bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prioritising referrals of individuals at-risk of RA: guidance based on results of a 10-year national primary care observational study
Authors: Garcia-Montoya Leticia , Nam Jacqueline L. , Duquenne Laurence , Villota-Eraso Catalina , Di Matteo Andrea , Hartley Collette , Mankia Kulveer , Emery Paul 
Published: January 2022

Abstract
Background
Musculoskeletal (MSK) symptoms are among the commonest reasons for primary care assessments; however, few individuals will be diagnosed with an inflammatory arthritis (IA) within the following year. The purpose of this study was to investigate, in individuals with new MSK symptoms, the association between patient factors and risk of progression to IA, in order to optimise primary care referrals to rheumatology.

Methods
Individuals ≥16 years old with new non-specific MSK symptoms and no clinical synovitis were recruited by primary care across the UK from July 2007 until May 2019. Those testing positive for the anti-CCP2 assay (anti-CCP+) were invited to Leeds for follow-up. Subjects with a negative result (anti-CCP−) were sent a 1-year questionnaire, and general practitioners were contacted to confirm whether the individual had been diagnosed with an IA by a rheumatologist. Predictors for progression were assessed using multivariable regression analysis.

Results
Six thousand seven hundred eighty individuals were recruited: 3% were anti-CCP+, of whom 45% progressed to IA, predominantly rheumatoid arthritis. Anti-CCP+ participants with high antibody levels had an odds ratio (OR) for progression to IA of 9.42 [P < 0.001, 95% CI (3.13–28.30)], hand pain, OR 2.74 [P = 0.043, 95% CI (1.03–7.27)] and foot pain, OR 4.10 [P = 0.003, 95% CI (1.59–10.54)]. In low-level anti-CCP+ individuals, absence of pain in hands or feet had a negative predictive value of 96% for progression to IA.
One-year follow-up data were available for 5640 anti-CCP− individuals, of whom 53 were diagnosed with IA (0.93%). Pain in hands, OR 2.51 [P = 0.018, 95% CI (1.17–5.39)] or knees, OR 3.03 [P = 0.003, 95% CI (1.47–6.25)] were associated with development of IA within 12 months.

Conclusions
This is the largest prospective primary care study of individuals at risk of IA, and the first one to prospectively investigate the outcome of MSK symptoms in a large anti-CCP− cohort. High anti-CCP levels and pain in hands/feet indicated an increased likelihood of progression to IA. In patients with low anti-CCP level and no pain in the hands/feet, progression is unlikely. In anti-CCP− patients, those with hand or knee pain were at increased risk of progression. This study demonstrates that routinely available tests and joint symptoms provide useful discrimination that may be used to prioritise referrals to rheumatology and avoid a delayed diagnosis.

Trial registration
NCT, NCT02012764. Registered 25 January 2007.
Complaints of daytime sleepiness, insomnia, hypnotic use, and risk of dementia: a prospective cohort study in the elderly
Authors: Cavaillès Clémence , Berr Claudine , Helmer Catherine , Gabelle Audrey , Jaussent Isabelle , Dauvilliers Yves 
Published: January 2022

Abstract
Background
Sleep disturbances are common in elderly and occur frequently in dementia. The impact of excessive daytime sleepiness (EDS), insomnia complaints, sleep quality, and hypnotics on the risk of all-cause dementia, Alzheimer disease (AD), and dementia with vascular component (DVC) remains unclear, as does the association between sleep profile and plasma β-amyloid levels.

Methods
Analyses were carried out on 6851 participants aged 65 years and over randomly recruited from three French cities and free of dementia at baseline. A structured interview and self-questionnaire assessed sleep complaints (EDS, insomnia complaints, sleep quality) and medications at baseline. Incident cases of dementia were diagnosed systematically over a 12-year period. Multivariate Cox models were used to estimate the risk of dementia associated with the sleep complaints considered individually and globally. Plasma β-amyloid levels were measured by an xMAP-based assay technology in 984 subjects.

Results
After adjustment for socio-demographic characteristics, lifestyle, APOE-ε4, cardiovascular factors, and depressive status, EDS had a higher risk of all-cause dementia (HR = 1.21; 95%CI = [1.01–1.46]) and DVC (HR = 1.58; 95%CI = [1.07–2.32]) but not AD. Persistent use of hypnotics increased the risk for all-cause dementia, specifically AD (HR = 1.28; 95%CI = [1.04–1.58]), but not DVC. No association was found for insomnia complaints and sleep quality taken as individual factors or combined with EDS on the risk of dementia. No association was found between β-amyloid, sleep complaints, and incident dementia.

Conclusions
The results suggest a deleterious role of EDS and hypnotics on dementia. Further studies are required to elucidate the mechanisms involved in these associations and whether its management can prevent the risk of dementia.
Extracellular vesicles from adipose-derived stem cells promote microglia M2 polarization and neurological recovery in a mouse model of transient middle cerebral artery occlusion
Authors: Hu Xiaowen , Pan Jiaji , Li Yongfang , Jiang Yixu , Zheng Haoran , Shi Rubing , Zhang Qi , Liu Chang , Tian Hengli , Zhang Zhijun , Tang Yaohui , Yang Guo-Yuan , Wang Yongting 
Published: January 2022

Abstract
Background
Adipose-derived stem cells (ADSCs) and their extracellular vesicles (EVs) have therapeutic potential in ischemic brain injury, but the underlying mechanism is poorly understood. The current study aimed to explore the contribution of miRNAs in ADSC-EVs to the treatment of cerebral ischemia.

Methods
After the intravenous injection of ADSC-EVs, therapeutic efficacy was evaluated by neurobehavioral tests and brain atrophy volume. The polarization of microglia was assessed by immunostaining and qPCR. We further performed miRNA sequencing of ADSC-EVs and analyzed the relationship between the upregulated miRNAs in ADSC-EVs and microglial polarization-related proteins using Ingenuity Pathway Analysis (IPA).

Results
The results showed that ADSC-EVs reduced brain atrophy volume, improved neuromotor and cognitive functions after mouse ischemic stroke. The loss of oligodendrocytes was attenuated after ADSC-EVs injection. The number of blood vessels, as well as newly proliferated endothelial cells in the peri-ischemia area were higher in the ADSC-EVs treated group than that in the PBS group. In addition, ADSC-EVs regulated the polarization of microglia, resulting in increased repair-promoting M2 phenotype and decreased pro-inflammatory M1 phenotype. Finally, STAT1 and PTEN were highlighted as two downstream targets of up-regulated miRNAs in ADSC-EVs among 85 microglia/macrophage polarization related proteins by IPA. The inhibition of STAT1 and PTEN by ADSC-EVs were confirmed in cultured microglia.

Conclusions
In summary, ADSC-EVs reduced ischemic brain injury, which was associated with the regulation of microglial polarization. miRNAs in ADSC-EVs partly contributed to their function in regulating microglial polarization by targeting PTEN and STAT1.
MicroRNA-377-3p inhibits hepatocellular carcinoma growth and metastasis through negative regulation of CPT1C-mediated fatty acid oxidation
Authors: Zhang Ting , Zhang Yanan , Liu Jie , Ma Yan , Ye Qinong , Yan Xinlong , Ding Lihua 
Published: January 2022

Abstract
Background
Altered lipid metabolism is closely related to the occurrence and development of hepatocellular carcinoma (HCC). Carnitine palmitoyltransferase 1C (CPT1C) is a member of CPT1 family and plays a key role in cancer development and progression. However, how microRNAs (miRNAs) regulate CPT1C-mediated fatty acid transport and oxidation remains to be elucidated.

Methods
Oil Red O staining, mitochondrial, and lipid droplets immunofluorescence staining were used to detect the functions of miR-377-3p and CPT1C in fatty acid oxidation. Colocalization of palmitate and mitochondria was performed to investigate the function of miR-377-3p and CPT1C in fatty acid transport into mitochondria. Fatty acid oxidation (FAO) assay was used to detect the function of miR-377-3p and CPT1C in FAO. Cell proliferation, migration and invasion assays and animal experiments were used to evaluate the role of miR-377-3p/CPT1C axis in HCC progression in vitro and in vivo. Immunofluorescence staining was used to identify the clinical significance of miR-377-3p and CPT1C in HCC patients.

Results
MiR-377-3p inhibits CPT1C expression by targeting its 3’-untranslated region. Through repression of CPT1C, miR-377-3p suppresses fatty acid oxidation by preventing fatty acid from entering into mitochondria and decreasing ATP production in HCC cells. Inhibiting fatty acid oxidation abolishes the ability of miR-377-3p/CPT1C axis to regulate HCC proliferation, migration, invasion and metastasis in vitro and in vivo. In HCC patients, CPT1C is significantly upregulated, and miR-377-3p expression and lipid droplets are negatively correlated with CPT1C expression. High expression of miR-377-3p and CPT1C predict better and worse clinical outcomes, respectively.

Conclusions
We uncover the key function and the relevant mechanisms of the miR-377-3p/CPT1C axis in HCC, which might provide a potential target for the treatment of HCC.
Oncological and functional outcomes following treatment of T1a glottic squamous cell carcinoma with transoral laser microsurgery
Authors: Curry Dennis E. , Forner David , Rigby Matthew H. , Trites Jonathan R. , Corsten Martin , Taylor S. Mark 
Published: January 2022

Background Laryngeal cancers of glottic origin comprise a large proportion of head and neck malignancies. Transoral laser microsurgery (TLM) and radiation therapy are mainstays in the treatment of early stage glottic cancer, but debate persists as to which modality is functionally superior. Furthermore, there is a paucity of North American data related to functional and oncological outcomes in T1a glottic cancer. Here, we assessed oncological and functional outcomes of T1a glottic squamous cell carcinoma (SCC) with TLM to supplement evidence from jurisdictions outside North America. Methods This study is a retrospective cohort study performed from a prospectively collected tertiary center institutional TLM database. Patients who were diagnosed with T1a glottic SCC and underwent TLM as their primary treatment were included. Functional outcomes were analyzed using the Voice Handicap Index-10 (VHI-10) questionnaire. Ultimate control with TLM only was considered to be those patients with locoregional control with repeat TLM procedures, but without addition of other modalities. Student's t-test was used to test significance and Kaplan–Meier survival analysis was used to assess oncological outcomes. Results 48 patients met study criteria. The mean follow-up time was 74 months. The 5-year locoregional, ultimate control with TLM only and laryngeal preservation rates were 83.2%, 90.4% and 100%, respectively. The overall survival and disease-specific survival were 87.2% and 100%, respectively. VHI-10 scores were available for 13/48 patients and mean scores improved non-significantly from pre-op (mean: 11.23; range: 2 to 30; median: 10) and post op (mean: 7.92; range: 0 to 18; median: 8) scoring (p-value = 0.15). Sub-stratification of voice data revealed a significant improvement between pre and post-operative scores (mean difference − 10.6, 95% CI: − 0.99 to − 20.21, p-value = 0.035) for patients with abnormal pre-operative scores (VHI > 11). Conclusion To our knowledge, the current work represents one of the first North American studies to report both functional and oncologic outcomes for TLM treatment of T1a glottic SCC. The oncologic and functional outcomes presented here add to existing evidence in favor of TLM as a safe and effective primary treatment option for early staged T1a glottic cancer. Graphical Abstract
Martian moons exploration MMX: sample return mission to Phobos elucidating formation processes of habitable planets
Authors: Kuramoto Kiyoshi , Kawakatsu Yasuhiro , Fujimoto Masaki , Araya Akito , Barucci Maria Antonietta , Genda Hidenori , Hirata Naru , Ikeda Hitoshi , Imamura Takeshi , Helbert Jörn , Kameda Shingo , Kobayashi Masanori , Kusano Hiroki , Lawrence David J. , Matsumoto Koji , Michel Patrick , Miyamoto Hideaki , Morota Tomokatsu , Nakagawa Hiromu , Nakamura Tomoki , Ogawa Kazunori , Otake Hisashi , Ozaki Masanobu , Russell Sara , Sasaki Sho , Sawada Hirotaka , Senshu Hiroki , Tachibana Shogo , Terada Naoki , Ulamec Stephan , Usui Tomohiro , Wada Koji , Watanabe Sei-ichiro , Yokota Shoichiro 
Published: January 2022

AbstractMartian moons exploration, MMX, is the new sample return mission planned by the Japan Aerospace Exploration Agency (JAXA) targeting the two Martian moons with the scheduled launch in 2024 and return to the Earth in 2029. The major scientific objectives of this mission are to determine the origin of Phobos and Deimos, to elucidate the early Solar System evolution in terms of volatile delivery across the snow line to the terrestrial planets having habitable surface environments, and to explore the evolutionary processes of both moons and Mars surface environment. To achieve these objectives, during a stay in circum-Martian space over about 3 years MMX will collect samples from Phobos along with close-up observations of this inner moon and carry out multiple flybys of Deimos to make comparative observations of this outer moon. Simultaneously, successive observations of the Martian atmosphere will also be made by utilizing the advantage of quasi-equatorial spacecraft orbits along the moons’ orbits.Graphical Abstract
Quantifying Collision Frequency and Intensity in Rugby Union and Rugby Sevens: A Systematic Review
Authors: Paul Lara , Naughton Mitchell , Jones Ben , Davidow Demi , Patel Amir , Lambert Mike , Hendricks Sharief 
Published: January 2022

Abstract
Background
Collisions in rugby union and sevens have a high injury incidence and burden, and are also associated with player and team performance. Understanding the frequency and intensity of these collisions is therefore important for coaches and practitioners to adequately prepare players for competition. The aim of this review is to synthesise the current literature to provide a summary of the collision frequencies and intensities for rugby union and rugby sevens based on video-based analysis and microtechnology.

Methods
A systematic search using key words was done on four different databases from 1 January 1990 to 1 September 2021 (PubMed, Scopus, SPORTDiscus and Web of Science).

Results
Seventy-three studies were included in the final review, with fifty-eight studies focusing on rugby union, while fifteen studies explored rugby sevens. Of the included studies, four focused on training—three in rugby union and one in sevens, two focused on both training and match-play in rugby union and one in rugby sevens, while the remaining sixty-six studies explored collisions from match-play. The studies included, provincial, national, international, professional, experienced, novice and collegiate players. Most of the studies used video-based analysis (n = 37) to quantify collisions. In rugby union, on average a total of 22.0 (19.0–25.0) scrums, 116.2 (62.7–169.7) rucks, and 156.1 (121.2–191.0) tackles occur per match. In sevens, on average 1.8 (1.7–2.0) scrums, 4.8 (0–11.8) rucks and 14.1 (0–32.8) tackles occur per match.

Conclusions
This review showed more studies quantified collisions in matches compared to training. To ensure athletes are adequately prepared for match collision loads, training should be prescribed to meet the match demands. Per minute, rugby sevens players perform more tackles and ball carries into contact than rugby union players and forwards experienced more impacts and tackles than backs. Forwards also perform more very heavy impacts and severe impacts than backs in rugby union. To improve the relationship between matches and training, integrating both video-based analysis and microtechnology is recommended. The frequency and intensity of collisions in training and matches may lead to adaptations for a “collision-fit” player and lend itself to general training principles such as periodisation for optimum collision adaptation.
Trial Registration PROSPERO registration number: CRD42020191112.
Advances in Interventional Therapies for Painful Diabetic Neuropathy: A Systematic Review
Authors: Xu Li , Sun Zhuo , Casserly Elizabeth , Nasr Christian , Cheng Jianguo , Xu Jijun 
Published: January 2022

BACKGROUND:
Painful diabetic neuropathy (PDN) is one of the major complications of diabetes mellitus. It is often debilitating and refractory to pharmaceutical therapies. Our goal was to systematically review and evaluate the strength of evidence of interventional management options for PDN and make evidence-based recommendations for clinical practice.

METHODS:
We searched PubMed, Scopus, Google Scholar, and Cochrane Llibrary and systematically reviewed all types of clinical studies on interventional management modalities for PDN.

RESULTS:
We identified and analyzed 10 relevant randomized clinical trials (RCTs), 8 systematic reviews/meta-analyses, and 5 observational studies of interventional modalities for PDN using pain as primary outcome. We assessed the risk of bias in grading of evidence and found that there is moderate to strong evidence to support the use of dorsal column spinal cord stimulation (SCS) in treating PDN in the lower extremities (evidence level: 1B+), while studies investigating its efficacy in the upper extremities are lacking. Evidence exists that acupuncture and injection of botulinum toxin-A provide relief in pain or muscle cramps due to PDN with minimal side effects (2B+/1B+). Similar level of evidence supports surgical decompression of lower limb peripheral nerves in patients with intractable PDN and superimposed nerve compression (2B±/1B+). Evidence for sympathetic blocks or neurolysis and dorsal root ganglion (DRG) stimulation is limited to case series (2C+).

CONCLUSIONS:
Moderate to strong evidence exists to support the use of SCS in managing lower extremity pain in patients who have failed conventional medical management for PDN. Acupuncture or injection of botulinum toxin-A can be considered as an adjunctive therapy for PDN. Surgical decompression of peripheral nerves may be considered in patients with PDN superimposed with nerve compression. High-quality studies are warranted to further evaluate the safety, efficacy, and cost-effectiveness of interventional therapies for PDN.
Maternal Fever Associated With Continuous Spinal Versus Epidural Labor Analgesia: A Single-Center Retrospective Study
Authors: Seiler F. Arran , Scavone Barbara M. , Shahul Sajid , Arnolds David E. 
Published: January 2022

BACKGROUND:
Neuraxial labor analgesia is associated with elevations in maternal temperature; the mechanism responsible is unknown. Proposed mechanisms have included infection, altered thermoregulation, and inflammation, potentially triggered by local anesthetics. Studies of the association between neuraxial labor analgesia and maternal fever have focused on epidural analgesia, and there have been no comparisons of the rate of maternal fever between continuous spinal and epidural labor analgesia.

METHODS:
We performed a retrospective study to compare the rate of maternal fever between patients who received continuous spinal versus epidural labor analgesia between June 2012 and March 2020. Each patient who received continuous spinal analgesia was matched to 2 patients who received epidural analgesia and had the same nulliparous status. The primary outcome of our study was the incidence of intrapartum maternal fever, which we defined as any temperature ≥38 °C before delivery and compared between the continuous spinal and epidural groups using Fisher exact test.

RESULTS:
We identified 81 patients who received continuous spinal analgesia and 162 matched controls who received epidural analgesia. Demographic and obstetric characteristics of the patients were similar between groups. While the duration of analgesia did not significantly differ, there was markedly increased bupivacaine consumption in women with epidural analgesia. Eight of 81 (9.9%; 95% confidence interval [CI], 5.1–18.3) women with continuous spinal analgesia developed an intrapartum fever compared to 18 of 162 (11.1%; 95% CI, 7.1–16.9) of women with epidural analgesia (P = .83; Fisher exact test).

CONCLUSIONS:
There was no significant difference in the rate of maternal fever between women with continuous spinal compared to epidural labor analgesia. While the route of administration and dose of bupivacaine differs between epidural and spinal labor analgesia, they are titrated to produce similar levels of neuraxial blockade. Our results are consistent with a model in which epidural related maternal fever is due to altered thermoregulation from a central neuraxial block and argue against a direct effect of bupivacaine or fentanyl, although we cannot rule out a concentration-independent effect of bupivacaine or fentanyl or an inflammatory effect of the catheter itself. These retrospective results highlight the importance of prospective and mechanistic study of neuraxial analgesia–related maternal fever.
Design of a robotic zebra finch for experimental studies on developmental song learning
Authors: Araguas Alice , Guellaï Bahia , Gauthier Philippe , Richer Florian , Montone Guglielmo , Chopin Adrien , Derégnaucourt Sébastien 
Published: January 2022

ABSTRACT
Birdsong learning has been consolidated as the model system of choice for exploring the biological substrates of vocal learning. In the zebra finch (Taeniopygia guttata), only males sing and they develop their song during a sensitive period in early life. Different experimental procedures have been used in the laboratory to train a young finch to learn a song. So far, the best method to achieve a faithful imitation is to keep a young bird singly with an adult male. Here, we present the different characteristics of a robotic zebra finch that was developed with the goal to be used as a song tutor. The robot is morphologically similar to a life-sized finch: it can produce movements and sounds contingently to the behaviours of a live bird. We present preliminary results on song imitation, and other possible applications beyond the scope of developmental song learning.