bluuebunny/crossref_metadata_2025 huggingface dataset:
Whether weekend warriors (WWs) achieve equivalent benefits in lipid accumulation products (LAP) reduction as other leisure-time physical activity patterns? -Results from a population-based analysis of NHANES 2007–2018
Authors: Dai Wei , Zhang DongYang , Wei ZhiYuan , Liu Pan , Yang QianKun , Zhang Li , Zhang Jie , Zhang Chao , Xue Hao , Xie Zhao , Luo Fei
Published: June 2024

Background

Obesity is characterized by excessive fat accumulation in the body. Physical activity (PA) is an effective intervention to combat obesity, but the effectiveness of different PA patterns on controlling obesity is unclear. Lipid accumulation product (LAP), derived from waist circumference and triglycerides, is a novel indicator for obesity evaluation. However, the association between PA patterns (i.e., weekend warriors and regularly active) and LAP remains unexplored. This study aims to elucidate the relationship between PA patterns and LAP in US adult population.

Methods

Adult individuals with complete data on LAP, PA patterns, and other covariates from the National Health and Nutrition Examination Survey (NHANES) database (2007–2018) were included in this study. Multivariate linear regression models were utilized to explore the association between PA patterns and LAP. Subgroup analyses, interaction tests, restricted cubic spline (RCS) regression analyses, and threshold and saturation effect analyses were also performed to investigate the stability and nonlinearity of PA-LAP association, respectively.

Results

A total of 11,212 participants were included in this study. After adjusting for all potential covariates, being regularly active (RA) (β=-8.85, P < 0.05) obtained significantly higher LAP reduction as opposed to being weekend warriors (WWs) (β=-4.70, P = 0.3841). Furthermore, subgroup analyses and interaction tests indicated that the PA-LAP association was more pronounced in individuals with higher education levels (P interaction = 0.0084) and diabetes (P interaction = 0.0062). Additionally, a significant, non-linear, and negative correlation between weekly total PA and LAP in non-inactive individuals was identified by RCS analysis (P for overall < 0.001, P for nonlinearity = 0.009). A threshold of 440 min in weekly total PA was found to arouse favorable LAP reduction.

Conclusions

Being regularly active obtained better LAP reduction as opposed to being WWs. For non-inactive adults, engaging in more than 440 min of PA per week helps to reduce LAP effectively.
Achieving ‘something that everybody has invested in’: perspectives of diverse stakeholders during co-creation of a transition to residency curriculum
Authors: Suliman Shireen , Allen Margaret , Al-Moslih Ayad , Carr Alison , Koopmans Richard , Könings Karen D.
Published: June 2024

Co-creation of education within the context of student inclusion alongside diverse stakeholders merits exploration. We studied the perspectives of students and teachers from different institutions who participated in co-creating a transition to residency curriculum. We conducted post-hoc in-depth interviews with 16 participants: final-year medical students, undergraduate, and postgraduate medical education stakeholders who were involved in the co-creation sessions. Findings build on the Framework of Stakeholders’ Involvement in Co-creation and identify the four key components of co-creation with diverse faculty: immersion in positive feelings of inclusivity and appreciation, exchange of knowledge, engagement in a state of reflection and analysis, and translation of co-creation dialogues into intended outcomes. Despite power dynamics, participants valued open communication, constructive feedback, mutual respect, and effective moderation. The study broadened our understanding of the co-creation process in diverse stakeholder settings. Incorporating key elements in the presence of power relations can enrich co-creation by leveraging wider expertise.
A novel single-cell model reveals ferroptosis-associated biomarkers for individualized therapy and prognostic prediction in hepatocellular carcinoma
Authors: Zhou Qiong , Tao Chunyu , Ge Yuli , Yuan Jiakai , Pan Fan , Lin Xinrong , Wang Rui
Published: June 2024

Background

Hepatocellular carcinoma (HCC) is a prevalent malignancy with a pressing need for improved therapeutic response and prognosis prediction. This study delves into a novel predictive model related to ferroptosis, a regulated cell death mechanism disrupting metabolic processes.

Results

Single-cell sequencing data analysis identified subpopulations of HCC cells exhibiting activated ferroptosis and distinct gene expression patterns compared to normal tissues. Utilizing the LASSO-Cox algorithm, we constructed a model with 10 single-cell biomarkers associated with ferroptosis, namely STMN1, S100A10, FABP5, CAPG, RGCC, ENO1, ANXA5, UTRN, CXCR3, and ITM2A. Comprehensive analyses using these biomarkers revealed variations in immune infiltration, tumor mutation burden, drug sensitivity, and biological functional profiles between risk groups. Specific associations were established between particular immune cell subtypes and certain gene expression patterns. Treatment response analyses indicated potential benefits from anti-tumor immune therapy for the low-risk group and chemotherapy advantages for the high-risk group.

Conclusions

The integration of this single-cell level model with clinicopathological features enabled accurate overall survival prediction and effective risk stratification in HCC patients. Our findings illuminate the potential of ferroptosis-related genes in tailoring therapy and prognosis prediction for HCC, offering novel insights into the intricate interplay among ferroptosis, immune response, and HCC progression.
Dysregulated RNA editing of EIF2AK2 in polycystic ovary syndrome: clinical relevance and functional implications
Authors: Kong Fan-Sheng , Feng Junjie , Yao Jin-Ping , Lu Yinghua , Guo Tao , Sun Meng , Ren Chun-Yan , Jin Yun-Yun , Ma Yaping , Chen Jian-Huan
Published: June 2024

Background

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive ages. Our previous study has implicated a possible link between RNA editing and PCOS, yet the actual role of RNA editing, its association with clinical features, and the underlying mechanisms remain unclear.

Methods

Ten RNA-Seq datasets containing 269 samples of multiple tissue types, including granulosa cells, T helper cells, placenta, oocyte, endometrial stromal cells, endometrium, and adipose tissues, were retrieved from public databases. Peripheral blood samples were collected from twelve PCOS and ten controls and subjected to RNA-Seq. Transcriptome-wide RNA-Seq data analysis was conducted to identify differential RNA editing (DRE) between PCOS and controls. The functional significance of DRE was evaluated by luciferase reporter assays and overexpression in human HEK293T cells. Dehydroepiandrosterone and lipopolysaccharide were used to stimulate human KGN granulosa cells to evaluate gene expression.

Results

RNA editing dysregulations across multiple tissues were found to be associated with PCOS in public datasets. Peripheral blood transcriptome analysis revealed 798 DRE events associated with PCOS. Through weighted gene co-expression network analysis, our results revealed a set of hub DRE events in PCOS blood. A DRE event in the eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2:chr2:37,100,559) was associated with PCOS clinical features such as luteinizing hormone (LH) and the ratio of LH over follicle-stimulating hormone. Luciferase assays, overexpression, and knockout of RNA editing enzyme adenosine deaminase RNA specific (ADAR) showed that the ADAR-mediated editing cis-regulated EIF2AK2 expression. EIAF2AK2 showed a higher expression after dehydroepiandrosterone and lipopolysaccharide stimulation, triggering changes in the downstrean MAPK pathway.

Conclusions

Our study presented the first evidence of cross-tissue RNA editing dysregulation in PCOS and its clinical associations. The dysregulation of RNA editing mediated by ADAR and the disrupted target EIF2AK2 may contribute to PCOS development via the MPAK pathway, underlining such epigenetic mechanisms in the disease.
How do lifestyle factors modify the association between genetic predisposition and obesity-related phenotypes? A 4-way decomposition analysis using UK Biobank
Authors: Zhang Mengrong , Ward Joey , Strawbridge Rona J. , Celis-Morales Carlos , Pell Jill P. , Lyall Donald M. , Ho Frederick K.
Published: June 2024

Background

Obesity and central obesity are multifactorial conditions with genetic and non-genetic (lifestyle and environmental) contributions. There is incomplete understanding of whether lifestyle modifies the translation from respective genetic risks into phenotypic obesity and central obesity, and to what extent genetic predisposition to obesity and central obesity is mediated via lifestyle factors.

Methods

This is a cross-sectional study of 201,466 (out of approximately 502,000) European participants from UK Biobank and tested for interactions and mediation role of lifestyle factors (diet quality; physical activity levels; total energy intake; sleep duration, and smoking and alcohol intake) between genetic risk for obesity and central obesity. BMI-PRS and WHR-PRS are exposures and obesity and central obesity are outcomes.

Results

Overall, 42.8% of the association between genetic predisposition to obesity and phenotypic obesity was explained by lifestyle: 0.9% by mediation and 41.9% by effect modification. A significant difference between men and women was found in central obesity; the figures were 42.1% (association explained by lifestyle), 1.4% (by mediation), and 40.7% (by modification) in women and 69.6% (association explained by lifestyle), 3.0% (by mediation), and 66.6% (by modification) in men.

Conclusions

A substantial proportion of the association between genetic predisposition to obesity/central obesity and phenotypic obesity/central obesity was explained by lifestyles. Future studies with repeated measures of obesity and lifestyle would be needed to clarify causation.
Clinical features and ALDH5A1 gene findings in 13 Chinese cases with succinic semialdehyde dehydrogenase deficiency
Authors: Dong Hui , Ma Xue , Chen Zhehui , Zhang Huiting , Song Jinqing , Jin Ying , Li Mengqiu , Lu Mei , He Ruxuan , Zhang Yao , Yang Yanling
Published: June 2024

Background and aims

To investigate the clinical features, ALDH5A1 gene variations, treatment, and prognosis of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency.

Materials and methods

This retrospective study evaluated the findings in 13 Chinese patients with SSADH deficiency admitted to the Pediatric Department of Peking University First Hospital from September 2013 to September 2023.

Results

Thirteen patients (seven male and six female patients; two sibling sisters) had the symptoms aged from 1 month to 1 year. Their urine 4-hydroxybutyrate acid levels were elevated and were accompanied by mildly increased serum lactate levels. Brain magnetic resonance imaging (MRI) showed symmetric abnormal signals in both sides of the globus pallidus and other areas. All 13 patients had psychomotor retardation, with seven showing epileptic seizures. Among the 18 variants of the ALDH5A1 gene identified in these 13 patients, six were previously reported, while 12 were novel variants. Among the 12 novel variants, three (c.85_116del, c.206_222dup, c.762C > G) were pathogenic variants; five (c.427delA, c.515G > A, c.637C > T, c.755G > T, c.1274T > C) were likely pathogenic; and the remaining four (c.454G > C, c.479C > T, c.1480G > A, c.1501G > C) were variants of uncertain significance. The patients received drugs such as L-carnitine, vigabatrin, and taurine, along with symptomatic treatment. Their urine 4-hydroxybutyric acid levels showed variable degrees of reduction.

Conclusions

A cohort of 13 cases with early-onset SSADH deficiency was analyzed. Onset of symptoms occurred from 1 month to 1 year of age. Twelve novel variants of the ALDH5A1 gene were identified.
Motor skill learning modulates striatal extracellular vesicles’ content in a mouse model of Huntington’s disease
Authors: Solana-Balaguer Júlia , Garcia-Segura Pol , Campoy-Campos Genís , Chicote-González Almudena , Fernández-Irigoyen Joaquín , Santamaría Enrique , Pérez-Navarro Esther , Masana Mercè , Alberch Jordi , Malagelada Cristina
Published: June 2024

Huntington’s disease (HD) is a neurological disorder caused by a CAG expansion in the Huntingtin gene (HTT). HD pathology mostly affects striatal medium-sized spiny neurons and results in an altered cortico-striatal function. Recent studies report that motor skill learning, and cortico-striatal stimulation attenuate the neuropathology in HD, resulting in an amelioration of some motor and cognitive functions. During physical training, extracellular vesicles (EVs) are released in many tissues, including the brain, as a potential means for inter-tissue communication. To investigate how motor skill learning, involving acute physical training, modulates EVs crosstalk between cells in the striatum, we trained wild-type (WT) and R6/1 mice, the latter with motor and cognitive deficits, on the accelerating rotarod test, and we isolated their striatal EVs. EVs from R6/1 mice presented alterations in the small exosome population when compared to WT. Proteomic analyses revealed that striatal R6/1 EVs recapitulated signaling and energy deficiencies present in HD. Motor skill learning in R6/1 mice restored the amount of EVs and their protein content in comparison to naïve R6/1 mice. Furthermore, motor skill learning modulated crucial pathways in metabolism and neurodegeneration. All these data provide new insights into the pathogenesis of HD and put striatal EVs in the spotlight to understand the signaling and metabolic alterations in neurodegenerative diseases. Moreover, our results suggest that motor learning is a crucial modulator of cell-to-cell communication in the striatum.
Elevated nuclear TDP-43 induces constitutive exon skipping
Authors: Carmen-Orozco Rogger P. , Tsao William , Ye Yingzhi , Sinha Irika R. , Chang Koping , Trinh Vickie T. , Chung William , Bowden Kyra , Troncoso Juan C. , Blackshaw Seth , Hayes Lindsey R. , Sun Shuying , Wong Philip C. , Ling Jonathan P.
Published: June 2024

Background

Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generate in vitro and in vivo model systems.

Methods

We analyzed RNA-seq datasets from mouse and human neurons overexpressing TDP-43 to explore species specific splicing patterns. We explored the dynamics between TDP-43 levels and exon repression in vitro. Furthermore we analyzed human brain samples and publicly available RNA datasets to explore the relationship between exon repression and disease.

Results

Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43.

Conclusions

Our findings emphasize the need for caution in interpreting TDP-43 overexpression data and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy.
Pediatric ultrasound practice in Italy: an exploratory survey
Authors: Musolino Anna Maria , Tei Monica , De Rose Cristina , Buonsenso Danilo , Supino Maria Chiara , Zampogna Stefania , Staiano Annamaria , Raponi Massimiliano , Amendolea Antonella , Colacino Vincenzo , Gori Laura , Manganaro Alessandro , Ricci Riccardo , D’Inzeo Victoria , Grosso Salvatore , Villani Alberto , Agostiniani Rino
Published: June 2024

Background

The aim of this exploratory survey is to describe the current state of US (ultrasound) technique across different pediatric settings nationwide.

Methods

A questionnaire was emailed to all members of the Italian Society of Pediatrics, including pediatric residents. The survey was open from December 2021 to March 2022.

Results

There were 1098 respondents. Seven hundred and seven pediatricians (84.1%) reported any use of US, while 51 (44.3%) residents denied it. The majority of participants (n = 956, 87.1%) reported to have a US machine available within the department, mostly cart-based (n = 516, 66.9%) and provided from 1 to 5 years prior to the survey (n = 330, 42.8%). Lung and neonatal cerebral regions were the most frequently scanned (n = 289, 18.7% and n = 218, 14.1%, respectively). The suspicion of pneumonia or respiratory distress represented the main reasons for performing US in emergency room (n = 390, 78% and n = 330, 66%, respectively). The majority of family pediatricians reported to scan lung and kidney/urinary tract regions (n = 30, 16.9%, and n = 23,12.9%, respectively). Regarding US training, the majority of respondents (n = 358, 34.6%) declared an experience-based education, with a deficient certification enabling the use of US in 71.6% (n = 552) of cases. The most common barriers included the lack of a well-defined training program (n = 627, 57.1%), unavailability of the US machine (n = 196, 17.9%) and legal responsibility concern (n = 175, 15.9%).

Conclusions

Despite the growing interest on pediatric US nationally, significant barriers still limit widespread adoption. These obstacles may be addressed through the dissemination of a specific US education plan and providing additional resources.
Registry-based randomised controlled trials: conduct, advantages and challenges—a systematic review
Authors: Shiely Frances , O Shea Niamh , Murphy Ellen , Eustace Joseph
Published: June 2024

Background

Registry-based randomised controlled trials (rRCTs) have been described as pragmatic studies utilising patient data embedded in large-scale registries to facilitate key clinical trial procedures including recruitment, randomisation and the collection of outcome data. Whilst the practice of utilising registries to support the conduct of randomised trials is increasing, the use of the registries within rRCTs is inconsistent. The purpose of this systematic review is to explore the conduct of rRCTs using a patient registry to facilitate trial recruitment and the collection of outcome data, and to discuss the advantages and challenges of rRCTs.

Methods

A systematic search of the literature was conducted using five databases from inception to June 2020: PubMed, Embase (through Ovid), CINAHL, Scopus and the Cochrane Controlled Register of Trials (CENTRAL). The search strategy comprised of MESH terms and key words related to rRCTs. Study selection was performed independently by two reviewers. A risk of bias for each study was completed. A narrative synthesis was conducted.

Results

A total 47,862 titles were screened and 24 rRCTs were included. Eleven rRCTs (45.8%) used more than one registry to facilitate trial conduct. Six rRCTs (25%) randomised participants via a specific randomisation module embedded within a registry. Recruitment ranged between 209 to 106,000 participants. Advantages of rRCTs are recruitment efficiency, shorter trial times, cost effectiveness, outcome data completeness, smaller carbon footprint, lower participant burden and the ability to conduct multiple trials from the same registry. Challenges are data collection/management, quality assurance issues and the timing of informed consent.

Conclusions

Optimising the design of rRCTs is dependent on the capabilities of the registry. New registries should be designed and existing registries reviewed to enable the conduct of rRCTs. At all times, data management and quality assurance of all registry data should be given key consideration. We suggest the inclusion of the term ‘registry-based’ in the title of all rRCT manuscripts and a clear simple breakdown of the registry-based conduct of the trial in the abstract to facilitate indexing in the major databases.
The integrin CD11b inhibits MSU-induced NLRP3 inflammasome activation in macrophages and protects mice against MSU-induced joint inflammation
Authors: Ehirchiou Driss , Bernabei Ilaria , Pandian Vishnuprabu Durairaj , Nasi Sonia , Chobaz Veronique , Castelblanco Mariela , So Alexander , Martinon Fabio , Li Xiaoyun , Acha-Orbea Hans , Hugle Thomas , Zhang Li , Busso Nathalie
Published: June 2024

Objective

In gout, monosodium urate crystals are taken up by macrophages, triggering the activation of the NLRP3 inflammasome and the maturation of IL-1β. This study aimed to investigate the role of integrin CD11b in inflammasome activation in macrophages stimulated by MSU.

Methods

BMDM from WT and CD11b KO mice were stimulated in vitro with MSU crystals. Cellular supernatants were collected to assess the expression of the inflammatory cytokines by enzyme-linked immunosorbent assay and western blot methods. The role of integrin CD11b in MSU-induced gouty arthritis in vivo was investigated by intra-articular injection of MSU crystals. Real-time extracellular acidification rate and oxygen consumption rate of BMDMs were measured by Seahorse Extracellular Flux Analyzer.

Results

We demonstrate that CD11b-deficient mice developed exacerbated gouty arthritis with increased recruitment of leukocytes in the joint and higher IL-1β levels in the sera. In macrophages, genetic deletion of CD11b induced a shift of macrophage metabolism from oxidative phosphorylation to glycolysis, thus decreasing the overall generation of intracellular ATP. Upon MSU stimulation, CD11b-deficient macrophages showed an exacerbated secretion of IL-1β. Treating wild-type macrophages with a CD11b agonist, LA1, inhibited MSU-induced release of IL-1β in vitro and attenuated the severity of experimental gouty arthritis. Importantly, LA1, was also effective in human cells as it inhibited MSU-induced release of IL-1β by peripheral blood mononuclear cells from healthy donors.

Conclusion

Our data identified the CD11b integrin as a principal cell membrane receptor that modulates NLRP3 inflammasome activation by MSU crystal in macrophages, which could be a potential therapeutic target to treat gouty arthritis in human patients.
Acute effects of multi-ingredient pre-workout dietary supplement on anaerobic performance in untrained men: a randomized, crossover, single blind study
Authors: Drwal Aleksander , Pałka Tomasz , Tota Lukasz , Wiecha Szczepan , Čech Pavol , Strzała Marek , Maciejczyk Marcin
Published: June 2024

Background

Multi-ingredient pre-workout dietary supplements (MIPS), which are combinations of different ingredients acting on different physiological mechanisms, can have a synergistic effect and improve performance. The aim of the study was to determine the acute effects of a multi-ingredient pre-workout supplement containing: beta-alanine, taurine, caffeine, L-tyrosine, and cayenne pepper (capsaicin) on anaerobic performance.

Methods

A randomized, crossover, single-blind study was designed. Twelve young, healthy, untrained men aged 22.4 ± 1.44 years participated in the study. The participants performed a supramaximal all-out test (20 s Wingate test) twice, day by day, in random order: test after placebo or MIPS consumption. In both trials, the following variables were measured in the exercise test: total work performed, peak power, mean power, time to reach peak power, and power decrease.

Results

MIPS was found to be effective in improving peak power (p = 0.009, ES = 0.77) and mean power (p = 0.04, ES = 0.62) in the Wingate test. However, the supplement consumption did not affect the amount of total work done (p = 0.10, ES = 0.48) in the test or power decrease (p = 0.07, ES = 0.53). The data indicate, that the improvement in anaerobic power was due to a significant improvement in pedaling speed, which was manifested in a significant improvement (i.e. shortening) in time to peak power (p = 0.003, ES = 0.88).

Conclusion

A multi-ingredient pre-workout dietary supplement was found to be effective in improving Wingate (anaerobic) performance.

Trial registration

NCT06363669, retrospectively registered on 11.04.2024 (ClinicalTrials.gov).
The value of apparent diffusion coefficient values in predicting Gleason grading of low to intermediate-risk prostate cancer
Authors: Yan Xu , Ma Ke , Zhu Li , Pan Yiqi , Wang Yuting , Shi Jiong , Mai Xiaoli
Published: June 2024

Objectives

To investigate the diagnostic performance of the apparent diffusion coefficient (ADC) for low to intermediate-risk prostate cancer (PCa), as well as its correlation with the prognostic Gleason score (GS).

Materials and methods

Retrospective analysis of MRI images and relevant clinical data from patients with prostate disease. The differences in ADC between different GS groups were compared, and the efficacy of ADC in PCa diagnosis were analyzed. Furthermore, the diagnostic performance of the mean ADC (ADCmean) and minimum ADC (ADCmin) values was compared.

Results

There were 1414 patients with 1631 lesions. In terms of GS, both ADCmin and ADCmean values of the GS 4 + 3 group were significantly lower than those of the GS 3 + 4 group, GS 3 + 3 group, and the benign group, with all differences being statistically significant (p < 0.01). The AUC values for diagnosing PCa based on ADCmin and ADCmean were 0.914 and 0.944, respectively. The corresponding diagnostic thresholds were 0.703 × 10−3 mm2/s for ADCmin and 0.927 × 10−3 mm2/s for ADCmean. The magnitudes of ADCmin and ADCmean values exhibited a negative correlation with GS values (ρ = −0.750, p < 0.001; ρ = −0.752, p < 0.001).

Conclusions

ADC values demonstrate an inverse relationship with the invasiveness of PCa, indicating that higher invasiveness is associated with lower ADC values. Additionally, ADC values exhibit high diagnostic potential, sensitivity, and specificity for distinguishing between GS 3 + 4 and GS 4 + 3 lesions. Moreover, the diagnostic value of ADCmean is even more significant, highlighting its crucial role in the diagnosis of low to intermediate-risk PCa.

Critical relevance statement

ADC values are a valuable tool for distinguishing different levels of aggressiveness in PCa. They help in the preoperative assessment of the biological characteristics of PCa, allowing clinicians to develop personalized treatment strategies, effectively mitigating the risk of unnecessary interventions.

Key Points

The preoperative GS is crucial for planning the clinical treatment of PCa.

The invasiveness of PCa is inversely correlated with ADC values.

ADC values play a crucial role in the accurate preoperative evaluation of low to intermediate-risk PCa, thus aiding clinicians in developing tailored treatment plans.

Graphical Abstract
Unlocking the potential: T1-weighed MRI as a powerful predictor of levodopa response in Parkinson’s disease
Authors: Yan Junyi , Luo Xufang , Xu Jiahang , Li Dongsheng , Qiu Lili , Li Dianyou , Cao Peng , Zhang Chencheng
Published: June 2024

Background

The efficacy of levodopa, the most crucial metric for Parkinson’s disease diagnosis and treatment, is traditionally gauged through the levodopa challenge test, which lacks a predictive model. This study aims to probe the predictive power of T1-weighted MRI, the most accessible modality for levodopa response.

Methods

This retrospective study used two datasets: from the Parkinson’s Progression Markers Initiative (219 records) and the external clinical dataset from Ruijin Hospital (217 records). A novel feature extraction method using MedicalNet, a pre-trained deep learning network, along with three previous approaches was applied. Three machine learning models were trained and tested on the PPMI dataset and included clinical features, imaging features, and their union set, using the area under the curve (AUC) as the metric. The most significant brain regions were visualized. The external clinical dataset was further evaluated using trained models. A paired one-tailed t-test was performed between the two sets; statistical significance was set at p < 0.001.

Results

For 46 test set records (mean age, 62 ± 9 years, 28 men), MedicalNet-extracted features demonstrated a consistent improvement in all three machine learning models (SVM 0.83 ± 0.01 versus 0.73 ± 0.01, XgBoost 0.80 ± 0.04 versus 0.74 ± 0.02, MLP 0.80 ± 0.03 versus 0.70 ± 0.07, p < 0.001). Both feature sets were validated on the clinical dataset using SVM, where MedicalNet features alone achieved an AUC of 0.64 ± 0.03. Key responsible brain regions were visualized.

Conclusion

The T1-weighed MRI features were more robust and generalizable than the clinical features in prediction; their combination provided the best results. T1-weighed MRI provided insights on specific regions responsible for levodopa response prediction.

Critical relevance statement

This study demonstrated that T1w MRI features extracted by a deep learning model have the potential to predict the levodopa response of PD patients and are more robust than widely used clinical information, which might help in determining treatment strategy.

Key Points

This study investigated the predictive value of T1w features for levodopa response.

MedicalNet extractor outperformed all other previously published methods with key region visualization.

T1w features are more effective than clinical information in levodopa response prediction.

Graphical Abstract
Temporal evolution of primary angiitis of the central nervous system (PACNS) on MRI following immunosuppressant treatment
Authors: Wagner Franca , Almeida Gonçalo G. , Willems Erik P. , Weber Johannes , Geiss Johannes , Hundsberger Thomas , Mordasini Pasquale , Wildermuth Simon , Leschka Sebastian , Waelti Stephan , Dietrich Tobias Johannes , Fischer Tim Steffen
Published: June 2024

Purpose

To systematically analyse the time course of vessel wall enhancement and associated stenosis in patients with primary angiitis of the central nervous system (PACNS) following immunosuppressive therapy.

Material and methods

Two neuroradiologists retrospectively analysed MRIs of patients with PACNS seen at the Bern University Hospital and the St. Gallen Cantonal Hospital between 2015 and 2020. MRIs were examined for the presence of vessel wall enhancement, length of vessel wall enhancement (mm), circumferential extent of enhancement (degree) and degree of stenosis (%). Descriptive statistics and measurements of interobserver reliability were obtained. To investigate the temporal profiles of the variables following the commencement of immunosuppressant treatment, four series of Bayesian generalised multi-level models were generated.

Results

A total of 23 patients with 43 affected vessels identified from 209 MRI exams were evaluated (mean follow-up: 715 days, standard deviation ± 487 days), leading to a complete dataset of 402 entries. Vessel wall enhancement and circumferential extent of enhancement decreased for approximately 1 year after the initiation of immunosuppressant therapy. Changes were more pronounced in younger patients. Disappearance of vessel wall enhancement (in at least one vessel) was seen in about half of patients after a median of 172 days interquartile range 113–244, minimum 54 days, maximum 627 days.

Conclusions

This study evaluated the typical time course of vessel wall enhancement in patients with PACNS. Our results could be a useful reference for radiologists and clinicians interpreting follow-up imaging in patients with PACNS.

Critical relevance statement

Routine clinical exams can be interpreted with more confidence when radiologists are aware of the typical temporal evolution of vessel wall enhancement in patients with primary angiitis of the central nervous system after initiation of immunosuppressive therapy.

Key Points

Few data exist for vessel wall imaging of primary angiitis of the central nervous system.

Following immunosuppressant therapy, vessel wall enhancement decreases for approximately one year.

These results may serve as a reference for radiologists performing follow-up imaging.

Graphical Abstract
Not only Van Gogh: a case of BRASH syndrome with concomitant digoxin toxicity
Authors: Costantini Ilaria , Mantelli Giovanni , Carollo Massimo , Losso Lorenzo , Morando Elia , Bacchion Matilde , Castri Mariapaola , Drezza Lucia , Ricci Giorgio
Published: June 2024

Background

Bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia syndrome is a potentially life-threatening clinical condition characterized by bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia. It constitutes a vicious circle in which the accumulation of pharmacologically active compounds and hyperkalemia lead to hemodynamic instability and heart failure.

Case presentation

A 66-year-old Caucasian female patient was admitted to the emergency department presenting with fatigue and bradycardia. Upon examination, the patient was found to be anuric and hypotensive. Laboratory investigations revealed metabolic acidosis and hyperkalemia. Clinical evaluation suggested signs of digoxin toxicity, with serum digoxin concentrations persistently elevated over several days. Despite the implementation of antikalemic measures, the patient’s condition remained refractory, necessitating renal dialysis and administration of digoxin immune fab.

Conclusion

Bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia syndrome is a life-threatening condition that requires prompt management. It is important to also consider potential coexisting clinical manifestations indicative of intoxication from other pharmacological agents. Specifically, symptoms associated with the accumulation of drugs eliminated via the kidneys, such as digoxin. These manifestations may warrant targeted therapeutic measures.
Mesenchymal stem cell therapy for therapy refractory complex Crohn’s perianal fistulas: a case series
Authors: Pronk A. J. M. , Beek K. J. , Wildenberg M.E. , Bemelman W. A. , Stoker J. , Buskens C. J.
Published: June 2024

Background

Mesenchymal stem cell treatment (MST) has emerged as a new therapeutic strategy for Crohn’s perianal fistulas. It has been demonstrated that a fibrotic tract on MRI with a MAGNIFI-CD score ≤ 6 is the best predictor for long-term clinical closure. Therefore, the aim of the current study was to analyse the effectiveness of MST for complex Crohn’s perianal fistulas based on MRI.

Methods

Consecutive patients with complex Crohn’s perianal fistulas, previously failing both anti-TNF treatment and surgical closure, who had surgical closure of the internal opening with MST were included. The primary endpoint was radiological remission of the fistula(s) defined as a MAGNIFI-CD ≤ 6 on MRI, read by an experienced radiologist.

Results

Between December 2019 and March 2023, 30 patients (15 males) with 48 fistula tracts were included with a median follow-up of 16.5 months. Radiological remission was achieved in thirteen patients (43.3%) after a median follow-up of 5.0 months (IQR 3.0–6.0). The median MAGNIFI-CD at baseline was 15.0 (IQR 7.0–20.0) which significantly decreased to 8.0 (IQR 3.0–15.0) after treatment (p = 0.001). Clinical closure was achieved in 21 patients (70.0%). Three patients (14.3%) developed a recurrence during long-term FU, all with clinically closed fistula(s), but no radiological remission. The median PDAI decreased significantly from 10.5 (IQR 7.0–14.0) to 4.0 (IQR 0.0-7.3) (p = 0.001).

Conclusion

MST is a promising treatment strategy for therapy refractory Crohn’s perianal fistulas, resulting in > 40% radiological remission, clinical closure in 70% and a significant improvement in quality of life. No recurrences were seen in patients with radiological remission.
Macrophages in tissue repair and regeneration: insights from zebrafish
Authors: Zhao Changlong , Yang Zhiyong , Li Yunbo , Wen Zilong
Published: June 2024

Macrophages play crucial and versatile roles in regulating tissue repair and regeneration upon injury. However, due to their complex compositional heterogeneity and functional plasticity, deciphering the nature of different macrophage subpopulations and unraveling their dynamics and precise roles during the repair process have been challenging. With its distinct advantages, zebrafish (Danio rerio) has emerged as an invaluable model for studying macrophage development and functions, especially in tissue repair and regeneration, providing valuable insights into our understanding of macrophage biology in health and diseases. In this review, we present the current knowledge and challenges associated with the role of macrophages in tissue repair and regeneration, highlighting the significant contributions made by zebrafish studies. We discuss the unique advantages of the zebrafish model, including its genetic tools, imaging techniques, and regenerative capacities, which have greatly facilitated the investigation of macrophages in these processes. Additionally, we outline the potential of zebrafish research in addressing the remaining challenges and advancing our understanding of the intricate interplay between macrophages and tissue repair and regeneration.
Combining genetic markers, on-farm information and infrared data for the in-line prediction of blood biomarkers of metabolic disorders in Holstein cattle
Authors: Mota Lucio F. M. , Giannuzzi Diana , Pegolo Sara , Toledo-Alvarado Hugo , Schiavon Stefano , Gallo Luigi , Trevisi Erminio , Arazi Alon , Katz Gil , Rosa Guilherme J. M. , Cecchinato Alessio
Published: June 2024

Background

Various blood metabolites are known to be useful indicators of health status in dairy cattle, but their routine assessment is time-consuming, expensive, and stressful for the cows at the herd level. Thus, we evaluated the effectiveness of combining in-line near infrared (NIR) milk spectra with on-farm (days in milk [DIM] and parity) and genetic markers for predicting blood metabolites in Holstein cattle. Data were obtained from 388 Holstein cows from a farm with an AfiLab system. NIR spectra, on-farm information, and single nucleotide polymorphisms (SNP) markers were blended to develop calibration equations for blood metabolites using the elastic net (ENet) approach, considering 3 models: (1) Model 1 (M1) including only NIR information, (2) Model 2 (M2) with both NIR and on-farm information, and (3) Model 3 (M3) combining NIR, on-farm and genomic information. Dimension reduction was considered for M3 by preselecting SNP markers from genome-wide association study (GWAS) results.

Results

Results indicate that M2 improved the predictive ability by an average of 19% for energy-related metabolites (glucose, cholesterol, NEFA, BHB, urea, and creatinine), 20% for liver function/hepatic damage, 7% for inflammation/innate immunity, 24% for oxidative stress metabolites, and 23% for minerals compared to M1. Meanwhile, M3 further enhanced the predictive ability by 34% for energy-related metabolites, 32% for liver function/hepatic damage, 22% for inflammation/innate immunity, 42.1% for oxidative stress metabolites, and 41% for minerals, compared to M1. We found improved predictive ability of M3 using selected SNP markers from GWAS results using a threshold of > 2.0 by 5% for energy-related metabolites, 9% for liver function/hepatic damage, 8% for inflammation/innate immunity, 22% for oxidative stress metabolites, and 9% for minerals. Slight reductions were observed for phosphorus (2%), ferric-reducing antioxidant power (1%), and glucose (3%). Furthermore, it was found that prediction accuracies are influenced by using more restrictive thresholds (−log10(P-value) > 2.5 and 3.0), with a lower increase in the predictive ability.

Conclusion

Our results highlighted the potential of combining several sources of information, such as genetic markers, on-farm information, and in-line NIR infrared data improves the predictive ability of blood metabolites in dairy cattle, representing an effective strategy for large-scale in-line health monitoring in commercial herds.
Trace amine associated receptor 1: predicted effects of single nucleotide variants on structure-function in geographically diverse populations
Authors: Shajan Britto , Marri Shashikanth , Bastiampillai Tarun , Gregory Karen J. , Hellyer Shane D. , Nair Pramod C.
Published: June 2024

Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmaceutical target under investigation for the treatment of several neuropsychiatric conditions. TAAR1 single nucleotide variants (SNV) have been found in patients with schizophrenia and metabolic disorders. However, the frequency of variants in geographically diverse populations and the functional effects of such variants are unknown. In this study, we aimed to characterise the distribution of TAAR1 SNVs in five different WHO regions using the Database of Genotypes and Phenotypes (dbGaP) and conducted a critical computational analysis using available TAAR1 structural data to identify SNVs affecting ligand binding and/or functional regions. Our analysis shows 19 orthosteric, 9 signalling and 16 micro-switch SNVs hypothesised to critically influence the agonist induced TAAR1 activation. These SNVs may non-proportionally influence populations from discrete regions and differentially influence the activity of TAAR1-targeting therapeutics in genetically and geographically diverse populations. Notably, our dataset presented with orthosteric SNVs D1033.32N (found only in the South-East Asian Region and Western Pacific Region) and T1945.42A (found only in South-East Asian Region), and 2 signalling SNVs (V1253.54A/T2526.36A, found in African Region and commonly, respectively), all of which have previously demonstrated to influence ligand induced functions of TAAR1. Furthermore, bioinformatics analysis using SIFT4G, MutationTaster 2, PROVEAN and MutationAssessor predicted all 16 micro-switch SNVs are damaging and may further influence the agonist activation of TAAR1, thereby possibly impacting upon clinical outcomes. Understanding the genetic basis of TAAR1 function and the impact of common mutations within clinical populations is important for the safe and effective utilisation of novel and existing pharmacotherapies.
A novel weight suppression score associates with distinct eating disorder and ultra-processed food addiction symptoms compared to the traditional weight suppression measure among adults seeking outpatient nutrition counseling
Authors: Wiss David A. , LaFata Erica M. , Tomiyama A. Janet
Published: June 2024

Background

Weight suppression has been defined as diet-induced weight loss, traditionally operationalized as the difference between one’s highest and current weight. This concept has been studied in the context of eating disorders, but its value in predicting treatment outcomes has been inconsistent, which may be partially attributed to its calculation.

Method

The current study operationalizes a novel weight suppression score, reflecting the midpoint between the lowest and highest adult weights among adults (N = 287, ages 21–75, 73.9% women) seeking outpatient treatment for disordered eating. This report compared the traditional weight suppression calculation to the novel weight suppression score in a simulated dataset to model their differential distributions. Next, we analyzed shared and distinct clinical correlates of traditional weight suppression versus the novel weight suppression score using clinical intake data.

Results

The novel weight suppression score was significantly associated with meeting criteria for both eating disorders and ultra-processed food addiction and was more sensitive to detecting clinically relevant eating disorder symptomatology. However, the novel weight suppression score (vs. traditional weight suppression) was associated with fewer ultra-processed food addiction symptoms.

Conclusion

The novel weight suppression score may be particularly relevant for those with eating disorders and ultra-processed food addiction, with more relevance to individual eating disorder compared to ultra-processed food addiction symptoms. Consideration of the novel weight suppression score in future research on eating behaviors should extend beyond just those with diagnosed eating disorders.
On data efficiency of univariate time series anomaly detection models
Authors: Sun Wu , Li Hui , Liang Qingqing , Zou Xiaofeng , Chen Mei , Wang Yanhao
Published: June 2024

In machine learning (ML) problems, it is widely believed that more training samples lead to improved predictive accuracy but incur higher computational costs. Consequently, achieving better data efficiency, that is, the trade-off between the size of the training set and the accuracy of the output model, becomes a key problem in ML applications. In this research, we systematically investigate the data efficiency of Univariate Time Series Anomaly Detection (UTS-AD) models. We first experimentally examine the performance of nine popular UTS-AD algorithms as a function of the training sample size on several benchmark datasets. Our findings confirm that most algorithms become more accurate when more training samples are used, whereas the marginal gain for adding more samples gradually decreases. Based on the above observations, we propose a novel framework called FastUTS-AD that achieves improved data efficiency and reduced computational overhead compared to existing UTS-AD models with little loss of accuracy. Specifically, FastUTS-AD is compatible with different UTS-AD models, utilizing a sampling- and scaling law-based heuristic method to automatically determine the number of training samples a UTS-AD model needs to achieve predictive performance close to that when all samples in the training set are used. Comprehensive experimental results show that, for the nine popular UTS-AD algorithms tested, FastUTS-AD reduces the number of training samples and the training time by 91.09–91.49% and 93.49–93.82% on average without significant decreases in accuracy.
Dynamics of gas and greenhouse gases production during fermentation of barley silage with lactic acid bacteria
Authors: Xue Yanlin , Wu Nier , Na Na , Sun Juanjuan , Sun Lin , Qili Moge , Li Dongyang , Li E. , Yang Baozhu
Published: June 2024

Greenhouse gases (GHGs) are generated during fermentation in silages, especially in barley silage. However, little is known regarding the dynamics of GHG production in silages during fermentation. In the present study, GHG accumulation and reduction were assessed in barley silage. Barley was harvested at the milk stage and ensiled without (CK) or with two commercial lactic acid bacterial (LAB) additives (L1 or L2). Gas and GHG (CO2, N2O, and CH4) production, fermentation quality, fermentation weight loss (FWL), and bacterial communities were analyzed at d 0, 1, 3, 6, 15, 35, and 90 after ensiling. Gas and GHG production rapidly increased in CK during the first 3 days and in L1 and L2 during the first day and then decreased (P < 0.05), and these values were higher in CK than in L1 and L2 from d 1 to d 35 (P < 0.05), with the peak production of gas and GHG observed at d 6 in CK and at d 3 in L1 and L2. Gas and GHG production were positively correlated with the count of Coliforms and the abundances of Enterobacter, Klebsiella, and Atlantibacter from d 0 to 6 (P < 0.05) but were negatively correlated with the abundances of Lentilactobacillus, Lactiplantibacillus, and Lacticaseibacillus from d 1 to 35 (P < 0.05). L1 and L2 had increasing pH and acetic acid (AA) and decreasing lactic acid after d 15 (P < 0.05). Lentilactobacillus in L1 and L2 dominated the bacterial communities from d 35 to 90 and correlated positively with pH and AA, and negatively with LA from d 6 to 90 (P < 0.05). FWL had a positive correlation with gas and GHG from d 1 to 35 (P < 0.05). The ensiling fermentation process can be divided into gas accumulation and reduction phases. Inoculation with LAB reduced gas and GHG production. The activities of enterobacteria were the main contributors to gas and GHG accumulation. Lentilactobacillus activity mainly caused deterioration of fermentation quality during the late fermentation phase. The GHGs generated in silage contributed to the FWL during fermentation.

Graphical Abstract