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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

Why do some philosophers (Nagel, McGinn, Chomsky), despite all we know about evolution and embryology, think that consciousness makes the mind-body relation a problem still unsolved and perhaps insoluble by those with human brains? They ask how consciousness arises in matter, not in living organisms, whereas non-philosophers ask how far down the ladder of life it extends and when it arises in individuals of sentient and intelligent species. They desire the privacy of Locke's closet, furnished with phenomenological properties; and besides replacing Aristotle's ‘folk’ conception of causation by Hume's, they mathematicise physical explanation in line with Newton's First Law of Motion. Non-philosophers operate with ‘vague’ concepts of life, sentience and intelligence which allow them to treat these things as truly and naturally emergent. Machines that perform intelligent tasks are no more conscious of the reasons for their movements than actors performing them on the stage.

After (1) a brief introduction I (2) compare accounts of what it is to say something I find in Plato, Frege and Grice, and I distinguish linguistic from practical meaning and words that signify things from ‘syncategorematic’ or ‘grammatical’ words. I then (3) argue that the relation between a signifying word and what it signifies must be understood in terms of two complementary acts, already recognised in antiquity, quantifying and predicating. Discussing quantification (4), I show how problems about universals can be avoided by accepting Aristotle's distinction between possible and actual existence. Discussing predication (5), I defend Aristotle's view that there are more forms of predication than one, and consider this issue in connection with non-mathematical discourse.

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.

Our paradigm for religion is Christianity, which appeared as a sub-society, the culture of which differed both from Jewish culture and from that of the Greeks and Romans. Human beings are essentially social, depending upon society for all rational thought and activity. As social beings we live with regard to customs we think good on the whole. Customs are rationalised by theoretical and moral beliefs. They contrast with nature and also with convention and habit. Religions, like families, are societies intermediate between individuals and states. So-called secular values concern the same things as religious and have comparable practical consequences.