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An increasing amount of contemporary philosophy of mathematics posits, and theorizes in terms of special kinds of mathematical modality. The goal of this paper is to bring recent work on higher-order metaphysics to bear on the investigation of these modalities. The main focus of the paper will be views that posit mathematical contingency or indeterminacy about statements that concern the 'width' of the set theoretic universe, such as Cantor's continuum hypothesis. Within a higher-order framework I show that contingency about the width of the set-theoretic universe refutes two orthodoxies concerning the structure of modal reality: the view that the broadest necessity has a logic of S5, and the 'Leibniz biconditionals' stating that what is possible, in the broadest sense of possible, is what is true in some possible world. Nonetheless, I suggest that the underlying picture of modal set-theory is coherent and has attractions. [ABSTRACT FROM AUTHOR]

Consensus guidelines outline that patients with primary retroperitoneal sarcoma (RPS) should be managed within specialist sarcoma centres (SSC). There is, however, a paucity of population-based data detailing incidence and outcomes in these patients. Hence, we aimed to evaluate patterns of care among RPS patients in England and compare outcomes for those undergoing surgery in high-volume specialist sarcoma centres (HV-SSC), low-volume SSC (LV-SSC), and non-SSC (N-SSC). Data on patients diagnosed with primary RPS between 2013 and 2018 were extracted from NHS Digital's National Cancer Registration and Analysis Service using the national cancer registration dataset. Diagnostic pathways, treatment, and survival outcomes were compared between HV-SSC, LV-SSC, and N-SSC. Uni- and multivariate analyses were calculated. Of 1878 patients diagnosed with RPS, 1120 (60%) underwent surgery within 12 months of diagnosis, with 847 (76%) operated on at SSC; of these, 432 patients (51%) were operated on in HV-SSC, and 415 (49%) in LV-SSC. One- and 5-year estimated overall survival (OS) rates for patients undergoing surgery in N-SSC were 70.6% (95% confidence interval [CI]: 64.8–75.7) and 42.0% (CI: 35.9–47.9), compared to 85.0% (CI: 81.1–88.1) and 51.7% (CI: 46.6–56.6) in LV-SSC (p < 0.01), and 87.4% (CI: 83.9–90.2) and 62.8% (CI: 57.9–67.4) in HV-SSC, (p < 0.01). After adjusting for patient- and treatment-related factors, patients treated in HV-SSC were found to have significantly longer OS than those treated at LV-SSC, with an adjusted hazard ratio of 0.78 (CI: 0.62–0.96, p < 0.05). Patients with RPS undergoing surgery in HV-SSC have significantly better survival outcomes than those treated in N-SSC and L-SSC. • 24% of patients diagnosed with primary RPS are managed outside SSC. • HV-SSC had better survival outcomes compared to LV-SSC and N-SSC. • HV-SSC are independently associated with longer OS on the multivariate analysis. [ABSTRACT FROM AUTHOR]

Here we report the development of a thermally stable, orally administered, candidate Zika vaccine using human serotype 5 adenovirus (AdHu5). We engineered AdHu5 to express the genes for the envelope and NS1 proteins of Zika virus. AdHu5 was formulated using a proprietary platform, OraPro, comprising a mix of sugars and modified amino acids that can overcome elevated temperatures (37 C), and an enteric coated capsule that protects the integrity of the AdHu5 from the acid in the stomach. This enables the delivery AdHu5 to the immune system of the small intestine. We show that oral delivery of AdHu5 elicited antigen-specific serum IgG immune responses in a mouse model and in a non-human primate model. Importantly, these immune responses were able reduce viral counts in mice and to prevent detectable viraemia in the non-human primates on challenge with live Zika virus. This candidate vaccine has significant advantages over many current vaccines that are maintained in a cold or ultra-cold chain and require parenteral administration. [ABSTRACT FROM AUTHOR]

This paper argues that the theory of structured propositions is not undermined by the Russell-Myhill paradox. I develop a theory of structured propositions in which the Russell-Myhill paradox doesn't arise: the theory does not involve ramification or compromises to the underlying logic, but rather rejects common assumptions, encoded in the notation of the λ-calculus, about what properties and relations can be built. I argue that the structuralist had independent reasons to reject these underlying assumptions. The theory is given both a diagrammatic representation and a logical representation in a novel language. In the latter half of the paper I turn to some technical questions concerning the treatment of quantification and demonstrate various equivalences between the diagrammatic and logical representations and a fragment of the λ-calculus. [ABSTRACT FROM AUTHOR]

Decision theory is founded on the principle that we ought to take the action that has the maximum expected value from among actions we are in a position to take. But prior to the notion of expected value is the notion of the actual value of that action: roughly, a measure of the good outcomes you would in fact procure if you were to take it. Surprisingly many decision theories operate without an analysis of actual value. I offer a definition of actual value, and show that a form of decision theory due to Stalnaker can be reformulated so as to be in line with the edict to maximize expected value. By contrast, I show that there is no quantity — given by my definition or otherwise — that plays the role of actual value in Jeffrey's decision theory. [ABSTRACT FROM AUTHOR]

We develop a theory of necessity operators within a version of higher-order logic that is neutral about how fine-grained reality is. The theory is axiomatized in terms of the primitive of being a necessity, and we show how the central notions in the philosophy of modality can be recovered from it. Various questions are formulated and settled within the framework, including questions about the ordering of necessities under strength, the existence of broadest necessities satisfying various logical conditions, and questions about their logical behaviour. We also wield the framework to probe the conditions under which a logicist account of necessities is possible, in which the theory is completely reducible to logic. [ABSTRACT FROM AUTHOR]

The article models combinatorial theory of possibility in a way that elucidates the connection between logical possibility and fundamentality. It mentions that the theory proposed is strong and settles many contentious questions of metaphysics; and mentions that a higher-order language may contain nonlogical constants belonging to different grammatical categories; and a mapping from sentences to sentences that replaces some of the nonlogical constants.

There are some properties, like being bald , for which it is vague where the boundary between the things that have it and the things that do not lies. A number of arguments threaten to show that such properties can still be associated with determinate and knowable boundaries: not between the things that have it and those that don't, but between the things such that it is borderline at some order whether they have it and the things for which it is not. I argue that these arguments, if successful, turn on a contentious principle in the logic of determinacy: Brouwer's Principle, that every truth is determinately not determinately false. Other paradoxes which do not appear to turn on this principle often tacitly make assumptions about assertion, knowledge and higher-order vagueness. In this paper I'll show how one can avoid sharp higher-order boundaries by rejecting these assumptions. [ABSTRACT FROM AUTHOR]

This paper formulates some paradoxes of inductive knowledge. Two responses in particular are explored: According to the first sort of theory, one is able to know in advance that certain observations will not be made unless a law exists. According to the other, this sort of knowledge is not available until after the observations have been made. Certain natural assumptions, such as the idea that the observations are just as informative as each other, the idea that they are independent, and that they increase your knowledge monotonically (among others) are given precise formulations. Some surprising consequences of these assumptions are drawn, and their ramifications for the two theories examined. Finally, a simple model of inductive knowledge is offered, and independently derived from other principles concerning the interaction of knowledge and counterfactuals. [ABSTRACT FROM AUTHOR]

We explore the view that Frege's puzzle is a source of straightforward counterexamples to Leibniz's law. Taking this seriously requires us to revise the classical logic of quantifiers and identity; we work out the options, in the context of higher‐order logic. The logics we arrive at provide the resources for a straightforward semantics of attitude reports that is consistent with the Millian thesis that the meaning of a name is just the thing it stands for. We provide models to show that some of these logics are non‐degenerate. [ABSTRACT FROM AUTHOR]

Kevin Scharp's 'Replacing Truth' is an ambitious and far reaching account of the semantic paradoxes. In this critical discussion we examine one the books central claims: to have provided a theory of truth that avoids the revenge paradoxes. In the first part we assess this claim, and in the second part we investigate some features of Scharp's preferred theory of truth, ADT, and compare it with existing theories such as the Kripke-Feferman theory. In the appendix a simple model of Scharp's theory is presented, and some potential consistent ways to strengthen the theory are suggested. [ABSTRACT FROM AUTHOR]

Individuals play a prominent role in many metaphysical theories. According to an individualistic metaphysics, reality is determined (at least in part) by the pattern of properties and relations that hold between individuals. A number of philosophers have recently brought to attention alternative views in which individuals do not play such a prominent role; in this paper I will investigate one of these alternatives. [ABSTRACT FROM AUTHOR]

(Note that the action of a perturbation may be extended in this manner to any type whatsoever, since once we have said what a perturbation does to things of type and of type we may use the same idea to define the action of the perturbation on type HT ht ; this is made a bit more explicit in the appendix.) Suppose HT ht contains the language of arithmetic, and we have a Gödel numbering of the expressions of HT ht . In fact, HT ht can simply be treated as an abbreviation for HT ht . When I i i is an individual, thought of as a perturbation, we will adopt the convention of writing HT ht instead of HT ht . We may then note that this is inconsistent with HT ht . [Extracted from the article]

Generalizing on some arguments due to Arthur Prior and Dmitry Mirimanoff, we provide some further limitative results on what can be thought. [ABSTRACT FROM AUTHOR]

In this paper the logic of broad necessity is explored. Definitions of what it means for one modality to be broader than another are formulated, and it is proven, in the context of higher-order logic, that there is a broadest necessity, settling one of the central questions of this investigation. It is shown, moreover, that it is possible to give a reductive analysis of this necessity in extensional language (using truth functional connectives and quantifiers). This relates more generally to a conjecture that it is not possible to define intensional connectives from extensional notions. This conjecture is formulated precisely in higher-order logic, and concrete cases in which it fails are examined. The paper ends with a discussion of the logic of broad necessity. It is shown that the logic of broad necessity is a normal modal logic between S4 and Triv, and that it is consistent with a natural axiomatic system of higher-order logic that it is exactly S4. Some philosophical reasons to think that the logic of broad necessity does not include the S5 principle are given. [ABSTRACT FROM AUTHOR]

Abstract: Those inclined to positions in the philosophy of time that take tense seriously have typically assumed that not all regions of space‐time are equal: one special region of space‐time corresponds to what is presently happening. When combined with assumptions from modern physics this has the unsettling consequence that the shape of this favored region distinguishes people in certain places or people traveling at certain velocities. In this paper I shall attempt to avoid this result by developing a tensed picture of reality that is nonetheless consistent with ‘hypersurface egalitarianism’—the view that all hypersurfaces are equal. [ABSTRACT FROM AUTHOR]

The principle of universal instantiation plays a pivotal role both in the derivation of intensional paradoxes such as Prior’s paradox and Kaplan’s paradox and the debate between necessitism and contingentism. We outline a distinctively free logical approach to the intensional paradoxes and note how the free logical outlook allows one to distinguish two different, though allied themes in higher-order necessitism. We examine the costs of this solution and compare it with the more familiar ramificationist approaches to higher-order logic. Our assessment of both approaches is largely pessimistic, and we remain reluctantly inclined to take Prior’s and Kaplan’s derivations at face value. [ABSTRACT FROM PUBLISHER]

The article discusses the logic of paradoxes of revenge. Topics discussed include the specific theory of determinacy of revenge paradoxes, the assessment of theory of propositions, and evaluation of assertion. It also mentioned the barrier of unclarity to knowledge and the clarity operator and inherent unassertability of language.

In this paper I present a precise version of Stalnaker’s thesis and show that it is both consistent and predicts our intuitive judgments about the probabilities of conditionals. The thesis states that someone whose total evidence is E should have the same credence in the proposition expressed by ‘if A then B’ in a context where E is salient as they have conditional credence in the proposition B expresses given the proposition A expresses in that context. The thesis is formalised rigorously and two models are provided that demonstrate that the new thesis is indeed tenable within a standard possible world semantics based on selection functions. Unlike the Stalnaker–Lewis semantics the selection functions cannot be understood in terms of similarity. A probabilistic account of selection is defended in its place.I end the paper by suggesting that this approach overcomes some of the objections often levelled at accounts of indicatives based on the notion of similarity. [ABSTRACT FROM AUTHOR]

One thousand fair causally isolated coins will be independently flipped tomorrow morning and you know this fact. I argue that the probability, conditional on your knowledge, that any coin will land tails is almost 1 if that coin in fact lands tails, and almost 0 if it in fact lands heads. I also show that the coin flips are not probabilistically independent given your knowledge. These results are uncomfortable for those, like Timothy Williamson, who take these probabilities to play a central role in their theorizing. [ABSTRACT FROM AUTHOR]

The article offers the author's insights on the proposed per capita cap on Medicaid expenditures by U.S. Representative Paul Ryan and its similarities with Medicaid's reimbursement method in 1965. He says that based on the previous system, the proposal will lead to limitations on benefits and coverage. He mentions that the removal of the caps in Medicaid has increased spending, but reduced mortality on children and infants and enable financial protection to families.

Endurance exercise training studies frequently show modest changes in VO2max with training and very limited responses in some subjects. By contrast, studies using interval training (IT) or combined IT and continuous training (CT) have reported mean increases in VO2max of up to ∼1.0 L · min−1. This raises questions about the role of exercise intensity and the trainability of VO2max. To address this topic we analyzed IT and IT/CT studies published in English from 1965–2012. Inclusion criteria were: 1)≥3 healthy sedentary/recreationally active humans <45 yrs old, 2) training duration 6–13 weeks, 3) ≥3 days/week, 4) ≥10 minutes of high intensity work, 5) ≥1∶1 work/rest ratio, and 6) results reported as mean ± SD or SE, ranges of change, or individual data. Due to heterogeneity (I2 value of 70), statistical synthesis of the data used a random effects model. The summary statistic of interest was the change in VO2max. A total of 334 subjects (120 women) from 37 studies were identified. Participants were grouped into 40 distinct training groups, so the unit of analysis was 40 rather than 37. An increase in VO2max of 0.51 L ·min−1 (95% CI: 0.43 to 0.60 L · min−1) was observed. A subset of 9 studies, with 72 subjects, that featured longer intervals showed even larger (∼0.8–0.9 L · min−1) changes in VO2max with evidence of a marked response in all subjects. These results suggest that ideas about trainability and VO2max should be further evaluated with standardized IT or IT/CT training programs. [ABSTRACT FROM AUTHOR]

A number of authors have objected to the application of non-classical logic to problems in philosophy on the basis that these non-classical logics are usually characterised by a classical metatheory. In many cases the problem amounts to more than just a discrepancy; the very phenomena responsible for non-classicality occur in the field of semantics as much as they do elsewhere. The phenomena of higher order vagueness and the revenge liar are just two such examples. The aim of this paper is to show that a large class of non-classical logics are strong enough to formulate their own model theory in a corresponding non-classical set theory. Specifically I show that adequate definitions of validity can be given for the propositional calculus in such a way that the metatheory proves, in the specified logic, that every theorem of the propositional fragment of that logic is validated. It is shown that in some cases it may fail to be a classical matter whether a given sentence is valid or not. One surprising conclusion for non-classical accounts of vagueness is drawn: there can be no axiomatic, and therefore precise, system which is determinately sound and complete. [ABSTRACT FROM AUTHOR]

This paper is a systematic exploration of non-wellfounded mereology. Motivations and applications suggested in the literature are considered. Some are exotic like Borges’ Aleph, and the trinity; other examples are less so, like time traveling bricks, and even Geach’s Tibbles the Cat. The authors point out that the transitivity of non-wellfounded parthood is inconsistent with extensionality. A non-wellfounded mereology is developed with careful consideration paid to rival notions of supplementation and fusion. Two equivalent axiomatizations are given, and are compared to classical mereology. We provide a class of models with respect to which the non-wellfounded mereology is sound and complete. [ABSTRACT FROM AUTHOR]

I consider two puzzles in which an agent undergoes a sequence of decision problems. In both cases it is possible to respond rationally to any given problem yet it is impossible to respond rationally to every problem in the sequence, even though the choices are independent. In particular, although it might be a requirement of rationality that one must respond in a certain way at each point in the sequence, it seems it cannot be a requirement to respond as such at every point for that would be to require the impossible. [ABSTRACT FROM AUTHOR]

Background: Antibody against CD40 is effective in enhancing immune responses to vaccines when chemically conjugated to the vaccine antigen. Unfortunately the requirement for chemical conjugation presents some difficulties in vaccine production and quality control which are compounded when multivalent vaccines are required. We explore here an alternative to chemical conjugation, involving the co-encapsulation of CD40 antibody and antigens in liposomal vehicles. Methodology/Principal Findings: Anti-mouse CD40 mAb or isotype control mAb were co-entrapped individually in cationic liposomal vehicles with pneumococcal polysaccharides or diphtheria and tetanus toxoids. Retention of CD40 binding activity upon liposomal entrapment was assessed by ELISA and flow cytometry. After subcutaneous immunization of BALB/c female mice, anti-polysaccharide and DT/TT responses were measured by ELISA. Simple co-encapsulation of CD40 antibody allowed for the retention of CD40 binding on the liposome surface, and also produced vaccines with enhanced imunogenicity. Antibody responses against both co-entrapped protein in the form of tetanus toxoid, and Streptococcus pneumoniae capsular polysaccharide, were enhanced by co-encapsulation with CD40 antibody. Surprisingly, liposomal encapsulation also appeared to decrease the toxicity of high doses of CD40 antibody as assessed by the degree of splenomegaly induced. Conclusions/Significance: Liposomal co-encapsulation with CD40 antibody may represent a practical means of producing more immunogenic multivalent vaccines and inducing IgG responses against polysaccharides without the need for conjugation. [ABSTRACT FROM AUTHOR]

Fragility fractures of the ankle are difficult to treat by conventional fixation due to poor bone quality, compromised soft tissues, and inherent instability. Conservative management of these patients also has its problems. We retrospectively reviewed 13 patients who underwent intramedullary nailing through the tibiotalocalcaneal joints in an attempt to achieve the dual aims of fracture control and early mobilisation. The Olerud and Molander scale was used as outcome measures. There were 12 females and 1 male with a mean age of 78.9 (range 64–93). Half of the patients were discharged from hospital within the first 2 weeks after the operation. All achieved a comparable function to their pre-operative state. The mean follow-up period was 11 months (range of 2–62 months). Six are now deceased from unrelated causes. The mean Olerud and Molander score was 50 (range 30–65). All the radiographs showed evidence of fracture union with no changes in the overall alignment of the joint. Given the low survivorship of this frail group of patients the main objectives are achieving early mobilisation whilst maintaining good fracture position. In our experience, tibiotalocalcaneal nailing is a very useful and successful way of treating fragility fractures of the ankle because it has a low risk of complications and restores function with impressive patient satisfaction. The potential benefits of this technique, we believe, outweigh the disability ensued from subtalar joint fusion. [ABSTRACT FROM AUTHOR]

DNA vaccination with mammalian-expressible plasmid DNA encoding protein antigens is known to be an effective means to elicit cell-mediated immunity, sometimes in the absence of a significant antibody response. This may be contrasted with protein vaccination, which gives rise to antibody responses with little evidence of cell-mediated immunity. This has led to considerable interest in DNA vaccination as a means to elicit cell-mediated immune responses against conserved viral antigens or intracellular cancer antigens, for the purpose of therapeutic vaccination. However, almost all current vaccines are used prophylactically and work by producing antibodies rather than cell mediated immune responses. In the present study we have therefore explored the combination of DNA and protein forms of an antigen using two exemplary prophylactic vaccine antigens, namely inactivated influenza virion and hepatitis-B surface antigen. We studied the effects of various combinations of DNA and protein on the antibody response. Co-administration of soluble forms of DNA and protein representations of the same antigen gave rise to the same level of antibody response as if protein were administered alone. In contrast, we found that when these antigens are entrapped in the same liposomal compartment, that there was a strong synergistic effect on the immune response, which was much greater than when either antigen was administered alone, or in various other modes of combination (e.g. co-administration as free entities, also pooled liposomal formulations where the two materials were contained in separate liposomal vehicles in the same suspension). The synergistic effect of liposomally co-entrapped DNA and protein exceeded, markedly, the well known adjuvant effects of plasmid DNA and liposomes. We have termed this new approach to vaccination ‘co-delivery’ and suggest that it may derive from the simultaneous presentation of antigen via MHC class-I (DNA) and MHC class-II (protein) pathways to CD8+ and CD4+ cells at the same antigen presenting cell – a mode of presentation that would commonly occur with live viral pathogens. We conclude that co-delivery is a very effective means to generate protective antibody responses against viral pathogens. [ABSTRACT FROM AUTHOR]

We have previously shown[sup [1-3]] that liposome-mediated plasmid DNA immunisation may be a preferred alternative to the use of naked DNA. Lipodine[sup ™] DNA formulations consist of liposomes containing entrapped DNA plasmid by the dehydration-rehydration (DRV) method.[sup [1]] Such liposome formulations are distinct from liposomes with externally complexed DNA in that the majority of the DNA is "internal" to the liposome structure and hence protected from DNAase degradation.[sup [3]] Previous studies on the immune response induced by DNA vaccines entrapped in Lipodine[sup ™] have focused on the humoural response. In the present study, we have expanded the analysis profile in order to include the cytotoxic T lymphocyte (CTL) component of the immune response. We have analysed the immune response induced by DNA entrapped in Lipodine[sup ™] compared to that induced by DNA alone when delivered subcutaneously, a route of administration not normally inducing significant plasmid DNA mediated immune activation. Our results indicate that delivery of a small dose of plasmid DNA in Lipodine[sup ™] results in an improved antibody response to the plasmid encoded antigen and a strong antigen specific CTL response compared to that induced by DNA delivered alone. [ABSTRACT FROM AUTHOR]

The original version of this article unfortunately contains mistakes. [ABSTRACT FROM AUTHOR]

Unruptured intracranial aneurysms (UIA) are common. For many the treatment risks outweigh their risk of subarachnoid haemorrhage and patients undergo surveillance imaging. There is little data to inform if and how to monitor UIAs resulting in widely varying practices. This study aimed to determine the current practice of unruptured UIA surveillance in the United Kingdom. A questionnaire was designed to address the themes of surveillance protocols for UIA including when surveillance is initiated, how frequently it is performed, and when it is terminated. Additionally, how aneurysm growth is managed and how clinically meaningful growth is defined were explored. The questionnaire was distributed to members of the British Neurovascular Group using probability-based cluster and non-probability purposive sampling methods. Responses were received from 30 of the 30 (100.0%) adult neurosurgical units in the United Kingdom of which 27 (90.0%) routinely perform surveillance for aneurysm growth. Only four units had a unit policy. The mean patient age up to which a unit would initiate follow-up of a low-risk UIA was 65.4 ± 9.0 years. The time points at which imaging is performed varied widely. There was an even split between whether units use a fixed duration of follow-up or an age threshold for terminating surveillance. Forty percent of units will follow-up patients more than 5 years from diagnosis. The magnitude in the change in size that was felt to constitute growth ranged from 1 to 3mm. No units routinely used vessel wall imaging although 27 had access to 3T MRI capable of performing it. There is marked heterogeneity in surveillance practices between units in the United Kingdom. This study will help units better understand their practice relative to their peers and provide a framework forplanning further research on aneurysm growth. [ABSTRACT FROM AUTHOR]

Relates the experience of a physician on disaster planning in the two southern states of Australia. Visits on the scene of the Ash Wednesday natural disaster; Involvement in resuscitation while maintaining practice in anesthesia; Necessity for disaster planning in any catastrophe.

Purpose: Due to the risk of intracranial aneurysm (IA) recurrence and the potential requirement for re-treatment following endovascular treatment (EVT), radiological follow-up of these aneurysms is necessary. There is little evidence to guide the duration and frequency of this follow-up. The aim of this study was to establish the current practice in neurosurgical units in the UK and Ireland. Methods: A survey was designed with input from interventional neuroradiologists and neurosurgeons. Neurovascular consultants in each of the 30 neurosurgical units providing a neurovascular service in the UK and Ireland were contacted and asked to respond to questions regarding the follow-up practice for IA treated with EVT in their department. Results: Responses were obtained from 28/30 (94%) of departments. There was evidence of wide variations in the duration and frequency of follow-up, with a minimum follow-up duration for ruptured IA that varied from 18 months in 5/28 (18%) units to 5 years in 11/28 (39%) of units. Young patient age, previous subarachnoid haemorrhage and incomplete IA occlusion were cited as factors that would prompt more intensive surveillance, although larger and broad-necked IA were not followed-up more closely in the majority of departments. Conclusions: There is a wide variation in the radiological follow-up of IA treated with EVT in the UK and Ireland. Further standardisation of this aspect of patient care is likely to be beneficial, but further evidence on the behaviour of IA following EVT is required in order to inform this process. [ABSTRACT FROM AUTHOR]

Summary: This analysis is the largest population‐based study to date to provide contemporary and comprehensive epidemiological estimates of all third edition of the International Classification of Diseases for Oncology (ICD‐O‐3) coded Langerhans cell histiocytosis (LCH) from England. People of all ages were identified from the National Cancer Registration Dataset using ICD‐O‐3 morphologies 9751–9754 for neoplasms diagnosed in 2013–2019. A total of 658 patients were identified, of whom 324 (49%) were children aged <15 years. The age‐standardised incidence rate was 4.46 (95% confidence interval [CI] 3.99–4.98) per million children and 1.06 (95% CI 0.94–1.18) per million adults aged ≥15 years. Prevalence of LCH was 9.95 (95% CI 9.14–10.81) per million persons at the end of 2019. The 1‐year overall survival (OS) was 99% (95% CI 97%–100%) for children and 90% (95% CI 87%–93%) for adults. Those aged ≥60 years had poorer OS than those aged <15 years (hazard ratio [HR] 22.12, 95% CI 7.10–68.94; p < 0.001). People in deprived areas had lower OS than those in the least deprived areas (HR 5.36, 95% CI 1.16–24.87; p = 0.03). There will inevitably be other environmental factors and associations yet to be identified, and the continued standardised data collection will allow further evaluation of data over time. This will be increasingly important with developments in LCH management following the large collaborative international trials such as LCH IV. [ABSTRACT FROM AUTHOR]

Genetic immunization by the use of plasmid DNA encoding antigens from bacteria, viruses, protozoa and cancers has often led to protective humoral and cell-mediated immunity, and has some practical advantages over conventional vaccines. However, naked DNA vaccines can be degraded by nucleases in situ, are unable to target antigen presenting cells (APCs), and exhibit poor performance when administered by routes other than the intramuscular, all of which have reduced the value of the approach. We have been able to avoid DNA degradation and also target DNA to APCs by the use of liposomes as DNA vaccine carriers. Entrapment of plasmid DNA within the aqueous spaces of cationic liposomes is effected by a one step procedure which results in most of the DNA being incorporated into a freeze dried, ready to use preparation. Animal experiments have shown that immunization by the intramuscular or the subcutaneous route with liposome-entrapped plasmid DNA encoding the hepatitis B surface antigen leads to much greater humoral (IgG subclasses) and cell mediated (splenic IFN-γ) immune responses than with naked DNA. In other experiments with a plasmid DNA encoding a model antigen (ovalbumin), a cytotoxic T lymphocyte (CTL) response was also observed. These results could be explained by the ability of liposomes to protect their DNA content from local nucleases and direct it to APCs in the lymph nodes draining the injected site. [Copyright &y& Elsevier]

Natural disasters impose a significant burden on society. Current disaster training programmes do not place an emphasis on equipping surgeons with non-technical skills for disaster response. This literature review sought to identify non-technical skills required of surgeons in disaster response through an examination of four categories of literature: 'disaster"; 'surgical'; 'organisational management'; and 'interprofessional'. Literature search criteria included electronic database searches, internet searches, hand searching, ancestry searching and networking strategies. Various potential non-technical skills for surgeons in disaster response were identified including: interpersonal skills such as communication, teamwork and leadership; cognitive strategies such flexibility, adaptability, innovation, improvisation and creativity; physical and psychological self-care; conflict management, collaboration, professionalism, health advocacy and teaching. Such skills and the role of interprofessionalism should be considered for inclusion in surgical disaster response training course curricula. [ABSTRACT FROM AUTHOR]

Interprofessional non-technical skills for surgeons in disaster response have not yet been developed. The aims of this study were to identify the non-technical skills required of surgeons in disaster response and training for disaster response and to explore the barriers and facilitators to interprofessional practice in surgical teams responding to disasters. Twenty health professionals, with prior experience in natural disaster response or education, participated in semi-structured in-depth interviews. A qualitative matrix analysis design was used to thematically analyze the data. Non-technical skills for surgeons in disaster response identified in this study included skills for austere environments, cognitive strategies and interprofessional skills. Skills for austere environments were physical self-care including survival skills, psychological self-care, flexibility, adaptability, innovation and improvisation. Cognitive strategies identified in this study were 'big picture' thinking, situational awareness, critical thinking, problem solving and creativity. Interprofessional attributes include communication, team-player, sense of humor, cultural competency and conflict resolution skills. 'Interprofessionalism' in disaster teams also emerged as a key factor in this study and incorporated elements of effective teamwork, clear leadership, role adjustment and conflict resolution. The majority of participants held the belief that surgeons needed training in non-technical skills in order to achieve best practice in disaster response. Surgeons considerring becoming involved in disaster management should be trained in these skills, and these skills should be incorporated into disaster preparation courses with an interprofessional focus. [ABSTRACT FROM AUTHOR]

Accurate placement of the pedicle screw is requisite for any successful spinal instrumentation procedure. Screw insertion can be achieved using free-hand and fluoroscopic- or navigation-guided techniques. We sought to assess the variation in accuracy between fluoroscopic- and navigation-guided techniques, which are both used in Sheffield Teaching Hospitals National Health Service Trust, a tertiary spine referral center. Using a retrospective study design, we assessed all the pedicle screws placed between 2013 and 2018. Radiographic and clinical assessment of all cases was performed. We studied 176 spinal instrumented cases, with a total of 831 screws implanted, out of which 296 (35.6%) were navigated and 535 (64.4%) were fluoroscopic guided. Pathology treated included spinal stenosis, spondylolisthesis, tumors, and trauma. Suboptimal screw position was identified in 2.03% (n = 6) of the navigation-guided series and 4.11% (n = 22) of the fluoroscopic-guided series with an overall screw misplacement rate of 3.4%. Evaluating surgeons' individual accuracy rates revealed that suboptimal screw placement registered a higher variation for the fluoroscopy-guided technique, and the misplacement rate was higher for surgeons with a lower volume of cases. Use of navigation during spinal instrumentation helps lower the rate of screw misplacement for spinal surgeons who are at the beginning of their learning curve or do not frequently perform this kind of procedure. Navigation-guided spinal instrumentation is more accurate compared with fluoroscopic-guided techniques and appears to have a lower complication rate. [ABSTRACT FROM AUTHOR]

Treatment of intracranial aneurysms with flow-diverting stents is a safe and minimally invasive technique. The goal is stable embolisation that facilitates stent endothelialisation, and elimination of the aneurysm. However, it is not fully understood why some aneurysms fail to develop a stable clot even with sufficient levels of flow reduction. Computational prediction of thrombus formation dynamics can help predict the post-operative response in such challenging cases. In this work, we propose a new model of thrombus formation and platelet dynamics inside intracranial aneurysms. Our novel contribution combines platelet activation and transport with fibrin generation, which is key to characterising stable and unstable thrombus. The model is based on two types of thrombus inside aneurysms: red thrombus (fibrin- and erythrocyte-rich) can be found in unstable clots, while white thrombus (fibrin- and platelet-rich) can be found in stable clots. The thrombus generation model is coupled to a CFD model and the flow-induced platelet index (FiPi) is defined as a quantitative measure of clot stability. Our model is validated against an in vitro phantom study of two flow-diverting stents with different sizing. We demonstrate that our model accurately predicts the lower thrombus stability in the oversized stent scenario. This opens possibilities for using computational simulations to improve endovascular treatment planning and reduce adverse events, such as delayed haemorrhage of flow-diverted aneurysms. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a severe in- flammatory and neurodegenerative disease with an autoimmune background. Despite the variety of therapeutics available against MS, the development of novel approaches to its treatment is of high importance in modem pharmaceutics. In this study, experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats has been treated with immunodominant peptides of the myelin basic protein (MBP) encapsulated in mannosylated small unilamellar vesicles. The results show that liposome-encapsulated MBP46-62 is the most effective in reducing maximal disease score during the first attack, while MBP124-139 and MBP147-170 can completely prevent the development of the exacerbation stage. Both mannosylation of liposomes and encapsulation of peptides are critical for the therapeutic effect, since neither naked peptides nor nonmannosylated liposomes, loaded or empty, have proved effective. The liposome-mediated synergistic effect of the mixture of 3 MBP peptides significantly suppresses the progression of protracted EAE, with the median cumulative disease score being reduced from 22 to 14 points, compared to the placebo group; prevents the production of circulating autoantibodies; down-regulates the synthesis of Th1 cytokines; and induces the production of brain-derived neurotrophic factor in the central nervous system. Thus, the proposed formulation ameliorates EAE, providing for a less severe first attack and rapid recovery from exacerbation, and offers a promising therapeutic modality in MS treatment. [ABSTRACT FROM AUTHOR]

The 'Ice Giants' Uranus and Neptune are a different class of planet compared to Jupiter and Saturn. Studying these objects is important for furthering our understanding of the formation and evolution of the planets, and unravelling the fundamental physical and chemical processes in the Solar System. The importance of filling these gaps in our knowledge of the Solar System is particularly acute when trying to apply our understanding to the numerous planetary systems that have been discovered around other stars. The Uranus Pathfinder (UP) mission thus represents the quintessential aspects of the objectives of the European planetary community as expressed in ESA's Cosmic Vision 2015-2025. UP was proposed to the European Space Agency's M3 call for medium-class missions in 2010 and proposed to be the first orbiter of an Ice Giant planet. As the most accessible Ice Giant within the M-class mission envelope Uranus was identified as the mission target. Although not selected for this call the UP mission concept provides a baseline framework for the exploration of Uranus with existing low-cost platforms and underlines the need to develop power sources suitable for the outer Solar System. The UP science case is based around exploring the origins, evolution, and processes at work in Ice Giant planetary systems. Three broad themes were identified: (1) Uranus as an Ice Giant, (2) An Ice Giant planetary system, and (3) An asymmetric magnetosphere. Due to the long interplanetary transfer from Earth to Uranus a significant cruise-phase science theme was also developed. The UP mission concept calls for the use of a Mars Express/Rosetta-type platform to launch on a Soyuz-Fregat in 2021 and entering into an eccentric polar orbit around Uranus in the 2036-2037 timeframe. The science payload has a strong heritage in Europe and beyond and requires no significant technology developments. [ABSTRACT FROM AUTHOR]

Abstract: Background: To examine the impact of changing dispatcher CPR instructions (400 compressions: 2 breaths, followed by 100:2 ratio) on rates of bystander CPR and survival in adults with presumed cardiac out-of-hospital arrest (OHCA) in Melbourne, Australia. Methods: The Victorian Ambulance Cardiac Arrest Registry (VACAR) was searched for OHCA where Emergency Medical Services (EMS) attempted CPR between August 2006 and August 2009. OHCA included were: (1) patients aged ≥18 years old; (2) presumed cardiac etiology; and (3) not witnessed by EMS. Results: For the pre- and post-study periods, 1021 and 2101 OHCAs met inclusion criteria, respectively. Rates of bystander CPR increased overall (45–55%, p <0.001) and by initial rhythm (shockable 55–70%, p <0.001 and non-shockable 40–46%, p =0.01). In VF/VT OHCA, there were improvements in the number of patients arriving at hospital with a return of spontaneous circulation (ROSC) (48–56%, p =0.02) and in survival to hospital discharge (21–29%, p =0.002), with improved outcomes restricted to patients receiving bystander CPR. After adjusting for factors associated with survival, the period of time following the change in CPR instructions was a significant predictor of survival to hospital discharge in VF/VT patients (OR 1.57, 95% CI: 1.15–2.20, p =0.005). Conclusion: Following changes to dispatcher CPR instructions, significant increases were seen in rates of bystander CPR and improvements were seen in survival in VF/VT patients who received bystander CPR, after adjusting for factors associated with survival. [Copyright &y& Elsevier]

Abstract: Tremendous efforts to produce an efficient vaccine for HIV infection have been unsuccessful. The ability of HIV to utilize sophisticated mechanisms to escape killing by host immune system rises dramatic problems in the development of antiviral therapeutics. The HIV infection proceeds by interaction of coat viral glycoprotein gp120 trimer with CD4+ receptor of the lymphocyte. Thus this surface antigen may be regarded as a favorable target for immunotherapy. In the present study, we have developed three different strategies to produce gp120-specific response in autoimmune prone mice (SJL strain) as potential tools for production “catalytic vaccine”. Therefore (i) reactive immunization by peptidylphosphonate, structural part of the coat glycoprotein, (ii) immunization by engineered fused epitopes of gp120 and encephalogenic peptide, a part of myelin basic protein, and (iii) combined vaccination by DNA and corresponding gp120 fragments incorporated into liposomes were investigated. In the first two cases monoclonal antibodies and their recombinant fragments with amidolytic and gp120-specific proteolytic activities were characterized. In the last case, catalytic antibodies with virus neutralizing activity proved in cell line models were harvested. [Copyright &y& Elsevier]

Finite-ground coplanar (FGC) waveguide lines on top of polyimide layers are frequently used to construct three-dimensional Si-SiGe monolithic microwave/millimeter-wave integrated circuits on silicon substrates. Requirements for high-density, low-cost, and compact RF front ends on silicon can lead, however, to high crosstalk between FGC lines and overall circuit performance degradation. This paper presents theoretical and experimental results and associated design guidelines for FGC line coupling on both high- and low.resistivity silicon wafers with a polyimide overlay. It is shown that a gap as small as 6 µm between two adjacent FGC lines can reduce crosstalk by at least 10 dB, that the nature of the coupling mechanism is not the same as with microstrip lines on polyimide layers, and that the coupling is not dependent on the Si resistivity. With careful layout design, isolation values of better than -30 dB can be achieved up to very high frequencies (50 GHz). [ABSTRACT FROM AUTHOR]

We report a novel method to provide excellent anatomical depiction of a dural arteriovenous fistula (dAVF) for surgical planning. A 78-year-old female presented with progressive back pain, deteriorating mobility and urinary incontinence with a background of obesity and severe osteoarthritis. Initial MRI suspected dAVF and subsequent spinal angiography encountered an extremely tortuous and arteriosclerotic aorta, hence catheterisation of the segmental-intercostal and lumbar vessels proved challenging. Contrast injection into the aortic arch via a pigtail catheter for arterial-phase CT angiogram of the descending aorta was performed. This modality of imaging delineated the dAVF showing extensive involvement of the whole spine accounting for the patient's symptoms. Furthermore this allowed characterisation of bony anatomy in relation to the fistula facilitating precise surgical approach. The dAVF was successfully disconnected through a localised laminectomy centred over the lesion. This specific technique for dAVF characterisation has not been previously reported, although trans-venous angiography has been used to some effect. In view of diagnostic and therapeutic technical difficulties that are often faced in such patients, this technique may be a useful alternative that is not only helpful in accurate diagnosis but helps in providing an invaluable guide for the surgical approach. This case highlights the difficulties that one may be faced within cases of tortuous vasculature and the obese patient population. With this in mind we demonstrate how a unique hybridised technique may provide valuable alternative to the neurosciences team should such a future scenario arise. [ABSTRACT FROM AUTHOR]