bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early discontinuation of PD-1 blockade upon achieving a complete or partial response in patients with advanced melanoma: the multicentre prospective Safe Stop trial
Authors: Mulder E. E. A. P. , de Joode K. , Litière S. , ten Tije A. J. , Suijkerbuijk K. P. M. , Boers-Sonderen M. J. , Hospers G. A. P. , de Groot J. W. B. , van den Eertwegh A. J. M. , Aarts M. J. B. , Piersma D. , van Rijn R. S. , Kapiteijn E. , Vreugdenhil G. , van den Berkmortel F. W. P. J. , Hoop E. Oomen-de , Franken M. G. , Ryll B. , Rutkowski P. , Sleijfer S. , Haanen J. B. A. G. , van der Veldt A. A. M. 
Published: March 2021

Abstract
Background
The introduction of programmed cell death protein 1 (PD-1) blockers (i.e. nivolumab and pembrolizumab) has significantly improved the prognosis of patients with advanced melanoma. However, the long treatment duration (i.e. two years or longer) has a high impact on patients and healthcare systems in terms of (severe) toxicity, health-related quality of life (HRQoL), resource use, and healthcare costs. While durable tumour responses have been observed and PD-1 blockade is discontinued on an individual basis, no consensus has been reached on the optimal treatment duration. The objective of the Safe Stop trial is to evaluate whether early discontinuation of first-line PD-1 blockade is safe in patients with advanced and metastatic melanoma who achieve a radiological response.

Methods
The Safe Stop trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 200 patients with advanced and metastatic cutaneous melanoma and a confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumours (RECIST) v1.1 will be included to early discontinue first-line monotherapy with nivolumab or pembrolizumab. The primary objective is the rate of ongoing responses at 24 months after discontinuation of PD-1 blockade. Secondary objectives include best overall and duration of response, need and outcome of rechallenge with PD-1 blockade, and changes in (serious) adverse events and HRQoL. The impact of treatment discontinuation on healthcare resource use, productivity losses, and hours of informal care will also be assessed. Results will be compared to those from patients with CR or PR who completed 24 months of treatment with PD-1 blockade and had an ongoing response at treatment discontinuation. It is hypothesised that it is safe to early stop first-line nivolumab or pembrolizumab at confirmed tumour response while improving HRQoL and reducing costs.

Discussion
From a patient, healthcare, and economic perspective, shorter treatment duration is preferred and overtreatment should be prevented. If early discontinuation of first-line PD-1 blockade appears to be safe, early discontinuation of PD-1 blockade may be implemented as the standard of care in a selected group of patients.

Trial registration
The Safe Stop trial has been registered in the Netherlands Trial Register (NTR), Trial NL7293 (old NTR ID: 7502), https://www.trialregister.nl/trial/7293. Date of registration September 30, 2018.
Analysis of PET parameters as prognosticators of survival and tumor extent in Oropharyngeal Cancer treated with surgery and postoperative radiotherapy
Authors: Choi Kyu Hye , Song Jin Ho , Park Eun Young , Hong Ji Hyun , Yoo Ie Ryung , Lee Youn Soo , Sun Dong-Il , Kim Min-Sik , Kim Yeon-Sil 
Published: March 2021

Abstract
Background
Positron-emission tomography (PET) is widely used to detect malignancies, but consensus on its prognostic value in oropharyngeal cancer has not been established. The purpose of this study was to analyze the PET parameters associated with tumor extent and survival in resectable oropharyngeal cancer.

Methods
The PET parameters in oropharyngeal cancer patients with regional node metastasis who underwent surgery and postoperative radiotherapy between January 2005 and January 2019 were analyzed. We calculated the SUVmax, tumor-to-liver ratio (TLR), metabolic tumor volume (MTV, volume over SUV 2.5), and total lesion glycolysis (TLG, MTV x mean SUV) of the primary lesion and metastatic nodes. Histologic findings, patient survival, and recurrence were reviewed in the medical records.

Results
Fifty patients were included, and the PET parameters were extracted for 50 primary lesions and 104 nodal lesions. In the survival analysis, MTV and TLG of the primary lesions showed significant differences in overall survival (OS) and recurrence-free survival (RFS). In the multiple regression analysis, TLG of the primary lesion was associated with the depth of invasion (DOI). MTV of the nodes was a significant factor affecting extranodal extension (ENE).

Conclusions
PET parameters could be related with OS, RFS, DOI of the primary tumor, and ENE. PET would be expected to be a useful diagnostic tool as a prognosticator of survival and pathologic findings in oropharyngeal cancer.
RGD4C peptide mediates anti-p21Ras scFv entry into tumor cells and produces an inhibitory effect on the human colon cancer cell line SW480
Authors: Huang Chen-Chen , Liu Fang-Rui , Feng Qiang , Pan Xin-Yan , Song Shu-Ling , Yang Ju-Lun 
Published: March 2021

Abstract
Background
We prepared an anti-p21Ras scFv which could specifically bind with mutant and wild-type p21Ras. However, it cannot penetrate the cell membrane, which prevents it from binding to p21Ras in the cytoplasm. Here, the RGD4C peptide was used to mediate the scFv penetration into tumor cells and produce antitumor effects.

Methods
RGD4C-EGFP and RGD4C-p21Ras-scFv recombinant expression plasmids were constructed to express fusion proteins in E. coli, then the fusion proteins were purified with HisPur Ni-NTA. RGD4C-EGFP was used as reporter to test the factors affecting RGD4C penetration into tumor cell. The immunoreactivity of RGD4C-p21Ras-scFv toward p21Ras was identified by ELISA and western blotting. The ability of RGD4C-p21Ras-scFv to penetrate SW480 cells and colocalization with Ras protein was detected by immunocytochemistry and immunofluorescence. The antitumor activity of the RGD4C-p21Ras-scFv was assessed with the MTT, TUNEL, colony formation and cell migration assays. Chloroquine (CQ) was used an endosomal escape enhancing agent to enhance endosomal escape of RGD4C-scFv.

Results
RGD4C-p21Ras-scFv fusion protein were successfully expressed and purified. We found that the RGD4C fusion protein could penetrate into tumor cells, but the tumor cell entry of was time and concentration dependent. Endocytosis inhibitors and a low temperature inhibited RGD4C fusion protein endocytosis into cells. The change of the cell membrane potential did not affect penetrability. RGD4C-p21Ras-scFv could penetrate SW480 cells, effectively inhibit the growth, proliferation and migration of SW480 cells and promote this cells apoptosis. In addition, chloroquine (CQ) could increase endosomal escape and improve antitumor activity of RGD4C-scFv in SW480 cells.

Conclusion
The RGD4C peptide can mediate anti-p21Ras scFv entry into SW480 cells and produce an inhibitory effect, which indicates that RGD4C-p21Ras-scFv may be a potential therapeutic antibody for the treatment of ras-driven cancers.
A smartphone ocular alignment measurement app in school screening for strabismus
Authors: Cheng Wenbo , Lynn Marissa H. , Pundlik Shrinivas , Almeida Cheryl , Luo Gang , Houston Kevin 
Published: March 2021

Abstract
Background
Strabismus is the leading risk factor for amblyopia, which should be early detected for minimized visual impairment. However, traditional school screening for strabismus can be challenged due to several factors, most notably training, mobility and cost. The purpose of our study is to evaluate the feasibility of using a smartphone application in school vision screening for detection of strabismus.

Methods
The beta smartphone application, EyeTurn, can measure ocular misalignment by computerized Hirschberg test. The application was used by a school nurse in a routine vision screening for 133 elementary school children. All app measurements were reviewed by an ophthalmologist to assess the rate of successful measurement and were flagged for in-person verification with prism alternating cover test (PACT) using a 2.4Δ threshold (root mean squared error of the app). A receiver operating characteristic (ROC) curve was used to determine the best sensitivity and specificity for an 8Δ threshold (recommended by AAPOS) with the PACT measurement as ground truth.

Results
The nurse obtained at least one successful app measurement for 93% of children (125/133). 40 were flagged for PACT, of which 6 were confirmed to have strabismus, including 4 exotropia (10△, 10△, 14△ and 18△), 1 constant esotropia (25△) and 1 accommodative esotropia (14△). Based on the ROC curve, the optimum threshold for the app to detect strabismus was determined to be 3.0△, with the best sensitivity (83.0%), specificity (76.5%). With this threshold the app would have missed one child with accommodative esotriopia, whereas conventional screening missed 3 cases of intermittent extropia.

Conclusions
Results support feasibility of use of the app by personnel without professional training in routine school screenings to improve detection of strabismus.
The severity and atypical presentations of COVID-19 infection in pediatrics
Authors: Saleh Nagwan Y. , Aboelghar Hesham M. , Salem Sherif S. , Ibrahem Reda A. , Khalil Fatma O. , Abdelgawad Ahmed S. , Mahmoud Asmaa A. 
Published: March 2021

Abstract
Background
Emergence of 2019-nCoV attracted global attention and WHO declared COVID-19 a public health emergency of international concern. Therefore we aimed to explore the severity and atypical manifestations of COVID-19 among children.

Methods
This is an observational cohort study conducted on 398 children with confirmed COVID-19 by using real-time reverse transcriptase polymerase chain reaction assay for detection of 2019-nCoV nucleic acid during the period from March to November 2020. Patients were subdivided regarding the severity of COVID-19 presentation into Group I (Non-severe COVID-19) was admitted into wards and Group II (Severe COVID-19) admitted into the PICU.

Results
Non- severe cases were 295cases (74.1%) and 103cases (25.9%) of severe cases. There was a significant difference between age groups of the affected children (P < 0.001) with a median (0–15 years). Boys (52%) are more affected than girls (48%) with significant differences (P < 0.001). 68.6%of confirmed cases had contact history to family members infected with COVID-19. 41.7% of severe patients needed mechanical ventilation. Death of 20.4% of severe cases. In COVID-19 patients, fever, headache, fatigue and shock were the most prominent presentations (95, 60.3, 57.8, and 21.8% respectively). 3.5% of children were manifested with atypical presentations; 1.25% manifested by pictures of acute pancreatitis, 1.25% presented by manifestations of deep venous thrombosis and 1.0% had multisystem inflammatory syndrome (MIS-C). Multivariate regression analysis showed that COVID-19 severity in children was significantly higher among children with higher levels of D-dimer, hypoxia, shock and mechanical ventilation.

Conclusion
Most children had a non-severe type of COVID-19 and children with severe type had higher levels of D-dimer, hypoxia, shock and mechanical ventilation.
Associations of sleep duration with physical fitness performance and self-perception of health: a cross-sectional study of Taiwanese adults aged 23–45
Authors: Gu Ming , Liu Chia-Chen , Hsu Chi-Chieh , Lu Chi-Jie , Lee Tian-Shyug , Chen Mingchih , Ho Chien-Chang 
Published: March 2021

Abstract
Background
The relationship between sleep duration and physical fitness is one aspect of sleep health. Potential factors associated with sleep duration interfere with physical fitness performance, but the impact trends on physical fitness indicators remain unclear.

Methods
This study examined associations between sleep duration and physical fitness among young to middle-aged adults in Taiwan. A total of 42,781 Taiwanese adults aged 23–45 participated in the National Physical Fitness Examination Survey 2013 (NPFES-2013) in Taiwan between October 2013 and March 2014. A standardized structural questionnaire was used to record participants’ sleep duration, which was stratified as short (< 6 h/day (h/d)), moderate (6–7 h/d; 7–8 h/d; 8-9 h), and long (≥ 9 h/d) sleep duration groups. Physical fitness was assessed based on four components: body composition (body mass index [BMI], waist-to-height ratio [WHtR], and waist-to-hip ratio [WHR]), muscle strength and endurance (1-min bent-leg sit-up test [BS]), flexibility (sit-and-reach test [SR]), and cardiorespiratory endurance index (3-min step test [CEI]).

Results
By using analysis of covariance (ANCOVA), after sex grouping and age adjustment, we observed that sleep duration was significantly associated with obesity, functional fitness, and self-perception of health. The sleep duration for low obesity-related values (BMI, WHtR, and WHR) for men was 7–9 h/d, and that for women was 7–8 h/d. Sleeping more than 8 h/d showed poor functional fitness performances (BS and SR). For both sexes, sleep duration of 8–9 h/d was the optimal sleep duration for self-perceptions of health.

Conclusions
Our research found that there were wide and different associations of sleep duration with physical fitness and self-perception of health among Taiwanese adults aged 23–45, and there were differences in these associated manifestations between men and women. This study could be of great importance in regional public health management in Taiwan, and provide inspirations for clinical research on physical fitness.
Identification and characterization of a new soybean promoter induced by Phakopsora pachyrhizi, the causal agent of Asian soybean rust
Authors: Cabre L. , Peyrard S. , Sirven C. , Gilles L. , Pelissier B. , Ducerf S. , Poussereau N. 
Published: March 2021

AbstractBackgroundPhakopsora pachyrhiziis a biotrophic fungal pathogen responsible for the Asian soybean rust disease causing important yield losses in tropical and subtropical soybean-producing countries.P. pachyrhizitriggers important transcriptional changes in soybean plants during infection, with several hundreds of genes being either up- or downregulated.ResultsBased on published transcriptomic data, we identified a predicted chitinase gene, referred to asGmCHIT1, that was upregulated in the first hours of infection. We first confirmed this early induction and showed that this gene was expressed as early as 8 h afterP. pachyrhizi inoculation. To investigate the promoter ofGmCHIT1,transgenic soybean plants expressing the green fluorescence protein (GFP) under the control of theGmCHIT1promoter were generated. Following inoculation of these transgenic plants withP. pachyrhizi, GFP fluorescence was detected in a limited area located around appressoria, the fungal penetration structures. Fluorescence was also observed after mechanical wounding whereas no variation in fluorescence of pGmCHIT1:GFP transgenic plants was detected after a treatment with an ethylene precursor or a methyl jasmonate analogue.ConclusionWe identified a soybean chitinase promoter exhibiting an early induction byP. pachyrhizilocated in the first infected soybean leaf cells. Our results on the induction ofGmCHIT1promoter byP. pachyrhizicontribute to the identification of a new pathogen inducible promoter in soybean and beyond to the development of a strategy for the Asian soybean rust disease control using biotechnological approaches.
Knowledge, awareness, and perception of dental students, interns, and freshly graduated dentists regarding dental implant complications in Saudi Arabia: a web-based anonymous survey
Authors: Saad Islam , Salem Suzan 
Published: March 2021

Abstract
Background
It is necessary for dental students and freshly graduated dentists to apply their education and practice to different clinical and preclinical procedures. The implant success rate and durability are high. Therefore, this study was designed to assess the level of knowledge, awareness and perception of dental students, interns and freshly graduated students regarding dental implant complications in Saudi Arabia.

Methods
A cross-sectional study design using a web-based method was conducted at different dental institutions in Saudi Arabia from December 2019 to March 2020. Data were collected from all (n = 288) undergraduate students, interns and freshly graduated dentists using a pretested standardized self-administered web-based questionnaire that was prepared and circulated using a template provided by Google Forms (Google, Inc., USA). Descriptive statistics and chi-square tests were performed to analyse the data using SPSS (version 20).

Results
A total of 288 participants completed the questionnaire, with a response rate of 83.4%. Of the total participants, 37.5% showed a good level of knowledge regarding dental implant procedures, and 38.9% showed the same level of knowledge regarding implant complications. The most important cause of complications associated with dental implants was case selection, which accounted for 54.17%. Most participants (58.33%) chose massive bone loss related to implant failure as the most common late dental complication, while 26.39% chose postoperative infection as the most common early dental complication. In addition, 30.56% of the participants selected screw loosening as the most frequent mechanical complication. However, lack of implant primary stability was the most common hard-tissue implant complication. Based on aesthetic and reversible complications, restorations that were too buccal or too palatal and prosthetic-related, respectively, were the least common dental implant complications.

Conclusions
The level of knowledge among participants regarding dental implant complications differed among the institutions participating in this study. This difference reflects a significant variation that necessitates reviewing and standardizing dental implant curricula among these institutions.
A mixed methods study to evaluate the impact of a student-run clinic on undergraduate medical education
Authors: Rockey Nathan G. , Weiskittel Taylor M. , Linder Katharine E. , Ridgeway Jennifer L. , Wieland Mark L. 
Published: March 2021

Abstract
Background
The purpose of this study was to evaluate the extent to which a longitudinal student-run clinic (SRC) is meeting its stated learning objectives, including providing critical community services and developing physicians who more fully appreciate the social factors affecting their patients’ health.

Methods
This was a mixed methods program evaluation of an SRC at Mayo Clinic Alix School of Medicine (MCASOM). A survey was conducted of medical students who had participated in the clinic and seven interviews and three focus groups were conducted with SRC patients, students, faculty, staff, and board members. Transcripts were coded for systematic themes and sub-themes. Major themes were reported. Survey and interview data were integrated by comparing findings and discussing areas of convergence or divergence in order to more fully understand program success and potential areas for improvement.

Results
Greater than 85% of student survey respondents (N = 90) agreed or strongly agreed that the SRC met each of its objectives: to provide a vital community service, to explore social determinants of health (SDH), to understand barriers to healthcare access and to practice patience-centered examination. Qualitative data revealed that the SRC contextualized authentic patient care experiences early in students’ medical school careers, but the depth of learning was variable between students. Furthermore, exposure to SDH through the program did not necessarily translate to student understanding of the impact of these social factors on patient’s health nor did it clearly influence students’ future practice goals.

Conclusions
The MCASOM SRC experience met core learning objectives, but opportunities to improve long-term impact on students were identified. Participation in the SRC enabled students to engage in patient care early in training that is representative of future practices. SRCs are an avenue by which students can gain exposure to real-world applications of SDH and barriers to healthcare access, but additional focus on faculty development and intentional reflection may be needed to translate this exposure to actionable student understanding of social factors that impact patient care.
Entrustability levels of general internal medicine residents
Authors: Dehghani Poudeh Mostafa , Mohammadi Aeen , Mojtahedzadeh Rita , Yamani Nikoo 
Published: March 2021

Abstract
Background
Entrustable professional activities (EPAs) are those activities that a health professional can perform without direct supervision in a defined environment. Bridging the gap between competencies and learning objectives, EPAs have made assessing the performances of health professional more realistic. The main objective of the present study was developing and customizing EPAs for Iranian Internal Medicine Residency Programs.

Results
After reviewing the publications, residency curricula and logbooks, and collecting experts’ ideas, the initial list of EPAs was developed. Then, in a focus group, the list was refined, the entrustability level of each residency year was determined, and finally, the EPA-competency cross-tab was established, and in the next step, through a one- round Delphi, the results were validated. Twenty-eight EPAs were developed. Some of them were definitely suitable for the higher levels of residency, such that they had to be accomplished under direct supervision until the end of the program. On the other hand, some of EPAs were those that residents, even from the first year, are expected to perform independently or under indirect supervision. Most of the EPAs cover a wide range of competencies.

Conclusion
Determining the entrustability level of each residency year in each EPA as well as the competency- EPA matrix has crucial effect on the quality of the graduates. It seems that our findings are applicable in developing countries like Iran.