. We explicitly derive FFT-based algorithms to compute the kernels and their derivatives. The computational complexity of parametrizing this subspace of orthogonal transformations is thus the same as the networks' iteration.

Mast cell leukemia (MCL) is the leukemic form of SM with at least 20% mostly immature mast cells on bone marrow aspirate. MCL may develop de novo, in the absence of a prior SM, or it may represent a progression from a previous SM. MCL may be sub-divided into the more frequent, aggressive acute form with signs of organ damage (C-findings) and the chronic form lacking C-findings and presenting a more stable course, although over time, progression to acute MCL is common. The 2022 WHO subtype of MCL with an associated hematological neoplasm was renamed MCL with an associated myeloid neoplasm in the 2022 International Consensus Classification (ICC). The relevance of the distinction between the leukemic and aleukemic forms based on the percentage of circulating mast cells is a matter of debate. The current knowledge on MCL is restricted mainly to single reports or case series with a limited number of larger studies. Our aim is to provide a comprehensive overview of this rare disease in terms of clinical manifestations, morphology, phenotype, molecular characteristics, differential diagnosis, outcome and treatment. A general overview on mastocytosis is also included.

Community-acquired methicillin-resistantIn this review, the authors discuss the current and emerging drug treatment strategies to tackle invasive CA-MRSA infections. Articles reported in this review were selected from through literature searches using the PubMed database.The availability of new drugs showing a potent in vitro activity against CA-MRSA represents a unique opportunity to face the threat of resistance while potentially reducing toxicity. All these compounds represent promising options to enhance our antibiotic armamentarium. However, data regarding the use of these new drugs in real-life studies are limited and their best placement in therapy and in terms of optimization of medical resources and balance of cost-effectiveness requires further investigation.

Background The objective of this study was to compare the clinical outcomes of patients receiving a short course (SC) vs a prolonged course (PC) of antifungal therapy for uncomplicated Candida bloodstream infections (BSIs). Methods All episodes of uncomplicated Candida BSI from September 1, 2018, to August 31, 2020, were reviewed. We compared the primary (all-cause 90-day mortality) and secondary study end points (1-year recurrent Candida BSI and all-cause 1-year mortality) among patients who underwent SC (5–11 days) or PC (12–24 days) therapy using propensity score analysis with the inverse probability of treatment weighting (IPTW) method. Results A total of 114 patients with uncomplicated Candida BSI were included: 35 (30.7%) were classified into the SC group (median [interquartile range {IQR}], 9 [7–11] days) and 79 (69.3%) into the PC group (median [IQR], 14 [14–16] days). Patients in the SC group compared with the PC group had a higher rate of hospitalization in the surgical ward (40.0% vs 19.0%; P = .02) or septic shock at the time of Candida BSI onset (11.4% vs 1.3%; P = .03). The risk of 90-day mortality was not different between the SC and PC groups (n = 8 [22.9%] vs 17 [21.5%], respectively; IPTW-adjusted subdistribution hazard ratio [sHR], 0.67; 95% CI, 0.31–1.47; P = .20). The risk for recurrent Candida BSI within 1 year of completing therapy (IPTW-adjusted sHR, 1.07; 95% CI, 0.20–5.80; P = .94) or for all-cause 1-year mortality (IPTW-adjusted HR, 0.72; 95% CI, 0.35–1.50; P = .38) did not differ between groups. Conclusions Receiving a short vs prolonged course of antifungal therapy did not affect mortality or BSI recurrence in patients with uncomplicated candidemia.

Background We studied immunological response against SARS-CoV-2 after two doses of vaccine in health care workers (HCW) at our Infectious Disease Unit Methods We enrolled prospectively HCW without (group A) and with previous infection (group B). We collected peripheral blood at baseline (before the BNT162b2 vaccine), T1 (before the 2nd dose), T2 and T6 (after 1 and 6 months after of 2nd dose). The activation induced cell marker assay (AIM) was performed with CD4 and CD8 Spike peptide megapools (MPs). We evaluated the Stimulation Index (SI) as AIM+ stimulated cells/negative control (positive response SI >= 2). Quantitative antibodies (Abs) to Spike-1 protein (S) and to nucleocapside protein (N) were detected with an electrochemiluminescence immunoassay. We tested at T6 the responses to alpha, beta, gamma, delta and epsilon variants MPs.We used the linear mixed model with random intercept adjusted for age and sex to compare specific times to T0. To assess differences over time between groups the interaction with time was tested. Results In group A 13/22 (59%) were female vs 5/7 (71%) group B, the mean age 40 vs 38 years, respectively. For CD4+ Spike the overall rate of change over time was significant at T1 (p=0.038) and at T2 (p< 0.001) vs T0 with a decreasing at T6 (p not significant) [Figure 1] with a trend of higher response in group A. In group B the CD8+ Spike reactivity increased at T1(p=0.037) and at T6 (p=0.005) vs T0. The interaction between SI and time was statistically significant at T1 (p=0.033); T2 (p= 0.046) and T6 (p=0.035) (mean values in group B higher than A). For overall population, the anti-S Abs significantly increased at T1 vs T0, T2 vs T0 and at T6 vs T0 [Figure 2A]. The group B at T6 retained a higher anti S response but the rate of change significantly differs between the two group (overall interaction: p< 0.001) [Figure 2B]. At T6 in both groups we found a high CD4+ T cells response to epsilon variant, even if not detected as circulant virus. Quantitative (U/ml) values of anti-S Antibodies. Conclusion The humoral response was persistent and increased in previous infected subjects. The CD4+T cells response after vaccination retained a response in uninfected subject, with an increasing trend and with a response to non-circulating variants. The vaccine could help the CD8+ T cells reactivity specific for Spike peptides. Disclosures Chiara Dentone, CD, Angelini: Advisor/Consultant|Gilead: Advisor/Consultant|Menarini: Advisor/Consultant|Novartis: Advisor/Consultant Lucia Taramasso, LT, Gilead: Advisor/Consultant|Janssen: Advisor/Consultant|ViiV: Advisor/Consultant Alessandro Sette, AS, Arcturus Therapeutics: Grant/Research Support|Astrazeneca: Advisor/Consultant|Avalia: Advisor/Consultant|CellCarta: Grant/Research Support|Flow Pharma: Grant/Research Support|Fortress: Advisor/Consultant|Gritstone Bio: Advisor/Consultant|ImmunoScape: Advisor/Consultant|Moderna: Advisor/Consultant|Repertoire: Advisor/Consultant Antonio Di Biagio, AD, Abbvie: Advisor/Consultant|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|MSD: Advisor/Consultant|ViiV: Advisor/Consultant Matteo Bassetti, PhD, Angelini: Advisor/Consultant|Astellas: Grant/Research Support|Bayer: Advisor/Consultant|Bayer: Honoraria|BioMe ́ rieux: Advisor/Consultant|BioMe ́ rieux: Honoraria|Cidara: Advisor/Consultant|Cidara: Honoraria|Cipla: Advisor/Consultant|Cipla: Honoraria|Gilead: Advisor/Consultant|Gilead: Honoraria|Menarini: Advisor/Consultant|Menarini: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Nabriva: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Board Member|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|Tetraphase: Advisor/Consultant.

Laugier-Hunziker syndrome (LHS) is a sporadic, acquired, and infrequent condition characterized by the onset of brown macules on the lips, the oral mucosa, and the acral glabrous skin (mainly fingers and toes) in middle-aged patients. In several cases melanonychia of fingernails and toenails coexists. No other systemic involvement is observed. A case of LHS in a 50-year-old woman is described, with particular attention to dermoscopic features. No dermoscopic specific findings of mucosal/cutaneous maculae have been to date described in the literature. Accumulation of dermoscopic observations of pigmented lesions in LHS is needed and if found to be distinct, it may contribute to a more accurate diagnosis in the future.

The use of rapid molecular tests may anticipate the identification of causative agents and resistance determinants in the blood of critically ill patients with sepsis. From April to December 2021, all intensive care unit patients with sepsis or septic shock who were tested with the T2Bacteria and T2Resistance assays were included in a retrospective, single center study. The primary descriptive endpoints were results of rapid molecular tests and concomitant blood cultures. Overall, 38 combinations of T2Bacteria and T2Resistance tests were performed. One or more causative agent(s) were identified by the T2Bacteria assay in 26% of episodes (10/38), whereas negative and invalid results were obtained in 66% (25/38) and 8% (3/38) of episodes, respectively. The same pathogen detected by the T2Bacteria test grew from blood cultures in 30% of cases (3/10). One or more determinant(s) of resistance were identified by the T2Resistance assay in 11% of episodes (4/38). Changes in therapy based on T2Bacteria and/or T2Resistance results occurred in 21% of episodes (8/38). In conclusion, T2Bacteria/T2Resistance results can influence early treatment decisions in critically ill patients with sepsis or septic shock in real-life practice. Large, controlled studies remain necessary to confirm a favorable impact on patients’ outcomes and antimicrobial stewardship interventions.

IntroductionImmunity to Human leukocyte antigen (HLA) cannot explain all cases of ABMR, nor the differences observed in the outcome of kidney recipients with circulating DSAs endowed with similar biologic characteristics. Thus, increasing attention has recently been focused on the role of immunity to non-HLA antigenic targets.MethodsWe analyzed humoral auto- and alloimmune responses to the non-HLA antigen glutathione S-transferase theta 1 (GSTT1), along with development of de novo (dn)HLA-DSAs, in a cohort of 146 pediatric non-sensitized recipients of first kidney allograft, to analyze its role in ABMR and graft loss. A multiplex bead assay was employed to assess GSTT1 antibodies (Abs).ResultsWe observed development of GSTT1 Abs in 71 recipients after transplantation, 16 with MFI > 8031 (4th quartile: Q4 group). In univariate analyses, we found an association between Q4-GSTT1Abs and ABMR and graft loss, suggesting a potential role in inducing graft damage, as GSTT1 Abs were identified within ABMR biopsies of patients with graft function deterioration in the absence of concomitant intragraft HLA-DSAs. HLA-DSAs and GSTT1 Abs were independent predictors of graft loss in our cohort. As GSTT1 Ab development preceded or coincided with the appearance of dnHLA-DSAs, we tested and found that a model with the two combined parameters proved more fit to classify patients at risk of graft loss.DiscussionOur observations on the harmful effects of GSTT1Abs, alone or in combination with HLA-DSAs, add to the evidence pointing to a negative role of allo- and auto-non-HLA Abs on kidney graft outcome.

Candida auris is responsible for hospital outbreaks worldwide. Some C. auris isolates may show concomitant resistance to azoles, echinocandins, and polyenes, thereby possibly leaving clinicians wit...

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

Serum beta-D-glucan (BDG) determination plays an important role in the diagnosis of candidemia among critically ill patients admitted to the intensive care unit (ICU). However, BDG levels measured may be lower in the case of infections caused by some non

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 Increases in cardiac troponin (cTn) in coronavirus disease 2019 (COVID-19) have been associated with worse prognosis. Nonetheless, data about the significance of cTn in elderly subjects with COVID-19 are lacking. METHODS From a registry of consecutive patients with COVID-19 admitted to a hub hospital in Italy from 25/02/2020 to 03/07/2020, we selected those ≥ 60 year-old and with cTnI measured within three days from the molecular diagnosis of SARS-CoV-2 infection. When available, a second cTnI value within 48 h was also extracted. The relationship between increased cTnI and all-cause in-hospital mortality was evaluated by a Cox regression model and restricted cubic spline functions with three knots. RESULTS Of 343 included patients (median age: 75.0 (68.0−83.0) years, 34.7% men), 88 (25.7%) had cTnI above the upper-reference limit (0.046 µg/L). Patients with increased cTnI had more comorbidities, greater impaired respiratory exchange and higher inflammatory markers on admission than those with normal cTnI. Furthermore, they died more (73.9%vs. 37.3%, P < 0.001) over 15 (6−25) days of hospitalization. The association of elevated cTnI with mortality was confirmed by the adjusted Cox regression model (HR = 1.61, 95%CI: 1.06−2.52, P = 0.039) and was linear until 0.3 µg/L, with a subsequent plateau. Of 191 (55.7%) patients with a second cTnI measurement, 49 (25.7%) had an increasing trend, which was not associated with mortality (univariate HR = 1.39, 95%CI: 0.87−2.22, P = 0.265). CONCLUSIONS In elderly COVID-19 patients, an initial increase in cTn is common and predicts a higher risk of death. Serial cTn testing may not confer additional prognostic information.

We prospectively studied immunological response against SARS-CoV-2 after vaccination among healthcare workers without (group A) and with previous infection (group B). The analyses were collected at T0 (before the BNT162b2), T1 (before the second dose), T2 and T6 (1 and 6 months after the second dose). For cellular immune response, the activation-induced cell marker assay was performed with CD4 and CD8 Spike peptide megapools expressed as Stimulation Index. For humoral immune response, we determined antibodies to Spike-1 and nucleocapsid protein. The linear mixed model compared specific times to T0. The CD4+ Spike response overall rate of change was significant at T1 (p = 0.038) and at T2 (p < 0.001), while decreasing at T6. For CD8+ Spike reactivity, the interaction between the time and group was significant (p = 0.0265), and the p value for group comparison was significant at the baseline (p = 0.0030) with higher SI in previously infected subjects. Overall, the anti-S Abs significantly increased from T1 to T6 compared to T0. The group B at T6 retained high anti-S titer (p < 0.001). At T6, in both groups we found a persistent humoral response and a high CD4+ T cell response able to cross recognize SARS-COV-2 variants including epsilon, even if not a circulating virus at that time.

Pseudomonas aeruginosa; Bacteremia; Neutropenia Pseudomonas aeruginosa; Bacteriemia; Neutropenia Pseudomonas aeruginosa; Bacterièmia; Neutropènia We sought to assess the characteristics and outcomes of neutropenic hematologic patients with Pseudomonas aeruginosa (PA) bloodstream infection (BSI) treated with ceftolozane-tazobactam (C/T). We conducted a multicenter, international, matched-cohort study of PA BSI episodes in neutropenic hematologic patients who received C/T. Controls were patients with PA BSI treated with other antibiotics. Risk factors for overall 7-day and 30-day case fatality rates were analyzed. We compared 44 cases with 88 controls. Overall, 91% of episodes were caused by multidrug-resistant (MDR) strains. An endogenous source was the most frequent BSI origin (35.6%), followed by pneumonia (25.8%). There were no significant differences in patient characteristics between groups. C/T was given empirically in 11 patients and as definitive therapy in 41 patients. Treatment with C/T was associated with less need for mechanical ventilation (13.6% versus 33.3%; P = 0.021) and reduced 7-day (6.8% versus 34.1%; P = 0.001) and 30-day (22.7% versus 48.9%; P = 0.005) mortality. In the multivariate analysis, pneumonia, profound neutropenia, and persistent BSI were independent risk factors for 30-day mortality, whereas lower mortality was found among patients treated with C/T (adjusted OR [aOR] of 0.19; confidence interval [CI] 95% of 0.07 to 0.55; P = 0.002). Therapy with C/T was associated with less need for mechanical ventilation and reduced 7-day and 30-day case fatality rates compared to alternative agents in neutropenic hematologic patients with PA BSI. IMPORTANCE Ceftolozane-tazobactam (C/T) has been shown to be a safe and effective alternative for the treatment of difficult to treat infections due to Pseudomonas aeruginosa (PA) in the general nonimmunocompromised population. However, the experience of this agent in immunosuppressed neutropenic patients is very limited. Our study is unique because it is focused on extremely immunosuppressed hematological patients with neutropenia and bloodstream infection (BSI) due to PA (mainly multidrug resistant [MDR]), a scenario which is often associated with very high mortality rates. In our study, we found that the use of C/T for the treatment of MDR PA BSI in hematological neutropenic patients was significantly associated with improved outcomes, and, in addition, it was found to be an independent risk factor associated with increased survival. To date, this is the largest series involving neutropenic hematologic patients with PA BSI treated with C/T. This study was supported by the Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), (CB21/13/00009), Madrid, Spain. The study was partially funded by the MSD Investigator Initiated Studies Program. The company declares no contributions toward the design and interpretation of the results of the study.

Supplementary Videos: Robustness and Flexibility of Neural Function through Dynamical Criticality

Rapid start of antiretroviral therapy (ART) pending genotypic resistance test (GRT) has been recently proposed, but the effectiveness of this strategy is still debated. The rate of virological success (VS), defined as HIV-RNA 50 copies/ml, with and without GRT was compared in drug-naïve individuals enrolled in the Italian ARCA cohort who started ART between 2015 and 2018. 521 individuals started ART: 397 without GRT (pre-GRT group) and 124 following GRT (post-GRT group). Overall, 398 (76%) were males and 30 (6%) were diagnosed with AIDS. In the pre-GRT group, baseline CD4+ cell counts were lower (p 0.001), and viral load was higher (p 0.001) than in the post-GRT group. The estimated probability of VS in pre-GRT versus post-GRT group was 72.54% (CI

In theoretical biology, robustness refers to the ability of a biological system to function properly even under perturbation of basic parameters (e.g., temperature or pH), which in mathematical models is reflected in not needing to fine-tune basic parameter constants; flexibility refers to the ability of a system to switch functions or behaviors easily and effortlessly. While there are extensive explorations of the concept of robustness and what it requires mathematically, understanding flexibility has proven more elusive, as well as also elucidating the apparent opposition between what is required mathematically for models to implement either. In this paper we address a number of arguments in theoretical neuroscience showing that both robustness and flexibility can be attained by systems that poise themselves at the onset of a large number of dynamical bifurcations, or dynamical criticality, and how such poising can have a profound influence on integration of information processing and function. Finally, we examine critical map lattices, which are coupled map lattices where the coupling is dynamically critical in the sense of having purely imaginary eigenvalues. We show that these map lattices provide an explicit connection between dynamical criticality in the sense we have used and “edge of chaos” criticality.

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.

Methicillin-resistant Staphylococcus aureus (MRSA) is among the most frequent causative agents of acute bacterial skin and skin-structure infections (ABSSSI) and has been associated with increased ...

Purpose of review To summarize the available efficacy and safety data of novel agents for treating acute bacterial skin and skin-structure infections (ABSSSI), focusing on those active against methicillin-resistant Staphylococcus aureus (MRSA). Recent findings There are now several agents active against MRSA that are approved for the treatment of ABSSSI, including tedizolid, ceftaroline, dalbavancin, telavancin, oritavancin, delafloxacin, and omadacycline. In addition, iclaprim has completed phase-3 randomized clinical trials (RCTs). Summary Considering the similar efficacy that arose from direct comparisons in phase-3 RCTs, in order to adopt the best approach for treating ABSSSI on patient-tailored basis, the different safety profiles and formulations of the different available agents should be balanced by taking into account the specific features of each treated patient in terms of baseline comorbidities, related risk of toxicity, need for hospitalization, possibility of early discharge, and expected adherence to outpatient oral therapy.

Candida auris (C. auris) is an emerging nosocomial pathogen, and a sharp rise in cases of colonization and infection has been registered in intensive care units (ICUs) during the ongoing coronavirus disease 2019 (COVID-19) pandemic. The unfavorable resistance profile of C. auris and the potential high mortality of C. auris infections represent an important challenge for physicians.We conducted a single-center retrospective study including all patients admitted to ICUs with isolation of C. auris in any non-sterile body site between February 20, 2020, and May 31, 2021. The primary aim of the study was to assess the cumulative incidence of C. auris candidemia in colonized patients. The secondary aim was to identify predictors of C. auris candidemia in the study population.During the study period, 157 patients admitted to ICUs in our hospital became colonized with C. auris; 59% of them were affected by COVID-19. Overall, 27 patients (17%) developed C. auris candidemia. The cumulative risk of developing C. auris candidemia was 25% at 60 days after first detection of C. auris colonization. Seven patients with C. auris candidemia (26%) also developed a late recurrent episode. All C. auris blood isolates during the first occurring episode were resistant to fluconazole and susceptible to echinocandins, while 15 (56%) were resistant to amphotericin B. During late recurrent episodes, emergent resistance to caspofungin and amphotericin B occurred in one case each. In the final multivariable model, only multisite colonization retained an independent association with the development of C. auris candidemia.Candida auris candidemia may occur in up to one fourth of colonized critically ill patients, and multisite colonization is an independent risk factor for the development of candidemia. Implementing adequate infection control measures remains crucial to prevent colonization with C. auris and indirectly the subsequent development of infection.

We sought to assess the characteristics and outcomes of neutropenic hematologic patients with Pseudomonas aeruginosa (PA) bloodstream infection (BSI) treated with ceftolozane-tazobactam (C/T). We conducted a multicenter, international, matched-cohort study of PA BSI episodes in neutropenic hematologic patients who received C/T. Controls were patients with PA BSI treated with other antibiotics. Risk factors for overall 7-day and 30-day case fatality rates were analyzed. We compared 44 cases with 88 controls. Overall, 91% of episodes were caused by multidrug-resistant (MDR) strains. An endogenous source was the most frequent BSI origin (35.6%), followed by pneumonia (25.8%). There were no significant differences in patient characteristics between groups. C/T was given empirically in 11 patients and as definitive therapy in 41 patients. Treatment with C/T was associated with less need for mechanical ventilation (13.6% versus 33.3%; P = 0.021) and reduced 7-day (6.8% versus 34.1%; P = 0.001) and 30-day (22.7% versus 48.9%; P = 0.005) mortality. In the multivariate analysis, pneumonia, profound neutropenia, and persistent BSI were independent risk factors for 30-day mortality, whereas lower mortality was found among patients treated with C/T (adjusted OR [aOR] of 0.19; confidence interval [CI] 95% of 0.07 to 0.55; P = 0.002). Therapy with C/T was associated with less need for mechanical ventilation and reduced 7-day and 30-day case fatality rates compared to alternative agents in neutropenic hematologic patients with PA BSI. IMPORTANCE Ceftolozane-tazobactam (C/T) has been shown to be a safe and effective alternative for the treatment of difficult to treat infections due to Pseudomonas aeruginosa (PA) in the general nonimmunocompromised population. However, the experience of this agent in immunosuppressed neutropenic patients is very limited. Our study is unique because it is focused on extremely immunosuppressed hematological patients with neutropenia and bloodstream infection (BSI) due to PA (mainly multidrug resistant [MDR]), a scenario which is often associated with very high mortality rates. In our study, we found that the use of C/T for the treatment of MDR PA BSI in hematological neutropenic patients was significantly associated with improved outcomes, and, in addition, it was found to be an independent risk factor associated with increased survival. To date, this is the largest series involving neutropenic hematologic patients with PA BSI treated with C/T. Ceftolozane-tazobactam (C/T) has been shown to be a safe and effective alternative for the treatment of difficult to treat infections due to Pseudomonas aeruginosa (PA) in the general nonimmunocompromised population. However, the experience of this agent in immunosuppressed neutropenic patients is very limited.

Data on the long-term durability of rilpivirine (RPV) are still scarce. A two-center retrospective study was performed, including all people living with HIV (PLWH) treated with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)/RPV or tenofovir alafenamide (TAF)/FTC/RPV in the period January 2013-December 2019. Aims of the study were to assess the rate of discontinuation of the RPV single-tablet regimen (STR) and identify factors associated with the risk of discontinuation according to Cox's regression analysis. A total of 684 PLWH were enrolled. Mean duration of RPV-STR treatment was 192.5 (±99.5) weeks for 123 antiretroviral therapy (ART)-naïve participants (18%) and 173.3 (± 85.6) weeks for 561 ART-experienced study participants (82%). During the study period, the incidence of discontinuation was 7.7 per 100 person-years. The estimated proportions of discontinuation after 48 and 96 weeks were 5.6% and 13.4%, respectively. Causes of discontinuation were loss to follow-up (30%), side effects (15%), ART optimization (14%), virological failure (VF) (12%), death or transfer to another center (9%), low adherence (7%), drug interactions (6%), simplification to dual therapy (3%), and unknown (3%). No differences were observed in cumulative probability of discontinuation between ART-naïve and -experienced PLWH. Heterosexual (hazard ratio [HR] 3.0, 95% confidence interval [CI] 1.4-6.8) and mother-to-child (HR 5.3, 95% CI 1.8-15.3) transmission of HIV infection and history of previous VF (HR 1.7, 95% CI 1.2-2.5) were associated with higher risk of discontinuation. High RPV-STR effectiveness and durability were confirmed in our real-life population of PLWH. Given these data, RPV has the potential to be a drug for life in patients selected according to current guidelines.

Introduction: The role of near-infrared spectroscopy (NIRS) for the evaluation of cerebral haemodynamics is gaining increasing popularity because of its noninvasive nature. The aim of this study was to evaluate the role of the integral components of regional cerebral oxygenation (rSO2) measured by NIRS [i.e., arterial-oxyhemoglobin (O2Hbi) and venous-deoxyhemoglobin (HHbi)-components], as indirect surrogates of cerebral blood flow (CBF) in a cohort of critically ill patients with coronavirus disease 2019 (COVID-19). We compared these findings to the gold standard technique for noninvasive CBF assessment, Transcranial Doppler (TCD).Methods: Mechanically ventilated patients with COVID-19 admitted to the Intensive Care Unit (ICU) of Policlinico San Martino Hospital, Genova, Italy, who underwent multimodal neuromonitoring (including NIRS and TCD), were included. rSO2 and its components [relative changes in O2Hbi, HHbi, and total haemoglobin (cHbi)] were compared with TCD (cerebral blood flow velocity, CBFV). Changes (Δ) in CBFV and rSO2, ΔO2Hbi, ΔHHbi, and ΔcHbi after systemic arterial blood pressure (MAP) modifications induced by different manoeuvres (e.g., rescue therapies and haemodynamic manipulation) were assessed using mixed-effect linear regression analysis and repeated measures correlation coefficients. All values were normalised as percentage changes from the baseline (Δ%).Results: One hundred and four measurements from 25 patients were included. Significant effects of Δ%MAP on Δ%CBF were observed after rescue manoeuvres for CBFV, ΔcHbi, and ΔO2Hbi. The highest correlation was found between ΔCBFV and ΔΔO2Hbi (R = 0.88, p < 0.0001), and the poorest between ΔCBFV and ΔΔHHbi (R = 0.34, p = 0.002).Conclusions: ΔO2Hbi had the highest accuracy to assess CBF changes, reflecting its role as the main component for vasomotor response after changes in MAP. The use of indexes derived from the different components of rSO2 can be useful for the bedside evaluation of cerebral haemodynamics in mechanically ventilated patients with COVID-19.

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.

Serum (1,3)-beta-d-glucan (BDG) assay is a non-culture-based test recommended for the diagnosis of invasive candidiasis owing to its faster results and higher sensitivity than blood cultures. Its performance might vary for different Candida species. The aim of this study was to determine in vitro levels of BDG in Candida auris culture supernatants and evaluate BDG levels in patients with C. auris candidemia sustained by these stains.C. auris strains were collected from blood cultures of patients who had a concomitant (-24 to +72 hours) serum BDG test (Fungitell assay). Supernatants of broth media culture of C. auris strains and two Candida albicans (controls) strains were prepared and tested for BDG.Ten C auris strains were included. Supernatants of two C. albicans considered as controls had a mean BDG level of 1155 pg/mL (considered 100% reactivity). The median BDG level in supernatants of C. auris strains was 275 pg/mL (IQR 165-523 pg/mL), with a median reactivity of 24% (range 6%-72%). In vivo, the median BDG level was 129 pg/mL (IQR, 28-199 pg/mL). Sensitivity of BDG for C. auris candidemia was 60%. All patients received antifungal treatment with an echinocandin initiated a median of 2 days (IQR -8 to 0) before blood collection for BDG.Our C. auris strains released lower amounts of BDG when compared to C. albicans. Clinical implications include lower sensitivity of serum BDG for the diagnosis of C. auris candidemia with a consequent impact on management protocols in settings with high prevalence of this species.

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.

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.

Antifungal agents both in early and in late phases of clinical development showing anti-The research on antifungal agents active against

Infections caused by Enterobacterales have become more difficult to treat due to increasing antibiotic resistance, in particular, in the case of production of carbapenemases. Bacterial peritonitis is a common complication of peritoneal dialysis, being Citrobacter spp., an uncommon cause of this syndrome. We report the first case of bacterial peritonitis in continuous ambulatory peritoneal dialysis (CAPD) caused by Citrobacter werkmanii resistant to all beta-lactams, gentamicin, and cotrimoxazole, and also the new anti-gram-negative molecules ceftazidime/avibactam and ceftolozane/tazobactam. The molecular analysis of the strain demonstrated the presence of blaVIM metallo-β-lactamase gene. The patient was effectively cured with a course of systemic tigecycline, colistin, and meropenem.

Serum beta-D-glucan (BDG) determination plays an important role in the diagnosis of candidemia among critically ill patients admitted to the intensive care unit (ICU). However, BDG levels measured may be lower in the case of infections caused by some non-albicans species, such as C. parapsilosis and C. auris. The aim of this single-center study was to investigate the sensitivity of serum BDG for the diagnosis of candidemia stratified according to causative Candida species in ICU patients. This was a single-center, retrospective study, including all adult patients admitted to ICU during the period 2018–2021. All episodes of candidemia with a determination of BDG available within 3 days before or after positive blood culture were recorded. The preplanned primary objective was to investigate the sensitivity of serum BDG to detect candidemia early and the effect of different Candida species. The secondary objective was to measure serum BDG in patients with candidemia from different Candida species. In total, 146 candidemia episodes in 118 patients were analyzed. Median BDG value for C. albicans candidemia (182 pg/mL) was higher than that observed for C. parapsilosis (78 pg/mL, p = 0.015) and C. auris (48 pg/mL, p = 0.022). The overall sensitivity of BDG for the diagnosis of candidemia was low (47%, 95% CI 39–55%). In conclusion, in critically ill patients admitted to ICU, serum BDG levels for candidemia were different among species, with lower levels confirmed for C. parapsilosis and C. auris. Serum BDG sensitivity for early detection of candidemia was lower than previously reported in other ICU populations.

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.