The participation paradigm in audience research

As today's media simultaneously converge and diverge, fusing and hybridizing across digital services and platforms, some researchers argue that audiences are dead-long live the user! But for others, it is the complex interweaving of continuities and changes that demands attention, especially now that audiencing has become a vital mode of engaging with all dimensions of daily life. This article asks how we should research audiences in a digital networked age. I argue that, while many avenues are being actively pursued, many researchers are concentrating on the notion of participation, asking, on the one hand, what modes of participation are afforded to people by the particular media and communication infrastructures which mediate social, cultural or political spheres of life? And, on the other hand, how do people engage with, accede to, negotiate or contest this as they explore and invent new ways of connecting with each other through and around media? The features of this emerging participation paradigm of audience research are examined in this article

Planktonic events may cause polymictic-dimictic regime shifts in temperate lakes

Water transparency affects the thermal structure of lakes, and within certain lake depth ranges, it can determine whether a lake mixes regularly (polymictic regime) or stratifies continuously (dimictic regime) from spring through summer. Phytoplankton biomass can influence transparency but the effect of its seasonal pattern on stratification is unknown. Therefore we analysed long term field data from two lakes of similar depth, transparency and climate but one polymictic and one dimictic, and simulated a conceptual lake with a hydrodynamic model. Transparency in the study lakes was typically low during spring and summer blooms and high in between during the clear water phase (CWP), caused when zooplankton graze the spring bloom. The effect of variability of transparency on thermal structure was stronger at intermediate transparency and stronger during a critical window in spring when the rate of lake warming is highest. Whereas the spring bloom strengthened stratification in spring, the CWP weakened it in summer. The presence or absence of the CWP influenced stratification duration and under some conditions determined the mixing regime. Therefore seasonal plankton dynamics, including biotic interactions that suppress the CWP, can influence lake temperatures, stratification duration, and potentially also the mixing regime

Comparing Palliation Strategies for Single-ventricle Anatomy With Transposed Great Arteries and Systemic Outflow Obstruction

OBJECTIVE: Patients with complex single-ventricle anatomy with transposed great arteries and systemic outflow obstruction (SV-TGA-SOO) undergo varied initial palliation with ultimate goal of Fontan circulation. We examine a longitudinal experience with multiple techniques, including the largest published cohort following palliative arterial switch operation (pASO), to describe outcomes and decision-making factors. METHODS: Neonates with SV-TGA-SOO who underwent initial surgical palliation from 1995 to 2022 at a single institution were retrospectively reviewed. RESULTS: In total, 71 neonates with SV-TGA-SOO underwent index surgical palliation at a median age of 7 days (interquartile range, 6-10) by pASO (n = 23), pulmonary artery band (PAB) with or without arch repair (n = 25), or modified Norwood with Damus-Kaye-Stansel aortopulmonary amalgamation (n = 23). Single-ventricle pathology included double-inlet left ventricle (n = 37, 52%), tricuspid atresia (n = 27, 38%), and others (n = 7, 10%). All mortalities (n = 5, 7%) occurred in the first interstage period after PAB (n = 3) and Norwood (n = 2). Subaortic obstruction in the PAB group was addressed by operative resection (n = 10 total, 7 at index operation) and/or delayed aortopulmonary amalgamation (n = 13, 52%). Two patients with pASO (9%) had early postoperative coronary complications, 1 requiring operative revision. Median follow-up for survivors was 10.4 years (interquartile range, 4.5-16.6 years). Comparing patients by their initial palliation type, notable significant differences included size of bulboventricular foramen, weight at initial operation, operation duration, postoperative length of stay, time to second-stage palliation, multiple pulmonary artery reinterventions, and left pulmonary artery interventions. There were no significant differences in overall survival, Fontan completion, reintervention-free survival in the first interstage period, pulmonary artery reintervention-free survival, long-term systemic valve competency, or ventricular dysfunction. CONCLUSIONS: Excellent mid- to long-term outcomes are achievable following neonatal palliation for SV-TGA-SOO via pASO, PAB, and modified Norwood, with comparable survival and Fontan completion. Initial palliation strategy should be individualized to optimize anatomy and physiology for successful Fontan by ensuring an unobstructed subaortic pathway and accessible pulmonary arteries. pASO is a reasonable strategy to consider for these heterogeneous lesions

A manifesto for researching entrepreneurial ecosystems

Entrepreneurial ecosystems are the focus of government economic policies around the world for their potential to generate entrepreneur-led economic development. The paper identifies key research questions and challenges to building effective public policy: (i) the limitations of existing data sources, (ii) the need to balance findings from quantitative and qualitative studies, (iii) the danger that entrepreneurial ecosystems will be just a policy fad, (iv) the narrow focus of policy and research on high tech firms and scale-ups, and (v) the need to balance research approaches between simplified models and a complex systems approach. There is a need for a better understanding of the diversity of policy contexts (level of government, country context) and model of ecosystem governance. A more granulated understanding of ecosystem thinking is required, with greater consideration of the diversity of actors and the institutional context, with more attention given to the heterogeneous nature of places and complex interactions between actors and networks. Looking to the future, the potential of new data sources and methodologies is identified. Future research should give greater consideration to the institutional context to understand how policy can better support entrepreneurial activity and the extent to which specific policies can be replicated elsewhere

A Phase I Dose Escalation Study of the LRP5 Antagonist BI 905681 in Patients with Advanced and Metastatic Solid Tumors

BACKGROUND: The Wnt pathway is involved in proliferation and tissue homeostasis. Aberrant activation promotes cancer cell proliferation and survival. Inhibition of the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) coreceptors that regulate Wnt signaling could prevent cancer cell proliferation. BI 905681 is a novel LRP5 antagonist that has demonstrated potent in vivo antitumor activity. PATIENTS AND METHODS: This was a phase I, dose escalation study (NCT04147247) evaluating BI 905681 in patients with advanced solid tumors over two dosing schedules (schedule A: every 3 weeks, 3-week cycles and schedule B: every 2 weeks, 4-week cycles). The primary endpoint was the maximum tolerated dose (MTD) of BI 905681 and the number of patients experiencing adverse events (AEs). Other endpoints were pharmacokinetics, pharmacodynamics, and efficacy. RESULTS: As a result of difficulties enrolling patients, the trial was terminated early and the MTD for schedule A could not be determined. Twenty-one patients received BI 905681 over five dose cohorts (schedule A: 1.0, 2.5, 5.0, 7.0, and 8.5 mg/kg). No patients received schedule B. No dose-limiting toxicities (DLTs) were reported during the MTD evaluation period. However, during the entire treatment period, two patients (9.5%) experienced a DLT of grade 1 C-telopeptide increase in the 5.0 and 8.5 mg/kg dose cohorts. The most frequent treatment-related AEs were diarrhea (23.8%), vomiting (23.8%), nausea (19.0%), and infusion-related reactions (IRRs; 14.3%). Despite premedication to mitigate IRRs, one patient experienced a grade 2 IRR. The pharmacokinetic profiles of BI 905681 were biphasic, with a rapid distribution phase in the beginning followed by a slower elimination phase. The objective response rate was 0%; 5 (23.8%) and 14 patients (66.7%) had a best overall response of stable disease and progressive disease, respectively. CONCLUSION: BI 905681 has minimal efficacy in an unselected patient population and was generally well tolerated

Questioning cultural narratives of economic development—an investigation of Kitchener-Waterloo

The version of record [Spigel, B. & Bathelt, H. (2019). Questioning cultural narratives of economic development - An investigation of Kitchener-Waterloo. Canadian Geographer, 63(2), 267-283.] is available online at: https://onlinelibrary.wiley.com/doi/abs/10.1111/cag.12512This paper investigates the relationship between culture and economy and scrutinizes cultural narratives of economic development in Kitchener-Waterloo, southern Ontario. It argues for the need to carefully conceptualize the link between culture and economic development to avoid boosting deterministic stereotypes. In the case of Kitchener-Waterloo, a notable hub of high-technology firms and technology development, a link is frequently drawn between the German community and culture and the region’s technology economy and entrepreneurial culture. A social capital analysis, however, reveals that the German ethnic community neither has the strong professional internal ties nor the external social ties to other regional communities that could constitute a lead role in economic development. Rather, the legacy of Kitchener-Waterloo’s ethnic German population has been absorbed into the region’s self-image and creates a feeling of belonging and common reference points for joint social and economic initiatives in the region

Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study

PURPOSE: Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. METHODS: MyPathway (ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort. \ud RESULTS: Between April 1, 2014 and November 1, 2016, 251 patients with 35 different tumor types received study treatment. The efficacy population contains 230 treated patients who were evaluated for response or discontinued treatment before evaluation. Fifty-two patients (23%) with 14 different tumor types had objective responses (complete, n = 4; partial, n = 48). Tumor-pathway cohorts with notable objective response rates included human epidermal growth factor receptor-2–amplified/overexpressing colorectal (38% [14 of 37]; 95% CI, 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1 V600-mutated non–small-cell lung cancer (43% [six of 14]; 95% CI, 18% to 71%). CONCLUSIONS: The four currently approved targeted therapy regimens in the MyPathway study produced meaningful responses when administered without chemotherapy in several refractory solid tumor types not currently labeled for these agents

Camonsertib in DNA Damage Response-Deficient Advanced Solid Tumors: Phase 1 Trial Results

Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose a recommended phase 2 dose (RP2D). Secondary objectives were to assess preliminary anti-tumor activity, to characterize camonsertib pharmacokinetics and relationship with pharmacodynamic biomarkers and to evaluate methods for detecting ATRi-sensitizing biomarkers. Camonsertib was well tolerated; anemia was the most common drug-related toxicity (32% grade 3). Preliminary RP2D was 160 mg weekly on days 1-3. Overall clinical response, clinical benefit and molecular response rates across tumor and molecular subtypes in patients who received biologically effective doses of camonsertib (\u3e100 mg d-1) were 13% (13/99), 43% (43/99) and 43% (27/63), respectively. Clinical benefit was highest in ovarian cancer, in tumors with biallelic LOF alterations and in patients with molecular responses