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Lupus nephritis is one of the most severe manifestations of systemic lupus erythematosus, affecting roughly 40% of all lupus patients. With the introduction of cyclophosphamide and mycophenolate mofetil, outcomes have dramatically improved. However, 10% of patients still progress towards end-stage kidney disease, which carries an elevated mortality rate. In recent years, several novel agents have been approved for use or have shown preliminary evidence of efficacy in lupus nephritis. These agents include belimumab, voclosporin, and obinutuzumab, among others. Efficacy has also been demonstrated in recent trials combining older drugs. However, determining which patients would benefit the most from novel agents or combined drug regimens and whether these drugs might serve as an alternative to current remission-induction drug regimens rather than as add-on therapies remain unresolved issues. In this review, we will explore the current evidence regarding the efficacy of novel agents. [ABSTRACT FROM AUTHOR]

Early-onset systemic lupus erythematous (SLE) is a distinct clinical entity characterized by the onset of disease manifestations during childhood. Despite some similarities to patients who are diagnosed during adulthood, early-onset SLE typically displays a greater disease severity, with aggressive multiorgan involvement, lower responsiveness to classical therapies, and more frequent flares. Lupus nephritis is one of the most severe complications of SLE and represents a major risk factor for long-term morbidity and mortality, especially in children. This review focuses on the clinical and histological aspects of early-onset lupus nephritis, aiming at highlighting relevant differences with adult patients, emphasizing long-term outcomes and discussing the management of long-term complications. We also discuss monogenic lupus, a spectrum of conditions caused by single gene variants affecting the complement cascade, extracellular and intracellular nucleic acid sensing and processing, and occasionally other metabolic pathways. These monogenic forms typically develop early in life and often have clinical manifestations that resemble sporadic SLE, whereas their response to standard treatments is poor. [ABSTRACT FROM AUTHOR]

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgAN causes end-stage kidney disease (ESKD) in 30–40% of all cases. The activation of the complement system by pathological circulating IgAs, which is often associated with low serum C3 levels (LowC3), seems to play a crucial role. Previous studies have shown an association between histological evidence of TMA, which is the result of alternative complement activation, and poor outcomes. However, it is not known to what extent the decrease in serum C3 levels reflects ongoing TMA injury. Our study aimed at assessing the association between LowC3 and ESKD and whether this association reflects ongoing TMA. Methods: We enrolled all patients with biopsy-proven IgAN and followed-up patients until their last visit, ESKD, or death. Results: Of the 56 patients included in the study, 12 (21%) presented low serum C3 (LowC3) at the time of renal biopsy. TMA was significantly more frequent in the LowC3 group [7/12 (58%) vs. 9/44 (20%), p = 0.02]. After adjusting for potential confounders, LowC3 was strongly associated with an increased hazard of ESKD (hazard ratio [HR]: 5.84 [95%CI: 1.69, 20.15; p = 0.005). The association was not affected by adjusting for TMA. The estimated overall proportion of the relation between C3 and ESKD mediated by TMA was low and not statistically significant. Conclusions: Our study provides evidence that C3 hypocomplementemia is associated with an increased risk of ESKD through mechanisms that are largely independent from TMA. [ABSTRACT FROM AUTHOR]

Technological development in terms of the power requirement for data acquisition and processing opens new perspectives in the field of environmental monitoring. Near real-time data flow about the sea condition and a possible direct interface with applications and services devoted to marine weather networks would have a significant impact on several aspects, such as, for example, safety and efficiency. In this scenario, the needs of buoy networks have been analyzed, and the estimation of directional wave spectra from buoys' data has been deeply investigated. Two methods have been implemented, namely the truncated Fourier series and the weighted truncated Fourier series, and they have been tested by both simulated and real experimental data, representative of typical Mediterranean Sea conditions. From simulation, the second method proved to be more efficient. From the application to real case studies, it emerged that it works effectively in real conditions, as confirmed by parallel meteorological observations. The estimation of the main propagation direction was possible with a small uncertainty of a few degrees, yet the method exhibits a limited directional resolution, which suggests the need for undertaking further studies, briefly addressed in the conclusions. [ABSTRACT FROM AUTHOR]

Prosociality and cooperation are key to what makes us human. But different cultural norms can shape our evolved capacities for interaction, leading to differences in social relations. How people share resources has been found to vary across cultures, particularly when stakes are high and when interactions are anonymous. Here we examine prosocial behavior among familiars (both kin and non-kin) in eight cultures on five continents, using video recordings of spontaneous requests for immediate, low-cost assistance (e.g., to pass a utensil). We find that, at the smallest scale of human interaction, prosocial behavior follows cross-culturally shared principles: requests for assistance are very frequent and mostly successful; and when people decline to give help, they normally give a reason. Although there are differences in the rates at which such requests are ignored, or require verbal acceptance, cultural variation is limited, pointing to a common foundation for everyday cooperation around the world. [ABSTRACT FROM AUTHOR]

Dynamic compensation is the (partial) correction of the measurement signals for the effects due to bandwidth limitations of measurement systems and constitutes a research topic in dynamic measurement. The dynamic compensation of an accelerometer is here considered, as obtained by a method that directly comes from a general probabilistic model of the measurement process. Although the application of the method is simple, the analytical development of the corresponding compensation filter is quite complex and had been previously developed only for first-order systems, whilst here a second-order system is considered, thus moving from a scalar to a vector problem. The effectiveness of the method has been tested both through simulation and by a dedicated experiment. Both tests have shown the capability of the method of significantly improve the performance of the measurement system when dynamic effects are more prevalent than additive observation noise. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS) is an autosomal dominant inherited disorder that primarily predisposes individuals to colorectal and endometrial cancer. It is associated with pathogenic variants in DNA mismatch repair (MMR) genes. In this study, we report the case of a 16-year-old boy who developed a precancerous colonic lesion and had a clinical suspicion of LS. The proband was found to have a somatic MSI-H status. Analysis of the coding sequences and flanking introns of the MLH1 and MSH2 genes by Sanger sequencing led to the identification of the variant of uncertain significance, namely, c.589-9_589-6delGTTT in the MLH1 gene. Further investigation revealed that this variant was likely pathogenetic. Subsequent next-generation sequencing panel analysis revealed the presence of two variants of uncertain significance in the ATM gene. We conclude that the phenotype of our index case is likely the result of a synergistic effect of these identified variants. Future studies will allow us to understand how risk alleles in different colorectal-cancer-prone genes interact with each other to increase an individual's risk of developing cancer. [ABSTRACT FROM AUTHOR]

In everyday interactions with one another, speakers not only say things but also do things like offer, complain, reject, and compliment. Through observation, it is possible to see that much of the time people unproblematically understand what others are doing. Research on conversation has further documented how speakers' word choice, prosody, grammar, and gesture all help others to recognize what actions they are performing. In this study, we rely on spontaneous naturally occurring conversational data where people have trouble making their actions understood to examine what leads to ambiguous actions, bringing together prior research and identifying recurrent types of ambiguity that hinge on different dimensions of social action. We then discuss the range of costs and benefits for social actors when actions are clear versus ambiguous. Finally, we offer a conceptual model of how, at a microlevel, action ascription is done. Actions in interaction are building blocks for social relations; at each turn, an action can strengthen or strain the bond between two individuals. Thus, a unified theory of action ascription at a microlevel is an essential component for broader theories of social action and of how social actions produce, maintain, and revise the social world. [ABSTRACT FROM AUTHOR]

Rules of behavior are fundamental to human sociality. Whether on the road, at the dinner table, or during a game, people monitor one another's behavior for conformity to rules and may take action to rectify violations. In this study, we examine two ways in which rules are enforced during games: instructions and reminders. Building on prior research, we identify instructions as actions produced to rectify violations based on another's lack of knowledge of the relevant rule; knowledge that the instruction is designed to impart. In contrast to this, the actions we refer to as reminders are designed to enforce rules presupposing the transgressor's competence and treating the violation as the result of forgetfulness or oversight. We show that instructing and reminding actions differ in turn design, sequential development, the epistemic stances taken by transgressors and enforcers, and in how the action affects the progressivity of the interaction. Data are in German and Italian from the Parallel European Corpus of Informal Interaction (PECII). [ABSTRACT FROM AUTHOR]

Severe respiratory syncytial virus (RSV) infection in infancy is associated with increased risk of recurrent wheezing in childhood. Both acute and long‐term alterations in airway functions are thought to be related to inefficient antiviral immune response. The airway epithelium, the first target of RSV, normally acts as an immunological barrier able to elicit an effective immune reaction but may also be programmed to directly promote a Th2 response, independently from Th2 lymphocyte involvement. Recognition of RSV transcripts and viral replication intermediates by bronchial epithelial cells brings about release of TSLP, IL‐33, HMGB1, and IL‐25, dubbed "alarmins." These epithelial cell‐derived proteins are particularly effective in stimulating innate lymphoid cells 2 (ILC2) to release IL‐4, IL‐5, and IL‐13. ILC2, reflect the innate counterparts of Th2 cells and, when activate, are potent promoters of airway inflammation and hyperresponsiveness in RSV bronchiolitis and childhood wheezing/asthma. Long‐term epithelial progenitors or persistent epigenetic modifications of the airway epithelium following RSV infection may play a pathogenetic role in the short‐ and long‐term increased susceptibility to obstructive lung diseases in response to RSV in the young. Additionally, ILC2 function may be further regulated by RSV‐induced changes in gut microbiota community composition that can be associated with disease severity in infants. A better understanding of the alarmin‐ILC interactions in childhood might provide insights into the mechanisms characterizing these immune‐mediated diseases and indicate new targets for prevention and therapeutic interventions. [ABSTRACT FROM AUTHOR]

To determine whether bond strength to eroded dentin is similar to values found for sound dentin, before and after additional treatments. MeSH terms and keywords relative to the topics 'adhesion to dentin' and 'eroded dentin' were searched in the Pubmed and the Scopus databases. In vitro studies that compared the bond strength to sound and eroded dentin were selected. The following data were included: pH-cycling model, materials, treatments, bond strength tests, and failure modes. Bond strength values were compared by meta-analyses and the failure modes were analyzed for random effects. The bond strength data of the 23 studies included were extracted by the reviewers and assessed by meta-analyses. Low risk of bias was found most frequently. Sound × Eroded Dentin comparisons revealed higher bond strength to sound dentin. When compared with untreated eroded dentin, treatments such as NaOCl, E64, CHX and PAA acid, PPA and RI primer, showed high and durable bond strength values (p˂0.0001). Mixed failures were the most frequent type (39.26%), followed by adhesive (38.21%) and cohesive failures (6.15%). The bond strength to eroded dentin can be improved by mechanical and chemical strategies, applied before or during the adhesive protocol. Eroded teeth, an increasingly frequent clinical condition found, require restorations with adhesive protocols that result in favorable and durable bond strength over time. [ABSTRACT FROM AUTHOR]

Primary effusion lymphoma (PEL) is a large B-cell lymphoma growing within bodycavities caused by the Kaposi sarcoma-associated herpesvirus (KSHV)/human herpesvirus-8 (KSHV/HHV-8). It is mainly reported in HIV-infected patients. The uncommon occurrence in the elderly supports a form paralleling classic Kaposi sarcoma (KS), i.e. classic PEL, whose characteristics are relatively underexplored. To better understand the diagnostic modalities and clinical-epidemiological features of classic PEL, articles reporting cases of PEL were identified through MEDLINE/EMBASE databases (January 1998-July 2020) and screened according to PRISMA guidelines to extract individual-level data. A comparison was also performed between classic PEL and classic KS to evaluate similarities and differences. We identified 105 subjects (median age 77 years; 86% males), mainly from Mediterranean countries (52%, first Italy) and Eastern Europe (7%). Common comorbidities were heart failure (32%), cirrhosis (16%), and malignancy (20%) including lymphoid neoplasms. Pleural cavity was the commonest site (67%). PEL diagnosis was based on cytomorphology (89%), evidence of KSHV/HHV-8 infection (94%), EBV co-infection (28%) and clonality of IGH (59%), IGK (14%), TRG (9%) alone or in multiple combinations. Compared to KS, age (P<.001), gender-ratio (P=.08) and mortality (P<.001) were significantly higher in PEL, whereas the frequency of PEL as a second primary was similar (P=.44). This is the first systematic review of classic PEL case reports highlighting heterogeneity and lack of a uniform multidisciplinary approach at diagnosis, in the absence of specific guidelines as it happens for rare cancers. It is conceivable that classic PEL is still underdiagnosed in Mediterranean countries wherein KSHV/HHV-8 is endemic. [ABSTRACT FROM AUTHOR]

The Water Framework Directive 2000/60/EC (WFD) requires Member States of the European Union (EU) to use a pool of bioindicators, that is, Biological Quality Elements (BQEs), including fish species and each Member State shall, in fact, certify the compliance with the ecological quality goals of the WFD. The New Italian Index of the Ecological State of Fish Communities (NISECI) is the WFD-compliant index for the analysis of the fish species BQE in Italian river water bodies, both wadable and non-wadable, that are not (using WFD definitions) heavily modified or artificial. The WFD requires each index to relate the conditions found in the field to reference conditions corresponding to the absence of anthropogenic alterations or to minor anthropogenic alterations. The present study defines the logical basis on the model of refinement for the reference conditions of the metrics and submetrics of NISECI relating to the biological condition of indigenous and non-indigenous species. The model was tested on an empirical basis using data from 284 ichthyological samplings taken from river basins throughout Italy. In order to clean random errors and stochastic noise due to possible different sampling methods, the data was only collected using protocols that guarantee adequately homogeneous and reliable data of abundance (overall and by size). The developed approach provided comparable and homogeneous results throughout Italian watersheds; this allowed a standardized and robust refinement of the threshold values of the demographic parameters of NISECI. The procedure used, consistent with the spatially based reference condition and expert judgement reference condition approaches envisaged by the WFD, improves the analytical performance of the NISECI by increasing its power of resolution and is applicable in every Italian zoogeographic and ecological context. [ABSTRACT FROM AUTHOR]

Idiopathic retroperitoneal fibrosis (IRF) is a rare condition characterized by the development of a peri-aortic and peri-iliac tissue showing chronic inflammatory infiltrates and pronounced fibrosis. Ureteral entrapment with consequent obstructive uropathy is one of the most common complications of IRF, which can lead to acute renal failure and, in the long term, to varying degrees of chronic kidney disease. IRF may be isolated or develop in association with autoimmune diseases (e.g. Hashimoto's thyroiditis and psoriasis) and other fibro-inflammatory disorders (often within the spectrum of immunoglobulin G4-related disease), which suggests that it should be considered as a potentially systemic condition. IRF is an immune-mediated disease: genetic variants (e.g. human leukocyte antigen (HLA)-DRB1*03) and environmental agents (mainly exposure to asbestos and smoking) are strongly associated with an increased risk of developing the disease, while a complex network of chemokines (e.g. CXCL12 and C-C moti chemokine 11 (CCL11)) and cytokines [e.g. interleukin (IL)-6, IL-12 and IL-13] is likely to orchestrate the inflammatory response and simultaneously promote fibrosis. Glucocorticoids, alone or in combination with traditional immunosuppressants such as methotrexate and mycophenolate mofetil, are usually efficacious and promptly induce disease remission; however, up to 50% of patients relapse, thus requiring repeat immunosuppressive courses. Biologic drugs, namely rituximab, are being explored for the treatment of IRF. In addition to medical therapies, interventional procedures (mainly ureteral stenting) are required to relieve ureteral obstruction, whereas surgical ureterolysis is generally reserved to refractory cases. If appropriately treated, then the overall and renal prognosis of IRF are good, with <5% patients developing end-stage renal disease. [ABSTRACT FROM AUTHOR]

The immunopathology of respiratory syncytial virus (RSV) infection varies considerably, severe disease occurring only in a minority of the affected children. The variability of the clinical presentation is in part explained by viral and environmental factors but, in infants and young children, disease severity is certainly linked to the physiologic immaturity of the innate and adaptive immune system. There is evidence that the maturation of the host immune response is positively influenced by the composition of the nasopharyngeal microbiome that, promoting an efficient reaction, can counteract the predisposition to develop viral respiratory infections and lower the risk of disease severity. However, interaction between the nasopharyngeal microbiota and respiratory viruses can be bidirectional since microbial dysbiosis may also represent a reflection of the disease‐induced alterations of the local milieu. Moreover, viruses like RSV can also increase the virulence of potential pathogens in nasopharynx, a main reservoir of bacteria, and therefore promote their spread to the lower airways causing superinfection. Moreover, if negative changes in microbial community composition in early life may constitute a heightened risk toward severe RSV respiratory infection, on the contrary specific groups of microorganisms seem to be associated with protection. A better understanding into the potential negative and positive role of the different nasopharyngeal bacterial species on RSV infection may improve primary prevention and possibly care of this highly contagious disorder. [ABSTRACT FROM AUTHOR]

An important task in biomechanics is human body articulations’ internal torques measurement. This is known as a kinetic or inverse-dynamics problem. Its solution requires a combination of kinematic and dynamic measurements with a biomechanical model, involving subject-related anthropometric parameters. The uncertainty-evaluation thereof is here considered. The method poses on a probabilistic model of the associated measurement system, according to the “Guide to the expression of uncertainty in measurement” general principles. We consider a comprehensive set of influence quantities, including markers’ misplacement or parasite movements. The anthropometric parameters’ uncertainty is discussed in detail. The proposed approach helps to identify the most influential experimental factors. [ABSTRACT FROM AUTHOR]

Dentin erosion is a frequent clinical condition that requires restorative interventions, especially in cases with moderate to severe wear. This requires clinicians to have knowledge about the characteristics of dentin, etiological factors involved, and restorative approaches to be made. Minimally invasive restorations have been indicated for rehabilitation of these cases, in order to preserve the largest possible amount of dental tissue. To achieve this, effective and durable adhesion to the eroded dentin must be obtained. However, the histological and morphological changes resulting from the erosive challenge have make eroded dentin a much more challenging substrate to treat than sound dentin. In order to minimize these limitations, mechanical and chemical strategies, as well as changes in the adhesive protocol, have been reported in the literature. The purpose of this review was to present these limitations and discuss the effectiveness of the strategies suggested, based on the results of bond strength to eroded dentin. [ABSTRACT FROM AUTHOR]

This article is concerned with how social categories (e.g., wife, mother, sister, tenant, guest) become visible through the actions that individuals perform in social interaction. Using audio and video recordings of social interaction as data and conversation analysis as a method, we examine how individuals display their rights or constraints to perform certain actions by virtue of occupying a certain social category. We refer to actions whose performance is sensitive to membership in a certain social category as category-sensitive actions. Most of the time, the social boundaries surrounding these actions remain invisible because participants in interaction typically act in ways that are consistent with their social status and roles. In this study, however, we specifically examine instances where category boundaries become visible as participants approach, expose, or transgress them. Our focus is on actions with relatively stringent category sensitivity such as requests, offers, invitations, or handling one's possessions. Ultimately, we believe these are the tip of an iceberg that potentially includes most, if not all, actions. [ABSTRACT FROM AUTHOR]

As part of the project reported on in this special issue, the present study provides an overview of the types of action accomplished by other-repetition in Italian, with particular reference to the variety of the language spoken in the northeastern province of Trento. The analysis surveys actions within the domain of initiating repair, actions that extend beyond initiating repair, and actions that are alternative to initiating repair. Pitch contour emerges as a central design feature of other-repetition in Italian, with six nuclear contours associated with distinct types of action, sequential trajectories, and response patterns. The study also documents the interplay of pitch contour with other prosodic features (pitch span and register) and visible behavior (head nods, eyebrow movements). (Repetition, conversation, prosody, intonation, action, Italian) [ABSTRACT FROM AUTHOR]

In this article, I introduce the aims and scope of a project examining other-repetition in natural conversation. This introduction provides the conceptual and methodological background for the five language-specific studies contained in this special issue, focussing on other-repetition in English, Finnish, French, Italian, and Swedish. Other-repetition is a recurrent conversational phenomenon in which a speaker repeats all or part of what another speaker has just said, typically in the next turn. Our project focusses particularly on other-repetitions that problematise what is being repeated and typically solicit a response. Previous research has shown that such repetitions can accomplish a range of conversational actions. But how do speakers of different languages distinguish these actions? In addressing this question, we put at centre stage the resources of prosody—the nonlexical acoustic-auditory features of speech—and bring its systematic analysis into the growing field of pragmatic typology—the comparative study of language use and conversational structure. (Repetition, conversation, prosody, pragmatics, typology) [ABSTRACT FROM AUTHOR]

This study explores the link between prosody and other-repetition in a moderately large collection from everyday English talk-in-interaction (n = 200). British English and North American English cases were analysed separately in order to track possible varietal differences. Of initial interest was the question whether focal pitch accents might disambiguate among other-repetition actions, both those related to repair and those that go beyond repair. The results indicate that only two out of six possible other-repetition actions are associated with distinct focal pitch contours in the two varieties. For all other repair and beyond-repair actions speakers use many of the same pitch contours nondistinctively. Overall, falling contours appear more frequently in British other-repetitions, while rising contours are more frequent in North American other-repetitions. In conclusion, it is argued that in addition to pitch contour, prosodic features such as pitch span, loudness, and timing are crucial in distinguishing other-repetition actions, as are nonprosodic factors such as epistemic access (often reflected in oh-prefacing) and visible behavior. (Repair initiation, surprise, challenge, registering, pitch accents, oh-preface, epistemics) [ABSTRACT FROM AUTHOR]

This study contributes to the body of cross-linguistic research on repetition, repair, and action-formation more generally. Using conversation-analytic and interactional-linguistic methods to analyse both position and composition in the formation of actions accomplished by other-repetitions in French, the study underscores the interplay between linguistic design, sequential organisation, and territories of knowledge and accountability in interaction. The actions conveyed by other-repetitions, and the responses made relevant, are affected by both (i) the design of the repetition turn itself—involving various features of prosody (e.g. intonation contour type and pitch span), grammar, and lexis—and (ii) the sequential location of the repetition, including the particulars of the talk that gets repeated and the relevancies set up by that previous talk. The study concludes with a discussion of its significance for research on action-formation as well as for research on the pragmatics of intonation. (Repair-initiation, surprise, acceptability, registering, intonation, epistemics, agency) [ABSTRACT FROM AUTHOR]

Severe and recurrent infections of the respiratory tract in early childhood constitute major risk factors for the development of bronchial hyper-responsiveness and obstructive respiratory diseases in later life. In the first years of life, the vast majority of respiratory tract infections (RTI) leading to wheezing and asthma are of a viral origin and severity and recurrence are the consequence of a greater exposure to infectious agents in a period when the immune system is still relatively immature. Therefore, boosting the efficiency of the host immune response against viral infections seems to be a rational preventative approach. In the last decades it has been demonstrated that living in farm environments, i.e. early-life exposure to microbes, may reduce the risk of allergic and infectious disorders, increasing the immune response efficacy. These findings have suggested that treatment with bacterial lysates could promote a nonspecific immunomodulation useful in the prevention of recurrent RTIs and of wheezing inception and persistence. Experimental and clinical studies showing the reduction of RTI frequency and severity in childhood and elucidating the involved mechanisms can support this hypothesis. [ABSTRACT FROM AUTHOR]

Expressions of politeness such as please are prominent elements of interactional conduct that are explicitly targeted in early socialization and are subject to cultural expectations around socially desirable behavior. Yet their specific interactional functions remain poorly understood. Using conversation analysis supplemented with systematic coding, this study investigates when and where interactants use please in everyday requests. We find that please is rare, occurring in only 7 percent of request attempts. Interactants use please to manage face-threats when a request is ill fitted to its immediate interactional context. Within this, we identify two environments in which please prototypically occurs. First, please is used when the requestee has demonstrated unwillingness to comply. Second, please is used when the request is intrusive due to its incompatibility with the requestee’s engagement in a competing action trajectory. Our findings advance research on politeness and extend Goffman’s theory of face-work, with particular salience for scholarship on request behavior. [ABSTRACT FROM AUTHOR]

A general probabilistic model of the measurement process is discussed, showing how it can address both static and dynamic measurements. Emphasis is placed on the latter, and two main kinds of dynamic measurements are considered: direct, where the goal is to monitor a phenomenon over time, and indirect, where an alternative representation is sought, such as, typically, the spectrum. It is shown that both cases can be treated in the same framework, through a proper interpretation of the variables involved. Then, direct measurements are investigated in greater detail, and the application of this approach is discussed, in the case of a Markovian model with a uniform prior for the measurand, and an illustrative numerical example is presented. These results may pave the way to a better harmonization of measurements, grounded on a sound scientific foundation. [ABSTRACT FROM AUTHOR]

The use of immune checkpoint inhibitors (ICIs) in cancer patients is rapidly growing. However, the potential impact of some widely used concomitant medications is still largely unclear. Emerging data suggest that gut microbiota may affect the efficacy of ICIs, leading to the hypothesis that concurrent antibiotics and proton pump inhibitors use could have a detrimental effect. In addition, steroid use might potentially impair the activity of immunotherapy, due its known immunosuppressive effects, and some safety concerns have been raised in patients receiving commonly used vaccination during ICIs. However, all randomized trials evaluating ICIs consistently excluded patients receiving high corticosteroid doses and data regarding other concomitant medications are lacking. Recently, several retrospective studies have tried to address this unmet medical need. Herein we discuss the latest evidence on the influence of these medications, critically analyzing the data reported so far and the possible implications in our clinical practice. [ABSTRACT FROM AUTHOR]

A deep revision of the guide to the expression of uncertainty in measurement (GUM) is proposed, that will maintain the same original goals and principles but differ from the current version by providing greater support for users to implement those principles. This new approach may overcome some of the setbacks that have been encountered over the years in the application of the GUM, thus making the practice of evaluating measurement uncertainty more widespread. [ABSTRACT FROM AUTHOR]

When taking a turn at talk, a speaker normally accomplishes a sequential action such as a question, answer, complaint, or request. Sometimes, however, a turn at talk may accomplish not a single but a composite action, involving a combination of more than one action. I show that factual declaratives (e.g., “the feed drip has finished”) are recurrently used to implement composite actions consisting of both an informing and a request or, alternatively, a criticism and a request. A key determinant between these is the recipient’s epistemic access to what the speaker is describing. Factual declaratives afford a range of possible responses, which can tell us how the composite action has been understood and give us insights into its underlying structure. Evidence for the stacking of composite actions, however, is not always directly available in the response and may need to be pieced together with the help of other linguistic and contextual considerations. Data are in Italian with English translation. [ABSTRACT FROM AUTHOR]

Purpose: Pembrolizumab-based regimens are conditioned by the expression of PD-L1, but durable response rate is limited by innate and acquired resistance mechanisms. Here, we focus on osteopontin (OPN), an upfront biomarker of senescence, which closely associated with natural history of non-small cell lung cancer (NSCLC). Methods: Seventy-nine patients eligible to pembrolizumab regimens—alone or in combination with chemotherapy—as first-line treatment of advanced NSCLC were enrolled. Predictive value of OPN toward iRECIST progression disease (PD) was set as first outcome. Secondary ones included performance status (ECOG) at baseline, early (first and best) responses, and overall survival (OS). Results: High Serum OPN characterized patients with worse ECOG-PS (p = 0.015) at baseline and subjects experienced PD/death at first (OR 1.17 [1.02 to 1.35]; p = 0.030) and best responses (0.04 [0.00 to 0.81]; p = 0.035). OPN was associated with time-to-progression (B -2.74 [−4.46 to −1.01]) and time-to death (−0.13 [−0.20 to −0.05]). Cox regression models unveil a predictive value for iRECIST-PD (HR 1.01 [1.00 to 1.02]; p = −0.005), RECIST-PD (HR 1.01 [1.00 to 1.02]; p = 0.017), and OS (HR 1.02 [1.01 to 1.03]; p = 0.001). These models were internally validated through bootstrap resampling and characterized by relevant discrimination ability at ROC curve analyses. Conclusion: Baseline levels of serum OPN is closely associated with performance status and short/long term outcomes in patients with advanced NSCLC, which are candidate to pembrolizumab-based regimens. As upfront biomarker of senescence, OPN may pave the way for future studies focusing on senescence patterns in NSCLC. [ABSTRACT FROM AUTHOR]

Measurement aims at obtaining a numerical description of objects/events/persons in the real world by means of a measuring system. Measurement is widely used as a key way for obtaining high quality information from the real world, across disciplines. In the present day, there is growing consensus in holding that measurement is characterized by the use of something that qualifies as a “measuring system”. Therefore, we discuss sufficient conditions for an empirical system to qualify as a measuring system and we present a formal model of the measuring system, in terms of empirical relations among objects to be measured and the measuring device. The theory applies to all the main structures of metrological interest – order, difference, intensive and extensive, and we hope that this may help to fill a gap in these studies. We also briefly address practical applications of the theory, including calibration, modelling of measuring devices and performance statement. [ABSTRACT FROM AUTHOR]

Objective Atypical manifestations have been described in patients with ANCA-associated vasculitides (AAV), such as pachymeningitis, orbital mass or chronic periaortitis. Because these manifestations have been associated to the spectrum of IgG4-related disease (IgG4-RD), we hypothesized that both diseases could overlap. Methods We conducted a European retrospective multicenter observational study including patients fulfilling ACR and Chapel Hill criteria for AAV and IgG4-RD Comprehensive Diagnostic Criteria. Results Eighteen patients were included (median age 55.5 years, 13 men). AAV and IgG4-RD were diagnosed concomitantly in 13/18 (72%) patients; AAV preceded IgG4-RD in 3/18 (17%) while IgG4-RD preceded AAV in 2/18 (11%). AAV diagnoses included granulomatosis with polyangiitis in 14 (78%), microscopic polyangiitis in 3 (17%), and eosinophilic granulomatosis with polyangiitis in one case. IgG4-RD diagnosis included definite IgG4-RD in 5 (28%) cases, probable IgG4-RD in 5 (28%) and possible IgG4-RD in 8 (44%). IgG4-RD manifestations were chronic periaortitis in 9/18 (50%) patients, orbital mass and tubulointerstitial nephritis in 4 (22%) cases, prevertebral fibrosis in 3 (17%), pachymeningitis and autoimmune pancreatitis in 2 (11%) cases. Patients required median number of 2 (range 0–4) lines of immunosuppressants in combination with glucocorticoids. During the follow-up (median 49,8 months, range 17,25–108 months), AAV manifestations relapsed in 10/18 (56%) cases and IgG4-RD lesions in 5/18 (28%). When used, mainly for relapses, rituximab showed response in all cases. Conclusion AAV and IgG4-RD may overlap. Clinicians should consider that atypical manifestations during AAV could be related to IgG4-RD rather than to refractory granulomatous or vasculitic lesions. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus ( RSV) is the most common agent of severe airway disease in infants and young children. Large epidemiologic studies have demonstrated a clear relationship between RSV infection and subsequent recurrent wheezing and asthma into childhood, thought to be predominantly related to long-term changes in neuroimmune control of airway tone rather than to allergic sensitization. These changes appear to be governed by the severity of the first RSV infection in infancy which in term depends on viral characteristics and load, but perhaps as importantly, on the genetic susceptibility and on the constitutional characteristic of the host. A variety of viral and host factors and their interplay modify the efficiency of the response to infection, including viral replication and the magnitude of structural and functional damage to the respiratory structures, and ultimately the extent, severity, and duration of subsequent wheezing. [ABSTRACT FROM AUTHOR]

People often begin stories in conversation by referring to person, time, and place. We study story beginnings in three societies and find place reference is recurrently used to (i) set the stage, foreshadowing the type of story and the kind of response due, and to (ii) make the story cohere, anchoring elements of the developing story. Recipients orient to these interactional affordances of place reference by responding in ways that attend to the relevance of place for the story and by requesting clarification when references are incongruent or noticeably absent. The findings are based on 108 story beginnings in three unrelated languages: Cha'palaa, a Barbacoan language of Ecuador; Northern Italian, a Romance language of Italy; and Siwu, a Kwa language of Ghana. The commonalities suggest we have identified generic affordances of place reference, and that storytelling in conversation offers a robust sequential environment for systematic comparative research. (Storytelling, place, narrative, conversation analysis, interactional linguistics)* [ABSTRACT FROM PUBLISHER]

• Importance of indirect measurement in engineering, biomechanics, meteorology and social sciences. • A model for indirect measurement with the same structure of that for direct measurement. • A common theoretical and epistemological foundation for direct and indirect measurements. • An evolutionary vision enabling a parallel development of disciplines and related measurements. The search for a general model/theory for measurement is a hot topic in the current debate in measurement science. A relevant point, in this context, is to consider whether direct and indirect measurement require different models or can be reduced to a common basis. It is here suggested that a common framework can be developed, although its implementation involves significant differences, especially in term of complexity, especially in regard of calibration. Therefore, in this perspective, direct and indirect measurement share a common foundation. Furthermore, an evolutionary perspective is here adopted, where the development of measurement is not subordinate to that of the related discipline, but it may rather proceed in parallel with the evolution of the discipline and even support and stimulate such evolution. [ABSTRACT FROM AUTHOR]

The frequency and function of regulatory T-cells (Tregs) in multiple myeloma (MM) are still matter of debate. The percentage and absolute number of circulating Tregs (CD4(+)CD25(+high  density)CD127(-/low  density)) from 39 patients with untreated MM and 44 patients with monoclonal gammopathies of uncertain significance (MGUS) were tested and compared with 20 healthy subjects as controls. The mean percentage number of circulating Tregs was 2.1%  ± 1.0 (range 0.75-6.1%) in MM patients; 2.1%  ± 0.9 (range 0.3-4.4%) in MGUS; and 1.5%  ± 0.4 (range 0.9-2.1%) in controls (p ns). Mean absolute number of Tregs was 36.3/μL ± 23.7 (range 6.7-149/μL) in MM; 38.8/μL ± 19.1 (range 4.3-87/μL) in MGUS; and 39.4/μL ± 12.5 (range 18-63/μL) in controls (p ns). After a median follow-up of 38 months, 5 MGUS and 2 smoldering MM (SMM) transformed into overt MM; however Tregs number did not predict this evolution. With respect to MM patients and after a median follow-up of 33 months, Tregs did not show any significant correlation with main clinical and laboratory characteristics. Finally, from a functional point of view, Tregs displayed an effective suppressor function, irrespective of disease status. This study indicates that the number of circulating Tregs does not differ in different monoclonal gammopathies and normal subjects and do not correlate with clinical features of MM. [ABSTRACT FROM AUTHOR]

Non-traumatic acute thoracic aortic syndromes (AAS) describe a spectrum of life-threatening aortic pathologies with significant implications on diagnosis, therapy and management. There is a common pathway for the various manifestations of AAS that eventually leads to a breakdown of the aortic intima and media. Improvements in biology and health policy and diffusion of technology into the community resulted in an associated decrease in mortality and morbidity related to aortic therapeutic interventions. Hybrid procedures, branched and fenestrated endografts, and percutaneous aortic valves have emerged as potent and viable alternatives to traditional surgeries. In this context, current state-of-the art multidetector CT (MDCT) is actually the gold standard in the emergency setting because of its intrinsic diagnostic value. Management of acute aortic disease has changed with the increasing realization that endovascular therapies may offer distinct advantages in these situations. This article provides a summary of AAS, focusing especially on the MDCT technique, typical and atypical findings and common pitfalls of AAS, as well as recent concepts regarding the subtypes of AAS, consisting of aortic dissection, intramural haematoma, penetrating atherosclerotic ulcer and unstable aortic aneurysm or contained aortic rupture. MDCT findings will be related to pathophysiology, timing and management options to achieve a definite and timely diagnostic and therapeutic definition. In the present article, we review the aetiology, pathophysiology, clinical presentation, outcomes and therapeutic approaches to acute aortic syndromes. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) has been historically considered a homogeneous disease and thus approached as a single entity when it comes to clinical studies design and new treatments developments. However, increasing knowledge in the genetic and molecular landscape of this disease challenges this concept, opening the possibility that different subtypes might show differential vulnerability to treatments. In this narrative review, we gather the most relevant advances in genetic and molecular characterization of SCLC, focusing on how these discoveries may be used to design the path for a personalized treatment approach. Indeed, we discuss the new classification based on differential protein expression, the prevalence and significance of oncogenic drivers (e.g., EGFR mutations and ALK rearrangements) in SCLC, the genetic characteristics of SCLC in patients with no smoking history, and the existing evidence supporting the use of liquid biopsy for capturing the heterogeneity of the disease. We use the keywords "small cell lung cancer", "SCLC", "EGFR", "ALK", "histological transformation", and "transcriptional factors" to identify original research manuscripts, clinical trials, case reports, and case series from PubMed. [ABSTRACT FROM AUTHOR]

A first order probabilistic logic is developed and presented in both intuitive and formal terms. It is shown how it can be successfully applied to the development of probabilistic representations for the main structures and scales involved in (one-dimensional) measurement. As a part of the current debate on the nature of probability in measurement, this result provides a way for overcoming the traditional opposition between Bayesian and orthodox statistics. [ABSTRACT FROM AUTHOR]

In their analysis of methods that participants use to manage the realization of practical courses of action, Kendrick and Drew (2016/this issue) focus on cases of assistance, where the need to be addressed is Self's, and Other lends a helping hand. In our commentary, we point to other forms of cooperative engagement that are ubiquitously recruited in interaction. Imperative requests characteristically expect compliance on the grounds of Other's already established commitment to a wider and shared course of actions. Established commitments can also provide the engine behind recruitment sequences that proceed nonverbally. And forms of cooperative engagement that are well glossed as assistance can nevertheless be demonstrably oriented to established commitments. In sum, we find commitment to shared courses of action to be an important element in the design and progression of certain recruitment sequences, where the involvement of Other is best defined as contribution. The commentary highlights the importance of interdependent orientations in the organization of cooperation. Data are in German, Italian, and Polish. [ABSTRACT FROM AUTHOR]

Among the strategies used by people to request others to do things, there is a particular family defined as pre-requests . The typical function of a pre-request is to check whether some precondition obtains for a request to be successfully made. A form like the Italian interrogative hai x ‘do you have x’, for example, is used to ask if an object is available — a requirement for the object to be transferred or manipulated. But what does it mean exactly to make a pre-request? What difference does it make compared to issuing a request proper? In this article, I address these questions by examining the use of hai x ‘do you have x’ interrogatives in a corpus of informal Italian interaction. Drawing on methods from conversation analysis and linguistics, I show that the status of hai x as a pre-request is reflected in particular properties in the domains of preference and sequence organisation, specifically in the design of blocking responses to the pre-request, and in the use of go-ahead responses, which lead to the expansion of the request sequence. This study contributes to current research on requesting as well as on sequence organisation by demonstrating the response affordances of pre-requests and by furthering our understanding of the processes of sequence expansion. [ABSTRACT FROM AUTHOR]

Childhood-onset idiopathic nephrotic syndrome affects 1.15–3.4 children/100,000 children/year in Western Countries. Immune-mediated mechanisms, particularly T cell-mediated, are thought to play a key pathogenic role. The genetic basis of the disease is still poorly understood. We tested the association between single nucleotide polymorphisms (SNPs) of four genes encoding Fc gamma receptors ( FCGR2A , FCGR2B , FCGR3A , FCGR3B ) and idiopathic nephrotic syndrome in a case-control study of paediatric patients. Children with idiopathic nephrotic syndrome (aged 1–16 years) were included. FCGR2A rs1801274 and FCGR3A rs396991 SNPs were genotyped using real-time PCR with the TaqMan method, while FCGR2B rs1050501 and FCGR3B NA1/NA2 were genotyped using Sanger sequencing. Fisher’s exact test was used to explore genetic association. We enrolled 103 idiopathic nephrotic syndrome patients and 181 healthy controls. A significant association was found between idiopathic nephrotic syndrome and FCGR2A rs1801274 SNP (both with the T allele and the TT genotype, p value = 0.0009, OR 1.81, 95% CI 1.27–2.59 and p value = 0.0007, OR 2.39, 95% CI 1.44–3.99, respectively). No associations were found for the remaining SNPs. Fc gamma receptors might modulate response to rituximab; since 60 of the enrolled patients were treated with rituximab, we also tested the association between the studied SNPs and rituximab efficacy in this patient subgroup, but found only a weak association with FCGR2A CC genotype (p value = 0.03). The FCGR2A rs1801274 SNP in the gene encoding the activating receptor CD32A confers susceptibility to idiopathic nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Minimal residual disease (MRD) of 30 adult AML patients was monitored by multiparameter flow cytometry (MFC) and WT1 expression before and after allogeneic stem cell transplantation (allo-SCT). Diagnostic performance of pre-transplant MRD measured by MFC was higher than that obtained by WT1 expression. Comparable results were displayed at day +30 post-transplant, while better values by WT1 compared to MFC were found at day +90. Positive MRD by MFC predicted a shorter disease free survival (DFS) before and 1 month after transplant ( p = 0.006 and p = 0.005), while only high WT1 levels at 1 month from the transplant significantly impacted on DFS ( p = 0.010). Our results support the idea that MRD monitoring by MFC should be suggested before and 30 days after the transplant, while WT1 expression should be preferred after this procedure. The assessment of MRD at day +30 from allo-SCT is recommended as post transplant check-point for the predictive role displayed, independently of the method used. [ABSTRACT FROM AUTHOR]

In acute myeloid leukemia (AML), the detection of minimal residual disease (MRD) as well as the degree of log clearance similarly identifies patients with poor prognosis. No comparison was provided between the two approaches in order to identify the best one to monitor follow-up patients. In this study, MRD and clearance were assessed by both multiparameter flow cytometry (MFC) and WT1 expression at different time points on 45 AML patients achieving complete remission. Our results by WT1 expression showed that log clearance lower than 1.96 after induction predicted the recurrence better than MRD higher than 77.0 copies WT1/10 ABL. Conversely, on MFC, MRD higher than 0.2 % after consolidation was more predictive than log clearance below 2.64. At univariate and multivariate analysis, positive MRD values and log clearance below the optimal cutoffs were associated with a shorter disease-free survival (DFS). At the univariate analysis, positive MRD values were also associated with overall survival (OS). Therefore, post-induction log clearance by WT1 and post-consolidation MRD by MFC represented the most informative approaches to identify the relapse. At the optimal timing of assessment, positive MRD and log-clearance values lower than calculated thresholds similarly predicted an adverse prognosis in AML. [ABSTRACT FROM AUTHOR]

Relapse represents the main cause of treatment failure after allogeneic stem cell transplant (allo-SCT). The detection of minimal residual disease (MRD) by multiparametric flow cytometry (MFC), chimerism, cytogenetics and molecular analysis may be critical to prevent relapse. Therefore, we assessed the overall agreement among chimerism (low level mixed chimerism [LL-MC] vs. complete chimerism [CC]), MFC and Wilms tumor 1 (WT1) mRNA to detect MRD and investigated the impact of MRD obtained from the three methods on patient outcome. Sixty-seven fresh bone marrow (BM) samples from 24 patients (17 acute myeloid leukemia [AML], seven acute lymphoblastic leukemia [ALL]) in complete remission (CR) after allo-SCT were investigated at different time points. A moderate agreement was found among the three techniques investigated. A higher concordance between positive results from MFC (75.0% vs. 32.7%, p = 0.010) and WT1 (58.3% vs. 29.1%, p = 0.090) was detected among LL-MC rather than CC samples. Relapse-free survival (RFS) and overall survival (OS) were found to be higher in MRD negative patients than in MRD positive patients analyzed with MFC and WT1. Our results discourage the use of low autologous signals as the only marker of MRD, and suggest the usefulness of MFC and WT1 real-time quantitative polymerase chain reaction (RQ-PCR) in stratifying patients with respect to risk of relapse. [ABSTRACT FROM AUTHOR]

Abstract: In the past, ratio scales have been a highly controversial issue between physicists and psychologists as regards the need for an empirical addition operation in order to attain them. This aspect is critical since such an operation is often unavailable in psychophysical experiments, as it is in physics, due to its intensive properties. We propose a reconsideration of ratio scales, showing how they can be obtained when ratio and difference empirical relations are available and when they satisfy proper compatibility conditions. We call such structures “intensive” and provide deterministic and probabilistic axiomatizations in the finite case. We also address the practical applications of these ideas to perceptual measurements. [Copyright &y& Elsevier]

Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS) and proteus syndrome are disorders known as PTEN hamartoma tumour syndrome (PHTS), that can show remarkable clinical overlap and are all caused by germline PTEN mutations. We here present two families, one affected by CS and the other affected by BRRS, both carriers of specific pathogenetic missense mutation in exon 5 of PTEN gene, within the catalitic domain. Both PHTS families exhibited extremely variable phenotypes, showing inter- and intra- familial variability. One of the two characterised mutations, the c.320A- > T; p.107Asp- > Val, identified in the CS family, was not previously described in the literature. Furthermore, the BRRS family, carrier of the c.406 T- > C; p.136Cys- > Arg mutation, shows a substantial alteration of PTEN protein expression that well correlates with intra-familial phenotypic variability. Finally, we describe an apparently sporadic case of an 80-year-old man, with a very low level of PTEN mRNA and protein expression, both in healthy and tumour colon mucosa, associated with a very atypical phenotype. He developed a metastatic colorectal carcinoma, macrocephaly and pheochromocytoma. According to literature data, our observations confirm that PTEN mutations of catalytic domain can cause different syndromes. We suggest that PTEN expression could represent one of the mechanisms involved in the remarkable heterogeneity of the clinical PHTS manifestations within affected families. Furthermore, constitutive strong decrease of PTEN expression in colon normal mucosa could be associated with late onset of colorectal cancer [ABSTRACT FROM AUTHOR]