Slipping Away: Slippage in Hazard Ratios Over Datacuts and Its Impact on Immuno-oncology Combination Economic Evaluations.

OBJECTIVES: This study examines the impact of slippage in hazard ratios (tending toward the null over subsequent datacuts) for overall survival for combination treatment with a PD-(L)-1 inhibitor and a tyrosine kinase inhibitor in advanced renal cell carcinoma. METHODS: Four trials' Kaplan-Meier curves were digitized over several datacuts and fitted with standard parametric curves. Accuracy and consistency of early data projections were calculated versus observed restricted mean survival time and fitted lifetime survival from the longest follow-up datacut. The change in economically justifiable price (eJP) was calculated fitting the same curve to both arms, using an assumed average utility of 0.7 and willingness-to-pay threshold of £30 000 per quality-adjusted life-year. The eJP represents the lifetime justifiable price increment for the new treatment, including differences in drug-, administration-, and disease-related costs. RESULTS: Slippage in hazard ratios was observed in trials with longer follow-up, potentially influenced by subsequent PD-(L)-1 use after tyrosine kinase inhibitor monotherapy, early stoppage of PD-(L)-1, and development of resistance. Lognormal and log-logistic curves were more likely to overpredict the observed result; Gompertz and gamma underpredicted. Statistical measures of goodness of fit did not select the curves that resulted in the RMST closest to what was observed in the final data cut. Large differences in incremental mean life-years were observed between even the penultimate and final datacuts for most of the fitted curves, meaningfully affecting the eJP. CONCLUSIONS: This work demonstrates the challenge in predicting treatment benefits with novel therapies using immature data. Incorporating information on the impact of subsequent treatment is likely to play a key role in improving predictions.

Post-hospitalisation COVID-19 cognitive deficits at one year are global and associated with elevated brain injury markers and grey matter volume reduction.

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who had required hospitalisation, compared to 2,927 normative matched controls. Cognitive deficits were global and associated with elevated brain injury markers, and reduced anterior cingulate cortex volume one year after COVID-19. The severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy were associated with greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies.

Time to Update-Requesting Inclusive Submission Categories for Oncology Research.

Time to update abstract submission categories to promote dissemination of global oncology research.

Functional-Molecular Mechanisms of Sympathetic-Parasympathetic Dysfunction in PVC-Induced Cardiomyopathy Revealed by Dual Stressor PVC-Exercise Challenge.

BACKGROUND: The significance of autonomic dysfunction in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remain unknown. OBJECTIVES: Utilizing a novel "dual stressor" provocative challenge combining exercise with premature ventricular contraction (PVCs), the authors characterized the functional and molecular mechanisms of cardiac autonomic (cardiac autonomic nervous system) remodeling in a PVC-CM animal model. METHODS: In 15 canines (8 experimental, 7 sham), we implanted pacemakers and neurotelemetry devices and subjected animals to 12 weeks of bigeminal PVCs to induce PVC-CM. Sympathetic nerve activity (SNA), vagal nerve activity (VNA), and heart rate were continuously recorded before, during, and after treadmill exercise challenge with and without PVCs, at baseline and after development of PVC-CM. Western blot and enzyme-linked immunosorbent assay were used to evaluate molecular markers of neural remodeling. RESULTS: Exercise triggered an increase in both SNA and VNA followed by late VNA withdrawal. With PVCs, the degree of exercise-induced SNA augmentation was magnified, whereas late VNA withdrawal became blunted. After PVC-CM development, SNA was increased at rest but failed to adequately augment during exercise, especially with PVCs, coupled with impaired VNA and heart rate recovery after exercise. In the remodeled cardiac autonomic nervous system, there was widespread sympathetic hyperinnervation and elevated transcardiac norepinephrine levels but unchanged parasympathetic innervation, indicating sympathetic overload. However, cardiac nerve growth factor was paradoxically downregulated, suggesting an antineurotrophic counteradaptive response to PVC-triggered sympathetic overload. CONCLUSIONS: Sympathetic overload, sympathetic dysfunction, and parasympathetic dysfunction in PVC-CM are unmasked by combined exercise and PVC challenge. Reduced cardiac neurotrophic factor might underlie the mechanisms of this dysfunction. Neuromodulation therapies to restore autonomic function could constitute a novel therapeutic approach for PVC-CM.

How triacylglycerol thermal history impacts film removal by surfactant solution.

HYPOTHESIS: The physical and mechanical properties of triacylglycerols (TAGs), or 'fats', depend on their composition and thermal history which, in turn, impact crystal structure and morphology. We examine whether thermal history can be mechanistically related to film removal by a surfactant solution. EXPERIMENTS: Model TAG mixtures, comprising triolein:tripalmitin:tristearin 0.5:0.3:0.2, were subjected to a range of cooling profiles from the melt (0.5-80°C/min, Newtonian and annealed), and the resulting solid films characterised by microscopy, X-ray diffraction, infrared spectroscopy, and contact angle measurements. Film removal from a model glass substrate by an aqueous surfactant solution of sodium dodecylsulphate and dodecyldimethylamine oxide at room temperature fixed at 25°C was examined under quiescent flow conditions. FINDINGS: Quantitative relations are established between TAG cooling profile, crystal structure and morphology, surface energy γSFE, and removal (or 'cleaning'). In general, films cooled slowly from the melt yield heterogeneous morphologies with predominantly ß1' phase, higher polar γSFE, and faster removal timescales. By contrast, rapid cooling results in homogeneous films, rich in ß2' phase, low polar γSFE, and long removal times. Our results elucidate the non-trivial impact of TAG thermal history, connecting the multiscale semi-crystalline structure to surface energy, and eventually to film delamination by micellar solutions.

Concentration Dependent Asymmetric Synergy in SDS-DDAO Mixed Surfactant Micelles.

We investigate the structure and interactions of a model anionic/amphoteric mixed surfactant micellar system, namely, sodium dodecyl sulfate (SDS) and N,N-dimethyldodecylamine N-oxide (DDAO), employing SANS, FTIR, DLS, and pH measurements, in the range 0.1-100 mM total surfactant concentration and 0-100% DDAO. Increasing surfactant concentration is found to elongate the prolate ellipsoid micelles (RPolar ∼ 25-40 Å), accompanied by up to a 6-fold increase in micellar charge. The surfactant synergy, in terms of micellar charge and size, diffusion coefficient, solution pH, and headgroup interactions, was found to vary with concentration. At lower concentrations (≤50 mM), the SDS-DDAO ratio of maximum synergy is found to be asymmetric (at 65-85% DDAO), which is rationalized using regular solution theory, suggesting an equilibrium between Na+ dissociation, DDAO protonation, and counterion concentration. At higher concentrations, maximum synergy shifts toward the equimolar ratio. Overall, our study expands and unifies previous reports, providing a comprehensive understanding for this model, synergetic mixed micellar system.

The clinical presentation of avoidant restrictive food intake disorder in children and adolescents is largely independent of sex, autism spectrum disorder and anxiety traits.

Background: Avoidant restrictive food intake disorder (ARFID) is a new eating disorder with a heterogeneous clinical presentation. It is unclear which patient characteristics contribute to its heterogeneity. Methods: To identify these patient characteristics, we performed symptom-level correlation and driver-level regression analyses in our cross-sectional study in up to 261 ARFID patients (51% female; median age = 12.7 years) who were assessed at the Maudsley Centre for Child and Adolescent Eating Disorders, London between November 2019 and July 2022. Findings: Symptoms across the three drivers 1) avoidance based on sensory characteristics of food; 2) apparent lack of interest in eating; and 3) concern about aversive consequences positively correlated with each other. Patients' anxiety traits showed the greatest positive correlations with symptoms of concern about aversive consequences of eating. Patient sex was not significantly associated with any of the three ARFID drivers. Patients with comorbid autism spectrum disorder (ASD; 28%) showed more food-related sensory sensitivities (RR = 1.26) and greater lack of interest in eating (RR = 1.18) than those of patients without ASD (49%). Interpretation: In our clinical sample, the ARFID drivers occurred together and did not show clinically meaningful differences between the sexes. ASD may accentuate food-related sensory sensitivities and lack of interest, but may not drive a completely different symptom presentation. ARFID is multi-faceted and heterogenous, requiring a comprehensive multidisciplinary assessment to sufficiently understand the drivers of the restrictive eating behaviour. Results need replication in larger samples with more statistical power. Funding: None.

The United Kingdom Eating Disorders Genetics Initiative.

OBJECTIVE: The United Kingdom Eating Disorders Genetics Initiative (EDGI UK), part of the National Institute for Health and Care Research (NIHR) Mental Health BioResource, aims to deepen our understanding of the environmental and genetic etiology of eating disorders. EDGI UK launched in February 2020 and is partnered with the UK eating disorders charity, Beat. Multiple EDGI branches exist worldwide. This article serves the dual function of providing an in-depth description of our study protocol and of describing our initial sample including demographics, diagnoses, and physical and psychiatric comorbidities. METHOD: EDGI UK recruits via media and clinical services. Anyone living in England, at least 16 years old, with a lifetime probable or clinical eating disorder is eligible to sign up online: edgiuk.org. Participants complete online questionnaires, donate a saliva sample for genetic analysis, and consent to medical record linkage and recontact for future studies. RESULTS: As of September 2022, EDGI UK recruited 7435 survey participants: 98% female, 93.1% white, 97.8% cisgender, 65.9% heterosexual, and 52.1% have a university degree. Over half (57.8%) of these participants have returned their saliva DNA kit. The most common diagnoses are anorexia nervosa (48.3%), purging disorder (37.8%), bulimia nervosa (37.5%), binge-eating disorder (15.8%), and atypical anorexia nervosa (7.8%). CONCLUSION: EDGI UK is the largest UK eating disorders study and efforts to increase its diversity are underway. It offers a unique opportunity to accelerate eating disorder research. Researchers and participants with lived experience can collaborate on projects with unparalleled sample size. PUBLIC SIGNIFICANCE STATEMENT: Eating disorders are debilitating and costly for society but are under-researched due to underfunding. EDGI UK is one of the largest eating disorder studies worldwide with ongoing recruitment. The collected data constitute a resource for secondary analysis. We will combine data from all international EDGI branches and the NIHR BioResource to facilitate research that improves our understanding of eating disorders and their comorbidities.

Predictors of self-reported research engagement and academic-career interest amongst medical students in the United Kingdom: a national cross-sectional survey.

BACKGROUND: We hypothesised that the gender/ethnic disparities and reductions in the UK academic-clinician workforce stem from research experience in medical school. This study investigated the factors influencing research engagement and academic-career interests among UK medical students. METHODS: Using a 42-item online questionnaire, a national multicentre cross-sectional survey of UK medical students was conducted over 9 weeks in the 2020/21 academic year. Multiple binary logistic and zero-inflated negative binomial regressions were used to evaluate associations between the predictor variables and research engagement (yes/no), number of research projects conducted, and academic-career interest (yes/no). P < 0.05 was considered statistically significant. RESULTS: In total, 1573 students participated from 36 medical schools. No ethnic/gender differences in research engagement were observed. However, compared to men, women had a 31% decrease in the odds of being interested in an academic-clinician career [odds ratio (OR): 0.69; 95% confidence interval (CI): 0.52, 0.92]. Positive predictors of interest in academia were being a PubMed-indexed author (OR: 2.19; 95% CI: 1.38, 3.47) and having at least one national/international presentation (OR: 1.40; 95% CI: 1.04, 1.88). Career progression was the primary motivating factor (67.1%) for pursuing research, whereas limited awareness of opportunities (68.0%) and time constraints (67.5%) were the most common barriers. CONCLUSION: There were no ethnic differences in research engagement or academic-career intent. Although there were no gender differences in research engagement, female students were less likely to be interested in an academic career. This could be tackled by providing targeted opportunities to increase research productivity and self-efficacy in medical schools. Key messages: What is already known on this topic: There has been a decline in the number of academic clinicians, with a disproportionate gender and ethnic representation in the academic workforce. Engaging medical students in research activities during their medical training could mitigate the declining number of academic clinicians. Differential attainment occurs in medical school and persists after graduation. What this study adds: Although there were no gender/ethnic differences in research engagement amongst UK medical students, our study suggests that female students were less likely to be interested in pursuing an academic career. Time constraints, a lack of awareness of opportunities, and difficulty in finding research supervisors/mentors were the most common barriers to research engagement, whereas PubMed-indexed authorship was the strongest positive predictor of interest in an academic career. How this study might affect research, practice, or policy: Medical schools should facilitate the selection of good-quality research mentors that would provide adequate support to ensure that their students' works are published in peer-reviewed journals. Medical schools should employ local research officers to increase students' awareness of research opportunities.

Predictors of self-reported research productivity amongst medical students in the United Kingdom: a national cross-sectional survey.

BACKGROUND: The number of academic clinicians in the UK is declining and there are demographic inequalities in the clinical-academic workforce. Increased research productivity by medical students is believed to reduce future attrition in the clinical-academic workforce. Thus, this study investigated the association between student demographics and research productivity amongst UK medical students. METHODS: This is a national multicentre cross-sectional study of UK medical students in the 2020/21 academic year. We appointed one student representative per medical school, and they disseminated a 42-item online questionnaire over nine weeks, through departmental emails and social media advertisements. The outcome measures were: (i) publications (yes/no) (ii) number of publications (iii) number of first-authored publications (iv) abstract presentation (yes/no). We utilised multiple logistic and zero-inflated Poisson regression analyses to test for associations between the outcome measures and predictor variables at a 5% significance level. RESULTS: There are 41 medical schools in the UK. We received 1573 responses from 36 UK medical schools. We failed to recruit student representatives from three newly formed medical schools, whilst two medical schools prohibited us from sending the survey to their students. Women had lower odds of having a publication (OR: 0.53, 95% CI: 0.33-0.85) and on average had fewer first-author publications than men (IRR: 0.57, 95% CI: 0.37-0.89). Compared to white students, mixed-ethnicity students had greater odds of having a publication (OR: 3.06, 95% CI: 1.67-5.59), an abstract presentation (OR: 2.12, 95% CI: 1.37-3.26), and on average had a greater number of publications (IRR: 1.87, 95% CI: 1.02-3.43). On average, students who attended independent UK secondary schools had a higher rate of first-author publications compared to those that attended state secondary schools (IRR: 1.97, 95% CI: 1.23-3.15). CONCLUSION: Our data suggest that there are gender, ethnic and socioeconomic inequalities in research productivity among UK medical students. To tackle this, and potentially improve diversity in clinical academia, we recommend that medical schools should facilitate targeted high quality research mentorship, funding and training, especially for under-represented-in-medicine students.

Dynamics of factors associated with rates of COVID-19 cases and deaths in African countries.

BACKGROUND: African countries have not had the high case and death rates from COVID-19 as was predicted early in the pandemic. It is not well understood what factors modulated the rate of COVID-19 cases and death on the continent. METHODS: We collated data from the World Bank data site, Our World in Data and Freedom House for African for 54 African countries who are members of the African Union. We used them as explanatory variables in two general linear model regression analyses. COVID cases and deaths per 100,000 obtained from WHO COVID-19 dashboard on August 12, 2021, as outcome variables in two prediction models. RESULTS: GDP, percentage of population under 14 years of age, Maternal Mortality Ratio, number of international tourists visiting per year and public transportation closures were not significant in predicting COVID-19 cases. Higher percentage of unemployed adults in the population, lower percentage of the population over 25 years of age with secondary education, internal travel restrictions increased spread of COVID-19 while international travel restrictions were associated with lower COVID-19 cases per 100,000 population. Higher levels of democratization results in higher cases of COVID-19. Unemployment, education and democratization were still significant for COVID-19 death in the same direction as they were for COVID-19 cases. Number of tourism visitors per year was also associated with higher COVID-19 death rates but not with case rates. CONCLUSION: In African countries, internal movement restrictions enacted to inhibit COVID-19, had the opposite effect and enabled COVID-19 spread. Low Education levels and high unemployment were associated with having higher death rates from COVID-19. More studies are needed to understand the impact of tourism on COVID-19 and other infectious diseases arising from other regions on African countries, in order to put in place adequate control protocols.

Multifaceted Structurally Coloured Materials: Diffraction and Total Internal Reflection (TIR) from Nanoscale Surface Wrinkling.

We investigate the combined effects of surface diffraction and total internal reflection (TIR) in the design of 3-dimensional materials exhibiting distinct structural colour on various facets. We employ mechanical wrinkling to introduce surface diffraction gratings (from the nano to the micron scales) on one face of an elastomeric rectangular parallelepiped-shaped slab and explore the roles, in the perceived colours, of wrinkling pattern, wavelength, the directionality of incident light and observation angles. We propose a simple model that satisfactorily accounts for all experimental observations. Employing polydimethylsiloxane (PDMS), which readily swells in the presence of various liquids and gases, we demonstrate that such multifaceted colours can respond to their environment. By coupling a right angle triangular prism with a surface grating, we demonstrate the straightforward fabrication of a so-called GRISM (GRating + prISM). Finally, using a range of examples, we outline possibilities for a predictive material design using multi-axial wrinkling patterns and more complex polyhedra.

Predictors of self-reported research self-efficacy and perception of research amongst medical students in the United Kingdom: a national cross-sectional survey.

PURPOSE: There has been a decline in the number of academic clinicians in the UK, and there are ethnic/gender disparities in the academic workforce. Higher research self-efficacy (RSE) and a positive perception of research (PoR) amongst students are associated with a higher motivation to engage in academic medicine. Hence, this study aimed to determine the factors that influence RSE and PoR amongst UK medical students. METHODS: This is a multicentre cross-sectional survey of medical students in 36 UK medical schools in the 2020/21 academic year. Multiple linear regression was used to investigate the association between students' demographics and RSE/PoR. P-values less than a Bonferroni-corrected significance level of .05/28 = .0018 were considered statistically significant. RESULTS: In total, 1573 individuals participated from 36 medical schools. There were no ethnic differences in PoR or RSE scores. Although there were no gender differences in PoR, female students had lower RSE scores than male students (adjusted ß = -1.75; 95% CI: -2.62, -0.89). Research experience before medical school (adjusted ß = 3.02; 95% CI: 2.11, 3.93), being in the clinical training phase (adjusted ß = 1.99; 95% CI: 1.09, 2.90), and completing a degree before medical school (adjusted ß = 3.66; 95% CI: 2.23, 5.09) were associated with higher RSE. CONCLUSION: There were no associations between the predictor variables and PoR. Female students had lower self-reported RSE scores. Future studies should investigate the role of targeted research mentorship in improving RSE amongst female medical students.

Biomimetic Coating-free Superomniphobicity.

Superomniphobic surfaces, which repel droplets of  polar and apolar liquids, are used for reducing frictional drag, packaging electronics and foods, and separation processes, among other applications. These surfaces exploit perfluorocarbons that are expensive, vulnurable to physical damage, and have a long persistence in the environment. Thus, new approaches for achieving superomniphobicity from common materials are desirable. In this context, microtextures comprising "mushroom-shaped" doubly reentrant pillars (DRPs) have been shown to repel drops of polar and apolar liquids in air irrespective of the surface make-up. However, it was recently demonstrated that DRPs get instantaneously infiltrated by the same liquids on submersion because while they can robustly prevent liquid imbibition from the top, they are vulnerable to lateral imbibition. Here, we remedy this weakness through bio-inspiration derived from cuticles of Dicyrtomina ornata, soil-dwelling bugs, that contain cuboidal secondary granules with mushroom-shaped caps on each face. Towards a proof-of-concept demonstration, we created a perimeter of biomimicking pillars around arrays of DRPs using a two-photon polymerization technique; another variation of this design with a short wall passing below the side caps was investigated. The resulting gas-entrapping microtextured surfaces (GEMS) robustly entrap air on submersion in wetting liquids, while also exhibiting superomniphobicity in air. To our knowledge, this is the first-ever microtexture that confers upon intrinsically wetting materials the ability to simultaneously exhibit superomniphobicity in air and robust entrapment of air on submersion. These findings should advance the rational design of coating-free surfaces that exhibit ultra-repellence (or superomniphobicity) towards liquids.

Proof-of-Concept for Gas-Entrapping Membranes Derived from Water-Loving SiO2/Si/SiO2 Wafers for Green Desalination.

Desalination through direct contact membrane distillation (DCMD) exploits water-repellent membranes to robustly separate counterflowing streams of hot and salty seawater from cold and pure water, thus allowing only pure water vapor to pass through. To achieve this feat, commercial DCMD membranes are derived from or coated with water-repellent perfluorocarbons such as polytetrafluoroethylene (PTFE) and polyvinylidene difluoride (PVDF). However, the use of perfluorocarbons is limiting due to their high cost, non-biodegradability, and vulnerability to harsh operational conditions. Unveiled here is a new class of membranes referred to as gas-entrapping membranes (GEMs) that can robustly entrap air upon immersion in water. GEMs achieve this function by their microstructure rather than their chemical make-up. This work demonstrates a proof-of-concept for GEMs using intrinsically wetting SiO2/Si/SiO2 wafers as the model system; the contact angle of water on SiO2 is θo ≈ 40°. Silica-GEMs had 300 µm-long cylindrical pores whose diameters at the (2 µm-long) inlet and outlet regions were significantly smaller; this geometrically discontinuous structure, with 90° turns at the inlets and outlets, is known as the "reentrant microtexture". The microfabrication protocol for silica-GEMs entails designing, photolithography, chrome sputtering, and isotropic and anisotropic etching. Despite the water loving nature of silica, water does not intrude silica-GEMs on submersion. In fact, they robustly entrap air underwater and keep it intact even after six weeks (>106 seconds). On the other hand, silica membranes with simple cylindrical pores spontaneously imbibe water (< 1 s). These findings highlight the potential of the GEMs architecture for separation processes. While the choice of SiO2/Si/SiO2 wafers for GEMs is limited to demonstrating the proof-of-concept, it is expected that the protocols and concepts presented here will advance the rational design of scalable GEMs using inexpensive common materials for desalination and beyond.