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Collective action in crisis?
Get PDFThis Introduction to the Special Issue ‘Collective Action in Crisis?’ explores two key themes. First, it seeks to deepen understanding of how collective action can be organized in crises, connecting established knowledge in the field with new insights from the articles of this Special Issue. Second, the question mark in our guiding theme invites critical reflection on whether the theories we use to understand collective action are themselves in crisis. Through this theme, we propose both a theoretical exploration and an empirical agenda, recognizing that crises amplify foundational concerns in organization studies around problems of collective action. We begin by ‘zooming out’ to provide an overview of foundational theoretical approaches to collective action during crises. Then, we ‘zoom in’ and foreground the specific value of middle-range theories and core concepts from organization and management studies. Our aim is to offer conceptual resources for scholars and practitioners tackling the critical task of organizing collective action in crises
Joint collective action increases support for social change and mitigates intergroup polarisation:A registered report
Get PDFOver the past decade, a surge in protests and social movements worldwide has offered promise for positive social change while also introducing divisions and tensions into society. In the current research, we examined the impact of joint collective action involving both advantaged and disadvantaged group members, as well as collective action solely involving disadvantaged group members, on public support for social change and intergroup polarisation. Two experimental studies (Studies 1a and 1b; N = 575) provided initial insights, revealing that joint collective action (vs. collective action by the disadvantaged) facilitated support for social change and mitigated intergroup polarisation. Building upon these initial findings, we propose two studies (Studies 2 and 3; projected N ∼ 1132) in the form of a registered report, aiming to delve into the psychological mechanisms underlying the observed effects (i.e., morality threat and perceived respect) and replicate these findings in varied protest contexts (i.e., gender and race relations). Additionally, we aim to examine if the (leadership vs. supportive) role of advantaged allies in joint collective action would have different impacts on disadvantaged group members' responses
Surgical Site Infection after Craniotomy in Neuro-Oncology (SINO): A protocol for an international prospective multicentre service evaluation across the United Kingdom and Ireland
Get PDFPembrolizumab in Patients With Advanced Clear Cell Gynecological Cancer:A Phase 2 Nonrandomized Clinical Trial
Get PDFImportance Advanced clear cell gynecological cancers (CCGCs) have a poor prognosis, with response rates to second-line chemotherapy less than 8%. Preliminary clinical activity with programmed cell death 1 protein (PD-1) inhibitors reported in CCGC merits further investigation.Objective To assess the clinical benefit of pembrolizumab in patients with previously treated advanced CCGC.Design, Setting, and Participants The PEACOCC trial is a single-arm multicenter phase 2 trial conducted at 5 UK centers investigating the clinical benefit and safety of pembrolizumab. PD-1 inhibitor–naive patients with histologically confirmed advanced CCGC, radiological disease progression following 1 or more prior courses of chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 1 were included. Patients were enrolled from March 2019 to October 2021, with data collected until July 2024.Interventions Pembrolizumab, 200 mg, intravenously every 21 days up to 2 years until progression, discontinuation due to toxic effects, or patient/clinician decision. Up to 1 year of retreatment on diseases progression, if stable disease, partial response, or complete response at 2 years.Main Outcomes and Measures The primary end point was progression-free survival (PFS) rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 to detect a 12-week PFS rate of 33% or greater and exclude a PFS rate of less than 15%, with 90% power and 1-sided 5% significance level. Secondary end points included objective response rate, duration of response, PFS, overall survival, safety, and quality of life.Results A total of 48 patients were eligible. The median (range) age was 58.5 (32-77) years, and 26 (54%) had an ECOG PS score of 0 and 22 (46%) had an ECOG PS score of 1; 41 (85%) had ovarian, 6 (13%) had endometrial, and 1 (2%) had cervical advanced CCGC. The median (range) courses prior therapy was 3 (1-6); 19 patients (40%) received prior anti-angiogenic therapy, and 19 (40%) had a platinum-free interval of more than 12 months. Grade 3 treatment-related adverse events were observed in 9 patients (19%), and no patients had grade 4 or 5 adverse events. A total of 45 of 46 patients (98%) had mismatch repair–proficient tumors. The 12-week PFS rate was 42% (95% CI, 28-57), and the best objective response rate was 25% (95% CI, 14-40), with 12 partial responses. After a median follow-up of 46.9 months (95% CI, 43.4-55.0), the median PFS was 2.7 months (95% CI, 1.3-5.4), and the median overall survival was 14.8 months (95% CI, 6.7-28.2).Conclusions and Relevance The PEACOCC trial showed clinical benefit with pembrolizumab in patients with previously treated advanced CCGC, of whom all except 1 had MMR-proficient disease. Clinical outcomes were durable with an overall tolerable safety profile, justifying further evaluation of pembrolizumab monotherapy for advanced CCGC in a randomized clinical trial.Trial Registration ClinicalTrials.gov Identifier: NCT0342556
Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant
Get PDFPIK3R1 encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β, or p110δ. Constitutional PIK3R1 mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction. We sought to investigate this. In dermal fibroblasts from an APDS2 patient, we found no increased PI3K signalling, with p110δ expression markedly reduced. In preadipocytes, the APDS2 variant was potently dominant negative, associating with Irs1 and Irs2 but failing to heterodimerise with p110α. This attenuation of p110α signalling by a p110δ-activating PIK3R1 variant potentially explains co-incidence of gain-of-function and loss-of-function PIK3R1 phenotypes
Associations between IL-6 and trajectories of depressive symptoms across the life course:Evidence from ALSPAC and UK Biobank cohorts
Get PDFBACKGROUND: Peripheral inflammatory markers, including serum interleukin 6 (IL-6), are associated with depression, but less is known about how these markers associate with depression at different stages of the life course.METHODS: We examined the associations between serum IL-6 levels at baseline and subsequent depression symptom trajectories in two longitudinal cohorts: ALSPAC (age 10-28 years; N = 4,835) and UK Biobank (39-86 years; N = 39,613) using multilevel growth curve modeling. Models were adjusted for sex, BMI, and socioeconomic factors. Depressive symptoms were measured using the Short Moods and Feelings Questionnaire in ALSPAC (max time points = 11) and the Patient Health Questionnaire-2 in UK Biobank (max time points = 8). RESULTS: Higher baseline IL-6 was associated with worse depression symptom trajectories in both cohorts (largest effect size: 0.046 [ALSPAC, age 16 years]). These associations were stronger in the younger ALSPAC cohort, where additionally higher IL-6 levels at age 9 years was associated with worse depression symptoms trajectories in females compared to males. Weaker sex differences were observed in the older cohort, UK Biobank. However, statistically significant associations (pFDR <0.05) were of smaller effect sizes, typical of large cohort studies.CONCLUSIONS: These findings suggest that systemic inflammation may influence the severity and course of depressive symptoms across the life course, which is apparent regardless of age and differences in measures and number of time points between these large, population-based cohorts.</p
Learning from the community:iterative co-production of a programme to support the development of attention, regulation and thinking skills in toddlers at elevated likelihood of autism or ADHD
Get PDFProgrammes designed to support children with known, or increased likelihood of, autism or ADHD often focus on reducing behaviours central to a clinical diagnosis. However, supporting children to pursue their own goals and cope with everyday life through fostering executive function (EF) development, without enforcing neuro-normative assumptions, may be more acceptable to neurodivergent people, and more beneficial. The co-production process for this neurodiversity-affirming programme involved: Review of research priorities identified during published public-and-clinician consultations; iterative programme development through two pilot rounds with a general community sample; and consultation with stakeholders (parents with a connection to autism or ADHD, alongside early years specialists, psychologists and therapists) to check acceptability of the proposal, and refine the logic model and materials. The logic model for the resultant programme-Supporting Toddlers with a connection to autism or ADHD to develop strong Attention, Regulation and Thinking skills (START)-involves three mechanisms of change: The child has appropriate play-based opportunities to practise EF skills; Parenting behaviours linked to strong EFs are encouraged; Parents are empowered to improve environmental-fit for their child so that EF stressors are reduced.</p
Interleukin 10 controls the balance between tolerance, pathogen elimination and immunopathology in birds
Get PDFEffective mucosal immunity in the intestine involves a fine balance between tolerance of the microbiome, recognition and elimination of pathogens, and inflammatory tissue injury. The anti-inflammatory cytokine IL10 regulates these processes in the intestines of mice and humans; the anti-inflammatory activity of IL10 is also conserved in birds. To determine the function of IL10 in avian mucosal immunity, we generated germ line modifications of the chicken IL10 locus to abolish or reduce IL10 expression. In vitro analysis of macrophage response to lipopolysaccharide confirmed the loss of IL10 protein expression, the lack of dosage compensation in heterozygotes, and prevention of autocrine inhibition of nitric oxide production in homozygous IL10 knockout macrophages. IL10-deficiency significantly altered the composition of the caecal microbiome, but unlike IL10-deficient mice and humans, IL10-deficient chickens did not exhibit spontaneous colitis. Following experimental challenge with Salmonella enterica serovar Typhimurium or Campylobacter jejuni in IL10-deficient chickens, enhanced clearance of the pathogens was associated with elevated transcription of pro-inflammatory genes and increased infiltration of inflammatory cells into gut mucosa. In IL10-deficient chickens challenged with the parasite Eimeria tenella, pathogen clearance was accelerated but caecal lesions were more severe and weight gain was compromised. Neither the heterozygous IL10 knockout nor a homozygous IL10 enhancer mutation had a major effect on pathogen clearance or inflammation in any of the challenge models. Our findings highlight the intrinsic compromise in mucosal immune response and have important implications for the development of strategies to combat avian and zoonotic pathogens in poultry
Large range sizes link fast life histories with high species richness across wet tropical tree floras
Get PDFUnderstanding how the traits of lineages are related to diversification is key for elucidating the origin of variation in species richness. Here, we test whether traits are related to species richness among lineages of trees from all major biogeographical settings of the lowland wet tropics. We explore whether variation in mortality rate, breeding system and maximum diameter are related to species richness, either directly or via associations with range size, among 463 genera that contain wet tropical forest trees. For Amazonian genera, we also explore whether traits are related to species richness via variation among genera in mean species-level range size. Lineages with higher mortality rates—faster life-history strategies—have larger ranges in all biogeographic settings and have higher mean species-level range sizes in Amazonia. These lineages also have smaller maximum diameters and, in the Americas, contain dioecious species. In turn, lineages with greater overall range size have higher species richness. Our results show that fast life-history strategies influence species richness in all biogeographic settings because lineages with these ecological strategies have greater range sizes. These links suggest that dispersal has been a key process in the evolution of the tropical forest flora
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