Estimating the impact of randomised control trial results on clinical practice: results from a survey and modelling study of androgen deprivation therapy plus radiotherapy for locally advanced prostate cancer

Background Recent trials have shown that the addition of external beam radiotherapy (EBRT) to androgen deprivation therapy (ADT) improves survival among men with locally advanced prostate cancer. Objective To examine the potential impact of these trials on changes in clinical practice and life-years saved. Design, setting, and participants A model was developed to examine the impact of changes in clinical practice in the UK. A survey of clinicians who treat men with prostate cancer in the UK and Canada was performed. Measurements Outcomes of interest were the proportion of patients treated with different approaches and the predicted number of life-years saved due to changes in clinical practice. Survey data were cross-tabulated and Pearson's χ2 tests were applied. Results and limitations The survey was completed by 193 clinicians (105 from the UK, 80 from Canada), of whom 70% were clinical/radiation oncologists, 8% were medical oncologists, and 15% were urologists. UK respondents were more likely to report a change in practice in response to the results (44% UK vs 21% Canada). Canadians were more likely to have already been using ADT plus radiotherapy (77% Canada vs 56% UK). The increase in the proportion of patients in the UK treated with ADT + EBRT could result in around 3730–5177 extra life-years at 15 yr from a cohort of 7930 men diagnosed in a single calendar year, compared to if all had been treated with ADT alone. Conclusions Trial findings have changed clinical practice, meaning that men with locally advanced prostate cancer are likely to survive longer. Patient summary Doctors in the UK have changed practice in response to evidence on the superiority of hormone therapy plus radiotherapy to hormone therapy alone. These changes will improve the survival of men with locally advanced prostate cancer. Further reductions in the use of hormone therapy alone could further improve survival

A qualitative study exploring the social and environmental context of recently acquired HIV infection among men who have sex with men in South-East England.

OBJECTIVES: A key UK public health priority is to reduce HIV incidence among gay and other men who have sex with men (MSM). This study aimed to explore the social and environmental context in which new HIV infections occurred among MSM in London and Brighton in 2015. DESIGN: A qualitative descriptive study, comprising in-depth interviews, was carried out as a substudy to the UK Register of HIV Seroconverters cohort: an observational cohort of individuals whose date of HIV seroconversion was well estimated. An inductive thematic analysis was conducted in NVivo, guided by a socio-ecological framework. SETTING: Participants were recruited from six HIV clinics in London and Brighton. Fieldwork was conducted between January and April 2015. PARTICIPANTS: All MSM eligible for the UK Register Seroconverter cohort (an HIV-positive antibody test result within 12 months of their last documented HIV-negative test or other laboratory evidence of HIV seroconversion) diagnosed within the past 12 months and aged ≥18 were eligible for the qualitative substudy. 21 MSM participated, aged 22-61 years and predominantly white. RESULTS: A complex interplay of factors, operating at different levels, influenced risk behaviours and HIV acquisition. Participants saw risk as multi-factorial, but the relative importance of factors varied for each person. Individual psycho-social factors, including personal history, recent life stressors and mental health, enhanced vulnerability towards higher risk situations, while features of the social environment, such as chemsex and social media, and prevalent community beliefs regarding treatment and HIV normalisation, encouraged risk taking. CONCLUSIONS: Recently acquired HIV infection among MSM reflects a complex web of factors operating at different levels. These findings point to the need for multi-level interventions to reduce the risk of HIV acquisition among high-risk MSM in the UK and similar settings

Verifying Real-Time Systems using Explicit-time Description Methods

Timed model checking has been extensively researched in recent years. Many new formalisms with time extensions and tools based on them have been presented. On the other hand, Explicit-Time Description Methods aim to verify real-time systems with general untimed model checkers. Lamport presented an explicit-time description method using a clock-ticking process (Tick) to simulate the passage of time together with a group of global variables for time requirements. This paper proposes a new explicit-time description method with no reliance on global variables. Instead, it uses rendezvous synchronization steps between the Tick process and each system process to simulate time. This new method achieves better modularity and facilitates usage of more complex timing constraints. The two explicit-time description methods are implemented in DIVINE, a well-known distributed-memory model checker. Preliminary experiment results show that our new method, with better modularity, is comparable to Lamport's method with respect to time and memory efficiency

Cost-effectiveness and social outcomes of a community-based treatment for podoconiosis lymphoedema in the East Gojjam zone, Ethiopia

Background Podoconiosis is a disease of the lymphatic vessels of the lower extremities that is caused by chronic exposure to irritant soils. It results in leg swelling, commonly complicated by acute dermatolymphangioadenitis (ADLA), characterised by severe pain, fever and disability. Methods We conducted cost-effectiveness and social outcome analyses of a pragmatic, randomised controlled trial of a hygiene and foot-care intervention for people with podoconiosis in the East Gojjam zone of northern Ethiopia. Participants were allocated to the immediate intervention group or the delayed intervention group (control). The 12-month intervention included training in foot hygiene, skin care, bandaging, exercises, and use of socks and shoes, and was supported by lay community assistants. The cost-effectiveness analysis was conducted using the cost of productivity loss due to acute dermatolymphangioadenitis. Household costs were not included. Health outcomes in the cost-effectiveness analysis were: the incidence of ADLA episodes, health-related quality of life captured using the Dermatology Life Quality Index (DLQI), and disability scores measured using the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0). Results The cost of the foot hygiene and lymphoedema management supplies was 529 ETB (69 I$, international dollars) per person per year. The cost of delivery of the intervention as part of the trial, including transportation, storage, training of lay community assistants and administering the intervention was 1,890 ETB (246 I$) per person. The intervention was effective in reducing the incidence of acute dermatolymphangioadenitis episodes and improving DLQI scores, while there were no significant improvements in the disability scores measured using WHODAS 2.0. In 75% of estimations, the intervention was less costly than the control. This was due to improved work productivity. Subgroup analyses based on income group showed that the intervention was cost-effective (both less costly and more effective) in reducing the number of acute dermatolymphangioadenitis episodes and improving health-related quality of life in families with monthly income <1,000 ETB (130 I$). For the subgroup with family income ≥1,000 ETB, the intervention was more effective but more costly than the control. Conclusions Whilst there is evident benefit of the intervention for all, the economic impact would be greatest for the poorest

Retrospective evaluation of the use of pembrolizumab in malignant mesothelioma in a real-world Australian population

Introduction: We investigated the efficacy and toxicity of pembrolizumab in patients with mesothelioma from a real-world Australian population. We aimed to determine clinical factors and predictive biomarkers that could help select patients who are likely to benefit from pembrolizumab. Method: Patients with mesothelioma who were treated with pembrolizumab as part of the Insurance and Care New South Wales compensation scheme were included. Clinical information was collected retrospectively. Tumor biomarkers such as programmed death-ligand 1 (PD-L1), BAP1, and CD3-positive (CD3+) tumor-infiltrating lymphocytes (TILs) were examined using archival formalin-fixed paraffin-embedded tumor samples. Results: A total of 98 patients were included with a median age of 70 years (range, 46–91 y); 92% were men; 76% had epithelioid subtype; 21% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Pembrolizumab was used as second-line or subsequent-line treatment in 94 patients and as first-line treatment in four patients. The overall response rate was 18%, and the disease control rate was 56%. The median progression-free survival (PFS) was 4.8 months (95% confidence interval: 3.6–6.2), and the median overall survival (OS) was 9.5 months (95% confidence interval: 6.6–13.7). Immune-related adverse events occurred in 27% of patients, of which nine (9%) were of grade 3 or higher. In the multivariable analysis, factors independently associated with longer PFS included baseline ECOG status of 0 (median PFS: 12 mo versus 4 mo, p < 0.01) and PD-L1 tumor proportion score of greater than or equal to 1% (median PFS: 6 mo versus 4 mo, p < 0.01). Baseline platelet count of less than or equal to 400 × 109/liter was independently associated with longer PFS and OS (median PFS: 6 mo versus 2 mo, p = 0.05; median OS: 10 mo versus 4 mo, p = 0.01), whereas lack of pretreatment dexamethasone was independently associated with OS but not PFS (median OS: 10 mo versus 3 mo, p = 0.01). The odds of response were higher for patients with baseline ECOG status of 0 (p = 0.02) and with greater than or equal to 5% CD3+ TILs in the tumor (p < 0.01). PD-L1 expression, BAP1 loss, and CD3+ TILs in the stroma were not significantly associated with the overall response rate. Conclusions: Immunotherapy is a reasonable treatment option for patients with mesothelioma. Our results are comparable to other clinical trials investigating pembrolizumab in mesothelioma in terms of response. Good performance status assessment remains the most robust predictor for patient outcomes. CD3+ TILs in the tumor may help select patients that are likely to respond to pembrolizumab, whereas factors such as PD-L1 expression, baseline platelet count, and lack of pretreatment dexamethasone may help predict survival outcomes from pembrolizumab treatment

Coal transitions—part 1: a systematic map and review of case study learnings from regional, national, and local coal phase-out experiences

A rapid coal phase-out is needed to meet the goals of the Paris Agreement, but is hindered by serious challenges ranging from vested interests to the risks of social disruption. To understand how to organize a global coal phase-out, it is crucial to go beyond cost-effective climate mitigation scenarios and learn from the experience of previous coal transitions. Despite the relevance of the topic, evidence remains fragmented throughout different research fields, and not easily accessible. To address this gap, this paper provides a systematic map and comprehensive review of the literature on historical coal transitions. We use computer-assisted systematic mapping and review methods to chart and evaluate the available evidence on historical declines in coal production and consumption. We extracted a dataset of 278 case studies from 194 publications, covering coal transitions in 44 countries and ranging from the end of the 19th century until 2021. We find a relatively recent and rapidly expanding body of literature reflecting the growing importance of an early coal phase-out in scientific and political debates. Previous evidence has primarily focused on the United Kingdom, the United States, and Germany, while other countries that experienced large coal declines, like those in Eastern Europe, are strongly underrepresented. An increasing number of studies, mostly published in the last 5 years, has been focusing on China. Most of the countries successfully reducing coal dependency have undergone both demand-side and supply-side transitions. This supports the use of policy approaches targeting both demand and supply to achieve a complete coal phase-out. From a political economy perspective, our dataset highlights that most transitions are driven by rising production costs for coal, falling prices for alternative energies, or local environmental concerns, especially regarding air pollution. The main challenges for coal-dependent regions are structural change transformations, in particular for industry and labor. Rising unemployment is the most largely documented outcome in the sample. Policymakers at multiple levels are instrumental in facilitating coal transitions. They rely mainly on regulatory instruments to foster the transitions and compensation schemes or investment plans to deal with their transformative processes. Even though many models suggest that coal phase-outs are among the low-hanging fruits on the way to climate neutrality and meeting the international climate goals, our case studies analysis highlights the intricate political economy at work that needs to be addressed through well-designed and just policies.BMBF, 01LA1826A, Ökonomie des Klimawandels - Verbundprojekt: Die politische Ökonomie eines globalen Kohleausstiegs (PEGASOS) - Teilprojekt 1: Koordination, Analyse der politischen Ökonomie vergangener KohleausstiegeBMBF, 01LA1810A, Ökonomie des Klimawandels - Verbundprojekt: Die Zukunft fossiler Energieträger im Zuge von Treibhausgasneutralität (FFF) - Teilprojekt 1: Implementierung von AusstiegspfadenBMBF, 01LN1704A, Nachwuchsgruppe Globaler Wandel: CoalExit - Die Ökonomie des Kohleausstiegs - Identifikation von Bausteinen für Rahmenpläne zukünftiger regionaler StrukturwandelBMBF, 01LG1910A, Qualitätssicherung von IPCC-AR6: Chapter Scientist für WG III, Kapitel 2 (Emissions trends and drivers

Global Spatial Risk Assessment of Sharks Under the Footprint of Fisheries

Effective ocean management and conservation of highly migratory species depends on resolving overlap between animal movements and distributions and fishing effort. Yet, this information is lacking at a global scale. Here we show, using a big-data approach combining satellite-tracked movements of pelagic sharks and global fishing fleets, that 24% of the mean monthly space used by sharks falls under the footprint of pelagic longline fisheries. Space use hotspots of commercially valuable sharks and of internationally protected species had the highest overlap with longlines (up to 76% and 64%, respectively) and were also associated with significant increases in fishing effort. We conclude that pelagic sharks have limited spatial refuge from current levels of high-seas fishing effort. Results demonstrate an urgent need for conservation and management measures at high-seas shark hotspots and highlight the potential of simultaneous satellite surveillance of megafauna and fishers as a tool for near-real time, dynamic management

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements