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BACKGROUND: Enrichment strategies from clinical trials for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) have not been tested in a real-life cohort.RESEARCH QUESTION: Do enrichment strategies for progressive ILD impact efficacy, repre-sentativeness, and feasibility in patients with SSc-ILD from the European Scleroderma Trials and Research (EUSTAR) database?STUDY DESIGN AND METHODS: We applied the inclusion criteria of major recent SSc-ILD trials (Study of the Efficacy and Safety of Tocilizumab in Participants With Systemic Sclerosis [focuSSced], Scleroderma Lung Study II [SLS II], and Safety and Efficacy of Nintedanib in Systemic Sclerosis [SENSCIS]) and assessed progressive ILD, which was defined as absolute change in FVC and as significant progression (FVC decline $10%). Data were compared with all patients and with patients who did not fulfill any inclusion criteria. RESULTS: In total, 2,258 patients with SSc-ILD were included: 31.2% of the patients met SENSCIS criteria; 5.8% of the patients met SLS II criteria; 1.6% of the patients met focuSSced criteria, and 67.7% (1,529) of the patients did not meet any criteria. In the first 12 + 3 months, the absolute FVC decline in all patients and in patients who fulfilled criteria from SENSCIS was -0.1%, in patients who fulfilled criteria from focuSSced was -3.7%, and in patients who fulfilled criteria from SLS II was 2.3%, with accompanying more progressors in focuSSced. The patient populations that fulfilled the different study inclusion criteria significantly differed in various clinical parameters. In the second 12-month period, SENSCIS-enriched patients had a further absolute FVC% decline as described for the total cohort. In contrast, patients who fulfilled the focuSSced and SLS II criteria showed numeric improvement of lung function. There were no significant associations of enrichment criteria and ILD progression.INTERPRETATION: The application of enrichment criteria from previous clinical trials showed enrichment for progression with variable success, which led to selected patient populations reducing feasibility of recruitment. These findings are important for future clinical trial design and interpretation of the results of published trials.CHEST 2023; 163(3):586-598

This research offers a description and analysis of the relatively hidden practice of self-injury: cutting, burning, branding, and bone breaking. Drawing on over 150 in-depth interviews and tens of thousands of website postings, e-mail communications, and Internet groups, we challenge the psycho-medical depiction of this phenomenon and discuss ways that the contemporary sociological practice of self-injury has evolved to challenge images of the population, etiology, practice, and social meanings associated with this behavior. We conclude by suggesting that self-injury, for some, is in the process of undergoing a moral passage from the realm of medicalized to voluntarily chosen deviant behavior in which participants’ actions may be understood with a greater understanding of the sociological factors that contribute to the prevalence of these actions.

Michael Freeden, Ideology Studies: New Advances and Interpretations (London: Routledge, 2022) 208 pp. Thomas Fröhlich and Axel Schneider, eds., Chinese Visions of Progress, 1895 to 1949 (Leiden: Brill, 2020), 323 pp. Manfred Hettling and Wolfgang Schieder, eds., Reinhart Koselleck als Historiker: Zu den Bedingungen möglicher Geschichten [Reinhart Koselleck as a historian: On the conditions of possible histories] (Göttingen: Vandenhoeck & Ruprecht Press, 2021), 461 pp. Jesper Vestermark Køber, Niklas Olsen, and Heidi Vad Jønsson, eds., Citizen Categories in the Danish Welfare State: From the Founding Epoch to the Neoliberal Era (Odense: University Press of Southern Denmark, 2021), 208 pages.

This study compared the effects of an increasing-intensity (UP) and a decreasing-intensity (DOWN) resistance training protocol on affective responses across six training sessions. Novice participants (Mage 43.5 ± 13.7 years) were randomly assigned to UP (n = 18) or DOWN (n = 17) resistance training groups. Linear mixed-effects models showed that the evolution of affective valence within each training session was significantly moderated by the group (b = −0.45, p ≤ .001), with participants in the UP group reporting a decline in pleasure during each session (b = −0.82) and the DOWN group reporting an improvement (b = 0.97; ps b = 0.57, p = .004). These findings indicate that a pattern of decreasing intensity throughout a resistance exercise session can elicit more positive affective responses and retrospective affective evaluations of resistance training.

Wir plädieren dafür, eine Reduktion des Wirtschaftsumfangs als eine linke Strategie sozial-ökologischer Transformation zu stärken. Der öko-modernisierende Weg, klimapolitisch entscheidende Ziele bis 2030 zu erreichen, wird wahrscheinlich scheitern. Umso dringlicher ist es, auch ohne immer weitergehenden Einsatz von finanziellen Ressourcen mit hohen Renditeerwartungen und Rebound-Effekten den ökologischen Fußabdruck des Globalen Nordens drastisch zu verringern. Dies wird auf heftige Widerstände treffen, weswegen die gesellschaftliche Linke heikle Fragen, blinde Flecken, Vorbehalte und Missverständnisse in Bezug auf eine sozial-ökologische Reduktion thematisieren sollte.

This research aims to examine construction of the portfolio and also to explore factor variable affected on portfolio return. Portfolio stock derived the Elton Gruber model and compared it with portfolio returns calculated using the Equal Weighted and market capitalization weighted. This research used stock that is member of the Sri-Kehati Business Index, and monthly data from January 2015 to June 2022. This research has finding that there are 6 stocks to become member of stocks portfolio using Elton Gruber Model. By using Coefficient of Variation (CV), the equal weighted has the good portfolio because it has lowest of variation. Using t-test, there are no significant differences for three portfolios. Market Shock, Exchange Rate, Interest Rate and COVID-19 significantly affect Portfolio Return of Elton Gruber Model. Equal Weighted and Market Capitalization Portfolio only affect by Market shock. Based on this research results, it has implication that Investors do not need Fund Manager to manage their portfolio if investor use equal weighted or market capitalization weighted mode. JEL classification numbers: B26, B41, C01, C13, C51, D53, E44. Keywords: Construction Portfolio, Return Portfolio, Market Capitalization, Equal Weighted, Oil Price, Exchange Rate and interest rate, COVID-19.

Der vorliegende Artikel beschäftigt sich mit der Frage, warum Menschen mit und ohne Beeinträchtigungen gemeinsam Forschung und Entwicklung betreiben sollen. Er stellt mögliche Herausforderungen und entsprechende Lösungsansätze in der partizipativen Forschung vor. In einer gemeinsamen Auseinandersetzung kann eine Partizipationskultur etabliert werden. Und zum Ende wird klar: «Die Mischung macht’s!»; sowohl personell, methodisch als auch sonst in vielerlei Hinsicht.

Background: Essential tremor (ET) is a common movement disorder in which cerebellar microscopic and volume alterations have been repeatedly reported although with disagreement between studies. However, pronounced heterogeneity was found with regard to cerebellar volume alterations. Objective: This study aimed to assess postmortem cerebellar volume in subjects with or without ET, as compared with subjects with multiple system atrophy (MSA), a well-established cerebellar neurodegeneration. Methods: Cases with ET (n = 29), MSA (n = 7), and non-demented control cases without any movement disorder (n = 22) were selected from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study with annual research-dedicated clinical assessments by neuropsychologists, subspecialist movement disorders, and cognitive/behavioral neurologists, with comprehensive neuropathological examinations after death. Group comparisons were controlled for common age-related neurodegenerative and cerebrovascular pathologies. Cerebellar volumes were calculated using digital images of slices taken at the time of autopsy, immediately after brain removal and before fixation. Results: Cerebellar volume was not reduced in ET subjects compared to controls. The two groups did not differ in terms of incidental cerebrovascular and Alzheimer’s disease neuropathology. In contrast, cerebellar volume was significantly reduced in subjects with MSA when compared to ET and control subjects. Conclusion: In a well-characterized cohort, postmortem cerebellar volume measurements suggest that there are no volume alterations in ET when compared to controls, in contrast to significant cerebellar atrophy in subjects with MSA.

O bioma pantaneiro tem atualmente grande notoriedade diante da exibição da telenovela ‘Pantanal”, gravada na região sul-mato-grossense, local com cenários turísticos, de imensa biodiversidade e aspectos que são transmitidos em “horário nobre” pela televisão brasileira. Na telenovela, são tratadas temáticas relevantes acerca das questões socioambientais, como a produção agropecuária sustentável, a relação da sociedade com a terra em uma perspectiva afetiva, a utilização de tecnologias limpas, problemas ambientais locais como queimadas, seca, extinção de espécies e as ações antrópicas na região. Dando ênfase a isto, optou-se pela discussão dos temas na ótica da Educação Ambiental. Assim, considerando a obra televisiva, apresentou-se uma discussão sobre como essa literatura pode corroborar com a reflexão das questões socioambientais presentes no bioma Pantanal, sobretudo na contribuição dos temas relacionadas às políticas públicas de Educação Ambiental, concernente aos processos jurídicos e educacionais presentes à constituição da dimensão ambiental numa perspectiva crítica. Deste modo, identificou-se diálogos entre os personagens a respeito de fake news e o negacionismo presente atualmente em discursos de cunho socioambiental. Ademais, os temas que são de ordem econômica, política, cultural e ambiental devem ser discutidos numa abordagem interdisciplinar e/ou transversal entre os componentes curriculares como Ciências, Biologia, Geografia, Matemática, História etc.

Aerostructural optimization traditionally uses a single or small number of cruise conditions to estimate the mission fuel burn objective function. In reality, a mission includes other flight segments contributing to fuel burn, such as climbing and descent. We aim to quantify how much performance is sacrificed by optimizing the design for a fuel burn approximation that ignores these other flight segments and flight conditions. To do this, we compare traditional approaches to mission-based optimization, which uses an accurate fuel burn objective computed by numerically integrating fuel flow across the mission profile. We find that mission-based optimization offers only marginal benefits over traditional single-point and multipoint approaches for aerostructural optimization of a narrow-body aircraft—only 1–2% in the most extreme cases. Thus, the traditional aerostructural optimization is acceptable, especially in cases where most fuel is burned during cruise. For the cases where climb fuel burn is significant, we introduce a simple change to traditional fuel burn approximation methods that allows the optimizer to find nearly all the fuel burn reduction of mission-based optimization but at the computational cost of multipoint optimization.

Background Outbreaks of healthcare-associated respiratory syncytial virus (HA-RSV) infections in children are well described, but less is known about sporadic HA-RSV infections. We assessed the epidemiology and clinical outcomes associated with sporadic HA-RSV infections. Methods We retrospectively identified hospitalized children ≤18 years old with HA-RSV infections in six children’s hospitals in the United States during the respiratory viral seasons October–April in 2016–2017, 2017–2018, and 2018–2019 and prospectively from October 2020 through November 2021. We evaluated outcomes temporally associated with HA-RSV infections including escalation of respiratory support, transfer to the pediatric intensive care unit (PICU), and in-hospital mortality. We assessed demographic characteristics and comorbid conditions associated with escalation of respiratory support. Results We identified 122 children (median age 16.0 months [IQR 6, 60 months]) with HA-RSV. The median onset of HA-RSV infections was hospital day 14 (IQR 7, 34 days). Overall, 78 (63.9%) children had two or more comorbid conditions; cardiovascular, gastrointestinal, neurologic/neuromuscular, respiratory, and premature/ neonatal comorbidities were most common. Fifty-five (45.1%) children required escalation of respiratory support and 18 (14.8%) were transferred to the PICU. Five (4.1%) died during hospitalization. In the multivariable analysis, respiratory comorbidities (aOR: 3.36 [CI95 1.41, 8.01]) were associated with increased odds of escalation of respiratory support. Conclusions HA-RSV infections cause preventable morbidity and increase healthcare resource utilization. Further study of effective mitigation strategies for HA-respiratory viral infections should be prioritized; this priority is further supported by the impact of the COVID-19 pandemic on seasonal viral infections.

New graduate students in biology programs may lack the quantitative skills necessary for their research and professional careers. The acquisition of these skills may be impeded by teaching and mentoring experiences that decrease rather than increase students’ beliefs in their ability to learn and apply quantitative approaches. In this opinion piece, we argue that revising instructional experiences to ensure that both student confidence and quantitative skills are enhanced may improve both educational outcomes and professional success. A few studies suggest that explicitly addressing productive failure in an instructional setting and ensuring effective mentoring may be the most effective routes to simultaneously increasing both quantitative self-efficacy and quantitative skills. However, there is little work that specifically addresses graduate student needs, and more research is required to reach evidence-backed conclusions.

The microtubule-associated protein 7 (MAP7) is a protein involved in cargo transport along microtubules (MTs) by interacting with kinesin-1 through the C-terminal kinesin-binding domain. Moreover, the protein is reported to stabilize MT, thereby playing a key role in axonal branch development. An important element for this latter function is the 112 amino-acid long N-terminal microtubule-binding domain (MTBD) of MAP7. Here we report NMR backbone and side-chain assignments that suggest a primarily alpha-helical secondary fold of this MTBD in solution. The MTBD contains a central long α-helical segment that includes a short four-residue ‘hinge’ sequence with decreased helicity and increased flexibility. Our data represent a first step towards analysing the complex interaction of MAP7 with MTs at an atomic level via NMR spectroscopy.

A veracidade de se pensar e realizar a educação de diversas e diferentes formas voz traz a possibilidade de construir e delimitar perspectivas e epistemologias particulares, o que inclui a Educação Ambiental (EA) e sua insurgência com o movimento ambientalista. Contudo, as pautas reivindicadas por este movimento foram sendo incorporadas ao aparato do sistema hegemônico do neoliberalismo, apropriando discursos e conceitos que poderiam fraturar cada vez mais o sistema vigente. Nesta perspectiva, este ensaio nos conduz à reflexão da apropriação do neoliberalismo no que confere aos discursos da EA e do âmbito educacional, especificamente do currículo, para a manutenção do status quo. Propomos em contraposição o aprofundamento dos debates e reflexões em torno da EA crítica, da Ecologia Política e da Epistemologia Ambiental, os quais possuem potenciais de mitigação e transformação gradativa da relação sociedade-natureza. Assim, ressaltamos a essencialidade destas discussões, tendo em vista nossa relação com a natureza, a crise ambiental e as mudanças do clima, tão bem como nosso modo de produção científica.

Advancing age is recognized as the primary risk factor for Alzheimer’s disease (AD); however approximately one third of dementia cases are attributable to modifiable risk factors such as hypertension, diabetes, smoking, and obesity. Recent research also implicates oral health and the oral microbiome in AD risk and pathophysiology. The oral microbiome contributes to the cerebrovascular and neurodegenerative pathology of AD via the inflammatory, vascular, neurotoxic, and oxidative stress pathways of known modifiable risk factors. This review proposes a conceptual framework that integrates the emerging evidence regarding the oral microbiome with established modifiable risk factors. There are numerous mechanisms by which the oral microbiome may interact with AD pathophysiology. Microbiota have immunomodulatory functions, including the activation of systemic pro-inflammatory cytokines. This inflammation can affect the integrity of the blood-brain barrier, which in turn modulates translocation of bacteria and their metabolites to brain parenchyma. Amyloid-β is an antimicrobial peptide, a feature which may in part explain its accumulation. There are microbial interactions with cardiovascular health, glucose tolerance, physical activity, and sleep, suggesting that these modifiable lifestyle risk factors of dementia may have microbial contributors. There is mounting evidence to suggest the relevance of oral health practices and the microbiome to AD. The conceptual framework presented here additionally demonstrates the potential for the oral microbiome to comprise a mechanistic intermediary between some lifestyle risk factors and AD pathophysiology. Future clinical studies may identify specific oral microbial targets and the optimum oral health practices to reduce dementia risk.

Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as “small vessel disease” or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia.

Este trabalho aborda a resistência dos agricultores familiares frente à expansão urbana. O lugar da pesquisa é o Assentamento Santa Rita de Cássia II, localizado em Nova Santa Rita, Rio Grande do Sul. Os agricultores familiares neste assentamento adotam estratégias de resistência para manter os seus campos ocupados com as suas atividades agrícolas. A pesquisa foi realizada com o uso de entrevistas nas suas formas semiestruturadas através da aplicação de questionários, que combinam perguntas fechadas e abertas e observações feitas em trabalhos de campo. De acordo com os resultados da pesquisa, as diferentes estratégias de resistência que os agricultores familiares utilizam no assentamento são os canais de produção agroecológica, especialmente a produção de arroz ecológico e de hortaliças, sem esquecer a contribuição do PAA e do Grupo Gestor do Arroz Ecológico, COCEARGS e COOTAP. A partir da importância da produção agroecológica, foi possível identificar que uma parcela significativa dos agricultores familiares adotou a produção orgânica como estratégia de resistência à expansão urbana. São produtos que carregam o simbolismo do MST, dos agricultores familiares que fazem esta luta, mas são também produtos ligados à discussão da economia sustentável e solidária. Matriz inserida na resistência dos agricultores familiares, construída por 80 famílias assentadas que produziram na Safra 2021-2022. Aqui é expresso o conteúdo das estratégias de resistência desses agricultores familiares, gerando territórios de produção agroecológica, de resistência e de emancipação. Palavras chave: Expansão urbana. PA SRC II. Produção agroecológica. Resistência dos Agricultores familiares assentados.

We present evidence for marked endothelial dysfunction in lean women with androgen excess polycystic ovary syndrome (AE-PCOS) that is 1) associated with free testosterone levels, 2) impaired relative to overweight/obese women with AE-PCOS, and 3) unchanged following short-term ethinyl estradiol supplementation. These data indicate an important direct effect of androgens on the vascular system in women with AE-PCOS. Our data also suggest that the relationship between androgens and vascular health differs between phenotypes of AE-PCOS.

BACKGROUND: Most COVID-19 patients were treated in primary health care (PHC) in Europe. OBJECTIVES: To demonstrate the scope of PHC workflow during the COVID-19 pandemic emphasising similarities and differences of patient's clinical pathways in Europe. METHODS: Descriptive, cross-sectional study with data acquired through a semi-structured questionnaire in PHC in 30 European countries, created ad hoc and agreed upon among all researchers who participated in the study. GPs from each country answered the approved questionnaire. Main variable: PHC COVID-19 acute clinical pathway. All variables were collected from each country as of September 2020. RESULTS: COVID-19 clinics in PHC facilities were organised in 8/30. Case detection and testing were performed in PHC in 27/30 countries. RT-PCR and lateral flow tests were performed in PHC in 23/30, free of charge with a medical prescription. Contact tracing was performed mainly by public health authorities. Mandatory isolation ranged from 5 to 14 days. Sick leave certification was given exclusively by GPs in 21/30 countries. Patient hotels or other resources to isolate patients were available in 12/30. Follow-up to monitor the symptoms and/or new complementary tests was made mainly by phone call (27/30). Chest X-ray and phlebotomy were performed in PHC in 18/30 and 23/30 countries, respectively. Oxygen and low-molecular-weight heparin were available in PHC (21/30). CONCLUSION: In Europe PHC participated in many steps to diagnose, treat and monitor COVID-19 patients. Differences among countries might be addressed at European level for the management of future pandemics. ispartof: Eur J Gen Pract vol:29 issue:2 pages:2182879- ispartof: location:England status: published

This study aims to determine the effect of Net Interest Margin (NIM), Non-Performing Loan (NPL), oil price, exchange rate, market power, and female BOD gender on bank risk in go public commercial banks listed on the IDX and KLSE (2009-2019). In this study, the sampling technique used was purposive sampling technique which resulted in 32 banks. The secondary data used is obtained from financial reports published on the official IDX and IDX websites. The data analysis method used in this research is panel data regression analysis. The results showed that the total assets variable affects NIM, NPL, Oil Prices, Exchange Rates, Market Power, and Female BOD Gender on Bank Risk in Go Public Commercial Banks listed on the IDX and KLSE. The regression test results can be concluded that the constant coefficient value of -0.770544 means that if the variable NIM (X1), NPL (X2), Exchange Rate (X3), Oil Price (X4), Market Power (X5), and Female BDO Gender (X6) is zero, then the amount of Bank Risk is -0.1770544. JEL classification numbers: C31, E51, G21, J16. Keywords: Bank, Profitability, Total Assets, Risk.

Objective To develop a computable representation for medical evidence and to contribute a gold standard dataset of annotated randomized controlled trial (RCT) abstracts, along with a natural language processing (NLP) pipeline for transforming free-text RCT evidence in PubMed into the structured representation. Materials and methods Our representation, EvidenceMap, consists of 3 levels of abstraction: Medical Evidence Entity, Proposition and Map, to represent the hierarchical structure of medical evidence composition. Randomly selected RCT abstracts were annotated following EvidenceMap based on the consensus of 2 independent annotators to train an NLP pipeline. Via a user study, we measured how the EvidenceMap improved evidence comprehension and analyzed its representative capacity by comparing the evidence annotation with EvidenceMap representation and without following any specific guidelines. Results Two corpora including 229 disease-agnostic and 80 COVID-19 RCT abstracts were annotated, yielding 12 725 entities and 1602 propositions. EvidenceMap saves users 51.9% of the time compared to reading raw-text abstracts. Most evidence elements identified during the freeform annotation were successfully represented by EvidenceMap, and users gave the enrollment, study design, and study Results sections mean 5-scale Likert ratings of 4.85, 4.70, and 4.20, respectively. The end-to-end evaluations of the pipeline show that the evidence proposition formulation achieves F1 scores of 0.84 and 0.86 in the adjusted random index score. Conclusions EvidenceMap extends the participant, intervention, comparator, and outcome framework into 3 levels of abstraction for transforming free-text evidence from the clinical literature into a computable structure. It can be used as an interoperable format for better evidence retrieval and synthesis and an interpretable representation to efficiently comprehend RCT findings.

To understand conservatism as an isolated ideology is an almost hopeless endeavor; after all, conservative thinking is always embedded into specific ideological constellations. While the mirror-image effect identified by Michael Freeden generally emphasizes the conceptual intertwining of conservatism with other ideologies, the example of German conservatism highlights its structural dependence on liberalism, described here as the liberal question. The article focuses on the context of radical conservatism and sheds light on the radicalization of German conservative thought in the nineteenth century focusing on the thinkers Hermann Wagener (1815–1889) and Paul de Lagarde (1827–1891). Despite their different biographical and political starting points, both Wagener and Lagarde developed a radicalized conservatism that made the (intellectual) struggle against liberalism the supreme task of their metapolitical agenda. In the context of the so-called Conservative Revolution in the Weimar Republic, this radical thinking condensed into a distinct political movement. The historical reconstruction of this episode of radicalization of German conservatism thus also serves to provide a differentiated view of contemporary right-wing phenomena in general.

Focal cortical dysplasias (FCDs) are malformations of cortical development and one of the most common pathologies causing pharmacoresistant focal epilepsy. Resective neurosurgery yields high success rates, especially if the full extent of the lesion is correctly identified and completely removed. The visual assessment of magnetic resonance imaging does not pinpoint the FCD in 30%-50% of cases, and half of all patients with FCD are not amenable to epilepsy surgery, partly because the FCD could not be sufficiently localized. Computational approaches to FCD detection are an active area of research, benefitting from advancements in computer vision. Automatic FCD detection is a significant challenge and one of the first clinical grounds where the application of artificial intelligence may translate into an advance for patients' health. The emergence of new methods from the combination of health and computer sciences creates novel challenges. Imaging data need to be organized into structured, well-annotated datasets and combined with other clinical information, such as histopathological subtypes or neuroimaging characteristics. Algorithmic output, that is, model prediction, requires a technically correct evaluation with adequate metrics that are understandable and usable for clinicians. Publication of code and data is necessary to make research accessible and reproducible. This critical review introduces the field of automatic FCD detection, explaining underlying medical and technical concepts, highlighting its challenges and current limitations, and providing a perspective for a novel research environment.