bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-Effectiveness of Instrumented Versus Uninstrumented Posterolateral Fusion for Single-level Degenerative Spondylolisthesis
Authors: Andresen Andreas K. , Andersen Mikkel Ø. , Carreon Leah Y. , Sørensen Jan 
Published: February 2025

Study design.
Randomized controlled trial

Objective.
The aim of this study was to investigate whether instrumented posterolateral fusion is cost-effective compared to un-instrumented posterolateral fusion in elderly patients who undergo fusion surgery for one-level degenerative spondylolisthesis with spinal stenosis.

Summary of Background Data.
For patients with persistent symptoms due to degenerative spondylolisthesis, surgical intervention may be recommended, typically decompression and fusion. Evidence on cost-effectiveness of choice of fusion method, related complications and outcome is sparse.

Methods.
This cost-effectiveness analysis is based on a single-center, open label, randomized controlled trial, where patients with symptomatic degenerative spondylolisthesis were randomly assigned 1:1 to either instrumented or un-instrumented posterolateral fusion. Quality-Adjusted Life Years were obtained from EQ-5D. Use of health services were obtained from patient charts and accumulated until 2 years after index surgery.

Results.
Of the 108 patients included in the study, 107 patients received the allocated intervention. There were no differences in preoperative demographics. Although the base price for the index instrumented surgery was significantly higher than the index uninstrumented surgery, average cost of surgery was only €146 higher in the instrumented group based on two-year cost data. The instrumented fusion group had a significantly lower reoperation rate (1/54 (1.9%)) than the uninstrumented fusion group 7/53 (13.2%), significantly less visits to the outpatient clinic, less Magnetic Resonance Imaging performed and fewer days of hospitalization. The base case incremental cost-effectiveness ratio was estimated at €1,536 per QALY gained over a two-year time horizon. Instrumented fusion was favored over uninstrumented fusion in sensitivity analyses including all reoperations or using hospital reimbursement rate.

Conclusion.
Insturumented fusion is cost-effective compared uninstrumented fusion, with an incremental cost-effectiveness ration well below the standard range of cost-effectivenes, the difference in cost was driven by lower re-operation rates and less healthcare resource utilization over a two-year time horizon.
The Role of Gliosis in Idiopathic Epiretinal Membranes: New Insights
Authors: Quarta Alberto , Zeppa Lucio , Ruggeri Maria Ludovica , Gironi Matteo , Aharrh-Gnama Agbeanda , Di Nicola Marta , Porreca Annamaria , Matarazzo Francesco , Toto Lisa , Mastropasqua Rodolfo 
Published: February 2025

Purpose: to compare cloudy and clear epiretinal membranes (ERMs) using multicolor scanning laser ophthalmoscopy (MC-SLO) per stage and to assess gliotic components’ impact on postoperative visual outcomes in ERM surgery patients.

Methods:
Baseline and 6-months measurements included Snellen acuity (SA), central retinal thickness (CRT), the presence of microcystic macular edema (MME), outer retinal cysts (ORC), disruptions of the ellipsoid zone (EZ) and external limiting membrane (ELM) and quantitative analysis on MC-SLO were analyzed. The study primarily evaluated postoperative SA improvement, CRT reduction, and the prevalence of ERM remnants. Additionally, the relationship between gliotic components and postoperative outcomes was analyzed.

Results:
In stage 2 ERMs, clear ERMs had a higher incidence of ERM remnants after surgery (81.8% vs. 30.8%, p = 0.037). Both groups experienced visual acuity improvement (clear ERMs: +25 ETDRS letter score, cloudy ERMs: +15 ETDRS letter score p = 0.013). In stage 3 ERMs, no significant differences in SA or CRT changes were noted, but clear ERMs showed more inner retinal dimples (p = 0.015). Gliosis area and EIFL thickness showed significant correlation in cloudy stage 3 ERMs (p = 0.011).

Conclusions:
Clear and cloudy ERMs differ in postoperative recovery. Cloudy stage 2 ERMs have less functional recovery but fewer remnants than clear ERMs. In stage 3, gliosis correlates with EIFL severity, and clear ERMs exhibit more inner retinal dimples.
Associations Between Epistemic Trust and the Severity of Personality Disorder
Authors: Knapen Saskia , Mensink Wendy , Swildens Wilma E. , Hoogendoorn Adriaan W. , Duits Puck , Hutsebaut Joost , Beekman Aartjan T.F. 
Published: February 2025

Abstract
Early childhood adversity may dispose an individual to adopt a rigid and pervasive hypervigilant position toward information coming from others, resulting in high levels of epistemic mistrust (EM), which is supposed to increase the risk of developing psychopathology. A more intrinsic relationship between EM and the development of personality disorders (PDs) is assumed. Although the theory of epistemic trust (ET) is rather novel, it has quickly become widely accepted in the field, despite much empirical evidence. This is the first study investigating the level of ET and associations between ET and PDs among patients with PD, anxiety disorders, and a community sample. Our results demonstrated more severe impairments in ET in patients, and associations found between ET and the severity and types of PDs corroborate the theoretically assumed model. Future research with larger samples and prospective designs is needed to explore further and substantiate the theoretical assumptions about ET.
Severe Iliopsoas Muscle Endometriosis Managed by a Multidisciplinary Team
Authors: Bray Harley , Delaloye Nicole , Kirkpatrick Iain D. C. , Baker Patricia , Shariff Farhana , Evans Devon 
Published: February 2025

BACKGROUND:
There is limited published guidance on management of iliopsoas muscle endometriosis, especially when muscle is extensively infiltrated.

CASE:
A 38-year-old patient presented with left leg neuropathy, atrophy, edema, and catamenial bruising. Magnetic resonance imaging identified a poorly defined multiseptated cystic mass in the iliacus and inferior psoas muscle consistent with an endometrioma. After failed medical management, a multidisciplinary team was assembled for operative intervention. Excision was incomplete because the mass replaced most of the psoas muscle and obscured the femoral nerve. Postoperatively, pathology confirmed endometriosis and symptoms improved.

CONCLUSION:
In cases of iliopsoas endometriosis, surgical judgment should balance the dogmatic goal of complete excision with the ethical principle of nonmaleficence. Drainage and partial excision may allow for preserved muscle function and avoidance of catastrophic neurovascular injury.
Liver fibrosis regression in people living with HIV after successful treatment for hepatitis C
Authors: Young Jim , Wang Shouao , Sacks-Davis Rachel , Stewart Ashleigh , van Santen Daniela K , van der Valk Marc , Doyle Joseph S , Matthews Gail , Berenguer Juan , Wittkop Linda , Lacombe Karine , Rauch Andri , Stoové Mark , Hellard Margaret , Klein Marina B ,   on behalf of the InCHEHC Collaboration
Published: February 2025

Background:
Successful treatment of hepatitis C virus (HCV) can lead to liver fibrosis regression. It is not known who will experience fibrosis regression or how quickly it will occur.

Methods:
We modelled transient elastography (TE) measurements from 1470 HIV-HCV coinfected participants followed in cohorts contributing data to InCHEHC, an international collaboration. Participants were eligible if they had at least one TE measurement in the year prior to starting a successful direct acting antiviral treatment for HCV. This measurement was used to classify participants into one of three fibrosis subgroups. We analysed measurement sequences in each subgroup using a covariate adjusted generalised additive mixed model, with an adaptive spline representing changes in the mean measurement before, during and after treatment.

Results:
Each fibrosis subgroup had a distinctly different response. Most participants with cirrhosis (F4, TE ≥14.6 KPa) prior to HCV treatment did not show meaningful fibrosis regression – almost 70% were predicted to remain above 12 KPa three years after treatment ended. Participants with significant fibrosis (F2-F3, TE ≥7.2 and <14.6KPa) showed appreciable regression in the first two years after treatment, falling on average to levels below 7.2 KPa. Those without fibrosis prior to treatment (F0-F1) did not progress.

Conclusion:
Most coinfected people with cirrhosis prior to HCV cure will remain cirrhotic. For those with significant fibrosis, regression can be expected within two years to levels not normally associated with an increased risk of endstage liver disease. A TE measurement two years after cure should give a reliable estimate of residual fibrosis.
Patient-specific responses toSMN2splice-modifying treatments in spinal muscular atrophy fibroblasts
Authors: Signoria Ilaria , Zwartkruis Maria M. , Geerlofs Lotte , Perenthaler Elena , Faller Kiterie M.E. , James Rachel , McHale-Owen Harriet , Green Jared W. , Kortooms Joris , Snellen Sophie H. , Asselman Fay-Lynn , Gillingwater Thomas H. , Viero Gabriella , Wadman Renske I. , van der Pol W. Ludo , Groen Ewout J.N. 
Published: February 2025

AbstractThe availability of three therapies for the neuromuscular disease spinal muscular atrophy (SMA) highlights the need to match patients to the optimal treatment. Two of these treatments (nusinersen and risdiplam) target splicing ofSMN2, but treatment outcomes vary from patient to patient. An incomplete understanding of the complex interactions between SMA genetics, SMN protein and mRNA levels, and gene-targeting treatments, limits our ability to explain this variability and identify optimal treatment strategies for individual patients. To address this, we analyzed responses to nusinersen and risdiplam in 45 primary fibroblast cell lines. Pre-treatmentSMN2-FL,SMN2Δ7mRNA, and SMN protein levels were influenced bySMN2copy number, age, and sex. After treatment, SMN and mRNA levels were more heterogeneous. In 43% of patients, response to both therapies was similar, but in 57% one treatment led to a significantly higher SMN increase than the other treatment. Younger age, higherSMN2copy number, and higher SMN levels before treatment predicted betterin vitroefficacy. These findings showcase patient-derived fibroblasts as a tool for identifying molecular predictors for personalized treatment.
Circulating cell-free DNA methylation profiles as noninvasive multiple sclerosis biomarkers: A proof-of-concept study
Authors: Fu Hailu , Huang Kevin , Zhu Wen , Zhang Lili , Bandaru Ravi , Wang Li , Liu Yaping , Xia Zongqi 
Published: February 2025

AbstractIn multiple sclerosis (MS), there is a critical need for non-invasive biomarkers to concurrently classify disease subtypes, evaluate disability severity, and predict long-term progression. In this proof-of-concept study, we performed low-coverage whole-genome bisulfite sequencing (WGBS) on 75 plasma cell-free DNA (cfDNA) samples and assessed the clinical utility of cfDNA methylation as a single assay for distinguishing MS patients from non-MS controls, identifying MS subtypes, estimating disability severity, and predicting disease trajectories. We identified thousands of differentially methylated CpGs and hundreds of differentially methylated regions (DMRs) that significantly distinguished MS from controls, separated MS subtypes, and stratified disability severity levels. These DMRs were highly enriched in immunologically and neurologically relevant regulatory elements (e.g.,active promoters and enhancers) and contained motifs associated with neuronal function and T-cell differentiation. To distinguish MS subtypes and severity groups, we achieved area-under-the-curve (AUC) values ranging from 0.67 to 0.81 using DMRs and 0.70 to 0.82 using inferred tissue-of-origin patterns from cfDNA methylation, significantly outperforming benchmark neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the same cohort. Finally, a linear mixed-effects model identified “prognostic regions” where baseline cfDNA methylation levels were associated with disease progression and predicted future disability severity (AUC=0.81) within a 4-year evaluation window. As we plan to generate higher-depth WGBS data and validation in independent cohorts, the present findings suggest the potential clinical utility of circulating cfDNA methylation profiles as promising noninvasive biomarkers in MS diagnosis and prognosis.
Self-versus caregiver-reported apathy across neurological disorders
Authors: Zhao Sijia , Scholcz Anna , Rouse Matthew A. , Klar Verena S. , Ganse-Dumrath Akke , Toniolo Sofia , Broulidakis M. John , Ralph Matthew A. Lambon , Rowe James B. , Garrard Peter , Thompson Sian , Irani Sarosh R , Manohar Sanjay , Husain Masud 
Published: February 2025

AbstractApathy is a prevalent and persistent neuropsychiatric syndrome across many neurological disorders, significantly impacting on both patients and caregivers. We systematically quantified discrepancies between self- and caregiver-reported apathy in 335 patients with a variety of diagnoses, frontotemporal dementia (behavioural variant and semantic dementia subtypes), Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, Alzheimer’s disease dementia, mild cognitive impairment, small vessel cerebrovascular disease, subjective cognitive decline and autoimmune encephalitis.Using the Apathy-Motivation Index (AMI) and its analogous caregiver version (AMI-CG), we found that caregiver-reported apathy consistently exceeded self-reported levels across all conditions. Moreover, self-reported apathy accounted for only 14.1% of the variance in caregiver ratings. This apathy reporting discrepancy was most pronounced in conditions associated with impaired insight, such as behavioural variant frontotemporal dementia, and was significantly correlated with cognitive impairment. Deficits in memory and fluency explained an additional 11.2% of the variance in caregiver-reported apathy, highlighting their crucial role in goal-directed behaviour. Specifically, executive function deficits (e.g., indexed by fluency) and memory impairments may contribute to behavioural inertia or recall of it.These findings highlight the need to integrate patient and caregiver perspectives in apathy assessments, especially for conditions with prominent cognitive impairment. To improve diagnostic accuracy and deepen our understanding of apathy across neurological disorders, we emphasise the need of standardised apathy assessment tools tailored to individuals with cognitive deficits. Understanding the cognitive mechanisms underpinning discordant apathy reporting in dementia might help to inform targeted clinical interventions and reduce caregiver burden.
Single-cell multiome analysis supports α-to-β transdifferentiation in human pancreas
Authors: Lee Michelle Y. Y. , Guessoum Omar , El-Mekkoussi Hilana , Conery Mitchell , Manduchi Elisabetta , Schug Jonathan , Descamps Hélène , Lahori Deeksha , Da Tong , Liu Chengyang , Naji Ali , Voight Benjamin F. , Li Mingyao , Kaestner Klaus H. 
Published: February 2025

AbstractSpontaneous transdifferentiation of pancreatic glucagon-producing alpha to insulin-secreting beta-cells has been observed in mouse but not in human islets1. Here, we analyzed the largest single-cell dataset of human islets to date, composed of 650,000 cells across 121 deceased organ donors, in search of transitional cell states. By integrating single-cell RNA-seq, single-nucleus ATAC-seq and single-nucleus multiome (joint RNA and ATAC profiling) datasets generated by the Human Pancreas Analysis Program (HPAP)2,3we identified two previously undescribed cell populations (c11 and c13 cells), which together represent transitional states between alpha- and beta-cells. Some c11 cells are insulin-positive while others are glucagon positive, but none are double-positive. C11 cells repress alpha-cell identity genes and activate beta-cell specific genes. Moreover, the transcriptomic and epigenetic profiles of c11 and c13 cells indicate a transitioning phenotype driven by lineage-specific transcription factors. Genetic lineage tracing in primary human islet cells confirmed alpha-to-beta cell transdifferentiation. C11 and c13 cells exist in all islet samples regardless of disease statuses, with type 2 diabetic samples having significantly more transitioning cells than matched non-diabetic controls. The discovery of these transitional cell types suggests a possibility for future therapy – transdifferentiating alpha-cells to beta-cell through activation of the c11 gene program.
A Drd1-cre mouse line with nucleus accumbens gene dysregulation exhibits blunted fentanyl seeking
Authors: Montemarano Annalisa , Fox Logan D. , Alkhaleel Farrah A. , Ostman Alexandria E. , Sohail Hajra , Pandey Samiksha , Fox Megan E. 
Published: February 2025

AbstractThe synthetic opioid fentanyl remains abundant in the illicit drug supply, contributing to tens of thousands of overdose deaths every year. Despite this, the neurobiological effects of fentanyl use remain largely understudied. The nucleus accumbens (NAc) is a central locus promoting persistent drug use and relapse, largely dependent on activity of dopamine D1 receptors. NAc D1 receptor-expressing medium spiny neurons (D1-MSNs) undergo molecular and physiological adaptations that contribute to negative affect during fentanyl abstinence, but whether these neuroadaptations also promote fentanyl relapse is unclear. Here, we obtained Drd1-cre120Mxumice to investigate D1-dependent mechanisms of fentanyl relapse. We serendipitously discovered this mouse line is resistant to fentanyl seeking, despite similar intravenous fentanyl self-administration, and greater fentanyl-induced locomotion, compared to wildtype counterparts. In drug naïve mice, we found Drd1-cre120Mxumice have elevated D1 receptor expression in NAc, alongside increased expression of MSN marker genesChrm4andPenk. We show Drd1-cre120Mxumice have increased sensitivity to the D1 receptor agonist SKF-38393, and exhibit divergent expression of MSN markers, opioid receptors, glutamate receptor subunits, and TrkB after fentanyl self-administration that may underly blunted fentanyl seeking. Finally, we show fentanyl-related behavior is unaltered by chemogenetic manipulation of D1-MSNs in Drd1-cre120Mxumice. Conversely, chemogenetic stimulation of putative D1-MSNs in wildtype mice recapitulated the blunted fentanyl seeking of Drd1-cre120Mxumice, supporting a role for aberrant D1-MSN signaling in this behavior. Together, our data uncover alterations in NAc gene expression and function with implications for susceptibility and resistance to developing fentanyl use disorder.
In Vivo Production of a Protein via the Delivery of Plasmid DNA by Computationally Designed Polymer Nanoparticles (PNP)
Authors: Fisher John D. , Petersen Shannon R. , Heynes Olivia , Patil Suteja , Tamayo-Mendoza Teresa , Oviedo Felipe , Guzman Gustavo , Reet Jared Van , Ting Jeffrey M. , Kevlahan Sean H. , Neenan Thomas X. , Murthy Shashi K. 
Published: February 2025

AbstractWhile monoclonal antibodies (mAbs) are a prominent class of pharmaceutical products there remain significant issues of cost, complexity, and especially delivery: concepts that overcome the need to infuse antibodies frequently are a desirable objective. An attractive approach is to deliver non-integrating DNA directly to muscle tissue, allowing the patient to act as their own so-called “protein factory.” Demonstrations of this concept have been made using lipid nanoparticles (LNPs) and viral vectors, but these delivery methods face significant challenges, including poor extrahepatic delivery, cargo compatibility, safety, redosability, and cost. Polymer nanoparticles (PNPs) offer a solution to these problems, but face their own challenges, such as the vast number of possible polymer structures, and polyplex formulation conditions. However, advances in machine learning, materials informatics, and high-throughput chemical synthesis techniques provide a foundation for addressing these challenges by efficiently exploring the polymer design space. Our SAYERTMplatform utilizes a large computational dataset of plasmid DNA (pDNA) - polymer interactions to facilitate targeting agent discovery and refinement via deep learning, and to drive discovery of novel PNPs for a wide variety of target tissues. In this work, we demonstrate our ability to design PNPs that can deliver pDNA encoding for PGT121, a broadly neutralizing anti-HIV antibody that targets a V3 glycan-dependent epitope site on the HIV-1 envelope glycoprotein. SAYER-designed polymers formed small and stable PNPs with PGT121 plasmids. Intravenous delivery demonstrated strong serum PGT121 protein levels at 1-day post-transfection and higher levels of protein expression when compared to other state-of-the-art DNA-delivery vehicles. More importantly, intramuscular delivery of Nanite PNPs enabled greater than 1.0 µg/mL peak protein expression levels, with meaningful, durable expression levels at > 56 days post-injection. Further, we showed that we can increase antibody levels and durability by redosing. A general trend of lower dose and lower N/P ratio providing higher antibody levels is seen when PNPs were delivered intramuscularly. These parameters, separate from polymer structure, provide different mechanisms to optimize PNP in vivo delivery performance using machine learning techniques. Extension of the concept to the continuous production of other antibodies, proteins or enzymes is possible, suggesting the broad applicability of pDNA depoting via PNPs as a therapeutic modality. Finally, we emphasize that this strategy of delivering a DNA-encoded secreted proteins via a safe and effective PNP in vivo could be applicable to a wide range of other disease modalities.