bluuebunny/crossref_metadata_2025_split huggingface dataset:
The immune microenvironment shapes transcriptional and genetic heterogeneity in chronic lymphocytic leukemia
Authors: Sun Clare , Chen Yun-Ching , Martinez Zurita Aina , Baptista Maria Joao , Pittaluga Stefania , Liu Delong , Rosebrock Daniel , Gohil Satyen Harish , Saba Nakhle S. , Davies-Hill Theresa , Herman Sarah E. M. , Getz Gad , Pirooznia Mehdi , Wu Catherine J. , Wiestner Adrian 
Published: April 2022

AbstractIn chronic lymphocytic leukemia (CLL), B-cell receptor signaling, tumor–microenvironment interactions, and somatic mutations drive disease progression. To better understand the intersection between the microenvironment and molecular events in CLL pathogenesis, we integrated bulk transcriptome profiling of paired peripheral blood (PB) and lymph node (LN) samples from 34 patients. Oncogenic processes were upregulated in LN compared with PB and in immunoglobulin heavy-chain variable (IGHV) region unmutated compared with mutated cases. Single-cell RNA sequencing (scRNA-seq) distinguished 3 major cell states: quiescent, activated, and proliferating. The activated subpopulation comprised only 2.2% to 4.3% of the total tumor bulk in LN samples. RNA velocity analysis found that CLL cell fate in LN is unidirectional, starts in the proliferating state, transitions to the activated state, and ends in the quiescent state. A 10-gene signature derived from activated tumor cells was associated with inferior treatment-free survival (TFS) and positively correlated with the proportion of activated CD4+ memory T cells and M2 macrophages in LN. Whole exome sequencing (WES) of paired PB and LN samples showed subclonal expansion in LN in approximately half of the patients. Since mouse models have implicated activation-induced cytidine deaminase in mutagenesis, we compared AICDA expression between cases with and without clonal evolution but did not find a difference. In contrast, the presence of a T-cell inflamed microenvironment in LN was associated with clonal stability. In summary, a distinct minor tumor subpopulation underlies CLL pathogenesis and drives the clinical outcome. Clonal trajectories are shaped by the LN milieu, where T-cell immunity may contribute to suppressing clonal outgrowth. The clinical study is registered at clinicaltrials.gov as NCT00923507.
Dynamic Finite Element Modeling and Simulation of Soft Robots
Authors: Ding Liang , Niu Lizhou , Su Yang , Yang Huaiguang , Liu Guangjun , Gao Haibo , Deng Zongquan 
Published: April 2022

AbstractSoft robots have become important members of the robot community with many potential applications owing to their unique flexibility and security embedded at the material level. An increasing number of researchers are interested in their designing, manufacturing, modeling, and control. However, the dynamic simulation of soft robots is difficult owing to their infinite degrees of freedom and nonlinear characteristics that are associated with soft materials and flexible geometric structures. In this study, a novel multi-flexible body dynamic modeling and simulation technique is introduced for soft robots. Various actuators for soft robots are modeled in a virtual environment, including soft cable-driven, spring actuation, and pneumatic driving. A pneumatic driving simulation was demonstrated by the bending modules with different materials. A cable-driven soft robot arm prototype and a cylindrical soft module actuated by shape memory alley springs inspired by an octopus were manufactured and used to validate the simulation model, and the experimental results demonstrated adequate accuracy. The proposed technique can be widely applied for the modeling and dynamic simulation of other soft robots, including hybrid actuated robots and rigid-flexible coupling robots. This study also provides a fundamental framework for simulating soft mobile robots and soft manipulators in contact with the environment.
The challenges of integrating signposting into general practice: qualitative stakeholder perspectives on care navigation and social prescribing in primary care
Authors: Brunton Lisa , Tazzyman Abigail , Ferguson Jane , Hodgson Damian , Nelson Pauline A. 
Published: April 2022

Abstract
Background
A national policy focus in England to address general practice workforce issues has led to a commitment to employ significant numbers of non-general practitioner (GP) roles to redistribute workload. This paper focuses on two such roles: the care navigation (CN) and social prescribing link worker (SPLW) roles, which both aim to introduce ‘active signposting’ into primary care, to direct patients to the right professional/services at the right time and free up GP time. There is a lack of research exploring staff views of how these roles are being planned and operationalised into general practice and how signposting is being integrated into primary care.

Methods
The design uses in-depth qualitative methods to explore a wide range of stakeholder staff views. We generated a purposive sample of 34 respondents who took part in 17 semi-structured interviews and one focus group (service leads, role holders and host general practice staff). We analysed data using a Template Analysis approach.

Results
Three key themes highlight the challenges of operationalising signposting into general practice: 1) role perception – signposting was made challenging by the way both roles were perceived by others (e.g. among the public, patients and general practice staff) and highlighted inherent tensions in the expressed aims of the policy of active signposting; 2) role preparedness – a lack of training meant that some receptionist staff felt unprepared to take on the CN role as expected and raised patient safety issues; for SPLW staff, training affected the consistency of service offer across an area; 3) integration and co-ordination of roles – a lack of planning and co-ordination across components of the health and care system challenged the success of integrating signposting into general practice.

Conclusions
This study provides new insights from staff stakeholder perspectives into the challenges of integrating signposting into general practice, and highlights key factors affecting the success of signposting in practice. Clarity of role purpose and remit (including resolving tensions inherent the dual aims of ‘active signposting’), appropriate training and skill development for role holders and adequate communication and engagement between stakeholders/partnership working across services, are required to enable successful integration of signposting into general practice.
Characteristics and determinants of loss to follow-up among tuberculosis (TB) patients who smoke in an industrial state of Malaysia: a registry-based study of the years 2013-2017
Authors: Sharani Zatil Zahidah , Ismail Nurhuda , Yasin Siti Munira , Zakaria Yuslina , Razali Asmah , Demong Nur Atiqah Rochin , Mohammad Mariam , Ismail Zaliha 
Published: April 2022

Abstract
Background
The increased risk of loss to follow-up among TB smokers raises concern over the secondary spread within the community. This study aimed to determine the factors associated with loss to follow-up among TB patients who smoke.

Methods
All registered TB patients who smoke in the state of Selangor between 2013 and 2017 via the Malaysian Tuberculosis Information System (MyTB) database were included for analysis. TB patients who smoke were considered those who are “current smoker” during the notification, while loss to follow-up was defined as a TB patient who had interrupted treatment for 2 months or longer. There were 3 main variable domains included for analysis: sociodemographic profiles, disease profiles, and comorbidities. Logistic regression analysis was used to identify determinants of loss to follow-up among TB patients who smoke.

Results
A total of 14.1% (N = 813) of TB patients who smoke loss to follow-up. The determinants of loss to follow-up among TB smokers were working age population aged 32-41 and 42-53 years old (AOR 1.08; 95%CI 1.23,2.08) and (AOR 1.44; 95%CI 1.11,1.87) respectively, Malaysian nationality (AOR 2.34; 95%CI 1.66,3.30), patients staying in urban area (AOR 1.55; 95% CI 1.23,1.97), income level less than RM2160 (AOR 1.59; 95% CI 1.14,2.20), un-employed (AOR 1.30; 95%CI 1.09-1.55), have low education level i.e., secondary school education, primary school education and no formal education (AOR 1.60; 95%CI 1.22,2.10), (AOR 1.73; 95%CI 1.16,2.57) and (AOR 2.29; 95% CI 1.57,3.33) respectively, previously treated TB cases (AOR 2.19; 95% CI 1.71,2.81), active TB case detection methods (AOR 2.06; 95%CI 1.40,3.02), moderate lesion x-ray (AOR 1.60; 95%CI 1.13,2.27) and HIV positive (AOR 1.36; 95%CI 1.02,1.82). All the significant factors gave rise to the final model of determinants, with a predictability of 67.2% (95% CI 65.0,69.3).

Conclusions
The high proportion of loss to follow-up among TB patients who smoke highlight the importance of providing early risk detection that examines the three main domains of risk factors such as socioeconomic, disease profiles and comorbidities. Potential integrated intervention should aim to reduce the proportion of smoking among TB patients through the stop smoking programme together with directly observed therapy (DOT).
Effects of periodontal clinical database software in resident training during COVID-19 pandemic: a prospective observational study
Authors: Zhu Wenjun , Feng Rongmei , Fu Yun 
Published: April 2022

Abstract
Background
Dental residents in Guangdong, China, had fewer medical practice opportunities because of the pandemic of COVID-19. This study aimed to evaluate whether a case-based learning (CBL) approach using a periodontal clinical database software (PCDS) could improve residents' achievement in the exam of the standardized residency training (SRT) program.

Methods
Forty-four dental residents volunteered and completed this trial. Within 12 weeks, all residents admitted periodontal patients 5 days a week and participated in a case-based learning course using PCDS once a week. Two online case-based examinations were used to evaluate their diagnostic and therapeutic performance before and after training. The total accuracy rate of examinations and the accuracy rate of subitems were analyzed using paired samples T-test. The Bonferroni correction is used for multiple testing adjustments, and p < 0.05 was considered statistical significance.

Results
After training, the total accuracy rate of SRT exams raised from 65 to 76%. There was a significant difference in the accuracy rate before and after training (Mean = 0.103, SD = 0.141, p < 0.001). The accuracy of radiographic examination (type of alveolar bone absorption and hard tissue lesion of tooth) and making treatment plan was significantly improved after training (p < 0.005). However, residents' performance in diagnosing periodontitis and predicting the prognosis of affected teeth was not improved.

Conclusions
The PCDS and CBL method effectively improved the residents' achievement in SRT examination, especially in identifying the type of resorption of alveolar bone and the hard tissue lesion of a tooth by radiographic examination and making an appropriate treatment plan for a periodontitis patient. More effective teaching approaches are needed to improve residents' accuracy of diagnosis of periodontitis using the 2018 classification in China.
Mechanisms of neuroinflammation in hydrocephalus after intraventricular hemorrhage: a review
Authors: Holste Katherine G. , Xia Fan , Ye Fenghui , Keep Richard F. , Xi Guohua 
Published: April 2022

AbstractIntraventricular hemorrhage (IVH) is a significant cause of morbidity and mortality in both neonatal and adult populations. IVH not only causes immediate damage to surrounding structures by way of mass effect and elevated intracranial pressure; the subsequent inflammation causes additional brain injury and edema. Of those neonates who experience severe IVH, 25–30% will go on to develop post-hemorrhagic hydrocephalus (PHH). PHH places neonates and adults at risk for white matter injury, seizures, and death. Unfortunately, the molecular determinants of PHH are not well understood. Within the past decade an emphasis has been placed on neuroinflammation in IVH and PHH. More information has come to light regarding inflammation-induced fibrosis and cerebrospinal fluid hypersecretion in response to IVH. The aim of this review is to discuss the role of neuroinflammation involving clot-derived neuroinflammatory factors including hemoglobin/iron, peroxiredoxin-2 and thrombin, as well as macrophages/microglia, cytokines and complement in the development of PHH. Understanding the mechanisms of neuroinflammation after IVH may highlight potential novel therapeutic targets for PHH.
Dosimetric feasibility of moderately hypofractionated/dose escalated radiation therapy for localised prostate cancer with intensity-modulated proton beam therapy using simultaneous integrated boost (SIB-IMPT) and impact of hydrogel prostate-rectum spacer
Authors: Ahmad Khalil Dalia , Jazmati Danny , Geismar Dirk , Wulff Jörg , Bäumer Christian , Kramer Paul Heinz , Steinmeier Theresa , Schulze Schleitthoff Stefanie , Plaude Sandija , Bischoff Martin , Tschirdewahn Stephan , Hadaschik Boris , Timmermann Beate 
Published: April 2022

Abstract
Purpose
To examine the dosimetric feasibility of hypofractionated/dose escalated radiation therapy in patients with localized prostate carcinoma using simultaneous integrated boost intensity-modulated proton beam therapy (SIB-IMPT) in absence or presence of prostate-rectum spacer.

Methods
IMPT technique was implemented in 23 patients with intermediate- and high-risk prostate cancer treated at West German Proton Therapy Centre from March 2016 till June 2018, using SIB technique prescribing 60 GyRBE and 72 GyRBE in 30 fractions to PTV1 (prostate and seminal vesicle) and PTV2 boost (prostate and proximal seminal vesicle), respectively. In 15 patients, a transperineal injection of hydrogel was applied prior to radiotherapy to increase the distance between prostate and rectum. Planning and all treatments were performed with a 120 ml fluid-filled endorectal balloon customised daily for each patient. For each patient, 2 lateral IMPT beams were implemented taking a field-specific range uncertainty (RU) into account. Dose volume histograms (DVH) were analyzed for PTV2, PTV2 with range uncertainty margin (PTV2RU), rectum, bladder, right/left femoral heads, and penile bulb. For late rectal toxicities, the normal tissue complication probabilities (NTCP) were calculated using different biological models. A DVH- and NTCP-based dosimetric comparison was carried out between non-spacer and spacer groups.

Results
For the 23 patients, high-quality plans could be achieved for target volume and for other organs at risk (OARs). For PTV2, the V107% was 0% and the Dmax did not exceed 106.2% of the prescribed dose. The volume PTV2RU covered by 95% of the dose ranged from 96.16 to 99.95%. The conformality index for PTV2RU was 1.12 ± 0.057 and the homogeneity index (HI) was 1.04 ± 0.014. Rectum Dmax and rectal volume receiving 73–50 Gy could be further reduced for the spacer-group. Significant reductions in mean and median rectal NTCPs (stenosis/necrosis, late rectal bleeding ≥ 2, and late rectal toxicities ≥ 3) were predicted for the spacer group in comparison to the non-spacer group.

Conclusion
Hypofractionated/dose escalated radiotherapy with SIB-IMPT is dosimetrically feasible. Further reduction of the rectal volumes receiving high and medium dose levels (73–50 Gy) and rectal NTCP could be achieved through injection of spacers between rectum and prostate.
Degos disease complicated by constrictive pericarditis in remote phase: a case report
Authors: Tadokoro Yuki , Kitamura Tadashi , Horai Tetsuya , Miyaji Kagami 
Published: April 2022

Abstract
Background
Degos disease, also known as malignant atrophic papulosis, is characterised by cutaneous manifestations due to chronic thrombo-obliterative vasculopathy. There have been reports of the rare late-onset Degos disease complicated by constrictive pericarditis (CP). This study reports a case of CP caused by Degos disease that developed 20 years after diagnosis.

Case presentation
A 62-year-old woman who had been taking aspirin for 20 years for Degos disease was hospitalised for worsening of heart failure. The patient was diagnosed with CP and underwent pericardiectomy. Pathological findings suggested the involvement of Degos disease. The postoperative course was uneventful, and her heart failure and Degos disease did not worsen.

Conclusions
The study findings suggests that Degos disease can cause long-term CP. Aspirin effectively inhibited the progression of Degos disease, and surgical treatment was necessary when heart failure due to CP was refractory to treatment.
Pragmatic trials can address diagnostic controversies: recent lessons from gestational diabetes
Authors: Raymond Jean , Long Hélène , Darsaut Tim 
Published: April 2022

Abstract
Objective
The aim of the paper is to discuss how a pragmatic definition could change our conception of diagnosis, using gestational diabetes mellitus (GDM) as an example.

Study design
We review the diagnostic controversy that followed an observational study showing a linear relationship between maternal glycaemia and adverse pregnancy outcomes and the resolution proposed 15 years later by a recent pragmatic trial comparing two screening approaches (one- vs two-step) with different diagnostic thresholds.

Results
The pragmatic trial involved approximately 24,000 women. The one-step screening strategy using lower GDM thresholds diagnosed twice as many women with GDM, but pregnancy outcomes were not different. We examine how the pragmatic approach integrates research into practice and defines the meaning of a diagnosis according to patient outcomes. The approach is ethically and scientifically sound as compared to the previous methodology, where observational research separated from care gave a theoretical definition of GDM that may have misled medical practice for two decades.

Conclusion
Pragmatic research integrated into practice can revolutionize our conception of medical diagnosis in the best medical interest of patients.
Association between depression and mortality in persons with asthma: a population-based cohort study
Authors: Lin Ping , Li Xiaoqian , Liang Zongan , Wang Ting 
Published: April 2022

Abstract
Background
The relation between depression and mortality in patients with asthma is not well known. This study aimed to assess the impact of depression on mortality in asthmatic patients in US adults.

Methods
This observational study used data from the 2005 to 2014 National Health and Nutrition Examination Survey (NHANES). Depression was measured using the Patient Health Questionnaire-9 (PHQ-9). We used survey-weight adjusted Cox proportional hazard models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between depression and all-cause mortality.

Results
A total of 1865 participants with asthma were included in this study. Among them, 264 (14.16%) had depressive symptoms. During 9970 person-years of follow-up, there were 24 (9.1%) deaths in 264 patients with depression compared with 100 (6.3%) deaths in 1601 patients without depression. For unadjusted analyses, depression was associated with an increased risk of all-cause mortality (HR, 2.22 [95% CI 1.32–3.73]). This association was persistent after adjustment for age, sex, race/ethnicity, and body mass index (HR, 2.71 [95% CI 1.58–4.66]). However, we did not observe a significant association between depression and mortality after controlling for extensive co-morbidities (HR, 1.92 [95% CI 0.82–4.45]). Subgroup analyses further revealed that depression was an independent risk factor for mortality only in the females (HR, 3.78 [95% CI 1.17, 12.26]) but not all asthmatic patients.

Conclusions
The present study suggested that depressive disorder was common in asthmatic patients and depression in asthmatic patients was associated with a higher mortality rate. Depression was an independent risk factor for mortality in female patients.
Infliximab therapy of relapsing tracheal stenosis in a pediatric patient with granulomatosis with polyangiitis: a case report
Authors: Schnell Alexander , Ruppel Renate , Tremel Christina , Galiano Matthias , Meßbacher Maria-Elena , Krickau Tobias 
Published: April 2022

Abstract
Background
Granulomatosis with polyangiitis is a granulomatous, necrotizing small-vessel vasculitis affecting both children and adults. However, subglottic tracheal stenosis appears more frequently in the pediatric cohort. To date, granulomatosis with polyangiitis is often treated with steroids, cyclophosphamide, azathioprine, or rituximab, but tumor-necrosis-factor-α-antagonistic drugs are increasingly gaining significance in treatment of refractory cases.

Case presentation
We report the case of a 15-year-old Caucasian male diagnosed with proteinase-3-positive granulomatosis with polyangiitis with acute shortness of breath. X-ray and magnet resonance imaging showed extensive subglottic narrowing. Forced expiratory volume in 1 s was reduced to 50% of age norm, with massively increased effective airway resistance. The patient initially responded very well to high-dose steroids and maintenance therapy with azathioprine. He was subsequently treated with four doses of rituximab, and levels of proteinase 3 antibodies normalized. After 6 months of clinical remission, the patient presented again with acute respiratory symptoms. Again, he was treated with high-dose steroids, but showed poor clinical response this time. Therefore, we decided to commence a tumor-necrosis-factor-α-antagonistic treatment with infliximab, under which our patient achieved clinical remission and normalization of lung function parameters.

Conclusions
The use of tumor-necrosis-factor-α-antagonistic agents might be a promising alternative for the treatment of refractory tracheal stenosis in pediatric patients with granulomatosis with polyangiitis.