bluuebunny/crossref_metadata_2025 huggingface dataset:
Cold atmospheric plasma activation of human gingival fibroblasts for improved wound healing
Authors: Silva Neusa , Marques Joana , Brito da Cruz Mariana , Luís Henrique , Mata António , Sério Susana
Published: October 2024

Soft tissue regeneration plays a crucial role after oral surgery, as the successful healing of the soft tissue is a primary indicator of an efficacious intervention. Cold atmospheric plasma (CAP) has recently emerged as a promising therapeutic modality, exhibiting notable effects on cell migration and proliferation. Despite its potential, the dental application of CAP remains underexplored. This in vitro study aims to elucidate the impact of CAP activated medium on human gingival fibroblast responses, for future wound healing strategies. The study was divided into four parts: initial characterization of the plasma Jet, assessment of cell concentration, exploration of treatment distance effects, and treatment time dynamics. Human gingival fibroblasts were exposed to complete DMEM medium (without sodium pyruvate) activated with CAP at treatment distances of 2, 5, 7, and 9 mm, and treatment times of 15, 60, 120, 180, and 300 s for 1, 2 and 3 d of culture. The cell viability was evaluated using resazurin-based method, while wound healing dynamics was assessed via the scratch assay technique using phase-contrast microscopy. The cell morphology was characterised through fluorescence microscopy using propidium iodide and phalloidin staining, complemented by scanning electron microscopy. The results revealed that treatment distances and exposure times can influence the cell behaviour depending on the cell concentration. For the selected concentration of 1 × 104 cells ml−1, a treatment distance of 9 mm appeared to enhance human gingival fibroblast viability compared to a treatment distance of 2 mm and the control group. The images revealed adherent cells with a pattern typical of fibroblasts. However, no differences were observed for exposure times of 15 s and 180 s. The observed results further evidence that the exposure of the medium to the CAP device promoted an increase in cell viability, proliferation, and attachment in human gingival fibroblasts.
Deciphering competing interactions of Kitaev-Heisenberg-Γ system in clusters: II. Dynamics of Majorana fermions
Authors: Moonsun Pervez Sheikh , Mandal Saptarshi
Published: October 2024

We perform a systematic and exact study of Majorana fermion dynamics in the Kitaev-Heisenberg-Γ model in a few finite-size clusters increasing in size up to twelve sites. We employ exact Jordan–Wigner transformations to evaluate certain measures of Majorana fermion correlation functions, which effectively capture matter and gauge Majorana fermion dynamics in different parameter regimes. An external magnetic field is shown to produce a profound effect on gauge fermion dynamics. Depending on certain non-zero choices of other non-Kitaev interactions, it can stabilise it to its non-interacting Kitaev limit. For all the parameter regimes, gauge fermions are seen to have slower dynamics, which could help build approximate decoupling schemes for appropriate mean-field theory. The probability of Majorana fermions returning to their original starting site shows that the Kitaev model in small clusters can be used as a test bed for the quantum speed limit.
Fast reconstruction 3D computed tomography image of stacked cell under faster scanning by dual-branch cross-fusion flat bottom network
Authors: Chao Long , Yin Hao , Wang Yi , Tan Chuandong , Chen Yusheng , Tan Hui , Duan Liming
Published: October 2024

Cone beam computed tomography (CT) fast scanning and reconstruction is a key step to achieve rapid detection of internal defects in batteries. In this work, we have achieved a faster CT scanning just in 5 s by reducing the x-ray exposure time in sparse view CT. However, the CT data is extremely incomplete by faster scanning; the existing reconstruction methods are difficult to reconstruct a high quality three-dimensional (3D) CT image of stacked cells. To address this issue, we propose a 3D CT image reconstruction network, which can reconstruct higher quality CT images from low quality 3D volume data. The input data of the reconstruction network is not 2D projection data, but 3D volume data. In this network, a high and low resolution dual-branch cross-fusion flat bottom structure is designed. The high resolution flat bottom branch aims to preserve detailed information, while the low resolution flat bottom branch focuses on capturing more semantic information. Cross-fusion between these branches mitigates the loss of semantic details. Additionally, the auxiliary loss function, the main loss function, and the 3D attention module are designed to enhance semantic accuracy and the learning performance of the network. The 3D training data is collected under a fast scanning strategy spanning 5–60 s. During the training phase, we use clipping block technology to cut the 3D volume data, enabling direct training on the 3D volume data. Our experimental results demonstrate that our 3D reconstruction network outperforms mainstream algorithms under this faster scanning strategy, which is able to reconstruct higher quality 3D CT images just in 15 s. Ablation experiments confirm the positive impact of the dual-branch cross-fusion flat bottom structure, attention module, and loss functions on improving the quality of 3D CT images.
Finite element analysis and design of a magnetostrictive material based vibration energy harvester with a magnetic flux path
Authors: K Wahi Sajan , Gupta Devansh , Santapuri Sushma
Published: October 2024

This work presents the development of a nonlinear 2D finite element (FE) framework for magnetostrictive material based energy harvesters of beam geometry. The FE model is developed in COMSOL Multiphysics and compared with existing literature for validation. The FE model is subsequently used to study the effect of a closed magnetic flux path, consisting of ferromagnetic components, on the harvester output. Specifically, the voltage output is obtained by performing simulations on unimorph type harvester devices with and without a closed magnetic flux path, both operating at the same natural frequency and volume of the magnetostrictive material Galfenol. The harvester design considered here consists of a magnetostrictive layer (Galfenol) bonded to a steel substrate layer, a tip mass, a pick-up coil and a magnetic flux path consisting of soft iron core and NdFeB permanent magnets. Our results demonstrate a voltage gain of around 70% for the closed flux path design. Furthermore, a proof of concept prototype of the modified flux path design is developed, tested under impulse loading, and the voltage, power output are compared with FE simulation results for validation. The simulation results match well with experimental observations at two operating frequencies for the flux path design.
Superconductor to metal quantum phase transition with magnetic field in Josephson coupled lead islands on Graphene
Authors: Gupta Suraina , Jana Santu Prasad , Pervin Rukshana , Gupta Anjan K
Published: October 2024

Superconductor (SC)-to-metal transition with magnetic field and gate-voltage is studied in a Josephson junction array comprising of randomly distributed lead islands on exfoliated single-layer graphene. The superconductivity onset temperature at low magnetic fields is fitted to the Werthamer–Helfand–Hohenberg theory to model the temperature dependence of the upper critical field. The magnetoresistance in the intermediate temperature and field regime is described using thermally activated flux flow dictated by field dependent activation barrier. The barrier also depends on the gate voltage which dictates the inter-island Josephson coupling and disorder. The magnetoresistance near the upper critical field at low temperatures shows signatures of a gate dependent continuous quantum phase transition between SC and metal. The finite size scaling analysis shows that this transition belongs to the

(
2
+
1
)

D-XY universality class without disorder.
Introduction
Authors: Logins Artūrs , Vollet Jacques-Henri
Published: October 2024

In this introductory chapter, we provide an overview of the knowledge-first program in epistemology by introducing some of its central elements. We focus, in particular, on what we see as its three main theses. The first one is that knowledge cannot be reductively analyzed into more fundamental constituents, the second one is that knowledge is the most general factive mental state, and the third one is that knowledge can be used in illuminating explanations of other important epistemological notions (such as evidence, reason, justification, and belief). Next, we situate our volume in the actual context of debates and existing volumes. Finally, we introduce the chapters of the present volume.
Natural Curiosity
Authors: Nagel Jennifer
Published: October 2024

Curiosity is an intrinsic desire for knowledge. This raises a puzzle about how unreflective animals can be curious. It is easy to understand how learning could be driven by factors such as hunger, but what proximal signal could guide animals towards knowledge itself? Recent work in reinforcement learning suggests that surprise functions as a reward signal for the curious animal. Reward for surprise can then be shown to amount to a desire for knowledge gain, where knowledge is a cognitive adaptation to reality. This adaptation results in a mental state whose stable existence depends essentially on the truth of its contents; that is, a factive mental state. Curious creatures benefit from an interaction between the prediction-error correction processes of basic learning and the active surprise-seeking force of their curiosity. This internally adversarial interaction accelerates knowledge gain in ways that are helpful for biological creatures in a complex natural world.
Depression and Pain
Authors: Miller-Matero Lisa R
Published: October 2024

Individuals with chronic pain are at risk for experiencing psychiatric symptoms, including depression, and this relationship is likely bidirectional. As depressive symptoms worsen or improve, pain-related variables, including pain severity, pain interference, and pain catastrophizing respond similarly. As such, psychological interventions have been developed and tested that can target pain and depression simultaneously. Interventions that have garnered the most attention include cognitive-behavioral therapy (CBT), mindfulness, and acceptance and commitment therapy (ACT). In addition, those with co-occurring pain and depression are at greater risk for opioid misuse and opioid use disorder. More recent work has focused on using similar psychological strategies to improve opioid-related outcomes. There remain challenges in managing comorbid pain, depression, and opioid use, including interventions resulting in modest effect sizes, generalizability, and low uptake and engagement in psychological interventions. Potential solutions include tailoring treatments and offering interventions in medical settings or via telehealth.
Other Psychiatric Disorders, Psychosocial Factors, Sleep, and Pain
Authors: Bair Matthew J , Owen-Smith Ashli A
Published: October 2024

Chronic pain is frequently comorbid with psychiatric disorders and sleep disturbances. While depression has been the most extensively studied psychiatric comorbidity in people with chronic pain, there has been growing research on the comorbidity between chronic pain and anxiety disorders, posttraumatic stress disorder (PTSD), bipolar disorder (BD), and schizophrenia. Most studies show that comorbid psychiatric disorders are associated with more severe pain and worse pain-related outcomes. This chapter reviews the epidemiology of comorbid chronic pain and other psychiatric disorders including anxiety disorders, PTSD, BD, and schizophrenia. The chapter reviews the impact of these comorbidities on clinical outcomes, discuss clinical assessment of chronic pain in the context of psychiatric comorbidities, summarize data on sleep disturbances in people with chronic pain and psychiatric disorders, and highlight pharmacological and non-pharmacological treatment options. It discusses research gaps and future directions for the study of chronic pain and comorbid psychiatric disorders.
Defund the Police, Refund for Harmony
Authors: Lewis Colin J , Kling Jennifer
Published: October 2024

Advocates for defunding police departments in the United States critique traditional policing methods as not only ineffective but also racist and oppressive. They call for funding alternative programs, such as quality healthcare, education, and other community vitalization initiatives, to address the social causes of crime. Sometimes, community policing is put forth as a possible middle ground between traditional policing and the Defund movement. Community policing, while promising, has serious theoretical and practical shortfalls as it is currently conceived. This chapter proposes bolstering community policing by scaffolding it at both the theoretical and practical levels with Confucian resources drawn from early Chinese and contemporary Taiwanese policing practices. This Confucian-inspired approach to policing reconciles community policing with the more radical aims of the Defund movement by tying policing practices to the promotion of true community flourishing.
Formulation and systemic therapy
Authors: Bell Frances , Nicolopoulos Jenny , Dolianitis Con
Published: October 2024

We report a 34-year-old man who developed a new pruritic rash 4 weeks after commencing a biologic medication for psoriasis.
Long-term health outcomes of young patients with low-complexity coronary disease: a weighted analysis according to revascularization strategy
Authors: Custódio Pedro , Garcez Luís , Madeira Sérgio , Magro Pedro , Vale Nelson , Madeira Márcio , Leal Sílvio , Nolasco Tiago , Brito João , Boshoff Sérgio , De Araújo Gonçalves Pedro , Marques Marta , Mesquita Gabriel Henrique , Calquinha João , Campante Teles Rui , Abecasis Miguel , Almeida Manuel , Sousa Uva Miguel , Mendes Miguel , Pedro Neves José , Raposo Luís
Published: October 2024

OBJECTIVES

Age is an important factor weighing on revascularization decisions. We analysed long-term health outcomes of young patients with low-complexity coronary anatomy suitable for both coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI), according to revascularization strategy.

METHODS

Patients 60 years old or less, undergoing invasive coronary angiography between January 2007 and December 2015, presenting with proximal left anterior descending artery involvement, left main or multivessel disease and a SYNTAX Score ≤22 were retrospectively selected. An inverse probability of treatment weight methodology generated a pseudopopulation with well-balanced characteristics, which was used to estimate the average treatment effect between PCI (n = 374) and CABG (n = 173).

RESULTS

Mean age was 53 ± 7 years old, 27% had diabetes mellitus and 48% presented with an acute coronary syndrome. Mean SYNTAX score was 13.6 ± 4.9 and 68% underwent PCI as index revascularization strategy. In the weighed population, the adjusted hazard of the primary end-point of all-cause death at total follow-up (median 9.3 years; interquartile range 6.9–11.7) was 0.40 (95% confidence interval 0.19–0.7) for CABG vs PCI (incidence rate 5.8 vs 14.0 deaths/1000-person-years). Accounting for death as competing risk, the cumulative hazard of new revascularization (sub-distribution hazard ratio 0.72; 95% confidence interval 0.32–1.25) and any cause hospital readmission (sub-distribution hazard ratio 0.70; 95% confidence interval 0.41–1.07) were lower in CABG patients, as opposed to death/stroke rates at 30 days which were higher with CABG (0.3% vs 1.7%; risk ratio = 5.84).

CONCLUSIONS

In this quasi-experimental analysis of young patients with coronary artery disease and an equivalent indication for both PCI and CABG, long-term health outcomes were favourably associated with CABG, as compared to PCI. These observations support the need for dedicated randomized trials with longer follow-up in order to better inform lifetime treatment options.
Integrating Ethics in Public Health Guideline Development: Case Study of Guidelines on Respiratory Isolation for Persons With Tuberculosis in Community Settings
Authors: Kates Olivia S , Shah Maunank
Published: October 2024

Public health interventions often involve explicit trade-offs in which the health of the many must be weighed against burdens imposed on individuals. We describe development of public health guidelines for respiratory isolation in community settings for persons with tuberculosis. While stopping the spread of disease is a core moral imperative in public health, the duty to prevent disease transmission does not supersede all other considerations. Community well-being must be balanced with individual well-being, liberty, and social justice. In response to these challenges, the National Tuberculosis Coalition of America's 2024 guidelines for persons with tuberculosis in community settings were developed using a modified GRADE approach supported by a complementary, comprehensive, and context-specific ethical framework. By addressing the distinct roles that evidence (subject to uncertainty), values, justificatory conditions, and procedural legitimacy all play in ethical guideline development, we promote rigor and transparency in the integration of ethics in public health guidelines.
Assessing Infectiousness and the Impact of Effective Treatment to Guide Isolation Recommendations for People With Pulmonary Tuberculosis
Authors: Nathavitharana Ruvandhi R , Pearl Abarna , Biewer Amanda , Tzelios Christie , Mase Sundari , Munsiff Sonal S , Nardell Edward
Published: October 2024

Determining the extent and duration of infectiousness of people with pulmonary tuberculosis (PWPTB) is critical for various aspects of tuberculosis care, including decisions regarding isolation. Studies suggest considerable heterogeneity in infectiousness of PWPTB. Pretreatment, measures of bacillary burden, including sputum smear microscopy, culture time to positivity, and Xpert MTB/RIF cycle threshold (Ct) value, predict the risk of transmission to contacts. Index patients with smear-negative disease pose lower infectious risk than those who have smear-positive disease, and household contact infection is more likely with index patients who have lower Xpert Ct values. Newer tools that enable detection of Mycobacterium tuberculosis complex from cough aerosol sampling and face mask sampling may be better predictors of contact infection risk. Clinical factors such as cough strength and frequency, and presence of cavitation on chest imaging, may also assist with risk prediction. Posttreatment, smear and culture status are poor predictors of infectiousness. While the exact duration of infectiousness post–treatment initiation remains uncertain, data from human-to-guinea pig transmission studies and clinical studies suggest that effective treatment results in a rapid decline in infectiousness, irrespective of smear or culture conversion. This is largely supported by early bactericidal activity and transcriptomic studies, as well as cough aerosol sampling studies, although a subset of patients may have persistent cough aerosol positivity. These findings can enable a more nuanced approach to isolation decision making while further research studies are awaited.
Concentrations of ceftazidime and avibactam in bile fluid—a prospective phase IIb study
Authors: Witowski Andrea , Palmowski Lars , Minichmayr Iris K , Zeitlinger Markus , Dorn Christoph , Lier Constantin , Adamzik Michael , Nowak Hartmuth , Rahmel Tim
Published: October 2024

Background

The rise in carbapenem-resistant bacteria and the limited number of effective antibiotics pose a major health-care threat. The combination of ceftazidime (CAZ) and avibactam (AVI) represents an approved treatment option for carbapenem-resistant intra-abdominal infections. However, data on the pharmacokinetic profile of AVI in the hepatobiliary compartment is lacking.

Objectives

To provide clinical in vivo data on the concentration of AVI in bile fluid as a surrogate for hepatobiliary excretion.

Methods

A single dose of 2000/500 mg CAZ/AVI was administered prolonged over 2 h to 10 patients prior to abdominal surgery, with bile samples available in nine patients in this phase IIb study (DRKS-ID: DRKS00023533). Antibiotic concentrations in plasma (0–8 h), bile (after resection) and pharmacodynamic parameters were determined.

Results

The mean concentration across individuals in bile was 33.5 mg/L (±20.5 mg/L) for CAZ and 7.1 mg/L (±3.5 mg/L) for AVI, resulting in bile/plasma ratios of 0.58 (±0.26) and 0.61 (±0.18). The Cmax in plasma was 87.2 mg/L (±25.0 mg/L) for CAZ and 18.6 mg/L (±6.29 mg/L) for AVI, with AUC0−∞ values of 351 h·mg/L (±104 h·mg/L) and 72.1 h·mg/L (±32.1 h·mg/L), respectively. Plasma concentrations of both CAZ and AVI remained more than 50% of the dosing interval above the minimum inhibitory concentrations (T>MIC > 50%; MICCAZ = 8 mg/L, MICAVI = 1 mg/L) in all patients. No antibiotic-associated side effects were reported during the 30-day follow-up.

Conclusions

The concentrations of CAZ and AVI in bile suggest their potential as a valuable therapeutic option for multi-resistant biliary infections.
Bildung and the moral topography of the self
Authors: Hilt Line Torbjørnsen , Halvorsen Øyvind Wiik
Published: October 2024

The ideal of authenticity that developed in the Romantic era emphasized that both individuals and places find their own authentic process for cultivating their identity and humanity, a notion that has become controversial in modern philosophy. This article will explore the concepts of authenticity and place and discuss their relevance for Bildung theory today. Based on the works of Charles Taylor, we will argue that Bildung can be seen as constituted by and constitutive of language and moral spaces that go beyond the self and its individuality. In this view, Bildung can be understood as a ‘moral topography of the self’ with both substantial and procedural aspects. However, language and moral spaces (i.e. communities) can both enable and constrict our Bildung processes. Drawing on Rahel Jaeggi, we thus argue that alienation is an equally important concept to understand the complex and dialectical relationship between individuals and communities in our current moment.
Gens sans argent: A New Holograph Manuscript by Thomas Hoccleve
Authors: Sobecki Sebastian
Published: October 2024

This article introduces an unknown personal holograph manuscript by Thomas Hoccleve: Cambridge, Trinity College, MS O. 7. 43. The new manuscript, only recently digitized, has never been associated with Hoccleve; in fact, it has lived under the radar of literary scholarship for the last six hundred years. The manuscript is here described, then it is demonstrated palaeographically that it is written in Hoccleve’s hand; the contents are discussed with some of the implications of this discovery. In conclusion, it is suggested that the manuscripts bequeathed in 1738 by Roger Gale to Trinity College could preserve four others that the poet may have owned, raising the probability that the Gale bequest represents a portion of Hoccleve’s private library.
PTBP1 mediates Sertoli cell actin cytoskeleton organization by regulating alternative splicing of actin regulators
Authors: Wang Yuexi , Chembazhi Ullas Valiya , Yee Danielle , Chen Sijie , Ji Jie , Wang Yujie , Nguyen Ka Lam , Lin PoChing , Ratti Antonia , Hess Rex A , Qiao Huanyu , Ko CheMyong , Yang Jing , Kalsotra Auinash , Mei Wenyan
Published: October 2024

Spermatogenesis is a biological process within the testis that produces haploid spermatozoa for the continuity of species. Sertoli cells are somatic cells in the seminiferous epithelium that orchestrate spermatogenesis. Cyclic reorganization of the Sertoli cell actin cytoskeleton is vital for spermatogenesis, but the underlying mechanism remains largely unclear. Here, we report that the RNA-binding protein PTBP1 controls Sertoli cell actin cytoskeleton reorganization by programming alternative splicing of actin cytoskeleton regulators. This splicing control enables ectoplasmic specializations, the actin-based adhesion junctions, to maintain the blood-testis barrier and support spermatid transport and transformation. Particularly, we show that PTBP1 promotes actin bundle formation by repressing the inclusion of exon 14 of Tnik, a kinase present at the ectoplasmic specialization. Our results thus reveal a novel mechanism wherein Sertoli cell actin cytoskeleton dynamics are controlled post-transcriptionally by utilizing functionally distinct isoforms of actin regulatory proteins, and PTBP1 is a critical regulatory factor in generating such isoforms.
oriTDB: a database of the origin-of-transfer regions of bacterial mobile genetic elements
Authors: Liu Guitian , Li Xiaobin , Guan Jiahao , Tai Cui , Weng Yuqing , Chen Xiaohua , Ou Hong- Yu
Published: October 2024

Conjugation and mobilization are two important pathways of horizontal transfer of bacterial mobile genetic elements (MGEs). The origin-of-transfer (oriT) region is crucial for this process, serving as a recognition site for relaxase and containing the DNA nicking site (nic site), which initiates the conjugation or mobilization. Here, we present a database of the origin-of-transfer regions of bacterial MGEs, oriTDB (https://bioinfo-mml.sjtu.edu.cn/oriTDB2/). Incorporating data from text mining and genome analysis, oriTDB comprises 122 experimentally validated and 22 927 predicted oriTs within bacterial plasmids, Integrative and Conjugative Elements, and Integrative and Mobilizable Elements. Additionally, oriTDB includes details about associated relaxases, auxiliary proteins, type IV coupling proteins, and a gene cluster encoding the type IV secretion system. The database also provides predicted secondary structures of oriT sequences, dissects oriT regions into pairs of inverted repeats, nic sites, and their flanking conserved sequences, and offers an interactive visual representation. Furthermore, oriTDB includes an enhanced oriT prediction pipeline, oriTfinder2, which integrates a functional annotation module for cargo genes in bacterial MGEs. This resource is intended to support research on bacterial conjugative or mobilizable elements and promote an understanding of their cargo gene functions.
PhageDive: the comprehensive strain database of prokaryotic viral diversity
Authors: Rolland Clara , Wittmann Johannes , Reimer Lorenz C , Sardà Carbasse Joaquim , Schober Isabel , Dudek Christian-Alexander , Ebeling Christian , Koblitz Julia , Bunk Boyke , Overmann Jörg
Published: October 2024

Prokaryotic viruses represent the most diverse and abundant biological entities on Earth. So far, data on bacteriophages are not standardized, not readily available for comparative analyses and cannot be linked to the rapidly growing (meta)genomic data. We developed PhageDive (https://phagedive.dsmz.de), a comprehensive database for prokaryotic viruses gathering all existing data dispersed across multiple sources, like scientific publications, specialized databases or internal files of culture collections. PhageDive allows to link own research data to the existing information through an easy and central access, providing fields for various experimental data (host range, genomic data, etc.) and available metadata (e.g. geographical origin, isolation source). An important feature is the link between experimental data, the culture collection number and the repository of the corresponding physical bioresource. To date, PhageDive covers 1167 phages from three different world-renowned public collections (DSMZ, Félix d’Hérelle Reference Center for Bacterial Viruses and NCTC) and features an advanced search function using all data fields from the sections like taxonomy or morphology by controlled vocabulary and ontologies. PhageDive is fully interoperable with other resources including NCBI, the Viral Host Range database (VHRdb) of Institute Pasteur or the BacDive and MediaDive databases of DSMZ.
CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2017–2021
Authors: Price Mackenzie , Ballard Christine , Benedetti Julia , Neff Corey , Cioffi Gino , Waite Kristin A , Kruchko Carol , Barnholtz-Sloan Jill S , Ostrom Quinn T
Published: October 2024

The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control and Prevention and the National Cancer Institute, is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US) and represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors available and supersedes all previous reports in terms of completeness and accuracy. All rates are age-adjusted using the 2000 US standard population and presented per 100,000 population. Between 2017 and 2021, the average annual age-adjusted incidence rate (AAAIR) of all primary malignant and non-malignant brain and other CNS tumors was 25.34 per 100,000 population (malignant AAAIR=6.89 and non-malignant AAAIR=18.46). This overall rate was higher in females compared to males (28.77 versus 21.78 per 100,000) and non-Hispanic Black persons compared to persons who were non-Hispanic White (26.60 versus 25.72 per 100,000), non-Hispanic American Indian/Alaska Native (23.48 per 100,000), non-Hispanic Asian or Pacific Islander (19.86 per 100,000), and Hispanic persons of all races (22.37 per 100,000). Gliomas accounted for 22.9% of all tumors. The most commonly occurring malignant brain and other CNS histopathology was glioblastoma (13.9% of all tumors and 51.5% of all malignant tumors), and the most common predominantly non-malignant histopathology was meningioma (41.7% of all tumors and 56.8% of all non-malignant tumors). Glioblastomas were more common in males, and meningiomas were more common in females. In children and adolescents (ages 0-19 years), the incidence rate of all primary brain and other CNS tumors was 6.02 per 100,000 population. There were 87,053 deaths attributed to malignant brain and other CNS tumors between 2017 and 2021. This represents an average annual mortality rate of 4.41 per 100,000 population and an average of 17,411 deaths per year. The five-year relative survival rate following diagnosis of a malignant brain or other CNS tumor was 35.7%. For a non-malignant brain or other CNS tumor the five-year relative survival rate was 92.0%.
EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma
Authors: Koh Lynnette Wei Hsien , Pang Qing You , Novera Wisna , Lim See Wee , Chong Yuk Kien , Liu Jinyue , Ang Samantha Ya Lyn , Loh Ron Weng Yee , Shao Huilin , Ching Jianhong , Wang Yulan , Yip Stephen , Tan Patrick , Li Shang , Low David Chyi Yeu , Phelan Anne , Rosser Gabriel , Tan Nguan Soon , Tang Carol , Ang Beng Ti
Published: October 2024

Background

Enhancer of zeste homolog 2 (EZH2), well known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied noncanonical function critical for sustained tumor growth. Recent GBM consortial efforts reveal complex molecular heterogeneity for which therapeutic vulnerabilities correlated with subtype stratification remain relatively unexplored. Current enzymatic EZH2 inhibitors (EZH2inh) targeting its canonical su(var)3–9, enhancer-of-zeste and trithorax domain show limited efficacy and lack durable response, suggesting that underlying differences in the noncanonical pathway may yield new knowledge. Here, we unveiled dual roles of the EZH2 CXC domain in therapeutically distinct, reactive oxygen species (ROS)-stratified tumors.

Methods

We analyzed differentially expressed genes between ROS classes by examining cis-regulatory elements as well as clustering of activities and pathways to identify EZH2 as the key mediator in ROS-stratified cohorts. Pull-down assays and CRISPR knockout of EZH2 domains were used to dissect the distinct functions of EZH2 in ROS-stratified GBM cells. The efficacy of NF-κB-inducing kinase inhibitor (NIKinh) and standard-of-care temozolomide was evaluated using orthotopic patient-derived GBM xenografts.

Results

In ROS(+) tumors, CXC-mediated co-interaction with RelB drives constitutive activation of noncanonical NF-κB2 signaling, sustaining the ROS(+) chemoresistant phenotype. In contrast, in ROS(−) subtypes, Polycomb Repressive Complex 2 methyltransferase activity represses canonical NF-κB. Addressing the lack of EZH2inh targeting its nonmethyltransferase roles, we utilized a brain-penetrant NIKinh that disrupts EZH2-RelB binding, consequently prolonging survival in orthotopic ROS(+)-implanted mice.

Conclusions

Our findings highlight the functional dichotomy of the EZH2 CXC domain in governing ROS-stratified therapeutic resistance, thereby advocating for the development of therapeutic approaches targeting its noncanonical activities and underscoring the significance of patient stratification methodologies.
Recurrent pancreatic cancer treated with N-803 and PD-L1 t-haNK followed by an EGFR-targeted nanocell drug conjugate
Authors: Moini Katayoun , Seery Tara , Nangia Chaitali , MacDiarmid Jennifer , Brahmbhatt Himanshu , Spilman Patricia , Sender Lennie , Soon-Shiong Patrick
Published: October 2024

Multimodal temporal therapy orchestrated to leverage immunotherapy, tumor-targeted chemotherapy, and natural killer (NK) cell therapy may provide an opportunity to induce immunogenic cell death for tumor response and increased survival in patients with recurrent cancer. The interleukin-15 (IL-15) superagonist N-803, an enhancer of NK cells, CD4 + T cells, cytotoxic CD8 + T cells, and memory T-cell activity, combined with off-the-shelf PD-L1-targeted high-affinity NK (PD-L1 t-haNK) cells represent novel immunotherapies designed to overcome an immunosuppressive tumor microenvironment (TME). The epidermal growth factor receptor-targeted antibody-nanocell conjugate E-EDV-D682 provides tumor-targeted chemotherapy in the form of its anthracycline metabolite PNU159682 (nemorubicin) cargo and is currently being studied in combination with immunomodulatory EDVs delivering the adjuvant α-galactosyl ceramide (GC). Here, we report the compassionate use treatment of this combination in a patient with recurrent, metastatic pancreatic cancer (mPC) after 3 lines of therapy. Under the initial single-patient Investigational New Drug (spIND) protocol, the patient received N-803, PD-L1 t-haNK cells, and the albumin doxorubicin conjugate aldoxorubicin for ~27 months. The patient’s disease became stable on this regimen, and a transient complete response was observed by ~14 months of therapy. Due to progression, a second spIND protocol was designed whereby the patient received E-EDV-D682 plus EDV-GC for more than 24 months, which resulted in stable disease and the patient’s continued survival at the time this report was written. The patient’s extended survival despite the dire prognosis associated with recurrent mPC points to the merits of this temporal combination regimen in overcoming immuno-chemo resistance with enhanced immune activity required for tumor response and extended survival.
Assessing the Adequacy of Morphological Models Using Posterior Predictive Simulations
Authors: Mulvey Laura P A , May Michael R , Brown Jeremy M , Höhna Sebastian , Wright April M , Warnock Rachel C M
Published: October 2024

Reconstructing the evolutionary history of different groups of organisms provides insight into how life originated and diversified on Earth. Phylogenetic trees are commonly used to estimate this evolutionary history. Within Bayesian phylogenetics a major step in estimating a tree is in choosing an appropriate model of character evolution. While the most common character data used is molecular sequence data, morphological data remains a vital source of information. The use of morphological characters allows for the incorporation fossil taxa, and despite advances in molecular sequencing, continues to play a significant role in neontology. Moreover, it is the main data source that allows us to unite extinct and extant taxa directly under the same generating process. We therefore require suitable models of morphological character evolution, the most common being the Mk Lewis model. While it is frequently used in both palaeobiology and neontology, it is not known whether the simple Mk substitution model, or any extensions to it, provide a sufficiently good description of the process of morphological evolution. In this study we investigate the impact of different morphological models on empirical tetrapod datasets. Specifically, we compare unpartitioned Mk models with those where characters are partitioned by the number of observed states, both with and without allowing for rate variation across sites and accounting for ascertainment bias. We show that the choice of substitution model has an impact on both topology and branch lengths, highlighting the importance of model choice. Through simulations, we validate the use of the model adequacy approach, posterior predictive simulations, for choosing an appropriate model. Additionally, we compare the performance of model adequacy with Bayesian model selection. We demonstrate how model selection approaches based on marginal likelihoods are not appropriate for choosing between models with partition schemes that vary in character state space (i.e., that vary in Q-matrix state size). Using posterior predictive simulations, we found that current variations of the Mk model are often performing adequately in capturing the evolutionary dynamics that generated our data. We do not find any preference for a particular model extension across multiple datasets, indicating that there is no “one size fits all” when it comes to morphological data and that careful consideration should be given to choosing models of discrete character evolution. By using suitable models of character evolution, we can increase our confidence in our phylogenetic estimates, which should in turn allow us to gain more accurate insights into the evolutionary history of both extinct and extant taxa.
Epidemiology, Process of Care, and Associated Outcomes of Pediatric Out-of-Hospital Cardiac Arrest in China: Results From a Prospective, Multicenter, Population-Based Registry
Authors: Zhao Xiangkai , Zheng Wen , Ma Yu , Hou Yaping , Zhu Yimin , Zheng Jiaqi , Wang Quan , Pan Chang , Zhang Jianbo , Wang Chunyi , Bian Yuan , Liu Rugang , Cheng Kai , Ma Jingjing , Ong Marcus Eng Hock , Xu Feng , Chen Yuguo ,   on behalf of the Baseline Investigation of Out-of-Hospital Cardiac Arrest (BASIC-OHCA) Coordinators and Investigators
Published: October 2024

OBJECTIVES:

To comprehensively describe the incidence, process of care, outcomes, and variation among different age groups of pediatric out-of-hospital cardiac arrest (OHCA) in China.

DESIGN:

The Baseline Investigation of Out-of-Hospital Cardiac Arrest (BASIC-OHCA) is a prospective, multicenter, population-based registry of emergency medical services (EMS)-assessed OHCA in China.

SETTING:

A total of 25 monitoring sites of all seven geographical regions were included, covering a pediatric population (age ≤ 19) of around 22.3 million in China.

PATIENTS:

Pediatric patients enrolled in BASIC-OHCA from August 2019 to December 2020 were included.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

A total of 1493 pediatric patients with EMS-assessed OHCA were enrolled, and resuscitation was attempted in 651 cases (43.6%). The crude incidence of EMS-assessed and EMS-treated OHCA was 5.5 (95% CI, 5.2–5.9) and 2.4 (95% CI, 2.2–2.6) per 100,000 pediatric population. Among 651 EMS-treated OHCA cases, 434 patients (66.7%) were male, and 353 (54.2%) had nonmedical causes (trauma, asphyxia, and drowning being the most common). There were 396 patients (60.8%) who collapsed at home, and the proportion of cases that occurred in public places such as streets and schools increased with age. There were 26 patients (4.0%) who had an initial shockable rhythm. For 626 non-EMS-witnessed patients, 152 patients (24.3%) received bystander cardiopulmonary resuscitation (CPR), 68 (10.9%) received dispatcher-assisted CPR, and 3 (0.5%) had automated external defibrillator applied. The survival to discharge or 30 days was 3.5% (23/651), and the favorable neurologic prognosis was 3.1% (20/651), with no differences among age groups.

CONCLUSIONS:

This study provides the first national exploration of pediatric OHCA in China. The high proportion of nonmedical causes underscores the importance of preventing accidents in children. Gaps in the chain of survival and patient outcomes provide a focus for improving the treatment of pediatric OHCA in China and other developing countries.
Tunable wave coupling in periodically rotated Miura-ori tubes
Authors: Tomita Sunao , Tachi Tomohiro
Published: October 2024

Origami folding structures are vital in shaping programmable mechanical material properties. Of particular note, tunable dynamical properties of elastic wave propagation in origami structures have been reported. Despite the promising features of origami metamaterials, the influence of the kinematics of tessellated origami structures on elastic wave propagation remain unexplored. This study proposes elastic metamaterials using connected Miura-ori tubes, the kinematics of which are coupled by folding and unfolding motions in a tubular axis; achieved by periodically connecting non-rotated and rotated Miura-ori tubes. The kinematics generate wave modes with localized deformations within the unit cell of the metamaterials, affecting the global elastic deformation of Miura-ori tubes via the coupling of wave modes. Dispersion analysis, using the generalized Bloch wave framework based on bar-and-hinge models, verifies the influence of kinematics in the connected tubes on elastic wave propagation. Furthermore, folding the connected tubes changes the coupling strength of wave modes between the kinematics and global elastic deformation of the tubes by breaking the ideal kinematics. The coupling of wave modescontributes to the formation of the band gaps and their tunability. These findings enable adaptive and
in situ
tunability of band structures to prohibit elastic waves in the desired frequency ranges.

This article is part of the theme issue ‘Origami/Kirigami-inspired structures: from fundamentals to applications’.
Geometric mechanics of kiri-origami-based bifurcated mechanical metamaterials
Authors: Li Yanbin , Zhou Caizhi , Yin Jie
Published: October 2024

We explore a new design strategy of leveraging kinematic bifurcation in creating origami/kirigami-based three-dimensional (3D) hierarchical, reconfigurable, mechanical metamaterials with tunable mechanical responses. We start from constructing three basic, thick, panel-based structural units composed of 4, 6 and 8 rigidly rotatable cubes in close-looped connections. They are modelled, respectively, as 4R, 6R and 8R (R stands for revolute joint) spatial looped kinematic mechanisms, and are used to create a library of reconfigurable hierarchical building blocks that exhibit kinematic bifurcations. We analytically investigate their reconfiguration kinematics and predict the occurrence and locations of kinematic bifurcations through a trial-correction modelling method. These building blocks are tessellated in 3D to create various 3D bifurcated hierarchical mechanical metamaterials that preserve the kinematic bifurcations in their building blocks to reconfigure into different 3D architectures. By combining the kinematics and considering the elastic torsional energy stored in the folds, we develop the geometric mechanics to predict their tunable anisotropic Poisson’s ratios and stiffnesses. We find that kinematic bifurcation can significantly effect mechanical responses, including changing the sign of Poisson’s ratios from negative to positive beyond bifurcation, tuning the anisotropy, and overcoming the polarity of structural stiffness and enhancing the number of deformation paths with more reconfigured shapes.

This article is part of the theme issue ‘Origami/Kirigami-inspired structures: from fundamentals to applications’.
Blunted anterior midcingulate response to reward in opioid users is normalized by prefrontal transcranial magnetic stimulation
Authors: Biernacki Kathryn , Goldstein Rita Z. , Güth Malte R. , Alia-Klein Nelly , Ray Suchismita , Baker Travis E.
Published: October 2024

Introduction

Abnormalities in goal-directed behavior, mediated by mesocorticolimbic reward function and structure, contribute to worse clinical outcomes including higher risk of treatment dropout and drug relapse in opioid users (OU).

Material and Method

In a sham-controlled randomized study design, we measured whether robot-assisted 10Hz transcranial magnetic stimulation (TMS) applied to the prefrontal cortex was able to modulate anterior midcingulate cortex (MCC) electrophysiological response to rewards, in OU and matched healthy controls.

Results

We show that OU exhibit a blunted anterior MCC reward response, compared to healthy controls (t(39) = 2.62, p = 0.01, d = 0.84), and that this is normalized following 10-Hz excitatory TMS (t(36)= .82, p = 0.42, d = 0.17).

Conclusions

Excitatory TMS modulated the putative reward function of the MCC in OU. Further work with increased sample sizes and TMS sessions is required to determine whether restoring MCC reward function increases reward-directed behaviors, which may enhance treatment success through the maintenance of treatment goals.
PILocarpine 1.25% Efficacy for management of Uncorrected Presbyopia (PILE-UP Study)
Authors: Saxena Rohit , Gupta Vinay , Velpandian T , Nidhi Tanya , Thakur Himani , Titiyal Jeewan S , Sharma Namrata
Published: October 2024

Purpose

This study aimed to evaluate the efficacy and safety of pilocarpine 1.25% eye drops for improving near vision acuity in presbyopic individuals.

Design

Non-randomized prospective interventional trial

Methods

This single-arm prospective interventional trial includesfifty presbyopic individuals aged between 40 to 55, administrated pilocarpine 1.25% eye-drops daily once (9 am, Hour 0) for one month. Visual parameters, including distance corrected near visual acuity (DCNVA), near add power, amplitude of accommodation (AoA), and depth of focus (DoF) along with ocular biometric parameters were assessed at baseline and after one month at hour 3 (12 noon) and hour 6 (3 p.m.). Adverse effects were monitored.

Results

After one month of pilocarpine treatment, a significant improvement was observed in DCNVA (0.64±0.2 to 0.26±0.11,P:<0.001) along with a decrease in near add power (1.43±0.43 D to 0.42±0.22 D,P:<0.001). The AoA increased (3.23±0.74D to 3.92±0.93D,P:0.005), and DoF widened (0.72±0.18D to 0.81±0.26D,P:0.038). No change in ocular biometry parameters was observed. The change in DCNVA showed strong positive correlations with change in near add (r: 0.84,P:<0.001) and AoA (r: 0.66,P:0.04). Adverse effects were mild and did not lead to discontinuation.

Conclusion

Pilocarpine 1.25% eye drops demonstrated statistically significant improvements in DCNVA, near add, AoA, and DoF after one month of treatment. Pilocarpine 1.25% eye drops shown increase in the amplitude of accommodation and depth of focus; without any significant change in ocular biometry parameters. The use of pilocarpine 1.25% eye drops can be an alternative intervention for enhancing near vision acuity of presbyopic subjects.