bluuebunny/crossref_metadata_2025_split huggingface dataset:
“Targeted Muscle Reinnervation at the Time of Amputation Decreases Recurrent Symptomatic Neuroma Formation”
Authors: Goodyear Evelyn G. , O’Brien Andrew L. , West Julie M. , Huayllani Maria T. , Huffman Allison C. , Souza Jason M. , Schulz Steven A. , Moore Amy M. 
Published: May 2023

Background:
Targeted Muscle Reinnervation (TMR) is an effective technique for the prevention and management of phantom limb pain (PLP) and residual limb pain (RLP) among amputees. The purpose of this study was to evaluate symptomatic neuroma recurrence and neuropathic pain outcomes between cohorts receiving TMR at the time of amputation (i.e., acute) versus TMR following symptomatic neuroma formation (i.e., delayed).

Methods:
A cross-sectional, retrospective chart review was conducted using patients receiving TMR between 2015 and 2020. Symptomatic neuroma recurrence and surgical complications were collected. A subanalysis was conducted for patients that completed Patient-Reported Outcome Measurement Information System (PROMIS) pain intensity, interference, and behavior as well as an 11-point numeric rating scale (NRS) forms.

Results:
105 limbs from 103 patients were identified with 73 acute TMR limbs and 32 delayed TMR limbs. 19% of the delayed TMR group had symptomatic neuromas recur in the distribution of original TMR compared to 1% of the acute TMR group (p<0.05). 85% the acute TMR group and 69% patients of the delayed TMR group completed pain surveys at final follow-up. Of this subanalysis, acute TMR patients reported significantly lower PLP PROMIS pain interference (p<0.05), RLP PROMIS pain intensity (p<0.05) and RLP PROMIS pain interference (p<0.05) in comparison to the delayed group.

Conclusions
Patients who underwent acute TMR reported improved pain scores and decreased rate of neuroma formation compared to TMR performed in a delayed fashion. These results highlight the promising role of TMR in the prevention of neuropathic pain and neuroma formation at time of amputation.

Level of Evidence:
Therapeutic, III
Six-month immune responses to mRNA-1273 vaccine in combination antiretroviral therapy treated late presenter people with HIV according to previous SARS-CoV-2 infection
Authors: Augello Matteo , Bono Valeria , Rovito Roberta , Tincati Camilla , d’Arminio Monforte Antonella , Marchetti Giulia 
Published: May 2023

Objective:Immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in people with HIV (PWH) with a history of late presentation (LP) and their durability have not been fully characterized.Design:In this prospective, longitudinal study, we sought to assess T-cell and humoral responses to SARS-CoV-2 mRNA vaccination up to 6 months in LP-PWH on effective combination antiretroviral therapy (cART) as compared to HIV-negative healthcare workers (HCWs), and to evaluate whether previous SARS-CoV-2 infection modulates immune responses to vaccine.Methods:SARS-CoV-2 spike (S)-specific T-cell responses were determined by two complementary flow cytometry methodologies, namely activation-induced marker (AIM) assay and intracellular cytokine staining (ICS), whereas humoral responses were measured by ELISA [anti-receptor binding domain (RBD) antibodies) and receptor-binding inhibition assay (spike-ACE2 binding inhibition activity), before vaccination (T0), 1 month (T1) and 5 months (T2) after the second dose.Results:LP-PWH showed at T1 and T2 significant increase of: S-specific memory and circulating T follicular helper (cTfh) CD4+T cells; polyfunctional Th1-cytokine (IFN-γ, TNF-α, IL-2)- and Th2-cytokine (IL-4)-producing S-specific CD4+T cells; anti-RBD antibodies and spike-ACE2 binding inhibition activity. Immune responses to vaccine in LP-PWH were not inferior to HCWs overall, yet S-specific CD8+T cells and spike-ACE2 binding inhibition activity correlated negatively with markers of immune recovery on cART. Interestingly, natural SARS-CoV-2 infection, while able to sustain S-specific antibody response, seems less efficacious in inducing a T-cell memory and in boosting immune responses to vaccine, possibly reflecting an enduring partial immunodeficiency.Conclusions:Altogether, these findings support the need for additional vaccine doses in PWH with a history of advanced immune depression and poor immune recovery on effective cART.
Predictors of Long-Term Visual Acuity in a Modern Cohort of Patients With Acute Idiopathic and Multiple Sclerosis–Associated Optic Neuritis
Authors: Jarocki Adrienne , Benard-Seguin Etienne , Gonzalez Lizbeth A. , Costello Fiona , Andrews Chris A. , Kerber Kevin , De Lott Lindsey B. 
Published: May 2023

Background:
For patients with idiopathic or multiple sclerosis (MS)–associated optic neuritis (ON), the largest multicenter clinical trial (Optic Neuritis Treatment Trial [ONTT]) showed excellent visual outcomes and baseline high-contrast visual acuity (HCVA) was the only predictor of HCVA at 1 year. We aimed to evaluate predictors of long-term HCVA in a modern, real-world population of patients with ON and compare with previously published ONTT models.

Methods:
We performed a retrospective, longitudinal, observational study at the University of Michigan and the University of Calgary evaluating 135 episodes of idiopathic or MS-associated ON in 118 patients diagnosed by a neuro-ophthalmologist within 30 days of onset (January 2011–June 2021). Primary outcome measured was HCVA (Snellen equivalents) at 6–18 months. Multiple linear regression models of 107 episodes from 93 patients assessed the association between HCVA at 6–18 months and age, sex, race, pain, optic disc swelling, symptoms (days), viral illness prodrome, MS status, high-dose glucocorticoid treatment, and baseline HCVA.

Results:
Of the 135 acute episodes (109 Michigan and 26 Calgary), median age at presentation was 39 years (interquartile range [IQR], 31–49 years), 91 (67.4%) were women, 112 (83.0%) were non-Hispanic Caucasians, 101 (75.9%) had pain, 33 (24.4%) had disc edema, 8 (5.9%) had a viral prodrome, 66 (48.9%) had MS, and 62 (46.6%) were treated with glucocorticoids. The median (IQR) time between symptom onset and diagnosis was 6 days (range, 4–11 days). The median (IQR) HCVA at baseline and at 6–18 months were 20/50 (20/22, 20/200) and 20/20 (20/20, 20/27), respectively; 62 (45.9%) had better than 20/40 at baseline and 117 (86.7%) had better than 20/40 at 6–18 months. In linear regression models (n = 107 episodes in 93 patients with baseline HCVA better than CF), only baseline HCVA (β = 0.076; P = 0.027) was associated with long-term HCVA. Regression coefficients were similar and within the 95% confidence interval of coefficients from published ONTT models.

Conclusions:
In a modern cohort of patients with idiopathic or MS-associated ON with baseline HCVA better than CF, long-term outcomes were good, and the only predictor was baseline HCVA. These findings were similar to prior analyses of ONTT data, and as a result, these are validated for use in conveying prognostic information about long-term HCVA outcomes.
MASIv2 enables standardization and integration of multi-modal single-cell and spatial omics data with one general framework
Authors: Xu Yang , Hayat Sikander 
Published: May 2023

AbstractData annotation and integration are two common tasks in large-scale and collaborative single-cell research. Rapid technological advancements have made diverse single-cell and spatial data modalities available. This data deluge brought up great challenges in data annotation and integration. Though different biological modalities preserve shared features to define the same cellular system, they often present unique angles to unravel a multi-level understanding about this system. Here, we present one general framework that uses modality-shared and -specific features for annotation and integration of single-cell and spatial omics data. We benchmark our framework with existing methods across different datasets and demonstrate its application in two real world tasks.
A Real-Time Deep Learning Approach for Inferring Intracranial Pressure from Routinely Measured Extracranial Waveforms in the Intensive Care Unit
Authors: Nair Shiker S. , Guo Alina , Boen Joseph , Aggarwal Ataes , Chahal Ojas , Tandon Arushi , Patel Meer , Sankararaman Sreenidhi , Azad Tej , Pirracchio Romain , Stevens Robert D. 
Published: May 2023

AbstractObjectiveIntracranial pressure (ICP) is a physiological variable used to assess the neurological state of patients with life-threatening intracranial pathology, such as traumatic brain injury or stroke. The current standard of care for measuring ICP requires a catheter to be inserted into the brain, which is associated with an appreciable risk of hemorrhage and infection. We hypothesize that ICP can be computed from extracranial waveforms routinely measured in the Intensive Care Unit (ICU), such as invasive arterial blood pressure (ABP), photoplethysmography (PPG), and electrocardiography (ECG).MethodsWe extracted 600 hours of simultaneous ABP, ECG, PPG, and ICP data (sampled at 125 Hz) across 10 different patients from the MIMIC III Waveform Database. These recordings were segmented into 10 second windows and used to train six different deep learning models with ABP, ECG, and PPG waveforms as input features. Models were evaluated in both a singlepatient analysis and multi-patient analysis.ResultsThe performances of the six deep learning models were compared, revealing two tiers of performance. Among the top-tier models, the mean average error (MAE) for inferring ICP was approximately 1.50 mmHg for singlepatient analysis and 5 mmHg for multi-patient analysis.ConclusionsThese preliminary and novel results indicate the feasibility and accuracy of noninvasive ICP estimation by training deep learning models with extracranial physiological data. With further validation, this approach could be implemented in a continuous real-time fashion, thereby reducing risks associated with invasive monitoring and allowing more timely treatment of patients with critical brain injuries.
Adipocytes regulate fibroblast function, and their loss contributes to fibroblast dysfunction in inflammatory diseases
Authors: Faust Heather J. , Cheng Tan-Yun , Korsunsky Ilya , Watts Gerald F.M. , Gal-Oz Shani T. , Trim William , Kongthong Kurt , Jonsson Anna Helena , Simmons Daimon P. , Zhang Fan , Padera Robert , Chubinskaya Susan ,   Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, Wei Kevin , Raychaudhuri Soumya , Lynch Lydia , Moody D. Branch , Brenner Michael B. 
Published: May 2023

AbstractFibroblasts play critical roles in tissue homeostasis, but in pathologic states can drive fibrosis, inflammation, and tissue destruction. In the joint synovium, fibroblasts provide homeostatic maintenance and lubrication. Little is known about what regulates the homeostatic functions of fibroblasts in healthy conditions. We performed RNA sequencing of healthy human synovial tissue and identified a fibroblast gene expression program characterized by enhanced fatty acid metabolism and lipid transport. We found that fat-conditioned media reproduces key aspects of the lipid-related gene signature in cultured fibroblasts. Fractionation and mass spectrometry identified cortisol in driving the healthy fibroblast phenotype, confirmed using glucocorticoid receptor gene (NR3C1) deleted cells. Depletion of synovial adipocytes in mice resulted in loss of the healthy fibroblast phenotype and revealed adipocytes as a major contributor to active cortisol generation viaHsd11β1expression. Cortisol signaling in fibroblasts mitigated matrix remodeling induced by TNFα- and TGFβ, while stimulation with these cytokines repressed cortisol signaling and adipogenesis. Together, these findings demonstrate the importance of adipocytes and cortisol signaling in driving the healthy synovial fibroblast state that is lost in disease.
Host-parasite interactions in perpetual darkness: macroparasite diversity in the cavefishAstyanax mexicanus
Authors: Santacruz Ana , Hernández-Mena David , Miranda-Gamboa Ramses , De León Gerardo Pérez-Ponce , Ornelas-García Claudia Patricia 
Published: May 2023

ABSTRACTAstyanax mexicanushas repeatedly colonized cave environments, displaying evolutionary parallelisms in many troglobitic traits. Despite being a model system for the study of adaptation to life in perpetual darkness, parasites infecting cavefish are practically unknown. In this study, we investigated the macroparasite communities of 18 cavefish populations from independent lineages and compared them with the parasite diversity of their sister surface fish populations, with the aim of better understanding the role that parasites play in the colonization of new environments. Thirteen parasite taxa were found in cavefish populations, including a subset of 10 of the 27 parasite taxa known for the surface populations. Parasites infecting the cavefish belong to five taxonomic groups: trematodes, monogeneans, nematodes, copepods, and acari. Monogeneans are the most dominant group, found in 14 caves. Macroparasites include species with direct life cycles and some trophically-transmitted parasites, including invasive species. Surprisingly, cave vs surface paired comparisons indicate higher parasite richness in the caves. The spatial variation in parasite composition across the caves suggests historical and geographical contingencies of the host-parasite colonization and the potential evolution of local adaptations. Base-line data on parasite diversity of cavefish populations ofA. mexicanussets the ground to explore the role of divergent parasite infections under contrasting ecological pressures (cave vs. surface environments) in the evolution of cave adaptive traits.
How to Scan DNA using Promiscuous Recognition and No Sliding Clamp: A Model for Pioneer Transcription Factors
Authors: Goluguri Rama Reddy , Sadqi Mourad , Nagpal Suhani , Muñoz Victor 
Published: May 2023

AbstractDNA scanning proteins slide on the DNA assisted by a clamping interface and uniquely recognize their cognate sequence motif. The transcription factors that control cell fate in eukaryotes must forgo these elements to gain access to both naked DNA and chromatin, so whether or how they scan DNA is unknown. Here we use single-molecule techniques to investigate DNA scanning by the Engrailed homeodomain (enHD) as paradigm of promiscuous recognition and open DNA interaction. We find that enHD scans DNA as fast and extensively as conventional scanners and 10,000,000 fold faster than expected for a continuous promiscuous slide. Our results indicate that such supercharged scanning involves stochastic alternants between local sequence sweeps of ∼85 bp and very rapid deployments to locations ∼500 bp afar. The scanning mechanism of enHD reveals a strategy perfectly suited for the highly complex environments of eukaryotic cells that might be generally used by pioneer transcription factors.TeaserEukaryotic transcription factors can efficiently scan DNA using a rather special mechanism based on promiscuous recognition.
MoleculeExperiment enables consistent infrastructure for molecule-resolved spatial transcriptomics data in Bioconductor
Authors: Couto Bárbara Zita Peters , Robertson Nicholas , Patrick Ellis , Ghazanfar Shila 
Published: May 2023

AbstractImaging-based spatial transcriptomics technologies have achieved subcellular resolution, enabling detection of individual molecules in their native tissue context. Data associated with these technologies promises unprecedented opportunity towards understanding cellular and subcellular biology. However, in R/Bioconductor there is a scarcity of existing computational infrastructure to represent such data, and particularly to summarise and transform it for existing widely adopted computational tools in single cell transcriptomics analysis, including SingleCellExperiment and SpatialExperiment classes. With the emergence of several commercial offerings of imaging-based spatial transcriptomics, there is a pressing need to develop consistent data structure standards for these technologies at the individual molecule level. To this end, we have developed MoleculeExperiment, an R/Bioconductor package, which i) stores molecule and cell segmentation boundary information at the molecule-level, ii) standardises this molecule-level information across different imaging-based ST technologies, including 10x Genomics’ Xenium, and iii) streamlines transition from a MoleculeExperiment object to a SpatialExperiment object. Overall, MoleculeExperiment is generally applicable as a data infrastructure class for consistent analysis of imaging-based spatial transcriptomics data.
Prominent role of PM10 but not of circulating inflammation in the link between air pollution and the risk of neurodegenerative disorders
Authors: Gialluisi Alessandro , Costanzo Simona , Veronesi Giovanni , Cembalo Assuntina , Tirozzi Alfonsina , Falciglia Stefania , Ricci Moreno , Martone Francesco , Zazzaro Gaetano , Ferrario Marco Mario , Gianfagna Francesco , Cerletti Chiara , Donati Maria Benedetta , Massari Stefania , de Gaetano Giovanni , Iacoviello Licia 
Published: May 2023

AbstractBackgroundSeveral studies revealed an implication of air pollution in neurodegenerative disorders, although this link and the potential underlying mechanisms remain unclear.ObjectivesTo analyze the impact of air pollution on neurodegenerative risk by testing multiple pollutants simultaneously, along with other potential risk/protective factors, and the role of circulating inflammation.MethodsIn the Moli-sani cohort (N=24,325; ≥35 years; 51.9% women, baseline 2005-2010), we estimated yearly levels of exposure to nitrogen oxides, ozone, particulate matter (PM10), sulfur dioxide and BTX hydrocarbons in 2006-2018, applying residence geo-localization of participants and Kriging interpolation algorithm to land measurements of air pollutants. We performed a principal component (PC) analysis of pollutant levels and tested associations of the resulting PC scores with the incident risk of dementia (AD) and Parkinson’s disease/parkinsonism (PD), through multivariable Cox PH regressions adjusted for age, sex, education level, and several professional and lifestyle exposures. Moreover, we tested whether a composite biomarker of circulating inflammation (INFLA-score) may explain part of these associations.ResultsOver 24,308 subjects with pollution data available (51.9% women, mean age 55.8(12.0) years), we extracted three PCs explaining ≥5% of pollution exposure variance: PC1 (38.2%, tagging PM10), PC2 (19.5%, O3/CO/SO2), PC3 (8.5%, NOx/BTX hydrocarbons). Over a median (IQR) follow-up of 11.2(2.0) years, we observed statistically significant associations of PC1 with an increased risk of both AD (HR[CI] = 1.06[1.04-1.08]; 218 cases) and PD (1.05[1.03-1.06]; 405 incident cases), independent on other covariates. These associations were confirmed testing average PM10 levels during follow-up time (25[19-31]% and 19[15-24]% increase of AD and PD risk, per 1 μg/m3of PM10). INFLA-score explained a negligible (<1%) proportion of these associations.DiscussionAir pollution – especially PM10 – is associated with increased neurodegenerative risk in the Italian population, independent on concurring risk factors, suggesting its reduction as a potential public health target.
Lipidomics for diagnosis and prognosis of pulmonary hypertension
Authors: Bordag Natalie , Nagy Bence Miklos , Zügner Elmar , Ludwig Helga , Foris Vasile , Nagaraj Chandran , Biasin Valentina , Bodenhofer Ulrich , Magnes Christoph , Maron Bradley A. , Ulrich Silvia , Lange Tobias J. , Hötzenecker Konrad , Pieber Thomas , Olschewski Horst , Olschewski Andrea 
Published: May 2023

AbstractBackgroundPulmonary hypertension (PH) poses a significant health threat with high morbidity and mortality, necessitating improved diagnostic tools for enhanced management. Current biomarkers for PH lack functionality and comprehensive diagnostic and prognostic capabilities. Therefore, there is a critical need to develop biomarkers that address these gaps in PH diagnostics and prognosis.MethodsTo address this need, we employed a comprehensive metabolomics analysis in 233 blood based samples coupled with machine learning analysis. For functional insights, human pulmonary arteries (PA) of idiopathic pulmonary arterial hypertension (PAH) lungs were investigated and the effect of extrinsic FFAs on human PA endothelial and smooth muscle cells was testedin vitro.ResultsPA of idiopathic PAH lungs showed lipid accumulation and altered expression of lipid homeostasis-related genes. In PA smooth muscle cells, extrinsic FFAs caused excessive proliferation and endothelial barrier dysfunction in PA endothelial cells, both hallmarks of PAH.In the training cohort of 74 PH patients, 30 disease controls without PH, and 65 healthy controls, diagnostic and prognostic markers were identified and subsequently validated in an independent cohort. Exploratory analysis showed a highly impacted metabolome in PH patients and machine learning confirmed a high diagnostic potential. Fully explainable specific free fatty acid (FFA)/lipid-ratios were derived, providing exceptional diagnostic accuracy with an area under the curve (AUC) of 0.89 in the training and 0.90 in the validation cohort, outperforming machine learning results. These ratios were also prognostic and complemented established clinical prognostic PAH scores (FPHR4p and COMPERA2.0), significantly increasing their hazard ratios (HR) from 2.5 and 3.4 to 4.2 and 6.1, respectively.ConclusionIn conclusion, our research confirms the significance of lipidomic alterations in PH, introducing innovative diagnostic and prognostic biomarkers. These findings may have the potential to reshape PH management strategies.
Copy-back viral genomes induce a cellular stress response that interferes with viral protein expression without affecting antiviral immunity
Authors: González Aparicio Lavinia J. , Yang Yanling , Hackbart Matthew S. , López Carolina B. 
Published: May 2023

AbstractAntiviral responses are often accompanied by translation inhibition and formation of stress granules (SG) in infected cells. However, the triggers for these processes and their role during infection remain subjects of active investigation. Copy-back viral genomes (cbVGs) are the primary inducers of the Mitochondrial Antiviral Signaling (MAVS) pathway and antiviral immunity during Sendai Virus (SeV) and Respiratory Syncytial virus (RSV) infections. The relationship between cbVGs and cellular stress during viral infections is unknown. Here we show that SG form during infections containing high levels of cbVGs, and not during infections with low levels of cbVGs. Moreover, using RNA fluorescent in situ hybridization to differentiate accumulation of standard viral genomes from cbVGs at a single-cell level during infection, we show that SG form exclusively in cells that accumulate high levels of cbVGs. PKR activation is increased during high cbVG infections and, as expected, PKR is necessary to induce virus-induced SG. However, SG form independent of MAVS signaling, demonstrating that cbVGs induce antiviral immunity and SG formation through two independent mechanisms. Furthermore, we show that translation inhibition and SG formation do not affect the overall expression of interferon and interferon stimulated genes during infection, making the stress response dispensable for antiviral immunity. Using live-cell imaging, we show that SG formation is highly dynamic and correlates with a drastic reduction of viral protein expression even in cells infected for several days. Through analysis of active protein translation at a single cell level, we show that infected cells that form SG show inhibition of protein translation. Together, our data reveal a new cbVG-driven mechanism of viral interference where cbVGs induce PKR-mediated translation inhibition and SG formation leading to a reduction in viral protein expression without altering overall antiviral immunity.One Sentence SummarycbVGs trigger the cellular stress response independent of the antiviral response during RSV and parainfluenza virus infection leading to a reduction of virus protein expression.