bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term safety and effectiveness of velaglucerase alfa in Gaucher disease: 6-year interim analysis of a post-marketing surveillance in Japan
Authors: Sagara Rieko , Ishigaki Masahide , Otsuka Manami , Murayama Kei , Ida Hiroyuki , Fernandez Jovelle 
Published: December 2021

Abstract
Background
Gaucher disease (GD) is caused by reduced lysosomal enzyme β-glucocerebrosidase activity. Heterogeneous genotypes and phenotypes have been observed within GD types and across ethnicities. Enzyme replacement therapy is generally recommended for patients with type 1 GD, the least severe form of GD. In Japan, velaglucerase alfa has a broad indication covering type 1, 2 or 3 GD.

Methods
All patients with type 1, 2, or 3 GD administered velaglucerase alfa 60 U/kg every 2 weeks via intravenous infusion after its launch date in Japan in 2014, were enrolled in a non-interventional, observational post-marketing surveillance (PMS). Individual patient data were reported via case report forms (CRFs). Key safety endpoints investigated included the incidence of infusion-related reactions (IRRs), the safety of velaglucerase alfa in patients with types 2 and 3 GD, from patients under one year of age to elderly patients (≥ 65 years of age). Long-term efficacy was also assessed.

Results
In total, 53 patients with GD were registered. CRFs were available for 41 (77.4%) patients at the 6-year interim analysis. Fourteen adverse drug reactions (ADRs) were reported in seven patients. All reported ADRs occurred in patients with type 2 GD. ADRs were reported by 63.6% (7/11) of patients with type 2 GD. Ten ADRs were reported in five patients aged < 4 years. No elderly patients experienced any ADR during the surveillance period. Five ADRs occurring in three (10.0%) patients were classified as IRRs, with one case of vomiting (moderate severity) resulting in treatment discontinuation. Ten serious adverse events were reported in five (16.7%) patients. Three fatal events were considered to be unrelated to treatment with velaglucerase alfa. Platelet counts increased after the administration of velaglucerase alfa and were generally maintained within the normal range over the administration period. Among eleven patients tested for neutralizing anti-velaglucerase alfa antibodies, two (18.2%) were assessed as positive results.

Conclusion
PMS data from patients with types 1–3 GD in Japan indicate that long-term treatment with velaglucerase alfa was well-tolerated and associated with increased platelet counts, which is consistent with observations made in studies outside of Japan.
Trial registration: NCT03625882 registered July 2014.
Challenges to the implementation and adoption of physical distancing measures against COVID-19 by internally displaced people in Mali: a qualitative study
Authors: Ag Ahmed Mohamed Ali , Ly Birama Apho , Diarra Niélé Hawa , Traore Fatoumata Bintou , Diarra Djeneba , Kande Inna Fatoumata , Dembele Mahamadou , Doumbia Seydou , Alami Hassane 
Published: December 2021

Abstract
Background
For almost a decade now, Mali has been facing a security crisis that led to the displacement of thousands of people within the country. Since March 2020, a health crisis linked to the COVID-19 pandemic also surfaced. To overcome this health crisis, the government implemented some physical distancing measures but their adoption proved difficult, particularly among internally displaced people (IDPs). The objective of this study is to identify the challenges relating to the implementation and adoption of physical distancing measures and to determine the main mitigation measures taken by IDPs to adjust to these new policies.

Methods
An exploratory qualitative research was conducted in Bamako and Ségou, two of the ten regions of Mali. The study counted 68 participants including 50 IDPs, seven administrative and health authorities, and 11 humanitarian actors. Sampling was guided by the principle of saturation and diversification, and data was collected through semi-structured individual interviews (n = 36) and focus groups (n = eight). Analysis was based on thematic content analysis through NVivo software.

Results
The main challenges identified concerning the implementation and adoption of physical distancing measures include the proximity in which IDPs live, their beliefs and values, the lack of toilets and safe water on sites, IDPs habits and economic situation, humanitarian actors’ lack of financial resources and authority, and social pressure from religious leaders. Implemented mitigation measures include the building of new shelters or their compartmentalization, the creation of income-generating activities and food banks, psychosocial support, promoting awareness of IDPs, and nightly police patrols and surveillance to discourage IDPs from going out. Finally, a call for action is suggested for the actors involved in IDPs support and management.

Conclusions
The study demonstrates the difficulty for IDPs to follow most of the physical distancing measures and informs about the risk of disease spreading among IDPs with its potential consequences. It also shows the inability of mitigation measures to control the outbreak and suggests actions to be considered.
A novel red fluorescence dopamine biosensor selectively detects dopamine in the presence of norepinephrine in vitro
Authors: Nakamoto Chihiro , Goto Yuhei , Tomizawa Yoko , Fukata Yuko , Fukata Masaki , Harpsøe Kasper , Gloriam David E. , Aoki Kazuhiro , Takeuchi Tomonori 
Published: December 2021

AbstractDopamine (DA) and norepinephrine (NE) are pivotal neuromodulators that regulate a broad range of brain functions, often in concert. Despite their physiological importance, untangling the relationship between DA and NE in the fine control of output function is currently challenging, primarily due to a lack of techniques to allow the observation of spatiotemporal dynamics with sufficiently high selectivity. Although genetically encoded fluorescent biosensors have been developed to detect DA, their poor selectivity prevents distinguishing DA from NE. Here, we report the development of a red fluorescent genetically encoded GPCR (G protein-coupled receptor)-activation reporter for DA termed ‘R-GenGAR-DA’. More specifically, a circular permutated red fluorescent protein (cpmApple) was replaced by the third intracellular loop of human DA receptor D1 (DRD1) followed by the screening of mutants within the linkers between DRD1 and cpmApple. We developed two variants: R-GenGAR-DA1.1, which brightened following DA stimulation, and R-GenGAR-DA1.2, which dimmed. R-GenGAR-DA1.2 demonstrated a reasonable dynamic range (ΔF/F0 = − 43%), DA affinity (EC50 = 0.92 µM) and high selectivity for DA over NE (66-fold) in HeLa cells. Taking advantage of the high selectivity of R-GenGAR-DA1.2, we monitored DA in presence of NE using dual-color fluorescence live imaging, combined with the green-NE biosensor GRABNE1m, which has high selectivity for NE over DA (> 350-fold) in HeLa cells and hippocampal neurons grown from primary culture. Thus, this is a first step toward the multiplex imaging of these neurotransmitters in, for example, freely moving animals, which will provide new opportunities to advance our understanding of the high spatiotemporal dynamics of DA and NE in normal and abnormal brain function.
The interphalangeal angle as a novel radiological measurement tool for Morton's neuroma – a matched case‐control study
Authors: Zaleski Martin , Tondelli Timo , Hodel Sandro , Rigling Dominic , Wirth Stephan 
Published: December 2021

AbstractBackgroundThe aim of this retrospective study was to examine if a correlation between Morton's Neuroma (MN) and an increased interphalangeal angle (IPA) or intermetatarsal angle (IMA) can be found in preoperative weightbearing dorsal‐plantar X‐rays of the foot.MethodsForty‐five patients with forty‐nine MN in the interspaces 2/3 or 3/4 and 49 controls were recruited for this study. Every MN was matched with an asymptomatic control without history of metatarsalgia. The diagnosis was made by clinical examination, magnetic resonance imaging (MRI) and positive histopathology after operative resection. IMA 1/5, 2/3, 2/4, 2/5, 3/4 and IPA 2/3, 3/4 were measured for both groups.ResultsThe IPA 3/4 was significantly enlarged by 2.8 degrees (p < 0.001) with Area under the curve (AUC) 0.75 (p < 0.001), sensitivity of 73% and specificity of 67% in feet with MN compared to controls. The IMA 3/4 was significantly enlarged by 1 degree (p < 0.048) with AUC 0.64 (p < 0.031), sensitivity of 71% and specificity of 43% in feet with MN compared to controls. No difference between IMA 2/4, 2/5, 1/5 or correlation between IPA or IMA and the size of the MN in the MRI was found.ConclusionThe results confirm the clinical observation of an increased IPA in patients with MN. An increased IPA should therefore be considered in the diagnosis of MN.
The effect of different vitrification protocols on cell survival in human ovarian tissue: a pilot study
Authors: Marschalek J. , Egarter C. , Nouri K. , Dekan S. , Ott J. , Frank M. , Pietrowski D. 
Published: December 2021

Abstract
Background
Vitrification has superseded the slow freezing method for cryopreservation of oocytes, embryos, and sperm, but there are as yet no standard protocols for its use in ovarian tissue cryopreservation (OTC). Published protocols diverge mainly with regard to the extent of supplementation of dimethyl sulfoxide (DMSO) to the vitrification medium, and to the use of an open or closed vitrification system.
We investigated the viability of cells after vitrification/warming, using ovarian tissue of transgender patients, by means of Fluorescence Activated Cells Sorting (FACS), and histomorphological analyses using a DMSO-containing (P1) and a DMSO-free protocol (P2) in an open or closed vitrification setting.

Results
Twelve ovarian samples were donated from female-to-male transgender patients: 6 were vitrified according to protocol 1, the other 6 according to protocol 2. The amount of viable cells was 90.1% (P1) and 88.4% (P2) before vitrification. After vitrification and subsequent warming, viable cells were reduced to 82.9% (P1, p = 0.093) and 72.4% (P2, p = 0.019). When comparing the closed and the open systems, the decline in cell viability from pre- to post-vitrification was significant only for the latter (p = 0.037). Histological examination reveals no significant differences with respect to degenerated follicles before or after vitrification.

Conclusion
These results led us to conclude that a protocol containing DMSO results in a higher viability of ovarian cells than a protocol that uses ethylene glycol as cryoprotective agent in vitrification. The use of an open vitrification system led to significant decline in the rate of viable cells.

Trial registration
NCT03649087, retrospectively registered 28.08.2018.
Single-cell characterization of CRISPR-modified transcript isoforms with nanopore sequencing
Authors: Kim Heon Seok , Grimes Susan M. , Hooker Anna C. , Lau Billy T. , Ji Hanlee P. 
Published: December 2021

AbstractWe developed a single-cell approach to detect CRISPR-modified mRNA transcript structures. This method assesses how genetic variants at splicing sites and splicing factors contribute to alternative mRNA isoforms. We determine how alternative splicing is regulated by editing target exon-intron segments or splicing factors by CRISPR-Cas9 and their consequences on transcriptome profile. Our method combines long-read sequencing to characterize the transcript structure and short-read sequencing to match the single-cell gene expression profiles and gRNA sequence and therefore provides targeted genomic edits and transcript isoform structure detection at single-cell resolution.
Interferon inducible pseudouridine modification in human mRNA by quantitative nanopore profiling
Authors: Huang Sihao , Zhang Wen , Katanski Christopher D. , Dersh Devin , Dai Qing , Lolans Karen , Yewdell Jonathan , Eren A. Murat , Pan Tao 
Published: December 2021

AbstractPseudouridine (Ψ) is an abundant mRNA modification in mammalian transcriptome, but its functions have remained elusive due to the difficulty of transcriptome-wide mapping. We develop a nanopore native RNA sequencing method for quantitative Ψ prediction (NanoPsu) that utilizes native content training, machine learning modeling, and single-read linkage analysis. Biologically, we find interferon inducible Ψ modifications in interferon-stimulated gene transcripts which are consistent with a role of Ψ in enabling efficacy of mRNA vaccines.
Effects of a periodized circuit training protocol delivered by telerehabilitation compared to face-to-face method for knee osteoarthritis: a protocol for a non-inferiority randomized controlled trial
Authors: Aily Jéssica Bianca , de Almeida Aline Castilho , de Noronha Marcos , Mattiello Stela Marcia 
Published: December 2021

Abstract
Background
Regular exercise is an effective method for reducing pain and disability in patients with knee osteoarthritis (OA), as well as improving body composition. Thus, a combination of both resistance and aerobic training (circuit training) has shown to be promising for this population. However, access to physical therapy is limited by physical distance, social isolation, and/or treatment costs. Remote rehabilitation seems to be an effective way to minimize these barriers, but the benefits are dependent on the participants’ adherence to the interventions provided at a distance. The objectives of this protocol are to compare the effects of a periodized circuit training applied via telerehabilitation with the same protocol applied in the face-to-face model for individuals with knee OA.

Methods
This study presents a single-blinded protocol for a non-inferiority randomized controlled trial. One hundred participants diagnosed with knee OA (grades II and III Kellgren and Lawrence system), aged 40 years or more, and BMI < 30 kg/m2 will be randomly divided into two groups: telerehabilitation (TR) and face-to-face (FtF) circuit training. The FtF group will perform a 14-week periodized circuit training protocol supervised by a physical therapist, 3 times a week. The TR group will perform the same exercise protocol at home, at least 3 times a week. In addition, the TR group will be able to follow the execution and orientations of the exercises by DVD, a website, and online file sharing tools, and they will receive periodic phone calls in order to motivate, clarify, and inform some aspects of knee OA. The primary outcomes are changes in self-reported pain intensity (visual analog scale (VAS)) and physical function (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)), with a primary end-point of 14 weeks and a secondary end-point of 26 weeks. Secondary outcomes include changes in other clinical outcomes, in morphological characteristics, adherence, acceptability, and treatment perspective.

Discussion
A circuit training through telerehabilitation may contribute to developing early intervention in the causative and potentiating factors of the knee OA, verifying the effects of a low-cost, non-pharmacological and non-invasive treatment.

Trial registration
Brazilian Registry of Clinical Trials (ReBEC) ID: RBR-662hn2. Registered on 31 March 2019. Link: http://www.ensaiosclinicos.gov.br; Universal Trial Number (UTN) of World Health Organization: U1111-1230-9517.
Combined effects of vitamin D supplementation and endurance exercise training on insulin resistance in newly diagnosed type 2 diabetes mellitus patients with vitamin D deficiency: study protocol for a randomized controlled trial
Authors: Xiang Mi , Sun Xiaomin , Wei Junxiang , Cao Zhen-Bo 
Published: December 2021

Abstract
Background
Although approximately 50% of Chinese with type 2 diabetes mellitus (T2DM) patients have vitamin D deficiency, studies regarding vitamin D supplementation on insulin resistance (IR) have mainly focused on non-Asians. Endurance exercise training (ET) enhances insulin-mediated glucose metabolism, which plays a critical role in T2DM prevention and control. However, the combined effects of vitamin D supplementation and ET on IR in T2DM patients are unclear. The objectives of this study is to investigate the synergistic effect of vitamin D supplementation combined with exercise training intervention on IR in T2DM patients.

Methods and analysis
We propose a 3-month randomized controlled trial among 60 T2DM patients aged 40–65, newly diagnosed with T2DM ≤ 1 year, and with stable HbA1c level (≤ 8.0%) in the past 3 months. The participants will be randomly allocated to the vitamin D group, vitamin D combined with exercise training group, exercise training group, and control group (CG) using a computer-generated random number sequence. At baseline, participants will undergo a medical review, anthropometric measurements, dual X-ray absorptiometry, a 75-g oral glucose tolerance test (OGTT), ankle-brachial index measurements, and physical fitness measurements and will complete related lifestyle questionnaires. Fasting blood lipid and glucose levels were also measured. In a 3-month intervention period, vitamin D intervention group will receive a dose of 1000 IU daily; exercise group will perform a 1-h endurance exercise 3 times per week (maximal heart rate, 60–80%), and the control group will receive apparently identical tablets. Additionally, all participants will be advised to maintain their normal diet and physical activities during the intervention. All measurements will be repeated at 3-month follow-up after the intervention with the primary outcome measure expressed as a change from baseline in insulin sensitivity and secretion. Secondary outcome measures will compare the changes in anthropometry, ankle-brachial index, and physical fitness factors (e.g., peak oxygen uptake, hand grip strength). Data will be managed and analyzed using the Statistical Package for the Social Sciences.

Discussion
This is the first study to conduct a randomized trial to clearly determine the independent and combined effects of vitamin D supplementation and endurance exercise trial on IR in Chinese T2DM patients as measured by OGTT. The findings from the proposed study will not only provide new evidences that vitamin D supplementation plays an important role in IR management but also develop a simple and efficient method to improve IR-associated metabolic diseases for T2DM patients.

Trial registration
Chinese Clinical Trial Registry ChiCTR1800015383, Registered on 28 March 2018
Ethionine-mediated reduction of S-adenosylmethionine is responsible for the neural tube defects in the developing mouse embryo-mediated m6A modification and is involved in neural tube defects via modulating Wnt/β-catenin signaling pathway
Authors: Zhang Li , Cao Rui , Li Dandan , Sun Yuqing , Zhang Juan , Wang Xiuwei , Khan Ajab , Liu Zhizhen , Niu Bo , Xu Jun , Xie Jun 
Published: December 2021

AbstractNeural tube defects (NTDs) remain one of the most life-threatening birth defects affecting infants. Most patients with NTDs eventually develop lifelong disability, which cause significant morbidity and mortality and seriously reduce the quality of life. Our previous study has found that ethionine inhibits cell viability by disrupting the balance between proliferation and apoptosis, and preventing neural stem cells from differentiating into neurons and astrocytes. However, how ethionine participates in the pathogenesis of neural tube development through N6-methyladenosine (m6A) modification remains unknown. This study aims to investigate METTL3- and ALKBH5-mediated m6A modification function and mechanism in NTDs. Herein, our results demonstrate that SAM play not only a compensatory role, it also leads to changes of m6A modification in neural tube development and regulation. Additionally, these data implicate that METTL3 is enriched in HT-22 cells, and METTL3 knockdown reduces cell proliferation and increases apoptosis through suppressing Wnt/β-catenin signaling pathway. Significantly, overexpression of ALKBH5 can only inhibit cell proliferation, but cannot promote cell apoptosis. This research reveals an important role of SAM in development of NTDs, providing a good theoretical basis for further research on NTDs. This finding represents a novel epigenetic mechanism underlying that the m6A modification has profound and lasting implications for neural tube development.
Gut microbiota imbalance in colorectal cancer patients, the risk factor of COVID-19 mortality
Authors: Cai Changjing , Zhang Xiangyang , Liu Yihan , Shen Edward , Feng Ziyang , Guo Cao , Han Ying , Ouyang Yanhong , Shen Hong 
Published: December 2021

Abstract
Background
COVID-19 pandemic is sweeping across the world. Previous studies have shown that gut microbiota is associated with COVID-19, and operational taxonomic unit (OTU) composed of Blautia genus, Lactobacillus genus, and Ruminococcus genus of Firmicutes is correlated with the severity of COVID-19. Gut microbiota imbalance in colorectal cancer patients may lead to the variation of OTU.

Results
Based on the GMrepo database, the gut microbiota of 1374 patients with colorectal neoplasms and 27,329 healthy people was analyzed to investigate the differences in the abundance of microbes between colorectal neoplasms patients and healthy people. Furthermore, We collected feces samples from 12 patients with colorectal cancer and 8 healthy people in Xiangya hospital for metabolomic analysis to investigate the potential mechanisms. Our study showed that the abundance of Blautia and Ruminococcus was significantly increased in colorectal neoplasms, which may increase the severity of COVID-19. The gender and age of patients may affect the severity of COVID-19 by shaping the gut microbiota, but the BMI of patients does not.

Conclusions
Our work draws an initial point that gut microbiota imbalance is a risk factor of COVID-19 mortality and gut microbiota may provide a new therapeutic avenue for colorectal cancer patients.