bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of the adaptive immune system and T cell dysfunction in neurodegenerative diseases
Authors: DeMaio Alexa , Mehrotra Shikhar , Sambamurti Kumar , Husain Shahid 
Published: October 2022

AbstractThe adaptive immune system and associated inflammation are vital in surveillance and host protection against internal and external threats, but can secondarily damage host tissues. The central nervous system is immune-privileged and largely protected from the circulating inflammatory pathways. However, T cell involvement and the disruption of the blood–brain barriers have been linked to several neurodegenerative diseases including Parkinson's disease, Alzheimer’s disease, and multiple sclerosis. Under normal physiological conditions, regulatory T cells (Treg cells) dampen the inflammatory response of effector T cells. In the pathological states of many neurodegenerative disorders, the ability of Treg cells to mitigate inflammation is reduced, and a pro-inflammatory environment persists. This perspective review provides current knowledge on the roles of T cell subsets (e.g., effector T cells, Treg cells) in neurodegenerative and ocular diseases, including uveitis, diabetic retinopathy, age-related macular degeneration, and glaucoma. Many neurodegenerative and ocular diseases have been linked to immune dysregulation, but the cellular events and molecular mechanisms involved in such processes remain largely unknown. Moreover, the role of T cells in ocular pathologies remains poorly defined and limited literature is available in this area of research. Adoptive transfer of Treg cells appears to be a vital immunological approach to control ocular pathologies. Similarities in T cell dysfunction seen among non-ocular neurodegenerative diseases suggest that this area of research has a great potential to develop better therapeutic agents for ocular diseases and warrants further studies. Overall, this perspective review article provides significant information on the roles of T cells in numerous ocular and non-ocular neurodegenerative diseases.
The effects of completion of continuum of care in maternal health services on adverse birth outcomes in Northwestern Ethiopia: a prospective follow-up study
Authors: Zelka Muluwas Amentie , Yalew Alemayehu Worku , Debelew Gurmesa Tura 
Published: October 2022

AbstractBackgroundGlobally, around 4 million babies die within the first month of birth annually with more than 3 million stillbirths. Of them, 99% of newborn deaths and 98% of stillbirths occur in developing countries. Despite giving priority to maternal health services, adverse birth outcomes are still major public health problems in the study area. Hence, a continuum of care (CoC) is a core key strategy to overcome those challenges. The study conducted on the effectiveness of continuum of care in maternal health services was scarce in developing countries and not done in the study area. We aimed to assess the effectiveness of continuum of care and determinants of adverse birth outcomes.MethodsCommunity and health facility-linked prospective follow-up study designs were employed from March 2020 to January 2021 in Northwestern Ethiopia. A multistage clustered sampling technique was used to recruit 2198 pregnant women. Data were collected by using a semi-structured and pretested questionnaire. Collected data were coded, entered, cleaned, and analyzed by STATA 14. Multilevel logistic regression model was used to identify community and individual-level factors. Finally, propensity score matching was applied to determine the effectiveness of continuum of care.ResultsThe magnitude of adverse birth outcomes was 12.4% (95% CI 12.2–12.7): stillbirth (2.8%; 95% CI 2.7–3.0), neonatal mortality (3.1%; 95% CI 2.9–3.2), and neonatal morbidity (6.8%; 95% CI 6.6–7.0). Risk factors were poor household wealth (AOR = 3.3; 95% CI 1.07–10.23), pregnant-related maternal complications during pregnancy (AOR = 3.29; 95% CI 1.68–6.46), childbirth (AOR = 6.08; 95% CI 2.36–15.48), after childbirth (AOR = 5.24; 95% CI 2.23–12.33), an offensive odor of amniotic fluid (AOR = 3.04; 95% CI 1.37–6.75) and history of stillbirth (AOR = 4.2; 95% CI 1.78–9.93). Whereas, receiving iron-folic acid (AOR = 0.44; 95% CI 0.14–0.98), initiating breastfeeding within 1 h (AOR = 0.22; 95% CI 0.10–0.50) and immunizing newborn (AOR = 0.33; 95% CI 0.12–0.93) were protective factors. As treatment effect, completion of continuum of care via time dimension (β = − 0.03; 95% CI − 0.05, − 0.01) and space dimension (β = − 0.03; 95% CI − 0.04, − 0.01) were significantly reduce perinatal death.ConclusionsAdverse birth outcomes were high as compared with national targets. Completion of continuum of care is an effective intervention for reducing perinatal death. Efforts should be made to strengthen the continuum of care in maternal health services, iron supplementation, immunizing and early initiation of breastfeeding.
A unilateral robotic knee exoskeleton to assess the role of natural gait assistance in hemiparetic patients
Authors: Lora-Millan Julio Salvador , Sanchez-Cuesta Francisco José , Romero Juan Pablo , Moreno Juan C. , Rocon Eduardo 
Published: October 2022

AbstractBackgroundHemiparetic gait is characterized by strong asymmetries that can severely affect the quality of life of stroke survivors. This type of asymmetry is due to motor deficits in the paretic leg and the resulting compensations in the nonparetic limb. In this study, we aimed to evaluate the effect of actively promoting gait symmetry in hemiparetic patients by assessing the behavior of both paretic and nonparetic lower limbs. This paper introduces the design and validation of the REFLEX prototype, a unilateral active knee–ankle–foot orthosis designed and developed to naturally assist the paretic limbs of hemiparetic patients during gait.MethodsREFLEX uses an adaptive frequency oscillator to estimate the continuous gait phase of the nonparetic limb. Based on this estimation, the device synchronically assists the paretic leg following two different control strategies: (1) replicating the movement of the nonparetic leg or (2) inducing a healthy gait pattern for the paretic leg. Technical validation of the system was implemented on three healthy subjects, while the effect of the generated assistance was assessed in three stroke patients. The effects of this assistance were evaluated in terms of interlimb symmetry with respect to spatiotemporal gait parameters such as step length or time, as well as the similarity between the joint’s motion in both legs.ResultsPreliminary results proved the feasibility of the REFLEX prototype to assist gait by reinforcing symmetry. They also pointed out that the assistance of the paretic leg resulted in a decrease in the compensatory strategies developed by the nonparetic limb to achieve a functional gait. Notably, better results were attained when the assistance was provided according to a standard healthy pattern, which initially might suppose a lower symmetry but enabled a healthier evolution of the motion of the nonparetic limb.ConclusionsThis work presents the preliminary validation of the REFLEX prototype, a unilateral knee exoskeleton for gait assistance in hemiparetic patients. The experimental results indicate that assisting the paretic leg of a hemiparetic patient based on the movement of their nonparetic leg is a valuable strategy for reducing the compensatory mechanisms developed by the nonparetic limb.
Adhered ECMO cannula in COVID-19 related severe acute respiratory failure
Authors: Kamalia Mohammed A. , Carlson Samuel F. , Melamed Joshua , Ubert Adam , Rossi Peter J. , Durham Lucian A. 
Published: October 2022

Abstract
Background
Crescent cannula adhesion in the setting of COVID-19 respiratory failure requiring extracorporeal membrane oxygenation (ECMO) support is a novel complication. The objective of this case presentation is to highlight this rare complication and to explore potential predisposing factors and our management strategies.

Case presentation
We present the case of a 25 y.o. patient with COVID-19 respiratory failure requiring ECMO support for 16-days in which a 32 Fr crescent cannula became adherent to the SVC and proximal jugular vein. Attempts to remove the cannula at the bedside failed due to immobility of the cannula. Ultrasound of the right neck was unremarkable, so he was taken to the hybrid OR where both TEE and fluoroscopy were unrevealing. An upper sternotomy was performed, and the superior vena cava and proximal jugular vein were dissected revealing a 2 cm segment of the distal SVC and proximal jugular vein that was densely sclerosed and adherent to the cannula. The vessel was opened across the adherent area at the level of the innominate vein and the cannula was then able to be withdrawn. The patient suffered no ill effects and had an unremarkable recovery to discharge.

Conclusions
To date, there have been no reports of crescent cannula adhesion related complications. In patients with COVID-19 respiratory failure requiring ECMO, clinicians should be aware of widespread hypercoagulability and the potential of unprovoked, localized venous sclerosis and cannula adhesion. We report our technique of decannulation in the setting of cannula adhesion and hope that presentation will shed further light on this complication allowing clinicians to optimize patient care.
The Korean undiagnosed diseases program phase I: expansion of the nationwide network and the development of long-term infrastructure
Authors: Kim Soo Yeon , Lee Seungbok , Woo Hyewon , Han Jiyeon , Ko Young Jun , Shim Youngkyu , Park Soojin , Jang Se Song , Lim Byung Chan , Ko Jung Min , Kim Ki Joong , Cho Anna , Kim Hunmin , Hwang Hee , Choi Ji Eun , Kim Man Jin , Moon Jangsup , Seong Moon-Woo , Park Sung Sup , Choi Sun Ah , Lee Ji Eun , Kwon Young Se , Sohn Young Bae , Kim Jon Soo , Kim Won Seop , Lee Yun Jeong , Kwon Soonhak , Kim Young Ok , Kook Hoon , Cho Yong Gon , Cheon Chong Kun , Kang Ki-Soo , Song Mi-Ryoung , Kim Young-Joon , Cha Hyuk-Jin , Choi Hee-Jung , Kee Yun , Park Sung-Gyoo , Baek Seung Tae , Choi Murim , Ryu Dong-Sung , Chae Jong-Hee 
Published: October 2022

Abstract
Background
Phase I of the Korean Undiagnosed Diseases Program (KUDP), performed for 3 years, has been completed. The Phase I program aimed to solve the problem of undiagnosed patients throughout the country and develop infrastructure, including a data management system and functional core laboratory, for long-term translational research. Herein, we share the clinical experiences of the Phase I program and introduce the activities of the functional core laboratory and data management system.

Results
During the program (2018–2020), 458 patients were enrolled and classified into 3 groups according to the following criteria: (I) those with a specific clinical assessment which can be verified by direct testing (32 patients); (II) those with a disease group with genetic and phenotypic heterogeneity (353 patients); and (III) those with atypical presentations or diseases unknown to date (73 patients). All patients underwent individualized diagnostic processes based on the decision of an expert consortium. Confirmative diagnoses were obtained for 242 patients (52.8%). The diagnostic yield was different for each group: 81.3% for Group I, 53.3% for Group II, and 38.4% for Group III. Diagnoses were made by next-generation sequencing for 204 patients (84.3%) and other genetic testing for 35 patients (14.5%). Three patients (1.2%) were diagnosed with nongenetic disorders. The KUDP functional core laboratory, with a group of experts, organized a streamlined research pipeline covering various resources, including animal models, stem cells, structural modeling and metabolic and biochemical approaches. Regular data review was performed to screen for candidate genes among undiagnosed patients, and six different genes were identified for functional research. We also developed a web-based database system that supports clinical cohort management and provides a matchmaker exchange protocol based on a matchbox, likely to reinforce the nationwide clinical network and further international collaboration.

Conclusions
The KUDP evaluated the unmet needs of undiagnosed patients and established infrastructure for a data-sharing system and future functional research. The advancement of the KUDP may lead to sustainable bench-to-bedside research in Korea and contribute to ongoing international collaboration.
Cancer-associated fibroblast-specific lncRNA LINC01614 enhances glutamine uptake in lung adenocarcinoma
Authors: Liu Tongyan , Han Chencheng , Fang Panqi , Ma Zhifei , Wang Xiaoxiao , Chen Hao , Wang Siwei , Meng Fanchen , Wang Cheng , Zhang Erbao , Dong Guozhang , Zhu Hongyu , Yin Wenda , Wang Jie , Zuo Xianglin , Qiu Mantang , Wang Jinke , Qian Xu , Shen Hongbing , Xu Lin , Hu Zhibin , Yin Rong 
Published: October 2022

Abstract
Background
Besides featured glucose consumption, recent studies reveal that cancer cells might prefer “addicting” specific energy substrates from the tumor microenvironment (TME); however, the underlying mechanisms remain unclear.

Methods
Fibroblast-specific long noncoding RNAs were screened using RNA-seq data of our NJLCC cohort, TCGA, and CCLE datasets. The expression and package of LINC01614 into exosomes were identified using flow cytometric sorting, fluorescence in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (RT-PCR). The transfer and functional role of LINC01614 in lung adenocarcinoma (LUAD) and CAFs were investigated using 4-thiouracil-labeled RNA transfer and gain- and loss-of-function approaches. RNA pull-down, RNA immunoprecipitation, dual-luciferase assay, gene expression microarray, and bioinformatics analysis were performed to investigate the underlying mechanisms involved.

Results
We demonstrate that cancer-associated fibroblasts (CAFs) in LUAD primarily enhance the glutamine metabolism of cancer cells. A CAF-specific long noncoding RNA, LINC01614, packaged by CAF-derived exosomes, mediates the enhancement of glutamine uptake in LUAD cells. Mechanistically, LINC01614 directly interacts with ANXA2 and p65 to facilitate the activation of NF-κB, which leads to the upregulation of the glutamine transporters SLC38A2 and SLC7A5 and eventually enhances the glutamine influx of cancer cells. Reciprocally, tumor-derived proinflammatory cytokines upregulate LINC01614 in CAFs, constituting a feedforward loop between CAFs and cancer cells. Blocking exosome-transmitted LINC01614 inhibits glutamine addiction and LUAD growth in vivo. Clinically, LINC01614 expression in CAFs is associated with the glutamine influx and poor prognosis of patients with LUAD.

Conclusion
Our study highlights the therapeutic potential of targeting a CAF-specific lncRNA to inhibit glutamine utilization and cancer progression in LUAD.
Exosomal circZNF451 restrains anti-PD1 treatment in lung adenocarcinoma via polarizing macrophages by complexing with TRIM56 and FXR1
Authors: Gao Jian , Ao Yong-Qiang , Zhang Ling-Xian , Deng Jie , Wang Shuai , Wang Hai-Kun , Jiang Jia-Hao , Ding Jian-Yong 
Published: October 2022

Abstract
Background
Although success was achieved in the therapy for a minority of advanced lung adenocarcinoma (LUAD) patients, anti-programmed death 1 (PD1) resistance was found in most LUAD patients. Here, we aimed to uncover a potential role of exosomal circular RNAs (circRNAs) in LUAD refractory to PD1 blockade.

Methods
circRNA sequencing and qRT-PCR were performed to determine the level of exosomal circRNAs in LUAD patients subsequently treated with anti-PD1. Then, the RNA pulldown, RNA immunoprecipitation, mass spectrometry, chromatin immunoprecipitation, luciferase reporter assays, flow cytometry, RNA sequencing, and in vitro and in vivo models were used to uncover the biological functions and underlying mechanism of circZNF451 in LUAD anti-PD1 treatment resistance.

Results
circRNA sequencing and qRT-PCR identified the up-regulation of exosomal circZNF451 from LUAD patients with progressive disease (PD) compared to those with partial remission (PR) after PD1 blockade therapy. Furthermore, elevated circZNF451 was revealed to be associated with poor prognosis of LUAD patients. Additionally, exosomal circZNF451 was demonstrated to induce an anti-inflammatory phenotype in macrophages and exhaustion of cytotoxic CD8+ T cells, and enhanced TRIM56-mediated degradation of FXR1 to activate the ELF4–IRF4 pathway in macrophages. By transgenic mice, knockout of ELF4 in macrophages was found to rescue immunotherapy efficacy in tumors with high level of exosomal circZNF451.

Conclusion
Exosomal circZNF451 reshapes the tumor immune microenvironment by inducing macrophages polarization via the FXR1- ELF4–IRF4 axis and is a novel biomarker for predicting the sensitivity of PD1 blockade in LUAD.
Retrospective analysis of GnRH-a prolonged protocol for in vitro fertilization in 18,272 cycles in China
Authors: Tian Lifeng , Xia Leizhen , Wu Qiongfang 
Published: October 2022

Abstract
Background
This large-cohort, retrospective study investigates the relationship between the number of oocytes retrieved and the clinical outcomes for patients receiving the GnRH-a prolonged protocol (mGnRH-a protocol) for fertilization in vitro or intracytoplasmic sperm injection–embryo transfer (IVF/ICSI-ET) treatment.

Results
We categorized 18,272 cycles into three groups by the number of oocytes retrieved (1–8, 9–17, and ≥ 18) during IVF with the GnRH-a prolonged protocol at the Reproductive Medical Center of Jiangxi Maternal and Child Health Hospital from January 2014 to December 2018 (excluding oocyte donation cycles), analyzing the associations among oocyte number and live birth rates (LBRs) or cumulative LBRs (CLBRs), as well as the rate of moderate-to-severe ovarian hyperstimulation syndrome (OHSS). We defined the primary outcome as LBR and the secondary outcome to include the rate of patients at high risk for OHSS. The LBR (with fresh ET) per cycle of oocyte pick-up increased as the number of retrieved oocytes increased from 1 to ~ 8, plateaued between 9 ~ 17, and steadily decreased thereafter. However, the CLBR per cycle continued to increase as the oocyte number increased, as did the incidence of moderate-to-severe OHSS.

Conclusions
Our results show a strong relationship between the number of oocytes retrieved and the CLBR following IVF treatment. The balance between treatment success and the risk of complications, especially OHSS, should be investigated further. We recommend a fresh-ET strategy for the GnRH-a prolonged protocol because the endometrial receptivity in the fresh cycles was better than those in the frozen cycles.
Pan-cancer analysis of cuproptosis regulation patterns and identification of mTOR-target responder in clear cell renal cell carcinoma
Authors: Long Shichao , Wang Ya , Chen Yuqiao , Fang Tianshu , Yao Yuanbing , Fu Kai 
Published: October 2022

Abstract
Background
The mechanism of cuproptosis, a novel copper-induced cell death by regulating tricarboxylic acid cycle (TCA)-related genes, has been reported to regulate oxidative phosphorylation system (OXPHOS) in cancers and can be regarded as potential therapeutic strategies in cancer; however, the characteristics of cuproptosis in pan-cancer have not been elucidated.

Methods
The multi-omics data of The Cancer Genome Atlas were used to evaluate the cuproptosis-associated characteristics across 32 tumor types. A cuproptosis enrichment score (CEScore) was established using a single sample gene enrichment analysis (ssGSEA) in pan-cancer. Spearman correlation analysis was used to identify pathway most associated with CEScore. Lasso-Cox regression was used to screen prognostic genes associated with OXPHOS and further construct a cuproptosis-related prognostic model in clear cell renal cell carcinoma (ccRCC).

Results
We revealed that most cuproptosis-related genes (CRGs) were differentially expressed between tumors and normal tissues, and somatic copy number alterations contributed to their aberrant expression. We established a CEScore index to indicate cuproptosis status which was associated with prognosis in most cancers. The CEScore was negatively correlated with OXPHOS and significantly featured prognosis in ccRCC. The ccRCC patients with high-risk scores show worse survival outcomes and bad clinical benefits of Everolimus (mTOR inhibitor).

Conclusions
Our findings indicate the importance of abnormal CRGs expression in cancers. In addition, identified several prognostic CRGs as potential markers for prognostic distinction and drug response in the specific tumor. These results accelerate the understanding of copper-induced death in tumor progression and provide cuproptosis-associated novel therapeutic strategies.
The effect of an integrated care intervention of multidisciplinary mental health treatment and employment services for trauma-affected refugees: study protocol for a randomised controlled trial
Authors: Bruhn Maja , Laugesen Henriette , Kromann-Larsen Matilde , Trevino Cathrine Selnes , Eplov Lene , Hjorthøj Carsten , Carlsson Jessica 
Published: October 2022

Abstract
Background
The complexity of past trauma and ongoing post-migration stressors challenges the existing mental health treatment for trauma-affected refugees. Therefore, interventions are needed to accommodate these complex challenges in mental health treatment. This study examines the effect of an add-on integrated care intervention compared to treatment as usual (TAU) for trauma-affected refugees in a randomised controlled trial (RCT).

Methods
The study is carried out at a Danish outpatient clinic and will include 197 treatment-seeking refugees with post-traumatic stress disorder (PTSD) who are unemployed and affiliated with municipal employment services. Mental health TAU comprises 10 sessions with a medical doctor (pharmacological treatment and psychoeducation) and 16–20 sessions with a psychologist (manual-based cognitive behavioural therapy) for a period of 8 to 12 months. The add-on intervention strengthens coordination between mental health treatment and employment interventions with three cross-sectoral collaborative meetings during the mental health treatment. The integrated care intervention draws attention to the bidirectional impact of mental health problems and post-migration stressors and focuses on cross-sectoral shared plans. The primary outcome is functioning, measured by WHODAS 2.0, the interviewer-administered 12-item version, with secondary outcomes measuring quality of life, mental health symptoms, and post-migration stressors.

Discussion
The RCT is novel in intervention design for trauma-affected refugees and will bring forward new perspectives and knowledge of integrated care interventions for trauma-affected refugees. The integrated care intervention is expected to reduce post-migration stressors that negatively affect the treatment of trauma-related mental health problems, thereby improving preconditions for enhanced treatment outcomes. The intervention builds on existing practices in the Danish healthcare and employment sectors, which ensures high scalability and sustainability for future practices.

Trial registration
ClinicalTrials.gov Identifier: NCT04244864, registered 28 January 2020. Protocol version: 17 September 2022, version 2.