bluuebunny/crossref_metadata_2025 huggingface dataset:
The phage protein paratox is a multifunctional metabolic regulator of Streptococcus
Authors: Muna Tasneem Hassan , Rutbeek Nicole R , Horne Julia , Lao Ying W , Krokhin Oleg V , Prehna Gerd
Published: December 2024

Streptococcus pyogenes, or Group A Streptococcus (GAS), is a commensal bacteria and human pathogen. Central to GAS pathogenesis is the presence of prophage encoded virulence genes. The conserved phage gene for the protein paratox (Prx) is genetically linked to virulence genes, but the reason for this linkage is unknown. Prx inhibits GAS quorum sensing and natural competence by binding the transcription factor ComR. However, inhibiting ComR does not explain the virulence gene linkage. To address this, we took a mass spectrometry approach to search for other Prx interaction partners. The data demonstrates that Prx binds numerous DNA-binding proteins and transcriptional regulators. We show binding of Prx in vitro with the GAS protein Esub1 (SpyM3_0890) and the phage protein JM3 (SpyM3_1246). An Esub1:Prx complex X-ray crystal structure reveals that Esub1 and ComR possess a conserved Prx-binding helix. Computational modelling predicts that the Prx-binding helix is present in several, but not all, binding partners. Namely, JM3 lacks the Prx-binding helix. As Prx is conformationally dynamic, this suggests partner-dependent binding modes. Overall, Prx acts as a metabolic regulator of GAS to maintain the phage genome. As such, Prx maybe a direct contributor to the pathogenic conversion of GAS.
SLAM-seq reveals independent contributions of RNA processing and stability to gene expression in African trypanosomes
Authors: Luzak Vanessa , Osses Esteban , Danese Anna , Odendaal Christoff , Cosentino Raúl O , Stricker Stefan H , Haanstra Jurgen R , Erhard Florian , Siegel T Nicolai
Published: December 2024

Gene expression is a multi-step process that converts DNA-encoded information into proteins, involving RNA transcription, maturation, degradation, and translation. While transcriptional control is a major regulator of protein levels, the role of post-transcriptional processes such as RNA processing and degradation is less well understood due to the challenge of measuring their contributions individually. To address this challenge, we investigated the control of gene expression in Trypanosoma brucei, a unicellular parasite assumed to lack transcriptional control. Instead, mRNA levels in T. brucei are controlled by post-transcriptional processes, which enabled us to disentangle the contribution of both processes to total mRNA levels. In this study, we developed an efficient metabolic RNA labeling approach and combined ultra-short metabolic labeling with transient transcriptome sequencing (TT-seq) to confirm the long-standing assumption that RNA polymerase II transcription is unregulated in T. brucei. In addition, we established thiol (SH)-linked alkylation for metabolic sequencing of RNA (SLAM-seq) to globally quantify RNA processing rates and half-lives. Our data, combined with scRNA-seq data, indicate that RNA processing and stability independently affect total mRNA levels and contribute to the variability seen between individual cells in African trypanosomes.
Pediatric brain tumor classification using deep learning on MR images with age fusion
Authors: Tampu Iulian Emil , Bianchessi Tamara , Blystad Ida , Lundberg Peter , Nyman Per , Eklund Anders , Haj-Hosseini Neda
Published: December 2024

Purpose

To implement and evaluate deep learning-based methods for the classification of pediatric brain tumors (PBT) in magnetic resonance (MR) data.

Methods

A subset of the “Children’s Brain Tumor Network” dataset was retrospectively used (n = 178 subjects, female = 72, male = 102, NA = 4, age range [0.01, 36.49] years) with tumor types being low-grade astrocytoma (n = 84), ependymoma (n = 32), and medulloblastoma (n = 62). T1w post-contrast (n = 94 subjects), T2w (n = 160 subjects), and apparent diffusion coefficient (ADC: n = 66 subjects) MR sequences were used separately. Two deep learning models were trained on transversal slices showing tumor. Joint fusion was implemented to combine image and age data, and 2 pre-training paradigms were utilized. Model explainability was investigated using gradient-weighted class-activation mapping (Grad-CAM), and the learned feature space was visualized using principal component analysis (PCA).

Results

The highest tumor-type classification performance was achieved when using a vision transformer model pre-trained on ImageNet and fine-tuned on ADC images with age fusion (Matthews correlation coefficient [MCC]: 0.77 ± 0.14, Accuracy: 0.87 ± 0.08), followed by models trained on T2w (MCC: 0.58 ± 0.11, Accuracy: 0.73 ± 0.08) and T1w post-contrast (MCC: 0.41 ± 0.11, Accuracy: 0.62 ± 0.08) data. Age fusion marginally improved the model’s performance. Both model architectures performed similarly across the experiments, with no differences between the pre-training strategies. Grad-CAMs showed that the models’ attention focused on the brain region. PCA of the feature space showed greater separation of the tumor-type clusters when using contrastive pre-training.

Conclusion

Classification of PBT on MR images could be accomplished using deep learning, with the top-performing model being trained on ADC data, which radiologists use for the clinical classification of these tumors.
Neuroimaging of postoperative pediatric cerebellar mutism syndrome: a systematic review
Authors: Obdeijn Iris V , van Baarsen Kirsten M , Avula Shivaram , Toescu Sebastian , Lequin Maarten H , Hoving Eelco W , Partanen Marita
Published: December 2024

Background

Postoperative pediatric cerebellar mutism syndrome (ppCMS) poses serious morbidity after posterior fossa tumor surgery. Neuroimaging studies aim to understand its pathophysiology, yet these vary in methodology and outcome measures. Therefore, we systematically reviewed the current literature to evaluate the evidence for differences in neuroimaging features between children with and without ppCMS.

Methods

Following PRISMA guidelines, a systematic review was conducted by searching for original articles on neuroimaging in children undergoing posterior fossa tumor surgery, comparing patients with and without ppCMS. Articles were selected based on predefined eligibility criteria. Data were systematically extracted, and risk of bias was evaluated.

Results

From the 866 articles identified, 50 studies fulfilled the inclusion criteria. Studies were categorized into 3 imaging domains: structural, diffusion, and functional imaging. Risk of bias assessment revealed a medium risk in most articles, predominantly due to unclear ppCMS definition and qualitative image analysis without blinding for ppCMS diagnosis. Preoperative structural imaging showed the association of ppCMS with midline tumor localization and involvement of the brainstem, superior cerebellar peduncle (SCP), or middle cerebellar peduncle. Postoperative structural and diffusion imaging highlighted SCP injury with reduced white matter integrity, while functional imaging demonstrated hypoperfusion in frontal lobes. Late follow-up showed T2-weighted hyperintensities in the inferior olivary nuclei of ppCMS patients.

Conclusion

Neuroimaging features suggest that ppCMS is associated with efferent cerebellar pathway injury and hypoperfusion in frontal lobes, with level 2 a/b evidence. Large-scale prospective longitudinal neuroimaging studies comparing pre- and postoperative imaging are needed to further elucidate the pathophysiological mechanism of ppCMS.
How do I prescribe and manage mIDH inhibitors in patients with IDH-mutant glioma?
Authors: Still Megan E H , Moor Rachel S F , Ghiaseddin Ashley P , Leibetseder Annette , Hottinger Andreas F , Berghoff Anna , Leung Denise
Published: December 2024

Recent interest has been in using mIDH inhibitors in patients with IDH-mutant gliomas. This review paper summarizes the indications, side effects, recommended dosing, and management for patients on ivosidenib and vorasidenib.
An evidence-based framework for postoperative surveillance of meningioma
Authors: Owusu-Adjei Brittany , Lim Jeewoo C , Hou Connie C , Mietus Constance J , Daci Rrita , Lambert William , Qureshi Hanya , Berry Bethany C , Marasco Madison R B , Paul Umika , Sirianni Rachael W , Johnson Mark D
Published: December 2024

Background

Meningiomas frequently recur after surgery. Existing guidelines for postoperative surveillance are based on customary practices or limited data. This may result in excessive or inadequate surveillance.

Methods

We compared 8 studies involving 1519 resected meningiomas with postoperative follow-up ranging from 7 to 23 years. Meningiomas were stratified using the World Health Organization and Simpson grading systems, and progression-free survival data were compared. Recurrence patterns were validated using 2 additional studies involving 2463 meningiomas.

Results

Incompletely resected meningiomas of all grades displayed recurrences throughout the observation period. The 5-year and 10-year cumulative incidence of recurrence for completely resected Grade 1 meningiomas was 10% and 20%, with no recurrences beyond 11 years. For completely resected Grade 2 meningiomas, the 5-year and 10-year cumulative incidence of recurrence was 24% and 50%, with ongoing recurrences throughout the observation period. Elevated recurrence rates for Grade 1/2 meningiomas persisted beyond 5 years. For completely resected Grade 3 meningiomas, the 5-year cumulative incidence of recurrence was 63%, and all recurred before 10 years.

Conclusions

Postoperative magnetic resonance imaging (MRI) at 48 h to determine the extent of resection and at 4 months to detect rapid regrowth is recommended. For completely resected Grade 1 meningiomas, annual MRI followed by discontinuation of surveillance if there is no recurrence after 11 years is reasonable. For completely resected Grade 2 meningiomas, annual MRI indefinitely is recommended. For Grade 3 meningiomas, MRI every 3-4 months for 2 years, followed by every 6 months indefinitely, is recommended. Incompletely resected meningiomas should be followed indefinitely.
Risk factors for type I leptomeningeal metastasis derived from non-small cell lung cancer and the impact of treatment for brain metastases on its development
Authors: Iuchi Toshihiko , Shingyoji Masato , Mizuno Satoko , Ashinuma Hironori , Hasegawa Yuzo , Setoguchi Taiki , Hosono Junji , Sakaida Tsukasa
Published: December 2024

Background

Preventing Type I leptomeningeal metastasis (LM) is critical when treating brain metastases (BMs). The aim of this study was to extract risk factors for Type I LM and to clarify the optimal treatment for BMs from the perspective of Type I LM prevention.

Methods

The clinical course of consecutive cases of BMs derived from non-small cell lung cancer (NSCLC) treated at our hospital was retrospectively evaluated. The relationship between clinicopathological factors, including molecular background, and Type I LM development was verified. In addition, the difference in the time to Type I LM because of treatment for BMs was evaluated to clarify the effectiveness of each treatment in preventing Type I LM.

Results

Of 784 patients with BMs, 44 exhibited Type I LM at the onset of BMs. Poor performance status (P < .0001) and mutated epidermal growth factor receptor (EGFR) gene (P = .004) were significant risk factors for Type I LM. Among the 740 patients without LMC at diagnosis, 85 developed Type I LM. Younger age (P = .011) and mutated EGFR (P < .0001) were risk factors for developing LMC after BMs. Osimertinib reduced the incidence of Type I LM (hazard ratio [HR]: 0.48; 95% confidence interval [CI]: 0.24-0.97) in EGFR-mutated cases. Immune checkpoint inhibitors (ICIs) showed a tendency to prolong the time to Type I LM (HR: 0.15; 95% CI: 0.02-1.11) in EGFR-wild-type cases.

Conclusions

Patients with EGFR-mutated NSCLC are prone to developing Type I LM. Osimertinib for EGFR-mutated cases and ICIs are expected to prevent Type I LM after the diagnosis of BMs.
The roadmap of two-dimensional materials toward next-generation image sensor
Authors: Zhang Na , Ouyang Decai , Li Yuan , Zhai Tianyou
Published: December 2024

This Prospective highlights the advances and challenges of 2D materials regarding the materials preparation, device integration, multifunctional applications, and comments on their potential as transformative candidates for future image sensors.
Cascade specific endogenous Fe3+ interference and in situ catalysis for tumor therapy with stemness suppression
Authors: Chen Jiajie , Wang Yitong , Huang Jian , Yang Zhibo , Niu Huicong , Su Xiaolian , Huang Jimin , Ma Hongshi , Zhu Yufang , Wu Chengtie , Shi Jianlin
Published: December 2024

Cancer stem-like cells (CSCs), featuring high tumorigenicity and invasiveness, are one of the critical factors leading to the failure of clinical cancer treatment such as metastasis and recurrence. However, current strategies suffer from the low stemness-inhibiting efficacy on CSCs by conventional molecular agents and the poor lethal effects against bulk tumor cells. Here we engineer a coordination nanomedicine by 2,5-dihydroxyterephthalic acid (DHT) complexing zinc ions (Zn2+) as a double-effect nanodisrupter of tumor iron (Fe) and redox homeostasis for catalysis-boosted tumor therapy with stemness inhibition. Taking advantage of the much higher binding force of DHT toward Fe3+, this nanomedicine can specifically chelate endogenous Fe3+ into its nanostructure and release Zn2+, and the in situ formed hexacoordinated Fe-DHT conformation is of much enhanced reducibility in order to promote reactive oxygen species (ROS) production in tumors. The nanomedicine-mediated Fe depletion and ROS generation collectively induce CSC differentiation via downregulating the Wnt signaling and inducing forkhead box O3 (FoxO3) activation, respectively. Notably, the combined tumor-selective ROS generation and Zn2+-induced antioxidation dysfunction potently trigger intratumoral oxidative damage leading to both cellular apoptosis and ferroptosis. This nanomedicine, capable of synchronously treating CSCs and bulk tumor cells, has been demonstrated to effectively inhibit the growth, postoperative recurrence and metastasis of orthotopic triple-negative breast tumors in vivo, offering an encouraging candidate of cancer therapeutic agents for treating CSCs-enriched malignancy.
Constructing new-generation ion exchange membranes under confinement regime
Authors: Li Xingya , Zuo Peipei , Ge Xiaolin , Yang Zhengjin , Xu Tongwen
Published: December 2024

Ion exchange membranes (IEMs) enable fast and selective ion transport and the partition of electrode reactions, playing an important role in the fields of precise ion separation, renewable energy storage and conversion, and clean energy production. Traditional IEMs form ion channels at the nanometer-scale via the assembly of flexible polymeric chains, which are trapped in the permeability/conductivity and selectivity trade-off dilemma due to a high swelling propensity. New-generation IEMs have shown great potential to break this intrinsic limitation by using microporous framework channels for ion transport under a confinement regime. In this Review, we first describe the fundamental principles of ion transport in charged channels from nanometer to sub-nanometer scale. Then, we focus on the construction of new-generation IEMs and highlight the microporous confinement effects from sub-2-nm to sub-1-nm and further to ultra-micropores. The enhanced ion transport properties brought by the intense size sieving and channel interaction are elucidated, and the corresponding applications including lithium separation, flow battery, water electrolysis, and ammonia synthesis are introduced. Finally, we prospect the future development of new-generation IEMs with respect to the intricate microstructure observation, in-situ ion transport visualization, and large-scale membrane fabrication.
Principle-based adept predictions of global warming from climate mean states
Authors: Cai Ming , Hu Xiaoming , Sun Jie , Hu Yongyun , Liu Guosheng , Wu Zhaohua , Ding Feng , Kang Wanying
Published: December 2024

Distinguishing anthropogenic warming from natural variability and reducing uncertainty in global-warming projections continue to present challenges. Here, we introduce a novel principle-based framework for predicting global warming from climate mean states that is based solely on carbon-dioxide-increasing scenarios without running climate models and relying on statistical trend analysis. By applying this framework to the climate mean state of 1980–2000, we accurately capture the subsequent global warming (0.403 K predicted versus 0.414 K observed) and polar warming amplification patterns. Our predictions from climate mean states of individual models not only exhibit a high map-correlation skill that is comparable to that of individual Coupled Model Intercomparison Project Phase 6 models for the observed warming, but also capture the temporal pace of their warming under the 1% annual CO2-increasing scenario. This work provides the first principle-based confirmation that anthropogenic greenhouse gases are the primary cause of the observed global warming from 1980–2000 to 2000–2020, independently of climate models and statistical analysis.
Long COVID in healthcare workers: longitudinal mixed-methods study
Authors: Grant A , Adams N N , MacIver E , Skåtun D , Scott N , Kennedy C , Douglas F , Hernandez-Santiago V , Torrance N
Published: December 2024

Background

Healthcare workers (HCWs) report higher rates of long coronavirus disease (COVID) (LC) than other occupational groups. It is still unclear whether LC is a lifelong condition. Workforce shortfalls are apparent due to sick leave, reduced hours and lower productivity.

Aims

To investigate the lived experience of LC on a range of HCWs, including impact on health-related quality-of-life (HRQL), use of health services, working and personal lives and household finances.

Methods

Longitudinal mixed methods with online surveys and qualitative interviews 6-months apart. HCWs including healthcare professionals, ancillary and administration staff who self-report LC were recruited through social media and National Health Service channels. Interviewees were purposively sampled from survey responses.

Results

The first survey was completed by 471 HCWs (S1) and 302 (64%) the follow-up (S2). A total of 50 HCWs were interviewed initially and 44 at second interview. All participants experienced various relapsing, remitting, changing and prolonged LC symptoms (mean 7.1 [SD 4.8] at S2) and a third reported day-to-day activities ‘limited a lot’. Most participants were working in a reduced capacity: reduced hours, different role or location. Healthcare was limited, and often unsatisfactory. Participants feared reinfection, their future, ability to work and financial security (59% (n = 174) at S2). They experienced stigma, distress, grief for their former self and some felt unsupported, however, as awareness of LC grew some experienced improved understanding and support.

Conclusions

Most participants continued working, managing complex and dynamic symptoms effecting their everyday life and ability to work. Most did not report significant improvements over time and feared for their future and financial security.
Utility of 18F-Fluorodeoxyglucose Positron Emission Tomography in Evaluating Disseminated Nontuberculous Mycobacterial Infection in Patients With Anti-interferon-γ Autoantibodies
Authors: Chuang Pei-Ju , Lan Wei-Cheng , Cheng Mei-Fang , Huang Chun-Kai , Hong Tzu-Chan , Lin Chi-Ying , Huang Yu-Shan , Chen Pao-Yu , Wu Un-In , Wang Jann-Tay , Sheng Wang-Huei , Chen Yee-Chun , Chang Shan-Chwen
Published: December 2024

Background

Managing disseminated nontuberculous mycobacterial (NTM) infection in patients with neutralizing anti-interferon-γ autoantibodies (AIGAs) poses substantial challenges due to the lack of established treatment guidance and predictive tools for clinical outcomes. In this study, we investigated the utility of 18F-fluorodeoxyglucose (2-[18F]FDG) positron emission tomography (PET) in guiding treatment decisions, with a focus on its ability to predict rehospitalization outcomes.

Methods

We conducted a post hoc analysis of the first available 2-[18F]FDG PET scans of patients with AIGAs and disseminated NTM infection from a prospective observational multicenter cohort. Cox proportional hazards regression was used to determine predictors for disease-related rehospitalization within 1 year of the examination.

Results

Of the patients with AIGAs evaluated, 41.9% required rehospitalization within 1 year following the initial 2-[18F]FDG PET evaluation. Slowly growing mycobacteria were isolated in 64.5% of patients. Multivariable analysis identified splenic involvement (adjusted hazard ratio, 7.97; 95% CI, 2.34–27.16; P < .001) as a significant predictor of disease-related rehospitalization within 1 year following the examination. Moreover, mediastinal node involvement (adjusted odds ratio, 14.77; 95% CI, 1.01–216.76; P = .049) and axial skeleton involvement (adjusted odds ratio, 14.93; 95% CI, 1.11–201.43; P = .042) were significantly associated with the isolation of slowly growing mycobacteria.

Conclusions

2-[18F]FDG PET appears useful in initial evaluation of disease extent and microbiology in patients with AIGAs and disseminated NTM infection. Identifying splenic involvement through this modality may help recognize patients at increased risk of disease-related rehospitalization within 1 year. These findings suggest that 2-[18F]FDG PET could inform management decisions in this challenging population.
Long-term Risk of Infection Among Patients Colonized With Antimicrobial-Resistant Pathogens: A Population-wide Cohort Study
Authors: Blagojevic Christina , Brown Kevin A , Diong Christina , Fridman Daniel J , Johnstone Jennie , Langford Bradley J , Lee Samantha M , MacFadden Derek R , Schwartz Kevin L , Daneman Nick
Published: December 2024

Background

Antimicrobial-resistant (AMR) pathogens represent an ongoing global health burden. Colonization is often a prerequisite for infection, but the risk of infection after AMR colonization is not well understood. Using population-level health administrative data, we sought to investigate the risk of infection with the same AMR organism after detection of colonization.

Methods

We conducted a retrospective population-wide cohort study among residents of Ontario, Canada, over a 5-year period to determine the risk of infection after detection of colonization with the following AMR pathogens: methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, extended-spectrum β-lactamase–producing Enterobacterales, and carbapenemase-producing Enterobacterales. We also examined the effects of age, sex, and health care setting of colonization detection on subsequent infection risk.

Results

There were 69 998 individuals with a positive AMR pathogen surveillance test result during the study period, 15.6% of which subsequently developed a sterile or nonsterile site infection within a median 57 days (IQR, 11–228). Infection rates varied among organisms: 18.3% for methicillin-resistant S aureus within a median 57 days (IQR, 10–239), 2.8% for vancomycin-resistant Enterococcus within a median 37 days (IQR, 11–119), 21.5% for extended-spectrum β-lactamase–producing Enterobacterales within a median 71 days (IQR, 18–231), and 20.3% for carbapenemase-producing Enterobacterales within a median 10 days (IQR, 3–42). A positive surveillance test result detected in a hospital was associated with increased infection risk after colonization as compared with the community setting.

Conclusions

The overall infection rate after colonization with an AMR pathogen was high for most organisms, highlighting the importance of detecting colonization from both an infection control and empiric antibiotic selection perspective.
Strong Association Between HIV Incidence and Herpes Simplex Virus Type 2 in Zambia and South Africa: Prospective Data From the HPTN 071 (PopART) Trial
Authors: Bradley J , Floyd S , Piwowar-Manning E , Laeyendecker O , Baker O R , Bell-Mandla N , Bwalya J , Moore A , Eshleman S H , Donnell D , Bock P , Fidler S , Ayles H , Hayes R J
Published: December 2024

Background

Herpes simplex virus type 2 (HSV2) is an important cofactor for HIV acquisition and transmission. Associations between the infections are reexamined in longitudinal data from an HIV prevention trial.

Methods

The HPTN 071 (PopART) trial evaluated a combination prevention intervention in 21 urban communities in Zambia and South Africa. HIV incidence was measured in a cohort of approximately 2000 adults (age, 18–44 years) selected randomly from each community and followed up for 36 months. Incidence of HSV2 infection was estimated, and the effects of risk factors were examined. The association between HIV incidence and HSV2 infection was examined at individual and community levels.

Results

An overall 10 539 participants were HSV2 negative at baseline and retested after 36 months. Estimated HSV2 incidence was 5.4 per 100 person-years (95% CI, 5.0–5.7) for women and 2.9 per 100 person-years (95% CI, 2.6–3.2) for men. When compared with those remaining HSV2 negative, HIV incidence was higher in those who were HSV2 positive at baseline (women: adjusted rate ratio [aRR], 3.24 [95% CI, 2.50–4.20]; men: aRR, 2.57 [95% CI, 1.60–4.11]) and even higher in those who seroconverted to HSV2 during follow-up (women: aRR, 5.94 [95% CI, 4.42–7.98]; men: aRR, 8.37 [95% CI, 5.18–13.52]). At the community level, strong associations were seen between HIV incidence and HSV2 prevalence (R2 = 0.48, P < .001) and incidence (R2 = 0.36, P = .004).

Conclusions

There were strong associations between HIV incidence and HSV2 prevalence and incidence at individual and community levels. HSV2 control could contribute to HIV prevention.
The Normative Structure of Multicultural Secularism
Authors: Thompson Simon , Modood Tariq
Published: December 2024

Our aim in this article is to describe the normative structure of what we call multicultural secularism, and to make a case for this particular conception of state–religion relations. On our account, multicultural secularism is secular since it maintains an appropriate degree of autonomy of the state from religion, and of religion from the state. The state does not interfere unjustifiably in religious matters, and religious communities do not have an excessive influence on the state. At the same time, we believe that such mutual autonomy—and hence secularity—can be maintained even when the state provides religions with a range of forms of recognition and accommodation. It is in this sense that our conception of secularism is multicultural, since it takes multiculturalism’s commitment to the positive valuing and recognition of difference and applies this specifically to religion. In this article, we intend to show why it should do so.
Phase I study of intratumoral injection of talimogene laherparepvec for the treatment of advanced pancreatic cancer
Authors: Runcie Karie , Bracero Yadriel , Samouha Avishai , Manji Gulam , Remotti Helen E , Gonda Tamas A , Saenger Yvonne
Published: December 2024

Background

Pancreatic ductal adenocarcinoma (PDAC) presents a redoubtable challenge due to late-stage diagnosis and limited treatment options, necessitating innovative therapeutic strategies.

Methods

Here, we report our results investigating the safety and efficacy of talimogene laherparepvec (T-VEC), an FDA-approved oncolytic herpes simplex virus type 1, in patients with advanced PDAC. Nine patients with treatment-refractory advanced PDAC received escalating doses of T-VEC via endoscopic injection.

Results

While no objective responses were observed, stable disease was achieved in 44% of patients, with a median overall survival of 7.8 months, including one patient who survived 28 months. Adverse events were manageable, with the maximum tolerated dose determined to be 108 PFU/mL.

Conclusion

Our findings underscore the feasibility of intratumoral T-VEC administration in advanced PDAC. Further investigation, particularly in combination with immunotherapies administered systemically is warranted to more optimally assess T-VEC in this challenging malignancy.

ClinicalTrials.gov Identifier: NCT03086642.
Investigation of a new model combining solar tower and a spherical solar still for water distillation
Authors: Lachhab Saad Eddin , Diyagh Hafsa , Boukharta Azzeddin , Bayoud Amine , Nabaoui Khalid , Ibrahmi E Al , Dlimi L , Bliya A
Published: December 2024

This paper presents a hybrid system using solar tower and tubular solar energy for desalination. Total radiation (dqspher) was calculated using MATLAB algorithms, encoding a 3x4 matrix for temperature, pressure, and air saturation transfer within the glass globe. The results are supported by the latest data published in the literature. Between angle 0° and 35°, the rate of dqspher exceeded 689,546 Kw/m2 in 5 hours. Desalinated water reached 4.2 L/m2 at a rate of 76.63%. The encouraging results promote the application of this technology for water desalination, ensuring efficiency, environmental friendliness and affordability.
Integration of DNA Methylation, MicroRNAome, Degradome and Transcriptome Provides Insights into Petunia Anther Development
Authors: Yue Yuanzheng , Zhu Wuwei , Wang Jiahui , Wang Tengteng , Shi Lisha , Thomas Hannah Rae , Hu Huirong , Wang Lianggui
Published: December 2024

Petunia hybrida is an annual herb flower that is prevalently cultivated both in public landscaping and home gardening. Anthers are vital reproductive organs for plants, but the molecular mechanism controlling petunia anther development remains elusive. In this work, we combined DNA methylation, microRNAome, degradome and transcriptome data to generate a comprehensive resource focused on exploring the complex molecular mechanism of petunia anther development. This study shows that DNA methylation could have an important impact in repressing the anther-expressed genes in the late stages of anther maturation. A total of 8,096 anther-preferential genes and 149 microRNAs (miRNAs) were identified that highly expressed in the five typical petunia anther developmental stages. Gene Ontology enrichment analysis of differentially expressed genes as well as miRNAs target genes revealed that metabolic, cellular and single-organism processes were significantly activated during the anther maturation processes. Moreover, a co-expression regulatory network for five typical anther development stages was constructed based on transcriptomic data, in which two hub transcription factors, PhERF48 and PhMS1, were demonstrated to be important regulatory genes for male fertility. Furthermore, two DNA demethylase proteins (PhDME and PhDML3) and three methyl-CpG-binding-domain proteins (PhMBD2, PhMBD3 and PhMBD4) were identified as potential critical DNA methylation regulators in petunia anther development. Our results provide new knowledge regarding the regulatory mechanism of petunia anther development, which will support the breeding of novel sterile petunia lines in the future.
Spatial and temporal dynamics of ichthyoplankton in a temperate estuary: identifying essential habitats for early life stages
Authors: Arevalo Elorri , Villeneuve Bertrand , Possémé Carl , Lançon Kévin , François Baptiste , Jan Gwilherm , Quinton Eric , Cabral Henrique N , Lepage Mario
Published: December 2024

Estuaries are important nursery habitats for the early life stages of fishes. Fish populations in the Gironde Estuary (South-Western France) have collapsed in recent decades, due to massive habitat destruction and poor water quality. In this context, we sampled the ichthyoplankton in the Gironde Estuary for one year to understand the spatio-temporal dynamics of fish larvae and identify key habitats. Total density of larvae was analyzed in relation to season (summer, winter, spring), area (oligo, meso, polyhaline), habitat type (confluences, mudflats) and depth (shallow, intermediate, deep). In total, 32 499 fish larvae were identified and divided into 14 taxa. Larval densities were largely dominated by an estuarine resident taxon, but marine estuarine-opportunist and diadromous species were also present. Summer was characterized by few taxa, including Engraulis encrasicolus, Dicentrarchus spp. or Pomatoschistus spp., in low density (0.16 ± 0.53 larvae m-3 on average). Larval densities were higher in winter (0.30 ± 2.13) and spring (29.50 ± 291.00). Diadromous species were particularly present in winter, and gobies (Pomatoschistus spp.) dominated the spring assemblage. The oligohaline area and intertidal mudflats appeared to be key habitats in terms of larval density and diversity and should be target locations of conservation/restoration measures.
Focused anatomic review: ultrasound-guided peripheral nerve stimulation of the sciatic, posterior tibial, and obturator nerves
Authors: Cho James S , Grisham Alanah , Wang Annette , Vazquez Rafael , Kelly Charles , Scemama Pascal , Hao David
Published: December 2024

Ultrasound-guided percutaneous peripheral nerve stimulation (PNS) is an emerging modality for managing pain by targeting specific nerves. This focused review examines the anatomy and ultrasound imaging techniques for the sciatic, posterior tibial, and obturator nerves. The current evidence is limited to proof-of-concept studies and case reports. Further research is needed to optimize technical approaches and address the unique challenges of peripheral nerve stimulation.
Why municipalities seek, secure, and fail to secure police shared service agreements
Authors: Mazeika David M
Published: December 2024

Policing is often the largest municipal expense exclusively provided by its own employees. Evidence suggests that sharing services may provide numerous benefits including reduced costs and improved service quality. This study outlines the motivation behind seeking shared police services, the reasons municipalities were or were not able to successfully enter a contract, and the effects of state efforts to encourage the sharing of services. Interviews were conducted with senior officials in addition to public document reviews in 13 municipalities in New Jersey and offered suggestions to enhance this form of service delivery.
Unveiling the Inconsistency of the Proca Theory with Nonminimal Coupling to Gravity
Authors: Hell Anamaria
Published: December 2024

We study the degrees of freedom of the Proca theory, nonminimally coupled to gravity. In the Minkowski background, this theory propagates five degrees of freedom: a massive longitudinal mode, two massive vector ones, and two massless tensor modes. At first sight, the nonlinear coupling between the metric perturbations and the vector field indicates that both longitudinal and tensor modes become strongly coupled, at the same scale. This would imply that no matter how small the photon mass is, if nonminimal coupling is taken into account, gravitational waves would necessarily be strongly coupled. We show that the way out of this inconsistency is through the introduction of the disformal coupling to the metric perturbations that resemble the vector-type disformal transformations. This way, the unphysical coupling between the two types of modes can be avoided, rendering the model consistent. As a result, we show that only the longitudinal modes enter a strong coupling regime, while both tensor and transverse modes remain weakly coupled at all scales up to the Planck length. Finally, using the same form of the disformal transformation, we introduce a disformal frame in which the recently reported runaway modes are absent.
Innovation behavior and sustainability performance: Empirical evidence on the farming sector
Authors: Frick Fabian , Vrolijk Hans , Sauer Johannes
Published: December 2024

Modern agriculture faces the challenge of supplying a growing world population with high-quality products while minimizing negative environmental and social impacts of its production and ensuring economic viability. Innovation is often considered key to achieving these goals, but its effectiveness remains an empirical question. Our study investigates how the adoption of new technologies affects farm sustainability with respect to its economic and environmental and one indicator of the social dimension. We use a comprehensive dataset on Dutch dairy and arable farms comprising financial and environmental data along with data on innovation activity that allows for a differentiated view on the effects of various innovations. First-difference estimations reveal that simultaneous positive effects across all three sustainability dimensions are not guaranteed. For example, new buildings show a positive association with economic indicators of dairy farms, but the associations between other innovation activities and other economic, environmental, and the social indicator remain inconclusive.
Electrospinning based biomaterials for biomimetic fabrication, bioactive protein delivery and wound regenerative repair
Authors: Dai Xinyi , Nie Wei , Shen Hua , Machens Hans-Günther , Böker Kai , Taheri Shahed , Lehmann Wolfgang , Shen Yi , Schilling Arndt F
Published: December 2024

Electrospinning is a remarkably straightforward and adaptable technique that can be employed to process an array of synthetic and natural materials, resulting in the production of nanoscale fibers. It has emerged as a novel technique for biomedical applications and has gained increasing popularity in the research community in recent times. In the context of tissue repair and tissue engineering, there is a growing tendency toward the integration of biomimetic scaffolds and bioactive macromolecules, particularly proteins and growth factors. The design of ‘smart’ systems provides not merely physical support, but also microenvironmental cues that can guide regenerative tissue repair. Electrospun nanofibrous matrices are regarded as a highly promising tool in this area, as they can serve as both an extracellular matrix (ECM)-mimicking scaffold and a vehicle for the delivery of bioactive proteins. Their highly porous architecture and high surface-to-volume ratio facilitate the loading of drugs and mass transfer. By employing a judicious selection of materials and processing techniques, there is considerable flexibility in efficiently customizing nanofiber architecture and incorporating bioactive proteins. This article presents a review of the strategies employed for the structural modification and protein delivery of electrospun nanofibrous materials, with a focus on the objective of achieving a tailored tissue response. The article goes on to discuss the challenges currently facing the field and to suggest future research directions.
Azithromycin-loaded PLGA microspheres coated with silk fibroin ameliorate inflammation and promote periodontal tissue regeneration
Authors: Ouyang Zhaoguang , Chen Xiaoyu , Wang Zhengyang , Xu Yue , Deng Zhe , Xing Liangyu , Zhang Li , Hu Meilin , Li Haocong , Lian Tengye , Gao Feng , Liu Chunyi , Zhou Yangyang , Sun Lu , Wang Ying ChengYao , Liu Dayong
Published: December 2024

Periodontitis, a widespread inflammatory disease, is the major cause of tooth loss in adults. While mechanical periodontal therapy benefits the periodontal disease treatment, adjunctive periodontal therapy is also necessary. Topically applied anti-inflammatory agents have gained considerable attention in periodontitis therapy. Although azithromycin (AZM) possesses excellent anti-inflammatory properties, its bioavailability is limited owing to poor water solubility and the absence of sustained release mechanisms. Herein, we synthesized biodegradable microspheres (AZM@PLGA-SF) for sustained AZM release to locally ameliorate periodontal inflammation and facilitate periodontal tissue regeneration. AZM was encapsulated in poly (lactic-co-glycolic acid) (PLGA) microspheres (AZM@PLGA) using single emulsion-solvent evaporation, followed by surface coating with silk fibroin (SF) via electrostatic adsorption, reducing the initial burst release of AZM. In vivo, local treatment with AZM@PLGA-SF microspheres significantly reduced periodontal inflammation and restored periodontal tissue to healthy levels. Mechanically, the formulated microspheres regulated the periodontal inflammatory microenvironment by reducing the levels of pro-inflammatory cytokines (tumor necrosis factor -α, interleukin [IL]-6, interferon-γ, IL-2, and IL-17A) in gingival crevicular fluid and promoted the expression of anti-inflammatory cytokines (IL-4 and IL-10). AZM@PLGA-SF microspheres demonstrated excellent biological safety. Therefore, we introduce an anti-inflammatory therapy for periodontitis with substantial potential for mitigating periodontal inflammation and encouraging the repair and regeneration of periodontal tissues.
Diagnosing a child presenting with symptoms suggesting Sjögren’s disease: a tool for clinical practice
Authors: Stern Sara M , Basiaga Matthew L , Cha Seunghee , Thatayatikom Akaluck , Treemacki Erin B , Randell Rachel L , Dizon Brian L P , Appenzeller Simone , Edens Cuoghi , Orrock Janet E , Tiger Sharon , Diianni Jamie , Amoafo Linda , Lieberman Scott M
Published: December 2024

Objective

Childhood SjD (cSjD) is a rare disease. There are no widely accepted diagnostic or classification criteria for cSjD. To fill this gap, members from the CARRA Sjögren Disease Workgroup and the International Childhood Sjögren Disease Workgroup created a clinical diagnostic algorithm. This study evaluated the accuracy of this algorithm using an international cohort of participants with clinician-diagnosed cSjD.

Methods

First, experts developed a cSjD diagnostic algorithm through a series of virtual workgroup meetings. Using the adult classification criteria as a framework, experts modified the algorithm through opinion and literature review. The group discussed and finalized each algorithm step by achieving majority rule. Then, R statistical software was used to evaluate each participant’s disease status in the diagnostic algorithm via an international cohort of 300 cSjD cases.

Results

The diagnostic algorithm has three distinct clinical pathways representing the key clinical presentation in cSjD: parotitis, extraglandular manifestations, and sicca symptoms. The algorithm showed an overall sensitivity of 75% in the population that had enough data to complete at least one pathway of the algorithm (n = 100 filtered out of 300). The parotitis (70%) and sicca pathways (82%) had the highest sensitivity, and the extraglandular pathway (52%) had the lowest.

Conclusion

As cSjD lacks a diagnostic strategy, this algorithm provides a clinical tool for evaluating children with cSjD-like symptoms. It performed well in an international cohort of cSjD, supporting the integration of this algorithm into clinical practice; however, its utility may be limited by low utilization of diagnostic testing in this population.
O003 Higher central circadian temperature amplitude is associated with greater metabolite rhythmicity in humans
Authors: Windred D , Anderson C , Jeppe K , Ftouni S , Grant L , Nijagal B , Rajaratnam S , McConville M , Tull D , Lockley S , Cain S , Phillips A
Published: December 2024

Introduction

Robust circadian rhythms are essential for optimal health. The central circadian clock controls temperature rhythms, which are known to organize the timing of peripheral circadian rhythms in rodents. In humans, however, it is unknown whether temperature rhythms relate to the organization of circadian rhythms throughout the body.

Methods

We assessed core body temperature amplitude and the rhythmicity of 929 blood plasma metabolites across a 40-hour constant routine protocol, controlling for behavioral and environmental factors that mask endogenous temperature rhythms, in 23 healthy individuals (mean [±SD] age = 25.4±5.7 years, 5 females). Valid core body temperature data were available in 17/23 (mean [±SD] age = 25.6±6.3 years, 1 female).

Results

Individuals with higher core body temperature amplitude had a greater number of metabolites exhibiting circadian rhythms (R²=0.37, p=.009). Higher core body temperature amplitude was also associated with less variability in the free-fitted periods of metabolite rhythms within an individual (R²=0.47, p=.002).

Discussion

These findings indicate that a more robust central circadian clock is associated with greater organization of circadian metabolite rhythms in humans. Metabolite rhythms may therefore provide a window into the strength of the central circadian clock.
O004 Incorporating Arousals into Sleep vs. Wakefulness Classification Outperforms Traditional Binary Classification at 1-Second Epoch Resolution
Authors: Somaskandhan P , Korkalainen H , Leppänen T , Töyräs J , Melehan K , Wilson D , Ruehland W , Mann D , Terrill P
Published: December 2024

Introduction

30-second epoch-based sleep scoring of polysomnography has key limitations in capturing physiological sleep-state dynamics. Particularly, epoch boundaries may not align with physiological sleep-state transitions (or transition frequencies); and the separate scoring of wakefulness and arousals artificially separates these phenomena.

Method

A deep-learning-based algorithm was developed for sleep vs. wakefulness/arousal classification with a 1-second epoch resolution. The Multi-Ethnic Study of Atherosclerosis Sleep dataset (n=2034) was used to first train and evaluate traditional sleep vs. wakefulness classification (Model 1). Afterwards, it was used to classify sleep vs. wakefulness/arousals, incorporating arousals with a heuristic correction for sleep-to-wake transitions when required (Model 2). Additionally, we analysed how segments with arousals are treated by both models.

Results

Model 1 achieved an overall concordance of 90.38% (Cohen’s kappa κ=0.80, global F1 score=0.89) with manual scoring in the evaluation set (n=306), while Model 2 attained a concordance of 91.04% (κ=0.82, F1=0.90). Model 2 had slightly improved performance compared to Model 1 in classifying both wakefulness (91.9% vs. 90.1%) and sleep (92.9% vs. 92.7), p<0.05 (McNemar’s test). Model 2 also more accurately classified arousal segments as a form of wakefulness (61.1% vs. 51.5%).

Discussion

Despite training on a conventionally annotated dataset with 30-second epochs, Model 2 with arousals incorporated outperformed Model 1’s traditional binary classification concordance at 1-second epoch resolution. These results highlight the potential of using shorter epochs for sleep classification by treating arousals similarly to wakefulness. This approach may capture nuanced sleep-wake transitional characteristics but requires validation against datasets scored on a continuous basis.