The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results.

Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. In our study, the PBD dimer is modified to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrates in vivo efficacy in models of HER2-positive and HER2-low cancers and is well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial.

Assessing the potential of portable X-ray fluorescence (XRF) as a rapid, onsite screening tool in the assessment of cadmium surface decontamination effectiveness.

Portable X-ray fluorescence has successfully been used to effectively evaluate occupational exposure to airborne and surface metal contaminants nondestructively. Traditional methods of assessing metal surface contamination involve the costly, time-consuming collection and laboratory analysis of wipe samples, making portable X-ray fluorescence an attractive alternative method for screening worksites by reducing delays in risk assessment decision-making. Existing research into this use of portable X-ray fluorescence has primarily been centered on the analysis of airborne and surface lead contamination. The extant literature is sparse on the use of portable X-ray fluorescence with other metals for surface contamination with respect to occupational exposure. The present study evaluated the use of portable X-ray fluorescence in the screening of cadmium surface contamination to determine if the effectiveness of decontamination measures can be ascertained by this technique. Wipe samples were collected and screened with portable X-ray fluorescence before being sent to the laboratory for definitive analysis to assess the correlation between portable X-ray fluorescence readings in percent mass with laboratory results in µg/ft2. Portable X-ray fluorescence readings demonstrated a strong linear correlation with laboratory results, as indicated by the R2 value of 0.993. Therefore, this technique may be further developed and deployed as a screening tool for wipe samples used for evaluating contamination and decontamination of metal-contaminated areas.

Economic effects for citizens and the government of a country-level tobacco endgame strategy: a modelling study.

BACKGROUND: Aotearoa-New Zealand (A/NZ) was the first country to pass a comprehensive commercial tobacco endgame strategy into law. Key components include the denicotinisation of smoked tobacco products and a major reduction in tobacco retail outlets. Understanding the potential long-term economic impacts of such measures is important for government planning. DESIGN: A tobacco policy simulation model that evaluated the health impacts of the A/NZ Smokefree Action Plan was extended to evaluate the economic effects from both government and citizen perspectives. Estimates were presented in 2021 US$, discounted at 3% per annum. RESULTS: The modelled endgame policy package generates considerable growth in income for the A/NZ population with a total cumulative gain of US$31 billion by 2050. From a government perspective, increased superannuation payments and reduced tobacco excise tax revenue result in a negative net financial position and a cumulative shortfall of US$11.5 billion by 2050. In a sensitivity analysis considering future labour force changes, the government's cumulative net position remained negative by 2050, but only by US$1.9 billion. CONCLUSIONS: A policy such as the A/NZ Smokefree Action Plan is likely to produce substantial economic benefits for citizens, and modest impacts on government finances related to reduced tobacco tax and increases in aged pensions due to increased life expectancy. Such costs can be anticipated and planned for and might be largely offset by future increases in the size of the labour force and the proportion of people 65+ years old working in the formal economy.

The total health gains and cost savings of eradicating cold housing in Australia.

BACKGROUND: Cold indoor temperature (<18 °C) is associated with hypertension-related and respiratory disease, depression, and anxiety. We estimate total health, health expenditure and income impacts of permanently lifting the temperature in living areas of the home to 18 °C in cold homes in South-eastern Australia (N = 17 million). METHODS: A proportional multistate lifetable model was used to estimate health adjusted life years (HALYs), health expenditure and income earnings, over the remainder of the lifespan of the population alive in 2021 (3% discount rate). Multiple data were integrated including the prevalence of cold housing (5.87%; mean temperature 15 °C), the effect of temperature to hypertension-related, respiratory disease, depression and anxiety. FINDINGS: Eradicating cold housing was predicted to lead to 89,600 (95% UI 47,700 to 177,000) lifetime HALYs gained over the population's remaining lifespan, nearly half of which occurred from 2021 to 2040. Respiratory disease (32.4%) and mental illness (60.6%) made large contributions to HALYs gained, but also had large uncertainty (95% UI 30.0%-42.9% and 45.1%-64.6%, respectively) due to uncertain estimates of their magnitude of causal association with cold housing. Health gains per capita were 6.1 times greater (95% UI 4.7 to 8.1) among the most compared to least deprived quintile. From 2021 to 2040, health expenditure decreased by AUD$0.87 billion (0.35-1.98) and income earnings increased by AUD$4.35 billion (1.89-9.81). INTERPRETATION: Eliminating cold housing would lead to substantial health gains, reductions in health inequalities, savings in health expenditure, and productivity gains. Next steps require research to reduce uncertainty about the magnitude of causal associations of cold with mental and respiratory health.

Tobacco endgame intervention impacts on health gains and Maori:non-Maori health inequity: a simulation study of the Aotearoa/New Zealand Tobacco Action Plan.

BACKGROUND: The Aotearoa/New Zealand Government is aiming to end the tobacco epidemic and markedly reduce Maori:non-Maori health inequalities by legislating: (1) denicotinisation of retail tobacco, (2) 95% reduction in retail outlets and (c) a tobacco free-generation whereby people born after 2005 are unable to legally purchase tobacco. This paper estimates future smoking prevalence, mortality inequality and health-adjusted life year (HALY) impacts of these strategies. METHODS: We used a Markov model to estimate future yearly smoking and vaping prevalence, linked to a proportional multistate life table model to estimate future mortality and HALYs. RESULTS: The combined package of strategies (plus media promotion) reduced adult smoking prevalence from 31.8% in 2022 to 7.3% in 2025 for Maori, and 11.8% to 2.7% for non-Maori. The 5% smoking prevalence target was forecast to be achieved in 2026 and 2027 for Maori males and females, respectively.The HALY gains for the combined package over the population's remaining lifespan were estimated to be 594 000 (95% uncertainty interval (UI): 443 000 to 738 000; 3% discount rate). Denicotinisation alone achieved 97% of these HALYs, the retail strategy 19% and tobacco-free generation 12%.By 2040, the combined package was forcat to reduce the gap in Maori:non-Maori all-cause mortality rates for people 45+ years old by 22.9% (95% UI: 19.9% to 26.2%) for females and 9.6% (8.4% to 11.0%) for males. CONCLUSION: A tobacco endgame strategy, especially denicotinisation, could deliver large health benefits and dramatically reduce health inequities between Maori and non-Maori in Aotearoa/New Zealand.

Epidemiologic and economic modelling of optimal COVID-19 policy: public health and social measures, masks and vaccines in Victoria, Australia.

Background: Identifying optimal COVID-19 policies is challenging. For Victoria, Australia (6.6 million people), we evaluated 104 policy packages (two levels of stringency of public health and social measures [PHSMs], by two levels each of mask-wearing and respirator provision during large outbreaks, by 13 vaccination schedules) for nine future SARS-CoV-2 variant scenarios. Methods: We used an agent-based model to estimate morbidity, mortality, and costs over 12 months from October 2022 for each scenario. The 104 policies (each averaged over the nine future variant scenarios) were ranked based on four evenly weighted criteria: cost-effectiveness from (a) health system only and (b) health system plus GDP perspectives, (c) deaths and (d) days exceeding hospital occupancy thresholds. Findings: More compared to less stringent PHSMs reduced cumulative infections, hospitalisations and deaths but also increased time in stage ≥3 PHSMs. Any further vaccination from October 2022 decreased hospitalisations and deaths by 12% and 27% respectively compared to no further vaccination and was usually a cost-saving intervention from a health expenditure plus GDP perspective. High versus low vaccine coverage decreased deaths by 15% and reduced time in stage ≥3 PHSMs by 20%. The modelled mask policies had modest impacts on morbidity, mortality, and health system pressure. The highest-ranking policy combination was more stringent PHSMs, two further vaccine doses (an Omicron-targeted vaccine followed by a multivalent vaccine) for ≥30-year-olds with high uptake, and promotion of increased mask wearing (but not Government provision of respirators). Interpretation: Ongoing vaccination and PHSMs continue to be key components of the COVID-19 pandemic response. Integrated epidemiologic and economic modelling, as exemplified in this paper, can be rapidly updated and used in pandemic decision making. Funding: Anonymous donation, University of Melbourne funding.

Surgeon preference for treatment allocation in older people facing major gastrointestinal surgery: an application of the discrete choice experiment methodology.

AIM: Variation in major gastrointestinal surgery rates in the older population suggests heterogeneity in surgical management. A higher prevalence of comorbidities, frailty and cognitive impairments in the older population may account for some variation. The aim of this study was to determine surgeon preference for major surgery versus conservative management in hypothetical patient scenarios based on key attributes. METHOD: A survey was designed according to the discrete choice methodology guided by a separate qualitative study. Questions were designed to test for associations between key attributes (age, comorbidity, urgency of presentation, pathology, functional and cognitive status) and treatment preference for major gastrointestinal surgery versus conservative management. The survey consisting of 18 hypothetical scenarios was disseminated electronically to UK gastrointestinal surgeons. Binomial logistic regression was used to identify associations between the attributes and treatment preference. RESULTS: In total, 103 responses were received after 256 visits to the questionnaire site (response rate 40.2%). Participants answered 1847 out of the 1854 scenarios (99.6%). There was a preference for major surgery in 1112/1847 (60.2%) of all scenarios. Severe comorbidities (OR 0.001, 95% CI 0.000-0.030; P = 0.000), severe cognitive impairment (OR 0.001, 95% CI 0.000-0.033; P = 0.000) and age 85 years and above (OR 0.028, 95% CI 0.005-0.168; P = 0.000) were all significant in the decision not to offer major gastrointestinal surgery. CONCLUSION: This study has demonstrated variation in surgical treatment preference according to key attributes in hypothetical scenarios. The development of fitness-stratified guidelines may help to reduce variation in surgical practice in the older population.

A framework for considering the utility of models when facing tough decisions in public health: a guideline for policy-makers.

The COVID-19 pandemic has brought the combined disciplines of public health, infectious disease and policy modelling squarely into the spotlight. Never before have decisions regarding public health measures and their impacts been such a topic of international deliberation, from the level of individuals and communities through to global leaders. Nor have models-developed at rapid pace and often in the absence of complete information-ever been so central to the decision-making process. However, after nearly 3 years of experience with modelling, policy-makers need to be more confident about which models will be most helpful to support them when taking public health decisions, and modellers need to better understand the factors that will lead to successful model adoption and utilization. We present a three-stage framework for achieving these ends.

A log-odds system for waning and boosting of COVID-19 vaccine effectiveness.

Immunity to SARS-CoV-2 following vaccination wanes over time in a non-linear fashion, making modelling of likely population impacts of COVID-19 policy options challenging. We observed that it was possible to mathematize non-linear waning of vaccine effectiveness (VE) on the percentage scale as linear waning on the log-odds scale, and developed a random effects logistic regression equation based on UK Health Security Agency data to model VE against Omicron following two and three doses of a COVID-19 vaccine. VE on the odds scale reduced by 47% per month for symptomatic infection after two vaccine doses, lessening to 35% per month for hospitalisation. Waning on the odds scale after triple dose vaccines was 35% per month for symptomatic disease and 19% for hospitalisation. This log-odds system for estimating waning and boosting of COVID-19 VE provides a simple solution that may be used to parametrize SARS-CoV-2 immunity over time parsimoniously in epidemiological models.

The individual, place, and wellbeing - a network analysis.

BACKGROUND: Previous research has examined individual-level and place characteristics as correlates of subjective wellbeing, with many studies concluding that individual factors (e.g. health, finances) are more strongly related to wellbeing. However, this 'dualistic' approach has been challenged, with some arguing that it is impossible to disentangle the effects of the two domains, and that wellbeing should be considered as part of a network of mutually reinforcing relationships between individual, community and place characteristics. We used network analysis to explore these complex associations. METHODS: Data were from a large sample of adults from a socioeconomically disadvantaged region of the United Kingdom (N = 4319). Wellbeing was assessed using the 7-item version of the Warwick-Edinburgh Mental Wellbeing Scale (SWEMWBS). Mixed graphical networks were estimated including wellbeing, place and individual-characteristic variables as nodes. RESULTS: We found a densely connected network in which wellbeing was associated, both directly and indirectly, with all of the individual, community and place characteristics assessed. Wellbeing was most strongly connected with individual characteristics, in particular financial difficulty and subjective physical health. However, controlling for all other variables in the network model, wellbeing was positively associated with local greenspace usage, civic agency, and neighbourhood cohesion, and negatively associated with housing disrepair. Greater specificity in these associations was observed when the wellbeing construct was broken down into its constituent parts. CONCLUSIONS: These findings highlight the complex relationships that exist between individual, community and place characteristics in the context of subjective wellbeing, and that all domains need to be considered when developing population-level strategies to improve wellbeing. Further consideration needs to be given to how this might happen in practice, for example through a combination of consistent use of community engagement methodologies alongside Health in All Policy (HiAP) approaches.

Healthcare professional preferences in the health and fitness assessment and optimization of older patients facing colorectal cancer surgery.

AIM: There are few age- and fitness-specific, evidence-based guidelines for colorectal cancer surgery. The uptake of different assessment and optimization strategies is variable. The aim of this study was to explore healthcare professional opinion about these issues using a mixed methods design. METHODS: Semi-structured qualitative interviews were undertaken with healthcare professionals from a single UK region involved in the treatment, assessment and optimization of colorectal surgery patients. Interviews were analysed using the framework approach. An online questionnaire survey was subsequently designed and disseminated to UK surgeons to quantitatively assess the importance of interview themes. Descriptive statistics were used to analyse questionnaire data. RESULTS: Thirty-seven healthcare professionals out of 42 approached (response rate 88%) were interviewed across five hospitals in the south Yorkshire region. Three broad themes were developed: attitudes towards treatment of the older patient, methods of assessment of suitability and optimization strategies. The questionnaire was completed by 103 out of an estimated 256 surgeons (estimated response rate 40.2%). There was a difference in opinion regarding the role of major surgery in older patients, particularly when there is coexisting dementia. Assessment was not standardized. Access to optimization strategies was limited, particularly in the emergency setting. CONCLUSION: There is wide variation in the process of assessment and provision of optimization strategies in UK practice. Lack of evidence-based guidelines, cost and time constraints restrict the development of services and pathways. Differences in opinion between surgeons towards patients with frailty or dementia may account for some of the variation in colorectal cancer outcomes.

EU-UK criminal justice and security cooperation after Brexit: A perspective.

The prospect of significantly reduced and potentially unstable EU-UK criminal justice cooperation under the 2020 Trade and Cooperation Agreement (TCA) unless criminal justice professionals and academics can help to shape its future development.Key wordsPost-Brexit readjustment process; The EU-UK Trade and Cooperation Agreement (TCA); EU-UK criminal justice cooperation.

A universal power law for modelling the growth and form of teeth, claws, horns, thorns, beaks, and shells.

BACKGROUND: A major goal of evolutionary developmental biology is to discover general models and mechanisms that create the phenotypes of organisms. However, universal models of such fundamental growth and form are rare, presumably due to the limited number of physical laws and biological processes that influence growth. One such model is the logarithmic spiral, which has been purported to explain the growth of biological structures such as teeth, claws, horns, and beaks. However, the logarithmic spiral only describes the path of the structure through space, and cannot generate these shapes. RESULTS: Here we show a new universal model based on a power law between the radius of the structure and its length, which generates a shape called a 'power cone'. We describe the underlying 'power cascade' model that explains the extreme diversity of tooth shapes in vertebrates, including humans, mammoths, sabre-toothed cats, tyrannosaurs and giant megalodon sharks. This model can be used to predict the age of mammals with ever-growing teeth, including elephants and rodents. We view this as the third general model of tooth development, along with the patterning cascade model for cusp number and spacing, and the inhibitory cascade model that predicts relative tooth size. Beyond the dentition, this new model also describes the growth of claws, horns, antlers and beaks of vertebrates, as well as the fangs and shells of invertebrates, and thorns and prickles of plants. CONCLUSIONS: The power cone is generated when the radial power growth rate is unequal to the length power growth rate. The power cascade model operates independently of the logarithmic spiral and is present throughout diverse biological systems. The power cascade provides a mechanistic basis for the generation of these pointed structures across the tree of life.

Protocol for a multi-centre observational and mixed methods pilot study to identify factors predictive of poor functional recovery after major gastrointestinal surgery and strategies to enhance uptake of perioperative optimization: Optimizing the care and treatment pathways for older patients facing major gastrointestinal surgery (OCTAGON).

INTRODUCTION: National datasets report large variations in outcomes from older people (≥65 years) between different UK surgical units. This implies that not all patients receive the same level of care or access to resources, such as rehabilitation or allied health professional input. This might impact functional decline. AIMS: Our aim is to evaluate the baseline status of older patients facing major gastrointestinal surgery and the impact of variation in perioperative assessment and provision of perioperative support on functional outcomes. Patients' experiences and views of assessment and optimization will be explored via integrated qualitative semi-structured interviews. METHODS AND ANALYSIS: This multi-centre, pilot cohort study will include patients ≥65 years presenting via both elective and emergency pathways at three to five South Yorkshire NHS hospitals (Clinical Trials registration NCT04545125). The primary outcome is functional recovery measured using the World Health Organization Disability Assessment Schedule 2.0 at 6 weeks post-operation. Secondary outcomes include feasibility, quality of life, length of stay and complication rate. An opportunistic sample size of 120 has been estimated and will inform the design of a future, adequately powered study. For the qualitative study, 20-30 semi-structured patient interviews will be undertaken with patients from the cohort study to explore experiences of assessment and optimization. Interviews will be digitally recorded, transcribed verbatim and analysed according to the framework approach. ETHICS AND DISSEMINATION: This study has been approved by the National Health Service Research Ethics Committee and is registered centrally with Health Research Authority. It has been adopted by the National Institute for Health Research Portfolio scheme. Dissemination will be via international and national surgical and geriatric conferences.

Do people living in disadvantaged circumstances receive different mental health treatments than those from less disadvantaged backgrounds?

BACKGROUND: Socio-economic status (SES) has been linked to treatment outcomes for mental health problems, whilst little to no literature has explored the effects of SES on access to both medication and psychological therapy. The aim of this study was to explore whether access to mental health treatments differed by SES. METHODS: The North West Coast Household Health Survey (HHS) collected data from residents aged 18+ from across 20 disadvantaged and 8 less disadvantaged neighbourhoods in 2015, and from 20 disadvantaged neighbourhoods in 2018. Logistic regression was used to explore the effects of SES on access to treatment (medication, psychological therapy) for people who had experienced mental health problems in the past 12 months. RESULTS: Of 6860 participants, 2932 reported experiencing mental health problems in the past 12 months. People from more disadvantaged backgrounds experienced greater rates of anxiety and depression. Anti-depressant and anti-psychotic medication treatment was significantly more common in residents with lower SES, as well as counselling. Regression analysis showed that residents from more disadvantaged neighbourhoods who reported mental distress were more likely to receive medication. CONCLUSIONS: This appears to be the first study showing higher levels of treatment with medication and psychological therapy in people from disadvantaged backgrounds. Future research needs to address the underlying factors associated with increased mental health treatment uptake in people from lower socio-economic backgrounds.

The impact of Brexit on the future of UK forensic science and technology.

This article seeks to assess the prospects of UK forensic science and technology in a post-Brexit world by analysing four interlocking issues: Brexit itself, the evolution of national criminal justice organisational and funding priorities, the increasing interrelationship of science and technology in the forensic domain and the relatively disadvantaged place of forensic science and technology within the contemporary 'scientific state' paradigm. The results are generally pessimistic for the likely future of forensic science. This conclusion is reinforced by scepticism about the wisdom of proceeding with Brexit. The article is structured to identify the potential implications of British political decisions on its national forensic science capabilities and capacity. Some aspects of the analysis are likely to have a wider resonance for international discourse about the future sustainability of forensic science and technology, however, particularly the interface between the globalisation of science and technology with justice.

Charge Density in Enzyme Active Site as a Descriptor of Electrostatic Preorganization.

Large protein macromolecules in enzymatic catalysis have been shown to exert a specific electric field that reduces the reorganization energy upon barrier crossing and thus reduces the reaction free energy barrier. In this work we suggest that the charge density in the active site of an enzyme investigated using formalisms embodied by the quantum theory of atoms in molecules (QTAIM) provides a sensitive and quantum mechanically rigorous probe of electrostatic preorganization. We focus on the active site of ketosteroid isomerase, a well-studied enzyme for which electrostatic preorganization has been modeled theoretically and studied experimentally. We study the charge density in the active site and the reaction mechanism in the presence of small external electric fields of various directions and magnitudes. We show that the geometry of the full charge density is a sensitive reporter on the external field experienced by the active site. Changes are observed in the relative positions of critical points and amount of charge at critical points as a function of the field. At the same time, a subset of these features correlates linearly with the barrier of the first reaction step in catalysis. Small changes in the barrier, within 1-2 kcal/mol, are reflected in the charge density, suggesting the existence of a field - reactant state charge density - reaction barrier correlation. Hence, QTAIM can be used for the analysis of electric field in enzyme active sites, and further investigations and exploitations of the found correlations may prove useful in enzyme design where preorganization is optimized.