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Abstract We examined three observations of green emission events (labeled as event A, B and C, respectively) associated with red sprites as captured by amateurs. In all cases, the green emissions were recorded atop of red sprite. Based on the location of causative strokes and background star fields for events A and B, their altitudes are confined between 88 and 100 km, with the maximum brightness at 90.7 and 95.5 km, respectively. Events B and C were lit up for a second time after the recurrence of a sprite element, extending their duration to approximately 1,084 ms and 732.6 ms, much longer than that (about 500 ms) for event A; the intensity of green emissions was also enhanced due to sprite recurrence. It is inferred that the recurrence of sprite elements could affect the ambient condition by further increasing electron density and strengthening the electric field for the ghost production.

Abstract Breast cancer is a prevalent and significant cause of mortality in women, and manifests as six molecular subtypes. Its further histologic classification into non-invasive ductal or lobular carcinoma (DCIS) and invasive carcinoma (ILC or IDC) underscores its heterogeneity. The ubiquitin–proteasome system plays a crucial role in breast cancer, with inhibitors targeting the 26S proteasome showing promise in clinical treatment. The Cullin-RING ubiquitin ligases, including CUL3, have direct links to breast cancer. This study focuses on CUL3 as a potential biomarker, leveraging high-throughput sequencing, gene expression profiling, experimental and data analysis tools. Through comprehensive analysis using databases like GEPIA2 and UALCAN, as well as TCGA datasets, CUL3's expression and its association with prognostic values were assessed. Additionally, the impact of CUL3 overexpression was explored in MCF-7 and MDA-MB-231 breast cancer cell lines, revealing distinct differences in molecular and phenotypic characteristics. We further profiled its expression and localization in breast cancer tissues identifying prominent differences between luminal A and TNBC tumors. Conclusively, CUL3 was found to be associated with cell cycle progression, and DNA damage response, exhibiting diverse roles depending on the tumor's molecular type. It exhibits a tendency to act as an oncogene in triple-negative tumors and as a tumor suppressor in luminal A types, suggesting a potential significance in breast cancer progression and therapeutic directions.

Abstract Background Western Montana, USA, experiences complex air pollution patterns with predominant exposure sources from summer wildfire smoke and winter wood smoke. In addition, climate change related temperatures events are becoming more extreme and expected to contribute to increases in hospital admissions for a range of health outcomes. Evaluating while accounting for these exposures (air pollution and temperature) that often occur simultaneously and may act synergistically on health is becoming more important. Methods We explored short-term exposure to air pollution on children’s respiratory health outcomes and how extreme temperature or seasonal period modify the risk of air pollution-associated healthcare events. The main outcome measure included individual-based address located respiratory-related healthcare visits for three categories: asthma, lower respiratory tract infections (LRTI), and upper respiratory tract infections (URTI) across western Montana for ages 0–17 from 2017–2020. We used a time-stratified, case-crossover analysis with distributed lag models to identify sensitive exposure windows of fine particulate matter (PM2.5) lagged from 0 (same-day) to 14 prior-days modified by temperature or season. Results For asthma, increases of 1 µg/m3 in PM2.5 exposure 7–13 days prior a healthcare visit date was associated with increased odds that were magnified during median to colder temperatures and winter periods. For LRTIs, 1 µg/m3 increases during 12 days of cumulative PM2.5 with peak exposure periods between 6–12 days before healthcare visit date was associated with elevated LRTI events, also heightened in median to colder temperatures but no seasonal effect was observed. For URTIs, 1 unit increases during 13 days of cumulative PM2.5 with peak exposure periods between 4–10 days prior event date was associated with greater risk for URTIs visits that were intensified during median to hotter temperatures and spring to summer periods. Conclusions Delayed, short-term exposure increases of PM2.5 were associated with elevated odds of all three pediatric respiratory healthcare visit categories in a sparsely population area of the inter-Rocky Mountains, USA. PM2.5 in colder temperatures tended to increase instances of asthma and LRTIs, while PM2.5 during hotter periods increased URTIs.

Twenty-eight new distribution records are reported for twenty-seven species of Paraguayan reptiles. Ten of these species are considered threatened at the national level (6 EN, 2 VU, 2 DD). Nineteen new departmental records are documented: Phrynops hilarii (Chelidae) in Misiones department; Homonota marthae, Phyllopezus przewalskii (Phyllodactylidae), Philodryas baroni and P. psammophidea (Colubridae) in Presidente Hayes department; Teius oculatus (Teiidae), Cercosaura schreibersii (Gymnophthalmidae), Ophiodes intermedius (Diploglossidae), Amphisbaena mertensii (Amphisbaenidae), Boiruna maculata and Philodryas aestiva (Colubridae) in Caazapá department; Amphisbaena alba (Amphisbaenidae) in Caaguazú and Cordillera departments; Bothrops moojeni (Viperidae), Eunectes notaeus (Boidae), Helicops leopardinus and Hydrodynastes gigas (Colubridae) in Guairá department; Apostolepis dimidiata, Atractus paraguayensis and Mussurana bicolor (Colubridae) in Itapúa department; and Epicrates crassus (Boidae) and Phalotris nigirilatus (Colubridae) in Concepción department. Significant range extensions of threatened or poorly-known species are also documented: The known distribution of the Endangered Salvator duseni (Teiidae) is extended 128.5 km to the east within Canindeyú department; that of the Vulnerable Boa occidentalis is extended 109.2 km to the southwest within Boquerón department; that of the Vulnerable Epicrates alvarezi (Boidae) is extended 136.6 km to the west within Boquerón department and 172.4 km to the northeast into Alto Paraguay department; that of Caiman yacare (Alligatoridae) is extended 132 km west within Boquerón department to the northern reaches of the Pilcomayo River. We also document an additional specimen of the rare Philodryas agassizii (Colubridae) and confirmation of the occurrence of the disputed form Phalotris “punctatus” in Paraguay.

Abstract Recent biological surveys of ancient inselbergs in southern Malawi and northern Mozambique have led to the discovery and description of many species new to science, and overlapping centres of endemism across multiple taxa. Combining these endemic taxa with data on geology and climate, we propose the ‘South East Africa Montane Archipelago’ (SEAMA) as a distinct ecoregion of global biological importance. The ecoregion encompasses 30 granitic inselbergs reaching > 1000 m above sea level, hosting the largest (Mt Mabu) and smallest (Mt Lico) mid-elevation rainforests in southern Africa, as well as biologically unique montane grasslands. Endemic taxa include 127 plants, 45 vertebrates (amphibians, reptiles, birds, mammals) and 45 invertebrate species (butterflies, freshwater crabs), and two endemic genera of plants and reptiles. Existing dated phylogenies of endemic animal lineages suggests this endemism arose from divergence events coinciding with repeated isolation of these mountains from the pan-African forests, together with the mountains’ great age and relative climatic stability. Since 2000, the SEAMA has lost 18% of its primary humid forest cover (up to 43% in some sites)—one of the highest deforestation rates in Africa. Urgently rectifying this situation, while addressing the resource needs of local communities, is a global priority for biodiversity conservation.

Abstract Despite groundbreaking advances in the additive manufacturing of polymers, metals, and ceramics, scaled and accurate production of structured carbons remains largely underdeveloped. This work reports a simple method to produce complex carbon materials with very low dimensional shrinkage from printed to carbonized state (less than 4%), using commercially available polypropylene precursors and a fused filament fabrication-based process. The control of macrostructural retention is enabled by the inclusion of fiber fillers regardless of the crosslinking degree of the polypropylene matrix, providing a significant advantage to directly control the density, porosity, and mechanical properties of 3D printed carbons. Using the same printed plastic precursors, different mechanical responses of derived carbons can be obtained, notably from stiff to highly compressible. This report harnesses the power of additive manufacturing for producing carbons with accurately controlled structure and properties, while enabling great opportunities for various applications.

Background: Accurate measurements of flow and ventricular volume and function are critical for clinical decision-making in cardiovascular medicine. Cardiac magnetic resonance (CMR) is the current gold standard for ventricular functional evaluation but is relatively expensive and time-consuming, thus limiting the scale of clinical applications. New volumetric acquisition techniques, such as four-dimensional flow (4D-flow) and three-dimensional volumetric cine (3D-cine) MRI, could potentially reduce acquisition time without loss in accuracy; however, this has not been formally tested on a large scale. Methods: 4DCarE (4D-flow MRI for cardiovascular evaluation) is a prospective, multi-centre study designed to test the non-inferiority of a compressed 20 min exam based on volumetric CMR compared with a conventional CMR exam (45–60 min). The compressed exam utilises 4D-flow together with a single breath-hold 3D-cine to provide a rapid, accurate quantitative assessment of the whole heart function. Outcome measures are (i) flow and chamber volume measurements and (ii) overall functional evaluation. Secondary analyses will explore clinical applications of 4D-flow-derived parameters, including wall shear stress, flow kinetic energy quantification, and vortex analysis in large-scale cohorts. A target of 1200 participants will enter the study across three sites. The analysis will be performed at a single core laboratory site. Pilot Results: We present a pilot analysis of 196 participants comparing flow measurements obtained by 4D-flow and conventional 2D phase contrast, which demonstrated moderate–good consistency in ascending aorta and main pulmonary artery flow measurements between the two techniques. Four-dimensional flow underestimated the flow compared with 2D-PC, by approximately 3 mL/beat in both vessels. Conclusions: We present the study protocol of a prospective non-inferiority study of a rapid cardiac MRI exam compared with conventional CMR. The pilot analysis supports the continuation of the study. Study Registration: This study is registered with the Australia and New Zealand Clinical Trials Registry (Registry number ACTRN12622000047796, Universal Trial Number: U1111-1270-6509, registered 17 January 2022—Retrospectively registered).

(1) Background: Since the death of George Floyd, the social movement Black Lives Matter continues to dominate the American political psyche, not only advancing a public dialogue but also escalating the polarization of supported solutions for policing and systemic discrimination. (2) Methods: Using a qualitative context analysis approach, we assessed over 350 sources related to social justice literature and policy-relevant documents to identify key policy solutions supported by the American Black Lives Matter movement compared to the Blue Lives Matter movement. We applied Fearon’s bargaining range of war model to analyze the extent to which the policy recommendations of these two opposing movements may overlap. The purpose was to identify and categorize agreement alternatives across various sectors. This research presents top policy solutions, assessing their bargaining ranges. (3) Results: 32 of the 36 top policy reform alternatives at the national level have sufficient bargaining ranges. This analysis indicates the importance of supporting various sectors like mental health/psychosocial policies and programs, which can (1) serve as a focal point of agreement between contending movements, and (2) decrease racial injustice through strategic bargaining. (4) Conclusions: In a divisively political landscape, it is crucial to identify starting points for negotiation among contending actors. Identifying bargaining opportunities can help seed a dialogue that may benefit all parties involved.

Two species of procyonid (Nasua nasua and Procyon cancrivorus) and one species of mephitid (Conepatus chinga) have long been documented to occur in Paraguay, but very little has been published about their ecology in the country since the early 19th Century works of Azara and Rengger. Data on the distribution and status of these species in the country is collated from museum specimens, published literature and reliable observations to provide a basis for future research. A hierarchical approach is taken towards types of record and maps are provided that distinguish these for all species. All three species remain common in the Chaco region west of the Paraguay River, and all are considered of Least Concern. However, this region is experiencing high levels of deforestation and data to assess the potential declines of the species is unavailable. The two species of procyonid are also widespread in the Oriental region, but the status of Conepatus chinga there is unclear. There are multiple reports from the Atlantic Forest region but documentation is limited to fecal molecular samples. Clarifying the distribution of that species in the Oriental region is a priority for research.

Social Impact Statement The exchange of plant material and data is essential for supporting collaborative research efforts to address global challenges. In order to promote collaboration between Plant Genetic Resource (PGR) organizations in conservation research and development and to improve the sustainable utilization of PGRs, constraints to plant material and data exchange must be addressed. This can only be achieved through the introduction of policy measures that will build trust among institutions and encourage facilitated plant material exchange, equitable benefit sharing, and compliance with Access and Benefit Sharing (ABS) instruments. The resulting improvements in the conservation and sustainable utilization of PGRs will improve food security, public health, livelihoods, sustainable development, and ecological sustainability. Summary The aim of this study was to assess the extent of plant material exchange between European and African Plant Genetic Resource (PGR) organizations for research and development. Data were collected from Index Seminum databases and through a survey questionnaire. They were statistically analyzed using a chi‐square test and Spearman correlation coefficient using SPSS, version 25. The study indicated that the extent of plant material exchange between African and European PGR organizations for research and development is insignificant compared with the exchange between European institutions. Plant material exchange usually included benefit sharing, and the most commonly shared benefits were knowledge transfer, participation in research, access to research results, and joint authorship of publications. Many of the respondents were not very familiar with Access and Benefit Sharing (ABS) principles and regulations. The major constraints to plant material exchange were found to be cumbersome bureaucratic procedures, poor knowledge of compliance requirements, lack of national ABS regulations, poor quality of data associated with collections, and lack of tracking mechanisms. The low level of plant material exchange between African and European institutions is also most probably due to limited human and technological capacity in African institutions that restrict their involvement in research and development. Therefore, there is a need to build trust and to increase human and technological capacities for research in African institutions to strengthen collaboration by ensuring facilitated exchange and equitable benefit sharing.

Abstract Background Bruton’s tyrosine kinase (BTK) is a key signaling node in B cell receptor (BCR) and Fc receptor (FcR) signaling. BTK inhibitors (BTKi) are an emerging oral treatment option for patients suffering from multiple sclerosis (MS). Remibrutinib (LOU064) is a potent, highly selective covalent BTKi with a promising preclinical and clinical profile for MS and other autoimmune or autoallergic indications. Methods The efficacy and mechanism of action of remibrutinib was assessed in two different experimental autoimmune encephalomyelitis (EAE) mouse models for MS. The impact of remibrutinib on B cell-driven EAE pathology was determined after immunization with human myelin oligodendrocyte glycoprotein (HuMOG). The efficacy on myeloid cell and microglia driven neuroinflammation was determined in the RatMOG EAE. In addition, we assessed the relationship of efficacy to BTK occupancy in tissue, ex vivo T cell response, as well as single cell RNA-sequencing (scRNA-seq) in brain and spinal cord tissue. Results Remibrutinib inhibited B cell-dependent HuMOG EAE in dose-dependent manner and strongly reduced neurological symptoms. At the efficacious oral dose of 30 mg/kg, remibrutinib showed strong BTK occupancy in the peripheral immune organs and in the brain of EAE mice. Ex vivo MOG-specific T cell recall response was reduced, but not polyclonal T cell response, indicating absence of non-specific T cell inhibition. Remibrutinib also inhibited RatMOG EAE, suggesting that myeloid cell and microglia inhibition contribute to its efficacy in EAE. Remibrutinib did not reduce B cells, total Ig levels nor MOG-specific antibody response. In brain and spinal cord tissue a clear anti-inflammatory effect in microglia was detected by scRNA-seq. Finally, remibrutinib showed potent inhibition of in vitro immune complex-driven inflammatory response in human microglia. Conclusion Remibrutinib inhibited EAE models by a two-pronged mechanism based on inhibition of pathogenic B cell autoreactivity, as well as direct anti-inflammatory effects in microglia. Remibrutinib showed efficacy in both models in absence of direct B cell depletion, broad T cell inhibition or reduction of total Ig levels. These findings support the view that remibrutinib may represent a novel treatment option for patients with MS.

Abstract Tree planting has the potential to improve the livelihoods of millions of people as well as to support environmental services such as biodiversity conservation. Planting however needs to be executed wisely if benefits are to be achieved. We have developed the GlobalUsefulNativeTrees (GlobUNT) database to directly support the principles advocated by the ‘golden rules for reforestation’, including planting tree mixtures that maximize the benefits to local livelihoods and the diversity of native trees. Developed primarily by combining data from GlobalTreeSearch with the World Checklist of Useful Plant Species (WCUPS), GlobUNT includes 14,014 tree species that can be filtered for ten major use categories, across 242 countries and territories. The 14,014 species represent roughly a quarter of the tree species from GlobalTreeSearch and a third of the plant species from WCUPS. GlobUNT includes over 8000 species used as materials (9261 species; 68.4% of the total in WCUPS for that use category) or medicines (8283; 31.1%), over 2000 species with environmental uses (3317; 36.9%), used as human food (3310; 47.0%) or fuel (2162; 85.5%), over 1000 species used as gene sources (1552; 29.8%), animal food (1494; 33.7%), social uses (1396; 53.8%) or poisons (1109; 36.8%), and 712 species (68.4%) as insect food.

Two structural abnormalities are reported in southern three-banded armadillos Tolypeutes matacus (Chlamyphoridae) from Paraguay. Additional reports of individuals with amputated legs are noted, and a potential explanation for the frequency of such occurrences associated with predation and their defensive behaviour is hypothesized. This is the first documented report of a band anomaly for adults of this species.

We report the first use of ERP measures to identify text engagement differences when reading digitally or in print. Depth of semantic encoding is key for reading comprehension, and we predicted that deeper reading of expository texts would facilitate stronger associations with subsequently-presented related words, resulting in enhanced N400 responses to unrelated probe words and a graded attenuation of the N400 to related and moderately related words. In contrast, shallow reading would produce weaker associations between probe words and text passages, resulting in enhanced N400 responses to both moderately related and unrelated words, and an attenuated response to related words. Behavioral research has shown deeper semantic encoding of text from paper than from a screen. Hence, we predicted that the N400 would index deeper reading of text passages that were presented in print, and shallower reading of texts presented digitally. Middle-school students (n = 59) read passages in digital and print formats and high-density EEG was recorded while participants completed single-word semantic judgment tasks after each passage. Following digital text presentation, the N400 response pattern to moderately-related words indicated shallow reading, tracking with responses to words that were unrelated to the text. Following print reading, the N400 responses to moderately-related words patterned instead with responses to related words, interpreted as an index of deeper reading. These findings provide evidence of differences in brain responses to texts presented in print and digital media, including deeper semantic encoding for print than digital texts.

Abstract Background Enumeration of circulating tumor cells (CTCs) has proven clinical significance for monitoring patients with metastatic cancers. Multiplexed gene expression profiling of CTCs is a potential tool for assessing disease status and monitoring treatment response. The Parsortix® technology enables the capture and harvest of CTCs from blood based on cell size and deformability. The HyCEAD™ (Hybrid Capture Enrichment Amplification and Detection) assay enables simultaneous amplification of short amplicons for up to 100 mRNA targets, and the Ziplex™ instrument quantifies the amplicons for highly sensitive gene expression profiling down to single cell levels. The aim of the study was to functionally assess this system. Methods The HyCEAD/Ziplex platform was used to quantify the expression levels for 72 genes using as little as 20 pg of total RNA or a single cultured tumor cell. Assay performance was evaluated using cells or total RNA spiked into Parsortix harvests of healthy donor blood. The assay was also evaluated using total RNA obtained from Parsortix harvests of blood from metastatic breast cancer (MBC) patients or healthy volunteers (HVs). Results Using genes with low expression in WBC RNA and/or in unspiked Parsortix harvests from HVs, the assay distinguished between the different breast cancer and ovarian cancer cell lines with as little as 20 pg of total RNA (equivalent to a single cell) in the presence of 1 ng of WBC RNA. Single cultured cells spiked into Parsortix harvests from 10 mL of HV blood were also detected and distinguished from each other. CVs from repeatability experiments were less than 20%. Hierarchical clustering of clinical samples differentiated most MBC patients from HVs. Conclusion HyCEAD/Ziplex provided sensitive quantification of expression of 72 genes from 20 pg of total RNA from cultured tumor cell lines or from single cultured tumor cells spiked into lysates from Parsortix harvests of HV blood. The HyCEAD/Ziplex platform enables the quantification of selected genes in the presence of residual nucleated blood cells in Parsortix harvests. The HyCEAD/Ziplex platform is an effective tool for multiplexed molecular characterization of mRNA in small numbers of tumor cells harvested from blood.

ABSTRACT The identity of the bird described from Paraguay by Félix de Azara as No. 372 Ypacahá del Pardo is confirmed as the immature plumage of the Spotted Rail Pardirallus maculatus maculatus (Boddaert, 1783). This description is the basis for the name Rallus rytirhynchos Vieillot, 1819 which is thus a junior subjective synonym and an available name. Rallus rytirhynchos Vieillot, 1819 is the type species of the genus Ortygonax Heine, 1890. Ortygonax Heine, 1890 is a junior subjective synonym of Pardirallus Bonaparte, 1856 and is also available for application.

Background Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. The levonorgestrel-releasing intrauterine system is an effective long-term treatment but is discontinued by many due to unpredictable bleeding, or adverse effects. The selective progesterone receptor modulator ulipristal acetate is used to treat symptomatic fibroids but long-term efficacy for the symptom of heavy menstrual bleeding, irrespective of presence of fibroids, is unknown. Objectives To determine whether ulipristal acetate is more effective at reducing the burden of heavy menstrual bleeding than levonorgestrel-releasing intrauterine system after 12 months of treatment in women with and without fibroids. We investigated mechanism of action of ulipristal acetate in a subset of 20 women. Design Randomised, open-label, parallel group, multicentre trial with embedded mechanistic study. Setting Ten UK hospitals. Participants Women with heavy menstrual bleeding aged 18 and over with no contraindications to levonorgestrel-releasing intrauterine system or ulipristal acetate. Interventions Three 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or continuous levonorgestrel-releasing intrauterine system following allocation in a 1 : 1 ratio using a web-based minimisation procedure. Main trial outcome measures Primary outcome was quality-of-life measured by menorrhagia multi-attribute scale at 12 months. Secondary outcomes included menstrual bleeding and patient satisfaction. Impact on fibroid size, endometrial appearance and liver function was also collected. Mechanistic study outcome Cellular markers for endometrial cell structure and function, determined from endometrial biopsies; volume of uterus and fibroids and microcirculation parameters were determined from magnetic resonance images. Results Sample size was increased from 220 to 302 as a result of temporary halt to recruitment due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate and the COVID-19 pandemic led to a premature closure of recruitment, with 118 women randomised to each treatment and 103 women completing 12-month menorrhagia multi-attribute scale scores prior to this point. Primary outcome scores substantially improved in both arms, but at 12 months there was no evidence of a difference between those receiving three cycles of ulipristal acetate [median score category: 76–99, interquartile range (51–75 to 100), n = 53] and levonorgestrel-releasing intrauterine system [median score category: 76–99, interquartile range (51–75 to 100), n = 50; adjusted odds ratio 0.55, 95% confidence interval 0.26 to 1.17; p = 0.12]. Rates of amenorrhoea were much higher in those allocated ulipristal acetate compared with the levonorgestrel-releasing intrauterine system (12 months: 64% vs. 25%, adjusted odds ratio 7.12, 95% confidence interval 2.29 to 22.2). There was no evidence of a difference in other participant-reported outcomes. There were no cases of endometrial malignancy and no hepatotoxicity due to ulipristal acetate use. Mechanistic study results Ulipristal acetate produced a reversible reduction in endometrial cell proliferation, as well as reversible alteration of other endometrial cellular markers. Ulipristal acetate did not produce a reduction in the volume of the uterus irrespective of coexisting fibroids, nor an effect on uterine microvascular blood flow. Limitations The urgent safety measures and premature closure of recruitment impacted final sample size. Conclusions We found no evidence of a difference in quality of life between the two treatments, but ulipristal acetate was superior to levonorgestrel-releasing intrauterine system at inducing amenorrhoea. Ulipristal acetate currently has restricted availability due to concerns regarding hepatotoxicity. Future work There is a need to develop new, safe, effective and fertility-sparing medical treatments for heavy menstrual bleeding. The observed acceptability and effectiveness of ulipristal acetate warrants further research into the selective progesterone receptor modulator class of pharmacological agents. Study registration This trial is registered as ISRCTN 20426843. Plain language summary What is the problem? Heavy menstrual bleeding is a common condition that affects the lives of many women. A hormone-releasing coil, fitted inside the womb, is effective in making periods lighter but can make them less regular. A medicine called ulipristal acetate or UPA, taken as a pill, has been shown to reduce rapidly menstrual bleeding in women with large, non-cancerous tumours in the womb, known as fibroids. It was not known whether UPA is effective in women who have heavy periods but do not have fibroids of any significant size. What did we plan to do? To find out which treatment was better at controlling heavy periods, 236 women were enrolled in a clinical trial where they received either the hormone coil or UPA. The choice of treatment was made at random by a computer rather than the wishes of researchers or patients, to ensure a fair comparison. Participants completed questionnaires about their symptoms and life quality at intervals up to 1 year. Twice during the trial, medicines regulatory authorities raised safety concerns about UPA causing liver problems. This resulted in the introduction of regular blood tests. The second time, recruitment to the trial stopped early. What did we find? Both treatments improved the symptoms of heavy menstrual bleeding in the majority of women. We found no evidence that UPA was better overall after 1 year of treatment, compared with the hormone coil, although fewer women on UPA continued to have periods. Laboratory studies on samples taken from the lining of the womb showed temporary changes due to UPA, which disappeared after treatment stopped. What does this mean? Both treatments improve the symptoms of menstrual bleeding and general wellbeing. Because of safety concerns UPA is not available for all women with heavy menstrual bleeding and new, safer medical treatments are needed. Scientific summary Background Heavy menstrual bleeding (HMB) is the most common gynaecological problem in women of reproductive age, affecting one in four women, and has adverse profound impact on health-related quality of life. Common causes of HMB include structural abnormalities such as uterine fibroids, adenomyosis and dysfunction of the endometrium. The levonorgestrel-releasing intrauterine system (LNG-IUS) is a proven, effective long-term treatment but about one-third of women cease use by two years due to unpredictable bleeding, hormonal adverse effects or lack of effectiveness. Furthermore, fibroids can make the LNG-IUS less effective. Alternative medical options for HMB exist, but are either less effective or associated with unacceptable adverse effects. Surgical interventions are effective at inducing bleeding control and improving quality of life but are typically incompatible with future fertility. Effective long-term medical treatments for women with HMB are needed. A class of drugs called selective progesterone receptor modulators (SPRMs) have potential to provide an effective oral treatment for HMB. SPRMs bind with progesterone receptors, resulting in tissue-specific effects in both myometrial and overlying endometrial tissue as well as shrinking uterine fibroids. The SPRM ulipristal acetate (UPA) has been successfully used to treat fibroids, but we do not know how effective UPA is for the treatment of women with HMB who do not have fibroids. Furthermore, there are uncertainties regarding the mechanism and location of action of UPA, as well as its longer-term safety. SPRMs induce distinctive, non-physiological endometrial changes, which can be confused with endometrial hyperplasia. More recently there has been concern regarding the potential for UPA to cause drug-induced liver injury (DILI). Post marketing surveillance reports resulted in a temporary halt in UPA use in 2018 and 2020. Use of UPA has since been reinstated since January 2021, albeit in a restricted context, reflecting the paucity of existing alternatives for HMB. Given these uncertainties, we designed the UCON trial to evaluate the safety, tolerability and effectiveness of UPA on HMB and to understand its mechanism of action. Clinical objectives Primary objective: to determine whether UPA is more effective at reducing the burden of HMB symptoms than LNG-IUS after 12 months of treatment. Secondary objectives: Ascertain whether UPA use beyond 3 months’ and up to 12 months’ duration is associated with histological changes to the endometrium and, if so, whether this compromises safety. Ascertain whether UPA is more effective than LNG-IUS in relation to menstrual blood loss, sexual activity, generic quality of life, satisfaction with treatment, patient-reported adverse events, and compliance at 3, 6 and 12 months. Determine the response to UPA and LNG-IUS treatment difference in the presence of uterine fibroids in terms of (1) alleviation of HMB and (2) change in uterine/fibroid volume. Collect data on liver function in women taking UPA, once safety concerns were raised. Mechanism of action study objectives To understand how UPA causes a reduction in menstrual bleeding and uterine/fibroid volume in women with HMB, we determined whether UPA administration: Alters endometrial cell function (e.g., and not limited to, proliferation, apoptosis, expression of steroid receptors, tumour suppressors and inflammatory mediators). Reduces blood plasma flow in the endometrium, uterine myometrium and fibroid tissue. Alters the volume fraction of the extracellular matrix in these tissues. Reduces uterine and fibroid volume. Design This was a randomised, open-label, parallel group, multicentre trial with embedded mechanistic study. Methods Setting The trial recruited participants in 10 sites in NHS hospital settings across the UK between 2015 and 2020. The mechanism of action study was conducted solely at the Edinburgh site. Participants For the main trial, informed consent was sought from premenopausal women (aged 18–50 years) with self-reported HMB, no contraindications to LNG-IUS or UPA. Those with uterine size greater than equivalent 14-week size or with submucosal fibroids >2cm were excluded. Other exclusion criteria relating to use of other treatments and current health status were applied, including history of severe hepatic impairment. Screening and randomisation Participants were recruited in gynaecology clinics by research nurses who screened patient referral letters. Following consent, haemoglobin and circulating estradiol levels were assessed, clinical history elicited and transvaginal and/or abdominal ultrasound and endometrial biopsy were obtained if not previously performed. Following this, and confirmation of eligibility, randomisation was via a web-based central service based at Birmingham Clinical Trials Unit to allocate women in a 1 : 1 ratio using a minimisation algorithm. Screened patients in Edinburgh were offered the opportunity to participate in the mechanistic study. Interventions and follow-up Those allocated to UPA received three courses of treatment, each course comprising a daily 5-mg oral dose for 12 weeks followed by a four-week break. Those allocated to the LNG-IUS had it fitted in hospital or primary care. Participants allocated to UPA returned to hospital to collect their repeat prescription at 3 and 6 months, and may have been seen by a member of the care team if required. They were then seen in clinic at 12 months for ultrasound scan (USS) and haemoglobin/serum estradiol measurement. Those allocated to the LNG-IUS group attended USS at 12 months. Follow-up at interim time points was conducted by postal questionnaire. Those partaking in the mechanism of action study underwent magnetic resonance imaging (MRI) following randomisation and at the end of treatment cycles two and three. An additional endometrial biopsy was obtained at the end of treatment cycle two. Outcome measures Primary Condition-specific quality of life score as measured by the menorrhagia multi-attribute scale (MMAS) questionnaire at 12 months. Summary scores range from 0 (worst affected) to 100 (not affected). Secondary Condition-specific quality of life score as measured by MMAS at 3 and 6 months Menstrual bleeding (pictorial blood loss assessment chart)* Cycle regularity (ordinal four-point scale)* Duration of period (ordinal three option scale)* Pelvic pain during periods, intercourse and at other times (visual analogue scales; 0 = best outcome, 10 = worse outcome)* Uterine fibroid symptom and quality of life instrument (only given to women diagnosed with fibroids)* Sexual function (sexual activity questionnaire)* Generic quality of life (EQ-5D-5L)* Satisfaction with treatment outcome (five-point Likert scale) Participant rating of effect of treatment on HMB over 12 months (four-point Likert scale) Whether participant is willing to recommend the treatment to a friend (yes/no) Surgical intervention Adherence to trial treatments and reasons for changing treatment, as reported by the participant Serious adverse events and reactions Uterine volume, evidence of adenomyosis, presence of fibroids, largest fibroid volume, endometrial thickness, endometrial appearance, evidence of ovarian cysts at 12 months (USS) Endometrial biopsy at 12 months (UPA group only) Liver function tests, from 20 March 2018 every four weeks (UPA group only) Haemoglobin and serum estradiol at 12 months * assessed at 3, 6 and 12 months Mechanism of action A: Effects on cellular markers of endometrial steroid receptors and metabolising enzymes (governing local endometrial steroid [ligand] availability), cell proliferation, cell survival (apoptosis); detection of genes implicated in control of proliferation in endometrium; B: Effects on uterine/fibroid structure addressed by obtaining volume measurements for the whole uterus, and for the total volume of fibroids when present, by using high resolution structural MRI and stereology; and C: Uterine vascularity using dynamic contrast-enhanced MRI (DCE-MRI). Urgent safety measures In November 2017, the European Medicines Agency (EMA) issued an urgent drug alert for UPA due to a small number of reports of serious liver injury. A detailed investigation by the regulatory authorities was undertaken and it was found that eight reports of serious liver injury were reported in Europe from an estimated 740,000 women using UPA for uterine fibroids. Restrictions on prescribing UPA were subsequently issued and the trial sponsor implemented an urgent safety measure (USM) in February 2018, which halted recruitment. Those allocated UPA were allowed to complete their current course of UPA treatment but not commence any further outstanding courses. In addition, they commenced monthly assessment of LFTs (as well as a post treatment test approximately 2 weeks after the last course of UPA). In August 2018, the halt on UPA prescribing was lifted and recruitment to UCON resumed in October 2018 with additional safety measures in place, including exclusion of those with any history of liver disease [defined as levels of alanine transaminase (ALT) or aspartate aminotransferase (AST) of more than two times the upper limit of normal] and LFT monitoring as described above. UPA was stopped if women had an ALT or AST more than three times the upper limit of normal and a hepatology opinion was sought. In March 2020, the EMA temporarily suspended use of UPA a second time due to ongoing concerns regarding hepatotoxicity and a further USM was issued. All treatment courses of UPA were immediately stopped. In view of the second USM, the investigators, in discussion with the funder, chose premature closure of recruitment to the study but planned follow-up actions continued as per protocol. Statistical considerations The study was powered to detect a clinically useful difference in MMAS score (13 points) between the two groups at twelve months. To detect a difference of this size [0.5 standard deviations (SDs)] with 90% power (p = 0.05) would require 86 women in each group (172 in total). To allow for a 20% loss to follow-up or pregnancy, the sample size was inflated to 220 women. Following the initial USM, this figure was inflated to 302 women to ensure that there were adequate responses in the primary analysis population (defined below) to detect the same size of difference. The original planned primary analysis population comprised all participants, regardless of adherence to treatment, employing suitable regression models to estimate difference between groups. The enforced non-compliance as a result of the withdrawal of UPA had substantial implications for the validity of the data reported by participants. It was therefore necessary to redefine analysis populations, considering the restrictions that prevented women taking their courses of UPA might influence their responses and any other new potential biases that may be apparent in either group due to, for example, knowledge of the safety concerns around UPA. The primary analysis population would now comprise participants with questionnaire responses received prior to the first USM (12 February 2018), along with questionnaire responses from participants recruited following the study restart (18 October 2018) provided that the responses were returned before the second USM (17 March 2020). Results Main trial A total of 4471 women were approached for the study, with 236 consented and randomised, of whom 181 (77%) returned primary outcome data at 12 months (103 within the primary analysis population). Baseline data were comparable between groups; 92% were white, 34% had fibroids and 8% adenomyosis. In the primary analysis population, MMAS scores substantially improved in both arms, but at 12 months there was no evidence of a difference between the UPA [median score category: 76–99, IQR (51–75 to 100), n = 53] and LNG-IUS [median score category: 76–99, IQR (51–75 to 100), n = 50] groups (adjusted OR 0.55, 95% CI 0.26 to 1.17; p = 0.12). Rates of amenorrhoea where much higher in those allocated UPA compared with LNG-IUS at each time point (3 months: 56% vs. 5%, adjusted OR 29.3, 95% CI 7.37 to 116; 6 months 53% vs. 10%, adjusted OR 11.7 95% CI 3.78 to 36.0; 12 months: 64% vs. 25%, adjusted OR 7.12, 95% CI 2.29 to 22.2). There was no evidence of a difference in the other patient-reported outcomes although there was considerable uncertainty. In those with uterine fibroids, there were no changes in fibroid or uterine volume in either treatment group at 12 months. On endometrial biopsy, seven participants (8%) had evidence of progesterone receptor modulator associated endometrial changes (PAEC) at 12 months, although none was observed at a further 6 months post treatment; there were no cases of endometrial malignancy. Rates of serious adverse events were low, and no patients required admission to hospital for management of deranged liver function tests due to UPA use. Mechanism of action study Effects of UPA administration on the uterus: UPA produced a reduction in cell proliferation in the endometrium, as well as alteration of other local endometrial cellular markers (steroid receptor and steroid metabolising enzyme expression) creating a local endometrial oestrogenic environment. The effects on endometrial cellular markers were reversed upon withdrawal of UPA treatment. Stereological analysis in 19 patients showed that UPA did not produce a reduction in the volume of the uterus, irrespective of coexisting fibroids or adenomyosis. DCE-MRI in 15 patients showed that UPA appears not to have an effect on uterine blood flow. If adenomyosis was present in the uterus, there was a significant increase in plasma volume in the endometrium. However, one of the five women with adenomyosis also had fibroids. Effects of UPA administration on uterine fibroids: DCE-MRI studies showed that UPA produced an average reduction in plasma volume in 11 fibroids, which may be interpreted as being due to a reduction in extracellular matrix components. This finding was not supported by stereological analysis, which failed to show a reduction in the total volume of fibroids in eight patients. However, it should be noted that the number of subjects studied is small. Conclusions Both UPA and LNG-IUS alleviated the adverse impact of heavy menstrual bleeding on quality of life but we found no evidence of a difference between groups over 12 months. UPA was evidently superior to LNG-IUS in terms of inducing amenorrhoea. We observed no difference in reduction in the volume of the uterus, whether or not fibroids were present and no difference in change in the volume of fibroids was observed. Analysis of selected markers of endometrial cellular function demonstrated UPA modulation of the progesterone receptor, resulting in molecular and cellular alteration in steroid receptors within the endometrium, consistent with the development of a local (endometrial) oestrogenic microenvironment. Despite this, there is no evidence of pathological endometrial changes. We demonstrated that alteration in the endometrial microenvironment reverses on cessation of UPA treatment, a key factor for a medical treatment of HMB, particularly for those who wish to preserve fertility. UPA now has restricted availability due to concerns regarding hepatotoxicity. Findings from this study may offer insights into mechanism of action of other SPRM class members. New, effective and acceptable oral medical treatment options are needed to address an important unmet clinical need. Recommendations for research Further studies of medical treatments for HMB Developing other SPRMs, not associated with DILI Other hormonal/non-hormonal medical treatments for HMB Patient populations that encompass both the symptoms of HMB and underlying aetiologies, including structurally normal uterus, adenomyosis and small fibroids Study design with outcome measures impact on menstrual bleeding pattern, pelvic pain and impact on haemoglobin and iron-deficiency, as well as quality of life Qualitative studies to determine what are the most important outcomes to women who suffer HMB Study registration This trial is registered as ISRCTN 20426843. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 8. See the NIHR Journals Library website for further project information.

Scaled manufacturing of ordered mesoporous materials has been historically challenging. This work reports a simple and generalizable method to directly convert low-cost thermoplastic elastomers to mesoporous polymer, carbon, and silica, with controlled pore textures by altering precursor identity.

While EGFR-targeted therapies have clinical benefit, drug-resistant brain metastases present a major obstacle. Here, the authors identify a genetic signature in brain metastatic lesions associated with osimertinib resistance and find RhoA to have an important role in the resulting phenotype.

Introduction There is uncertainty about the advantages and disadvantages of laparoscopic hysterectomy compared with abdominal hysterectomy, particularly the relative rate of complications of the two procedures. While uptake of laparoscopic hysterectomy has been slow, the situation is changing with greater familiarity, better training, better equipment and increased proficiency in the technique. Thus, a large, robust, multicentre randomised controlled trial (RCT) is needed to compare contemporary laparoscopic hysterectomy with abdominal hysterectomy to determine the safest and most cost-effective technique.Methods and analysis A parallel, open, non-inferiority, multicentre, randomised controlled, expertise-based surgery trial with integrated health economic evaluation and an internal pilot with an embedded qualitative process evaluation. A within trial-based economic evaluation will explore the cost-effectiveness of laparoscopic hysterectomy compared with open abdominal hysterectomy. We will aim to recruit 3250 women requiring a hysterectomy for a benign gynaecological condition and who were suitable for either laparoscopic or open techniques. The primary outcome is major complications up to six completed weeks postsurgery and the key secondary outcome is time from surgery to resumption of usual activities using the personalised Patient-Reported Outcomes Measurement Information System Physical Function questionnaire. The principal outcome for the economic evaluation is to be cost per QALY at 12 months’ postsurgery. A secondary analysis is to be undertaken to generate costs per major surgical complication avoided and costs per return to normal activities.Ethics and dissemination The study was approved by the West Midlands-Edgbaston Research Ethics Committee, 18 February 2021 (Ethics ref: 21/WM/0019). REC approval for the protocol version 2.0 dated 2 February 2021 was issued on 18 February 2021.We will present the findings in national and international conferences. We will also aim to publish the findings in high impact peer-reviewed journals. We will disseminate the completed paper to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the BSGE.Trial registration number ISRCTN14566195.

A method for the accurate calculation of the cut-off wavenumbers of a waveguide with an arbitrary cross section and a number of inner conductors is demonstrated. Concepts of integral and infinite-matrix (summation) operator-valued functions depending nonlinearly on the frequency spectral parameter provide a secure basis for formulating the spectral problem, and the Method of Analytical Regularization is employed to implement an effective algorithm. The algorithm is based on a mathematically rigorous solution of the homogeneous Dirichlet problem for the Helmholtz equation in the interior of the waveguide, excluding the regions occupied by the inner conductor boundaries. A highly efficient method of calculating the cut-off wavenumbers and the corresponding non-trivial solutions representing the modal distribution is developed. The mathematical correctness of the problem statement, the method, and the ability to calculate the cut-off wavenumbers with any prescribed and proven accuracy provide a secure basis for treating these as “benchmark solutions”. In this paper, we use this new approach to validate previously obtained results against our benchmark solutions. Furthermore, we demonstrate its universality in solving some new problems, which are barely accessible by existing methods.

We present a detailed investigation of photometric, spectroscopic, and polarimetric observations of the Type II SN 2023ixf. Earlier studies have provided compelling evidence for a delayed shock breakout from a confined dense circumstellar matter (CSM) enveloping the progenitor star. The temporal evolution of polarization in the SN 2023ixf phase revealed three distinct peaks in polarization evolution at 1.4 days, 6.4 days, and 79.2 days, indicating an asymmetric dense CSM, an aspherical shock front and clumpiness in the low-density extended CSM, and an aspherical inner ejecta/He-core. SN 2023ixf displayed two dominant axes, one along the CSM-outer ejecta and the other along the inner ejecta/He-core, showcasing the independent origin of asymmetry in the early and late evolution. The argument for an aspherical shock front is further strengthened by the presence of a high-velocity broad absorption feature in the blue wing of the Balmer features in addition to the P-Cygni absorption post-16 days. Hydrodynamical light-curve modeling indicated a progenitor mass of 10 M _⊙ with a radius of 470 R _⊙ and explosion energy of 2 × 10 ^51 erg, along with 0.06 M _⊙ of ^56 Ni, though these properties are not unique due to modeling degeneracies. The modeling also indicated a two-zone CSM: a confined dense CSM extending up to 5 × 10 ^14 cm with a mass-loss rate of 10 ^−2 M _⊙ yr ^−1 and an extended CSM spanning from 5 × 10 ^14 to at least 10 ^16 cm with a mass-loss rate of 10 ^−4 M _⊙ yr ^−1 , both assuming a wind-velocity of 10 km s ^−1 . The early-nebular phase observations display an axisymmetric line profile of [O i ], redward attenuation of the emission of H α post 125 days, and flattening in the Ks -band, marking the onset of dust formation.

Background: Palpation skills are universally taught in physical therapy education programs worldwide. Accurate palpation is necessary for diagnosis and to guide interventional approaches. The primary purpose of this investigation was to measure ultrasonographic-confirmed palpation accuracy of the medial tibiofemoral joint space among second year Doctor of Physical Therapy students examining participants with characteristics representative of patients seen in clinical practice. Methods: Five second-year Doctor of Physical Therapy students served as examiners. Thirty-six participants contributed 67 knees for examination. The primary outcome was ultrasonographic-confirmed palpation accuracy, and the secondary outcomes evaluated the association between palpation accuracy and participant characteristics. Results: Pooled examiner accuracy was 39%. Chi-Square analyses revealed no association between pooled examiner palpation accuracy and BMI category (x2=1.46, p=0.48), age category (x2=0.21, p=0.65), sex (x2=1.47, p=0.23), skin tone (x2=0.06, p=0.81), or side of the examined knee (x2=0.27, p=0.61). Individual examiner palpation accuracy ranged from 14% to 75%, revealing a significant difference across examiners (x2=15.0, p=0.005). Two examiners had a combined accuracy of 64%, while the remaining 3 had a combined accuracy of 24%. Chi-Square analyses revealed no association between "successful" vs "unsuccessful" examiners and BMI category (x2=3.54, p=0.17), age category (x2=1.39, p=0.24), sex (x2=4.22, p=0.04), skin tone (x2=0.001, p=0.97), or side of the examined knee (x2=0.08, p=0.77). Conclusion: This investigation provides original data of ultrasonographic-confirmed palpation accuracy among secondyear Doctor of Physical Therapy students examining participants with characteristics representative of patients seen in clinical practice. Results may help inform instructional approaches and curricular design in physical therapy education.

Abstract Children in rural settings are under‐represented in clinical trials, potentially contributing to rural health disparities. We performed a scoping review describing available literature on barriers and facilitators impacting participation in pediatric clinical trials in rural and community‐based (nonclinical) settings. Articles identified via PubMed, CINAHL, Embase, and Web of Science were independently double‐screened at title/abstract and full‐text levels to identify articles meeting eligibility criteria. Included articles reported on recruitment or retention activities for US‐based pediatric clinical studies conducted in rural or community‐based settings and were published in English through January 2021. Twenty‐seven articles describing 31 studies met inclusion criteria. Most articles reported on at least one study conducted in an urban or suburban or unspecified community setting (n = 23 articles; 85%); fewer (n = 10; 37%) reported on studies that spanned urban and rural settings or were set in rural areas. More studies discussed recruitment facilitators (n = 25 studies; 81%) and barriers (n = 19; 61%) versus retention facilitators (n = 15; 48%) and barriers (n = 8; 26%). Descriptions of recruitment and retention barriers and facilitators were primarily experiential or subjective. Recruitment and retention facilitators were similar across settings and included contacts/reminders, community engagement, and relationship‐building, consideration of participant logistics, and incentives. Inadequate staff and resources were commonly cited recruitment and retention barriers. Few studies have rigorously examined optimal ways to recruit and retain rural participants in pediatric clinical trials. To expand the evidence base, future studies examining recruitment and retention strategies should systematically assess and report rurality and objectively compare relative impact of different strategies.

A new species of Phalotris from the nasutus group, Phalotris shawnella sp. nov., is described. It can be distinguished from the other members of the group by having the following combination of characters: 1) fifth supralabial in contact with parietal, 2) vertebral stripe present, 3) yellowish nuchal collar (2 or 3 dorsal scales long), 4) dull reddish color of head, 5) broad, solidly or near solidly dark, lateral bands, 6) red-orange ventral scales lightly and irregularly spotted with black mainly on the posterior half of the body and 7) a bilobed, extremely asymmetrical hemipenis, with enlarged, curved, lateral spines. The species is only known from a recent specimen collected in the Cerrado zone of northeastern Paraguay at Rancho Laguna Blanca, San Pedro department, and two photographic records of live specimens from this and an additional locality. Limited ecological data based on observations of a captive individual, and a wild record, are provided, and a conservation assessment is performed for this extremely limited range Paraguayan endemic snake.

ACCESS-S2 is a major upgrade to the Australian Bureau of Meteorology’s multi-week to seasonal prediction system. It was made operational in October 2021, replacing ACCESS-S1. The focus of the upgrade is the addition of a new weakly coupled data assimilation system to provide initial conditions for atmosphere, ocean, land and ice fields. The model is based on the UK Met Office GloSea5-GC2 seasonal prediction system and is unchanged from ACCESS-S1, aside from minor corrections and enhancements. The performance of the assimilation system and the skill of the seasonal and multi-week forecasts have been assessed and compared to ACCESS-S1. There are improvements in the ACCESS-S2 initial conditions compared to ACCESS-S1, particularly for soil moisture and aspects of the ocean, notably the ocean currents. More realistic soil moisture initialisation has led to increased skill for forecasts over Australia, especially those of maximum temperature. The ACCESS-S2 system is shown to have increased skill of El Nino–Southern Oscillation forecasts over ACCESS-S1 during the challenging autumn forecast period. Analysis suggests that ACCESS-S2 will deliver improved operational forecast accuracy in comparison to ACCESS-S1. Assessments of the operational forecasts are underway. ACCESS-S2 represents another step forward in the development of seasonal forecast systems at the Bureau of Meteorology. However, key rainfall and sea surface temperature biases in ACCESS-S1 remain in ACCESS-S2, indicating where future efforts should be focused.

BackgroundCOVID-19 data have been generated across the United Kingdom as a by-product of clinical care and public health provision, as well as numerous bespoke and repurposed research endeavors. Analysis of these data has underpinned the United Kingdom’s response to the pandemic, and informed public health policies and clinical guidelines. However, these data are held by different organizations, and this fragmented landscape has presented challenges for public health agencies and researchers as they struggle to find relevant data to access and interrogate the data they need to inform the pandemic response at pace. ObjectiveWe aimed to transform UK COVID-19 diagnostic data sets to be findable, accessible, interoperable, and reusable (FAIR). MethodsA federated infrastructure model (COVID - Curated and Open Analysis and Research Platform [CO-CONNECT]) was rapidly built to enable the automated and reproducible mapping of health data partners’ pseudonymized data to the Observational Medical Outcomes Partnership Common Data Model without the need for any data to leave the data controllers’ secure environments, and to support federated cohort discovery queries and meta-analysis. ResultsA total of 56 data sets from 19 organizations are being connected to the federated network. The data include research cohorts and COVID-19 data collected through routine health care provision linked to longitudinal health care records and demographics. The infrastructure is live, supporting aggregate-level querying of data across the United Kingdom. ConclusionsCO-CONNECT was developed by a multidisciplinary team. It enables rapid COVID-19 data discovery and instantaneous meta-analysis across data sources, and it is researching streamlined data extraction for use in a Trusted Research Environment for research and public health analysis. CO-CONNECT has the potential to make UK health data more interconnected and better able to answer national-level research questions while maintaining patient confidentiality and local governance procedures.

The concept of exploiting tumor intrinsic deficiencies in DNA damage repair mechanisms by inhibiting compensatory DNA repair pathways is well established. For example, ATM-deficient cells show increased sensitivity to the ATR inhibitor ceralasertib. DNA damage response (DDR)-deficient cells are also more sensitive to DNA damaging agents like the DNA crosslinker pyrrolobenzodiazepine (PBD) SG-3199. However, additional antitumor benefits from targeting the DDR pathways, which could operate through the activation of the innate immune system are less well studied. DNA accumulation in the cytosol acts as an immunogenic danger signal, inducing the expression of type-I interferon (IFN) stimulated genes (ISGs) by the activation of the cGAS-STING pathway. Here, we demonstrate that ATM −/− FaDu tumor cells have higher basal expression of ISGs when compared to WT cells and respond to ceralasertib and PBD SG-3199 by inducing higher levels of ISGs in a cGAS-STING-dependent manner. We show that sensitive tumor cells treated with ceralasertib and PBD SG-3199 activate dendritic cells (DCs) via a type-I IFN-dependent mechanism. However, STING deficiency in tumor cells does not prevent DC activation, suggesting that transactivation of the STING pathway occurs within DCs. Furthermore, depletion of the cytosolic DNA exonuclease TREX1 in tumor cells increases DC activation in response to PBD SG-3199-treated tumor cells, indicating that an increase in tumor-derived cytosolic DNA may further enhance DC activation. In summary, in this study, we show that ceralasertib and PBD SG-3199 treatment not only intrinsically target tumor cells but also extrinsically increase tumor cell immunogenicity by inducing DC activation, which is enhanced in ATM-deficient cells.

Chronic blistering at the skin and/or mucous membranes, accompanied by a varying degree of inflammation, is the clinical hallmark of pemphigoid diseases that impose a major medical burden. Pemphigoid diseases are caused by autoantibodies targeting structural proteins of the epithelial basement membrane. One major pathogenic pathway of skin blistering and inflammation is activation of myeloid cells following Fc gamma receptor-dependent binding to the skin-bound immune complexes. This process requires activation of specific kinases, such as PI3Kδ, which have emerged as potential targets for the treatment of pemphigoid diseases. Yet, it is unknown if global cutaneous kinase activity present in lesional pemphigoid disease correlates with therapeutic effects following treatment with a given target-selective kinase inhibitor. To address this, we here first determined the kinase activity in three different mouse models of pemphigoid diseases: Antibody transfer-induced mucous membrane pemphigoid (MMP), antibody transfer-induced epidermolysis bullosa acquisita (EBA) and immunization-induced EBA. Interestingly, the kinome signatures were different among the three models. More specifically, PI3Kδ was within the kinome activation network of antibody transfer-induced MMP and immunization-induced EBA, but not in antibody transfer-induced EBA. Next, the therapeutic impact of the PI3Kδ-selective inhibitor parsaclisib was evaluated in the three model systems. In line with the kinome signatures, parsaclisib had therapeutic effects in antibody transfer-induced MMP and immunization-induced EBA, but not in autoantibody-induced EBA. In conclusion, kinase activation signatures of inflamed skin, herein exemplified by pemphigoid diseases, correlate with the therapeutic outcomes following kinase inhibition, demonstrated here by the PI3Kδ inhibitor parsaclisib.

Abstract Background Early mobilization after surgery is a key recommendation for people with hip fracture, however this is achieved by only 50% of people. Recumbent bike riding has been used in other populations with limited mobility and has potential to allow early exercise in people post hip fracture. The primary aim of this pilot trial was to demonstrate the feasibility of a trial protocol designed to determine the effect of early post-operative cycling in bed on outcomes in people with hip fracture. Methods Single-blinded, multi-site randomized controlled pilot trial. Fifty-one people with hip fracture were recruited within 4 days of surgery from two sites in Victoria. Participants were randomly allocated to receive either usual care (n = 25) or usual care plus active cycling in bed (n = 26). The cycling intervention was delivered on weekdays until the participant could walk 15 m with assistance of one person. The primary outcomes were trial feasibility and safety. Clinical outcomes, including mobility (Modified Iowa Level of Assistance Scale) and delirium were measured at day seven post-operatively and at hospital discharge by an assessor blinded to group. Additional outcomes at discharge included gait speed, cognition and quality of life. Results The intervention was safe, feasible and acceptable to patients and staff. Delivery of the intervention was ceased on (median) day 9.5 (IQR 7, 12); 73% of scheduled sessions were delivered; (median) 4 sessions (IQR 2.0, 5.5) were delivered per participant with (median) 9 min 34 s (IQR 04:39, 17:34) of active cycling per session. The trial protocol was feasible, however at day seven 75% of participants had not met the criterion (able to walk 15 m with assistance of one person) to cease the cycling intervention.. Conclusion In bed cycling is feasible post-operatively following hip fracture, however seven days post-operatively is too early to evaluate the impact of the cycling intervention as many participants were still receiving the intervention. A fully powered RCT to explore the effectiveness and cost efficiency of this novel intervention is warranted. Trial registration The trial was prospectively registered (25/09/2017) with the Australian New Zealand Clinical Trials Registry ACTR N12617001345370 .

Background Myotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardiorespiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown.Methods Eleven genetically diagnosed DM1 patients were recruited to examine the extent to which 12 weeks of cycling can recuperate clinical and physiological metrics. Furthermore, we studied the underlying molecular mechanisms through which exercise elicits benefits in skeletal muscle of DM1 patients.RESULTS DM1 was associated with impaired muscle function, fitness, and lung capacity. Cycling evoked several clinical, physical, and metabolic advantages in DM1 patients. We highlight that exercise-induced molecular and cellular alterations in patients do not conform with previously published data in murine models and propose a significant role of mitochondrial function in DM1 pathology. Finally, we discovered a subset of small nucleolar RNAs (snoRNAs) that correlated to indicators of disease severity.Conclusion With no available cures, our data support the efficacy of exercise as a primary intervention to partially mitigate the clinical progression of DM1. Additionally, we provide evidence for the involvement of snoRNAs and other noncoding RNAs in DM1 pathophysiology.Trial registration This trial was approved by the HiREB committee (no. 7901) and registered under ClinicalTrials.gov (NCT04187482).Funding Neil and Leanne Petroff. Canadian Institutes of Health Research Foundation (no. 143325).

We report on four new country records of tiger beetles in Paraguay and 22 new departmental records based on specimens in Paraguayan collections. We also provide substantial increases to the knowledge on distributions of numerous species in the country through additional specimen records. The first tiger beetle records from south- western Ñeembucú are also provided. New country records are illustrated and comments on previous works dealing with the Paraguayan Cicindelid fauna are summarised.

Objectives The aim of this study was to identify patient, hospital and transitional factors associated with unplanned 30-day readmissions in patients who had a total hip arthroplasty (THA).Design A cross-sectional survey was performed. All patients attending a 6-week follow-up after a THA in the Australian Capital Territory (ACT) at four public and private clinics in the ACT from 1 February 2018 to 31 January 2019, were invited to complete an ACT Transition from Hospital to Home Orthopaedic Survey.Participants Within the ACT, 431 patients over the age of 16 attending their 6-week post-surgery consultation following a THA entered and completed the survey (response rate 77%).Primary outcome measure The primary outcome measure was self-reported readmissions for any reason within 30 days of discharge after a THA. Multiple logistic regression was used to estimate ORs of factors associated with unplanned 30-day readmissions.Results Of the 431 participants (representing 40% of all THAs conducted in the ACT during the study period), 27 (6%) were readmitted within 30 days of discharge. After controlling for age and sex, patients who did not feel rested on discharge were more likely to be readmitted within 30 days than those who felt rested on discharge (OR=5.75, 95% CI: (2.13 to 15.55), p=0.001). There was no association between post-hospital syndrome (ie, in-hospital experiences of pain, sleep and diet) overall and readmission. Patients who suffered peripheral vascular disease (PVD) were significantly more likely to have an unplanned 30-day readmission (OR=16.9, 95% CI: (3.06 to 93.53), p=0.001). There was no significant difference between private and public patient readmissionsConclusions Hospitals should develop strategies that maximise rest and sleep during patients’ hospital stay. Diagnosis and optimum treatment of pre-existing PVD prior to THA should also be a priority to minimise the odds of subsequent unplanned readmissions.

Objectives The aim of this study was to investigate factors associated with unplanned 30-day readmissions following a total knee arthroplasty (TKA), including association with post-hospital syndrome, patient enablement and transition from hospital to home.Design, setting and participants A cross-sectional written survey of public and private patients attending a 6-week follow-up appointment after TKA at one of four clinical services in the Australian Capital Territory (ACT) between 1 February 2018 and 31 January 2019. Multiple logistic regression analyses were used to measure associations between patient, hospital and transitional care factors with unplanned 30-day readmissions, while controlling for known confounders.Results Of the 380 participants who completed the survey (n=380, 54% of TKAs undertaken over the study period), 3.4% (n=13; 95% CI: 1.8 to 5.8) were subsequently readmitted within 30 days of discharge after a primary hospitalisation. Public patients were significantly more likely to be readmitted within 30 days compared with private patients (adjusted OR=6.31, 95% CI: 1.59 to 25.14, p=0.009), and patients who attended rehabilitation were significantly less likely to be readmitted within 30 days of discharge than those who did not (adjusted OR=0.16, 95% CI: 0.04 to 0.57, p=0.005). There were no associations between post-hospital syndrome or patient enablement and 30-day readmissions in this study.Conclusion Reasons underlying the difference in unplanned readmission rates for public versus private patients need to be explored, including differences in surgical waiting times and the consequences for impairment and disease complexity. Strategies to foster increased participation post-surgical rehabilitation programmes need to be developed as an avenue to mitigate the burden of unplanned 30-day readmissions on individuals and health systems.

Almost half of the 400+ species described in Félix de Azara’s “Apuntamientos para la historia natural de los páxaros del Paraguay y Rio de la Plata” were new to science at the time of its publication; however, not all of these have yet been correctly identified. Azara’s No. 21 “Gavilán pardo obscuro” has long been misidentified as a dark phase of the Short-tailed Hawk Buteo brachyurus. However, the description of plumage, jizz, habitat and measurements are inconsistent with that species and Azara’s No. 21 can, in fact, be convincingly identified as a juvenile Swainson’s Hawk Buteo swainsoni, the earliest Paraguayan report of this species. No scientific names were apparently ever based on Azara No. 21.

Societal Impact Statement Biodiversity loss is happening at an unprecedented rate. Understanding and protecting biodiversity has never been more urgent, and scientific research is key to this. Fair and transparent access and benefit sharing policies enable research to take place, whilst supporting sustainable livelihoods of communities and ensuring benefits are shared. Current national legislation has been unevenly implemented and, in this article, we recommend frameworks be developed to standardize the provision and use of genetic resources for non‐commercial research. Summary Access to genetic resources for scientific research is vital to support and promote the conservation and sustainable use of the world's biodiversity. The regulatory framework for research is stipulated by Access and Benefit Sharing (ABS) legislation at a national level, but other elements – legal transparency, respect, cooperation, and trust – are essential for its effective and sustainable implementation. Despite the intention of this “ABS regime” to protect natural resources and associated knowledge from misappropriation, several studies have questioned whether national regulatory approaches have led to constraints on research and conservation. We analyse evidence and provide case studies on how these regulations are affecting research. We find that the number of Internationally Recognized Certificates of Compliance (IRCC) of the Nagoya Protocol (NP), the key compliance mechanism of the ABS system, doubled in the six months prior to February 2020 and analyse why this may be the case. Additionally, a survey of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) Authorities in 28 countries, found differences in the way the Registered Scientific Institute scheme is interpreted and used to facilitate scientific research. Our results suggest while the regulatory systems are perceived as hindering research and conservation, regulatory mechanisms enabling responsible research are becoming increasingly functional. We argue that functional and transparent systems are needed for both regulators and researchers, to ensure that non‐commercial research can continue smoothly, and present conclusions to support research for the benefit of all countries and partners involved, through appropriate frameworks for implementation and reporting.

Abstract Background We are performing a combined randomised and observational study comparing internal fixation to non-surgical management for common wrist fractures in older patients. This paper describes the statistical analysis plan. Methods/design A Combined Randomised and Observational Study of Surgery for Fractures In the distal Radius in the Elderly (CROSSFIRE) is a randomised controlled trial comparing two types of usual care for treating wrist fractures in older patients, surgical fixation using volar locking plates and non-surgical treatment using closed reduction and plaster immobilisation. The primary aim of this comparative-effectiveness study is to determine whether surgery is superior to non-surgical treatment with respect to patient-reported wrist function at 12 months post treatment. The secondary outcomes include radiographic outcomes, complication rates and patient-reported outcomes including quality of life, pain, treatment success and cosmesis. Primary analysis will use a two-sample t test and an intention-to-treat analysis using the randomised arm of the study. Statistical analyses will be two-tailed and significance will be determined by p

Although governments and higher education institutions across Europe are promoting agendas for widening the educational participation and increasing the social mobility of young people from lower socio-economic groups, very little has been written about the experiences of these individuals when seeking and entering employment. We aim to address this gap. Using a qualitative research approach, we explore the career expectations, experiences and limitations of first-generation university engineering students and graduates in Germany. The article draws upon the work of Pierre Bourdieu to demonstrate how social and cultural capitals instilled by parents and social peers are invaluable in developing personal and professional networks and eventual entry into the engineering professions. A lack of, or underdeveloped, capitals can inhibit career opportunities and ultimately the social mobility and professional choices of graduate engineers. Our research discovered that university graduates from less advantaged backgrounds face a ‘class ceiling’ at university, in obtaining an internship and then when gaining entry to and working in the engineering profession; they encounter ‘sticky steps’ at each stage of their career ladder.

Discontinuous fibre reinforced composites enable the manufacture of integrated structural components via the complex flow process of compression moulding. However, such processes can lead to the formation of detrimental weld-lines. Here, the meso-structure of carbon fibre sheet moulding compounds (C-SMC) was analysed using conventional non-destructive techniques and automated eddy current (EC) scanning, as well as destructive methods, in an attempt to identify defects such as weld-lines in this class of materials. Compression-moulded plaques with forced weld-lines in two different configurations (adjacent and opposing flow joints) were analysed, showing up to 80% strength reduction versus a defect-free plaque. The EC-determined local fibre orientation and elucidated local microstructure matched those obtained using conventional techniques, showing a dramatic fibre tow alignment parallel to the weld-lines. It was found that failure occurred in proximity to the “non-uniformity” defect regions identified by EC analyses, demonstrating the use of robot-guided EC for successful defect detection in C-SMC structures.

La Reserva Natural del Bosque Mbaracayú (RNBM) es un área protegida de 64.405 ha en Canindeyú, nordeste de Paraguay. La mayor parte de su cobertura es de Bosque Atlántico del Alto Paraná, pero incorpora también un área significante de Cerrado. Además de ocasionales investigaciones biológicas y la caza por métodos tradicionales por parte de los indígenas Aché, el bosque ha estado prácticamente intocado durante los últimos 35-40 años y, como resultado, alberga una comunidad faunística casi completa y representativa de esta región. Este artículo reporta sobre las especies de mamíferos residentes en la Reserva, que han sido verificadas por uno o más especímenes. De las más de 40 colecciones de mamíferos revisadas en Europa, América del Norte y del Sur, se conocen diez que contienen un total de 4.929 especímenes provenientes de la RNBM. Los especímenes representan una fauna diversa de mamíferos, abarcando 20 familias y 71 especies. Sumado con otros registros verificables, al menos 84 especies de mamíferos habitan en la Reserva. Reportes recientemente verificados de mamíferos adicionales en la Reserva sugieren que la investigación continuada debe ser apoyada.

Cholesterol plays a key role in the molecular and mesoscopic organisation of lipid membranes and it is expected that changes in its molecular structure (e.g., through environmental factors such as oxidative stress) may affect adversely membrane properties and function. In this study, we present evidence that oxidation of cholesterol has significant effects on the mechanical properties, molecular and mesoscopic organisation and lipid–sterol interactions in condensed monolayers composed of the main species found in the inner leaflet of the erythrocyte membrane. Using a combination of experimental methods (static area compressibility, surface dilatational rheology, fluorescence microscopy, and surface sensitive X-ray techniques) and atomistic molecular dynamics simulations, we show that oxidation of cholesterol to 7-ketocholesterol leads to stiffening of the monolayer (under both static and dynamic conditions), significant changes in the monolayer microdomain organisation, disruption in the van der Waals, electrostatic and hydrophobic interactions between the sterol and the other lipid species, and the lipid membrane hydration. Surface sensitive X-ray techniques reveal that, whilst the molecular packing mode is not significantly affected by cholesterol oxidation in these condensed phases, there are subtle changes in membrane thickness and a significant decrease in the coherence length in monolayers containing 7-ketocholesterol.

As many as 40% of the world’s plant species are currently threatened with extinction, and botanic gardens have an important role to play in restoring habitats and supporting plant species recovery in situ. Specialist horticultural skills are essential for proactive plant conservation and management. However, there are a number of impediments to deploying horticultural expertise where it is needed the most, including lack of information about which species and recovery programmes need expertise, where that expertise can be found, and institutional or practical impediments such as availability of time and funding. In this paper, the author presents details on tools and resources developed by Botanic Gardens Conservation International designed to engage and support the participation of horticulturists in plant conservation.

Discrimination is a form of chronic stress and hair cortisol concentration is an emerging biomarker of chronic stress. In a sample of 83 first-year college students (age x⋅⋅−=17.65, SD=48, 69% female, 84% United States-born, 24% Asian, 21% Latinx, and 55% White), the current study investigates associations between hair cortisol concentration with discrimination stress assessed across two timeframes: past year and past two weeks. Significant associations were observed for past year discrimination and hair cortisol concentration levels, but not for discrimination over the past two weeks. The current study contributes to a growing body of evidence linking discrimination stress exposure to neuroendocrine functioning.

Poor medication adherence is a global phenomenon that has received a significant amount of research attention yet remains largely unsolved. Medication non-adherence can blur drug efficacy results in clinical trials, lead to substantial financial losses, increase the risk of relapse and hospitalisation, or lead to death. The most common methods of measuring adherence are post-treatment measures; that is, adherence is usually measured after the treatment has begun. What the authors are proposing in this multidisciplinary study is a new technique for predicting the factors that are likely to cause non-adherence before or during medication treatment, illustrated in the context of potential non-adherence to COVID-19 antiviral medication. Fault Tree Analysis (FTA), allows system analysts to determine how combinations of simple faults of a system can propagate to cause a total system failure. Monte Carlo simulation is a mathematical algorithm that depends heavily on repeated random sampling to predict the behaviour of a system. In this study, the authors propose a new technique called Non-Adherence Tree Analysis (NATA), based on the FTA and Monte Carlo simulation techniques, to improve adherence. Firstly, the non-adherence factors of a medication treatment lifecycle are translated into what is referred to as a Non-Adherence Tree (NAT). Secondly, the NAT is coded into a format that is translated into the GoldSim software for performing dynamic system modelling and analysis using Monte Carlo. Finally, the GoldSim model is simulated and analysed to predict the behaviour of the NAT. NATA is dynamic and able to learn from emerging datasets to improve the accuracy of future predictions. It produces a framework for improving adherence by analysing social and non-social adherence barriers. Novel terminologies and mathematical expressions have been developed and applied to real-world scenarios. The results of the application of NATA using data from six previous studies in relation to antiviral medication demonstrate a predictive model which suggests that the biggest factor that could contribute to non-adherence to a COVID-19 antiviral treatment is a therapy-related factor (the side effects of the medication). This is closely followed by a condition-related factor (asymptomatic nature of the disease) then patient-related factors (forgetfulness and other causes). From the results, it appears that side effects, asymptomatic factors and forgetfulness contribute 32.44%, 22.67% and 18.22% respectively to discontinuation of medication treatment of COVID-19 antiviral medication treatment. With this information, clinicians can implement relevant interventions and measures and allocate resources appropriately to minimise non-adherence.

Introduction Infection is a major complication following joint replacement (JR) surgery. However, little data exist on baseline use of antibiotics following primary JR and how use changes with subsequent revision surgery. Objectives & Approach Our study objectives were to describe community use of antibiotics before and after primary total hip replacement (THR) and change in use pre and post revision procedure. Registry data were linked with national medication dispensing data using probabilistic record linkage. Patients with THR for osteoarthritis in a private hospital between 1999 and 2017 were included. Three groups were analysed: patients with primary procedures revised for infection, revised for non-infection reasons and those not revised. Rate of antibiotic dispensing/month was calculated as number of patients dispensed at least one antibiotic in a given month divided by number of patients at-risk. Results There were 102,577 patients included in the non-revised group, 3,156 revised for non-infection and 520 revised for infection. Prior to primary THR, baseline antibiotic dispensing rate was 9-11%/month in all groups. Post-primary rates were similar (10-11%) for non-revised and revised non-infection patients but higher (16-17%) for revised-infection patients. In 1, 6 and 12 months preceding revision for infection, antibiotic use was 55%, 27% and 22%, respectively. For patients revised for non-infection, antibiotic use was 21%, 14%, 13%, respectively. One-month following revision for infection, 82% of patients were dispensed antibiotics, remaining high (38%) at 6-months and 28% at 12-months. In the revision non-infection group, antibiotic use was 48% first month post-surgery, reducing rapidly to 15% at 6-months. Conclusion / Implications Non-revision and revision non-infection patients had similar antibiotic dispensing before and after surgery. Revision infection patients however, maintained higher antibiotic dispensing post-primary, pre and post revision. This may reflect either ongoing infection, need for long-term suppressive therapy or reluctance of treating physicians to terminate treatment.