bluuebunny/crossref_metadata_2025 huggingface dataset:
Decellularized dermis allograft for the treatment of venous leg ulceration: the DAVE RCT
Authors: Onida Sarah , Tan Matthew , Balan Valeria , Heatley Francine , Peerbux Sarrah , Bolton-Saghdaoui Layla , Lane Tristan , Epstein David , Gohel Manjit , Norrie John , Lee Robert , Lomas Richard , Davies Alun H
Published: February 2025

Background

Venous leg ulcers (VLUs) cause significant impairment to patients’ quality of life (QoL) and up to 30% do not heal at 6 months. Decellularized dermis (DCD) allografts have been shown to be effective in improving healing rates of diabetic foot ulcers in RCTs. The DAVE RCT aimed to determine whether DCD is an effective, safe, and cost-effective treatment adjunct for VLUs.

Methods

This was a multicentre RCT performed in the UK. Patients with lower limb ulcers ≥18 years with VLU, venous incompetence on duplex ultrasound, an ankle : brachial pressure index ≥ 0.8 and an index VLU present for at least 3 months and ≥2 cm2 in size were included. Patients were randomized to either the intervention (DCD graft and standard of care) or control arm (standard of care alone). The primary outcome was the proportion of patients with a healed index ulcer at 12 weeks.

Results

From October 2019 to October 2022, 36 and 35 participants were randomized into the intervention and control arms respectively. Patient characteristics at baseline were similar between groups. Healing was recorded in 5.7% of the intervention group and 15.2% in the control group (OR 0.34, 95% c.i. 0.03 to 2.31). There were no significant differences in the secondary outcomes including the percentage change in ulcer area, time to healing, recurrence rates, and QoL. There were five serious adverse events attributed to DCD application. Early trial termination was advised after the interim data analysis due to a lower-than-expected primary outcome rate (11.3%).

Conclusions

Decellularized dermis grafts did not improve healing rates of venous leg ulcers, although the trial was terminated early due to poor healing rates in both the intervention and control arms. Important clinical benefits or harms of decellularized dermis grafts could not be excluded due to the small sample size.

Trial registration

ISRCTN 21541209
Exploring functional connectivity in clinical and data-driven groups of preterm and term adults
Authors: Hadaya Laila , Váša František , Dimitrakopoulou Konstantina , Saqi Mansoor , Shergill Sukhwinder S , Edwards A David , Batalle Dafnis , Leech Robert , Nosarti Chiara
Published: February 2025

Adults born very preterm (i.e., at <33 weeks’ gestation) are more susceptible to long-lasting structural and functional brain alterations and cognitive and socio-emotional difficulties, compared to full-term controls. However, behavioural heterogeneity within very preterm and full-term individuals makes it challenging to find biomarkers of specific outcomes. To address these questions, we parsed brain-behaviour heterogeneity in participants subdivided according to their clinical birth status (very preterm vs full-term) and/or data-driven behavioural phenotype (regardless of birth status).

Participants were followed up in adulthood (median age 30 years) as part of a wider longitudinal case-control cohort study. The Network Based Statistic approach was used to identify topological components of resting state functional connectivity differentiating between i) 116 very preterm and 83 full-term adults (43% and 57% female, respectively), and ii) data-driven behavioural subgroups identified using consensus clustering (n= 156, 46% female). Age, sex, socio-economic status, and in-scanner head motion were used as confounders in all analyses. Post-hoc two-way group interactions between clinical birth status and behavioural data-driven subgrouping classification labels explored whether functional connectivity differences between very preterm and full-term adults varied according to distinct behavioural outcomes.

Very preterm compared to full-term adults had poorer scores in selective measures of cognitive and socio-emotional processing and displayed complex patterns of hyper- and hypo-connectivity in subsections of the default mode, visual, and ventral attention networks. Stratifying the study participants in terms of their behavioural profiles (irrespective of birth status), identified two data-driven subgroups: An “At-risk” subgroup, characterised by increased cognitive, mental health, and socio-emotional difficulties, displaying hypo-connectivity anchored in frontal opercular and insular regions, relative to a “Resilient” subgroup with more favourable outcomes. No significant interaction was noted between clinical birth status and behavioural data-driven subgrouping classification labels in terms of functional connectivity.

Functional connectivity differentiating between very preterm and full-term adults was dissimilar to functional connectivity differentiating between the data-driven behavioural subgroups. We speculate that functional connectivity alterations observed in very preterm relative to full-term adults may confer both risk and resilience to developing behavioural sequelae associated with very preterm birth, while the localised functional connectivity alterations seen in the “At-risk” subgroup relative to the “Resilient” subgroup may underlie less favourable behavioural outcomes in adulthood, irrespective of birth status.
Horizontal transfer of msp130 genes and the evolution of metazoan biocalcification
Authors: Chess Macie M , Foley Saoirse , Ettensohn Charles A
Published: February 2025

The formation of calcified skeletons is crucial for the development, physiology, and ecology of many marine metazoans. The evolutionary origins of the genetic toolkit required for biocalcification are widely debated. MSP130 proteins, originally identified through their expression specifically by sea urchin skeletal cells, have been hypothesized to have been acquired by metazoans from bacteria through horizontal gene transfer (HGT). Here, we provide support for an HGT-based origin of metazoan MSP130 proteins by conducting phylogenetic and in silico protein analyses utilizing high-quality genomes. We show that msp130 genes underwent duplications within almost all biocalcifying bilaterian phyla and identify highly conserved intron-exon junctions specific to bilaterian msp130 genes. The absence of MSP130 proteins in calcifying, non-bilaterian metazoans and other basal eukaryotes suggests that an ancestral msp130 gene underwent an HGT event that predates bilaterians, but not metazoans. We report striking structural similarities between bilaterian and bacterial MSP130 proteins, with each containing a seven-bladed, barrel-like motif that encompasses a choice-of-anchor domain, and identify highly conserved, predicted Ca2+-binding sites associated with the barrels. These findings point to a conserved, ancient function for MSP130 proteins in biocalcification and support the view that lateral transfer of bacterial genes supported the appearance of calcified animal skeletons.
Innateness transcriptome gradients characterize mouse T lymphocyte populations
Authors: Ascui Gabriel , Cedillo-Castelan Viankail , Mendis Alba , Phung Eleni , Liu Hsin-Yu , Verstichel Greet , Chandra Shilpi , Murray Mallory Paynich , Luna Cindy , Cheroutre Hilde , Kronenberg Mitchell
Published: February 2025

A fundamental dichotomy in lymphocytes separates adaptive T and B lymphocytes, with clonally expressed antigen receptors, from innate lymphocytes, which carry out more rapid responses. Some T cell populations, however, are intermediates between these 2 poles, with the capacity to respond rapidly through T cell receptor activation or by cytokine stimulation. Here, using publicly available datasets, we constructed linear mixed models that not only define a gradient of innate gene expression in common for mouse innate-like T cells, but also are applicable to other mouse T lymphoid populations. A similar gradient could be identified for chromatin landscape based on ATAC-seq (assay for transposase-accessible chromatin using sequencing) data. The gradient included increased transcripts related to many traits of innate immune responses, with increased scores related to evidence for antigen experience. While including genes typical for T helper 1 (Th1) responses, the innateness gene program could be separated from Th1, Th2, and Th17 responses. Lymphocyte populations with higher innateness scores correlated with lower calcium-dependent T cell receptor–mediated cell activation, with some downstream signaling proteins dependent on calcium or affecting metabolism prephosphorylation. Therefore, as a group, different mouse innate-like T cell populations had related gene expression programs and activation pathways that are different from naive CD4 and CD8 T cells.
Cicero's Catilinarian Orations
Authors: May James M.
Published: February 2025

In 63 BCE, during the final months of his term as consul, Cicero, through diligence, careful investigation, and a series of other fortuitous events, uncovered a plot to overthrow the state. The leader and mastermind of the conspiracy was Lucius Sergius Catilina (Catiline), a nobly born but disaffected senator, who had experienced defeat in the consular elections two years running. In possession of considerable physical abilities and great personal magnetism, Catiline had assembled a group of similarly disgruntled conspirators, who were hard-pressed by the ongoing economic crisis plaguing Rome and who were aiming, among other things, at the cancellation of debts, redistribution of land, and a radical (and violent) change of leadership. The four speeches that Cicero delivered concerning the conspiracy, known as the Catilinarian orations, or simply the Catilinarians (Marci Tullii Ciceronis orationes in Catilinam [In Catilinam I–IV]), are justly famous and familiar to most every student who has studied Latin. After thwarting an assassination attempt at his house on the morning of 7 November, Cicero convened a meeting of the Senate, during which he delivered a fiery speech, perhaps his most famous (the First Catilinarian oration), repeatedly urging Catiline (who was in attendance) to leave Rome and join his revolutionary army. On the next day, the consul called a public meeting in the forum and delivered the Second Catilinarian oration, a scathing invective in which he characterizes Catiline and his followers, contrasting them with the loyal Romans who oppose them. On 3 December, in another speech to the people (the Third Catilinarian oration), he reports on the arrest of several conspirators and reveals crucially incriminating evidence against them. Two days later, the Senate deliberated the fate of the conspirators in custody. Silanus, the consul-elect, proposed execution, while Julius Caesar argued for life imprisonment. Cicero, in his Fourth Catilinarian oration, reviews the arguments and pledges his loyal support for the will of the Senate. Silanus’s proposal, bolstered considerably by a powerful speech by the younger Cato, carried the day and the five conspirators in custody ultimately met their fate by strangulation that evening in the Tullianum, Rome’s prison. Although hailed as a hero in the immediate aftermath, the action of executing Roman citizens without a trial would return to haunt Cicero in the near future. Catiline, after fleeing Rome, joined fellow-conspirator Gaius Manlius and his assembled troops in northern Italy; he, along with several thousand soldiers, died in a pitched battle near Pistoria, northwest of Florence, in January 62 BCE.
Arts of the Tea Ceremony
Authors: Corbett Rebecca
Published: February 2025

Chanoyu (literally “hot water for tea”), alternately known as Sadō/Chadō (“The Way of Tea”), often described as “tea ceremony” in English, is an art of social interaction based around the preparation and consumption of matcha (powdered green tea). Considered an art form in its own right, since its development in the sixteenth century, tea culture has provided an important context for the creation, consumption, and display of art forms such as calligraphy, painting, ceramics, lacquerware, and metalwork, to name but a few. Scholarship on chanoyu began in the early twentieth century and burgeoned in the postwar period. Much of the scholarship is dominated by authors associated with the Urasenke School of Tea which has become the largest school both within Japan and internationally in the postwar period and has its own publishing arm, Tankōsha. There is therefore a bias in existing scholarship toward this school, its style of practice and history, however, this has begun to be corrected in recent years. There has been a trend away from focusing on a linear narrative of the development of chanoyu with a focus on the three so–called “founders” of chanoyu: Murata Jukō (Shukō) (b. 1422/3–d. 1502); Takeno Joo (b. 1502–d. 1555); and Sen no Rikyū (b. 1522–d. 1591). More attention is given to developments after the formative period in which they lived, as well as more nuanced approaches to the contributions of these leading figures. The material culture of tea has become an increasingly fruitful area of study, with attention being given not only to the objects themselves but to patterns of consumption, the role of tea practitioners as producers of tea utensils and patrons of craftsman, and the function of tea utensils in gift exchange, identity construction, and for cultivating political capital. Another burgeoning area of study is the role of women in both historical and contemporary tea practice, and what the study of tea brings to women’s lives. This is correcting the male-centered narratives of earlier scholarship. Much tea scholarship is historical but there is a growing interest in bringing academic perspectives to bear on contemporary practice. Recent English-language scholarship has moved away from the term “tea ceremony” because it is not a translation of any existing Japanese term, nor does it capture the breadth of the practice. The term “tea culture” or even simply “tea” is now preferred as it is more encompassing of the various art forms included within chanoyu.
Asiatic acid improves the damage of HaCaT cells induced by nitrogen mustard through inhibiting endoplasmic reticulum stress
Authors: Liu Haoyin , Cheng Jin , Ye Feng , Dong Xunhu , Ge Wei , Wang Xiaogang , Zhao Yuanpeng , Dan Guorong , Chen Mingliang , Sai Yan
Published: February 2025

Nitrogen mustard (NM) belongs to vesicant agents. Blisters are one of the important characteristics of NM skin damage. It is urgent to further elucidate the mechanism and develop effective countermeasures for the skin damage induced by NM. The endoplasmic reticulum (ER) is an important intracellular organelle, playing an important role in maintaining cellular homeostasis. In this study, we explored the role of endoplasmic reticulum stress (ERS) and the protective effect of asiatic acid (AA) in the HaCaT cells induced by NM. It was found that the key regulatory proteins of ERS, such as glucose regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), inositol requiring enzyme 1 (IRE1), Phospho-IRE1 (pIRE1), and TNF receptor associated factor 2 (TRAF2) were increased respectively in HaCaT cells exposed to NM compared with those of the control group, showing an increasing trend with the increase of NM exposure concentration and exposure time. Additionally, the protein expression of Caspase-3 and the Cleaved-Caspase-3 was also increased by NM in HaCaT cells, resulting in the apoptosis of HaCaT cells. Meanwhile, the content of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) was also increased in HaCaT cells exposed to NM. Further study showed that AA pretreatment could decrease the protein expression of GRP78, XBP1 and IRE1, pIRE1, TRAF2, Caspase-3, and Cleaved-Caspase-3. And moreover, AA also could reduce the content of TNF-α and IL-6. Overall, the present study showed that AA played an important protective effect in HaCaT cells exposed to NM through the inhibition of the ERS-induced apoptosis and inflammatory response.
A Novel Competency-Based, Time-Variable Mid-Career Fellowship Program in Hospice and Palliative Medicine
Authors: Heath Janae K. , Devlin Shannon , Leiter Richard E. , Lindenberger Elizabeth , Shameklis Jaclyn , Dingfield Laura
Published: February 2025

Problem

The field of hospice and palliative medicine (HPM) is grappling with a significant workforce shortage. An untapped source of growth for the HPM specialist workforce is mid-career physicians interested in specialist training and certification. This study describes a pilot competency-based, time-variable (CBTV) fellowship program for mid-career physicians interested in HPM, called the Mid-Career Fellowship.

Approach

The pilot program was approved by the Accreditation Council for Graduate Medical Education (ACGME) Advancing Innovation in Residency Education program in consultation with certification boards. The Mid-Career Fellowship enrolled 2 mid-career fellows in July 2019 at the University of Pennsylvania, ultimately expanding in July 2020 and July 2021 to 7 participating sites. Clinical training in the fellowship was scheduled on an interrupted, part-time basis, with full- or partial-week clinical HPM rotations scheduled to accommodate fellows’ other professional and academic responsibilities. Mid-career fellows’ progression on HPM competencies was assessed through direct observation during HPM clinical rotations using validated assessments and the ACGME HPM milestones framework. Participants and traditional HPM fellows were surveyed for their perceptions of the program.

Outcomes

From July 2019-June 2024, the Mid-Career Fellowship had enrolled 22 individuals and produced 14 graduates across the 7 participating sites. As of June 2024, 12 of 14 (86%) graduates had entered full- or part-time practice in an HPM specialty. Two mid-career fellows have passed the biannual HPM board certification, with additional fellows being eligible to sit for the certification exam in fall 2024.

Next Steps

Aspects of the program could be adapted by other specialties facing workforce shortages. Future work is needed to determine the long-term impact of this training and the role of similar programs in other specialties. The authors’ next steps will be to conduct qualitative analyses of such programs’ impact on professional development for participants.
Increased Risks of Major Cardiac Adverse Events in Stimulant Use Disorder as Compared With Other Substance Use Disorders: A Propensity-score Matching Cohort Study
Authors: Garel Nicolas , Greenway Kyle T. , Lavin Paola , Pike C. William , Hyde Rebecca , Jutras-Aswad Didier , Tate Steven D. , Lembke Anna
Published: February 2025

Objectives:

Individuals with stimulant use disorders (StSUDs) present an elevated risk of cardiovascular complications compared with the general population. However, it remains unclear whether, within the subpopulation of individuals with substance use disorders (SUDs), those specifically affected by StSUDs face even higher cardiovascular complications.

Methods:

We conducted a retrospective cohort study using the EVERSANA databank, spanning from January 2015 to December 2023. The EVERSANA data set comprises deidentified electronic health record data aggregated and standardized across the United States. Participants included patients diagnosed with SUDs, encompassing alcohol, cannabis, opioids, stimulants, tobacco, hallucinogens, sedative-hypnotics, or inhalants. We employed the International Classification of Disease 10th (ICD-10) version codes to define the presence of StSUD and SUD. Major adverse cardiac events (MACE) were assessed, and Cox proportional hazard ratios were adjusted using high-dimensional propensity score (hdPS) matching to account for potential confounders.

Results:

Among 137,106 patients with SUD, 7706 (5.6%) had StSUD. The cohort was 50.2% female, 53.0% non-White, with a mean age of 49.1 years (SD±15). After adjustment, stimulant users exhibited significantly higher MACE rates (HR=1.37, 95% CI: 1.22–1.53, P<0.001), including an elevated risk of death (HR=1.23, 95% CI: 1.02–1.47, P=0.026).

Conclusion:

Individuals with StSUD face increased MACE compared with those with nonstimulant SUDs.
Post Void Residuals: Medications for Opioid Use Disorder, Patient Outcomes, and How Not to Get Fooled by Urine Toxicology Results
Authors: Pytell Jarratt D. , Fiellin David A.
Published: February 2025

As opioid-related mortality has increased in the United States, greater emphasis has been placed on ensuring access to medications for opioid use disorder(MOUD) and improving outcomes. While abstinence using urine toxicology testing was a mainstay of assessing MOUD treatment outcomes, there have been major shifts in clinical, research, and public health communities away from placing untoward emphasis on these metrics. Herein we challenge the purported objective truth of urine testing and highlight how we can be easily fooled into thinking a patient is or is not abstinent. We highlight the potential value of patient-reported outcomes (PROMs) that are easily obtained and may more accurately reflect the benefits of MOUD, such as decreases in overdose, retention in treatment, and improved health outcomes.
The Experiences of Health Care Providers Serving Under-Resourced Patients With Chronic Disease Through an Interprofessional Model of Care in the Southeastern United States
Authors: Fifolt Matthew , White-Williams Connie , Hernandez Alison , Blunck Elizabeth , Shirey Maria R. , Talley Michele
Published: February 2025

This study explored the perspectives of interprofessional collaborative practice health care providers in 2 clinics in the southeastern United States. The research team conducted key stakeholder interviews with 22 health care providers between 2022 and 2023. Study findings revealed 4 themes: Interprofessional Team Roles, Value of Behavioral Health Integration, Holistic Patient-Centered Focus, and Empathy-Driven Health Care. Health care providers highlighted the importance of the resources available within the team and the role of empathy in establishing trust, respect, and care satisfaction among health care providers and patients.
Patterns of Perspectives on Oncology Healthcare Needs Among Women With Gynecologic Cancer
Authors: Yu Shu-Chuan , Guo Jong-Long , Sun Chia-Hui , Chang Ching-Hao , Chen Shu-Fen , Huang Chiu-Mieh
Published: February 2025

Background

Gynecologic cancer significantly impacts women’s healthcare needs; however, these needs are often underexplored from the patients’ perspectives.

Objective

To identify and describe the patterns of perspectives on the oncology healthcare needs of women with gynecologic cancer.

Methods

This Q-methodology study was conducted between January and October 2023 using 60 female patients with gynecologic cancer. Thirty-six Q statements were constructed based on the guidelines of the Cancer Diagnosis and Treatment Quality Assurance Measures, and 10 gynecological nursing staff members were interviewed to explore their experiences with current clinical practices in hospitals. The study adhered to SQUIRE 2.0 (Standards for QUality Improvement Reporting Excellence). PQ Method 2.35 software was used to identify different patterns of patients’ perspectives.

Results

The final model retained 4 factors, explaining 59% of the variance. These factors emphasized (1) family-centered communication over palliative care information, (2) patient-centered communication over rehabilitation information, (3) psychological and physiological adaptation over receiving information in advance, and (4) treatment and side effect information over palliative care information.

Conclusions

Clustering patients by perspectives can assist healthcare providers in understanding patient expectations. The emerging perspectives highlight the patients’ expectations of communication regarding their treatment plans. Palliative care was the least evident healthcare need across the 4 groups of patients.

Implication for Practice

The findings capture 4 unique perspectives of patients’ expectations with healthcare needs. These insights can inform researchers and practitioners in developing needs-matched healthcare for women with gynecologic cancer.
Changing Intimate Partner Violence Screening and Intervention: Focus Group Perspectives
Authors: Galambos Colleen , Jerofke-Owen Teresa , Paquette Heidi , Piacentine Linda , Schubert Erin , Vang Mychoua , Arrington Erica , Lodh Nil , Gecsi Kimberly S.
Published: February 2025

Background:

Many survivors of intimate partner violence (IPV) remain unconnected to professional help. Screenings in health settings may improve connections to support services.

Purpose:

The purpose of this study was to gather data to help inform an IPV screening intervention in an obstetrics/gynecology health clinic.

Methods:

A qualitative analysis was employed using a summative content analysis approach of the transcripts of 2 focus groups consisting of health care providers, advocates, and survivors of IPV.

Results:

Four thematic categories and additional subcategories emerged from the analysis, including (1) current process (what is done); (2) need (what is not done); (3) concerns (roadblocks); and (4) suggestions (next steps).

Conclusions:

Information obtained from this analysis was used to inform our intervention. Specifically, all clinic providers and staff received training on IPV, screening for IPV was done on all patients using an IPV screening tool, and patients were privately screened.
Moving Beyond CT Body Composition Analysis
Authors: Haubold Johannes , Pollok Olivia Barbara , Holtkamp Mathias , Salhöfer Luca , Schmidt Cynthia Sabrina , Bojahr Christian , Straus Jannis , Schaarschmidt Benedikt Michael , Borys Katarzyna , Kohnke Judith , Wen Yutong , Opitz Marcel , Umutlu Lale , Forsting Michael , Friedrich Christoph M. , Nensa Felix , Hosch René
Published: February 2025

Objectives

Deep learning for body composition analysis (BCA) is gaining traction in clinical research, offering rapid and automated ways to measure body features like muscle or fat volume. However, most current methods prioritize computed tomography (CT) over magnetic resonance imaging (MRI). This study presents a deep learning approach for automatic BCA using MR T2-weighted sequences.

Methods

Initial BCA segmentations (10 body regions and 4 body parts) were generated by mapping CT segmentations from body and organ analysis (BOA) model to synthetic MR images created using an in-house trained CycleGAN. In total, 30 synthetic data pairs were used to train an initial nnU-Net V2 in 3D, and this preliminary model was then applied to segment 120 real T2-weighted MRI sequences from 120 patients (46% female) with a median age of 56 (interquartile range, 17.75), generating early segmentation proposals. These proposals were refined by human annotators, and nnU-Net V2 2D and 3D models were trained using 5-fold cross-validation on this optimized dataset of real MR images. Performance was evaluated using Sørensen-Dice, Surface Dice, and Hausdorff Distance metrics including 95% confidence intervals for cross-validation and ensemble models.

Results

The 3D ensemble segmentation model achieved the highest Dice scores for the body region classes: bone 0.926 (95% confidence interval [CI], 0.914–0.937), muscle 0.968 (95% CI, 0.961–0.975), subcutaneous fat 0.98 (95% CI, 0.971–0.986), nervous system 0.973 (95% CI, 0.965–0.98), thoracic cavity 0.978 (95% CI, 0.969–0.984), abdominal cavity 0.989 (95% CI, 0.986–0.991), mediastinum 0.92 (95% CI, 0.901–0.936), pericardium 0.945 (95% CI, 0.924–0.96), brain 0.966 (95% CI, 0.927–0.989), and glands 0.905 (95% CI, 0.886–0.921). Furthermore, body part 2D ensemble model reached the highest Dice scores for all labels: arms 0.952 (95% CI, 0.937–0.965), head + neck 0.965 (95% CI, 0.953–0.976), legs 0.978 (95% CI, 0.968–0.988), and torso 0.99 (95% CI, 0.988–0.991). The overall average Dice across body parts (2D = 0.971, 3D = 0.969, P = ns) and body regions (2D = 0.935, 3D = 0.955, P < 0.001) ensemble models indicates stable performance across all classes.

Conclusions

The presented approach facilitates efficient and automated extraction of BCA parameters from T2-weighted MRI sequences, providing precise and detailed body composition information across various regions and body parts.
Recurrent Giant Subcutaneous Tumor in Juvenile Hyaline Fibromatosis
Authors: Wang Xinyao , Wei Jia , Wang Xiaoqiang
Published: February 2025

This case report presents a 5-year-old boy diagnosed with juvenile hyaline fibromatosis (JHF), an extremely rare autosomal recessive disorder characterized by the abnormal accumulation of collagen. The patient exhibited a recurrent giant subcutaneous tumor measuring 20 cm in diameter, along with multiple tumors in the oral cavity, gingiva, and joints, leading to significant facial deformity and functional impairments. Previous surgeries at ages 1 and 2 for tumor removal resulted in recurrence. Surgical intervention was performed to excise the large tumor and alleviate symptoms. Pathologic analysis confirmed the diagnosis of JHF. This case highlights the challenges in managing JHF and the need for multidisciplinary approaches in treatment.
Application of Anterolateral Thigh Chimeric Flap in Reconstruction of Orbitomaxillary Defects
Authors: Li Wen-Wen , Zhou Xiao-Long , Chen Lei , Yu Zi-Li , Jia Jun
Published: February 2025

Objective:

This study aimed to investigate the feasibility and applicability of anterolateral thigh chimeric flap in the reconstruction of orbitomaxillary defects.

Methods:

This retrospective study involved 3 patients with orbitomaxillary defects due to maxillary or maxillary sinus tumors invading the orbit, who underwent anterolateral thigh chimeric flap reconstruction from November 2013 to February 2023.

Results:

All 3 patients were males, with maxillary sinus or maxillary tumors invading the orbit, and all underwent extended maxillectomy and orbital exenteration. Anterolateral thigh chimeric flaps were used to repair the postoperative defects. The size of flaps ranged from 12 cm×6 cm to 13 cm×10 cm. There were no postoperative complications and the patients recovered well.

Conclusion:

Anterolateral thigh chimeric flap is safe and reliable for the reconstruction of orbitomaxillary complex defects caused by maxillary tumor surgery.
Intraoperative nerve imaging with sodium fluorescein
Authors: Park Roy K. , Arús Bernardo A. , Lee Jennifer Y. , Weitzenberg Merle M. , Lee Melissa C. , Nyaeme Mark S. , Barthel Julia , Balsamo Giuseppe , Baik Fred M. , Speirs Katie , Blume Berit , Heller-Algazi Metar , Chmyrov Andriy , Plettenburg Oliver , Megwalu Uchechukwu C. , Weitz Jürgen , Distler Marius , Bruns Oliver T. , Valdez Tulio A.
Published: February 2025

Nerve damage during surgery is a common and serious complication, often leading to chronic pain, functional impairments, and diminished quality of life. However, existing methods for intraoperative nerve identification remain insufficient, especially for detecting small or hidden nerve branches. Here we present a new application of a clinically approved fluorescent agent, sodium fluorescein, to enhance nerve visualization during surgery. Utilizing both clinical and customized imaging systems, fluorescein remarkably improved nerve contrast, revealing structures undetectable with white light, including small branches embedded within tissues. With its established safety profile, low cost, and immediate clinical applicability, sodium fluorescein offers the potential to revolutionize surgical practice by minimizing nerve injuries and improving patient outcomes. Clinical Trial Registration:NCT06054178.

Graphical abstract
Finding the Clinical Traces of Cognitive Impairment in Patients with Heart Failure: A Natural Language Processing Study of Clinical Letters from Routine Care
Authors: Overmars L. Malin , van Es Bram , Tan Sander C. , Vonk Jet M. J. , Muller Majon , De Groot Mark C. H. , Biessels Geert Jan , Van der Meer M.G. , van Solinge Wouter W. , Haitjema Saskia , Bots Michiel L. , Exalto Lieza G.
Published: February 2025

Cognitive impairment is common in patients with heart failure, but to which extent cognitive complaints are evaluated and listed in clinical practice is unknown. Therefore, this study aims to identify whether cognitive complaints are listed in clinical notes of patients with heart failure, consistent with listed complaints in clinical notes of patients attending memory clinics, by using natural language processing (NLP) techniques. Patients with heart failure and patients attending a memory outpatient clinic were identified by using echocardiography reports and presence of memory outpatient clinic codes stored in the Utrecht Individual-Oriented Database (UPOD) from 2011 to 2023. Named Entity Detection and Linking (NER+L) strategies MedCAT and MedCATTrainer were used to extract listed complaints in clinical notes by patient group, and it was assessed whether cognitive complaints were listed in clinical notes of patients with heart failure. Among 5803 patients with heart failure, dyspnea (57.1%), chest pain (48.4%), and oedema (43.6%) were the most listed complaints. In 967 patients attending memory clinics, memory problem (80.9%), getting lost (24.1%), and being morose (22.5%) were the most listed complaints. Notably, in patients with heart failure, the reporting of memory problems was low at 2.6%. This study shows a low reporting frequency of cognitive complaints in clinical notes of patients with heart failure, even though both conditions often co-occur according to cross-sectional studies. This points towards a potential underrecognition of cognitive complaints in patients with heart failure during clinical practice.
Covalent Destabilizing Degrader of AR and AR-V7 in Androgen-Independent Prostate Cancer Cells
Authors: Zammit Charlotte M , Nadel Cory , Lin Ying , Koirala Sajjan , Potts Patrick Ryan , Nomura Daniel K
Published: February 2025

Androgen-independent prostate cancers, correlated with heightened aggressiveness and poor prognosis, are caused by mutations or deletions in the androgen receptor (AR) or expression of truncated variants of AR that are constitutively activated. Currently, drugs and drug candidates against AR target the steroid-binding domain to antagonize or degrade AR. However, these compounds cannot therapeutically access largely intrinsically disordered truncated splice variants of AR, such as AR-V7, that only possess the DNA binding domain and are missing the ligand binding domain. Targeting intrinsically disordered regions within transcription factors has remained challenging and is considered undruggable. Herein, we leveraged a cysteine-reactive covalent ligand library in a cellular screen to identify degraders of AR and AR-V7 in androgen-independent prostate cancer cells. We identified a covalent compound EN1441 that selectively degrades AR and AR-V7 in a proteasome-dependent manner through direct covalent targeting of an intrinsically disordered cysteine C125 in AR and AR-V7. EN1441 causes significant and selective destabilization of AR and AR-V7, leading to aggregation of AR/AR-V7 and subsequent proteasome-mediated degradation. Consistent with targeting both AR and AR-V7, we find that EN1441 completely inhibits total AR transcriptional activity in androgen-independent prostate cancer cells expressing both AR and AR-V7 compared to AR antagonists or degraders that only target the ligand binding domain of full-length AR, such as enzalutamide and ARV-110. Our results put forth a pathfinder molecule EN1441 that targets an intrinsically disordered cysteine within AR to destabilize, degrade, and inhibit both AR and AR-V7 in androgen-independent prostate cancer cells and highlights the utility of covalent ligand discovery approaches in directly targeting, destabilizing, inhibiting, and degrading classically undruggable transcription factor targets.
SoEM-Web: a user-friendly platform for the analysis and visualization of small-organelle-enriched metagenomics data
Authors: Oh Jooseong , Kim Hanjin , Park Chungoo
Published: February 2025

Background

Marine microeukaryotes play a crucial role in global biogeochemical cycles and ecosystem functioning. However, their diversity and distribution patterns remain poorly understood. To improve the biodiversity assessment of environmental samples, we recently developed a PCR-free, small-organelle-enriched metagenomics (SoEM) method, accompanied by a bioinformatics workflow for analyzing SoEM metagenomic data. However, the complexity of these analyses typically requires extensive bioinformatics expertise, potentially limiting their broader adoption.

Methods

To address this challenge, we present SoEM-Web, a user-friendly web application for the interactive analysis, classification, and visualization of SoEM metagenomic data. SoEM-Web integrates all necessary procedures, including raw sequencing data preprocessing, paired-end read merging, automated taxonomic identification, and diversity visualization, into a streamlined workflow accessible through an intuitive interface. This application is designed to facilitate SoEM data analysis for researchers who may not have advanced bioinformatics skills.

Results

We demonstrated the capabilities of SoEM-Web by reanalyzing previously published datasets. This reanalysis not only confirmed the utility of the platform but also revealed additional taxa, emphasizing the value of updated reference datasets. The application successfully simplifies complex bioinformatics processes, enhancing accessibility and reproducibility in marine microeukaryote diversity research. SoEM-Web aims to enhance accessibility and reproducibility in marine microeukaryote diversity research. The web server is freely available athttp://compsysbio.re.kr/soem-web/.
Tracing the evolution and genomic dynamics of mating-type loci inCryptococcuspathogens and closely related species
Authors: Coelho Marco A. , David-Palma Márcia , Marincowitz Seonju , Aylward Janneke , Pham Nam Q. , Yurkov Andrey M. , Wingfield Brenda D. , Wingfield Michael J. , Sun Sheng , Heitman Joseph
Published: February 2025

Sexual reproduction in basidiomycete fungi is governed byMATloci (P/RandHD), which exhibit remarkable evolutionary plasticity, characterized by expansions, rearrangements, and gene losses often associated with mating system transitions. The sister generaCryptococcusandKwoniellaprovide a powerful framework for studyingMATloci evolution owing to their diverse reproductive strategies and distinct architectures, spanning bipolar and tetrapolar systems with either linked or unlinkedMATloci. Building on recent large-scale comparative genomic analyses, we generated additional chromosome-level assemblies uncovering distinct evolutionary trajectories shapingMATloci organization. Contrasting with the small-scale expansions and gene acquisitions observed inKwoniella, our analyses revealed independent expansions of theP/Rlocus in tetrapolarCryptococcus, possibly driven by pheromone gene duplications. Notably, these expansions coincided with an enrichment of AT-rich codons and a pronounced GC-content reduction, likely associated with recombination suppression and relaxed codon usage selection. Diverse modes ofMATlocus linkage were also identified, including three previously unrecognized transitions: one resulting in a pseudobipolar arrangement and two leading to bipolarity. All the three transitions involved translocations. In the pseudobipolar configuration, theP/RandHDloci remained on the same chromosome but genetically unlinked, whereas the bipolar transitions additionally featured rearrangements that fused the two loci into a nonrecombining region. Mating assays confirmed a sexual cycle inC. decagattii, demonstrating its ability to undergo mating and sporulation. Progeny analysis inK. mangrovensisrevealed substantial ploidy variation and aneuploidy, likely stemming from haploid-diploid mating, yet evidence of recombination and loss of heterozygosity indicates that meiotic exchange occurs despite irregular chromosome segregation. Our findings underscore the importance of continued diversity sampling and provides further evidence for convergent evolution of fusedMATloci in basidiomycetes, offering new insights into the genetic and chromosomal changes driving reproductive transitions.
Mavacamten inhibits myosin activity by stabilising the myosin interacting-heads motif and stalling motor force generation
Authors: McMillan Sean N. , Pitts Jaime R. T. , Barua Bipasha , Winkelmann Donald A. , Scarff Charlotte A.
Published: February 2025

Most sudden cardiac deaths in young people arise from hypertrophic cardiomyopathy, a genetic disease of the heart muscle, with many causative mutations found in the molecular motor beta-cardiac myosin that drives contraction. Therapeutic intervention has until recently been limited to symptomatic relief or invasive procedures. However, small molecule modulators of cardiac myosin are promising therapeutic options to target disease progression. Mavacamten is the first example to gain FDA approval but its molecular mode of action remains unclear, limiting our understanding of its functional effects in disease. To better understand this, we solved the cryoEM structures of beta-cardiac heavy meromyosin in three ADP.Pi-bound states, the primed motor domain in the presence and absence of mavacamten, and the sequestered autoinhibited interacting-heads motif (IHM) in complex with mavacamten, to 2.9 Å, 3.4 Å and 3.7 Å global resolution respectively. Together with quantitative crosslinking mass spectrometric analysis, these structures reveal how mavacamten inhibits myosin. Mavacamten stabilises ADP.Pi binding, stalling the motor domain in a primed state, reducing motor dynamics required for actin-binding cleft closure, and slowing progression through the force generation cycle. Within the two-headed myosin molecule, these effects are propagated and lead to stabilisation of the IHM, through increased contacts at the motor-motor interface. Critically, while mavacamten treatment can thus rescue cardiac muscle relaxation in diastole, it can also reduce contractile output in systole in the heart.
Decay of the CTCF paralog BORIS in neognathous birds
Authors: Palitzsch Katja , Wiehe Thomas , Heger Peter
Published: February 2025

BORIS (brother of the regulator of imprinted sites), the paralog of the genome organizer CTCF, originated at least 318 million years ago (Mya), in the ancestor of amniotes (mammals, reptiles, and birds). Based on results from chicken (Gallus gallus), the gene was thought to be absent from birds. Using comparative genomics of 59 bird species, we show that birds possess BORIS, but frequently experience severe degradation of the gene, as observed inGallus gallus. The degradation events are restricted to neognathous birds, specific for the BORIS coding sequence, and occur multiple times independently on different branches. They comprise a wide range of molecular decay, from individual point mutations to the inactivation and/or loss of particular zinc fingers, to the almost complete disintegration of the gene. The decay is accompanied by relaxed evolutionary constraints on BORIS codons across neognathous birds and coincides with the accumulation of species-specific repetitive elements in degenerate loci. BORIS represents a case of a presently ongoing, convergent, and specific gene loss within a lineage. As possible explanation, we propose a link between the loss of BORIS and a shift in sperm and/or genital morphology during the evolution of Neognathae.

Significance Statement

The gene BORIS was believed to be absent from birds. However, genome analysis of 59 bird species reveals its presence, though it often underwent severe degradation in neognathous birds. These independent degradation events affect the BORIS coding sequence and range from point mutations to near complete gene disintegration. This decay correlates with relaxed evolutionary constraints and species-specific accumulation of repetitive elements. A potential link between BORIS loss and changes in sperm or genital morphology during neognathous bird evolution is suggested.
Dual Antiplatelet Therapy (DAPT) in Patients with NSTEMI Undergoing CABG
Authors: Bansal Agam , Reed Grant W. , Wang Tom , Tamis-Holland Jacqueline , Jaber Wael A. , Kapadia Samir R. , Menon Venu
Published: February 2025

Background

Dual antiplatelet therapy (DAPT), combining acetylsalicylic acid (aspirin) and a P2Y12 inhibitor, is recommended for patients with non-ST segment elevation myocardial infarction (NSTEMI) undergoing coronary artery bypass grafting (CABG). However, real-world adoption and effectiveness of DAPT in this context has not been adequately evaluated.

Methods

We conducted a retrospective propensity-matched cohort analysis using data from the TriNetX research network, which includes electronic health records from over 70 healthcare organizations across the United States. The study included patients aged >18 years diagnosed with NSTEMI who underwent CABG within one month of presentation from January 2015 to January 2024. Outcomes for patients on DAPT were compared with those on aspirin monotherapy using standardized mean differences, risk ratios, and Cox proportional hazard models for survival analysis.

Results

From a cohort of 21,092 NSTEMI patients eligible for DAPT post-CABG, 55.28% received DAPT predominantly consisting of aspirin and clopidogrel. After propensity score matching, DAPT was associated with significantly reduced all-cause mortality at 1-year (8.1% vs 5.5%, OR: 1.52) and 5-year (14.4% vs 10.6%, OR: 1.41) follow-ups compared to aspirin monotherapy. There were no significant differences in rates of major bleeding, ischemic strokes, or repeat revascularization between the two groups.

Conclusion

The underutilization of DAPT in real-world settings, despite guideline recommendations, reflects a potential gap between clinical practice and evidence-based guidelines. Our findings support the effectiveness of DAPT in reducing mortality without increasing major bleeding risks, underscoring the need for more widespread adoption and potentially more robust clinical trials to confirm these observational findings.
Structural basis of neurofibromin tetramerization and dimer-tetramer equilibrium
Authors: Si Shutian , Tüting Christian , Lohse Swanhild , Landfester Katharina , Lieberwirth Ingo , Kastritis Panagiotis L. , Harder Anja
Published: February 2025

Human neurofibromin (NF1) is a tumor suppressor multidomain protein known to regulate cellular functions as a dimer. Using cryo-EM, we discovered that neurofibromin can form more highly organized structures and describe tetramerization and a dynamic dimer-to-tetramer equilibrium with extensive interlocked interfaces as well as structural flexibility. The new tetramer structure generates and modifies interaction surfaces and controls protein functions such as microtubule recruitment, thereby providing novel insights into cellular functions.