`What is a Thing?': Topos Theory in the Foundations of Physics

The goal of this paper is to summarise the first steps in developing a fundamentally new way of constructing theories of physics. The motivation comes from a desire to address certain deep issues that arise when contemplating quantum theories of space and time. In doing so we provide a new answer to Heidegger's timeless question ``What is a thing?''. Our basic contention is that constructing a theory of physics is equivalent to finding a representation in a topos of a certain formal language that is attached to the system. Classical physics uses the topos of sets. Other theories involve a different topos. For the types of theory discussed in this paper, a key goal is to represent any physical quantity $A$ with an arrow \breve{A}_\phi:\Si_\phi\map\R_\phi where \Si_\phi and $\R_\phi$ are two special objects (the `state-object' and `quantity-value object') in the appropriate topos, $\tau_\phi$. We discuss two different types of language that can be attached to a system, $S$. The first, \PL{S}, is a propositional language; the second, \L{S}, is a higher-order, typed language. Both languages provide deductive systems with an intuitionistic logic. With the aid of \PL{S} we expand and develop some of the earlier work (By CJI and collaborators.) on topos theory and quantum physics. A key step is a process we term `daseinisation' by which a projection operator is mapped to a sub-object of the spectral presheaf \Sig--the topos quantum analogue of a classical state space. The topos concerned is \SetH{}: the category of contravariant set-valued functors on the category (partially ordered set) \V{} of commutative sub-algebras of the algebra of bounded operators on the quantum Hilbert space \Hi.Comment: To appear in ``New Structures in Physics'' ed R. Coeck

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Developmental programming of obesity and type 2 diabetes

Obesity and type 2 diabetes are serious health issues in the developed world and are becoming increasingly important on a global scale. Furthermore, the marked increases in both childhood obesity and type 2 diabetes will translate to further increases in adult obesity, diabetes and associated co-morbidities in the near future; as such it has been ranked as a critical public health threat. It is a widely held view that the primary cause of obesity is the development of an obesogenic environment, due to ease of access to highly calorific food and reduced energy expenditure in work and leisure activities. In addition there is strong evidence for a genetic component to human obesity with the identification of a number of genes associated with human obesity. However, on its own the genetic component of this condition cannot account for the dramatic increase in the prevalence of obesity in recent years. Of relevance and as highlighted by epidemiological and experimental studies, is the relationship between the periconceptual, fetal and early infant phases of life and the subsequent development of adult obesity. The terms “developmental programming” and the “Developmental Origins of Adult Health and Disease” are preferentially used to describe these relationships. Despite initial controversy when these relationships were first suggested, both prospective clinical and experimental studies have clearly shown that the propensity to develop abnormalities of cardiovascular, endocrine and metabolic homeostasis in adulthood are increased when fetal development has been adversely affected. This pathogenesis is not based on genetic defects but on altered gene expression seen as a result of fetal adaptation to an adverse intrauterine environment. The relative role of genetic versus environmental factors and the mechanisms underlying developmental programming remain speculative. It is generally argued that in response to an adverse intrauterine environment, the fetus adapts its physiological development to maximise its immediate chances for survival. Owing to the plasticity of the fetus, these adaptations may include resetting of metabolic homeostasis and endocrine systems and the down-regulation of growth, commonly reflected in an altered birth phenotype. It is thought that whilst these changes in fetal physiology (i.e. the prenatal environment) may be beneficial for short term survival in utero they may be maladaptive in postnatal life, contributing to poor health outcomes when offspring are exposed to catch-up growth, diet-induced obesity and other factors. The “predictive adaptive response” hypothesis proposes that the degree of mismatch between the pre- and postnatal environments is a major determinant of subsequent disease. This review will address recent work in animal models and observations in the clinical and epidemiological settings on in utero adaptations and subsequent development of obesity and type 2 diabete

Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition

The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most important advances in epidemiology research of recent years. There is now increasing evidence that alterations in the fetal environment have long-term consequences on metabolic and endocrine pathophysiology in adult life. This process has been termed "fetal programming," and we have shown that undernutrition of the mother during gestation leads to obesity, hypertension, hyperphagia, hyperinsulinemia, and hyperleptinemia in offspring. Using this model of maternal undernutrition throughout pregnancy, we investigated whether prenatal influences may lead to alterations in postnatal locomotor behavior, independent of postnatal nutrition. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum (ad libitum group) or at 30% of ad libitum intake (undernourished group). Offspring from UN mothers were significantly smaller at birth than AD offspring. At weaning, offspring were assigned to one of two diets [control or hypercaloric (30% fat)]. At ages of 35 days, 145 days, and 420 days, voluntary locomotor activity was assessed. At all ages studied, offspring from undernourished mothers were significantly less active than offspring born of normal birth weight for all parameters measured, independent of postnatal nutrition. Sedentary behavior in programmed offspring was exacerbated by postnatal hypercaloric nutrition. This work is the first to clearly separate prenatal from postnatal effects and shows that lifestyle choices themselves may have a prenatal origin. We have shown that predispositions to obesity, altered eating behavior, and sedentary activity are linked and occur independently of postnatal hypercaloric nutrition. Moreover, the prenatal influence may be permanent as offspring of undernourished mothers were still significantly less active compared with normal offspring at an advanced adult age, even in the presence of a healthy diet throughout postnatal life

Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat

Growth hormone (GH) therapy is often associated with adverse side effects, including impaired insulin sensitivity. GH treatment of children with idiopathic short stature does not lead to an optimized final adult height. It has been demonstrated that FFA reduction induced by pharmacological antilipolysis can stimulate GH secretion per se in both normal subjects and those with GH deficiency. However, to date, no investigation has been undertaken to establish efficacy of combination treatment with GH and FFA regulators on linear body growth. Using a model of maternal undernutrition in the rat to induce growth-restricted offspring, we investigated the hypothesis that combination treatment with GH and FFA regulators can enhance linear body growth above that of GH alone. At postnatal day 28, male offspring of normally nourished mothers (controls) and offspring born with low birth weight [small for gestational age (SGA)] were treated with saline, GH, or GH (5 mg.kg(-1).day(-1)) in combination with acipimox (GH + acipimox, 20 mg.kg(-1).day(-1)) or fenofibrate (GH + fenofibrate, 30 mg.kg(-1).day(-1)) for 40 days. GH plus acipimox treatment significantly enhanced linear body growth in the control and SGA animals above that of GH, as quantified by tibial and total body length. Treatment with GH significantly increased fasting plasma insulin, insulin-to-glucose ratio, and plasma volumes in control and SGA animals but was not significantly different between saline and GH-plus-acipimox-treated animals. GH-induced lipolysis was blocked by GH plus acipimox treatment in both control and SGA animals, concomitant with a significant reduction in fasting plasma FFA and insulin concentrations. This is the first study to show that GH plus acipimox combination therapy, via pharmacological blocking of lipolysis during GH exposure, can significantly enhance the efficacy of GH in linear growth promotion and ameliorate unwanted metabolic side effect