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Neural precursor cells (NPCs) are generated in the subventricular zone (SVZ) and travel through the rostral migratory stream (RMS) to replace olfactory bulb interneurons in the brains of most adult mammals. Following brain injury, SVZ-derived NPCs can divert from the RMS and migrate toward injured brain regions but arrive in numbers too low to promote functional recovery without experimental intervention. Our lab has biofabricated a “living scaffold” that replicates the structural and functional features of the endogenous RMS. This tissue-engineered rostral migratory stream (TE-RMS) is a new regenerative medicine strategy designed to facilitate stable and sustained NPC delivery into neuron-deficient brain regions following brain injury or neurodegenerative disease and an in vitro tool to investigate the mechanisms of neuronal migration and cell–cell communication. We have previously shown that the TE-RMS replicates the basic structure and protein expression of the endogenous RMS and can direct immature neuronal migration in vitro and in vivo. Here, we further describe profound morphological changes that occur following precise physical manipulation and subsequent self-assembly of astrocytes into the TE-RMS, including significant cytoskeletal rearrangement and nuclear elongation. The unique cytoskeletal and nuclear architecture of TE-RMS astrocytes mimics astrocytes in the endogenous rat RMS. Advanced imaging techniques reveal the unique morphology of TE-RMS cells that has yet to be described of astrocytes in vitro. The TE-RMS offers a novel platform to elucidate astrocyte cytoskeletal and nuclear dynamics and their relationship to cell behavior and function.

Aim: To describe initial treatment patterns and survival of patients diagnosed with non-small-cell lung cancer (NSCLC) in Denmark, before immune checkpoint inhibitor and later-generation tyrosine kinase inhibitor use. Patients & methods: Adults diagnosed with incident NSCLC (2005–2015; follow-up: 2016). Initial treatments and overall survival (OS) are reported. Results: 31,939 NSCLC patients (51.6% stage IV) were included. Increasing use of curative radiotherapy/chemoradiation for stage I, II/IIIA and IIIB NSCLC coincided with improved 2-year OS. Systemic anticancer therapy use increased for patients with stage IV non-squamous NSCLC (53.0–60.6%) but not squamous NSCLC (44.9–47.3%). 1-year OS improved in patients with stage IV non-squamous NSCLC (23–31%) but not squamous NSCLC (22–25%). Conclusion: Trends indicated improved OS as treatments evolved between 2005 and 2015, but the effect was limited to 1-year OS in stage IV disease.

Salt marshes and seagrass meadows can sequester and store high quantities of organic carbon (OC) in their sediments relative to other marine and terrestrial habitats. Assessing carbon stocks, carbon sources, and the transfer of carbon between habitats within coastal seascapes are each integral in identifying the role of blue carbon habitats in coastal carbon cycling. Here, we quantified carbon stocks, sources, and exchanges in seagrass meadows, salt marshes, and unvegetated sediments in six bays along the California coast. In the top 20 cm of sediment, the salt marshes contained approximately twice as much OC as seagrass meadows did, 4.92 ± 0.36 kg OC m−2 compared to 2.20 ± 0.24 kg OC m−2, respectively. Both salt marsh and seagrass sediment carbon stocks were higher than previous estimates from this region but lower than global and US-wide averages, respectively. Seagrass-derived carbon was deposited annually into adjacent marshes during fall seagrass senescence. However, isotope mixing models estimate that negligible amounts of this seagrass material were ultimately buried in underlying sediment. Rather, the vast majority of OC in sediment across sites was likely derived from planktonic/benthic diatoms and/or C3 salt marsh plants.

Synopsis Robustness and resilience are widely used in the biological sciences and related disciplines to describe how systems respond to change. Robustness is the ability to tolerate change without adapting or moving to another state. Resilience refers to the ability for a system to sustain a perturbation and maintain critical functions. Robustness and resilience transcend levels of biological organization, though they do not scale directly across levels. We live in an era of novel stressors and unprecedented change, including climate change, emerging environmental contaminants, and changes to the Earth's biogeochemical and hydrological cycles. We envision a common framework for developing models to predict the robustness and resilience of biological functions associated with complex systems that can transcend disciplinary boundaries. Conceptual and quantitative models of robustness and resilience must consider cross-scale interactions of potentially infinite complexity, but it is impossible to capture everything within a single model. Here, we discuss the need to balance accuracy and complexity when designing models, data collection, and downstream analyses to study robustness and resilience. We also consider the difficulties in defining the spatiotemporal domain when studying robustness and resilience as an emergent property of a complex system. We suggest a framework for implementing transdisciplinary research on robustness and resilience of biological systems that draws on participatory stakeholder engagement methods from the fields of conservation and natural resources management. Further, we suggest that a common, simplified model development framework for describing complex biological systems will provide new, broadly relevant educational tools. Efficient interdisciplinary collaboration to accurately develop a model of robustness and resilience would enable rapid, context-specific assessment of complex biological systems with benefits for a broad range of societally relevant problems.

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Private grant from Kowa Pharmaceuticals to Brigham and Woman's Hospital Calcific aortic valve stenosis (CAVS) is the most prevent valvular heart disease in the western world increasing exponentially with age, with an 112% increase in CAVS deaths in the last three decades; however no therapeutic treatment is currently available. Recently, lipoprotein(a) [Lp(a)] has been demonstrated to be an independent and causal risk factor for CAVS, yet the understanding of its cellular uptake and catabolism is limited thus underscoring the need for further investigation. This study aimed to determine a target receptor, unique for Lp(a) on the surface of valvular interstitial cells (VICs) and ascertain the role of the receptor on the development of VIC calcification. Unbiased ligand-receptor capture mass spectrometry (TriCEPS) was used to identify target receptor, with western blotting, ELISA, qPCR, alizarin red calcium staining and immunofluorescence used to validate the targets in vitro via siRNA inhibition and overexpression. Transmission electron microscopy (TEM) was used to determine uptake of Lp(a) within excised human valves. Identification of small molecule inhibitors was assessed computationally via the L1000 dataset, with the top hit candidate validated in vitro. Genotype-phenotype studies were examined using the United Kingdom Biobank (UKBB) and the Millions Veterans Program. Linear regression was used to evaluate association between aortic stenosis and plasma Lp(a) levels, and a phenotype-wide association analysis was then performed against this generated ‘genotype’. Ligand-receptor capture mass spectrometry was used to detect novel membrane proteins with specific binding to Lp(a); MFSD5, MRC2, LDLR were identified as possible candidates. MFSD5 RNAscope demonstrated its presence in human aortic valves. Lp(a) uptake in VICs was confirmed via western blot and TEM. MFSD5 siRNA significantly reduced dil-labelled Lp(a) uptake in human VICs (p=0.003) and HEPG2 cells (p=0.0003), conversely MFSD5 overexpression increased uptake (p=0.0345, p=0.0318), whilst specificity of MFSD5 to Lp(a) alone was shown via no change in LDL uptake following MFSD5 inhibition (p=0.616, p=0.991). MFSD5 inhibition reduced RUNX2 (p=0.0124) and Osteocalcin (p The current study demonstrates the novel Lp(a) receptor MFSD5 may be responsible for uptake of Lp(a) within VICs, resulting in the development of aortic valve calcification, highlighting the need for further exploration into the role of MFSD5 in aortic valve disease.

Neurocritical care significantly impacts outcomes after moderate-to-severe acquired brain injury, but it is rarely applied in preclinical studies. We created a comprehensive neurointensive care unit (neuroICU) for use in swine to account for the influence of neurocritical care, collect clinically relevant monitoring data, and create a paradigm that is capable of validating therapeutics/diagnostics in the unique neurocritical care space. Our multidisciplinary team of neuroscientists, neurointensivists, and veterinarians adapted/optimized the clinical neuroICU (e.g., multimodal neuromonitoring) and critical care pathways (e.g., managing cerebral perfusion pressure with sedation, ventilation, and hypertonic saline) for use in swine. Moreover, this neurocritical care paradigm enabled the first demonstration of an extended preclinical study period for moderate-to-severe traumatic brain injury with coma beyond 8 h. There are many similarities with humans that make swine an ideal model species for brain injury studies, including a large brain mass, gyrencephalic cortex, high white matter volume, and topography of basal cisterns, amongst other critical factors. Here we describe the neurocritical care techniques we developed and the medical management of swine following subarachnoid hemorrhage and traumatic brain injury with coma. Incorporating neurocritical care in swine studies will reduce the translational gap for therapeutics and diagnostics specifically tailored for moderate-to-severe acquired brain injury.

Presentation We describe a case of reactivation of latent pulmonary tuberculosis (TB) invading the larynx and causing dysphonia. Diagnosis A previously healthy 30-year old woman was found to have bilateral pulmonary TB 5-months after being thoroughly investigated for hoarseness. Initial chest x-ray (CXR) and CT-neck were normal. Vocal cord biopsies were negative for granulomata. Treatment The patient was commenced on standard four drug Anti-TB treatment (ATT) and completed a one-year course. Unfortunately, the development of a laryngeal web caused persistent dysphonia. Discussion Patients with laryngeal TB are more likely to present to ENT surgeons, because of the initial symptom of hoarseness. Multiple tests must be completed before out-ruling TB. HRCT or sputum culture is recommended, as TB may not be evident on initial CXR. A collaborative approach between Respiratory and ENT teams is required. Prompt diagnosis is essential. Speech therapy input will be important in our patient's recovery.

Objective: The timeline followback (TLFB) interview is the gold standard for the quantitative assessment of alcohol use. However, self-reported “drinks” can vary in alcohol content. If this variability is not accounted for, it can compromise the reliability and validity of TLFB data. To improve the precision of the TLFB data, we developed a detailed standard operating procedure (SOP) to calculate standard drinks more accurately from participant reports. Method: For the new SOP, the volume and alcohol content by volume (ABV) of distinct types of alcoholic beverages were determined based on product websites and other reliable sources. Recipes for specific cocktails were constructed based on recipes from bartending education websites. One standard drink was defined as 0.6 oz (14 g) of absolute alcohol. Standard drink totals were contrasted for the new SOP approach and the standard procedure, which generally assumed that one self-reported drink was equivalent to one standard drink. Results: Relative to the standard TLFB procedure, higher numbers of standard drinks were reported after implementing the TLFB SOP. Conclusions: Variability in procedures for conversion of self-reported alcohol consumption to standard drinks can confound the interpretation of TLFB data. The use and reporting of a detailed SOP can significantly reduce the potential for such inconsistencies. Detailed and consistent procedures for calculation of standard drinks can enhance the quality of TLFB drinking data.

Mild traumatic brain injury affects millions of individuals annually primarily through falls, traffic collisions, or blunt trauma and can generate symptoms that persist for years. Closed-head rotational loading is the most common cause of mild traumatic brain injury and is defined by a rapid rotational acceleration of brain tissue within an intact skull. Injury kinematics—the mechanical descriptors of injury-inducing motion—explain movement of the head, which govern energy transfer, and, therefore, determine injury severity. However, the relationship between closed-head rotational injury kinematics—such as angular velocity, angular acceleration, and injury duration—and outcome after mild traumatic brain injury is not completely understood. To address this gap in knowledge, we analysed archived surgical records of 24 swine experiencing a diffuse closed-head rotational acceleration mild traumatic brain injury against 12 sham animals. Kinematics were contrasted against acute recovery outcomes, specifically apnea time, extubation time, standing time, and recovery duration. Compared to controls, animals experiencing a mild traumatic brain injury were far more likely to have apnea (P < 0.001), shorter time to extubation (P = 0.023), and longer time from extubation to standing (P = 0.006). Using least absolute shrinkage and selection operator-based regressions, kinematic parameters, including maximum negative angular velocity and time from peak angular velocity to maximum angular deceleration, were selected to explain variation in apnea time, standing time, and recovery duration. Simplified linear models employing the least absolute shrinkage and selection operator-selected variables explained a modest degree of variation in apnea time (adjusted R2 = 0.18), standing time (adjusted R2 = 0.19), and recovery duration (adjusted R2 = 0.27). Neuropathology was correlated with multiple injury kinematics, with maximum angular acceleration exhibiting the strongest correlation (R2 = 0.66). Together, these data suggest the interplay between multiple injury kinematics, including maximum negative angular velocity (immediately preceding cessation of head motion) and time from peak angular velocity to maximum angular deceleration, best explain acute recovery metrics and neuropathology after mild traumatic brain injury in swine. Future experiments that independently manipulate individual kinematic parameters could be instrumental in developing translational diagnostics for clinical mild traumatic brain injury.

Shallow slope failures due to erosion are common occurrences along roadways. The use of deep-rooted vegetative covers is a potential solution to stabilize newly constructed slopes or repair shallow landslides. This study compared species that may provide slope stabilization for sites in the Piedmont region of the southeastern USA. Six species were tested on experimental plots under natural rainfall conditions, and vegetation health and establishment were monitored. Two methods were used to measure surface erosion, measurement of total suspended solids in collected runoff and erosion pins. While measurement uncertainty was high for both methods, differences were evident between species in the spatial distribution of surface erosion that was related to the quality of vegetation establishment. For three species that established well, soil cores were collected to measure root biomass at depths up to 40 cm. Vetiver grass (Vetiveria zizaniodies) had substantially higher mean root biomass (3.75 kg/m3) than juniper shrubs (Juniperus chinensis; 0.45 kg/m3) and fescue grass (Lolium arundinaceum; 1.28 kg/m3), with the most pronounced difference in the deepest soil layers. Seeding with turf grass such as fescue is a common practice for erosion control in the region but replacing this with vetiver on steep slopes may help prevent shallow landslides due to the additional root reinforcement. Additional work is needed to measure the magnitude of the strength gain.

Rapid urbanization has sharply increased the pressure of urban water issues (e.g., urban flooding and water pollution) in the Chinese megacities during last three decades. Sustainable urban water management approaches, such as Nature Based Solutions (NBS) and Low Impact Developments (LIDs), have successfully delivered long-term benefits to cities in Europe and North America. Similarly, the Chinese Sponge City Program (SCP) initiated in 2013 and experimented in 30 pilot Chinese cities. This paper reviewed the first stage of the SCP from 2015 to 2020 by using observation, Semi-Structured Interview (SSI) and Focus Group Approach (FGA) in context of Gui'an New Distinct, SW China to investigate the SCP progress and issues: (1). whether it is effectively solving urban water issues; (2). if there are any major challenges and barriers in the SCP practice. The findings of this case study provide potential solutions for improving the SCP and sustainable urban water management and possibly transform to other Sponge Cities in China.

ObjectivesTo assess how a decade of developments in systematic anticancer therapy (SACT) for advanced non-small cell lung cancer (NSCLC) affected overall survival (OS) in a large UK University Hospital.DesignReal-world retrospective observational cohort study using existing data recorded in electronic medical records.SettingA large National Health Service (NHS) university teaching hospital serving 800 000 people living in a diverse metropolitan area of the UK.Participants2119 adults diagnosed with advanced NSCLC (tumour, node, metastasis stage IIIB or IV) between 2007 and 2017 at Leeds Teaching Hospitals NHS Trust.Main outcomes and measuresOS following diagnosis and the analysis of factors associated with receiving SACT.ResultsMedian OS for all participants was 2.9 months, increasing for the SACT-treated subcohort from 8.4 months (2007–2012) to 9.1 months (2013–2017) (p=0.02); 1-year OS increased from 33% to 39% over the same period for the SACT-treated group. Median OS for the untreated subcohort was 1.6 months in both time periods. Overall, 30.6% (648/2119) patients received SACT; treatment rates increased from 28.6% (338/1181) in 2007–2012 to 33.0% (310/938) in 2013–2017 (p=0.03). Age and performance status were independent predictors for SACT treatment; advanced age and higher performance status were associated with lower SACT treatment rates.ConclusionAlthough developments in SACT during 2007–2017 correspond to some changes in survival for treated patients with advanced NSCLC, treatment rates remain low and the prognosis for all patients remains poor.

Background and aims Given the enormous global burden of depressive illness, there is an urgent need to develop novel and more effective treatments for major depressive disorder (MDD). Recent findings have suggested that psychedelic drugs may have a role in the treatment of depressive symptoms, and a number of groups are in the process of developing protocols to study this question systematically. Given the subjective quality of both the psychedelic experience and depressive symptomatology, great care must be taken when designing a protocol to study the clinical efficacy of psychedelic drugs. This study will discuss many factors to consider when designing a clinical trial of psilocybin for MDD. Methods We provide a thorough review of pertinent research into antidepressant clinical trial methodology and review practical considerations that are relevant to the study of psychedelic-assisted treatment for depression. Results We discuss participant selection (including diagnostic accuracy, exclusion criteria, characteristics of the depressive episode, and the use of concurrent medications), study interventions (including dosing regimens, placebo selection, non-pharmacological components of treatment, and the importance of blinding), trial duration, outcome measures, and safety considerations. Conclusions Careful and transparent study design and data analysis will maximize the likelihood of generating meaningful, reproducible results, and identifying a treatment-specific effect. Meeting the highest standards for contemporary trial design may also broaden the acceptance of psychedelic research in the scientific community at large.

Mosquito-borne arboviruses, including a diverse array of alphaviruses and flaviviruses, lead to hundreds of millions of human infections each year. Current methods for species-level classification of arboviruses adhere to guidelines prescribed by the International Committee on Taxonomy of Viruses (ICTV), and generally apply a polyphasic approach that might include information about viral vectors, hosts, geographical distribution, antigenicity, levels of DNA similarity, disease association and/or ecological characteristics. However, there is substantial variation in the criteria used to define viral species, which can lead to the establishment of artificial boundaries between species and inconsistencies when inferring their relatedness, variation and evolutionary history. In this study, we apply a single, uniform principle – that underlying the Biological Species Concept (BSC) – to define biological species of arboviruses based on recombination between genomes. Given that few recombination events have been documented in arboviruses, we investigate the incidence of recombination within and among major arboviral groups using an approach based on the ratio of homoplastic sites (recombinant alleles) to non-homoplastic sites (vertically transmitted alleles). This approach supports many ICTV-designations but also recognizes several cases in which a named species comprises multiple biological species. These findings demonstrate that this metric may be applied to all lifeforms, including viruses, and lead to more consistent and accurate delineation of viral species.

Salt marshes and seagrass meadows can sequester and store high quantities of organic carbon (OC) in their sediments relative to other marine and terrestrial habitats. Assessing carbon stocks, carbon sources, and the transfer of carbon between habitats within coastal seascapes are each integral in identifying the role of blue carbon habitats in coastal carbon cycling. Here, we quantified carbon stocks, sources, and exchanges in seagrass meadows, salt marshes, and unvegetated sediments in six bays along the Pacific coast of California. The salt marshes studied here contained approximately twice as much OC as did seagrass meadows, 23.51 ± 1.77 kg OC m−3 compared to 11.01 ± 1.18 kg OC m−3, respectively. Both seagrass and salt marsh sediment carbon stocks were higher than previous estimates from this region but lower than global and U.S.-wide averages, respectively. Seagrass-derived carbon was deposited annually into adjacent marshes during fall seagrass senescence. However, isotope mixing models estimate that negligible amounts of this seagrass material were ultimately buried in underlying sediment. Rather, the vast majority of OC in sediment across sites was likely derived from planktonic/benthic diatoms and C3 salt marsh plants.

Mild traumatic brain injury (mTBI) affects millions of individuals annually primarily through falls, traffic collisions, or blunt trauma and can generate symptoms that persist for years. Closed-head rotational injury is the most common form of mTBI and is defined by a rapid change in acceleration within an intact skull. Injury kinematics – the mechanical descriptors of injury-inducing motion – explain movement of the head, energy transfer to the brain, and, therefore, determine injury severity. However, the relationship between closed-head rotational injury kinematics – such as angular velocity, angular acceleration, and injury duration – and outcome after mTBI is currently unknown. To address this gap in knowledge, we analyzed archived surgical records of 24 swine experiencing a diffuse closed-head rotational acceleration mTBI against 12 sham animals. Kinematics were contrasted against acute recovery outcomes, specifically apnea, extubation time, standing time, and recovery duration. Compared to controls, animals with mTBI were far more likely to have apnea (p2=0.27), standing time (R2=0.39) and recovery duration (R2=0.42). Neuropathology was correlated with multiple kinematics, with maximum acceleration exhibiting the strongest correlation (R2=0.66). Together, these data suggest the interplay between multiple injury kinematics, including minimum velocity and middle to minimum acceleration time, best explain acute recovery parameters and neuropathology after mTBI in swine. Future experiments that independently manipulate individual kinematics could be instrumental in developing translational diagnostics for clinical mTBI.HIGHLIGHTSAcute recovery parameters including apnea, extubation time, and recovery duration were altered after a single closed-head mTBI in swine.Lasso-based regressions utilized kinematic parameters, including minimum velocity and middle to minimum acceleration time, to relate kinematics to apnea time, standing time, and recovery duration.Lasso regression equations were able to modestly predict apnea time (R2=0.27) and moderately predict standing time (R2=0.39) and recovery duration (R2=0.42).Injury kinematic parameters, primarily maximum acceleration, were correlated with white matter pathology after mTBI.

Aim: This observational study evaluated treatment patterns and survival for patients with stage I–IIIA non-small-cell lung cancer (NSCLC). Materials & methods: Adults newly diagnosed with NSCLC in 2012–2016 at IPO-Porto hospital were included. Treatment data were available for patients diagnosed in 2015–2016. Results: 495 patients were included (median age: 67 years). The most common treatments were surgery alone or with another therapy (stage I: 66%) and systemic anticancer therapy plus radiotherapy (stage II: 54%; stage IIIA: 59%). One-year OS (95% CI) for patients with stage I, II and IIIA NSCLC (diagnosed 2012–2016) were 92% (88–96), 71% (62–82) and 69% (63–75), respectively; one-year OS (95% CI) for treated patients with stage I–II or stage IIIA NSCLC (diagnosed 2015–2016) were 89% (81–97) and 86% (75–98) for non-squamous cell and 76% (60–95) and 49% (34–70) for squamous cell NSCLC. Conclusion: Treatment advances are strongly needed for stage I–IIIA NSCLC, especially for patients with squamous cell histology.

Introduction: For persons with hemophilia, optimization of joint outcomes is an important unmet need. The aim of this initiative was to determine use of ultrasound in evaluating arthropathy in persons with hemophilia, and to move toward consensus among hemophilia care providers regarding the preferred ultrasound protocols for global adaptation. Methods: A global survey of hemophilia treatment centers was conducted that focused on understanding how and why ultrasound was being used and endeavored to move toward consensus definitions of both point-of-care musculoskeletal ultrasound (POC-MSKUS) and full diagnostic ultrasound, terminology to describe structures being assessed by ultrasound, and how these assessments should be interpreted. Next, an in-person meeting of an international group of hemophilia health care professionals and patient representatives was held, with the objective of achieving consensus regarding the acquisition and interpretation of POC-MSKUS and full diagnostic ultrasound for use in the assessment of musculoskeletal (MSK) pathologies in persons with hemophilia. Results: The recommendations were that clear definitions of the types of ultrasound examinations should be adopted and that a standardized ultrasound scoring/measurement system should be developed, tested, and implemented. The scoring/measurement system should be tiered to allow for a range of complexity yet maintain the ability for comparison across levels. Conclusion: Ultrasound is an evolving technology increasingly used for the assessment of MSK outcomes in persons with hemophilia. As adoption increases globally for clinical care and research, it will become increasingly important to establish clear guidelines for image acquisition, interpretation, and reporting to ensure accuracy, consistency, and comparability across groups. © 2021 The authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis(ISTH).

In recent years, regulatory bodies have increasingly recognized the utility of real-world evidence (RWE) for supplementing and supporting clinical trial data in new drug applications. Nevertheless, the integration of RWE into established regulatory processes is complex and the generation of ‘regulatory-grade’ real-world data faces operational, methodological, data-related and policy-related challenges. In parallel with this evolving role for RWE, immuno-oncology therapies have emerged as leading cancer treatments and are expected to continue to play a central role in the future. In this article, we review the current literature on the use of RWE for regulatory submissions, with a focus on novel anticancer immunotherapies, and discuss the utility and current limitations of RWE in the context of drug development and regulatory approvals.