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Greenhouse gas (GHG) emissions from livestock production must be urgently tackled to substantially reduce their contribution to global warming. Simply reducing livestock numbers to this end risks impacting negatively on food security, rural livelihoods and climate change adaptation. We argue that significant mitigation of livestock emissions can be delivered immediately by improving animal health and hence production efficiency, but this route is not prioritized because its benefits, although intuitive, are poorly quantified. Rigorous methodology must be developed to estimate emissions from animal disease and hence achievable benefits from improved health through interventions. If, as expected, climate change is to affect the distribution and severity of health conditions, such quantification becomes of even greater importance. We have therefore developed a framework and identified data sources for robust quantification of the relationship between animal health and greenhouse gas emissions, which could be applied to drive and account for positive action. This will not only help mitigate climate change but at the same time promote cost-effective food production and enhanced animal welfare, a rare win-win in the search for a sustainable planetary future.

Randomised clinical trials (RCTs) are vital for medical progress. Unfortunately, ‘traditional’ RCTs are expensive and inherently slow. Moreover, their generalisability has been questioned. There is considerable overlap in routine health care data (RHCD) and trial-specific data. Therefore, integration of RHCD in an RCT has great potential, as it would reduce the effort and costs required to collect data, thereby overcoming some of the major downsides of a traditional RCT. However, use of RHCD comes with other challenges, such as privacy issues, as well as technical and practical barriers. Here, we give a current overview of related initiatives on national cardiovascular registries (Netherlands Heart Registration, Heart4Data), showcasing the interrelationships between and the relevance of the different registries for the practicing physician. We then discuss the benefits and limitations of RHCD use in the setting of a pragmatic RCT from a cardiovascular perspective, illustrated by a case study in heart failure.

The rise of animals across the Ediacaran–Cambrian transition marked a step-change in the history of life, from a microbially dominated world to the complex macroscopic biosphere we see today.1,2,3 While the importance of bioturbation and swimming in altering the structure and function of Earth systems is well established,4,5,6 the influence of epifaunal animals on the hydrodynamics of marine environments is not well understood. Of particular interest are the oldest “marine animal forests,”7 which comprise a diversity of sessile soft-bodied organisms dominated by the fractally branching rangeomorphs.8,9 Typified by fossil assemblages from the Ediacaran of Mistaken Point, Newfoundland,8,10,11 these ancient communities might have played a pivotal role in structuring marine environments, similar to modern ecosystems,7,12,13 but our understanding of how they impacted fluid flow in the water column is limited. Here, we use ecological modeling and computational flow simulations to explore how Ediacaran marine animal forests influenced their surrounding environment. Our results reveal how organism morphology and community structure and composition combined to impact vertical mixing of the surrounding water. We find that Mistaken Point communities were capable of generating high-mixing conditions, thereby likely promoting gas and nutrient transport within the “canopy.” This mixing could have served to enhance local-scale oxygen concentrations and redistribute resources like dissolved organic carbon. Our work suggests that Ediacaran marine animal forests may have contributed to the ventilation of the oceans over 560 million years ago, well before the Cambrian explosion of animals., Copyright © 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). The linked document is the published version of the article., NHM Repository

Our understanding of the evolutionary origin of Chordata, one of the most disparate and ecologically significant animal phyla, is hindered by a lack of unambiguous stem-group relatives. Problematic Cambrian fossils that have been considered as candidate chordates include vetulicolians (1) Yunnanozoon (2) and the iconic Pikaia (3) However, their phylogenetic placement has remained poorly constrained, impeding reconstructions of character evolution along the chordate stem lineage. Here we reinterpret the morphology of Pikaia, providing evidence for a gut canal and, crucially, a dorsal nerve cord—a robust chordate synapomorphy. The identification of these structures underpins a new anatomical model of Pikaia that shows that this fossil was previously interpreted upside down.We reveal a myomere configuration intermediate between amphioxus and vertebrates and establish morphological links between Yunnanozoon, Pikaia, and uncontroversial chordates. In this light, we perform a new phylogenetic analysis, using a revised, comprehensive deuterostome dataset, and establish a chordate stem lineage. We resolve vetulicolians as a paraphyletic group comprising the earliest diverging stem chordates, subtending a grade of more derived stem-group chordates comprising Yunnanozoon and Pikaia. Our phylogenetic results reveal the stepwise acquisition of characters diagnostic of the chordate crown group. In addition, they chart a phase in early chordate evolution defined by the gradual integration of the pharyngeal region with a segmented axial musculature, supporting classical evolutionary-developmental hypotheses of chordate origins4 and revealing a ‘‘lost chapter’’ in the history of the phylum., Copyright © 2024 Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). The linked document is the published version of the article., NHM Repository

Inflammatory processes induced by brain injury are important for recovery; however, when uncontrolled, inflammation can be deleterious, likely explaining why most anti-inflammatory treatments have failed to improve neurological outcomes after brain injury in clinical trials. In the thalamus, chronic activation of glial cells, a proxy of inflammation, has been suggested as an indicator of increased seizure risk and cognitive deficits that develop after cortical injury. Furthermore, lesions in the thalamus, more than other brain regions, have been reported in patients with viral infections associated with neurological deficits, such as SARS-CoV-2. However, the extent to which thalamic inflammation is a driver or by-product of neurological deficits remains unknown. Here, we found that thalamic inflammation in mice was sufficient to phenocopy the cellular and circuit hyperexcitability, enhanced seizure risk, and disruptions in cortical rhythms that develop after cortical injury. In our model, down-regulation of the GABA transporter GAT-3 in thalamic astrocytes mediated this neurological dysfunction. In addition, GAT-3 was decreased in regions of thalamic reactive astrocytes in mouse models of cortical injury. Enhancing GAT-3 in thalamic astrocytes prevented seizure risk, restored cortical states, and was protective against severe chemoconvulsant-induced seizures and mortality in a mouse model of traumatic brain injury, emphasizing the potential of therapeutically targeting this pathway. Together, our results identified a potential therapeutic target for reducing negative outcomes after brain injury.

Microglia are critical regulators of brain development that engulf synaptic proteins during postnatal synapse remodeling. However, the mechanisms through which microglia sense the brain environment are not well defined. Here, we characterized the regulatory program downstream of interleukin-33 (IL-33), a cytokine that promotes microglial synapse remodeling. Exposing the developing brain to a supraphysiological dose of IL-33 altered the microglial enhancer landscape and increased binding of stimulus-dependent transcription factors including AP-1/FOS. This induced a gene expression program enriched for the expression of pattern recognition receptors, including the scavenger receptor MARCO. CNS-specific deletion of IL-33 led to increased excitatory/inhibitory synaptic balance, spontaneous absence-like epileptiform activity in juvenile mice, and increased seizure susceptibility in response to chemoconvulsants. We found that MARCO promoted synapse engulfment, and Marco-deficient animals had excess thalamic excitatory synapses and increased seizure susceptibility. Taken together, these data define coordinated epigenetic and functional changes in microglia and uncover pattern recognition receptors as potential regulators of postnatal synaptic refinement.

Deuterostomes are characterized by some of the most widely divergent body plans in the animal kingdom. These striking morphological differences have hindered efforts to predict ancestral characters, with the origin and earliest evolution of the group remaining ambiguous. Several iconic Cambrian fossils have been suggested to be early deuterostomes and hence could help elucidate ancestral character states. However, their phylogenetic relationships are controversial. Here, we describe new, exceptionally preserved specimens of the discoidal metazoan Rotadiscus grandis from the early Cambrian Chengjiang biota of China. These reveal a previously unknown double spiral structure, which we interpret as a chordate-like covering to a coelomopore, located adjacent to a horseshoe-shaped tentacle complex. The tentacles differ in key aspects from those seen in lophophorates and are instead more similar to the tentacular systems of extant pterobranchs and echinoderms. Thus, Rotadiscus exhibits a chimeric combination of ambulacrarian and chordate characters. Phylogenetic analyses recover Rotadiscus and closely related fossil taxa as stem ambulacrarians, filling a significant morphological gap in the deuterostome tree of life. These results allow us to reconstruct the ancestral body plans of major clades of deuterostomes, revealing that key traits of extant forms, such as a post-analregion, gillbars, and a U-shaped gut, evolved through convergence., Copyright © 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)., NHM Repository, NHM Repository

Rangeomorphs are among the oldest putative eumetazoans known from the fossil record. Establishing how they fed is thus key to understanding the structure and function of the earliest animal ecosystems. Here, we use computational fluid dynamicstotesthypothesizedfeedingmodesforthefence-likerangeomorphPectinifrons abyssalis, comparing this to the morphologically similar extant carnivorous sponge Chondrocladia lyra. Our results reveal complex patterns of flow around P. abyssalis unlike those previously reconstructed for any other Ediacaran taxon. Comparisons with C. lyra reveal substantial differences between the two organisms, suggesting they converged on a similar fence-like morphology for different functions. We argue that the flow patterns recovered for P. abyssalis do not support either a suspension feeding or osmotrophic feeding habit. Instead, our results indicate that rangeomorph fronds may represent organs adapted for gas exchange. If correct, this interpretation could require a dramatic reinterpretation of the oldest macroscopic animals., Copyright. © 2023 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). The attached file is the published version of the article., NHM Repository

Background: Normalization Process Theory (NPT) identifies mechanisms that have been demonstrated to play an important role in implementation processes. It is now widely used to inform feasibility, process evaluation, and implementation studies in healthcare and other areas of work. This qualitative synthesis of NPT studies aims to better understand how NPT explains observed and reported implementation processes, and to explore the ways in which its constructs explain the implementability, enacting and sustainment of complex healthcare interventions. Methods: We will systematically search Scopus, PubMed and Web of Science databases and use the Google Scholar search engine for citations of key papers in which NPT was developed. This will identify English language peer-reviewed articles in scientific journals reporting (a) primary qualitative or mixed methods studies; or, (b) qualitative or mixed methods evidence syntheses in which NPT was the primary analytic framework. Studies may be conducted in any healthcare setting, published between June 2006 and 31 December 2021. We will perform a qualitative synthesis of included studies using two parallel methods: (i) directed content analysis based on an already developed coding manual; and (ii) unsupervised textual analysis using Leximancer® topic modelling software. Other: We will disseminate results of the review using peer reviewed publications, conference and seminar presentations, and social media (Facebook and Twitter) channels. The primary source of funding is the National Institute for Health Research ARC North Thames. No human subjects or personal data are involved and no ethical issues are anticipated.

While cortical injuries, such as traumatic brain injury (TBI) and neocortical stroke, acutely disrupt the neocortex, most of their consequent disabilities reflect secondary injuries that develop over time. Thalamic neuroinflammation has been proposed to be a biomarker of cortical injury and of the long-term cognitive and neurological deficits that follow. However, the extent to which thalamic neuroinflammation depends on the type of cortical injury or its location remains unknown. Using two mouse models of focal neocortical injury that do not directly damage subcortical structures-controlled cortical impact and photothrombotic ischemic stroke-we found that chronic neuroinflammation in the thalamic region mirrors the functional connections with the injured cortex, and that sensory corticothalamic regions may be more likely to sustain long-term damage than nonsensory circuits. Currently, heterogeneous clinical outcomes complicate treatment. Understanding how thalamic inflammation depends on the injury site can aid in predicting features of subsequent deficits and lead to more effective, customized therapies.

Zuozhen Tian,1 Frances S Shofer,1,2 Alec Z Sandroni,1 Lan Zhao,3 Carla R Scanzello,4,5 Yejia Zhang1,6 1Department of Physical Medicine & Rehabilitation, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; 2Department of Emergency Medicine, University of Pennsylvania, Philadelphia, PA, USA; 3Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA; 4Division of Rheumatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 5Section of Rheumatology, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA; 6Section of Rehabilitation Medicine, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USACorrespondence: Yejia Zhang, Department of Physical Medicine & Rehabilitation, Hospital of the University of Pennsylvania, Philadelphia, PA, USA, Email yejia.zhang@pennmedicine.upenn.edu; yejia.zhang@va.govObjective: To examine the effects of human interleukin (IL) 8 expression on mouse behavior.Methods: A mouse line expressing human IL8 in the intervertebral discs (IVD) and cartilaginous tissues (hIL8+) was generated. Mouse spontaneous behaviors, including locomotion, climbing, rearing, grooming, eating, drinking, and immobility were recorded with a fully automatic, non-invasive platform.Results: Distance traveled by the hIL8+ mice declined with age compared with control littermates, and male hIL8+ mice traveled a shorter distance than male controls and females of either genotype (p < 0.05). The hIL8+ mice also spent less time in locomotion than control mice (p < 0.01), and male hIL8+ mice spent the least amount of time and had lowest count in locomotion compared with the other 3 groups at 12 weeks of age or greater (p < 0.05). The hIL8+ mice spent less time climbing than controls, and male mice spent less time climbing than female mice of the same genotype (p < 0.01). The hIL8+ mice spent more time eating

Despite their clinical success, chimeric antigen receptor (CAR)-T cell therapies for B cell malignancies are limited by lengthy, costly and labor-intensive ex vivo manufacturing procedures that might lead to cell products with heterogeneous composition. Here we describe an implantable Multifunctional Alginate Scaffold for T Cell Engineering and Release (MASTER) that streamlines in vivo CAR-T cell manufacturing and reduces processing time to a single day. When seeded with human peripheral blood mononuclear cells and CD19-encoding retroviral particles, MASTER provides the appropriate interface for viral vector-mediated gene transfer and, after subcutaneous implantation, mediates the release of functional CAR-T cells in mice. We further demonstrate that in vivo-generated CAR-T cells enter the bloodstream and control distal tumor growth in a mouse xenograft model of lymphoma, showing greater persistence than conventional CAR-T cells. MASTER promises to transform CAR-T cell therapy by fast-tracking manufacture and potentially reducing the complexity and resources needed for provision of this type of therapy.

Background: Normalization Process Theory (NPT) identifies mechanisms that have been demonstrated to play an important role in implementation processes. It is now widely used to inform feasibility, process evaluation, and implementation studies in healthcare and other areas of work. This qualitative synthesis of NPT studies aims to better understand how NPT explains observed and reported implementation processes, and to explore the ways in which its constructs explain the implementability, enacting and sustainment of complex healthcare interventions. Methods: We will systematically search Scopus, PubMed and Web of Science databases and use the Google Scholar search engine for citations of key papers in which NPT was developed. This will identify English language peer-reviewed articles in scientific journals reporting (a) primary qualitative or mixed methods studies; or, (b) qualitative or mixed methods evidence syntheses in which NPT was the primary analytic framework. Studies may be conducted in any healthcare setting, published between June 2006 and 31 December 2021. We will perform a qualitative synthesis of included studies using two parallel methods: (i) directed content analysis based on an already developed coding manual; and (ii) unsupervised textual analysis using Leximancer® topic modelling software. Other: We will disseminate results of the review using peer reviewed publications, conference and seminar presentations, and social media (Facebook and Twitter) channels. The primary source of funding is the National Institute for Health Research ARC North Thames. No human subjects or personal data are involved and no ethical issues are anticipated.

Persistent abnormalities in microcirculatory function are associated with poor clinical outcomes in patients with circulatory shock. We sought to identify patients with acutely reversible microcirculatory dysfunction using a low-dose topical nitroglycerin solution and handheld videomicroscopy during circulatory shock after cardiac surgery. Forty subjects were enrolled for the study, including 20 preoperative control and 20 post-operative patients with shock. To test whether microcirculatory dysfunction is acutely reversible during shock, the sublingual microcirculation was imaged with incident dark field microscopy before and after the application of 0.1 mL of a 1% nitroglycerin solution (1 mg/mL). Compared to the control group, patients with shock had a higher microcirculation heterogeneity index (MHI 0.33 vs. 0.12, p < 0.001) and a lower microvascular flow index (MFI 2.57 vs. 2.91, p < 0.001), total vessel density (TVD 22.47 vs. 25.90 mm/mm 2, p = 0.005), proportion of perfused vessels (PPV 90.76 vs. 95.89%, p < 0.001) and perfused vessel density (PVD 20.44 vs. 24.81 mm/mm 2, p < 0.001). After the nitroglycerin challenge, patients with shock had an increase in MFI (2.57 vs. 2.97, p < 0.001), TVD (22.47 vs. 27.51 mm/mm 2, p < 0.009), PPV (90.76 vs. 95.91%, p < 0.001), PVD (20.44 vs. 26.41 mm/mm 2, p < 0.001), venular RBC velocity (402.2 vs. 693.9 µm/s, p < 0.0004), and a decrease in MHI (0.33 vs. 0.04, p < 0.001. Thirteen of 20 patients showed a pharmacodynamic response, defined as an increase in PVD > 1.8 SD from shock baseline. Hemodynamics and vasoactive doses did not change during the 30-min study period. Our findings suggest a topical nitroglycerin challenge with handheld videomicroscopy can safely assess for localized recruitment of the microcirculatory blood flow in patients with circulatory shock and may be a useful test to identify nitroglycerin responsiveness.

Pteridinium simplex is an iconic erniettomorph taxon best known from late Ediacaran successions in South Australia, Russia, and Namibia. Despite nearly 100 years of study, there remain fundamental questions surrounding the paleobiology and paleoecology of this organism, including its life position relative to the sediment–water interface, and how it fed and functioned within benthic communities. Here, we combine a redescription of specimens housed at the Senckenberg Forschungsinstitut und Naturmuseum Frankfurt with field observations of fossiliferous surfaces, to constrain the life habit of Pteridinium and gain insights into the character of benthic ecosystems shortly before the beginning of the Cambrian. We present paleontological and sedimentological evidence suggesting that Pteridinium was semi-infaunal and lived gregariously in aggregated communities, preferentially adopting an orientation with the long axis perpendicular to the prevailing current direction. Using computational fluid dynamics simulations, we demonstrate that this life habit could plausibly have led to suspended food particles settling within the organism's central cavity. This supports interpretation of Pteridinium as a macroscopic suspension feeder that functioned similarly to the coeval erniettomorph Ernietta, emblematic of a broader paleoecological shift toward benthic suspension-feeding strategies over the course of the latest Ediacaran. Finally, we discuss how this new reconstruction of Pteridinium provides information concerning its potential relationships with extant animal groups and state a case for reconstructing Pteridinium as a colonial metazoan., Copyright © The Author(s), 2022. Published by Cambridge University Press on behalf of The Paleontological Society. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (https://creativecommons.org/ licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited., NHM Repository

Background: Normalization Process Theory (NPT) identifies mechanisms that have been demonstrated to play an important role in implementation processes. It is now widely used to inform feasibility, process evaluation, and implementation studies in healthcare and other areas of work. This qualitative synthesis of NPT studies aims to better understand how NPT explains observed and reported implementation processes, and to explore the ways in which its constructs explain the implementability, enacting and sustainment of complex healthcare interventions. Methods: We will systematically search Scopus, PubMed and Web of Science databases and use the Google Scholar search engine for citations of key papers in which NPT was developed. This will identify English language peer-reviewed articles in scientific journals reporting (a) primary qualitative or mixed methods studies; or, (b) qualitative or mixed methods evidence syntheses in which NPT was the primary analytic framework. Studies may be conducted in any healthcare setting, published between June 2006 and 31 December 2021. We will perform a qualitative synthesis of included studies using two parallel methods: (i) directed content analysis based on an already developed coding manual; and (ii) unsupervised textual analysis using Leximancer® topic modelling software. Other: We will disseminate results of the review using peer reviewed publications, conference and seminar presentations, and social media (Facebook and Twitter) channels. The primary source of funding is the National Institute for Health Research ARC North Thames. No human subjects or personal data are involved and no ethical issues are anticipated.

Background: Normalisation Process Theory (NPT) is frequently used to inform qualitative research that aims to explain and evaluate processes that shape late-stage translation of innovations in the organisation and delivery of healthcare. A coding manual for qualitative researchers using NPT will facilitate transparent data analysis processes and will also reduce the cognitive and practical burden on researchers. Objectives: (a) To simplify the theory for the user. (b) To describe the purposes, methods of development, and potential application of a coding manual that translates normalisation process theory (NPT) into an easily usable framework for qualitative analysis. (c) To present an NPT coding manual that is ready for use. Method: Qualitative content analysis of papers and chapters that developed normalisation process theory, selection and structuring of theory constructs, and testing constructs against interview data and published empirical studies using NPT. Results: A coding manual for NPT was developed. It consists of 12 primary NPT constructs and conforms to the Context-Mechanism-Outcome configuration of realist evaluation studies. Contexts are defined as settings in which implementation work is done, in which strategic intentions, adaptive execution, negotiating capability, and reframing organisational logics are enacted. Mechanisms are defined as the work that people do when they participate in implementation processes and include coherence-building, cognitive participation, collective action, and reflexive monitoring. Outcomes are defined as effects that make visible how things change as implementation processes proceed and include intervention mobilisation, normative restructuring, relational restructuring, and sustainment. Conclusion: The coding manual is ready to use and performs three important tasks. It consolidates several iterations of theory development, makes the application of NPT simpler for the user, and links NPT constructs to realist evaluat

Visual perception in natural environments depends on the ability to focus on salient stimuli while ignoring distractions. This kind of selective visual attention is associated with gamma activity in the visual cortex. While the nucleus reticularis thalami (nRT) has been implicated in selective attention, its role in modulating gamma activity in the visual cortex remains unknown. Here, we show that somatostatin- (SST) but not parvalbumin-expressing (PV) neurons in the visual sector of the nRT preferentially project to the dorsal lateral geniculate nucleus (dLGN), and modulate visual information transmission and gamma activity in primary visual cortex (V1). These findings pinpoint the SST neurons in nRT as powerful modulators of the visual information encoding accuracy in V1 and represent a novel circuit through which the nRT can influence representation of visual information.

INTRODUCTION: Lactic acidosis after cardiac surgery with cardiopulmonary bypass is common and associated with an increase in postoperative morbidity and mortality. A number of potential causes for an elevated lactate after cardiopulmonary bypass include cellular hypoxia, impaired tissue perfusion, ischemic-reperfusion injury, aerobic glycolysis, catecholamine infusions, and systemic inflammatory response after exposure to the artificial cardiopulmonary bypass circuit. Our goal was to examine the relationship between early abnormalities in microcirculatory convective blood flow and diffusive capacity and lactate kinetics during early resuscitation in the intensive care unit. We hypothesized that patients with impaired microcirculation after cardiac surgery would have a more severe postoperative hyperlactatemia, represented by the lactate time-integral of an arterial blood lactate concentration greater than 2.0 mmol/L. METHODS: We measured sublingual microcirculation using incident darkfield video microscopy in 50 subjects on intensive care unit admission after cardiac surgery. Serial measurements of systemic hemodynamics, blood gas, lactate, and catecholamine infusions were recorded each hour for the first 6 h after surgery. Lactate area under the curve (AUC) was calculated over the first 6 h. The lactate AUC was compared between subjects with normal and low perfused vessel density (PVD < 18 mm/mm2), high microcirculatory heterogeneity index (MHI > 0.4), and low vessel-by-vessel microvascular flow index (MFIv < 2.6). RESULTS: Thirteen (26%) patients had a low postoperative PVD, 20 patients (40%) had a high MHI, and 26 (52%) patients had a low MFIv. Patients with low perfused vessel density had higher lactate AUC compared with subjects with a normal PVD (22.3 [9.4-31.0] vs. 2.6 [0-8.8]; P < 0.0001). Patients with high microcirculatory heterogeneity had a higher lactate AUC compared with those with a normal MHI (2.5 [0.1-8.2] vs. 13.1 [3.7-31.1]; P

Molecular timescales estimate that early animal lineages diverged tens of millions of years before their earliest unequivocal fossil evidence. The Ediacaran macrobiota (~574 to 538 million years ago) are largely eschewed from this debate, primarily due to their extreme phylogenetic uncertainty, but remain germane. We characterize the development of Charnia masoni and establish the affinity of rangeomorphs, among the oldest and most enigmatic components of the Ediacaran macrobiota. We provide the first direct evidence for the internal interconnected nature of rangeomorphs and show that Charnia was constructed of repeated branches that derived successively from pre-existing branches. We find homology and rationalize morphogenesis between disparate rangeomorph taxa, before producing a phylogenetic analysis, resolving Charnia as a stem-eumetazoan and expanding the anatomical disparity of that group to include a long-extinct bodyplan. These data bring competing records of early animal evolution into closer agreement, reformulating our understanding of the evolutionary emergence of animal bodyplans.

Visual perception in natural environments depends on the ability to focus on salient stimuli while ignoring distractions. This kind of selective visual attention is associated with gamma activity in the visual cortex. While the nucleus reticularis thalami (nRT) has been implicated in selective attention, its role in modulating gamma activity in the visual cortex remains unknown. Here, we show that somatostatin- (SST) but not parvalbumin-expressing (PV) neurons in the visual sector of the nRT preferentially project to the dorsal lateral geniculate nucleus (dLGN), and modulate visual information transmission and gamma activity in primary visual cortex (V1). These findings pinpoint the SST neurons in nRT as powerful modulators of the visual information encoding accuracy in V1 and represent a novel circuit through which the nRT can influence representation of visual information.

Although traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of mild TBI (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic system. Increased C1q expression colocalized with neuron loss and chronic inflammation and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are a source of thalamic C1q. The corticothalamic circuit could thus be a new target for treating TBI-related disabilities.

Right ventricular dysfunction is a hallmark of advanced pulmonary vascular, lung parenchymal, and left heart disease, yet the underlying mechanisms that govern (mal)adaptation remain incompletely characterized. Owing to the knowledge gaps in our understanding of the right ventricle (RV) in health and disease, the National Heart, Lung, and Blood Institute (NHLBI) commissioned a working group to identify current challenges in the field. These included a need to define and standardize normal RV structure and function in populations; access to RV tissue for research purposes and the development of complex experimental platforms that recapitulate the in vivo environment; and the advancement of imaging and invasive methodologies to study the RV within basic, translational, and clinical research programs. Specific recommendations were provided, including a call to incorporate precision medicine and innovations in prognosis, diagnosis, and novel RV therapeutics for patients with pulmonary vascular disease.

Molecular timescales estimate that early animal lineages diverged tens of millions of years before their earliest unequivocal fossil evidence. The Ediacaran macrobiota (~574 to 538 million years ago) are largely eschewed from this debate, primarily due to their extreme phylogenetic uncertainty, but remain germane. We characterize the development of Charnia masoni and establish the affinity of rangeomorphs, among the oldest and most enigmatic components of the Ediacaran macrobiota. We provide the first direct evidence for the internal interconnected nature of rangeomorphs and show that Charnia was constructed of repeated branches that derived successively from pre-existing branches. We find homology and rationalize morphogenesis between disparate rangeomorph taxa, before producing a phylogenetic analysis, resolving Charnia as a stem-eumetazoan and expanding the anatomical disparity of that group to include a long-extinct bodyplan. These data bring competing records of early animal evolution into closer agreement, reformulating our understanding of the evolutionary emergence of animal bodyplans.

BACKGROUND: One factor leading to the high mortality rate seen in sepsis is the subtle, dynamic nature of the disease, which can lead to delayed detection and under-resuscitation. This study investigated whether serial hemodynamic parameters obtained from a non-invasive cardiac output monitor (NICOM) predicts disease severity in patients at risk for sepsis. METHODS: Prospective clinical trial of the NICOM device in a convenience sample of adult ED patients at risk for sepsis who did not have obvious organ dysfunction at the time of triage. Hemodynamic data were collected immediately following triage and 2 hours after initial measurement and compared in two outcome groupings: (1) admitted vs. dehydrated, febrile, hypovolemicdischarged patients; (2) infectious vs. non-infectious sources. Receiver operator characteristic (ROC) curves were calculated to determine whether the NICOM values predict hospital admission better than a serum lactate. RESULTS: 50 patients were enrolled, 32 (64 %) were admitted to the hospital. Mean age was 49.5 (± 16.5) years and 62 % were female. There were no significant associations between changes in hemodynamic variables and patient disposition from the ED or diagnosis of infection. Lactate was significantly higher in admitted patients and those with infection (p = 0.01, p = 0.01 respectively). The area under the ROC [95 % Confidence Intervals] for lactate was 0.83 [0.64-0.92] compared to 0.59 [0.41-0.73] for cardiac output (CO), 0.68 [0.49-0.80] for cardiac index (CI), and 0.63 [0.36-0.80] for heart rate (HR) for predicting hospital admission. CONCLUSIONS: CO and CI, obtained at two separate time points, do not help with early disease severity differentiation of patients at risk for severe sepsis. Although mean HR was higher in those patients who were admitted, a serum lactate still served as a better predictor of patient admission from the ED.

​Maf (c-Maf) and Mafb transcription factors (TFs) have compensatory roles in repressing somatostatin (SST+) interneuron (IN) production in medial ganglionic eminence (MGE) secondary progenitors in mice. Maf and Mafb conditional deletion (cDKO) decreases the survival of MGE-derived cortical interneurons (CINs) and changes their physiological properties. Herein, we show that (1) Mef2c and Snap25 are positively regulated by Maf and Mafb to drive IN morphological maturation; (2) Maf and Mafb promote Mef2c expression which specifies parvalbumin (PV+) INs; (3) Elmo1, Igfbp4 and Mef2c are candidate markers of immature PV+ hippocampal INs (HIN). Furthermore, Maf/Mafb neonatal cDKOs have decreased CINs and increased HINs, that express Pnoc, an HIN specific marker. Our findings not only elucidate key gene targets of Maf and Mafb that control IN development, but also identify for the first time TFs that differentially regulate CIN vs. HIN production.

Background: Effective transdiagnostic treatments for patients presenting with principal or comorbid symptoms of anxiety and depression enable more efficient provision of mental health care and may be particularly suitable for the varied population seen in primary healthcare settings. Mindfulness-integrated cognitive behavior therapy (MiCBT) is a transdiagnostic intervention that integrates aspects of CBT, including exposure skills targeting avoidance, with training in mindfulness meditation skills adopted from the Vipassana or insight tradition taught by the Burmese teachers U Ba Khin and Goenka. MiCBT is distinguished from both cognitive therapy and mindfulness-based cognitive therapy by the use of a theoretical framework which proposes that the locus of reinforcement of behavior is the interoceptive experience (body sensations) that co-arises with self-referential thinking. Consequently, MiCBT has a strong focus on body scanning to develop interoceptive awareness and equanimity. Designed for clinical purposes, the four-stage systemic approach of MiCBT, comprising intra-personal (Stage 1) exposure (Stage 2), interpersonal (Stage 3), and empathic (Stage 4) skillsets, is a distinguishing feature among other mindfulness-based interventions (MBIs). The aim of this study is to investigate whether and how group MiCBT decreases depression and anxiety symptoms for patients with a range of common mental health conditions. Method(s): Participants (n = 120) recruited via medical practitioner referral will be randomized to MiCBT or a wait-list control. Inclusion criteria are age 18-75; fluent in English and having a Kessler Psychological Distress Scale (K10) score of 20 or more. The MiCBT treatment group receive an 8-week MiCBT intervention delivered in a private psychology practice. Participants complete a suite of online self-report measures and record the amount of meditation practice undertaken each week. The control group receive usual treatment and complete the measures

Background: Effective transdiagnostic treatments for patients presenting with principal or comorbid symptoms of anxiety and depression enable more efficient provision of mental health care and may be particularly suitable for the varied population seen in primary healthcare settings. Mindfulness-integrated cognitive behavior therapy (MiCBT) is a transdiagnostic intervention that integrates aspects of CBT, including exposure skills targeting avoidance, with training in mindfulness meditation skills adopted from the Vipassana or insight tradition taught by the Burmese teachers U Ba Khin and Goenka. MiCBT is distinguished from both cognitive therapy and mindfulness-based cognitive therapy by the use of a theoretical framework which proposes that the locus of reinforcement of behavior is the interoceptive experience (body sensations) that co-arises with self-referential thinking. Consequently, MiCBT has a strong focus on body scanning to develop interoceptive awareness and equanimity. Designed for clinical purposes, the four-stage systemic approach of MiCBT, comprising intra-personal (Stage 1) exposure (Stage 2), interpersonal (Stage 3), and empathic (Stage 4) skillsets, is a distinguishing feature among other mindfulness-based interventions (MBIs). The aim of this study is to investigate whether and how group MiCBT decreases depression and anxiety symptoms for patients with a range of common mental health conditions. Method(s): Participants (n = 120) recruited via medical practitioner referral will be randomized to MiCBT or a wait-list control. Inclusion criteria are age 18-75; fluent in English and having a Kessler Psychological Distress Scale (K10) score of 20 or more. The MiCBT treatment group receive an 8-week MiCBT intervention delivered in a private psychology practice. Participants complete a suite of online self-report measures and record the amount of meditation practice undertaken each week. The control group receive usual treatment and complete the measures

Environments of human insecurity are a widespread problem in our globalised world, particularly for migrant workers, one of the most vulnerable groups in society today. These experiences of insecurity have been heightened in the context of the COVID-19 pandemic. In this article, we examine the collective experience of insecurity among migrant workers in Malaysia. In our analysis, we outline collective insecurity at two levels: the micro level of migrant workers’ daily, subjective experiences of insecurity; and the macro level, in which insecurity is a consequence of structural forces, specifically the globalisation of labour. These two levels interact symbiotically, producing states of insecurity that are concretely experienced as anxiety and fear. Migrant workers in Malaysia also practice agency through small forms of resistance that they use to bolster one another and reduce their insecure experiences. Throughout the COVID-19 pandemic and subsequent Movement Control Order (MCO) in Malaysia, migrant workers have been further marginalised by the state, but they have also become connected to one another through acts of solidarity and resistance. However, the sustainability of these forms remains unclear.

Environments of human insecurity are a widespread problem in our globalised world, particularly for migrant workers, one of the most vulnerable groups in society today. These experiences of insecurity have been heightened in the context of the COVID-19 pandemic. In this article, we examine the collective experience of insecurity among migrant workers in Malaysia. In our analysis, we outline collective insecurity at two levels: the micro level of migrant workers’ daily, subjective experiences of insecurity; and the macro level, in which insecurity is a consequence of structural forces, specifically the globalisation of labour. These two levels interact symbiotically, producing states of insecurity that are concretely experienced as anxiety and fear. Migrant workers in Malaysia also practice agency through small forms of resistance that they use to bolster one another and reduce their insecure experiences. Throughout the COVID-19 pandemic and subsequent Movement Control Order (MCO) in Malaysia, migrant workers have been further marginalised by the state, but they have also become connected to one another through acts of solidarity and resistance. However, the sustainability of these forms remains unclear.

BACKGROUND: Effective transdiagnostic treatments for patients presenting with principal or comorbid symptoms of anxiety and depression enable more efficient provision of mental health care and may be particularly suitable for the varied population seen in primary healthcare settings. Mindfulness-integrated cognitive behavior therapy (MiCBT) is a transdiagnostic intervention that integrates aspects of CBT, including exposure skills targeting avoidance, with training in mindfulness meditation skills adopted from the Vipassana or insight tradition taught by the Burmese teachers U Ba Khin and Goenka. MiCBT is distinguished from both cognitive therapy and mindfulness-based cognitive therapy by the use of a theoretical framework which proposes that the locus of reinforcement of behavior is the interoceptive experience (body sensations) that co-arises with self-referential thinking. Consequently, MiCBT has a strong focus on body scanning to develop interoceptive awareness and equanimity. Designed for clinical purposes, the four-stage systemic approach of MiCBT, comprising intra-personal (Stage 1) exposure (Stage 2), interpersonal (Stage 3), and empathic (Stage 4) skillsets, is a distinguishing feature among other mindfulness-based interventions (MBIs). The aim of this study is to investigate whether and how group MiCBT decreases depression and anxiety symptoms for patients with a range of common mental health conditions. METHODS: Participants (n = 120) recruited via medical practitioner referral will be randomized to MiCBT or a wait-list control. Inclusion criteria are age 18-75; fluent in English and having a Kessler Psychological Distress Scale (K10) score of 20 or more. The MiCBT treatment group receive an 8-week MiCBT intervention delivered in a private psychology practice. Participants complete a suite of online self-report measures and record the amount of meditation practice undertaken each week. The control group receive usual treatment and complete the measures at

​Maf (c-Maf) and Mafb transcription factors (TFs) have compensatory roles in repressing somatostatin (SST+) interneuron (IN) production in medial ganglionic eminence (MGE) secondary progenitors in mice. Maf and Mafb conditional deletion (cDKO) decreases the survival of MGE-derived cortical interneurons (CINs) and changes their physiological properties. Herein, we show that (1) Mef2c and Snap25 are positively regulated by Maf and Mafb to drive IN morphological maturation; (2) Maf and Mafb promote Mef2c expression which specifies parvalbumin (PV+) INs; (3) Elmo1, Igfbp4 and Mef2c are candidate markers of immature PV+ hippocampal INs (HIN). Furthermore, Maf/Mafb neonatal cDKOs have decreased CINs and increased HINs, that express Pnoc, an HIN specific marker. Our findings not only elucidate key gene targets of Maf and Mafb that control IN development, but also identify for the first time TFs that differentially regulate CIN vs. HIN production.

Environments of human insecurity are a widespread problem in our globalised world, particularly for migrant workers, one of the most vulnerable groups in society today. These experiences of insecurity have been heightened in the context of the COVID-19 pandemic. In this article, we examine the collective experience of insecurity among migrant workers in Malaysia. In our analysis, we outline collective insecurity at two levels: the micro level of migrant workers’ daily, subjective experiences of insecurity; and the macro level, in which insecurity is a consequence of structural forces, specifically the globalisation of labour. These two levels interact symbiotically, producing states of insecurity that are concretely experienced as anxiety and fear. Migrant workers in Malaysia also practice agency through small forms of resistance that they use to bolster one another and reduce their insecure experiences. Throughout the COVID-19 pandemic and subsequent Movement Control Order (MCO) in Malaysia, migrant workers have been further marginalised by the state, but they have also become connected to one another through acts of solidarity and resistance. However, the sustainability of these forms remains unclear.

Environments of human insecurity are a widespread problem in our globalised world, particularly for migrant workers, one of the most vulnerable groups in society today. These experiences of insecurity have been heightened in the context of the COVID-19 pandemic. In this article, we examine the collective experience of insecurity among migrant workers in Malaysia. In our analysis, we outline collective insecurity at two levels: the micro level of migrant workers’ daily, subjective experiences of insecurity; and the macro level, in which insecurity is a consequence of structural forces, specifically the globalisation of labour. These two levels interact symbiotically, producing states of insecurity that are concretely experienced as anxiety and fear. Migrant workers in Malaysia also practice agency through small forms of resistance that they use to bolster one another and reduce their insecure experiences. Throughout the COVID-19 pandemic and subsequent Movement Control Order (MCO) in Malaysia, migrant workers have been further marginalised by the state, but they have also become connected to one another through acts of solidarity and resistance. However, the sustainability of these forms remains unclear.

Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment.

Mafb and c-Maf transcription factor (TF) expression is enriched in medial ganglionic eminence (MGE) lineages, beginning in late-secondary progenitors and continuing into mature parvalbumin (PV+) and somatostatin (SST+) interneurons. However, the functions of Maf TFs in MGE development remain to be elucidated. Herein, Mafb and c-Maf were conditionally deleted, alone and together, in the MGE and its lineages. Analyses of Maf mutant mice revealed redundant functions of Mafb and c-Maf in secondary MGE progenitors, where they repress the generation of SST+ cortical and hippocampal interneurons. By contrast, Mafb and c-Maf have distinct roles in postnatal cortical interneuron (CIN) morphological maturation, synaptogenesis, and cortical circuit integration. Thus, Mafb and c-Maf have redundant and opposing functions at different steps in CIN development.

Organisms in possession of a frondose body plan are amongst the oldest and most enigmatic members of the soft‐bodied Ediacaran macrobiota. Appraisal of specimens from the late Ediacaran Ediacara Member of South Australia reveals that the frondose taxon Arborea arborea probably possessed a fluid‐filled holdfast disc, the size and form of which could vary within populations. Mouldic preservation of internal anatomical features provides evidence for tissue differentiation, and for bundles of tubular structures within the stalk of the organism. These structures connect in a fascicled arrangement to individual lateral branches, before dividing further into individual units housed on those branches. The observed fascicled branching arrangement, which seemingly connects individual units to the main body of the organism, is consistent with a biologically modular construction for Arborea, and raises the possibility of a colonial organization. In conjunction with morphological characters previously recognized by other authors, including apical‐basal and front‐back differentiation, we propose that to the exclusion of all alternative known possibilities, Arborea can be resolved as a total group eumetazoan.

The ‘Cambrian Explosion’ describes the rapid increase in animal diversity and abundance, as manifest in the fossil record, between ~540 and 520 million years ago (Ma). This event, however, is nested within a far more ancient record of macrofossils extending at least into the late Ediacaran at ~571 Ma. The evolutionary events documented during the Ediacaran–Cambrian interval coincide with geochemical evidence for the modernisation of Earth’s biogeochemical cycles. Holistic integration of fossil and geochemical records leads us to challenge the notion that the Ediacaran and Cambrian worlds were markedly distinct, and places biotic and environmental change within a longer-term narrative. We propose that the evolution of metazoans may have been facilitated by a series of dynamic and global changes in redox conditions and nutrient supply, which, potentially together with biotic feedbacks, enabled turnover events that sustained multiple phases of radiation. We argue that early metazoan diversification should be recast as a series of successive, transitional radiations that extended from the late Ediacaran and continued through the early Palaeozoic. We conclude that while the Cambrian Explosion represents a radiation of crown-group bilaterians, it was simply one phase amongst several metazoan radiations, some older and some younger.

The Ediacaran macrofossil Charnia masoni Ford is perhaps the most iconic member of the Rangeomorpha: a group of seemingly sessile, frondose organisms that dominates late Ediacaran benthic, deep‐marine fossil assemblages. Despite C. masoni exhibiting broad palaeogeographical and stratigraphical ranges, there have been few morphological studies that consider the variation observed among populations of specimens derived from multiple global localities. We present an analysis of C. masoni that evaluates specimens from the UK, Canada and Russia, representing the largest morphological study of this taxon to date. We describe substantial morphological variation within C. masoni and present a new morphological model for this species that has significant implications both for interpretation of rangeomorph architecture, and potentially for existing taxonomic schemes. Previous reconstructions of Charnia include assumptions regarding the presence of structures seen in other rangeomorphs (e.g. an internal stalk) and of homogeneity in higher order branch morphology; observations that are not borne out by our investigations. We describe variation in the morphology of third and fourth order branches, as well as variation in gross structure near the base of the frond. The diagnosis of Charnia masoni is emended to take account of these new features. These findings highlight the need for large‐scale analyses of rangeomorph morphology in order to better understand the biology of this long‐enigmatic group.

Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment.

Mafb and c-Maf transcription factor (TF) expression is enriched in medial ganglionic eminence (MGE) lineages, beginning in late-secondary progenitors and continuing into mature parvalbumin (PV+) and somatostatin (SST+) interneurons. However, the functions of Maf TFs in MGE development remain to be elucidated. Herein, Mafb and c-Maf were conditionally deleted, alone and together, in the MGE and its lineages. Analyses of Maf mutant mice revealed redundant functions of Mafb and c-Maf in secondary MGE progenitors, where they repress the generation of SST+ cortical and hippocampal interneurons. By contrast, Mafb and c-Maf have distinct roles in postnatal cortical interneuron (CIN) morphological maturation, synaptogenesis, and cortical circuit integration. Thus, Mafb and c-Maf have redundant and opposing functions at different steps in CIN development.

Organisms in possession of a frondose body plan are amongst the oldest and most enigmatic members of the soft‐bodied Ediacaran macrobiota. Appraisal of specimens from the late Ediacaran Ediacara Member of South Australia reveals that the frondose taxon Arborea arborea probably possessed a fluid‐filled holdfast disc, the size and form of which could vary within populations. Mouldic preservation of internal anatomical features provides evidence for tissue differentiation, and for bundles of tubular structures within the stalk of the organism. These structures connect in a fascicled arrangement to individual lateral branches, before dividing further into individual units housed on those branches. The observed fascicled branching arrangement, which seemingly connects individual units to the main body of the organism, is consistent with a biologically modular construction for Arborea, and raises the possibility of a colonial organization. In conjunction with morphological characters previously recognized by other authors, including apical‐basal and front‐back differentiation, we propose that to the exclusion of all alternative known possibilities, Arborea can be resolved as a total group eumetazoan.

The Ediacaran macrofossil Charnia masoni Ford is perhaps the most iconic member of the Rangeomorpha: a group of seemingly sessile, frondose organisms that dominates late Ediacaran benthic, deep‐marine fossil assemblages. Despite C. masoni exhibiting broad palaeogeographical and stratigraphical ranges, there have been few morphological studies that consider the variation observed among populations of specimens derived from multiple global localities. We present an analysis of C. masoni that evaluates specimens from the UK, Canada and Russia, representing the largest morphological study of this taxon to date. We describe substantial morphological variation within C. masoni and present a new morphological model for this species that has significant implications both for interpretation of rangeomorph architecture, and potentially for existing taxonomic schemes. Previous reconstructions of Charnia include assumptions regarding the presence of structures seen in other rangeomorphs (e.g. an internal stalk) and of homogeneity in higher order branch morphology; observations that are not borne out by our investigations. We describe variation in the morphology of third and fourth order branches, as well as variation in gross structure near the base of the frond. The diagnosis of Charnia masoni is emended to take account of these new features. These findings highlight the need for large‐scale analyses of rangeomorph morphology in order to better understand the biology of this long‐enigmatic group.