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Skin and soft tissue infections (SSTIs) are the most common diseases caused by Staphylococcus aureus (S. aureus), which can progress to threatening conditions due to recurrences and systemic complications. Staphylococcal protein A (SpA) is an immunomodulator antigen of S. aureus, which allows bacterial evasion from the immune system by interfering with different types of immune responses to pathogen antigens. Immunization with SpA could potentially unmask the pathogen to the immune system, leading to the production of antibodies that can protect from a second encounter with S. aureus, as it occurs in skin infection recurrences. Here, we describe a study in which mice are immunized with a mutated form of SpA mixed with the Adjuvant System 01 (SpAmut/AS01) before a primary S. aureus skin infection. Although mice are not protected from the infection under these conditions, they are able to mount a broader pathogen-specific functional immune response that results in protection against systemic dissemination of bacteria following an S. aureus second infection (recurrence). We show that this “hidden effect” of SpA can be partially explained by higher functionality of induced anti-SpA antibodies, which promotes better phagocytic activity. Moreover, a broader and stronger humoral response is elicited against several S. aureus antigens that during an infection are masked by SpA activity, which could prevent S. aureus spreading from the skin through the blood.

This work focuses on a particular figure of the monster: the hermaphrodite who has been considered significant since ancient times. In Middle Ages, the hermaphrodites were executed because of their deformity. This attitude changed later on and they started to be condemned as perverts. During the XIX century, Teratology wanted to include them in a monsters’ classification but the scientists found this work very difficult because they were influenced by novelists who considered the hermaphrodite a perfection’s emblem. In this case, it’s important to underline that Balzac and Hugo wrote about “double” monsters. It means that Balzac talked about people who were both male and female, while Hugo talked about characters with both dark and sublime soul. Balzac in particular considered the androgyne perfect because he didn’t show significant differences. So, this essay wants to analyze the debates about hermaphrodite and its doubleness.

Coherent multi-transducer ultrasound (CoMTUS) imaging creates an extended effective aperture through the coherent combination of multiple arrays, which results in images with enhanced resolution, extended field-of-view, and higher sensitivity. However, this also creates a large discontinuous effective aperture that presents additional challenges for current beamforming methods. The discontinuities may increase the level of grating and side lobes and degrade contrast. Also, direct transmissions between multiple arrays, happening at certain transducer relative positions, produce undesirable cross-talk artifacts. Hence, the position of the transducers and the scan sequence play key roles in the beamforming algorithm and imaging performance of CoMTUS. This work investigates the role of the distribution of the individual arrays and the scan sequence in the imaging performance of a coherent dual-array system. First, the imaging performance for different configurations was assessed numerically using the point-spread-function, and then optimized settings were tested on a tissue mimicking phantom. Finally, a subset of the proposed optimum imaging schemes was experimentally validated on two synchronized ULA OP-256 systems equipped with identical linear arrays. Results show that CoMTUS imaging performance can be enhanced by optimizing the relative position of the arrays and the scan sequence together, and that the use of apodization can reduce cross-talk artifacts without degrading spatial resolution. Adding weighted compounding further decreases artifacts and helps to compensate for the differences in the brightness across the image. Setting the maximum steering angle according to the spatial configuration of the arrays reduces the sidelobe energy up to 10 dB plus an extra 4 dB reduction is possible when increasing the number of PWs compounded.

BackgroundThe World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear.MethodsWe obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance.ResultsA total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted.ConclusionsGenotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.).

The spread of high frame rate and 3-D imaging techniques has raised pressing requirements for ultrasound systems. In particular, the processing power and data transfer rate requirements may be so demanding to hinder the real-time (RT) implementation of such techniques. This paper first analyzes the general requirements involved in RT ultrasound systems. Then, it identifies the main bottlenecks in the receiving section of a specific RT scanner, the ULA-OP 256, which is one of the most powerful available open scanners and may therefore be assumed as a reference. This case study has evidenced that the “star” topology, used to digitally interconnect the system’s boards, may easily saturate the data transfer bandwidth, thus impacting the achievable frame/volume rates in RT. The architecture of the digital scanner was exploited to tackle the bottlenecks by enabling a new “ring“ communication topology. Experimental 2-D and 3-D high-frame-rate imaging tests were conducted to evaluate the frame rates achievable with both interconnection modalities. It is shown that the ring topology enables up to 4400 frames/s and 510 volumes/s, with mean increments of +230% (up to +620%) compared to the star topology.

One hundred and twenty-two Mycobacterium chimaera strains isolated in Italy from cardiac surgery-related patients, cardiac surgery-unrelated patients and from heater-cooler units, were submitted to whole-genome sequencing and to subsequent SNP analysis. All but one strains isolated from cardiac surgery-related patients belonged to Subgroup 1.1 (19/23) or Subgroup 1.8 (3/23). Only 28 out of 79 strains isolated from heater-cooler units belonged to groupings other than 1.1 and 1.8. The strains isolated from cardiac surgery-unrelated patients were instead distributed across the phylogenetic tree. Our data, the first on isolates from Italy, are in agreement with a recent large genomic study suggesting a common source, represented by strains belonging to Subgroups 1.1 and 1.8, of cardiac surgery-related Mycobacterium chimaera infections. The strains belonging to groupings other than 1.1 and 1.8 isolated from heather-cooler units evidently resulted from contaminations at hospital level and had no share in the Mycobacterium chimaera outbreak. One Mycobacterium chimaera strain investigated in this study proved distant from every previously known Mycobacterium chimaera Groups (1, 2, 3 and 4) and we propose to assign to a novel group, named "Group 5".

Abstract Background A substantial increase in pulmonary and extra-pulmonary diseases due to non-tuberculous mycobacteria (NTM) has been documented worldwide, especially among subjects suffering from chronic respiratory diseases and immunocompromised patients. Many questions remain regarding the epidemiology of pulmonary disease due to NTM (NTM-PD) mainly because reporting of NTM-PD to health authorities is not mandated in several countries, including Italy. This manuscript describes the protocol of the first Italian registry of adult patients with respiratory infections caused by NTM (IRENE). Methods IRENE is an observational, multicenter, prospective, cohort study enrolling consecutive adult patients with either a NTM respiratory isolate or those with NTM-PD. A total of 41 centers, including mainly pulmonary and infectious disease departments, joined the registry so far. Adult patients with all of the following are included in the registry: 1) at least one positive culture for any NTM species from any respiratory sample; 2) at least one positive culture for NTM isolated in the year prior the enrolment and/or prescribed NTM treatment in the year prior the enrolment; 3) given consent to inclusion in the study. No exclusion criteria are applied to the study. Patients are managed according to standard operating procedures implemented in each IRENE clinical center. An online case report form has been developed to collect patients’ demographics, comorbidities, microbiological, laboratory, functional, radiological, clinical, treatment and outcome data at baseline and on an annual basis. An IRENE biobank has also been developed within the network and linked to the clinical data of the registry. Conclusions IRENE has been developed to inform the clinical and scientific community on the current management of adult patients with NTM respiratory infections in Italy and acts as a national network to increase the disease’s awareness. Trial registration Clinicaltrial.gov: NCT03339063.

Abstract Photoacoustics is a hybrid modality used to image biological tissues. As optical absorption of tissues depends on the wavelength of the transmitted light, multispectral photoacoustic datasets can be obtained by changing this wavelength. This study presents a regularization method to segment multispectral photoacoustic images based on both the spatial and spectral features of the dataset pixels. The proposed processing is adapted from the spatiotemporal mean-shift approach and cluster patterns with similar spectral profiles, i.e., the variation of the received amplitude among the wavelengths, independent of their initial position. The segmentation performance of this method has been experimentally tested on multispectral photoacoustic tomographic data. We initially used a phantom that contained fresh and stale liver samples, and then a second phantom that contained two blood dilutions or a colored absorber. Experimentally, a clustering performance greater than 98% is achieved. This method makes it possible to discriminate between different media, between the same medium as fresh or stale, and between the same medium with different dilutions.

We performed a cross-border molecular epidemiology analysis of multidrug-resistant tuberculosis in Peru, Spain, and Italy. This analysis revealed frequent transmission in Peru and exportation of a strain that recreated similar levels of transmission in Europe during 2007–2017. Transnational efforts are needed to control transmission of multidrug-resistant tuberculosis globally.

Background: The possibility of inter-human transmission of Mycobacterium abscessus in cystic fibrosis centres has been recently hypothesized suggesting the need for the molecular characterization of strains isolated from such patients. Materials and Methods: One hundred and forty one isolates of M. abscessus grown from sputum samples of 29 patients with cystic fibrosis were genotyped resorting to variable number of tandem repeats (VNTR) determination and whole genome sequencing (WGS). Results: Out of 29 VNTR profiles, 15 were unique to the same number of patients while seven were shared by multiple patients. WGS showed that only two of the patients sharing common VNTR patterns were indeed infected by the same strain. The shared VNTR patterns were mostly present among the isolates of M. abscessus subsp. abscessus. Conclusion: As expected WGS showed a clearly higher discriminatory power in comparison with VNTR and appeared the only molecular epidemiology tool suitable to effectively discriminate the isolates of M. abscessus subsp. abscessus.

Purpose: This study aims to analyze the relationship between the abnormal return and R&D expenses in Brazilian public firms. Originality/value: The determinants of firms' abnormal return provide information relevant to investors' decision-making. In this context, we verified whether the innovation, measured by R&D expenses, could be a key factor for the abnormal returns in Brazilian firms. Design/methodology/approach: We analyzed Brazilian public firms, from 2009 to 2016, by panel data regressions, in a sample composed by 1,597 firm-year observations. We collected information about R&D expenses in the footnotes. When a firm only mentioned about R&D expenses but did not disclose spent value in the Income Statement, we consider that the firm did not invest in the period and we attribute zero as a value. We highlighted that few firms mentioned R&D expenses in their footnotes and/or declared that they invested in R&D, only 44 firms in all sample, pointing the importance of better disclosure practices of these investments. Findings: The results demonstrate a negative and statistically significant relationship between innovation and the abnormal return. That is, current R&D expenses lead to a lower current abnormal return. It could be linked with the fact that R&D expenses tend to produce returns just in longer periods, demanding more time to recover these investments, due to their complex characteristics related to accounting measurement of R&D expenses. Consequently, an abnormal return could be perceived only in subsequent periods. Objetivo: O estudo tem como objetivo analisar a relação entre o retorno anormal e as despesas com P&D em empresas listadas brasileiras. Originalidade/valor: Os determinantes do retorno anormal das empresas fornecem informações relevantes para a tomada de decisões dos investidores. Nesse contexto, foi analisado se a inovação, mensurada pelas despesas com P&D, pode ser um fator-chave para o retorno anormal das empresas brasileiras. Design/metodologia/abordagem: Foram analisadas as empresas brasileiras de capital aberto, de 2009 a 2016, em uma amostra composta por 1.597 observações, por meio de análise de regressão com dados em painel. As informações sobre despesas com P&D foram coletadas nas notas explicativas. Se a empresa mencionou apenas as despesas com P&D e não divulgou o valor gasto na Demonstração do Resultado do Exercício, considerou-se que a empresa não investiu no período e o valor zero foi atribuído. Destaca-se que somente 44 empresas da amostra mencionaram as despesas com P&D em suas notas explicativas e/ou declararam que investiram em P&D, sinalizando a importância de melhores práticas de divulgação desses investimentos. Resultados: Os resultados evidenciam uma relação negativa e estatisticamente significativa entre a inovação e o retorno anormal. Ou seja, um investimento corrente por meio de despesas com P&D leva a um menor retorno anormal corrente. Isso poderia estar ligado ao fato de que as despesas com P&D tendem a produzir retornos apenas em períodos mais longos, exigindo um tempo maior para recuperar esses investimentos, devido às características complexas relacionadas à mensuração contábil das despesas com P&D. Consequentemente, o retorno anormal só poderia ser percebido em períodos subsequentes.

Infections due to Mycobacterium chimaera associated with a heater-cooler device used during the open-heart surgery have been reported worldwide. These cases represent the first outbreak caused by a non-tuberculous mycobacterium at a global level. Salient features of the infection are long latency and high mortality. Different aspects of the M. chimaera outbreak, from the first detected cases to the present burden are reviewed in this study. Although the source has been found and thwarted, new cases continue to be detected due to the late manifestation of symptomatology. The treatment remains poorly effective and mortality is around 50%.

O presente artigo analisou a relação entre as práticas de divulgação de ativos biológicos e a concentração acionária nas empresas do agronegócio brasileiro. Foram analisadas as demonstrações contábeis de 27 empresas de capital aberto, para o período de 2011 a 2015. As evidências indicam que o nível de divulgação de ativos biológicos é ainda modesto nestas empresas, e que a concentração acionária típica do setor não afeta o nível de divulgação desses ativos. Os resultados confirmam estudos anteriores em relação aos efeitos do porte e da representatividade dos ativos biológicos na atividade das empresas.

Multispectral photoacoustic imaging is a powerful noninvasive medical imaging technique that provides access to functional information. In this study, a set of methods is proposed and validated, with experimental multispectral photoacoustic images used to estimate the concentration of chromophores. The unmixing techniques used in this paper consist of two steps: (1) automatic extraction of the reference spectrum of each pure chromophore; and (2) abundance calculation of each pure chromophore from the estimated reference spectra. The compared strategies bring positivity and sum-to-one constraints, from the hyperspectral remote sensing field to multispectral photoacoustic, to evaluate chromophore concentration. Particularly, the study extracts the endmembers and compares the algorithms from the hyperspectral remote sensing domain and a dedicated algorithm for segmentation of multispectral photoacoustic data to this end. First, these strategies are tested with dilution and mixing of chromophores on colored 4% agar phantom data. Then, some preliminary in vivo experiments are performed. These consist of estimations of the oxygen saturation rate (sO2) in mouse tumors. This article proposes then a proof-of-concept of the interest to bring hyperspectral remote sensing algorithms to multispectral photoacoustic imaging for the estimation of chromophore concentration.

Pulmonary infections caused by Mycobacterium abscessus (MA) have increased over recent decades, affecting individuals with underlying pathologies such as chronic obstructive pulmonary disease, bronchiectasis and, especially, cystic fibrosis. The lack of a representative and standardized model of chronic infection in mice has limited steps forward in the field of MA pulmonary infection. To overcome this challenge, we refined the method of agar beads to establish MA chronic infection in immunocompetent mice. We evaluated bacterial count, lung pathology and markers of inflammation and we performed longitudinal studies with magnetic resonance imaging (MRI) up to three months after MA infection. In this model, MA was able to establish a persistent lung infection for up to two months and with minimal systemic spread. Lung histopathological analysis revealed granulomatous inflammation around bronchi characterized by the presence of lymphocytes, aggregates of vacuolated histiocytes and a few neutrophils, mimicking the damage observed in humans. Furthermore, MA lung lesions were successfully monitored for the first time by MRI. The availability of this murine model and the introduction of the successfully longitudinal monitoring of the murine lung lesions with MRI pave the way for further investigations on the impact of MA pathogenesis and the efficacy of novel treatments.

Ultrasound vector Doppler techniques for three-dimensional (3-D) blood velocity measurements are currently limited by low temporal resolution and high computational cost. In this paper, an efficient 3-D high-frame-rate vector Doppler method, which estimates the displacements in the frequency domain, is proposed. The novel method extends to 3-D an approach so far proposed for two-dimensional (2-D) velocity measurements by approximating the (x, y, z) displacement of a small volume through the displacements estimated for the 2-D regions parallel to the y and x directions, respectively. The new method was tested by simulation and experiments for a 3.7 MHz, 256-element, 2-D piezoelectric sparse spiral array. Simulations were also performed for an equivalent 7 MHz Capacitive Micromachined Ultrasonic Transducer spiral array. The results indicate performance (bias ± standard deviation: 6.5 ± 8.0) comparable to the performance obtained by using a linear array for 2-D velocity measurements. These results are particularly encouraging when considering that sparse arrays were used, which involve a lower signal-to-noise ratio and worse beam characteristics with respect to full 2-D arrays.