bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential expression and analysis of extrachromosomal circular DNAs as serum biomarkers in pulmonary arterial hypertension
Authors: Zhang Chun , Du Qiang , Zhou Xiao , Qu Tianyu , Liu Yingying , Ma Kai , Shen Ziling , Wang Qun , Zhang Zaikui , Zhang Ruifeng 
Published: April 2024

Abstract
Background
Extrachromosomal circular DNAs (eccDNAs) have been reported to play a key role in the occurrence and development of various diseases. However, the characterization and role of eccDNAs in pulmonary arterial hypertension (PAH) remain unclear.

Methods
In the discovery cohort, we first explored eccDNA expression profiles by Circle-sequencing analysis. The candidate eccDNAs were validated by routine polymerase chain reaction (PCR), TOPO-TA cloning and Sanger sequencing. In the validation cohort, 30 patients with PAH and 10 healthy controls were recruited for qPCR amplification to detect the candidate eccDNAs. Datas at the baseline were collected, including clinical background, biochemical variables, echocardiography and hemodynamic factors. Receiver operating characteristic curve was used to investigate the diagnostic effect of the eccDNA.

Results
We identified a total of 21,741 eccDNAs in plasma samples of 3 IPAH patients and 3 individuals in good health, and the expression frequency, GC content, length distribution, and genome distribution of the eccDNAs were thoroughly characterized and analyzed. In the validation cohort, 687 eccDNAs were differentially expressed in patients with IPAH compared with healthy controls (screening threshold: |FC|≥2 and P < 0.05). Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the specific eccDNAs in IPAH were significantly enriched in calcium channel activity, the mitogen-activated protein kinase pathway, and the wnt signaling pathway. Verification queue found that the expression of eccDNA-chr2:131208878–131,424,362 in PAH was considerably higher than that in healthy controls and exhibited a high level of accuracy in predicting PAH with a sensitivity of 86.67% and a specificity of 90%. Furthermore, correlation analysis disclosed a significant association between serum eccDNA-chr2:131208878–131,424,362 and mean pulmonary artery pressure (mPAP) (r = 0.396, P = 0.03), 6 min walking distance (6MWD) (r = -0.399, P = 0.029), N-terminal pro-B-type natriuretic peptide (NT-proBNP) (r = 0.685, P < 0.001) and cardiac index (CI) (r = − 0.419, P = 0.021).

Conclusions
This is the first study to identify and characterize eccDNAs in patients with PAH. We revealed that serum eccDNA-chr2:131208878–131,424,362 is significantly overexpressed and can be used in the diagnosis of PAH, indicating its potential as a novel non-invasive biomarker.
Neutrophil extracellular traps promote proliferation of pulmonary smooth muscle cells mediated by CCDC25 in pulmonary arterial hypertension
Authors: Sun Hongxiao , Du Zhanhui , Zhang Xu , Gao Shuai , Ji Zhixian , Luo Gang , Pan Silin 
Published: April 2024

Abstract
Background
Previous studies have indicated that neutrophil extracellular traps (NETs) play a pivotal role in pathogenesis of pulmonary arterial hypertension (PAH). However, the specific mechanism underlying the impact of NETs on pulmonary artery smooth muscle cells (PASMCs) has not been determined. The objective of this study was to elucidate underlying mechanisms through which NETs contribute to progression of PAH.

Methods
Bioinformatics analysis was employed in this study to screen for potential molecules and mechanisms associated with occurrence and development of PAH. These findings were subsequently validated in human samples, coiled-coil domain containing 25 (CCDC25) knockdown PASMCs, as well as monocrotaline-induced PAH rat model.

Results
NETs promoted proliferation of PASMCs, thereby facilitating pathogenesis of PAH. This phenomenon was mediated by the activation of transmembrane receptor CCDC25 on PASMCs, which subsequently activated ILK/β-parvin/RAC1 pathway. Consequently, cytoskeletal remodeling and phenotypic transformation occur in PASMCs. Furthermore, the level of NETs could serve as an indicator of PAH severity and as potential therapeutic target for alleviating PAH.

Conclusion
This study elucidated the involvement of NETs in pathogenesis of PAH through their influence on the function of PASMCs, thereby highlighting their potential as promising targets for the evaluation and treatment of PAH.
Did the prolonged residual efficacy of clothianidin products lead to a greater reduction in vector populations and subsequent malaria transmission compared to the shorter residual efficacy of pirimiphos-methyl?
Authors: Odjo Esdras Mahoutin , Akpodji Christian S. T. , Djènontin Armel , Salako Albert Sourou , Padonou Gil Germain , Adoha Constantin Jésukèdè , Yovogan Boulais , Adjottin Bruno , Tokponnon Filémon T. , Osse Razaki , Agbangla Clement , Akogbeto Martin C. 
Published: April 2024

Abstract
Background
The residual activity of a clothianidin + deltamethrin mixture and clothianidin alone in IRS covered more than the period of malaria transmission in northern Benin. The aim of this study was to show whether the prolonged residual efficacy of clothianidin-based products resulted in a greater reduction in vector populations and subsequent malaria transmission compared with the shorter residual efficacy of pirimiphos-methyl.

Methods
Human bait mosquito collections by local volunteers and pyrethrum spray collections were used in 6 communes under IRS monitoring and evaluation from 2019 to 2021. ELISA/CSP and species PCR tests were performed on Anopheles gambiae sensu lato (s.l.) to determine the infectivity rate and subspecies by commune and year. The decrease in biting rate, entomological inoculation rate, incidence, inhibition of blood feeding, resting density of An. gambiae s.l. were studied and compared between insecticides per commune.

Results
The An. gambiae complex was the major vector throughout the study area, acounting for 98.71% (19,660/19,917) of all Anopheles mosquitoes collected. Anopheles gambiae s.l. collected was lower inside treated houses (45.19%: 4,630/10,245) than outside (54.73%: 5,607/10,245) after IRS (p < 0.001). A significant decrease (p < 0.001) in the biting rate was observed after IRS in all departments except Donga in 2021 after IRS with clothianidin 50 WG. The impact of insecticides on EIR reduction was most noticeable with pirimiphos-methyl 300 CS, followed by the clothianidin + deltamethrin mixture and finally clothianidin 50 WG. A reduction in new cases of malaria was observed in 2020, the year of mass distribution of LLINs and IRS, as well as individual and collective protection measures linked to COVID-19. Anopheles gambiae s.l. blood-feeding rates and parous were high and similar for all insecticides in treated houses.

Conclusion
To achieve the goal of zero malaria, the optimal choice of vector control tools plays an important role. Compared with pirimiphos-methyl, clothianidin-based insecticides induced a lower reductions in entomological indicators of malaria transmission.
Effect of a vapor barrier in combination with active external rewarming for cold-stressed patients in a prehospital setting: a randomized, crossover field study
Authors: Mydske Sigurd , Brattebø Guttorm , Østerås Øyvind , Wiggen Øystein , Assmus Jörg , Thomassen Øyvind 
Published: April 2024

Abstract
Background
Use of a vapor barrier in the prehospital care of cold-stressed or hypothermic patients aims to reduce evaporative heat loss and accelerate rewarming. The application of a vapor barrier is recommended in various guidelines, along with both insulating and wind/waterproof layers and an active external rewarming device; however, evidence of its effect is limited. This study aimed to investigate the effect of using a vapor barrier as the inner layer in the recommended “burrito” model for wrapping hypothermic patients in the field.

Methods
In this, randomized, crossover field study, 16 healthy volunteers wearing wet clothing were subjected to a 30-minute cooling period in a snow chamber before being wrapped in a model including an active heating source either with (intervention) or without (control) a vapor barrier. The mean skin temperature, core temperature, and humidity in the model were measured, and the shivering intensity and thermal comfort were assessed using a subjective questionnaire. The mean skin temperature was the primary outcome, whereas humidity and thermal comfort were the secondary outcomes. Primary outcome data were analyzed using analysis of covariance (ANCOVA).

Results
We found a higher mean skin temperature in the intervention group than in the control group after approximately 25 min (p < 0.05), and this difference persisted for the rest of the 60-minute study period. The largest difference in mean skin temperature was 0.93 °C after 60 min. Humidity levels outside the vapor barrier were significantly higher in the control group than in the intervention group after 5 min. There were no significant differences in subjective comfort. However, there was a consistent trend toward increased comfort in the intervention group compared with the control group.

Conclusions
The use of a vapor barrier as the innermost layer in combination with an active external heat source leads to higher mean skin rewarming rates in patients wearing wet clothing who are at risk of accidental hypothermia.

Trial registration
ClinicalTrials.gov identifier: NCT05779722.
Statistical analysis plan for a cluster randomised trial in Madhya Pradesh, India: community health promotion and medical provision and impact on neonates (CHAMPION2)
Authors: Magill Nicholas , Shivalli Siddharudha , Fazzio Ila , Elbourne Diana , Keddie Suzanne , Reddy Padmanabh , Nair Rakhi , Gopal Madan , Karnati Sridevi , Reddy Harshavardhan , Boone Peter , Frost Chris 
Published: April 2024

Abstract
Background
Neonatal mortality in India has fallen steadily and was estimated to be 24 per 1000 live births in the year 2017. However, neonatal mortality remains high in rural parts of the country. The Community Health Promotion and Medical Provision and Impact On Neonates (CHAMPION2) trial investigates the effect of a complex health intervention on neonatal mortality in the Satna District of Madhya Pradesh.

Methods/design
The CHAMPION2 trial forms one part of a cluster-randomised controlled trial with villages (clusters) randomised to receive either a health (CHAMPION2) or education (STRIPES2) intervention. Villages receiving the health intervention are controls for the education intervention and vice versa. The primary outcome is neonatal mortality. The effect of the active intervention on the primary outcome (compared to usual care) will be expressed as a risk ratio, estimated using a generalised estimating equation approach with robust standard errors that take account of clustering at village level. Secondary outcomes include maternal mortality, stillbirths, perinatal deaths, causes of death, health care and knowledge, hospital admissions of enrolled women during pregnancy or in the immediate post-natal care period or of their babies (during the neonatal period), maternal blood transfusions, and the cost effectiveness of the intervention. A total of 196 villages have been randomised and over 34,000 women have been recruited in CHAMPION2.

Discussion
This update to the published trial protocol gives a detailed plan for the statistical analysis of the CHAMPION2 trial.

Trial registration
Registry of India: CTRI/2019/05/019296. Registered on 23 May 2019. https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MzExOTg=&Enc=&userName=champion2
The effect of movement system impairment-based classification treatment compared to routine physiotherapy on pain, disability, alignment, and movement impairments in individuals with tibiofemoral rotation syndrome: a randomized controlled trial
Authors: Mousavi Forouzan , Kajbafvala Mehrnaz , Mohsenifar Holakoo , Salehi Reza , Hejazi Anahita 
Published: April 2024

Abstract
Background
Knee pain is a common musculoskeletal problem. Lower extremity movement impairments could alter stresses in different planes and contribute to knee pain. Classifying these impairments may be helpful in the diagnosis and treatment of knee problems. Movement system impairment (MSI)-based classification is a system to evaluate movement impairments. Trials that involve this classification are limited. Therefore, it will be of interest to examine the effect of movement system impairment-based classification treatment compared to routine physiotherapy in individuals with tibiofemoral rotation syndrome.

Methods
Twenty-two individuals with knee pain aged 18–40 years (2 males, 20 females) diagnosed with tibiofemoral rotation (TFR) syndrome were included. After initial evaluation, individuals were randomly assigned into two treatment groups (MSI-based treatment and routine physiotherapy). Both treatment groups contained 8 treatment sessions over 4 weeks. Alignment and movement impairments data form, a numeric rating scale (NRS), and the Kujala Disability Questionnaire were assessed at baseline and after a four-week intervention. Independent samples t-test and Mann-Whitney U test were used for quantitative variables, and Fisher’s exact test was employed for qualitative variables to compare the groups. One-way Analysis of variance (ANOVA) and paired samples t-test were utilized to within-group changes of quantitative variables, and qualitative variables were analyzed with the McNemar test.

Results
The results showed that pain intensity and disability significantly decreased within and between groups after intervention (P > 0.05). There were also statistically significant differences between treatment groups for 3 out of 6 alignment and movement impairments (PS-FAdd/IR, Step down-Add/Valgus, and STS-Add/Valgus) (P > 0.05). Within-group differences for alignment and movement impairments were significant only for the MSI-based treatment group (P > 0.05).

Conclusions
The findings suggest that a specific MSI-based treatment, considering a homogenous group of individuals with knee pain, may contribute to pain, disability, and alignment and movement impairments improvement. Therefore, it is important to notice the classification-based treatment for individuals with knee pain.

Trial Registration Number (TRN) and date of registration
The trial was registered at the (https://www.irct.ir), (IRCT20210505051181N3) on 17/7/2021.
Associations of plasma neurofilament light chain with cognition and neuroimaging measures in community-dwelling early old age men
Authors: Tang Rongxiang , Buchholz Erik , Dale Anders M. , Rissman Robert A. , Fennema-Notestine Christine , Gillespie Nathan A. , Hagler Donald J , Lyons Michael J. , Neale Michael C. , Panizzon Matthew S. , Puckett Olivia K. , Reynolds Chandra A. , Franz Carol E. , Kremen William S. , Elman Jeremy A. 
Published: April 2024

Abstract
Background
Plasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations.

Methods
We examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61–73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter.

Results
After adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals.

Conclusions
These results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.
Ontological representation, modeling, and analysis of parasite vaccines
Authors: Huffman Anthony , Zhang Xumeng , Lanka Meghana , Zheng Jie , Masci Anna Maria , He Yongqun 
Published: April 2024

Abstract
Background
Pathogenic parasites are responsible for multiple diseases, such as malaria and Chagas disease, in humans and livestock. Traditionally, pathogenic parasites have been largely an evasive topic for vaccine design, with most successful vaccines only emerging recently. To aid vaccine design, the VIOLIN vaccine knowledgebase has collected vaccines from all sources to serve as a comprehensive vaccine knowledgebase. VIOLIN utilizes the Vaccine Ontology (VO) to standardize the modeling of vaccine data. VO did not model complex life cycles as seen in parasites. With the inclusion of successful parasite vaccines, an update in parasite vaccine modeling was needed.

Results
VIOLIN was expanded to include 258 parasite vaccines against 23 protozoan species, and 607 new parasite vaccine-related terms were added to VO since 2022. The updated VO design for parasite vaccines accounts for parasite life stages and for transmission-blocking vaccines. A total of 356 terms from the Ontology of Parasite Lifecycle (OPL) were imported to VO to help represent the effect of different parasite life stages. A new VO class term, ‘transmission-blocking vaccine,’ was added to represent vaccines able to block infectious transmission, and one new VO object property, ‘blocks transmission of pathogen via vaccine,’ was added to link vaccine and pathogen in which the vaccine blocks the transmission of the pathogen. Additionally, our Gene Set Enrichment Analysis (GSEA) of 140 parasite antigens used in the parasitic vaccines identified enriched features. For example, significant patterns, such as signal, plasma membrane, and entry into host, were found in the antigens of the vaccines against two parasite species: Plasmodium falciparum and Toxoplasma gondii. The analysis found 18 out of the 140 parasite antigens involved with the malaria disease process. Moreover, a majority (15 out of 54) of P. falciparum parasite antigens are localized in the cell membrane. T. gondii antigens, in contrast, have a majority (19/24) of their proteins related to signaling pathways. The antigen-enriched patterns align with the life cycle stage patterns identified in our ontological parasite vaccine modeling.

Conclusions
The updated VO modeling and GSEA analysis capture the influence of the complex parasite life cycles and their associated antigens on vaccine development.
Protocol for the development of a consensus practice guideline To address clinical and regulatory barriers to buprenorphine dispensing in community pharmacy
Authors: Varisco Tyler J. , Fish Hannah , Bolin Joshua , Dadiomov David , Hill Lucas G. , Essien Ekere J. , Wanat Matthew A. , Ginsburg Diane , Waggener Jeanne , Yazdanfard Sahar , Song Juhyeon , Chi Whanhui , Thornton Douglas 
Published: April 2024

Abstract
Background
Less than half of community pharmacies in the United States stock buprenorphine products indicated for the treatment of opioid use disorder. This lack of access to buprenorphine in community pharmacies is a significant barrier to care. To address this issue, this protocol outlines a comprehensive approach to develop a practice guideline aimed at improving access to safe and effective opioid use disorder treatment in community pharmacies.

Methods
The guideline development process will proceed in three phases, following a technique closely aligned with the Institute of Medicine’s guidance on guideline development. The first phase will involve conducting qualitative interviews with pharmacists in three states to identify their beliefs toward buprenorphine dispensing. As limitations on buprenorphine supply are related to constraints at all levels of the drug supply and regulatory system, the second phase, we will recruit representatives from regulatory agencies, pharmacy organizations, the Drug Enforcement Administration, pharmaceutical wholesalers as well as addiction medicine physicians and psychiatric pharmacists to develop consensus recommendations through a modified Delphi design. This will be followed by a public comment period and external expert review of the recommendations led by the National Association of Boards of Pharmacy. Finally, in the third phase, a national, mixed media dissemination campaign will be led by the National Community Pharmacists Association (NCPA) to convey recommendations to practicing pharmacists.

Discussion
The guideline development process aims to incorporate the perspectives of multiple stakeholders and emphasize the importance of addressing the regulatory and pharmacy-specific aspects of care in addition to clinical evidence and guidance. The development of this guideline will provide targeted, multidisciplinary guidance for pharmacists, improving access to safe and effective opioid use disorder treatment in the community setting.

Preregistration
This protocol was registered with the Open Science Framework in March of 2023. Registration may be found at: https://doi.org/10.17605/OSF.IO/6S9DY.
LINC complex alterations are a key feature of sporadic and familial ALS/FTD
Authors: Sirtori Riccardo , J. Gregoire Michelle , M. Potts Emily , Collins Alicia , Donatelli Liviana , Fallini Claudia 
Published: April 2024

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects motor neurons, leading to progressive muscle weakness and loss of voluntary muscle control. While the exact cause of ALS is not fully understood, emerging research suggests that dysfunction of the nuclear envelope (NE) may contribute to disease pathogenesis and progression. The NE plays a role in ALS through several mechanisms, including nuclear pore defects, nucleocytoplasmic transport impairment, accumulation of mislocalized proteins, and nuclear morphology abnormalities. The LINC complex is the second biggest multi-protein complex in the NE and consists of the SUN1/2 proteins spanning the inner nuclear membrane and Nesprin proteins embedded in the outer membrane. The LINC complex, by interacting with both the nuclear lamina and the cytoskeleton, transmits mechanical forces to the nucleus regulating its morphology and functional homeostasis. In this study we show extensive alterations to the LINC complex in motor and cortical iPSC-derived neurons and spinal cord organoids carrying the ALS causative mutation in the C9ORF72 gene (C9). Importantly, we show that such alterations are present in vivo in a cohort of sporadic ALS and C9-ALS postmortem spinal cord and motor cortex specimens. We also found that LINC complex disruption strongly correlated with nuclear morphological alterations occurring in ALS neurons, independently of TDP43 mislocalization. Altogether, our data establish morphological and functional alterations to the LINC complex as important events in ALS pathogenic cascade, making this pathway a possible target for both biomarker and therapy development.