Potential Role Research Articles

The protective effect of DNase I in retinal vein occlusion.

Retinal vein occlusion (RVO) ranks as the second most prevalent retinal vascular disease, following diabetic retinopathy. Neutrophil extracellular traps (NETs) play an important role in vascular diseases. This study aimed to elucidate the relationship between NETs and RVO, and to discern the potential role of deoxyribonuclease I (DNase I) in the prevention and treatment of RVO through the modulation of NETs. We analyzed circulating NETs biomarkers, namely cell-free DNA (cf-DNA), myeloperoxidase (MPO)-DNA, and neutrophil elastase (NE), in 30 RVO patients and 30 healthy individuals. We established an RVO mouse model using a retinal laser, and the mice were categorized into two groups: the DNase I group and the control group. Retinal images were taken at predetermined time points, and the state of the retinal vessels was assessed. Both tissue and blood samples were harvested for analysis of NETs expression through methods such as western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA). Our finding indicate an increase in circulating NETs biomarkers in human and mouse RVO cases, while also verifying the presence of NETs in the retinal thrombus of the RVO model. Both in vitro and in vivo tests revealed that DNase I attenuated NETs formation. Moreover, DNase I injections led to diminished NETs biomarker levels and a reduced duration of the thrombus after the RVO model establishment. Consequently, DNase I, a well-established modulator of NETs formation, might exhibit protective properties in the prevention and treatment of RVO.

Secondary school teachers' perceptions of the shared creative processes and the potential role of technology in the expressive arts

AbstractWith the introduction of Curriculum for Wales and the restructuring of subjects into Areas of Learning and Experience (AoLE), each AoLE is encouraged to have ‘an identifiable disciplinary and instrumental core’. When considered in combination with the COVID‐19 pandemic and increased technology use within teaching, both the shared creative processes and the potential role of technology are important to conceptualise. This paper provides insight into expressive arts teachers' perceptions of the macro‐level creative processes shared across each subject area through a technology lens. A new tripartite classification provides clarity regarding the macro‐level creative processes (Creative opportunities, Critical responses and Performance/production) and the role of technology to enable equal opportunities and wider accessibility for learners to access, and potentially succeed within, the creative process.

Jailing is failing: psychiatry can help.

There is accumulating evidence that imprisonment is expensive but does little to address the underlying drivers of offending. At the same time, it is now recognised that a large proportion of prisoners are diagnosable with significant psychiatric disorders. In this piece we explore the potential role of psychiatry in addressing the societal challenge of a failing prison system. We argue that core psychiatric skills of engaging in balanced, values-based thinking and implementing sound clinical processes can play an important role in reducing reoffending risk. We briefly discuss some of the key challenges involved and outline several relevant service models.

Prosocial behavior and work reattachment in healthcare: the mediating and moderating influence of mindfulness and awe

PurposeAmidst the stressful work environment in the healthcare sector, employees struggle to maintain prosocial behavior and work reattachment. The potential role of awe and mindfulness in addressing these issues remains unexplored. This study investigates how coworker prosocial behavior affects work reattachment while considering the mediating role of mindfulness and the moderating role of awe.Design/methodology/approachUsing a quantitative research design, data were collected through a survey questionnaire from 356 healthcare professionals in Pakistan. The data were analyzed in SPSS and AMOS for reliability and validity statistics, as well as for hypothesis testing.FindingsThe findings revealed a significant link between coworker prosocial behavior and work reattachment. Mindfulness acted as a mediator between coworker prosocial behavior and work reattachment, while awe had a positive moderating effect on these relationships.Practical implicationsThe findings emphasize the need for fostering these elements to manage stress, support employees and improve work reattachment.Originality/valueThe existing literature lacks empirical evidence regarding the impact of coworker prosocial behavior on employee outcomes, and this study contributes by examining the roles of awe and mindfulness in the healthcare sector.

Fatty acid esters of hydroxy fatty acids: A potential treatment for obesity-related diseases.

Obesity, a burgeoning worldwide health system challenge, is associated with multiple chronic diseases, including diabetes and chronic inflammation. Fatty acid esters of hydroxy fatty acids (FAHFAs) are newly identified lipids with mitigating and anti-inflammatory effects in diabetes. Increasing work has shown that FAHFAs exert antioxidant activity and enhance autophagy in neuronal cells and cardiomyocytes. We systematically summarized the biological activities of FAHFAs, including their regulatory effects on diabetes and inflammation, antioxidant activity, and autophagy augmentation. Notably, the structure-activity relationships and potential biosynthesis of FAHFAs are thoroughly discussed. FAHFAs also showed potential roles as diagnostic biomarkers. FAHFAs are a class of resources with promising applications in the biomedical field that require in-depth research and hotspot development, as their structure has not been fully resolved and their biological activity has not been fully revealed.

OsGADD45a1: a multifaceted regulator of rice architecture, grain yield, and blast resistance.

The homolog gene of the Growth Arrest and DNA Damage-inducible 45 (GADD45) in rice functions in the regulation of plant architecture, grain yield, and blast resistance. The Growth Arrest and DNA Damage-inducible 45 (GADD45) family proteins, well-established stress sensors and tumor suppressors in mammals, serve as pivotal regulators of genotoxic stress responses and tumorigenesis. In contrast, the homolog and role of GADD45 in plants have remained unclear. Herein, using forward genetics, we identified an activation tagging mutant AC13 exhibited dwarf characteristics resulting from the loss-of-function of the rice GADD45α homolog, denoted as OsGADD45a1. osgadd45a1 mutants displayed reduced plant height, shortened panicle length, and decreased grain yield compared to the wild-type Kitaake. Conversely, no obvious differences in plant height, panicle length, or grain yield were observed between wild-type and OsGADD45a1 overexpression plants. OsGADD45a1 displayed relatively high expression in germinated seeds and panicles, with localization in both the nucleus and cytoplasm. RNA-sequencing analysis suggested a potential role for OsGADD45a1 in the regulation of photosynthesis, and binding partner identification indicates OsGADD45a1 interacts with OsRML1 to regulate rice growth. Intriguingly, our study unveiled a novel role for OsGADD45a1 in rice blast resistance, as osgadd45a1 mutant showed enhanced resistance to Magnaporthe oryzae, and the expression of OsGADD45a1 was diminished upon blast fungus treatment. The involvement of OsGADD45a1 in rice blast fungus resistance presents a groundbreaking finding. In summary, our results shed light on the multifaceted role of OsGADD45a1 in rice, encompassing biotic stress response and the modulation of several agricultural traits, including plant height, panicle length, and grain yield.

Genetic variant detection in a South African haemophilia B population.

Haemophilia B is characterised by a deficiency of factor IX (FIX) protein due to genetic variants in the FIX gene (F9). Genetic testing may have a vital role in effectively managing haemophilia B. However, in many developing countries, comprehensive genetic variant detection is unavailable. This study aimed to address the lack of genetic data in our country by conducting genetic variant detection on people affected by haemophilia B in our region. Twenty-one participants were screened with a direct Sanger sequencing method to identify variants in the F9 gene. The identified variants were then compared to previously published variants and/or to a reference database. A total of ten F9 genetic changes were detected, with five of them being novel. These identified variants were distributed across different domains of the FIX protein. Only one participant had a history of inhibitor formation against FIX replacement therapy. Notably, this participant had two distinct genetic changes present adjacent to each other. Thus, we hypothesise that the presence of multiple variants within the same functional region of the gene may increase the risk for inhibitor development. The discovery of novel pathogenic variations in the F9 gene highlights the importance of genetic analysis in specific geographical regions. The possible link between a complex variant and inhibitor formation illustrates the potential role that genetic screening has as a pre-treatment tool in predicting treatment reactions and outcomes.

Reconstructing Rural Settlements Based on Investigation of Consolidation Potential: Mechanisms and Paths

Rural settlement consolidation (RSC) is an important tool for improving rural habitat environments, and the potential evaluation of RSC is the premise for rural settlement planning. This paper identified the potential sources of RSC in different reconstruction modes and built an influencing factor system for RSC. We analyzed the spatial differentiation patterns of the theoretical potential and the realistic potential, and we identified the factors influencing the potential realization based on an empirical investigation in China. Influenced by multiple constraints, the potential transition from theoretical to realistic was spatially differentiated and showed a spatial agglomeration at the village level. Rural depopulation had a direct impact on the theoretical potential of RSC, while the distance to the downtown, rural population, per capita GDP, and production and living conditions played an important role in the realistic potential. Particularly, rural settlement basic conditions, rural population, and arable land resources profoundly affected farmer exit willingness and the potential transition from theoretical to realistic. Four optimization paths for rural settlement reconstruction linking to land use policies were proposed, which could provide valuable information for rural settlement planning in socioeconomic transformation regions.

Introduction: Student Experiences of COVID-19 Around the Globe: Insights from the Pandemic Journaling Project.

The COVID-19 crisis has taken a significant toll on the mental health of many students around the globe. In addition to the traumatic effects of loss of life and livelihood within students' families, students have faced other challenges, including disruptions to learning and work; decreased access to health care services; emotional struggles associated with loneliness and social isolation; and difficulties exercising essential rights, such as rights to civic engagement, housing, and protection from violence. Such disruptions negatively impact students' developmental, emotional, and behavioral health and wellbeing and also become overlaid upon existing inequities to generate intersectional effects. With these findings in mind, this special issue investigates how COVID-19 has affected the mental health and wellbeing of high school and college students in diverse locations around the world, including the United States, Mexico, Brazil, China, and South Africa. The contributions collected here analyze data collected through the Pandemic Journaling Project, a combined research study and online journaling platform that ran on a weekly basis from May 2020 through May 2022, along with complementary projects and using additionalresearch methods, such as semi-structured interviews and autobiographical writing by students. The collection offers a nuanced, comparative window onto the diverse struggles that students and educators experienced at the height of the pandemic and considers potential solutions for addressing the long-term impacts of COVID-19. It also suggests a potential role for journaling in promoting mental wellbeing among youth, particularly in the Global South.

Performance of a commercially available Generative Pre-trained Transformer (GPT) in describing radiolucent lesions in panoramic radiographs and establishing differential diagnoses.

To evaluate the performance of a commercially available Generative Pre-trained Transformer (GPT) in describing and establishing differential diagnoses for radiolucent lesions in panoramic radiographs. Twenty-eight panoramic radiographs, each containing a single radiolucent lesion, were evaluated in consensus by three examiners and a commercially available ChatGPT-3.5 model. They provided descriptions regarding internal structure (radiodensity, loculation), periphery (margin type, cortication), shape, location (bone, side, region, teeth/structures), and effects on adjacent structures (effect, adjacent structure). Diagnostic impressions related to origin, behavior, and nature were also provided. The GPT program was additionally prompted to provide differential diagnoses. Keywords used by the GPT program were compared to those used by the examiners and scored as 0 (incorrect), 0.5 (partially correct), or 1 (correct). Mean score values and standard deviation were calculated for each description. Performance in establishing differential diagnoses was assessed using Rank-1, -2, and - 3. Descriptions of margination, affected bone, and origin received the highest scores: 0.93, 0.93, and 0.87, respectively. Shape, region, teeth/structures, effect, affected region, and nature received considerably lower scores ranging from 0.22 to 0.50. Rank-1, -2, and - 3 demonstrated accuracy in 25%, 57.14%, and 67.85% of cases, respectively. The performance of the GPT program in describing and providing differential diagnoses for radiolucent lesions in panoramic radiographs is variable and at this stage limited in its use for clinical application. Understanding the potential role of GPT systems as an auxiliary tool in image interpretation is imperative to validate their clinical applicability.

Occurrence of the ossification of petrosphenoid ligament: a retrospective radiologic study from computed tomographic images.

Various ligaments present in the skull base are of clinical and surgical importance. One among them, is the petrosphenoid ligament (PSL). PSL may ossify either in a partial or complete form and forms the roof of Dorello's canal underneath which the abducens nerve passes. Studies argued both protective and adverse effects of the ossified PSL. Hence, the incidence of PSL ossification has become a relevant subject in clinical practice to radiologists, neurologists and neurosurgeons for understanding its potential role in abducens nerve compression. We have undertaken this study to investigate the incidence of PSL ossification from multidetector computed tomography (MDCT) images of the patients who had been referred to the Medical Imaging Department of Mubarak Al-Kabeer Hospital in Kuwait. We retrospectively assessed a total of 200 patients' head CT scans (400 petroclival regions) between January 2021 and June 2022 in which 59% were males (n = 118) and 41% were females (n = 82) aged between 18 and 91 years. A total of 37 patients (26 male, 11 female) aged between 18-84 years were presented with ossification of PSL. Among these 37 patients, 28 patients were presented with unilateral ossified PSL, and 9 patients were presented with bilateral ossified PSL, amounting to the total of 46 ossified PSL from 400 CT images of the petroclival regions (11.5%). The genderwise and sidewise occurrence of the PSL ossification seen in different age groups were not statistically significant (p > 0.05). Among all the ossified cases, there was no patient presented with abducens nerve palsy. We believe our results provide baseline data in the region for understanding PSL ossification and its impact on the abducens nerve palsy.

Morphological and Biochemical Characterization of Phyllosphere Bacteria

Phyllosphere bacteria, residing on the surfaces of plant leaves, play crucial roles in plant health and environmental processes. This study aimed to investigate the morphological and biochemical traits of the isolated phyllosphere bacteria from cereal plant species. Isolates were collected from the leaves of different cereal plants and subjected to morphological and biochemical assays were performed to characterize their metabolic capabilities. Results revealed a diverse array of morphotypes, including cocci and bacilli, indicating the presence of varied bacterial species in the phyllosphere. Furthermore, a set of biochemical analyses highlighted metabolic versatility among isolates, with varying abilities to utilize different carbon sources and produce enzymes. These findings underscore the heterogeneity and metabolic diversity of phyllosphere bacteria, suggesting their potential roles in nutrient cycling, plant growth promotion and disease suppression. Further exploration of these characteristics could elucidate the mechanisms underlying plant-microbe interactions in the phyllosphere and inform strategies for sustainable agriculture and environmental management.

Radiomic-Based Biomarkers for the Evaluation of Prosthetic Heart Valve Infective Endocarditis in Non-Attenuation Correction [18F]FDG PET/CT Images

Although there have been crucial advancements in the diagnostic and treatment approaches, the mortality rate of infective endocarditis is still an ongoing challenge in clinical practice. [18F]FDG PET/CT imaging has recently proven its potential role in the early identification of prosthetic valve endocarditis (PVE). Due to radiomics’ rising applicability, recent studies exhibit promising outcomes in the clinical setting. The aim of the present study is the evaluation of potential radiomic-based biomarkers of non-attenuation-corrected (NAC) [18F]FDG PET images for the diagnosis of PVE. An adequate pre-processing and segmentation of the prosthetic ring metabolic activity were performed. A reproducibility analysis prior to the image-based biomarkers’ identification was conducted in terms of the intraclass correlation coefficient (ICC) derived from the variations in the radiomic extraction configurations (bin number and voxel size). After the reliability analysis, statistical analysis was performed by means of the Mann–Whitney U Test to study the differences between the PVE groups. Only p values < 0.05 after the Benjamini Hochberg correction procedure for multiple comparisons were considered statistically significant. Eight ML classification models for PVE classification based on radiomic features were evaluated. Overall, 45.2% and 95.7% of the radiomic features showed a consistency ICC above 0.82, demonstrating great reproducibility against variations in the bin number and interpolation thickness, respectively. Variations in interpolation thickness demonstrated great reproducibility in absolute agreement with 80.0% robust features, proving a non-dependency relationship with radiomic values. In the present study, the utility of potential radiomic-based biomarkers in the diagnosis of PVE in NAC [18F]FDG PET/CT images has been evaluated. Future studies will be required to validate the use of this technology as a valuable tool to support the current PVE diagnostic criteria.

POLR3A-mutated Wiedemann-Rautenstrauch fibroblasts display differential profile of intron retention and expression of TP53 isoforms

BACKGROUND: Wiedemann-Rautenstrauch Syndrome (WRS) is a neonatal progeroid syndrome for which biallelic pathogenic variants in RNA polymerase III subunit A (POLR3A) have recently been described. POLR3 is a 17 subunits protein complex responsible for the transcription of short RNAs including all the transfer RNAs (tRNAs), the 5 S subunit of ribosomal RNA, the short nuclear RNA U6, among other regulatory RNAs. OBJECTIVE: We aim to evaluate the impact of POLR3A pathogenic variants on the relative expression of the short nuclear RNA U6 and on the differential profile of intron retention RNA U6, p53 isoforms and in fibroblasts derived from patients with WRS and control fibroblasts. METHODS: RNA was extracted by the TRIzol method; intron retention analysis was performed by using IRFinder from an mRNA sequencing (RNA-Seq) platform; P53 isoforms, short nuclear RNA U6 and additional genes related to cell senescence were measured by RT-PCR. RESULTS: No significant differences were found in the percentage of intron retention (control: 7.8%, WRS1 : 6.3%and WRS2 : 8.14%). Genes showing higher intron retention profile in both groups were mainly related to RNA binding pathways, cell cycle regulation, positive regulation of transcription, positive regulation of inflammatory pathways, negative regulation of apoptosis, RNA transcription, mitochondria, and regulation of translation initiation. However, in WRS fibroblasts the genes with more intron retention were those related to the immune response and mitochondrial function; while in control those related to the response to oxidative stress had the most introns retained. WRS1 showed higher expression of short nuclear RNA U6 compared to control and WRS2; while both WRS cells showed higher expression of p53β and lower percentage of Δ133p63α, consistent with a higher expression of the cellular senescence markers p16 and p21. CONCLUSIONS: These results demonstrated the important role of POLR3A in the maintenance of cellular homeostasis and highlight its potential role in cell senescence in WRS.

Identification of molecular signatures in epicardial adipose tissue in heart failure with preserved ejection fraction.

The molecular signatures in epicardial adipose tissue (EAT) that contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF) are poorly characterized. In this study, we sought to elucidate molecular signatures including genetic transcripts and long non-coding RNAs (lncRNAs) in EAT that might modulate HFpEF development. RNA sequencing (RNA-seq) was performed to identify differentially expressed lncRNAs and mRNAs in EAT samples from patients with HFpEF (n=5) and without HF (control, n=5) who underwent coronary artery bypass grafting. The sequencing results were validated using quantitative real-time PCR (qRT-PCR). Bioinformatics analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) of differentially expressed RNAs was performed to predict enriched functions. HFpEF patients had higher EAT thickness and NT-proBNP levels than the control group. A total of 64471 transcripts were detected including 35395 protein-coding sequences, corresponding to 16854 genes in EAT. RNA-seq identified a total of 741 dysregulated mRNA transcripts (394 up-regulated and 347 down-regulated) and 334 differentially expressed lncRNA transcripts (222 up-regulated and 112 down-regulated) in the HFpEF group compared with the control group (P<0.05). qRT-PCR analysis confirmed that two lncRNAs ENST00000561775 (P=0.0194) and ENST00000519093 (P=0.027) and an mRNA POSTN (P=0.003) were differentially expressed. Functional enrichment analysis of the differentially expressed mRNAs suggested their potential roles in immune response involving cytokine interaction and chemokine signalling. We are the first group to report on the lncRNA and mRNA landscape in EAT in HFpEF patients. Our study suggests the possible role of lncRNAs in EAT.

Multifaceted roles of Meg3 in cellular senescence and atherosclerosis

Background and aimsLong noncoding RNAs are involved in the pathogenesis of atherosclerosis. As long noncoding RNAs maternally expressed gene 3 (Meg3) prevents cellular senescence of hepatic vascular endothelium and obesity-induced insulin resistance, we decided to examine its role in cellular senescence and atherosclerosis. Methods and ResultsBy analyzing our data and human and mouse data from the Gene Expression Omnibus database, we found that Meg3 expression was reduced in humans and mice with cardiovascular disease, indicating its potential role in atherosclerosis. In Ldlr−/− mice fed a Western diet for 12 weeks, Meg3 silencing by chemically modified antisense oligonucleotides attenuated the formation of atherosclerotic lesions by 34.9% and 20.1% in male and female mice, respectively, revealed by en-face Oil Red O staining, which did not correlate with changes in plasma lipid profiles. Real-time quantitative PCR analysis of cellular senescence markers p21 and p16 revealed that Meg3 deficiency aggravates hepatic cellular senescence but not cellular senescence at aortic roots. Human Meg3 transgenic mice were generated to examine the role of Meg3 gain-of-function in the development of atherosclerosis induced by PCSK9 overexpression. Meg3 overexpression promotes atherosclerotic lesion formation by 29.2% in Meg3 knock-in mice independent of its effects on lipid profiles. Meg3 overexpression inhibits hepatic cellular senescence, while it promotes aortic cellular senescence likely by impairing mitochondrial function and delaying cell cycle progression. ConclusionsOur data demonstrate that Meg3 promotes the formation of atherosclerotic lesions independent of its effects on plasma lipid profiles. In addition, Meg3 regulates cellular senescence in a tissue-specific manner during atherosclerosis. Thus, we demonstrated that Meg3 has multifaceted roles in cellular senescence and atherosclerosis.

CNP Ameliorates Macrophage Inflammatory Response and Atherosclerosis.

CNP (C-type natriuretic peptide), an endogenous short peptide in the natriuretic peptide family, has emerged as an important regulator to govern vascular homeostasis. However, its role in the development of atherosclerosis remains unclear. This study aimed to investigate the impact of CNP on the progression of atherosclerotic plaques and elucidate its underlying mechanisms. Plasma CNP levels were measured in patients with acute coronary syndrome. The potential atheroprotective role of CNP was evaluated in apolipoprotein E-deficient (ApoE-/-) mice through CNP supplementation via osmotic pumps, genetic overexpression, or LCZ696 administration. Various functional experiments involving CNP treatment were performed on primary macrophages derived from wild-type and CD36 (cluster of differentiation 36) knockout mice. Proteomics and multiple biochemical analyses were conducted to unravel the underlying mechanism. We observed a negative correlation between plasma CNP concentration and the burden of coronary atherosclerosis in patients. In early atherosclerotic plaques, CNP predominantly accumulated in macrophages but significantly decreased in advanced plaques. Supplementing CNP via osmotic pumps or genetic overexpression ameliorated atherosclerotic plaque formation and enhanced plaque stability in ApoE-/- mice. CNP promoted an anti-inflammatory macrophage phenotype and efferocytosis and reduced foam cell formation and necroptosis. Mechanistically, we found that CNP could accelerate HIF-1α (hypoxia-inducible factor 1-alpha) degradation in macrophages by enhancing the interaction between PHD (prolyl hydroxylase domain-containing protein) 2 and HIF-1α. Furthermore, we observed that CD36 bound to CNP and mediated its endocytosis in macrophages. Moreover, we demonstrated that the administration of LCZ696, an orally bioavailable drug recently approved for treating chronic heart failure with reduced ejection fraction, could amplify the bioactivity of CNP and ameliorate atherosclerotic plaque formation. Our study reveals that CNP enhanced plaque stability and alleviated macrophage inflammatory responses by promoting HIF-1α degradation, suggesting a novel atheroprotective role of CNP. Enhancing CNP bioactivity may offer a novel pharmacological strategy for treating related diseases.

School-based promotion of physical literacy: a scoping review.

The role of physical activity in children's healthy development is undisputed, with school-based interventions being seen as a priority. The promotion of physical literacy (PL) seems to be promising due to its holistic approach, combining physical, cognitive, and affective domains. To develop recommendations for possible measures, we compiled existing literature on existing school-based PL interventions. Five databases (MEDLINE, Web of Science, SPORTDiscus, ERIC, and PsycInfo) were searched between July 6 and July 10, 2023, by combining the terms "physical literacy," "school," "program," "workshop," "intervention," and "curriculum" as well as a manual search. Records were screened in a two-stage process by two independent authors using a priori criteria. Eligible studies concerned PL interventions in the school context. The included records were sorted according to school type/population, structure, content, PL domains addressed, and evaluation. In total, 706 articles were found through the database search and an additional 28 articles through the manual search. After removing duplicates, 502 publications remained, which were screened by title and abstract, leaving 82 full texts. These were cut down to 37 articles describing 31 different programs (19 in primary schools, eight in secondary schools, one in both primary and secondary schools, and three unspecified). Most interventions were conducted during physical education classes (n = 12). All three PL domains were addressed by five interventions, while 11 interventions solely concerned the physical domain. In addition, 21 interventions evaluated their effects on PL. Most evaluations showed small to moderate but inconsistent effects on several PL-related constructs (e.g., self-efficacy, motivation, movement skills). Interventions incorporating all three domains reported positive effects on physical competence and enjoyment. Although there is a growing body of data related to school-based PL promotion, their effects and practical application remains relatively underdeveloped: study designs, study quality, PL assessments, and results are heterogeneous. Corresponding research adhering to the holistic approach of PL will be crucial in clarifying the potential lifelong role of PL in promoting physical activity, increasing health and well-being and to actually enable development of recommendations for action.

Applying complex adaptive systems research results to combat simulations of the generation-after-next

Combat has seen fundamental changes over the past century—with new domains of warfighting (e.g., cyber, space); the introduction of nuclear and precision weapons; ubiquitous, all source intelligence; mixes of national, coalition, and private forces operating; and numerous other examples. Over this same period, combat simulations, and the attendant training, experimentation, and analyses they support, have increased in scale, scope, and resolution. But with respect to their fundamental effectiveness, have they substantively moved beyond the foundation created by Lanchester in the early 20th century? Differential equations of mean field approximations have been complemented by discrete-event simulations at many scales; however, the underlying conceptual framework of force-on-force conflict and tightly constrained, potentially fragile, service-specific command and control remains. In this position paper, we argue that new conceptualizations, better aligned with the modern warfighting landscape, are needed across all applications of military modeling. We examine the potential role of complex adaptive systems in this endeavor.

Correlation between trophoblast cell-surface antigen-2 (Trop-2) expression and pathological complete response in patients with HER2-positive early breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab.

The prognostic and predictive role of trophoblast cell-surface antigen-2 (Trop-2) overexpression in human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer is currently unknown. We retrospectively analyzed Trop-2 expression and its correlation with clinicopathologic features and pathological complete response (pCR) in HER2-positive early breast cancer (EBC) patients treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab in the PHERGain study. Trop-2 expression at baseline was determined in formalin-fixed, paraffin-embedded primary tumor biopsies by immunohistochemistry and was first classified into expressing (Trop-2-positive) or not-expressing (Trop-2-negative) tumors. Then, it was classified by histochemical score (H-score) according to its intensity into low (0-9), intermediate (10-49), and high (≥ 50). The association between clinicopathologic features, pCR, and Trop-2 expression was performed with Fisher's exact test. Forty-one patients with tissue evaluable for Trop-2 expression were included, with 28 (68.3%) Trop-2-positive tumors. Overall, 17 (41.46%), 14 (34.15%), and 10 (24.40%) tumors were classified as low, intermediate, and high, respectively. Trop-2 expression was significantly associated with decreased pCR rates (50.0% vs. 92.3%; odds ratio [OR] 0.05; 95% CI, 0.002-0.360]; p adjusted = 0.01) but was not correlated with any clinicopathologic features (p ≥ 0.05). Tumors with the highest Trop-2H-score were less likely to obtain a pCR (OR 0.03; 95% CI, 0.001-0.290, p adjusted < 0.01). This association was confirmed in univariate and multivariate regression analyses. These findings suggest a potential role of Trop-2 expression as a biomarker of resistance to neoadjuvant chemotherapy plus dual HER2 blockade and may become a strategic target for future combinations in HER2-positive EBC patients.