bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptive tutorials versus web-based resources in radiology: a mixed methods analysis in junior doctors of efficacy and engagement
Authors: Wade Stuart W. T. , Moscova Michelle , Tedla Nicodemus , Moses Daniel A. , Young Noel , Kyaw Merribel , Velan Gary M. 
Published: September 2020

Abstract
Background
Radiology education is limited in undergraduate Medicine programs. Junior doctors might not have the necessary background to effectively order and interpret diagnostic imaging investigations. Furthermore, junior doctors are often time-poor, balancing clinical commitments with ongoing learning, leadership and teaching responsibilities. Previous studies have demonstrated the efficacy of radiology-themed online adaptive tutorials for senior medical students. Such adaptive tutorials might therefore be an efficient and effective form of radiology education for junior doctors.

Methods
A randomised controlled crossover trial was performed to evaluate the impact of adaptive tutorials on learning the indications for, and interpretation of, basic imaging studies, compared with peer-reviewed web-based resources. Ninety-one volunteer junior doctors, comprising 53 postgraduate year 1 (PGY 1) and 38 postgraduate year 2 (PGY 2), were randomly allocated into two groups. In the first phase of the trial, focusing on head CT, one group accessed adaptive tutorials while the other received web-based resources. In the second phase of the trial, focusing on chest CT, the groups crossed over. Following each phase of the trial, participants completed exam-style online assessments. At the conclusion of the study, participants also completed an online questionnaire regarding perceived engagement and efficacy of each type of educational resource.

Results
Junior doctors completed the adaptive tutorials significantly faster than the relevant web-based resources for both head CT and chest CT (p = 0.03 and < 0.01 respectively). Mean quiz scores were higher in the groups receiving adaptive tutorials on head CT and chest CT (86.4% vs 83.5 and 77.7% vs 75% respectively). However, in contrast to previous studies in senior medical students, these differences were not statistically significant. Participants reported higher engagement and perceived value of adaptive tutorials, compared with web-based resources.

Conclusions
Adaptive tutorials are more time-efficient than existing web-based resources for learning radiology by junior doctors, while both types of resources were equally effective for learning in this cohort. Junior doctors found the adaptive tutorials more engaging and were more likely to recommend these resources to their colleagues.
Repositioning liothyronine for cancer immunotherapy by blocking the interaction of immune checkpoint TIGIT/PVR
Authors: Zhou Xiuman , Du Jiangfeng , Wang Hongfei , Chen Chunxia , Jiao Ling , Cheng Xiangrui , Zhou Xiaowen , Chen Shaomeng , Gou Shanshan , Zhao Wenshan , Zhai Wenjie , Chen Junhui , Gao Yanfeng 
Published: September 2020

Abstract
Background
Inhibitors targeting immune checkpoint were proved effective in cancer immunotherapy, such as PD-1/PD-L1 blockade. The novel immune checkpoint TIGIT/PVR plays critical roles in suppressing the anti-tumor effects of CD8+ T and NK cells, and dual blockade of TIGIT/PVR and PD-1/PD-L1 by antibody can elicit synergistic effects in tumor models and clinical trials. However, small molecules for TIGIT/PVR blockade have not been investigated.

Methods
The expression of PVR in tumors were analyzed by using TCGA, Oncomine and GEO database, and in cancer cell lines examined by flow cytometry. Natural product compounds were docked to PVR for virtual screening by using the software Molecular Operating Environment (MOE). Candidate compounds were further tested by biolayer interferometry-based binding assay, microscale thermophoresis assay and cell based blocking assay. The in vitro activity of the candidate compound was determined by MTT, peripheral blood mononuclear cells (PBMCs) activation assay and coculture assay. The anti-tumor effects and mechanism were also investigated by using MC38 tumor-bearing mice model and immune cell depletion tumor model.

Results
PVR was over-expressed in many tumor tissues and cancer cell lines, making it a promising therapeutic target. Through virtual screening, binding, and blocking assay, liothyronine was discovered to bind PVR and block the interaction of TIGIT/PVR. Liothyronine could enhance the function of CD4+ and CD8+ T cells in PBMCs. Besides, in the Jurkat-hTIGIT and CHOK1-hPVR coculture assay, liothyronine could reverse the IL-2 secretion inhibition resulted by TIGIT/PVR ligation. Although had no influence on the proliferation of tumor cells in vitro, liothyronine could significantly inhibit tumor growth when administrated in vivo, by enhancing CD8+ T cell infiltration and immune responses in the tumor bearing mice. The immune cell depletion model showed that the anti-tumor effects of liothyronine depends on CD4+ T cells, CD8+ T cells and NK cells.

Conclusions
A small molecule liothyronine was discovered to serve as a potential candidate for cancer immunotherapy by blocking the immune checkpoint TIGIT/PVR.

Graphical abstract
Perspectives in melanoma: meeting report from the “Melanoma Bridge” (December 5th–7th, 2019, Naples, Italy)
Authors: Ascierto Paolo A. , Puzanov Igor , Agarwala Sanjiv S. , Blank Christian , Carvajal Richard D. , Demaria Sandra , Dummer Reinhard , Ernstoff Marc , Ferrone Soldano , Fox Bernard A. , Gajewski Thomas F. , Garbe Claus , Hwu Patrick , Lo Roger S. , Long Georgina V. , Luke Jason J. , Osman Iman , Postow Michael A. , Sullivan Ryan J. , Taube Janis M. , Trinchieri Giorgio , Zarour Hassane M. , Caracò Corrado , Thurin Magdalena 
Published: September 2020

AbstractThe melanoma treatment landscape changed in 2011 with the approval of the first anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 checkpoint inhibitor and of the first BRAF-targeted monoclonal antibody, both of which significantly improved overall survival (OS). Since then, improved understanding of the tumor microenvironment (TME) and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. The approval of new immune and targeted therapies has further improved outcomes for patients with advanced melanoma and other combination modalities are also being explored such as chemotherapy, radiotherapy, electrochemotherapy and surgery. In addition, different strategies of drugs administration including sequential or combination treatment are being tested. Approaches to overcome resistance and to potentiate the immune response are being developed. Increasing evidence emerges that tissue and blood-based biomarkers can predict the response to a therapy. The latest findings in melanoma research, including insights into the tumor microenvironment and new biomarkers, improved understanding of tumor immune response and resistance, novel approaches for combination strategies and the role of neoadjuvant and adjuvant therapy, were the focus of discussions at the Melanoma Bridge meeting (5–7 December, 2019, Naples, Italy), which are summarized in this report.
Toward a hemorrhagic trauma severity score: fusing five physiological biomarkers
Authors: Bhat Ankita , Podstawczyk Daria , Walther Brandon K. , Aggas John R. , Machado-Aranda David , Ward Kevin R. , Guiseppi-Elie Anthony 
Published: September 2020

Abstract
Background
To introduce the Hemorrhage Intensive Severity and Survivability (HISS) score, based on the fusion of multi-biomarker data; glucose, lactate, pH, potassium, and oxygen tension, to serve as a patient-specific attribute in hemorrhagic trauma.

Materials and methods
One hundred instances of Sensible Fictitious Rationalized Patient (SFRP) data were synthetically generated and the HISS score assigned by five clinically active physician experts (100 [5]). The HISS score stratifies the criticality of the trauma patient as; low(0), guarded(1), elevated(2), high(3) and severe(4). Standard classifier algorithms; linear support vector machine (SVM-L), multi-class ensemble bagged decision tree (EBDT), artificial neural network with bayesian regularization (ANN:BR) and possibility rule-based using function approximation (PRBF) were evaluated for their potential to similarly classify and predict a HISS score.

Results
SVM-L, EBDT, ANN:BR and PRBF generated score predictions with testing accuracies (majority vote) corresponding to 0.91 ± 0.06, 0.93 ± 0.04, 0.92 ± 0.07, and 0.92 ± 0.03, respectively, with no statistically significant difference (p > 0.05). Targeted accuracies of 0.99 and 0.999 could be achieved with SFRP data size and clinical expert scores of 147[7](0.99) and 154[9](0.999), respectively.

Conclusions
The predictions of the data-driven model in conjunction with an adjunct multi-analyte biosensor intended for point-of-care continual monitoring of trauma patients, can aid in patient stratification and triage decision-making.
Impact of different omega-3 fatty acid sources on lipid, hormonal, blood glucose, weight gain and histopathological damages profile in PCOS rat model
Authors: Komal Fiza , Khan Muhammad Kamran , Imran Muhammad , Ahmad Muhammad Haseeb , Anwar Haseeb , Ashfaq Usman Ali , Ahmad Nazir , Masroor Amna , Ahmad Rabia Shabir , Nadeem Muhammad , Nisa Mahr Un 
Published: September 2020

AbstractBackgroundOmega-3 fatty acids (Ω-3 PUFAs) may help to improve health status in polycystic ovarian syndrome (PCOS) by reducing numerous metabolic disorders (insulin sensitivity, hyperinsulinemia, lipid profile, obesity and inflammation). To evaluate the current objective, 16 weeks (6 weeks of adjustment period followed by 10 weeks of collection period) research trial was planned to check the impact of different sources of Ω-3 PUFAs (synthetic Ω-3, flaxseed and fish oil) on nutrient digestibility, weight gain, productive (lipid profile, glucose and insulin), reproductive profile (progesterone, follicle stimulating hormone (FSH), estrogen, luteinizing hormone (LH) and prolactin) and histological study of ovarian tissues in Wistar female rats.MethodsForty-five rats of 130 ± 10 g weight were divided into 5 groups, each having 9 rats: NC (negative control without PCOS), PC (positive control with PCOS), SO (synthetic omega-3 containing ALA, EPA and DHA), FO (flaxseed oil) and F (fish oil) fed at 300 mg/kg/orally/daily of these sources were added in the basal diets while PC and NC received only the basal diet. Food and water were offered ad libitum. PCOS was induced in the rats fed of PC, SO, FO and F diets group by single intramuscular injection of estradiol-valerate (4 mg/rat/IM). Body weight and blood glucose was recorded weekly. At 16thweek of trial, blood samples were collected for lipid and hormonal analysis. Ovarian tissues were removed for pathological evaluation. Digestibility was measured by total collection method.ResultsCholesterol, triglycerides and low-density lipoproteins were reduced in SO, FO and F groups when compared with rats of PC group. However, increasing trend of high-density lipoprotein (HDL) was found in same groups. The highest HDL (36.83 ± 0.72 mg/dL) was observed in rats fed F diet. In case of a hormonal profile, testosterone, LH and insulin levels showed a significant reduction after treatments. Blood glucose results showed significantly reducing trend in all the rats fed with Ω-3 PUFAs sources than PC from 5 to 10th week of trial. However, similar trend was noticed in rat’s body weight at the end of 6th week. In ovarian morphology, different stages of follicles were observed in groups fed SO, FO and F diets. Nutrient digestibility in PCOS induced rats was remained non-significant.ConclusionsThe three sources of Ω-3 PUFAs had effective role in improving lipid and hormonal profile, reducing blood glucose, weight gain and histopathological damages in PCOS rats. However, fish oil source might be an innovative approach to cure PCOS via reducing the weight and metabolic anomalies due to EPA and DHA.
A phase 2 study of combined chemo-immunotherapy with cisplatin-pembrolizumab and radiation for unresectable vulvar squamous cell carcinoma
Authors: Yeku Oladapo , Russo Andrea L. , Lee Hang , Spriggs David 
Published: September 2020

Abstract
Background
Unresectable or metastatic vulvar cancer has relatively poor outcomes despite chemotherapy-sensitized radiation therapy and combination cytotoxic therapy. Despite the virus-associated and immunogenic nature of this disease, novel immunotherapy options that exploit this advantage are currently lacking. Platinum agents such as cisplatin have been shown to prime dendritic cells for T-cell costimulation, promote downregulation of inhibitory checkpoint molecules, and sensitize tumor cells to cytotoxic T-cell killing. Radiation therapy has also been shown to promote immunogenetic cell death as monotherapy and in combination with cisplatin. In combination with pembrolizumab, cisplatin-sensitized radiation is hypothesized to increase overall response rates and recurrence-free survival in patients with vulvar cancer, via induction of an anti-tumor inflammatory response.

Methods
We propose a single-arm phase II clinical trial of pembrolizumab combined with cisplatin-sensitized radiation therapy for women with unresectable, locally advanced, or metastatic vulvar cancer. The first three patients with locally advanced or unresectable disease will receive cycle 1 of pembrolizumab followed by a break and resumption of pembrolizumab at cycle 4 and as part of a safety cohort. All other patients, including the fourth patient with locally advanced/unresectable disease, will receive weekly cisplatin and pembrolizumab every 3 weeks, concurrently with daily radiation therapy. Following the completion of Cis-RT, patients will continue pembrolizumab maintenance for a total of 12 cycles. Archived tissue will be used for HPV status, MSI status, PD-L1, and TIL stratification post hoc. Imaging will be performed at baseline and every 3 cycles (21-day cycles) as per standard-of-care. Laboratory analysis will occur on the first day of each cycle.

Discussion
The combination of cisplatin-sensitized radiation and immune checkpoint blockade has not been evaluated in the upfront setting for vulvar cancer. In this rare malignancy, there are limited interventional clinical trials. This trial is designed to be as accessible as possible by allowing patients to receive cisplatin and radiation locally according to accepted standard-of-care while receiving pembrolizumab and adverse event monitoring at a centralized site. A robust suite of translational correlative studies has also been built into the trial to evaluate tumor-directed immune activation.
Trial registration NCT04430699
Exploring perspectives, preferences and needs of a telemonitoring program for women at high risk for preeclampsia in a tertiary health facility of Karachi: a qualitative study protocol
Authors: Feroz Anam , Saleem Sarah , Seto Emily 
Published: September 2020

Abstract
Background
In Pakistan, deaths from preeclampsia/eclampsia (PE/E) represent one-third of maternal deaths reported at tertiary care hospitals. To reduce the morbidity and mortality associated with PE/E, an accessible strategy is to support pregnant women at high risk for preeclampsia (HRPE) by closely monitoring their blood pressures at home (i.e., telemonitoring) for the earliest signs of preeclampsia. This could lead to the earliest possible detection of high blood pressure, resulting in early intervention such as through medications, hospitalization, or delivery of the baby. The study aims to explore the perspectives, preferences and needs of telemonitoring (TM) for pregnant women at HRPE in Karachi, to inform future implementation strategies.

Methods
The study will employ an exploratory qualitative research design. The study will be conducted at the Jinnah Postgraduate Medical Centre (JPMC) hospital and Aga Khan University Hospital (AKUH) in Karachi, Sindh, Pakistan. Data will be collected through key-informant interviews (KIIs) and in-depth patient interviews (IDPIs). IDPIs will be conducted with the pregnant women at HRPE who are visiting the out-patient department/ antenatal clinics of JPMC hospital for antenatal check-ups and immunizations. KIIs will be conducted with the obstetricians, Maternal, neonatal and child health (MNCH) specialists and health care providers at JPMC, as well as TM experts from Karachi. Study data will be analyzed through conventional content analysis. Interviews are anticipated to begin in April 2020 and to be completed during the summer of 2020.

Discussion
This is the first study to explore the use of TM program for pregnant women at HRPE in a tertiary health facility in Karachi. The research will help explore perceived benefits associated with the use of a TM program alongside potential facilitators and barriers that may help inform the future implementation of a TM program for pregnant women at HRPE in Karachi.
Recurrent uterine tumors resembling ovarian sex-cord tumors with the growth regulation by estrogen in breast cancer 1-nuclear receptor coactivator 2 fusion gene: a case report and literature review
Authors: Chang Bin , Bai Qianming , Liang Lin , Ge Huijuan , Yao Qianlan 
Published: September 2020

Abstract
Background
Uterine tumors resembling ovarian sex-cord tumors (UTROSCTs) are rare mesenchymal neoplasms predominantly arising in perimenopausal and postmenopausal women. UTROSCTs with growth regulation by estrogen in breast cancer 1 (GREB1)-rearrangement or GREB1-rearranged uterine tumors are exceptionally rare, with only 12 previously reported cases. Here, we report a case of UTROSCT with the GREB1-nuclear receptor coactivator 2 (NCOA2) fusion gene.

Case presentation
A 57-year-old woman presented with a 10.0 cm uterine mass. The tumor was composed of short spindle or epithelioid cells, arranged in diffused sheets, nested, and trabecular/cordlike. The tumor harbored the GREB1-NCOA2 fusion gene, as confirmed by RNA sequencing. The tumor recurred in the pelvis at 30 months after the initial diagnosis. We also compared the clinical and pathologic features of this case with those of the 12 previously published uterine GREB1-rearranged tumors. Of the combined 13 cases (present case and 12 previous cases), the mean age of patients was 64.8 years (range, 51–74 years). Of the nine reported cases of GREB1-rearranged tumor with follow up, four cases recurred or metastasized (44.4%). Microscopically, most tumors (10/12, 83.3%) showed infiltrative growth, and two were well demarcated. Mitotic figures ranged from 0 to 14 per 10 high-power fields (2 mm2; mean: 3.6). Lymphovascular invasion and necrosis were each present in two cases (2/12, 16.7% and 2/7, 28.6%, respectively).

Conclusions
This case provided further evidence that UTROSCTs with GREB1-rearrangement may have a high risk of recurrence/metastasis. Further studies are necessary to clarify the clinical features of this type of tumor, particularly the prognosis, potential treatment, and range of possible molecular events.
Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1
Authors: Johnson Erik C. B. , Ho Kaitlyn , Yu Gui-Qiu , Das Melanie , Sanchez Pascal E. , Djukic Biljana , Lopez Isabel , Yu Xinxing , Gill Michael , Zhang Weiping , Paz Jeanne T. , Palop Jorge J. , Mucke Lennart 
Published: September 2020

Abstract
Background
Alzheimer’s disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-β peptide (Aβ), which is derived from APP through sequential proteolytic cleavage by BACE1 and γ-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement.

Methods
To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized Aβ sequence.

Results
Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble Aβ, Aβ oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform activity, a type of network dysfunction that also occurs in a substantive proportion of humans with AD. Pharmacological inhibition of BACE1 effectively reduced levels of amyloidogenic APP C-terminal fragments (C99), soluble Aβ, Aβ oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable.

Conclusions
hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-Aβ treatments.
Efficacy and safety of electro-acupuncture (EA) on insomnia in patients with lung cancer: study protocol of a randomized controlled trial
Authors: Yue Hongyu , Zhou Shuang , Wu Huangan , Yin Xuan , Li Shanshan , Liang Tingting , Li Yan , Fang Zhihong , Zhang Xufeng , Wang Linglin , Han Min , Chen Xiaolei , Zhang Ming , Zhang Wei , Zhang Zhangjin , Xu Shifen 
Published: September 2020

AbstractBackgroundCancer-related insomnia (CRI) is one of the most prevalent complaints among cancer survivors and severely impairs patients’ quality of life. As a popular non-pharmacological alternative treatment, acupuncture provides a good clinical curative effect on insomnia. The aim of this trial is to evaluate efficacy and safety of electro-acupuncture on insomnia in patients with lung cancer.MethodThis is a protocol for a multicenter randomized single-blinded sham-controlled trial. We will randomly assign 252 eligible patients with lung cancer-related insomnia into two groups at a ratio of 1:1, the treatment group (EA) and the control group (sham EA). All treatment will be given 3 times per week for 8 weeks, and a 12-week follow-up will be conducted. The primary outcome will be measured by the Pittsburgh Sleep Quality Index (PSQI). The secondary outcomes will include sleep parameters recorded from the actigraphy, scores from Quality of Life Questionnaire Core-30 (QLQ-C30), and Patient Health Questionnaire-9 (PHQ-9). All adverse effects during the trial will be assessed by the Treatment Emergent Symptom Scale (TESS). All analyses will be based on ITT principle and performed with the statistical software SPSS (version 24.0) byttest, rank-sum test, chi-square, and so on. A two-sided significance level will be set at 5%.DiscussionThis large-sample trial protocol will evaluate the efficacy of electro-acupuncture on insomnia in patients with lung cancer. This protocol, if proven to be effective, will contribute to filling the gap in treatment options in the CRI field and provide a promising intervention for insomnia in lung cancer survivors.Trial registrationChiCTR ChiCTR1900026395. Registered on 8 October 2019,http://www.chictr.org.cn/showproj.aspx?proj=44068