Search

Abstract Cystic Fibrosis (CF) and its treatment result in an altered gut microbiota composition compared to non-CF controls. However, the impact of this on gut microbiota functionality has not been extensively characterised. Our aim was to conduct a proof-of-principle study to investigate if measurable changes in gut microbiota functionality occur in adult CF patients compared to controls. Metagenomic DNA was extracted from faecal samples from six CF patients and six non-CF controls and shotgun metagenomic sequencing was performed on the MiSeq platform. Metabolomic analysis using gas chromatography-mass spectrometry was conducted on faecal water. The gut microbiota of the CF group was significantly different compared to the non-CF controls, with significantly increased Firmicutes and decreased Bacteroidetes. Functionality was altered, with higher pathway abundances and gene families involved in lipid (e.g. PWY 6284 unsaturated fatty acid biosynthesis (p = 0.016)) and xenobiotic metabolism (e.g. PWY-5430 meta-cleavage pathway of aromatic compounds (p = 0.004)) in CF patients compared to the controls. Significant differences in metabolites occurred between the two groups. This proof-of-principle study demonstrates that measurable changes in gut microbiota functionality occur in CF patients compared to controls. Larger studies are thus needed to interrogate this further.

ABSTRACT In this study, a young Cheddar curd was used to produce two types of surface-ripened cheese, using two commercial smear-culture mixes of yeasts and bacteria. Whole-metagenome shotgun sequencing was used to screen the microbial population within the smear-culture mixes and on the cheese surface, with comparisons of microorganisms at both the species and the strain level. The use of two smear mixes resulted in the development of distinct microbiotas on the surfaces of the two test cheeses. In one case, most of the species inoculated on the cheese established themselves successfully on the surface during ripening, while in the other, some of the species inoculated were not detected during ripening and the most dominant bacterial species, Glutamicibacter arilaitensis, was not a constituent of the culture mix. Generally, yeast species, such as Debaryomyces hansenii and Geotrichum candidum, were dominant during the first stage of ripening but were overtaken by bacterial species, such as Brevibacterium linens and G. arilaitensis, in the later stages. Using correlation analysis, it was possible to associate individual microorganisms with volatile compounds detected by gas chromatography-mass spectrometry in the cheese surface. Specifically, D. hansenii correlated with the production of alcohols and carboxylic acids, G. arilaitensis with alcohols, carboxylic acids and ketones, and B. linens and G. candidum with sulfur compounds. In addition, metagenomic sequencing was used to analyze the metabolic potential of the microbial populations on the surfaces of the test cheeses, revealing a high relative abundance of metagenomic clusters associated with the modification of color, variation of pH, and flavor development. IMPORTANCE Fermented foods, in particular, surface-ripened cheese, represent a model to explain the metabolic interactions which regulate microbial succession in complex environments. This study explains the role of individual species in a heterogeneous microbial environment, i.e., the exterior of surface-ripened cheese. Through whole-metagenome shotgun sequencing, it was possible to investigate the metabolic potential of the resident microorganisms and show how variations in the microbial populations influence important aspects of cheese ripening, especially flavor development. Overall, in addition to providing fundamental insights, this research has considerable industrial relevance relating to the production of fermented food with specific qualities.

In the United States, there are plans to produce up to 30 GW of offshore wind power by the year 2030, resulting in numerous seabed lease areas which are currently going through the leasing or construction and operations phase. A key challenge associated with offshore wind is optimal routing and installation of the subsea power cables, which transmit power from the main offshore wind energy production area to a land-based station, where it connects to the electrical grid. By traversing a vast extent of the seafloor, the installation and operational phases of subsea power cables have the potential to result in a range of environmental impacts, which may negatively affect sensitive biological, physical, human and/or cultural resource receptors. Presented here is a case study from southeastern North Carolina to identify optimal seabed cable routes and coastal landfalls for a recently leased offshore wind farm by using a combination of publicly available data, coupled with standard environmental impact assessment methodologies and geographic information system (GIS)-based heat maps. The study identified a range of high-risk areas, in addition to a number of potential low-risk routes and landfall areas which minimize seabed user conflicts and impacts on environmentally sensitive locations. Although additional high-resolution and site-specific environmental, geological and biological surveys are required to develop a robust cable installation plan, the preliminary steps from this research optimize early-phase marine spatial planning for offshore wind projects and other similar subsea industries.

Abstract Introduction Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are the most common four‐repeat tauopathies (4RT), and both frequently occur with varying degree of Alzheimer's disease (AD) copathology. Intriguingly, patients with 4RT and patients with AD are at opposite ends of the wakefulness spectrum—AD showing reduced wakefulness and excessive sleepiness whereas 4RT showing decreased homeostatic sleep. The neural mechanisms underlying these distinct phenotypes in the comorbid condition of 4RT and AD are unknown. The objective of the current study was to define the alpha oscillatory spectrum, which is prominent in the awake resting‐state in the human brain, in patients with primary 4RT, and how it is modified in comorbid AD‐pathology. Method In an autopsy‐confirmed case series of 4R‐tauopathy patients (n = 10), whose primary neuropathological diagnosis was either PSP (n = 7) or CBD (n = 3), using high spatiotemporal resolution magnetoencephalography (MEG), we quantified the spectral power density within alpha‐band (8–12 Hz) and examined how this pattern was modified in increasing AD‐copathology. For each patient, their regional alpha power was compared to an age‐matched normative control cohort (n = 35). Result Patients with 4RT showed increased alpha power but in the presence of AD‐copathology alpha power was reduced. Conclusions Alpha power increase in PSP‐tauopathy and reduction in the presence of AD‐tauopathy is consistent with the observation that neurons activating wakefulness‐promoting systems are preserved in PSP but degenerated in AD. These results highlight the selectively vulnerable impacts in 4RT versus AD‐tauopathy that may have translational significance on disease‐modifying therapies for specific proteinopathies.

Abstract A comprehensive statistical study is conducted on O+ and H+ outflows obtained from the TEAMS/FAST data during the 23rd solar cycle (1996–2007). The study investigates interhemispheric asymmetry in ionospheric outflows during local summer, winter, and equinox seasons. Data are classified into two distinct periods: the pre‐storm and geomagnetic storm phases. Numerous statistical asymmetries are identified. The findings indicate that the dayside cusp consistently demonstrates more outflow rates of O+ and H+ in the northern hemisphere than southern hemisphere during geomagnetic storms in all seasons as well as during the pre‐storm period in the summer season with the exception of H+ during summer storms. Conversely, the nightside O+ and H+ outflow rates are higher in the southern hemisphere during pre‐storm and storm periods in the summer season. Additionally, the dawnside and duskside outflow rates of O+ and H+ are predominantly stronger in the southern hemisphere.

In order to help inform efforts to fulfill the National Science Foundation (NSF) Geospace Environment Modeling (GEM) community’s ethical goal toward pursuing diversity, equity, inclusion, and justice (DEIJ) the authors administered the 2023 GEM Climate Survey to attendees of the 2023 GEM Workshop. Its main goals were to 1) obtain organized demographic information about the GEM community, and 2) to provide a quantitative assessment of the GEM community’s perceptions of its own culture primarily with respect to inclusion and belonging. Responses indicate the GEM community is comparable or slightly more diverse than heliophysics as a whole and the American Geophysical Union (AGU) general membership, but still not close to reflecting the population of the United States or the world. The average responses to survey items about feelings of belonging in the GEM community indicate that members feel they belong in the GEM community, that the GEM community climate is broadly inclusive, and that efforts to support that cultural climate are improving over time. This is true across the entire population regardless of career stage, as well as for female respondents; Lesbian, Gay, Bisexual, Transgender, Queer/Questioning, Pansexual, Asexual (LGBTQPA+) respondents; Asian/Asian Subcontinent respondents; and non-Asian respondents of color. Division of the dataset into subgroups also indicates work to build a fully inclusive community is not complete, particularly with respect to workplace hostility these groups witness. This report recommends continuing work to capture the time history of demographics and trends in the community culture in response to inclusion efforts and initiatives.

The Lunar Environment heliospheric X-ray Imager (LEXI) and Solar wind Magnetosphere Ionosphere Link Explorer (SMILE) missions will image the Earth’s dayside magnetopause and cusps in soft X-rays after their respective launches in the near future, to specify global magnetic reconnection modes for varying solar wind conditions. To support the success of these scientific missions, it is critical to develop techniques that extract the magnetopause locations from the observed soft X-ray images. In this research, we introduce a new geometric equation that calculates the subsolar magnetopause position (\begin{document}$ {R}_{\mathrm{s}} $\end{document}) from a satellite position, the look direction of the instrument, and the angle at which the X-ray emission is maximized. Two assumptions are used in this method: (1) The look direction where soft X-ray emissions are maximized lies tangent to the magnetopause, and (2) the magnetopause surface near the subsolar point is almost spherical and thus \begin{document}$ {R}_{\mathrm{s}} $\end{document} is nearly equal to the radius of the magnetopause curvature. We create synthetic soft X-ray images by using the Open Geospace General Circulation Model (OpenGGCM) global magnetohydrodynamic model, the galactic background, the instrument point spread function, and Poisson noise. We then apply the fast Fourier transform and Gaussian low-pass filters to the synthetic images to remove noise and obtain accurate look angles for the soft X-ray peaks. From the filtered images, we calculate \begin{document}$ {R}_{\mathrm{s}} $\end{document} and its accuracy for different LEXI locations, look directions, and solar wind densities by using the OpenGGCM subsolar magnetopause location as ground truth. Our method estimates \begin{document}$ {R}_{\mathrm{s}} $\end{document} with an accuracy of \begin{document}$ {10\;\mathrm{c}\mathrm{m}}^{-3} $\end{document}. The accuracy improves for greater solar wind densities and during southward interplanetary magnetic fields. The method captures the magnetopause motion during southward interplanetary magnetic field turnings. Consequently, the technique will enable quantitative analysis of the magnetopause motion and help reveal the dayside reconnection modes for dynamic solar wind conditions. This technique will support the LEXI and SMILE missions in achieving their scientific objectives.

Summary: Outer radial glia (oRG) emerge as cortical progenitor cells that support the development of an enlarged outer subventricular zone (oSVZ) and the expansion of the neocortex. The in vitro generation of oRG is essential to investigate the underlying mechanisms of human neocortical development and expansion. By activating the STAT3 signaling pathway using leukemia inhibitory factor (LIF), which is not expressed in guided cortical organoids, we define a cortical organoid differentiation method from human pluripotent stem cells (hPSCs) that recapitulates the expansion of a progenitor pool into the oSVZ. The oSVZ comprises progenitor cells expressing specific oRG markers such as GFAP, LIFR, and HOPX, closely matching human fetal oRG. Finally, incorporating neural crest-derived LIF-producing cortical pericytes into cortical organoids recapitulates the effects of LIF treatment. These data indicate that increasing the cellular complexity of the organoid microenvironment promotes the emergence of oRG and supports a platform to study oRG in hPSC-derived brain organoids routinely.

Summary: Gustatory receptors (GRs) are critical for insect chemosensation and are potential targets for controlling pests and disease vectors, making their structural investigation a vital step toward such applications. We present structures of Bombyx mori Gr9 (BmGr9), a fructose-gated cation channel, in agonist-free and fructose-bound states. BmGr9 forms a tetramer similar to distantly related insect odorant receptors (ORs). Upon fructose binding, BmGr9’s channel gate opens through helix S7b movements. In contrast to ORs, BmGr9’s ligand-binding pocket, shaped by a kinked helix S4 and a shorter extracellular S3-S4 loop, is larger and solvent accessible in both agonist-free and fructose-bound states. Also, unlike ORs, fructose binding by BmGr9 involves helix S5 and a pocket lined with aromatic and polar residues. Structure-based sequence alignments reveal distinct patterns of ligand-binding pocket residue conservation in GR subfamilies associated with different ligand classes. These data provide insight into the molecular basis of GR ligand specificity and function.

Abstract This study presents observations of magnetopause reconnection and erosion at geosynchronous orbit, utilizing in situ satellite measurements and remote sensing ground‐based instruments. During the main phase of a geomagnetic storm, Geostationary Operational Environmental Satellites (GOES) 15 was on the dawnside of the dayside magnetopause (10.6 MLT) and observed significant magnetopause erosion, while GOES 13, observing duskside (14.6 MLT), remained within the magnetosphere. Combined observations from the THEMIS satellites and Super Dual Auroral Radar Network radars verified that magnetopause erosion was primarily caused by reconnection. While various factors may contribute to asymmetric erosion, the observations suggest that the weak reconnection rate on the duskside can play a role in the formation of asymmetric magnetopause shape. This discrepancy in reconnection rate is associated with the presence of cold dense plasma on the duskside of the magnetosphere, which limits the reconnection rate by mass loading, resulting in more efficient magnetopause erosion on the dawnside.

Background:. The role of physician credentialing has been widely considered in quality and outcome improvement studies. However, the association between surgeon characteristics and health-care costs remains unclear. Methods:. Our objective was to determine the association of orthopaedic surgeon characteristics with health outcomes and costs, utilizing Medicare data. We used 100% Fee-for-Service Medicare data from 2015 to 2019 to identify all patients ≥65 years of age who underwent 2 common orthopaedic surgical procedures, total hip and knee replacement. After determining whether the patients had been readmitted after discharge from their initial admission for surgery, we computed 3 metrics of total medical expenditure: the costs of the initial surgery admission and 30-day and 180-day episode-based bundles of care. Hierarchical linear regression and logistic regression models were used to evaluate patient and surgeon characteristics associated with care costs and the likelihood of readmission. Results:. We identified 2,269 surgeons who performed total knee replacements on 298,934 patients and 1,426 surgeons who performed total hip replacements on 204,721 patients. Patient characteristics associated with higher initial surgery costs included increasing age, female sex, racial minority status, and a higher Charlson Comorbidity Index. Surgeon characteristics associated with lower readmission rates included practice in the Northeast region and a higher patient volume; having malpractice claims was associated with higher readmission rates. Conclusions:. A higher volume of patients treated by the orthopaedic surgeon was associated with lower overall costs and readmission rates. Information on surgeons’ malpractice claims and annual volume should be made publicly available to assist patients, payer networks, and hospitals in surgeon selection and oversight. These results could also inform the guidelines of physician credentialing organizations. Level of Evidence:. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Summary: Fungal β-glucans are major drivers of trained immunity which increases long-term protection against secondary infections. Heterogeneity in β-glucan source, structure, and solubility alters interaction with the phagocytic receptor Dectin-1 and could impact strategies to improve trained immunity in humans. Using a panel of diverse β-glucans, we describe the ability of a specific yeast-derived whole-glucan particle (WGP) to reprogram metabolism and thereby drive trained immunity in human monocyte-derived macrophages in vitro and mice bone marrow in vivo. Presentation of pure, non-soluble, non-aggregated WGPs led to the formation of the Dectin-1 phagocytic synapse with subsequent lysosomal mTOR activation, metabolic reprogramming, and epigenetic rewiring. Intraperitoneal or oral administration of WGP drove bone marrow myelopoiesis and improved mature macrophage responses, pointing to therapeutic and food-based strategies to drive trained immunity. Thus, the investment of a cell in a trained response relies on specific recognition of β-glucans presented on intact microbial particles through stimulation of the Dectin-1 phagocytic response.

Abstract Objective To investigate differences in angiotensin‐converting‐enzyme‐2 (ACE2) and bitter taste receptor (TAS2R38) expression between patient age groups and comorbidities to characterize the pathophysiology of coronavirus 19(COVID‐19) pandemic. ACE2 is the receptor implicated to facilitate SARS‐CoV‐2 infections and levels of expression may correlate to the severity of COVID‐19 infection. TAS2R38 has many non‐gustatory roles in disease, with some evidence of severe COVID‐19 disease in certain receptor phenotypes. Methods We conducted a prospective cohort study and collected nasal and lingual tissue from healthy pediatric (n = 22) and adult (n = 25) patients undergoing general anesthesia for elective procedures. RNA isolation and qPCR were performed with primers targeting ACE2 and TAS2R38. Results A total of 25 adult (52% male; 44% obese) and 22 pediatric (50% male; 36% obese) patients were enrolled, pediatric tissue had 43% more nasal ACE2 RNA expression than adults with a median fold change of 0.69 (IQR 0.37, 0.98) in adults and 0.99 (IQR 0.74, 1.43) in children (p

Abstract It has been established that the human gut microbiota is central to health, and, consequently, there has been a growing desire to positively modulate its composition and/or function through, for example, the use of fermented foods, prebiotics or probiotics. Here, we compare the relative impact of the daily consumption of an inulin-enriched diet (n = 10), a commercial probiotic-containing fermented milk product (FMP) (n = 10), or a traditional kefir FMP (n = 9), over a 28-day period on the gut microbiome and urine metabolome of healthy human adults. None of the treatments resulted in significant changes to clinical parameters or biomarkers tested. However, shotgun metagenomic analysis revealed that kefir consumption resulted in a significant change in taxonomy, in the form of an increased abundance of the sub-dominant FMP-associated species Lactococcus raffinolactis, which further corresponded to shifts in the urine metabolome. Overall, our results indicated that daily consumption of a single portion of kefir alone resulted in detectable changes to the gut microbiota and metabolome of consumers.

This review explores the concept of futility timeouts and the use of traumatic brain injury (TBI) as an independent predictor of the futility of resuscitation efforts in severely bleeding trauma patients. The national blood supply shortage has been exacerbated by the lingering influence of the COVID-19 pandemic on the number of blood donors available, as well as by the adoption of balanced hemostatic resuscitation protocols (such as the increasing use of 1:1:1 packed red blood cells, plasma, and platelets) with and without early whole blood resuscitation. This has underscored the urgent need for reliable predictors of futile resuscitation (FR). As a result, clinical, radiologic, and laboratory bedside markers have emerged which can accurately predict FR in patients with severe trauma-induced hemorrhage, such as the Suspension of Transfusion and Other Procedures (STOP) criteria. However, the STOP criteria do not include markers for TBI severity or transfusion cut points despite these patients requiring large quantities of blood components in the STOP criteria validation cohort. Yet, guidelines for neuroprognosticating patients with TBI can require up to 72 h, which makes them less useful in the minutes and hours following initial presentation. We examine the impact of TBI on bleeding trauma patients, with a focus on those with coagulopathies associated with TBI. This review categorizes TBI into isolated TBI (iTBI), hemorrhagic isolated TBI (hiTBI), and polytraumatic TBI (ptTBI). Through an analysis of bedside parameters (such as the proposed STOP criteria), coagulation assays, markers for TBI severity, and transfusion cut points as markers of futilty, we suggest amendments to current guidelines and the development of more precise algorithms that incorporate prognostic indicators of severe TBI as an independent parameter for the early prediction of FR so as to optimize blood product allocation.

With the increasing spread of infectious diseases worldwide, there is an urgent need for novel strategies to combat them. Cryogenic sample electron microscopy (cryo-EM) techniques, particularly electron tomography (cryo-ET), have revolutionized the field of infectious disease research by enabling multiscale observation of biological structures in a near-native state. This review highlights the recent advances in infectious disease research using cryo-ET and discusses the potential of this structural biology technique to help discover mechanisms of infection in native environments and guiding in the right direction for future drug discovery.

Abstract The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.

Abstract Despite ongoing debate, the amyloid β-protein (Aβ) remains the prime therapeutic target for the treatment of Alzheimer’s disease (AD). However, rational drug design has been hampered by a lack of knowledge about neuroactive Aβ. To help address this deficit, we developed live-cell imaging of iPSC-derived human neurons (iNs) to study the effects of the most disease relevant form of Aβ-oligomeric assemblies (oAβ) extracted from AD brain. Of ten brains studied, extracts from nine caused neuritotoxicity, and in eight cases this was abrogated by Aβ immunodepletion. Here we show that activity in this bioassay agrees relatively well with disruption of hippocampal long-term potentiation, a correlate of learning and memory, and that measurement of neurotoxic oAβ can be obscured by more abundant non-toxic forms of Aβ. These findings indicate that the development of novel Aβ targeting therapeutics may benefit from unbiased activity-based discovery. To test this principle, we directly compared 5 clinical antibodies (aducanumab, bapineuzumab, BAN2401, gantenerumab, and SAR228810) together with an in-house aggregate-preferring antibody (1C22) and established relative EC50s in protecting human neurons from human Aβ. The results yielded objective numerical data on the potency of each antibody in neutralizing human oAβ neuritotoxicity. Their relative efficacies in this morphological assay were paralleled by their functional ability to rescue oAβ-induced inhibition of hippocampal synaptic plasticity. This novel paradigm provides an unbiased, all-human system for selecting candidate antibodies for advancement to human immunotherapy.

Abstract Background The perimenopausal transition is accompanied by psychiatric symptoms in over 10% of women. Symptoms commonly include depressed mood and anhedonia and less commonly include psychosis. Psychiatric symptoms have been linked to the depletion and/or variability of circulating estradiol, and estradiol treatment reduces perimenopausal anhedonia and psychosis in some women. Estrogen fluctuations may disrupt function in the mesolimbic reward system in some women, leading to psychiatric symptoms like anhedonia or psychosis. The Perimenopausal Effects of Estradiol on Anhedonia and Psychosis Study (PEEPs) is a mechanistic clinical trial that aims to (1) identify relationships between perimenopausal-onset anhedonia and psychosis and neuromolecular markers of mesolimbic reward responses and (2) determine the extent to which estradiol treatment-induced changes in mesolimbic reward responses are associated with alleviation of perimenopausal onset anhedonia or psychosis. Methods This study will recruit 100 unmedicated women ages 44–55 in the late-stage perimenopausal transition, sampling across the range of mild-to-high anhedonia and absent-to-moderate psychosis symptoms. Patients will be randomized to receive either estradiol or placebo treatment for 3 weeks. Clinical outcome measures will include symptoms of anhedonia (measured with Snaith–Hamilton Pleasure Scale; SHAPS) and psychosis (measured with Brief Psychiatric Rating Scale; BPRS psychosis subscale) as well as neural markers of mesolimbic reward system functioning, including reward-related fMRI activation and PET-derived measure of striatal dopamine binding. Pre-treatment associations between (1) SHAPS/BPRS scores and (2) reward-related striatal dopamine binding/BOLD activation will be examined. Furthermore, longitudinal mixed models will be used to estimate (1) symptom and neuromolecular trajectories as a function of estradiol vs. placebo treatment and (2) how changes in reward-related striatal dopamine binding and BOLD activation predict variability in symptom trajectories in response to estradiol treatment. Discussion This clinical trial will be the first to characterize neural and molecular mechanisms by which estradiol treatment ameliorates anhedonia and psychosis symptoms during the perimenopausal transition, thus laying the groundwork for future biomarker research to predict susceptibility and prognosis and develop targeted treatments for perimenopausal psychiatric symptoms. Furthermore, in alignment with the National Institute for Mental Health Research Domain Criteria initiative, this trial will improve our understanding of a range of disorders characterized by anhedonia, psychosis, and reward system dysfunction. Trial registration ClinicalTrials.gov NCT05282277

Abstract Objectives To investigate the association between assisted reproductive technology (ART) use and childhood cancer subtype. Study Design We deployed a cross‐sectional survey of 1701 parents of children with cancer about their ART use, demographics, and gestational and perinatal factors. Multivariable logistic regression modeled the association between ART use, birthweight and multiple gestation status with childhood cancer, by subtype. Results ART use was highest among children with osteosarcoma relative to children with other cancer types, and this association was statistically significant in multivariable models (OR = 4.4; 95% CI = 1.7–11.3; p = 0.0020). ART use was also elevated among children with hepatoblastoma, but this relationship appeared to be due to the strong associations between ART use and lower birthweight in our sample. No specific ART modality appeared to drive these associations. In univariate models, multiple gestation was associated with a 2.7‐fold increased odds of hepatoblastoma (OR = 2.71; 95% CI = 1.14–6.42; p = 0.02) and a 1.6‐fold increased odds of neuroblastoma (OR = 1.62; 95% CI = 1.03–2.54; p = 0.03), but these associations were not retained in multivariable models. Conclusions Associations between ART use and hepatoblastoma risk may be attributable to birthweight, a known hepatoblastoma risk factor. ART use may also be associated with osteosarcoma, independent of birthweight, an association not previously observed in studies limited to cancers diagnosed before adolescence. Evaluating long‐term health outcomes in children conceived by ART, throughout adolescence and potentially into adulthood, appears warranted.

Summary: A comprehensive metagenomics-based investigation of the microorganisms present within milk kefir communities from across the globe was carried out with a view to defining the milk kefir pan-metagenome, including details relating to core and non-core components. Milk kefir samples, generated by inoculating full fat, pasteurized cow’s milk with 64 kefir grains sourced from 25 different countries, were analyzed. We identified core features, including a consistent pattern of domination by representatives from the species Lactobacillus helveticus or the sub-species Lactobacillus kefiranofaciens subsp. kefiranofaciens, Lactococcus lactis subsp. lactis or Lla. cremoris subsp. cremoris in each kefir. Notably, even in kefirs where the lactococci did not dominate, they and 51 associated metabolic pathways were identified across all metagenomes. These insights can contribute to future efforts to create tailored kefir-based microbial communities for different applications and assist regulators and producers to ensure that kefir products have a microbial composition that reflects the artisanal beverage.

Study objectiveThis proof-of-concept study aimed to determine whether the combined features of two non-rapid eye movement (NREM) sleep biomarkers acquired predominantly in-home could characterize different neurodegenerative disorders.MethodsSleep spindle duration and non-REM hypertonia (NRH) were evaluated in seven groups including a control group (CG = 61), and participants with isolated REM sleep behavior disorder (iRBD = 19), mild cognitive impairment (MCI = 41), Parkinson disease (PD = 16), Alzheimer disease dementia (ADem = 29), dementia with Lewy Bodies or Parkinson disease dementia (LBD = 19) and progressive supranuclear palsy (PSP = 13). One-way analysis of variance (ANOVA), Mann–Whitney U, intra-class (ICC) and Spearman ranked correlations, Bland–Altman plots and Kappa scores, Chi-square and Fisher exact probability test, and multiple-logistic regression were focused primarily on spindle duration and NRH and the frequencies assigned to the four normal/abnormal spindle duration/NRH combinations.ResultsANOVA identified group differences in age, sleep efficiency, REM, NRH (p

The use of probiotics, prebiotics and synbiotics in poultry diets beneficially stimulates the gut microbiome thus promoting the health and welfare of the animals. In this study, we analyzed 7 poultry probiotics (Lactobacillus plantarum – B1 and B4, Lactobacillus rhamnosus – B3, Bifidobacterium lactis – B2, Carnobacterium divergens – B5, Propionibacterium thoenii – B6, Clostridium butyricum – B7) and 12 prebiotics, differing in chemical composition and source of origin (fungi, algae, animal, etc.). The main goal of our research was to select the most promising candidates to develop synbiotic combinations. We determined the growth kinetics of all probiotics in the presence of prebiotics in a series of in vitro studies to select optimal combinations. Five out of seven investigated probiotics were significantly stimulated by astragalus polysaccharide, and this prebiotic was characterized in our work as the most effective. Moreover, in the case of three probiotics, B2, B3 and B4, significant growth stimulation has been found when beta-glucan, vegetable protein hydrolysate and liquid seaweed extract were supplied. Strain B1 (L. plantarum) was stimulated by 6 out of 12 prebiotics. The growth of B4 (L. plantarum) and B2 (B. lactis) was enhanced by prebiotics after 2 h of incubation. A high growth rate of 3.13% was observed in the case of L. plantarum (B4) and a 3.37% higher rate for B. lactis (B3), compared to the growth of probiotics in the control medium with glucose but no prebiotics. The best candidates for synbiotic combinations based on this in vitro work are the strains belonging to L. plantarum (B4), L. rhamnosus (B3) and B. lactis (B2), consistent with prebiotics such as astragalus polysaccharides and vegetable protein hydrolysate. These combinations will be subject to future in vivo poultry trials involving the in ovo microbiome modulation.

Iatrogenic vascular air embolism is a relatively infrequent event but is associated with significant morbidity and mortality. These emboli can arise in many clinical settings such as neurosurgery, cardiac surgery, and liver transplantation, but more recently, endoscopy, hemodialysis, thoracentesis, tissue biopsy, angiography, and central and peripheral venous access and removal have overtaken surgery and trauma as significant causes of vascular air embolism. The true incidence may be greater since many of these air emboli are asymptomatic and frequently go undiagnosed or unreported. Due to the rarity of vascular air embolism and because of the many manifestations, diagnoses can be difficult and require immediate therapeutic intervention. An iatrogenic air embolism can result in both venous and arterial emboli whose anatomic locations dictate the clinical course. Most clinically significant iatrogenic air emboli are caused by arterial obstruction of small vessels because the pulmonary gas exchange filters the more frequent, smaller volume bubbles that gain access to the venous circulation. However, there is a subset of patients with venous air emboli caused by larger volumes of air who present with more protean manifestations. There have been significant gains in the understanding of the interactions of fluid dynamics, hemostasis, and inflammation caused by air emboli due to in vitro and in vivo studies on flow dynamics of bubbles in small vessels. Intensive research regarding the thromboinflammatory changes at the level of the endothelium has been described recently. The obstruction of vessels by air emboli causes immediate pathoanatomic and immunologic and thromboinflammatory responses at the level of the endothelium. In this review, we describe those immunologic and thromboinflammatory responses at the level of the endothelium as well as evaluate traditional and novel forms of therapy for this rare and often unrecognized clinical condition.

Introduction: For the last several decades, continuous monitoring of the solar wind has been carried out by spacecraft at the first Earth-Sun Lagrange point (L1). Due to computational expense or model limitations, those data often must be propagated to some point closer to the Earth in order to be usable by those studying the interaction between Earth’s magnetosphere and the solar wind. The current most widely used tool to propagate measurements from L1 (roughly 235 RE upstream) to Earth is the planar propagation method, which includes a number of known limitations. Motivated by these limitations, this study introduces a new algorithm called the Probabilistic Regressor for Input to the Magnetosphere Estimation (PRIME).Methods: PRIME is based on a novel probabilistic recurrent neural network architecture, and is capable of incorporating solar wind time history from L1 monitors to generate predictions of near-Earth solar wind as well as estimate uncertainties for those predictions.Results: A statistical validation shows PRIME’s predictions better match MMS magnetic field and plasma measurements just upstream of the bow shock than measurements from Wind propagated to MMS with a minimum variance analysis-based planar propagation technique. PRIME’s continuous rank probability score (CRPS) is 0.214σ on average across all parameters, compared to the minimum variance algorithm’s CRPS of 0.350σ. PRIME’s performance improvement over minimum variance is dramatic in plasma parameters, with an improvement in CRPS from 2.155 cm−3 to 0.850 cm−3 in number density and 16.15 km/s to 9.226 km/s in flow velocity VX GSE.Discussion: Case studies of particularly difficult to predict or extreme conditions are presented to illustrate the benefits and limitations of PRIME. PRIME’s uncertainties are shown to provide reasonably reliable predictions of the probability of particular solar wind conditions occurring.Conclusion: PRIME offers a simple solution to common limitations of solar wind propagation algorithms by generating accurate predictions of the solar wind at Earth with physically meaningful uncertainties attached.

Abstract Hematopoietic cell transplantation (HCT) treats many blood conditions but remains underused due to complications such as graft‐versus‐host disease (GvHD). In GvHD, donor immune cells attack the patient, requiring powerful immunosuppressive drugs like glucocorticoids (GCs) to prevent death. In this study, we tested the hypothesis that donor cell conditioning with the glucocorticoid fluticasone propionate (FLU) prior to transplantation could increase hematopoietic stem cell (HSC) engraftment and reduce GvHD. Murine HSCs treated with FLU had increased HSC engraftment and reduced severity and incidence of GvHD after transplantation into allogeneic hosts. While most T cells died upon FLU treatment, donor T cells repopulated in the hosts and appeared less inflammatory and alloreactive. Regulatory T cells (Tregs) are immunomodulatory and survived FLU treatment, resulting in an increased ratio of Tregs to conventional T cells. Our results implicate an important role for Tregs in maintaining allogeneic tolerance in FLU‐treated grafts and suggest a therapeutic strategy of pre‐treating donor cells (and not the patients directly) with GCs to simultaneously enhance engraftment and reduce GvHD upon allogeneic HCT.

ABSTRACT Leaves harbor distinct microbial communities that can have an important impact on plant health and microbial ecosystems worldwide. Nevertheless, the ecological processes that shape the composition of leaf microbial communities remain unclear, with previous studies reporting contradictory results regarding the importance of bacterial dispersal versus host selection. This discrepancy could be driven in part because leaf microbiome studies typically consider the upper and lower leaf surfaces as a single entity despite these habitats possessing considerable anatomical differences. We characterized the composition of bacterial phyllosphere communities from the upper and lower leaf surfaces across 24 plant species. Leaf surface pH and stomatal density were found to shape phyllosphere community composition, and the underside of leaves had lower richness and higher abundances of core community members than upper leaf surfaces. We found fewer endemic bacteria on the upper leaf surfaces, suggesting that dispersal is more important in shaping these communities, with host selection being a more important force in microbiome assembly on lower leaf surfaces. Our study illustrates how changing the scale in which we observe microbial communities can impact our ability to resolve and predict microbial community assembly patterns on leaf surfaces. IMPORTANCE Leaves can harbor hundreds of different bacterial species that form unique communities for every plant species. Bacterial communities on leaves are really important because they can, for example, protect their host against plant diseases. Usually, bacteria from the whole leaf are considered when trying to understand these communities; however, this study shows that the upper and lower sides of a leaf have a very different impact on how these communities are shaped. It seems that the bacteria on the lower leaf side are more closely associated with the plant host, and communities on the upper leaf side are more impacted by immigrating bacteria. This can be really important when we want to treat, for example, crops in the field with beneficial bacteria or when trying to understand host-microbe interactions on the leaves.

Introduction Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication.Methods and analysis The FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1); (2) 4 weeks following concurrent chemoradiation (FET-PET2); and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival; (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging; and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival.Ethics and dissemination The study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications.Trial registration number ANZCTR ACTRN12619001735145

Background and Aims: Smartphone applications aimed at patients with gastroesophageal reflux disease (GERD) have been downloaded more than 100,000 times, yet no systematic assessment of their quality has been completed. This study aimed to objectively assess the quality of GERD smartphone applications for patient education and disease management. Methods: The Apple App Store and Google Play Store were systematically searched for relevant applications. Two independent reviewers performed the application screening and eligibility assessment. Included applications were graded using the validated Mobile Application Rating Scale, which encompasses 4 domains (engagement, functionality, aesthetics, and information) as well as an overall application quality score. The associations between overall application quality, user ratings and download numbers were evaluated. Results: Of the 4816 unique applications identified, 46 met inclusion criteria (patient education = 37, disease management = 9). Mean overall application quality score was 3.02 ± 0.40 out of 5 (“acceptable”), with 61% (28/46) rated as “poor” (score 2.0–2.9). Applications scored highest for aesthetics (3.24 ± 0.48) and functionality (3.88 ± 0.37) and lowest for information (2.58 ± 0.64) and engagement (2.39 ± 0.65). Disease management applications were of significantly higher quality than education-focused applications (3.59 ± 0.38 vs 2.88 ± 0.26, P < .001). There was no correlation between graded quality and either user ratings or the number of downloads. Conclusion: While numerous smartphone applications exist to support patients with GERD, their quality is variable. Patient education applications are of particularly low quality. Our findings can help to inform the selection of applications by patients and guide clinicians’ recommendations. This study also highlights the need for higher-quality, evidence-informed applications aimed at GERD patient education.

Abstract This paper describes the fabrication of cicada-wing-inspired antimicrobial surfaces using Glancing Angle Deposition (GLAD). From the study of an annual cicada (Neotibicen Canicularis, also known as dog-day cicada) in North America, it is found that the cicada wing surfaces are composed of unique three-dimensional (3D) nanofeature arrays, which grant them extraordinary properties including antimicrobial (antifouling) and antireflective. However, the morphology of these 3D nanostructures imposes challenges in artificially synthesizing the structures by utilizing and scaling up the template area from nature. From the perspective of circumventing the difficulties of creating 3D nanofeature arrays with top-down nanofabrication techniques, this paper introduces a nanofabrication process that combines bottom-up steps: self-assembled nanospheres are used as the bases of the features, while sub-100 nm pillars are grown on top of the bases by GLAD. Scanning electron micrographs show the resemblance of the synthesized cicada wing mimicry samples to the actual cicada wings, both quantitatively and qualitatively. The synthetic mimicry samples are hydrophobic with a water contact angle of 125˚. Finally, the antimicrobial properties of the mimicries are validated by showing flat growth curves of Escherichia coli (E. coli) and by direct observation under scanning electron microscopy (SEM). The process is potentially suitable for large-area antimicrobial applications in food and biomedical industries.

Human cytomegalovirus (HCMV) is the most common vertically transmitted infection worldwide, yet there are no vaccines or therapeutics to prevent congenital HCMV (cCMV) infection. Emerging evidence indicates that antibody Fc effector functions may be a previously underappreciated component of maternal immunity against HCMV. We recently reported that antibody-dependent cellular phagocytosis (ADCP) and IgG activation of FcγRI/FcγRII were associated with protection against cCMV transmission, leading us to hypothesize that additional Fc-mediated antibody functions may be important. In this same cohort of HCMV-transmitting (n = 41) and nontransmitting (n = 40) mother-infant dyads, we report that higher maternal sera antibody–dependent cellular cytotoxicity (ADCC) activation is also associated with lower risk of cCMV transmission. We investigated the relationship between ADCC and IgG responses against 9 viral antigens and found that ADCC activation correlated most strongly with sera IgG binding to the HCMV immunoevasin protein UL16. Moreover, we determined that higher UL16-specific IgG binding and FcγRIII/CD16 engagement were associated with the greatest risk reduction in cCMV transmission. Our findings indicate that ADCC-activating antibodies against targets such as UL16 may represent an important protective maternal immune response against cCMV infection that can guide future HCMV correlates studies and vaccine or antibody-based therapeutic development.

Manipulating the microbiome of cropland soils has the potential to accelerate soil carbon sequestration, but strategies to do so need to be carefully vetted. Here, we highlight the general steps required to develop, implement, and validate such microbe-based strategies.

Optimizing the signal-to-noise ratio (SNR) is critical to achieve high sensitivities across broad spectral ranges in dual-comb interferometry. Sensitivity can be improved through time-averaging, but only at the cost of reduced temporal resolution. We show that it is instead possible to use high-bandwidth detection combined with frequency-domain averaging of multiple copies of the dual-comb beat note. By controlling the signal and noise stationarity properties, one can even reduce the fundamental shot noise contribution compared to the normal, single copy, dual-comb operation where integration time is matched to, or larger than the repetition period. In principle, the use of Na aliased frequency-domain copies will improve SNR by up to Na, or equivalently, reduce acquisition time by a factor of Na. We demonstrate dual-comb interferometry using Na = 5 aliases, achieving the predicted fivefold reduction in shot noise power density at low frequencies. Over the full spectrum, unaveraged relative intensity noise limits the SNR, but we measure a 1.65× fold improvement in detection of CO2, corresponding to a 2.7× reduction in acquisition time for a given precision.

Introduction: Magnetopause reconnection is known to impact the dayside ionosphere by driving fast ionospheric flows, auroral transients, and high-density plasma structures named polar cap patches. However, most of the observed reconnection impact is limited to one hemisphere, and a question arises as to how symmetric the impact is between hemispheres.Methods: We address the question using interhemispheric observations of poleward moving radar auroral forms (PMRAFs), which are a “fossil” signature of magnetopause reconnection, during a geomagnetic storm. We are particularly interested in the temporal repetition and spatial structure of PMRAFs, which are directly affected by the temporal and spatial variation of magnetopause reconnection. PMRAFs are detected and traced using SuperDARN complemented by DMSP, Swarm, and GPS TEC measurements.Results: The results show that PMRAFs occurred repetitively on time scales of about 10 min. They were one-to-one related to pulsed ionospheric flows, and were collocated with polar cap patches embedded in a Tongue of Ionization. The temporal repetition of PMRAFs exhibited a remarkably high degree of correlation between hemispheres, indicating that PMRAFs were produced at a similar rate, or even in close synchronization, in the two hemispheres. However, the spatial structure exhibited significant hemispherical asymmetry. In the Northern Hemisphere, PMRAFs/patches had a dawn-dusk elongated cigar shape that extended >1,000 km, at times reaching >2,000 km, whereas in the Southern Hemisphere, PMRAFs/patches were 2–3 times shorter.Conclusion: The interesting symmetry and asymmetry of PMRAFs suggests that both magnetopause reconnection and local ionospheric conditions play important roles in determining the degree of symmetry of PMRAFs/patches.

Abstract Interactions between solar wind ions and neutral hydrogen atoms in Earth's exosphere can lead to the emission of soft X‐rays. Upcoming missions such as SMILE and LEXI aim to use soft X‐ray imaging to study the global structure of the magnetosphere. Although the magnetosheath and dayside magnetopause can often be driven by kinetic physics, it has typically been omitted from fluid simulations used to predict X‐ray emissions. We study the possible results of soft X‐ray imaging using hybrid simulations under quasi‐radial interplanetary magnetic fields, where ion‐ion instabilities drive ultra‐low frequency foreshock waves, leading to turbulence in the magnetosheath, affecting the dynamics of the cusp and magnetopause. We simulate soft X‐ray emission to determine what may be seen by missions such as LEXI, and evaluate the possibility of identifying kinetic structures. While kinetic structures are visible in high‐cadence imaging, current instruments may not have the time resolution to discern kinetic signals.

Epigenetic mechanisms allow cells to fine-tune gene expression in response to environmental stimuli. For decades, it has been known that mitochondria have genetic material. Still, only recently have studies shown that epigenetic factors regulate mitochondrial DNA (mtDNA) gene expression. Mitochondria regulate cellular proliferation, apoptosis, and energy metabolism, all critical areas of dysfunction in gliomas. Methylation of mtDNA, alterations in mtDNA packaging via mitochondrial transcription factor A (TFAM), and regulation of mtDNA transcription via the micro-RNAs (mir 23-b) and long noncoding RNAs [RNA mitochondrial RNA processing (RMRP)] have all been identified as contributing to glioma pathogenicity. Developing new interventions interfering with these pathways may improve glioma therapy.

Intro: Campylobacter is the most common bacterial cause of foodborne gastroenteritis in Australia, however outbreaks caused by the pathogen are relatively uncommon. On 4 March 2022, the Victorian Department of Health was notified of a gastrointestinal illness in 20 guests following attendance at a wedding reception on 12 February 2022. Four individuals were notified with laboratory confirmed campylobacteriosis, and an investigation was undertaken to determine the full extent of the outbreak and prevent further illness. Methods: A nested case-control study was conducted to determine the likely source of infection. Cases were defined as attendees of the wedding reception, with onset of diarrhoea and/or abdominal pain 1-10 days after attending the function. Controls were randomly selected from the remaining non-ill guests. Cases and controls were interviewed using a standardised menu-based questionnaire, and odds ratios (ORs) calculated of consumed foods. Food preparation processes were documented, and food samples collected. Findings: A total of 29 wedding guests met the case definition, with onset of illness between 2-5 days and major symptoms including diarrhoea (90%), abdominal pain (100%), headache (79%), and fever (62%). Two cases were hospitalised, one with ongoing neurological sequelae. Illness was found to be significantly associated with consumption of a duck breast brioche canape containing duck liver parfait following univariate analysis and stratification by other implicated foods (OR=2.85, 95% CI [1.03-7.86]). Cases aged 10-29 years were 13.2 times more likely to have eaten duck than controls in that age group. Discussion: The investigation found the duck canape was the likely vehicle of infection in this outbreak. Consistent with the literature on Campylobacter transmission, it is likely that inadequate cooking of the duck liver for the parfait was the contributing factor that led to illness. Conclusion: This outbreak investigation highlights the risks posed by poultry dishes if undercooked, and that education of food handlers remains a priority.

Both glioblastoma (GBM) and dementia are devastating diseases with limited treatments that are usually not curative. Having clinically diagnosed dementia with an associated biopsy-proven etiology and a coexisting GBM diagnosis is a rare occurrence. The relationship between the development of neurodegenerative dementia and GBM is unclear, as there are conflicting reports in the literature. We present two cases of simultaneous biopsy-proven dementia, one with Alzheimer’s disease (AD) and GBM, and one with cerebral amyloid angiopathy (CAA) and GBM. We discuss how these diseases may be associated. Whether one pathologic process begins first or develops concurrently is unknown, but certain molecular pathways of dementia and GBM appear directly related while others inversely related. Further investigations of these close molecular relationships between dementia and GBM could lead to development of improved diagnostic tools and therapeutic interventions for both diseases.

The fate of flux tube material once it is eroded from of the plasmasphere through a dayside plume remains unknown. The eroded plasmasphere material can be either swept away by the solar wind and lost from Earth’s system, or recirculated into the inner magnetosphere. Recirculating plasmasphere material could plausibly enter the central plasma sheet and contribute to the ring current. This work uses numerical models to explore this possibility. Historically this has been a difficult question to answer due to the fact that solar wind, ionosphere, and plasmaspheric plasmas are all dominated by hydrogen making it difficult to distinguish the source of plasma from observation alone. Recent advances in computing have enabled us to answer this question. Using the Space Weather Modeling Framework (SWMF) to couple the Block-Adaptive-Tree-Solar-Roe-Up-Wind-Scheme (BATS-R-US), Dynamic Global Core Plasma Model (DGCPM), and the Ridley Ionosphere Model (RIM), we can track the motion of the plasmaspheric material once it leaves the plasmasphere in a self-consistent manner.

IntroductionImproved therapies for glioblastoma (GBM) are desperately needed and require preclinical evaluation in models that capture tumor heterogeneity and intrinsic resistance seen in patients. Epigenetic alterations have been well documented in GBM and lysine-specific demethylase 1 (LSD1/KDM1A) is amongst the chromatin modifiers implicated in stem cell maintenance, growth and differentiation. Pharmacological inhibition of LSD1 is clinically relevant, with numerous compounds in various phases of preclinical and clinical development, but an evaluation and comparison of LSD1 inhibitors in patient-derived GBM models is lacking.MethodsTo assess concordance between knockdown of LSD1 and inhibition of LSD1 using a prototype inhibitor in GBM, we performed RNA-seq to identify genes and biological processes associated with inhibition. Efficacy of various LSD1 inhibitors was assessed in nine patient-derived glioblastoma stem cell (GSC) lines and an orthotopic xenograft mouse model.ResultsLSD1 inhibitors had cytotoxic and selective effects regardless of GSC radiosensitivity or molecular subtype. In vivo, LSD1 inhibition via GSK-LSD1 led to a delayed reduction in tumor burden; however, tumor regrowth occurred. Comparison of GBM lines by RNA-seq was used to identify genes that may predict resistance to LSD1 inhibitors. We identified five genes that correlate with resistance to LSD1 inhibition in treatment resistant GSCs, in GSK-LSD1 treated mice, and in GBM patients with low LSD1 expression.ConclusionCollectively, the growth inhibitory effects of LSD1 inhibition across a panel of GSC models and identification of genes that may predict resistance has potential to guide future combination therapies.

BackgroundThe extraordinarily high prevalence of treatment-resistant depression (TRD), coupled with its high economic burden to both healthcare systems and society, underscore how critical it is that resources are managed optimally to address the significant challenge it presents.ObjectiveTo review the literature on economic evaluation in TRD systematically, with the aim of informing future studies by identifying key challenges specific to the area, and highlighting good practices.MethodsA systematic literature search across seven electronic databases was conducted to identify both within-trial and model-based economic evaluations in TRD. Quality of reporting and study design was assessed using the Consensus Health Economic Criteria (CHEC). A narrative synthesis was conducted.ResultsWe identified 31 evaluations, including 11 conducted alongside a clinical trial and 20 model-based evaluations. There was considerable heterogeneity in the definition of treatment-resistant depression, although with a trend for more recent studies to use a definition of inadequate response to two or more antidepressive treatments. A broad range of interventions were considered, including non-pharmacological neuromodulation, pharmacological, psychological, and service-level interventions. Study quality as assessed by CHEC was generally high. Frequently poorly reported items related to discussion of ethical and distributional issues, and model validation. Most evaluations considered comparable core clinical outcomes – encompassing remission, response, and relapse. There was good agreement on the definitions and thresholds for these outcomes, and a relatively small pool of outcome measures were used. Resource criteria used to inform the estimation of direct costs, were reasonably uniform. Predominantly, however, there was a high level of heterogeneity in terms of evaluation design and sophistication, quality of evidence used (particularly health state utility data), time horizon, population considered, and cost perspective.ConclusionEconomic evidence for interventions in TRD is underdeveloped, particularly so for service-level interventions. Where evidence does exist, it is hampered by inconsistency in study design, methodological quality, and availability of high quality long-term outcomes evidence. This review identifies a number of key considerations and challenges for the design of future economic evaluations. Recommendations for research and suggestions for good practice are made.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=259848&VersionID=1542096, identifier CRD42021259848.

Irrespective of the reason for hypoperfusion, hypocoagulable and/or hyperfibrinolytic hemostatic aberrancies afflict up to one-quarter of critically ill patients in shock. Intensivists and traumatologists have embraced the concept of SHock-INduced Endotheliopathy (SHINE) as a foundational derangement in progressive shock wherein sympatho-adrenal activation may cause systemic endothelial injury. The pro-thrombotic endothelium lends to micro-thrombosis, enacting a cycle of worsening perfusion and increasing catecholamines, endothelial injury, de-endothelialization, and multiple organ failure. The hypocoagulable/hyperfibrinolytic hemostatic phenotype is thought to be driven by endothelial release of anti-thrombogenic mediators to the bloodstream and perivascular sympathetic nerve release of tissue plasminogen activator directly into the microvasculature. In the shock state, this hemostatic phenotype may be a counterbalancing, yet maladaptive, attempt to restore blood flow against a systemically pro-thrombotic endothelium and increased blood viscosity. We therefore review endothelial physiology with emphasis on glycocalyx function, unique biomarkers, and coagulofibrinolytic mediators, setting the stage for understanding the pathophysiology and hemostatic phenotypes of SHINE in various etiologies of shock. We propose that the hyperfibrinolytic phenotype is exemplified in progressive shock whether related to trauma-induced coagulopathy, sepsis-induced coagulopathy, or post-cardiac arrest syndrome-associated coagulopathy. Regardless of the initial insult, SHINE appears to be a catecholamine-driven entity which early in the disease course may manifest as hyper- or hypocoagulopathic and hyper- or hypofibrinolytic hemostatic imbalance. Moreover, these hemostatic derangements may rapidly evolve along the thrombohemorrhagic spectrum depending on the etiology, timing, and methods of resuscitation. Given the intricate hemochemical makeup and changes during these shock states, macroscopic whole blood tests of coagulative kinetics and clot strength serve as clinically useful and simple means for hemostasis phenotyping. We suggest that viscoelastic hemostatic assays such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are currently the most applicable clinical tools for assaying global hemostatic function—including fibrinolysis—to enable dynamic resuscitation with blood products and hemostatic adjuncts for those patients with thrombotic and/or hemorrhagic complications in shock states.

Much of what we know about the solar wind’s interaction with the Earth’s magnetosphere has been gained from isolated in-situ measurements by single or multiple spacecraft. Based on their observations, we know that reconnection, whether on the dayside magnetopause or deep within the Earth’s magnetotail, controls the bulk flow of solar wind energy into and through the global system and that nightside activity provides the energized particles that power geomagnetic storms. But by their very nature these isolated in-situ measurements cannot provide an instantaneous global view of the entire system or its cross-scale dynamics. To fully quantify the dynamics of the coupled solar wind-magnetosphere requires comprehensive end-to-end global imaging of the key plasma structures that comprise the magnetosphere which have spatial resolutions that exceeds anything possible with multi-point or constellation situ measurements. Global, end-to-end, imaging provides the pathway to understanding the system as a whole, its constituent parts, and its cross-scale processes on a continuous basis, as needed to quantify the flow of solar wind energy through the global magnetospheric system. This paper describes how a comprehensively-instrumented single spacecraft in a high-altitude, high-inclination orbit coupled with ground-based instruments provides the essential observations needed to track and quantify the flow of solar wind energy through the magnetosphere. This includes observations of the solar wind plasma and magnetic field input, the magnetopause location in soft X-rays, the auroral oval in far ultraviolet, the ring current in energetic neutrals, the plasmasphere in extreme ultraviolet, the exosphere in Lyman-α, and the microstructure of the nightside auroral oval from ground-based all sky cameras.