A Policy Framework for Leveraging Generative AI to Address Enduring Challenges in Clinical Trials

Can artificial intelligence improve clinical trial design? Despite their importance in medicine, over 40% of trials involve flawed protocols. We introduce and propose the development of application-specific language models (ASLMs) for clinical trial design across three phases: ASLM development by regulatory agencies, customization by Health Technology Assessment bodies, and deployment to stakeholders. This strategy could enhance trial efficiency, inclusivity, and safety, leading to more representative, cost-effective clinical trials.</p

Resisting or negotiating wind energy dispossession:class and caste in changing rural Kutch

This article analyses the political reactions of Kutch district villagers, in Western India, facing wind turbine projects as a complex political terrain of resistance shaped by the materiality of dispossession and local configurations of agrarian power. I argue that the terrain of resistance got diluted and dispersed towards individual actions aimed at negotiating dispossession through caste capital, while other power and caste scenarios have rendered collective resistance movements possible, up to a certain point. Deploying a class-caste analysis of land conflicts in rural India, this reveals continuity not only with traditional agrarian struggles but also with caste politics and excluding forms of mobilisation

Practice recommendations for culturally sensitive communication at the end of life in intensive care:A modified eDelphi study

BackgroundClinicians need specific knowledge and skills to effectively communicate with patients and their family when a patient is dying in the ICU. End-of-life communication is compounded by language differences and diverse cultural and religious beliefs.AimThe aim was to develop and evaluate practice recommendations for culturally sensitive communication at the end of life.MethodModified two-round eDelphi study. An Australian national sample of 58 expert ICU clinicians of nursing and medical backgrounds participated in an online survey to rate the relevance of 13 practice recommendations. Ten clinicians participated in a subsequent expert panel interview to provide face validity and comprehensive details about the practical context of the recommendations. Survey data were analysed using descriptive statistics, interview data using deductive content analysis.ResultsAll 13 practice recommendations achieved item content validity index (I-CVI) above 0.8, and scale content validity index (S-CVI) of 0.95, indicating sufficient consensus. Recommendations prioritising use of professional interpreters and nurse involvement in family meetings achieved near perfect agreement amongst participants. Recommendations to facilitate family in undertaking cultural, spiritual and religious rituals and customs, advocate for family participation in treatment limitation discussions, and clinician access to professional development opportunities about culturally sensitive communication also achieved high level consensus.ConclusionThese practice recommendations provide guidance for ICU clinicians in their communication with patients and families from culturally diverse backgrounds.Background: Clinicians need specific knowledge and skills to effectively communicate with patients and their family when a patient is dying in the ICU. End-of-life communication is compounded by language differences and diverse cultural and religious beliefs. Aim: The aim was to develop and evaluate practice recommendations for culturally sensitive communication at the end of life. Method: Modified two-round eDelphi study. An Australian national sample of 58 expert ICU clinicians of nursing and medical backgrounds participated in an online survey to rate the relevance of 13 practice recommendations. Ten clinicians participated in a subsequent expert panel interview to provide face validity and comprehensive details about the practical context of the recommendations. Survey data were analysed using descriptive statistics, interview data using deductive content analysis. Results: All 13 practice recommendations achieved item content validity index (I-CVI) above 0.8, and scale content validity index (S-CVI) of 0.95, indicating sufficient consensus. Recommendations prioritising use of professional interpreters and nurse involvement in family meetings achieved near perfect agreement amongst participants. Recommendations to facilitate family in undertaking cultural, spiritual and religious rituals and customs, advocate for family participation in treatment limitation discussions, and clinician access to professional development opportunities about culturally sensitive communication also achieved high level consensus. Conclusion: These practice recommendations provide guidance for ICU clinicians in their communication with patients and families from culturally diverse backgrounds. Implications for clinical practice: Clinicians want practice recommendations that are understandable and broadly applicable across diverse ICU contexts. The high consensus scores confirm these practice recommendations are relevant and feasible to clinicians who provide end-of-life care for patients and their family members. The recommendations also provide clear guidance for ICU leaders, managers and organisational policy makers.</p

Mechanisms of RNA Polymerase II Termination at the 3′-End of Genes

RNA polymerase II (RNAPII) is responsible for the synthesis of a diverse set of RNA molecules, including protein-coding messenger RNAs (mRNAs) and many short non-coding RNAs (ncRNAs). For this purpose, RNAPII relies on a multitude of factors that regulate the transcription cycle, from initiation and promoter-proximal pausing, through elongation and finally termination. RNAPII transcription termination at the end of genes ensures the release of RNAPII from the DNA template and its efficient recycling for further rounds of transcription. Termination of RNAPII is tightly coupled to 3′-end mRNA processing, which constitutes an important trigger for the subsequent transcription termination event. In this review, we discuss the current understanding of RNAPII termination mechanisms, focusing on ‘canonical’ termination at the 3′-end of genes. We also integrate the allosteric and ‘torpedo’ models into a unified model of termination, and describe the different termination factors that have been identified to date, paying special attention to the human factors and their mechanism of action at the molecular level. Indeed, in recent years the development of novel approaches in structural biology, biochemistry and cell biology have together led to a more detailed comprehension of the different mechanisms of RNAPII termination, and a better understanding of their importance in regulating gene expression, especially under cellular stress and pathological situations.RNA polymerase II (RNAPII) is responsible for the synthesis of a diverse set of RNA molecules, including protein-coding messenger RNAs (mRNAs) and many short non-coding RNAs (ncRNAs). For this purpose, RNAPII relies on a multitude of factors that regulate the transcription cycle, from initiation and promoter-proximal pausing, through elongation and finally termination. RNAPII transcription termination at the end of genes ensures the release of RNAPII from the DNA template and its efficient recycling for further rounds of transcription. Termination of RNAPII is tightly coupled to 3′-end mRNA processing, which constitutes an important trigger for the subsequent transcription termination event. In this review, we discuss the current understanding of RNAPII termination mechanisms, focusing on ‘canonical’ termination at the 3′-end of genes. We also integrate the allosteric and ‘torpedo’ models into a unified model of termination, and describe the different termination factors that have been identified to date, paying special attention to the human factors and their mechanism of action at the molecular level. Indeed, in recent years the development of novel approaches in structural biology, biochemistry and cell biology have together led to a more detailed comprehension of the different mechanisms of RNAPII termination, and a better understanding of their importance in regulating gene expression, especially under cellular stress and pathological situations.</p

Filopodia:integrating cellular functions with theoretical models

Filopodia, widely distributed on cell surfaces, are distinguished by their dynamic extensions, playing pivotal roles in a myriad of biological processes. Their functions span from mechanosensing and guidance to cell–cell communication during cellular organization in the early embryo. Filopodia have significant roles in pathogenic processes, such as cancer invasion and viral dissemination. Molecular mapping of the filopodome has revealed generic components essential for filopodia functions. In parallel, recent insights into biophysical mechanisms governing filopodia dynamics have provided the foundation for broader investigations of filopodia's biological functions. We highlight recent discoveries of engagement of filopodia in various stages of development and pathogenesis and present an overview of intricate molecular and physical features of these cellular structures across a spectrum of cellular activities.</p

Patterns and Drivers of Pollen Temperature Tolerance

Pollen, a pivotal stage in the plant reproductive cycle, is highly sensitive to temperature fluctuations, impacting seed quality and quantity. While the importance of understanding pollen temperature limits (Tmin, Topt, Tmax – collectively PTLs) is recognized, a comprehensive synthesis of underlying drivers is lacking. Here, we examined PTLs, correlating them with vegetative tissue thermotolerance and assessing variability at the intra- and interspecific levels across 191 species with contrasting phylogeny, cultivation history, growth form and ecology. At the species level, the PTLs range from 9.0 to 42.4°C, with considerable differences among individual species. Vegetative tissue showed greater tolerance to both low and high temperatures than pollen. A significant, though weak, correlation was observed between PTLs and leaf temperature tolerance. Pollen heat tolerance was independent of that in leaves and stems. The greatest intraspecific variability was observed in pollen cold tolerance (Tmin), followed by Topt and Tmax. Phylogenetic analysis revealed family-level conservation in all three pollen temperature tolerance measures. Climate emerged as a significant PTL driver of pollen cold tolerance, with species from colder and stable climates exhibiting enhanced cold tolerance. Cultivated and wild species did not differ in their pollen temperature tolerances. Herbaceous plants showed higher tolerance to high temperatures compared to shrubs and trees, potentially reflecting divergent thermal conditions during anthesis. This study provides the first formal analysis of complex relationships between pollen temperature limits, plant characteristics and environmental factors, providing crucial insights into climate change impacts on plant reproduction.</p

Recent advances in applying metabolomics to uncover dietary impact on cardiometabolic health

Purpose of review Cardiometabolic diseases are a major global health concern, with diet playing a crucial role in their prevention and management. Recent advancements in the identification of metabolic signatures related to dietary patterns offer a more objective assessment of individualized dietary exposure and provide deeper insights into diet-disease associations. Recent findings Recent studies have shown that distinct metabolic signatures are associated with the adherence to various dietary patterns. These signatures show even stronger associations with cardiometabolic disease incidence, independent of traditional risk factors and self-reported adherence to such dietary patterns. Emerging dietary approaches, such as sustainable diets, health outcome-focused diets, and population data-driven dietary patterns, also hold promise for improving cardiometabolic health. Additionally, metabolic signatures could offer insights into diet-disease associations in underrepresented populations, addressing genetic and lifestyle differences. Summary Application of metabolomics provides a more precise understanding of how dietary patterns influence cardiometabolic health. Although the number of studies remains limited, and current evidence is inconsistent, the approach has significant potential for improving clinical and public health strategies. Future research should prioritize prospective studies and address population- and outcome-specific dietary needs to enable targeted interventions that optimize cardiometabolic health.</p

The antitumor activity of TGFβ-specific T cells is dependent on IL-6 signaling

Although interleukin (IL)-6 is considered immunosuppressive and tumor-promoting, emerging evidence suggests that it may support antitumor immunity. While combining immune checkpoint inhibitors (ICIs) and radiotherapy in patients with pancreatic cancer (PC) has yielded promising clinical results, the addition of an anti-IL-6 receptor (IL-6R) antibody has failed to elicit clinical benefits. Notably, a robust TGFβ-specific immune response at baseline in PC patients treated solely with ICIs and radiotherapy correlated with improved survival. Recent preclinical studies demonstrated the efficacy of a TGFβ-based immune modulatory vaccine in controlling PC tumor growth, underscoring the important role of TGFβ-specific immunity in PC. Here, we explored the importance of IL-6 for TGFβ-specific immunity in PC. In a murine model of PC, coadministration of the TGFβ-based immune modulatory vaccine with an anti-IL-6R antibody rendered the vaccine ineffective. IL-6R blockade hampered the development of vaccine-induced T-cells and tumoral T-cell infiltration. Furthermore, it impaired the myeloid population, resulting in increased tumor-associated macrophage infiltration and an enhanced immunosuppressive phenotype. In PC patients, in contrast to those receiving only ICIs and radiotherapy, robust TGFβ-specific T-cell responses at baseline did not correlate with improved survival in patients receiving ICIs, radiotherapy and IL-6R blockade. Peripheral blood immunophenotyping revealed that IL-6R blockade altered the T-cell and monocytic compartments, which was consistent with the findings in the murine model. Our data suggest that the antitumor efficacy of TGFβ-specific T cells in PC depends on the presence of IL-6 within the tumor. Consequently, caution should be exercised when employing IL-6R blockade in patients receiving cancer immunotherapy.</p

Occupational psychosocial stressors and ergonomic strain during pregnancy and sex-specific risk of childhood asthma

ObjectivesPrevious studies have indicated that maternal occupational psychosocial stressors may affect the risk of asthma in the offspring, but their results are inconsistent. Maternal occupational ergonomic strain is associated with predictors of fetal lung development, including preterm birth and low birthweight; however, it is not known, whether ergonomic strain during pregnancy is a risk factor for asthma in offspring. The aim was to investigate maternal psychosocial stressors and ergonomic strain during pregnancy relative to the risk of offspring asthma.MethodsLive- and firstborn singletons (1996–2018) and their mothers were identified from Danish nationwide registers. Job code at time of conception was assigned to each mother and linked with exposure estimates from job exposure matrices (JEMs) of psychosocial stressors and ergonomic strain. Diagnoses of childhood asthma were retrieved from the Danish National Patient Register. Incidence rate ratios (IRR) of asthma were estimated using Poisson regression; adjusted for maternal asthma, age at conception, socioeconomic position, and body mass index, and calendar year.ResultsMaternal employment in occupations with low decision authority (IRR: 1.08, 95% CI 1.00–1.16) and high ergonomic strain (IRR: 1.09, 95% CI 1.02–1.16) was associated with increased risk of asthma among male offspring. Largely similar, but less consistent, associations were observed among female offspring due to low decision authority.ConclusionWe found a minor increased risk of asthma among offspring whose mothers worked in an occupation with low decision authority or high ergonomic strain, most pronounced among male offspring.Objectives: Previous studies have indicated that maternal occupational psychosocial stressors may affect the risk of asthma in the offspring, but their results are inconsistent. Maternal occupational ergonomic strain is associated with predictors of fetal lung development, including preterm birth and low birthweight; however, it is not known, whether ergonomic strain during pregnancy is a risk factor for asthma in offspring. The aim was to investigate maternal psychosocial stressors and ergonomic strain during pregnancy relative to the risk of offspring asthma. Methods: Live- and firstborn singletons (1996–2018) and their mothers were identified from Danish nationwide registers. Job code at time of conception was assigned to each mother and linked with exposure estimates from job exposure matrices (JEMs) of psychosocial stressors and ergonomic strain. Diagnoses of childhood asthma were retrieved from the Danish National Patient Register. Incidence rate ratios (IRR) of asthma were estimated using Poisson regression; adjusted for maternal asthma, age at conception, socioeconomic position, and body mass index, and calendar year. Results: Maternal employment in occupations with low decision authority (IRR: 1.08, 95% CI 1.00–1.16) and high ergonomic strain (IRR: 1.09, 95% CI 1.02–1.16) was associated with increased risk of asthma among male offspring. Largely similar, but less consistent, associations were observed among female offspring due to low decision authority. Conclusion: We found a minor increased risk of asthma among offspring whose mothers worked in an occupation with low decision authority or high ergonomic strain, most pronounced among male offspring.</p