\u3cem\u3eAlderwood Associatesv. Washington Environmental Council\u3c/em\u3e: State Action and the Washington State Constitution

In Alderwood Associates v. Washington Environmental Council, the Washington Supreme Court reversed a temporary restraining order forbidding the defendant\u27s solicitation or demonstration on plaintiff\u27s privately owned shopping mall. Although there was no majority opinion because the court split four-one-four, the result of the several opinions is that the Washington constitution now bars private as well as state action that interferes with the gathering of initiative signatures on certain private property. However, four justices also concluded that the free speech sections of the Washington constitution restricts private as well as state action. The Alderwood result is desirable, but could have been reached without an abandonment of the state action requirement. Such an abandonment, although subscribed to by less than a majority, strays from principled constitutional analysis and inhibits further reasoned development of the state constitution

\u3cem\u3eAlderwood Associatesv. Washington Environmental Council\u3c/em\u3e: State Action and the Washington State Constitution

In Alderwood Associates v. Washington Environmental Council, the Washington Supreme Court reversed a temporary restraining order forbidding the defendant\u27s solicitation or demonstration on plaintiff\u27s privately owned shopping mall. Although there was no majority opinion because the court split four-one-four, the result of the several opinions is that the Washington constitution now bars private as well as state action that interferes with the gathering of initiative signatures on certain private property. However, four justices also concluded that the free speech sections of the Washington constitution restricts private as well as state action. The Alderwood result is desirable, but could have been reached without an abandonment of the state action requirement. Such an abandonment, although subscribed to by less than a majority, strays from principled constitutional analysis and inhibits further reasoned development of the state constitution

Animal husbandry in the Early and Middle Neolithic settlement at Kopydłowo in the Polish lowlands: a multi-isotope perspective

The aim of this article is to examine the isotopic characterisation of domestic animals as it relates to birthing location and seasonality, diet, pasturing pattern, foddering and climatic conditions of herding and to determine variation between these aspects of cattle and caprine husbandry of the Neolithic Linearbandkultur (LBK) and Trichterbecherkultur (TRB) communities from Kopydłowo in Kujavia—one of the major centres of early farming in the European lowlands. Carbon and nitrogen stable isotope analysis was undertaken on faunal bone collagen; carbon, oxygen and strontium isotope ratios were measured from tooth enamel. Isotopic signatures may have been caused by different strategies of management of herds of these animal species. Different and more widely distributed carbon, nitrogen and strontium isotopic data for TRB cattle in comparison with its LBK counterparts is indicative of the exploitation of increasingly diverse ecological zones and more varied pastoral practises. The distribution of oxygen isotope values on caprine tooth made it possible to recognise herding seasonality. Irrespective of the chronology, cattle, sheep and goats kept by the inhabitants had C3 plant-based diet

Development of the Warwick Axial Spondyloarthritis faTigue and Energy questionnaire (WASTEd) – a new patient-reported outcome measure

Objective To co-produce and test a potential new patient-reported outcome measure (PROM) - the Warwick Axial Spondyloarthritis faTigue and Energy questionnaire (WASTEd), providing vital qualitative confirmation of conceptual relevance, clarity, and acceptability. Methods Informed by measurement theory, we collaborated with patient partners throughout a three-stage, iterative process of PROM development. Stage 1: Informed by patient interviews, reviews exploring patients’ fatigue experiences, and existing PROMs of fatigue, an initial measurement framework of axSpA fatigue and energy and candidate items were defined. Stage 2: The relevance and acceptability of the measurement framework and candidate items were assessed qualitatively by focus group participants. Stage three: Patients participated in pretesting interviews to assess item comprehensiveness, relevance, acceptability, and comprehensibility. Results Stage one informed the development of an initial five-domain measurement framework, with 59 candidate items. In stage two, five patients and seven healthcare professionals participated in four focus groups to derive a 40-item model of fatigue and energy. Collaborative engagement with patient research partners further supported refinement of questionnaire structure and content. Pretesting with ten patients across two interview rounds in stage three produced a four-domain, 30-item long-form questionnaire. Conclusions An active collaboration with patients and healthcare professionals has supported the co-production of a potential new PROM of axSpA fatigue, underpinned by strong evidence of face and content validity. The WASTEd extends the assessment of fatigue beyond severity, highlighting the importance of symptom frequency, energy, and self-management. Future research will involve psychometric evaluation, supporting item-reduction, structural refinement, and confirmation of PROM validity

Updated standardized definitions for efficacy endpoints in adjuvant breast cancer clinical trials: STEEP Version 2.0

Purpose The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed.Methods We conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non-breast cancer deaths and new nonbreast primary cancers from the invasive disease-free survival end point.Results Among 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low.Conclusion We recommend an additional end point, invasive breast cancer-free survival, which includes all invasive disease-free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes

Impact of Social Stories on social and emotional health of autism spectrum primary school children:the ASSSIST2 RCT with economic evaluation

BACKGROUND: Differences in the way autistic children experience the world can contribute to anxiety and stress. Carol Gray's Social Stories™ are a highly personalised intervention to support children by providing social information about specific situations in an individual story. OBJECTIVES: This randomised controlled trial aimed to establish whether Social Stories are clinically effective and cost-effective in improving social responsiveness and social and emotional health in children on the autism spectrum in schools. DESIGN: A multisite pragmatic cluster randomised controlled trial comparing Social Stories with care as usual. SETTING: Eighty-seven schools (clusters) across Yorkshire and the Humber. PARTICIPANTS: Two hundred and forty-nine children were randomised via a bespoke system hosted at York Trials Unit (129 Social Stories and 120 care as usual). Recruitment was completed in May 2021. Participants were children aged 4-11 years with a diagnosis of autism, alongside teachers, interventionists and caregivers. Recruitment was via schools, NHS trusts, support groups and local publicity. INTERVENTION: The intervention included training for educational professionals and caregivers covering psychoeducation and implementation of Social Stories. Stories were written around contextualised goals around the child's need for social information. Interventionists read the Social Story™ with the child at least six times over 4 weeks during school. MAIN OUTCOME MEASURE: The primary outcome was the Social Responsiveness Scale-2 completed by teachers at 6 months (the primary end point), which measures social awareness, cognition, communication and behaviour. Data were collected from caregivers and educational professionals at 6 weeks and 6 months through questionnaires. Blinding of participants was not possible. RESULTS: At 6 months, the estimated difference in expected teacher-reported Social Responsiveness Scale-2 T-score (the primary end point) was -1.61 (95% confidence interval -4.18 to 0.96, p  = 0.220), slightly favouring the intervention group. The estimated differences for the parent-reported secondary outcomes at 6 months were small and generally favoured the control group except the measure of children's quality-adjusted life-year (+ 0.001, 95% confidence interval -0.032 to 0.035) and parental stress (-1.49, 95% confidence interval -5.43 to 2.46, p  = 0.460), which favoured the intervention group. Children in the intervention group met their individual goals more frequently than children who received usual care alone (0.97 confidence interval 0.21 to 1.73, p  = 0.012). The intervention is likely to save small costs (-£191 per child, 95% confidence interval -767.7 to 337.7) and maintain a similar quality of life compared to usual care. The probability of Social Stories being a preferred option is 75% if the society is willing to pay £20,000 per quality-adjusted life-year gained. Limitations include considerable disruptions during the coronavirus disease 2019 pandemic. CONCLUSION: Social Stories are used in schools and represent a low-cost intervention. There is no clinically evident impact on social responsiveness, anxiety and/or depression, parental stress or general health. Benefits were observed for specific behavioural goals as assessed by the teacher, and Social Stories may serve as a useful tool for facilitating dialogue between children and school staff to address specific behavioural challenges. Usage should be at the school's discretion. FUTURE WORK: Given the uncertainty of the results in light of coronavirus disease 2019, further work to establish the impact of Social Stories is merited. TRIAL REGISTRATION: This trial is registered as ISRCTN11634810. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/111/91) and is published in full in Health Technology Assessment; Vol. 28, No. 39. See the NIHR Funding and Awards website for further award information

Towards a methodology for cluster searching to provide conceptual and contextual "richness" for systematic reviews of complex interventions: case study (CLUSTER)

Background Systematic review methodologies can be harnessed to help researchers to understand and explain how complex interventions may work. Typically, when reviewing complex interventions, a review team will seek to understand the theories that underpin an intervention and the specific context for that intervention. A single published report from a research project does not typically contain this required level of detail. A review team may find it more useful to examine a “study cluster”; a group of related papers that explore and explain various features of a single project and thus supply necessary detail relating to theory and/or context. We sought to conduct a preliminary investigation, from a single case study review, of techniques required to identify a cluster of related research reports, to document the yield from such methods, and to outline a systematic methodology for cluster searching. Methods In a systematic review of community engagement we identified a relevant project – the Gay Men’s Task Force. From a single “key pearl citation” we conducted a series of related searches to find contextually or theoretically proximate documents. We followed up Citations, traced Lead authors, identified Unpublished materials, searched Google Scholar, tracked Theories, undertook ancestry searching for Early examples and followed up Related projects (embodied in the CLUSTER mnemonic). Results Our structured, formalised procedure for cluster searching identified useful reports that are not typically identified from topic-based searches on bibliographic databases. Items previously rejected by an initial sift were subsequently found to inform our understanding of underpinning theory (for example Diffusion of Innovations Theory), context or both. Relevant material included book chapters, a Web-based process evaluation, and peer reviewed reports of projects sharing a common ancestry. We used these reports to understand the context for the intervention and to explore explanations for its relative lack of success. Additional data helped us to challenge simplistic assumptions on the homogeneity of the target population. Conclusions A single case study suggests the potential utility of cluster searching, particularly for reviews that depend on an understanding of context, e.g. realist synthesis. The methodology is transparent, explicit and reproducible. There is no reason to believe that cluster searching is not generalizable to other review topics. Further research should examine the contribution of the methodology beyond improved yield, to the final synthesis and interpretation, possibly by utilizing qualitative sensitivity analysis

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist