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Background: Temperate grass (eg, ryegrass) pollen is a major driver of seasonal allergic rhinitis (SAR) and asthma risks, including thunderstorm asthma. Data for the effectiveness of temperate grass pollen allergen immunotherapy (AIT) in SAR patients from the southern hemisphere, who are frequently polysensitized to subtropical grass pollens, are limited. The 300 IR 5-grass pollen sublingual immunotherapy tablet (300 IR 5-grass SLIT) is known to be effective in polysensitized SAR patients with primary allergy to temperate grasses, however, the influence of polysensitization to subtropical grass pollen on treatment responses has yet to be specifically addressed. Key aims of this study were to measure patient treatment satisfaction during 300 IR 5-grass SLIT treatment and evaluate how polysensitization to subtropical grass pollens affects treatment responses. Methods: A prospective observational study was conducted in 63 patients (aged ≥5 years) in several temperate regions of Australia prescribed 300 IR 5-grass SLIT for SAR over 3 consecutive grass pollen seasons. Ambient levels of pollen were measured at representative sites. Patient treatment satisfaction was assessed using a QUARTIS questionnaire. Rhinoconjunctivitis Total Symptom Score (RTSS) and a Hodges-Lehmann Estimator analysis was performed to evaluate if polysensitization to subtropical grass pollen affected SAR symptom intensity changes during SLIT. Results: A diagnosis of ryegrass pollen allergy was nearly universal. There were 74.6% (47/63) polysensitized to subtropical and temperate grass pollens. There were 23.8% (15/63) monosensitized to temperate grass pollens. From the first pollen season, statistically significant improvements occurred in SAR symptoms compared with baseline in both monosensitized and polysensitized patients, particularly in those polysensitized (P = 0.0297). Improvements in SAR symptoms were sustained and similar in both groups in the second and third pollen seasons, reaching 70–85% improvement (P

Subcutaneous (SC) administration of rituximab provides an opportunity for reduced patient treatment burden and increased healthcare efficiencies as an alternative to intravenous (IV) rituximab. There is minimal evidence comparing costs associated with SC and IV rituximab in a US setting. This research assessed the impact of transitioning patients from IV to SC rituximab for treatment of non-Hodgkin’s lymphoma (NHL) from the US payer, provider, and patient perspective. We developed a model to estimate cost differences for transitioning 20% of a patient cohort from IV to SC rituximab. We included patients with incident diffuse large B-cell lymphoma, incident and recurrent follicular lymphoma, and incident and recurrent chronic lymphocytic leukemia. In the model, each patient received the same number of doses and that there was no difference in discontinuation between cohorts due to non-inferior efficacy and a similar safety profile. Model inputs were collected from published literature and publicly available data. Scenario analyses tested the impact of availability of low-cost biosimilars. In the base case (1,000,000 covered lives), we estimated a total of 157 patients, with 769 total drug administrations. A transition of 20% of patients from IV to SC was projected to generate $153,000 in payer savings, increase provider capacity by 270 hours, and free 470 hours of patient time. Scenario analyses suggest SC administration will be cost saving for payers even with a market where biosimilars approach 50% market share. A 20% transition to SC rituximab in a single cohort of patients has the potential to generate significant US health system value in the form of payer savings, increased practice capacity, and patient time.

Global sea-level rise caused by a warming climate increases flood risk from storm surge events for those who live in coastal and low-lying areas. Estimates of global thermosteric sea-level rises are well constrained by model projections, but local variability in dynamic sea-level arising from seasonal and interannual changes is less well characterised. In this paper we use satellite altimetry observations coupled with CMIP6 model projections to understand drivers of change in dynamic sea-level over the UK shelf seas. We find a northward shift in the atmospheric jet stream and a weakening of the Atlantic meridional overturning circulation to be the key drivers of local dynamic sea-level variability. Using a storyline approach to constrain climate system responses to changes in atmospheric greenhouse gas concentrations, we find that dynamic sea-level is predicted to rise between 15–39 cm by 2080–2099 along the east coast of England (ECE). Under a worst-case scenario, assuming maximum variability as seen in the CMIP6 projections, ECE dynamic sea-level rise could reach 58 cm by 2100. We illustrate the impact of this dynamic sea-level rise in addition to non-dynamic components on the risks posed by storm surge events in ECE using an idealised example. If a storm surge event of the magnitude of the one experienced in ECE on the 5th of December 2013 was to occur in 2100, an additional 1414 km ^2 of land would potentially be affected in our worst-case idealised example, 22.4% of which can be attributed to dynamic sea-level rise.

Summary Objective Internet delivery of behavioural weight control interventions offers potential for broad geographic reach and accessibility, but weight losses online fall short of those produced with the same programme delivered in‐person. This pilot study examined feasibility and preliminary efficacy of a video‐based platform for delivering weekly chat as part of a 6‐month, 24‐session online group behavioural weight control programme compared with the established text‐based format, which has produced the best online weight losses to date. Method Women with obesity (N = 32) were randomized to either (a) weekly video group chat sessions and provided with a cellular‐enabled scale (Video) or (b) Text‐based weekly chat sessions and given a digital scale (Text) and followed for 6 months to determine weight loss and treatment engagement. Results Women randomized to the ideo condition lost more weight than those in the Text condition (−5.0 ± 6.0% vs. −3.0 ± 4.1%, respectively) at 6 months, although the difference was not statistically significant. However, women in the Video condition had significantly greater treatment engagement, with greater self‐monitoring and website utilization than those in the Text condition. Conclusions Videoconference delivery of group‐based online weight control accompanied by a cellular‐connected scale may promote greater treatment engagement and weight loss than text‐based chat. A larger, adequately powered study is warranted to determine which elements drive these enhanced treatment outcomes.

Group A Streptococcus is a globally significant human pathogen. The extensive variability of the GAS genome, virulence phenotypes and clinical outcomes, render it an excellent candidate for the application of genotype-phenotype association studies in the era of whole-genome sequencing. We have catalogued the distribution and diversity of the transcription regulators of GAS, and employed phylogenetics, concordance metrics and machine learning (ML) to test for associations. In this review, we communicate the lessons learnt in the context of the recent bacteria genotype-phenotype association studies of others that have utilised both genome-wide association studies (GWAS) and ML. We envisage a promising future for the application GWAS in bacteria genotype-phenotype association studies and foresee the increasing use of ML. However, progress in this field is hindered by several outstanding bottlenecks. These include the shortcomings that are observed when GWAS techniques that have been fine-tuned on human genomes, are applied to bacterial genomes. Furthermore, there is a deficit of easy-to-use end-to-end workflows, and a lag in the collection of detailed phenotype and clinical genomic metadata. We propose a novel quality control protocol for the collection of high-quality GAS virulence phenotype coupled to clinical outcome data. Finally, we incorporate this protocol into a workflow for testing genotype-phenotype associations using ML and ‘linked’ patient-microbe genome sets that better represent the infection event.

Background:. Acute compartment syndrome of the foot is a controversial topic. Release of the foot has been seen as complicated because of large incisions and postoperative morbidity, and there has been debate over whether this procedure is actually effective for releasing all areas of increased pressure. New sensor technology affords the opportunity to advance our understanding of acute compartment syndrome of the foot and its treatment. The purpose of the present study was to determine whether percutaneous decompression could be performed for the treatment of compartment syndrome in a forefoot model. Methods:. The present study utilized a validated continuous pressure sensor to model compartment syndrome in human cadaveric feet. We utilized a pressure-controlled saline solution infusion system to induce increased pressure. A novel percutaneous release of the forefoot was investigated to assess its efficacy in achieving decompression. Results:. For all cadaveric specimens, continuous pressure monitoring was accomplished with use of a continuous pressure sensor. There were 4 discrete compartment areas that could be reliably pressurized in all feet. The average baseline, pressurized, and post-release pressures (and standard deviations) were 4.5 ± 2.9, 43.8 ± 7.7, and 9.5 ± 3.6 mm Hg, respectively. Percutaneous decompression produced a significant decrease in pressure in all 4 compartments (p < 0.05). Conclusions:. With use of continuous compartment pressure monitoring, 4 consistent areas were established as discrete compartments in the foot. All 4 compartments were pressurized with a standard pump system. With use of 2 small dorsal incisions, all 4 compartments were successfully released, with no injuries identified in the cutaneous nerve branches, extensor tendons, or arteries. These results have strong implications for the future of modeling compartment syndrome as well as for guiding clinical studies. Clinical Relevance:. A reproducible and accurate method of continuous pressure monitoring of foot compartments after trauma is needed (1) to reliably identify patients who are likely to benefit from compartment release and (2) to help avoid missed or evolving cases of acute compartment syndrome. In addition, a reproducible method for percutaneous compartment release that minimizes collateral structural damage and the need for secondary surgical procedures is needed.

Abstract It is a critical time to reflect on the National Ecological Observatory Network (NEON) science to date as well as envision what research can be done right now with NEON (and other) data and what training is needed to enable a diverse user community. NEON became fully operational in May 2019 and has pivoted from planning and construction to operation and maintenance. In this overview, the history of and foundational thinking around NEON are discussed. A framework of open science is described with a discussion of how NEON can be situated as part of a larger data constellation—across existing networks and different suites of ecological measurements and sensors. Next, a synthesis of early NEON science, based on >100 existing publications, funded proposal efforts, and emergent science at the very first NEON Science Summit (hosted by Earth Lab at the University of Colorado Boulder in October 2019) is provided. Key questions that the ecology community will address with NEON data in the next 10 yr are outlined, from understanding drivers of biodiversity across spatial and temporal scales to defining complex feedback mechanisms in human–environmental systems. Last, the essential elements needed to engage and support a diverse and inclusive NEON user community are highlighted: training resources and tools that are openly available, funding for broad community engagement initiatives, and a mechanism to share and advertise those opportunities. NEON users require both the skills to work with NEON data and the ecological or environmental science domain knowledge to understand and interpret them. This paper synthesizes early directions in the community’s use of NEON data, and opportunities for the next 10 yr of NEON operations in emergent science themes, open science best practices, education and training, and community building.

Recently, the abnormal level of zinc emerged as a powerful indicator or risk factor for metabolic, endocrine, neurodegenerative and cardiovascular diseases, including cancer. Electrochemical detection has been explored to quantify zinc in a precise, rapid, and non-expensive way; however, most of the current electrochemical systems lack in specificity. In this work we studied a highly selective and sensitive electrochemical method to detect quickly and reliably free zinc ions (Zn2+). The surface of the working electrode was modified with zincon electropolymerized on carbon nanotube (CNT) to enable the binding of zinc in complex body fluids. After being physicochemically characterized, the performances of the zincon-CNT complex was electrochemically assessed. Square Wave Voltammetry (SWV) was used to determine the calibration curve and the linear range of zinc quantification in artificial saliva and urine. This zincon- CNT system could specifically quantify mobile Zn2+ in salivary and urinary matrices with a sensitivity of ~100 ng·mL−1 and a limit of detection (LOD) of ~20 ng·mL−1. Zincon-modified CNT presented as a desirable candidate for the detection and quantification of free zinc in easily body fluids that potentially can become a diagnostic non-invasive testing platform.

The glycine receptor (GlyR), a ligand-gated ion channel, is critical for inhibitory neurotransmission in brainstem, spinal cord, and in supraspinal regions. Recent data from several laboratories have shown that GlyRs are expressed in the brain reward circuitry and that α1 and α2 are the principal subunits expressed in the nucleus accumbens (nAc). In the present study, we studied the sensitivity to ethanol of homomeric and heteromeric α3 GlyR subunits in HEK293 cells and dissociated neurons from the nAc. Finally, we explored ethanol-related behaviors in a Glra3 knockout mouse (Glra3–/–). Studies in HEK293 cells showed that while homomeric α3 GlyR subunits were insensitive to ethanol, heteromeric α3β GlyR subunits showed higher sensitivity to ethanol. Additionally, using electrophysiological recordings in dissociated accumbal neurons, we found that the glycine current density increased in Glra3–/– mice and the GlyRs were less affected by ethanol and picrotoxin. We also examined the effect of ethanol on sedation and drinking behavior in Glra3–/– mice and found that the duration in the loss of righting reflex (LORR) was unchanged compared to wild-type (WT) mice. On the other hand, using the drinking in the dark (DID) paradigm, we found that Glra3–/– mice have a larger ethanol consumption compared to WT mice, and that this was already high during the first days of exposure to ethanol. Our results support the conclusion that heteromeric α3β, but not homomeric α3, GlyRs are potentiated by ethanol. Also, the increase in GlyR and GABAAR mediated current densities in accumbal neurons in the KO mice support the presence of compensatory changes to α3 knock out. The increase in ethanol drinking in the Glra3–/– mice might be associated to the reduction in β and compensatory changes in other subunits in the receptor arrangement.

Startle disease is a rare disorder associated with mutations in GLRA1 and GLRB, encoding glycine receptor (GlyR) α1 and β subunits, which enable fast synaptic inhibitory transmission in the spinal cord and brainstem. The GlyR β subunit is important for synaptic localization via interactions with gephyrin and contributes to agonist binding and ion channel conductance. Here, we have studied three GLRB missense mutations, Y252S, S321F, and A455P, identified in startle disease patients. For Y252S in M1 a disrupted stacking interaction with surrounding aromatic residues in M3 and M4 is suggested which is accompanied by an increased EC50 value. By contrast, S321F in M3 might stabilize stacking interactions with aromatic residues in M1 and M4. No significant differences in glycine potency or efficacy were observed for S321F. The A455P variant was not predicted to impact on subunit folding but surprisingly displayed increased maximal currents which were not accompanied by enhanced surface expression, suggesting that A455P is a gain-of-function mutation. All three GlyR β variants are trafficked effectively with the α1 subunit through intracellular compartments and inserted into the cellular membrane. In vivo, the GlyR β subunit is transported together with α1 and the scaffolding protein gephyrin to synaptic sites. The interaction of these proteins was studied using eGFP-gephyrin, forming cytosolic aggregates in non-neuronal cells. eGFP-gephyrin and β subunit co-expression resulted in the recruitment of both wild-type and mutant GlyR β subunits to gephyrin aggregates. However, a significantly lower number of GlyR β aggregates was observed for Y252S, while for mutants S321F and A455P, the area and the perimeter of GlyR β subunit aggregates was increased in comparison to wild-type β. Transfection of hippocampal neurons confirmed differences in GlyR-gephyrin clustering with Y252S and A455P, leading to a significant reduction in GlyR β-positive synapses. Although none of the mutations studied is directly located within the gephyrin-binding motif in the GlyR β M3-M4 loop, we suggest that structural changes within the GlyR β subunit result in differences in GlyR β-gephyrin interactions. Hence, we conclude that loss- or gain-of-function, or alterations in synaptic GlyR clustering may underlie disease pathology in startle disease patients carrying GLRB mutations.

Many people wish to avoid harming animals, yet most people also consume meat. This theoretical ‘meat paradox’ is a form of cognitive dissonance and has grave negative consequences for animal welfare and the environment. Yet, despite these consequences, the meat paradox literature is sparse. The current structured literature review (SLR) explores primary literature up to May 2020, supporting the paradox and uniquely reviewing all known triggers of the paradox (e.g., exposure to meat’s animal origins), all known strategies to overcome the paradox (e.g., avoiding thinking about consumed animals) and how different people (e.g., those of different genders, occupations, ages, dietary preferences, cultures or religions) utilise varying strategies to overcome the paradox. For instance, the review uniquely demonstrates how dietary identity, dietary adherence and meat consumption frequency, among other demographic and psychographic factors, all affect moral (dis)engagement from animals. Overall, this paper has wide-ranging theoretical implications for the meat paradox and social psychological literature, and practical implications for meat reduction policies.

Matrix metalloproteinases (MMPs) are essential proteins acting directly in the breakdown of the extra cellular matrix and so in cancer invasion and metastasis. Given its impact on tumor angiogenesis, monitoring MMP-14 provides strategic insights on cancer severity and treatment. In this work, we report a new approach to improve the electrochemical interaction of the MMP-14 with the electrode surface while preserving high specificity. This is based on the detection of the hemopexin (PEX) domain of MMP-14, which has a greater availability with a stable and low-cost commercial molecule, as a recognition element. This molecule, called NSC-405020, is specific of the PEX domain of MMP-14 within the binding pocket. Through the covalent grafting of the NSC-405020 molecule on carbon nanotubes (CNTs), we were able to detect and quantify MMP-14 using electrochemical impedance spectroscopy with a linear range of detection of 10 ng⋅mL−1 to 100 ng⋅mL−1, and LOD of 7.5 ng⋅mL−1. The specificity of the inhibitory small molecule was validated against the PEX domain of MMP-1. The inhibitor loaded CNTs system showed as a desirable candidate to become an alternative to the conventional recognition bioelements for the detection of MMP-14.

Accurate assessment of burn severity is a critical need for an improved understanding of fire behavior and ecology and effective post-fire management. Although NASA Landsat satellites have a long history of use for remotely sensed mapping of burn severity, the recently launched (2015 and 2017) European Space Agency Sentinel-2 satellite constellation offers increased temporal and spatial resolution with global coverage, combined with free data access. Evaluations of burn severity derived from Landsat and Sentinel generally show comparable results, but these studies only assessed a small number of fires with limited field data. We used 912 ground calibration plots from 26 fires that burned between 2016 and 2019 in western North America to compare Sentinel- and Landsat-derived burn severity estimates with the field-based composite burn index. We mapped burn severity using two methods; the well-established paired scene approach, in which a single pre- and post-fire scene are selected for each fire, and also a mean image compositing approach that automatically integrates multiple scenes using the cloud-based remote sensing platform Google Earth Engine. We found that Sentinel generally performed as well or better than Landsat for four spectral indices of burn severity, particularly when using atmospherically corrected Sentinel imagery. Additionally, we tested the effects of mapping burn severity at Sentinel’s finer spatial resolution (10 m) on estimates of the spatial complexity of stand-replacing fire, resulting in a 5% average reduction per-fire in area mapped as high-severity patch interiors (24,273 ha total) compared to mapping at the resolution of Landsat (30 m). These findings suggest Sentinel may improve ecological discrimination of fine-scale fire effects, but also warrant caution when comparing estimates of burn severity spatial patterns derived at different resolutions. Overall, these results indicate that burn severity mapping will benefit substantially from the integration of Sentinel imagery through increased imagery availability, and that Sentinel’s higher spatial resolution improves opportunities for examining finer-scale fire effects across ecosystems.

Background: Embryo culture and cryopreservation causes detrimental effects on blastocyst gene expression. While combined antioxidants (acetyl-L-carnitine/N-acetyl-L-cysteine/[Formula: see text]-lipoic acid (A3)) in culture and vitrification media have beneficial effects on embryo and fetal development, their impact on fetal gene expression has not been assessed. Therefore, the effects of antioxidants on global gene expression were examined from fetal and placental tissue of transferred blastocysts and compared to in vivo derived embryos. Aim: To determine the effect of A3 in culture and vitrification media on mouse blastocyst, fetal and placental gene expression. Method: Embryo transfers were conducted on in vivo flushed blastocysts or blastocysts cultured or vitrified with and without A3. Transcriptional profiles of E14 fetal liver and placental tissue in all groups were quantified using RNAseq and functional analyses (KEGG). Results: Compared to in vivo derived embryos, in vitro culture altered the expression of 3601 fetal liver and 408 placental genes. Functional analysis showed upregulation/enrichment of oxidative phosphorylation and mitochondrial function and activity. Similarly, vitrification led to 2018 liver and 216 placental differentially expressed genes (DEGs). Upregulated KEGG pathways were enriched for cell and tissue development and cell cycle regulation. Down regulated pathways were associated with metabolism and immune response. Interestingly, exposure to A3 during development significantly reduced the number of DEGs with 1855 and 4 identified in liver and placentae respectively with no KEGG pathways identified. Correspondingly, exposure to A3 during vitrification reduced the number of DEGs to 1017 in liver and 206 in placentae. Functional pathway enrichment was similar to embryos vitrified without A3, although with decreased expression. Conclusion: Supplementation with antioxidants reduce the number of DEGs and biological processes altered by in vitro culture and vitrification, in fetal liver and placentae, establishing a more in vivo like gene expression profile which may help maintain the viability of vitrified human embryos.

Background: Diet-induced nutritional changes in the maternal reproductive tract stimulate embryonic adaptations to maintain growth and survival, directly impacting child and adult health via developmental programming. This is plausibly facilitated by an interrelationship between metabolism and epigenetic control of gene expression, termed ‘metaboloepigenetics’, resulting in heritable modifications that affect long-term offspring health and viability. The ketogenic diet (KD) is increasingly popular amongst sub-fertile women trying to conceive, and results in elevated maternal ketone levels, including beta-hydroxybutyrate (bOHB). The impact of high bOHB levels on embryonic development, physiology, and developmental programming remains unknown. Aim: To assess how bOHB affects preimplantation mouse embryo development, metaboloepigenetic regulation, and post-transfer viability. Method: Preimplantation mouse embryos were cultured in vitro with or without 2 mM bOHB, representing serum concentrations with KD consumption. Day 5 blastocyst cell number and lineage allocation was assessed via differential nuclear stain, metabolism of bOHB and carbohydrates was assessed by ultramicrofluorescence, and acetylation of histone 3 lysine 9 (H3K9ac) and lysine 27 (H3K27ac) were assessed by immunofluorescence. Day 4 blastocysts were transferred to pseudo-pregnant females for analysis of embryonic day 14.5 placental and fetal development. Results: A reduction in total and trophectoderm cell number (P

Background: At the time of implantation, the blastocyst produces a significant amount of lactic acid (LA), creating a microenvironment characterized by high lactate and low pH. Historically considered a ‘by-product’ of metabolism, studies have revealed lactate to be a key regulator of cell function, with a lactate-specific receptor, GPR81, recently identified. Further, lactate is an important signalling molecule in cancers promoting ECM breakdown, angiogenesis and immunosuppression, processes vital for successful implantation. Hence, LA could be an early embryonic signal to facilitate endometrial remodelling for receptivity and implantation. Aim: To determine the role of blastocyst-derived lactate on cellular functions/remodelling and transcriptional changes essential for endometrial receptivity and successful implantation. Methods: To assess functional changes to the endometrium, hormonally primed ECC-1 and Ishikawa cells were exposed to LA, LA + neutralized pH (nLA) or acidic pH (pHL), before analysis of tight junction integrity (TER), cellular proliferation and changes to gene expression. LA’s effects on endometrial stromal cell decidualization and migratory capacity, as well as HUVEC endothelial tube formation/angiogenesis, were also determined. Results: Cellular TER and proliferation were significantly downregulated in ECC-1 cells exposed to 2.5, 5 and 7.5mM LA ( P

Aquaculture and marine renewable energy are two expanding sectors of the Blue Economy in Europe. Assessing the long-term environmental impacts in terms of eutrophication and noise is a priority for both the EU Water Framework Directive and the Marine Strategy Framework Directive, and cumulative impacts will be important for the Maritime Spatial Planning under the Integrated Maritime Policy. With the constant expansion of aquaculture production, it is expected that farms might be established further offshore in more remote areas, as high-energy conditions offer an opportunity to generate more power locally using Marine Renewable Energy (MRE) devices. A proposed solution is the co-location of MRE devices and aquaculture systems using Multi-Purpose Platforms (MPPs) comprising offshore wind turbines (OWTs) that will provide energy for farm operations as well as potentially shelter the farm. Disentangling the impacts, conflicts and synergies of MPP elements on the surrounding marine ecosystem is challenging. Here we created a high-resolution spatiotemporal Ecospace model of the West of Scotland, in order to assess impacts of a simple MPP configuration on the surrounding ecosystem and how these impacts can cascade through the food web. The model evaluated the following specific ecosystem responses: (i) top-down control pathways due to distribution changes among top-predators (harbor porpoise, gadoids and seabirds) driven by attraction to the farming sites and/or repulsion/killing due to OWT operations; (ii) bottom-up control pathways due to salmon farm activity providing increasing benthic enrichment predicated by a fish farm particle dispersal model, and sediment nutrient fluxes to the water column by early diagenesis of organic matter (recycled production). Weak responses of the food-web were found for top-down changes, whilst the results showed high sensitivity to increasing changes of bottom-up drivers that cascaded through the food-web from primary producers and detritus to pelagic and benthic consumers, respectively. We assessed the sensitivity of the model to each of these impacts and the cumulative effects on the ecosystem, discuss the capabilities and limitations of the Ecospace modeling approach as a potential tool for marine spatial planning and the impact that these results could have for the Blue Economy and the EU’s New Green Deal.

Abstract. Collagen fleece is a relatively new development. It represents another option in the battle against infection. It is a cheap, biocompatible, and resorbable local antibiotic delivery mechanism with favorable drug release kinetics and low risk of adverse effects or toxicity. Benefit may be conferred when used in contaminated cases. Significantly more research is still needed before the adoption of collagen fleece as the standard of care. However, we can likely conclude that there are no major adverse effects and it can be safely used as an adjunct in addition to conventional therapies for the prophylaxis and treatment of infections.

One of the significant challenges to using information and ideas generated through ecosystem models and analyses for ecosystem-based fisheries management is the disconnect between modeling and management needs. Here we present a case study from the U.S. West Coast, the stakeholder review of NOAA’s annual ecosystem status report for the California Current Ecosystem established by the Pacific Fisheries Management Council’s Fisheries Ecosystem Plan, showcasing a process to identify management priorities that require information from ecosystem models and analyses. We then assess potential ecosystem models and analyses that could help address the identified policy concerns. We screened stakeholder comments and found 17 comments highlighting the need for ecosystem-level synthesis. Policy needs for ecosystem science included: (1) assessment of how the environment affects productivity of target species to improve forecasts of biomass and reference points required for setting harvest limits, (2) assessment of shifts in the spatial distribution of target stocks and protected species to anticipate changes in availability and the potential for interactions between target and protected species, (3) identification of trophic interactions to better assess tradeoffs in the management of forage species between the diet needs of dependent predators, the resilience of fishing communities, and maintenance of the forage species themselves, and (4) synthesis of how the environment affects efficiency and profitability in fishing communities, either directly via extreme events (e.g., storms) or indirectly via climate-driven changes in target species availability. We conclude by exemplifying an existing management process established on the U.S. West Coast that could be used to enable the structured, iterative, and interactive communication between managers, stakeholders, and modelers that is key to refining existing ecosystem models and analyses for management use.

Abstract Objective Nuclear Factor One X (NFIX) is a transcription factor expressed by neural stem cells within the developing mouse brain and spinal cord. In order to characterise the pathways by which NFIX may regulate neural stem cell biology within the developing mouse spinal cord, we performed an microarray-based transcriptomic analysis of the spinal cord of embryonic day (E)14.5 Nfix −/− mice in comparison to wild-type controls. Data description Using microarray and differential gene expression analyses, we were able to identify differentially expressed genes in the spinal cords of E14.5 Nfix −/− mice compared to wild-type controls. We performed microarray-based sequencing on spinal cords from n = 3 E14.5 Nfix −/− mice and n = 3 E14.5 Nfix +/+ mice. Differential gene expression analysis, using a false discovery rate (FDR) p-value of p ± 1.5, revealed 1351 differentially regulated genes in the spinal cord of Nfix −/− mice. Of these, 828 were upregulated, and 523 were downregulated. This resource provides a tool to interrogate the role of this transcription factor in spinal cord development.

Abstract Background Neuroinflammation can modulate brain development; however, the influence of an acute peripheral immune challenge on neuroinflammatory responses in the early postnatal brain is not well characterized. To address this gap in knowledge, we evaluated the peripheral and central nervous system (CNS) immune responses to a mixed immune challenge in early postnatal rats of varying strains and sex. Methods On postnatal day 10 (P10), male and female Lewis and Brown Norway rats were injected intramuscularly with either a mix of bacterial and viral components in adjuvant, adjuvant-only, or saline. Immune responses were evaluated at 2 and 5 days post-challenge. Cytokine and chemokine levels were evaluated in serum and in multiple brain regions using a Luminex multiplex assay. Multi-factor ANOVAs were used to compare analyte levels across treatment groups within strain, sex, and day of sample collection. Numbers and activation status of astrocytes and microglia were also analyzed in the cortex and hippocampus by quantifying immunoreactivity for GFAP, IBA-1, and CD68 in fixed brain slices. Immunohistochemical data were analyzed using a mixed-model regression analysis. Results Acute peripheral immune challenge differentially altered cytokine and chemokine levels in the serum versus the brain. Within the brain, the cytokine and chemokine response varied between strains, sexes, and days post-challenge. Main findings included differences in T helper (Th) type cytokine responses in various brain regions, particularly the cortex, with respect to IL-4, IL-10, and IL-17 levels. Additionally, peripheral immune challenge altered GFAP and IBA-1 immunoreactivity in the brain in a strain- and sex-dependent manner. Conclusions These findings indicate that genetic background and sex influence the CNS response to an acute peripheral immune challenge during early postnatal development. Additionally, these data reinforce that the developmental time point during which the challenge occurs has a distinct effect on the activation of CNS-resident cells.

Abstract Background Chronic rhinosinusitis (CRS) is a complex disease that incorporates many different conditions. Currently, primary CRS is considered a disease of broad airway inflammation, however, the previous classification of CRS with and without nasal polyposis fails to adequately classify patients based upon their etiology of illness. Our aim with this review is discuss the clinical presentation, radiology, endoscopy, histopathology, and treatment algorithm of three different phenotypes of primary CRS: central compartment atopic disease, eosinophilic CRS, and non-eosinophilic CRS. Methods A narrative review of a tertiary rhinology center’s research themes and how they are applied to clinical protocols and practice was assessed. Discussion Diagnosis and treatment of upper and lower airway conditions become increasingly important as phenotypes and endotypes are being described. There are well-described therapies to treat the different phenotypes of CRS, based upon the presumed underlying cause of the inflammatory process. Research continues to shed more light on different endotypes and phenotypes of airway inflammation, however, clinical differentiation of CRS can be applied in clinic practice with three simple phenotypes of CRS. Understanding these different phenotypes and their etiologies allows for further management beyond the ‘maximum medical therapy and then surgery’ approach that has often been used in the management of CRS.

Abstract Background Prompted by the revolution in high-throughput sequencing and its potential impact for treating cancer patients, we initiated a clinical research study to compare the ability of different sequencing assays and analysis methods to analyze glioblastoma tumors and generate real-time potential treatment options for physicians. Methods A consortium of seven institutions in New York City enrolled 30 patients with glioblastoma and performed tumor whole genome sequencing (WGS) and RNA sequencing (RNA-seq; collectively WGS/RNA-seq); 20 of these patients were also analyzed with independent targeted panel sequencing. We also compared results of expert manual annotations with those from an automated annotation system, Watson Genomic Analysis (WGA), to assess the reliability and time required to identify potentially relevant pharmacologic interventions. Results WGS/RNAseq identified more potentially actionable clinical results than targeted panels in 90% of cases, with an average of 16-fold more unique potentially actionable variants identified per individual; 84 clinically actionable calls were made using WGS/RNA-seq that were not identified by panels. Expert annotation and WGA had good agreement on identifying variants [mean sensitivity = 0.71, SD = 0.18 and positive predictive value (PPV) = 0.80, SD = 0.20] and drug targets when the same variants were called (mean sensitivity = 0.74, SD = 0.34 and PPV = 0.79, SD = 0.23) across patients. Clinicians used the information to modify their treatment plan 10% of the time. Conclusion These results present the first comprehensive comparison of technical and machine augmented analysis of targeted panel and WGS/RNA-seq to identify potential cancer treatments.

Nuclear factor one X (NFIX) is a transcription factor required for normal ependymal development. Constitutive loss of Nfix in mice (Nfix−/−) is associated with hydrocephalus and sloughing of the dorsal ependyma within the lateral ventricles. Previous studies have implicated NFIX in the transcriptional regulation of genes encoding for factors essential to ependymal development. However, the cellular and molecular mechanisms underpinning hydrocephalus in Nfix−/− mice are unknown. To investigate the role of NFIX in hydrocephalus, we examined ependymal cells in brains from postnatal Nfix−/− and control (Nfix+/+) mice using a combination of confocal and electron microscopy. This revealed that the ependymal cells in Nfix−/− mice exhibited abnormal cilia structure and disrupted localisation of adhesion proteins. Furthermore, we modelled ependymal cell adhesion using epithelial cell culture and revealed changes in extracellular matrix and adherens junction gene expression following knockdown of NFIX. Finally, the ablation of Nfix from ependymal cells in the adult brain using a conditional approach culminated in enlarged ventricles, sloughing of ependymal cells from the lateral ventricles and abnormal localisation of adhesion proteins, which are phenotypes observed during development. Collectively, these data demonstrate a pivotal role for NFIX in the regulation of cell adhesion within ependymal cells of the lateral ventricles.

High-density lipoproteins (HDL) play a critical role in cholesterol homeostasis. Apolipoprotein E (APOE), particularly the E4 allele, is a significant risk factor for Alzheimer’s disease but is also a key HDL-associated protein involved in lipid transport in both the periphery and central nervous systems. The objective was to determine the influence of the APOE genotype on HDL function and size in the context of Alzheimer’s disease. HDL from 194 participants (non-demented controls, mild cognitive impairment, and Alzheimer’s disease dementia) were isolated from the plasma. The HDL cholesterol efflux capacity (CEC), lecithin-cholesterol acyltransferase (LCAT) activity, and particle diameter were measured. Neuropsychological test scores, clinical dementia rating, and magnetic resonance imaging scores were used to determine if cognition is associated with HDL function and size. HDL CEC and LCAT activity were reduced in APOE3E4 carriers compared to APOE3E3 carriers, regardless of diagnosis. In APOE3E3 carriers, CEC and LCAT activity were lower in patients. In APOE3E4 patients, the average particle size was lower. HDL LCAT activity and particle size were positively correlated with the neuropsychological scores and negatively correlated with the clinical dementia rating. We provide evidence for the first time of APOE genotype-specific alterations in HDL particles in Alzheimer’s disease and an association between HDL function, size, and cognitive function.

(1) Background: Mixotrophic growth is commonly associated with higher biomass productivity and lower energy consumption. This paper evaluates the impact of using different carbon sources on growth, protein profile, and nutrient uptake for Dunaliella tertiolecta CCAP 19/30 to assess the potential for mixotrophic growth. (2) Methods: Two experimental sets were conducted. The first assessed the contribution of atmospheric carbon to D. tertiolecta growth and the microalgae capacity to grow heterotrophically with an organic carbon source to provide both carbon and energy. The second set evaluated the impact of using different carbon sources on its growth, protein yield and quality. (3) Results: D. tertiolecta could not grow heterotrophically. Cell and optical density, ash-free dry weight, and essential amino acids index were inferior for all treatments using organic carbon compared to NaHCO3. Neither cell nor optical density presented significant differences among the treatments containing organic carbon, demonstrating that organic carbon does not boost D. tertiolecta growth. All the treatments presented similar nitrogen, phosphorus, sulfur recovery, and relative carbohydrate content. (4) Conclusions: Based on the results of this paper, D. tertiolecta CCAP 19/30 is an obligated autotroph that cannot grow mixotrophically using organic carbon.

Coastal retention zones occur in the lee of headlands and within bays of coastal upwelling environments. Because retention zones can concentrate and retain communities of coastal planktonic organisms that would otherwise be advected offshore by wind-driven transport, they are ecologically significant. While the consequences of these zones for plankton retention and recruitment have been examined, the degree to which they remain retentive under variable upwelling intensity is less well understood. This aspect of coastal plankton ecology was studied during 2012 in the retentive upwelling shadow of northern Monterey Bay, California. Environmental and biological data show that exceptionally strong upwelling can greatly diminish resident plankton populations in the upwelling shadow. Results indicate that wind-driven circulation, essential to primary productivity and the formation of retention zones, can surpass levels that allow accumulation and retention of plankton communities.

Objective The objectives of this study were to: (1) document violent and controlling behaviours within intimate partnerships during the perinatal period; and (2) determine individual, interpersonal and household-level factors influencing the risk of perinatal intimate partner violence (IPV).Design Cross-sectional survey.Setting The Ottawa Hospital, Department of Obstetrics and Gynecology, Ottawa, Ontario, Canada.Participants Patients who gave birth at The Ottawa Hospital and were >20 days post partum between 17 March and 16 June 2020.Main outcomes and measures Perinatal IPV was defined as regular controlling behaviours or act-based forms of emotional/physical/sexual abuse in the 12 months before pregnancy, during pregnancy and/or post partum. Log-binomial multivariable regression models were used to compute adjusted risk ratios (aRRs) and 95% CIs to identify potential risk factors for IPV: maternal age, postpartum depression, parity, increase in partner substance use and household income.Results Among 216 participants, the median maternal age was 33 years (IQR: 30–36). In total, 52 (24.07%) reported some form of perinatal IPV, 37 (17.13%) reported regular controlling behaviour and 9 (4.17%) reported both. Household income below the municipal median was the strongest risk factor for perinatal IPV (aRR: 3.24, 95% CI: 1.87 to 5.59). There was no apparent association between maternal age (aRR: 0.99, 95% CI: 0.94 to 1.04), postpartum depression (aRR: 1.03, 95% CI: 1.00 to 1.07), nulliparity (aRR: 1.18, 95% CI: 0.71 to 1.97) or increases in partner substance use (aRR: 0.73, 95% CI: 0.42 to 1.25) with IPV.Conclusion One in four individuals in this study experienced perinatal IPV. Household income was the strongest risk factor, and surprisingly, many hypothesised risk factors (eg, mental health, partner substance use, etc) were not significantly associated with perinatal IPV in this sample. This highlights the challenges in both measuring IPV and identifying individuals exposed to perinatal IPV during the high stress of the COVID-19 pandemic.

Malignant musculoskeletal tumors about the shoulder girdle region involving the scapula are fairly rare, but when diagnosed, challenging and complex surgical treatment may be warranted with the primary goal of improving patient survival. These tumors are typically extensive and infiltrative at the time of presentation, requiring radical resection to achieve margins and obtain local tumor control. Historically, forequarter amputation or flail extremity were the mainstays of treatment in these cases. Presently, with recent advances in diagnostics, imaging, adjuvant therapies, and surgical treatment, many patients presenting with malignant tumors involving the scapula are candidates for limb salvage surgery. Reconstruction with endoprosthesis seems to have gained acceptance as the preferred surgical treatment for such lesions, as this intervention has resulted in improved postoperative function and cosmesis, with an acceptable complication rate. We present our experience with recent advancement in these surgical efforts in the form of shoulder girdle reconstruction with total scapular reverse total shoulder prosthesis after radical tumor excision.

A higher incidence of colorectal cancer (CRC) is found in males compared to females. Young women (18–44 years) with CRC have a better survival outcome compared to men of the same age or compared to older women (over 50 years), indicating a global incidence of sexual dimorphism in CRC rates and survival. This suggests a protective role for the sex steroid hormone estrogen in CRC development. Key proliferative pathways in CRC tumorigenesis exhibit sexual dimorphism, which confer better survival in females through estrogen regulated genes and cell signaling. Estrogen regulates the activity of a class of Kv channels (KCNQ1:KCNE3), which control fundamental ion transport functions of the colon and epithelial mesenchymal transition through bi-directional interactions with the Wnt/β-catenin signalling pathway. Estrogen also modulates CRC proliferative responses in hypoxia via the novel membrane estrogen receptor GPER and HIF1A and VEGF signaling. Here we critically review recent clinical and molecular insights into sexual dimorphism of CRC biology modulated by the tumor microenvironment, estrogen, Wnt/β-catenin signalling, ion channels, and X-linked genes.

Purpose of the study: Osteonecrosis of the hip mostly affects young individuals and often progresses to a debilitating disease. Several treatment modalities exist, but none are completely satisfactory. This study evaluates the clinical outcome of patients treated with core decompression and insertion of a porous tantalum implant in the femoral head. This procedure is similar to commonly performed procedures, but has the additional advantages of providing structural support to the necrotic femoral head while having no donor-site morbidity. Methods: We evaluated 15 patients with 18 osteonecrotic hips with Steinberg stage III (3 hips) and IV (15 hips) disease. The mean age of the patients was 42 years-old (eldest 66), and the mean time for follow-up was 23 months. The outcome measure was hip function, evaluated with the Harris hip score, and the end point was total hip arthroplasty, or referral for this procedure. Results: The success rate at twelve months postoperatively was 77.8%, and the overall success rate was 44.5%. Failures occurred at a mean time of 11.7 months, and one complication, a periprosthetic fracture, occurred 4 months postoperatively. On average, patients who did well improved their Harris hip scores by 21.7 points, and patients who eventually required arthroplasty decreased their scores by 14 points. Conlusions: Core decompression with porous tantalum implants showed encouraging success rates and early clinical results in patients with advanced stage osteonecrosis, but further larger scale studies are required to identify the population best suited for this procedure.

Chlorpropham is a carbamate herbicide that inhibits cell division and has been widely used as a potato sprout suppressant. Recently we showed that the microalga Dunaliella salina treated with chlorpropham massively accumulated the colourless carotenoids phytoene and phytofluene. Phytoene and phytofluene are valued for their antioxidant, UV-absorption and skin protectant properties; however, they are present in very low quantities in nature. The low toxicity herbicide chlorpropham seems a promising catalyst to produce phytoene in large quantities from CO2 and solar energy with D. salina. This study explored chlorpropham uptake by the algal cells, the formation of potential intermediate metabolites, and the removal of residual chlorpropham from harvested D. salina biomass. Algal biomass rapidly concentrated chlorpropham from culture media. However, washing the harvested biomass with fresh culture medium twice and five times removed ~83 and ~97% of the chlorpropham from the biomass, respectively, and retained algal cell integrity. Furthermore, chloroaniline, a common metabolite of chlorpropham degradation, was not detected in chlorpropham-treated cultures, which were monitored every two days for thirty days. Cells treated with chlorpropham for either 10 min or 24 h continued to over-accumulate phytoene after resuspension in an herbicide-free medium. These data imply that whilst Dunaliella cells do not possess the intracellular capacity to degrade chlorpropham to chloroaniline, the effect of chlorpropham is irreversible on cell nuclear division and hence on carotenoid metabolism.