Real-world outcomes with durvalumab after chemoradiotherapy in patients with unresectable stage III NSCLC: interim analysis of overall survival from PACIFIC-R.

BACKGROUND: Based on the findings of the PACIFIC trial, consolidation durvalumab following platinum-based chemoradiotherapy (CRT) is a global standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). An earlier analysis from the ongoing PACIFIC-R study (NCT03798535) demonstrated the effectiveness of this regimen in terms of progression-free survival (PFS). Here, we report the first planned overall survival (OS) analysis. PATIENTS AND METHODS: PACIFIC-R is an observational/non-interventional, retrospective study of patients with unresectable, stage III NSCLC who started durvalumab (10 mg/kg intravenously every 2 weeks) within an AstraZeneca-initiated early access program between September 2017 and December 2018. Primary endpoints are OS and investigator-assessed PFS, estimated using the Kaplan-Meier method. RESULTS: By 30 November 2021, the full analysis set included 1154 participants from 10 countries (median follow-up in censored patients: 38.7 months). Median OS was not reached, and the 3-year OS rate was 63.2% (95% confidence interval 60.3% to 65.9%). Three-year OS rates were numerically higher among patients with programmed death-ligand 1 (PD-L1) expression on ≥1% versus <1% of tumor cells (TCs; 67.0% versus 54.4%) and patients who received concurrent CRT (cCRT) versus sequential CRT (sCRT) (64.8% versus 57.9%). CONCLUSIONS: PACIFIC-R data continue to provide evidence for the effectiveness of consolidation durvalumab after CRT in a large, diverse, real-world population. Better outcomes were observed among patients with PD-L1 TCs ≥1% and patients who received cCRT. Nevertheless, encouraging outcomes were still observed among patients with TCs <1% and patients who received sCRT, supporting use of consolidation durvalumab in a broad population of patients with unresectable, stage III NSCLC.

The impact of low-mode symmetry on inertial fusion energy output in the burning plasma state.

Indirect Drive Inertial Confinement Fusion Experiments on the National Ignition Facility (NIF) have achieved a burning plasma state with neutron yields exceeding 170 kJ, roughly 3 times the prior record and a necessary stage for igniting plasmas. The results are achieved despite multiple sources of degradations that lead to high variability in performance. Results shown here, for the first time, include an empirical correction factor for mode-2 asymmetry in the burning plasma regime in addition to previously determined corrections for radiative mix and mode-1. Analysis shows that including these three corrections alone accounts for the measured fusion performance variability in the two highest performing experimental campaigns on the NIF to within error. Here we quantify the performance sensitivity to mode-2 symmetry in the burning plasma regime and apply the results, in the form of an empirical correction to a 1D performance model. Furthermore, we find the sensitivity to mode-2 determined through a series of integrated 2D radiation hydrodynamic simulations to be consistent with the experimentally determined sensitivity only when including alpha-heating.

Burning plasma achieved in inertial fusion.

Obtaining a burning plasma is a critical step towards self-sustaining fusion energy1. A burning plasma is one in which the fusion reactions themselves are the primary source of heating in the plasma, which is necessary to sustain and propagate the burn, enabling high energy gain. After decades of fusion research, here we achieve a burning-plasma state in the laboratory. These experiments were conducted at the US National Ignition Facility, a laser facility delivering up to 1.9 megajoules of energy in pulses with peak powers up to 500 terawatts. We use the lasers to generate X-rays in a radiation cavity to indirectly drive a fuel-containing capsule via the X-ray ablation pressure, which results in the implosion process compressing and heating the fuel via mechanical work. The burning-plasma state was created using a strategy to increase the spatial scale of the capsule2,3 through two different implosion concepts4-7. These experiments show fusion self-heating in excess of the mechanical work injected into the implosions, satisfying several burning-plasma metrics3,8. Additionally, we describe a subset of experiments that appear to have crossed the static self-heating boundary, where fusion heating surpasses the energy losses from radiation and conduction. These results provide an opportunity to study α-particle-dominated plasmas and burning-plasma physics in the laboratory.

Observation of Hydrodynamic Flows in Imploding Fusion Plasmas on the National Ignition Facility.

Inertial confinement fusion implosions designed to have minimal fluid motion at peak compression often show significant linear flows in the laboratory, attributable per simulations to percent-level imbalances in the laser drive illumination symmetry. We present experimental results which intentionally varied the mode 1 drive imbalance by up to 4% to test hydrodynamic predictions of flows and the resultant imploded core asymmetries and performance, as measured by a combination of DT neutron spectroscopy and high-resolution x-ray core imaging. Neutron yields decrease by up to 50%, and anisotropic neutron Doppler broadening increases by 20%, in agreement with simulations. Furthermore, a tracer jet from the capsule fill-tube perturbation that is entrained by the hot-spot flow confirms the average flow speeds deduced from neutron spectroscopy.

Paving the way for application of next generation risk assessment to safety decision-making for cosmetic ingredients.

Next generation risk assessment (NGRA) is an exposure-led, hypothesis-driven approach that has the potential to support animal-free safety decision-making. However, significant effort is needed to develop and test the in vitro and in silico (computational) approaches that underpin NGRA to enable confident application in a regulatory context. A workshop was held in Montreal in 2019 to discuss where effort needs to be focussed and to agree on the steps needed to ensure safety decisions made on cosmetic ingredients are robust and protective. Workshop participants explored whether NGRA for cosmetic ingredients can be protective of human health, and reviewed examples of NGRA for cosmetic ingredients. From the limited examples available, it is clear that NGRA is still in its infancy, and further case studies are needed to determine whether safety decisions are sufficiently protective and not overly conservative. Seven areas were identified to help progress application of NGRA, including further investments in case studies that elaborate on scenarios frequently encountered by industry and regulators, including those where a 'high risk' conclusion would be expected. These will provide confidence that the tools and approaches can reliably discern differing levels of risk. Furthermore, frameworks to guide performance and reporting should be developed.

Optimal choice of multiple line-of-sight measurements determining plasma hotspot velocity at the National Ignition Facility.

The measurement of plasma hotspot velocity provides an important diagnostic of implosion performance for inertial confinement fusion experiments at the National Ignition Facility. The shift of the fusion product neutron mean kinetic energy as measured along multiple line-of-sight time-of-flight spectrometers provides velocity vector components from which the hotspot velocity is inferred. Multiple measurements improve the hotspot velocity inference; however, practical considerations of available space, operational overhead, and instrumentation costs limit the number of possible line-of-sight measurements. We propose a solution to this classical "experiment design" problem that optimizes the precision of the velocity inference for a limited number of measurements.

Sensitivity and Accumulation of Perfluorooctanesulfonate and Perfluorohexanesulfonic Acid in Fathead Minnows (Pimephales promelas) Exposed over Critical Life Stages of Reproduction and Development.

Per- and polyfluoroalkyl substances (PFAS) have emerged as contaminants of environmental concern following release from industrial practices and use of aqueous film-forming foam (AFFF). Of the identified PFAS in surface water samples from known AFFF release sites, perfluorooctanesulfonate (PFOS) and perfluorohexanesulfonic acid (PFHxS) are frequently detected. The focus of the present study was to determine the effects of PFOS and PFHxS to the native (and common) fathead minnow, Pimephales promelas, over critical life stages of reproduction and development. Two separate, 42-d experiments were carried out using sexually mature fish, exposed to either PFOS or PFHxS. Measured exposure concentrations for PFOS and PFHxS were 0, 44, 88, 140, and 231 µg/L and 0, 150, 300, 600, and 1200 µg/L, respectively. At day 21 of the adult exposure, eggs were collected and reared for 21 d to determine the effects of PFOS or PFHxS on development, growth, and survival of larvae. The no-observable-effect concentration (NOEC) for PFOS was 44 µg/L, and the lowest-observable-effect concentration was 88 µg/L based on reduced growth in juvenile (F1) fish. Effects from PFOS exposures that did not follow a standard dose-response curve were reduced gonadosomatic index in adult males (at 44 µg/L) and reduced fecundity in females (at 140 µg/L). There was no toxicity on apical endpoints to report on adult or juvenile fish exposed to PFHxS up to 1200 µg/L. Importantly, we note that both PFOS and PFHxS accumulated in gonads and liver of adult fish following the respective exposures. The present study supports previous literature on PFOS toxicity and accumulation in fathead minnows but resulted in a lower NOEC than previously established for this species. Environ Toxicol Chem 2021;40:811-819. © 2020 SETAC.

Impact of choice of volumetry software and nodule management guidelines on recall rates in lung cancer screening.

PURPOSE: Appropriate lung nodule management is essential to minimizing unnecessary patient recall in lung cancer screening. Two European guidelines provide differing recommendations in that participants with nodules ≥100 mm3 or ≥80 mm3 respectively should be recalled, at baseline. Nodule size estimation is known to vary between volumetry software packages (VSPs). The aim of this study was to examine the impact of choice of VSP on participant recall rates, when applying different European nodule management guidelines. An additional aim was to compare recall rates between 7 VSPs and manual diameter measurements. METHODS: 156 small-sized lung nodules (50-150 mm3) from the UK Lung Screening trial were measured using 7 different VSPs (VSP1-7) and also using manual diameter. The type of VSP used in the NELSON study (VSP1), on which European nodule management guidelines are based, provided the reference standard. Nodule size was compared using Bland Altman, and recall rates by Mcnemar's test. RESULTS: Compared to the reference standard, a 100 mm3 threshold for recall, resulted in no difference in recall rates only for VSP 5 & 7. Using an 80mm3 threshold resulted in no difference in recall rates for VSP2 & 6. Recall rates were significantly higher for VSP 4 regardless of threshold and when using manual diameter measurements. CONCLUSIONS: Appropriate nodule size thresholds for recall in screening depend on the type of volumetry software used. The results highlight the importance of benchmarking of volumetry packages.

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

Presentation of lung cancer in primary care.

Survival from lung cancer has seen only modest improvements in recent decades. Poor outcomes are linked to late presentation, yet early diagnosis can be challenging as lung cancer symptoms are common and non-specific. In this paper, we examine how lung cancer presents in primary care and review roles for primary care in reducing the burden from this disease. Reducing rates of smoking remains, by far, the key strategy, but primary care practitioners (PCPs) should also be pro-active in raising awareness of symptoms, ensuring lung cancer risk data are collected accurately and encouraging reluctant patients to present. PCPs should engage in service re-design and identify more streamlined diagnostic pathways-and more readily incorporate decision support into their consulting, based on validated lung cancer risk models. Finally, PCPs should ensure they are central to recruitment in future lung cancer screening programmes-they are uniquely placed to ensure the right people are targeted for risk-based screening programmes. We are now in an era where treatments can make a real difference in early-stage lung tumours, and genuine progress is being made in this devastating illness-full engagement of primary care is vital in effecting these improvements in outcomes.

The Impact of Replacement Conventional Dentures on Eating Experience.

INTRODUCTION: Despite much research on the impact of edentulism and prosthetic rehabilitation on food and nutrient intake, there is little information on how replacing complete dentures affects social and emotional issues around eating. OBJECTIVES: To investigate, in a cohort study, how replacing conventional complete dentures affects eating-related quality of life (ERQoL). A secondary aim was to test the responsiveness of an Emotional and Social Issues Related to Eating (ESIRE) questionnaire to change in ERQoL. METHODS: Participants, recruited from the Dental Hospital, Newcastle-upon-Tyne, UK, completed the self-administrated ESIRE questionnaire before and after provision of new conventional complete dentures. Paired t test was used to determine any change between pre- and posttreatment ESIRE scores, which can range from 0 (poor) to 100 (excellent). Cohen's d effect size was used to measure the magnitude of change in ERQoL. Standardized response mean (SRM) was used to measure the responsiveness of the ESIRE questionnaire to changes in ERQoL. RESULTS: Fifty-five participants aged 52 to 85 y (mean, 72 y), including 21 males (42%) and 29 females (58%), completed the study. A statistically significant improvement in the total ESIRE scores was found, mean (SE) +20.3 (3.30), P < 0.001. Equally, all domains of the ESIRE questionnaire showed significant improvements: enjoyment of food/eating, +27.3 (3.63), P < 0.001; self-consciousness/embarrassment, +18.1 (3.88), P < 0.001; interruption to meals, +13.3 (5.27), P < 0.05; confidence when eating, +18.7 (4.84), P < 0.001; time for eating/preparation of meals, +18.5 (4.85), P < 0.001); and functional ability to eat, +18.2 (3.67), P < 0.001). Cohen's d was large (0.95) for the total score and ranged from medium (0.37) to large (1.30) for all domains. Value of SRM was large (0.87) for the total score and ranged from medium (0.36) to large (1.1) for all domains. CONCLUSION: Denture replacement can directly improve ERQoL. The ESIRE questionnaire was responsive to clinically important changes in ERQoL. KNOWLEDGE TRANSFER STATEMENT: The results of this study improve the understanding of the impact of denture replacement on eating-related quality of life (ERQoL). Clinicians are encouraged to pay more attention to the impact of wearing conventional complete dentures on social and emotional issues around eating. The findings should motivate clinicians and inspire specialists in prosthodontics and oral rehabilitation to continue providing conventional complete dentures as a suitable treatment option for edentulous patients.

The Crystal Backlighter Imager: A spherically bent crystal imager for radiography on the National Ignition Facility.

The Crystal Backlighter Imager (CBI) is a quasi-monochromatic, near-normal incidence, spherically bent crystal imager developed for the National Ignition Facility (NIF), which will allow inertial confinement fusion capsule implosions to be radiographed close to stagnation. This is not possible using the standard pinhole-based area-backlighter configuration, as the self-emission from the capsule hotspot overwhelms the backlighter signal in the final stages of the implosion. The CBI mitigates the broadband self-emission from the capsule hot spot by using the extremely narrow bandwidth inherent to near-normal-incidence Bragg diffraction. Implementing a backlighter system based on near-normal reflection in the NIF chamber presents unique challenges, requiring the CBI to adopt novel engineering and operational strategies. The CBI currently operates with an 11.6 keV backlighter, making it the highest energy radiography diagnostic based on spherically bent crystals to date. For a given velocity, Doppler shift is proportional to the emitted photon energy. At 11.6 keV, the ablation velocity of the backlighter plasma results in a Doppler shift that is significant compared to the bandwidth of the instrument and the width of the atomic line, requiring that the shift be measured to high accuracy and the optics aligned accordingly to compensate. Experiments will be presented that used the CBI itself to measure the backlighter Doppler shift to an accuracy of better than 1 eV. These experiments also measured the spatial resolution of CBI radiographs at 7.0 µm, close to theoretical predictions. Finally, results will be presented from an experiment in which the CBI radiographed a capsule implosion driven by a 1 MJ NIF laser pulse, demonstrating a significant (>100) improvement in the backlighter to self-emission ratio compared to the pinhole-based area-backlighter configuration.

Environmental barriers to sociality in an obligate eusocial sweat bee.

Understanding the ecological and environmental contexts in which eusociality can evolve is fundamental to elucidating its evolutionary origins. A sufficiently long active season is postulated to have been a key factor facilitating the transition to eusociality. Many primitively eusocial species exhibit an annual life cycle, which is thought to preclude the expression of eusociality where the active season is too short to produce successive worker and reproductive broods. However, few studies have attempted to test this idea experimentally. We investigated environmental constraints on the expression of eusociality in the obligate primitively eusocial sweat bee Lasioglossum malachurum, by transplanting nest foundresses from the south to the far north of the United Kingdom, far beyond the natural range of L. malachurum. We show that transplanted bees can exhibit eusociality, but that the short length of the season and harsher environmental conditions could preclude its successful expression. In one year, when foundresses were transplanted only after provisioning first brood (B1) offspring, workers emerged in the north and provisioned a second brood (B2) of reproductives. In another year, when foundresses were transplanted prior to B1 being provisioned, they were just as likely to initiate nesting and provisioned just as many B1 cells as foundresses in the south. However, the life cycle was delayed by approximately 7 weeks and nests suffered 100% B1 mortality. Our results suggest that short season length together with poor weather conditions represent an environmental barrier to the evolution and expression of eusociality in sweat bees.

Limited social plasticity in the socially polymorphic sweat bee Lasioglossum calceatum.

ABSTRACT: Eusociality is characterised by a reproductive division of labour, where some individuals forgo direct reproduction to instead help raise kin. Socially polymorphic sweat bees are ideal models for addressing the mechanisms underlying the transition from solitary living to eusociality, because different individuals in the same species can express either eusocial or solitary behaviour. A key question is whether alternative social phenotypes represent environmentally induced plasticity or predominantly genetic differentiation between populations. In this paper, we focus on the sweat bee Lasioglossum calceatum, in which northern or high-altitude populations are solitary, whereas more southern or low-altitude populations are typically eusocial. To test whether social phenotype responds to local environmental cues, we transplanted adult females from a solitary, northern population, to a southern site where native bees are typically eusocial. Nearly all native nests were eusocial, with foundresses producing small first brood (B1) females that became workers. In contrast, nine out of ten nests initiated by transplanted bees were solitary, producing female offspring that were the same size as the foundress and entered directly into hibernation. Only one of these ten nests became eusocial. Social phenotype was unlikely to be related to temperature experienced by nest foundresses when provisioning B1 offspring, or by B1 emergence time, both previously implicated in social plasticity seen in two other socially polymorphic sweat bees. Our results suggest that social polymorphism in L. calceatum predominantly reflects genetic differentiation between populations, and that plasticity is in the process of being lost by bees in northern populations. SIGNIFICANCE STATEMENT: Phenotypic plasticity is thought to play a key role in the early stages of the transition from solitary to eusocial behaviour, but may then be lost if environmental conditions become less variable. Socially polymorphic sweat bees exhibit either solitary or eusocial behaviour in different geographic populations, depending on the length of the nesting season. We tested for plasticity in the socially polymorphic sweat bee Lasioglossum calceatum by transplanting nest foundresses from a northern, non-eusocial population to a southern, eusocial population. Plasticity would be detected if transplanted bees exhibited eusocial behaviour. We found that while native bees were eusocial, 90% of transplanted bees and their offspring did not exhibit traits associated with eusociality. Environmental variables such as time of offspring emergence or temperatures experienced by foundresses during provisioning could not explain these differences. Our results suggest that the ability of transplanted bees to express eusociality is being lost, and that social polymorphism predominantly reflects genetic differences between populations.

Curriculum content and assessment of pre-clinical dental skills: A survey of undergraduate dental education in Europe.

INTRODUCTION: Since 1981, the qualifications for various healthcare professionals across the European Union have enjoyed mutual recognition in accordance with the EU Directive 81/1057/EEC. Whilst the directive includes dental practitioners, it is recognised that significant variation exists in curriculum structure, content and scope of practice across institutions. This article aimed to explore pan-European practice in relation to curriculum content, teaching and learning strategies and assessment of pre-clinical dental skills. METHOD: A request to complete an online questionnaire, in English, was sent electronically to skills leads at all Association of Dental Education in Europe member schools. The questionnaire collected information in relation to institution and country, regulatory requirements to demonstrate safety, details of specific pre-clinical skills courses, learning materials and teaching staff. RESULTS: Forty-eight institutions, from 25 European countries responded. Seven countries (n=7, 28%) reported no requirement to demonstrate student operative safety prior to patient treatment. Several core and operative clinical skills are common to the majority of institutions. The most commonly taught core skills related directly to the clinical environment such as cross-infection control and hand washing. The least common were skills that indirectly related to patient care, such as communication skills and working as a team. CONCLUSION: There are clear differences within European pre-clinical dental education, and greater efforts are needed to demonstrate that all European students are fit to practice before they start treating patients. Learning outcomes, teaching activities and assessment activities of pre-clinical skills should be shared collaboratively to further standardise curricula.

The Graduating European Dentist: Contemporaneous Methods of Teaching, Learning and Assessment in Dental Undergraduate Education.

It is often the case that good teachers just "intuitively" know how to teach. Whilst that may be true, there is now a greater need to understand the various processes that underpin both the ways in which a curriculum is delivered, and the way in which the students engage with learning; curricula need to be designed to meet the changing needs of our new graduates, providing new, and robust learning opportunities, and be communicated effectively to both staff and students. The aim of this document is to draw together robust and contemporaneous methods of teaching, learning and assessment that help to overcome some of the more traditional barriers within dental undergraduate programmes. The methods have been chosen to map specifically to The Graduating European Dentist, and should be considered in parallel with the benchmarking process that educators and institutions employ locally.

The Graduating European Dentist-Domain II: Safe and Effective Clinical Practice.

This position paper outlines the areas of competence and learning outcomes of "The Graduating European Dentist" that specifically relate to Safe and Effective Clinical Practice. Dentists are required to ensure that they are capable of providing appropriate care for their patients, whilst also effectively managing and leading the wider clinical team. The care that is provided should align to a contemporaneous evidence base wherever possible, and the quality of care and the management systems that underpin it should be regularly audited and improved.