Hope, hype, and cure: Ethics and four-letter words in pediatric cancer care.

Cancer occupies a special place in the collective consciousness, influencing how hope is expressed. Patients, families, and clinical teams hope for the best possible medical outcome, yet may perceive a given outcome as more or less likely to occur. Hope, hype, and cure exist along a continuum. These four-letter words influence care delivery, including uptake of innovative therapies. Physicians shape patient/parental hope. What physicians say may be viewed as less important than how it is said. Subtle changes in how hope is understood may contribute to hype and perspectives on cure. Through listening to children/parents, physicians respect and reinforce patients'/families' hopes.

Dark loops: contagion effects, consistency and chemosocial matrices in psychedelic-assisted therapy trials.

What happens when an emerging programme of medical research overlaps with a surging social movement? In this article we draw on the anthropological term 'chemosociality' to describe forms of sociality born of shared chemical exposure. Psychedelic administration in the context of recent clinical trials appears to have been particularly chemosocial in nature. We argue that one consequence is that psychedelic-assisted therapy (PAT) clinical research trials tend to breach key assumptions underlying the logic of causal inference used to establish efficacy. We propose the concept of dark loops to describe forms of sociality variously emerging from, and impacting participant experiences in, PAT trials. These dark loops are not recorded, let alone incorporated into the causal pathways in the interpretation of psychedelic trial data to date. We end with three positions which researchers might adopt in response to these issues: chemosocial minimisation where research is designed to attenuate or eliminate the effects of dark loops in trials; chemosocial description where dark loops (and their impacts) are openly and candidly documented and chemosocial valorisation where dark loops are hypothesised to contribute to trial outcomes and actively drawn upon for positive effect. Our goal is to fold in an appreciation of how the increasingly-discussed hype surrounding psychedelic research and therapeutics continues to shape the phenomena under study in complex ways, even as trials become larger and more rigorous in their design.

Proteomic and Mutant Analysis of Hydrogenase Maturation Protein Gene hypE in Symbiotic Nitrogen Fixation of Mesorhizobium huakuii.

Hydrogenases catalyze the simple yet important redox reaction between protons and electrons and H2, thus mediating symbiotic interactions. The contribution of hydrogenase to this symbiosis and anti-oxidative damage was investigated using the M. huakuii hypE (encoding hydrogenase maturation protein) mutant. The hypE mutant grew a little faster than its parental 7653R and displayed decreased antioxidative capacity under H2O2-induced oxidative damage. Real-time quantitative PCR showed that hypE gene expression is significantly up-regulated in all the detected stages of nodule development. Although the hypE mutant can form nodules, the symbiotic ability was severely impaired, which led to an abnormal nodulation phenotype coupled to a 47% reduction in nitrogen fixation capacity. This phenotype was linked to the formation of smaller abnormal nodules containing disintegrating and prematurely senescent bacteroids. Proteomics analysis allowed a total of ninety differentially expressed proteins (fold change > 1.5 or <0.67, p < 0.05) to be identified. Of these proteins, 21 are related to stress response and virulence, 21 are involved in transporter activity, and 18 are involved in energy and nitrogen metabolism. Overall, the HypE protein is essential for symbiotic nitrogen fixation, playing independent roles in supplying energy and electrons, in bacterial detoxification, and in the control of bacteroid differentiation and senescence.

Deletion of mFICD AMPylase alters cytokine secretion and affects visual short-term learning in vivo.

Fic domain-containing AMP transferases (fic AMPylases) are conserved enzymes that catalyze the covalent transfer of AMP to proteins. This posttranslational modification regulates the function of several proteins, including the ER-resident chaperone Grp78/BiP. Here we introduce a mouse FICD (mFICD) AMPylase knockout mouse model to study fic AMPylase function in vertebrates. We find that mFICD deficiency is well tolerated in unstressed mice. We also show that mFICD-deficient mouse embryonic fibroblasts are depleted of AMPylated proteins. mFICD deletion alters protein synthesis and secretion in splenocytes, including that of IgM, an antibody secreted early during infections, and the proinflammatory cytokine IL-1ß, without affecting the unfolded protein response. Finally, we demonstrate that visual nonspatial short-term learning is stronger in old mFICD-/- mice than in wild-type controls while other measures of cognition, memory, and learning are unaffected. Together, our results suggest a role for mFICD in adaptive immunity and neuronal plasticity in vivo.

Cold Spray: Over 30 Years of Development Toward a Hot Future.

Cold Spray (CS) is a deposition process, part of the thermal spray family. In this method, powder particles are accelerated at supersonic speed within a nozzle; impacts against a substrate material triggers a complex process, ultimately leading to consolidation and bonding. CS, in its modern form, has been around for approximately 30 years and has undergone through exciting and unprecedented developmental steps. In this article, we have summarized the key inventions and sub-inventions which pioneered the innovation aspect to the process that is known today, and the key breakthroughs related to the processing of materials CS is currently mastering. CS has not followed a liner path since its invention, but an evolution more similar to a hype cycle: high initial growth of expectations, followed by a decrease in interest and a renewed thrust pushed by a number of demonstrated industrial applications. The process interest is expected to continue (gently) to grow, alongside with further development of equipment and feedstock materials specific for CS processing. A number of current applications have been identified the areas that the process is likely to be the most disruptive in the medium-long term future have been laid down.

Investigation of the Detailed AMPylated Reaction Mechanism for the Huntingtin Yeast-Interacting Protein E Enzyme HYPE.

AMPylation is a prevalent posttranslational modification that involves the addition of adenosine monophosphate (AMP) to proteins. Exactly how Huntingtin-associated yeast-interacting protein E (HYPE), as the first human protein, is involved in the transformation of the AMP moiety to its substrate target protein (the endoplasmic reticulum chaperone binding to immunoglobulin protein (BiP)) is still an open question. Additionally, a conserved glutamine plays a vital key role in the AMPylation reaction in most filamentation processes induced by the cAMP (Fic) protein. In the present work, the detailed catalytic AMPylation mechanisms in HYPE were determined based on the density functional theory (DFT) method. Molecular dynamics (MD) simulations were further used to investigate the exact role of the inhibitory glutamate. The metal center, Mg2+, in HYPE has been examined in various coordination configurations, including 4-coordrinated, 5-coordinated and 6-coordinated. DFT calculations revealed that the transformation of the AMP moiety of HYPE with BiP followed a sequential pathway. The model with a 4-coordinated metal center had a barrier of 14.7 kcal/mol, which was consistent with the experimental value and lower than the 38.7 kcal/mol barrier of the model with a 6-coordinated metal center and the 31.1 kcal/mol barrier of the model with a 5-coordinated metal center. Furthermore, DFT results indicated that Thr518 residue oxygen directly attacks the phosphorus, while the His363 residue acts as H-bond acceptor. At the same time, an MD study indicated that Glu234 played an inhibitory role in the α-inhibition helix by regulating the hydrogen bond interaction between Arg374 and the Pγ of the ATP molecule. The revealed sequential pathway and the inhibitory role of Glu234 in HYPE were inspirational for understanding the catalytic and inhibitory mechanisms of Fic-mediated AMP transfer, paving the way for further studies on the physiological role of Fic enzymes.

Creating a Scalable Physical Activity Breaks Resource Through the Multisensory Multilevel Health Education Model: H.Y.P.E. The Breaks!

Physically active children have lower rates of obesity, diabetes, hypertension, and depression than their inactive counterparts, and further evidence suggests that integrating physical activity breaks into the school day improves children's classroom behavior, fitness, and cognitive functions. The current article focuses on the development and implementation of free, scalable, short activity breaks called H.Y.P.E. The Breaks! (Helping Young People Energize)-a series of 2-, 6-, and 10-minute-long dance and hip-hop-based physical activity videos, which can be used in the classroom or at home. H.Y.P.E. The Breaks! is deconstructed through the lens of the multisensory multilevel health education model, which leverages art, culture, and science in the design and implementation of health programs, and highlights the importance of framing and operationalizing program components across the different behavioral levels of influence of the socioecological model. The article also discusses the uptake of H.Y.P.E. The Breaks! during the COVID-19 (coronavirus disease 2019) pandemic, when major declines in children's physical activity were observed.

[Second chance for renal artery denervation]. / Vtoroi shans dlia denervatsii pochechnykh arterii.

The article is a review of contemporary randomized studies on radiofrequency denervation of renal arteries, followed by critical assessment of their advantages and disadvantages for possible optimization of endovascular treatment of resistant arterial hypertension.

A Fluorescence Polarization-Based High-Throughput Screen to Identify the First Small-Molecule Modulators of the Human Adenylyltransferase HYPE/FICD.

The covalent transfer of the AMP portion of ATP onto a target protein-termed adenylylation or AMPylation-by the human Fic protein HYPE/FICD has recently garnered attention as a key regulatory mechanism in endoplasmic reticulum homeostasis, neurodegeneration, and neurogenesis. As a central player in such critical cellular events, high-throughput screening (HTS) efforts targeting HYPE-mediated AMPylation warrant investigation. Herein, we present a dual HTS assay for the simultaneous identification of small-molecule activators and inhibitors of HYPE AMPylation. Employing the fluorescence polarization of an ATP analog fluorophore-Fl-ATP-we developed and optimized an efficient, robust assay that monitors HYPE autoAMPylation and is amenable to automated, high-throughput processing of diverse chemical libraries. Challenging our pilot screen with compounds from the LOPAC, Spectrum, MEGx, and NATx libraries yielded 0.3% and 1% hit rates for HYPE activators and inhibitors, respectively. Further, these hits were assessed for dose-dependency and validated via orthogonal biochemical AMPylation assays. We thus present a high-quality HTS assay suitable for tracking HYPE's enzymatic activity, and the resultant first small-molecule manipulators of HYPE-promoted autoAMPylation.

Nutrient mitigation under the impact of climate and land-use changes: A hydro-economic approach to participatory catchment management.

Excessive nutrient loadings into rivers are a well-known ecological problem. Implemented mitigation measures should ideally be cost-effective, but perfectly ranking alternative nutrient mitigation measures according to cost-effectiveness is a difficult methodological challenge. Furthermore, a particularly practical challenge is that cost-effective measures are not necessarily favoured by local stakeholders, and this may impede their successful implementation in practice. The objective of this study was to evaluate the cost-effectiveness of mitigation measures using a methodology that includes a participatory process and social learning to ensure their successful implementation. By combining cost data, hydrological modelling and a bottom-up approach for three different European catchment areas (the Latvian Berze, the Swedish Helge and the German Selke rivers), the cost-effectiveness of 16 nutrient mitigation measures were analysed under current conditions as well as under selected scenarios for future climate and land-use changes. Fertiliser reduction, wetlands, contour ploughing and municipal wastewater treatment plants are the measures that remove nutrients with the highest cost-effectiveness in the respective case study context. However, the results suggest that the cost-effectiveness of measures not only depends on their design, specific location and the conditions of the surrounding area, but is also affected by the future changes the area may be exposed to. Climate and land-use changes do not only affect the cost-effectiveness of measures, but also shape the overall nutrient loads and potential target levels in a catchment.

Blocking the Hype-Hypocrisy-Falsification-Fakery Pathway is Needed to Safeguard Science.

In chemistry and other sciences, hype has become commonplace, compounded by the hypocrisy of those who tolerate or encourage it while disapproving of the consequences. This reduces the credibility and trust upon which all science depends for support. Hype and hypocrisy are but first steps down a slippery slope towards falsification of results and dissemination of fake science. Systemic drivers in the contemporary structure of the science establishment encourage exaggeration and may lure the individual into further steps along the hype-hypocrisy-falsification-fakery continuum. Collective, concerted intervention is required to effectively discourage entry to this dangerous pathway and to restore and protect the probity and reputation of the science system. Chemists must play and active role in this effort.

Hope, hype and harms of Big Data.

Big Data are characterised by greater volumes of data from a greater variety of sources which are produced and processed at greater velocity. Huge digitised datasets from electronic medical records, registries, administrative datasets and genomic databanks can now be analysed by advanced computer programs to reveal patterns, trends and associations previously indiscernible using conventional analytic methods. These new insights may have important implications for clinical care. But Big Data can be limited by inaccuracies and bias inherent to observational datasets and which cannot be eliminated simply by using ever enlarging data sets or more sophisticated software. The hope and hype of Big Data cannot be allowed to override potential for harm, and the need for concurrent development of new research designs, better analytic methods and rigorous evaluation of predictive accuracy and effects on care and outcomes.

From a Patient Advocate's Perspective: Does Cancer Immunotherapy Represent a Paradigm Shift?

PURPOSE OF REVIEW: In 2016, the American Society of Clinical Oncology (ASCO) announced immunotherapy as the year's top cancer advance in its "Clinical Cancer Advances 2016: ASCO's Annual Report on Progress Against Cancer." Further, ASCO again named "Immunotherapy 2.0" as the 2017 advance of the year, emphasizing the recent, rapid pace of research into new agents that harness and enhance the innate abilities of the immune system to recognize and fight cancers-and stressing that such agents have extended the lives of many patients with late-stage cancers for which there have been few treatment options. This article discusses the history of cancer immunotherapy and the recent promising advances, yet also presents a note of caution on limitations of immunotherapies, their potential harms, and the critical need for oncologists to appropriately engage with and educate patients to effectively manage their expectations. RECENT FINDINGS: Learning how to effectively harness the immune system to treat cancer represents an investigative journey of more than 100 years. However, after many failures and disappointments, this decade has seen several important successes. In 2011, the Food and Drug Administration (FDA) approved the first immunotherapy agent known as a "checkpoint inhibitor." Beginning in 2014, several additional checkpoint blockage drugs have been FDA-approved, and new indications and drug combinations have emerged. Further, on August 30, 2017, the FDA announced its first approval of a new form of immunotherapy known as CAR T cell therapy. Since the 2011 approval of the first checkpoint inhibitor, cancer immunotherapy research among the pharmaceutical industry and research institutions has exploded, with thousands of clinical trials currently taking place. The current "cancer immunotherapy revolution" is in the headlines daily and is also the primary topic of conversation among major cancer research conferences and symposia attendees. However, a once quiet voice has begun to emerge, where an increasing number of scientists, clinicians, and patient advocates are stressing the need for caution concerning the limitations and potential harms associated with cancer immunotherapy. Many oncologists, scientists, medical professional associations, and advocates agree that no recent cancer advance has been as successful, transformative, and potentially paradigm-shifting as immunotherapy. With this decade, we have seen the approval of several immunotherapy agents that have successfully treated a percentage of patients with notoriously resistant cancers, an increasing number of combination immunotherapy treatments, and new indications for approved agents. However, patients need to be aware that much of the popular media has breathlessly inflated positive outcomes of cancer immunotherapies, while neglecting to stress that just a small percentage of patients actually benefit from such treatments. Further, they often completely overlook the unique, potentially life-threatening harms that may be associated with these agents and fail to cover negative findings where immunotherapies have appeared to paradoxically accelerate cancer growth. Fortunately, the majority of journal articles presenting trial results and comprehensive review articles appropriately discuss the important limitations associated with immunotherapies, the unique spectrum of adverse effects, and the need for further research to improve our ability to identify those patients who are most likely to benefit from specific agents, sparing other patients from exposure to agents that will not be effective, yet may carry potentially life-threatening toxicities.

Beyond the hype? The response to sexual violence in the Democratic Republic of the Congo in 2011 and 2014.

The Democratic Republic of the Congo (DRC) has witnessed a high prevalence of sexual violence since the wars of the mid-1990s. The huge response to it commenced around the turn of the century, but turned to 'hype' towards 2010. The paper defines 'hypes' as phenomena characterised by a media frenzy, eagerness by non-governmental organisations, and pragmatic local responses. Interviews and analyses conducted in 2011 revealed misuse of services and misrepresentation at different levels. The paper goes on to review medical and legal assistance and to provide evidence of incremental improvements in the response since 2012. It has become better coordinated, with more engagement by the DRC government, more community-oriented, and has incorporated a broader notion of gender-based violence. Nonetheless, concern remains about its impact and its continued dependence on international resources. There is apprehension too about social reactions to the problems of corruption and impunity, seemingly adding to the confusion surrounding gender relations in the country.

Media attention regarding sudden cardiac death associated with domperidone use does not affect in hospital ECG recording.

PURPOSE: In March 2013, regulatory warnings concerning the potential risks of domperidone caused considerable media attention in the Netherlands. The aim of the study was to assess the effect of regulatory warnings and the resulting media hype on the frequency of electrocardiogram (ECG) monitoring of inpatients using domperidone. We also studied the effect on the frequency of prescribing domperidone by physicians. METHODS: A 2-centre, observational, retrospective cohort study was performed. Inpatients using domperidone in 2 hospitals in the Netherlands during a period of 384 days before and after the media hype were included. The main outcomes were (1) the proportion of domperidone users with ECGs before and/or during domperidone treatment, (2) the proportion of patients with an ECG before and during treatment, and (3) the proportion of patients with an ECG during treatment. Secondary outcome was the proportion of domperidone prescriptions comparing the before- and after-period. RESULTS: Four hundred twenty-eight patients were included. The main outcomes [respectively (1) relative risk (RR) 1.02, 95% confidence interval (CI), 0.85-1.21; (2) RR 1.06, 95% CI, 0.60-1.85; and (3) RR 1.27, 95% CI, 0.80-2.01) were not different. After stratifying for hospital, no significant differences were found. A statistically significant decrease (RR 0.40, 95% CI, 0.35-0.45) in numbers of prescriptions was found for the university medical centre only. CONCLUSIONS: No effect of the media hype was found on the intensity of ECG monitoring in domperidone users. In the university medical centre, domperidone prescriptions were reduced.

HypE-specific nanobodies as tools to modulate HypE-mediated target AMPylation.

The covalent addition of mono-AMP to target proteins (AMPylation) by Fic domain-containing proteins is a poorly understood, yet highly conserved post-translational modification. Here, we describe the generation, evaluation, and application of four HypE-specific nanobodies: three that inhibit HypE-mediated target AMPylation in vitro and one that acts as an activator. All heavy chain-only antibody variable domains bind HypE when expressed as GFP fusions in intact cells. We observed localization of HypE at the nuclear envelope and further identified histones H2-H4, but not H1, as novel in vitro targets of the human Fic protein. Its role in histone modification provides a possible link between AMPylation and regulation of gene expression.

A novel link between Fic (filamentation induced by cAMP)-mediated adenylylation/AMPylation and the unfolded protein response.

The maintenance of endoplasmic reticulum (ER) homeostasis is a critical aspect of determining cell fate and requires a properly functioning unfolded protein response (UPR). We have discovered a previously unknown role of a post-translational modification termed adenylylation/AMPylation in regulating signal transduction events during UPR induction. A family of enzymes, defined by the presence of a Fic (filamentation induced by cAMP) domain, catalyzes this adenylylation reaction. The human genome encodes a single Fic protein, called HYPE (Huntingtin yeast interacting protein E), with adenylyltransferase activity but unknown physiological target(s). Here, we demonstrate that HYPE localizes to the lumen of the endoplasmic reticulum via its hydrophobic N terminus and adenylylates the ER molecular chaperone, BiP, at Ser-365 and Thr-366. BiP functions as a sentinel for protein misfolding and maintains ER homeostasis. We found that adenylylation enhances BiP's ATPase activity, which is required for refolding misfolded proteins while coping with ER stress. Accordingly, HYPE expression levels increase upon stress. Furthermore, siRNA-mediated knockdown of HYPE prevents the induction of an unfolded protein response. Thus, we identify HYPE as a new UPR regulator and provide the first functional data for Fic-mediated adenylylation in mammalian signaling.

The "Magical Theory" of AI in Medicine: Thematic Narrative Analysis.

BACKGROUND: The discourse surrounding medical artificial intelligence (AI) often focuses on narratives that either hype the technology's potential or predict dystopian futures. AI narratives have a significant influence on the direction of research, funding, and public opinion and thus shape the future of medicine. OBJECTIVE: The paper aims to offer critical reflections on AI narratives, with a specific focus on medical AI, and to raise awareness as to how people working with medical AI talk about AI and discharge their "narrative responsibility." METHODS: Qualitative semistructured interviews were conducted with 41 participants from different disciplines who were exposed to medical AI in their profession. The research represents a secondary analysis of data using a thematic narrative approach. The analysis resulted in 2 main themes, each with 2 other subthemes. RESULTS: Stories about the AI-physician interaction depicted either a competitive or collaborative relationship. Some participants argued that AI might replace physicians, as it performs better than physicians. However, others believed that physicians should not be replaced and that AI should rather assist and support physicians. The idea of excessive technological deferral and automation bias was discussed, highlighting the risk of "losing" decisional power. The possibility that AI could relieve physicians from burnout and allow them to spend more time with patients was also considered. Finally, a few participants reported an extremely optimistic account of medical AI, while the majority criticized this type of story. The latter lamented the existence of a "magical theory" of medical AI, identified with techno-solutionist positions. CONCLUSIONS: Most of the participants reported a nuanced view of technology, recognizing both its benefits and challenges and avoiding polarized narratives. However, some participants did contribute to the hype surrounding medical AI, comparing it to human capabilities and depicting it as superior. Overall, the majority agreed that medical AI should assist rather than replace clinicians. The study concludes that a balanced narrative (that focuses on the technology's present capabilities and limitations) is necessary to fully realize the potential of medical AI while avoiding unrealistic expectations and hype.

Reproducibility in chemistry research.

Chemistry is a reproducible science whose pillars - synthesis and analysis - actually comprise a huge collection of highly reproducible experimental methods to synthesize and analyze substances. The historical development of chemistry, furthermore, shows that reproducibility of methods has been the companion of novelty and creative innovation. The "publish or perish" principle dominating global academia since over two decades, however, intrinsically contributes to the publication of non-reproducible research outcomes also in chemistry. A study on reproducibility of chemistry research seems therefore timely, especially now that chemists are slowly but inevitably adopting open science and its tools such as the preprint, open access, and data sharing. We conclude presenting three simple guidelines for enhanced publication of research findings in chemistry.

Exploring diverse interests of collaborators in smart cities: A topic analysis using LDA and BERT.

Smart cities have emerged as a promising solution to the problems associated with urbanization. However, research that holistically considers diverse stakeholders in smart cities is scarce. This study utilizes data from four types of collaborators (academia, public sector, industry, and civil society actors) to identify key topics and suggest research areas for developing smart cities. We used latent Dirichlet allocation and Bidirectional Encoder Representations from Transformers for topic extraction and analysis. The analysis reveals that sustainability and digital platform have received similar levels of interest from academia, industry, and government, whereas governance, resource, and green space are less frequently mentioned than technology-related topics. Hype cycle analysis, which considers public and media expectations, reveals that smart cities experienced rapid growth from 2015 to 2021, but the growth rate has slowed since 2022. This means that a breakthrough improvement in the current situation is required. Accordingly, we propose resolving the unbalanced distribution of topic interests among collaborators, especially in the areas of governance, environment, economy, and healthcare. We expect that our findings will help researchers, policymakers, and industry stakeholders in understanding which topics are underdeveloped in their fields and taking active measures for the future development of smart cities.