bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationship Between Perceived Discrimination and Blood Pressure in Black Adults: A Narrative Review
Authors: Cayo Sandy , Colbert Alison
Published: February 2025

Background:

Cardiovascular disease is the leading cause of death in the United States, with disproportionately higher morbidity and mortality rates among Black people. Experiences of discrimination and racism constitute a public health crisis. Given the significant race- and ethnicity-related disparities in cardiovascular health, it's essential to understand the mechanisms by which these disparities occur.

Purpose:

The purpose of this review was to identify and synthesize the current literature on the relationship between perceived discrimination and its impact on blood pressure among Black adults.

Methods:

A literature search was conducted to locate relevant research. To be included, articles had to report on quantitative studies that were conducted in the United States among Black adults, used discrimination as an independent variable, and used blood pressure or hypertension as an outcome variable. These articles also had to have been peer-reviewed and published in English between 2010 and 2021. Discrimination was categorized as everyday, lifetime, or both.

Results:

Eleven studies met all criteria and were included for analysis. Eight of these studies reported an association between increased racial discrimination and higher blood pressure; moreover, of the eight studies that reported this finding, seven specified lifetime discrimination.

Conclusions:

This narrative review found significant evidence supporting a positive association between perceived lifetime discrimination and blood pressure in Black adults. But the relationship isn't clearly understood, and future research should explore the underlying mechanisms and potential confounders. Priorities include more rigorous assessment of Black individuals' experiences with both lifetime and everyday discrimination and how these interact with confounders (such as stress), so that blood pressure control can be better achieved in this population. Specific areas for investigation include considering how we measure discrimination, the impact of provider bias and discrimination, and the impact of discrimination on medication adherence. This work is essential to developing the urgently needed, evidence-based interventions that will help to prevent racial and ethnic discrimination and mitigate its effects.
Chronotype and Nursing Shift Work
Authors: Kalra Yogita
Published: February 2025

The relief of finding an explanation for night shift exhaustion
Neglect, Recklessness, and Deliberate Indifference in the Face of a Serious Neurosurgical Pathology: Lessons From the Tragic Fate of Prisoner Elliot Earl Williams
Authors: Spence Lawson E. , Botterbush Kathleen S. , Zhang Justin K. , Berger Todd A. , Mercier Philippe A. , Mattei Tobias A.
Published: February 2025

The US prison system, which houses nearly 2 million people, depends on its healthcare agents to provide the first line of diagnosis and treatment for any medical needs that arise during incarceration. Given the high rates of illness and injuries in this population, there is a pressing need for high-quality medical care. However, surgeons often observe that the system frequently fails to provide adequate healthcare services to incarcerated individuals. This study examines an instance of neglect, recklessness, and deliberate indifference in the facet of a serious acute traumatic spinal pathology, which made it to the lay press headlines several years ago. This case involves a prisoner who suffered a cervical spine trauma and, because of delayed diagnosis and treatment, ultimately progressed to quadriplegia and death. Through an analysis of the case’s background, legal context, and outcomes, alongside a review of the formal legal complaint filed with the US District Court for the Northern District of Oklahoma, this article provides a detailed root-cause analysis of the systemic failures which led to this unfortunate outcome. Ultimately, the tragic case of US Veteran Elliott Earl Williams serves as a unique learning opportunity for surgeons, physicians, healthcare workers, correctional staff, and facility administrators so that the healthcare system for inmates can be improved to prevent future similar cases.
Lumbar Stiffness After Pan-Lumbar Arthrodesis Adversely Affects Patient-Reported Outcomes But does not Compromise Patient Satisfaction in Adult Spinal Deformity
Authors: Park Se-Jun , Park Jin-Sung , Kang Dong-Ho , Kang Minwook , Jung Kyunghun , Lim Yun-Mi , Kim Hyun-Jun , Lee Chong-Suh
Published: February 2025

Study design.

Retrospective study

Objectives.

To investigate the effect of lumbar stiffness on patient-reported outcomes (PROs) and satisfaction in patients undergoing adult spinal deformity (ASD) surgery.

Summary of background data.

Lumbar stiffness following pan-lumbar arthrodesis may impair the activities of daily living. However, the effect lumbar stiffness on the PROs and patient satisfaction in Asian populations remains unclear.

Methods.

Patients who underwent ≥ 5-level fusion including the sacrum were selected for the study. Radiographic and clinical outcomes were evaluated at postoperative 2 years. Lumbar stiffness was evaluated using the modified lumbar stiffness disability index (M-LSDI), which comprises 10 questionnaires with higher scores indicating greater disability. The PRO measures included the visual analog scale (VAS), Oswestry Disability Index (ODI), Scoliosis Research Socitey-22 (SRS-22), Short Form-36 (SF-36) physical component score (PCS), and SF-36 mental component score (MCS). Patients were divided into two groups based on their 2-year SRS-22 satisfaction scores: high satisfaction (≥ 4.0) and low satisfaction (< 4.0).

Results.

A total of 194 patients were included in the study (female, 87.6%; mean age, 69.1 years; and mean fusion length, 8.0). All PROs significantly improved after surgery with regard to VAS, ODI, SRS-22, and SF-36. The M-LSDI score was worsened significantly from 22.3 preoperatively to 26.6 postoperatively. Correlation analysis showed that the 2-year M-LSDI scores were negatively associated PRO measures, including VAS, ODI, SRS-22, SF-36 PCS, and SF-36 MCS. Multivariate regression analysis revealed that the 2-year M-LSDI score did not affect patient satisfaction status; the 2-year SRS-22 score was an independent factor for high satisfaction.

Conclusions.

After surgery, significant improvements were observed in all RROs. Although the postoperative increase in M-LSDI scores were significant, the changes were small. The degree of lumbar stiffness negatively influenced all PRO measures but did not affect patient satisfaction at 2 years postoperatively.
Incidence and Predictors of Growth Modulation and Overcorrection after Anterior Vertebral Body Tethering
Authors: Pahys Joshua M. , Hwang Steven W. , McGarry Maureen , Quinonez Alejandro , Grewal Harsh , Samdani Amer F.
Published: February 2025

Study Design.

Retrospective review of a prospectively collected single-center adolescent idiopathic scoliosis (AIS) database

Objective.

To evaluate the incidence and predictors of growth modulation and overcorrection after vertebral body tethering (VBT) in AIS.

Background.

Little data exists regarding which AIS patients will exhibit growth modulation and/or overcorrection after VBT compared to those whose curve correction will remain unchanged (no modulation).

Materials and Methods.

A total of 279 patients with AIS with a minimum 2-year follow-up (range 2-10 years) were included. There were 262 thoracic and 65 thoracolumbar VBT surgeries performed. Univariate and multivariate regression analyses were performed to identify the potential clinical/radiographic predictive factors for growth modulation and overcorrection.

Results.

Patients with growth modulation and those with no modulation after thoracic VBT were significantly more immature (younger, premenarchal, lower Sanders score/Risser grade, open triradiate cartilage [TRC]) and physically smaller (lower height, weight, and body mass index [BMI]; P<0.02). Patients with growth modulation vs. no modulation after thoracolumbar VBT had lower preoperative Sanders score, weight, and BMI (P<0.04). Preoperative and first-erect thoracic and lumbar curve magnitudes did not affect growth modulation vs. no modulation. Patients with thoracic overcorrection were physically smaller (lower height/weight/BMI) and had lower preoperative and first-erect thoracic curves than patients with growth modulation without overcorrection (P<0.04). Patients with thoracolumbar overcorrection had open-TRC and lower first-erect lumbar curves than patients with growth modulation without overcorrection (P<0.04). Open-TRC (odds ratio: 6.8, P<0.001) and lower BMI (P<0.001) were the only significant predictive factors for thoracic growth modulation in multivariate analysis; none were identified for thoracolumbar growth modulation. Sixty-four percent of patients with overcorrection required revision surgery versus 18% of those with no modulation (P<0.001).

Conclusion.

AIS patients with open-TRC and lower BMI had a statistically higher rate of thoracic growth modulation and overcorrection after VBT in multivariate analysis. Preoperative and first-erect curve magnitudes did not affect the incidence of growth modulation.
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.
Efficacy of Colchicine in Stroke Prevention in Patients With Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials
Authors: Jain Hritvik , Ahmed Raheel , Tariq Muhammad Daoud , Fox Sebastian , Ahmed Mushood , Odat Ramez M. , Passey Siddhant , Jain Jyoti , Shah Siddharth , Cheema Ameer Haider , Chahal Anwar
Published: February 2025

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. Low-dose colchicine is a novel and nonstandard management approach for patients with CVDs who are at an increased risk of adverse events. However, few studies have reported the risk of stroke with colchicine, with controversial results. This meta-analysis aimed to compare the efficacy of colchicine and placebo for stroke prevention in patients with CVD. Major electronic databases were screened for randomized controlled trials (RCTs) comparing colchicine and placebo in patients with CVDs from inception to June 2024. Pooled estimates were calculated as risk ratios (RRs) with 95% confidence intervals (CIs) using an inverse-variance random-effects model. Statistical significance was set at P < 0.05. A total of 15 RCTs encompassing 25,116 patients with CVDs were included (12,568: colchicine and 12,548: placebo). The pooled analysis demonstrated a significant reduction in stroke [RR, 0.80 (95% CI, 0.64–0.99); P = 0.04] with colchicine compared with placebo. The risk of all-cause mortality [RR, 1.00 (95% CI, 0.77–1.28)] was comparable between the 2 groups. On subgroup analysis, low-dose colchicine (0.5 mg/day) demonstrated a significantly lower risk of stroke compared with high-dose (>0.5 mg/day) colchicine, which failed to achieve statistical significance. Based on this meta-analysis, colchicine significantly reduced stroke in patients with CVDs compared with placebo. This effect was most significant with low-dose colchicine at 0.5 mg/day. However, no differences were observed in all-cause mortality. Further long-term RCTs are warranted to investigate stroke prevention using colchicine in this population.
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.
The usefulness of serum leucine-rich alpha-2 glycoprotein as a novel biomarker in monitoring inflammatory bowel disease: a systematic review and meta-analysis
Authors: Ojaghi Shirmard Fatemeh , Pourfaraji Seyed Morteza , Saeedian Behrad , Bagheri Tannaz , Ismaiel Abdulrahman , Matsumoto Satohiro , Babajani Nastaran
Published: February 2025

Inflammatory bowel disease (IBD) is a condition of unknown origin. It does not have a definite cure and its response to various treatments can be evaluated based on symptom-based measures, invasive procedures, or biomarker levels, highlighting the need for an accurate biomarker. Since C-reactive protein (CRP) and fecal calprotectin have their shortcomings, the need for a novel biomarker remains critical. Systematic searches of PubMed, Scopus, Web of Science, and Embase were performed In January 2024. PROSPERO number is CRD42024507383. We assessed the accuracy of leucine-rich alpha-2 glycoprotein (LRG) in identifying disease activity among patients with IBD using a bivariate diagnostic random-effects model. Fourteen studies involving 1794 individuals conducted in Japan were selected for our systematic review. The sensitivity and specificity of LRG levels for detecting disease activity were analyzed in patients with IBD and in two subgroups (ulcerative colitis and Crohn’s disease). The synthesized sensitivity and specificity were 75.4% [95% confidence interval (CI), 68.9–80.9%] and 77.3% (95% CI, 69.9–83.2%), respectively, in patients with IBD, 73.1% (95% CI, 62.7–81.5%) and 81.9% (95% CI, 73.9–87.8%), respectively, in patients with CD, and the secondary analysis of the ulcerative colitis subgroup showed a pooled sensitivity and specificity of 72.8 and 59.7%, respectively. Our systematic review and meta-analysis demonstrated that LRG could be useful in detecting IBD activity. It is superior for detecting disease activity, especially in patients with normal CRP levels. The LRG was more accurate in monitoring disease activity in patients with CD than in patients with IBD.
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

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.
Fall prevention
Authors: Anderson Joan , Breda Karen Lucas
Published: February 2025

As frontline workers, nurses are constantly in touch with patients who are at risk for falls. Although interventions are in place, thousands of falls occur each year. Join the authors on this quality improvement journey to address bed alarm knowledge gaps.
Skeletal health
Authors: Travers Jennifer , Bazaar Celina
Published: February 2025

The skeletal system is constantly changing. Comprised of bones, cartilage, and other connective tissues, it provides structural support and stores vital minerals for the body. Nurses play an important role in educating patients about the importance nutrition and exercise play in bone health.
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.
A vector representation for phylogenetic trees
Authors: Chauve Cedric , Colijn Caroline , Zhang Louxin
Published: February 2025

Good representations for phylogenetic trees and networks are important for enhancing storage efficiency and scalability for the inference and analysis of evolutionary trees for genes, genomes and species. We propose a new representation for rooted phylogenetic trees that encodes a tree on

n

ordered taxa as a vector of length

2
n

in which each taxon appears exactly twice. Using this new tree representation, we introduce a novel tree rearrangement operator, termed an
HOP
, that results in a tree space of linear diameter and quadratic neighbourhood size. We also introduce a novel metric, the
HOP distance
, which is the minimum number of HOPs to transform a tree into another tree. The HOP distance can be computed in near-linear time—a rare instance of tree rearrangement distance that is tractable. Our experiments show that the HOP distance is better correlated to the Subtree-Prune-and-Regraft distance than the widely used Robinson–Foulds distance. We also describe how the proposed tree representation can be further generalized to tree-child networks, showcasing its versatility and potential applications in broader evolutionary analyses.

This article is part of the theme issue ‘"A mathematical theory of evolution": phylogenetic models dating back 100 years’.
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

The 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

In 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

Apathy 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

Spontaneous 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

The 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

While 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.
Influence of sustained cognitive loading on finger circulatory and thermoperceptual responsiveness to localized cooling
Authors: Moes Maaike Iris , Elia Antonis , Eiken Ola , Keramidas Michail E.
Published: February 2025

Our aim was to examine whether finger vasomotor and thermoperceptual responses to local cooling would be modulated by sustained cognitive loading. To this end, finger temperature, circulatory (i.e., cutaneous vascular conductance, CVC) and perceptual responses were monitored, in twelve healthy men, during and after a 30-min hand immersion in 8°C water, performed either immediately after a 60-min continual execution of a cognitive task battery (cognitive→cold trial), or during the simultaneous performance of the cognitive task (cognitive+cold trial). Subjects responses were compared with those obtained in a control cold-provocation trial, wherein they watched an emotionally-neutral documentary. The cognitive task temporary enhanced the perceived levels of mental effort and fatigue in both intervention trials. In the cognitive→cold trial, the cold-induced reduction in finger CVC and increase in mean arterial pressure were blunted (P < 0.01), and the thermal discomfort was alleviated (P = 0.05). In the cognitive+cold trial, no intertrial differences were noted during the cold-water immersion phase (P ≥ 0.28), but the finger CVC was enhanced during the last part of the rewarming phase (P = 0.05). Present findings, therefore, demonstrate that (i) in moderately mentally-fatigued individuals, finger cold-induced vasoconstriction is transiently attenuated, and thermal discomfort is mitigated, and (ii) superimposition of cognitive loading on cold stress does not alter finger vasoreactivity or thermosensitivity during cooling, but facilitates finger reperfusion following cooling.
Betaproteobacterial clade IInosZactivated under high N2O concentrations in paddy soil microcosms
Authors: Mise Kazumori , Masuda Yoko , Senoo Keishi , Itoh Hideomi
Published: February 2025

Aims: Microbial communities in paddy soils act as potential sinks of nitrous oxide (N2O), a notorious greenhouse gas, but their potential to reduce external N2O is unclear. The direct observation of N2O reduction in submerged field soils is technically difficult. Here, we aimed to identify soil microbial clades that underpin the strong N2O mitigation capacity. Methods and Results: We constructed paddy soil microcosms with external N2O amendment that enabled the simultaneous evaluation of N2O reductase gene (nosZ) transcripts and N2O consumption. Although the amount of N2O amended was large, it was mostly consumed after 6–8 days of microcosm incubation. Metatranscriptomic sequencing revealed that betaproteobacterialnosZ, especially those classified as clade IInosZbelonging to the ordersRhodocyclalesorNitrosomonadales, occupied >50% of thenosZtranscripts in three of the five paddy soils used. On the other hand, publicly available shotgun metagenomic sequences of 46 paddy soils were not dominated by betaproteobacterial clade IInosZsequences, although they were ubiquitous. The same applied to the 16S rRNA sequences ofRhodocyclalesorNitrosomonadales. Conclusions: The results indicated that betaproteobacterial N2O reducers potentially serve as powerful N2O sinks.Betaproteobacteriaholding clade IInosZcan be targets of biostimulation, although further studies are required to understand their ecophysiology.
Evolution of BA.2.86 to JN.1 reveals functional changes in non-structural viral proteins are required for fitness of SARS-CoV-2
Authors: Tsujino Shuhei , Tsuda Masumi , Nao Naganori , Okumura Kaho , Wang Lei , Oda Yoshitaka , Mimura Yume , Li Jingshu , Hashimoto Rina , Matsumura Yasufumi , Suzuki Rigel , Suzuki Saori , Yoshimatsu Kumiko , Nagao Miki ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ito Jumpei , Takayama Kazuo , Sato Kei , Matsuno Keita , Tamura Tomokazu , Tanaka Shinya , Fukuhara Takasuke
Published: February 2025

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19), is still circulating among humans, leading to the continuous evolution. SARS-CoV-2 Omicron JN.1 evolved from a distinct SARS-CoV-2 lineage, BA.2.86, spread rapidly worldwide. It is unclear why BA.2.86 did not become dominant and was quickly replaced by JN.1, which possesses one amino acid substitution in the spike protein (S:L455S) and two in the non-spike proteins NSP6 and ORF7b (NSP6:R252K and ORF7b:F19L) compared to BA.2.86. Here, we utilized recombinant viruses to elucidate the impact of these mutations on the virological characteristics of JN.1. We found that the mutation in the spike attenuated viral replication, but the non-spike mutations enhanced replication, suggesting the mutations in the non-spike proteins compensate for the one in the spike to improve viral fitness, as the mutations in the spike contribute to further immune evasion. Our findings suggest that functional changes in both the spike and non-spike proteins are necessary in the evolution of SARS-CoV-2 to enable evasion of adaptive immunity within the human population while sustaining replication.

IMPORTANCE

Because the spike protein is strongly associated with certain virological properties of SARS-CoV-2, such as immune evasion and infectivity, most previous studies on SARS-CoV-2 variants have focused on spike protein mutations. However, the non-spike proteins also contribute to infectivity, as observed throughout the evolution of Omicron subvariants. In this study, we demonstrate a “trade-off” strategy in SARS-CoV-2 Omicron JN.1 in which the reduced infectivity caused by spike mutation is compensated by non-spike mutations. Our results provide insight into the evolutionary scenario of the emerging virus in the human population.
Development of a novel hybrid alphavirus-Nipah virus pseudovirion for rapid quantification of neutralization antibodies
Authors: Hetrick Brian , Nakka Sravya Sowdamini , Yu Dongyang , Swineford Sarah , Storm Nadia , Griffiths Anthony , Wu Yuntao
Published: February 2025

Nipah virus (NiV) is an emergent paramyxovirus that causes serious disease in humans and animals. Accurate quantification of neutralizing antibodies (nAB) against NiV is essential for vaccine development. The current standard, the plaque reduction neutralization test (PRNT), requires authentic infectious NiV and BSL-4 containment, taking 4-7 days to complete. In this study, we developed a hybrid alphavirus-Nipah virus pseudovirion (Ha-NiV) composed of a non-replicating Nipah virus virus-like particle (VLP) that encapsulates an RNA genome from a fast-expressing SFV (Semliki Forest Virus) alphaviral vector. Ha-NiV can infect NiV target cells but is replication incompetent, enabling rapid quantification of nAB (6-18 hours) in BSL-2 conditions. We validated Ha-NiV using sera from Nipah virus-infected African green monkeys and established a good correlation (R2= 0.86) with PRNT, demonstrating comparable specificity and sensitivity. These results demonstrate that the Ha-NiV assay can serve as a novel platform for convenient and rapid quantification of nAB in BSL-2 settings.
Prevalence and consequences ofAPCmosaicism in patients with colorectal adenomas
Authors: Terlouw Diantha , Suerink Manon , Buitelaar Yentl , van Leerdam Monique E , Hes Frederik J , van Egmond Demi , Ruano Dina , Wagner Anja , Groenendijk Floris H , Meijssen Isabelle C , Overwater Eline , Bajwa-ten Broeke Sanne W , Mensenkamp Arjen R , Nagtegaal Iris D , Tops Carli M , Langers Alexandra M J , van Wezel Tom , Morreau Hans , Nielsen Maartje
Published: February 2025

Background and aims

A substantial proportion of patients with adenomatous polyposis have no germline pathogenic variant inAPC. The aim of this study was to determine the prevalence ofAPCmosaicism in these patients with unexplained polyposis and to draft guidelines forAPCmosaicism testing and surveillance.

Methods

APCmosaicism was analyzed by targeted Next-Generation sequencing in 542 patients with a broad spectrum of polyposis phenotypes.

Results

The rate ofAPCmosaicism was 9.4%. This rate was 14.3% (46/322) in patients who meet the scope of national hereditary polyposis testing guidelines (≥10 adenomas before the age of 60 or with ≥20 adenomas before the age of 70). In patients who do not meet the scope of national guidelines, the detection rate was 2.3% (5/219). In patients with ≥20 adenomas before the age of 60, or ≥30 adenomas before the age of 70 the detection rate was ≥10%. Of 34 mosaic patients who underwent an esophagogastroduodenoscopy, 26% were diagnosed with gastroduodenal polyps. In one patient, the mosaic variant was detected in semen, but none of the children tested in this cohort inherited the mosaic variant.

Conclusion

We recommendAPCmosaicism testing at least in patients negative for germline pathogenic variants with (1) ≥20 adenomas before the age of 60 or (2) ≥30 adenomas before the age of 70. Regular colonoscopy and at least one gastroduodenoscopy should be offered toAPCmosaics, with frequency of follow-up based on findings. Offering germline testing for offspring should be considered.