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The delivery of pediatric surgical care for acute appendicitis involves general surgeons (GS) and pediatric surgeons (PS), but the differences in clinical practice are primarily undescribed. We examined charge differences between GS and PS for the treatment of pediatric acute appendicitis.We performed a retrospective review of the North Carolina hospital discharge database (2013-2017) in pediatric patients (≤18 y) who had surgery for appendiceal pathology (acute or chronic appendicitis and other appendiceal pathology). We performed a bivariate analysis of surgical charges over the type of surgical providers (GS, PS, other specialty, and unassigned surgeons).Over the study period, 21,049 patients had appendicitis or other diseases of the appendix, and 15,230 (72.4%) underwent appendectomy. Patients who were operated on by PS were younger (10 y, interquartile range (IQR): 6-13 versus 13 y, IQR: 9-16, P 0.001). Acute appendicitis was diagnosed in 2860 (44.3%) and 3173 (49.2%) of the PS and GS cohorts, respectively, P = 0.008. PS compared to GS performed a higher percentage of laparoscopic (n = 2,697, 89.4% versus n = 2,178, 65.5%) than open appendectomies (n = 280, 9.3% versus n = 1,118, 33.6%), P 0.001. The overall hospital charges were $28,081 (IQR: $21,706-$37,431) and $24,322 (IQR: $17,906-$32,226) for PS and GS, respectively, P 0.001. Surgical charges where higher for PS than GS, $12,566 (IQR: $9802-$17,462) and $8051 (IQR: $5872-$2331), respectively. When controlling for diagnosis, surgical approach, emergent status, age, and surgical cost of appendiceal surgery, and hospital charges following appendiceal surgery were $4280 higher for PS than GS (95% CI: 3874-4687).The total charge for operations for appendiceal disease is significantly higher for PS compared to GS. Pediatric surgeons had increased surgical charges compared to GS but decreased radiology charges. The specific reasons for these differences are not clearly delineated in this data set and persist after controlling for relevant covariates. However, these data demonstrate that increasing value in pediatric appendicitis may require specialty-based targets.

Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, such as huntingtin in Huntington's disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3). Age at onset of disease decreases with increasing polyglutamine length in these proteins and the normal length also varies. PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs $\textit{in vivo}$ as a result of alternative splicing, causes toxicity. Although such mutant proteins are prone to aggregation, toxicity is also associated with soluble forms of the proteins. The function of the polyQ tracts in many normal cytoplasmic proteins is unclear. One such protein is the deubiquitinating enzyme ataxin 3 (refs 7, 8), which is widely expressed in the brain. Here we show that the polyQ domain enables wild-type ataxin 3 to interact with beclin 1, a key initiator of autophagy. This interaction allows the deubiquitinase activity of ataxin 3 to protect beclin 1 from proteasome-mediated degradation and thereby enables autophagy. Starvation-induced autophagy, which is regulated by beclin 1, was particularly inhibited in ataxin-3-depleted human cell lines and mouse primary neurons, and $\textit{in vivo}$ in mice. This activity of ataxin 3 and its polyQ-mediated interaction with beclin 1 was competed for by other soluble proteins with polyQ tracts in a length-dependent fashion. This competition resulted in impairment of starvation-induced autophagy in cells expressing mutant huntingtin exon 1, and this impairment was recapitulated in the brains of a mouse model of Huntington's disease and in cells from patients. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ataxin 3 itself. Our data thus describe a specific function for a wild-type polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identify a deleterious function of such mutations distinct from their propensity to aggregate.

Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons. Autophagy is a powerful process for removing such proteins. In this Review, we consider how certain neurodegenerative diseases may be associated with impaired autophagy and how this may affect pathology. We also discuss how autophagy induction may be a plausible therapeutic strategy for some conditions and review studies in various models that support this hypothesis. Finally, we briefly describe some of the signaling pathways that may be amenable to therapeutic targeting for these goals.

Expansions of polyglutamine (polyQ) tracts in different proteins cause 9 neurodegenerative conditions, such as Huntington disease and various ataxias. However, many normal mammalian proteins contain shorter polyQ tracts. As these are frequently conserved in multiple species, it is likely that some of these polyQ tracts have important but unknown biological functions. Here we review our recent study showing that the polyQ domain of the deubiquitinase ATXN3/ataxin-3 enables its interaction with BECN1/beclin 1, a key macroautophagy/autophagy initiator. ATXN3 regulates autophagy by deubiquitinating BECN1 and protecting it from proteasomal degradation. Interestingly, expanded polyQ tracts in other polyglutamine disease proteins compete with the shorter ATXN3 polyQ stretch and interfere with the ATXN3-BECN1 interaction. This competition results in decreased BECN1 levels and impaired starvation-induced autophagy, which phenocopies the loss of autophagic function mediated by ATXN3. Our findings describe a new autophagy-protective mechanism that may be altered in multiple neurodegenerative diseases.

Author(s): Siddiqi, Farah H; Menzies, Fiona M; Lopez, Ana; Stamatakou, Eleanna; Karabiyik, Cansu; Ureshino, Rodrigo; Ricketts, Thomas; Jimenez-Sanchez, Maria; Esteban, Miguel Angel; Lai, Liangxue; Tortorella, Micky D; Luo, Zhiwei; Liu, Hao; Metzakopian, Emmanouil; Fernandes, Hugo JR; Bassett, Andrew; Karran, Eric; Miller, Bruce L; Fleming, Angeleen; Rubinsztein, David C | Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The first section of the paper argues that, in the context of Wittgenstein’s intentional understanding of the truth-functional construction of sentences, the independence of elementary sentences is required for every application of a truth-operation to have the same significance. The second section of the paper presents a ‘top-down’ interpretation of Tractarian analysis. There is no characterization of the bottom level of analysis apart from the general sentence-form; the only constraint on analysis is that apparently manifest logical relationships among colloquial sentences with sense be represented or otherwise accommodated using only the logical resources built into the general sentence-form. The third section of the paper considers how those logical resources might be applied in Tractarian analysis. Central here is the use of form-series to construct infinitary truth-functions. The section develops a view of Tractarian complexes which accommodates some colloquially manifest logical relations as presuppositions that are made explicit in analysis. Finally, I note that Tractarian analysis, as presented in this paper, is immune to the ‘color exclusion’ objection as formulated in Wittgenstein’s 1929 paper “Some Remarks on Logical Form.”

Autophagy is a conserved pathway that delivers cytoplasmic contents to the lysosome for degradation. Here we consider its roles in neuronal health and disease. We review evidence from mouse knockout studies demonstrating the normal functions of autophagy as a protective factor against neurodegeneration associated with intracytoplasmic aggregate-prone protein accumulation as well as other roles, including in neuronal stem cell differentiation. We then describe how autophagy may be affected in a range of neurodegenerative diseases. Finally, we describe how autophagy upregulation may be a therapeutic strategy in a wide range of neurodegenerative conditions and consider possible pathways and druggable targets that may be suitable for this objective.

A new class of biomimetic, bioresorbable apatitic calcium phosphate cement (CPC) biomaterial was recently developed. The handling characteristics and the ability to harden at body temperature in the presence of physiological saline makes it an attractive clinical bone substitute and delivery vehicle for therapeutic agents in orthopaedic applications. The major challenge with the material system consists in formulating an injectable paste with options for cell delivery in order to regenerate new bone faster with high quality. In this study, three different additives and/or viscosity modifiers (carboxymethylcellulose, silk and alginate) were incorporated into the CPC matrix. Injectability, cell viability and cell proliferation were evaluated by SEM, chemical content, and gene expression for osteogenesis of hMSCs. Injectable composites of CPC-gels for cell protection were achieved. The alginate provided the best outcomes, based on cell proliferation, ALP and collagen production, and osteogenic transcript increases for ALP, type I collagen, BSP and OP. Osteogenic analysis indicated lineage-specific differentiation of hMSCs into osteogenic outcomes in this CPC matrix. The results suggest that gel mixed CPC combination materials can be used as a cell delivery vehicle for bone regeneration.

Autophagy is a conserved, intracellular, lysosomal degradation pathway. While mechanistic aspects of this pathway are increasingly well defined, it remains unclear how autophagy modulation impacts normal physiology. It is, however, becoming clear that autophagy may play a key role in regulating developmental pathways. Here we describe for the first time how autophagy impacts stem cell differentiation by degrading Notch1. We define a novel route whereby this plasma membrane-resident receptor is degraded by autophagy, via uptake into ATG16L1-positive autophagosome-precursor vesicles. We extend our findings using a physiologically relevant mouse model with a hypomorphic mutation in Atg16L1, a crucial autophagy gene, which shows developmental retention of early-stage cells in various tissues where the differentiation of stem cells is retarded and thus reveal how modest changes in autophagy can impact stem cell fate. This may have relevance for diverse disease conditions, like Alzheimer's Disease or Crohn's Disease, associated with altered autophagy., The molecular mechanisms behind how autophagy may impact on developmental pathways and cell fate decisions are unclear. Here Wu et al. identify Notch receptors being taken up into ATG16L1-positive autophagosomes and, using a mouse mutant model, show that changes in autophagy can impact on stem cell fate.

In 1906, after giving up hope of vindicating logicism, Frege lists the results of his life's work that survive Russell's paradox. He begins: Almost everything is connected with the Begriffsschrift. Concepts conceived as functions. Relations as functions with two arguments. Concept-extensions or classes are not primary for me. Unsaturatedness of both concepts and functions. The essence of concepts and functions recognized. Twenty-two years earlier, in happier times, Frege took for his third guiding principle in Die Grundlagen der Arithmetik the admonition, 'never to lose sight of the distinction between concept and object'. We cannot understand Frege's view of his epochal achievements in logic - let alone mark the distance that separates his understanding of quantificational logic from contemporary views - without an appreciation of the concept-object distinction, the centrality Frege assigns to it and its connections to his other views. The distinction embodies the quantificational understanding of generality that Frege sets against older conceptions of logic. This quantificational understanding of generality gives Frege the principle for determining the logical segmentation of sentences and the contents or thoughts expressed by sentences. I hold that Frege’s Context Principle sets forth this connection between logical segmentation and quantificational generality. Sections 1–3 lay out Frege’s concept–object distinction and its place in his philosophy of logic. Section 4 describes Frege’s introduction of higher-level concepts and his assimilation of sentences to proper names. Sections 5 and 6 explore the charge that the concept–object distinction incoherently undermines itself in the so-called Kerry paradox. Sections 7 and 8 discuss the bearing of the Context Principle and the concept–object distinction on Frege’s logicism.

Gottlob Frege (1848–1925) was unquestionably one of the most important philosophers of all time. He trained as a mathematician, and his work in philosophy started as an attempt to provide an explanation of the truths of arithmetic, but in the course of this attempt he not only founded modern logic but also had to address fundamental questions in the philosophy of language and philosophical logic. Frege is generally seen (along with Russell and Wittgenstein) as one of the fathers of the analytic method, which dominated philosophy in English-speaking countries for most of the twentieth century. His work is studied today not just for its historical importance but also because many of his ideas are still seen as relevant to current debates in the philosophies of logic, language, mathematics and the mind. The Cambridge Companion to Frege provides a route into this lively area of research.

Carnap and Quine are usually presented as great philosophical opponents. And so they were. Their opposition should not blind us to the equally significant affinities in their philosophical outlooks. Burton Dreben encapsulates both the affinity and opposition at the end of his paper ‘Quine’: Word and Object is dedicated to ‘Rudolf Carnap, teacher and friend’. To me the book gives the mirror-image of Carnap’s philosophy: it shows how Carnap is transformed once his most basic assumption is dropped, namely the fundamental distinction between philosophy and science, between the analytic and the synthetic. (Dreben 1990, p. 88)

The logical empiricism of the Vienna Circle presented itself as the reconciliation of a thoroughgoing empiricism as regards substantive knowledge with the certainty and necessity of mathematics. According to empiricism, sense experience is the only source of substantive knowledge of facts, but sense experience might always have been different from what it actually was. Moreover, anything we extrapolate from what we experience may be falsified by further experiences. Knowledge grounded in sense experience is thus knowledge of contingencies, and except perhaps for knowledge of what is immediately experienced (“Red here now”), it is revisable on the basis of further experiences. In contrast, knowledge of mathematics appears to be unrevisably certain substantive knowledge of necessary truths. The contingencies of our sense experience thus seem to afford no basis for knowledge of mathematics. In a word, empiricism must be false, because mathematics is substantive a priori knowledge. The logical empiricist approach to this dilemma is to deny that knowledge of mathematics is substantive knowledge. The apriority and necessity of mathematics is the apriority and necessity of logic. Logic is in its turn grounded in tacit conventions for the use of certain symbols, symbols that do not themselves stand for anything, like the signs for negation and conjunction. As Hans Hahn put it: [Logic] only deals with the way we talk about objects ; logic first comes into being through language. And the certainty and universal validity of a proposition of logic . . . flows precisely from this, that it says nothing about any objects . . .We learn – by training, as I should like to put it – to assign the designation “red” to some of these objects, and we make an agreement to assign the designation “not red” to any others. On the basis of this agreement we can now state the following proposition with absolute certainty: None of these objects is assigned both the designation “red” and the designation “not red,” which is usually expressed briefly as follows: No object is both red and not red.” (Hahn, 1933/1987, 29)

To make informed management decisions, healthcare executives must have timely and useful information about the performance of their organizations. A review of the methods used by the Health Resources and Services Administration's Bureau of Primary Health Care to evaluate the performance of community health centers (CHCs) revealed a lack of such information. This information gap motivated the development of a comparative performance scorecard for the federally funded CHCs in North Carolina. The scorecard includes 19 indicators in four performance dimensions (access to care, financial performance, human resources, and utilization and productivity). A survey of participating CHC executive directors showed that the comparative performance scorecard is a useful tool for managing and evaluating the performance of CHCs.

The paper examines Wittgenstein's criticisms of Frege's and Russell's views of logical segmentation encapsulated at Tractatus 4.431 and 4.063. These criticisms proceed from Wittgenstein's 1913 conception of atomic sentences as models of reality and the distinctive conception of sense embedded in this conception. While Russell mistakenly assimilates the structure of truth‐functionally compound sentences to that of atomic sentences, Frege mistakenly makes the converse assimilation.

Ricketts treats shifts in Russell’s views about truth and judgment between 1905 and 1910, a period during which Russell attempted to articulate an atomistic, pluralist, and realist metaphysical alternative to the Idealistic Monism of Bradley in which reality is constituted by a plurality of mind-independent entities standing in relations external to them. Russell did not simply dismiss Idealism; significant aspects of the development of his alternative stem from his attempt to answer Bradley’s criticisms. Ricketts focuses on three elements of Russell’s early metaphysics: propositions not facts are metaphysically fundamental; a proposition is not a mere list of its components; and propositions are not representational, so that truth of propositions is not analyzed in terms of relations to truth-makers. Russell’s problem was to explain the unity of the proposition in face of Bradley’s challenge such that unity cannot be accounted for by external relations. Since for Russell truth is not explained by relation to fact, he was driven to a view in which truth and falsity are two irreducible ways in which propositional constituents are related by a relation that is itself one of these constituents. Unfortunately this position is self-thwarting; any attempt to state that truth is a quality of the relation holding the proposition together will, on Russell’s view, express a proposition in which truth is a constituent independent of that relation. This incoherence, on Ricketts’s reading, is what motivates Russell to a metaphysics in which facts are fundamental, in order to serve the role of truth-makers of propositions.

Wittgenstein's enigmatic conception of sentences as pictures and his attempt to recast logic in essentially truth-functional terms have long fascinated readers of the Tractatus. I hope in this essay to clarify the content and motivation of Wittgenstein's view of sentences as pictures and to relate this conception to his views on logic. At the beginning of the foreword to the Tractatus, Wittgenstein tells his readers that the Tractatus is not a textbook, that perhaps only someone who has had the thoughts it expresses will understand it. The foreword also suggests that the Tractatus is in large measure a response to and critique of Frege's and Russell's views. My strategy then is to examine how aspects of the Tractatus emerge against the backdrop of problems that Frege's and Russell's views posed for Wittgenstein. THE OLD LOGIC Wittgenstein rejected Frege's and Russell's universalist conception of logic - what he disparaged as the old logic - while retaining their inchoate but guiding assumptions first that logic frames all thought, and second that it is possible to give a clear, completely explicit, and unambiguous expression to the contents judged true or false. To begin with, let us survey some of the leading features of the old logic and then consider briefly some of Wittgenstein's dissatisfactions with it.

The principles of logic are, let us remember, the principles of valid reasoning that set the standards of consistency. Inquiry into any subject matter whatsoever draws implicitly on these principles and must conform to these standards on pain of incoherence. Logic then has a privileged position among the sciences, and this position raises two questions. First, what is the subject matter of logic; what content for logical principles does justice to their role in setting standards of consistency? Second, from what vantage point are we able to isolate and elucidate the basic notions that enter into the formulation of logic? These questions become all the more pressing, once the study of logic is separated sharply from empirical psychological investigations of human cognition. The magnitude of Frege's innovation in logic makes him acutely aware of the logocentric predicament. Frege puts forward his begriffsschrift as a formulation of the principles of valid reasoning. In developing a conception of logic that supports this identification, Frege addresses the issues raised by the logocentric predicament. Indeed, an examination of Frege's conception of logic can serve to clarify those issues. However, in the end, this conception of logic is unsatisfactory. For there are deep tensions between Frege's official construal of the content of the axioms of the begriffsschrift, and his view of judgment that underlies the identification of the begriffsschrift as logic. Wittgenstein's Tractatus is, in large measure, a response to these tensions in Frege's thought. Wittgenstein largely