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SummaryNonalcoholic fatty liver disease (NAFLD) is multifactorial in nature, affecting over a billion people worldwide. The gut microbiome has emerged as an associative factor in NAFLD, yet mechanistic contributions are unclear. Here, we show fast food (FF) diets containing high fat, added cholesterol, and fructose/glucose drinking water differentially impact short- vs. long-term NAFLD severity and progression in conventionally-raised, but not germ-free mice. Correlation and machine learning analyses independently demonstrate FF diets induce early and specific gut microbiota changes that are predictive of NAFLD indicators, with corresponding microbial community instability relative to control-fed mice. Shotgun metagenomics showed FF diets containing high cholesterol elevate fecal pro-inflammatory effectors over time, relating to a reshaping of host hepatic metabolic and inflammatory transcriptomes. FF diet-induced gut dysbiosis precedes onset and is highly predictive of NAFLD outcomes, providing potential insights into microbially-based pathogenesis and therapeutics.HighlightsGerm-free mice are protected from fast-food diet-induced NAFLD.Fast-food diets rapidly shift gut microbiota composition and function.Increasing dietary cholesterol exacerbates hepatic inflammation only in SPF mice.Fast-food diet-induced gut dysbiosis precedes and predicts late-stage NAFLD severity.

Radiation Portal Monitors (RPMs) are our primary border defense against nuclear smuggling, but are they still the best way to spend limited funds? The purpose of this research is to strategically compare RPM defense at the border with state-side mobile detectors. Limiting the problem to a comparison of two technologies, a decision-maker can prioritize how to best allocate resources, by reinforcing the border with stationary overt RPMs, or by investing in Mobile Radiation Detection Systems (MRDs) which are harder for an adversary to detect but may have other weaknesses. An abstract, symmetric network was studied to understand the impact of initial conditions on a network. An asymmetric network, loosely modeled on a state transportation system, is then examined for the technology that will maximally suppress the adversary's success rate. We conclude that MRDs, which have the advantage of discrete operation, outperform RPMs deployed to a border. We also conclude that MRDs maintain this strategic advantage if they operate with one-tenth the relative efficiency of their stationary counter-parts or better. Keywords: Terrorism, Smuggling, Second line of defense, Transportation, Border, RPM

Epidemiological simulations as a method are used to better understand and predict the spreading of infectious diseases, for example of COVID-19.This paper presents an approach that combines a well-established approach from transportation modelling that uses person-centric data-driven human mobility modelling with a mechanistic infection model and a person-centric disease progression model. The model includes the consequences of different room sizes, air exchange rates, disease import, changed activity participation rates over time (coming from mobility data), masks, indoors vs. outdoors leisure activities, and of contact tracing. The model is validated against the infection dynamics in Berlin (Germany).The model can be used to understand the contributions of different activity types to the infection dynamics over time. The model predicts the effects of contact reductions, school closures/vacations, masks, or the effect of moving leisure activities from outdoors to indoors in fall, and is thus able to quantitatively predict the consequences of interventions. It is shown that these effects are best given as additive changes of the reinfection rate R. The model also explains why contact reductions have decreasing marginal returns, i.e. the first 50% of contact reductions have considerably more effect than the second 50%.Our work shows that is is possible to build detailed epidemiological simulations from microscopic mobility models relatively quickly. They can be used to investigate mechanical aspects of the dynamics, such as the transmission from political decisions via human behavior to infections, consequences of different lockdown measures, or consequences of wearing masks in certain situations. The results can be used to inform political decisions.Author summaryEvidently, there is an interest in models that are able to predict the effect of interventions in the face of pandemic diseases. The so-called compartmental models have difficulties to include effects that stem from spatial, demographic or temporal inhomongeneities. Person-centric models, often using social contact matrices, are difficult and time-consuming to build up. In the present paper, we describe how we built a largely data-driven person-centric infection model within less than a month when COVID-19 took hold in Germany. The model is based on our extensive experience with mobility modelling, and a synthetic data pipeline that starts with mobile phone data, while taking the infection dynamics and the disease progression from the literature. The approach makes the model portable to all places that have similar so-called activity-based models of travel in place, which are many places world-wide, and the number is continuously increasing. The model has been used since its inception to regularly advise the German government on expected consequences of interventions.

BACKGROUND: Whole blood is optimal for resuscitation of traumatic hemorrhage. Walking Blood Banks provide fresh whole blood (FWB) where conventional blood components or stored, tested whole blood are not readily available. There is an increasing interest in this as an emergency resilience measure for isolated communities and during crises including the coronavirus disease 2019 pandemic. We conducted a systematic review and meta-analysis of the available evidence to inform practice. METHODS: Standard systematic review methodology was used to obtain studies that reported the delivery of FWB (PROSPERO registry CRD42019153849). Studies that only reported whole blood from conventional blood banking were excluded. For outcomes, odds ratios (ORs) and 95% confidence interval (CI) were calculated using random-effects modeling because of high risk of heterogeneity. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system. RESULTS: Twenty-seven studies published from 2006 to 2020 reported >10,000 U of FWB for >3,000 patients (precise values not available for all studies). Evidence for studies was "low" or "very low" except for one study, which was "moderate" in quality. Fresh whole blood patients were more severely injured than non-FWB patients. Overall, survival was equivalent between FWB and non-FWB groups for eight studies that compared these (OR, 1.00 [95% CI, 0.65-1.55]; p = 0.61). However, the highest quality study (matched groups for physiological and injury characteristics) reported an adjusted OR of 0.27 (95% CI, 0.13-0.58) for mortality for the FWB group (p < 0.01). CONCLUSION: Thousands of units of FWB from Walking Blood Banks have been transfused in patients following life-threatening hemorrhage. Survival is equivalent for FWB resuscitation when compared with non-FWB, even when patients were more severely injured. Evidence is scarce and of relative low quality and may underestimate potential adverse events. Whereas Walking Blood Banks may be an attractive resilience measure, caution is still advised. Walking Blood Banks should be subject to prospective evaluation to optimize care and inform policy. LEVEL OF EVIDENCE: Systematic/therapeutic, level 3.

Background: Achondroplasia (ACH) is the most common skeletal dysplasia and the most frequent form of dwarfism. ACH is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene and results in impairment of the endochondral ossification processes. C-type natriuretic peptide (CNP) promotes chondrocyte development through inhibition of the FGFR3 pathway, specifically through activation of NPRB. CNP is a desirable target as it is known to increase chondrocyte development without off-target effects (Bocciardi, 2007). TransCon CNP is a long-acting prodrug of CNP designed to optimize safety and efficacy with a once-weekly dose. The Phase 1 clinical trial with TransCon CNP demonstrated that doses up to 150 μg CNP/kg were well-tolerated in healthy adult male volunteers, with no clinically significant trends observed in clinical laboratory assessments, vital sign measurements, ECG parameters, or physical examination findings. Methods: The phase 2 ACcomplisH trial will be conducted at over 35 sites worldwide. The primary objective of the trial will be to evaluate the safety and efficacy of once-weekly TransCon CNP compared to placebo at 12 months in prepubertal children, aged 2-10 years old, with ACH. Approximately 60 subjects will be randomized 3:1 to receive either weekly TransCon CNP or placebo. Following screening and verification of clinical ACH with genetic confirmation, subjects will remain within the dose cohort for 52 weeks of treatment. TransCon CNP will be dosed 6 to 100 μg CNP/kg/week across 4 cohorts, with an optional 5th cohort at up to 200 μg CNP/kg/week. An independent Data Monitoring Committee will review safety data prior to initiation of a higher dose cohort. The primary endpoint will evaluate annualized height velocity at 52 weeks of TransCon CNP or placebo. Key secondary endpoints will examine change in upper to lower body segment ratio at week 52, safety, pharmacokinetics (PK), and quality of life associated with weekly TransCon CNP. Conclusion: CNP is targeted specifically to the underlying pathology of ACH through inhibition FGFR3. No effective medicinal product is currently available for the treatment of ACH. TransCon CNP is designed to provide sustained exposure of CNP. This ongoing Phase 2 ACcomplisH trial is designed to assess the efficacy, safety, and PK of TransCon CNP by weekly administration compared to placebo.

Background: FGF21 is an endogenous hormone that regulates carbohydrate, lipid and energy metabolism. FGF21 analogs improve liver and metabolic abnormalities in non-alcoholic steatohepatitis (NASH). BIO89-100 is a long-acting glycoPEGylated FGF21, with promising tolerability and pharmacodynamic effects and potential for QW or Q2W dosing. Methods: This Phase 1b/2a trial enrolled 81 subjects with liver fat ≥10% by MRI-PDFF and either biopsy-confirmed NASH (BC-NASH) or phenotypic NASH (PNASH: central obesity with either type 2 diabetes mellitus or with evidence of liver injury by ALT or FibroScan vibration controlled transient elastography score above defined thresholds). Subjects were randomized to 12 weeks of treatment at one of 6 doses (3, 9, 18 or 27mg weekly [QW]; 18 or 36mg Q2W) or placebo. Key endpoints were safety, tolerability, pharmacokinetics, change in liver fat content as measured by MRI-PDFF and liver and metabolic markers. Results: Baseline characteristics were generally similar between pooled BIO89-100 v. pooled placebo groups, and between BC-NASH v. PNASH subjects. At week 13, all BIO89-100 dose groups showed significant relative reductions up to 70% (placebo adjusted p45 U/L (35 U/L decrease from baseline, p

Background: Achondroplasia (ACH) is the most common form of dwarfism occurring in 1 in 22,000 births (95% CI 18,500 to 26,000). This skeletal dysplasia is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene located on chromosome 4p16.3 and results in sustained activation of the FGFR3 pathway leading to impaired chondrogenesis and endochondral bone formation. Both typical childhood growth patterns and the impaired linear growth of ACH are modulated by the delicate balance between growth-inhibiting FGFR3/mitogen-activated phosphokinase and growth-promoting c-type natriuretic peptide/natriuretic peptide receptor B. Individuals with ACH frequently develop clinically significant comorbidities, many with onset during childhood. Currently, there are no therapies addressing the underlying pathology. Most available treatments are surgical with goals to alleviate the symptoms from specific comorbidities (i.e. foramen magnum and spinal stenosis or recurrent otitis media). Since the available therapies do not address the underlying etiology, individuals with ACH often undergo multiple surgeries and myriad other forms of supportive care throughout their lives. The precise timing of comorbidity onset and the natural history of many of the skeletal dysplasia features are incompletely defined. This information is needed to inform the design and conduct of pathology-targeted intervention studies. Aim: The purpose of this study is to gather information about the precise timing of comorbidity onset, the longitudinal growth trajectory, and the evolution of body proportionality in children with ACH. Methods and Future Results: The ACHieve study (NCT03875534) is a multi-center, longitudinal, observational cohort study in children with ACH from birth up to 8 years at enrollment. In this non-therapeutic study, children are evaluated every six months for up to 5 years in 25 centers from North America, Europe and Oceania. The first patient was enrolled in 2019 and a total of 84 children have been enrolled to date. At each assessment, children undergo comprehensive anthropometric studies, (including body proportionality measurements and recumbent or standing height) and information on the timing and nature of ACH-related comorbidities and their treatments are collected. Additional information about the baseline demographics, including sex, age distribution, race/ethnicity, and height standard deviation scores will be presented at the time of conference. Conclusions: The ACHieve study will provide additional insight into the natural history of growth, body proportionality, and comorbidities in children with ACH. These observations will serve as a benchmark for future intervention trials targeting the pathology of the underlying skeletal dysplasia.

OBJECTIVE Parental diabetes history is a well-known risk factor for type 2 diabetes and considered strong evidence for a genetic basis of type 2 diabetes. Whether this relationship is affected by other known risk factors, specifically obesity, remains unclear, possibly due to a relative paucity of lean diabetic patients. RESEARCH DESIGN AND METHODS This issue was investigated using data from a high-risk population from Mexico (National Health Survey 2000, n = 27,349), with observations replicated using U.S. citizens of Mexican descent from the National Health and Nutrition Examination Survey 2001–2002 and 2003–2004 (n = 1,568). RESULTS As expected, positive parental diabetes was a significant risk factor for type 2 diabetes, regardless of age, sex, or adiposity level. However, positive parental diabetes conferred greater risk in leaner individuals than in their overweight peers (P = 0.001). In other words, the effect of BMI on type 2 diabetes risk was smaller in the presence of parental diabetes history. CONCLUSIONS These findings suggest that parental diabetes is a stronger risk factor for type 2 diabetes in the absence of obesity. Thus, studies in lean diabetic patients could help identify type 2 diabetes susceptibility genes. This study reinforces the concept that parental diabetes and BMI are independent type 2 diabetes risk factors and suggests that glycemic screening may be helpful in assessing type 2 diabetes risk in individuals with parental diabetes history, regardless of their overweight status.

The paper presents goodness and truth as analogous formal concepts. I first argue that saying something is true of something and saying it is false of it are basic ways of speaking truly or falsely. I then consider thinking a property a good one for something to acquire and thinking it a bad, equate this with having something as a positive or negative objective, an object of desire or aversion, and argue that these are basic ways of thinking rightly or wrongly. Finally I discuss the notions of a way of speaking or thinking, making special reference to Frege’s ‘Negation’ and ‘The Thought.’

Foreword GODFREY VESEY Reason in mystery NORMAN KRETZMANN Logos and Trinity: patterns of Platonist influence on early Christianity JOHN DILLON The philosophy in Christianity: Arius and Athanasius MAURICE WILES Could God become Man? RICHARD SWINBURNE Augustine's philosophy of being CHRISTOPHER STEAD Predestination and freedom in Augustine's ethics GERALD O'DALY God as creator KEITH WARD Foreknowledge and the vulnerability of God I. R. LUCAS On not knowing too much about God A. H. ARMSTRONG Where two are to become one: mysticism and monism GRACE JANTZEN Faith and goodness ELEONORE STUMP Hope STEWART SUTHERLAND Christian averroism, fideism, and the "two-fold truth" STUART BROWN Does philosophy 'leave everything as it is'? Even theology RENFORD BAMBROUGH.

At the beginning of the De A nima, having observed that it is difficult to say even how we should set about enquiring into the soul, Aristotle lists a number of questions: (1) To what logical kind of thing does soul belong? Does 'soul' signify a particular individual and a substance, or does it rather express a quality amount or the like? (402 a 24-5). (2) Is a soul a thing which exists in dunamis or rather a kind of entelecheia words usually translated 'potentiality' and 'actuality'? (402 a 25-6). (3) Is a soul a thing with parts? (402 b 1). (4) Is all soul the same in kind or are there different souls, the soul of a horse, the soul of a dog, the soul of a man, and so on? (402 b 1-8). These questions are not answered in Book I, which consists mainly of an examination of the views of other thinkers. (1) and (2), however, are tackled in De An. II. 1, and (4) in II. 3. Aristotle decides that the notion of a soul is, in a way, the notion of a particular individual and a substance; that it is the notion of an entelecheia; and that there are as many different souls as there are kinds of living thing. This paper will be concerned chiefly with the second point, which is, I think, at once the obscurest and the most important. Aristotle's formal definition of soul, reached through a series of approximations, is translated by D. W. Hamlyn (Aristotle's De Anima, Books II and III, p. 9) as follows

In 1956 Hugh R. King attacked the traditional view that Aristotle postulates what the tradition calls 'prime matter'. He drew replies from Friedrich Solmsen in 1958 and A. R. Lacey in 1965. In an appendix to my translation of Physics I-II in 1970 I offered independent arguments for a position similar to King's. My arguments were criticized by H. M. Robinson in 1974 and R. M. Dancy in 1978. Now C. J. F. Williams, in another appendix, though he thinks that Solmsen and Robinson have 'made out their case', makes it out afresh with special reference to the De Generatione el Corruptione. If Williams is to escape the charge of flogging a dead horse, I must attempt a rejoinder. What exactly is the doctrine which some of us deny, and others assert, that Aristotle held? Williams formulates it as follows (p. 21 1)

It is often held that movement can be defined in terms of places and times. Thus Russell says:We must entirely reject the notion of a state of motion. Motion consists merely in the occupation of different places at different times, subject to continuity as explained in Part V (Principles of Philosophy §447).

The starting in 1960 of the British Journal of Aesthetics was a courageous act. In those days people liked to call aesthetics a ‘dreary’ intellectual region, and high-flying philosophers seldom descended into it. But when in the decade that followed new philosophy departments were created and old ones expanded, aesthetics took up some of the spare capacity. Courses were laid on, and books and articles appeared which could match the quality of work in better established branches of philosophy like ethics and epistemology. The question now is whether the lean years which have begun will eat up the fat years of the sixties and seventies. As courses are cut and vacancies left unfilled, aesthetics is likely to be the first branch of philosophy to suffer.

From the way we speak it appears that we think changes do not merely come about but are brought about. Can we really think this? Have we any idea of the bringing or being brought about of a change distinct from our idea of its coming about? In the first part of this paper I shall try to describe some of the forms of causal thinking which are reflected in our ordinary causal judgments. In the second, having criticized two current analyses of the notion of change, I shall argue that to think of a change as something which comes about is to think of it as a causal explanandum, and to think of a change as a coming about of something is to think of it as a causal explanans.

By "The Art of Apelles" I mean the art for which Apelles is most famous, that of representing things in pigments on flat surfaces. Arts are differentiated and defined largely by their products. In what follows I shall use the word "picture" for the products of the art of Apelles-and not, say, for abstract or non-representational paintings. I shall try to say what it is for one thing to be a picture of another and what the word "picture" means in this slightly restricted but quite common use. Pictures seem to have affinities on the one hand with verbal descriptions and on the other with such things as imitations, forgeries, toys, impostors, artificial limbs and decoy ducks. Some theories of what a picture is exploit the first set of affinities and some the second. I start by considering two well known theories, one of each sort. Although both may be said to derive from Wittgenstein, the first receives its fullest development in Prof. Nelson Goodman's The Languages of Art and the second in Mr Roger Scruton's Art and Imagination. The second theory seems to me nearer the mark. One advantage it has over the first is that it allows for the obvious fact that a picture must in some degree resemble what it depicts. But Scruton's version is open to fatal objections. Hence I go on to offer an alternative version, a salient point in which is that the notion of a picture is, in a sense I try to explain, a formal concept. The works of Apelles included: a portrait of Philip of Macedon; a picture of Aphrodite rising from the sea and wringing out her hair; and a picture of Calumny, preceded by Envy, Intrigue and Deception, and followed by Repentance and Truth, dragging her victim before a man with large ears, attended by Ignorance and Superstition. Since all these works have been lost they will do conveniently as examples.

M atter' says Zeller in his account of Aristotle's metaphysics 'is the source of individual existence, in all those things at least which are formed of the union of Matter and Form.... Between the Individuals into which the in/imae species resolve themselves no difference of kind or Form any longer exists, and consequently they must be distinguished from one another by their Matter.'" Zeller is here only restating an interpretation which had always been orthodox and which still holds the field today. It was accepted without question by Lukasiewicz, G. E. M. Anscombe and K. R. Popper, in the symposium 'The principle of individuation', Proceedings of the Aristotelian Society, Supplementary Volume for 1953, and has recently been defended by A. C. Lloyd (Mind 1970). In this paper I shall try to cast doubt on it.