bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying Variables Associated with Long-Term Quality of Life After Severe Lower Limb Trauma Using the LIMB-Q
Authors: Schuckink Kool Floor H.N. , Mureau Marc A.M. , van Bijnen Sybe , Stirler Vincent M.A. , Mundy Lily R. , de Jong Tim
Published: January 2025

Background:

Severe lower limb trauma is associated with substantial impact on health-related quality of life. In some cases, severity of the trauma necessitates a decision between reconstruction and amputation. Therefore, the aim of this study was to identify variables associated with long-term quality of life using the LIMB-Q, and to compare outcomes between patients undergoing amputation versus those receiving reconstructive surgery.

Methods:

This retrospective, cross-sectional study, conducted at two Dutch healthcare institutions, involved patients with severe lower limb trauma who completed the LIMB-Q between February 2020 and October 2022.

Results:

This study consisted of 87 patients divided in two groups: an amputation group (n=32) and a reconstruction group (n=55). The most common injury types were 3B/C crush injuries according to the Gustilo-Anderson classification. Clinical variables significantly associated with different LIMB-Q subdomain scores included age at trauma on Function (p = 0.045), fracture related infection (FRI) on Function (p = 0.009) and chronic pain on Function, Symptoms and Work (p = 0.009, p = 0.009, and p = 0.027, respectively). No significant long-term differences were found comparing the amputation to the reconstruction group.

Conclusions:

Age at trauma, FRI, and chronic pain were variables, significantly associated with LIMB-Q subdomain scores in a group of 87 severe lower limb trauma patients. Long-term amputation and reconstruction groups report similar LIMB-Q scores, underscoring the importance of personalized treatment choices.
The Mark Cuban Cost Plus Drug Company Effect on Urogynecologic Drugs
Authors: Xu Raymond , Escott Megan , El Haraki Amr Sherif
Published: January 2025

Importance

The Mark Cuban Cost Plus Drug Company (ie, Cost Plus Drugs) is a service that makes generic drugs affordable. Cortese et al recently published the top 9 most commonly used oral medications in treatment of urologic conditions and showed that Cost Plus Drugs would have provided an estimated $1.29 billion reduction in 2020 costs if they replaced the Medicare prices.

Objectives

We sought to investigate the savings for all drugs commonly used in urogynecology.

Study Design

We reviewed the generic drugs provided by Cost Plus Drugs and selected those commonly used for the treatment of urogynecologic conditions (N = 16). For each of the 16 drugs we identified the Cost Plus Drugs prices for the 30- and 90-count quantities. We then also calculated the 2021 Medicare spending for the 16 drugs. The potential savings were calculated as the difference between Cost Plus Drugs and Medicare 30- and 90-count prices, multiplied by the volume-adjusted number of units dispensed to Medicare beneficiaries in 2021.

Results

The total estimated savings when using Cost Plus Drugs compared to Medicare was $462,375,491.53 and $618,833,850.34 for 30- and 90-count pricing, respectively. The price of a 42.5-gram tube of vaginal estrogen cream was $22.48 on Cost Plus Drugs, compared to $293.66 through Medicare Part D.

Conclusions

Cost Plus Drugs is a novel program that has tremendous implications on costs savings in the context of prescription drugs and is particularly true for drugs used in the treatment of urogynecologic conditions, specifically vaginal estrogen.
Early achievement of hemostasis defined by transfusion velocity: A possible mechanism for whole blood survival benefit
Authors: Chipman Amanda M. , Luther James F. , Guyette Francis X. , Cotton Bryan A. , Cannon Jeremy W. , Schreiber Martin A. , Moore Ernest E. , Namias Nicholas , Minei Joseph P. , Yazer Mark H. , Vincent Laura , Cotton Abigail L. , Agarwal Vikas , Brown Joshua B. , Leeper Christine M. , Neal Matthew D. , Forsythe Raquel M. , Wisniewski Stephen R. , Sperry Jason L. ,   the SWAT Study Group
Published: January 2025

INTRODUCTION

Whole blood resuscitation is associated with survival benefits in observational cohort studies. The mechanisms responsible for outcome benefits have not been adequately determined. We sought to characterize the achievement of hemostasis across patients receiving early whole blood versus component resuscitation. We hypothesized that achieving hemostasis would be associated with outcome benefits and patients receiving whole blood would be more likely to achieve hemostasis.

METHODS

We performed a post hoc retrospective secondary analysis of data from a recent prospective observational cohort study comparing early whole blood and component resuscitation in patients at risk of hemorrhagic shock. Achievement of hemostasis was defined by receiving a single unit of blood or less, including whole blood or red cells, in any 60-minute period, over the first 4 hours from the time of arrival. Time-to-event analysis with log-rank comparison and regression modeling were used to determine the independent benefits of achieving hemostasis and whether achieving hemostasis was associated with whole blood resuscitation.

RESULTS

For the current analysis, 1,047 patients met the inclusion criteria for the study. When we compared patients who achieved hemostasis versus those who did not, achievement of hemostasis had significantly more hemostatic coagulation parameters, had lower transfusion requirements, and was independently associated with 4-hour, 24-hour and 28-day survival. Whole blood patients were significantly more likely to achieve hemostasis (88.9% vs. 81.1%, p < 0.001). Whole blood patients achieved hemostasis earlier (log-rank χ2 = 8.2, p < 0.01) and were independently associated with over twofold greater odds of achieving hemostasis (odds ratio, 2.4; 95% confidence interval, 1.6–3.7; p < 0.001).

CONCLUSION

Achievement of hemostasis is associated with significant outcome benefits. Early whole blood resuscitation is associated with a greater independent odds of achieving hemostasis and at an earlier time point. Reaching a nadir transfusion rate early following injury represents a possible mechanism of whole blood resuscitation and its attributable outcome benefits.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level III.
Electroacupuncture alleviates motor dysfunction after intracerebral hemorrhage via the PPARγ-EAAT2 pathway
Authors: Chen Hequn , Ren Huiling , Lu Xudong , Shi Guosheng , Zhao Qinglin , Zhao Dawei , Bu Wei
Published: January 2025

Nowadays, intracerebral hemorrhage (ICH) is the main cause of death and disability, and motor impairment is a common sequel to ICH. Electroacupuncture (EA) has been widely used for functional recovery after ICH. However, its role and associated regulatory mechanisms in rehabilitation after ICH remain poorly understood. This study investigated whether EA can have a neuroprotective effect in motor function after ICH by inhibiting glutamate-mediated excitotoxicity on the primary motor cortex. The model was established using autologous tail artery blood, followed by administration of EA at Quchi (LI11) and Zusanli (ST36) for 3 or 7 consecutive days. The rats’ behavior was examined by modified neurological severity score (mNSS) and open-field test (OFT). Nissl staining, immunofluorescence detection, and transmission electron microscopy were used to observe the degree of neuron damage. The level of the cortical glutamate was detected by the ELISA. Peroxisome proliferator-activated receptor gamma (PPARγ) expression was detected by immunohistochemistry and western blot. The protein and mRNA expression of excitatory amino acid transporter 2 (EAAT2) was detected by western blot and quantitative real-time PCR. Our data demonstrated that EA significantly reduces glutamate levels, alleviates neuronal damage, and promotes motor function recovery in rats after ICH. In addition, EA upregulates PPARγ and EAAT2 expression. However, the protective effect of EA on motor function and EAAT2 expression are partially abolished by T0070907, an antagonist of PPARγ. EA at LI11 and ST36 improved glutamate excitotoxicity and promoted motor function recovery after ICH by activating the PPARγ-EAAT2 pathway and reducing the glutamate level.
Caught in the Crossfire: A Single Institution’s 10-Year Experience with Pediatric Firearm Injury
Authors: Cochran Elizabeth D , Machchhar Arti , Qiao Jingbo , Chung Dai H
Published: January 2025

Introduction:

Pediatric firearm-related injuries are now the leading cause of death among children in the United States. We sought to characterize the experience of a large free-standing children’s hospital treating children with firearm injuries.

Methods:

We reviewed all 2012-2022 gunshot wound encounters using the institutional trauma database of an urban Level 1 pediatric trauma center in Texas. Patient demographics, incident characteristics, and clinical outcomes were analyzed. Statistical analysis was performed using ANOVA and chi-square tests to evaluate the influence of socioeconomic factors. Injuries from recreational firearms like BB and pellet guns were excluded from this analysis.

Results:

Two hundred eleven pediatric patients were treated for gunshot wounds during the study period. There was an upward trend in the number of injuries per year, ranging from 6 in 2012 to 39 in 2021. The average patient age was 10.2 years. Violent injuries accounted for 51.7%, while accidental injuries led to 44.1%, and self-inflicted injuries made up 4.3%. Based on the Child Opportunity Index. 63.0% of patients lived in neighborhoods in the lowest opportunity quartile, while only 2.8% of patients lived in neighborhoods in the highest opportunity quartile. 22.7% of patients sustained injuries characterized as “major trauma,” as indicated by an Injury Severity Score of >15, and 8.5% of patients died.

Conclusions:

Firearms pose a substantial risk to children in the United States. There has been an increasing trend in pediatric firearm injuries over the last decade. The majority of children treated for firearm injury at our institution sustained injuries in the setting of gun violence. Injury prevention efforts should be aimed at decreasing intentional pediatric firearm injuries.
Simple vs Complex Aortic Arch Repair in Acute Type A Aortic Dissection
Authors: Pendarvis Jordyn , Sharaf Omar M , Bilgili Ahmet , Jiang Zhihua , Jeng Jaden A , Demos Daniel S , Spratt John R , Hess Phillip , Beaver Thomas M , Upchurch Gilbert R , Martin Tomas D , Jeng Eric I
Published: January 2025

Background:

The purpose of this study is to evaluate the clinical outcomes of patients undergoing a simpler (hemiarch) vs complex (zone 2 arch) aortic repair for acute type A aortic dissection (TAAD).

Methods:

Adults (≥18 years) who underwent hemiarch or zone 2 arch repair for acute, hyperacute, or acute on chronic TAAD at a single institution between January 2018 and April 2024 were reviewed. Disabling stroke was defined as modified Rankin scale ≥4. Statistical analysis included univariate comparisons, Kaplan-Meier analysis, and multivariable modeling.

Results:

Two hundred eighty-three acute TAAD patients underwent hemiarch (44.5%, n=126) and/or zone 2 arch (55.5%, n=157) repair. Hemiarch patients were older (63.3±14.1 vs 56.3±12.2 years, P<0.001), but had lower rates of preoperative cerebrovascular disease (11.1%[n=14] vs 21.7%[n=34], P=0.03), chronic kidney disease (16.7%[n=21] vs 33.1%[n=52], P=0.003), and previous sternotomy (13.5%[n=17] vs 35.0%[n=55], P<0.001). Cardiopulmonary bypass and cross clamp times were shorter in hemiarch patients (214±78.5 vs 261±62.3 minutes, P<0.001; 135±54.4 vs 182±60.0 minutes, P<0.001, respectively). Postoperatively, there was no difference in the rate of disabling stroke (4.5%[n=13], P=0.12), tracheostomy (14.8%[n=43], P=0.15), pneumonia (17.2%[n=50], P=0.24), or renal failure requiring permanent dialysis (6.2%[n=18], P=0.47). In multivariable analysis, older age (HR 1.05, 95% CI=1.02-1.08) was a risk factor for longitudinal mortality, while complex aortic arch repair did not confer increased risk (HR 0.68, 95% CI=0.35-1.31).

Conclusions:

Complex aortic arch reconstruction provides a framework for down-stream endovascular procedures for the remaining aorta and can be performed in acute TAAD without increased risk of morbidity or mortality compared with a simpler repair.
Quantification of Pseudomonas aeruginosa biofilms using electrochemical methods
Authors: Riordan Lily , Lasserre Perrine , Corrigan Damion , Duncan Katherine R
Published: January 2025

Currently 2.29% of deaths worldwide are caused by antimicrobial resistance (AMR), compared to 1.16% from malaria, and 1.55% from human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDs). Furthermore, deaths resulting from AMR are projected to increase to more than 10 million per annum by 2050. Biofilms are common in hospital settings, such as medical implants and pose a particular problem as they have shown resistance to antibiotics up to 1000-fold higher than planktonic cells because of dormant states and reduced growth rates. This is compounded by the fact that many antibiotics target mechanisms of active metabolism and are therefore less effective. The work presented here aimed to develop a method for biofilm quantification which could be translated into the clinical setting, as well as used in the screening of antibiofilm agents. This was carried out alongside crystal violet staining, as a published point of reference. Using electrochemical impedance spectroscopy and square wave voltammetry, P. aeruginosa biofilm formation was detected within an hour after seeding P. aeruginosa on the sensor. A 40% decrease in impedance modulus was shown when P. aeruginosa biofilm had formed, compared to the media only control. As such, this work offers a starting point for the development of real-time biofilm sensing technologies, which can be translated into implantable materials.
Paludibacillus litoralis gen. nov., sp. nov.: a novel species of a novel genus in the family Paracoccaceae, isolated from the sediment of a tidal flat located in Zhoushan, China
Authors: He Dong-yan , Gao Jia-wei , Wang Yu-ruo , Cao Ke , Cao Yun-fei , Li Yang , Wang Lu-yao , Wang Xing-cheng , Xu Lin , Sun Cong
Published: January 2025

A Gram-stain-negative, aerobic and rod-shaped bacterium, designated as HZG-20T, was isolated from a tidal flat in Zhoushan, Zhejiang Province, China. The 16S rRNA sequence similarities between strain HZG-20T and Pikeienuella piscinae RR4-56T, Coraliihabitans acroporae NNCM2T, Parvibaculum indicum P31T and Zhengella mangrovi X9-2-2T were 98.9, 91.7, 91.0 and 91.0%, respectively. Colonies of strain HZG-20T were 1.4 mm in diameter, milky white, round, smooth and convex after cultivating on marine agar at 30 °C for 48 h. Cells were catalase and oxidase-negative. Growth occurred at 15–37 ℃ (optimum, 28 ℃), pH 5.0–9.0 (optimum, pH 6.0–8.0) and with 0–8% (w/v) NaCl (optimum, 1–3%). It contained Menaquinone-8 (H2) as the sole respiratory quinone, and C16:0 (11.8–13.6%), C18:1
 ω9c (6.8–13.3%) and C15:0 anteiso (10.9–27.7%) as the major cellular fatty acids. The main polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, one unidentified phospholipid, one unidentified aminolipid, one unidentified phosphoglycolipid, two unidentified glycolipids (GL1–GL2) and three unidentified lipids (L1–L3). The genome of strain HZG-20T was 3 835 886 bp in length, comprised 3746 protein-coding genes, with DNA G+C content of 67.1 mol%. The phylogenetic and phylogenomic trees indicated that strain HZG-20T formed an independent and stable clade with P. piscinae RR4-56T. However, the average nucleotide identity, digit DNA–DNA hybridization and average amino acid identity values between strain HZG-20T and P. piscinae RR4-56T, C. acroporae NNCM2T, P. indicum P31T and Z. mangrovi X9-2-2T were 81.6, 71.1, 68.7 and 69.5%; 23.0, 18.5, 17.9 and 17.5%; and 78.2, 56.8, 56.5 and 61.9%, respectively, together with distinct chemotaxonomic features, indicating strain HZG-20T should not be assigned to known genera. As a result, a novel species of a novel genus within the family Paracoccaceae, designated as Paludibacillus litoralis gen. nov., sp. nov., was proposed. The type strain is HZG-20T (MCCC 1K08468T=KCTC 82692T).
Children’s outdoor play at early learning and child care centres: examining the impact of environmental play features on children's play behaviour
Authors: Ramsden Rachel , Pike Ian , Thorne Sally , Brussoni Mariana
Published: January 2025

Early learning and child care centres are critical settings to support children’s regular, repeated and quality time spent in outdoor play. Gibson’s theory of affordances highlights the importance of the human-environment relationship, emphasizing how children use environmental information to inform their behaviour. This study aims to understand the association between children’s outdoor play behaviour and common environmental play features in early learning and child care outdoor play spaces, through the behaviour patterns of children. Children’s play behaviour was collected via observational behaviour mapping at eight early learning and child care centres in the Greater Vancouver region between September 2021 and November 2022, as part of the PROmoting Early Childhood Outside study. A multivariate logistic regression model examined the association between outdoor play behaviour and environmental play features, via odds ratio and 95% confidence intervals. The results indicate environmental play features, including gardening areas, playhouses, climbing structures and tricycle paths supported increased opportunities for children’s outdoor play. Gardening areas, playhouses, sandboxes, outdoor stages and fixed water features provided opportunities for exploratory play, while climbing structures and trike paths provided opportunities for physical play. Opportunities for diverse forms of play were less realized in dedicated open play areas, with the availability of loose parts and moveable equipment primarily influencing these spaces. The results of this study have important implications for future early learning and child care outdoor space design. Further research should consider children’s dynamic movement and transition between outdoor affordances, and the influence of loose parts on the use of environmental play features.
Realfreq: Real-time base modification analysis for nanopore sequencing
Authors: Samarasinghe Suneth , Deveson Ira , Gamaarachchi Hasindu
Published: January 2025

Motivation

Nanopore sequencers allow sequencing data to be accessed in real-time. This allows live analysis to be performed, while the sequencing is running, reducing the turnaround time of the results. We introducerealfreq, a framework for obtaining real-time base modification frequencies while a nanopore sequencer is in operation.

Results

Realfreqcalculates and allows access to the real-time base modification frequency results while the sequencer is running. We demonstrate that the data analysis rate withrealfreqon a laptop computer can keep up with the output data rate of a nanopore MinION sequencer, while a desktop computer can keep up with a single PromethION 2 solo flowcell.

Availability and Implementation

Realfreq is a free and open-source application implemented in C programming language and shell scripts. The source code and the documentation forrealfreqcan be found athttps://github.com/imsuneth/realfreq.
ARTEMIS integrates autoencoders and schrodinger bridges to predict continuous dynamics of gene expression, cell population and perturbation from time-series single-cell data
Authors: Alatkar Sayali Anil , Wang Daifeng
Published: January 2025

Cellular processes like development, differentiation, and disease progression are highly complex and dynamic (e.g., gene expression). These processes often undergo cell population changes driven by cell birth, proliferation, and death. Single-cell sequencing enables gene expression measurement at the cellular resolution, allowing us to decipher cellular and molecular dynamics underlying these processes. However, the high costs and destructive nature of sequencing restrict observations to snapshots of unaligned cells at discrete time points, limiting our understanding of these processes and complicating the reconstruction of cellular trajectories. To address this challenge, we propose ARTEMIS, a generative model integrating a variational autoencoder (VAE) with unbalanced Diffusion Schrodinger Bridge (uDSB) to model cellular processes by reconstructing cellular trajectories, reveal gene expression dynamics, and recover cell population changes. The VAE maps input time-series single-cell data to a continuous latent space, where trajectories are reconstructed by solving the Schrodinger bridge problem using forward-backward stochastic differential equations (SDEs). A drift function in the SDEs captures deterministic gene expression trends. An additional neural network estimates time-varying kill rates for single cells along trajectories, enabling recovery of cell population changes. Using three scRNA-seq datasets, pancreatic beta-cell differentiation, zebrafish embryogenesis, and epithelial mesenchymal transition (EMT) in cancer cells, we demonstrate that ARTEMIS: (i) outperforms state-of-art methods to predict held-out timepoints, (ii) recovers relative cell population changes over time, and (iii) identifies "drift" genes driving deterministic expression trends in cell trajectories. Furthermore, in silico perturbations show that these genes influence processes like EMT.
Care Phenotypes in Critical Care
Authors: Weishaupt LL , Wang T , Schamroth J , Morandini P , Matos J , Hampton LL , Gallifant J , Fiske A , Dundas N , David K , Celi LA , Carrel A , Byers J , Angelotti G
Published: January 2025

The Social Determinants of Health (SDoH) have long been recognised as significant drivers of health inequalities. Within healthcare settings, large EHR datasets have increasingly enabled the use of machine learning (ML) to explore how patient background and demographic factors mediate and predict clinical outcomes. The intensive care unit (ICU) in particular provides a rich source of data for such research. However, major limitations with current approaches persist, including (i) overreliance on individual demographic labels or measures of difference, (ii) the impracticality of highly intersectional patient groups and (iii) that the underlying accuracy and validity of these demographic constructs is low. The main objective of this study was to take a novel approach, to first understand who within the ICU setting receives sub-standard care and use this to create new, objective labels based on quality of care and outcomes (Care Phenotypes) when different patients interface with the health system. Using the MIMIC-IV database, we focused on highly protocolised, essential care procedures (turning, mouth care) in mechanically ventilated ICU patients. We performed a series of regression analyses to understand in which patients treatment deviated from these protocols. In a cohort of 8,919 ICU patients undergoing IMV, consistent patterns in sup-optimal protocol adherence for certain groups, notably heavier patients. Compared to equivalently sick peers, for every extra weight decile, a patient can expect a reduction of one percentile in frequency of turning care (0.0760 turning interval percentile per weight percentile, p<0.05). Furthermore, patients who receive fewer turnings should also expect to receive fewer mouth care procedures, in a quantile ratio of 1 to 5 (0.2055 mouth care interval quantile per turning interval quantile, p<0.05). The findings in this initial analysis provide support to the concept of first looking at the actual care delivered to patients to illuminate the relationship between patient demographics and outcomes of interest. The Care Phenotypes approach has the potential to improve fairness evaluations for machine learning in healthcare, support causal inference research and play a larger role in research into healthcare disparities.
Somatic and Stem Cell Bank to Study the Contribution of African Ancestry to Dementia: African iPSC Initiative
Authors: Maina Mahmoud B , Isah Murtala B , Marsh Jacob , Muhammad Zaid , Babazau Larema , Idris Abdulrahman Alkhamis , Aladyeva Ekaterina , Miller Nadia , Starr Emma , Miller Katherine , Lee Scott , Minaya Miguel , Wray Selina , Harari Oscar , Goni Baba W , Serpell Louise C , Karch Celeste
Published: January 2025

Africa, home to 1.4 billion people and the highest genetic diversity globally, harbors unique genetic variants crucial for understanding complex diseases like neurodegenerative disorders. However, African populations remain underrepresented in induced pluripotent stem cell (iPSC) collections, limiting the exploration of population-specific disease mechanisms and therapeutic discoveries. To address this gap, we established an open-access African Somatic and Stem Cell Bank. In this initial phase, we generated 10 rigorously characterized iPSC lines from fibroblasts representing five Nigerian ethnic groups and both sexes. These lines underwent extensive profiling for pluripotency, genetic stability, differentiation potential, and Alzheimer's disease and Parkinson's disease risk variants. CRISPR/Cas9 technology was used to introduce frontotemporal dementia-associated MAPT mutations (P301L and R406W). This collection offers a renewable, genetically diverse resource to investigate disease pathogenicity in African populations, facilitating breakthroughs in neurodegenerative research, drug discovery, and regenerative medicine.
Motor evoked potentials as a side effect biomarker for deep brain stimulation programming
Authors: Testini Paola , Wang Austin , Cole Eric , Miocinovic Svjetlana
Published: January 2025

Objectives

To determine if motor evoked potentials (mEP) – stimulation-induced muscle activation measured using electromyography – can serve as a biomarker of corticobulbar (CBT) and corticospinal (CST) tract activation for deep brain stimulation (DBS) programming.

Methods

In 12 patients with Parkinson’s disease and subthalamic or pallidal DBS, contact mapping determined clinical motor side effect thresholds. For equivalent stimulation parameters, EMG was recorded from cranial and arm muscles to determine the presence, peak amplitudes and latencies of mEP. Clinical and mEP thresholds were compared and accuracy metrics calculated to assess similarity between mEP and reported side effects.

Results

The mEP amplitudes increased with stimulation intensity. Latencies were shorter for cranial muscles, which were more likely to generate an mEP. Clinical and mEP thresholds were significantly correlated (R2= 0.31; p=0.0006), although most mEP thresholds were lower than clinical side effect thresholds. The mEP accuracy in predicting side effects was 0.72, with a sensitivity of 0.68 and a specificity of 0.73.

Conclusions

EMG-recorded mEP correlated well with clinical side effects, and mEP often indicated subclinical CBT and CST activations.

Significance

This study characterizes motor potentials evoked by DBS and demonstrates their utility as an objective biomarker for motor side effect threshold detection during DBS programming.

Highlights

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Deep brain stimulation can activate corticospinal/bulbar tract and evoke motor potentials in muscles measurable by surface EMG

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Motor evoked potential thresholds correlate significantly with clinical side effect thresholds but occur at lower stimulation intensities

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Motor evoked potentials may be a useful side effect biomarker for deep brain stimulation programming
Peripherin: a novel early diagnostic and prognostic plasmatic biomarker in Amyotrophic Lateral Sclerosis
Authors: Bombaci Alessandro , Marco Giovanni De , Casale Federico , Salamone Paolina , Marchese Giulia , Fuda Giuseppe , Calvo Andrea , Chiò Adriano
Published: January 2025

Background and aim

Motor neuron diseases (MND) are heterogeneous and complex neurodegenerative disorders. Biomarkers could facilitate early diagnosis, prognosis determination, and patient stratification. Among the most studied biomarkers are neurofilaments, with peripherin (PRPH), a specific type predominantly expressed in peripheral nervous system neurons, gaining attention. To date, no studies have evaluated PRPH levels in human plasma.

Methods

sandwich-ELISA was used to quantify plasma peripherin from 120 MND (100 ALS, 4 PMA, 15 PLS), 73 MND-mimics (including myelopathy, radiculopathy, axonal neuropathies, Hirayama disease, IBM, benign fasciculation syndrome, functional syndrome, myasthenia, post-polio syndrome) and 38 healthy-controls (HCs). Plasma was collected at the time of diagnosis or some months earlier. 41 ALS were evaluated longitudinally. ALSFRSr, MRC, spirometry, genetic tests, disease progression rate (PR), blood examinations, and neuropsychological tests were performed. Statistical analyses included Kruskal-Wallis, Mann-Whitney, Cox-regression, and Kaplan-Meier curves.

Results

PRPH plasma levels is different between groups (p<0.0001); Bonferroni’s correction shows higher PRPH in MND compared to MND-mimics and HCs. Comparing PLS with HSP PRPH resulted to be higher (p=0.0001). Differences are confirmed co-variating for age and sex. ROC curve shows a good capability of PRPH to discriminate ALS from MND mimics (AUC= 0.85).

PRPH levels correlated directly with ALSFRSr, and with lower body involvement while inversely with PR. Higher PRPH levels were associated with survival advantages.

Discussion

Plasma PRPH levels are elevated in MND, particularly ALS, from the early disease stages, distinguishing MND from mimics and correlating with clinical parameters and survival. Further multicentre studies incorporating additional biomarkers are required to refine the diagnostic and prognostic utility of PRPH in MND.
Sotrovimab versus usual care in patients admitted to hospital with COVID-19: a randomised, controlled, open-label, platform trial (RECOVERY)
Authors: Horby Peter W , Emberson Jonathan R , Peto Leon , Staplin Natalie , Campbell Mark , Pessoa-Amorim Guilherme , Stewart Richard , Ghosh Dipansu , Cooke Graham , Blencowe Natalie , Moreno-Cuesta Jeronimo , Desai Purav , Hine Paul , Underwood Jonathan , Easom Nicholas , Majumdar Jaydip , Bhagani Sanjay , Baillie J Kenneth , Buch Maya H , Faust Saul N , Jaki Thomas , Jeffery Katie , Juszczak Edmund , Knight Marian , Lim Wei Shen , Montgomery Alan , Mukherjee Aparna , Mumford Andrew , Rowan Kathryn , Thwaites Guy , Mafham Marion , Haynes Richard , Landray Martin J ,   Group RECOVERY Collaborative
Published: January 2025

Background

Sotrovimab is a neutralising monoclonal antibody that has been proposed as a treatment for patients admitted to hospital with COVID-19.

Methods

In this randomised, controlled, open-label platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19 pneumonia. In the sotrovimab comparison, eligible and consenting patients were randomly allocated to either usual care alone or usual care plus a single 1g dose of sotrovimab, using web-based unstratified randomisation. Participants were retrospectively categorised according to their baseline serum SARS-CoV-2 nucleocapsid antigen concentration as ‘high-antigen’ or ‘low-antigen’, using the median concentration as a cut-off. The primary outcome was 28-day mortality assessed by intention to treat. Secondary outcomes were time to discharge alive from hospital, and, among those not on invasive ventilation at baseline, progression to invasive ventilation or death. Recruitment closed on 31 March 2024 when funding ended. ISRCTN (50189673) andclinicaltrials.gov(NCT04381936).

Findings

From 4 January 2022 to 19 March 2024, 1723 patients were recruited to the sotrovimab comparison. 720 (42%) were classified as high-antigen, 717 (42%) as low-antigen, and 286 (17%) had unknown antigen status. Over 80% of patients were vaccinated, over 80% had anti-spike antibodies at randomisation, and almost all were infected with Omicron variants. In the prespecified primary efficacy population of high-antigen patients, 82/355 (23%) allocated sotrovimab versus 106/365 (29%) allocated usual care died within 28 days (rate ratio 0.75; 95% CI 0.56-0.99; p=0.046). In an analysis of all randomised patients (regardless of antigen status), 177/828 (21%) allocated sotrovimab versus 201/895 (22%) allocated usual care died within 28 days (rate ratio 0.95; 95% CI 0.77-1.16; p=0.60).

Interpretation

In patients hospitalised with COVID-19, sotrovimab was associated with reduced mortality in the primary analysis population of patients with a high serum SARS-CoV-2 antigen concentration at baseline, but not in the overall population.

Funding

UK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).
Implementation and Impact of a Diversity Supplement Repository
Authors: Gholami Maryam , Kintzer Eva , Wong Mitchell , Smith David , Depp Colin
Published: January 2025

The National Institutes of Health (NIH) diversity supplements represent an opportunity to enhance diversity in the biomedical research workforce. Despite their potential impact, practical barriers prevent effective use of these resources. The Altman Clinical and Translational Research Institute (ACTRI) at the University of California San Diego (UCSD) developed and implemented of an institutional repository and support system to improve diversity supplement applications. The centralized repository and support system incorporated three strategies: (1) a secure web-based repository housing successful examples of supplements, (2) match making for diversity supplements and mentors, and (3) web-based resources for potential applicants. The repository was implemented in June 2021 and includes 51 supplement samples across 14 divisions of NIH as of November 2024. The repository has been accessed by 51 potential applicants since implementation in 2021. Few investigators have requested match making. Early indicators show a doubling in diversity supplement applications compared to pre-implementation period at UCSD. We outlined our approach to addressing some of the barriers in diversity supplement applications, which could provide a model for other institutions. Pending solutions to some of the lessons learned, coordinated efforts aimed at diversity supplements could be a practical approach toward a more diverse biomedical research workforce.
Digital health app data reveals an effect of ovarian hormones on long COVID and myalgic encephalomyelitis symptoms
Authors: Goodship Abigail , Preston Rory , Hicks Joseph T , Leeming Harry , Morgenstern Christian , Male Victoria
Published: January 2025

Background. Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) disproportionately affect females, suggesting modulation by sex hormones. We sought to investigate whether symptom severity is influenced by changes in sex hormones over the menstrual cycle, or by hormonal contraception. Methods. We carried out a retrospective analysis of menstrual and symptom data, prospectively collected via the Visible app from individuals with long COVID, ME/CFS, or both, who had regular menstrual cycles, between 7 September 2022 and 6 March 2024. Mixed-effects models were used to examine associations between symptom severity, menstrual cycle phase and contraception type. Findings. 948 users were included; 100% of users were female and 92.6% identified as women. The most tracked symptoms were fatigue (99.5% of users), brain fog (88.3%), headaches (85.1%) and muscle aches (78.6%). All menstrual cycle phases showed a modest, but significant, improvement compare to the menstrual phase, most markedly in the early luteal (IRR 0.963%, 95% CI: 0.958 - 0.968), but also the follicular (IRR = 0.985, 95% CI: 0.981 - 0.990) and late luteal phase (IRR = 0.980, 95% CI: 0.974-0.985). Crashes (sudden and severe worsening of symptoms following exertion) were significantly more frequent during menstruation than in other phases. Users of combined hormonal contraception (n=70) had a statistically significant reduction in overall symptom score (OR = 0.827, 95% CI: 0.690 - 0.992) and crash incidence (OR = 0.548, 95% CI: 0.350 - 0.856) compared to those not using hormonal contraception (=786). Interpretation. Menstruation is associated with worsened symptoms in long COVID and ME/CFS. Users of combined hormonal contraception report a lower symptom burden than non-users, suggesting a modulatory role of ovarian hormones. These findings could empower menstruating people living with long COVID and ME/CFS to anticipate cyclical changes in symptoms and plan their activities accordingly, and could also inform their use of contraception.
Registered Clinical Trial Trends Evolved Differently in East Asia versus the United States during 2014 to 2023
Authors: Lee Eun Hye , Lee San , Shin Jae Il , Ioannidis John P.A.
Published: January 2025

Introduction

East Asia, including China, Japan, South Korea, and Taiwan, has become a major hub for clinical trials. However, comprehensive comparisons betweenClinicalTrials.govand local registries remain limited. This study analyzes registered clinical trial trends in East Asia over the past decade (2014–2023) and compares them to trends in the United States.

Methods

We extracted clinical trial data through the International Clinical Trials Registry Platform (ICTRP), including data from local registries andClinicalTrials.govfor China, Japan, South Korea, Taiwan, and the United States. We analyzed overall clinical trial trends and filtered randomized controlled trials (RCTs), categorizing them by location, target size, and disease category.

Results

China experienced rapid growth in clinical trials, surpassing both Japan and the United States in total trials and RCTs. By 2023, China led with 16,612 total trials (7,798 RCTs), while the United States registered 9,100 (4,619 RCTs). Except for China, all other countries showed some decline in recent years. Neoplastic diseases and cardiovascular and metabolic diseases were prominent in both regions, but the U.S. showed growing focus on mental health. China’s RCTs were predominantly domestic, while the U.S. maintained a higher proportion of international trials. Japan, South Korea, and Taiwan showed moderate growth, with fewer international trials than the United States. We recorded some inconsistencies and missing information across existing registries.

Conclusion

The study highlights the increasing prominence of East Asia, particularly China, in registered clinical trials, though with a primarily domestic focus. Improvements in existing trial registries covering East Asia are desirable.
JNK2 pathway in colonocytes enhances gut barrier integrity in response to microbial acetate
Authors: Chongtham Chen , Biswas Trisha , Kumari Namaste , Kar Raunak ,   Jyotsna, Jayalakshmi S , Pant Archana , Patil Veena S. , Arimbasseri Gopalakrishnan Aneeshkumar
Published: January 2025

The weaning process accompanies changes in the nutritional profile, metabolism, and gut immune tolerance of offspring. However, the molecular changes associated with this transition and their implications for gut health are not well understood. Here, we show that post-weaning milk-based diets modulate the gut microbiome of pups by enrichingDubosiella newyorkensis.This, in turn, enhances gut barrier function by activating the JNK2 pathway in the epithelium through acetate. However, an inflammation-inducing lard-based high-fat diet, a brief pharmacological inhibition of JNK2, or a two-week delay in the initiation of milk-based diets post-weaning leads to the activation of P38 in the epithelial cells, which leads to inflammation. These observations reveal a microbiome-dependent, short-chain fatty acid-driven dichotomy between JNK2 and P38 pathways in the gut epithelium that modulate gut inflammation. These results provide a framework connecting diets, microbiome, and molecular changes in the epithelium, which may aid the design of microbiome-directed dietary interventions.
Fasting-induced hepatic gluconeogenesis is compromised inAnxa6−/−mice
Authors: Alvarez-Guaita A , Bernaus-Esqué M , Blanco-Muñoz P , Liu Y , Sebastian D , Meneses-Salas E , Nguyen MKL , Zorzano A , Tebar F , Enrich C , Grewal T , Rentero C
Published: January 2025

Maintaining constant blood glucose levels is essential for energizing glucose-dependent tissues. During the fed state, insulin lowers elevated blood glucose, while in the fasted state, glucagon maintains blood glucose levels through hepatic stimulation of fatty acid oxidation, glycogenolysis, and gluconeogenesis (GNG). The liver plays a crucial role in these metabolic adaptations. Deregulation of GNG is a hallmark of type 2 diabetes mellitus (T2DM), driven by hepatic insulin resistance, elevated glucagon levels, and excess circulating free fatty acids. Despite normal insulin-sensitive control of glucose levels and effective glycogen mobilization,Anxa6knockout (Anxa6−/−) mice display rapid hypoglycaemia during fasting. This metabolic disarrangement, in particular during the early stages of fasting is characterized by a low respiratory exchange ratio (RER) and increased lipid oxidation during the diurnal period, indicating a reliance on lipid oxidation due to hypoglycaemia. Elevated glucagon levels during fasting suggest deficiencies in GNG. Further analysis reveals thatAnxa6−/−mice are unable to utilize alanine for hepatic GNG, highlighting a specific impairment in the glucose-alanine cycle in fastedAnxa6−/−mice, underscoring the critical role of ANXA6 in maintaining glucose homeostasis under metabolic stress. During fasting, slightly reduced expression levels of alanine aminotransferase 2 (Gpt2) and lactate dehydrogenase (Ldha2), enzymes converting alanine to pyruvate, and the hepatic alanine transporter SNAT4 might contribute to these observations in theAnxa6−/−mice. These findings identify that ANXA6 deficiency causes an inability to maintain glycolytic metabolism under fasting conditions due to impaired alanine-dependent GNG.
Reaching reproduction in a large carnivore: role of early environment and intrinsic traits
Authors: Auclair Lea , Di Bernardi Cecilia , Sand Hakan , Akesson Mikael , Zimmermann Barbara , Flagstad Oystein , Wabakken Petter , Wikenros Camilla
Published: January 2025

To reach reproduction, individuals must survive the juvenile stage, a critical period of low survival rates in large carnivores. We analysed data from 582 wolves (Canis lupus) identified by DNA during their first year in Sweden and Norway, to investigate intrinsic and extrinsic factors within the natal territory affecting the probability to reach reproduction, i.e. having pups surviving at least 5 months of age. Factors included main prey density, road density, human density, and proximity to non-breeding zones, as well as sex, inbreeding and being collared. Of the 582 wolves identified, 21% reached reproduction. Human density and whether a wolf was collared were the most significant factors. Both were associated with an increased probability to reach reproduction, potentially linked to poaching. Degree of inbreeding was negatively associated with the probability to reach reproduction, while gravel road density and being born in Sweden were positively associated with it. Our findings suggest an influence of legal and illegal human activities on the juvenile stage of wolves for the probability to reach reproduction. Our study enhances the understanding of how early-life conditions and intrinsic traits shape reproduction and underscores the challenges of wolf conservation in anthropized landscapes.
Identification of a novel false-positive mechanism in RapidFire mass spectrometry and application in drug discovery
Authors: Lin De , Pearson Lesley-Anne , Ahmad Shamshad , O’Neill Sandra , Post John , Robinson Colin , Scott Duncan E. , Gilbert Ian H.
Published: January 2025

False-positives plague High Throughput Screening in general and are costly as they consume resource and time to resolve. Methods that can rapidly identify such compounds at the initial screen are therefore of great value. Advances in mass spectrometry have led to the ability to screen inhibitors in drug discovery applications by direct detection of an enzyme reaction product. The technique is free from some of the artefacts that trouble classical assays such as fluorescence interference. Its direct nature negates the need for coupling enzymes and hence is simpler with fewer opportunities for artefacts. Despite its myriad advantages, we report here a mechanism for false-positive hits which has not been reported in the literature. Further we have developed a pipeline for detecting these false-positive hits and suggest a method to mitigate against them.

Graphical Abstract
Transcription driven repurposing of cardiotonic steroids for Lithium treatment of severe depression
Authors: Killick Richard , Hooper Claudie , Fernandes Cathy , Elliott Christina , Aarsland Dag , Kjosavik Svein R. , Østerhus Ragnhild Djønne , Williams Gareth
Published: January 2025

Lithium is prescribed as a mood stabiliser in bipolar disorder and severe depression. However, the mechanism of action of Lithium is unknown and there are major side effects associated with prolonged medication. This motivates a search for safer alternative drug repurposing candidates.

Given that the drug mechanism may be encoded in transcriptional changes we have generated the gene expression profile for acute Lithium treatment of cortical neuronal cultures. We found that the Lithium associated transcription response harbours a significant component that is the reverse of that seen in human brain samples from patients with Major Depression, Bipolar Disorder and a mouse model of depression. Interrogating publicly available drug driven expression data we found that cardiotonic steroids drive gene expression in a correlated manner to our acute Lithium profile. An analysis of the psychiatric medication cohort of the Norwegian Prescription Database showed that cardiotonic prescription is associated with a lower incidence of lithium prescription.

Our transcriptional and epidemiological observations point towards cardiotonic steroids as possible repurposing candidates for Lithium. These observations motivate a controlled trial to establish a causal connection and genuine therapeutic benefit in the context of depression.