XVII.— Remarks on some new or little-known species of Thynnidæ ( Hymenoptera )

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Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial

BACKGROUND: Dysregulated inflammation is associated with poor outcomes in COVID-19. We aimed to assess the efficacy of namilumab (a granulocyte-macrophage colony stimulating factor inhibitor) and infliximab (a tumour necrosis factor inhibitor) in hospitalised patients with COVID-19, to prioritise agents for phase 3 trials. METHODS: In this randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST), we recruited patients (aged ≥16 years) admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater, at nine hospitals in the UK. Participants were randomly assigned with equal probability to usual care or usual care plus a single intravenous dose of namilumab (150 mg) or infliximab (5 mg/kg). Randomisation was stratified by care location within the hospital (ward vs intensive care unit [ICU]). Patients and investigators were not masked to treatment allocation. The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models. This trial is now complete and is registered with ISRCTN, 40580903. FINDINGS: Between June 15, 2020, and Feb 18, 2021, we screened 299 patients and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35). For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group. The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment–time interactions were –0·09 (95% CI –0·19 to 0·00) for namilumab and 0·06 (–0·05 to 0·17) for infliximab. 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with 145 in 29 (54%) of 54 in the usual care group. 102 adverse events occurred in 20 (69%) of 29 patients in the infliximab group compared with 112 in 17 (50%) of 34 in the usual care group. Death occurred in six (11%) patients in the namilumab group compared with ten (19%) in the usual care group, and in four (14%) in the infliximab group compared with five (15%) in the usual care group. INTERPRETATION: Namilumab, but not infliximab, showed proof-of-concept evidence for reduction in inflammation—as measured by CRP concentration—in hospitalised patients with COVID-19 pneumonia. Namilumab should be prioritised for further investigation in COVID-19. FUNDING: Medical Research Council

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

The relationship between white matter microstructure and general cognitive ability in patients with schizophrenia and healthy participants in the ENIGMA Consortium

Objective: Schizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants. Methods: The meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition. Results: Meta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges’ g]=0.27, CI=0.17–0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05–0.35) and healthy participant groups (effect size=0.32, CI=0.18–0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18–0.37), the patient group (effect size=0.23, CI=0.09–0.38), and the healthy participant group (effect size=0.31, CI=0.18–0.44). Conclusions: This study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association

Confusion and dependence in uses of history

Many people argue that history makes a special difference to the subjects of biology and psychology, and that history does not make this special difference to other parts of the world. This paper will show that historical properties make no more or less of a difference to biology or psychology than to chemistry, physics, or other sciences. Although historical properties indeed make a certain kind of difference to biology and psychology, this paper will show that historical properties make the same kind of difference to geology, sociology, astronomy, and other sciences. Similarly, many people argue that nonhistorical properties make a special difference to the nonbiological and the nonpsychological world. This paper will show that nonhistorical properties make the same difference to all things in the world when it comes to their causal behavior and that historical properties make the same difference to all things in the world when it comes to their distributions. Although history is special, it is special in the same way to all parts of the worl

A Climate Change Vulnerability Assessment of California's At-Risk Birds

Conservationists must develop new strategies and adapt existing tools to address the consequences of anthropogenic climate change. To support statewide climate change adaptation, we developed a framework for assessing climate change vulnerability of California's at-risk birds and integrating it into the existing California Bird Species of Special Concern list. We defined climate vulnerability as the amount of evidence that climate change will negatively impact a population. We quantified climate vulnerability by scoring sensitivity (intrinsic characteristics of an organism that make it vulnerable) and exposure (the magnitude of climate change expected) for each taxon. Using the combined sensitivity and exposure scores as an index, we ranked 358 avian taxa, and classified 128 as vulnerable to climate change. Birds associated with wetlands had the largest representation on the list relative to other habitat groups. Of the 29 state or federally listed taxa, 21 were also classified as climate vulnerable, further raising their conservation concern. Integrating climate vulnerability and California's Bird Species of Special Concern list resulted in the addition of five taxa and an increase in priority rank for ten. Our process illustrates a simple, immediate action that can be taken to inform climate change adaptation strategies for wildlife

Do two and three year old children use an incremental first-NP-as-agent bias to process active transitive and passive sentences? : A permutation analysis

We used eye-tracking to investigate if and when children show an incremental bias to assume that the first noun phrase in a sentence is the agent (first-NP-as-agent bias) while processing the meaning of English active and passive transitive sentences. We also investi-gated whether children can override this bias to successfully distinguish active from passive sentences, after processing the remainder of the sentence frame. For this second question we used eye-tracking (Study 1) and forced-choice pointing (Study 2). For both studies, we used a paradigm in which participants simultaneously saw two novel actions with reversed agent-patient relations while listening to active and passive sentences. We compared English-speaking 25-month-olds and 41-month-olds in between-subjects sentence struc-ture conditions (Active Transitive Condition vs. Passive Condition). A permutation analysis found that both age groups showed a bias to incrementally map the first noun in a sentence onto an agent role. Regarding the second question, 25-month-olds showed some evidence of distinguishing the two structures in the eye-tracking study. However, the 25-month-olds did not distinguish active from passive sentences in the forced choice pointing task. In contrast, the 41-month-old children did reanalyse their initial first-NP-as-agent bias to the extent that they clearly distinguished between active and passive sentences both in the eye-tracking data and in the pointing task. The results are discussed in relation to the development of syntactic (re)parsing