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Abstract Background Alternative cancer clinics, who provide treatment associated with earlier time to death, actively seek to create favorable views of their services online. An unexplored means where alternative cancer clinics can shape their appeal is their Google search results. Methods We retrieved the Google listing and Google reviews of 47 prominent alternative cancer clinics on August 22, 2022. We then conducted a content analysis to assess the information cancer patients are faced with online. Results Google listings of alternative treatment providers rarely declared the clinic was an alternative clinic versus a conventional primary cancer treatment provider (12.8% declared; 83.0% undeclared). The clinics were highly rated (median, 4.5 stars of 5). Reasons for positive reviews included treatment quality (n = 519), care (n = 420), and outcomes (n = 316). 288 reviews presented the clinics to cure or improve cancer. Negative reviews presented alternative clinics to financially exploit patients with ineffective treatment (n = 98), worsen patients’ condition (n = 72), provide poor care (n = 41), and misrepresent outcomes (n = 23). Conclusions The favorable Google listing and reviews of alternative clinics contribute to harmful online ecosystems. Reviews provide compelling narratives but are an ineffective indicator of treatment outcomes. Google lacks safeguards for truthful reviews and should not be used for medical decision-making.

BackgroundWhile the evidence base on web-based cancer misinformation continues to develop, relatively little is known about the extent of such information on the world’s largest e-commerce website, Amazon. Multiple media reports indicate that Amazon may host on its platform questionable cancer-related products for sale, such as books on purported cancer cures. This context suggests an urgent need to evaluate Amazon.com for cancer misinformation. ObjectiveThis study sought to (1) examine to what extent are misleading cancer cure books for sale on Amazon.com and (2) determine how cancer cure books on Amazon.com provide misleading cancer information. MethodsWe searched “cancer cure” on Amazon.com and retrieved the top 1000 English-language book search results. We reviewed the books’ descriptions and titles to determine whether the books provided misleading cancer cure or treatment information. We considered a book to be misleading if it suggested scientifically unsupported cancer treatment approaches to cure or meaningfully treat cancer. Among books coded as misleading, we conducted an inductive latent thematic analysis to determine the informational value the books sought to offer. ResultsNearly half (494/1000, 49.4%) of the sampled “cancer cure” books for sale on Amazon.com appeared to contain misleading cancer treatment and cure information. Overall, 17 (51.5%) out of 33 Amazon.com results pages had 50% or more of the books coded as misleading. The first search result page had the highest percentage of misleading books (23/33, 69.7%). Misleading books (n=494) contained eight themes: (1) claims of efficacious cancer cure strategies (n=451, 91.3%), (2) oversimplifying cancer and cancer treatment (n=194, 39.3%), (3) falsely justifying ineffective treatments as science based (n=189, 38.3%), (4) discrediting conventional cancer treatments (n=169, 34.2%), (5) finding the true cause of cancer (n=133, 26.9%), (6) homogenizing cancer (n=132, 26.7%), (7) discovery of new cancer treatments (n=119, 24.1%), and (8) cancer cure suppression (n=82, 16.6%). ConclusionsThe results demonstrate that misleading cancer cure books are for sale, visible, and prevalent on Amazon.com, with prominence in initial search hits. These misleading books for sale on Amazon can be conceived of as forming part of a wider, cross-platform, web-based information environment in which misleading cancer cures are often given prominence. Our results suggest that greater enforcement is needed from Amazon and that cancer-focused organizations should engage in preemptive misinformation debunking.

Abstract The commercial determinants of health (CDoH) are attracting increased interest and are of great importance when discussing how trade affects health. Through a citation analysis of recent foundational CDoH documents (a Lancet paper series and an Oxford University textbook), we find that fully 71% of all citations reference the health sciences. The health sciences may be well suited to documenting the specific pathways of how commercial (by)products and practices harm human health. However, to operationalize upstream solutions for mitigating these harms, our citation analysis suggests that the field can engage political scientists, economists, sociologists, the trade law and business, as well as advocates in civil society and journalism, more so than it currently does. With CDoH explicitly referring to the interaction between commerce and health, CDoH researchers might be uniquely positioned to get health on the agenda of others, which requires that CDoH methods, datasets, evidence reviews, and proposed interventions are drawn from the widest possible range of sources.

Abstract Background The field of the commercial determinants of health (CDOH) refers to the commercial products, pathways and practices that may affect health. The field is growing rapidly, as evidenced by the WHO programme on the economic and commercial determinants of health and a rise in researcher and funder interest. Systematic reviews (SRs) and evidence synthesis more generally will be crucial tools in the evolution of CDOH as a field. Such reviews can draw on existing methodological guidance, though there are areas where existing methods are likely to differ, and there is no overarching guidance on the conduct of CDOH-focussed systematic reviews, or guidance on the specific methodological and conceptual challenges. Methods/results CODES provides guidance on the conduct of systematic reviews focussed on CDOH, from shaping the review question with input from stakeholders, to disseminating the review. Existing guidance was used to identify key stages and to provide a structure for the guidance. The writing group included experience in systematic reviews and other forms of evidence synthesis, and in equity and CDOH research (both primary research and systematic reviews). Conclusions This guidance highlights the special methodological and other considerations for CDOH reviews, including equity considerations, and pointers to areas for future methodological and guideline development. It should contribute to the reliability and utility of CDOH reviews and help stimulate the production of reviews in this growing field.

Background Greater availability of alcohol is associated with higher consumption and harms. The legal systems, by which premises are licensed to sell alcohol in England and Scotland, differ in several ways. The ‘Exploring the impact of alcohol licensing in England and Scotland’ study measured public health team activity regarding alcohol licensing from 2012 to 2019 and identified seven differences between England and Scotland in the timing and type of activities undertaken. Objectives To qualitatively describe the seven previously identified differences between Scotland and England in public health approaches to alcohol licensing, and to examine, from the perspective of public health professionals, what factors may explain these differences. Methods Ninety-four interviews were conducted with 52 professionals from 14 English and 6 Scottish public health teams selected for diversity who had been actively engaging with alcohol licensing. Interviews focused primarily on the nature of their engagement (n = 66) and their rationale for the approaches taken (n = 28). Interview data were analysed thematically using NVivo. Findings were constructed by discussion across the research team, to describe and explain the differences in practice found. Findings Diverse legal, practical and other factors appeared to explain the seven differences. (1) Earlier engagement in licensing by Scottish public health teams in 2012–3 may have arisen from differences in the timing of legislative changes giving public health a statutory role and support from Alcohol Focus Scotland. (2) Public Health England provided significant support from 2014 in England, contributing to an increase in activity from that point. (3) Renewals of statements of licensing policy were required more frequently in Scotland and at the same time for all Licensing Boards, probably explaining greater focus on policy in Scotland. (4) Organisational structures in Scotland, with public health stakeholders spread across several organisations, likely explained greater involvement of senior leaders there. (5) Without a public health objective for licensing, English public health teams felt less confident about making objections to licence applications without other stakeholders such as the police, and instead commonly negotiated conditions on licences with applicants. In contrast, Scottish public health teams felt any direct contact with applicants was inappropriate due to conflicts of interest. (6) With the public health objective in Scotland, public health teams there were more active in making independent objections to licence applications. Further in Scotland, licensing committee meetings are held to consider all new applications regardless of whether objections have been submitted; unlike in England where there was a greater incentive to resolve objections, because then a meeting was not required. (7) Finally, Scottish public health teams involved the public more in licensing process, partly because of statutory licensing forums there. Conclusions The alcohol premises licensing systems in England and Scotland differ in important ways including and beyond the lack of a public health objective for licensing in England. These and other differences, including support of national and local bodies, have shaped opportunities for, and the nature of, public health engagement. Further research could examine the relative success of the approaches taken by public health teams and how temporary increases in availability are handled in the two licensing systems. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Reseacrh programme as award number 15/129/11. Plain language summary When alcohol becomes more widely available, harms tend to increase. In England and Scotland, this availability is controlled by local councils. They ‘licence’ shops, bars and other venues to allow them to sell alcohol. Local health teams, including doctors, often advise councils on licensing. In earlier work, we found seven differences in what Scottish and English health teams do on licensing. In this study, we explore these seven differences and why they came about. To do this, we interviewed 94 professionals working in public health across both countries. Scottish health teams got involved in licensing earlier than in England. This was partly because of when certain laws changed. Also, they were helped earlier by national organisations that try to reduce harm from alcohol. Scottish teams were more involved in local policies on licensing. This was probably because these policies changed more often in the Scottish system. Scottish teams involved the public more. This was partly because Scottish councils must set up ‘local licensing forums’. Scottish teams also objected more often to licence applications. They generally felt that they could be more actively involved, because of a law in Scotland that says licensing must protect public health. This law does not apply in England. In England, health teams were more likely to talk to businesses that wanted licences. They were less likely to try to block applications. When they agreed changes to applications with businesses instead of objecting, fewer formal licensing meetings were needed. This was not the case in Scotland. Also, Scottish teams did not feel it was okay for them to talk to businesses. In summary, there are important differences in licensing law between Scotland and England. These matter for how health teams in the two countries engage with local councils, businesses and the public on licensing matters.

Background International systematic reviews suggest an association between alcohol availability and increased alcohol-related harms. Alcohol availability is regulated through separate locally administered licensing systems in England and Scotland, in which local public health teams have a statutory role. The system in Scotland includes a public health objective for licensing. Public health teams engage to varying degrees in licensing matters but no previous study has sought to objectively characterise and measure their activity, examine their effectiveness, or compare practices between Scotland and England. Aim To critically assess the impact and mechanisms of impact of public health team engagement in alcohol premises licensing on alcohol-related harms in England and Scotland. Methods We recruited 39 diverse public health teams in England (n = 27) and Scotland (n = 12). Public health teams more active in licensing were recruited first and then matched to lower-activity public health teams. Using structured interviews (n = 66), documentation analysis, and expert consultation, we developed and applied the Public Health Engagement In Alcohol Licensing (PHIAL) measure to quantify six-monthly activity levels from 2012 to 2019. Time series of PHIAL scores, and health and crime outcomes for each area, were analysed using multivariable negative binomial mixed-effects models to assess correlations between outcome and exposure, with 18-month average PHIAL score as the primary exposure metric. In-depth interviews (n = 53) and a workshop (n = 10) explored public health team approaches and potential mechanisms of impact of alcohol availability interventions with public health team members and licensing stakeholders (local authority licensing officers, managers and lawyers/clerks, police staff with a licensing remit, local elected representatives). Findings Nineteen public health team activity types were assessed in six categories: (1) staffing; (2) reviewing and (3) responding to licence applications; (4) data usage; (5) influencing licensing stakeholders/policy; and (6) public involvement. Usage and intensity of activities and overall approaches varied within and between areas over time, including between Scotland and England. The latter variation could be explained by legal, structural and philosophical differences, including Scotland’s public health objective. This objective was felt to legitimise public health considerations and the use of public health data within licensing. Quantitative analysis showed no clear evidence of association between level of public health team activity and the health or crime outcomes examined, using the primary exposure or other metrics (neither change in, nor cumulative, PHIAL scores). Qualitative data suggested that public health team input was valued by many licensing stakeholders, and that alcohol availability may lead to harms by affecting the accessibility, visibility and norms of alcohol consumption, but that the licensing systems have limited power to act in the interests of public health. Conclusions This study provides no evidence that public health team engagement in local licensing matters was associated with measurable downstream reductions in crime or health harms, in the short term, or over a 7-year follow-up period. The extensive qualitative data suggest that public health team engagement is valued and appears to be slowly reorienting the licensing system to better address health (and other) harms, especially in Scotland, but this will take time. A rise in home drinking, alcohol deliveries, and the inherent inability of the licensing system to reduce – or in the case of online sales, to contain – availability, may explain the null findings and will continue to limit the potential of these licensing systems to address alcohol-related harms. Future work Further analysis could consider the relative success of different public health team approaches in terms of changing alcohol availability and retailing. A key gap relates to the nature and impact of online availability on alcohol consumption, harms and inequalities, alongside development and study of relevant policy options. A national approach to licensing data and oversight would greatly facilitate future studies and public health input to licensing. Limitations Our interview data and therefore PHIAL scores may be limited by recall bias where documentary evidence of public health activity was not available, and by possible variability in grading of such activity, though steps were taken to minimise both. The analyses would have benefited from additional data on licensing policies and environmental changes that might have affected availability or harms in the study areas. Study registration The study was registered with the Research Registry (researchregistry6162) on 26 October 2020. The study protocol was published in BMC Medical Research Methodology on 6 November 2018. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme as award number 15/129/11. Plain language summary Research finds that when alcohol is more easily available, because more places sell alcohol or have longer opening hours, people tend to drink more and harms tend to increase. In England and Scotland, ‘Licensing Committees’ in local governments have power over which venues are given a licence to sell alcohol legally. They make decisions based on local policy and on licensing goals set out in law. Licensing laws are slightly different in both nations, and health representatives are often involved in trying to influence local licensing decisions and policies, to reduce alcohol-related harms. We aimed to find out what public health teams have done to influence alcohol licensing and whether their actions have affected alcohol-related harms. We recruited 39 public health teams (Scotland: 12; England: 27) and measured how active they were on licensing matters. We gathered detailed information (from interviews and papers) about their actions from 2012 to 2019, and asked them and others involved in licensing (including police, and local authority licensing teams and lawyers) about how their efforts might make a difference to harms. We gathered local data on alcohol-related health harms and crimes during 2009–19. We analysed whether any changes in these harms were related to the level of public health team activity, and explored differences between Scotland and England. Public health teams across Scotland and England took varied approaches to engaging in alcohol licensing, and their work was often welcomed by others working in the licensing system. However, we found no clear relationship between the level of licensing-related activity that public health teams engaged in and the levels of alcohol-related health harms or crime. This may be because their actions make only a modest difference to licensing decisions, or because it may take longer than the study period for them to have a sizeable impact. Reducing alcohol-related harms through licensing may require strengthening national licensing laws and the powers of public health teams, including by addressing online sales and home deliveries.

Mental ill health has complex and interrelated underlying causes, with wider determinants of health often overlooked as risk factors. The 'commercial determinants of health' are gradually receiving more attention and recognition but there is a relative lack of awareness of the commercial determinants of mental health. This aim of this umbrella review was to synthesise systematic review level evidence for the association between commercial determinants and mental health outcomes. This umbrella review included evidence from high, middle, and low-income countries. We included terms related to broader commercial activities and terms focused on six key unhealthy commodities (tobacco, alcohol, ultra-processed foods, gambling, social media, fossil fuels) and the impacts of fossil fuel consumption (climate change, air pollution, wider pollution). We included 65 reviews and found evidence from high quality reviews for associations between alcohol, tobacco, gambling, social media, ultra-processed foods and air pollution and depression; alcohol, tobacco, gambling, social media, climate change and air pollution with suicide; climate change and air pollution with anxiety; and social media with self-harm. There was a lack of evidence examining wider practices of commercial industries. Our umbrella review demonstrates that by broadening the focus on commercial determinants, the influence of commercial products and activities on mental ill health can be better understood. The lack of research examining broader commercial practices on mental ill health is an area that should be addressed. Our review highlights the existing base of high-quality evidence for many of these unhealthy commodities' impacts on mental ill health and indicates that commercial determinants is a valuable framework for understanding the drivers of mental ill health.

BackgroundAlternative cancer treatment is associated with a greater risk of death than cancer patients undergoing conventional treatments. Anecdotal evidence suggests cancer patients view paid advertisements promoting alternative cancer treatment on social media, but the extent and nature of this advertising remain unknown. This context suggests an urgent need to investigate alternative cancer treatment advertising on social media. ObjectiveThis study aimed to systematically analyze the advertising activities of prominent alternative cancer treatment practitioners on Meta platforms, including Facebook, Instagram, Messenger, and Audience Network. We specifically sought to determine (1) whether paid advertising for alternative cancer treatment occurs on Meta social media platforms, (2) the strategies and messages of alternative cancer providers to reach and appeal to prospective patients, and (3) how the efficacy of alternative treatments is portrayed. MethodsBetween December 6, 2021, and December 12, 2021, we collected active advertisements from alternative cancer clinics using the Meta Ad Library. The information collected included identification number, URL, active/inactive status, dates launched/ran, advertiser page name, and a screenshot (image) or recording (video) of the advertisement. We then conducted a content analysis to determine how alternative cancer providers communicate the claimed benefits of their services and evaluated how they portrayed alternative cancer treatment efficacy. ResultsWe identified 310 paid advertisements from 11 alternative cancer clinics on Meta (Facebook, Instagram, or Messenger) marketing alternative treatment approaches, care, and interventions. Alternative cancer providers appealed to prospective patients through eight strategies: (1) advertiser representation as a legitimate medical provider (n=289, 93.2%); (2) appealing to persons with limited treatments options (n=203, 65.5%); (3) client testimonials (n=168, 54.2%); (4) promoting holistic approaches (n=121, 39%); (5) promoting messages of care (n=81, 26.1%); (6) rhetoric related to science and research (n=72, 23.2%); (7) rhetoric pertaining to the latest technology (n=63, 20.3%); and (8) focusing treatment on cancer origins and cause (n=43, 13.9%). Overall, 25.8% (n=80) of advertisements included a direct statement claiming provider treatment can cure cancer or prolong life. ConclusionsOur results provide evidence alternative cancer providers are using Meta advertising products to market scientifically unsupported cancer treatments. Advertisements regularly referenced “alternative” and “natural” treatment approaches to cancer. Imagery and text content that emulated evidence-based medical providers created the impression that the offered treatments were effective medical options for cancer. Advertisements exploited the hope of patients with terminal and poor prognoses by sharing testimonials of past patients who allegedly were cured or had their lives prolonged. We recommend that Meta introduce a mandatory, human-led authorization process that is not reliant upon artificial intelligence for medical-related advertisers before giving advertising permissions. Further research should focus on the conflict of interest between social media platforms advertising products and public health.

Summary: Background: Public health teams (PHTs) in England and Scotland engage to varying degrees in local alcohol licensing systems to try to reduce alcohol-related harms. No previous quantitative evidence is available on the effectiveness of this engagement. We aimed to quantify the effects of PHT engagement in alcohol licensing on selected health and crime outcomes. Methods: 39 PHTs in England (n = 27) and Scotland (n = 12) were recruited (of 40 contacted) for diversity in licensing engagement level and region, with higher activity areas matched to lower activity areas. Each PHT's engagement in licensing for each 6 month period from April 2012 to March 2019 was quantified using a new measure (PHIAL) developed using structured interviews, documentary analyses, and expert consultation. Outcomes examined were ambulance callouts, alcohol-related hospital admissions, alcohol-related and alcohol-specific mortality and violent, sexual and public order offences. Timeseries were analysed using multivariable negative binomial mixed-effects models. Correlations were assessed between each outcome and 18-month average PHIAL score (primary metric), cumulative PHIAL scores and change in PHIAL scores. Additionally, 6-month lagged correlations were also assessed. Findings: There was no clear evidence of any associations between the primary exposure metric and the public health or crime outcomes examined, nor between cumulative PHIAL scores or change in PHIAL score and any outcomes. There were no significant associations in England or Scotland when analysed separately or between outcomes and lagged exposure metrics. Interpretation: There is no clear evidence that allocating PHT resources to engaging in alcohol licensing is associated with downstream reductions in alcohol-related health harms or crimes, in the short term or over a seven year follow-up period. Such engagement likely has benefits in shaping the licensing system to take account of health issues longer term, but as current systems cannot reduce alcohol availability or contain online sales, their potential benefits are somewhat constrained. Funding: The ExILEnS project is funded by the NIHR Public Health Research Programme (project number 15/129/11). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Background: In England and Scotland, local governments regulate the sale of alcohol by awarding licences to premises to permit the sale of alcohol for consumption on or off the premises, under certain conditions; without such a licence, alcohol cannot be legally sold. In recent years, many local public health teams have become proactive in engaging with alcohol licensing, encouraging licensing authorities to act in ways intended to improve population health. Objective: This research aimed to explore and understand the approaches and activities of public health stakeholders (i.e. NHS staff and other public health professionals) in seeking to influence local alcohol licensing policy and decisions, and the views of licensing stakeholders (i.e. licensing officers/managers, police staff with a licensing remit, elected members and licensing lawyers/clerks) on the acceptability and effectiveness of these approaches. Participants: Local public health teams in England and Scotland were directly informed about this multisite study. Scoping calls were conducted with interested teams to explore their level of activity in alcohol licensing from 2012 across several categories. Twenty local authority areas with public health teams active in licensing matters were recruited purposively in England (n = 14) and Scotland (n = 6) to vary by region and rurality. Fifty-three in-depth telephone interviews (28 with public health stakeholders and 25 with licensing stakeholders outside health, such as local authority licensing teams/lawyers or police) were conducted. Interview transcripts were analysed thematically in NVivo 12 (QSR International, Warrington, UK) using inductive and deductive approaches. Results: Public health stakeholders’ approaches to engagement varied, falling into three main (and sometimes overlapping) types. (1) Many public health stakeholders in England and all public health stakeholders in Scotland took a ‘challenging’ approach to influencing licensing decisions and policies. Reducing health harms was felt to necessitate a focus on reducing availability and generating longer-term culture change, citing international evidence on the links between availability and alcohol-related harms. Some of these stakeholders viewed this as being a narrow, ‘nanny state’ approach, whereas others welcomed public health expertise and its evidence-based approach and input. (2) Some public health stakeholders favoured a more passive, ‘supportive’ approach, with some reporting that reducing availability was unachievable. They reported that, within the constraints of current licensing systems, alcohol availability may be contained (at least in theory) but cannot be reduced, because existing businesses cannot be closed on availability grounds. In this ‘supportive’ approach, public health stakeholders supplied licensing teams with data on request or waited for guidance from licensing teams on when and how to get involved. Therefore, public health action supported the licensing team in their aim of promoting ‘safe’ and ‘responsible’ retailing of alcohol and/or focused on short-term outcomes other than health, such as crime. (3) Some public health stakeholders favoured a ‘collaborative’ approach in which they worked in close partnership with licensing teams; this could include a focus on containing availability or responsible retail of alcohol, or both. Conclusions: In engaging with alcohol licensing, public health stakeholders adapted their approaches, sometimes resulting in a diminished focus on public health goals. Sampling did not include lower-activity areas, in which experiences might differ. The extent to which current licensing systems enable achievement of public health goals is questionable and the effectiveness of public health efforts merits quantitative evaluation. Study registration: The study is registered with the Research Registry as researchregistry6162. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in Public Health Research. See the NIHR Journals Library website for further project information.

Background and aim For decades, corporations such as the tobacco and fossil fuel industries have used youth education programmes and schools to disseminate discourses, ideas and values favourable to their positions, and to pre-empt regulation that threatens profits. However, there is no systematic research into alcohol industry-funded youth education programmes. This article serves to address this important gap in the literature. Methods Using a discourse theoretical approach informed by poststructural discourse theory and critical discourse analysis, we analysed teaching materials from three school-based youth education initiatives which focus on alcohol consumption and health harms: Drinkaware for Education, The Smashed Project (funded by Diageo), and Talk About Alcohol (Alcohol Education Trust). These materials, some of which are disseminated internationally, are provided to schools through intermediary bodies in receipt of alcohol industry funding. Findings The analysis found that these materials drew from and presented discourses of personal responsibility, moderate alcohol consumption, and involved a narrowing of the problem definition and causes. The locus of the problem is located by the discourses within individuals including youth, with causes of youth alcohol consumption repeatedly presented as peer pressure and ‘poor choices’, with little or no mention of alcohol industry marketing or other practices. All programmes promoted familiarisation and normalisation of alcohol as a ‘normal’ adult consumer product which children must learn about and master how to use responsibly when older. The discourses constructed in these materials closely align with those of other alcohol industry corporate social responsibility discourses which employ selective presentation of harms, including misinformation about cancer, and ambiguous terms such as “responsible drinking”. Furthermore, the role of alcohol price, availability and access, and the impacts of alcohol and the industry on inequities were not articulated within the discourses. The research was limited to an analysis of teaching materials and further research is needed to explore their impact on youth, teachers and wider discourses and social norms. Conclusion Alcohol industry-sponsored youth education programmes serve industry interests and promote moderate consumption while purportedly educating children about harms and influences of alcohol use. There are considerable conflicts of interest in the delivery of alcohol education programmes funded by the alcohol industry and intermediary bodies in receipt of such funding. Alcohol education materials should be developed independent from industry, including funding, and should empower children and young people to understand and think critically about alcohol, including harms and drivers of consumption, and effective interventions needed to protect them and others from alcohol-related harms. Independent organisations can use this analysis to critique their materials to strengthen alignment with meeting student and public health interests. The ongoing exposure of children and young people to such conflicted and misleading materials needs urgent attention from policymakers, practitioners, teachers and parents, and resources dependent on industry support should cease being used in schools.

Objectives Most non-communicable diseases are preventable and largely driven by the consumption of harmful products, such as tobacco, alcohol, gambling and ultra-processed food and drink products, collectively termed unhealthy commodities. This paper explores the links between unhealthy commodity industries (UCIs), analyses the extent of alignment across their corporate political strategies, and proposes a cohesive systems approach to research across UCIs.Methods We held an expert consultation on analysing the involvement of UCIs in public health policy, conducted an analysis of business links across UCIs, and employed taxonomies of corporate political activity to collate, compare and illustrate strategies employed by the alcohol, ultra-processed food and drink products, tobacco and gambling industries.Results There are clear commonalities across UCIs’ strategies in shaping evidence, employing narratives and framing techniques, constituency building and policy substitution. There is also consistent evidence of business links between UCIs, as well as complex relationships with government agencies, often allowing UCIs to engage in policy-making forums. This knowledge indicates that the role of all UCIs in public health policy would benefit from a common approach to analysis. This enables the development of a theoretical framework for understanding how UCIs influence the policy process. It highlights the need for a deeper and broader understanding of conflicts of interests and how to avoid them; and a broader conception of what constitutes strong evidence generated by a wider range of research types.Conclusion UCIs employ shared strategies to shape public health policy, protecting business interests, and thereby contributing to the perpetuation of non-communicable diseases. A cohesive systems approach to research across UCIs is required to deepen shared understanding of this complex and interconnected area and also to inform a more effective and coherent response.

When the Fun Stops, Stop, is a prominent 'responsible gambling' campaign in the UK, originally funded and delivered by the industry-initiated and funded Senet Group. Since the Senet Group's dissolution in 2020, the campaign has been overseen by the Betting and Gambling Council (BGC), the main gambling industry trade body. There has been no prior analysis of the activities, ideas and framing adopted by the Senet Group, who claimed to be acting as an industry 'watchdog' and oversaw what they characterised as a major public education campaign. We collated written and image-based material related to the Senet Group and its When the Fun Stops, Stop campaign from multiple sources. Guided by Entman's four functions of framing, we analysed the Senet Group's framing of the issues it sought to address, particularly harmful gambling, as well as its causes, and the solutions, focusing on the group's main activity: the delivery of the When the Fun Stops, Stop campaign. We also critically appraised an evaluation of the campaign funded by the Senet Group, using the findings to interrogate the stated claims about the campaign's effectiveness. The analysis showed that the Senet Group's framing of the problem, its causes, and proposed responses resemble those adopted by other industries and industry-funded groups. This involves portraying any harms caused by their products as limited to an atypical minority, rejecting upstream determinants of harm, and promoting individually-targeted voluntary measures, all contrary to the evidence of what works in health promotion, and what would characterise a public health approach. Neither the existing evidence base nor the evidence presented by the Senet Group support their claims about the campaign's effectiveness. These findings add to concerns about industry-funded campaigns in other areas. To minimise conflicts of interest, interventions intended to address gambling-related harms, such as public education campaigns, should be evidence-based and developed, implemented and evaluated completely independent of the industry and industry-funded organisations.

Abstract Background Recent regulatory changes in the system by which premises are licensed to sell alcohol, have given health representatives a formal role in the process in England and Scotland. The degree to which local public health teams engage with this process varies by locality in both nations, which have different licensing regimes. This study aims to critically assess the impact on alcohol-related harms - and mechanisms - of public health stakeholders’ engagement in alcohol premises licensing from 2012 to 2018, comparing local areas with differing types and intensities of engagement, and examining practice in Scotland and England. Methods The study will recruit 20 local authority areas where public health stakeholders have actively engaged with the alcohol premises licensing system (the ‘intervention’) and match them to a group of 20 lower activity areas using genetic matching. Four work packages are included: (1) Structured interviews and documentary analysis will examine the type and level of intervention activity from 2012 to 2018, creating a novel composite measure of the intensity of such activity and will assess the local licensing system and potential confounding activities over the same period. In-depth interviews with public health, licensing, police and others will explore perceived mechanisms of change, acceptability, and impact. (2) Using longitudinal growth models and time series analyses, the study will evaluate the impact of high and low levels of activity on alcohol-related harms using routine data from baseline 2009 to 2018. (3) Intervention costs, estimated National Health Service cost savings and health gains will be evaluated using the Sheffield Alcohol Policy Model to estimate impact on alcohol consumption and health inequalities. (4) The study will engage public health teams to create a new theory of change for public health involvement in the licensing process using our data. We will share findings with local, national and international stakeholders. Discussion This interdisciplinary study examines, for the first time, whether and how public health stakeholders’ involvement in alcohol licensing impacts on alcohol harms. Using mixed methods and drawing on complex systems thinking, it will make an important contribution to an expanding literature evaluating interventions not suited to traditional epidemiological research.

Short-fibre paper residuals (deinking paper fibre (DPF) or paper mill sludge) represents a major waste formed during the processing of recycled paper and is known to contain significant quantities of copper. It is often spread onto agricultural land to help increase soil pH and improve structure by adding soil organic matter (SOM). A number of agricultural sites in England and Wales that had received large and repeated applications were sampled to investigate the long-term effects of this practice on soil quality and plant copper content. We found that the composition of DPF waste has changed significantly between 1999 and 2006 with concentrations of Cu increasing and organic matter content declining. Whilst repeated additions of DPF to agricultural land always increased soil Cu, an associated increase in SOM was not always apparent. There was no link between SOM and bioavailable Cu nor between soil bioavailable Cu and plant Cu. In contrast to previous reports, our findings indicate that improvement in soil quality following the long-term application of DPF was site-specific and in some cases it may have reduced soil quality rather than enhanced it. [ABSTRACT FROM AUTHOR]

Candidate HIV vaccines must show an immune response in order to be considered for further testing and development. What constitutes a “response,” however, is still not clear. While the hunt for a protective vaccine continues, hypotheses are being formed by studying the immune responses across cohorts of people with differing responses to the infection, as well as the immune responses formed by healthy people to other viruses, ones that are generally common and well controlled. Here we examine the functional profile of the immune responses of a group of HIV + long-term non-progressors as measured by intracellular cytokine staining using polychromatic flow cytometry, and compare these responses to those of a larger group of other HIV + people. We describe some of the types of patterns in immune response that are of interest to vaccine researchers, and compare several statistical tests appropriate for this type of data. [ABSTRACT FROM AUTHOR]

As the first line of host defense, neutrophils are stimulated by pro-inflammatory cytokines from resting state, facilitating the execution of immunomodulatory functions in activation state. Sulfhydryl modification has a regulatory role in a wide variety of physiological functions through mediation of signaling transductions in various cell types. Recent research suggested that two kinds of sulfhydryl modification, S-nitrosylation by exogenous nitric oxide (NO) and alkylation by N-ethylmaleimide (NEM), could induce calcium entry through a non-store-operated pathway in resting rat neutrophils and DDT₁MF-2 cells, while in active human neutrophils a different process has been observed by us. In the present work, data showed that NEM induced a sharp rising of cytosolic calcium concentration ([Ca²⁺](c)) without external calcium, followed by a second [Ca²⁺](c) increase with readdition of external calcium in phorbol 12-myristate 13-acetate (PMA)-activated human neutrophils. Meanwhile, addition of external calcium did not cause [Ca²⁺](c) change of Ca²⁺-free PMA-activated neutrophils before application of NEM. These data indicated that NEM could induce believable store-operated calcium entry (SOCE) in PMA-activated neutrophils. Besides, we found that sodium nitroprusside (SNP), a donor of exogenous NO, resulted in believable SOCE in PMA-activated human neutrophils via S-nitrosylation modification. In contrast, NEM and SNP have no effect on [Ca²⁺](c) of resting neutrophils which were performed in suspension. Furthermore, 2-Aminoethoxydiphenyl borate, a reliable blocker of SOCE and an inhibitor of inositol 1,4,5-trisphosphate (IP₃) receptor, evidently abolished SNP and NEM-induced calcium entry at 75 µM, while preventing calcium release in a concentration-dependent manner. Considered together, these results demonstrated that NEM and SNP induced calcium entry through an IP₃-sensitive store-operated pathway of human neutrophils via sulfhydryl modification in a PMA-induced activation-dependent manner.

The formation and dimensions of G-wires by different short G-rich DNA sequences in solution were investigated by dynamic light scattering (DLS) and polyacrilamide gel electrophoresis (PAGE). To explore the basic principles of wire formation, we studied the effects of base sequence, method of preparation, temperature, and oligonucleotide concentration. Both DLS and PAGE show that thermal annealing induces much less macromolecular self-assembly than dialysis. The degree of assembly and consequently length of G-wires (5-6 nm) are well resolved by both methods for DNA sequences with intermediate length, while some discrepancies appear for the shortest and longest sequences. As expected, the longest DNA sequence gives the longest macromolecular aggregates with a length of about 11 nm as estimated by DLS. The quadruplex topologies show no concentration dependence in the investigated DNA concentration range (0.1 mM–0.4 mM) and no structural change upon heating.

Abstract Background There is significant interest in the value of motivational approaches that enhance participant readiness to change, but less is known about clients’ self-reports of problematic behavior when participating in such interventions. Methods We examined whether participants in a motivationally-based intervention for DUI offenders changed their reports of substance use at postintervention (when reporting on the same 30 days that they reported on at preintervention). Specifically, Study 1 (N = 8,387) tested whether participants in PRIME For Life (PFL) changed their reports about baseline substance levels when asked at postintervention versus at preintervention. Study 2 (N = 192) compared changes in self-reported baseline drinking between PFL and intervention as usual (IAU) participants. Results Many participants in Study 1 did not change their reports about how much they used substances during the 30-day period before baseline. Among those who did, the most common change was an increase in reported amounts of baseline drug use, and typical and peak alcohol use. This sample also showed changes in reports of their baseline pattern of high-risk-use (consistent versus occasional). At postintervention, participants who were younger, single, or endorsing more indicators of alcohol dependence were more likely to later report greater frequency of baseline drug use, and greater peak and typical number of baseline drinks. Gender, education, and race were also associated with reporting inconsistency on some behaviors. In Study 2, PFL participants showed greater increases in reports of peak alcohol use compared to IAU, but both conditions showed similar increases for drugs and typical alcohol use. Conclusions In both research and clinical settings, a segment of participants may initially report less substance use than they do when asked later about the same baseline period. These preliminary findings suggest clinicians and researchers may find postintervention evaluations yield reports of greater baseline alcohol or drug use for some people. For some behaviors, this may occur more often in interventions that target client motivation. Future research should attempt to identify which reports – preintervention vs. postintervention – better reflect actual baseline substance use.

Abstract Background Computational methods to predict transcription factor binding sites (TFBS) based on exhaustive algorithms are guaranteed to find the best patterns but are often limited to short ones or impose some constraints on the pattern type. Many patterns for binding sites in prokaryotic species are not well characterized but are known to be large, between 16–30 base pairs (bp) and contain at least 2 conserved bases. The length of prokaryotic species promoters (about 400 bp) and our interest in studying a small set of genes that could be a cluster of co-regulated genes from microarray experiments led to the development of a new exhaustive algorithm targeting these large patterns. Results We present Searchpattool, a new method to search for and select the most specific (conservative) frequent patterns. This method does not impose restrictions on the density or the structure of the pattern. The best patterns (motifs) are selected using several statistics, including a new application of a z-score based on the number of matching sequences. We compared Searchpattool against other well known algorithms on a Bacillus subtilis group of 14 input sequences and found that in our experiments Searchpattool always performed the best based on performance scores. Conclusion Searchpattool is a new method for pattern discovery relative to transcription factor binding sites for species or genes with short promoters. It outputs the most specific significant patterns and helps the biologist to choose the best candidates.

Abstract: Respiratory syncytial virus (RSV) is an important cause of respiratory infection in people of all ages, and is the leading cause of hospitalization in infants. Although commercially available monoclonal antibody is available for passive prophylaxis of neonates at risk of severe disease, there is no available vaccine to prevent RSV. Measurement of neutralizing activity will be a key endpoint for vaccine evaluation. Assessment of neutralizing antibody against RSV has been limited to traditional plaque reduction, which is time-consuming and inherently operator dependent and highly variable. Here, we describe a flow cytometry-based RSV-specific neutralization assay which is more rapid than traditional methods, highly sensitive and highly reproducible. [ABSTRACT FROM AUTHOR]

The article presents a study on the safety and efficacy of vaccines to prevent Ebola virus disease (EVD) in Liberia. Information is provided on the chimpanzee adeno-virus 3 vaccine (ChAd3-EBO-Z) and recombinant vesicular stomatitis vaccine (rVSVAG-ZEBOV-GP) vaccines. Particular attention is given to the challenges of conducting medical research during an outbreak.

Description: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective., Methods: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create "living" guidelines that would be widely accessible and capable of frequent updating as important new information became available., Recommendations: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel's final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Background: Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions., Methods: A post hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, coronavirus disease 2019 (COVID-19) vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS individuals starting at 14 days after completion of the primary series through the blinded phase for each of the 4 trials. An analysis of participants living with well-controlled human immunodeficiency virus was conducted using the same methods., Results: A total of 3852/30 351 (12.7%) Moderna participants, 3088/29 868 (10.3%) Novavax participants, 3549/32 380 (11.0%) AstraZeneca participants, and 5047/43 788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (vs placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants versus non-TIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with human immunodeficiency virus., Conclusions: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared with those with non-TIS in the 4 COVID-19 vaccine randomized controlled efficacy trials., Competing Interests: Potential conflicts of interest. O. A. received salary support from research funding paid to UCLA by Moderna, Inc. A. T. reports that this project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. C. L. G.’s institution received funding from the NIH for salary support for her role as site Principal Investigator for the Moderna Phase 3 trial and site Principle and Co-Chair for the Novavax Phase 3 trial. N. R. received research grants from Pfizer, Merck, Sanofi, Quidel, Immorna, Vaccine Company, and Lilly through her institution, consulting fees from Krog, honoraria as speaker for Virology education, and travel support from Sanofi and Moderna. N. R. serves on safety committees for ICON and EMMES and is a member of the Moderna, Sanofi, Seqirus, and Pfizer selected Advisory boards. I. H. is an employee of AstraZeneca and holds/may hold stock in AstraZeneca. A. R. F. reports grant support from Janssen, Pfizer, Moderna, CyanVac, VaxCo, and BioFire Diagnostics; advisory board fees from Arrowhead and GSK; travel reimbursement from GSK and Sanofi and fees for DSMB from Novavax. B. L. is an employee of Moderna, Inc. and may own stock/stock options in the company. J. S. declares support for the submitted work from the Janssen Pharmaceutical Companies of Johnson & Johnson and partial support (in the form of funding to his institution) from BARDA for the submitted work, declares support from the Janssen Pharmaceutical Companies of Johnson & Johnson and BARDA funding for part of this work, has patents on invention of the Janssen COVID-19 vaccine, and has Johnson & Johnson stock and stock options. P. A. G. reports a patent for a COVID-19 monoclonal antibody from Aridis Pharmaceuticals. V. C. reports payments made to Emory University from Gilead Sciences. K. N. receives grants from NIH to participate in overall organization of COVID vaccine trials and for participation in vaccine trials and has a grant for Vaxco for a phase 1 testing of a broadly reactive COVID-19 vaccine. L. D. is an employee of Novavax, Inc. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Protein-based vaccines for coronavirus disease 2019 (COVID-19) provide a traditional vaccine platform with long-lasting protection for non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogens and may complement messenger RNA vaccines as a booster dose. While NVX-CoV2373 showed substantial early efficacy, the durability of protection has not been delineated., Methods: The PREVENT-19 vaccine trial used a blinded crossover design; the original placebo arm received NVX-CoV2373 after efficacy was established. Using novel statistical methods that integrate surveillance data of circulating strains with post-crossover cases, we estimated placebo-controlled vaccine efficacy and durability of NVX-CoV2373 against both pre-Delta and Delta strains of SARS-CoV-2., Results: Vaccine efficacy against pre-Delta strains of COVID-19 was 89% (95% CI, 75-95%) and 87% (72-94%) at 0 and 90 days after 2 doses of NVX-CoV2373, respectively, with no evidence of waning (P = .93). Vaccine efficacy against the Delta strain was 88% (71-95%), 82% (56-92%), and 77% (44-90%) at 40, 120, and 180 days, respectively, with evidence of waning (P < .01). In sensitivity analyses, the estimated Delta vaccine efficacy at 120 days ranged from 66% (15-86%) to 89% (74-95%) per various assumptions of the surveillance data., Conclusions: NVX-CoV2373 has high initial efficacy against pre-Delta and Delta strains of COVID-19 with little evidence of waning for pre-Delta strains through 90 days and moderate waning against Delta strains over 180 days., Competing Interests: Potential conflicts of interest. M. P. F. reports support for meetings and/or travel from NIAID. A. M. received funds from the National Cancer Institute. C. A. M. received funds to their institution from the National Institutes of Health Coronavirus Prevention Network. Y. H., H. A., and K. K. received funds to their institution from NIAID. Y. H. received funds to their institution from the World Health Organization. K. K. also received funds to their institution for Novavax: A 2-Part Phase 2/3 Open-Label Study to Evaluate the Safety and Immunogenicity of a XBB.1.5 (Omicron Subvariant) SARS-CoV-2 rS Vaccine Booster Dose in Previously mRNA COVID-19 Vaccinated and Baseline SARS-CoV-2 Seropositive COVID-19 Vaccine Naïve Participants and has leadership as the National Co-Chair Novavax Phase 3 Trials of NIAID. L. M. D., W. W., and I. C. are employees and stockholders of Novavax, Inc. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Abstract: The COVID-19 pandemic affected clinical placements for nursing students throughout the United States, especially in rural areas. Public service announcements were created through a collaborative service-learning project between the school of nursing and the university radio station. Baccalaureate nursing students developed and delivered short public service announcements focused on issues of loneliness, stress, and anxiety and provided information about community resources. The alignment of this meaningful project with course learning outcomes gave students exposure to the social determinants of health as well as best practices in mental health outreach., Competing Interests: The authors have declared no conflict of interest., (Copyright © 2023 National League for Nursing.)

Designing clinical trials for emerging infectious diseases such as COVID-19 is challenging because information needed for proper planning may be lacking. Pre-specified adaptive designs can be attractive options, but what happens if a trial with no such design needs to be modified? For example, unexpectedly high efficacy (approximately 95%) in two COVID-19 vaccine trials might cause investigators in other COVID-19 vaccine trials to increase the number of interim analyses to allow earlier stopping for efficacy. If such a decision is based solely on external data, there are no issues, but what if internal trial data by arm are also examined? Fortunately, the conditional error principle of Müller and Schäfer (2004) can be used to ensure no inflation of the type 1 error rate, even if no interim analyses were planned. We study the properties, including limitations, of this method. We provide a shiny app to evaluate changes in timing of interim analyses in response to outcome data by arm in clinical trials., (Published by Oxford University Press on behalf of The International Biometric Society 2024.)

Background: The threat of a possible Marburg virus disease outbreak in Central and Western Africa is growing. While no Marburg virus vaccines are currently available for use, several candidates are in the pipeline. Building on knowledge and experiences in the designs of vaccine efficacy trials against other pathogens, including SARS-CoV-2, we develop designs of randomized Phase 3 vaccine efficacy trials for Marburg virus vaccines., Methods: A core protocol approach will be used, allowing multiple vaccine candidates to be tested against controls. The primary objective of the trial will be to evaluate the effect of each vaccine on the rate of virologically confirmed Marburg virus disease, although Marburg infection assessed via seroconversion could be the primary objective in some cases. The overall trial design will be a mixture of individually and cluster-randomized designs, with individual randomization done whenever possible. Clusters will consist of either contacts and contacts of contacts of index cases, that is, ring vaccination, or other transmission units., Results: The primary efficacy endpoint will be analysed as a time-to-event outcome. A vaccine will be considered successful if its estimated efficacy is greater than 50% and has sufficient precision to rule out that true efficacy is less than 30%. This will require approximately 150 total endpoints, that is, cases of confirmed Marburg virus disease, per vaccine/comparator combination. Interim analyses will be conducted after 50 and after 100 events. Statistical analysis of the trial will be blended across the different types of designs. Under the assumption of a 6-month attack rate of 1% of the participants in the placebo arm for both the individually and cluster-randomized populations, the most likely sample size is about 20,000 participants per arm., Conclusion: This event-driven design takes into the account the potentially sporadic spread of Marburg virus. The proposed trial design may be applicable for other pathogens against which effective vaccines are not yet available.

Objectives: Prior research has hypothesized the Sequential Organ Failure Assessment (SOFA) score to be a poor predictor of mortality in mechanically ventilated patients with COVID-19. Yet, several U.S. states have proposed SOFA-based algorithms for ventilator triage during crisis standards of care. Using a large cohort of mechanically ventilated patients with COVID-19, we externally validated the predictive capacity of the preintubation SOFA score for mortality prediction with and without other commonly used algorithm elements., Design: Multicenter, retrospective cohort study using electronic health record data., Setting: Eighty-six U.S. health systems., Patients: Patients with COVID-19 hospitalized between January 1, 2020, and February 14, 2021, and subsequently initiated on mechanical ventilation., Interventions: None., Measurements and Main Results: Among 15,122 mechanically ventilated patients with COVID-19, SOFA score alone demonstrated poor discriminant accuracy for inhospital mortality in mechanically ventilated patients using the validation cohort (area under the receiver operating characteristic curve [AUC], 0.66; 95% CI, 0.65-0.67). Discriminant accuracy was even poorer using SOFA score categories (AUC, 0.54; 95% CI, 0.54-0.55). Age alone demonstrated greater discriminant accuracy for inhospital mortality than SOFA score (AUC, 0.71; 95% CI, 0.69-0.72). Discriminant accuracy for mortality improved upon addition of age to the continuous SOFA score (AUC, 0.74; 95% CI, 0.73-0.76) and categorized SOFA score (AUC, 0.72; 95% CI, 0.71-0.73) models, respectively. The addition of comorbidities did not substantially increase model discrimination. Of 36 U.S. states with crisis standards of care guidelines containing ventilator triage algorithms, 31 (86%) feature the SOFA score. Of these, 25 (81%) rely heavily on the SOFA score (12 exclusively propose SOFA; 13 place highest weight on SOFA or propose SOFA with one other variable)., Conclusions: In a U.S. cohort of over 15,000 ventilated patients with COVID-19, the SOFA score displayed poor predictive accuracy for short-term mortality. Our findings warrant reappraisal of the SOFA score's implementation and weightage in existing ventilator triage pathways in current U.S. crisis standards of care guidelines., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Advances in therapeutic drugs have increased life-expectancies for HIV-infected individuals, but the need for an effective vaccine remains. We assessed safety and immunogenicity of HIV-1 vaccine, Trimer 4571 (BG505 DS-SOSIP.664) adjuvanted with aluminum hydroxide (alum), in HIV-negative adults., Methods: We conducted a phase I, randomized, open-label, dose-escalation trial at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Eligible participants were HIV-negative, healthy adults between 18-50 years. Participants were randomized 1:1 to receive Trimer 4571 adjuvanted with 500 mcg alum by either the subcutaneous (SC) or intramuscular (IM) route at weeks 0, 8, and 20 in escalating doses of 100 mcg or 500 mcg. The primary objectives were to evaluate the safety and tolerability of Trimer 4571 with a secondary objective of evaluating vaccine-induced antibody responses. The primary and safety endpoints were evaluated in all participants who received at least one dose of Trimer 4571. Trial results were summarized using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03783130., Findings: Between March 7 and September 11, 2019, 16 HIV-negative participants were enrolled, including six (38%) males and ten (62%) females. All participants received three doses of Trimer 4571. Solicited reactogenicity was mild to moderate in severity, with one isolated instance of severe injection site redness (6%) following a third 500 mcg SC administration. The most commonly reported solicited symptoms included mild injection site tenderness in 14 (88%) and mild myalgia in six (38%) participants. The most frequent unsolicited adverse event attributed to vaccination was mild injection site pruritus in six (38%) participants. Vaccine-induced seropositivity occurred in seven (44%) participants and resolved in all but one (6%). No serious adverse events occurred. Trimer 4571-specific binding antibodies were detected in all groups two weeks after regimen completion, primarily focused on the glycan-free trimer base. Neutralizing antibody activity was limited to the 500 mcg dose groups., Interpretation: Trimer 4571 was safe, well tolerated, and immunogenic in this first-in-human trial. While this phase 1 trial is limited in size, our results inform and support further evaluation of prefusion-stabilized HIV-1 envelope trimers as a component of vaccine design strategies to generate broadly neutralizing antibodies against HIV-1., Funding: Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health., Competing Interests: CC, HG, JRM, and PDK are listed on patent applications involving Trimer 4571. All other authors declare no competing interests., (© 2022 The Authors.)

Background: Ebola virus RNA persists in the semen of male Ebola survivors for months to years after the acute infection, and male-to-female sexual transmission of the virus is well documented. We investigated whether remdesivir can safely reduce persistence of seminal Ebola virus RNA., Methods: We recruited men with persistent seminal Ebola RNA in Liberia and Guinea. Participants were randomized 1:1 to receive intravenous remdesivir (GS-5734; Gilead Sciences) or matching placebo administered once daily by intravenous infusion over 1 hour on 5 consecutive days. Stratification was by country and number of positive (1 or 2) preenrollment semen tests. We evaluated the difference in mean assay negativity rate (ANR), that is, the proportion of negative tests for each participant in each group in the treatment (days 1-28) and follow-up (months 2-6) phases on an intention-to-treat basis., Results: We enrolled 38 men from July 2016 through June 2018. The mean treatment phase ANRs were 85% (standard deviation [SD] = 24%) and 76% (SD = 30%) in the remdesivir and placebo arms, respectively (P = .270). The mean follow-up phase ANRs were 96% (SD = 10%) and 81% (SD = 29%) in the remdesivir and placebo arms, respectively (P = .041). The 5-day remdesivir regimen was well tolerated with no safety concerns., Conclusions: In this small trial, remdesivir 100 mg/day for 5 days safely reduced the presence of Ebola virus RNA in the semen of Ebola survivors 2 to 6 months after administration. A larger follow-up study is necessary to confirm results. Clinical Trials Registration . NCT02818582., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Chemically synthesized, small peptides that bind with high affinity and specificity to CD8-expressing (CD8+) tumor-infiltrating T cells, yet retain the desirable characteristics of small molecules, hold valuable potential for diagnostic molecular imaging of immune response. Here, we report the development of 18 F-labeled peptides targeting human CD8α with nanomolar affinity via the strain-promoted sydnone-alkyne cycloaddition with 4-[ 18 F]fluorophenyl sydnone. The 18 F-sydnone is produced in one step, in high radiochemical yield, and the peptide labeling proceeds rapidly. A hydrophilic chemical linker results in a tracer with favorable pharmacokinetic properties and improved image contrast, as demonstrated by in vivo PET imaging studies.

The test-negative study design is often used to estimate vaccine effectiveness in influenza studies, but it has also been proposed in the context of other infectious diseases, such as cholera, dengue, or Ebola. It was introduced as a variation of the case-control design, in an attempt to reduce confounding bias due to health-care-seeking behavior, and has quickly gained popularity because of its logistic advantages. However, examination of the directed acyclic graphs that describe the test-negative design reveals that without strong assumptions, the estimated odds ratio derived under this sampling mechanism is not collapsible over the selection variable, such that the results obtained for the sampled individuals cannot be generalized to the whole population. In this paper, we show that adjustment for severity of disease can reduce this bias and, under certain assumptions, makes it possible to unbiasedly estimate a causal odds ratio. We support our findings with extensive simulations and discuss them in the context of recently published cholera test-negative studies of the effectiveness of cholera vaccines., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective: The opioid epidemic has increased parentally acquired HIV infection. To inform the development of a long-acting prevention strategy, we evaluated the protective efficacy of broadly neutralizing antibodies (bNAbs) against intravenous simian-human immunodeficiency virus (SHIV) infection in macaques., Design: Five cynomolgus macaques were injected once subcutaneously with 10-1074 and 3BNC117 (10 mg each kg-1) and were repeatedly challenged intravenously once weekly with SHIVAD8-EO (130 TCID50), until infection was confirmed via plasma viral load assay. Two control macaques, which received no antibody, were challenged identically., Methods: Plasma viremia was monitored via RT-qPCR assay. bNAb concentrations were determined longitudinally in plasma samples via TZM-bl neutralization assays using virions pseudotyped with 10-1074-sensitive (X2088&#95;c9) or 3BNC117-sensitive (Q769.d22) HIV envelope proteins., Results: Passively immunized macaques were protected against a median of five weekly intravenous SHIV challenges, as compared to untreated controls, which were infected following a single challenge. Of the two bNAbs, 10-1074 exhibited relatively longer persistence in vivo. The median plasma level of 10-1074 at SHIV breakthrough was 1.1 μg ml-1 (range: 0.6-1.6 μg ml-1), whereas 3BNC117 was undetectable. Probit modeling estimated that 6.6 μg ml-1 of 10-1074 in plasma corresponded to a 99% reduction in per-challenge infection probability, as compared to controls., Conclusions: Significant protection against repeated intravenous SHIV challenges was observed following administration of 10-1074 and 3BNC117 and was due primarily to 10-1074. Our findings extend preclinical studies of bNAb-mediated protection against mucosal SHIV acquisition and support the possibility that intermittent subcutaneous injections of 10-1074 could serve as long-acting preexposure prophylaxis for persons who inject drugs.

Multiple candidate vaccines to prevent COVID-19 have entered large-scale phase 3 placebo-controlled randomized clinical trials, and several have demonstrated substantial short-term efficacy. At some point after demonstration of substantial efficacy, placebo recipients should be offered the efficacious vaccine from their trial, which will occur before longer-term efficacy and safety are known. The absence of a placebo group could compromise assessment of longer-term vaccine effects. However, by continuing follow-up after vaccination of the placebo group, this study shows that placebo-controlled vaccine efficacy can be mathematically derived by assuming that the benefit of vaccination over time has the same profile for the original vaccine recipients and the original placebo recipients after their vaccination. Although this derivation provides less precise estimates than would be obtained by a standard trial where the placebo group remains unvaccinated, this proposed approach allows estimation of longer-term effect, including durability of vaccine efficacy and whether the vaccine eventually becomes harmful for some. Deferred vaccination, if done open-label, may lead to riskier behavior in the unblinded original vaccine group, confounding estimates of long-term vaccine efficacy. Hence, deferred vaccination via blinded crossover, where the vaccine group receives placebo and vice versa, would be the preferred way to assess vaccine durability and potential delayed harm. Deferred vaccination allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain them on placebo, yet still allows important insights about immunologic and clinical effectiveness over time.

Background: Although several COVID-19 vaccines have been found to be effective in rigorous evaluation and have emerging availability in parts of the world, their supply will be inadequate to meet international needs for a considerable period of time. There also will be continued interest in vaccines that are more effective or have improved scalability to facilitate mass vaccination campaigns. Ongoing clinical testing of new vaccines also will be needed as variant strains continue to emerge that may elude some aspects of immunity induced by current vaccines. Randomized clinical trials meaningfully enhance the efficiency and reliability of such clinical testing. In clinical settings with limited or no access to known effective vaccines, placebo-controlled randomized trials of new vaccines remain a preferred approach to maximize the reliability, efficiency and interpretability of results. When emerging availability of licensed vaccines makes it no longer possible to use a placebo control, randomized active comparator non-inferiority trials may enable reliable insights., Methods: In this article, "hybrid" methods are proposed to address settings where, during the conduct of a placebo-controlled trial, a judgment is made to replace the placebo arm by a licensed COVID-19 vaccine due to emerging availability of effective vaccines in regions participating in that trial. These hybrid methods are based on proposed statistics that aggregate evidence to formally test as well as to estimate the efficacy of the experimental vaccine, by combining placebo-controlled data during the first period of trial conduct with active-controlled data during the second period., Results: Application of the proposed methods is illustrated in two important scenarios where the active control vaccine would become available in regions engaging in the experimental vaccine's placebo-controlled trial: in the first, the active comparator's vaccine efficacy would have been established to be 50%-70% for the 4- to 6-month duration of follow-up of its placebo-controlled trial; in the second, the active comparator's vaccine efficacy would have been established to be 90%-95% during that duration. These two scenarios approximate what has been seen with adenovirus vaccines or mRNA vaccines, respectively, assuming the early estimates of vaccine efficacy for those vaccines would hold over longer-term follow-up., Conclusion: The proposed hybrid methods could readily play an important role in the near future in the design, conduct and analysis of randomized clinical trials performed to address the need for multiple additional vaccines reliably established to be safe and have worthwhile efficacy in reducing the risk of symptomatic disease from SARS-CoV-2 infections.

The global decline in malaria has stalled 1 , emphasizing the need for vaccines that induce durable sterilizing immunity. Here we optimized regimens for chemoprophylaxis vaccination (CVac), for which aseptic, purified, cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ) were inoculated under prophylactic cover with pyrimethamine (PYR) (Sanaria PfSPZ-CVac(PYR)) or chloroquine (CQ) (PfSPZ-CVac(CQ))-which kill liver-stage and blood-stage parasites, respectively-and we assessed vaccine efficacy against homologous (that is, the same strain as the vaccine) and heterologous (a different strain) controlled human malaria infection (CHMI) three months after immunization ( https://clinicaltrials.gov/ , NCT02511054 and NCT03083847). We report that a fourfold increase in the dose of PfSPZ-CVac(PYR) from 5.12 × 10 4 to 2 × 10 5 PfSPZs transformed a minimal vaccine efficacy (low dose, two out of nine (22.2%) participants protected against homologous CHMI), to a high-level vaccine efficacy with seven out of eight (87.5%) individuals protected against homologous and seven out of nine (77.8%) protected against heterologous CHMI. Increased protection was associated with Vδ2 γδ T cell and antibody responses. At the higher dose, PfSPZ-CVac(CQ) protected six out of six (100%) participants against heterologous CHMI three months after immunization. All homologous (four out of four) and heterologous (eight out of eight) infectivity control participants showed parasitaemia. PfSPZ-CVac(CQ) and PfSPZ-CVac(PYR) induced a durable, sterile vaccine efficacy against a heterologous South American strain of P. falciparum, which has a genome and predicted CD8 T cell immunome that differs more strongly from the African vaccine strain than other analysed African P. falciparum strains.

Background: People with human immunodeficiency virus (HIV) can present with new or worsening symptoms associated with Mycobacterium avium complex (MAC) infection shortly after antiretroviral therapy (ART) initiation as MAC immune reconstitution inflammatory syndrome (MAC-IRIS). In this study, we assessed the utility of several laboratory tests as predictors of MAC-IRIS., Methods: People with HIV with clinical and histologic and/or microbiologic evidence of MAC-IRIS were identified and followed up to 96 weeks post-ART initiation within a prospective study of 206 ART-naive patients with CD4 <100 cells/µL., Results: Fifteen (7.3%) patients presented with MAC-IRIS within a median interval of 26 days after ART initiation. Patients who developed MAC-IRIS had lower body mass index, lower hemoglobin levels, higher alkaline phosphatase (ALP), and increased CD38 frequency and mean fluorescence intensity on CD8+ T cells at the time of ART initiation compared with non-MAC IRIS patients. A decision tree inference model revealed that stratifying patients based on levels of ALP and D-dimer could predict the likelihood of MAC-IRIS. A binary logistic regression demonstrated that higher levels of ALP at baseline were associated with increased risk of MAC-IRIS development., Conclusions: High ALP levels and increased CD8+ T-cell activation with low CD4 counts at ART initiation should warrant suspicion for subsequent development of MAC-IRIS., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)