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In the present work, we developed an effective antimicrobial surface film based on sustainable microfibrillated cellulose. The resulting porous cellulose thin film is barely noticeable to human eyes due to its submicrometer thickness, of which the surface coverage, porosity, and microstructure can be modulated by the formulations and the coating process. Using goniometers and a quartz crystal microbalance, we observed a threefold reduction in water contact angles and accelerated water evaporation kinetics on the cellulose film (more than 50% faster than that on a flat glass surface). The porous cellulose film exhibits a rapid inactivation effect against SARS-CoV-2 in 5 min, following deposition of virus-loaded droplets, and an exceptional ability to reduce contact transfer of liquid, e.g., respiratory droplets, to surfaces such as an artificial skin by 90% less than that from a planar glass substrate. It also shows excellent antimicrobial performance in inhibiting the growth of both Gram-negative and Gram-positive bacteria (Escherichia coli and Staphylococcus epidermidis) due to the intrinsic porosity and hydrophilicity. Additionally, the cellulose film shows nearly 100% resistance to scraping in dry conditions due to its strong affinity to the supporting substrate but with good removability once wetted with water, suggesting its practical suitability for daily use. Importantly, the coating can be formed on solid substrates readily by spraying, which requires solely a simple formulation of a plant-based cellulose material with no chemical additives, rendering it a scalable, affordable, and green solution as antimicrobial surface coating. Implementing such cellulose films could thus play a significant role in controlling future pan- and epidemics, particularly during the initial phase when suitable medical intervention needs to be developed and deployed.

Improving academic outcomes for economically disadvantaged students has proven challenging, particularly for children at older ages. We present two large-scale randomized controlled trials of a high-dosage tutoring program delivered to secondary school students in Chicago. One innovation is to use paraprofessional tutors to hold down cost, thereby increasing scalability. Participating in math tutoring increases math test scores by 0.18 to 0.40 standard deviations, and increases math and nonmath course grades. These effects persist into future years. The data are consistent with increased personalization of instruction as a mechanism. The benefit-cost ratio is comparable to many successful early childhood programs. (JEL H75, I21, I24, I26, I32, J13, J15)

This debate paper argues that the Office for Students (OfS) has adopted standards of evidence that are inappropriate. These standards offer a problematic typology of different evaluation types, present a flawed hierarchy, and over-prioritise experimental approaches. As the OfS uses these standards of evidence to guide the evaluation of widening participation (WP) activities, this risks misrepresenting the evidence base for different activities, and prioritising methods that may not be the most appropriate. The goal of developing explanations of how WP activities work in particular contexts requires a more nuanced approach to evaluation. Recommendations are made for future practice: the OfS should review its standards of evidence and there should be greater debate in this area, evaluation should assess how WP activities work in particular contexts, and practitioners should make use of theory-driven, qualitative methods.

Purpose: Lack of preparation for working with patients near the end of life (EoL) can lead to poor outcomes for patients and burnout for clinicians. Additionally, graduate students must also receive preparation in professional communication skills necessary for family and interprofessional interactions. Simulation provides an opportunity to practice and demonstrate these skills in a safe environment. This study examined student performance and perceptions following a simulation of clinical communication in the context of an EoL care (EoLC) conference discussion. Method: By utilizing a formative simulation with standardized patients, students demonstrated skills associated with navigating an EoLC conference discussion. The supervising educators and standardized patients evaluated students on their clinical communication and debriefing skills through rubrics. Students also provided feedback on the simulation experience. Results: Results from this simulation indicated that most students demonstrated effective clinical communication skills. Judgments from educators and standardized patients corroborate students' skill demonstration in the areas of content delivery, delivering compassionate care, communicating evidence, representing their roles, and reflection. Students struggled more in the areas of terminology use and using summary and validation skills. Student feedback about the simulation was resoundingly positive. Students remarked how the simulation advanced their learning, helped them reflect on their clinical communication skills, and provided them with exposure to fragile medical patients. Conclusion: This study provides an example of a high-fidelity replicable simulation that can be implemented to measure and encourage student skill development in clinical communication and EoLC.

Background: Recent studies have demonstrated increased microglial activation using 11 C-PK11195 positron emission tomography imaging, indicating central nervous system inflammation, in cerebral small vessel disease. However, whether such areas of neuroinflammation progress to tissue damage is uncertain. We determined whether white matter destined to become white matter hyperintensities (WMH) at 1 year had evidence of altered inflammation at baseline. Methods: Forty subjects with small vessel disease (20 sporadic and 20 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and 20 controls were recruited to this case-control observational study from in- and out-patient clinics at Addenbrooke’s Hospital, Cambridge, UK and imaged at baseline with both 11 C-PK11195 positron emission tomography and magnetic resonance imaging; and magnetic resonance imaging including diffusion tensor imaging was repeated at 1 year. WMH were segmented at baseline and 1 year, and areas of new lesion identified. Baseline 11 C-PK11195 binding potential and diffusion tensor imaging parameters in these voxels, and normal appearing white matter, was measured. Results: Complete positron emission tomography-magnetic resonance imaging data was available for 17 controls, 16 sporadic small vessel disease, and 14 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy participants. 11 C-PK11195 binding in voxels destined to become new WMH was lower than in normal appearing white matter, which did not progress to WMH (−0.133[±0.081] versus −0.045 [±0.044]; P −6 versus 1045 [±149]×10 −6 mm 2 /s and 0.37±0.05 versus 0.29±0.06, both P Conclusions: White matter tissue destined to develop into new WMH over the subsequent year is associated with both lower neuroinflammation, and white matter ultrastructural damage at baseline. Our results suggest that this tissue is already damaged 1 year prior to lesion formation. This may reflect that the role of neuroinflammation in the lesion development process occurs at an early stage, although more studies over a longer period would be needed to investigate this further.

Full list of authors: Amaro-Seoane, Pau; Andrews, Jeff; Sedda, Manuel Arca; Askar, Abbas.; Baghi, Quentin; Balasov, Razvan; Bartos, Imre; Bavera, Simone S.; Bellovary, Jillian; Berry, Christopher P. L.; Berti, Emanuele; Bianchi, Stefano; Blecha, Laura; Blondin, Stephane; Bogdanovic, Tamara; Boissier, Samuel; Bonetti, Matteo; Bonoli, Silvia; Bortolas, Elisa; Breivik, Katelyn; Capelo, Pedro R.; Caramete, Laurentiu; Cattorini, Federico; Charisi, Maria; Chaty, Sylvain; Chen, Xian; Chruslinska, Martyna; Chua, Alvin J. K.; Church, Ross; Colpi, Monica; D'Orazio, Daniel; Danielski, Camilla; Davies, Melvyn B.; Dayal, Pratika; De Rosa, Alessandra; Derdzinski, Andrea; Destounis, Kyriakos; Dotti, Massimo; Dutan, Ioana; Dvorkin, Irina; Fabj, Gaia; Foglizzo, Thierry; Ford, Saavik; Fouvry, Jean-Baptiste; Franchini, Alessia; Fragos, Tassos; Fryer, Chris; Gaspari, Massimo; Gerosa, Davide; Graziani, Luca; Groot, Paul; Habouzit, Melanie; Haggard, Daryl; Haiman, Zoltan; Han, Wen-Biao; Istrate, Alina; Johansson, Peter H.; Khan, Fazeel Mahmood; Kimpson, Tomas; Kokkotas, Kostas; Kong, Albert; Korol, Valeriya; Kremer, Kyle; Kupfer, Thomas; Lamberts, Astrid; Larson, Shane; Lau, Mike; Liu, Dongliang; Lloyd-Ronning, Nicole; Lodato, Giuseppe; Lupi, Alessandro; Ma, Chung-Pei; Maccarone, Tomas; Mandel, Ilya; Mangiagli, Alberto; Mapelli, Michela; Mathis, Stephane; Mayer, Lucio; McGee, Sean; McKernan, Berry; Miller, M. Coleman; Mota, David F.; Mumpower, Matthew; Nasim, Syeda S.; Nelemans, Gijs; Noble, Scott; Pacucci, Fabio; Panessa, Francesca; Paschalidis, Vasileios; Pfister, Hugo; Porquet, Delphine; Quenby, John; Ricarte, Angelo; Roepke, Friedrich K.; Regan, John; Rosswog, Stephan; Ruiter, Ashley; Ruiz, Milton; Runnoe, Jessie; Schneider, Raffaella; Schnittman, Jeremy; Secunda, Amy; Sesana, Alberto; Seto, Naoki; Shao, Lijing; Shapiro, Stuart; Sopuerta, Carlos; Stone, Nicholas C.; Suvorov, Arthur; Tamanini, Nicola; Tamfal, Tomas; Tauris, Thomas; Temmink, Karel; Tomsick, John; Toonen, Silvia; Torres-Orjuela, Alejandro; Toscani, Martina; Tsokaros, Antonios; Unal, Caner; Vazquez-Aceves, Veronica; Valiante, Rosa; van Putten, Maurice; van Roestel, Jan; Vignali, Christian; Volonteri, Marta; Wu, Kinwah; Younsi, Ziri; Yu, Shenghua; Zane, Silvia; Zwick, Lorenz; Antonini, Fabio; Baibhav, Vishal; Barausse, Enrico; Bonilla Rivera, Alexander; Branchesi, Marica; Branduardi-Raymont, Graziella; Burdge, Kevin; Chakraborty, Srija; Cuadra, Jorge; Dage, Kristen; Davis, Benjamin; de Mink, Selma E.; Decarli, Roberto; Doneva, Daniela; Escoffier, Stephanie; Gandhi, Poshak; Haardt, Francesco; Lousto, Carlos O.; Nissanke, Samaya; Nordhaus, Jason; O'Shaughnessy, Richard; Portegies Zwart, Simon; Pound, Adam; Schussler, Fabian; Sergijenko, Olga; Spallicci, Alessandro; Vernieri, Daniele; Vigna-Gomez, Alejandro.-- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/., The Laser Interferometer Space Antenna (LISA) will be a transformative experiment for gravitational wave astronomy, and, as such, it will offer unique opportunities to address many key astrophysical questions in a completely novel way. The synergy with ground-based and space-born instruments in the electromagnetic domain, by enabling multi-messenger observations, will add further to the discovery potential of LISA. The next decade is crucial to prepare the astrophysical community for LISA’s first observations. This review outlines the extensive landscape of astrophysical theory, numerical simulations, and astronomical observations that are instrumental for modeling and interpreting the upcoming LISA datastream. To this aim, the current knowledge in three main source classes for LISA is reviewed; ultra-compact stellar-mass binaries, massive black hole binaries, and extreme or interme-diate mass ratio inspirals. The relevant astrophysical processes and the established modeling techniques are summarized. Likewise, open issues and gaps in our understanding of these sources are highlighted, along with an indication of how LISA could help making progress in the different areas. New research avenues that LISA itself, or its joint exploitation with upcoming studies in the electromagnetic domain, will enable, are also illustrated. Improvements in modeling and analysis approaches, such as the combination of numerical simulations and modern data science techniques, are discussed. This review is intended to be a starting point for using LISA as a new discovery tool for understanding our Universe. © The Author(s) 2023, corrected publication 2023., P. Dayal acknowledges support from the European Research council (ERC-717001) and from the Netherlands Research Council NWO (016.VIDI.189.162). P.H. Johansson acknowledges the support from the European Research Council (ERC-818930). S. Toonen acknowledges support from the Netherlands Research Council NWO (VENI 639.041.645 Grants) C. Unal is supported by European Structural and Investment Funds and the Czech Ministry of Education, Youth and Sports (Project CoGraDS - CZ.02.1.01/0.0/0.0/15_003/0000437). S. Chaty acknowledges the LabEx UnivEarthS for the funding of Interface project I10 “From binary evolution towards merging of compact objects”. A. De Rosa acknowledges financial contribution from the agreement ASI-INAF n.2017-14-H.O E. Berti is supported by NSF Grants No. PHY-1912550 and AST-2006538, NASA ATP Grants No. 17-ATP17-0225 and 19-ATP19-0051, NSF-XSEDE Grant No. PHY-090003, and NSF Grant PHY-20043. D. Gerosa is supported by European Union’s H2020 ERC Starting Grant No. 945155–GWmining, Leverhulme Trust Grant No. RPG-2019-350 and Royal Society Grant No. RGS-R2-202004. T. Bogdanovic acknowledges support by the NASA award No. 80NSSC19K0319 and by the NSF award AST-1908042. D. Porquet acknowledges funding support from CNES. C. Danielski acknowledges financial support from the State Agency for Research of the Spanish MCIU through the “Center of Excellence Severo Ochoa” award to the Instituto de Astrofísica de Andalucía (SEV-2017-0709) B.L. Davis acknowledges support from Tamkeen under the NYU Abu Dhabi Research Institute Grant CAP3. F. Pacucci acknowledges support from a Clay Fellowship by the SAO and from the Black Hole Initiative, which is funded by grants from the John Templeton Foundation and the Gordon and Betty Moore Foundation. A.J. Ruiter acknowledges support from the Australian Research Council Future Fellowship Grant FT170100243. V. Paschalidis is supported by NSF Grant PHY-1912619 and NASA Grant 80NSSC20K1542 to the University of Arizona, and NSF-XSEDE Grant TG-PHY190020. D. Haggard acknowledges support from the NSERC Discovery Grant and Canada Research Chairs programs, and the Bob Wares Science Innovation Prospectors Fund. M. Toscani acknowledges European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant Agreement No. 823823 (RISE DUSTBUSTERS project) and COST Action CA16104 - Gravitational waves, black holes and fundamental physics, supported by COST (European Cooperation in Science and Technology). M. Chruslinska, A. Istrate and G. Nelemans acknowledge support from Netherlands Research Council NWO. T. Fragos and S. Bavera acknowledge support from a Swiss National Science Foundation Professorship Grant (project numbers PP00P2_176868 and PP00P2_211006)., With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2021-001131-S).

IntroductionHard armour plates provide coverage to essential anatomical structures in the torso that, if injured, would likely be responsible for death before damage control surgery can be undertaken. Existing front and rear OSPREY plates in conjunction with Mark 2 plates used at the sides in current UK Armed Forces personal armour systems are provided in a single size, used by both female and male users.MethodsCT scans of 45 female UK military personnel were analysed. Distances between anatomical structures representing threshold (absolute minimum) and objective (the maximum level of coverage beyond which there is limited further benefit) coverage of the torso were determined and compared with OSPREY and Mark 2 plate dimensions. Sample characteristics were compared with the 2006/2007 UK Armed Forces Anthropometric Survey.ResultsNo statistical difference was found between sample means for stature (p=0.131) and mass (p=0.853) from those of the anthropometric survey in this sample. The height of both the front OSPREY plates exceeded the threshold coverage (suprasternal notch to lower border of the 10th rib) for all women studied. The height of the Mark 2 plate exceeds the objective coverage from the side for all women studied.ConclusionsBased on a plate height providing threshold coverage of all women up to the 50th percentile, the height of the front and rear OSPREY plates could be reduced by 36mm and 31mm respectively. Based on a presumption that a side plate should cover up to the 95th percentile, the Mark 2 plate achieves the objective height and width for the female population studied. Strong evidence was found to support the UK Ministry of Defence requirement for procurement of new front and rear plates of multiple heights for both female and male users.

The purpose of this study was to examine state-level early learning standards specific to physical development, including fundamental motor skills and gross motor development for preschool-aged children in the United States. All standards related to motor development and specific to children ages 3–5 years were extracted from publicly available online documents from all 50 states. Upon initial review, 961 standards were extracted from all documents. Through aggregation of similar skills and elimination of duplicates across states, 48 unique skills were identified. Frequencies and proportions of states that included each skill in their standards were calculated. Descriptive results indicate that none of the 48 skills were included as a standard across all 50 states. Only three skills, running, jumping, and throwing a ball overhand were a standard in over 75% of states. Most of the skills were standards in less than 50% of states. Trends from these data show that a wide range of motor skills are included within preschool physical development standards within the United States, with large variability among states. Considering this variability, and currently low levels of motor competence among young children, additional evaluation, and future creation of best practice preschool physical development standards are warranted.

Natural infection with SARS-CoV-2 induces a robust circulating memory B cell (Bmem) population, which remains stable in number at least 8 months post-infection despite the contraction of antibody levels after 1 month. Multiple vaccines have been developed to combat the virus. These include two new formulations, mRNA and adenoviral vector vaccines, which have varying efficacy rates, potentially related to their distinct capacities to induce humoral immune responses. The mRNA vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) elicit significantly higher serum IgG and neutralizing antibody levels than the adenoviral vector ChAdOx1 (AstraZeneca) and Ad26.COV2.S (Janssen) vaccines. However, all vaccines induce Spike- and RBD-specific Bmem, which are vital in providing long-lasting protection in the form of rapid recall responses to subsequent infections. Past and current SARS-CoV-2 variants of concern (VoC) have shown the capacity to escape antibody neutralization to varying degrees. A booster dose with an mRNA vaccine following primary vaccination restores antibody levels and improves the capacity of these antibodies and Bmem to bind viral variants, including the current VoC Omicron. Future experimental research will be essential to evaluate the durability of protection against VoC provided by each vaccine and to identify immune markers of protection to enable prognostication of people who are at risk of severe complications from COVID-19.

Refereed/Peer-reviewed Background: Current evidence favors a multidisciplinary biopsychosocial approach to the management of chronic non-specific low back pain (CLBP). However, it is unclear whether such an approach is facilitated by current clinical guidelines. This rapid review set out to examine the extent to which clinical guideline recommendations for managing CLBP address domains of the biopsychosocial approach. Methods: MEDLINE, EMBASE, CINAHL, and the gray literature were searched for any clinical guidelines targeting the management of CLBP, published within the last 6 years. Title/abstract and full-text screening were undertaken by two reviewers using the accelerated approach. Data extraction and critical appraisal were completed by two reviewers, independently. Extracted data were synthesized in narrative form. Results: Fifteen guidelines met the review inclusion criteria. One-half of the guidelines were considered to be of medium quality. All guidelines provided management recommendations addressing the biological domain of the biopsychosocial approach; 13 (87%) guidelines reported recommendations addressing the psychological domain, and 8 (53%) guidelines presented recommendations addressing the social domain. Only 53% (8/15) of guidelines reported recommendations addressing all three domains of the biopsychosocial approach. Guideline recommendations both across and within the biopsychosocial domains were varied and inconsistent. Conclusions: The CLBP clinical guidelines included in this review provided detailed guidance on the biological domain, yet limited attention and detail were afforded to the psychological and social domains. Several recommendations are presented on how to improve the quality of future CLBP guidelines, and to help foster the provision of a biopsychosocial approach to CLBP management.

INTRODUCTION: Studies show that the COVID-19 pandemic disproportionately affected people with diabetes and those from disadvantaged backgrounds. During the first 6 months of the UK lockdown, > 6.6 M glycated haemoglobin (HbA1c) tests were missed. We now report variability in the recovery of HbA1c testing, and its association with diabetes control and demographic characteristics. METHODS: In a service evaluation, we examined HbA1c testing across ten UK sites (representing 9.9% of England's population) from January 2019 to December 2021. We compared monthly requests from April 2020 to those in the equivalent 2019 months. We examined effects of (i) HbA1c level, (ii) between-practice variability, and (iii) practice demographics. RESULTS: In April 2020, monthly requests dropped to 7.9-18.1% of 2019 volumes. By July 2020, testing had recovered to 61.7-86.9% of 2019 levels. During April-June 2020, we observed a 5.1-fold variation in the reduction of HbA1c testing between general practices (12.4-63.8% of 2019 levels). There was evidence of limited prioritization of testing for patients with HbA1c > 86 mmol/mol during April-June 2020 (4.6% of total tests vs. 2.6% during 2019). Testing in areas with the highest social disadvantage was lower during the first lockdown (April-June 2020; trend test p < 0.001) and two subsequent periods (July-September and October-December 2020; both p < 0.001). By February 2021, testing in the highest deprivation group had a cumulative fall in testing of 34.9% of 2019 levels versus 24.6% in those in the lowest group. CONCLUSION: Our findings highlight that the pandemic response had a major impact on diabetes monitoring and screening. Despite limited test prioritization in the > 86 mmol/mol group, this failed to acknowledge that those in the 59-86 mmol/mol group require consistent monitoring to achieve the best outcomes. Our findings provide additional evidence that those from poorer backgrounds were disproportionately disadvantaged. Healthcare services should redress this health inequality.

The determination of the number of mixture components (the order) of a finite mixture model has been an enduring problem in statistical inference. We prove that the closed testing principle leads to a sequential testing procedure (STP) that allows for confidence statements to be made regarding the order of a finite mixture model. We construct finite sample tests, via data splitting and data swapping, for use in the STP, and we prove that such tests are consistent against fixed alternatives. Simulation studies and real data examples are used to demonstrate the performance of the finite sample tests-based STP, yielding practical recommendations of their use as confidence estimators in combination with point estimates such as the Akaike information or Bayesian information criteria. In addition, we demonstrate that a modification of the STP yields a method that consistently selects the order of a finite mixture model, in the asymptotic sense. Our STP is not only applicable for order selection of finite mixture models, but is also useful for making confidence statements regarding any sequence of nested models.

Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 ( TBK1 ) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg 228 →His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72 , TBK1 , and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.

Primary intraocular tumours are infrequent in birds. A 2-year-old male Lady Gouldian finch (Erythrura gouldiae) originally presented to the referring veterinarian after the owner noticed mild swelling of the right eye. After the eye had enlarged rapidly and bulged from the orbit, the bird was seen at the referral hospital. Enucleation was attempted but the bird died after sedation. The eye was removed and, on sectioning, a mass was seen primarily in the vitreous chamber with extension through the sclera to the retrobulbar area. After routine histology, immunohistochemistry and electron microscopy, the mass was diagnosed as an embryonal tumour of probable retinal origin. This type of tumour has rarely been documented in birds and we could find no references to any report in Estrildidae.

Vladislav Berdunov,1 Steve Millen,2 Andrew Paramore,2 Jane Griffin,3 Sarah Reynia,2 Nina Fryer,2 Rebecca Brown,1 Louise Longworth1 1PHMR Ltd, London, UK; 2Exact Sciences, London, UK; 3Jane Griffin Associates, East Molesey, UKCorrespondence: Vladislav Berdunov, PHMR Ltd, Berkeley Works, Berkley Grove, London, NW1 8XY, UK, Tel +44 20 3432 7450, Email vlad.berdunov@phmr.comBackground: The 21-gene assay (the Oncotype DX Breast Recurrence Score® test) is a validated multigene assay which produces the Recurrence Score® result (RS) to inform decisions on the use of adjuvant chemotherapy in human epidermal growth factor receptor 2-negative (HER2-), hormone receptor positive (HR+) early invasive breast cancer. A model-based economic evaluation estimated the cost-effectiveness of the 21-gene assay against the use of clinical risk tools alone based on the latest evidence from prospective studies.Methods: The proportion of patients assigned to chemotherapy conditional on their RS result was obtained from retrospective data from the Clalit registry. The probability of distant recurrence with endocrine and chemo-endocrine therapy conditional on RS result was obtained from TAILORx and NSABP B-20 trials. The cost-effectiveness of the 21-gene assay compared to using clinical risk tools alone was estimated in terms of cost per quality-adjusted life-year (QALY) over a lifetime horizon.Results: The 21-gene assay was more effective (0.17 more quality-adjusted life years) at a lower cost (-£ 519) over a lifetime compared to clinical risk alone. The model results were sensitive to assumptions around the magnitude of benefit of chemotherapy in the high RS result subgroup. Other assumptions underpinning the model, such as the proportion of patients assigned to chemotherapy in the low and mid-range RS result subgroups and long-term distant recurrence probabilities, had a smaller impact on the results.Conclusion: The analysis showed that the cost-effectiveness of the 21-gene assay is sensitive to assumptions for chemotherapy sparing for patients with RS 0– 25 whose outcomes with endocrine therapy are no worse compared to chemotherapy-assigned patients, and a chemotherapy benefit in the RS 26– 100 group. Future studies need to incorporate a wider set of tumour profiling tests other than the 21-gene assay to allow a direct comparison of their cost-effectiveness.Keywords: cost-effectiveness, multigene assay, breast cancer, chemotherapy, the Oncotype DX test, 21-gene assay

The authors wish to thank J.M. Torrejón for the organization of the Athena-multi-messenger Workshops, held on November 27 - 29, 2018, in Alicante, Spain and on 5 May 2020 - 6 May 2020 in videoconference., In this paper we explore the scientific synergies between Athena and some of the key multi-messenger facilities that should be operative concurrently with Athena. These facilities include LIGO A+, Advanced Virgo+ and future detectors for ground-based observation of gravitational waves (GW), LISA for space-based observations of GW, IceCube and KM3NeT for neutrino observations, and CTA for very high energy observations. These science themes encompass pressing issues in astrophysics, cosmology and fundamental physics such as: the central engine and jet physics in compact binary mergers, accretion processes and jet physics in Super-Massive Binary Black Holes (SMBBHs) and in compact stellar binaries, the equation of state of neutron stars, cosmic accelerators and the origin of Cosmic Rays (CRs), the origin of intermediate and high-Z elements in the Universe, the Cosmic distance scale and tests of General Relativity and the Standard Model. Observational strategies for implementing the identified science topics are also discussed. A significant part of the sources targeted by multi-messenger facilities is of transient nature. We have thus also discussed the synergy of Athena with wide-field high-energy facilities, taking THESEUS as a case study for transient discovery. This discussion covers all the Athena science goals that rely on follow-up observations of high-energy transients identified by external observatories, and includes also topics that are not based on multi-messenger observations, such as the search for missing baryons or the observation of early star populations and metal enrichment at the cosmic dawn with Gamma-Ray Bursts (GRBs)., Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature., This research has been supported by the European Union’s Horizon 2020 programme under the AHEAD (grant agreement number 654215) and AHEAD2020 project (grant agreement n. 871158). FJC and SMN acknowledges funding under project RTI2018-096686-B-C21 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”, and by the Unidad de Excelencia María de Maeztu, ref. MDM-2017-0765.

Refereed/Peer-reviewed Introduction: Different cultures and societal structures influence the ethical experiences of physiotherapists. Objective: The study aimed to discover and describe contextual shades of ethical situations experienced by physiotherapists in their global practice. Methods: This paper reports the qualitative analysis of responses to an optional open question in an internationally distributed online survey (ESPI study) with 1,212 participants from 94 countries. All responses were coded to five categories describing the data’s relationship to the survey list of ethical situations. Data that described new ethical situations were analyzed thematically. Results: Three hundred and fifty four individual responses to the optional survey question reported400 ethical issues. Three hundred and seventy-eight of these issues were associated with the original survey questions. Twenty-two responses raised four new themes of ethical issues: lack of regulatory and/or accreditation policy and infrastructure, lack of recognition of the role and position of physiotherapists in healthcare, economic factors driving the conduct of practice, and political threats. Discussion: Local contexts and pressures of workplaces and societies in which physiotherapists practice make it almost impossible for some practitioners to comply with codes of ethics. Physiotherapists need support and preparation to respond to local affordances and the complexity, ambiguity, and sometimes messiness of ethical situations encountered in their practice. Conclusion: The findings highlight the relevance of cross-cultural research in the field of physiotherapy, and the necessity of investigating and bridging the gap between professional ethics theory and practice in diverse settings.

Snakebite envenoming is a global public health issue that causes significant morbidity and mortality, particularly in low-income regions of the world. The clinical manifestations of envenomings vary depending on the snake’s venom, with paralysis, haemorrhage, and necrosis being the most common and medically relevant effects. To assess the efficacy of antivenoms against dermonecrosis, a preclinical testing approach involvesin vivomouse models that mimic local tissue effects of cytotoxic snakebites in humans. However, current methods for assessing necrosis severity are time-consuming and susceptible to human error. To address this, we present the Venom Induced Dermonecrosis Analysis tool (VIDAL), a machine-learning-guided image-based solution that can automatically identify dermonecrotic lesions in mice, adjust for lighting biases, scale the image, extract lesion area and discolouration, and calculate the severity of dermonecrosis. We also introduce a new unit, the dermonecrotic unit (DnU), to better capture the complexity of dermonecrosis severity. Our tool is comparable to the performance of state-of-the-art histopathological analysis, making it an accessible, accurate, and reproducible method for assessing dermonecrosis. Given the urgent need to address the neglected tropical disease that is snakebite, high-throughput technologies such as VIDAL are crucial in developing and validating new and existing therapeutics for this debilitating disease.

Objectives To explore the relationship between indices of hypoxia and vascular function from 18F-fluoromisonidazole ([18F]-FMISO)-PET/MRI with immunohistochemical markers of hypoxia and vascularity in oestrogen receptor–positive (ER +) breast cancer. Methods Women aged > 18 years with biopsy-confirmed, treatment-naïve primary ER + breast cancer underwent [18F]-FMISO-PET/MRI prior to surgery. Parameters of vascular function were derived from DCE-MRI using the extended Tofts model, whilst hypoxia was assessed using the [18F]-FMISO influx rate constant, Ki. Histological tumour sections were stained with CD31, hypoxia-inducible factor (HIF)-1α, and carbonic anhydrase IX (CAIX). The number of tumour microvessels, median vessel diameter, and microvessel density (MVD) were obtained from CD31 immunohistochemistry. HIF-1α and CAIX expression were assessed using histoscores obtained by multiplying the percentage of positive cells stained by the staining intensity. Regression analysis was used to study associations between imaging and immunohistochemistry variables. Results Of the lesions examined, 14/22 (64%) were ductal cancers, grade 2 or 3 (19/22; 86%), with 17/22 (77%) HER2-negative. [18F]-FMISO Ki associated negatively with vessel diameter (p = 0.03), MVD (p = 0.02), and CAIX expression (p = 0.002), whilst no significant relationships were found between DCE-MRI pharmacokinetic parameters and immunohistochemical variables. HIF-1α did not significantly associate with any PET/MR imaging indices. Conclusion Hypoxia measured by [18F]-FMISO-PET was associated with increased CAIX expression, low MVD, and smaller vessel diameters in ER + breast cancer, further corroborating the link between inadequate vascularity and hypoxia in ER + breast cancer. Key Points • Hypoxia, measured by [18F]-FMISO-PET, was associated with low microvessel density and small vessel diameters, corroborating the link between inadequate vascularity and hypoxia in ER + breast cancer. • Increased CAIX expression was associated with higher levels of hypoxia measured by [18F]-FMISO-PET. • Morphologic and functional abnormalities of the tumour microvasculature are the major determinants of hypoxia in cancers and support the previously reported perfusion-driven character of hypoxia in breast carcinomas.

Background Guidelines recommend the assessment of cortisol secretion in patients with adrenal incidentalomas (AI) using the overnight dexamethasone suppression test (ONDST). This requires attendance to a health care facility and venepuncture. Alternatively, the ONDST can be done by measuring salivary cortisol and cortisone which can be collected at home. We aimed to assess the utility of these measurements in patients with AI. Materials and Methods A retrospective analysis of data from 173 patients with AI who underwent an ONDST and salivary cortisol/cortisone diurnal studies. Serum and salivary cortisol and salivary cortisone were collected at 09:00, late night and at 09:00 post dexamethasone. Dexamethasone levels were measured in the post dexamethasone samples. Serum and salivary samples were analysed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Stata. Results We identified a strong correlation between salivary cortisone and serum cortisol post 1 mg dexamethasone (r = 0.95). Stepwise multivariate regression showed that post-dexamethasone salivary cortisone, baseline serum cortisol, salivary cortisone suppression (pre: post-dexamethasone ratio) and sex as the only significant or near significant independent variables. Performance of predictive indices using these four parameters (sensitivity = 88.5%, specificity = 91.2%; kappa 0.80) and post-dexamethasone salivary cortisone alone (sensitivity = 85.3%, specificity = 91.7%; kappa 0.77) were comparable when used to predict an ONDST serum cortisol of ≤50 nmol/L. No correlation was observed with any of the other measured parameters. Conclusion In AI patients, post dexamethasone, salivary cortisone correlates very strongly with serum cortisol in the ONDST and could therefore be used as an alternative sampling method which does not require venepuncture or attendance to hospital.

Protein structure determination is a critical aspect of biological research, enabling us to understand protein function and potential applications. Recent advances in deep learning and artificial intelligence have led to the development of several protein structure prediction tools, such as AlphaFold2 and ColabFold. However, their performance has primarily been evaluated on well-characterised proteins, and comparisons using proteins with poor reference templates are lacking. In this study, we evaluated three modelling tools on their prediction of over 1000 snake venom toxin structures with no reference templates. Our findings show that AlphaFold2 (AF2) performed the best across all assessed parameters. We also observed that ColabFold (CF) only scored slightly worse than AF2, while being computationally less intensive. All tools struggled with regions of intrinsic disorder, such as loops and propeptide regions, and performed well in predicting the structure of functional domains. Overall, our study highlights the importance of exercising caution when working with proteins that have poor reference templates, are large, and contain flexible regions. Nonetheless, leveraging computational structure prediction tools can provide valuable insights into the modelling of protein interactions with different targets and reveal potential binding sites, active sites, and conformational changes, as well as into the design of potential molecular binders for reagent, diagnostic, or therapeutic purposes.StatementRecent advances in machine learning have led to the development of new protein structure prediction tools. However, these tools have mainly been tested on well-known proteins and their performance on proteins without known templates is unclear. This study evaluated the performance of three tools on over 1000 snake venom toxins. We found that while caution is required when studying poorly characterised proteins, these tools offer valuable opportunities to understand protein function and applications.

Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.