bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of the R3-AFP model for risk prediction of HCC recurrence after liver transplantation in the SiLVER randomized clinical trial
Authors: Piñero Federico , Lai Quirino , Costentin Charlotte , Degroote Helena , Schnitzbauer Andreas , Geissler Edward K. , Duvoux Christophe ,   on behalf of the International SiLVER Study Group
Published: September 2024

Explant-based models for assessing HCC recurrence after liver transplantation serve as the gold standard, guiding post-liver transplantation screening and immunosuppression adjustment. Incorporating alpha-fetoprotein (AFP) levels into these models, such as the novel R3-AFP score, has notably enhanced risk stratification. However, validation of these models in high-evidence data is mandatory. Therefore, the aim of the present research was to validate the R3-AFP score in a randomized clinical trial. We analyzed the intention-to-treat population from the 2-arm SiLVER trial (NCT00355862), comparing calcineurin-based ([calcineurin inhibitors]—Group A) versus mammalian target of rapamycin inhibitors–based (sirolimus—Group B) immunosuppression for post-liver transplantation HCC recurrence. Competing risk analysis estimated sub-hazard ratios, with testing of discriminant function and calibration. Overall, 508 patients from the intention-to-treat analysis were included (Group A, n = 256; Group B, n = 252). The R3-AFP score distribution was as follows: 42.6% low-risk (n = 216), 35.7% intermediate-risk (n = 181), 19.5% high-risk (n = 99), and 2.2% very-high-risk (n = 11) groups. The R3-AFP score effectively stratified HCC recurrence risk, with increasing risk for each stratum. Calibration of the R3-AFP model significantly outperformed other explant-based models (Milan, Up-to-7, and RETREAT), whereas discrimination power (0.75 [95% CI: 0.69; 0.81]) surpassed these models, except for the RETREAT model (p = 0.49). Subgroup analysis showed lower discrimination power in the mammalian target of rapamycin group versus the calcineurin inhibitors group (p = 0.048). In conclusion, the R3-AFP score accurately predicted HCC recurrence using high-quality evidence-based data, exhibiting reduced performance under mammalian target of rapamycin immunosuppression. This highlights the need for further research to evaluate surveillance schedules and adjuvant regimens.
Emergency esophagectomy for esophageal perforation following balloon dilation due to stenosis post-endoscopic submucosal dissection for esophageal cancer: a case report
Authors: Pham Binh Van , Nguyen Duy Duc , Tran Manh Dai , Nguyen Thanh Duy , Thai An Duc , Nguyen Hoa Thi Thanh
Published: September 2024

Introduction and importance:

Esophageal perforation from endoscopic dilation is rare (0.53–0.6% incidence) but serious, with mortality rates of 12.5–20%. Optimal treatment is debated and depends on the medical facility’s capabilities, the patient’s symptoms, the extent of perforation, and the severity of associated lesions. Treatment options include medical management (fasting, antibiotics), esophageal stenting, surgical closure, or emergency esophagectomy. Early diagnosis and treatment are crucial to reduce mortality and hospital stay.

Case presentation:

A 49-year-old male with lower third esophageal cancer (stage cT1aN0M0) underwent endoscopic submucosal dissection (ESD) and developed esophageal stenosis. Dilation attempts led to esophageal perforation, necessitating emergency esophagectomy with gastric conduit reconstruction. The patient improved and was discharged on day 10 post-operation without complications.

Clinical discussion:

Managing esophageal perforation post-endoscopic dilation is complex. This case highlights the importance of rapid recognition and intervention. Esophageal dilation, while effective for stenosis, carries a perforation risk. Treatment decisions must be tailored to individual patients, considering perforation severity, patient’s health, and facility resources. Here, severe perforation and clinical condition warranted emergency esophagectomy. The successful outcome underscores the efficacy of this surgical intervention when performed timely at specialized centers.

Conclusion:

Emergency esophagectomy with gastric conduit reconstruction for treating esophageal perforation due to stenosis post-endoscopic submucosal dissection for esophageal cancer is considered a safe procedure and can be performed at an experienced esophageal surgery center.
Total Cranial Vault Remodelling Versus Minimally Invasive Suturectomy With Postoperative Helmet Therapy in Sagittal Craniosynostosis
Authors: Witters Leonie , Vercruysse Herman , De Praeter Mania
Published: September 2024

Different surgical techniques have been explored over time to treat children with scaphocephaly. The objective of this study is to compare morbidity and cosmetic outcomes in total cranial vault remodelling (TCVR) and minimally invasive suturectomy with postoperative helmet therapy (MISPH) in patients with scaphocephaly. The authors performed a retrospective comparative cohort study, including 43 patients with isolated sagittal craniosynostosis who underwent TCVR (n=17) or MISPH (n=26) at the Antwerp University Hospital between April 2008 and December 2022. MISPH was associated with significantly shorter procedure duration (TCVR 199 ± 48 min, MISPH 69 ± 12 min, P<0.001), decreased blood loss (TCVR 610 ± 298 mL, MISPH 85 ± 73 mL, P<0.001) and lower transfusion rate (TCVR 100%, MISPH 54%, P<0.001). Mean length of stay at the intensive care unit and the hospital were significantly shorter after MISPH (TCVR 6 ± 1 d, MISPH 3 ± 0.5 d). The change in CI after TCVR was significantly larger than after MISPH during the first postoperative year. However, the CI in the MISPH group was significantly higher during the first year compared with the TCVR group. Mean CI of the MISPH group reached normal limits during the first year, while in the TCVR group, mean CI reached normal values 5 years after surgery. The authors could not find a statistically significant difference in cosmetic outcome between the 2 groups. The authors conclude that MISPH is associated with decreased morbidity and comparable cosmetic results when compared with TCVR in the treatment of scaphocephaly.
Extracorporeal Photopheresis Enhances the Frequency and Function of Highly Suppressive FoxP3+ Treg Subsets in Heart Transplanted Individuals
Authors: Mottola Maria , Bruzzaniti Sara , Piemonte Erica , Lepore Maria Teresa , Petraio Andrea , Romano Renata , Castiglione Antonella , Izzo Lavinia , Perna Francesco , De Falco Chiara , Brighel Federico , Formisano Luigi , Gravina Maria Teresa , Marino Marina , De Feo Marisa , Matarese Giuseppe , Galgani Mario
Published: September 2024

Background.

Extracorporeal photopheresis (ECP) has emerged as a prophylactic and therapeutic immunomodulatory option for managing acute rejection in heart transplants (HTx). The underlying mechanisms through which ECP exerts its immunomodulatory effects remain under investigation. Regulatory T cells (Treg) are a heterogeneous subset of immune lymphocytes that ensure the maintenance of tissue homeostasis, avoiding graft rejection. The transcription factor forkhead box protein 3 (FoxP3) is an essential molecular marker of Treg, acting as a “master regulator” of their genesis, stability, and functions. No study has investigated whether ECP impacts FoxP3 expression and its highly suppressive variants containing the exon 2 (FoxP3-E2), particularly in HTx.

Methods.

In the current study, we recruited 14 HTx participants who had undergone ECP therapy. We explored the effect of in vivo ECP on CD4+FoxP3+ Treg frequency and in vitro suppressive function in 8 HTx participants before (T0) and after 3 (T1), 6 (T2), and 12 (T3) mo of treatment. As a control group, we included 4 HTx individuals who had not undergone ECP therapy.

Results.

We found that ECP increases the frequency of CD4+FoxP3+ Treg subset with highly suppressive phenotype, including CD4+FoxP3-E2+ Treg. At functional levels, we observed that ECP treatment in HTx individuals effectively improves Treg suppressive ability in controlling the proliferation of autologous conventional CD4+ T lymphocytes.

Conclusions.

Our findings collectively suggest that ECP exerts its immunomodulatory effects in HTx individuals by positively impacting the frequency and regulatory function of the FoxP3+ Treg compartment.
Fermentation and quality characteristics of ALE beer with the addition of Muscat Bailey A grape
Authors: Lee Sanghyuk , Choi Kyu-Taek , Choi Jun-Su , Lee Jong-Hyeon , Lee Sae-Byuk
Published: September 2024

This study investigated the fermentation characteristics and quality attributes of ale beer brewed with MBA grapes to enhance the diversity of Korean domestic ale beers. The grapes were added to the wort in two forms: must and juice, at ratios of 10% and 20%. The results showed that while ale beer with 20% grape addition began fermentation a day later, all samples completed fermentation well on the sixth day. Increasing MBA grape content lowered the pH and increased total acidity and malic acid content without significantly affecting the sour taste. Higher grape addition also decreased the beer’s IBU and bitterness scores in sensory evaluation. The addition of must addition enhanced redness due to anthocyanins, significantly increasing color intensity and EBC value of ale beer. Ale beer with the addition of must exhibited higher antioxidant capacities in total phenolic compound content, DPPH radical scavenging, and FRAP activities compared to that with the addition of juice. Sensory evaluation indicated that ale beer with 20% juice addition was preferred for its color, aroma, sweetness, body, and overall preference. The addition of MBA must improved antioxidant capacity, but ale beer with 20% juice had superior sensory qualities.
Deciphering the functional impact of Alzheimer’s Disease-associated variants in resting and proinflammatory immune cells
Authors: Bond Marielle L. , Quiroga-Barber Ivana Y. , D’Costa Susan , Wu Yijia , Bell Jessica L. , McAfee Jessica C. , Kramer Nicole E. , Lee Sool , Patrucco Mary , Phanstiel Douglas H. , Won Hyejung
Published: September 2024

Genome-wide association studies have identified loci associated with Alzheimer’s Disease (AD), but identifying the exact causal variants and genes at each locus is challenging due to linkage disequilibrium and their largely non-coding nature. To address this, we performed a massively parallel reporter assay of 3,576 AD-associated variants in THP-1 macrophages in both resting and proinflammatory states and identified 47 expression-modulating variants (emVars). To understand the endogenous chromatin context of emVars, we built an activity-by-contact model using epigenomic maps of macrophage inflammation and inferred condition-specific enhancer-promoter pairs. Intersection of emVars with enhancer-promoter pairs and microglia expression quantitative trait loci allowed us to connect 39 emVars to 76 putative AD risk genes enriched for AD-associated molecular signatures. Overall, systematic characterization of AD-associated variants enhances our understanding of the regulatory mechanisms underlying AD pathogenesis.
Single unit electrophysiology recordings and computational modeling can predict octopus arm movement
Authors: Gedela Nitish Satya Sai , Salim Sachin , Radawiec Ryan D. , Richie Julianna , Chestek Cynthia , Draelos Anne , Pelled Galit
Published: September 2024

The octopus simplified nervous system holds the potential to reveal principles of motor circuits and improve brain-machine interface devices through computational modeling with machine learning and statistical analysis. Here, an array of carbon electrodes providing single-unit electrophysiology recordings were implanted into the octopus anterior nerve cord. The number of spikes and arm movements in response to stimulation at different locations along the arm were recorded. We observed that the number of spikes occurring within the first 100ms after stimulation were predictive of the resultant movement response. Computational models showed that temporal electrophysiological features could be used to predict whether an arm movement occurred with 88.64% confidence, and if it was a lateral arm movement or a grasping motion with 75.45% confidence. Both supervised and unsupervised methods were applied to gain streaming measurements of octopus arm movements and how their motor circuitry produces rich movement types in real time. Deep learning models and unsupervised dimension reduction identified a consistent set of features that could be used to distinguish different types of arm movements. These models generated predictions for how to evoke a particular, complex movement in an orchestrated sequence for an individual motor circuit.
Genetic variation in the activity of a TREM2-p53 signaling axis determines oxygen-induced lung injury
Authors: Abe Yohei , Spann Nathaneal J. , Tang Wenxi , Zeng Fenghua , Richard John Lalith Charles , Seymour Cadence , Jansky Sean , Mooney Miguel , Huff Robert , Chanthavixay Kelly , Dhar Debanjan , Ganguly Souradipta , Guo Jason L. , Lopez David M. , Longaker Michael T. , Benner Christopher , Glass Christopher K. , Sajti Eniko
Published: September 2024

Bronchopulmonary dysplasia (BPD), a chronic lung disease, is the most common major complication of preterm birth. Supplemental oxygen administration, while lifesaving in the neonatal period, remains a key determinant of BPD pathophysiology. Exposure of the immature lung to increased levels of oxygen elicits an inflammatory response resulting in abnormal lung development. However, not every premature infant is equally sensitive to develop BPD. Using genetically diverse mouse strains, we show that the innate immune response activated in the lungs of mice sensitive to hyperoxia that develop BPD-like lung injury differs from mice resilient to disease. Specifically, we identified a selective upregulation of triggering receptor expressed on myeloid cells 2 (TREM2) on lung macrophages and monocytes in the hyperoxia-sensitive C57BL/6J mouse strain. We show that loss of function of TREM2 signaling in myeloid cells resulted in a dramatically improved phenotype after neonatal hyperoxia exposure characterized by a dampened immune response, preserved alveolar structure, and preserved cell proliferative potential supporting normal lung development. At the molecular level, inhibition of TREM2 signaling dampened the magnitude of p53 activation and resulted in cell cycle arrest instead of apoptosis. These findings show that TREM2 is a critical regulator of the pathogenic innate immune response to hyperoxia and highlight its importance as a potential therapeutic target for mitigating injury in the hyperoxia-exposed developing lung.
metagWGS, a comprehensive workflow to analyze metagenomic data using Illumina or PacBio HiFi reads
Authors: Mainguy Jean , Vienne Maïna , Fourquet Joanna , Darbot Vincent , Noirot Céline , Castinel Adrien , Combes Sylvie , Gaspin Christine , Milan Denis , Donnadieu Cécile , Iampietro Carole , Bouchez Olivier , Pascal Géraldine , Hoede Claire
Published: September 2024

Background

To study communities of micro-organisms taxonomically and functionally, metagenomic analyses are now often used. If there is no reference gene catalogue, ade novoapproach is required. Because genomes are easier to interpret than contigs, the recovery of metagenome-assembled genomes (MAGs) by binning of contigs from metagenomic data has recently become a common task for microbial studies. However, during this process, there is a significant loss of information between the assembly and the binning of contigs. This is why it is important to produce taxonomic and functional matrices for all contigs and not just those included in correct bins. In addition, Pacbio HiFi reads (long and of good quality) are now a possible, albeit more expensive, alternative to short Illumina reads. We therefore developed a workflow that is easy to install with dependencies fixed using singularity images and easy to use on a computing cluster, that is capable of analyzing either short or long reads, and that should allow analysis at the contig and/or bin level, depending on the user’s choice.

Following is a presentation of metagWGS, a fully automated workflow for metagenomic data analysis. It uses a new tool for refining bins (called Binette) that we will demonstrate is more efficient than competing tools.

Methods

metagWGS is a Nextflow workflow distributed with two singularity images and complete documentation to facilitate its installation and use.

Because the main original features of metagWGS concern binning (short and long reads) and the analysis of HiFi reads, we compared metagWGS with the MAG construction workflow proposed by PacBio to a public dataset used by Pacbio to promote its workflow.

Results

metagWGS differs from existing workflows by (i) offering flexible approaches for the assembly; (ii) supporting short reads (Illumina) or PacBio HiFi reads; (iii) combining multiple binning algorithms with a new bin refinement tool, referred to as “Binette”, to achieve high-quality genome bins; and (iv) providing taxonomic and functional annotation for all genes, all contigs built and bins.

metagWGS produces more medium (708) and high-quality (255) bins on 11 public metagenomic samples from human gut data than the Pacbio HiFi dedicated workflow, referred to as the HiFi-MAGS-pipeline (659 medium quality bins and 231 high quality bins), primarily due to the better performance of Binette.
AvianLexiconAtlas: A database of descriptive categories of English-language bird names around the world
Authors: Morrison Erin S. , Pandolfi Guinevere P. , Aguillon Stepfanie M. , Ali Jarome R. , Archard Olivia , Baldassarre Daniel T. , Baquero Illeana , Bennett Kevin F.P. , Bonney Kevin M. , Bryant Riley , Catanach Rosanne M. , Catanach Therese A. , Chavoshan Ida , Davis Sarah N. , Goodman Brooke D. , Gulson-Castillo Eric R. , Hack Matthew , Hudon Jocelyn , Leighton Gavin M. , Long Kira M. , Ma Ziqi , McCoy Dakota E. , McLaughlin J.F. , Moreno Gaia Rueda , Mota Talia M. , Noguchi Lara , Nwigwe Ugo , Pegan Teresa , Provost Kaiya L. , Rasband Shauna A. , Salter Jessie Frances , Silvernail Lauren C. , Simard Jared A. , Skeen Heather R. , Soto-Patiño Juliana , Suh Young Ha , Wang Qingyue , Warshauer Matthew E. , Yan Sissy , Zalinski Betsy , Zhao Ziqi , Shultz Allison J.
Published: September 2024

Common names of species are important for communicating with the general public. In principle, these names should provide an accessible way to engage with and identify species. The common names of species have historically been labile without standard guidelines, even within a language. Currently, there is no systematic assessment of how often common names communicate identifiable and biologically relevant characteristics about species. This is a particular issue in ornithology, where common names are used more often than scientific names for species of birds in written and spoken English, even by professional researchers. To gain a better understanding of the types of terminology used in the common names of bird species and their frequency of use, we used a crowdsourcing approach and recruited 85 professional ornithologists and non-professional participants to classify unique descriptors in the English-language common names of all recognized bird species from around the world. Each species’ common name was assigned to one of ten categories associated with aspects of avian biology, ecology, or human culture. Across 10,906 species of birds, 89% have names describing the biology of the species, while the remaining 11% of species have names derived from human cultural references or local non-English languages. Species with common names based on features of avian biology are more likely to be related to each other or be from the same geographic region. The crowdsourced data collection also revealed that many common names contained specialized or historic terminology unknown to many of the data collectors, and this was documented in a glossary and gazetteer alongside the dataset. As the first comprehensive assessment of the state of terminology in English-language common names of birds, the AvianLexiconAtlas database sheds light on historical approaches to nomenclature and provides insight into how the general public currently engages with species through their names.
Manufacturing-Aware Generative Model Architectures Enable Biological Sequence Design and Synthesis at Petascale
Authors: Weinstein Eli N. , Gollub Mattia G. , Slabodkin Andrei , Gardner Cameron L. , Dobbs Kerry , Cui Xiao-Bing , Amin Alan N. , Church George M. , Wood Elizabeth B.
Published: September 2024

We introduce a method to reduce the cost of synthesizing proteins and other biological sequences designed by a generative model by as much as a trillion-fold. In particular, we make our generative models manufacturing-aware, such that model-designed sequences can be efficiently synthesized in the real world with extreme parallelism. We demonstrate by training and synthesizing samples from generative models of antibodies, T cell antigens and DNA polymerases. For example, we train a manufacturing-aware generative model on 300 million observed human antibodies and synthesize∼1017generated designs from the model, achieving a sample quality comparable to a state-of-the-art protein language model, at a cost of 103dollars. Using previous methods, synthesis of a library of the same accuracy and size would cost roughly a quadrillion (1015) dollars.
Population structure of the endangered Siberian flying squirrel (Pteromys volans) revealed by genomic and mitochondrial data
Authors: Ito dos Santos Fernanda , Lilley Thomas , Laine Veronika N. , Prost Stefan , Kurhinen Juri , Susi Hanna , Gashev Sergey , Saveljev Alexander , Bondarchuk Svetlana , Babina Svetlana , Shishikin Aleksander , Tirski Dmitry , Vasina Aleksandra , Karpin Vladimir , Kekkonen Jaana A
Published: September 2024

The Siberian flying squirrel (Pteromys volans) is an arboreal rodent with a distribution range that covers large parts of the Eurasian taiga forest zone. However, extensive forestry has resulted in widespread local population declines and extinctions in recent decades. Even though it is widely distributed in Eurasia, almost nothing is known about its phylogeography. Here we used genome-wide single nucleotide polymorphisms (SNPs) and mitochondrial DNA (mtDNA) to investigate population structure, connectivity and genetic diversity in different sites throughout its distribution. Overall, the species shows low nucleotide diversity and heterozygosity. Locations in Finland, on the western edge of the distribution, had the lowest diversities in genomic SNPs and mtDNA, while individuals in the Far East (Sikhote-Alin, Russia) show the highest diversity. These findings fit with a rapid range expansion from the Far East to the west. We found a strong genetic differentiation between Sikhote-Alin and all other populations investigated, which might warrant a revision of their taxonomic classification. The inferred low genetic diversities at the western edge of their distribution are especially worrisome as they are currently experiencing strong population declines and major habitat changes, which can be especially detrimental when standing variation is low. Thus, stressing the need for the revision of the species conservation status.
A Comprehensive UHPLC-MS/MS and Extraction Method for Spinach (Spinacia oleracea) Flavonoids
Authors: Dzakovich Michael P. , Le Elaine A. , Tak Alvin L. , Chacko Shaji K.
Published: September 2024

Spinach produces an array of unique flavonoids not commonly found in other fruits and vegetables. These molecules likely serve as defense agents against biotic and abiotic stress and may have health beneficial properties for humans. Current methods to analyze spinach flavonoids are incomplete and only capture a portion of this uncharacterized pathway. A comprehensive analysis method is needed to determine how genetics, environmental conditions, and other factors influence spinach flavonoid biosynthesis. We developed and validated a high-throughput extraction and ultra high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method to separate and quantify 39 spinach flavonoid species in 11.5 minutes. Spinach flavonoids without authentic standards were putatively identified using MS/MS fragmentation experiments, precursor scans, and matches to high-resolution MS literature reports. Our extraction method enables up to 48 samples to be extracted in 60 minutes with recovery estimates between 100.5 – 107.8%. To assess the suitability of our method and generate benchmark estimates for 39 spinach flavonoids, we grew a panel of 30 genetically diverse spinach accessions and compared quantification data generated with a traditional or our high-throughput approach. Data generated by either approach were comparable, estimating total flavonoid averages of 75.1 – 170.1 or 93.1 – 187.26 mg/100 g fresh weight for the high-throughput and traditional method, respectively. Many estimates generated by our analysis method represent the first quantitative literature reports of these compounds. These experiments indicate that our extraction and analysis method is efficient, robust, and an important tool needed to study the biosynthesis and biological role of spinach flavonoids.
LM-Merger: A workflow for merging logical models with an application to gene regulation
Authors: Li Luna Xingyu , Aguilar Boris , Gennari John H , Qin Guangrong
Published: September 2024

Motivation

Gene regulatory network (GRN) models provide mechanistic understanding of genetic interactions that regulate gene expression and, consequently, influence cellular behavior. Dysregulated gene expression plays a critical role in disease progression and treatment response, making GRN models a promising tool for precision medicine. While researchers have built many models to describe specific subsets of gene interactions, more comprehensive models that cover a broader range of genes are challenging to build. This necessitates the development of automated approaches for merging existing models.

Results

We present LM-Merger, a workflow for semi-automatically merging logical GRN models. The workflow consists of five main steps: (a) model identification, (b) model standardization and annotation, (c) model verification, (d) model merging, and (d) model evaluation. We demonstrate the feasibility and benefit of this workflow with two pairs of published models pertaining to acute myeloid leukemia (AML). The integrated models were able to retain the predictive accuracy of the original models, while expanding coverage of the biological system. Notably, when applied to a new dataset, the integrated models outperformed the individual models in predicting patient response. This study highlights the potential of logical model merging to advance systems biology research and our understanding of complex diseases.

Availability and implementation

The workflow and accompanying tools, including modules for model standardization, automated logical model merging, and evaluation, are available athttps://github.com/IlyaLab/LogicModelMerger/.
“We’re here to help them if they want to come”: A qualitative exploration of hospital staff perceptions and experiences with outpatient non-attendance
Authors: Selim Shayma Mohammed , McPhail Steven M , Carter Hannah E , Malatzky Christina , Kularatna Sanjeewa , Naicker Sundresan
Published: September 2024

Background

Patient non-attendance remains a major challenge for health services. Few studies have examined how health service providers think about, potentially address, and prioritise non-attendance within the scope of their practice. This study aimed to (1) explore healthcare professionals’ perspectives, beliefs, and opinions about the impact of patient non-attendance within a publicly-funded outpatient physiotherapy clinic context; (2) explore perceived barriers and facilitators associated with the implementation of non-attendance mitigation strategies; and (3) identify health service staff generated solutions to address perceived barriers and enhance facilitators.

Methods

A focus group discussion and semi-structured interviews were conducted between June 2023 to January 2024 with 27 physiotherapy department clinic outpatient staff involved in operationalising clinic referral processing, appointment scheduling, or providing care to patients. Data was analysed using a hybrid inductive/deductive framework analysis approach.

Results

Participants indicated that non-attendance had predominantly negative implications for the health service, healthcare provider, and patient. The interconnected issue of non-attendance encompassed multiple areas and were broadly categorised into five inductively identified themes: impact of non-attendance, perceptions of value, material deprivation, service delivery and built environment, and professional role and identity. Non-attendance mitigation strategies generated by participants were deductively mapped to the theoretical domains framework (TDF) to explore behavioural determinants that may influence successful implementation. This included knowledge, reinforcement, goals, optimism, memory, attention and decision-making, environmental resources and context, and emotions.

Conclusions

Staff identified multiple strategies for reducing non-attendance; implementing many of these strategies would require additional resourcing. Research determining the effectiveness of such strategies both in the short-term and long-term following implementation into practice remains a priority for future investigation.
CelloType: A Unified Model for Segmentation and Classification of Tissue Images
Authors: Pang Minxing , Roy Tarun Kanti , Wu Xiaodong , Tan Kai
Published: September 2024

Cell segmentation and classification are critical tasks in spatial omics data analysis. We introduce CelloType, an end-to-end model designed for cell segmentation and classification of biomedical microscopy images. Unlike the traditional two-stage approach of segmentation followed by classification, CelloType adopts a multi-task learning approach that connects the segmentation and classification tasks and simultaneously boost the performance of both tasks. CelloType leverages Transformer-based deep learning techniques for enhanced accuracy of object detection, segmentation, and classification. It outperforms existing segmentation methods using ground-truths from public databases. In terms of classification, CelloType outperforms a baseline model comprised of state-of-the-art methods for individual tasks. Using multiplexed tissue images, we further demonstrate the utility of CelloType for multi-scale segmentation and classification of both cellular and non-cellular elements in a tissue. The enhanced accuracy and multi-task-learning ability of CelloType facilitate automated annotation of rapidly growing spatial omics data.
Plaintiff experiences of the medico-legal environment in Ireland
Authors: McCarthy Suzanne , Donnelly Mary , Joy Aislinn , Lehane Elaine , O’Sullivan Peter , Spain Eimear
Published: September 2024

Introduction

The recent surge in clinical claims in Ireland has sparked concerns about the unsustainable trajectory of medical negligence litigation. Current evaluations have primarily focused on the financial and temporal aspects of litigation, leaving a gap in understanding the experiences of plaintiffs within the adversarial system. This study aims to fill this gap by critically exploring the experiences of those affected by medical negligence and the ensuing legal process.

Methods

A qualitative descriptive approach was employed to explore the experiences of plaintiffs following patient safety incidents and their interactions with the legal process. Semi-structured, open-ended interviews were conducted with participants who had been involved in medical negligence litigation in Ireland. Participants were eligible for inclusion if they were aged 18 years or over and were involved in medical negligence litigation in Ireland (as a plaintiff), whether the case was resolved by negotiated settlement, a form of alternative dispute resolution (e.g. mediation), or trial hearing. Maximum variation sampling was used to capture a diverse range of experiences, with sample size determined by the concept of ‘information power.’ Recruitment was facilitated by the Health Service Executive (HSE) through invitations sent by The National Open Disclosure Office. Interviews were conducted in-person or online, recorded, transcribed, and analysed thematically. Ethical approval was obtained from the Social Research Ethics Committee of University College Cork.

Findings

This research presents the views and experiences of fifteen participants; eleven participants shared their experiences relating to an adverse event which impacted a family member (one participant spoke about two family members), nine of whom were children (including both minors and adult children), and three were a spouse. Of the twelve individuals discussed, eight were deceased. Five main themes were identified from the analysis: i) Navigating the aftermath of a patient safety event: Communication, Support and Abandonment; ii) The pathway from adverse event to litigation; iii) Experiences of the Legal System; iv) Emotional and Mental Health Impact of Litigation on Plaintiffs; v) Advocating for Change: Participant Recommendations.

Discussion

This research highlights the profound impact of actions taken after a patient safety event on patients, families, healthcare professionals, and organisations, and the importance of Open Disclosure in meeting ethical obligations and ensuring healthcare accountability. It explores the complex relationships between financial compensation, justice-seeking, and the healthcare and legal systems. The findings contribute significant insights to the discourse on medical negligence in Ireland.
Access to Allogeneic Cell Transplantation Based on Donor Search Prognosis: An Interventional Trial
Authors: Dehn Jason G. , Logan Brent , Shaw Bronwen E. , Devine Steven , Ciurea Stefan O. , Horowitz Mary , He Naya , Pusic Iskra , Srour Samer A. , Arai Sally , Juckett Mark , Uberti Joseph , Hill LaQuisa , Vasu Sumithira , Hogan William J. , Hayes-Lattin Brandon , Westervelt Peter , Bashey Asad , Farhadfar Nosha , Grunwald Michael R. , Leifer Eric , Symons Heather , Saad Ayman , Vogel Jenny , Erickson Connor , Buck Kelly , Lee Stephanie J. , Pidala Joseph
Published: September 2024

Importance

Patients requiring allogeneic hematopoietic cell transplantation have variable likelihoods of identifying an 8/8 HLA-matched unrelated donor. A Search Prognosis calculator can estimate the likelihood.

Objective

To determine if using a search algorithm based on donor search prognosis can result in similar incidence of transplant between patients Very Likely (>90%) vs Very Unlikely (<10%) to have a matched unrelated donor.

Design

This interventional trial utilized a Search Prognosis-based biologic assignment algorithm to guide donor selection. Trial enrollment from June 13, 2019-May 13, 2022; analysis of data as of September 7, 2023 with median follow-up post-evaluability of 14.5 months.

Settings

National multi-center Blood and Marrow Transplantation Clinical Trials Network 1702 study of US participating transplant centers.

Participants

Acute myeloid and lymphoid leukemias, myelodysplastic syndrome, Hodgkin’s and non-Hodgkin’s lymphomas, severe aplastic anemia, and sickle cell disease patients referred to participating transplant centers were invited to participate. 2225 patients were enrolled and 1751 were declared evaluable for this study. Patients were declared evaluable once it was determined no suitable HLA-matched related donor was available.

Intervention

Patients assigned to the Very Likely arm were to proceed with matched unrelated donor, while Very Unlikely were to utilize alternative donors. A third stratum, Less Likely (∼25%) to find a matched unrelated donor, were observed under standard center practices, but were not part of the primary objective.

Main Outcome

Cumulative incidence of transplantation by Search Prognosis arm

Results

Evaluable patients included 1751 of which 413 (24%) were from racial/ethnic minorities. Search prognosis was 958 (55%) Very Likely, 517 (30%) Less Likely and 276 (16%) Very Unlikely. 1171 (67%) received HCT, 384 (22%) died without HCT, and 196 (11%) remained alive without HCT. Among the 1,234 patients, the adjusted cumulative incidence (95% CI) of HCT at 6-months was 59.8% (56.7-62.8) in the Very Likely group versus 52.3% (46.1-58.5) in the Very Unlikely (P=0.113).

Conclusions

A prospective Search Prognosis-based algorithm can be effectively implemented in a national multicenter clinical trial. This approach resulted in rapid alternative donor identification and comparable rates of HCT in patients Very Likely and Very Unlikely to find a matched unrelated donor.

Trial Registration:NCT#03904134
No Increased Risk of Major Adverse Cardiovascular Events following Nicotinamide Exposure
Authors: Wheless Lee , Guennoun Ranya , Michalski-McNeely Basia , Gonzalez Katlyn M , Weiss Rachel , Zhang Siwei , Yao Lydia , Madden Chris , Chen Hua-Chang , Triozzi Jefferson L , Tao Ran , Wilson Otis , Wells Quinn S , Hung Adriana , Bibee Kristin , Hartman Rebecca I , Xu Yaomin ,   VA Million Veteran Program
Published: September 2024

IMPORTANCE

Nicotinamide metabolites have recently been implicated in increased risk of major cardiovascular events (MACE). Supportive data about clinical risk of MACE for nicotinamide users is lacking.

OBJECTIVE

To determine whether nicotinamide use results in an increase of MACE.

DESIGN, SETTING, PARTICIPANTS

Retrospective cohort study of two patient cohorts, Vanderbilt University Medical Center (VUMC) and Military Veteran Program (MVP). The risk of MACE in patients exposed to nicotinamide was compared to the risk of MACE in unexposed patients. In the VUMC cohort, 1228 patients were exposed to nicotinamide based on keyword entry for “nicotinamide” or “niacinamide” and hand-review of charts, while 253 were unexposed but had documented recommendation for use. In the MVP cohort, there were 1594 with exposure to nicotinamide propensity score matched to 2694 without exposure.

EXPOSURES

The primary exposure for the VUMC cohort was a confirmed exposure to nicotinamide in chart review. The primary exposure for the MVP cohort was medication entry for “nicotinamide” or “niacinamide”.

MAIN OUTCOME(S) AND MEASURE(S)

The primary outcome was development of MACE based on a validated phenotype.

RESULTS

Between both cohorts, 6039 patients were included, of whom 5125 were male with a mean age of 63.2 years. Neither cohort had significant differences in mean age, sex, race and ethnicity between the nicotinamide exposed and unexposed groups. In the VUMC cohort, there was no significant association between nicotinamide exposure and the primary outcome of MACE (HR 0.76, 95% CI 0.46 – 1.25, p = 0.28). MACE prior to nicotinamide exposure was strongly associated with subsequent MACE (HR 9.01, 95% CI 5.90 – 13.70, p < 0.001). In the MVP cohort, we adjusted for MACE risk factors as potential confounding variables and saw no significant association between nicotinamide exposure and MACE (HR 1.00 95% CI 0.75 – 1.32), while history of prior MACE remained strongly associated with subsequent MACE (HR 9.50, 95% CI 6.38 – 14.1).

CONCLUSIONS AND RELEVANCE

In this retrospective cohort study of 6039 adults from two different patient populations, we found no increased risk of MACE in patients with nicotinamide exposure.
Biological markers of brain network connectivity and pain sensitivity distinguish low coping from high coping Veterans with persistent post-traumatic headache
Authors: Monroe Katrina S. , Schiehser Dawn M. , Parr Aaron W. , Simmons Alan N. , Hays Weeks Chelsea C. , Bailey Barbara A. , Shahidi Bahar
Published: September 2024

Headache is the most common type of pain following mild traumatic brain injury. Roughly half of those with persistent post-traumatic headache (PPTH) also report neck pain which is associated with greater severity and functional impact of headache. This observational cohort study aimed to identify biological phenotypes to help inform mechanism-based approaches in the management of PPTH with and without concomitant neck pain. Thirty-three military Veterans (mean (SD) = 37±16 years, 29 males) with PPTH completed a clinical assessment, quantitative sensory testing, and magnetic resonance imaging of the brain and cervical spine. Multidimensional phenotyping was performed using a Random Forest analysis and Partitioning Around Medoids (PAM) clustering of input features from three biologic domains: 1) resting state functional connectivity (rsFC) of the periaqueductal gray (PAG), 2) quality and size of cervical muscles, and 3) mechanical pain sensitivity and central modulation of pain. Two subgroups were distinguished by biological features that included forehead pressure pain threshold and rsFC between the PAG and selected nodes within the default mode, salience, and sensorimotor networks. Compared to the High Pain Coping group, the Low Pain Coping group exhibited higher pain-related anxiety (p=0.009), higher pain catastrophizing (p=0.004), lower pain self-efficacy (p=0.010), and greater headache-related disability (p=0.012). Findings suggest that greater functional connectivity of pain modulation networks involving the PAG combined with impairments in craniofacial pain sensitivity, but not cervical muscle health, distinguish a clinically important subgroup of individuals with PPTH who are less able to cope with pain and more severely impacted by headache.
Explicit solution of the SVIR (Susceptible-Vaccinated-Infectious-Recovered) epidemic model
Authors: Yoshida Norio
Published: September 2024

An explicit solution of an initial value problem for the Susceptible-Vaccinated-Infectious-Recovered (SVIR) epidemic model is obtained, and various properties of the explicit solution are investigated. It is shown that the parametric form of the explicit solution satisfies some linear differential system including a positive solution of an integral equation. In this paper integral equations play an important role in establishing the explicit solution of the SVIR epidemic model, in particular, the number of infected individuals can be represented in a simple form by using a positive solution of an integral equation. Uniqueness of positive solutions of the SVIR epidemic model is also investigated, and it is shown that the explicit solution is a unique solution in the class of positive solutions.
Sidechain chemistry-encoded solid/liquid phase transitions of condensates
Authors: Chen Feipeng , Han Yongxu , Li Xiufeng , Guo Wei , Wu Changjin , Xia Jiang , Zeng Xiangze , Shum Ho Cheung
Published: September 2024

Nature effectively leverages multivalent interactions among fundamental building blocks in solvents to create remarkable materials for various purposes. One prominent example is the formation of biomolecular condensates through the phase separation of proteins and nucleic acids. In particular, these condensates play crucial roles in regulating cellular functions and constructing natural materials. During the phase separation, solvents not only provide liquid environments for solvating molecules but play crucial roles in affecting the material properties of condensates. However, it remains controversial in the literature that alcohol molecules, as one type of solvents, can solidify some condensates while also melting others, leading to liquid-to-solid phase transition (LSPT) or solid-to-liquid phase transitions (SLPT), respectively. The mechanism underlying the alcohol-induced solid/liquid phase transitions of condensates remains poorly understood. Here, we combine systematic experimental characterizations with molecular dynamics simulations to demonstrate that the phase transitions of condensates depend on their sidechain chemistry and dominant molecular interactions. Specifically, “hydrophilic” condensates, which consist of many charged sidechains, undergo LSPT by adding alcohols due to strengthened electrostatic interactions. In contrast, “hydrophobic” condensates comprised of abundant aromatic sidechains undergo SLPT with the addition of alcohols because of weakened cation-π and π-π interactions. Importantly, these findings are generally applicable for predicting phase transitions of a wide range of condensates formed by synthetic polyelectrolytes and intrinsically disordered proteins based on their sidechain hydrophobicity or amino acid compositions. Our work not only reconciles a conundrum in the literature but provides a fundamental framework for understanding the responsiveness of condensates to environmental stimuli. These insights are instrumental for developing therapeutic drugs to treat pathological aggregates and engineering stimuli-responsive biomaterials from the perspective of sidechain chemistry and molecular interactions.
Bisulphite sequencing in the presence of cytosine-conversion errors
Authors: Ellis Thomas James , Nyzhynska Viktoria , Pisupati Rahul , Mollá-Morales Almudena , Nordborg Magnus
Published: September 2024

Bisulphite treatment of DNA converts unmethylated cytosines to thymine, and is a common method to infer the methylation status of cytosines when coupled with sequencing. ‘Tagmentation’ approaches to bisulphite sequencing use a transposase to simultaneously make double-stranded breaks and ligate adaptors to the resulting fragments, allowing for higher throughput with less starting material. However, it has also been noted that certain tagmentation protocols have an unusually high number unmethylated cytosines that are not converted to thymine. Here we describe this phenomenon in detail, and find that results are consistent with single strand nicks by the transposase, followed by strand displacement of part or all of the DNA fragment, leading to erroneous incorporation of methylated cytosines. Nevertheless we show that these errors can be accounted for in downstream analysis and need not impede biological conclusions. We provide a Python package to allow users to implement this framework. Ultimately the additional effort of accounting for errors must be traded off against the scalability of the protocol in planning experiments.
A single ancestralANP32locus in ticks creates multiple protein variants that all support the Thogoto virus polymerase
Authors: Zhang Zhenyu , Nipper Thomas , Aziati Ishmael D. , Boon Adrianus C. M. , Mehle Andrew
Published: September 2024

Viral polymerases rely on cellular cofactors to support efficient transcription of viral genes and replication of the viral genome. The RNA-dependent RNA polymerase of influenza virus, an orthomyxovirus, requires cellular ANP32A or ANP32B proteins for genome replication. However, little is known about whether ANP32 proteins are required by other orthomyxoviruses like the tick-borne thogotoviruses. Recent structural studies coupled with functional assays suggested that the Thogoto virus polymerase uses both ANP32A and ANP32B from brown dog ticks. We clarify here that this tick vector encodes a singleANP32locus corresponding toANP32A. This single gene produces multiple protein variants through alternative splicing and start-site selection, all of which enhance Thogoto virus polymerase. Thogoto virus polymerase activity is also enhanced by human and chicken ANP32 proteins. Thus, ANP32A is a deeply conserved pro-viral cofactor and Thogoto virus shows remarkable plasticity utilizing ANP32 homologues separated by almost 1 billion years of evolution.