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Background Regulatory agencies warned against fluoroquinolones for the management of minor infections because of the risk of emerging adverse events (collagen-associated adverse events, neuropsychiatric toxicity and long-term disability). We aimed to assess quality and credibility of evidence as well as causality regarding these putative associations. Methods MEDLINE, Scopus, Web of Science and PROSPERO were searched, from inception to August 2019, for systematic reviews with meta-analyses investigating emerging adverse events. Two investigators extracted data to grade quality (through validated AMSTAR-2 tool), rank credibility of the evidence (convincing, highly suggestive, suggestive, weak) through adapted criteria including E-value calculation, and assess causality (Hill's criteria). Results Seven systematic reviews of observational studies providing 16 risk estimates [seven, five and four, respectively, for aortic aneurysm/dissection (AAD), retinal detachment (RD) and any tendon disorders (ATD)] met inclusion criteria. No systematic reviews with meta-analysis investigating the risk of neuropsychiatric toxicity or long-term disability were found. The associations between fluoroquinolones and AAD/ATD showed highly suggestive credibility and were supported by strong evidence of causality (double increased risk, especially within first 2 months of treatment). Conflicting data concerning the emergence of RD were retrieved, resulting in weak evidence of causality. Quality of the evidence ranged from high to low for AAD, from moderate to critically low for RD, and it was moderate for ATD. Conclusion Our analysis supports credible, plausible and highly suggestive associations with AAD (rare occurrence but strong causality) and ATD. Limitations of both umbrella reviews and observational evidence should be considered.

Alienation has been recently revived as a central concept in critical theory. Current debates, however, tend to focus on normative rather than on explanatory issues. In this paper, I confront the latter and advance an account of alienation that bears on the mechanisms that bring it about in order to locate alienation as a distinctive social and psychological fact and to dissolve a paradox it seems to involve. In particular, I argue that alienation can be explained as a disruption induced by social factors in the sense of mental ownership that comes with the first personal awareness of being a subject of attitudes, emotions, and actions, and outline how social factors can play a structuring causal role in the process that brings it about. In the first section, I introduce the theme and explain why it is important to focus on the mechanisms that underlie alienation. In the second section, I maintain that understanding how alienation works is crucial to make sense of false consciousness. In the third section, I consider the relevance of mental ownership to explaining alienation and discuss existing evidence about whether and how it can fail. In the final section, I argue that disturbances in the simulation routines that support social cognition might underpin alienation, and outline how social factors might play a structuring causal role in this connection.

Direct oral anticoagulants are now recommended by major guidelines as first-choice agents for both stroke prevention in non-valvular atrial fibrillation and treatment/prevention of venous thromboembolism in non-cancer patients. Although there are no published head-to-head trials comparing different direct oral anticoagulants, a growing body of evidence from indirect comparisons and observational studies is suggesting that each direct oral anticoagulant may have a specific risk profile. This review aims to (1) synthesize and critically assess the latest evidence in comparative effectiveness and safety research in the aforementioned consolidated therapeutic uses, by performing an overview of systematic reviews and (2) highlight current challenges, namely underexplored areas, where research should be directed, also considering ongoing unpublished studies. The evidence gathered so far on the risk-benefit profile of direct oral anticoagulants is appraised in the light of existing guidelines to discuss whether further implementation should be proposed.

Background: Direct oral anticoagulants (DOACs), as substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, are susceptible to drug–drug interactions (DDIs). Hepatitis C direct-acting antiviral agents (DAAs), via P-glycoprotein or CYP3A4 inhibition, may increase DOAC exposure with relevant bleeding risk. We performed a systematic review on DDIs between DOACs and DAAs. Methods: Two reviewers independently identified studies through electronic databases, until 7 July 2020, supplementing the search by reviewing conference abstracts and the ClinicalTrials.gov website. Results: Of 1386 identified references, four articles were finally included after applying the exclusion criteria. Three phase I clinical studies in healthy volunteers assessed interactions between dabigatran and glecaprevir/pibrentasvir, odalasvir/simeprevir, or sofosbuvir/velpatasvir/voxilaprevir, showing an increase in the dabigatran area under the concentration–time curve (AUC) by 138%, 103%, and 161%, respectively. Conclusions: DOACs and DAAs are under-investigated for DDI risk. Real-world studies are needed to assess the clinical relevance of the pharmacokinetic interactions with dabigatran and describe the actual spectrum of possible DDIs between DAAs and other DOACs.

In this chapter, I consider the claim for pluralism commonly advanced in political philosophy as a claim concerning the standards, methods, and norms for forming belief and judgment about certain kinds of facts. After distinguishing between descriptive and normative epistemic pluralism, I contend that in this context pluralism needs to rest on grounds that are stronger than fallibilism yet weaker than relativism in order to enjoy a distinct standing. The idea of reasonable pluralism seems to devise a variety of normative pluralism designed to meet this demand. I argue, however, that this is an unstable position and suggest that an epistemic view of deliberation may be better suited to making sense of political justification. The latter view, though, is bound to dispense with normative pluralism.

Ideology is commonly defined along functional, epistemic, and genetic dimensions. This article advances a reasonably unified account that specifies how they connect and locates the mechanisms at work. I frame the account along a recent distinction between anchoring and grounding, endorse an etiological reading of functional explanations, and draw on current work about the epistemology of delusion, looping effects, and structuring causes to explain how ideologies originate, reproduce, and possibly collapse. This eventually allows articulating how the legitimating function of ideologies relates to the constitutive and causal role they play when embedded into the facts they are originally designed to anchor.

A major barrier to designing inclusive built environments is inherent to the very idea of inclusive design: this idea prescribes designing environments that address the needs of the widest possible audience in order to consider human diff erences, yet taking diff erences seriously may imply severely restricting 'the widest possible audience'. Inclusive design thus faces a paradox that is naturally connected with a question of justice. In confronting this paradox, we are investigating to what extent the theory of justice as fairness may apply to design. According to this theory, whether a design allows for equitable use is to be deliberated by users under a veil of ignorance concerning their own capacities or limitations. Since this can hardly apply to single artefacts, the social distribution of usability seems the proper domain of fairness in design. Under this reading, diff erences in usability are acceptable if overall usability for the 'worst off ' is maximized. What this means for built environment design is explored in this article: how to understand usability, how to distribute it socially, and how to identify the 'worst off ' in this context? In considering these questions, we seek to contribute to strengthening the theoretical basis of inclusive design, while off ering built environment professionals a hold in confronting its paradox

Inclusive design approaches like universal design prescribe addressing the needs of the widest possible audience in order to consider human differences. Taking differences seriously, however, may imply that “the widest possible audience” is severely restricted. In confronting this paradox, we recruit Rawls’ theory of justice as fairness. Applying Rawls’ principles to universal design implies that users derive which design allows for equitable use by deliberating under a veil of ignorance concerning their own capacities or limitations. Rather than addressing everyone’s needs, being designed universally then means matching what everyone would choose under the condition sketched. Since this can hardly apply to single artefacts, we suggest considering the social distribution of usability as the proper domain of fairness in design instead. Under this reading, just design concerns how usability is distributed across relevant users. Differences in usability are acceptable if overall usability for the worst offs is maximized. ispartof: The Design Journal vol:20 pages:S3162-S3170 ispartof: location:ITALY, Sapienza Univ Rome, Fac Architecture, Rome status: published

On Jaeggi's reading, the immanent and progressive character of ideology critique are rooted in the connection between its explanatory and its normative tasks. I argue that this claim can be cashed out in terms of the mechanisms involved in a functional explanation of ideology and that stability plays a crucial role in this connection. On this reading, beliefs can be said to be ideological if (a) they have the function of supporting existing social practices, (b) they are the output of systematically distorted processes of belief formation, (c) the conditions in which distorting mechanisms triggers can be traced back to structural causal factors shaped by the social practice their outputs are designed to support. Functional problems thus turn out to be interlocked with normative problems because ideology fails to provide principles to regulate cooperation that would be accepted under conditions of non-domination, hence failing to anchor a stable cooperative scheme. By explaining ideology as parasitic on domination, ideology critique points to the conditions under which cooperation stabilize as those of a practice whose principles are accepted without coercion. Thus, it entails a conception of justice whose principles are articulated as part of a theory of social cooperation.

Background: Globally, the number of people aged 80 years or over, the “oldest old,” is the fastest growing population group. Because of the strong association between age and gallstone disease, both prevalence and incidence of this disease are increasing. The feasibility of the cholecystectomy in octogenarians has been evaluated in several studies that confirmed the safety of the operation. However, the safety of this procedure in nonagenarians is still controversial. The aim of this study was to evaluate the safety of cholecystectomies in nonagenarians and identify related predictors for postoperative hospital length of stay (LOS) and in-hospital mortality up to 30 days postoperatively. Methods: More than 500 cholecystectomies, both open and laparoscopic, were performed between January 2000 and September 2015 at our institution in patients 80 years and older. These statistics include both elective and emergent admissions. A retrospective review of charts over the last 15 years was conducted to compare mortality and length of postoperative stay among two patient groups: 319 octogenarians and 36 nonagenarians. Parameters evaluated include demographics, surgical presentation, American Society of Anesthesiologists (ASA) score, main diagnosis, comorbidities, type of surgery performed, LOS and in-hospital mortality. All data were analyzed with STATA (v.13) software, using a multivariate logistic regression after determining the statistically significant variables through a stepwise regression. Conclusions: We found out that being nonagenarian, compared to octogenarian, is not a significant risk factor in terms of LOS and in-hospital mortality within 30 days postoperatively. Despite that, the mortality rate among nonagenarians is still remarkably high as almost every patient was admitted in an emergent setting. The most remarkable predictor for mortality among the two groups was an “afternoon/night emergency” surgical presentation (OR 25.5, CI 1.53–42.35, p = 0.02). Thus, the surgical emergency management for gallbladder disease at our institution should be critically reevaluated. Performing the procedure in laparoscopy predicted a significant reduction (−5 days, CI −8.5 to −1.4, p = 0.006) of LOS, while presenting with “gallbladder and bile duct stones” (+6.3 days, CI 1.5–11.1, p = 0.01) or “acalculous cholecystitis” (+4.7 days, CI 0.4–9.2, p = 0.03) had the opposite effect. Despite the remarkable mortality rate of our series, being nonagenarian should not be considered as a reason to avoid gallbladder surgery in case of need. Our study suggests that nonagenarians are more suitable surgical candidates than may have previously expected.

Inclusive design prescribes addressing the needs of the widest possible audience in order to consider human differences. Taking differences seriously, however, may imply severely restricting “the widest possible audience”. In confronting this paradox, we investigate to what extent Rawls’ theory of justice as fairness applies to design. By converting the paradox into the question of how design can be fair, we show that the demand for equitability shifts from the design output to the design process. We conclude that the two main questions about justice find application in design: the question about the standards of justice and the question about its metrics. We endorse a Rawlsian approach to the former, while some revision may be due regarding the latter. ispartof: Design Studies vol:54 pages:1-22 status: published

Direct-acting oral anticoagulants (DOACs), by virtue of pharmacological properties perceived as innovative, are changing the therapeutic scenario of patients requiring short- and long-term anticoagulation. The evidence gathered so far (from pre-approval pivotal trials to real-world post-marketing observational data) consistently confirms that DOACs are overall comparable to vitamin-K antagonists (VKAs) in terms of safety, efficacy, effectiveness and unequivocally documents a clinically relevant reduced risk of intracranial bleeding in the settings of non-valvular atrial fibrillation (AF) and venous thromboembolism. The following issues are attracting considerable clinical interest: (a) identifying specific subpopulations of patients with AF most likely to benefit from one of these agents (the so-called tailored therapy), and (b) expanding therapeutic indications in emerging diseases characterized by arterial and venous thromboembolic risk. In these scenarios, the risk–benefit profile of DOACs, as compared to VKAs or heparins, is still incompletely characterized. In cardiology, the challenging task of selecting a suitable or even the most appropriate DOAC for patients with AF and a particular phenotype prompted experts to provide suggestions based on careful review of subgroups of patients from pivotal RCTs. However, in the past few months, variegated multicenter trials have been published (RE-CIRCUIT, PIONEER-AF-PCI, GEMINI-ACS-1), with potential influence on clinical practice. Therefore, this review aims to update the latest evidence on the evolving therapeutic uses of DOACs in the cardiovascular area, addressing potential impact for clinicians.

Direct-acting oral anticoagulants (DOACs) were claimed to cause a potential paradigm shift in the therapeutic scenario of patients requiring short- and long-term anticoagulation, by virtue of their pharmacological properties, perceived as innovative. The evidence gathered so far (from pre-approval pivotal trials to real-world post-marketing observational data) consistently confirmed that DOACs are overall comparable to vitamin-K antagonists (VKAs) in terms of safety, efficacy and effectiveness and unequivocally documented a consistent and clinically relevant reduced risk of intracranial bleeding in the settings of non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE). Interestingly, two parallel paths can be identified in the current research scenario: A) in the aforementioned consolidated therapeutic indications, an innovative approach is directed towards tailored treatment strategies, to identify patients most likely to benefit from one of the different anticoagulant drugs, in particular subpopulations at increased risk of adverse events (e.g., bleeding); B) in unconventional settings, DOACs are gaining interest for potential use in emerging diseases characterized by arterial and venous thromboembolic risk. In these scenarios, the risk-benefit profile of DOACs, as compared to VKAs or heparins, is less defined. The aim of this review is to critically assess the body of evidence underlying emerging therapeutic uses of DOACs (e.g., heparin-induced thrombocytopenia, anti-phospholipid antibody syndrome), including evolving issues in special populations (e.g., patients with VTE and cancer or cirrhosis). This will be achieved by analyzing the strength (i.e., systematic reviews, randomized clinical trials, observational studies, case report/series) and consistency (i.e., concordance) of both published and unpublished evidence registered in major public repositories.

In this article I consider the relevance of Tomasello’s work on social cognition to the theory of communicative action. I argue that some revisions are needed to cope with Tomasello’s results, but they do not affect the core of the theory. Moreover, they arguably reinforce both its explanatory power and the plausibility of its normative claims. I proceed in three steps. First, I compare and contrast Tomasello’s views on the ontogeny of human social cognition with the main tenets of Habermas’ theory of communicative action. Second, I suggest how to reframe the role of language in the theory of communicative rationality in order to integrate the two theories. Third, I show how this affects social ontology, supporting the view that the construction of social reality is normatively constrained by the bounds of reason.

Since 2008, the direct-acting oral anticoagulants (DOACs) have expanded the therapeutic options of cardiovascular diseases with recognized clinical and epidemiological impact, such as non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE), and also in the preventive setting of orthopedic surgical patients. The large body of evidence, not only from pivotal clinical trials but also from ‘real-world’ postmarketing observational findings (e.g. analytical epidemiological studies and registry data) gathered to date allow for a first attempt at verifying a posteriori whether or not the pharmacological advantages of the DOACs actually translate into therapeutic innovation, with relevant implications for clinicians, regulators and patients. This review aims to synthesize the risk–benefit profile of DOACs in the aforementioned consolidated indications through an ‘evidence summary’ approach gathering the existent evidence-based data, particularly systematic reviews with meta-analyses of randomized controlled trials, as well as observational studies, comparing DOACs with vitamin K antagonists. Clinical evidence will be discussed and compared with major international guidelines to identify whether an update is needed. Controversial clinically relevant safety issues will be also examined in order to highlight current challenges and unsettled questions (e.g. actual bleeding risk in susceptible populations). It is anticipated that the large number of publications on NVAF or VTE (44 systematic reviews with meta-analyses and 12 observational studies retained in our analysis) suggests the potential existence of overlapping studies and calls for common criteria to qualitatively and quantitatively assess discordances, thus guiding future research. Electronic supplementary material The online version of this article (doi:10.1007/s40264-016-0464-3) contains supplementary material, which is available to authorized users.

Non-vitamin K oral anticoagulants, also known as direct oral anticoagulants (DOACs), have entered the market in 2008 with the expected breakthrough potential of circumventing limitations related to treatment with vitamin K antagonists (eg, warfarin) by virtue of their pharmacological properties. Although data derived from premarketing randomized clinical trials have largely demonstrated the clinical benefit of DOACs, especially in terms of reduced risk of intracranial bleeding, it is important to monitor the safety in the postmarketing phase, which better reflects real-world patients with comorbidities and polypharmacotherapy, in order to assess the actual risk-benefit profile. In this critical review, we aimed to evaluate the evidence on the latest debated safety issues. In the first section, we will discuss: 1) the need for pharmacovigilance (ie, the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems in the real-world setting), and 2) the importance of properly interpreting postmarketing data to avoid unnecessary alarm. In the second section, emerging and debated safety issues potentially associated with the use of DOACs in the postmarketing setting will be assessed: 1) the potential coronary risk (which emerged during the preapproval period); 2) the occurrence of liver injury (a risk undetected in clinical trials and highlighted by case reports or series); and 3) the potential for renal damage (a still unclear safety issue). It is anticipated that hepatic and renal issues still require dedicated postauthorization safety studies to ultimately assess causality.

In this article, I argue that a capacity for mindreading conceived along the line of simulation theory provides the cognitive basis for forming we-centric representations of actions and goals. This explains the plural first personal stance displayed by we-intentions in terms of the underlying cognitive processes performed by individual minds, while preserving the idea that they cannot be analyzed in terms of individual intentional states. The implication for social ontology is that this makes sense of the plural subjectivity of joint actions without making group agents require either a corporate body or the unity of consciousness.

Underlying the development of inclusive design approaches seems to be the assumption that inclusivity automatically leads to good design. What good design means, however, and how this relates to inclusivity, is not very clear. In this paper we try to shed light on these questions. In doing so, we provide an argument for conceiving design as a deliberative enterprise. We point out how inclusivity and normative objectivity can be reconciled, by defining the norm of good design in terms of a deliberative cooperation between designers and the people they design for. In this view, a design is inclusive when it is produced by exploiting the information and competences at the disposal of the designer and the people she designs for in qualified circumstances. ispartof: Design Studies vol:34 issue:1 pages:93-110 status: published

After defining what is meant by inclusivity and quality in design respectively, we will point out the more general question underlying this discussion, which, reduced to its general form, is relevant to every activity that has a normative dimension. The paper provides an argument for design as a deliberative enterprise.

Research on the relationship between design and the creation of knowledge is a relatively recent phenomenon. In architecture, for instance, it was not so long ago that designers tended to view knowledge with disdain, as a hindrance to unfettered creativity or an encapsulation of “freeze-dried prejudices.”1 Recently, however, the American Institute of Architects (AIA) devoted the December 2004 issue of its AIA Journal entirely to the theme of knowledge, which strongly suggests that times are changing. Increasingly, the act of designing is considered to be or involve some kind of knowledge production.2 This directly follows from the type of knowledge designing relies on, which is practicebased and tacit,3 (i.e., embedded within the very act of designing).4 On the other hand, it is possible—at least in a rough and ready way—to appreciate the distinction between the aim, or intention, of producing knowledge and other aims,5 such as designing an object or a building. To state it a bit more bluntly, a client typically hires an architect to design a building, not to produce knowledge. Why then is it so difficult to set clear boundaries between design and scholarly research? Questions about the relationship between both are far from new. According to Nigel Cross, they reappear about every forty years,6 and have been written about by many authors before. Already in 1973, Horst Rittel and Melvin Webber pointed out the difference between the kind of problems designers and planners deal with and those that scientists handle.7 More recently, Johannes Eekels and Norbert Roozenburg made a methodological comparison of the structures of design and research in engineering, and concluded that both are strongly interwoven and mutually dependent, yet fundamentally different.8 Although it seems time to move on from making all sorts of comparisons between design and research, this paper tries to shed more light on the issue from a conceptual and psychological point of view. To this end, it calls in the philosophy of mind—rather than the philosophy of science, as is usually the case9 —and more precisely the notion of intentionality. Instead of considering design as a mix of knowledge creation and application, the process is decomposed into distinct yet interacting mental acts, in which designers establish relationships with (objects in) the world. A detailed analysis of this relationship forms the basis for a nuanced, yet fundamental, comparison with

The contribution of Husserl’s phenomenology to the foundations of social and political theory can be appraised at both the methodological and the normative level. First, it makes intersubjective interaction central to the constitution of social reality. Second, it stresses reciprocity as a constitutive feature of intersubjectivity. In this context, individuals can be seen to be both ‘constituting’ and ‘constituted by’ their participation in communities, under a constraint of mutual recognition as intentional agents. This view is in no way atomistic, as it allows individual identities to be constituted intersubjectively; still, it remains individualistic, since it does not permit the ontological independence of collective entities. At the epistemological level, this provides a foundation of methodological individualism; at the normative level, it suggests that social order is a deliberative task and political legitimacy ultimately rests on moral principles of reciprocity and equal respect.

This paper reports on the opening intervention of the Workshop: the title, objectives and structure are explained. The study day was proposed as a multidisciplinary comparison of the relationship between architecture and autism. The starting assumption was that this is not merely a relationship necessary to improve the living conditions of autistic people and their families, but also potentially useful to broaden the possibilities and viewpoints of architecture rather than limiting them. Some theoretical references are presented to support this hypothesis, which could guide the new technical possibilities which engineering and technology can make practicable to enrich the sensitive responsiveness of architecture. Il paper riporta l’intervento di apertura del Workshop: vengono motivati il titolo, gli obiettivi e la struttura. La giornata di studi viene proposta come un confronto multidisciplinare di indagine sulla relazione tra Architettura e Autismo. L’assunto di partenza è che si tratti non solo di una relazione necessaria a migliorare le condizioni di vita delle persone autistiche e delle loro famiglie, ma anche potenzialmente utile ad ampliare le possibilità e i punti di vista dell’architettura più che di limitarli. Vengono esposti alcuni riferimenti teorici a supporto di questa ipotesi, che possano orientare le nuove possibilità tecniche che l’ingegneria e la tecnologia rendono praticabili per arricchire la reattività sensibile dell’architettura.

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