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Abstract Background In England, the number of takeaway food outlets (‘takeaways’) has been increasing for over two decades. Takeaway management zones around schools are an effective way to restrict the growth of new takeaways but their impacts on population health have not been estimated. Methods To model the impact of takeaway management zones on health, we used estimates of change in and exposure to takeaways (across home, work, and commuting buffers) based on a previous evaluation suggesting that 50% of new outlets were prevented from opening because of management zones. Based on previous cross-sectional findings, we estimated changes in body mass index (BMI) from changes in takeaway exposure, from 2018 to 2040. We used PRIMEtime, a proportional multistate lifetable model, and BMI change to estimate the impact of the intervention, in a closed-cohort of adults (25–64 years), on incidence of 12 non-communicable diseases, obesity prevalence, quality-adjusted life years (QALYs), and healthcare costs saved by 2040 in six local authorities (LAs) across the rural–urban spectrum in England (Wandsworth, Manchester, Blackburn with Darwen, Sheffield, North Somerset, and Fenland). Results By 2031, compared to no intervention, reductions in outlet exposure ranged from 3 outlets/person in Fenland to 28 outlets/person in Manchester. This corresponded to mean per person reductions in BMI of 0.08 and 0.68 kg/m2, respectively. Relative to no intervention, obesity prevalence was estimated to be reduced in both sexes in all LAs, including by 2.3 percentage points (PP) (95% uncertainty interval:2.9PP, 1.7PP) to 1.5PP (95%UI:1.9PP, 1.1PP) in males living in Manchester and Wandsworth by 2040, respectively. Model estimates showed reductions in incidence of disease, including type II diabetes (e.g. 964 (95% UI: 1565, 870) fewer cases/100,000 population for males in Manchester)), cardiovascular diseases, asthma, certain cancers, and low back pain. Savings in healthcare costs (millions) ranged from £1.65 (95% UI: £1.17, £2.25)/100,000 population in North Somerset to £2.02 (95% UI: £1.39, £2.83)/100,000 population in Wandsworth. Gains in QALYs/100,000 person were broadly similar across LAs. Conclusions Takeaway management zones in England have the potential to meaningfully contribute towards reducing obesity prevalence and associated healthcare burden in the adult population, at the local level and across the rural–urban spectrum.

Abstract Background Neighbourhood exposure to takeaways can contribute negatively to diet and diet-related health outcomes. Urban planners within local authorities (LAs) in England can modify takeaway exposure through denying planning permission to new outlets in management zones around schools. LAs sometimes refer to these as takeaway “exclusion zones”. Understanding the long-term impacts of this intervention on the takeaway retail environment and health, an important policy question, requires methods to forecast future takeaway growth and subsequent population-level exposure to takeaways. In this paper we describe a novel two-stage method to achieve this. Methods We used historic data on locations of takeaways and a time-series auto-regressive integrated moving average (ARIMA) model, to forecast numbers of outlets within management zones to 2031, based on historical trends, in six LAs with different urban/rural characteristics across England. Forecast performance was evaluated based on root mean squared error (RMSE) and mean absolute scaled error (MASE) scores in time-series cross-validation. Using travel-to-work data from the 2011 UK census, we then translated these forecasts of the number of takeaways within management zones into population-level exposures across home, work and commuting domains. Results Our ARIMA models outperformed exponential smoothing equivalents according to RMSE and MASE. The model was able to forecast growth in the count of takeaways up to 2031 across all six LAs, with variable growth rates by RUC (min–max: 39.4-79.3%). Manchester (classified as a non-London urban with major conurbation LA) exhibited the highest forecast growth rate (79.3%, 95% CI 61.6, 96.9) and estimated population-level takeaway exposure within management zones, increasing by 65.5 outlets per capita to 148.2 (95% CI 133.6, 162.7) outlets. Overall, urban (vs. rural) LAs were forecast stronger growth and higher population exposures. Conclusions Our two-stage forecasting approach provides a novel way to estimate long-term future takeaway growth and population-level takeaway exposure. While Manchester exhibited the strongest growth, all six LAs were forecast marked growth that might be considered a risk to public health. Our methods can be used to model future growth in other types of retail outlets and in other areas.

CAR-T cell and T cell engager therapies have demonstrated transformational efficacy against hematological malignancies, but achieving efficacy in solid tumors has been more challenging, in large part because of on-target/off-tumor toxicities and sub-optimal T cell anti-tumor cytotoxic functions. Here, we discuss engineering solutions that exploit biological properties of solid tumors to overcome these challenges. Using logic gates as a framework, we categorize the numerous approaches that leverage two inputs instead of one to achieve better cancer selectivity or efficacy in solid tumors with dual-input CAR-Ts or multi-specific TCEs. In addition to the “OR gate” and “AND gate” approaches that leverage dual tumor antigen targeting, we also review “contextual AND gate” technologies whereby continuous cancer-selective inputs such a pH, hypoxia, target density, tumor proteases, and immune-suppressive cytokine gradients can be creatively incorporated in therapy designs. We also introduce the notion of “output directionality” to distinguish dual-input strategies that mechanistically impact cancer cell killing or T cell fitness. Finally, we contrast the feasibility and potential benefits of the various approaches using CAR-T and TCE therapeutics and discuss why the promising “IF/THEN” and “NOT” gate types pertain more specifically to CAR-T therapies, but can also succeed by integrating both technologies.

Local and national policymakers are seeking innovative solutions to create healthier food environments around the world. Between 2009 and 2017, 35 local authorities across England (UK) adopted planning guidance designed to limit the proliferation of hot food takeaways near schools. Whilst these policies are intended to improve population health, they are also likely to have economic impacts. Often a decision to introduce such policies comes down to consideration of whether the short-term economic imperatives of allowing new takeaway outlets to open outweighs the potential long-term public health implications and associated economic consequences. These potential negative and positive economic impacts have not previously been clearly described and are summarised here. The aim of this paper is to provide an overview of the potential economic impacts of takeaway management zones. In particular, we present a Causal Loop Diagram (CLD) that outlines the possible economic impacts of takeaway management zones based on researcher knowledge of the interventions and the industry. Potential negative impacts fall across sectors and may include a loss of employment opportunities and reductions in local and national tax receipts, and may impact the economic vitality of local communities. In the longer term, there is the potential for positive impacts such as reductions in healthcare resource utilisation, social care expenditure and sickness-related absence from work. Part of a robust case would a better economic understanding, that would enable local authorities to improve understanding of the trade-offs associated with the policy, such as short-versus long-term, and business-related versus society-related health benefits and costs.

Abstract The discovery of Mn-Ca complex in photosystem II stimulates research of manganese-based catalysts for oxygen evolution reaction (OER). However, conventional chemical strategies face challenges in regulating the four electron-proton processes of OER. Herein, we investigate alpha-manganese dioxide (α-MnO2) with typical MnIV-O-MnIII-HxO motifs as a model for adjusting proton coupling. We reveal that pre-equilibrium proton-coupled redox transition provides an adjustable energy profile for OER, paving the way for in-situ enhancing proton coupling through a new “reagent”— external electric field. Based on the α-MnO2 single-nanowire device, gate voltage induces a 4-fold increase in OER current density at 1.7 V versus reversible hydrogen electrode. Moreover, the proof-of-principle external electric field-assisted flow cell for water splitting demonstrates a 34% increase in current density and a 44.7 mW/cm² increase in net output power. These findings indicate an in-depth understanding of the role of proton-incorporated redox transition and develop practical approach for high-efficiency electrocatalysis.

This paper examines reinterpretations of solidarity with Latin America through a student-led project at the University of Leeds. The project, ‘Thinking Inside the Box: 1973’ (hereafter, TITB), was a collaboration between the University of London – specifically, King’s College London, Queen Mary University of London, and the London School of Economics – and the Universities of Leeds and Liverpool in 2023. The broader framework of TITB seeks to generate liberatory and transformative learning by approaching the educative process with students as co-creators and co-curators of knowledge. The approach draws from decolonial theory by seeking to challenge the hierarchical practices of mainstream education in which the teacher imposes knowledge on the student. In dialogue with Freirian concepts of collective interpretation and ‘conscientisation’ (Freire, 1968), scholars and students involved in the project used archives to run a series of events and public engagements. It connects students to each other and to a range of archival materials, broadly themed around 20th century Latin America, to inspire them in designing, developing and delivering an output of significant impact by engaging with local communities; in this case, the Chilean diaspora of the dictatorship. The project promotes the co-curation of knowledge, teaching and learning, and supports students to practice autonomy in their journeys of content and skills acquisition (Grimaldi, Carvalho and Natale, 2022; Grimaldi and Rofe, 2023).

Background: A vital role of hospital employee health is the management, characterization, and targeted prevention of bloodborne pathogen exposures (BPPE) among healthcare workers. A comprehensive review of a health center’s BPPE over time was conducted to identify areas for improvement and target education and training, given changes in BBPE standard operating procedures (SOPs) over time. Methods: A retrospective descriptive analysis was conducted on deidentified BBPE cases reported to employee health at VA Connecticut Healthcare System from 1995-2023 (N=296) using R statistical software. Results: The highest number of BBPE occurred among trainee physicians (N=103, 34.8%, especially surgery and internal medicine), registered nurses (N=60, 20.3%), and non-trainee physicians (N=45, 15.2%). The most frequently implicated devices were hollow-bore (N=103, 34.8%) and suture needles (N=60, 20.3%). Most BBPE occurred during surgical procedures (N=114, 38.5%) or medication administration (N=52, 17.6%). Over half of BBPE occurred during afternoons/nights (N=172, 58.1%). Over half occurred with use of personal protective equipment (PPE) (N=181, 61.1%). The majority of BBPE implicated finger injuries (N=220, 74.3%). Blood was the most frequently reported exposure (N=127, 42.9%), a similar percentage of records did not specifically name a body fluid type (N=121) or whether PPE was used (N=110). In most cases, the source patient was identified (N=282, 95.3%) and tested (N=272, 91.9%). Forty-three sources (14.5%) had positive BBP testing, which included HIV (N=14, 4.7%), hepatitis C (N=23, 7.8%), and hepatitis B (N=6, 2.0%). Most employees presented to employee health for initial evaluation (N=231, 78%) and underwent post-exposure testing (N=266, 89.9%); most had evidence of immunity to hepatitis B (N=246, 83.1%). Eighty-three employees (28%) received HIV PEP (average=1.9 days). Most records did not indicate if this was a first-time BBPE (N=250, 84.5%). No employee records indicated seroconversion for a bloodborne pathogen. Conclusions: Physicians and RNs, those performing surgical procedures and administering medications, and those on second and third shifts are at highest risk and may benefit from additional interventions such as exposure assessment or education. Required recordkeeping has been variable over time. Updated national SOPs have been adapted to employee health, though additional details could be considered for quality improvement purposes, such as duration of employment, level of training, and prior BBPE prevention education. It is unclear if some information such as history of BBPE or PPE use was elicited but not documented – this information could be helpful in management of BBPEs.

Background: Complex interactions between political economy factors and corporate power are increasingly recognized to prevent transformative policy action on non-communicable disease (NCD) prevention. System science offers promising methods for analysing such causal complexity. This study uses qualitative system dynamics methods to map the political economy of diet-related NCD (DR-NCD) prevention policy-making aiming to better understand the policy inertia observed in this area globally.Methods We interviewed 25 key policy actors. We analysed the interviews using purposive text analysis (PTA). We developed individual then combined casual loop diagrams to generate a shared model representing the DR-NCD prevention policy-making system. Key variables/linkages identified from the literature were also included in the model. We validated the model in several steps including through stakeholder validation interviews.Results We identified several inter-linked feedback processes related to political economy factors that may entrench different forms of corporate power (instrumental, structural, and discursive) in DR-NCD prevention policy-making in South Africa over time. We also identified a number of feedback processes that have the potential to limit corporate power in this setting.Conclusion Using complex system methods can be useful for more deeply understanding DR-NCD policy inertia. It is also useful for identifying potential leverage points within the system which may shift the existing power dynamics to facilitate greater political commitment for healthy, equitable, and sustainable food system transformation.

Background and objectives On 6 April 2022, the UK government implemented mandatory kilocalorie (kcal) labelling regulations for food and drink products sold in the out-of-home food sector (OHFS) in England. Previous assessments of kcal labelling practices in the UK OHFS found a low prevalence of voluntary implementation and poor compliance with labelling recommendations. This study aimed to examine changes in labelling practices preimplementation versus post implementation of mandatory labelling regulations in 2022.Methods In August–December 2021 (preimplementation) and August–November 2022 (post implementation), large OHFS businesses (250 or more employees) subject to labelling regulations were visited. At two time points, a researcher visited the same 117 food outlets (belonging to 90 unique businesses) across four local authorities in England. Outlets were rated for compliance with government regulations for whether kcal labelling was provided at any or all point of choice, provided for all eligible food and drink items, provided per portion for sharing items, if labelling was clear and legible and if kcal reference information was displayed.Results There was a significant increase (21% preimplementation vs 80% post implementation, OR=40.98 (95% CI 8.08 to 207.74), p

BackgroundThe soft drinks industry levy (SDIL) in the United Kingdom has led to a significant reduction in household purchasing of sugar in drinks. In this study, we examined the potential medium- and long-term implications for health and health inequalities among children and adolescents in England.Methods and findingsWe conducted a controlled interrupted time series analysis to measure the effects of the SDIL on the amount of sugar per household per week from soft drinks purchased, 19 months post implementation and by index of multiple deprivation (IMD) quintile in England. We modelled the effect of observed sugar reduction on body mass index (BMI), dental caries, and quality-adjusted life years (QALYs) in children and adolescents (0 to 17 years) by IMD quintile over the first 10 years following announcement (March 2016) and implementation (April 2018) of the SDIL. Using a lifetable model, we simulated the potential long-term impact of these changes on life expectancy for the current birth cohort and, using regression models with results from the IMD-specific lifetable models, we calculated the impact of the SDIL on the slope index of inequality (SII) in life expectancy. The SDIL was found to have reduced sugar from purchased drinks in England by 15 g/household/week (95% confidence interval: -10.3 to -19.7). The model predicts these reductions in sugar will lead to 3,600 (95% uncertainty interval: 946 to 6,330) fewer dental caries and 64,100 (54,400 to 73,400) fewer children and adolescents classified as overweight or obese, in the first 10 years after implementation. The changes in sugar purchasing and predicted impacts on health are largest for children and adolescents in the most deprived areas (Q1: 11,000 QALYs [8,370 to 14,100] and Q2: 7,760 QALYs [5,730 to 9,970]), while children and adolescents in less deprived areas will likely experience much smaller simulated effects (Q3: -1,830 QALYs [-3,260 to -501], Q4: 652 QALYs [-336 to 1,680], Q5: 1,860 QALYs [929 to 2,890]). If the simulated effects of the SDIL are sustained over the life course, it is predicted there will be a small but significant reduction in slope index of inequality: 0.76% (95% uncertainty interval: -0.9 to -0.62) for females and 0.94% (-1.1 to -0.76) for males.ConclusionsWe predict that the SDIL will lead to medium-term reductions in dental caries and overweight/obesity, and long-term improvements in life expectancy, with the greatest benefits projected for children and adolescents from more deprived areas. This study provides evidence that the SDIL could narrow health inequalities for children and adolescents in England.

INTRODUCTION The UN General Assembly in September 2021 will bring countries together at a critical time for marshalling collective action to tackle the global environmental crisis. They will meet again at the biodiversity summit in Kunming, China and the climate conference (COP26) in Glasgow, UK. Ahead of these pivotal meetings, we – the editors of health journals worldwide – call for urgent action to keep average global temperature increases below 1.5°C, halt the destruction of nature, and protect health. Health is already being harmed by global temperature increases and the destruction of the natural world, a state of affairs health professionals have been bringing attention to for decades.1 The science is unequivocal; a global increase of 1.5°C above the pre-industrial average and the continued loss of biodiversity risk catastrophic harm to health pulmonary morbidity and mortality.5,6 Harms disproportionately affect the most vulnerable, including among children, older populations, ethnic minorities, poorer communities and those with underlying health problems.2,4 Global heating is also contributing to the decline in global yield potential for major crops, falling by 1.8-5.6% since 1981; this, together with the effects of extreme weather and soil depletion, is hampering efforts to reduce undernutrition.4 Thriving ecosystems are essential to human health, and the widespread destruction of nature, including habitats and species, is eroding water and food security and increasing the chance of pandemics.3,7,8 The consequences of the environmental crisis fall disproportionately on those countries and communities that have contributed least to the problem and are least able to mitigate the harms. Yet no country, no matter how wealthy, can shield itself from these impacts. Allowing the consequences to fall disproportionately on the most vulnerable will breed more conflict, food insecurity, forced displacement and zoonotic disease – with severe implications for all countries and communities. As with the covid-19 pandemic, we are globally as strong as our weakest member. Rises above 1.5°C increase the chance of reaching tipping points in natural systems that could lock the world into an acutely unstable state. This would critically impair our ability to mitigate harms and to prevent catastrophic, runaway environmental change.9,10

Objectives To find what proportion of a broad set of health journals have published on climate change and health, how many articles they have published, and when they first published on the subject.Design Bibliometric study.Setting and participants We conducted electronic searches in Ovid MEDLINE ALL for articles about climate change and human health published from 1860 to 31 December 2022 in 330 health journals. There were no limits by language or publication type. Results were independently screened by two raters for article eligibility.Results After screening there were 2932 eligible articles published across 253 of the 330 journals between 1947 and 2022; most (2795/2932; 95%) were published in English. A few journals published articles in the early 90s, but there has been a rapid increase since about 2006. We were unable to categorise the types of publication but estimate that fewer than half are research papers. While articles were published in journals in 39 countries, two-thirds (1929/2932; 66%) were published in a journal published in the UK or the USA. Almost a quarter (77/330; 23%) of the journals published no eligible articles, and almost three-quarters (241/330; 73%) published five articles or fewer. The publication of joint editorials in over 200 journals in 2021 and 2022 boosted the number of journals publishing something on climate change and health. A third of the (112/330; 34%) journals in our sample published at least one of the joint editorials, and almost a third of those (32/112; 29%) were publishing on climate change and health for the first time.Conclusions Health journals are rapidly increasing the amount they publish on climate change and health, but despite climate change being the major threat to global health many journals had until recently published little or nothing. A joint editorial published in multiple journals increased coverage, and for many journals it was the first thing they published on climate change and health.

Abstract Chimeric antigen receptors (CARs) are engineered to target T cells specifically to tumor cells, resulting in the engineered T cell killing the tumor cell. This technology has been developed to target a range of cancers, with the most notable successes in the treatment of B-cell malignancies where four approved therapies, all targeting CD19, are on the market. These four products differ in the costimulation domains, with axicabtagene ciloleucel (Yescarta) and brexucabtagene autoleucel (Tecartus) both utilizing the CD28 costimulation domain whilst tisagenlecleucel (Kymriah) and lisocabtagene maraleucel (Breyanzi) both utilizing the 4-1BB costimulation domain. There are clearly defined differences in how the CD28 and 4-1BB domains signal, yet it is difficult to ascertain which domain affords a superior mechanism of action given many other differences between these products, including overall CAR architecture and manufacturing methods. Additionally, while in vitro and preclinical in vivo studies have compared CARs with different costimulation domains, it remains a challenge to extrapolate differences observed in this biology across different experimental systems to the overall product performance. While there has been extensive preclinical and clinical work looking at CARs with a variety of targeting domains and architectures, this review will focus on the differences between the four marketed anti-CD19 CAR-Ts, with an additional focus on the impact of hinge and transmembrane domain on CAR activity and interaction with the target cell as well as other proteins on the surface of the T-cell.

Abstract Background Regulations mandating kilocalorie (kcal) labelling for large businesses in the out-of-home food sector (OHFS) came into force on 6th April 2022 as a policy to reduce obesity in England. To provide indicators of potential reach and impact, kcal labelling practices were studied in the OHFS, and customer purchasing and consumption behaviours prior to implementation of the mandatory kcal labelling policy in England. Methods From August-December 2021, large OHFS businesses subject to the kcal labelling regulations were visited prior to regulations coming into force on 6th April 2022. 3308 customers were recruited from 330 outlets and collected survey information on the number of kcal purchased and consumed by customers, customers’ knowledge of the kcal content of their purchases, and customers noticing and use of kcal labelling. In a subset of 117 outlets, data was collected on nine recommended kcal labelling practices. Results The average number of kcals purchased (1013 kcal, SD = 632 kcal) was high with 69% of purchases exceeding the recommendation of a maximum of 600 kcal per meal. Participants underestimated the energy content of their purchased meals by on average 253 kcal (SD = 644 kcals). In outlets providing kcal labelling in which customer survey data was collected, a minority of customers reported noticing (21%) or using (20%) kcal labelling. Out of the 117 outlets assessed for kcal labelling practices, 24 (21%) provided any in-store kcal labelling. None of the outlets met all nine aspects of recommended labelling practices. Conclusions Prior to implementation of 2022 kcal labelling policy, the majority of sampled OHFS large business outlets in England did not provide kcal labelling. Few customers noticed or used the labels and on average customers purchased and consumed substantially more energy than recommended in public health guidelines. The findings suggest that reliance on voluntary action for kcal labelling implementation failed to produce widespread, consistent, and adequate kcal labelling practices.

Following the development of a value of vaccination (VoV) framework for health technology assessment/cost-effectiveness analysis (HTA/CEA), and identification of three vaccination benefits for near-term inclusion in HTA/CEA, this final paper provides decision makers with methods and examples to consider benefits of health systems strengthening (HSS), equity, and macroeconomic gains. Expert working groups, targeted literature reviews, and case studies were used. Opportunity cost methods were applied for HSS benefits of rotavirus vaccination. Vaccination, with HSS benefits included, reduced the incremental cost-effectiveness ratio (ICER) by 1.4–50.5% (to GBP 11,552–GBP 23,016) depending on alternative conditions considered. Distributional CEA was applied for health equity benefits of meningococcal vaccination. Nearly 80% of prevented cases were among the three most deprived groups. Vaccination, with equity benefits included, reduced the ICER by 22–56% (to GBP 7014–GBP 12,460), depending on equity parameters. Macroeconomic models may inform HTA deliberative processes (e.g., disease impact on the labour force and the wider economy), or macroeconomic outcomes may be assessed for individuals in CEAs (e.g., impact on non-health consumption, leisure time, and income). These case studies show how to assess broader vaccination benefits in current HTA/CEA, providing decision makers with more accurate and complete VoV assessments. More work is needed to refine inputs and methods, especially for macroeconomic gains.

Abstract Objective: The UK Soft Drinks Industry Levy (SDIL) (announced in March 2016; implemented in April 2018) aims to incentivise reformulation of soft drinks to reduce added sugar levels. The SDIL has been applauded as a policy success, and it has survived calls from parliamentarians for it to be repealed. We aimed to explore parliamentary reaction to the SDIL following its announcement until two years post-implementation in order to understand how health policy can become established and resilient to opposition. Design: Searches of Hansard for parliamentary debate transcripts that discussed the SDIL retrieved 186 transcripts, with 160 included after screening. Five stages of Applied Thematic Analysis were conducted: familiarisation and creation of initial codebooks; independent second coding; codebook finalisation through team consensus; final coding of the dataset to the complete codebook; and theme finalisation through team consensus. Setting: The United Kingdom Parliament Participants: N/A Results: Between the announcement (16/03/2016) – royal assent (26/04/2017), two themes were identified 1: SDIL welcomed cross-party 2: SDIL a good start but not enough. Between royal assent – implementation (5/04/2018), one theme was identified 3: The SDIL worked – what next? The final theme identified from implementation until 16/03/2020 was 4: Moving on from the SDIL. Conclusions: After the announcement, the SDIL had cross-party support and was recognised to have encouraged reformulation prior to implementation. Lessons for governments indicate that the combination of cross-party support and a policy’s documented success in achieving its aim can help cement the resilience of it to opposition and threats of repeal.

Importance The study summarises the selection prescreen criteria currently used in the UK for a uterus transplant and highlights the number of women who are suitable to proceed.Objectives To assess the demographics, motivations, reasons and suitability among women with absolute uterine factor infertility (AUFI) to undergo uterine transplantation (UTx).Design A cross-sectional survey.Setting An electronic questionnaire was sent via email to women with AUFI who had previously been referred to the UTx research team or approached the Womb Transplant UK Charity. The questions assessed suitability to undergo UTx based on demographic information, perceptions to adoption and surrogacy and reasons why UTx was preferable. Responses were assessed against the study selection criteria.Participants Women with AUFI.Results 210 women completed the questionnaire. The most common aetiology of AUFI in our cohort was Mayer-Rokitansky-Küster-Hauser (68%; n=143) whereas 29% (n=62) had previously undergone hysterectomy. 63% (n=132) of the cohort had previously considered adoption, 5% (n=11) had attempted it and 2 (1%) had successfully adopted. The most common reason cited to undergo UTx over adoption was to experience gestation (n=63; 53%), while 37% (n=44) wanted a biologically related child. 76% (n=160) of participants had previously considered surrogacy, 22 (10%) had attempted it and 2 (1%) had successfully become mothers using a surrogate. The most common reason to undergo UTx over surrogacy was to experience gestation (n=77; 54%). 15% (n=21) were concerned about the legal implications, 14% (n=20) identified the financial cost as a barrier and 8% (n=12) could not consider it due to religious reasons. On adhering to the selection criteria, 65 (31%) women were suitable to proceed with the trial.Conclusion The study demonstrates that implementing commonly used selection criteria for a UTx led to an attrition rate of more than two-thirds of women who requested to initially undergo the process. As more studies present outcomes following UTx, critical assessment of the selection criteria currently used is warranted to ensure potential recipients are not being unnecessarily excluded.Trial registration number NCT02388802.

ABSTRACTIn this investigation, we tested the hypothesis that a physiologically based pharmacokinetic (PBPK) model incorporating measured in vitro metrics of off-target binding can largely explain the inter-antibody variability in monoclonal antibody (mAb) pharmacokinetics (PK). A diverse panel of 83 mAbs was evaluated for PK in wild-type mice and subjected to 10 in vitro assays to measure major physiochemical attributes. After excluding for target-mediated elimination and immunogenicity, 56 of the remaining mAbs with an eight-fold variability in the area under the curve ([Formula: see text]: 1.74 × 106 −1.38 × 107 ng∙h/mL) and 10-fold difference in clearance (2.55–26.4 mL/day/kg) formed the training set for this investigation. Using a PBPK framework, mAb-dependent coefficients F1 and F2 modulating pinocytosis rate and convective transport, respectively, were estimated for each mAb with mostly good precision (coefficient of variation (CV%) 1. The predictive utility of the developed PBPK model was evaluated against a separate panel of 14 mAbs biased toward high clearance, among which area under the curve of PK data of 12 mAbs was predicted within 2.5-fold error, and the positive and negative predictive values for clearance prediction were 85% and 100%, respectively. MAb heparin chromatography assay output allowed a priori identification of mAb candidates with unfavorable PK.

ABSTRACTBiologic drug discovery pipelines are designed to deliver protein therapeutics that have exquisite functional potency and selectivity while also manifesting biophysical characteristics suitable for manufacturing, storage, and convenient administration to patients. The ability to use computational methods to predict biophysical properties from protein sequence, potentially in combination with high throughput assays, could decrease timelines and increase the success rates for therapeutic developability engineering by eliminating lengthy and expensive cycles of recombinant protein production and testing. To support development of high-quality predictive models for antibody developability, we designed a sequence-diverse panel of 83 effector functionless IgG1 antibodies displaying a range of biophysical properties, produced and formulated each protein under standard platform conditions, and collected a comprehensive package of analytical data, including in vitro assays and in vivo mouse pharmacokinetics. We used this robust training data set to build machine learning classifier models that can predict complex protein behavior from these data and features derived from predicted and/or experimental structures. Our models predict with 87% accuracy whether viscosity at 150 mg/mL is above or below a threshold of 15 centipoise (cP) and with 75% accuracy whether the area under the plasma drug concentration–time curve (AUC0–672 h) in normal mouse is above or below a threshold of 3.9 × 106 h x ng/mL.

Abstract Background The UK Soft Drinks Industry Levy (SDIL) was announced in March 2016, became law in April 2017, and was implemented in April 2018. Empirical analyses of commercial responses have not been undertaken to establish the scale, direction or nuance of industry media messaging around fiscal policies. We aimed to develop a detailed understanding of industry reactions to the SDIL in publicly available media, including whether and how these changed from announcement to implementation. Methods We searched Factiva to identify articles related to sugar, soft-drinks, and the SDIL, between 16th March 2016–5th April 2018. Articles included were UK publications written in English and reporting a quotation from an industry actor in response to the SDIL. We used a longitudinal thematic analysis of public statements by the soft-drinks industry that covered their reactions in relation to key policy milestones. Results Two hundred and ninety-eight articles were included. After the announcement in March 2016, there was strong opposition to the SDIL. After the public consultation, evolving opposition narratives were seen. After the SDIL became law, reactions reflected a shift to adapting to the SDIL. Following the publication of the final regulations, statements sought to emphasise industry opportunities and ensure the perceived profitability of the soft drinks sector. The most significant change in message (from opposition to adapting to the SDIL) occurred when the SDIL was implemented (6th April 2018). Conclusion Reactions to the SDIL changed over time. Industry modified its media responses from a position of strong opposition to one that appeared to focus on adaptation and maximising perceived profitability after the SDIL became law. This shift suggests that the forces that shape industry media responses to fiscal policies do not remain constant but evolve in response to policy characteristics and the stage of the policy process to maximise beneficial framing.

Vegetable growers on the central coast of California are under regulatory pressure to reduce nitrate loading to ground and surface water supplies. California also implemented legislation that limits agricultural pumping in regions such as the central coast where the aquifers have been over-extracted for crop irrigation. Growers could potentially use less N fertilizer, address water quality concerns, and conserve water by improving water management and matching nitrogen applications to the N uptake pattern of their crops. Two tools available to growers, the soil nitrate quick test (SNQT) and reference evapotranspiration (ETo) data have been previously shown to improve the management of water and fertilizer nitrogen in vegetable production systems. However, adoption of these practices has not been widespread. These techniques can be time consuming to use, and vegetable growers often have many crops to manage. To address such time constraints, the CropManage online application (cropmanage.ucanr.edu) was developed to facilitate implementation of the SNQT and evapotranspiration-based irrigation scheduling. CropManage additionally helps growers account for plant available N from background levels of nitrate in irrigation water. Trials were conducted in commercial vegetable fields in the Salinas Valley during 2012–2019 to evaluate CropManage fertilizer and irrigation recommendations relative to the grower practice. Results demonstrated that in many cases fertilizer or irrigation reductions could be attained by following CropManage recommendations without jeopardizing yield. In lettuce, the total fertilizer N applied under CropManage guidance was reduced by an average of 31 % compared to the grower standard practice. Lettuce yield within the CropManage treatment averaged 107 % of the grower practice. CropManage guidance in broccoli reduced N and applied water by 24 % and 27 %, respectively, compared to the grower standard practice, while average yield was similar between treatments. Management tools such as CropManage can support operational efficiencies and compliance with regulatory targets designed to improve groundwater quality.

ObjectiveTo assess the motivations and perceptions of the general public in the United Kingdom toward donating their uterus for Uterus Transplantation after death (UTx).DesignA cross sectional study.SettingA 32-item electronic questionnaire.PopulationOne hundred fifty nine females over the age of 16 living in the United Kingdom, consented and took part in the study.Main outcome measuresThe motivations and perceptions toward UTx among the general public including the willingness to donate and barriers preventing donation.ResultsOne hundred fifty nine women completed the questionnaire. The majority had never heard of UTx (n = 107, 71%) and most were not aware the uterus could be donated after death (n = 130, 92%). 43% of the cohort were willing to donate their uterus after death (n = 57). 8% stated they wished to donate their organs but not their uterus (n = 10). 30% of women (n = 42) believed the child born following UTx would have genetic links to the donor. Over half of the respondents (n = 65, 51%) strongly agreed or agreed they would feel joy in the knowledge that donation would lead to bringing a new life into the world. A quarter of respondents strongly agreed or agreed (n = 45, 25%) that the use of their uterus by another woman would feel like an extension of life.ConclusionThe findings indicate a favorable opinion toward UTx and a positive attitude toward donation of the uterus after death among the general public in the United Kingdom. The findings also highlight the need for education around UTx now this therapeutic option is available.

Objectives The UK Soft Drinks Industry Levy (SDIL), implemented in 2018, has been successful in reducing the sugar content and purchasing of soft drinks, with limited financial impact on industry. Understanding the views of food and drink industry professionals involved in reacting to the SDIL is important for policymaking. However, their perceptions of the challenges of implementation and strategic responses are unknown. The aim of this study, therefore, was to explore how senior food and drink industry professionals viewed the SDIL.Design We undertook a qualitative descriptive study using elite interviews. Data were analysed using Braun and Clarke’s thematic analysis, taking an inductive exploratory and descriptive approach not informed by prior theory or frameworks.Setting and participants Interviews were conducted via telephone with 14 senior professionals working in the food and drink industry.Results Five main themes were identified: (1) a level playing field…for some; industry accepted the SDIL as an attempt to create a level playing field but due to the exclusion of milk-based drinks, this was viewed as inadequate, (2) complex to implement, but no lasting negative effects; the SDIL was complex, expensive and time consuming to implement, with industry responses dependent on leadership buy-in, (3) why us?—the SDIL unfairly targets the drinks industry; soft drinks are an unfair target when other categories also contain high sugar, (4) the consumer is king; consumers were a key focus of the industry response to this policy and (5) the future of the SDIL; there appeared to be a wider ripple effect, which primed industry to prepare for future regulation in support of health and environmental sustainability.Conclusions Insights from senior food and drink industry professionals illustrate how sugar-sweetened beverage taxes might be successfully implemented and improve understanding of industry responses to taxes and other food and drink policies.Trial registration number ISRCTN18042742.

Organic cool-season vegetable growers on the Central Coast face challenges in applying nitrogen (N) to balance yields with new environmental regulations. It is hard to time fertilizer applications while calculating N mineralization of soil organic matter and organic fertilizers to plant-available N. Organic fertilizers with high phosphorus (P) to N ratios may elevate P levels and harm surface water quality. In this study, we evaluated (1) mineralization of soil organic matter and fertilizers, (2) effectiveness of residual soil nitrate-N tests and (3) long-term impacts of organic fertilizers on P levels and soil microbial activity. We found that mineralization of N from soil organic matter provided limited N to leafy green vegetables. Soil tests were more reliable in heavier than sandier soils. Application rates of 4-4-2 were calculated to meet N demands, resulting in an oversupply of P. However, only 9% to 17% of fertilizer P solubilized without elevating available soil P levels. While it's difficult for organic vegetable growers to use cover crops, organic fertilizers increased carbon levels, resulting in higher levels of soil microbial activity.

Variable stars in stellar clusters can offer key constraints on stellar evolution and pulsation models, utilizing estimates of host cluster properties to constrain stellar physical parameters. We present a catalog of 86 luminous (F814W < 19) variable stars in M31 clusters identified by mining the archival Panchromatic Hubble Andromeda Treasury (PHAT) survey using a combination of statistical analysis of sparse PHAT light curves and difference imaging. We determine the evolutionary phases and initial masses of these variable stars by matching them with theoretical isochrones generated using host cluster properties from the literature. We calculate the probability of PHAT photometry being blended due to the highly crowded nature of cluster environments for each cluster-variable star, using these probabilities to inform our level of confidence in the derived properties of each star. Our 86 cluster-variable stars have initial masses between 0.8 and 67 M _⊙ . Their evolutionary phases span the main sequence, more evolved hydrogen- and helium-burning phases, and the post–asymptotic giant branch. We identify numerous candidate variable star types: RV Tauri variables, red supergiants, and slowly pulsating B-type supergiants, along with Wolf–Rayet stars, α Cygni and Mira variables, a classical Cepheid, and a possible superasymptotic giant. We characterize 12 cluster-variable stars at higher confidence based on their difference image quality and lower blending probability. Ours is the first systematic study of variable stars in extragalactic stellar clusters leveraging the superior resolution of the Hubble Space Telescope and demonstrating the unique power of stellar clusters in constraining the fundamental properties of variable stars.

Platelet-rich plasma is an autologous plasma containing platelets prepared from fresh whole blood drawn from a peripheral vein. Through processing, it can be prepared to contain supraphysiologic levels of platelets at three to five times greater than the level of normal plasma. PRP has been explored both in vivo and ex vivo in the human endometrium model in its ability to harness the intrinsic regenerative capacity of the endometrium. Intrauterine autologous PRP infusions have been shown to increase endometrial thickness and reduce the rate of intrauterine adhesions. In the setting of recurrent implantation failure, intrauterine infusion of PRP has been shown to increase clinical pregnancy rate. PRP also appears to hold a potential role in select patients with premature ovarian insufficiency, poor ovarian responders and in improving outcomes following frozen–thawed transplantation of autologous ovarian tissue. Further studies are required to explore the potential role of PRP in reproductive medicine further, to help standardise PRP protocols and evaluate which routes of administration are most effective.

It is increasingly recognised within public health scholarship that policy change depends on the nature of the power relations surrounding and embedded within decision-making spaces. It is only through sustained shifts in power in all its forms (visible, hidden and invisible) that previously excluded perspectives have influence in policy decisions. Further, consideration of the underlying neoliberal paradigm is essential for understanding how existing power dynamics and relations have emerged and are sustained. In their analysis of political and governance factors, Townsend et al have provided critical insight into future potential strategies for increasing attention to health concerns in trade policy. In this commentary we explore how incorporating theories of power more rigorously into similar political analyses, as well as more explicit critical consideration of the neoliberal political paradigm, can assist in analysing if and how strategies can effectively challenge existing power relations in ways that are necessary for transformative policy change.

Abstract Background While there is a growing body of legally-focused analyses exploring the potential restrictions on public health policy space due to international trade rules, few studies have adopted a more politically-informed approach. This paper applies an integrated political economy and power analysis approach to understand how power relations and dynamics emerging as a result of the international trade and investment regime influence nutrition and alcohol regulatory development in a case study of South Africa. Methods We interviewed 36 key stakeholders involved in nutrition, alcohol and/or trade/investment policymaking in South Africa. Interview transcripts and notes were imported into NVivo and analyzed using thematic analysis. We used a conceptual framework for analyzing power in health policymaking to guide the analysis. Results Under the neoliberal paradigm that promotes trade liberalization and market extension, corporate power in nutrition and alcohol policymaking has been entrenched in South Africa via various mechanisms. These include via close relationships between economic policymakers and industry; institutional structures that codify industry involvement in all policy development but restrict health input in economic and trade policy decisions; limited stakeholder knowledge of the broader linkages between trade/investment and food/alcohol environments; high evidentiary requirements to prove public health policy effectiveness; both deliberate use of neoliberal frames/narratives as well as processes of socialization and internalization of neoliberal ideas/values shaping perceptions and policy preferences and ultimately generating policy norms prioritizing economic/trade over health objectives. Conclusions Exposing power in policymaking can expand our own ideational boundaries of what is required to promote transformative policy change. This work points to a number of potential strategies for challenging corporate power in nutrition and alcohol policymaking in the context of international trade and investment liberalization in South Africa.

Change to global climate, including both its progressive character and episodic extremes, constitutes a critical societal challenge. We apply here a framework to analyze Climate-induced Extremes on the Food, Energy, Water System Nexus (C-FEWS), with particular emphasis on the roles and sensitivities of traditionally-engineered (TEI) and nature-based (NBI) infrastructures. The rationale and technical specifications for the overall C-FEWS framework, its component models and supporting datasets are detailed in an accompanying paper (Vörösmarty et al., this issue). We report here on initial results produced by applying this framework in two important macro-regions of the United States (Northeast, NE; Midwest, MW), where major decisions affecting global food production, biofuels, energy security and pollution abatement require critical scientific support. We present the essential FEWS-related hypotheses that organize our work with an overview of the methodologies and experimental designs applied. We report on initial C-FEWS framework results using five emblematic studies that highlight how various combinations of climate sensitivities, TEI-NBI deployments, technology, and environmental management have determined regional FEWS performance over a historical time period (1980–2019). Despite their relative simplicity, these initial scenario experiments yielded important insights. We found that FEWS performance was impacted by climate stress, but the sensitivity was strongly modified by technology choices applied to both ecosystems (e.g., cropland production using new cultivars) and engineered systems (e.g., thermoelectricity from different fuels and cooling types). We tabulated strong legacy effects stemming from decisions on managing NBI (e.g., multi-decade land conversions that limit long-term carbon sequestration). The framework also enabled us to reveal how broad-scale policies aimed at a particular net benefit can result in unintended and potentially negative consequences. For example, tradeoff modeling experiments identified the regional importance of TEI in the form wastewater treatment and NBI via aquatic self-purification. This finding, in turn, could be used to guide potential investments in point and/or non-point source water pollution control. Another example used a reduced complexity model to demonstrate a FEWS tradeoff in the context of water supply, electricity production, and thermal pollution. Such results demonstrated the importance of TEI and NBI in jointly determining historical FEWS performance, their vulnerabilities, and their resilience to extreme climate events. These infrastructures, plus technology and environmental management, constitute the “policy levers” which can actively be engaged to mitigate the challenge of contemporary and future climate change.

Climate change continues to challenge food, energy, and water systems (FEWS) across the globe and will figure prominently in shaping future decisions on how best to manage this nexus. In turn, traditionally engineered and natural infrastructures jointly support and hence determine FEWS performance, their vulnerabilities, and their resilience in light of extreme climate events. We present here a research framework to advance the modeling, data integration, and assessment capabilities that support hypothesis-driven research on FEWS dynamics cast at the macro-regional scale. The framework was developed to support studies on climate-induced extremes on food, energy, and water systems (C-FEWS) and designed to identify and evaluate response options to extreme climate events in the context of managing traditionally engineered (TEI) and nature-based infrastructures (NBI). This paper presents our strategy for a first stage of research using the framework to analyze contemporary FEWS and their sensitivity to climate drivers shaped by historical conditions (1980–2019). We offer a description of the computational framework, working definitions of the climate extremes analyzed, and example configurations of numerical experiments aimed at evaluating the importance of individual and combined driving variables. Single and multiple factor experiments involving the historical time series enable two categories of outputs to be analyzed: the first involving biogeophysical entities (e.g., crop production, carbon sequestered, nutrient and thermal pollution loads) and the second reflecting a portfolio of services provided by the region’s TEI and NBI, evaluated in economic terms. The framework is exercised in a series of companion papers in this special issue that focus on the Northeast and Midwest regions of the United States. Use of the C-FEWS framework to simulate historical conditions facilitates research to better identify existing FEWS linkages and how they function. The framework also enables a next stage of analysis to be pursued using future scenario pathways that will vary land use, technology deployments, regulatory objectives, and climate trends and extremes. It also supports a stakeholder engagement effort to co-design scenarios of interest beyond the research domain.

Aim: The aim of this study was to investigate the change if any, in the motivations of women seeking a UTx and determine the impact of the COVID-19 pandemic. Methods: A cross-sectional survey. Results: 59% of women answered they were more motivated in achieving a pregnancy following the COVID-19 pandemic. 80% strongly agreed or agreed the pandemic had no impact on their motivation for a UTx, and 75% strongly agreed or agreed their desire for a baby strongly outweighs the risks of undergoing a UTx during a pandemic. Conclusion: Women continue to express a high level of motivation and desire for a UTx despite the risks imposed by the COVID-19 pandemic.

Abstract Background Public health concerns relating to international investment liberalization have centred on the potential for investor-state dispute settlement (ISDS)-related regulatory chill. However, the broader political and economic dimensions that shape the relationship between the international investment regime and non-communicable disease (NCD) policy development have been less well explored. This review aimed to synthesise the available evidence using a political economy approach, to understand why, how and under what conditions transnational corporations may use the international investment regime to promote NCD prevention policy non-decisions. Main body Methods: Mechanisms explaining why/how the international investment regime may be used by transnational health-harmful commodity corporations (THCCs) to encourage NCD prevention policy non-decisions, including regulatory chill, were iteratively developed. Six databases and relevant grey literature was searched, and evidence was extracted, synthesized and mapped against the various proposed explanatory mechanisms. Findings: Eighty-nine sources were included. THCCs may be incentivised to use the ISDS mechanism since the costs may be outweighed by the benefits of even just delaying regulatory adoption, particularly since the chilling effect tends to ripple out across jurisdictions. Drivers of regulatory chill may include ambiguity in treaty terms, inconsistency in arbitral rulings, potential arbitrator bias and the high cost of arbitration. Evidence indicates ISDS can delay policy adoption both within the country directly involved but also in other jurisdictions. Additionally, governments are adopting standard assessments of public health regulatory proposals for trade and ISDS risk. Various economic, political and industry-related factors likely interact to increase (or decrease) the ultimate risk of regulatory chill. Some evidence indicates that THCCs take advantage of governments’ prioritization of foreign investment over NCD prevention objectives to influence the NCD prevention regulatory environment. Conclusions While ISDS-related regulatory chill is a real risk under certain conditions, international investment-related NCD prevention policy non-decisions driven by broader political economy dynamics may well be more widespread and impactful on NCD regulatory environments. There is therefore a clear need to expand the research agenda on investment liberalization and NCD policy beyond regulatory chill and engage with theories and approaches from international relations and political science, including political economy and power analyses.

The concept of food and nutrition policy has broadened from simply being an aspect of health policy, to policy interventions from across a wide range of sectors, but still with potentially important impact on nutritional outcomes. This wider and more complex conceptualisation involves policy with multiple objectives and stakeholder influences. Thus, it becomes particularly important to understand the dynamics of these policy processes, including policy design and implementation. To add to this literature, we apply the Kaleidoscope Model for understanding policy change in developing country contexts to the case-study of an agricultural input subsidy (AIS) programme in Malawi, the Farm Input Subsidy Programme (FISP), exploring the dynamics of the FISP policy process including nutritional impact. Over a three-month period between 2017 and 2019 we conducted in-depth interviews with key stakeholders at national and district levels, and focus groups with people from rural districts in Malawi. We also undertook a review of literature relating to the political economy of the FISP. We analysed the data thematically, as per the domains of the Kaleidoscope Model. The analysis across the FISP policy process including policy design and implementation highlights how stakeholders' ideas, interests and influence have shaped the evolution of FISP policy including constraints to policy improvement-and the nutritional impacts of this. This approach extends the literature on the tensions, contradictions and challenges in food and nutrition policy by examining the reasons that these occur in Malawi with the FISP. We also add to the political science and policy analysis literature on policy implementation, extending the concept of veto players to include those targeted by the policy. The findings are important for consideration by policymakers and other stakeholders seeking to address malnutrition in rural, food-insecure populations in Malawi and other low-income settings.

Um pequeno grupo de editores de revistas da área médica reuniu-se informalmente em Vancouver, Colúmbia Britânica, em 1978, para estabelecer diretrizes para o formato dos originais submetidos a suas revistas. Esse grupo ficou conhecido como o Grupo de Vancouver. Seus requisitos para apresentação de originais, que incluíam os formatos de referências bibliográficas desenvolvidos pela Biblioteca Nacional de Medicina (National Library of Medicine - NLM), foram publicados pela primeira vez em 1979. O Grupo de Vancouver se expandiu e evoluiu para o Comitê Internacional de Editores de Revistas Médicas (International Committee of Medical Journal Editors - ICMJE), que se reúne anualmente. Gradualmente, este comitê vem ampliando seus alvos de atenção. O comitê produziu quatro edições prévias dos requisitos uniformes. Ao longo dos anos, surgiram questões que vão além da preparação dos originais. Algumas delas são tratadas agora nos requisitos uniformes; outras são contempladas em pareceres separados. Cada parecer foi publicado em uma revista científica; todos estão reproduzidos no final deste artigo.

The release of fine particles during mechanical landfill mining (LFM) operations is a potential environmental pollution and human health risk. Previous studies demonstrate that a significant proportion (40–80% wt) of the content of fine soil-like materials within the size range 1, indicating the extent of pollution within the study area. The hazard quotient values indicated high exposure-related risks for Pb (16.95), Zn (3.56), Cd (1.47), and As (1.46) for allotment land use and As (1.96) for residential land use. The cancer-related risk values were higher than the acceptable range of 1.0 × 10−6 to 1.0 × 10−4. The cancer risk factor indicated that Cr and As were the major human health risk hazards.

Abstract Background Trade and health scholars have raised concern that international trade and particularly investment disputes may be used by transnational health harmful commodity corporations (THCCs) to effectively generate public health regulatory chill. The purpose of this study was to contribute to the limited evidence base of trade or investment dispute-related regulatory chill using a case study of nutrition and alcohol policy in South Africa. Methods We conducted 35 semi-structured interviews with 36 key stakeholders involved in nutrition, alcohol and/or trade/investment policymaking in South Africa. Interview transcripts were analyzed using thematic analysis. We used Schram et al’s theory on three forms of regulatory chill (anticipatory, response and precedential) to guide the analysis. We report evidence on each form of regulatory chill as well as specific contextual factors that may influence the risk of regulatory chill. Results Trade obligations were found to generate a significantly greater anticipatory-type chilling effect on nutrition and alcohol regulation than South Africa’s investment treaty obligations. Response chill was reported to have occurred in relation to South Africa’s proposed tobacco plain packaging regulation while awaiting the outcome of both Australia’s investor-state and WTO state-state disputes. No cases were reported of THCCs threatening an investor-state dispute over nutrition or food regulations, but there were reported cases of THCCs using arguments related to South Africa’s trade obligations to oppose policy action in these areas. No evidence of nutrition or alcohol policy precedential chill were identified. Factors affecting the risk of policy chill include legitimacy and perceived bias of the dispute system, costs involved in pursuing a regulation/defending a dispute and capacity to pay, social acceptability of the industry, a product’s perceived risk to health and confidence in a successful dispute outcome e.g. through cross-border policy learning. Conclusions Our findings indicate that currently, South Africa’s trade obligations have a more prominent role in inhibiting nutrition and alcohol action than investment treaty-related concerns. However, given the potential for wider use of the ISDS mechanism by THCCs in the future, strategies to protect public health policy space in the context of both international trade and investment treaty and dispute settlement contexts remain important.

La publicación de este artículo es una iniciativa organizada por la Alianza Global por el Clima y la Salud (GCHA, por sus siglas en inglés) a través de la Alianza de Salud del Reino Unido sobre el Cambio Climático (UKHACC, por sus siglas en inglés) y los miembros del Grupo de Trabajo Latinoamericano sobre Cambio Climático y Salud. La convocatoria tiene un doble objetivo: que los líderes mundiales acuerden los cambios necesarios para mantener el aumento de la temperatura global por debajo de 1,5°C y que los profesionales de la salud adquieran una mayor relevancia en el debate global sobre la crisis climática y la pérdida de la biodiversidad. La convocatoria se desarrolla en el contexto de la próxima celebración de la Asamblea General de Naciones Unidas que se iniciará el 14 de septiembre de 2021, así como también de la celebración de la conferencia climática COP26 que este año se realizará en Glasgow. Este artículo, cuya autoría pertenece principalmente a editores de 18 prestigiosas revistas científicas ampliamente representativas de los continentes y disciplinas de la salud del mundo, ya ha sido publicada simultáneamente en más de 200 revistas científicas internacionales (https://www.bmj.com/content/full-list-authors-and-signatories-climate-emergency-editorial-september-2021). En esta ocasión, la Revista Argentina de Salud Pública se suma a esta iniciativa conjunta a través de la publicación del artículo en español, con el fin de promover su difusión en los países de la Región. El editorial expresa también la necesidad de restablecer la diversidad biológica y proteger la salud, y de que los países de altos ingresos hagan mayores recortes en sus emisiones de carbono y transfieran fondos a los países de ingresos bajos y medianos. Además, exhorta a la intervención de los gobiernos en el rediseño de los sistemas de transporte, las ciudades, la producción y distribución de alimentos, los mercados para las inversiones financieras, los sistemas de salud, entre otros aspectos, lo que redundaría en amplios beneficios para la salud.

BackgroundTissue factor (TF) generates proteases that can signal through PAR-1 and PAR-2. We have previously demonstrated PAR-1 signalling primes innate myeloid cells to be exquisitely sensitive to interferon-gamma (IFNγ). In this work we explored how TF mediated PAR-2 signalling modulated responsiveness to IFNγ and investigated the interplay between PAR-1/-2 signalling on macrophages.MethodologyWe characterised how TF through PAR-2 influenced IFNγ sensitivity in vitro using PCR and flow cytometry. and how it influenced oxazolone-induced delayed type hypersensitivity (DTH) responses in vivo. We investigated how basal signalling through PAR-2 influenced PAR-1 signalling using a combination of TF-inhibitors and PAR-1 &-2 agonists and antagonists. Finally, we investigated whether this system could be targeted therapeutically using 3-mercaptopropionyl-F-Cha-Cha-RKPNDK (3-MP), which has actions on both PAR-1 and -2.ResultsTF delivered a basal signal through PAR-2 that upregulated SOCS3 expression and blunted M1 polarisation after IFNγ stimulation, opposing the priming achieved by signalling through PAR-1. PAR-1 and -2 agonists or antagonists could be used in combination to modify this basal signal in vitro and in vivo. 3-MP, by virtue of its PAR-2 agonist properties was superior to agents with only PAR-1 antagonist properties at reducing M1 polarisation induced by IFNγ and suppressing DTH. Tethering a myristoyl electrostatic switch almost completely abolished the DTH response.ConclusionsTF-mediated signalling through PARs-1 and -2 act in a homeostatic way to determine how myeloid cells respond to IFNγ. 3-MP, an agent that simultaneously inhibits PAR-1 whilst delivering a PAR-2 signal, can almost completely abolish immune responses dependent on M1 polarisation, particularly if potency is enhanced by targeting to cell membranes; this has potential therapeutic potential in multiple diseases.