Reasons for reason-giving in unplanned discourse

Most studies of reason-giving have focussed on formal, planned situations rather than on how reason-giving functions in relatively unplanned discourse. This study looks at reason-giving by respondents to an anonymous telephone public-opinion survey, e xploring the relationship between fact, policy, and value claims and the types of reasons used to support those claims. The results resonate with two important areas in argumentation theory: argument fields and critical thinking. Further, I suggest that reason-giving can serve as a method for individuals to present themselves as human and thoughtfully reasonable

Bacterial Stress Responses To 1-Megahertz Pulsed Ultrasound In The Presence Of Microbubbles

Members of a panel of stress-responsive biosensors have been used to study the effect of megahertz frequency ultrasound onEscherichia coli. Insonification causes acoustic cavitation, the collapse of oscillating microbubbles in solution, which can damage bacterial cells. A focused 1-MHz ultrasound transducer, capable of generating a spatial peak pulse average intensity of 500 W/cm2, was used to treat liquid bacterial cultures. Stress-responsive promoters fused to luxCDABE allowed the continuous measurement of light produced as a result of protein damage, DNA damage, oxidative stress, and membrane perturbation. A promoter responsive to ammonia limitation was not transcriptionally activated under test conditions. In contrast to bacteria in exponentially growing cultures, those in stationary-phase cultures were more resistant to the effects of ultrasound treatment. Quantification of the degree of acoustic cavitation due to symmetric bubble collapse was measured by a 20-MHz passive transducer, the output of which appears to be only partially correlated with cellular damage and survival. The methods and results summarized here provide the basis for further investigation into applications, including the purification of water samples

Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy

AbstractBCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263. High-throughput screening identified anthracyclines including doxorubicin and CDK9 inhibitors including dinaciclib that synergized with ABT-263 through downregulation of MCL-1. As doxorubicin and dinaciclib also reduced BCL-XL, the combinations of BCL-2 inhibitor ABT-199 (venetoclax) with doxorubicin or dinaciclib provided effective therapeutic strategies for SCLC. Altogether, our study highlights the need for mechanism-guided targeting of anti-apoptotic BCL-2 proteins to effectively activate the mitochondrial cell death programme to kill cancer cells.</jats:p

Systemic design and its discontents: Designing for emergence and accountability

“Any machine constructed for the purpose of making decisions, if it does not possess the power of learning, will be completely literal-minded. Woe to us if we let it decide our conduct, unless we have previously examined the laws of its action, and know fully that its conduct will be carried out on principles acceptable to us! (Wiener, 1950)” In this paper we seek to advance the discourse and prospective impact of systemic design through challenges and opportunities centred in perspectives from psychology and ethics. We argue that systemic design is adolescent. It has a growing sense of its power and potential, yet it is prone to clumsiness and yawning lapses. To advance its role in fostering inclusion and flourishing, how might we lead systemic design to greater maturity, responsibility, self-awareness, in a word, to accountability? We assess that systemic design is on track to fulfill its potential as a holistic practice and discourse, akin to an advanced form of service design. Yet for this to happen the community must undertake more careful processes of development. Systemic design needs to balance its ambition and confidence with humility and ethical commitment. Toward this end we propose that systemic design covet skills, insights and awareness from its ‘aunts and uncles’. We indicate that greater use of psychology is needed to inform descriptive work, and more ethics is needed to uphold normative purposes. We advocate developing systemic design theory and practice through the further introduction of concepts from social and group psychology, as well as ethical governance. This groundwork is timely and needs-based, as it sheds light on potentially manipulative techniques at the intersection of choice, persuasion, influence, politics, and other nonlinear, societal forces. Our proactive goal is to better equip systemic design to address complex problems at the level of UN Sustainable Development Goals (SDGs), including equity, diversity and inclusion. We examine developments at the intersection of democracy, social media and automation that are highly unsettling, including the use of Facebook users’ data by Cambridge Analytica in the context of the Brexit campaign and the 2016 US election. In this light we articulate an urgent and remedial call for the systemic design community to develop and uphold a code of professional ethics and conduct, not unlike those adopted by engineers, doctors, management consultants and planners. Pathways We ask, has psychology successfully lent its wisdom to other disciplines? Indeed, behavioural economics is one pathway that has found significant value and traction. This project, which synthesizes demonstrably irrational human motivations and biases into the brittle, positivist models of classical economics, has begat a more resilient and mature hybrid. We take encouragement from experiment and exploration in arenas that hold strong interest for systemic design: policy, governance, community development, economic cooperation, innovation. To better understand inherent systemic design’s risks, and establish historical and critical context, we ground this study with reference to early twentieth century work, including Norbert Wiener, considered “father of cybernetics,” and Freud’s American nephew, Edward L. Bernays, portrayed as “father of public relations.” More than any single figure Bernays understood and anticipated spaces and practices of persuasion including marketing, public relations, and consumer psychology. In the early twentieth century Bernays pioneered forms of ‘advertising without advertising’, that is to say product placement. His works provide considerable architecture for modern mass culture. From their titles alone we may glimpse both the power and pitfalls of industrial, design-fueled techniques of persuasion: Propaganda, 1928; Public relations, 1952; The Engineering of Consent, 1955. Our brief critical review reveals that Bernays ideas are unsettling in their relevance to contemporary concerns and its frank assertion that democracy requires guidance and constraint by a shadowy elite. Bernays’s work has never been well known to the public. This is all the more surprising considering his long and influential shadow. We argue that his work is critical to understanding the use and misuse of persuasion for social purposes. Bernays describes ‘engineering consent’ as follows: “Use of an engineering approach—that is, action based only on thorough knowledge of the situation and on the application of scientific principles and tried practices to the task of getting people to support ideas and programs. (Bernays, 1955)” Purposes We lay out tactical scaffolding for the psychological maturation of systemic design through a discussion of projects led by the authors. Here the values, design principles and choices demonstrate alternatives to the twentieth-century manipulation model and to other inherited, status quo approaches. Skelton outlines the open software platform Betaville, a massively participatory, editable, urban mirror world project elaborated by an international network of partners and collaborators. Van Alstyne presents Strategic Innovation Lab, a large, decade-old Toronto-based social lab dedicated to envisioning possible and preferable futures through participatory foresight. Our strategic goal is to better prepare the systemic design community for two purposes. We want to address complex problems at the level of UN SDGs, including reduction of poverty, hunger, inequality, consumption, and GHG emissions, while boosting wellbeing, sanitation, social justice, innovation, and strong institutions. More troublingly we want to stem and mitigate consequences arising from broad design and deployment of automated and augmented systems in which emergent dynamics lead to unsettling social and political effects. This work extends and deepens the theoretical framework “Designing for Emergence” (Van Alstyne & Logan, 2007), presented in RSD5 Toronto (Van Alstyne & Logan, 2016). Understanding innovation and knowing how we might give rise to desirable, emergent processes within systems requires us to understand emergence — bottom-up forces of morphogenesis. As one exchange at RSD6 pointed out: We don’t design systems, we design pathways through systems. In summary, the purpose and process we are advocating for the systemic design community is to advance our maturity and thereby our positive impact for the many, not the few. In other words, we want to learn to act more responsively and responsibly, to do both risk-taking and risk-management. Is this enterprise deeply intertwined with psychology and ethics? Clearly. Does this describe the primary opportunity and challenge facing Systemic Design as a community? We think it does

Fluid intake and clinicopathological characteristics of bladder cancer:the West Midlands Bladder Cancer Prognosis Programme (BCPP)

Objective Between 10 and 20% of bladder cancer patients who are diagnosed with nonmuscle-invasive bladder cancer will progress to muscle-invasive disease. Risk of progression depends on several factors at diagnosis including age, tumour stage, grade, size and number, and the presence or absence of carcinoma in situ. Fluid intake may be related to these factors. Methods Data of 1123 participants from the West Midlands Bladder Cancer Prognosis Programme were used. Data collection was via a semistructured questionnaire, and case report forms were used to collect clinicopathological data. Fluid intake was measured for six main categories: alcoholic fluids, hot fluids, fruit fluids, milk, fizzy drinks, and water, and converted into quintile variables. Multilevel mixed-effects linear regression was performed for every beverage category per clinicopathological variable and corrected for age, gender, and smoking status. Results Age at diagnosis was distributed differently amongst those in different total fluid intake quintiles (predicted means 71.5, 70.9, 71.5, 69.9, and 67.4, respectively) and showed a significant inverse linear trend in alcohol (P <0.01), hot fluids (P <0.01), and total fluids intake (P <0.01), in nonmuscle-invasive bladder cancer patients. Conclusion Our results suggest an inverse association for alcohol intake and total fluid intake with age at diagnosis. These results should be confirmed by future studies, alongside a possible (biological) mechanism that could influence tumour growth, and the effect of micturition frequency

Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy

Cypher is a member of a recently emerging family of proteins containing a PDZ domain at their NH2 terminus and one or three LIM domains at their COOH terminus. Cypher knockout mice display a severe form of congenital myopathy and die postnatally from functional failure in multiple striated muscles. Examination of striated muscle from the mutants revealed that Cypher is not required for sarcomerogenesis or Z-line assembly, but rather is required for maintenance of the Z-line during muscle function. In vitro studies demonstrated that individual domains within Cypher localize independently to the Z-line via interactions with α-actinin or other Z-line components. These results suggest that Cypher functions as a linker-strut to maintain cytoskeletal structure during contraction

Evaluation of a village-based digital health kiosks program: A protocol for a cluster randomized clinical trial

Background To address disparities in healthcare quality and access between rural and urban areas in China, reforms emphasize strengthening primary care and digital health utilization. Yet, evidence on digital health approaches in rural areas is lacking. Objective This study will evaluate the effectiveness of Guangdong Second Provincial General Hospital's Digital Health Kiosk program, which uses the Dingbei telemedicine platform to connect rural clinicians to physicians in upper-level health facilities and provide access to artificial intelligence-enabled diagnostic support. We hypothesize that our interventions will increase healthcare utilization and patient satisfaction, decrease out-of-pocket costs, and improve health outcomes. Methods This cluster randomized control trial will enroll clinics according to a partial factorial design. Clinics will be randomized to either a control arm with clinician medical training, a second arm additionally receiving Dingbei telemedicine training, or a third arm with monetary incentives for patient visits conducted through Dingbei plus all prior interventions. Clinics in the second and third arm will then be orthogonally randomized to a social marketing arm that targets villager awareness of the kiosk program. We will use surveys and Dingbei administrative data to evaluate clinic utilization, revenue, and clinician competency, as well as patient satisfaction and expenses. Results We have received ethical approval from Guangdong Second Provincial General Hospital (IRB approval number: GD2H-KY IRB-AF-SC.07-01.1), Peking University (IRB00001052-21007), and the University of North Carolina at Chapel Hill (323385). Study enrollment began April 2022. Conclusions This study has the potential to inform future telemedicine approaches and assess telemedicine as a method to address disparities in healthcare access. Trial registration number: ChiCTR210005387

PRL-3, a Metastasis Associated Tyrosine Phosphatase, Is Involved in FLT3-ITD Signaling and Implicated in Anti-AML Therapy

Combination with other small molecule drugs represents a promising strategy to improve therapeutic efficacy of FLT3 inhibitors in the clinic. We demonstrated that combining ABT-869, a FLT3 inhibitor, with SAHA, a HDAC inhibitor, led to synergistic killing of the AML cells with FLT3 mutations and suppression of colony formation. We identified a core gene signature that is uniquely induced by the combination treatment in 2 different leukemia cell lines. Among these, we showed that downregulation of PTP4A3 (PRL-3) played a role in this synergism. PRL-3 is downstream of FLT3 signaling and ectopic expression of PRL-3 conferred therapeutic resistance through upregulation of STAT (signal transducers and activators of transcription) pathway activity and anti-apoptotic Mcl-1 protein. PRL-3 interacts with HDAC4 and SAHA downregulates PRL-3 via a proteasome dependent pathway. In addition, PRL-3 protein was identified in 47% of AML cases, but was absent in myeloid cells in normal bone marrows. Our results suggest such combination therapies may significantly improve the therapeutic efficacy of FLT3 inhibitors. PRL-3 plays a potential pathological role in AML and it might be a useful therapeutic target in AML, and warrant clinical investigation

Online Focus Group Discussions to Engage Stigmatized Populations in Qualitative Health Research: Lessons Learned

Community participation in research involving stigmatized populations has been sub-optimal, and digital tools could potentially increase participation in qualitative research. This study aims to describe the implementation of an online chat-based FGD (Focus Group Discussion) with men who have sex with men (MSM) in China as part of formative research for the PIONEER project, determine the advantages and limitations associated with the approach, and assess the feasibility of deepening community participation in STI research. Participants were involved in four days of asynchronous FGDs on sexually transmitted diseases and answered questions about the online FGD method. Online FGDs allowed us to deepen participant engagement through bidirectional communication channels. Data from online FGDs directly informed recruitment strategies and community participation for a clinical trial. Overall, 63% (29/46) of men who had never participated in offline LGBTQ + activities joined online FGDs. Many participants (89%, 41/46) noted that online FGDs were more convenient, less socially awkward, and more anonymous than in-person qualitative research. We highlighted potential risks as well as mitigation strategies when using online FGDs. Online FGDs were feasible among this group of sexual minorities and may be particularly useful in many cities where stigma limits in-person research participation

Outcomes of a radiation sparing approach in medulloblastoma by subgroup in young children: an institutional review.

OBJECTIVE To describe disease outcomes including overall survival and relapse patterns by subgroup in young pediatric patients treated for medulloblastoma with a radiation-sparing approach. METHODS Retrospective analysis of clinical outcomes includes treatment, relapse, and salvage therapy and late effects in children treated for medulloblastoma with a radiation-sparing approach at British Columbia Children's Hospital (BCCH) between 2000 and 2020. RESULTS There were 30 patients (median age 2.8 years, 60% male) treated for medulloblastoma with a radiation-sparing approach at BCCH. Subgroups included Sonic Hedgehog (SHH) (n = 14), group 3 (n = 7), group 4 (n = 6), and indeterminate status (n = 3). Three- and 5-year event-free survival (EFS) were 49.0% (30.2-65.4%) and 42.0% (24.2-58.9%) and overall survival (OS) 66.0% (95% CI 46.0-80.1%) and 62.5% (95% CI 42.5 and 77.2%), respectively, with a median follow-up of 9.5 years. Relapse occurred in 12/25 patients following a complete response, of whom six (group 4: n = 4; group 3: n = 1; unknown: n = 1) were successfully salvaged with craniospinal axis (CSA) RT and remain alive at a median follow-up of 7 years. Disease/treatment-related morbidity included endocrinopathies (n = 8), hearing loss n = 16), and neurocognitive abnormalities (n = 9). CONCLUSIONS This radiation sparing treatment approach for young patients with medulloblastoma resulted in a durable cure in most patients with SHH subgroup medulloblastoma. In those patients with groups 3 and 4 medulloblastoma, relapse rates were high; however, most group 4 patients were salvaged with RT