bluuebunny/crossref_metadata_2025 huggingface dataset:
Desmoplastic reaction in the microenvironment of head and neck and other solid tumors: the therapeutic barrier
Authors: Okuyama Kohei , Tsuchiya Maiko , Debnath Kala Chand , Islam Shajedul , Yanamoto Souichi
Published: February 2025

Head and neck squamous cell carcinoma (HNSCC) remains a challenge due to limited prognostic biomarkers and therapeutic options. The tumor microenvironment (TME), particularly the desmoplastic reaction (DR) characterized by stromal fibrosis, plays a crucial role in cancer progression and resistance to therapy. This review aims to summarize the biological significance of DR in HNSCC initiation, progression, and treatment resistance. Histologically, DR in HNSCC correlates with invasion patterns and clinical outcomes, affecting disease-free and overall survival. The interaction between cancer-associated fibroblasts (CAFs) and TME influences immune responses, including resistance to immunotherapy. Notably, human papillomavirus-driven HNSCC exhibits distinct DR characteristics that further influence the prognosis. DR promotes epithelial-mesenchymal transition and cancer cell invasion through CAF-mediated extracellular matrix remodeling and signaling pathways such as transforming growth factor-beta. DR also affects bone invasion and chemotherapy resistance by modulating stromal responses. Therapeutic strategies targeting DR and stromal components show promise in overcoming therapeutic resistance including resistance to immune checkpoint inhibitors. Understanding the role of DR in HNSCC biology and its impact on treatment response is critical to developing effective therapeutic interventions.
Nomogram Prediction of Response to Neoadjuvant Chemotherapy Plus Pembrolizumab in Locally Advanced Hypopharyngeal Squamous Cell Carcinoma
Authors: Hu Zhangwei , Chen Yi , Ma Renqiang , Sun Wei , Chen Lin , Cai Zhimou , Wen Weiping , Lei Wenbin
Published: February 2025

Importance

The objective response (ORR) rate in patients with locally advanced hypopharyngeal squamous cell-carcinoma (LA-HPSCC) following neoadjuvant chemotherapy (NACT) of albumin-bound paclitaxel plus carboplatin is low. At present, it is unclear whether the addition of pembrolizumab could increase the ORR or not.

Objective

To investigate whether the addition of pembrolizumab could increase the ORR, and to develop a nomogram to predict the response of pembrolizumab addition.

Design

Retrospective cohort study.

Setting

This study was conducted at a single institution.

Participants

This study included 129 patients who conformed to the inclusion criteria.

Intervention or Exposures

NACT with or without pembrolizumab for patients with LA-HPSCC.

Main Outcome Measures

The ORR was analyzed according to the RECIST 1.1 criteria and a nomogram was developed based on least absolute shrinkage and selection operator and multivariable Cox regression analysis. Predictive accuracy and discriminative ability of the nomogram were evaluated by receiver operating characteristics, precision recall, calibration curves, and decision curve analysis.

Results

Eighty-two patients received NACT and 47 also received pembrolizumab. ORR was higher in patients receiving additional pembrolizumab (66.0% vs 47.6%, χ2 = 4.074, P = .044). The nomogram identified pretreatment levels of lymphocytes and red blood cells as independent predictors of a high ORR, while basophil levels were an independent predictor of a low ORR. Calibration curve showed that the nomogram-based predictions corresponded well with actual observations. C-index of the nomogram was 0.925 (0.848-1.002) and the area under curve was 0.925. Decision curve analysis affirmed that the nomogram had important clinical value.

Conclusions and Relevance

Pembrolizumab could improve the ORR in LA-HPSCC patients treated with NACT. Furthermore, a risk-prediction nomogram incorporating readily assessable routine pretreatment blood parameters can accurately estimate the response to NACT with pembrolizumab, leading to precise treatment and minimizing the waste of medical resources.
Here There Be Ghosts: Mapping Artful Inquiry
Authors: Riley Kathryn , Melchior Shelly , McKinnon-Crowley Saralyn
Published: February 2025

Our work is an exploration of three women’s post-doctoral encounters both within and outside of academia. We say “outside” because our collective encounters as post-doctoral scholars at major R1 institutions in the United States and Canada impacted not only the work we were able to produce within our roles, but it also began to impact our lives in both large and small ways outside of them. Our storied letter writing as artful inquiry offers an attempt to vent, to heal, through the spilling over of all once held so tightly within; Using our words as materials, our stories provoke and activate the imagining and (re)imagining of our individual and now collective journeys in academia and beyond.
Equity Dreaming With an Erotic Praxis: Reading as Pleasure Activism
Authors: P. Mitchell Reagan
Published: February 2025

This article’s contribution utilizes eroticism to re-imagine the meanings of what it is to feel fully and pleasurably as becoming, in tandem with existing, moving through, and/or being present to one’s traumas. Therefore, what possibilities emerge when the erotic is emboldened as an engagement of transgressing and melting binaries of self and community? And further, reading with an erotic praxis, while the content of the text engaged might not be deemed erotic, what are the possibilities presented when the overall practice of reading, regardless of the material being deemed academic and/or leisure, is approached as erotic?.
Cell-free osteoarthritis treatment with dual-engineered chondrocyte-targeted extracellular vesicles derived from mechanical loading primed mesenchymal stem cells
Authors: Wang Peng , Zhao Haiyue , Chen Wei , Guo Yuhui , Zhang Shuo , Xing Xin , Yang Shuai , Wang Fengkun , Wang Juan , Shao Zengwu , Zhang Yingze
Published: February 2025

Osteoarthritis (OA) is an age-related chronic inflammatory disease, predominantly characterized by chondrocyte senescence and extracellular matrix (ECM) degradation. Although mesenchymal stem cells (MSCs) derived extracellular vesicles (EVs) are promising for promoting cartilage regeneration, their clinical application is limited by inconsistent therapeutic effects and insufficient targeting capabilities. Mechanical loading shows potential to optimize MSC-EVs for OA treatment, while the underlying mechanism is not clear. In this study, EVs derived from mechanical loading-primed MSCs (ML-EVs) demonstrate prominent efficacy in maintaining ECM homeostasis and relieving chondrocyte senescence, thereby mitigating OA. Subsequent miRNA sequencing reveals that ML-EVs exert their effects by delivering miR-27b-3p, which targets ROR1 mRNA in chondrocytes and suppresses downstream NF-κB pathways. By modulating the ROR1/NF-κB axis, miR-27b-3p effectively restrains ECM degradation and chondrocyte senescence. To optimize therapeutic efficacy of EVs, miR-27b-3p is overexpressed within EVs (miROE-EVs), and a chondrocyte-targeted peptide (CTP) is conjugated to their surface, thereby constructing dual-engineered chondrocyte-targeted EVs (CTP/miROE-EVs). CTP/miROE-EVs exhibit excellent ability to specifically target cartilage and ameliorate OA pathology. In conclusion, this study underscores the critical role of mechanical loading in augmenting effectiveness of EVs in mitigating OA and introduces dual-engineered EVs that specifically target chondrocytes, providing a promising therapeutic strategy for OA.
Chinese internet policies: Historical reflections and new research directions
Authors: Jiang Min
Published: February 2025

This contribution briefly traces the trajectory of Chinese Internet regulatory policies in the last 30 years and sketches some new research directions in this area attuned to changing domestic dynamics and global geopolitics.
Full-Percutaneous Trans-Kambin Lumbar Interbody Fusion With a Large-Footprint Interbody Cage
Authors: Morgenstern Christian , Morgenstern Rudolf
Published: February 2025

Study Design

Exploratory prospective observational cohort.

Objectives

Aim of this study was to evaluate clinical and radiologic outcome, and surgical efficiency of a novel universal delivery system that allows full-percutaneous extraforaminal, trans-Kambin lumbar interbody fusion with a large-footprint lumbar interbody cage using only fluoroscopic imaging and open-surgery instrumentation.

Methods

We prospectively evaluated patients that underwent elective trans-Kambin TLIF surgery with a large-footprint interbody cage using a novel universal delivery system. Clinical follow-up was evaluated pre-and post-operatively with Visual Analogic Scale (VAS) and Oswestry Disability Index (ODI) scores, while radiologic follow-up was performed with a computed tomography scan and standing films post-operatively at hospital discharge and 1 year follow-up.

Results

A total of 47 patients were evaluated. Clinically, post-operative VAS and ODI scores significantly ( P < 0.001) improved compared to pre-operative scores and 29.4 months mean follow-up. Radiologic evaluation yielded an intervertebral fusion rate of 90% of the operated levels and a significant increase in segmental lordosis by 3.7°. Median surgical time for interbody cage insertion per level was 28 minutes. Complications included 14 (29%) cases with transitory post-operative radiculitis, 4 (8%) cases with partial muscle weakness and 2 (4%) cases that required revision surgery. Post-operative ambulation started at a median 5 hours and median hospital length of stay was 28 hours.

Conclusions

A new universal delivery system allows overcoming most limitations of current full-endoscopic trans-Kambin fusion as it allows a time- efficient full-percutaneous insertion of a large-footprint interbody cage under fluoroscopy imaging only, with standard open-surgery instruments and optional endoscopic visualization.
Academic Leaders’ Perspectives on Entrepreneurship at Finnish Universities: A Comparative Case Study
Authors: Hytti Ulla , Montonen Tero , Eriksson Päivi , Peura Kirsi
Published: February 2025

This case study focuses on academic leaders’ perspectives regarding entrepreneurship at two Finnish universities. It illustrates how university rectors and deans representing a multiplicity of academic traditions make sense of divergent ideas and expectations about what kind of entrepreneurship is sought and implemented in their university. Academic leaders’ understandings are important because they influence how entrepreneurial activities are approached and adopted as part of university strategies and policies. The entrepreneurial university concept undergirds the theoretical frame of the study. Through 15 interviews with academic leaders (rectors and deans) at two multi-faculty universities in Finland, we conduct a narrative analysis of meanings attached to entrepreneurship in the context of universities’ societal impact. The findings highlight how entrepreneurship is presented simultaneously as necessary for all but limited to some disciplines and individuals. Furthermore, adopting a future-oriented perspective allows entrepreneurship to be depicted as important for the younger generations, though not requiring actions by decision-makers presently.
Exploring the Potential of Research–Practice Partnerships to Support State Education Leaders as Agents of Change
Authors: Goldstein Hannah , Weddle Hayley
Published: February 2025

State education agencies have increasing influence over educational policy and practice, with responsibilities ranging from vision setting to monitoring compliance with accountability policy. Although state education agency leaders are well positioned to advance change, capacity building at this level of the education system has been traditionally limited. Research–practice partnerships (RPPs) represent a promising venue to support the ability of state leaders to facilitate educational change. In this qualitative study, we drew on semistructured interviews with state education agency leaders and observations of RPP meetings to examine the state-level structures that pose challenges to leaders’ efforts to make change and how participating in an RPP can support leaders in addressing these challenges. Findings reveal how RPP engagement supported state leaders with navigating complex organizational silos and bureaucratic processes by promoting relationship building and supporting the use of evidence-based resources. These insights may inform future research and capacity-building efforts at the state level of the education system.
How behavioral science interventions can disrupt the cycle of bias in AI-assisted police work
Authors: Dittmann Andrea G. , Dobson Kyle S. H. , Schweitzer Shane
Published: February 2025

When making decisions in high-pressure situations, police officers experience cognitive demands and often lack access to data about the people with whom they are interacting. Artificial intelligence (AI) tools that provide such data can potentially improve officers’ ability to respond effectively to calls and thus bolster public safety. However, research in diverse social sciences has documented persistent biases in AI-assisted work. We propose a framework for understanding how bias can creep into AI-assisted police work and how to intervene. In a cycle of bias, AI tools provide biased information to officers, which in turn promotes biased responses during interactions with the public, ultimately resulting in biased incident reports that amplify the original biases in the AI systems. Our proposed interventions focus on training and nudges that increase officers’ use of deliberative processing, empathic mindsets, and perspective-getting techniques and encourage the writing of detailed, debiased incident reports. We recommend taking a cognitive view of policing and drawing on insights from behavioral science research to maximize the benefits of AI tools while minimizing the risk that they will amplify biases.
AI for Victim Justice in Refugee Status Determination: Enhancing Fairness and Protection
Authors: Gadekar Archana , Singh Akhilendra
Published: February 2025

The modern welfare state has taken help from artificial intelligence (AI) (to enhance their operations) in order to suppress their appetite for good governance. India is an economically vibrant and welfare-oriented state in South Asia; however, it shares a 15,200-km-long border with seven other countries. The border that India is sharing is crisscrossed by varied geographical terrain inclusive of rivers, forests, mountains, deserts and so on. Geographical diversity marks the border to be porous, and poorly guarded. Porous borders and unstable neighbourhood enliven the ‘refuge emigration’ a persistent problem in India. The crucial stage in addressing the persistent refugee issue involves the process of refugee status determination (RSD). The bipartite standard of ‘well-founded fear of persecution’ is a key aspect of RSD (it entails assessing both the claimant’s subjective fear and the objective validation of that fear). However, credibility assessment, country of origin information analysis, risk prediction and decision support systems are many of the facets in which AI can provide valuable assistance. This research article explores the potential of AI in revolutionizing the process of RSD. Additionally, it delves into the ethical considerations, human rights implications and data protection regulations that must be carefully addressed when integrating AI into this critical domain.
Benchmarking linear analysis procedures for reinforced concrete moment frames in ASCE 41
Authors: Najarian Mehdi , Matamoros Adolfo , Montoya Arturo
Published: February 2025

Although linear procedures are used more often than nonlinear procedures for the comprehensive assessment of reinforced concrete (RC) buildings according to ASCE 41, there is much less research on their validation and calibration. This article presents the first of a two-part study on benchmarking linear procedures for RC structures. The main objective of this article was to perform a comparison between global metrics of deformation calculated with the linear static, linear dynamic, and nonlinear dynamic analysis procedures implemented according to the provisions of ASCE 41. The deformation metrics evaluated quantify mean and maximum response, as well as the distribution of deformations over building height. A parametric study was performed with RC moment frames where the following parameters were varied: quality of detailing, intensity of shaking, frame configuration, and effective stiffness. It was found that if the mean drift ratio calculated with the linear model exceeded 2%, the difference between deformations calculated with linear and nonlinear models increased with increasing lateral deformation and decreasing quality of detailing. Recommendations are provided to limit the use of linear procedures in buildings where the probability of collapse is significant. Effective stiffness coefficients for linear procedures were also evaluated. In structures with good detailing, effective stiffness coefficients in ASCE 41 were found to be low for the lowest levels of hazard and high for highest levels of hazard considered. In frames with poor quality of detailing the inferred effective mean stiffness coefficient had a large dispersion, so it is recommended that linear procedures not be used.
Physiological analysis of cognitive load variations during complex information processing
Authors: Armougum Allan , Gaston-Bellegarde Alexandre , Joie-La Marle Chantal , Piolino Pascale
Published: February 2025

Information processing in complex contexts generates higher cognitive demand than in optimal contexts. Though information processing is cognitively less demanding in experts, due to their high level of prior knowledge and considerable number of schemas, a rise in the information complexity in non-optimal context could generate an expertise reversal effect. In our study, we analysed how incidental presentation of information affects cognitive load of train travellers with different expertise levels during navigation in an immersive virtual train station. Analyses of electroencephalography and electrodermal activities as physiological metrics, NASA-Task Load Index as subjective measure and binding memory score as behavioural measure of performance during a recognition phase, helped to quantify cognitive load during the study. With rise in expertise of the investigated train station, participants showed equal or higher cognitive load than participants with lower expertise level, from encoding to recognition phase of the experiment, suggesting an expertise reversal effect. Participants with less expertise did not show any statistically significant difference in cognitive load level from encoding to recognition phase. These findings suggest that complex environmental contexts could contribute to reduce schemas update with increasing expertise level, generating expertise reversal effect.
Early COVID-19 and protection from Omicron in a highly vaccinated population in Ontario, Canada: a matched prospective cohort study
Authors: Shigayeva Altynay , Kandel Christopher , Farooqi Lubna , Zhong Zoe , Gingras Anne-Claude , Coleman Brenda L. , Gilbert Lois , Gold Wayne L. , Major Maria , Mazzulli Tony , Mubareka Samira , Vojicic Jelena , Yang Jingyan , Zhang Pingping , Martin Catherine , Kyaw Moe H. , McLaughlin John M. , McGeer Allison
Published: February 2025

Objectives

Predictions regarding the on-going burden of SARS-CoV-2, and vaccine recommendations, require an understanding of infection-associated immune protection. We assessed whether early COVID-19 provided protection against Omicron infection.

Methods

We enrolled a cohort of adults in Ontario, Canada, with COVID-19 prior to October 2020 (early infection, EI), and a matched cohort with COVID-19 testing and a negative PCR (non-EI). Participants completed baseline surveys then surveys every two weeks until January 2023. Multivariable Cox regression was used to assess factors associated with COVID-19 infection during the first 14 months of Omicron.

Results

Overall, 624 EI (70%) and 175 (77%) non-EI participants met criteria for analysis; 590 (95%) EI and 164 (94%) non-EI had received at least 2 COVID-19 vaccine doses prior to Omicron. Of 624 EI, 175 (28%) had one SARS-CoV-2 re-infection and 8 (1.3%) had two, compared to 84 (48%) non-EI participants with one, 5 (2.9%) with two and 1 (0.6%) with 3 infections (P < 0.0001). In multivariable analysis of risk factors for Omicron infection, the overall hazard ratio (HR, 95%CI) associated with EI was 0.56 (0.43–0.74); HRs for BA.1/2, BA.4/5 and mixed BA.5/BQ.1/XBB periods were 0.66 (0.45–0.97), 0.44 (0.28–0.68) and 0.71 (0.32–1.56). EI and BA.1/2 infection combined reduced later Omicron infection (HR 0.07 (0.03–0.21) compared to no prior infection. Older age, non-White ethnicity, no children in household, and lower neighbourhood income were associated with reduced risk of infection.

Conclusions

In our highly vaccinated population, early SARS-CoV-2 infection was associated with a 44% reduction in symptomatic COVID-19 during the first 14 months of Omicron, providing significant protection against re-infection for more than 2 years.
The Hippo pathway promotes platinum-based chemotherapy by inhibiting MTF1-dependent heavy metal response
Authors: Chen Hui , Xu Yue , Chen Dingshan , Xiao Di , Yang Bing , Wang Wenqi , Han Han
Published: February 2025

The platinum-based compounds are widely used in treating various types of cancer through their heavy metal component platinum. However, the development of chemoresistance often limits their clinical effectiveness. In this study, we report the roles of heavy metal response and its associated Hippo pathway in regulating platinum-based chemotherapy. Our data show that the MTF1-dependent heavy metal response induces cancer cell resistance to platinum-based compounds both in vitro and in vivo. This resistance is mitigated by Hippo pathway-mediated phosphorylation of MTF1. Moreover, pharmacological activation of the Hippo pathway sensitizes cancer cells to platinum-based compounds. Clinically, lung adenocarcinoma (LUAD) patients with high MTF1 activity exhibit poor overall survival rates, and Hippo pathway inactivation is positively correlated with elevated MTF1 transcriptional activity in platinum-treated LUAD patients. Collectively, our findings not only unveil a critical role of the Hippo-MTF1 pathway in regulating the response to platinum-based chemotherapy, but also suggest new strategies to enhance its efficacy by targeting the heavy metal response.
Development of the pulmonary fibrosis, pulmonary vascular resistance, six minute walk distance, B-type natriuretic peptide, age (PVD-B65) risk score for patients with chronic lung disease and pulmonary hypertension
Authors: Gayen Shameek , Pescatore Jay , Bittner Matthew , Naranjo Mario , Criner Gerard J. , Weaver Sheila ,   Temple Lung Center Pulmonary Vascular Disease Working Group, D’Alonzo Gilbert , Illipparambil Lijo , Rali Parth , Pourshahid Seyedmohammad
Published: February 2025

Background

Pulmonary hypertension (PH) confers increased mortality in patients with chronic lung disease, yet there remains a lack of validated risk assessment tools to prognosticate these patients. We aimed to create a risk assessment tool to stratify patients with chronic lung disease and PH by risk of one-year mortality from time of PH diagnosis.

Methods

This was a retrospective cohort study of patients with chronic lung disease and PH. We identified predictors of one-year mortality via multivariable Cox regression and assigned point values to the identified predictors based on their hazard ratios to comprise the risk score. Patients were stratified into low, intermediate, and high-risk based on total scores. Kaplan–Meier survival analysis comparing the stratified groups was performed. Internal statistical validation was performed via Cox regression with bootstrapping.

Results

The identified predictors of one-year mortality that comprised our risk assessment tool were pulmonary fibrosis without emphysema, pulmonary vascular resistance > 5 WU, six-minute walk distance < 150 m, BNP > 200 pg/mL, and age > 65 years (PVD-B65). Once patients were stratified into the three risk groups, Kaplan–Meier survival analysis demonstrated significant differences in one-year survival between the subgroups (logrank p = 0.002). The risk assessment model demonstrated internal validation via bootstrapping (p < 0.05).

Conclusion

The PVD-B65 risk assessment tool is a novel, internally validated one-year mortality risk calculator for patients with chronic lung disease and PH that encompasses factors related to pulmonary parenchymal and vascular remodeling. It may help risk stratify and guide therapeutic interventions in patients with chronic lung disease and PH.
Developing a master of science in health research ethics program in Northern Nigeria: a needs assessment
Authors: Bieniek Caitlin , Tsiga-Ahmed Fatimah I. , Adamu Aishatu L. , Wudil Usman J. , Wester C. William , Iliyasu Zubairu , Aliyu Muktar H. , Gordon Elisa J. , Rose Elizabeth S.
Published: February 2025

Background

Nigeria is an emerging hub of biomedical research, requiring additional trained bioethicists for ethical oversight of research studies. There are currently two graduate-level health research ethics programs in Nigeria. However, both are in the southern part of the country and no such training programs exist in the north. Strengthening the health research ethics skills and knowledge of Nigerian researchers across the country is necessary given the growing genetics research infrastructure.

Methods

To inform the creation of a Master of Science in Health Research Ethics program in northern Nigeria, we conducted a needs assessment comprised of semi-structured interviews with nine Nigerian bioethics experts. We used the Interpretative Phenomenological Analysis (IPA) method to analyze interview transcriptions. Two authors independently read and coded each respondent’s transcript to identify emergent themes that represented each respondent’s answers. Within these overarching themes, the data points were grouped into subthemes.

Results

Four primary themes emerged with ten subthemes. Respondents believed that the program can fill a gap and strengthen capacity in health research ethics. They emphasized that the curriculum should be developed with an interdisciplinary lens and locally contextualized, and that students should be taught how to think critically through ethical scenarios. Respondents stressed that program leaders should recruit faculty and students locally who have the bandwidth to participate in the program. Finally, respondents noted the program should have university support to be sustainable.

Conclusion

Our findings will guide the creation of a master’s degree program that aims to build capacity in health research ethics in northern Nigeria and enhance the country’s growing prominence in global biomedical research. Through our needs assessment, we identified structural and content factors that can guide us in leveraging the strengths of the local institution and leaders in health research ethics while mitigating challenges in establishing this program.
Opioid consumption frequency and its associations with potential life problems during opioid agonist treatment in individuals with prescription-type opioid use disorder: exploratory results from the OPTIMA Study
Authors: Bouthillier Anne , Bastien Gabriel , McAnulty Christina , Bakouni Hamzah , Le Foll Bernard , Socias M. Eugenia , Jutras-Aswad Didier
Published: February 2025

Background

Traditional treatment approaches for prescription-type opioid use disorder (POUD), centered on abstinence, have limitations and hinder the development of interventions that meet the needs of people with POUD. Reduction in use without complete abstinence presents a promising avenue for intervention enhancement, but supporting data is scarce regarding its translation into positive patient outcomes. This study explores whether reducing opioid use frequency (OUF) during opioid agonist treatment correlates with reduced potential life problems in individuals with POUD, including those using fentanyl.

Methods

This study is an exploratory analysis of the OPTIMA trial, a pragmatic, open-label, randomized controlled study comparing the effectiveness of flexible take-home dosing of buprenorphine/naloxone and supervised methadone in reducing opioid use amongst individuals with POUD. OUF was assessed every two weeks for 24 weeks after treatment initiation using the Timeline Followback. Potential life problems were evaluated at baseline and study completion using the Addiction Severity Index Self-Report. The 114 participants who completed both baseline and end-of-study questionnaires were included. A repeated-measures generalized linear mixed model (GLMM) was used to evaluate the influence of OUF on potential life problems.

Results

Reducing OUF was significantly associated with fewer problems related to medical status (p = 0.049), psychiatric status (p = 0.019), and alcohol problem severity (p = 0.001). The interaction was non-significant for employment (p = 0.264), family status (p = 0.352) and legal status (p = 0.050). Life improvements emerged with ≤ 21 days of opioid use per 28-day period.

Conclusion

Findings underscore the significance of harm reduction goals focusing on opioid use reduction, which translated in improvements across many life domains.

Trial registration

Study was registered with ClinicalTrials.gov (NCT03033732) prior to participant enrollment.
Fractional hitting sets for efficient multiset sketching
Authors: Rouzé Timothé , Martayan Igor , Marchet Camille , Limasset Antoine
Published: February 2025

The exponential increase in publicly available sequencing data and genomic resources necessitates the development of highly efficient methods for data processing and analysis. Locality-sensitive hashing techniques have successfully transformed large datasets into smaller, more manageable sketches while maintaining comparability using metrics such as Jaccard and containment indices. However, fixed-size sketches encounter difficulties when applied to divergent datasets. Scalable sketching methods, such as , provide valuable solutions but still lack resource-efficient, tailored indexing. Our objective is to create lighter sketches with comparable results while enhancing efficiency. We introduce the concept of Fractional Hitting Sets, a generalization of Universal Hitting Sets, which cover a specified fraction of the k-mer space. In theory and practice, we demonstrate the feasibility of achieving such coverage with simple but highly efficient schemes. By encoding the covered k-mers as super-k-mers, we provide a space-efficient exact representation that also enables optimized comparisons. Our novel tool, , implements this scheme, and experimental results with real bacterial collections closely match our theoretical findings. In comparison to , achieves similar outcomes while utilizing an order of magnitude less space and memory and operating several times faster. This highlights the potential of our approach in addressing the challenges presented by the ever-expanding landscape of genomic data. is an open-source software and can be accessed at https://github.com/TimRouze/supersampler. The data required to reproduce the results presented in this manuscript is available at https://github.com/TimRouze/supersampler/experiments.
Radiological assessment of cup anteversion with a novel 3D-printed highly-porous titanium dual mobility cup
Authors: Puteo Nicole , Valentino Edoardo Matteo , Davidoni Vittorio , Tigani Domenico
Published: February 2025

Background

Cup anteversion after primary total hip arthroplasty (THA) with monobloc dual mobility cups (DMC) is difficult to measure on anterior-posterior (AP) pelvic radiographs because of the implant radiopacity and cup design which do not allow for an accurate visualization of the radiographic projection of the cup equatorial rim and the femoral head. This study aims to radiographically investigate on the reliability and accuracy of different measurement methods for cup anteversion in monobloc DMC THA, by comparing a novel titanium cup with conventional cup designs.

Methods

97 THAs with a monobloc 3D-printed titanium DMC were radiographically assessed for cup radiographic anteversion (RA) one month postoperatively. RA were measured by three blinded observers through Lewinnek, Woo-Morrey methods and an open access mathematical software (GeoGebra), used as reference method. Intra- and interobserver reliability of RA measurements were evaluated for each method using intraclass correlation coefficient (ICC). Accuracy was assessed comparing Lewinnek and Woo-Morrey methods with GeoGebra. Moreover, further 98 THAs with conventional different brand DMC were radiographically assessed as control group by using the same methods.

Results

ICC for intra- and interobserver reliability for RA measurements with GeoGebra, Lewinnek and Woo-Morrey methods were 0.975–0.980, 0.978 − 0.965, and 0.979 − 0.958, respectively, for the titanium DMC group. Lewinnek resulted more accurate for RA than Woo-Morrey, differing by + 0.4° (p = 0.06) and + 4.4° (p < 0.001) from GeoGebra, respectively. ICC for intra- and interobserver reliability for GeoGebra, Lewinnek and Woo-Morrey methods were 0.848 − 0.756, 0.843 − 0.801, and 0.965 − 0.958, respectively, for the control DMC group. Lewinnek and Woo-Morrey methods differed by -2.3° and + 5.1° from GeoGebra, respectively (p < 0.001).

Conclusions

RA measurements are more consistent, repeatable and accurate with a titanium DMC than standard DMC, due to the minor radiopacity of the former cup which enable RA measurements on AP radiographs. Conversely, RA measurements of conventional DMC are more consistent but less accurate if performed on cross-table lateral radiographs by Woo-Morrey method than AP radiographs.
Generalized pustular psoriasis: a multicentric study on patient characteristics and clinical burden
Authors: Livideanu Cristina Bulai , Gottlieb Jérémy , Jullien Denis , Passeron Thierry , Vildy Sophie , Delaporte Emmanuel , Paul Carle , Chollet Julien , Najean Marie , San Denis , Taieb Charles , Charles Bénédicte , Mahe Emmanuel , Becherel Pierre-André , Misery Laurent
Published: February 2025

The objective of this study was to assess the demographic characteristics and impact on quality of life (QoL) of patients with PPG in France through a multicentre study. The results of the study are as follows: The PRO [PUSH-D, PHQ-9 et GAD-7] revealed that more than half of the patients exhibited a significant impact on their quality of life. High scores for fatigue, stress, skin and joint pain were reported, with 65% of patients at risk of mild to severe depression. The clinical burden was also assessed. A total of 48.8% of patients were hospitalised, while 39% took sick leave. This study is the first to assess the PUSH-D, PHQ-9 and GAD-7 scores in patients with PPG, which highlighted a significant clinical burden and negative impact on their daily lives.
The transcription factor combination MEF2 and KLF7 promotes axonal sprouting in the injured spinal cord with functional improvement and regeneration-associated gene expression
Authors: Attwell Callan L. , Maldonado-Lasunción Inés , Eggers Ruben , Bijleveld Bastiaan A. , Ellenbroek Ward M. , Siersema Natascha , Razenberg Lotte , Lamme Dédé , Fagoe Nitish D. , van Kesteren Ronald E. , Smit August B. , Verhaagen Joost , Mason Matthew R. J.
Published: February 2025

Background

Axon regeneration after injury to the central nervous system (CNS) is limited by an inhibitory environment but also because injured neurons fail to initiate expression of regeneration associated genes (RAGs). The potential of strong RAG expression to promote regeneration in the CNS is exemplified by the conditioning lesion model, whereby peripheral nerve injury promotes regeneration of centrally projecting branches of the injured neurons. RAG expression could potentially be induced by delivery of the right set of transcription factors (TFs). We here aim to identify TF combinations that activate this program.

Methods

We first analysed binding site motifs in promoters of the RAG program to identify nine candidate growth-promoting TFs. These were systematically screened in vitro to identify combinations that had potent neurite-growth promoting activity. Next, adeno-associated viral vectors were used to express these TF combinations in vivo in L4/L5 dorsal root ganglia to test whether they would promote regeneration in a spinal cord injury model (dorsal column lesion) in female rats. To determine whether they could activate the RAG program we carried out gene expression profiling on laser-dissected dorsal root ganglion neurons specifically expressing these TF combinations, and of DRG neurons that had been axotomized.

Results

Promoter analysis identified ATF3, Jun, CEBPD, KLF7, MEF2, SMAD1, SOX11, STAT3 and SRF as candidate RAG-activating TFs. In vitro screening identified two TF combinations, KLF7/MEF2 and ATF3/KLF7/MEF2, that had potent neurite-growth promoting activity, the latter being the more powerful. In vivo, KLF7/MEF2, but not ATF3/KLF7/MEF2 or KLF7 or MEF2 alone, promoted axonal sprouting into the dorsal column lesion site and led to improved functional recovery. Gene expression profiling revealed that unexpectedly, the MEF2-VP16 construct used had little transcriptional activity in vivo, suggesting additional steps may be required to achieve full MEF2 activity. All combinations except MEF2 alone induced RAG expression mirroring that induced by axotomy to significant extents, while ATF3/KLF7/MEF2, KLF7 and ATF3, but not KLF7/MEF2 also induced apoptosis-related genes which may hinder regeneration.

Conclusions

The TF combination KLF7/MEF2 partially mimics the conditioning lesion effect, inducing axonal sprouting into a dorsal column lesion and driving significant RAG expression, and also promotes functional improvement.
Blood molecular subtypes to guide precision treatment strategies in systemic juvenile idiopathic arthritis
Authors: Baek In-Woon , Rhim Jung Woo , Park Kyung-Su , Kim Ki-Jo
Published: February 2025

Background

Systemic juvenile idiopathic arthritis (sJIA) is the most severe subtype of JIA, with a combination of diverse clinical manifestations and a variable clinical course. A comprehensive understanding of molecular signatures at the systems level and the discovery of molecular subtypes are the initial steps toward personalized medicine in sJIA.

Methods

A blood transcriptomic dataset was collected from patients with systemic JIA (sJIA) (n = 168), polyarticular JIA (n = 254), oligoarticular JIA (n = 96), enthesitis-related arthritis (n = 40), and healthy controls (n = 220). Gene expression profiles were filtered for differentially expressed genes and unsupervised clustering, gene set enrichment, and network-based centrality analyses. The molecular signatures of three novel sJIA subgroups (designated as C1, C2, and C3) were investigated, focusing on their distinct features and treatment responses.

Results

Neutrophil degranulation and the IL-1 signaling pathway were the shared key processes for the three subgroups. Proinflammatory signals, including TNF, IL-6, TLR, and G-CSF signaling pathways, were identified with variation across the subgroups. C1 was the most inflammatory subset with a high-risk profile for macrophage activation syndrome. The C2 subset had the most activated IL-1 and IL-18 signaling pathways. C2 and C3 have higher levels of interferon-stimulated signatures. In a canakinumab-treated dataset, treatment response was correlated with IL1B expression and NF-κB signaling pathway, and neutrophil activation-associated processes were effectively suppressed in a good responder group. GSK3B and p38 MAPK inhibitors showed a significant counteracting effect on the perturbed gene expression of sJIA.

Conclusions

Neutrophil activation was the key feature in active sJIA. The three molecular subtype scheme enables the formulation of precision medicine strategies in sJIA.
Engineered Bacillus subtilis WB600/ZD prevents Salmonella Infantis-induced intestinal inflammation and alters the colon microbiota in a mouse model
Authors: Li Wei , Wang Xue , Chen Keyuan , Zhu Yaohong , Yang Guiyan , Jin Yipeng , Wang Jiufeng
Published: February 2025

Antimicrobial peptides (AMPs) are instrumental in maintaining intestinal homeostasis and have emerged as potential therapeutic candidates for ameliorating intestinal bacterial infections. However, the intrinsic instability associated with the in vivo delivery of AMPs constitutes a substantial impediment to their therapeutic efficacy in treating infections. In this study, we genetically modified Bacillus subtilis (B. subtilis) WB600 to express Zophobas atratus defensin (ZD), an antimicrobial peptide with broad-spectrum activity isolated from Zophobas atratus, for oral administration. This engineered strain effectively protects against Salmonella Infantis (S. Infantis) infection in mice. Pretreatment with WB600/ZD prevented NF-κB pathway activation induced by S. Infantis infection and increased expression of antioxidant and tight junction proteins, thus alleviating the severity of intestinal inflammation in both the jejunum and ileum (P < 0.01). Moreover, WB600/ZD pretreatment facilitated the growth of beneficial bacteria such as Lachnospiraceae, Butyricicoccus, Eubacterium_xylanophilum, and Clostridia_UCG-014 while decreasing the abundance of pathogenic bacteria such as Escherichia-Shigella and Salmonella (P < 0.05). In conclusion, this study underscores the protective effects of WB600/ZD on S. Infantis-induced intestinal inflammation, suggesting that oral delivery of B. subtilis WB600/ZD may be a promising prophylactic strategy for combating bacterial infections in the intestine.
Limited transmission of avian influenza viruses, avulaviruses, coronaviruses and Chlamydia sp. at the interface between wild birds and a free-range duck farm
Authors: Le Gall-Ladevèze Chloé , Vollot Benjamin , Hirschinger Julien , Lèbre Laëtitia , Aaziz Rachid , Laroucau Karine , Guérin Jean-Luc , Paul Mathilde , Cappelle Julien , Le Loc’h Guillaume
Published: February 2025

Recent outbreaks of highly pathogenic avian influenza in Europe have raised questions regarding the epidemiological role of commensal wild birds on free-range poultry farms. This study aimed to assess the prevalence of avian influenza viruses (AIV), avulaviruses, coronaviruses and Chlamydia sp. in commensal wild birds on a free-range duck farm in southwestern France and to evaluate possible transmission events at the wild‒domestic interface. From 2019 through 2021, a longitudinal study was conducted on wild birds, domestic ducks and their shared environment on farms. Commensal wild birds were captured and sampled for blood and swabs, and fresh feces from cattle egrets visiting the farm were collected. In parallel, domestic ducks were sampled, and environmental samples were collected. The presence of the four pathogens was tested by q(RT-)PCR, and the immunity of wild birds to AIV and Newcastle disease virus (NDV) was tested by ELISA. Wild birds were found to shed AIV and Chlamydia only, with a low prevalence (< 3%). The seroprevalence rates were less than 10% for AIV and less than 4.5% for NDV. No significant temporal trend was identified. Ducks and their environment frequently test simultaneously positive for the same pathogens (19 to 44% of flocks), mostly during fall‒winter. In addition to unrelated temporal patterns, the identification of pathogens in wild birds seemed unrelated to that in domestic ducks. These results suggest a low transmissibility of the avian pathogens tested in our study at the wild‒domestic interface and highlight the limited contribution of commensal wild birds in comparison with free-range poultry to the global microbiological pressure on the environment.
A novel high-throughput screen identifies phenazine-1-carboxylic acid as an inhibitor of African swine fever virus replication in primary porcine alveolar macrophages
Authors: Lan Jing , Luo Rui , Liu Di , Qi Changxing , Song Xin , Lu Zhanhao , Huang Ruojia , Yang Yuying , Sun Yuan , Zhang Yonghui , Wang Tao , Qiu Hua-Ji
Published: February 2025

African swine fever (ASF), caused by African swine fever virus (ASFV), has resulted in significant economic impacts on the global swine industry. Currently, there is no safe and effective commercial vaccine available for ASFV. Thus, the development of effective and readily available therapeutics for ASF is urgently needed. To conduct high-throughput screening (HTS) for anti-ASFV drugs, we initially developed a recombinant dual-reporter virus (rASFV-Gluc/EGFP) using the virulent strain ASFV HLJ/18 (ASFV-WT). The enhanced green fluorescent protein (EGFP)- and Gaussia luciferase (Gluc)-encoding genes were incorporated downstream of the ASFV MGF300-4L gene without disrupting viral genes. The growth kinetics, hemadsorption, and transmission electron microscopy analysis of rASFV-Gluc/EGFP in primary porcine alveolar macrophages (PAMs) revealed that rASFV-Gluc/EGFP exhibits similar biological characteristics to ASFV-WT. Furthermore, analysis of Gluc activities, fluorescence, and next-generation sequencing indicated that rASFV-Gluc/EGFP maintains good genetic stability after 20 consecutive passages in PAMs. Using the HTS platform established with rASFV-Gluc/EGFP, we screened and identified phenazine-1-carboxylic acid (PCA) as an effective inhibitor of ASFV replication from 246 small molecule compounds in PAMs. Importantly, PCA was found to reduce ASFV replication by as much as 100-fold at a concentration of 25 μM. Overall, this study suggests that rASFV-Gluc/EGFP is suitable for rapid screening of anti-ASFV drugs. Importantly, we showed that PCA has significant anti-ASFV activity in PAMs.
Site-selective dimethylation of flavonoids using fusion flavonoid O-methyltransferases
Authors: Lee Kyungha , Bhoo Seong Hee , Lee Sang-Won , Cho Man-Ho
Published: February 2025

Flavonoids are often decorated with methyl groups, which are catalyzed by flavonoid O-methyltransferases (FOMTs). Most FOMTs methylate flavonoids in a regiospecific manner. Because of the regiospecific nature of FOMTs, the synthesis of polymethoxyflavonoids is accomplished by multiple O-methylation steps. The multistep synthesis of dimethoxyflavonoids can be efficiently performed by a one-pot procedure using a multienzyme biocatalyst. For the one-pot production of dimethoxyflavonoids, fusion FOMTs were generated by the combination of two different regiospecific FOMTs. RdOMT10 (flavonoid 3-OMT), OsNOMT (flavonoid 7-OMT), and ObFOMT5 (flavonoid 4'-OMT) were used in the FOMT fusion. The fusion FOMTs (OsNOMT/ObFOMT5, OsNOMT/RdOMT10, and ObFOMT5/RdOMT10) were heterologously expressed in Escherichia coli. Activity assays of the recombinant fusion FOMTs demonstrated that OsNOMT/ObFOMT5, OsNOMT/RdOMT10, and ObFOMT5/RdOMT10 catalyze 7/4'-O-methylations, 7/3-O-methylations, and 4'/3-O-methylations of flavonoids, respectively. OsNOMT/ObFOMT5 and OsNOMT/RdOMT10 showed strong dimethylation activity towards diverse flavonoids and were therefore used in the site-selective bioconversion of flavonoids into dimethoxyflavonoids. The E. coli cells bearing OsNOMT/ObFOMT5 successfully converted flavonoids into 7,4'-dimethoxyflavonoids. The engineered E. coli expressing OsNOMT/RdOMT10 converted flavonoids into 3,7-dimethoxyflavonoids. This result indicates that the fusion FOMTs are useful multienzyme biocatalysts for the site-selective production of dimethoxyflavonoids by one-pot bioconversion.