Search

We independently analyzed two large public domain datasets that contain 1H-NMR spectral data from lung cancer and sex studies. The biobanks were sourced from the Karlsruhe Metabolomics and Nutrition (KarMeN) study and Bayesian Automated Metabolite Analyzer for NMR data (BATMAN) study. Our approach of applying novel artificial intelligence (AI)-based algorithms to NMR is an attempt to globalize metabolomics and demonstrate its clinical applications. The intention of this study was to analyze the resulting spectra in the biobanks via AI application to demonstrate its clinical applications. This technique enables metabolite mapping in areas of localized enrichment as a measure of true activity while also allowing for the accurate categorization of phenotypes.

Summary: Background: Severe COVID-19 is associated with innate immunopathology, and CD14, a proximal activator of innate immunity, has been suggested as a potential therapeutic target. Methods: We conducted the COVID-19 anti-CD14 Treatment Trial (CaTT), a Phase II randomized, double-blind, placebo-controlled trial at 5 US-sites between April 12, 2021 and November 30, 2021 (NCT04391309). Hospitalized adults with COVID-19 requiring supplemental oxygen (

OBJECTIVES:. To analyze the temporal trend in enrollment rates in a COVID-19 platform trial during the first three waves of the pandemic in the United States. DESIGN:. Secondary analysis of data from the I-SPY COVID randomized controlled trial (RCT). SETTING:. Thirty-one hospitals throughout the United States. PATIENTS:. Patients who were approached, either directly or via a legally authorized representative, for consent and enrollment into the I-SPY COVID RCT. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Among 1,338 patients approached for the I-SPY COVID trial from July 30, 2020, to February 17, 2022, the number of patients who enrolled (n = 1,063) versus declined participation (n = 275) was used to calculate monthly enrollment rates. Overall, demographic and baseline clinical characteristics were similar between those who enrolled versus declined. Enrollment rates fluctuated over the course of the COVID-19 pandemic, but there were no significant trends over time (Mann-Kendall test, p = 0.21). Enrollment rates were also comparable between vaccinated and unvaccinated patients. In multivariable logistic regression analysis, age, sex, region of residence, COVID-19 severity of illness, and vaccination status were not significantly associated with the decision to decline consent. CONCLUSIONS:. In this secondary analysis of the I-SPY COVID clinical trial, there was no significant association between the enrollment rate and time period or vaccination status among all eligible patients approached for clinical trial participation. Additional studies are needed to better understand whether the COVID-19 pandemic has altered clinical trial participation and to develop strategies for encouraging participation in future COVID-19 and critical care clinical trials.

Summary: Background: GM1 gangliosidosis is a rare, fatal, neurodegenerative disease caused by mutations in the GLB1 gene and deficiency in β-galactosidase. Delay of symptom onset and increase in lifespan in a GM1 gangliosidosis cat model after adeno-associated viral (AAV) gene therapy treatment provide the basis for AAV gene therapy trials. The availability of validated biomarkers would greatly improve assessment of therapeutic efficacy. Methods: The liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to screen oligosaccharides as potential biomarkers for GM1 gangliosidosis. The structures of pentasaccharide biomarkers were determined with mass spectrometry, as well as chemical and enzymatic degradations. Comparison of LC-MS/MS data of endogenous and synthetic compounds confirmed the identification. The study samples were analyzed with fully validated LC-MS/MS methods. Findings: We identified two pentasaccharide biomarkers, H3N2a and H3N2b, that were elevated more than 18-fold in patient plasma, cerebrospinal fluid (CSF), and urine. Only H3N2b was detectable in the cat model, and it was negatively correlated with β-galactosidase activity. Following intravenous (IV) AAV9 gene therapy treatment, reduction of H3N2b was observed in central nervous system, urine, plasma, and CSF samples from the cat model and in urine, plasma, and CSF samples from a patient. Reduction of H3N2b accurately reflected normalization of neuropathology in the cat model and improvement of clinical outcomes in the patient. Interpretations: These results demonstrate that H3N2b is a useful pharmacodynamic biomarker to evaluate the efficacy of gene therapy for GM1 gangliosidosis. H3N2b will facilitate the translation of gene therapy from animal models to patients. Funding: This work was supported by grants U01NS114156, R01HD060576, ZIAHG200409, and P30 DK020579 from the National Institutes of Health (NIH) and a grant from National Tay-Sachs and Allied Diseases Association Inc.

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer that predominantly impacts White patients. Overall incidence and the proportion of minority patients with MCC are both rising. In the more common skin cancer, melanoma, racial disparities are well-documented in stage at presentation and patient survival. Whether racial and ethnic disparities exist in MCC remains unclear. The study of MCC disparities is hampered by limitations in data registries, including SEER and NCDB, and an evolving natural history due to the advent of immunotherapy. Published MCC immunotherapy clinical trials consistently reported the racial diversity among enrolled subjects but failed to include patients’ ethnicities. Efforts to improve data capture in cancer registries and create multi-institutional clinical databases will allow for more effective study of racial and ethnic disparities in rare cancers like MCC. Such studies are needed to advance policies promoting equity in care.

Knowledge of the effects of climate change on agro-ecosystems is fundamental to identifying local actions aimed to maintain productivity and reduce environmental issues. This study investigates the effects of climate perturbation on the European crop and grassland production systems, combining the findings from two specific biogeochemical models. Accurate and high-resolution management and pedoclimatic data were employed. Results have been verified for the period 1978–2004 (historical period) and projected until 2099 with two divergent intensities: the Intergovernmental Panel on Climate Change (IPCC) climate projections, Representative Concentration Pathway (RCP) 4.5 and RCP8.5. We have provided a detailed overview of productivity and the impacts on management (sowing dates, water demand, nitrogen use efficiency). Biogenic greenhouse gas balance (N2O, CH4, CO2) was calculated, including an assessment of the gases' sensitivity to the leading drivers, and a net carbon budget on production systems was compiled. Results confirmed a rise in productivity in the first half of the century (+5 % for croplands at +0.2 t DM ha−1 yr−1, +1 % for grasslands at +0.1 t DM ha−1 yr−1; DM denotes dry matter), whereas a significant reduction in productivity is expected during the period 2050–2099, caused by the shortening of the length of the plant growing cycle associated with rising temperatures. This effect was more pronounced for the more pessimistic climate scenario (−6.1 % for croplands and −7.7 % for grasslands), for the Mediterranean regions and in central European latitudes, confirming a regionally distributed impact of climate change. Non-CO2 greenhouse gas emissions were triggered by rising air temperatures and increased exponentially over the century, often exceeding the CO2 accumulation of the explored agro-ecosystems, which acted as potential C sinks. The emission factor for N2O was 1.82 ± 0.07 % during the historical period and rose to up to 2.05 ± 0.11 % for both climate projections. The biomass removal (crop yield, residues exports, mowing and animal intake) converted croplands and grasslands into net C sources (236 ± 107 Tg CO2 eq. yr−1 in the historical period), increasing from 19 % to 26 % during the climate projections, especially for RCP4.5. Nonetheless, crop residue restitution might represent a potential management strategy to overturn the C balance. Although with a marked latitudinal gradient, water demand will double over the next few decades in the European croplands, whereas the benefit in terms of yield (+2 % to +10 % over the century) will not contribute substantially to balance the C losses due to climate perturbation.

Measurement(s) wood carbon concentrations Technology Type(s) elemental analyzer Factor Type(s) species Sample Characteristic - Organism Plant Sample Characteristic - Environment terrestrial biome Sample Characteristic - Location Globe

Early in vertebrate evolution, a single homeobox (Hox) cluster in basal chordates was quadrupled to generate the Hox gene clusters present in extant vertebrates. Here we ask how this expanded gene pool may have influenced the evolution of the visual system. We suggest that a single neurosensory cell type split into ciliated sensory cells (photoreceptors, which transduce light) and retinal ganglion cells (RGC, which project to the brain). In vertebrates, development of photoreceptors is regulated by the basic helix-loop-helix (bHLH) transcription factor Neurod1 whereas RGC development depends on Atoh7 and related bHLH genes. Lancelet (a basal chordate) does not express Neurod or Atoh7 and possesses a few neurosensory cells with cilia that reach out of the opening of the neural tube. Sea-squirts (Ascidians) do not express Neurod and express a different bHLH gene, Atoh8, that is likely expressed in the anterior vesicle. Recent data indicate the neurosensory cells in lancelets may correspond to three distinct eye fields in ascidians, which in turn may be the basis of the vertebrate retina, pineal and parapineal. In this review we contrast the genetic control of visual structure development in these chordates with that of basal vertebrates such as lampreys and hagfish, and jawed vertebrates. We propose an evolutionary sequence linking whole-genome duplications, initially to a split between photoreceptor and projection neurons (RGC) and subsequently between pineal and lateral eye structures.

Recent results from MAST Upgrade are presented, emphasising understanding the capabilities of this new device and deepening understanding of key physics issues for the operation of ITER and the design of future fusion power plants. The impact of MHD instabilities on fast ion confinement have been studied, including the first observation of fast ion losses correlated with Compressional and Global Alfvén Eigenmodes. High-performance plasma scenarios have been developed by tailoring the early plasma current ramp phase to avoid internal reconnection events, resulting in a more monotonic q profile with low central shear. The impact of m / n = 3/2, 2/1 and 1/1 modes on thermal plasma confinement and rotation profiles has been quantified, and scenarios optimised to avoid them have transiently reached values of normalised beta approaching 4.2. In pedestal and ELM physics, a maximum pedestal top temperature of ∼350 eV has been achieved, exceeding the value achieved on MAST at similar heating power. Mitigation of type-I ELMs with n = 1 RMPs has been observed. Studies of plasma exhaust have concentrated on comparing conventional and Super-X divertor configurations, while X-point target, X-divertor and snowflake configurations have been developed and studied in parallel. In L-mode discharges, the separatrix density required to detach the outer divertors is approximately a factor 2 lower in the Super-X than the conventional configuration, in agreement with simulations. Detailed analysis of spectroscopy data from studies of the Super-X configuration reveal the importance of including plasma-molecule interactions and D _2 Fulcher band emission to properly quantify the rates of ionisation, plasma-molecule interactions and volumetric recombination processes governing divertor detachment. In H-mode with conventional and Super-X configurations, the outer divertors are attached in the former and detached in the latter with no impact on core or pedestal confinement.

The Southern Great Plains of the United States is a region with a sharp zonal precipitation gradient that is prone to rapid transitions in precipitation extremes. Transitions from pluvial to drought conditions can lead to the green-up of vegetation during extreme rainfall, posing a considerable fire risk as the region rapidly transitions into drought. Such transitions have been studied in depth across regions such as California; however, limited studies have examined their impacts across the Southern Great Plains. The aim of this study was to examine the role of preceding precipitation whiplash events in providing fuel for wildfires, with 2017–2018 investigated as a case study. This study specifically demonstrates the relationship between precipitation, vegetation, and wildfires for the first time across the Southern Great Plains. Lag correlation analysis of historical data at our study site showed anomalously high precipitation 8 months prior to Spring wildfires, resulting in a significantly higher number of wildfires and acres burned. In particular, this study examined a highly impactful precipitation whiplash event that occurred during the Fall of 2017 across the Oklahoma and Texas panhandles, which preceded a mega-fire event in the Spring of 2018. Precipitation anomalies that were 137% of normal during the 2017 growing season rapidly cascaded into drought conditions with precipitation anomalies 21% of normal throughout the cool winter season. Excessive precipitation supported vigorous vegetation recovery and growth, with vegetation indices peaking at approximately 1 standard deviation above average during August 2017. However, the subsequent drought period rapidly desiccated the terrestrial surface. As a result, dozens of wildfires burned a total of 556 347 acres during March and April 2018, resulting in at least two fatalities, dozens of homes destroyed, and over 500 personnel dispatched to fight and mitigate the fires. Overall, this study highlights the significant role of preceding Fall precipitation whiplash events in fueling Spring wildfires across the Southern Great Plains, particularly exemplified by the impactful 2017–2018 case, highlighting the complex dynamics between extreme precipitation, vegetation growth, and subsequent fire risks in the region.

Community collaboration is a cornerstone of modern public health efforts. This work aimed to use community-engaged research to explore COVID-19 vaccination, testing, and infection in a minoritized community. This study was conducted in Miami, Florida, from March 2021 to February 2022 in community partner sites and the Miami Adult Studies on HIV (MASH) cohort. Sociodemographic characteristics, vaccination and testing beliefs, and COVID-19 challenges were self-reported. COVID-19 vaccinations were verified with medical records, testing history was self-reported, and severe acute respiratory syndrome coronavirus 2 positivity was determined via real-time reverse transcription–polymerase chain reaction (rt-PCR). Of 1689 participants, the median age was 57, 51% were male, 49% were non-Hispanic Black, 66% reported an income < USD 15,000/year, and 75.9% received at least one dose of a COVID-19 vaccine. Belief that COVID-19 vaccination is effective was associated with lower odds of COVID-19 positivity and was the strongest predictor of vaccination. Challenges accessing health care, housing, food, and transportation were associated with lower odds of vaccination. Employment, health insurance, higher education, and greater perceived test accuracy were associated with greater odds of COVID-19 testing. Social determinants of health and the belief that vaccines are effective and tests are accurate predicted behaviors and thus should be considered during public health crises in vulnerable communities.

It has been reported that hyaluronic acid (HA) with a 35 kDa molecular weight (HA35) acts biologically to protect tissue from injury, but its biological properties are not yet fully characterized. This study aimed to evaluate the cellular effects and biodistribution of HA35 compared to HA with a 1600 kDa molecular weight (HA1600). We assessed the effects of HA35 and HA1600 on cell migration, NO and ROS generation, and gene expression in cultured macrophages, microglia, and lymphocytes. HA35 was separately radiolabeled with 99mTc and 125I and administered to C57BL/6J mice for in vivo biodistribution imaging. In vitro studies indicated that HA35 and HA1600 similarly enhanced cell migration through HA receptor binding mechanisms, reduced the generation of NO and ROS, and upregulated gene expression profiles related to cell signaling pathways in immune cells. HA35 showed a more pronounced effect in regulating a broader range of genes in macrophages and microglia than HA1600. Upon intradermal or intravenous administration, radiolabeled HA35 rapidly accumulated in the liver, spleen, and lymph nodes. In conclusion, HA35 not only exhibits effects on cellular bioactivity comparable to those of HA1600 but also exerts biological effects on a broader range of immune cell gene expression. The findings herein offer valuable insights for further research into the therapeutic potential of HA35 in inflammation-mediated tissue injury.

There is substantial experimental and clinical interest in providing effective ways to both prevent and slow the onset of hearing loss. Auditory hair cells, which occur along the basilar membrane of the cochlea, often lose functionality due to age-related biological alterations, as well as from exposure to high decibel sounds affecting a diminished/damaged auditory sensitivity. Hearing loss is also seen to take place due to neuronal degeneration before or following hair cell destruction/loss. A strategy is necessary to protect hair cells and XIII cranial/auditory nerve cells prior to injury and throughout aging. Within this context, it was proposed that cochlea neural stem cells may be protected from such aging and environmental/noise insults via the ingestion of protective dietary supplements. Of particular importance is that these studies typically display a hormetic-like biphasic dose–response pattern that prevents the occurrence of auditory cell damage induced by various model chemical toxins, such as cisplatin. Likewise, the hormetic dose–response also enhances the occurrence of cochlear neural cell viability, proliferation, and differentiation. These findings are particularly important since they confirmed a strong dose dependency of the significant beneficial effects (which is biphasic), whilst having a low-dose beneficial response, whereas extensive exposures may become ineffective and/or potentially harmful. According to hormesis, phytochemicals including polyphenols exhibit biphasic dose–response effects activating low-dose antioxidant signaling pathways, resulting in the upregulation of vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Modulation of the vitagene network through polyphenols increases cellular resilience mechanisms, thus impacting neurological disorder pathophysiology. Here, we aimed to explore polyphenols targeting the NF-E2-related factor 2 (Nrf2) pathway to neuroprotective and therapeutic strategies that can potentially reduce oxidative stress and inflammation, thus preventing auditory hair cell and XIII cranial/auditory nerve cell degeneration. Furthermore, we explored techniques to enhance their bioavailability and efficacy.

Abstract Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants and an AD-specific polygenic risk score (PGRS), adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed. We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. We did not observe associations between the PGRS and any analyte. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case–control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

The SARS-CoV-2 spike has been evolving in the human population. The variants of concern alpha and beta evolved to optimise spike openness and so ability to bind its receptor ACE2, the affinity towards the receptor, and stability upon receptor binding.

Introduction Sciatica is a common condition and is associated with higher levels of pain, disability, poorer quality of life, and increased use of health resources compared with low back pain alone. Although many patients recover, a third develop persistent sciatica symptoms. It remains unclear, why some patients develop persistent sciatica as none of the traditionally considered clinical parameters (eg, symptom severity, routine MRI) are consistent prognostic factors.The FORECAST study (factors predicting the transition from acute to persistent pain in people with ‘sciatica’) will take a different approach by exploring mechanism-based subgroups in patients with sciatica and investigate whether a mechanism-based approach can identify factors that predict pain persistence in patients with sciatica.Methods and analysis We will perform a prospective longitudinal cohort study including 180 people with acute/subacute sciatica. N=168 healthy participants will provide normative data. A detailed set of variables will be assessed within 3 months after sciatica onset. This will include self-reported sensory and psychosocial profiles, quantitative sensory testing, blood inflammatory markers and advanced neuroimaging. We will determine outcome with the Sciatica Bothersomeness Index and a Numerical Pain Rating Scale for leg pain severity at 3 and 12 months.We will use principal component analysis followed by clustering methods to identify subgroups. Univariate associations and machine learning methods optimised for high dimensional small data sets will be used to identify the most powerful predictors and model selection/accuracy.The results will provide crucial information about the pathophysiological drivers of sciatica symptoms and may identify prognostic factors of pain persistence.Ethics and dissemination The FORECAST study has received ethical approval (South Central Oxford C, 18/SC/0263). The dissemination strategy will be guided by our patient and public engagement activities and will include peer-reviewed publications, conference presentations, social media and podcasts.Trial registration number ISRCTN18170726; Pre-results.

Abstract A three‐dimensional ensemble‐variational global aerosol data assimilation system based on the Joint Effort for Data assimilation Integration (JEDI) was developed for the Global Ensemble Forecast System‐Aerosols (GEFS‐Aerosols) coupled with the Goddard Chemistry Aerosol Radiation and Transport (GOCART) model at the National Centers for Environmental Prediction. Aerosol mass mixing ratios in GEFS‐Aerosols were selected as control or analysis variables and were adjusted by assimilating 550 nm Aerosol Optical Depth (AOD) retrievals from the Visible Infrared Imaging Radiometer Suite (VIIRS) instruments onboard the Suomi National Polar‐orbiting Partnership (S‐NPP) satellite produced by the National Environmental Satellite, Data, and Information Service (NESDIS) at National Oceanic and Atmospheric Administration (NOAA). The original NOAA/NESDIS S‐NPP VIIRS Level 2.0 550 nm AOD retrievals were converted to JEDI Interface for Observation Data Access format. AOD forward operator and its tangent‐linear and adjoint models were implemented based on GOCART in JEDI Unified Forward Operator. A stochastically perturbed emission (SPE) approach was developed in the Common Community Physics Package‐based GEFS‐Aerosols to account for aerosol emission uncertainty. One‐month retrospective and three‐month near‐real‐time experiments consistently showed improved GEFS‐Aerosols analyses and forecasts from assimilating VIIRS 550 nm AOD retrievals against independent NASA Aqua and Terra Moderate Resolution Imaging Spectroradiometer AOD retrievals, Aerosol Robotic Network AOD, and independent AOD and aerosol analyses from NASA and European Centre for Medium‐Range Weather Forecasts. Through scaling and perturbing aerosol emissions, SPE enhanced ensemble error‐spread consistency and further improved AOD assimilation. The valid‐time‐shifting ensemble approach in a cost‐effective manner of populating background ensembles showed positive impacts on AOD assimilation.

Behavioral responses to sonar have been observed in a number of baleen whales, including minke whales (Balaenoptera acutorostrata). Previous studies used acoustic minke whale boing detections to localize and track individual whales on the U.S. Pacific Missile Range Facility (PMRF) in Kaua ‘i, Hawai‘i before, during, and after Navy training activities. These analyses showed significant changes in central North Pacific minke whale distribution and swimming behavior during Navy sonar events. For the purposes of contextualizing changes in animal movement relative to Navy sonar, we expanded on this research to examine the natural variation in minke whale movement when Navy sonar was not present. This study included 2,245 acoustically derived minke whale tracks spanning the years 2012–2017 over all months that minke whales were detected (October–May). Minke whale movement was examined relative to calling season, day of the year, hour of day, wind speed, calling state (nominal or rapid), and distance to the nearest calling conspecific. Hidden Markov models were used to identify two kinematic states (slower, less directional movement and faster, more directional movement). The findings indicate that minke whales were more likely to travel in a faster and more directional state when they were calling rapidly, when other vocalizing minke whales were nearby, during certain times of the day and calling seasons, and in windier conditions, but these changes in movement were less intense than the changes observed during exposure to Navy sonar, when swim speeds were the fastest. These results start to put behavioral responses to Navy sonar into an environmental context to understand the severity of responses relative to natural changes in behavior.

Abstract Transferrin receptor (TFRC) is the major mediator for iron entry into a cell. Under excessive iron conditions, TFRC is expected to be reduced to lower iron uptake and toxicity. However, the mechanism whereby TFRC expression is maintained at high levels in iron‐enriched cancer cells and the contribution of TFRC to cancer development are enigmatic. Here the work shows TFRC is induced by adenomatous polyposis coli (APC) gene loss‐driven β‐catenin activation in colorectal cancer, whereas TFRC‐mediated intratumoral iron accumulation potentiates β‐catenin signaling by directly enhancing the activity of tankyrase. Disruption of TFRC leads to a reduction of colonic iron levels and iron‐dependent tankyrase activity, which caused stabilization of axis inhibition protein 2 (AXIN2) and subsequent repression of the β‐catenin/c‐Myc/E2F Transcription Factor 1/DNA polymerase delta1 (POLD1) axis. POLD1 knockdown, iron chelation, and TFRC disruption increase DNA replication stress, DNA damage response, apoptosis, and reduce colon tumor growth. Importantly, a combination of iron chelators and DNA damaging agents increases DNA damage response and reduces colon tumor cell growth. TFRC‐mediated iron import is at the center of a novel feed‐forward loop that facilitates colonic epithelial cell survival. This discovery may provide novel strategies for colorectal cancer therapy.

Summary: Background: An urgent need exists to rapidly screen potential therapeutics for severe COVID-19 or other emerging pathogens associated with high morbidity and mortality. Methods: Using an adaptive platform design created to rapidly evaluate investigational agents, hospitalised patients with severe COVID-19 requiring ≥6 L/min oxygen were randomised to either a backbone regimen of dexamethasone and remdesivir alone (controls) or backbone plus one open-label investigational agent. Patients were enrolled to the arms described between July 30, 2020 and June 11, 2021 in 20 medical centres in the United States. The platform contained up to four potentially available investigational agents and controls available for randomisation during a single time-period. The two primary endpoints were time-to-recovery (

Summary: African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across groups. Differences in African ancestries contribute more to variability in PRS accuracy than other large cohort differences considered between individuals in the United Kingdom versus Uganda. We computed PRS in African ancestry populations using existing European-only versus ancestrally diverse genetic studies; the increased diversity produced the largest accuracy gains for hemoglobin concentration and white blood cell count, reflecting large-effect ancestry-enriched variants in genes known to influence sickle cell anemia and the allergic response, respectively. Differences in PRS accuracy across African ancestries originating from diverse regions are as large as across out-of-Africa continental ancestries, requiring commensurate nuance.

Throughout their evolution seabirds have not had to contend with the collision risk posed by discrete objects that extend into their flight space above the water surface. However, the recent introduction of offshore wind turbines has significantly increased the potential for collisions. Bird collision risk with Offshore Wind Farm (OWF) turbines is now a major consenting consideration for OWF projects due to potential local population impacts on birds, especially those associated with protected sites. Therefore, the possibility of reducing those risks through a simple mitigation is highly desirable. Key elements for the design of vision-based mitigation measures aimed at reducing the collision of marine birds with wind turbines should be based upon knowledge of the vision of birds, not the vision of humans. May et al. (2020) tested a vision-based wind turbine mitigation measure and reported a modelled 70% reduction in annual turbine-blade collision mortality rate at a terrestrial location in a suite of 19 bird species. The aim of the present proposals is to extend this vision-based mitigation approach and increase its applicability to a broad suite of bird species considered vulnerable to collisions with wind turbines at sea. Key aspects of the vision, behaviour and ecology of marine birds which contribute to their collision risk under a range of natural viewing conditions are reviewed. The same information is then employed to give insights into the requirements of vision-based mitigation measures. We argue that the internal visual contrast of wind turbines should be increased using achromatic patterns applied to blades and pylons. These patterns should reduce the collision vulnerability of marine birds in general and should be effective under a range of visibility conditions determined by natural light levels and weather conditions. The measures should allow birds with different flight speeds and visual acuities to detect turbines sufficiently early to allow alteration of flight direction and avoid collision. The proposed mitigation requires changes to the appearance of wind turbines that can be implemented at the time of manufacture. They do not interfere with statutory requirements already required for the marking of turbines for the benefit of shipping and aircraft.

IntroductionPreterm birth is associated with altered growth patterns and an increased risk of cardiometabolic diseases, with breast milk (BM) being a counteracting factor. Preterm infants also show alterations in adipokines and gut hormones influencing appetite and metabolism. Since these hormones are present in BM, it is possible that their levels may equilibrate deficiencies improving infant growth. We aimed to assess 1) the BM levels of ghrelin, resistin, leptin, insulin, peptide YY, and the gastrointestinal peptide in women with preterm and term labor; 2) the relationship between BM hormones and neonatal growth; and 3) the influence of maternal body composition and diet on these BM hormones.MethodsBM from 48 women (30 term and 18 preterm labor) was collected at days 7, 14, and 28 of lactation. Maternal body composition was evaluated by bioimpedance, and neonate anthropometric parameters were collected from medical records. The maternal dietary pattern was assessed by a 72-h dietary recall at days 7 and 28 of lactation. BM hormones were analyzed by the U-Plex Ultra-sensitive method. Data were analyzed using linear regression models. BM from women with preterm labor had lower ghrelin levels, with the other hormones being significantly higher compared to women with term delivery.ResultsIn premature infants, growth was positively associated with BM ghrelin, while, in term infants, it was positively associated with insulin and negatively with peptide YY. In the first week of lactation, women with preterm labor had higher body fat compared to women with term labor. In this group, ghrelin levels were positively associated with maternal body fat and with fiber and protein intake. In women with term labor, no associations between anthropometric parameters and BM hormones were found, and fiber intake was negatively associated with peptide YY.DiscussionPreterm labor is a factor influencing the levels of BM adipokines and gut hormones, with BM ghrelin being a relevant hormone for premature infant growth. Since ghrelin is lower in BM from women with preterm labor and the levels are associated with maternal fat storage and some dietary components, our data support the importance to monitor diet and body composition in women who gave birth prematurely to improve the BM hormonal status.

Introduction: Benzodiazepine tapering and cessation has been associated with diverse symptom constellations of varying duration. Although described in the literature decades ago, the mechanistic underpinnings of enduring symptoms that can last months or years have not yet been elucidated. Objective: This secondary analysis of the results from an Internet survey sought to better understand the acute and protracted withdrawal symptoms associated with benzodiazepine use and discontinuation. Methods: An online survey ( n = 1207) was used to gather information about benzodiazepine use, including withdrawal syndrome and protracted symptoms. Results: The mean number of withdrawal symptoms reported by a respondent in this survey was 15 out of 23 symptoms. Six percent of respondents reported having all 23 listed symptoms. A cluster of least-frequently reported symptoms (whole-body trembling, hallucinations, seizures) were also the symptoms most frequently reported as lasting only days or weeks, that is, short-duration symptoms. Symptoms of nervousness/anxiety/fear, sleep disturbances, low energy, and difficulty focusing/distractedness were experienced by the majority of respondents (⩾85%) and, along with memory loss, were the symptoms of longest duration. Prolonged symptoms of anxiety and insomnia occurred in many who have discontinued benzodiazepines, including over 50% who were not originally prescribed benzodiazepines for that indication. It remains unclear if these symptoms might be caused by neuroadaptive and/or neurotoxic changes induced by benzodiazepine exposure. In this way, benzodiazepine withdrawal may have acute and long-term symptoms attributable to different underlying mechanisms, which is the case with alcohol withdrawal. Conclusions: These findings tentatively support the notion that symptoms which are acute but transient during benzodiazepine tapering and discontinuation may be distinct in their nature and duration from the enduring symptoms experienced by many benzodiazepine users.

Transformative results of adeno-associated virus (AAV) gene therapy in patients with spinal muscular atrophy and Leber’s congenital amaurosis led to approval of the first two AAV products in the United States to treat these diseases. These extraordinary results led to a dramatic increase in the number and type of AAV gene-therapy programs. However, the field lacks non-invasive means to assess levels and duration of therapeutic protein function in patients. Here, we describe a new magnetic resonance imaging (MRI) technology for real-time reporting of gene-therapy products in the living animal in the form of an MRI probe that is activated in the presence of therapeutic protein expression. For the first time, we show reliable tracking of enzyme expression after a now in-human clinical trial AAV gene therapy (ClinicalTrials.gov: NTC03952637) encoding lysosomal acid beta-galactosidase (βgal) using a self-immolative βgal-responsive MRI probe. MRI enhancement in AAV-treated enzyme-deficient mice (GLB-1−/−) correlates with βgal activity in central nervous system and peripheral organs after intracranial or intravenous AAV gene therapy, respectively. With >1,800 gene therapies in phase I/II clinical trials (ClinicalTrials.gov), development of a non-invasive method to track gene expression over time in patients is crucial to the future of the gene-therapy field.

Abstract. Background:. To determine the feasibility of using wearables in patients undergoing radical cystectomy to monitor postoperative heart rate and activity and attempt to correlate these factors to complications and readmissions. Materials and methods:. We conducted a prospective study of 20 patients undergoing radical cystectomy for bladder cancer between June 2017 and March 2018. Each patient was provided with a Garmin Vívofit heart rate (HR) activity tracker and instructed to wear it on their wrist for 30 days postoperatively. Heart rate, steps, and sleep data were collected during this time. Patients were called at 10-day intervals and surveyed for complications and device compliance. Univariable mixed effects logistic regression models were used to compare daily activity tracker measures with occurrence of an adverse event. Odds ratios, 95% confidence intervals, and p-values were reported. Results:. Median age was 65 (interquartile range 61–74) years. Patients had usable data for a median of 59.3% (interquartile range 25–71.7%) of the time. Five patients experienced a postoperative event (1 readmission for sepsis from urinary tract source, 1 inpatient rapid response called for tachycardic event, 3 unscheduled visits related to dehydration), where event data was recorded over a total of 17 days. Higher step count was associated with reduced odds of an adverse event (odds ratio 0.31, 95% confidence interval 0.10–0.98 per 1000 steps, p = 0.047). Conclusions:. Postoperative activity and heart rate monitoring in cystectomy patients is feasible though current wearables are not well suited for this task.

The quantitative integration of geophysical measurements with data and information from other disciplines is becoming increasingly important in answering the challenges of undercover imaging and of the modelling of complex areas. We propose a review of the different techniques for the utilisation of structural, petrophysical, and geological information in single physics and joint inversion as implemented in the Tomofast-x open-source inversion platform. We detail the range of constraints that can be applied to the inversion of potential field data. The inversion examples we show illustrate a selection of scenarios using a realistic synthetic data set inspired by real-world geological measurements and petrophysical data from the Hamersley region (Western Australia). Using Tomofast-x's flexibility, we investigate inversions combining the utilisation of petrophysical, structural, and/or geological constraints while illustrating the utilisation of the L-curve principle to determine regularisation weights. Our results suggest that the utilisation of geological information to derive disjoint interval bound constraints is the most effective method to recover the true model. It is followed by model smoothness and smallness conditioned by geological uncertainty and cross-gradient minimisation.

Abstract Background For children and adults, the standard treatment for obstructive sleep apnea is the delivery of continuous positive airway pressure (CPAP). Though effective, CPAP masks can be uncomfortable to patients, contributing to adherence concerns. Recently, nasal high flow (NHF) therapy has been investigated as an alternative, especially in CPAP-intolerant children. The present study aimed to compare and contrast the positive airway pressures and expired gas washout generated by NHF versus CPAP in child nasal airway replicas. Methods NHF therapy was investigated at a flow rate of 20 L/min and compared to CPAP at 5 cmH2O and 10 cmH2O for 10 nasal airway replicas, built from computed tomography scans of children aged 4–8 years. NHF was delivered with three different high flow nasal cannula models provided by the same manufacturer, and CPAP was delivered with a sealed nasal mask. Tidal breathing through each replica was imposed using a lung simulator, and airway pressure at the trachea was recorded over time. For expired gas washout measurements, carbon dioxide was injected at the lung simulator, and end-tidal carbon dioxide (EtCO2) was measured at the trachea. Changes in EtCO2 compared to baseline values (no intervention) were assessed. Results NHF therapy generated an average positive end-expiratory pressure (PEEP) of 5.17 ± 2.09 cmH2O (mean ± SD, n = 10), similar to PEEP of 4.95 ± 0.03 cmH2O generated by nominally 5 cmH2O CPAP. Variation in tracheal pressure was higher between airway replicas for NHF compared to CPAP. EtCO2 decreased from baseline during administration of NHF, whereas it increased during CPAP. No statistical difference in tracheal pressure nor EtCO2 was found between the three high flow nasal cannulas. Conclusion In child airway replicas, NHF at 20 L/min generated average PEEP similar to CPAP at 5 cm H2O. Variation in tracheal pressure was higher between airway replicas for NHF than for CPAP. The delivery of NHF yielded expired gas washout, whereas CPAP impeded expired gas washout due to the increased dead space of the sealed mask.

Abstract The COVID-19 pandemic caused by SARS-CoV-2 has infected millions worldwide, therefore there is an urgent need to increase our diagnostic capacity to identify infected cases. Although RT-qPCR remains the gold standard for SARS-CoV-2 detection, this method requires specialised equipment in a diagnostic laboratory and has a long turn-around time to process the samples. To address this, several groups have recently reported the development of loop-mediated isothermal amplification (LAMP) as a simple, low cost and rapid method for SARS-CoV-2 detection. Herein we present a comparative analysis of three LAMP-based assays that target different regions of the SARS-CoV-2: ORF1ab RdRP, ORF1ab nsp3 and Gene N. We perform a detailed assessment of their sensitivity, kinetics and false positive rates for SARS-CoV-2 diagnostics in LAMP or RT-LAMP reactions, using colorimetric or fluorescent detection. Our results independently validate that all three assays can detect SARS-CoV-2 in 30 min, with robust accuracy at detecting as little as 1000 RNA copies and the results can be visualised simply by color changes. Incorporation of RT-LAMP with fluorescent detection further increases the detection sensitivity to as little as 100 RNA copies. We also note the shortcomings of some LAMP-based assays, including variable results with shorter reaction time or lower load of SARS-CoV-2, and false positive results in some experimental conditions and clinical saliva samples. Overall for RT-LAMP detection, the ORF1ab RdRP and ORF1ab nsp3 assays have faster kinetics for detection but varying degrees of false positives detection, whereas the Gene N assay exhibits no false positives in 30 min reaction time, which highlights the importance of optimal primer design to minimise false-positives in RT-LAMP. This study provides validation of the performance of LAMP-based assays as a rapid, highly sensitive detection method for SARS-CoV-2, which have important implications in development of point-of-care diagnostics for SARS-CoV-2.