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We outline progress in the development of novel perforated X-ray attenuators for fine-pitch (50{400 mm) spectro- scopic X-ray detectors composed of hundreds or thousands of pixels. Simple attenuators made of solid slabs of material drastically suppress the low energy signal which can reduce the scientific value of observations. By contrast, perforated attenuators can be designed to suit the shape and intensity of the expected incident spectrum, thus allowing a wider spectral range to be reliably measured. This is achieved by fabricating regions of different thicknesses on spatial scales smaller than the pixels and replicated over grids of hundreds or thousands of pixels. Perforated attenuators can enhance the scientific value of observations because they can enable multiple physical processes that dominate different regions of the X-ray spectrum to be observed simultaneously, e.g. lower energy thermal and higher energy non-thermal processes in solar flares. For this reason, a perforated attenuator will be own onboard the FOXSI-4 sounding rocket as part of a solar are campaign. In this paper we describe specific designs and fabrication methods and demonstrate the concept by measuring the transmission profiles of a number of prototypes. We conclude that such designs can be reliably produced with current fabrication techniques including microlithography and macroporous silicon technology, and can achieve transmission profiles desirable for solar are observations. Work described in this paper is the subject of pending patents.

The Liza Phase 1 development project features the Liza Destiny Floating Production, Storage, and Offloading (FPSO) vessel, moored 190 km offshore Guyana in 1,743 m (5,719 ft) of water, and four subsea drill centers supporting 17 wells. Not only was this a Greenfield development that required an integrated team to prepare for Operations; it was also located in a New Frontier that required development of logistics and marine infrastructure to support multi drillship and FPSO operations in challenging metocean and tidal conditions. In addition, early operations and production testing was further complicated by the COVID-19 pandemic and safety protocols put in place to keep the workforce safe.Three aspects of achieving First Oil are discussed, highlighting challenges and lessons learned:Managing subsea completions, well cleanup, and flow assurance while drilling was ongoing Enabling accurate data collection from Multi-Phase Flow Meters (MPFMs) and downhole pressure gauges, which was critical to developing foundational understanding of well performance for reservoir characterization and management Establishing an integrated asset team and workflows to ensure life cycle value capture by managing complex marine operations, commissioning, and surveillance while meeting stringent COVID-19 protocolsLessons learned from Destiny Operations will be incorporated into future projects, including a robust digital strategy centered on a fiber ring to shore, which will enable high-speed communications for future FPSOs, and an onshore integrated operations control center for improvement of long-term operations. Early understanding of reservoir connectivity and performance from data collection will continue to inform the reservoir management strategy so as to maximize asset value for the country of Guyana.

It is unclear whether survivors of stroke or transient ischemic attack (TIA) routinely receive, and understand, education about secondary prevention medications.To investigate whether survivors of stroke/TIA understand explanations about their prescribed prevention medications and associations with medication adherence, control of risk factors, and unmet needs.A survey was administered among survivors of stroke/TIA (random sample N = 1500) from the Australian Stroke Clinical Registry (Victoria and Queensland, 2016). Participants reported whether they understood explanations about each prescribed medication, as well as their unmet needs, perceived control of risk factors, and 30-day medication adherence. Linked pharmacy claims data were also used to determine medication adherence in the previous two years (proportion of days covered ≥80%). Outcomes were analyzed using multivariable logistic regression or multivariable negative binomial regression for frequency of unmet needs.Overall, 630/1455 eligible survivors completed the survey at ≈2.5 years post-admission (median age 69 years; 37% female). Most participants reported using prevention medications (76% antihypertensive; 84% antithrombotic; 76% lipid-lowering) but only 66-75% reported they understood explanations about their medication (75% antihypertensive; 66% antithrombotic; 74% lipid-lowering). Participants who understood explanations about their medication more often reported 30-day adherence for antihypertensive (adjusted odds ratios [aOR]: 1.96; 95% CI: 1.20-3.19), antithrombotic (aOR: 2.03; 95% CI: 1.31-3.14) and lipid-lowering medications (aOR: 1.73; 95% CI: 1.08-2.76). Similar associations were observed for antihypertensive and antithrombotic medications when pharmacy claims data were used to infer 2-year medication adherence. Understanding explanations about medications was also associated with perceived control of risk factors (hypertension: aOR: 11.08; 95% CI: 6.04-20.34; cholesterol aOR: 8.26; 95% CI: 4.72-14.47) and up to 33% fewer unmet needs related to secondary prevention.Expanded efforts are needed to improve the delivery of information about prevention medications to promote medication adherence, control of risk factors, and potentially prevent unmet needs following stroke/TIA.

Closed-loop insulin delivery systems have the potential to address suboptimal glucose control in children and adolescents with type 1 diabetes. We compared safety and efficacy of the Cambridge hybrid closed-loop algorithm with usual care over 6 months in this population.In a multicentre, multinational, parallel randomised controlled trial, participants aged 6-18 years using insulin pump therapy were recruited at seven UK and five US paediatric diabetes centres. Key inclusion criteria were diagnosis of type 1 diabetes for at least 12 months, insulin pump therapy for at least 3 months, and screening HbAOf 147 people initially screened, 133 participants (mean age 13·0 years [SD 2·8]; 57% female, 43% male) were randomly assigned to either the closed-loop group (n=65) or the control group (n=68). Mean baseline HbAThe Cambridge hybrid closed-loop algorithm had an acceptable safety profile, and improved glycaemic control in children and adolescents with type 1 diabetes. To ensure optimal efficacy of the closed-loop system, usage needs to be consistently high, as demonstrated with CamAPS FX.National Institute of Diabetes and Digestive and Kidney Diseases.

To investigate cerebrovascular event (CVE) denials reported by registered patients to the Australian Stroke Clinical Registry, and to examine the factors associated with CVE denial.CVE denials reported from January 1, 2017 to June 30, 2018 were followed up with hospitals to verify their discharge diagnosis. CVE denials were compared with all non-CVE denial registrants and a 5% random sub-sample of non-CVE deniers according to patient and clinical characteristics, quality of care indicators and health outcomes. Multilevel, multivariable logistic regression models were used. Factors explored were age, sex, stroke severity, type of stroke, treatment in a stroke unit, length of stay and discharge destination. Level was defined as hospital.Overall, 339/23,830 (2%) CVE denials were reported during the 18-month period. Hospitals confirmed 117 (61%) of CVE denials as a verified diagnosis of stroke or transient ischaemic attack (TIA). Compared to non-CVE deniers, CVE deniers were younger, had a shorter median length of stay (four days versus one day) and were more likely to be diagnosed with a TIA (64%) compared to the other types of stroke (11% intracerebral haemorrhage; 20% ischaemic; 5% undetermined).Very few patients denied their CVE, with the majority of denials subsequently confirmed as eligible for registry inclusion. Diagnosis of a TIA and shorter length of stay were associated with CVE denial. These findings provide evidence that very few cases are incorrectly entered into a national registry, and highlight the characteristics of those unlikely to accept their clinical diagnosis where further education of diagnosis may be needed.

The etiopathogenesis of chronic otitis media epitympanalis/cholesteatoma and its proliferative destructive course with possible complications such as destruction of bony structures with hearing loss, vestibular dysfunction, facial nerve paralysis and intracranial complications are still unexplained. Surgery is still the way to go. New studies are increasingly looking at the innate immune system.Our studies were carried out in a mouse model in WT mice and immundeficient KO-mice, as well as in cholesteatoma and healthy ear canal skin and middle ear tissue, which was removed during ear surgery. The expression analyses were carried out at the gene and protein level using TNF as the major target for therapy evaluation. By means of TUNEL staining and immunohistochemistry the level of apoptosis was evaluated.The uncontrolled undirected cholesteatoma growth shows an immunomodulatory profile with up and down-regulation of various gene networks, especially those involved in TNF downstream and upstream signaling pathways. TNF in cholesteatoma is modulated both inflammatorily and apoptotically and therefore is suitable as a possible therapeutic approach in various models.Cholesteatoma might be immunomodulatory regulated.Die Ätiopathogenese der chronischen Otitis media epitympanalis bzw. des Cholesteatoms und ihr proliferierender destruierender Verlauf mit möglichen Komplikationen wie Destruktion der knöchernen Strukturen mit Hörverlust, vestibulärer Dysfunktion, Gesichtsnervenlähmung und intrakraniellen Komplikationen sind immer noch ungeklärt. Die Therapie der Wahl ist nach wie vor die operative Sanierung. Aktuelle Studien befassen sich immer mehr mit dem angeborenen Immunsystem.Unsere Untersuchungen erfolgten im Mausmodell an WT-Mäusen und immundefizienten KO-Mäusen sowie an Gewebeproben vom Cholesteatom, gesunder Gehörgangshaut und gesunder Mittelohrschleimhaut, die während sanierenden Ohroperationen entnommen wurden. Die Expressionsanalysen erfolgten auf Gen- und Proteinebene mit TNF als Major Target zur Therapieevaluation. Mittels TUNEL-Färbung und Immunhistochemie an Kryoschnitten wurde die Apoptose-Rate durch TNF bestimmt.Das ungerichtet-expansive Cholesteatomwachstum zeigt ein immunmodulatorisches Profil mit Hoch- und Runterregulation von verschiedenen Gen-Netzwerken, vor allem Molekülen der TNF-Down- und -Upstream-Signalwege. Dabei wird TNF sowohl inflammatorisch als auch apoptotisch moduliert und eignet sich als möglicher Therapieansatz in verschiedenen Modellen.Es gibt Hinweise auf eine immunmodulatorische Regulation im Cholesteatom.

Inflammation is a complex biological response to harmful stimuli including infection, tissue damage, and toxins. Thus, it is not surprising that cochlear damage by noise includes an inflammatory component. One mechanism by which inflammation is generated by tissue damage is the activation of damage-associated molecular patterns (DAMPs). Many of the cellular receptors for DAMPS, including Toll-like receptors, NOD-like receptors, and DNA receptors, are also receptors for pathogens, and function in the innate immune system. DAMP receptors are known to be expressed by cochlear cells, and binding of molecules released by damaged cells to these receptors result in the activation of cell stress pathways. This leads to the generation of pro-inflammatory cytokines and chemokines that recruit pro-inflammatory leukocytes. Extensive evidence indicates pro-inflammatory cytokines including TNF alpha and interleukin 1 beta, and chemokines including CCL2, are induced in the cochlea after noise exposure. The recruitment of macrophages into the cochlea has also been demonstrated. These provide substrates for noise damage to be enhanced by inflammation. Evidence is provided by the effectiveness of anti-inflammatory drugs in ameliorating noise-induced hearing loss. Involvement of inflammation provides a wide variety of additional anti-inflammatory and pro-resolution agents as potential pharmacological interventions in noise-induced hearing loss.

A major component of slowly reversible hearing loss which develops with sustained exposure to noise has been attributed to release of ATP in the cochlea activating P2X(2) receptor (P2X(2)R) type ATP-gated ion channels. This purinergic humoral adaptation is thought to enable the highly sensitive hearing organ to maintain function with loud sound, protecting the ear from acoustic overstimulation. In the study that established this hearing adaptation mechanism as reported by Housley et al. (Proc Natl Acad Sci U S A 110:7494–7499, 2013), the activation kinetics were determined in mice from auditory brainstem response (ABR) threshold shifts with sustained noise presentation at time points beyond 10 min. The present study was designed to achieve finer resolution of the onset kinetics of purinergic hearing adaptation, and included the use of cubic (2f(1)–f(2)) distortion product otoacoustic emissions (DPOAEs) to probe whether the active mechanical outer hair cell ‘cochlear amplifier’ contributed to this process. We show that the ABR and DPOAE threshold shifts were largely complete within the first 7.5 min of moderate broadband noise (85 dB SPL) in wildtype C57Bl/6J mice. The ABR and DPOAE adaptation rates were both best fitted by a single exponential function with ~ 3 min time constants. ABR and DPOAE threshold shifts with this noise were minimal in mice null for the P2rx2 gene encoding the P2X(2)R. The findings demonstrate a considerably faster purinergic hearing adaptation to noise than previously appreciated. Moreover, they strongly implicate the outer hair cell as the site of action, as the DPOAEs stem from active cochlear electromotility. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11302-019-09648-3) contains supplementary material, which is available to authorized users.

Novel metabolomic profiling techniques combined with traditional biomarkers provide knowledge of mechanisms underlying metabolic health. Twin studies describe the impact of genes and environment on variation in traits. This study aims to identify relationships between traditional markers of metabolic health and the plasma metabolomic profile using a twin modeling approach and determine whether covariation is caused by shared genetic and environmental factors. Using a classic twin design, this study examined covariation between anthropometric, clinical chemistry, and metabolomic profiles. Cholesky decomposition modeling was used to determine the genetic and environmental path coefficients through successive anthropometric and clinical chemistry traits onto metabolomic derived metabolites. This study shows that WC, TAG, and a metabolomic signature composed of 7 metabolites are inter-related, and that covariation can be attributed to common genetic, shared and unique environmental factors as well as unique environmental factors specific to the metabolite. This quantitative modeling connecting the traditional anthropometry and clinical chemistry traits with the more recent and potentially more sensitive metabolomic profile approach may provide further insight on the pleiotropic genes or modifiable environmental factors influencing variation in metabolic health.

Defensins are an extensive family of host defense peptides found ubiquitously across plant and animal species. In addition to protecting against infection by pathogenic microorganisms, some defensi...

Placozoa are a morphologically simplistic group of marine animals found globally in tropical and subtropical environments. They consist of two named species, Trichoplax adhaerens and more recently Hoilungia hongkongensis, both with roughly six morphologically distinct cell types. With a sequenced genome, a limited number of cell types, and a simple flattened morphology, Trichoplax is an ideal model organism from which to explore the biology of an animal with a cellular complexity analagous to that of the earliest animals. Using a new approach for identification of gene expression patterns, this research looks at the relationship of Chordin/TgfΒ signaling and the axial patterning system of Placozoa. Our results suggest that placozoans have an oral–aboral axis similar to cnidarians and that the parahoxozoan ancestor (common ancestor of Placozoa and Cnidaria) was likely radially symmetric.

We discuss the safety and controversy regarding the administration of glucose before thiamine with regards to precipitation of Wernicke’s Encephalopathy in the severely malnourished and alcoholic patient population. Herein we review clinical features, pathophysiology and the relevant literature to provide an evidenced-based recommendation that thiamine replacement should not delay glucose administration acutely in the malnourished patient population.

Graphics workloads make highly dynamic use of resources such as execution units (EUs), and thus can benefit from fast, fine-grain dynamic voltage and frequency scaling (DVFS) and retentive sleep. This paper presents a 14-nm graphics processing unit (GPU) prototype with modified EUs which include an integrated voltage regulator (IVR). The IVR enables energy-efficient EU turbo operation, data retention, and $V_{\text {MIN}}$ optimization per EU. Silicon measurements show that IVR-enabled EU turbo operation offers up to 32% (average 29%) energy reduction at constant performance.

Soulet (2018) asserts that the calculation of the 14C reservoir age for the geochronology of the Black Sea sediments suffers from a fundamental flaw. He contends that Yanchilina et al. (2017) obtained reservoir ages by first sorting the δ18O and δ13C values of the mollusks as a function of their corresponding 14C age before aligning the mollusk isotope curves to those of the nearby Sofular Cave. Sorting by 14C age would lead to an incorrect calendar age for each δ18O and δ13C measurement because it does not take into account changing reservoir ages. We reply here that this sorting by 14C age was not the procedure taken. The radiocarbon reservoir ages were derived after tuning the δ18O and δ13C composition of the mollusks, sorted by their δ18O, δ13C, radiocarbon age and stratigraphic location in each core, to the δ18O and δ13C composition of the U/Th dated Sofular Cave stalagmites as a function of calendar age, shown to reflect Black Sea surface water δ18O and δ13C composition. After the calendar age was derived for each mollusk, it was then converted to a corresponding Northern Hemisphere atmospheric 14C age using Reimer et al. (2009). The 14C reservoir age was subsequently calculated from the difference between the measured 14C age of the mollusks and the calculated Northern Hemisphere atmospheric 14C age of the mollusks, R(t) = 14Cshell(t) − 14Catm(t) (e.g., Ryan, 2007; Kwiecien et al., 2009; Jull et al., 2013; Philippsen, 2013; Soulet, 2015; Soulet et al., 2016). The Reimer et al. (2009) calibration used in our original study differs

Background Older aged adults and those with pre-existing conditions are at highest risk for severe COVID-19 associated outcomes. Methods Using a large dataset of genome-wide RNA-seq profiles derived from human dermal fibroblasts (GSE113957) we investigated whether age affects the expression of pattern recognition receptor (PRR) genes and ACE2, the receptor for SARS-CoV-2. Results Extremes of age are associated with increased expression of selected PRR genes, ACE2 and four genes that encode proteins that have been shown to interact with SAR2-CoV-2 proteins. Conclusions Assessment of PRR expression might provide a strategy for stratifying the risk of severe COVID-19 disease at both the individual and population levels.

Regeneration is one of the most fascinating and yet least understood processes of animals. Echinoderms, one of the closest related invertebrate groups to humans, can contribute to our understanding of the genetic basis of regenerative processes. Amongst echinoderms, sea cucumbers have the ability to grow back most of their body parts following injury, including the intestine and nervous tissue. The cellular and molecular events underlying these abilities in sea cucumbers have been most extensively studied in the species Holothuria glaberrima. However, research into the regenerative abilities of this species have been impeded due to the lack of adequate genomic resources. Here, we report the first draft genome assembly of H. glaberrima and demonstrate its value for future genetic studies. Using only short sequencing reads, we assembled the genome into 2,960,762 scaffolds totaling 1.5 gigabases with an N50 of 15 kilobases. Our BUSCO assessment of the genome resulted in 882 (90.2%) complete and partial genes from 978 genes queried. We incorporated transcriptomic data from several different life history stages to annotate 41,076 genes in our final assembly. To demonstrate the usefulness of the genome, we fully annotated the melanotransferrin (Mtf) gene family, which have a potential role in regeneration of the sea cucumber intestine. Using these same data, we extracted the mitochondrial genome, which showed high conservation to that of other holothuroids. Thus, these data will be a critical resource for ongoing studies of regeneration and other studies in sea cucumbers.

Purpose To examine the potential benefit of reevaluation of original slides and p16 immunohistochemistry (IHC) of tonsillectomy specimens for primary tumor identification in cases of human papillomavirus (HPV) positive squamous cell carcinoma (SCC) of the head and neck of unknown primary. Materials and methods Through a retrospective review, we identified all patients 18 or older who presented at our institution from 2003 to 2015 with histologically confirmed HPV-positive SCC in a cervical lymph node with unidentified primary tumor after initial workup. For patients for whom specimens were available, an expert head and neck pathologist re-reviewed original hematoxylin and eosin (H&E) slides to confirm absence of tumor and performed p16 IHC and deep sectioning of tissue blocks to identify potential tumor foci. Results Among 735 patient records assessed, 80 were HPV-positive SCC with unknown primary, 28 of which did not have a primary tumor identified, and 20 with original specimens available. Upon re-review of 103 original H&E slides, invasive SCC was identified for 2 patients. Deep sectioning and p16 IHC did not identify additional primary tumors. Conclusion Re-review of original slides by an expert head and neck pathologist, but not p16 staining or deeper H&E sections, was able to identify additional tumors.

The Spectrometer/Telescope for Imaging X-rays (STIX) is the HXR instrument onboard Solar Orbiter designed to observe solar flares over a broad range of flare sizes, between 4-150 keV. We report the first STIX observations of microflares recorded during the instrument commissioning phase in order to investigate the STIX performance at its detection limit. This first result paper focuses on the temporal and spectral evolution of STIX microflares occuring in the AR12765 in June 2020, and compares the STIX measurements with GOES/XRS, SDO/AIA, and Hinode/XRT. For the observed microflares of the GOES A and B class, the STIX peak time at lowest energies is located in the impulsive phase of the flares, well before the GOES peak time. Such a behavior can either be explained by the higher sensitivity of STIX to higher temperatures compared to GOES, or due to the existence of a nonthermal component reaching down to low energies. The interpretation is inconclusive due to limited counting statistics for all but the largest flare in our sample. For this largest flare, the low-energy peak time is clearly due to thermal emission, and the nonthermal component seen at higher energies occurs even earlier. This suggests that the classic thermal explanation might also be favored for the majority of the smaller flares. In combination with EUV and SXR observations, STIX corroborates earlier findings that an isothermal assumption is of limited validity. Future diagnostic efforts should focus on multi-wavelength studies to derive differential emission measure distributions over a wide range of temperatures to accurately describe the energetics of solar flares. Commissioning observations confirm that STIX is working as designed. As a rule of thumb, STIX detects flares as small as the GOES A class. For flares above the GOES B class, detailed spectral and imaging analyses can be performed., Comment: 19 pages, 11 figures

The Agriculture Conservation Planning Framework (ACPF) applies high‐spatial resolution soils and topographic data, now available for many areas of the United States, to precisely locate opportunities for the placement of conservation practices in agricultural watersheds. Application of the ACPF, developed in midwestern landscapes, to watersheds in the eastern United States represents both opportunity and challenge to conservation planning. Based on experience in applying ACPF to eight watersheds in the eastern United States, from Vermont to North Carolina, we assess the toolbox's application in the eastern United States through the lens of strengths, weaknesses, opportunities, and threats (SWOT) analysis framework. We see a great future for the ACPF, but its adoption and utility require interaction with scientists and conservation planners familiar with the region to avoid misapplication and ensure appropriate adaptation and interpretation.

Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine is immunogenic and protects against COVID-19. However, data on vaccine immunogenicity are needed for the 40 million people living with HIV (PWH), who may have less functional immunity and more associated co-morbidities than the general population. Methods: Between the 5th and 24th November 2020, 54 adults with HIV, aged 18-55 years, were enrolled into a single arm open label vaccination study within the protocol of the larger phase 2/3 COV002 trial. A prime-boost regimen of ChAdOx1 nCoV-19, with two doses (5 × 1010 vp) was given 4-6 weeks apart. All participants were on antiretroviral therapy (ART) with undetectable plasma HIV viral loads and CD4+ T cell counts >350 cells/µl at enrolment. Data were captured on adverse events. Humoral responses were measured by anti-spike IgG ELISA and antibody-mediated live virus neutralisation. Cell-mediated immune responses were measured by ex-vivo interferon-γ enzyme-linked immunospot assay (ELISpot) and T cell proliferation. All outcomes were compared with a HIV uninfected group from the main COV002 study. Findings: 54 participants with HIV (median age 42.5 years (IQR 37.2-49.8)) received two doses of ChAdOx1 nCoV-19. Median CD4+ T cell count at enrolment was 694 cells/µl (IQR 562-864). Results are reported for 56 days of follow-up. Local and systemic reactions occurring during the first 7 days after prime vaccination included pain at the injection site (49%), fatigue (47%), headache (47%), malaise (34%), chills (23%), and muscle or (36%) joint pain (9%), the frequencies of which were similar to the HIV-negative participants. There were no serious adverse events. Anti-spike IgG responses by ELISA peaked at Day 42 (median 1440 ELISA units, IQR 704-2728) and were sustained out to Day 56. There was no correlation with CD4+ T cell count or age and the magnitude of the anti-spike IgG response at Day 56 (P>0.05 for both). ELISpot and T cell proliferative responses peaked between Day 14 and 28 after prime and were sustained through to Day 56. When compared to participants without HIV there was no statistical difference in magnitude or persistence of SARS-CoV-2 spike-specific humoral or cellular responses (P>0.05 for all analyses). Interpretation: In this study of PWH, vaccination with ChAdOx1 nCoV-19 was well tolerated and there was no difference in humoral and cell-mediated immune responses compared to an adult cohort without HIV who received the same vaccination regime. Trial Registration: Trial Registration number is NCT04400838. Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Declaration of Interest: Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19 (AZD1222). AstraZeneca reviewed the data from the study and the final manuscript before 474 submission, but the authors retained editorial control. SCG is cofounder of Vaccitech (a collaborator in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine. TL is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was consultant to Vaccitech. PMF is a consultant to Vaccitech. AJP is Chair of the UK Department of Health and Social Care’s JCVI, but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts (SAGE). AVSH is a cofounder of and consultant to Vaccitech and is named as an inventor on a patent covering design and use of ChAdOx1-vectored vaccines (PCT/GB2012/000467). Ethical Approval: Written informed consent was obtained from all participants, and the trial was done in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. This study was approved in the UK by the Medicines and Healthcare products Regulatory Agency (reference 21584/0424/001-0001) and the South Central Berkshire Research Ethics Committee (reference 20/SC/0145). Vaccine use was authorised by Genetically Modified Organisms Safety Committees at each participating site.

The Focusing Optics X-ray Solar Imager (FOXSI) sounding rocket payload achieved its third successful flight on September 7, 2018. FOXSI uses glancing-incidence Wolter-I mirrors combined with fine-pitch Si and CdTe detectors to perform direct solar Hard X-Ray (HXR) imaging spectroscopy. For FOXSI’s latest flight, several upgrades were made to the instrument, including updating the optics and detectors as well as adding new honeycomb type collimators to reduce Ghost rays background. We provide an overview of these updates as well as a discussion of their measured performance.

We study the nature of energy release and transfer for two sub-A class solar microflares observed during the second flight of the Focusing Optics X-ray Solar Imager (FOXSI-2) sounding rocket experiment on 2014 December 11. FOXSI is the first solar-dedicated instrument to utilize focusing optics to image the Sun in the hard X-ray (HXR) regime, sensitive to the energy range 4-20 keV. Through spectral analysis of the two microflares using an optically thin isothermal plasma model, we find evidence for plasma heated to temperatures of ~10 MK and emissions measures down to ~$10^{44}~$cm$^{-3}$. Though nonthermal emission was not detected for the FOXSI-2 microflares, a study of the parameter space for possible hidden nonthermal components shows that there could be enough energy in nonthermal electrons to account for the thermal energy in microflare 1, indicating that this flare is plausibly consistent with the standard thick-target model. With a solar-optimized design and improvements in HXR focusing optics, FOXSI-2 offers approximately five times greater sensitivity at 10 keV than the Nuclear Spectroscopic Telescope Array (NuSTAR) for typical microflare observations and allows for the first direct imaging spectroscopy of solar HXRs with an angular resolution at scales relevant for microflares. Harnessing these improved capabilities to study the evolution of small-scale events, we find evidence for spatial and temporal complexity during a sub-A class flare. These studies in combination with contemporanous observations by the Atmospheric Imaging Assembly onboard the Solar Dynamics Observatory (SDO/AIA) indicate that the evolution of these small microflares is more similar to that of large flares than to the single burst of energy expected for a nanoflare., 20 pages, 16 figures, 2 tables; Submitted to ApJ

ObjectivePatient-reported outcomes (PROs) provide self-reported patient assessments of their quality of life, daily functioning, and symptom severity after experiencing an illness and having contact with the health system. Feeding back summarised PROs data, aggregated at the health-service level, to healthcare professionals may inform clinical practice and quality improvement efforts. However, little is known about the best methods for providing these summarised data in a way that is meaningful for this audience. Therefore, the aim of this scoping review was to summarise the emerging approaches to PROs data for ‘service-level’ feedback to healthcare professionals.SettingHealthcare professionals receiving PROs data feedback at the health-service level.Data sourcesDatabases selected for the search were Embase, Ovid Medline, Scopus, Web of Science and targeted web searching. The main search terms included: ‘patient-reported outcome measures’, ‘patient-reported outcomes’, ‘patient-centred care’, ‘value-based care’, ‘quality improvement’ and ‘feedback’. Studies included were those that were published in English between January 2009 and June 2019.Primary and secondary outcome measuresData were extracted on the feedback methods of PROs to patients or healthcare providers. A standardised template was used to extract information from included documents and academic publications. Risk of bias was assessed using Joanna Briggs Institute Levels of Evidence for Effectiveness.ResultsOverall, 3480 articles were identified after de-duplication. Of these, 19 academic publications and 22 documents from the grey literature were included in the final review. Guiding principles for data display methods and graphical formats were identified. Seven major factors that may influence PRO data interpretation and use by healthcare professionals were also identified.ConclusionWhile a single best format or approach to feedback PROs data to healthcare professionals was not identified, numerous guiding principles emerged to inform the field.

IMPORTANCE: Tinnitus affects at least 16 million US adults, but its pathophysiology is complicated, and treatment options remain limited. A heritable component has been identified in family and twin studies; however, no large-scale genome-wide association studies (GWAS) have been accomplished. OBJECTIVE: To identify genetic risk loci associated with tinnitus, determine genetic correlations, and infer possible relationships of tinnitus with hearing loss and neuropsychiatric disorders and traits. DESIGN, SETTING, AND PARTICIPANTS: A GWAS of self-reported tinnitus was performed in the UK Biobank (UKB) cohort using a linear mixed-model method implemented in BOLT-LMM (linear mixed model). Replication of significant findings was sought in the nonoverlapping US Million Veteran Program (MVP) cohort. A total of 172 995 UKB (discovery) and 260 832 MVP (replication) participants of European ancestry with self-report regarding tinnitus and hearing loss underwent genomic analysis. Linkage-disequilibrium score regression and mendelian randomization were performed between tinnitus and hearing loss and neuropsychiatric disorders. Data from the UKB were acquired and analyzed from September 24, 2018, to December 13, 2019. Data acquisition for the MVP cohort was completed July 22, 2019. Data analysis for both cohorts was completed on February 11, 2020. MAIN OUTCOMES AND MEASURES: Estimates of single nucleotide variation (SNV)–based heritability for tinnitus, identification of genetic risk loci and genes, functional mapping, and replication were performed. Genetic association and inferred causality of tinnitus compared with hearing loss and neuropsychiatric disorders and traits were analyzed. RESULTS: Of 172 995 UKB participants (53.7% female; mean [SD], 58.0 [8.2] years), 155 395 unrelated participants underwent SNV-based heritability analyses across a range of tinnitus phenotype definitions that explained approximately 6% of the heritability. The GWAS based on the most heritable model in the full UKB cohort identified 6 genome-wide significant loci and 27 genes in gene-based analyses, with replication of 3 of 6 loci and 8 of 27 genes in 260 832 MVP cohort participants (92.8% men; mean [SD] age, 63.8 [13.2] years). Mendelian randomization indicated that major depressive disorder had a permissive effect (β = 0.133; P = .003) and years of education had a protective effect (β = −0.322, P =

Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.

Otitis media, the most common disease of childhood, is characterized by extensive changes in the morphology of the middle ear cavity. This includes hyperplasia of the mucosa that lines the tympanic cavity, from a simple monolayer of squamous epithelium into a greatly thickened, respiratory-type mucosa. The processes that control this response, which is critical to otitis media pathogenesis and recovery, are incompletely understood. Given the central role of protein phosphorylation in most intracellular processes, including cell proliferation and differentiation, we screened a library of kinase inhibitors targeting members of all the major families in the kinome for their ability to influence the growth of middle ear mucosal explants in vitro. Of the 160 inhibitors, 30 were found to inhibit mucosal growth, while two inhibitors enhanced tissue proliferation. The results suggest that the regulation of infection-mediated tissue growth in the ME mucosa involves multiple cellular processes that span the kinome. While some of the pathways and processes identified have been previously implicated in mucosa hyperplasia others are novel. The results were used to generate a global model of growth regulation by kinase pathways. The potential for therapeutic applications of the results are discussed.

Older aged adults and those with pre-existing conditions are at highest risk for severe COVID-19 associated outcomes. Using a large dataset of genome-wide RNA-seq profiles derived from human dermal fibroblasts (GSE113957) we investigated whether age affects the expression of pattern recognition receptor (PRR) genes and ACE2, the receptor for SARS-CoV-2. Older age was associated with increased expression of PRR genes, ACE2 and four genes that encode proteins that have been shown to interact with SAR2-CoV-2 proteins. Assessment of PRR expression might provide a strategy for stratifying the risk of severe COVID-19 disease at both the individual and population levels.

BACKGROUND Early applications of metabolomics in nutrition and health research identified associations between dietary patterns and metabolomic profiles. Twin studies show that diet-related phenotypes and diet-associated metabolites are influenced by genes. However, studies have not examined whether diet-metabolite associations are explained by genetic or environmental factors and whether these associations are reproducible over multiple time points. OBJECTIVE This research aims to examine the genetic and environmental factors influencing covariation in diet-metabolite associations that are reproducible over time in healthy twins. METHODS The UCD Twin Study is a semi-longitudinal classic twin study that collected repeated dietary, anthropometric, and urinary data over 2 months. Correlation analysis identified associations between diet quality measured using the Healthy Eating Index (HEI) and urinary metabolomic profiles at 3 time points. Diet-associated metabolites were examined using linear regression to identify those significantly influenced by familial factors between twins and those significantly influenced by unique factors. Cholesky decomposition modeling quantified the genetic and environmental path coefficients through associated dietary components onto the metabolites. RESULTS The HEI was associated with 14 urinary metabolites across 3 metabolomic profiles (r: ±0.15-0.49). For 8 diet-metabolite associations, genetic or shared environmental factors influencing HEI component scores significantly influenced variation in metabolites (β: 0.40-0.52). A significant relation was observed between dietary intakes of whole grain and acetoacetate (β: -0.50, P

OBJECTIVE Female medical students and surgical trainees are more likely to lack confidence in their clinical abilities than their male peers despite equal or superior performance. This study aims to examine the role of gender in medical student experience and confidence performing technical skills in surgical clerkship. DESIGN This was a single-center survey study conducted over 2 academic years (2016-2018). Students were surveyed on their experience and confidence performing a set of 9 technical skills during surgical clerkship and to identify skill-specific barriers to learning. SETTING This study was performed at Western University, London, Ontario, Canada. PARTICIPANTS All third-year medical students were invited to participate. RESULTS A total of 253 students participated yielding a survey response rate of 74.0%. Both male and female students reported similar levels of preclerkship interest in a surgical career, enjoyment in performing technical skills, confidence in ability to learn surgical skills and pursuit of available learning opportunities. At the conclusion of their surgical rotations, female students reported less experience and confidence performing technical skills compared to their male colleagues. Female students were more likely to cite an insufficient number of learning opportunities from consultant and resident teachers, time constraints, and lack of confidence as barriers to the achievement of technical proficiency. CONCLUSIONS Female gender was associated with less procedural experience and inferior confidence performing procedural skills. It is important for educators to be aware of this gender disparity and to actively promote equitable learning opportunities for female trainees.

Single-cell transcriptomics was used to profile cells of the normal murine middle ear. Clustering analysis of 6770 transcriptomes identified 17 cell clusters corresponding to distinct cell types: five epithelial, three stromal, three lymphocyte, two monocyte, two endothelial, one pericyte and one melanocyte cluster. Within some clusters, cell subtypes were identified. While many corresponded to those cell types known from prior studies, several novel types or subtypes were noted. The results indicate unexpected cellular diversity within the resting middle ear mucosa. The resolution of uncomplicated, acute, otitis media is too rapid for cognate immunity to play a major role. Thus innate immunity is likely responsible for normal recovery from middle ear infection. The need for rapid response to pathogens suggests that innate immune genes may be constitutively expressed by middle ear cells. We therefore assessed expression of innate immune genes across all cell types, to evaluate potential for rapid responses to middle ear infection. Resident monocytes/macrophages expressed the most such genes, including pathogen receptors, cytokines, chemokines and chemokine receptors. Other cell types displayed distinct innate immune gene profiles. Epithelial cells preferentially expressed pathogen receptors, bactericidal peptides and mucins. Stromal and endothelial cells expressed pathogen receptors. Pericytes expressed pro-inflammatory cytokines. Lymphocytes expressed chemokine receptors and antimicrobials. The results suggest that tissue monocytes, including macrophages, are the master regulators of the immediate middle ear response to infection, but that virtually all cell types act in concert to mount a defense against pathogens.