bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic delivery of recombinant glucocerebrosidase enzyme-containing extracellular vesicles to human cells from Gaucher disease patients
Authors: Janpipatkul Keatdamrong , Sutjarit Nareerat , Tangprasittipap Amornrat , Chaiamarit Tai , Innachai Pawarit , Suksen Kanoknetr , Chokpanuwat Tanida , Tim-Aroon Thipwimol , Anurathapan Usanarat , Jearawiriyapaisarn Natee , Tubsuwan Alisa , Bowornpinyo Supareak , Asavapanumas Nithi , Chairoungdua Arthit , Bhukhai Kanit , Hongeng Suradej 
Published: October 2024

Abstract
Background
Gaucher disease (GD) is one of the most common types of lysosomal storage diseases (LSDs) caused by pathogenic variants of lysosomal β-glucocerebrosidase gene (GBA1), resulting in the impairment of Glucocerebrosidase (GCase) enzyme function and the accumulation of a glycolipid substrate, glucosylceramide (GlcCer) within lysosomes. Current therapeutic approaches such as enzyme replacement therapy and substrate reduction therapy cannot fully rescue GD pathologies, especially neurological symptoms. Meanwhile, delivery of lysosomal enzymes to the endocytic compartment of affected human cells is a promising strategy for treating neuropathic LSDs.

Result
Here, we describe a novel approach to restore GCase enzyme in cells from neuropathic GD patients by producing extracellular vesicle (EVs)-containing GCase from cells overexpressing GBA1 gene. Lentiviral vectors containing modified GBA1 were introduced into HEK293T cells to produce a stable cell line that provides a sustainable source of functional GCase enzyme. The GBA1-overexpressing cells released EV-containing GCase enzyme, that is capable of entering into and localizing in the endocytic compartment of recipient cells, including THP-1 macrophage, SH-SY5Y neuroblastoma, and macrophages and neurons derived from induced pluripotent stem cells (iPSCs) of neuropathic GD patients. Importantly, the recipient cells exhibit higher GCase enzyme activity.

Conclusion
This study presents a promising therapeutic strategy to treat severe types of LSDs. It involves delivering lysosomal enzymes to the endocytic compartment of human cells affected by conditions such as GDs with neurological symptoms, as well as potentially other neurological disorders impacting lysosomes.
High-affinity antibodies specific to the core region of the tau protein exhibit diagnostic and therapeutic potential for Alzheimer’s disease
Authors: Arastoo Mohammad , Penny Lewis K. , Lofthouse Richard , Abdallah Aya , Abrahamsson Anna , Marini Pietro , Melis Valeria , Riedel Gernot , Harrington Charles R. , Wischik Claude M. , Porter Andrew , Palliyil Soumya 
Published: October 2024

Abstract
Background
Recent advances in blood-based biomarker discovery are paving the way for simpler, more accessible diagnostic tools that can detect early signs of Alzheimer’s disease (AD). Recent successes in the development of amyloid-targeting immunotherapy approaches mark an important advancement in providing new options for the treatment of AD. We have developed a set of high-affinity monoclonal antibodies (mAbs) to tau protein that have the potential as tools for diagnosis and treatment of AD.

Methods
Sheep were immunised with either full-length tau (1-441) or truncated paired helical filament (PHF)-core tau (297–391). A stringent bio-panning and epitope selection strategy, with a particular focus directed to epitopes within the disease-relevant PHF-core tau, was used to identify single-chain antibodies (scAbs). These scAbs were ranked by affinity for each epitope class, with leads converted to high-affinity mAbs. These antibodies and their potential utility were assessed by their performance in tau immunoassays, as well as their ability to prevent tau aggregation and propagation. Further characterisation of these antibodies was performed by immunohistochemical staining of brain sections and immuno-gold electronmicroscopy of isolated PHFs.

Results
Our work resulted in a set of high-affinity antibodies reacting with multiple epitopes spanning the entire tau protein molecule. The tau antibodies directed against the core tau unit of the PHF inhibited pathological aggregation and seeding using several biochemical and cell assay systems. Through staining of brain sections and PHFs, the panel of antibodies revealed which tau epitopes were available, truncated, or occluded. In addition, highly sensitive immunoassays were developed with the ability to distinguish between and quantify various tau fragments.

Conclusion
This article introduces an alternative immunodiagnostic approach based on the concept of a “tauosome” – the diverse set of tau fragments present within biological fluids. The development of an antibody panel that can distinguish a range of different tau fragments provides the basis for a novel approach to potential diagnosis and monitoring of disease progression. Our results further support the notion that tau immunotherapy targeting the PHF-core needs to combine appropriate selection of both the target epitope and antibody affinity to optimise therapeutic potential.
Discordant definitions of small airway dysfunction between spirometry and parametric response mapping: the HRCT-based study
Authors: Chen Bin , Gao Pan , Yang Yuling , Ma Zongjing , Sun Yingli , Lu Jinjuan , Qi Lin , Li Ming 
Published: October 2024

Abstract
Objectives
To analyze the lung structure of small airway dysfunction (SAD) defined by spirometry and parametric response mapping (PRM) using high-resolution computed tomography (HRCT), and to analyze the predictive factors for SAD.

Methods
A prospective study was conducted with 388 participants undergoing pulmonary function test (PFT) and inspiratory-expiratory chest CT scans. The clinical data and HRCT assessments of SAD patients defined by both methods were compared. A prediction model for SAD was constructed based on logistic regression.

Results
SAD was defined in 122 individuals by spirometry and 158 by PRM. In HRCT visual assessment, emphysema, tree-in-bud sign, and bronchial wall thickening have higher incidence in SAD defined by each method. (p < 0.001). Quantitative CT showed that spirometry-SAD had thicker airway walls (p < 0.001), smaller lumens (p = 0.011), fewer bronchi (p < 0.001), while PRM-SAD had slender blood vessels. Predictive factors for spirometry-SAD were age, male gender, the volume percentage of emphysema in PRM (PRMEmph), tree-in-bud sign, bronchial wall thickening, bronchial count; for PRM-SAD were age, male gender, BMI, tree-in-bud sign, emphysema, the percentage of blood vessel volume with a cross-sectional area less than 1 mm2 (BV1/TBV). The area under curve (AUC) values for the fitted predictive models were 0.855 and 0.808 respectively.

Conclusions
Compared with PRM, SAD defined by spirometry is more closely related to airway morphology, while PRM is sensitive to early pulmonary dysfunction but may be interfered by pulmonary vessels. Models combining patient information and HRCT assessment have good predictive value for SAD.

Critical relevance statement
HRCT reveals lung structural differences in small airway dysfunction defined by spirometry and parametric response mapping. This insight aids in understanding methodological differences and developing radiological tools for small airways that align with pathophysiology.

Key Points

Spirometry-SAD shows thickened airway walls, narrowed lumen, and reduced branch count, which are closely related to airway morphology.

PRM shows good sensitivity to early pulmonary dysfunction, although its assessment of SAD based on gas trapping may be affected by the density of pulmonary vessels and other lung structures.

Combining patient information and HRCT features, the fitted model has good predictive performance for SAD defined by both spirometry and PRM (AUC values are 0.855 and 0.808, respectively).

Graphical Abstract
Effects of microbe-derived antioxidants on growth performance, hepatic oxidative stress, mitochondrial function and cell apoptosis in weaning piglets
Authors: Yu Chengbing , Luo Yuxiao , Shen Cheng , Luo Zhen , Zhang Hongcai , Zhang Jing , Xu Weina , Xu Jianxiong 
Published: October 2024

Abstract
Background
Weaning causes redox dyshomeostasis in piglets, which leads to hepatic oxidative damage. Microbe-derived antioxidants (MA) have great potential for anti-oxidation. This study aimed to investigate changes in hepatic redox system, mitochondrial function and apoptosis after weaning, and effects of MA on growth performance and liver health in weaning piglets.

Methods
This study consisted of 2 experiments. In the both experiments, piglets were weaned at 21 days of age. In Exp. 1, at 21 (W0), 22 (W1), 25 (W4), 28 (W7), and 35 (W14) days of age, 6 piglets were slaughtered at each timepoint. In Exp. 2, piglets were divided into 2 groups: one received MA gavage (MA) and the other received saline gavage (CON). At 25 days of age, 6 piglets from each group were sacrificed.

Results
In Exp. 1, weaning caused growth inhibition and liver developmental retardation from W0 to W4. The mRNA sequencing between W0 and W4 revealed that pathways related to “regulation of apoptotic process” and “reactive oxygen species metabolic process” were enriched. Further study showed that weaning led to higher hepatic content of reactive oxygen species (ROS), H2O2 and O2−. Weaning enhanced mitochondrial fission and suppressed their fusion, activated mitophagy, thus triggering cell apoptosis. In Exp. 2, MA improved growth performance of piglets with higher average daily gain (ADG) and average daily feed intake (ADFI). The hepatic ROS, as well as products of oxidative damage malonaldehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the MA group decreased significantly than that of the CON group. The MA elevated mitochondrial membrane potential, increased activity of mitochondrial respiratory chain complexes (MRC) I and IV, enhanced mitochondrial fusion and reduced mitophagy, thus decreasing cell apoptosis.

Conclusions
The present study showed that MA improved the growth performance of weaning piglets and reversed weaning-induced oxidative damage, mitochondrial dysfunction, and apoptosis. Our results suggested that MA had promising prospects for maintaining liver health in weaning piglets and provided a reference for studies of liver diseases in humans.

Graphical Abstract
Improvements in executive functions by domain-specific cognitive training in youth elite soccer players
Authors: Heilmann Florian , Knöbel Simon , Lautenbach Franziska 
Published: October 2024

AbstractThis study examined the impact of sport-specific cognitive training (CT) on executive functions (EFs) in youth soccer players. Thirty-one athletes (13–15 years) participated, 13 in the intervention group (IG) and 18 in the control group (CG). The IG underwent an 8-week soccer-focused CT program, while the CG maintained regular training. The assessments included working memory, inhibition, and cognitive flexibility tasks. The results revealed no significant improvements in EFs in the IG compared to those in the CG. Both groups showed enhanced cognitive flexibility, possibly due to general cognitive development or learning effects. The study suggested that an 8-week sport-specific CT may not enhance EFs in young soccer players, potentially due to a ceiling effect in highly skilled athletes. These findings should be considered when designing cognitive training programs for athletes, and future research could explore the optimal duration of such programs.
Towards validating invalidated knowledge: a discourse analysis of firsthand accounts of hearing voices
Authors: Ynnesdal Haugen Lill Susann 
Published: October 2024

Abstract
Background
As Foucault historically traced, dialogs about madness were silenced with the emergence of biomedical psychiatry. The silence entailed the epistemic violence of invalidating persons who hear voices as knowers, arguably leaving them without validating sensemaking languages for firsthand experiences. This article analyzes five Norwegian firsthand accounts of hearing voices, and how they differed from the predominating biomedical psychiatry discourse, in search of validating languages and knowledge that may facilitate making sense of voice-hearing for persons who hear voices.

Methods
The text material consisted of four sets of blogs authored by four young women and a short interview with a man, all of whom had firsthand experiences of voice-hearing in a Norwegian context. Ian Parker’s version of Foucauldian discourse analysis was used to analyze the material.

Results
Six discourses were identified: biomedical psychiatry-discourse, discourse of reason, psychodynamic discourse, discourse of personal characteristics, spiritual discourse and discourse of personal relationships between hearer and voices. Within the discourses of biomedical psychiatry and reason, voice-hearing was rendered as hallucinations, unreason, and as a problem to be solved, preferably by professionals, thus silencing the person who hears voices. In contrast, within the discourses of psychodynamics, personal characteristics, spirituality, and personal relationships between hearer and voices, voice-hearing has diverse meanings, and they grant voice hearers greater freedom concerning voice-hearing. The psychodynamic discourse nonetheless aligns with the discourses of reason and biomedical psychiatry in allowing professionals the prerogative of determining the meaning of voice-hearing. The remaining three discourses appear to facilitate more space for voice-hearers to narrate and engage with their voice-hearing at their discretion, with little to no professional impingement.

Conclusions
Discursive complexity notwithstanding, I consider that particularly the discourses of personal characteristics, spirituality, and personal relationships facilitate languages that may enable a person to narrate their own experiences and actions at their own discretion, without needing an expert commentator on the side. To have such languages available is argued to entail clear strides towards more empowered positions in one’s life.
Review of the technology used for structural characterization of the GMO genome using NGS data
Authors: Moon Kahee , Basnet Prakash , Um Taeyoung , Choi Ik-Young 
Published: October 2024

AbstractThe molecular characterization of genetically modified organisms (GMOs) is essential for ensuring safety and gaining regulatory approval for commercialization. According to CODEX standards, this characterization involves evaluating the presence of introduced genes, insertion sites, copy number, and nucleotide sequence structure. Advances in technology have led to the increased use of next-generation sequencing (NGS) over traditional methods such as Southern blotting. While both methods provide high reproducibility and accuracy, Southern blotting is labor-intensive and time-consuming due to the need for repetitive probe design and analyses for each target, resulting in low throughput. Conversely, NGS facilitates rapid and comprehensive analysis by mapping whole-genome sequencing (WGS) data to plasmid sequences, accurately identifying T-DNA insertion sites and flanking regions. This advantage allows for efficient detection of T-DNA presence, copy number, and unintended gene insertions without additional probe work. This paper reviews the current status of GMO genome characterization using NGS and proposes more efficient strategies for this purpose.
Association of Participation in Medicare's Oncology Care Model With Spending, Utilization, and Quality Outcomes Among Commercially Insured and Medicare Advantage Members
Authors: Mullangi Samyukta , Ukert Benjamin , Devries Andrea , Debono David , Santos Jason , Fisch Michael J. , Schleicher Stephen M. , Navathe Amol S. , Bekelman Justin E. , Schwartz Aaron L. , Parikh Ravi B. 
Published: October 2024

PURPOSE
The Oncology Care Model (OCM), a value-based payment model for traditional Medicare beneficiaries with cancer, yielded total spending reductions that were outweighed by incentive payments, resulting in net losses to the Centers for Medicare & Medicaid Services. We studied whether the OCM yielded spillover effects in total episode spending, utilization, and quality among commercially insured and Medicare Advantage (MA) members, who were not targeted by the program.

PATIENTS AND METHODS
This observational study used administrative claims from a large national payer, yielding 157,189 total patients with commercial insurance or MA with solid malignancies who initiated 229,376 systemic anticancer therapy episodes before (2012-2015) and during (2016-2021) the OCM at 125 OCM-participating practices (a subset of total OCM practices) and a 1:10 propensity-matched set of 860 non-OCM practices. We used difference-in-differences analyses to assess the association between the OCM and total episode spending, defined as medical spending during a 6-month episode. Secondary outcomes included hospitalization and emergency department (ED) utilization and quality measures.

RESULTS

From the pre-OCM to the OCM period, mean total episode payments increased from $45,504 in US dollars (USD) to $46,239 USD for OCM-participating practices, and increased from $50,519 USD to $58,591 USD for non-OCM practices (adjusted difference-in-differences –$6,287 USD [95% CI, –$10,076 USD to –$2,498 USD],
P
= .001). The OCM was associated with adjusted spending decreases for both high-risk (–$6,756 USD [95% CI, –$10,731 USD to –$2,781 USD],
P
= .001) and low-risk (–$4,171 USD [95% CI, –$7,799 USD to –$543 USD],
P
= .025) episodes. OCM-associated spending reductions were strongest for outpatient (–$5,243 USD [95% CI, –$8,589 USD to –$1,897 USD],
P
= .002) and infused/injected anticancer drug (–$3,031 USD [95% CI, –$5,193 USD to –$869 USD],
P
= .006) spending. There were no associations between OCM participation and changes in hospital or ED utilization nor quality of care.

CONCLUSION
The OCM was associated with reductions in spending for nontargeted members, a spillover effect.
State of Geographic Access to Cancer Treatment Trials in the United States: Are Studies Located Where Patients Live?
Authors: Kirkwood M. Kelsey , Schenkel Caroline , Hinshaw Dominique C. , Bruinooge Suanna S. , Waterhouse David M. , Peppercorn Jeffrey M. , Subbiah Ishwaria M. , Levit Laura A. 
Published: October 2024

PURPOSE
In this study, we describe the geographic distribution of US cancer treatment trials to identify disparities and opportunities for targeted improvements in access to research for people with cancer.

METHODS
US-based phase I-III cancer treatment trials registered on ClinicalTrials.gov were tabulated for the years they were open to enrollment (2017-2022), overall and by county, and supplemented with data from the US Census Bureau, National Cancer Institute, Centers for Disease Control and Prevention, and US Department of Agriculture. We evaluated geographic differences in trial availability. We assessed 5-year trends in trials per capita and mapped 1-hour drive time areas around sites.

RESULTS
A total of 6,710 trials were open to enrollment in 2022 across 1,836 sites. Trials increased by 4%, whereas sites decreased by 3% annually per capita from 2017. Seventy percent of US counties had no reported active trials in 2022 (2,211/3,143), representing 19% of people age ≥55 years. Eighty-six percent of nonmetropolitan counties had no trials versus 44% of metropolitan counties. Trial availability varied by county-level cancer mortality and social vulnerability (an index derived from demographic and socioeconomic data from the US Census). Eighteen percent of counties without trials had oncologist care sites (n = 618). Notably, 26% of people age ≥55 years lived beyond an hour drive of a site with ≥100 trials.

CONCLUSION
Most US counties have limited to no trial offerings, a disparity magnified in counties that are nonmetropolitan, with high social vulnerability, and with high cancer mortality. Effort to facilitate diverse site participation is needed to promote equitable access to trials and to ensure patients participating in trials match the characteristics of patients who will receive interventions once approved. Counties with oncology care sites but no trials provide potential expansion areas.
Neuromodulation for Neuropathic Pain Syndromes
Authors: Shirvalkar Prasad 
Published: October 2024

ABSTRACT

OBJECTIVE
This article reviews the principles, applications, and emerging trends of neuromodulation as a therapeutic approach for managing painful neuropathic diseases. By parsing evidence for possible mechanisms of action and clinical trial outcomes for various diseases, this article focuses on five common therapy modalities: cutaneous, peripheral nerve, spinal cord, and brain stimulation, and intrathecal drug delivery.

LATEST DEVELOPMENTS
Recent advances in both invasive and noninvasive neuromodulation for pain have introduced personalized and closed-loop techniques, integrating real-time feedback mechanisms and combining therapies to improve physical and psychosocial function. Novel stimulation waveforms may influence distinct neural tissues to rectify pathologic pain signaling.

ESSENTIAL POINTS
With appropriate patient selection, peripheral nerve stimulation or epidural stimulation of the spinal cord can provide enduring relief for a variety of chronic pain syndromes. Newer technology using high frequencies, unique waveforms, or closed-loop stimulation may have selective advantages, but our current understanding of therapy mechanisms is very poor. For certain diagnoses and patients who meet clinical criteria, neuromodulation can provide profound, long-lasting relief that significantly improves quality of life. While many therapies are supported by data from large clinical trials, there is a risk of bias as most clinical studies were funded by device manufacturers or insurance companies, which increases the importance of real-world data analysis. Emerging methods like invasive or noninvasive brain stimulation may help us dissect basic mechanisms of pain processing and hold promise for personalized therapies for refractory pain syndromes. Finally, intrathecal delivery of drugs directly to segments of the spinal cord can also modify pain signaling to provide therapy for severe pain syndromes.