bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transparency in quality of radiotherapy for breast cancer in the Netherlands: a national registration of radiotherapy-parameters
Authors: Maliko Nansi , Stam Marcel R. , Boersma Liesbeth J. , Vrancken Peeters Marie-Jeanne T. F. D. , Wouters Michel W. J. M. , KleinJan Eline , Mulder Maurice , Essers Marion , Hurkmans Coen W. , Bijker Nina 
Published: April 2022

Abstract
Background
Radiotherapy (RT) is part of the curative treatment of approximately 70% of breast cancer (BC) patients. Wide practice variation has been reported in RT dose, fractionation and its treatment planning for BC. To decrease this practice variation, it is essential to first gain insight into the current variation in RT treatment between institutes. This paper describes the development of the NABON Breast Cancer Audit-Radiotherapy (NBCA-R), a structural nationwide registry of BC RT data of all BC patients treated with at least surgery and RT.

Methods
A working group consisting of representatives of the BC Platform of the Dutch Radiotherapy Society selected a set of dose volume parameters deemed to be surrogate outcome parameters, both for tumour control and toxicity. Two pilot studies were carried out in six RT institutes. In the first pilot study, data were manually entered into a secured web-based system. In the second pilot study, an automatic Digital Imaging and Communications in Medicine (DICOM) RT upload module was created and tested.

Results
The NBCA-R dataset was created by selecting RT parameters describing given dose, target volumes, coverage and homogeneity, and dose to organs at risk (OAR). Entering the data was made mandatory for all Dutch RT departments. In the first pilot study (N = 1093), quite some variation was already detected. Application of partial breast irradiation varied from 0 to 17% between the 6 institutes and boost to the tumour bed from 26.5 to 70.2%. For patients treated to the left breast or chest wall only, the average mean heart dose (MHD) varied from 0.80 to 1.82 Gy; for patients treated to the breast/chest wall only, the average mean lung dose (MLD) varied from 2.06 to 3.3 Gy. In the second pilot study 6 departments implemented the DICOM-RT upload module in daily practice. Anonymised data will be available for researchers via a FAIR (Findable, Accessible, Interoperable, Reusable) framework.

Conclusions
We have developed a set of RT parameters and implemented registration for all Dutch BC patients. With the use of an automated upload module registration burden will be minimized. Based on the data in the NBCA-R analyses of the practice variation will be done, with the ultimate aim to improve quality of BC RT.
Trial registration Retrospectively registered.
High-mobility group box chromosomal protein-1 deletion alleviates osteoporosis in OVX rat model via suppressing the osteoclastogenesis and inflammation
Authors: Yu Haotao , Zhou Wei , Zhong Zhihong , Qiu Ruixin , Chen Guoquan , Zhang Ping 
Published: April 2022

Abstract
Background
Osteoporosis is a skeletal metabolic disease that constitutes a great threaten to human health. However, there is currently no gold standard for its treatment. High-mobility group box chromosomal protein-1 (HMGB-1) has been reported to play an important role in various orthopedic diseases. Till now, its role in osteoporosis remains elusive.

Methods
Rats underwent ovariectomy (OVX) were used to construct a postmenopausal model of osteoporosis. Then, rats were divided into sham groups without OVX surgery, OVX model group, HMGB-1 knockdown (HMGB-1 KD) OVX model groups. The expression of HMGB1 was evaluated by qRT-PCR and western blotting. Subsequently, the changes of trabeculae were evaluated by micro-computed tomography (CT) assay. Skeletal necrosis and metabolism were further analyzed by hematoxylin–eosin (HE) staining, Alcian blue staining and Masson’s trichrome staining. The contents of serum alkaline phosphatase (ALP) and osteocalcin were detected by ELISA assay. Expression of osteoclast-associated receptor (OSCAR) and tartrate-resistant acid phosphatase (TRAP) were determined to investigate the effects of HMGB-1 loss on osteoclastogenesis.

Results
Single HMGB-1 deletion exerted no significant effect on rat trabeculae, serum ALP and osteocalcin. Noticeably, HMGB1 knockdown dramatically ameliorated OVX-induced changes in above indexes. Trabeculae structures of OVX rats were sparse with disorder arrangement, which were greatly recovered after HMGB-1 deletion. Enhanced osteoclastogenesis was observed in OVX rats by increasing number of TRAP + cells and expression of TRAP and OSCAR, and loss of HMGB1 ameliorated osteoclastogenesis in OVA rats. Moreover, HMGB-1 deletion antagonized OVX-evoked downregulation of osteoblast activity markers osterix (OSX), collagen type I alpha 1(COL1A1) and distal-less homeobox 2 (DLX2) protein. Furthermore, loss of HMGB-1 attenuated fluctuation of inflammatory factors in OVX rats. Additionally, HMGB-1 deficiency inhibited OVX-evoked activation of the Toll-like receptor (TLR) 4/NF-κB signaling pathway. Moreover, reactivating the TLR4 signaling further aggravated OVX-induced osteoporosis, which was reversed by HMGB1 knockdown.

Conclusion
HMGB-1 deletion alleviated OVX-triggered osteoporosis by suppressing osteoclastogenesis and inflammatory disorder via the inhibition of the TLR4 signaling. Therefore, HMGB-1 may be a promising therapeutic target for osteoporosis.
Clinical characteristics of multicentric reticulohistiocytosis and distinguished features from rheumatoid arthritis: a single-center experience in China
Authors: Zou Xiao-juan , Qiao Lin , Li Feng , Chen Hua , Yang Yun-jiao , Xu Dong , Zheng Wen-Jie , Jiang Zhen-yu , Wang Li , Wu Qing-jun , Zhang Feng-Chun 
Published: April 2022

Abstract
Objective
To investigate the clinical features of multicentric reticulohistiocytosis (MRH).

Methods
The clinical manifestations, laboratory examination results and histologic characteristics of eleven patients with MRH were collected and compared with those of 33 patients with rheumatoid arthritis.

Results
In total, 72.7% of the MRH patients were women. The median age was 46 years (range 33–84 years). Diagnosed by specific pathologic features, all MRH patients exhibited cutaneous involvement. The dorsa of the hands, arms, face and auricle were the most commonly affected areas. Nodules were also located on the legs, scalp, trunk, neck, and even the hypoglossis and buccal mucosa. Ten MRH patients (90.9%) had symmetric polyarthritis. Compared with rheumatoid arthritis (RA) patients, MRH patients were more likely to have distal interphalangeal joint (DIP) involvement (63.6% vs 24.2%, P = 0.017) and less likely to have elbow (36.4% vs 72.7%, P = 0.003), ankle (45.5% vs 93.9%, P < 0.001) and metacarpophalangeal joint (MCP) (36.4% vs 78.8%, P = 0.009) involvement. Positivity for rheumatoid factor (RF) (36.4% vs 84.6%, P = 0.001) and anti-CCP antibody (9.1% vs 81.8%, P = 0.000), as well as the median RF titer [43.8 (31.7–61.0) vs 175.4 (21.3–940.3), P = 0.021], in MRH patients was lower than in RA patients. Elevation of the erythrocyte sedimentation rate (ESR) was also less common in MRH patients than in RA patients (36.4% vs 72.7%, P = 0.030). After treatment with median- to large-dose corticosteroids and disease-modifying antirheumatic drugs, 8 patients achieved complete remission and 2 patients partial remission (skin lesions ameliorated, joint lesions not ameliorated).

Conclusion
Always pathologically diagnosed, MRH is a systemic disease involving RA-like erosive polyarthritis and a specific distribution of skin nodules characterized by "coral beads". More DIP involvement and less elbow, ankle and MCP involvement are seen in MRH than in RA. In addition, less positivity and lower-titer RF, uncommon presence of anti-CCP antibodies and ESR elevation may be helpful to distinguish MRH from RA.
Emerging role of RNA sensors in tumor microenvironment and immunotherapy
Authors: Yang Rui , Yu Sihui , Xu Tianhan , Zhang Jiawen , Wu Sufang 
Published: April 2022

AbstractRNA sensors detect foreign and endogenous RNAs to protect the host by initiating innate and adaptive immune response. In tumor microenvironment (TME), activation of RNA sensors induces tumor-inhibitory cytotoxic T lymphocyte responses and inhibits the activity of immunosuppressive cells though stimulating type I IFN signaling pathway. These characteristics allow RNA sensors to be prospective targets in tumor immunotherapy. Therefore, a comprehensive understanding of the roles of RNA sensors in TME could provide new insight into the antitumor immunotherapy. Moreover, RNA sensors could be prominent triggering targets to synergize with immunotherapies. In this review, we highlight the diverse mechanisms of RNA sensors in cancer immunity and their emerging contributions in cancer immunotherapy, including monotherapy with RNA sensor agonists, as well as combination with chemotherapy, radiotherapy, immune checkpoint blockade or cancer vaccine.
Standardised data collection in prehospital critical care: a comparison of medical problem categories and discharge diagnoses
Authors: Tommila Miretta , Pappinen Jukka , Raatiniemi Lasse , Saviluoto Anssi , Toivonen Tuukka , Björkman Johannes , Nurmi Jouni 
Published: April 2022

Abstract
Background
Prehospital medical problem reporting is essential in the management of helicopter emergency medical services (HEMS) operations. The consensus-based template for reporting and documenting in physician-staffed prehospital services exists and the classification of medical problems presented in the template is widely used in research and quality improvement. However, validation of the reported prehospital medical problem is lacking. This study aimed to describe the in-hospital diagnoses, patient characteristics and medical interventions in different categories of medical problems.

Methods
This retrospective, observational registry study examined the 10 most common in-hospital International Statistical Classification of Disease (ICD-10) diagnoseswithin different prehospital medical problem categories, defined by the HEMS physician/paramedic immediately after the mission was completed. Data were gathered from a national HEMS quality registry and a national hospital discharge registry. Patient characteristics and medical interventions related to different medical problem categories are also described.

Results
A total of 33,844 patients were included in the analyses. All the medical problem categories included a broad spectrum of ICD-10 diagnoses (the number of diagnosis classes per medical problem category ranged from 73 to 403). The most frequent diagnoses were mainly consistent with the reported medical problems. Overlapping of ICD-10 diagnoses was mostly seen in two medical problem categories: stroke and acute neurology excluding stroke. Additionally, typical patient characteristics and disturbances in vital signs were related to adequate medical problem categories.

Conclusions
Medical problems reported by HEMS personnel have adequate correspondence to hospital discharge diagnoses. However, the classification of cerebrovascular accidents remains challenging.
Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci
Authors: Chen Hongjie , Fan Shaoqi , Stone Jennifer , Thompson Deborah J. , Douglas Julie , Li Shuai , Scott Christopher , Bolla Manjeet K. , Wang Qin , Dennis Joe , Michailidou Kyriaki , Li Christopher , Peters Ulrike , Hopper John L. , Southey Melissa C. , Nguyen-Dumont Tu , Nguyen Tuong L. , Fasching Peter A. , Behrens Annika , Cadby Gemma , Murphy Rachel A. , Aronson Kristan , Howell Anthony , Astley Susan , Couch Fergus , Olson Janet , Milne Roger L. , Giles Graham G. , Haiman Christopher A. , Maskarinec Gertraud , Winham Stacey , John Esther M. , Kurian Allison , Eliassen Heather , Andrulis Irene , Evans D. Gareth , Newman William G. , Hall Per , Czene Kamila , Swerdlow Anthony , Jones Michael , Pollan Marina , Fernandez-Navarro Pablo , McConnell Daniel S. , Kristensen Vessela N. ,   NBCS Investigators, Rothstein Joseph H. , Wang Pei , Habel Laurel A. , Sieh Weiva , Dunning Alison M. , Pharoah Paul D. P. , Easton Douglas F. , Gierach Gretchen L. , Tamimi Rulla M. , Vachon Celine M. , Lindström Sara 
Published: April 2022

AbstractBackgroundMammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants.MethodsWe conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia.ResultsWe identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype atp < 0.05. TWAS further identified two novel genes (SHOX2andCRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes.ConclusionsOur findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.
A quasi-randomised controlled trial of online distribution of home-based hepatitis C self-testing for key populations in Malaysia: a study protocol
Authors: Shilton Sonjelle , Sem Xiaohui , Chan Huan-Keat , Chung Han Yang , Karunanithy Anu , Markby Jessica , Chan Po-Lin , Luhmann Niklas , Johnson Cheryl , Nabeta Pamela , Nasir Nazrila Hairizan Bt , Ongarello Stefano , Reipold Elena Ivanova , Hassan Muhammad Radzi Abu 
Published: April 2022

Abstract
Background
Malaysia has an estimated hepatitis C virus (HCV) prevalence of 1.9% among its adult population and a history of providing HCV treatment in the public sector. In 2019, Malaysia launched a 5-year national strategic plan for viral hepatitis control and has been expanding HCV testing and treatment to the primary care and community levels, while actively engaging key populations in services for hepatitis care. The Ministry of Health (MoH) is seeking to specifically understand how to better target HCV services at men who have sex with men (MSM); HCV self-testing could increase the uptake of HCV testing among this group.

Methods
We aim to integrate HCV antibody self-testing into an existing online platform used for HIV self-testing, to evaluate the acceptability and impact of an online HCV self-testing programme in Malaysia. This is a non-blinded parallel group quasi-randomised superiority study comparing HCV self-testing via an online distribution model with the standard care, which involves attending a clinic for facility-based HCV antibody testing (control, 2:1). Participants will be randomised to either the HCV self-testing via online distribution arm, in which either an oral fluid- or blood-based HCV self-test kit will be mailed to them, or the control arm, where they will be provided with information about the nearest centre with HCV testing. The primary outcome is the number and proportion of participants who report completion of testing. Secondary outcomes include the number and proportion of participants who (a) receive a positive result and are made aware of their status, (b) are referred to and complete HCV RNA confirmatory testing, and (c) start treatment. Acceptability, feasibility, attitudes around HCV testing, and cost will also be evaluated. The target sample size is 750 participants.

Discussion
This study is one of the first in the world to explore the real-world impact of HCV self-testing on key populations using online platforms and compare this with standard HCV testing services. The outcomes of this study will provide critical evidence about testing uptake, linkage to care, acceptability, and any social harms that may emerge due to HCV self-testing.

Trial registration
ClinicalTrials.gov NCT04982718
Transcranial direct current stimulation to modulate brain reactivity to food cues in overweight and obese adults: study protocol for a randomized controlled trial with fMRI (NeuroStim-Obesity)
Authors: Ghobadi-Azbari Peyman , Malmir Nastaran , Vartanian Meghedi , Mahdavifar-Khayati Rasoul , Robatmili Somaye , Hadian Venus , Derafsheh Sara , Nitsche Michael A. , Nosratabadi Masoud , Farhoudian Ali , Ekhtiari Hamed 
Published: April 2022

Abstract
Background
With increasing obese populations worldwide, developing interventions to modulate food-related brain processes and functions is particularly important. Evidence suggests that transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) may modulate the reward–control balance towards facilitation of cognitive control and possible suppression of reward-related mechanisms that drive food cue-induced craving. This protocol describes a clinical trial that investigates the neurocognitive mechanisms of action for tDCS to modulate food cue-reactivity and cravings in people with obesity.

Method
The NeuroStim-Obesity trial is a prospective, randomized, sham-controlled, double-blind single-session tDCS trial targeting food craving in those with obesity or overweighed. Once randomized, 64 adults with obesity or overweighed complete one session in which they receive either active or sham tDCS over the DLPFC (anode F4 and cathode F3, 2 mA intensity for 20 min). The primary outcome is change in neural response to the food cue-reactivity task in the ventral striatum after a single-session bilateral tDCS compared to sham stimulation. Secondary outcomes include changes in food craving evaluated by the Food Craving Questionnaire-State (FCQ-S). We will also explore the predictive role of brain structure and functional networks assessed by structural and functional magnetic resonance imaging (MRI) during both task performance and the resting-state that are acquired pre- and post-intervention to predict response to tDCS.

Discussion
The results will provide novel insight into neuroscience for the efficacy of tDCS and will advance the field towards precision medicine for obesity. Exploratory results will examine the potential predictive biomarkers for tDCS response and eventually provide personalized intervention for the treatment of obesity.

Trial registration
Iranian Registry of Clinical Trials (IRCT) IRCT20121020011172N4. Retrospectively registered on 4 June 2020
Impact of diabetes mellitus on risk of major complications after hip fracture: a systematic review and meta-analysis
Authors: Shen Qiu , Ma Yunping 
Published: April 2022

Abstract
Background
The impact of diabetes mellitus (DM) on adverse outcomes in hip fracture patients is unclear. Furthermore, no review has synthesized evidence on this subject. Therefore, the current study was designed to answer the following research question: Does DM increase the risk of mortality and major systemic complications in patients with hip fractures?

Methods
PubMed, Embase, and Google Scholar were searched from 1st January 2000 to 1st August 2021 for studies comparing DM and non-DM patients with hip fractures. Outcomes of interest were pooled using risk ratios (RR). The study was registered on PROSPERO (CRD42021268525).

Results
Sixteen studies were included. Meta-analysis revealed a statistically significant increased risk of mortality in diabetics as compared to non-diabetics after 1 year (RR: 1.24 95% CI 1.08, 1.43 I2 = 62% p = 0.003). Pooled analysis of eight studies reporting adjusted mortality outcomes also demonstrated similar results (RR: 1.17 95% CI 1.09, 1.25 I2 = 74% p < 0.0001). We noted a statistically significant increase in the risk of cardiac complications (RR: 1.44 95% CI 1.17, 1.78 I2 = 19% p = 0.0005) and risk of renal failure in diabetics as compared to non-diabetics (RR: 1.32 95% CI 1.04, 1.68 I2 = 0% p = 0.02); but no difference in the risk of cerebrovascular (RR: 1.45 95% CI 0.74, 2.85 I2 = 47% p = 0.28), pulmonary (RR: 0.94 95% CI 0.73, 1.23 I2 = 8% p = 0.67) and thromboembolic complications (RR: 0.81 95% CI 0.56, 1.17 I2 = 28% p = 0.26).

Conclusion
Our results indicate that diabetics have an increased risk of mortality as compared to non-diabetics. Scarce data indicates that the risk of cardiac complications and renal failure are increased in patients with DM but there is no difference in the risk of cerebrovascular, pulmonary, or thromboembolic complications. Further studies are needed to strengthen the current conclusions.
RNA sensor MDA5 suppresses LINE-1 retrotransposition by regulating the promoter activity of LINE-1 5′-UTR
Authors: Yan Jiaxiu , Zhao Yifei , Du Juan , Wang Yu , Wang Shaohua , Wang Qing , Zhao Xu , Xu Wei , Zhao Ke 
Published: April 2022

Abstract
Background
Type 1 long interspersed elements, or LINE-1, are the only retroelements that replicate autonomously in human cells. The retrotransposition process of LINE-1 can trigger the activation of the innate immune system and has been proposed to play a role in the development of several autoimmune diseases, including Aicardi-Goutières syndrome (AGS). In contrast, all known AGS-associated proteins, except MDA5, have been reported to affect LINE-1 activity. Thus, MDA5 is likely to also function as a LINE-1 suppressor.

Results
MDA5 was found to potently suppress LINE-1 activity in a reporter-based LINE-1 retrotransposition assay. Although MDA5 is an endogenous RNA sensor able to activate the innate immune system, increased interferon (IFN) expression only contributed in part to MDA5-mediated LINE-1 suppression. Instead, MDA5 potently regulated the promoter activity of LINE-1 5′-UTR, as confirmed by transiently expressed myc-tagged MDA5 or knockdown of endogenous MDA5 expression. Consequently, MDA5 effectively reduced the generation of LINE-1 RNA and the subsequent expression of LINE-1 ORF1p and ORF2p. Interestingly, despite MDA5 being a multi-domain protein, the N-terminal 2CARD domain alone is sufficient to interact with LINE-1 5′-UTR and inhibit LINE-1 promoter activity.

Conclusion
Our data reveal that MDA5 functions as a promoter regulator; it directly binds to the LINE-1 5′-UTR and suppresses its promoter activity. Consequently, MDA5 reduces LINE-1 RNA and protein levels, and ultimately inhibits LINE-1 retrotransposition. In contrast, MDA5-induced IFN expression only plays a mild role in MDA5-mediated LINE-1 suppression. In addition, the N-terminal 2CARD domain was found to be a functional region for MDA5 upon inhibition of LINE-1 replication. Thus, our data suggest that besides being an initiator of the innate immune system, MDA5 is also an effector against LINE-1 activity, potentially forming a feedback loop by suppressing LINE-1-induced innate immune activation.