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Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. W. C., C. H., J. L. D., S. T., H. H., P. V., R. P., A. B., and C. R. K. are all funded or part-funded through GRAIL as part of the SUMMIT Study. SUMMIT is sponsored and conducted by University College London and funded by GRAIL LLC through a research grant awarded to S. M. J. as principal investigator. S. M. J. is a paid Advisory Board member Astra-Zeneca, Bard1 Bioscience, Achilles Therapeutics, and Jansen; receives assistance for travel to meetings from Astra Zeneca, Takeda; receives grant income from GRAIL Inc, Owlstone; and receives share options from Optellum and BARD1 Lifescience. A. N. is part-funded through the UCLH Biomedical Research Centre. A. D. receives personal fees from Boehringer Ingelheim, Roche, Galacto Biotech, Galapagos, Brainomix and Vicore. A. H. receives consulting fees from Evidera and assistance for travel to meetings from GRAIL. None declared (J. M., T. L., K. G., A.-M. H., J. T., L. F., S. D.).

Background and Aims: Optimising smoking cessation (SC) referral strategies within lung cancer screening (LCS) could significantly reduce lung cancer mortality. This study aimed to measure acceptance of referral to SC support by either practitioner-referral or self-referral among participants attending a hospital-based lung health check appointment for LCS as part of the Lung Screen Uptake Trial., Design: Single-blinded two-arm randomised controlled trial., Setting: England., Participants: Six hundred forty-two individuals ages 60 to 75 years, who self-reported currently smoking or had a carbon monoxide reading over 10 ppm during the lung health check appointment., Intervention and Comparator: Participants were randomised (1:1) to receive either a contact information card for self-referral to a local stop smoking service (SSS) (self-referral, n = 360) or a SSS referral made on their behalf by the nurse or trial practitioner (practitioner-referral, n = 329)., Measurements: The primary outcome was acceptance of the practitioner-referral (defined as participants giving permission for their details to be shared with the local SSS) compared with acceptance of the self-referral (defined as participants taking the physical SSS contact information card to refer themselves to the local SSS)., Findings: Half (49.8%) accepted the practitioner-made referral to a local SSS, whereas most (88.5%) accepted the self-referral. The odds of accepting the practitioner-referral were statistically significantly lower (adjusted odds ratio = 0.10; 95% confidence interval = 0.06-0.17) than the self- referral. In analyses stratified by group, greater quit confidence, quit attempts and Black ethnicity were associated with increased acceptance within the practitioner-referral group. There were no statistically significant interactions between acceptance by referral group and any of the participants' demographic or smoking characteristics., Conclusions: Among participants in hospital-based lung cancer screening in England who self-reported smoking or met a carbon monoxide cut-off, both practitioner-referral and self-referral smoking cessation strategies were highly accepted. Although self-referral was more frequently accepted, prior evidence suggests practitioner-referrals increase quit attempts, suggesting practitioner-referrals should be the first-line strategy within lung cancer screening, with self-referral offered as an alternative., (© 2023 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Gullies on Mars resemble water-carved channels on Earth, but they are mostly at elevations where liquid water is not expected under current climate conditions. It has been suggested that sublimation of carbon dioxide ice alone could have formed Martian gullies. We used a general circulation model to show that the highest-elevation Martian gullies coincide with the boundary of terrain that experienced pressures above the triple point of water when Mars' rotational axis tilt reached 35°. Those conditions have occurred repeatedly over the past several million years, most recently ~630,000 years ago. Surface water ice, if present at these locations, could have melted when temperatures rose >273 kelvin. We propose a dual gully formation scenario that is driven by melting of water ice followed by carbon dioxide ice sublimation.

Background. Personal autonomy in lung cancer screening is advocated internationally, but health systems diverge in their approach, mandating either shared decision making (with a health care professional) or individual decision making. Studies of other cancer screening programs have found that individual preferences for the level of involvement in screening decisions vary across different sociodemographic groups and that aligning approaches with individual preferences has the potential to improve uptake. Method. For the first time, we examined preferences for decision control among a cohort of UK-based high-risk lung cancer screening candidates ( N = 727). We used descriptive statistics to report the distribution of preferences and chi-square tests to examine associations between decision preferences and sociodemographic variables. Results. Most (69.7%) preferred to be involved in the decision with varying degrees of input from a health care professional. Few (10.2%) wanted to make the decision alone. Preferences were also associated with educational attainment. Conclusion. These findings suggest one-size-fits-all approaches may be inadequate in meeting diverse preferences, particularly those placing sole onus on the individual., Highlights: Preferences for involvement in decision making about lung cancer screening are heterogeneous among high-risk individuals in the United Kingdom and vary by educational attainment.Further work is needed to understand how policy makers might implement hybrid approaches to accommodate individual preferences and optimize lung cancer screening program outcomes., Competing Interests: This work was conducted at the Research Department of Behavioural Science and Health, University College London. The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SB, JW, and SLQ have no conflicts of interest to declare. SMJ is the chief investigator for an academic study (SUMMIT), which is sponsored and conducted by UCL and funded by GRAIL, Inc, through a research grant. JLD is, and MR has previously been, supported as investigators by this funding. SMJ has been paid by Astra Zeneca, BARD1 Bioscience, Jansen, and Achilles Therapeutics for being an Advisory Board Expert and travel to one US conference. SMJ receives grant funding from Owlstone for a separate research study. MR received travel funding for a conference from Takeda and an honorarium for planning and speaking at educational meetings from Astra Zeneca. All authors perceive that these disclosures pose no academic conflict for this study. All authors declare no other relationships or activities that could appear to have influenced the submitted work. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Financial support for this study was provided in part by a National Awareness and Early Diagnosis Initiative (NAEDI) project grant (C1418/A17976) from Cancer Research UK and a consortium of funders (Department of Health [England]; Economic and Social Research Council; Health and Social Care R&D Division, Public Health Agency, Northern Ireland; National Institute for Social Care and Health Research, Wales; and the Scottish government). This work was partly undertaken at UCLH/UCL who received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centre’s funding scheme. SLQ is supported by a CRUK Population Research Fellowship (C50664/A24460) and a Barts Charity grant (MRC&U0036). JW is supported by a CRUK career development fellowship (C7492/A17219). SMJ was a Wellcome Trust Senior Fellow in Clinical Science (WT107963AIA). SMJ is supported by CRUK, the Rosetrees Trust, the Roy Castle Lung Cancer foundation, the Stoneygate Trust, the Garfield Weston Trust and UCLH Charitable Foundation. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing and publishing the report. Relevant deidentified data are available upon reasonable request from SLQ., (© The Author(s) 2023.)

Background: Lung cancer screening with low-dose CT reduces lung cancer mortality, but screening requires equitable uptake from candidates at high risk of lung cancer across ethnic and socioeconomic groups that are under-represented in clinical studies. We aimed to assess the uptake of invitations to a lung health check offering low-dose CT lung cancer screening in an ethnically and socioeconomically diverse cohort at high risk of lung cancer., Methods: In this multicentre, prospective, longitudinal cohort study (SUMMIT), individuals aged 55-77 years with a history of smoking in the past 20 years were identified via National Health Service England primary care records at practices in northeast and north-central London, UK, using electronic searches. Eligible individuals were invited by letter to a lung health check offering lung cancer screening at one of four hospital sites, with non-responders re-invited after 4 months. Individuals were excluded if they had dementia or metastatic cancer, were receiving palliative care or were housebound, or declined research participation. The proportion of individuals invited who responded to the lung health check invitation by telephone was used to measure uptake. We used univariable and multivariable logistic regression analyses to estimate associations between uptake of a lung health check invitation and re-invitation of non-responders, adjusted for sex, age, ethnicity, smoking, and deprivation score. This study was registered prospectively with ClinicalTrials.gov, NCT03934866., Findings: Between March 20 and Dec 12, 2019, the records of 2 333 488 individuals from 251 primary care practices across northeast and north-central London were screened for eligibility; 1 974 919 (84·6%) individuals were outside the eligible age range, 7578 (2·1%) had pre-existing medical conditions, and 11 962 (3·3%) had opted out of particpation in research and thus were not invited. 95 297 individuals were eligible for invitation, of whom 29 545 (31·0%) responded. Due to the COVID-19 pandemic, re-invitation letters were sent to only a subsample of 4594 non-responders, of whom 642 (14·0%) responded. Overall, uptake was lower among men than among women (odds ratio [OR] 0·91 [95% CI 0·88-0·94]; p<0·0001), and higher among older age groups (1·48 [1·42-1·54] among those aged 65-69 years vs those aged 55-59 years; p<0·0001), groups with less deprivation (1·89 [1·76-2·04] for the most vs the least deprived areas; p<0·0001), individuals of Asian ethnicity (1·14 [1·09-1·20] vs White ethnicity; p<0·0001), and individuals who were former smokers (1·89 [1·83-1·95] vs current smokers; p<0·0001). When ethnicity was subdivided into 16 groups, uptake was lower among individuals of other White ethnicity than among those with White British ethnicity (0·86 [0·83-0·90]), whereas uptake was higher among Chinese, Indian, and other Asian ethnicities than among those with White British ethnicity (1·33 [1·13-1·56] for Chinese ethnicity; 1·29 [1·19-1·40] for Indian ethnicity; and 1·19 [1·08-1·31] for other Asian ethnicity)., Interpretation: Inviting eligible adults for lung health checks in areas of socioeconomic and ethnic diversity should achieve favourable participation in lung cancer screening overall, but inequalities by smoking, deprivation, and ethnicity persist. Reminder and re-invitation strategies should be used to increase uptake and the equity of response., Funding: GRAIL., Competing Interests: Declaration of interests JLD, CH, ST, HH, and PV were employed by University College London (UCL) as clinical research fellows through SUMMIT Study funding provided by GRAIL. SMJ has received travel expenses from AstraZeneca, BARD1 Bioscience, Optellum, Jansen, Takeda, Evidera, and Achilles Therapeutics for participation on advisory boards; has received honoraria for lectures from Chiesi; and has received travel expenses from AstraZeneca for a US conference. AH has received one honorarium for an advisory board meeting for GRAIL; has received consulting fees from Evidera (for a GRAIL-initiated project); and has previously owned shares in Illumina. NN has received honoraria for advisory, education, and consultancy work from Amgen, AstraZeneca, Bristol-Meyers Squibb, Guardant Health, Janssen, Lilly & Co, Merck Sharp & Dohme, Olympus, Oncimmune, OncLive, PeerVoice, Pfizer, and Takeda, all outside of the submitted work. AN has received consulting fees from Aidence BV, Faculty Science Limited, and MSD; and has received expenses for travelling to a conference from Takeda. A-MM, JT, LF, VB, KG, FB, CL, TA, JM, AD, and SLQ declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Low-Dose Computed Tomography (LDCT) screening for lung cancer can result in several potential outcomes of varying significance. Communication methods used in Lung Cancer Screening (LCS) programmes must, therefore, ensure that participants are prepared for the range of possible results and follow-up. Here, we assess perceptions of a written preparatory information booklet provided to participants in a large LCS cohort designed to convey this information., Materials and Methods: All participants in the SUMMIT Study (NCT03934866) were provided with a results preparation information booklet, entitled 'The SUMMIT Study: Next Steps' at their baseline appointment which outlined potential results, their significance, and timelines for follow up. Results from the LDCT scan and Lung Health Check were subsequently sent by letter. Perceptions of this booklet were assessed among participants with indeterminate pulmonary findings when they attended a face-to-face appointment immediately before their three-month interval scan. Specifically, questions assessed the perceived usefulness of the booklet and the amount of information contained in it., Results: 70.1% (n = 1,412/2,014) participants remembered receiving the booklet at their appointment. Of these participants, 72.0% (n = 1,017/1,412) found it quite or very useful and 68.0% (n = 960/1,412) reported that it contained the right amount of information. Older participants, those from the least deprived socioeconomic quintile and those of Black ethnicity were less likely to report finding the booklet either quite or very useful, or that it contained the right amount of information. Participants who remembered receiving the booklet were more likely to be satisfied with the process of results communication by letter., Conclusion: Providing written information that prepares participants for possible LDCT results and their significance appears to be a useful resource and a helpful adjunct to a written method of results communication for large scale LCS programmes., Competing Interests: Declaration of Competing Interest SUMMIT is sponsored and conducted by University College London and funded by GRAIL through a research grant awarded to SMJ as principal investigator. SLQ collaborates on the SUMMIT study and has received honorarium from Elsevier for writing a book chapter. AN is a member of the advisory board for Aidence BV and Faculty Science Ltd, has received a consultation fee from MSD and honorarium for travel to a conference from Takeda. AN is an Executive Committee member for the British Society of Thoracic Imaging, Lung Taskforce member for the British Lung Foundation and clinical lead for the NHS England Targeted Lung Health Checks Programme. AH has received an honorarium for an advisory bord meeting for GRAIL, a consultation fee for Evidera Inc for a GRAIL initiated project, and previously owned shares in Illumina. SMJ has received honoraria for travel, consultancy or speaking from Astra Zeneca, BARD1 Bioscience, Optellum, Jansen, Takeda, Evidera and Achilles Therapeutics.  SMJ received grant funding from Owlstone for a separate research study and has a family member who is an employee of Astra Zeneca.  AC (2) received a HEE NIHR Pre-Doctoral Clinical Academic Fellowship. All authors perceive that these disclosures pose no academic conflict for this study and declare no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

The optimal management of small but growing nodules remains unclear. The SUMMIT study nodule management algorithm uses a specific threshold volume of 200 mm 3 before referral of growing solid nodules to the multidisciplinary team for further investigation is advised, with growing nodules below this threshold kept under observation within the screening programme. Malignancy risk of growing solid nodules of size >200 mm 3 at initial 3-month interval scan was 58.3% at a per-nodule level, compared with 13.3% in growing nodules of size ≤200 mm 3 (relative risk 4.4, 95% CI 2.17 to 8.83). The positive predictive value of a combination of nodule growth (defined as percentage volume change of ≥25%), and size >200 mm 3 was 65.9% (29/44) at a cancer-per-nodule basis, or 60.5% (23/38) on a cancer-per-participant basis. False negative rate of the protocol was 1.9% (95% CI 0.33% to 9.94%). These findings support the use of a 200 mm 3 minimum volume threshold for referral as effective at reducing unnecessary multidisciplinary team referrals for small growing nodules, while maintaining early-stage lung cancer diagnosis., Competing Interests: Competing interests: AWC, CH, JLD, ST, HH, PV, RP and AB are all funded or part-funded through GRAIL as part of the SUMMIT Study. SUMMIT is sponsored and conducted by University College London and funded by GRAIL LLC through a research grant awarded to SMJ as principal investigator. SMJ’s full disclosures are as a Paid Advisory Board member Astra-Zeneca, Bard1 Bioscience, Achilles Therapeutics, Jansen. Assistance for travel to meetings from Astra Zeneca, Takeda, and grant income from GRAIL Inc, Owlstone and share options from Optellum; BARD1 Lifescience. AN is part-funded through the UCLH Biomedical Research Centre. AD’s disclosures are personal fees from Boehringer Ingelheim, Roche, Galacto Biotech, Galapagos, Brainomix and Vicore. AH’s disclosures are consulting fees to Evidera and assistance for travel to meetings from GRAIL., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: COPD is a major comorbidity in lung cancer screening (LCS) cohorts, with a high prevalence of undiagnosed COPD. Combining symptom assessment with spirometry in this setting may enable earlier diagnosis of clinically significant COPD and facilitate increased understanding of lung cancer risk in COPD. In this study, we wished to understand the prevalence, severity, clinical phenotype and lung cancer risk of individuals with symptomatic undiagnosed COPD in a LCS cohort., Methods: 16 010 current or former smokers aged 55-77 years attended a lung health check as part of the SUMMIT Study. A respiratory consultation and spirometry were performed alongside LCS eligibility assessment. Those with symptoms, no previous COPD diagnosis and airflow obstruction were labelled as undiagnosed COPD. Baseline low-dose computed tomography (LDCT) was performed in those at high risk of lung cancer (PLCO m2012 score ≥1.3% and/or meeting USPSTF 2013 criteria)., Results: Nearly one in five (19.7%) met criteria for undiagnosed COPD. Compared with those previously diagnosed, those undiagnosed were more likely to be male (59.1% versus 53.2%; p<0.001), currently smoking (54.9% versus 47.6%; p<0.001) and from an ethnic minority group (p<0.001). Undiagnosed COPD was associated with less forced expiratory volume in 1 s impairment (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 1 and 2: 85.3% versus 68.4%; p<0.001) and lower symptom/exacerbation burden (GOLD A and B groups: 95.6% versus 77.9%; p<0.001) than those with known COPD. Multivariate analysis demonstrated that airflow obstruction was an independent risk factor for lung cancer risk on baseline LDCT (adjusted OR 2.74, 95% CI 1.73-4.34; p<0.001), with a high risk seen in those with undiagnosed COPD (adjusted OR 2.79, 95% CI 1.67-4.64; p<0.001)., Conclusions: Targeted case-finding within LCS detects high rates of undiagnosed symptomatic COPD in those most at risk. Individuals with undiagnosed COPD are at high risk for lung cancer., Competing Interests: Conflict of interest: S. Tisi, J.L. Dickson, C. Horst, H. Hall and P. Verghese are all funded or part-funded through GRAIL Inc., as part of the SUMMIT Study. S.M. Janes was a Wellcome Trust Senior Fellow in Clinical Science (WT107963AIA); is supported by Cancer Research UK (CRUK) programme grant EDDCPGM\100002, the Rosetrees Trust, the Roy Castle Lung Cancer foundation, the Garfield Weston Trust and UCLH Charitable Foundation; and reports fees for advisory board work from AstraZeneca, Bard1 Bioscience, Achilles Therapeutics and Jansen, assistance for travel to meetings from AstraZeneca and Takeda, grant income from GRAIL Inc. and Owlstone, and share options from Optellum and Bard1 Lifescience Ltd. S.L. Quaife is supported by a Cancer Research UK (CRUK) Population Research Fellowship (C50664/A24460) and Barts Charity (MRC&U0036). A. Nair is part-funded through the UCLH Biomedical Research Centre. A. Devaraj reports personal fees from Boehringer Ingelheim, Roche, Galacto Biotech, Galapagos and Vicore. A. Hackshaw reports consulting fees from Evidera Inc. and assistance for travel to meetings from GRAIL Inc. J.R. Hurst reports assistance for travel from AstraZeneca and Boehringer Ingelheim, and payment for lectures and presentations from AstraZeneca, Boehringer Ingelheim, Nutricia and Takeda. There are no disclosures from K. Gyertson, V. Bowyer, C. Levermore, A-M. Mullin, J. Teague and L. Farrelly., (Copyright ©The authors 2022.)

Lung cancer screening (LCS) eligibility is largely determined by tobacco consumption. Primary care smoking data could guide LCS invitation and eligibility assessment. We present observational data from the SUMMIT Study, where individual self-reported smoking status was concordant with primary care records in 75.3%. However, 10.3% demonstrated inconsistencies between historic and most recent smoking status documentation. Quantified tobacco consumption was frequently missing, precluding direct LCS eligibility assessment. Primary care recorded "ever-smoker" status, encompassing both recent and historic documentation, can be used to target LCS invitation. Identifying those with missing or erroneous "never-smoker" smoking status is crucial for equitable invitation to LCS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Eligibility for lung cancer screening (LCS) requires assessment of lung cancer risk, based on smoking history alongside demographic and medical factors. Reliance on individual face-to-face eligibility assessment risks inefficiency and costliness. The SUMMIT Study introduced a telephone-based lung cancer risk assessment to guide invitation to face-to-face LCS eligibility assessment, which significantly increased the proportion of face-to-face attendees eligible for LCS. However, levels of agreement between phone screener and in-person responses were lower in younger individuals and minority ethnic groups. Telephone-based risk assessment is an efficient way to optimise selection for LCS appointments but requires further iteration to ensure an equitable approach., Competing Interests: Competing interests: JLD, CH, ST, HH, PV, JM, AH and SMJ are investigators for the SUMMIT Study within which the present study cohort is embedded. SUMMIT is sponsored and conducted by University College London and funded by GRAIL LLC. through a research grant awarded to SMJ as principal investigator. SLQ collaborates on the SUMMIT study and has received honorarium from Elsevier for writing a book chapter. AN is a member of the advisory board for Aidence BV. AH has received an honorarium for an advisory board meeting for GRAIL, a consultation fee for Evidera Inc for a GRAIL initiated project, and previously owned shares in Illumina. SMJ has received honoraria from Astra Zeneca, BARD1 Bioscience and Jansen for being an Advisory Board Expert and travel to a US conference. SMJ received grant funding from Owlstone for a separate research study and has a family member who is an employee of Astra Zeneca. SMJ has received travel funding for a conference from Takeda and an honorarium for planning and speaking at educational meetings from Astra Zeneca. All authors perceive that these disclosures pose no academic conflict for this study and declare no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Successful lung cancer screening delivery requires sensitive, timely reporting of low-dose computed tomography (LDCT) scans, placing a demand on radiology resources. Trained non-radiologist readers and computer-assisted detection (CADe) software may offer strategies to optimise the use of radiology resources without loss of sensitivity. This report examines the accuracy of trained reporting radiographers using CADe support to report LDCT scans performed as part of the Lung Screen Uptake Trial (LSUT)., Methods: In this observational cohort study, two radiographers independently read all LDCT performed within LSUT and reported on the presence of clinically significant nodules and common incidental findings (IFs), including recommendations for management. Reports were compared against a 'reference standard' (RS) derived from nodules identified by study radiologists without CADe, plus consensus radiologist review of any additional nodules identified by the radiographers., Results: A total of 716 scans were included, 158 of which had one or more clinically significant pulmonary nodules as per our RS. Radiographer sensitivity against the RS was 68-73.7%, with specificity of 92.1-92.7%. Sensitivity for detection of proven cancers diagnosed from the baseline scan was 83.3-100%. The spectrum of IFs exceeded what could reasonably be covered in radiographer training., Conclusion: Our findings highlight the complexity of LDCT reporting requirements, including the limitations of CADe and the breadth of IFs. We are unable to recommend CADe-supported radiographers as a sole reader of LDCT scans, but propose potential avenues for further research including initial triage of abnormal LDCT or reporting of follow-up surveillance scans., Key Points: • Successful roll-out of mass screening programmes for lung cancer depends on timely, accurate CT scan reporting, placing a demand on existing radiology resources. • This observational cohort study examines the accuracy of trained radiographers using computer-assisted detection (CADe) software to report lung cancer screening CT scans, as a potential means of supporting reporting workflows in LCS programmes. • CADe-supported radiographers were less sensitive than radiologists at identifying clinically significant pulmonary nodules, but had a low false-positive rate and good sensitivity for detection of confirmed cancers., (© 2022. The Author(s).)

Objectives: Pulmonary nodules are commonly found in Lung Cancer Screening (LCS), with results typically communicated by face-to-face or telephone consultation. Providing LCS on a population basis requires resource efficient and scalabe communication methods. Written communication provides one such method. Here, we assess participant satisfaction with this approach in a LCS setting and investigate characteristics associated with dissatisfaction., Materials and Methods: The SUMMIT Study is a prospective observational cohort study which aims to assess the implementation of Low-Dose Computed Tomography (LDCT) scanning for LCS in a high-risk population and validate a multi-cancer early detection blood test (NCT03934866). Participants with indeterminate pulmonary nodules requiring a three-month interval LDCT were informed of their result by postal letter and given a face-to-face appointment with a study practitioner at their interval LDCT appointment. At this appointment, having previously received their results letter, participants were verbally asked questions to assess their satisfaction with, and preferences for, methods of results communication., Results: 1,900 participants were included in the analysis. 82.8% (n = 1573) were satisfied with receiving their results by letter, with 2.9% (n = 55) reporting dissatisfaction. 86.3% (n = 1640) stated it was their preferred communication method and 77.3% (n = 1469) reported that their letter contained the right amount of information. Participants from less deprived socioeconomic quintiles were more likely to report that the letter contained insufficient information and individuals aged ≥ 70 years were less likely to do so. Although 13.7% (n = 261) participants had discussed their results with their General Practitioner (GP) prior to the study visit, 83.9% (n = 219) of these participants were satisfied with receiving results by letter, with the same proportion preferring this communication method., Conclusion: We report high participant satisfaction with the reporting of pulmonary nodule results by letter in a LCS setting. We believe this provides a feasible route forward for large-scale screening programmes., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Lung cancer is the leading cause of cancer death worldwide. The absence of symptoms in early-stage (I/II) disease, when curative treatment is possible, results in >70% of cases being diagnosed at late stage (III/IV), when treatment is rarely curative. This contributes greatly to the poor prognosis of lung cancer, which sees only 16.2% of individuals diagnosed with the disease alive at 5 years. Early detection is key to improving lung cancer survival outcomes. As a result, there has been longstanding interest in finding a reliable screening test. After little success with chest radiography and sputum cytology, in 2011 the United States National Lung Screening Trial demonstrated that annual low-dose computed tomography (LDCT) screening reduced lung cancer-specific mortality by 20%, when compared with annual chest radiography. In 2020, the NELSON study demonstrated an even greater reduction in lung cancer-specific mortality for LDCT screening at 0, 1, 3 and 5.5 years of 24% in men, when compared to no screening. Despite these impressive results, a call to arms in the 2017 European position statement on lung cancer screening (LCS) and the widespread introduction across the United States, there was, until recently, no population-based European national screening programme in place. We address the potential barriers and outstanding concerns including common screening foes, such as false-positive tests, overdiagnosis and the negative psychological impact of screening, as well as others more unique to LDCT LCS, including appropriate risk stratification of potential participants, radiation exposure and incidental findings. In doing this, we conclude that whilst the evidence generated from ongoing work can be used to refine the screening process, for those risks which remain, appropriate and acceptable mitigations are available, and none should serve as barriers to the implementation of national unified LCS programmes across Europe and beyond., Competing Interests: Disclosure There are no disclosures relevant to this review. SMJ‘s full disclosures are Paid Advisory Board member Astra-Zeneca, Bard1 Bioscience, Achilles Therapeutics, Jansen. Assistance for travel to a meetings Astra Zeneca, Takeda, and grant income from GRAIL Inc, Owlstone and share options from Optellum; BARD1 Lifescience Ltd. AN is a member of the Advisory Board for Aidence, the Netherlands., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Introduction: Low uptake of low-dose computed tomography lung cancer screening by high-risk groups compromises its effectiveness and equity as a population-level early detection strategy. Numerous psychological factors are implicated qualitatively or retrospectively, but prospective data are needed to validate their associations with uptake behavior and specify psychological targets for intervention., Methods: This is a prospective, longitudinal cohort study evaluating psychological correlates of lung cancer screening uptake. Ever-smokers (aged 55-77 y) were invited to a lung health check, at which low-dose computed tomography screening was offered through the SUMMIT Study-a multicenter screening implementation trial. One week after their screening invitation, 44,000 invitees were mailed the self-regulatory questionnaire for lung cancer screening. Regression analyses evaluated the constructs' associations with uptake (telephoning for an appointment) and sociodemographic characteristics., Results: Higher odds of uptake were associated with both positive and negative perceptions. Positive perceptions included lung cancer controllability, benefits of early diagnosis, improved survival when lung cancer is detected early, willingness to be treated, and believing smoking cessation is effective in reducing risk. Negative perceptions included a higher lung cancer risk perception, negative beliefs about the consequences of lung cancer, perceiving lung cancer as stigmatized, and a negative emotional response. Although current smokers held the highest risk perceptions, they also reported negative perceptions that could undermine how they behave in response to their risk., Conclusions: Interventions to improve uptake should focus on changing perceptions that affect how an individual reacts when they believe their risk of lung cancer is high., (Copyright © 2021. Published by Elsevier Inc.)

Competing Interests: Competing interests: The SUMMIT Study is funded by GRAIL. SMJ is a Wellcome Trust Senior Fellow in Clinical Science and supported by the Rosetrees Trust, UCLH Charitable Foundation and the Roy Castle Lung Cancer Foundation. This work was partially supported by the UCLH/UCL Department of Health’s NIHR Biomedical Research Centre’s funding scheme, the CRUK Lung Cancer Centre of Excellence and CRUK Early Detection Centre. AD declares personal fees from Boehringer Ingelheim, GlaxoSmithKline (GSK), Galapagos and Galecto. CH, JLD, ST and MR are funded or part-funded by GRAIL as part of the SUMMIT Study. AN declares that he is a member of the Advisory Board for Aidence, The Netherlands, and he is part-funded by the UCLH Biomedical Research Centre (BRC).

The Lung Screen Uptake Trial tested a novel invitation strategy to improve uptake and reduce socioeconomic and smoking-related inequalities in lung cancer screening (LCS) participation. It provides one of the first UK-based 'real-world' LCS cohorts. Of 2012 invited, 1058 (52.6%) attended a 'lung health check'. 768/996 (77.1%) in the present analysis underwent a low-dose CT scan. 92 (11.9%) and 33 (4.3%) participants had indeterminate pulmonary nodules requiring 3-month and 12-month surveillance, respectively; 36 lung cancers (4.7%) were diagnosed (median follow-up: 1044 days). 72.2% of lung cancers were stage I/II and 79.4% of non-small cell lung cancer had curative-intent treatment., Competing Interests: Competing interests: SMJ, MR, JLD, CH, ST and HH are supported by funding for a large trial of low dose CT screening, called the ‘SUMMIT Study’ by GRAIL Inc. SLQ and NN collaborate on the SUMMIT Study. SMJ has received honoraria from AstraZeneca, BARD1 Bioscience and Janssen for being an Advisory Board Expert and travel to a US conference. SMJ received grant funding from Owlstone for a separate research study and has a family member who has a financial association with AstraZeneca. MR has received travel funding for a conference from Takeda and an honorarium for planning and speaking at educational meetings from AstraZeneca., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Rationale: Individuals eligible for lung cancer screening (LCS) by low-dose computed tomography (LDCT) are also at risk of chronic obstructive pulmonary disease (COPD) due to age and smoking exposure. Whether the LCS episode is useful for early detection of COPD is not well established. Objectives: To explore associations between symptoms, comorbidities, spirometry, and emphysema in participants enrolled in the Lung Screen Uptake Trial. Methods: This cross-sectional study was a prespecified analysis nested within Lung Screen Uptake Trial, which was a randomized study testing the impact of differing invitation materials on attendance of 60- to 75-year-old smokers and ex-smokers to a "lung health check" between November 2015 and July 2017. Participants with a smoking history ≥30 pack-years and who quit ≤15 years ago, or meeting a lung cancer risk of ≥1.51% via the Prostate Lung Colorectal Ovarian model or ≥2.5% via the Liverpool Lung Project model, were offered LDCT. COPD was defined and classified according to the GOLD (Global Initiative for Obstructive Lung Disease) criteria using prebronchodilator spirometry. Analyses included the use of descriptive statistics, chi-square tests to examine group differences, and univariable and multivariable logistic regression to explore associations between symptom prevalence, airflow limitation, and visually graded emphysema. Results: A total of 560 of 986 individuals included in the analysis (57%) had prebronchodilator spirometry consistent with COPD; 67% did not have a prior history of COPD and were termed "undiagnosed." Emphysema prevalence in those with known and "undiagnosed" COPD was 73% and 68%, respectively. A total of 32% of those with "undiagnosed COPD" had no emphysema on LDCT. Inhaler use and symptoms were more common in the "known" than the "undiagnosed" COPD group (63% vs. 33% with persistent cough [ P  < 0.001]; 73% vs. 33% with dyspnea [ P  < 0.001]). Comorbidities were common in all groups. Adjusted odds ratio (aOR) of respiratory symptoms were more significant for airflow obstruction (aOR GOLD 1 and 2, 1.57; confidence interval [CI], 1.14-2.17; aOR GOLD 3 and 4, 4.6; CI, 2.17-9.77) than emphysema (aOR mild, 1.12; CI, 0.81-1.55; aOR moderate, 1.33; CI, 0.85-2.09; aOR severe, 4.00; CI, 1.57-10.2). Conclusions: There is high burden of "undiagnosed COPD" and emphysema in LCS participants. Adding spirometry findings to the LDCT enhances identification of individuals with COPD.Clinical trial registered with www.clinicaltrials.gov (NCT02558101).

Copper-catalyzed cross-coupling reactions have become one of the most powerful methods for generating carbon-heteroatom bonds, an important framework of many organic molecules. However, copper-catalyzed C(sp 3 )-O cross-coupling of alkyl halides with alkyl alcohols remains elusive because of the sluggish nature of oxidative addition to copper. To address this challenge, we have developed a catalytic copper system, which overcomes the copper oxidative addition barrier with the aid of visible light and effectively facilitates the cross-couplings of glycosyl bromides with aliphatic alcohols to afford C(sp 3 )-O bonds with high levels of diastereoselectivity. Importantly, this catalytic system leads to a mild and efficient method for stereoselective construction of α -1,2- cis glycosides, which are of paramount importance, but challenging. In general, stereochemical outcomes in α -1,2- cis glycosidic C-O bond-forming processes are unpredictable and dependent on the steric and electronic nature of protecting groups bound to carbohydrate coupling partners. Currently, the most reliable approaches rely on the use of a chiral auxiliary or hydrogen-bond directing group at the C2- and C4-position of carbohydrate electrophiles to control α -1,2- cis selectivity. In our approach, earth-abundant copper not only acts as a photocatalyst and a bond-forming catalyst, but also enforces the stereocontrolled formation of anomeric C-O bonds. This cross-coupling protocol enables highly diastereoselective access to a wide variety of α -1,2- cis -glycosides and biologically relevant α -glycan oligosaccharides. Our work provides a foundation for developing new methods for the stereoselective construction of natural and unnatural anomeric carbon(sp 3 )-heteroatom bonds., Competing Interests: The authors declare no competing financial interest.

Rationale: Low uptake of low-dose computed tomography (LDCT) lung cancer screening, particularly by current smokers of a low socioeconomic position, compromises effectiveness and equity. Objectives: To compare the effect of a targeted, low-burden, and stepped invitation strategy versus control on uptake of hospital-based Lung Health Check appointments offering LDCT screening. Methods: In a two-arm, blinded, between-subjects, randomized controlled trial, 2,012 participants were selected from 16 primary care practices using these criteria: 1 ) aged 60 to 75 years, 2 ) recorded as a current smoker within the last 7 years, and 3 ) no prespecified exclusion criteria contraindicating LDCT screening. Both groups received a stepped sequence of preinvitation, invitation, and reminder letters from their primary care practitioner offering prescheduled appointments. The key manipulation was the accompanying leaflet. The intervention group's leaflet targeted psychological barriers and provided low-burden information, mimicking the concept of the U.K. Ministry of Transport's annual vehicle test ("M.O.T. For Your Lungs"). Measurements and Main Results: Uptake was 52.6%, with no difference between intervention (52.3%) and control (52.9%) groups in unadjusted (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.82-1.16) or adjusted (OR, 0.98; 95% CI, 0.82-1.17) analyses. Current smokers were less likely to attend (adjusted OR, 0.70; 95% CI, 0.56-0.86) than former smokers. Socioeconomic deprivation was significantly associated with lower uptake for the control group only ( P  < 0.01). Conclusions: The intervention did not improve uptake. Regardless of trial arm, uptake was considerably higher than previous clinical and real-world studies, particularly given that the samples were predominantly lower socioeconomic position smokers. Strategies common to both groups, including a Lung Health Check approach, could represent a minimum standard.Clinical trial registered with www.clinicaltrials.gov (NCT02558101) and registered prospectively with the International Standard Registered Clinical/Social Study (N21774741).

Introduction: Lung cancer screening (LCS) by low-dose computed tomography (LDCT) offers an opportunity to impact both lung cancer and coronary heart disease mortality through detection of coronary artery calcification (CAC). Here, we explore the value of CAC and cardiovascular disease (CVD) risk assessment in LCS participants in the Lung Screen Uptake Trial (LSUT)., Methods: In this cross-sectional study, current and ex-smokers aged 60-75 were invited to a 'lung health check'. Data collection included a CVD risk assessment enabling estimation of 10 year CVD risk using the QRISK2 score. Participants meeting the required lung cancer risk underwent an ungated, non-contrast LDCT. Descriptive data, bivariate associations and a multivariate analysis of predictors of statin use are presented., Results: Of 1005 individuals enrolled, 680 were included in the final analysis. 421 (61.9%) had CAC present and in 49 (7.2%), this was heavy. 668 (98%) of participants had a QRISK2≥10% and QRISK2 was positively associated with increasing CAC grade (OR 4.29 (CI 0.93 to 19.88) for QRISK2=10%-20% and 12.29 (CI 2.68 to 56.1) for QRISK2≥20% respectively). Of those who qualified for statin primary prevention (QRISK2≥10%), 56.8% did not report a history of statin use. In the multivariate analysis statin use was associated with age, body mass index and history of hypertension and diabetes., Conclusions: LCS offers an important opportunity for instituting CVD risk assessment in all LCS participants irrespective of the presence of LDCT-detected CAC. Further studies are needed to determine whether CAC could enhance uptake and adherence to primary preventative strategies., Competing Interests: Competing interests: SMJ, MR, JLD and CH are supported by funding for a large trial of low dose CT screening, called the ‘SUMMIT Study’ by GRAIL Inc. SQ collaborates on the SUMMIT study. SMJ has received honoraria from Astra Zeneca, BARD1 Bioscience and Achilles Therapeutics for being an Advisory Board Expert and travel to a US conference. SMJ receives grant funding from Owlstone for a separate research study and has a family member with a financial association with Astra Zeneca. MR has received travel funding for a conference from Takeda and an honorarium for speaking at educational meeting from Astra Zeneca. AN is a member of the Advisory Board for Aidence Artificial Intelligence. RS has received honoraria, consulting and speaker fees from Amgen, Sanofi and Bayer. SMJ, MR, JLD, CH, SQ, AN and RS perceive that these disclosures pose no academic conflict for this study. All other authors have no other competing interests to declare., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Rationale: Lung cancer screening has the potential to save lives, but it also carries a risk of potential harms. Explaining the benefits and harms of screening in a way that is balanced and comprehensible to individuals with various levels of education is essential. Although a shared decision-making approach is mandated by the Centers for Medicare & Medicaid Services, there have been no randomized studies to evaluate the impact of different forms of lung screening information. Objectives: To evaluate the impact of a novel information film on informed decision-making in individuals considering participating in lung cancer screening. Methods: A subset of participants from LSUT (Lung Screen Uptake Trial) were randomly allocated either to view the information film and receive a written information booklet or to receive the booklet alone. The primary outcome was the objective knowledge score after intervention. Secondary outcomes included subjective knowledge, decisional conflict, final screening participation, and acceptability of the materials. Univariate and multivariate analyses were performed to determine differences in pre- and postintervention knowledge scores in both groups and between groups for the primary and secondary outcomes. Results: In the final analysis of 229 participants, both groups showed significantly improved subjective and objective knowledge scores after intervention. This improvement was greatest in the film + booklet group, where mean objective knowledge improved by 2.16 points (standard deviation [SD] 1.8) compared with 1.84 points (SD 1.9) in the booklet-alone group (β coefficient 0.62; confidence interval, 0.17-1.08; P = 0.007 in the multivariable analysis). Mean subjective knowledge increased by 0.92 points (SD 1.0) in the film + booklet group and 0.55 points (SD 1.1) in the booklet-alone group (β coefficient 0.32; CI, 0.05-0.58; P = 0.02 in the multivariable analysis). Decisional certainty was higher in the film + booklet (mean 8.5/9 points [SD 1.3], group than in the booklet-alone group (mean 8.2/9 points [SD 1.5]). Both information materials were well accepted, and there were no differences in final screening participation rates between groups. Conclusions: The information film improved knowledge and reduced decisional conflict without affecting lung-screening uptake. Clinical trial registered with clinicaltrials.gov (NCT02558101).

Objective: Previous studies examine clinical outcomes of insulin therapy in neonatal intensive care units (NICUs), without first developing safe and effective control protocols. This research quantifies the safety and performance of a computerised model-based control algorithmSTAR-GRYPHON (Stochastic TARgeted Glucose Regulation sYstem to Prevent Hyper- and hypO-glycaemia in Neonates)., Design: Retrospective observational study of glycaemic control in very/extremely low birthweight infants treated with insulin from Christchurch Women's Hospital NICU between January 2013 and June 2017. Blood glucose (BG) outcomes and control performance is compared with retrospective data (n=22) and literature., Interventions: Insulin infusion doses were calculated from 3 to 4 hourly BG measurements using a computerised model-based control algorithm, STAR-GRYPHON., Main Outcome Measures: Mean BG, time in targeted range and incidence of hypoglycaemia., Results: STAR-GRYPHON (n=35) had lower mean BG concentration (7.0mmol/L vs 7.9 mmol/L), higher %BG within the 4.0-8.0 mmol/L target range (71.1% vs 50.9%) and lower %BG <4.0 mmol/L (0.6% vs 2.1%). There were only 2 BG <2.6 mmol/L (over n=2, 5.5% of patients, 0.03% of all BG outcomes), one of which may be attributed to clinical error. These results show better control to target and lower incidence of hypoglycaemia than most literature results from intensive insulin therapy protocols or study groups in children and infants., Conclusions: Model-based protocols can safely and effectively control BG in very premature infants and should be used in future studies to determine the effect of insulin therapy on clinical outcomes., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Elevated blood glucose (BG) concentrations (Hyperglycaemia) are a common complication in critically ill patients. Insulin therapy is commonly used to treat hyperglycaemia, but metabolic variability often results in poor BG control and low BG (hypoglycaemia)., Objective: This paper presents a model-based virtual trial method for glycaemic control protocol design, and evaluates its generalisability across different populations., Methods: Model-based insulin sensitivity (SI) was used to create virtual patients from clinical data from three different ICUs in New Zealand, Hungary, and Belgium. Glycaemic results from simulation of virtual patients under their original protocol (self-simulation) and protocols from other units (cross simulation) were compared., Results: Differences were found between the three cohorts in median SI and inter-patient variability in SI. However, hour-to-hour intra-patient variability in SI was found to be consistent between cohorts. Self and cross-simulation results were found to have overall similarity and consistency, though results may differ in the first 24-48 h due to different cohort starting BG and underlying SI., Conclusions and Significance: Virtual patients and the virtual trial method were found to be generalisable across different ICUs. This virtual trial method is useful for in silico protocol design and testing, given an understanding of the underlying assumptions and limitations of this method.

Critical care, like many healthcare areas, is under a dual assault from significantly increasing demographic and economic pressures. Intensive care unit (ICU) patients are highly variable in response to treatment, and increasingly aging populations mean ICUs are under increasing demand and their cohorts are increasingly ill. Equally, patient expectations are growing, while the economic ability to deliver care to all is declining. Better, more productive care is thus the big challenge. One means to that end is personalised care designed to manage the significant inter- and intra-patient variability that makes the ICU patient difficult. Thus, moving from current "one size fits all" protocolised care to adaptive, model-based "one method fits all" personalised care could deliver the required step change in the quality, and simultaneously the productivity and cost, of care. Computer models of human physiology are a unique tool to personalise care, as they can couple clinical data with mathematical methods to create subject-specific models and virtual patients to design new, personalised and more optimal protocols, as well as to guide care in real-time. They rely on identifying time varying patient-specific parameters in the model that capture inter- and intra-patient variability, the difference between patients and the evolution of patient condition. Properly validated, virtual patients represent the real patients, and can be used in silico to test different protocols or interventions, or in real-time to guide care. Hence, the underlying models and methods create the foundation for next generation care, as well as a tool for safely and rapidly developing personalised treatment protocols over large virtual cohorts using virtual trials. This review examines the models and methods used to create virtual patients. Specifically, it presents the models types and structures used and the data required. It then covers how to validate the resulting virtual patients and trials, and how these virtual trials can help design and optimise clinical trial. Links between these models and higher order, more complex physiome models are also discussed. In each section, it explores the progress reported up to date, especially on core ICU therapies in glycemic, circulatory and mechanical ventilation management, where high cost and frequency of occurrence provide a significant opportunity for model-based methods to have measurable clinical and economic impact. The outcomes are readily generalised to other areas of medical care.

Background: Continuous glucose monitoring (CGM) technology has become more prevalent in the intensive care unit (ICU), offering potential benefits of increased safety and reduced workload in glycemic control (GC). The drift and higher point accuracy errors of CGM devices over traditional intermittent blood glucose (BG) measures have so far limited their application in the ICU. This study delineates the trade-offs of performance, safety and workload that CGM sensors provide in GC protocols., Methods: Clinical data from 236 patients were used for clinically validated virtual trials. A CGM-enabled version of the STAR GC protocol was used to evaluate the use of guard rails and rolling windows. Safety was assessed through percentage of patients who had a severe hypoglycemic episode (BG < 40 mg/dl) as well as percentage of resampled BG < 72 mg/dl. Performance was assessed as percentage of resampled measurements in the 80-126 mg/dl and the 80-144 mg/dl target bands. Workload was measured by number of manual BG measures per day., Results: CGM-enabled versions of STAR decreased the number of required blood draws by up to 74%, while maintaining performance (76.6% BG measurements in the 80-126 mg/dl range vs 62.8% clinically, 87.9% in the 80-144 mg/dl range vs 83.7% clinically) and maintaining patient safety (1.13% of patients experienced a severe hypoglycemic event vs 0.85% clinically, 1.37% of BG measurements were less than 72 mg/dl vs 0.51% clinically)., Conclusion: CGM sensor traces were reproduced in virtual trials to guide GC. Existing GC protocols such as STAR may need to be adjusted only slightly to gain the benefits of the increased temporal measurements of CGM sensors, through which workload may be significantly decreased while maintaining GC performance and safety.

Background: Continuous glucose monitoring (CGM) devices have been effective in managing diabetes and offer potential benefits for use in the intensive care unit (ICU). Use of CGM devices in the ICU has been limited, primarily due to the higher point accuracy errors over currently used traditional intermittent blood glucose (BG) measures. General models of CGM errors, including drift and random errors, are lacking, but would enable better design of protocols to utilize these devices. This article presents an autoregressive (AR) based modeling method that separately characterizes the drift and random noise of the GlySure CGM sensor (GlySure Limited, Oxfordshire, UK)., Methods: Clinical sensor data (n = 33) and reference measurements were used to generate 2 AR models to describe sensor drift and noise. These models were used to generate 100 Monte Carlo simulations based on reference blood glucose measurements. These were then compared to the original CGM clinical data using mean absolute relative difference (MARD) and a Trend Compass., Results: The point accuracy MARD was very similar between simulated and clinical data (9.6% vs 9.9%). A Trend Compass was used to assess trend accuracy, and found simulated and clinical sensor profiles were similar (simulated trend index 11.4° vs clinical trend index 10.9°)., Conclusion: The model and method accurately represents cohort sensor behavior over patients, providing a general modeling approach to any such sensor by separately characterizing each type of error that can arise in the data. Overall, it enables better protocol design based on accurate expected CGM sensor behavior, as well as enabling the analysis of what level of each type of sensor error would be necessary to obtain desired glycemic control safety and performance with a given protocol.

Background: Hyperglycaemia is associated with adverse outcomes in the intensive care unit, and initial studies suggested outcome benefits of glycaemic control (GC). However, subsequent studies often failed to replicate these results, and they were often unable to achieve consistent, safe control, raising questions about the benefit or harm of GC as well as the nature of the association of glycaemia with mortality and clinical outcomes. In this study, we evaluated if non-survivors are harder to control than survivors and determined if glycaemic outcome is a function of patient condition and eventual outcome or of the glycaemic control provided., Methods: Clinically validated, model-based, hour-to-hour insulin sensitivity (SI) and its hour-to-hour variability (%ΔSI) were identified over the first 72 h of therapy in 145 patients (119 survivors, 26 non-survivors). In hypothesis testing, we compared distributions of SI and %ΔSI in 6-hourly blocks for survivors and non-survivors. In equivalence testing, we assessed if differences in these distributions, based on blood glucose measurement error, were clinically significant., Results: SI level was never equivalent between survivors and non-survivors (95% CI of percentage difference in medians outside ±12%). Non-survivors had higher SI, ranging from 9% to 47% higher overall in 6-h blocks, and this difference became statistically significant as glycaemic control progressed. %ΔSI was equivalent between survivors and non-survivors for all 6-hourly blocks (95% CI of difference in medians within ±12%) and decreased in general over time as glycaemic control progressed., Conclusions: Whereas non-survivors had higher SI levels, variability was equivalent to that of survivors over the first 72 h. These results indicate survivors and non-survivors are equally controllable, given an effective glycaemic control protocol, suggesting that glycaemia level and variability, and thus the association between glycaemia and outcome, are essentially determined by the control provided rather than by underlying patient or metabolic condition.

Very/extremely premature infants often experience glycaemic dysregulation, resulting in abnormally elevated (hyperglycaemia) or low (hypoglycaemia) blood glucose (BG) concentrations, due to prematurity, stress, and illness. STAR-GRYPHON is a computerised protocol that utilises a model-based insulin sensitivity parameter to directly tailor therapy for individual patients and their changing conditions, unlike other common insulin protocols in this cohort. From January 2013 to January 2015, 13 patients totalling 16 hyperglycaemic control episodes received insulin under STAR-GRYPHON. A significant improvement in control was achieved in comparison to a retrospective cohort, with a 26% absolute improvement in BG within the targeted range and no hypoglycaemia. This improvement was obtained predominantly due to the reduction of hyperglycaemia (%BG>10.0 mmol/l: 5.6 vs. 17.7%, p<0.001), and lowering of the median per-patient BG [6.9 (6.1-7.9) vs. 7.8 (6.6-9.1) mmol/l, p<0.001, Mann-Witney U test]. While cohort-wide control results show good control overall, there is high intra-patient variability in BG behaviour, resulting in overly conservative treatments for some patients. Patient insulin sensitivity differs between and within patients over time, with some patients having stable insulin sensitivity, while others change rapidly. These results demonstrate the trade-off between safety and performance in a highly variable and fragile cohort.

Background: Models of human glucose-insulin physiology have been developed for a range of uses, with similarly different levels of complexity and accuracy. STAR (Stochastic Targeted) is a model-based approach to glycaemic control. Elevated blood glucose concentrations (hyperglycaemia) are a common complication of stress and prematurity in very premature infants, and have been associated with worsened outcomes and higher mortality. This research identifies and validates the model parameters for model-based glycaemic control in neonatal intensive care., Methods: C-peptide, plasma insulin, and BG from a cohort of 41 extremely pre-term (median age 27.2 [26.2-28.7] weeks) and very low birth weight infants (median birth weight 839 [735-1000] g) are used alongside C-peptide kinetic models to identify model parameters associated with insulin kinetics in the NICING (Neonatal Intensive Care Insulin-Nutrition-Glucose) model. A literature analysis is used to determine models of kidney clearance and body fluid compartment volumes. The full, final NICING model is validated by fitting the model to a cohort of 160 glucose, insulin, and nutrition data records from extremely premature infants from two different NICUs (neonatal intensive care units)., Results: Six model parameters related to insulin kinetics were identified. The resulting NICING model is more physiologically descriptive than prior model iterations, including clearance pathways of insulin via the liver and kidney, rather than a lumped parameter. In addition, insulin diffusion between plasma and interstitial spaces is evaluated, with differences in distribution volume taken into consideration for each of these spaces. The NICING model was shown to fit clinical data well, with a low model fit error similar to that of previous model iterations., Conclusions: Insulin kinetic parameters have been identified, and the NICING model is presented for glycaemic control neonatal intensive care. The resulting NICING model is more complex and physiologically relevant, with no loss in bedside-identifiability or ability to capture and predict metabolic dynamics., (Copyright © 2016. Published by Elsevier Inc.)

Background: Model-based glycemic control relies on sufficiency of underlying models to describe underlying patient physiology. In particular, very preterm infant glucose-insulin metabolism can differ significantly from adults, and is relatively unstudied. In this study, C-peptide concentrations are used to develop insulin-secretion models for the purposes of glycemic control in neonatal intensive care., Methods: Plasma C-peptide, insulin, and blood glucose concentrations (BGC) were retrospectively analyzed from a cohort of 41 hyperglycemic very preterm (median age 27.2 [26.2-28.7] weeks) and very low birth-weight infants (median birth weight 839 [735-1000] g). A 2-compartment model of C-peptide kinetics was used to estimate insulin secretion. Insulin secretion was examined with respect to nutritional intake, exogenous and plasma insulin concentration, and BGC., Results: Insulin secretion was found to be highly variable between patients and over time, and could not be modeled with respect to age, weight, or protein or dextrose intake. In 13 of 54 samples exogenous insulin was being administered, and insulin secretion was lower. However, low data numbers make this result inconclusive. Insulin secretion was found to increase with BG, with a stronger association in female infants than males (R(2) = .51 vs R(2) = .13, and R(2) = .26 for the combined cohort)., Conclusions: A sex-based insulin secretion model was created and incorporated into a model-based glycemic control framework. Nutritional intake did not predict insulin secretion, indicating that insulin secretion is a complex function of a number of metabolic factors., (© 2015 Diabetes Technology Society.)

Background: Hyperglycaemia is a common complication of prematurity and is associated with neonatal mortality and morbidity, yet the aetiology is incompletely understood. C-peptide has been used in adults to estimate endogenous insulin secretion due to its simple clearance kinetics., Objective: To determine insulin secretion calculated from plasma C-peptide concentrations in hyperglycaemic preterm babies., Methods: This is a retrospective analysis of a cohort of 41 very preterm babies with a median gestational age of 27.2 weeks (26.2-28.7) enrolled in a randomised controlled trial of tight glycaemic control when they developed hyperglycaemia (2 consecutive blood glucose concentrations, BGC, > 8.5 mmol·l(-1)). Insulin secretion was determined using a steady state analysis of a 2-compartment C-peptide kinetic model., Results: BGC, plasma insulin concentration, plasma C-peptide concentrations, and insulin secretion were higher at randomisation than 1-2 weeks following randomisation (p ≤ 0.02). Insulin secretion was higher in girls at 11.7 mU·l(-1)·kg(-1)·min(-1) (5.3-18.7) vs. 4.7 mU·l(-1)·kg(-1)·min(-1) (2.1-8.3; p < 0.005), with no difference in clinical characteristics, BGC, plasma insulin concentration, or nutrition between the sexes (p > 0.25). Insulin secretion was lower in samples taken during exogenous insulin delivery at 3.7 mU·l(-1)·kg(-1)·min(-1) (1.8-6.9) vs. 9.8 mU·l(-1)·kg(-1)·min(-1) (4.7-17.8; p = 0.02)., Conclusions: Insulin secretion was higher when babies had higher BGC, indicating that endogenous insulin secretion is sensitive to BGC. Girls had higher insulin secretion, at similar blood glucose and plasma insulin concentrations, than boys., (© 2015 S. Karger AG, Basel.)

Introduction: Hyperglycaemia is a common complication of stress and prematurity in extremely low-birth-weight infants. Model-based insulin therapy protocols have the ability to safely improve glycaemic control for this group. Estimating non-insulin-mediated brain glucose uptake by the central nervous system in these models is typically done using population-based body weight models, which may not be ideal., Method: A head circumference-based model that separately treats small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) infants is compared to a body weight model in a retrospective analysis of 48 patients with a median birth weight of 750g and median gestational age of 25 weeks. Estimated brain mass, model-based insulin sensitivity (SI) profiles, and projected glycaemic control outcomes are investigated. SGA infants (5) are also analyzed as a separate cohort., Results: Across the entire cohort, estimated brain mass deviated by a median 10% between models, with a per-patient median difference in SI of 3.5%. For the SGA group, brain mass deviation was 42%, and per-patient SI deviation 13.7%. In virtual trials, 87-93% of recommended insulin rates were equal or slightly reduced (Δ<0.16mU/h) under the head circumference method, while glycaemic control outcomes showed little change., Conclusion: The results suggest that body weight methods are not as accurate as head circumference methods. Head circumference-based estimates may offer improved modelling accuracy and a small reduction in insulin administration, particularly for SGA infants., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Both stress and prematurity can induce hyperglycemia in the neonatal intensive care unit, which, in turn, is associated with worsened outcomes. Endogenous glucose production (EGP) is the formation of glucose by the body from substrates and contributes to blood glucose (BG) levels. Due to the inherent fragility of the extremely low birth weight (ELBW) neonates, true fasting EGP cannot be explicitly determined, introducing uncertainty into glycemic models that rely on quantifying glucose sources. Stochastic targeting, or STAR, is one such glycemic control framework., Methods: A literature review was carried out to gather metabolic and EGP values on preterm infants with a gestational age (GA) &lt;32 weeks and a birth weight (BW) &lt;2 kg. The data were analyzed for EGP trends with BW, GA, BG, plasma insulin, and glucose infusion (GI) rates. Trends were modeled and compared with a literature-derived range of population constant EGP models using clinically validated virtual trials on retrospective clinical data., Results: No clear relationship was found for EGP and BW, GA, or plasma insulin. Some evidence of suppression of EGP with increasing GI or BG was seen. Virtual trial results showed that population-constant EGP models fit clinical data best and gave tighter control performance to a target band in virtual trials., Conclusions: Variation in EGP cannot easily be quantified, and EGP is sufficiently modeled as a population constant in the neonatal intensive care insulin-nutrition-glucose model. Analysis of the clinical data and fitting error suggests that ELBW hyperglycemic preterm neonates have unsuppressed EGP in the higher range than that seen in literature., (© 2013 Diabetes Technology Society.)

Background: STAR (stochastic targeted) is a glycemic control model-based framework for critically ill neonates that has shown benefits in reducing hypoglycemia and hyperglycemia. STAR uses a stochastic matrix method to forecast future changes in a patient's insulin sensitivity and then applies this result to a physiological model to select an optimal insulin treatment. Nasogastric aspiration may be used as an indicator to suggest periods of care when enteral feed absorption is compromised, improving the performance of glycemic control. An analysis has been carried out to investigate the effect of poorly absorbed feeds on glycemic control., Method: Clinical data were collected from eight patients on insulin therapy and enteral feed, which included large or significantly milky aspirates. Patients had a median gestational age of 25 weeks and postnatal age of 5.5 days. Virtual patients were created using the NICING model, and insulin sensitivity (SI) profiles were fit. Alternative feed profiles were generated whereby enteral feed absorption was redistributed with time to account for poor feed absorption. The effect of poor feed absorption, as indicated by aspirates, is investigated., Results: The average percentage change of SI 4 h before a significant aspirate was 1.16%, and 1.49% in the 4 h following the aspirate. No distinct relationship was found between the fractional change in SI and the volume of the aspirate. Accounting for aspirates had a clinically negligible impact on glycemic control in virtual trials., Conclusion: Accounting for aspirates by manipulating enteral feed profiles had a minimal influence on both modeling and controlling glycemia in neonates. The impact of this method is clinically insignificant, suggesting that a population constant for the rate of glucose absorption in the gut adequately models feed absorption within the STAR framework., (© 2013 Diabetes Technology Society.)

Thermokarst is a land surface lowered and disrupted by melting ground ice. Thermokarst is a major driver of landscape change in the Arctic, but has been considered to be a minor process in Antarctica. Here, we use ground-based and airborne LiDAR coupled with timelapse imaging and meteorological data to show that 1) thermokarst formation has accelerated in Garwood Valley, Antarctica; 2) the rate of thermokarst erosion is presently ~ 10 times the average Holocene rate; and 3) the increased rate of thermokarst formation is driven most strongly by increasing insolation and sediment/albedo feedbacks. This suggests that sediment enhancement of insolation-driven melting may act similarly to expected increases in Antarctic air temperature (presently occurring along the Antarctic Peninsula), and may serve as a leading indicator of imminent landscape change in Antarctica that will generate thermokarst landforms similar to those in Arctic periglacial terrains.

The discovery on Mars of recurring slope lineae (RSL), thought to represent seasonal brines, has sparked interest in analogous environments on Earth. We report on new studies of Don Juan Pond (DJP), which exists at the upper limit of ephemeral water in the McMurdo Dry Valleys (MDV) of Antarctica, and is adjacent to several steep-sloped water tracks, the closest analog for RSL. The source of DJP has been interpreted to be deep groundwater. We present time-lapse data and meteorological measurements that confirm deliquescence within the DJP watershed and show that this, together with small amounts of meltwater, are capable of generating brines that control summertime water levels. Groundwater input was not observed. In addition to providing an analog for RSL formation, CaCl(2) brines and chloride deposits in basins may provide clues to the origin of ancient chloride deposits on Mars dating from the transition period from "warm/wet" to "cold/dry" climates.

Transplant recipients require immunosuppression to prevent allograft rejection, placing them at risk of opportunistic infections including fungal infection. Difficulties in managing fungal infections include: establishing diagnosis, poor treatment response, drug interactions and toxicity. We report our single centre experience of treating fungal infections using systemic non-Amphotericin current generation antifungals. Patients receiving inpatient antifungal therapy from September 2005 to December 2010 were identified from pharmacy records. Fungal infections were retrospectively classified according to European Organization for Research and Treatment of Cancer (EORTC) criteria. Treatment outcomes were classified in a manner similar to those used in clinical trials. Two hundred and forty-nine recipients received antifungal treatment, 204 lungs and 45 hearts. One hundred and one patients received Voriconazole, 82 Caspofungin and 65 received both agents. One patient was unsuccessfully treated with additional Amphotericin. Treatment duration varied from 1.5 to 12 weeks. One hundred and sixty-five patients had a complete response, 24 had a partial response and in 60 patients treatment was unsuccessful. The response to systemic non-Amphotericin based antifungal therapy was high. We propose that diagnostic criteria without positive identification of a fungus allow treatment to be started early with few clinically relevant side effects., (© 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.)

MESSENGER observations from Mercury orbit reveal that a large contiguous expanse of smooth plains covers much of Mercury's high northern latitudes and occupies more than 6% of the planet's surface area. These plains are smooth, embay other landforms, are distinct in color, show several flow features, and partially or completely bury impact craters, the sizes of which indicate plains thicknesses of more than 1 kilometer and multiple phases of emplacement. These characteristics, as well as associated features, interpreted to have formed by thermal erosion, indicate emplacement in a flood-basalt style, consistent with x-ray spectrometric data indicating surface compositions intermediate between those of basalts and komatiites. The plains formed after the Caloris impact basin, confirming that volcanism was a globally extensive process in Mercury's post-heavy bombardment era.

W/C emulsions were stabilized using hydrophobic silica particles adsorbed at the interface, resulting in average droplet diameters as low as 7.5 microm. A porous cross-linked shell was formed about a hydrophilic (colloidal and fumed) silica core with a trifunctional silylating agent, (heptadecafluoro-1,1,2,2-tetrahydrodecyl)triethyoxysilane, to render the particles CO(2)-philic. The stability of emulsions comprising equal weights of CO(2) and water was assessed with visual observations of settling fronts and the degree of emulsion coalescence, and the average drop size was measured by optical microscopy. The effect of CO(2) density on both emulsion stability and droplet size was determined quantitatively. The major destabilizing mechanism of the emulsions was settling, whereas Ostwald ripening and coalescence were not visible at any density, even over 7 days. Flocculation of the settling droplets did not occur, although gelation of the emulsions through particle interactions resulted after longer periods of time. CO(2)-philic particles offer a new route to highly stable W/C emulsions, with particle energies of attachment on the order of 10(6)kT, even at CO(2) densities as low as 0.78 g ml(-1). At these low densities, surfactants rarely stabilize emulsions as the result of poor surfactant tail solvation.

A nonionic-methylated branched hydrocarbon surfactant, octa(ethylene glycol) 2,6,8-trimethyl-4-nonyl ether (5b-C12E8) emulsifies up to 90% CO2 in water with polyhedral cells smaller than 10 microm, as characterized by optical microscopy. The stability of these concentrated CO2/water (C/W) emulsions increases with pressure and in some cases exceeds 24 h. An increase in pressure weakens the attractive van der Waals interactions between the CO2 cells across water and raises the disjoining pressure. It also enhances the solution of the surfactant tail and drives the surfactant from water towards the water-CO2 interface, as characterized by the change in emulsion phase behavior and the decrease in interfacial tension (gamma) to 2.1 mN/m. As the surfactant adsorption increases, the greater tendency for ion adsorption is likely to increase the electrostatic repulsion in the thin lamellae and raise the disjoining pressure. As pressure increases, the increase in disjoining pressure and decrease in the capillary pressure (due to the decrease in gamma) each favor greater stability of the lamellae against rupture. The electrical conductivity is predicted successfully as a function of Bruggeman's model for concentrated emulsions. Significant differences in the stability are observed for concentrated C/W emulsions at elevated pressure versus air/W or C/W foams at atmospheric pressure.

Porous polyethylene oxide-b-polyfluorooctylmethacrylate (PEO-b-PFOMA) diblock copolymer films were drop cast onto substrates from Freon (1,1,2-trichlorotrifluoroethane) in a humid atmosphere. The pores in the films exhibit long range hexagonal order in some cases, depending on the PFOMA-to-PEO molecular weight ratio. Films with the best ordered pores were formed with PFOMA-to-PEO ratios of 70 kDa:2 kDa. The pores in the polymer films derive from water droplets that condense as Freon evaporates. The polymer stabilizes the water droplets, or "breath figures," which act as an immiscible template that molds the porous film. Increased polymer hydrophobicity reduces the water wettability of the air/Freon interface, which in turn decreases water droplet nucleation, thus influencing the final pore size and spatial order in the polymer films. We describe how water droplet nucleation influences the final pore size and packing order in the polymer films.