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Disruptive technologies can have far-reaching impacts on society. They may challenge or destabilize cherished ethical values and disrupt legal systems. There is a convergent interest among ethicists and legal scholars in such “second-order disruptions” to norm systems. Thus far, however, ethical and legal approaches to technological norm-disruption have remained largely siloed. In this paper, we propose to integrate the existing ‘dyadic’ models of disruptive change in the ethical and legal spheres, and shift focus to the relations between and mutual shaping of values, technology, and law. We argue that a ‘triadic’ values-technology-regulation model—“the technology triad”—is more descriptively accurate, as it allows a better mapping of second-order impacts of technological changes (on values and norms, through changes in legal systems—or on legal systems, through changes in values and norms). Simultaneously, a triadic model serves to highlight a broader portfolio of ethical, technical, or regulatory interventions that can enable effective ethical triage of—and a more resilient response to—such Socially Disruptive Technologies. We illustrate the application of the triadic framework with two cases, one historical (how the adoption of the GDPR channeled and redirected the evolution of the ethical value of ‘privacy’ when that had been put under pressure by digital markets), and one anticipatory (looking at anticipated disruptions caused by the ongoing wave of generative AI systems).

Treatment of the tumor and dural margin with surgery and sometimes radiation are cornerstones of therapy for meningioma. Molecular classifications have provided insights into the biology of disease; however, response to treatment remains heterogeneous. In this study, we used retrospective data on 2,824 meningiomas, including molecular data on 1,686 tumors and 100 prospective meningiomas, from the RTOG-0539 phase 2 trial to define molecular biomarkers of treatment response. Using propensity score matching, we found that gross tumor resection was associated with longer progression-free survival (PFS) across all molecular groups and longer overall survival in proliferative meningiomas. Dural margin treatment (Simpson grade 1/2) prolonged PFS compared to no treatment (Simpson grade 3). Molecular group classification predicted response to radiotherapy, including in the RTOG-0539 cohort. We subsequently developed a molecular model to predict response to radiotherapy that discriminates outcome better than standard-of-care classification. This study highlights the potential for molecular profiling to refine surgical and radiotherapy decision-making.

Climate change and global warming necessitate the shift toward low-emission, carbon-free fuels. Although hydrogen boasts zero carbon content and high performance, its utilization is impeded by the complexities and costs involved in liquefaction, preservation, and transportation. Ammonia has emerged as a viable alternative that offers potential as a renewable energy storage medium and supports the global economy’s decarbonization. With its broader applicability in large power output applications, decentralized energy sources, and industrial locations off the grid, ammonia is increasingly regarded as an essential fuel for the future. Although ammonia provides a sustainable solution for future low-carbon energy fields, its wide-scale adoption is limited by NOXemissions and poor combustion performance under certain conditions. As research on ammonia combustion expands, recent findings reveal factors impacting the chemical reaction pathways of ammonia-based fuels, including the equivalence ratio, fuel mixture, pressure, and temperature. Investigations into ammonia combustion and NOXemissions, at both laboratory and industrial scales, have identified NOXproduction peaks at equivalence ratios of 0.8–0.9 for ammonia/hydrogen blends. The latest studies about the NOXemissions of the ammonia flame at different conditions and their generating pathways are reviewed in this work. Effective reduction in NO production from ammonia-based flames can be achieved with richer blends, which generate more NHiradicals. Other advanced NOXmitigation techniques such as plasma-assisted combustion have been also explored. Further research is required to address these challenges, reduce emissions, and improve efficiencies of ammonia-based fuel blends. Finally, the extinction limit of ammonia turbulent flame, its influential factors, and different strategies to promote the ammonia flame stability were discussed. The present review contributes to disseminating the latest advancements in the field of ammonia combustion and highlights the importance of refining reaction mechanisms, computational models, and understanding fundamental phenomena for practical implications.

IMPORTANCE: The use of real-world data (RWD) external control arms in prospective studies is increasing. The advantages, including the immediate availability of a control population, must be balanced with the requirements of meeting evidentiary standards. OBJECTIVE: To address the question of whether and to what extent the methods of RWD studies compare to standard methods used in randomized clinical trials. EVIDENCE REVIEW: A systematic search across 4 electronic databases and Google Scholar was conducted from January 1, 2000, to October 23, 2023. Studies were included in the systematic review if they compared an intervention arm in a clinical trial to an RWD control arm in patients with hematological cancers and if they were published between 2000 and 2023. FINDINGS: Thirty-two prospective intervention studies incorporating external control data from RWD sources of patients with hematological cancers were identified. A total of 4306 patients from intervention arms and 10 594 from RWD control arms were included across all studies. Only 2 studies (6%) included prospectively collected RWD. The complete trial inclusion criteria were applied to the RWD cohort in 7 studies (22%). Four studies (13%) published the statistical analysis plan and prespecified use of RWD. A total of 23 studies (72%) applied matching algorithms for trial and RWD cohorts, including matching for demographic, disease, and/or therapy-related characteristics. The end point criteria were the same as the trial in 8 studies (25%). In contrast, 12 studies (38%) used different end points, and 12 (38%) did not provide an end point definition for the RWD. Twelve studies (38%) had a median follow-up difference of less than a year between arms. Eight studies (25%) reported toxic effect data for the trial arm, of which 5 studies reported toxic effect data for the RWD arm. CONCLUSIONS AND RELEVANCE: In this systematic review, limitations were observed in the application of clinical trial eligibility criteria to RWD, statistical rigor and application of matching methods, the definition of end points, follow-up, and reporting of adverse events, which may challenge the conclusions reported in studies using RWD.

Background: Natural health products have emerged as a potential symptomatic therapeutic approach for people with Parkinson’s disease (PD).Objective: To determine the prevalence of natural health product use, interest in natural health products, awareness of potential herb-drug interactions, and consultation of healthcare professionals regarding natural health products use among people with PD.Methods: Cross-sectional 4-item survey embedded in the PRIME-NL study, which is a population-based cohort of PD.Results: Of 367 people with PD, 36% reported having used natural health products to alleviate PD-related symptoms, with coffee, cannabis and turmeric being the most popular. Furthermore, 71% of people with PD were interested in learning more about natural health products. 39% of natural health products users were aware that these products could interact with PD medication and 39% had discussed their use with their healthcare professional.Conclusions: Natural health products are commonly used to alleviate symptoms by people with PD, but most users are unaware that these products can interact with PD medication and do not discuss their consumption with their healthcare professional.

Natural health products have emerged as a potential symptomatic therapeutic approach for people with Parkinson’s disease (PD). To determine the prevalence of natural health product use, interest in natural health products, awareness of potential herb-drug interactions, and consultation of healthcare professionals regarding natural health products use among people with PD. Cross-sectional 4-item survey embedded in the PRIME-NL study, which is a population-based cohort of PD. Of 367 people with PD, 36% reported having used natural health products to alleviate PD-related symptoms, with coffee, cannabis and turmeric being the most popular. Furthermore, 71% of people with PD were interested in learning more about natural health products. 39% of natural health products users were aware that these products could interact with PD medication and 39% had discussed their use with their healthcare professional. Natural health products are commonly used to alleviate symptoms by people with PD, but most users are unaware that these products can interact with PD medication and do not discuss their consumption with their healthcare professional. Parkinson’s disease is a complex neurodegenerative disorder for which current treatments are limited to symptomatic relief, and prescribed medication often causes side effects. In this context, there is an increasing interest in non-pharmacological interventions, and people living with Parkinson’s disease may want to explore natural health products to alleviate disease-associated symptoms. Examples of these products include cannabis, coffee, or velvet bean (as a natural source of Levodopa). However, it remains unclear how many people with Parkinson’s disease have ever used, or wish to use, natural health products to relieve disease-related symptoms. In addition, limited information is available to evaluate whether they are aware of possible interactions between these products and prescribed medication. Therefore, the aim of this study was to investigate these questions in a large representative group of people with Parkinson’s disease. A total of 367 people responded to the survey, and 36% reported that they had used natural health products to relieve Parkinson’s disease-related symptoms. Among the supplements listed in our survey, coffee (16%), cannabis (13%) and turmeric (10%) were the most popular. Additionally, 71% of participants were interested in learning more about natural health products, and we found that 39% of natural health product users were aware of possible interactions with prescribed Parkinson’s disease medication. However, it appeared that only 39% of users had discussed these supplements with their healthcare provider. These observations are important because a concern regarding the integration of natural health products into clinical practice is their potential interactions with prescribed medication. Therefore, these findings support the need for additional research efforts into the health benefits and safety of these products. We conclude that natural health products are used by people with Parkinson’s disease to provide symptomatic relief, and open discussions with their healthcare providers are encouraged to ensure efficacy and safety.

Alport syndrome (AS) is a hereditary kidney disorder of type IV collagen caused by pathogenic variants in the COL4A3, COL4A4, and COL4A5genes. Previously several cases of digenic AS, caused by two pathogenic variants in two of the three COL4Agenes, have been reported. Patients with digenic AS may present with a more severe phenotype compared to patients with single variants, depending on the percentage affected type IV trimeric collagen chain. We report a newly discovered case of trigenic AS. A 52-year-old female presented with hematuria at the age of 24 years and developed hypertension by the age of 30. Over the years, she developed chronic kidney disease; the most recent eGFR was 44 mL/min/1.73 m2. She has symmetric high-tone sensorineural hearing loss. Full genetic analysis revealed a heterozygous pathogenic variant c.2691del in COL4A3,a heterozygous pathogenic variant c.1663dup in COL4A4,and a complete heterozygous deletion of COL4A5. We describe the first patient with AS caused by pathogenic variants in all three COL4Agenes, designated trigenic AS. This case report emphasizes the importance of examining all three COL4Agenes, even in patients with a mild Alport phenotype, for optimal follow-up of the patient and adequate genetic counseling of family members.

MRI, ultrasound, and conventional radiography each play distinct roles in the evaluation of juvenile idiopathic arthritis (JIA), with MRI being the preferred imaging modality of choice for assessing both inflammatory and destructive changes. These various imaging modalities provide valuable insights into JIA in pediatric patients. However, challenges persist in terms of achieving precision, ensuring validity, and distinguishing between pathologic findings and normal anatomic variations. Establishing normal reference values and implementing scoring systems can aid in the precise evaluation of disease activity and provide information to assist treatment decisions for children with JIA. Ongoing advancements in imaging techniques and standardization initiatives aim to bolster the accuracy of JIA diagnosis and assessment, ultimately leading to enhanced patient care and treatment outcomes.

People with Parkinson’s disease (PD) experience a range of progressive motor and non-motor symptoms, that negatively affect their daily functioning, social participation and quality of life. Allied health therapies have emerged as an effective treatment approach—complementary to pharmacological and neurosurgical treatments—which reduces the impact of PD in daily life. In this article, we propose criteria for what constitutes specialized allied health care for PD, and we review allied health research in PD in terms of meeting these criteria and its outcomes for monodisciplinary approaches as well as multi- or interdisciplinary allied health interventions. We focus on the three most studied allied health disciplines in PD: physical therapy, occupational therapy and speech-language therapy. Overall, the available evidence underscores the importance and potential benefits of specialized allied health care for people with PD. Our proposed criteria and recommendations for future research might help in further delineating specialized allied health care.

Diel rhythms are observed across taxa and are important for maintaining synchrony between the environment and organismal physiology. A striking example of this is the diel vertical migration undertaken by zooplankton, some of which, such as the 5 mm-long copepod Pleuromamma xiphias(P. xiphias), migrate hundreds of meters daily between the surface ocean and deeper waters. Some of the molecular pathways that underlie the expressed phenotype at different stages of this migration are entrained by environmental variables (e.g., day length and food availability), while others are regulated by internal clocks. We identified a series of proteomic biomarkers that vary across ocean DVM and applied them to copepods incubated in 24 h of darkness to assess circadian control. The dark-incubated copepods shared some proteomic similarities to the ocean-caught copepods (i.e., increased abundance of carbohydrate metabolism proteins at night). Shipboard-incubated copepods demonstrated a clearer distinction between night and day proteomic profiles, and more proteins were differentially abundant than in the in situcopepods, even in the absence of the photoperiod and other environmental cues. This pattern suggests that there is a canalization of rhythmic diel physiology in P. xiphiasthat reflects likely circadian clock control over diverse molecular pathways.

Video Abstract1_3mw2euyiKaltura

Sinking or floating is the natural state of planktonic organisms and particles in the ocean. Simulating these conditions is critical when making measurements, such as respirometry, because they allow the natural exchange of substrates and products between sinking particles and water flowing around them and prevent organisms that are accustomed to motion from changing their metabolism. We developed a rotating incubator, the RotoBOD (named after its capability to rotate and determine biological oxygen demand, BOD), that uniquely enables automated oxygen measurements in small volumes while keeping the samples in their natural state of suspension. This allows highly sensitive rate measurements of oxygen utilization and subsequent characterization of single particles or small planktonic organisms, such as copepods, jellyfish, or protists. As this approach is nondestructive, it can be combined with several further measurements during and after the incubation, such as stable isotope additions and molecular analyses. This makes the instrument useful for ecologists, biogeochemists, and potentially other user groups such as aquaculture facilities. Here, we present the technical background of our newly developed apparatus and provide examples of how it can be utilized to determine oxygen production and consumption in small organisms and particles.

ABSTRACTPrevious research suggests that the entrepreneurial ecosystems (EEs) support factors are critical for the systemic development of micro, small. and medium enterprises (MSMEs). However, there is limited understanding of how MSME owner's/manager’s characteristics impact their perspectives of the EE support factors for business development. This study addresses this research gap to adopt a coherent approach to understand the EE in supporting MSMEs to achieve transformational entrepreneurship (TE), which builds sustainable businesses for long-term societal benefits. The MSMEs characteristics alongside the EE factors were tested with 576 MSMEs in Nigeria. The MSME owner's/manager’s characteristics were positively correlated to their perspective of EE support factors (access to finance, markets, resources, and policies and regulations), which were inadequate. The findings will assist theory and practice development to understand and focus on the EE discussed in the context of TE in Nigeria, offering potential insights for similar developing economies.

Objectives: This qualitative study aims to analyze current PM regulation and market access requirements and proposes potential solutions to mitigate current challenges. Methods: Twenty-two semi-structured interviews were conducted with experts from pharmaceutical industry, regulatory authorities, national health technology assessment (HTA) bodies, pediatricians, and academia from the Netherlands (NL), Germany (DE), the United Kingdom (UK), and France (FR) to get insight into the pediatric research, the regulatory and reimbursement processes, challenges, and solutions. Themes for further testing were developed on how to facilitate pediatric market access. Atlas.ti 9 was used to analyze the findings. Results: Heterogeneity in requirements for the European Medicines Agency (EMA) and HTA approvals are noted. By example, DE grants direct reimbursement after regulatory approval, the other countries require additional reimbursement which generate delays and challenges in patient access after marketing authorization. Key components in facilitating PM market access include multi-stakeholder collaboration, transparency, patient representatives, informed consent guidance, real-world evidence, and appropriate clinical trial designs. Pricing models based on the economic capabilities of individual countries could further reduce delays and challenges in market access. The additional specific pediatric incentives should be taken as best practice to encourage innovation in pediatric conditions. Conclusion: This study highlights differences in requirements for regulatory and reimbursement approval, along with international differences in pricing and reimbursement procedures for pediatric market access.

The objective of this study was to explore to what extent patients with axial spondyloarthritis (axSpA) link experienced pain in the neck, back, and hips to inflammation and/or structural damage. Patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort visiting the outpatient clinic between 2016 and 2019 filled out two additional questions in relation to the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) question 2: (1) “To what extent do you think the pain you experience in your neck, back, and hips is related to inflammation caused by axSpA?” and (2) “To what extent do you think the pain you experience in your neck, back, and hips is related to damage of the spine and joints caused by axSpA?” Answers had to be depicted on a numeric rating scale from 0 (none) to 10 (very much); a difference of ≥2 points between the scores of these questions was considered clinically relevant in favor of the highest scoring question. A total of 688 patients with axSpA (24% with nonradiographic axSpA [nr‐axSpA]) were included (62% male, mean ± SD age 48 ± 14 years, and mean ± SD Ankylosing Spondylitis Disease Activity Score [ASDAS] 2.3 ± 1.0). Seventy‐five percent of patients could not link the origin of their pain, 15% linked axial pain predominantly to inflammation, and 10% linked axial pain predominantly to damage. Patients in the inflammation group were younger, had shorter symptom duration, were more frequently diagnosed with nr‐axSpA, had higher ASDASCRP, had more often elevated CRP levels, had fewer comorbidities, had better spinal mobility, and had less spinal radiographic damage. In our large observational cohort, the majority of patients with axSpA could not differentiate the origin of experienced axial pain. If patients were able to link axial pain to clinical inflammation or damage, it was in concordance with clinical assessments and radiographic outcome, which may be helpful in establishing the origin of pain and supporting better patient‐centered treatment decisions.

Studies on the effect of computer-aided detection (CAD) in a daily clinical screening and surveillance colonoscopy population practice are scarce. The aim of this study was to evaluate a novel CAD system in a screening and surveillance colonoscopy population.

Heavy menstrual bleeding (HMB) is associated with a reduced quality of life and limitations in social and physical functioning. Data on HMB in women with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, are scarce.

The Extracorporeal Life Support Organization (ELSO) maintains the world’s largest extracorporeal membrane oxygenation (ECMO) registry by volume, center participation, and international scope. This 2022 ELSO Registry Report describes the program characteristics of ECMO centers, processes of ECMO care, and reported outcomes. Neonates (0–28 days), children (29 days–17 years), and adults (≥18 years) supported with ECMO from 2009 through 2022 and reported to the ELSO Registry were included. This report describes adjunctive therapies, support modes, treatments, complications, and survival outcomes. Data are presented descriptively as counts and percent or median and interquartile range (IQR) by year, group, or level. Missing values were excluded before calculating descriptive statistics. Complications are reported per 1,000 ECMO hours. From 2009 to 2022, 154,568 ECMO runs were entered into the ELSO Registry. Seven hundred and eighty centers submitted data during this time (557 in 2022). Since 2009, the median annual number of adult ECMO runs per center per year increased from 4 to 15, whereas for pediatric and neonatal runs, the rate decreased from 12 to 7. Over 50% of patients were transferred to the reporting ECMO center; 20% of these patients were transported with ECMO. The use of prone positioning before respiratory ECMO increased from 15% (2019) to 44% (2021) for adults during the coronavirus disease-2019 (COVID-19) pandemic. Survival to hospital discharge was greatest at 68.5% for neonatal respiratory support and lowest at 29.5% for ECPR delivered to adults. By 2022, the Registry had enrolled its 200,000th ECMO patient and 100,000th patient discharged alive. Since its inception, the ELSO Registry has helped centers measure and compare outcomes across its member centers and strategies of care. Continued growth and development of the Registry will aim to bolster its utility to patients and centers.

Invariant natural killer T cells are a rare, heterogeneous T-cell subset with cytotoxic and immunomodulatory properties. During thymic development, murine invariant natural killer T cells go through different maturation stages differentiating into distinct sublineages, namely, invariant natural killer T1, 2, and 17 cells. Recent reports indicate that invariant natural killer T2 cells display immature properties and give rise to other subsets, whereas invariant natural killer T1 cells seem to be terminally differentiated. Whether human invariant natural killer T cells follow a similar differentiation model is still unknown. To define the maturation stages and assess the sublineage commitment of human invariant natural killer T cells during thymic development, in this study, we performed single-cell RNA sequencing analysis on human Vα24+Vβ11+invariant natural killer T cells isolated from thymocytes. We show that these invariant natural killer T cells displayed heterogeneity, and our unsupervised analysis identified 5 clusters representing different maturation stages, from an immature profile with high expression of genes important for invariant natural killer T cell development and proliferation to a mature, fully differentiated profile with high levels of cytotoxic effector molecules. Evaluation of expression of sublineage-defining gene sets revealed mainly cells with an invariant natural killer T2 signature in the most immature cluster, whereas the more differentiated ones displayed an invariant natural killer T1 signature. Combined analysis with a publicly available single-cell RNA sequencing data set of human invariant natural killer T cells from peripheral blood suggested that the 2 main subsets exist both in thymus and in the periphery, while a third more immature one was restricted to the thymus. Our data point to the existence of different maturation stages of human thymic invariant natural killer T cells and provide evidence for sublineage commitment of invariant natural killer T cells in the human thymus.Human thymus contains different maturation stages of invariant natural killer T cells and facilitates sublineage commitment with invariant natural killer T2 properties in the most immature cells and an invariant natural killer T1 signature in the more differentiated clusters.Human thymus contains different maturation stages and facilitates sublineage commitment of invariant natural killer T cells.

IMPORTANCE: Neoadjuvant short-course radiotherapy was routinely applied for nonlocally advanced rectal cancer (cT1-3N0-1M0 with >1 mm distance to the mesorectal fascia) in the Netherlands following the Dutch total mesorectal excision trial. This policy has shifted toward selective application after guideline revision in 2014. OBJECTIVE: To determine the association of decreased use of neoadjuvant radiotherapy with cancer-related outcomes and overall survival at a national level. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, population-based, nationwide cross-sectional cohort study analyzed Dutch patients with rectal cancer who were treated in 2011 with a 4-year follow-up. A similar study was performed in 2021, analyzing all patients that were surgically treated in 2016. From these cohorts, all patients with cT1-3N0-1M0 rectal cancer and radiologically unthreatened mesorectal fascia were included in the current study. The data of the 2011 cohort were collected between May and October 2015, and the data of the 2016 cohort were collected between October 2020 and November 2021. The data were analyzed between May and October 2022. MAIN OUTCOMES AND MEASURES: The main outcomes were 4-year local recurrence and overall survival rates. RESULTS: Among the 2011 and 2016 cohorts, 1199 (mean [SD] age, 68 [11] years; 430 women [36%]) of 2095 patients (57.2%) and 1576 (mean [SD] age, 68 [10] years; 547 women [35%]) of 3057 patients (51.6%) had cT1-3N0-1M0 rectal cancer and were included, with proportions of neoadjuvant radiotherapy of 87% (2011) and 37% (2016). Four-year local recurrence rates were 5.8% and 5.5%, respectively (P = .99). Compared with the 2011 cohort, 4-year overall survival was significantly higher in the 2016 cohort (79.6% vs 86.4%; P < .001), with lower non–cancer-related mortality (13.8% vs 6.3%; P < .001). CONCLUSIONS AND RELEVANCE: The results of this cross-sectional study suggest that an absolute 50% reduction in radiotherapy use for nonlocally advanced rectal cancer did not compromise cancer-related outcomes at a national level. Optimizing clinical staging and surgery following the Dutch total mesorectal excision trial has potentially enabled safe deintensification of treatment.