The effect of comorbidities on diagnostic interval for lung cancer in England: a cohort study using electronic health record data.

BackgroundComorbid conditions may delay lung cancer diagnosis by placing demand on general practioners’ time reducing the possibility of prompt cancer investigation (“competing demand conditions”), or by offering a plausible non-cancer explanation for signs/symptoms (“alternative explanation conditions”).MethodPatients in England born before 1955 and diagnosed with incident lung cancer between 1990 and 2019 were identified in the Clinical Practice Research Datalink and linked hospital admission and cancer registry data. Diagnostic interval was defined as time from first presentation in primary care with a relevant sign/symptom to the diagnosis date. 14 comorbidities were classified as ten “competing demand“ and four “alternative explanation” conditions. Associations with diagnostic interval were investigated using multivariable linear regression models.ResultsComplete data were available for 11870 lung cancer patients. In adjusted analyses diagnostic interval was longer for patients with “alternative explanation” conditions, by 31 and 74 days in patients with one and ≥2 conditions respectively versus those with none. Number of “competing demand” conditions did not remain in the final adjusted regression model for diagnostic interval.ConclusionsConditions offering alternative explanations for lung cancer symptoms are associated with increased diagnostic intervals. Clinical guidelines should incorporate the impact of alternative and competing causes upon delayed diagnosis.</p

Genital modifications in prepubescent minors: when may clinicians ethically proceed?

When is it ethically permissible for clinicians to surgically intervene into the genitals of a legal minor? We distinguish between voluntary and nonvoluntary procedures and focus on nonvoluntary procedures, specifically in prepubescent minors ("children"). We do not address procedures in adolescence or adulthood. With respect to children categorized as female at birth who have no apparent differences of sex development (i.e., non-intersex or "endosex" females) there is a near-universal ethical consensus in the Global North. This consensus holds that clinicians may not perform any nonvoluntary genital cutting or surgery, from "cosmetic" labiaplasty to medicalized ritual "pricking" of the vulva, insofar as the procedure is not strictly necessary to protect the child's physical health. All other motivations, including possible psychosocial, cultural, subjective-aesthetic, or prophylactic benefits as judged by doctors or parents, are seen as categorically inappropriate grounds for a clinician to proceed with a nonvoluntary genital procedure in this population. We argue that the main ethical reasons capable of supporting this consensus turn not on empirically contestable benefit-risk calculations, but on a fundamental concern to respect the child's privacy, bodily integrity, developing sexual boundaries, and (future) genital autonomy. We show that these ethical reasons are sound. However, as we argue, they do not only apply to endosex female children, but rather to all children regardless of sex characteristics, including those with intersex traits and endosex males. We conclude, therefore, that as a matter of justice, inclusivity, and gender equality in medical-ethical policy (we do not take a position as to criminal law), clinicians should not be permitted to perform any nonvoluntary genital cutting or surgery in prepubescent minors, irrespective of the latter's sex traits or gender assignment, unless urgently necessary to protect their physical health. By contrast, we suggest that voluntary surgeries in older individuals might, under certain conditions, permissibly be performed for a wider range of reasons, including reasons of self-identity or psychosocial well-being, in keeping with the circumstances, values, and explicit needs and preferences of the persons so concerned. Note: Because our position is tied to clinicians' widely accepted role-specific duties as medical practitioners within regulated healthcare systems, we do not consider genital procedures performed outside of a healthcare context (e.g., for religious reasons) or by persons other than licensed healthcare providers working in their professional capacity.</p

The role of GPI-anchored membrane-bound alkaline phosphatase in the mode of action of Bt Cry1A toxins in the diamondback moth

The insecticidal Cry proteins produced by the bacterium Bacillus thuringiensis (Bt) are extensively used for pest control in formulated sprays and in genetically modified crops, but resistance to Bt toxins threatens their sustainable use in agriculture. Understanding the molecular mechanisms involved in Bt pathogenesis is crucial for the development of effective resistance management strategies. Previously, we showed a strong correlation between Cry1Ac resistance in Plutella xylostella (L.) and down-regulation of the glycosylphosphatidylinositol (GPI)-anchored membrane-bound alkaline phosphatase (mALP) and aminopeptidase (APN) and members of the ATP-binding cassette (ABC) transporter subfamily C (ABCC), but we do not yet have a clear understanding of the relative contribution of each midgut receptor type. Here, a P. xylostella strain homozygous for the PxmALP gene knockout was generated using CRISPR/Cas9 and the results showed that this strain had a 294-fold resistance to Cry1Ac toxin and 394-fold cross-resistance to Cry1Ab. Moreover, a triple knockout strain lacking PxmALP, PxABCC2, and PxABCC3 exhibited 9,660-fold resistance to Cry1Ac and 5,662-fold cross-resistance to Cry1Ab. These resistance levels surpassed those observed in the previously described double PxABCC2 and PxABCC3 knockout mutant, revealing a functional redundancy between ABC transporters and PxmALP. In addition, the activity of Cry1A toxins against Sf9 cells expressing PxmALP, PxABCC2 or PxABCC3 confirmed that each of these can act as a functional receptor. Our findings are crucial for unraveling the relative role of multiple receptors and the molecular mechanisms underlying Bt resistance in insects.</p

Arbitrage opportunities and efficiency tests in crypto options

We test the joint efficiency of the bitcoin and ether options and perpetual futures markets and identify the determinants of arbitrage opportunities. Our novel fiat-currency-free put–call parity relationship motivates new arbitrage tests for options-only and option-perpetual cross-markets. Bitcoin and ether derivatives markets are becoming more efficient, especially for options of maturity > 15 days. Bitcoin derivative markets are generally more efficient than ether derivative markets, but arbitrage strategies can still be highly profitable even under conservative transaction cost scenarios, which include slippage for large orders, especially during periods of high trading volumes or when the blockchain traffic becomes more congested.</p

Assembling privatisation policy and practice in Saudi Arabia

New Public Management (NPM) has proved to be irresistible among governments in discussions about public sector reform. Traditionally, it encompasses a concerted effort to improve accountability, decentralisation and cost-efficiency. Unfortunately, it often fails to deliver these promises, and research reveals complexities of dissemination, resulting in a persistent divergence between theoretical promises and real-world implementation. Despite this, the NPM doctrine has been transferred from Western countries to developing countries and in Saudi Arabia, it has become the primary policy objective. This thesis investigates the evolution and enactment of the Saudi government’s policy for privatisation. The ontology of privatisation policy is examined by addressing three subsidiary questions: (1) how has privatisation policy evolved over the last twenty years? (2) who or what are the dominant actors driving change? and (3) how does it compare to the promises presented in the Saudi government’s official policy discourses and publications? An actor-network theory-inspired performative case study is developed to trace the re-assembling of privatisation between 1995 and 2022. The findings demonstrate inertia and an incapacity to turn the black-box of the privatisation policy into reality with a prolonged period of stasis due to counterbalancing struggles and suspicions between three dominant actors: leadership, delegated authority and urgency. This thesis contributes to Callon’s (1980;1986) study of translation and displacement and his conceptualisation of the socio-logical structure of problematics, certainties and suspicions. Fundamentally, problematics are observed as being synonymous with cognitive intentions rather than specific spokespeople. As a result of this, there is a persistence of suspicions that continue to destabilise certainties. Practical recommendations describe the need for a closer evaluation of each sector’s socio-economic strengths and weaknesses alongside developing a more comprehensive privatisation plan with sectoral milestones, a schedule for implementation and more realistic timescales. Furthermore, specific transformational processes are recommended underpinned by complexity leadership.</p

Contract, Social Relations and the Outsourcing of Publicly Funded Health Care

A prominent and consistent element of Chris Newdick’s work can be understood as a focus on the nature of relations in health care and health care law. Specifically, he has emphasised and defended the importance of social solidarity and community as core values against the dominant focus on and championing of an individual sense of autonomy in those areas. This article takes up the theme of relations in a different context, exploring the nature of the social relations underpinning the increasing role played by the private sector in delivering publicly funded health care. It does so by considering two instances of outsourcing – the Private Finance Initiative and the UK Government’s awarding of contracts as part of its response to the COVID-19 pandemic. It is argued that those examples disclose relations between the state, citizens, and what the sociologist Wolfgang Streeck calls the marktvolk (the people of the market) that cannot be comprehended via the notions of solidarity and community traditionally associated with a publicly funded health care system like the UK’s National Health Service. Indeed, the social relations involving the marktvolk – including, for instance, the importance of one’s status and duties of loyalty based on acquaintance – tend to have the effect of, in Newdick’s phrase, ‘corroding [the traditional form of] social solidarity’. Thus, while important, it is not only the stress on individual autonomy and rights that has this corrosive effect; other forms of social relations – including those involving elites and revolving around capital – have this impact too and demand exploration.</p

Mail art methods and the social and cultural geographies of families affected by rare disease

Building on geographic scholarship around disability and drawing on a programme of arts-based research, we bring attention to the social and cultural geographies of families affected by rare disease. Seeking creative methodological opportunities, we invited families to send us postcards as a means of sharing experiences and reflections. We contextualize the emergence of the postcard as a modality of communication, situating our work within a wider epistolary and artistic tradition, before examining the opportunities postcarding might produce for geographic and broader qualitative research, noting the forms conduciveness to multimodality and recent calls for more engagement with the medium. We detail our own practices of participatory postcarding and the questions, challenges, and hopes such raised. Analysing the postcards received, we discuss how such helps understand the shifting social and cultural geographies of rare disease, reflecting on themes of (in)accessibility and exclusion, changing domestic geographies, and the importance of, and challenges associated with, family-based identities and communities in the context of rare disease. Such highlights opportunities for disability geography to engage in cross-cutting conversations and agenda-building with the nascent area of family geographies, along with further geographic inquiry into the spaces and worlds of rare disease.</p

Conditioning- and reward-related dendritic and presynaptic plasticity of nucleus accumbens neurons in male and female sign-tracker rats

For a subset of individuals known as sign-trackers, discrete Pavlovian cues associated with rewarding stimuli can acquire incentive properties and exert control over behaviour. Because responsiveness to cues is a feature of various neuropsychiatric conditions, rodent models of sign-tracking may prove useful for exploring the neurobiology of individual variation in psychiatric vulnerabilities. Converging evidence points towards the involvement of dopaminergic neurotransmission in the nucleus accumbens core (NAc) in the development of sign-tracking, yet whether this phenotype is associated with specific accumbal postsynaptic properties is unknown. Here, we examined dendritic spine structural organisation, as well as presynaptic and postsynaptic markers of activity, in the NAc core of male and female rats following a Pavlovian conditioned approach procedure. In contrast to our prediction that cue re-exposure would increase spine density, experiencing the discrete lever-cue without reward delivery resulted in lower spine density than control rats for which the lever was unpaired with reward during training; this effect was tempered in the most robust sign-trackers. Interestingly, this same behavioural test (lever presentation without reward) resulted in increased levels of a marker of presynaptic activity (synaptophysin), and this effect was greatest in female rats. While some behavioural differences were observed in females during initial Pavlovian training, final conditioning scores did not differ from males and were unaffected by the oestrous cycle. This work provides novel insights into how conditioning impacts the neuronal plasticity of the NAc core, whilst highlighting the importance of studying the behaviour and neurobiology of both male and female rats.</p

The perceived beauty of art is not strongly calibrated to the statistical regularities of real-world scenes.

Aesthetic judgements are partly predicted by image statistics, although the extent to which they are calibrated to the statistics of real-world scenes and the ‘visual diet’ of daily life is unclear. Here, we investigated the extent to which the beauty ratings of Western oil paintings from the JenAesthetics dataset can be accounted for by real-world scene statistics. We computed spatial and chromatic image statistics for the paintings and a set of real-world scenes captured by a head-mounted camera as participants went about daily lives. Partial least squares regression (PLSR) indicated that 6-15% of the variance in beauty ratings of the art can be accounted for by the art’s image statistics. The luminance contrast of paintings made an important contribution to the PLSR models: paintings were perceived as more beautiful the greater the variation in luminance. PLSR models which expressed the art’s image statistics relative to real-world scene statistics explained a similar amount of variance than models using the art’s image statistics. The importance of an image statistic to perceived beauty was not related to how closely art reproduces the value from the real world. The findings suggest that beauty judgements of art are not strongly calibrated to the real world.</p

Unveiling the Distant Universe: Characterizing z ≥ 9 Galaxies in the First Epoch of COSMOS-Web

We report the identification of 15 galaxy candidates at z ≥ 9 using the initial COSMOS-Web JWST observations over 77 arcmin2 through four Near Infrared Camera filters (F115W, F150W, F277W, and F444W) with an overlap with the Mid-Infrared Imager (F770W) of 8.7 arcmin2. We fit the sample using several publicly available spectral energy distribution (SED) fitting and photometric redshift codes and determine their redshifts between z = 9.3 and z = 10.9 (〈z〉 = 10.0), UV magnitudes between M UV = −21.2 and −19.5 (with 〈M UV〉 = −20.2), and rest-frame UV slopes (〈β〉 = −2.4). These galaxies are, on average, more luminous than most z ≥ 9 candidates discovered by JWST so far in the literature, while exhibiting similar blue colors in their rest-frame UV. The rest-frame UV slopes derived from SED fitting are blue (β ∼ [−2.0, −2.7]) without reaching extremely blue values as reported in other recent studies at these redshifts. The blue color is consistent with models that suggest the underlying stellar population is not yet fully enriched in metals like similarly luminous galaxies in the lower-redshift Universe. The derived stellar masses with 〈 log 10 ( M ⋆/M ⊙)〉 ≈ 8-9 are not in tension with the standard Lambda cold dark matter (ΛCDM) model, and our measurement of the volume density of such UV-luminous galaxies aligns well with previously measured values presented in the literature at z ∼ 9-10. Our sample of galaxies, although compact, is significantly resolved.</p