Knowledge, chance, and contrast

The late 1980s and early 1990s saw the rise of contextualist theories of knowledge ascriptions (and denials). Contextualists about ‘knows’ maintain that utterances of the form ‘S knows p’ and ‘S doesn’t know p’ resemble utterances such as ‘Peter is here’ and ‘Peter is not here’, in the sense that their truth-conditions vary depending upon features of the context in which they are uttered. In recent years, contextualism about ‘knows’ has come under heavy attack. This has been associated with a proliferation of defences of so-called invariantist accounts of knowledge ascriptions, which stand united in their rejection of contextualism. The central goal of the present work is two-fold. In the first instance, it is to bring out the serious pitfalls in many of those recent defences of invariantism. In the second instance, it is to establish that the most plausible form of invariantism is one that is sceptical in character. Of course, the prevailing preference in epistemology is for non- sceptical accounts. The central conclusions of the thesis might therefore be taken to show that – despite recent attacks on its plausibility – some form of contextualism about ‘knows’ must be correct. However, this project is not undertaken without at least the suspicion that embracing (a particular form of) sceptical invariantism is to be preferred to embracing contextualism. In the course of the discussion, I therefore not only attempt to rebut some standard objections to sceptical invariantism, but also to reveal – in at least a preliminary way – how the sceptical invariantist might best argue for the superiority of her account to that of the contextualist

Hoops and Barns: a new dilemma for Sosa

This paper critically assesses Sosa’s normative framework for performances as well as its application to epistemology. We first develop a problem for one of Sosa’s central theses in the general theory of performance normativity according to which performances attain fully desirable status if and only if they are fully apt. More specifically, we argue that given Sosa’s account of full aptness according to which a performance is fully apt only if safe from failure, this thesis can’t be true. We then embark on a rescue mission on behalf of Sosa and work towards a weakened account of full aptness. The key idea is to countenance a distinction between negligible and non-negligible types of risk and to develop an account of full aptness according to which even performances that are endangered by risk can be fully apt, so long as the risk is of a negligible type. While this alternative account of full aptness solves the problem we developed for Sosa earlier on, there is also bad news for Sosa. When applied to epistemology, the envisaged treatment of barn façade cases as cases in which the agent falls short of fully apt belief will no longer work. We show that, as a result, Sosa faces a new version of a familiar dilemma for virtue epistemology. Either he construes full aptness as strong enough to get barn façade cases right in which case his view will run right into the problem we develop. Or else he construes full aptness as weak enough to avoid this problem but then he will not be able to deal with barn façade cases in the way envisaged

Influenza virus protecting RNA : an effective prophylactic and therapeutic antiviral

Another influenza pandemic is inevitable, and new measures to combat this and seasonal influenza are urgently needed. Here we describe a new concept in antivirals based on a defined, naturally occurring defective influenza RNA that has the potential to protect against any influenza A virus in any animal host. This protecting RNA (244 RNA) is incorporated into virions which although non-infectious, deliver the RNA to those cells of the respiratory tract that are naturally targeted by infectious influenza virus. A small intranasal dose of this 244 protecting virus (120 ng) completely protected mice against a simultaneous lethal (10 LD50) challenge with influenza A/WSN (H1N1) virus. 244 virus also protected mice against a strong challenge dose of all other subtypes tested (H2N2, H3N2, H3N8). This prophylactic activity was maintained in the animal for at least 1 week prior to challenge. 244 virus was 10 to 100-fold more active than previously characterised influenza A defective viruses, and the protecting activity was confirmed to reside in the 244 RNA molecule by recovering a protecting virus entirely from cloned cDNA. There was clear therapeutic benefit when protecting 244 virus was administered 24-48 h after lethal challenge, an effect which has not been previously observed with any defective virus. Protecting virus reduced, but did not abolish, replication of challenge virus in mouse lungs during both prophylactic and therapeutic treatments. Protecting virus is a novel antiviral which has the potential to combat influenza infections in humans, particularly when the infecting strain is not known, or is resistant to antiviral drugs

Cloned defective interfering influenza virus protects ferrets from pandemic 2009 influenza A virus and allows protective immunity to be established

Influenza A viruses are a major cause of morbidity and mortality in the human population, causing epidemics in the winter, and occasional worldwide pandemics. In addition there are periodic outbreaks in domestic poultry, horses, pigs, dogs, and cats. Infections of domestic birds can be fatal for the birds and their human contacts. Control in man operates through vaccines and antivirals, but both have their limitations. In the search for an alternative treatment we have focussed on defective interfering (DI) influenza A virus. Such a DI virus is superficially indistinguishable from a normal virus but has a large deletion in one of the eight RNAs that make up the viral genome. Antiviral activity resides in the deleted RNA. We have cloned one such highly active DI RNA derived from segment 1 (244 DI virus) and shown earlier that intranasal administration protects mice from lethal disease caused by a number of different influenza A viruses. A more cogent model of human influenza is the ferret. Here we found that intranasal treatment with a single dose of 2 or 0.2 µg 244 RNA delivered as A/PR/8/34 virus particles protected ferrets from disease caused by pandemic virus A/California/04/09 (A/Cal; H1N1). Specifically, 244 DI virus significantly reduced fever, weight loss, respiratory symptoms, and infectious load. 244 DI RNA, the active principle, was amplified in nasal washes following infection with A/Cal, consistent with its amelioration of clinical disease. Animals that were treated with 244 DI RNA cleared infectious and DI viruses without delay. Despite the attenuation of infection and disease by DI virus, ferrets formed high levels of A/Cal-specific serum haemagglutination-inhibiting antibodies and were solidly immune to rechallenge with A/Cal. Together with earlier data from mouse studies, we conclude that 244 DI virus is a highly effective antiviral with activity potentially against all influenza A subtypes

The TURis system for transurethral resection of the prostate: a NICE medical technology guidance

The transurethral resection in saline (TURis) system was notified by the company Olympus Medical to the National Institute of Health and Care Excellence’s (NICE’s) Medical Technologies Evaluation Programme. Following selection for medical technologies guidance, the company developed a submission of clinical and economic evidence for evaluation. TURis is a bipolar surgical system for treating men with lower urinary tract symptoms due to benign prostatic enlargement. The comparator is any monopolar transurethral resection of the prostate (mTURP) system. Cedar, a collaboration between Cardiff and Vale University Health Board, Cardiff University and Swansea University in the UK, acted as an External Assessment Centre (EAC) for NICE to independently critique the company’s submission of evidence. Eight randomised trials provided evidence for TURis, demonstrating efficacy equivalent to that of mTURP for improvement of symptoms. The company presented meta-analyses of key outcome measures, and the EAC made methodological modifications in response to the heterogeneity of the trial data. The EAC analysis found that TURis substantially reduced the relative risks of transurethral resection syndrome (relative risk 0.18 [95 % confidence interval 0.05–0.62]) and blood transfusion (relative risk 0.35 [95 % confidence interval 0.19–0.65]). The company provided a de novo economic model comparing TURis with mTURP. The EAC critiqued the model methodology and made modifications. This found TURis to be cost saving at £70.55 per case for existing Olympus customers and cost incurring at £19.80 per case for non-Olympus customers. When an additional scenario based on the only available data on readmission (due to any cause) from a single trial was modelled, the estimated cost saving per case was £375.02 for existing users of Olympus electrosurgery equipment and £284.66 per case when new Olympus equipment would need to be purchased. Meta-analysis of eight randomised trials showed that TURis is associated with a statistically significantly reduced risk of transurethral resection syndrome and a reduced need for blood transfusion—two factors that may drive cost saving for the National Health Service. The clinical data are equivocal as to whether TURis shortens the hospital stay. Limited data from a single study suggest that TURis may reduce the rate of readmission after surgery. The NICE guidance supports adoption of the TURis technology for performing transurethral resection of the prostate in men with lower urinary tract symptoms due to benign prostatic enlargemen

Thopaz+ portable digital system for managing chest drains: a NICE medical technology guidance

The Thopaz+ portable digital system was evaluated by the Medical Technologies Advisory Committee (MTAC) of the National Institute for Health and Care Excellence (NICE). The manufacturer, Medela, submitted a case for the adoption of Thopaz+ that was critiqued by Cedar, on behalf of NICE. Due to a lack of clinical evidence submitted by the manufacturer, Cedar carried out its own literature search. Clinical evidence showed that the use of Thopaz+ led to shorter drainage times, a shorter hospital stay, lower rates of chest drain re-insertion and higher patient satisfaction compared to conventional chest drainage when used in patients following pulmonary resection. One comparative study of the use of Thopaz+ in patients with spontaneous pneumothorax was identified and showed shorter drainage times and a shorter length of hospital stay compared to conventional drainage. No economic evidence was submitted by the manufacturer, but a simple decision tree model was included. The model was improved by Cedar and showed a cost saving of £111.33 per patient when Thopaz+ was used instead of conventional chest drainage in patients following pulmonary resection. Cedar also carried out a sub-group analysis of the use of Thopaz+ instead of conventional drainage in patients with pneumothorax where a cost saving of £550.90 was observed. The main cost driver for the model and sub-group analysis was length of stay. The sub-group analysis was based on a single comparative study. However, the MTAC received details of an unpublished audit of Thopaz+ which confirmed its efficacy in treating patients with pneumothorax. Thopaz+ received a positive recommendation in Medical Technologies Guidance 37

Prescribing patterns in premenstrual syndrome

BACKGROUND: Over 300 therapies have been proposed for premenstrual syndrome. To date there has been only one survey conducted in the UK of PMS treatments prescribed by GPs, a questionnaire-based study by the National Association of Premenstrual Syndrome in 1989. Since then, selective serotonin re-uptake inhibitors have been licensed for severe PMS/PMDD, and governmental recommendations to reduce the dosage of vitamin B6 (the first choice over-the-counter treatment for many women with PMS) have been made. This study investigates the annual rates of diagnoses and prescribing patterns for premenstrual syndrome (1993–1998) within a computerised general practitioner database. METHODS: Retrospective survey of prescribing data for premenstrual syndrome between 1993–1998 using the General Practice Research Database for the West Midlands Region which contains information on 282,600 female patients RESULTS: Overall the proportion of women with a prescription-linked diagnosis of premenstrual syndrome has halved over the five years. Progestogens including progesterone were the most commonly recorded treatment for premenstrual syndrome during the whole study period accounting for over 40% of all prescriptions. Selective serotonin-reuptake inhibitors accounted for only 2% of the prescriptions in 1993 but rose to over 16% by 1998, becoming the second most commonly recorded treatment. Vitamin B6 accounted for 22% of the prescriptions in 1993 but dropped markedly between 1997 and 1998 to 11%. CONCLUSIONS: This study shows a yearly decrease in the number of prescriptions linked to diagnoses for premenstrual syndrome. Progestogens including progesterone, is the most widely prescribed treatment for premenstrual syndrome despite the lack of evidence demonstrating their efficacy

Panspermia, Past and Present: Astrophysical and Biophysical Conditions for the Dissemination of Life in Space

Astronomically, there are viable mechanisms for distributing organic material throughout the Milky Way. Biologically, the destructive effects of ultraviolet light and cosmic rays means that the majority of organisms arrive broken and dead on a new world. The likelihood of conventional forms of panspermia must therefore be considered low. However, the information content of dam-aged biological molecules might serve to seed new life (necropanspermia).Comment: Accepted for publication in Space Science Review

The TURis System for Transurethral Resection of the Prostate: A NICE Medical Technology Guidance

The transurethral resection in saline (TURis) system was notified by the company Olympus Medical to the National Institute of Health and Care Excellence’s (NICE’s) Medical Technologies Evaluation Programme. Following selection for medical technologies guidance, the company developed a submission of clinical and economic evidence for evaluation. TURis is a bipolar surgical system for treating men with lower urinary tract symptoms due to benign prostatic enlargement. The comparator is any monopolar transurethral resection of the prostate (mTURP) system. Cedar, a collaboration between Cardiff and Vale University Health Board, Cardiff University and Swansea University in the UK, acted as an External Assessment Centre (EAC) for NICE to independently critique the company’s submission of evidence. Eight randomised trials provided evidence for TURis, demonstrating efficacy equivalent to that of mTURP for improvement of symptoms. The company presented meta-analyses of key outcome measures, and the EAC made methodological modifications in response to the heterogeneity of the trial data. The EAC analysis found that TURis substantially reduced the relative risks of transurethral resection syndrome (relative risk 0.18 [95 % confidence interval 0.05–0.62]) and blood transfusion (relative risk 0.35 [95 % confidence interval 0.19–0.65]). The company provided a de novo economic model comparing TURis with mTURP. The EAC critiqued the model methodology and made modifications. This found TURis to be cost saving at £70.55 per case for existing Olympus customers and cost incurring at £19.80 per case for non-Olympus customers. When an additional scenario based on the only available data on readmission (due to any cause) from a single trial was modelled, the estimated cost saving per case was £375.02 for existing users of Olympus electrosurgery equipment and £284.66 per case when new Olympus equipment would need to be purchased. Meta-analysis of eight randomised trials showed that TURis is associated with a statistically significantly reduced risk of transurethral resection syndrome and a reduced need for blood transfusion—two factors that may drive cost saving for the National Health Service. The clinical data are equivocal as to whether TURis shortens the hospital stay. Limited data from a single study suggest that TURis may reduce the rate of readmission after surgery. The NICE guidance supports adoption of the TURis technology for performing transurethral resection of the prostate in men with lower urinary tract symptoms due to benign prostatic enlargemen