bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying entrustable professional activities for MD program in biochemistry—A modified Delphi approach
Authors: Rajaragupathy Sujatha , Govindarajan Sumitra , Ganesan Jeyachandran , Subramanian Kavitha , Doraiswamy Vijaya , Balasubramaniam Gayathri , Andra Suryanarayana Meenakshi Sundaram , Veeruswamy Aruna 
Published: May 2023

AbstractEntrustable professional activities (EPAs) facilitate competency‐based assessments. India is on the verge of implementing competency‐based training for postgraduate programs. MD degree in Biochemistry is a unique program available exclusively in India. Postgraduate programs in most specialties have started working toward EPA‐based curriculum, in both India and other countries. However, EPAs for MD Biochemistry course are yet to be defined. This study aims to identify EPAs for postgraduate training program in Biochemistry. Identification and attaining consensus on the list of EPAs for MD Biochemistry curriculum was done by modified Delphi method. The study was conducted in three rounds. In round 1, tasks expected from an MD Biochemistry graduate were identified by working group followed by expert panel validation. The tasks were organized and reframed to EPAs. Two rounds of online survey were conducted to achieve a consensus on the list of EPAs. Consensus measure was calculated. A cut‐off value of 80% and above was considered to reflect good consensus. The working group identified 59 tasks. This was validated by 10 experts based on which, 53 items were retained. These tasks were reframed into 27 EPAs. In round 2, 11 EPAs achieved good consensus. Among the remaining EPAs, 13 achieved consensus of 60%–80% and were selected for round 3. Five EPAs achieved good consensus in this round. A total of 16 EPAs were identified for MD Biochemistry curriculum. This study provides a frame of reference for experts to develop an EPA‐based curriculum in the future.
Examination performance with flipped classroom as instructional strategy in the carbohydrate metabolism course unit at a Philippine medical school: Estimation of average treatment effect from observational data
Authors: Van Haute Michael , Monzon Jan David 
Published: May 2023

AbstractWhile the innovativeness of the flipped classroom (FC) approach promotes active participation and higher‐order thinking among students, there are concerns about its effectiveness in terms of knowledge retention. Currently, there are no studies involving medical school biochemistry that evaluate this aspect of effectiveness. Thus, we conducted a historical control study that analyzed observational data from two freshman batches of the Doctor of Medicine program in our institution. Class 2021 (n = 250) served as the traditional lecture (TL) group while Class 2022 (n = 264) served as the FC group. Data on relevant observed covariates (age, sex, National Medical Admission Test or NMAT score, undergraduate degree) and the outcome variable (carbohydrate metabolism course unit examination percentage scores, as indicator of knowledge retention) were included in the analysis. Propensity scores were calculated using logit regression conditional on these observed covariates. Afterwards, 1:1 nearest‐neighbor propensity score matching (PSM) was performed to produce an estimated average treatment effect (ATE) measure afforded by FC (as adjusted mean difference in examination scores between the two batches), balancing on the covariates. Nearest‐neighbor matching using the calculated propensity scores effectively balanced the two groups (standardized bias <10%), producing 250 matched student‐pairs that received either TL or FC. Following PSM, the FC group was found to have a significantly higher adjusted mean examination score compared to the TL group (adjusted mean difference = 5.62%, 95% CI: 2.54%, 8.72%; p < 0.001). Using this approach, we were able to demonstrate benefit of FC over TL in terms of knowledge retention, as reflected by the estimated ATE.
Aconitum carmichaelii triggers neurotoxicity and Parkinson‐like symptoms through initiation of ROS‐mitochondrial apoptosis and the Nox5/DJ‐1 signaling pathway
Authors: Pang Meijun , Song Xin , Miao Yaodong , Wang Yiwen , Zhou Chang , Geng Zihan , Du Jiayin , Moussian Bernard , Su Yanfang , Liu Xiuyun , Ming Dong 
Published: May 2023

AbstractBackground
Aconitum carmichaelii, the mother root of Aconitum, has a long‐applied history for treating many diseases in China. Increased use of it has prompted significant concerns regarding its extensive cardiotoxicity and neurotoxicity. The molecular mechanisms underlying A. carmichaelii‐induced neurotoxicity are poorly understood.MethodsWe took advantage of the zebrafish model to investigate the neurotoxic mechanism of A. carmichaelii. In addition to the behavior and neuronal activity testing, gene expression of neuronal oxidative stress, and apoptosis levels were also analyzed.ResultsIn contrast to the excitatory effect of low‐dose A. carmichaelii decoction, hypoactivity of locomotor behavior, and neural activity, especially telencephalon, were detected in the 20 mg/mL group. High doses of A. carmichaelii induced excessive ROS by downregulating DJ‐1 and activating Nox5, and further triggered cell apoptosis through the bax/bcl2a‐caspase‐9 pathway in zebrafish larva. Mitochondrial protection‐related genes PinK1 and Parkin were upregulated to protect against mitochondrial dysfunction during cellular stress. The ROS scavenger‐NAC significantly alleviated neurotoxicity in the 20 mg/mL group.ConclusionThe study reveals the potential mechanism of A. carmichaelii‐induced neurotoxicity and provides new insights into a significant risk marker of A. carmichaelii poisoning.
Increase in age at onset of moyamoya disease in China over 25 years
Authors: Ma Zhiyang , Chen Dayu , Wang Sheng , Zhu Yaozu , Chen Jincao 
Published: May 2023

AbstractBackgroundTo explore whether the age at onset (AAO) of Chinese patients with moyamoya disease (MMD) increased over time due to a reduced exposure to leptospiral infection.MethodsWe performed an independent, multicenter, retrospective study based on data from patients with MMD who initially attended four tertiary hospitals in Hubei, China, from 1996 to 2020. After stratifying the year of MMD onset into five periods (1996–2000, 2001–2005, 2006–2010, 2011–2015, and 2016–2020), we analyzed the temporal trends in AAO and compared different classes of AAO (early‐onset, < 20 years; intermediate‐onset, 20–49 years; late‐onset, ≥ 50 years) in each period.ResultsWe included 1858 patients in this study, with 878 women and 980 men. Their median (IQR) AAO was 47 (39‒55) years. The case AAO significantly increased at the rate of 0.94 years per year (r = 0.406, p < .0001), while no trend was observed in birth years through time (p = .512). The birth cohorts who grew up in the leptospirosis epidemic years was stably susceptible to MMD. The median (IQR) AAO has increased significantly from 26 (14–37) years (1996–2000) to 51 (43–57) years (2016–2020) (p < .0001). The proportion of early‐onset MMD was significantly higher in 1996–2000 (33.3%, p < .0001) and 2001–2005 (10.4%, p < .001). The AAO shows an aging trend that the proportion of late‐onset MMD went from 4.5% (2001–2005) to 54.5% (2016–2020) (p < .0001).ConclusionsThe AAO of MMD was increasing during a recent 25‐year period in China, which may reflect a birth cohort effect that resulted from environmental changes. The disparity risk of birth cohorts with MMD changed with leptospirosis epidemics, suggesting leptospiral exposure might be a potential risk factor.
Forging organizational resilience through green value co‐creation: The role of green technology, green operations, and green transaction capabilities
Authors: Borah Prasad Siba , Dogbe Courage Simon Kofi , Dzandu Michael D. , Pomegbe Wisdom Wise Kwabla 
Published: May 2023

AbstractThe study assessed the mediating role of green organizational capabilities (green technology development, green operations, and green transactions), in the relationship between green value co‐creation and organizational resilience among Chinese manufacturing firms, that is, firms' ability to build strong organizational resilience in response to the COVID‐19 pandemic. It focused on manufacturing firms operating within Shenzhen, a coastal city located within the Guangdong province in southeastern China. The sample comprised 234 firms. Data were analysed using a covariance‐based structural equation modeling. Findings revealed that green value co‐creation had no direct effect on organizational resilience, rather, its effect was realized indirectly through green organizational capabilities. The study concludes that manufacturing companies can augment their organizational capabilities by leveraging the knowledge of their customers through green value co‐creation to build strong organizational resilience. Theoretical and managerial implications have been provided.
Biomimetic scaffold‐based stem cell transplantation promotes lung regeneration
Authors: Wang Linjie , Feng Meng , Zhao Yazhen , Chen Bing , Zhao Yannan , Dai Jianwu 
Published: May 2023

AbstractTherapeutic options are limited for severe lung injury and disease as the spontaneous regeneration of functional alveolar is terminated owing to the weakness of the inherent stem cells and the dyscrasia of the niche. Umbilical cord mesenchymal‐derived stem cells (UC‐MSCs) have been applied to clinical trials to promote lung repair through stem cell niche restruction. However, the application of UC‐MSCs is hampered by the effectiveness of cell transplantation with few cells homing to the injury sites and poor retention, survival, and proliferation in vivo. In this study, we constructed an artificial three‐dimensional (3D) biomimetic scaffold‐based MSCs implant to establish a beneficial regeneration niche for endogenous stem cells in situ lung regeneration. The therapeutic potential of 3D biomimetic scaffold‐based MSCs implants was evaluated by 3D culture in vitro. And RNA sequencing (RNA‐Seq) was mapped to explore the gene expression involved in the niche improvement. Next, a model of partial lung resection was established in rats, and the implants were implanted into the operative region. Effects of the implants on rat resected lung injury repair were detected. The results revealed that UC‐MSCs loaded on biomimetic scaffolds exerted strong paracrine effects and some UC‐MSCs migrated to the lung from scaffolds and had long‐term retention to suppress inflammation and fibrosis in residual lungs and promoted vascular endothelial cells and alveolar type II epithelial cells to enter the scaffolds. Then, under the guidance of the ECM‐mimicking structures of scaffolds and the stimulation of the remaining UC‐MSCs, vascular and alveolar‐like structures were formed in the scaffold region. Moreover, the general morphology of the operative lung was also restored. Taken together, the artificial 3D biomimetic scaffold‐based MSCs implants induce in situ lung regeneration and recovery after lung destruction, providing a promising direction for tissue engineering and stem cell strategies in lung regeneration.
Expression of Tryptophan Metabolism Enzymes in Patients with Diffuse Large B‐cell Lymphoma and NK/T‐cell Lymphoma
Authors: Guo Dan , Wang Yuming , Wu Xunyao , Gao Yike , Wang Anqi , Zhang Zixin , Zhao Kun , Wang Xiaoxi , Liu Meiyu , Zhang Yaran , Li Mei , Chen Rui , Sun Jian , Zhang Yan 
Published: May 2023

AbstractBackgroundMetabolites of tryptophan (Trp) metabolism in the tumor microenvironment play crucial immunosuppressive roles in various cancers. However, the role of Trp metabolism in diffuse large B‐cell lymphoma (DLBCL) or natural killer/T‐cell lymphoma (NK/TCL) remains unelucidated.MethodsWe investigated the potential role of Trp metabolism in a cohort of 43 patients with DLBCL and 23 with NK/TCL. We constructed tissue microarrays and performed in situ staining of Trp‐catabolizing enzymes and PD‐L1 using immunohistochemistry (IHC).ResultsWe observed 14.0% positive staining of IDO1 in DCBCL and 60.9% in NK/TCL; 55.8% of IDO2 in DCBCL and 95.7% in NK/TCL; 79.1% of TDO2 in DCBCL and 43.5% in NK/TCL; 29.7% of IL4I1 in DCBCL and 39.1% in NK/TCL. However, IDO1, IDO2, TDO2, and IL4I1 positivity did not significantly differ between PD‐L1+ and PD‐L1− biopsy tissue samples of NK/TCL; nonetheless, a positive correlation of IDO1 (r = 0.87, p < 0.001), IDO2 (r = 0.70, p < 0.001), TDO2 (r = 0.63, p < 0.001), and IL4I1 (r = 0.53, p < 0.05) with PD‐L1 expression was observed in the TCGA‐DLBCL dataset. Finally, immunohistochemical (IHC) analysis revealed the lack of superior prognostic effect with higher expression of Trp enzymes in DLBCL and NK/TCL. Furthermore, IDO1, IDO2, TDO2, and IL4I1 expression, as well as survival rates, did not significantly differ across all groups in the TCGA‐DLBCL cohort.ConclusionCollectively, our findings provide novel insights into the enzymes involved in Trp metabolism in DLBCL and NK/TCL and their association with PD‐L1 expression, which offers potential strategies to combine Trp‐metabolism enzyme inhibitors with anti‐PD‐L1 or other immunotherapeutic strategies in clinical DLBCL or NK/TCL treatment.
General population reference values for the Functional Assessment of Cancer Therapy‐Lung and PROMIS‐29
Authors: Mohindra Nisha A. , Peipert John Devin , Blum Steven I. , Shaw James W. , Penrod John R. , Cella David 
Published: May 2023

AbstractBackgroundTherapeutic advances in lung cancer have turned attention toward patient‐reported outcome measures (PROMs) as important clinical outcomes. The Functional Assessment of Cancer Therapy‐Lung (FACT‐L) is a common endpoint in lung cancer trials. This study calculated FACT‐L reference values for the United States (US) general population.MethodsAdults from the US general population (N = 2001) were surveyed between September 2020 and November 2020. Surveys contained 126 questions, including the FACT‐L [36 items; FACT‐G and four subscales (Physical Well‐Being [PWB], Social Well‐Being [SWB], Emotional Well‐Being [EWB], and Functional Well‐Being [FWB]) and the Lung Cancer Subscale (LCS), and a Trial Outcome Index (TOI)]. Reference values for each FACT‐L scale were calculated with means for the total sample and separately for participants with: no comorbidities, COVID‐19 as only comorbidity, no COVID‐19.ResultsIn the total sample, the reference scores were as follows: PWB = 23.1; SWB = 16.8; EWB = 18.5; FWB = 17.6; FACT‐G = 76.0; LCS = 23.0, TOI = 63.7, and FACT‐L Total = 99.0. Scores were lower for those reporting a prior diagnosis of COVID‐19, especially for SWB (15.7) and FWB (15.3). SWB scores were lower than previous references values.ConclusionsThese data provide US general adult population reference value set for FACT‐L. While some of the subscale results were lower than those found in the reference data for other PROMs, these data were obtained in a more contemporaneous time frame juxtaposed with the COVID‐19 pandemic and may represent a new peri‐pandemic norm. Thus, these reference values will be useful for future clinical research.
Investigating potential disparities in clinical trial eligibility and enrollment at anNCI‐designated comprehensive cancer center
Authors: Patel Monica A. , Shah Jennifer L. , Brinley Floyd John , Abrahamse Paul H. , Veenstra Christine M. , Schott Anne F. 
Published: May 2023

AbstractBackgroundAlthough barriers to trial accrual are well‐reported, few studies have explored trial eligibility and trial offers as potential drivers of disparities in cancer clinical trial enrollment.MethodsWe identified patients with gastrointestinal (GI) or head/neck (HN) malignancies who were seen as new patients at the University of Michigan Health Rogel Cancer Center in 2016. By exhaustive review of the electronic medical record, we assessed the primary outcomes: (1) eligibility for, (2) documented offer of, and (3) enrollment in a clinical trial. All 41 of the clinical trials available to these patients were considered. Independent variables included clinical and non‐clinical patient‐related factors. We assessed associations between these variables and the primary outcomes using multivariable regression.ResultsOf 1446 patients, 43% were female, 15% were over age 75, 6% were Black. 305 (21%) patients were eligible for a clinical trial. Among eligible patients, 154 (50%) had documentation of a trial offer and 90 (30%) enrolled. Among the GI cohort, bivariate analyses demonstrated that older age was associated with decreased trial eligibility. Bivariate analyses also demonstrated that Black race was associated with increased trial offer. After adjustment, patients 75 or older were less likely to be eligible for a clinical trial in the GI cohort; however, we found no significant associations between race and any of the outcomes after adjustment. Among eligible GI patients, we found no significant associations between non‐clinical factors and enrollment. Among the HN cohort, bivariate analyses demonstrated that female sex, older age, Black race, and unpartnered marital status were associated with decreased likelihood of trial offer; however, we found no significant associations between race, age, and marital status and any of the outcomes after adjustment. We found no significant associations between non‐clinical factors and eligibility after adjustment; however, women were less likely to be offered and to enroll in a clinical trial in the HN cohort.ConclusionFactors associated with eligibility, documented offer, and enrollment differed between disease site cohorts at our institution. Future work is needed to ensure the equitable inclusion of women and elderly patients in clinical trials.
Pegylated liposomal doxorubicin (PLD) in daily practice—A single center experience of treatment with PLD in patients with comorbidities and older patients with metastatic breast cancer
Authors: Wallrabenstein T. , Daetwyler E. , Oseledchyk A. , Rochlitz C. , Vetter M. 
Published: May 2023

AbstractPurposeReal‐world data about pegylated liposomal doxorubicin (PLD) in patients with metastatic breast cancer (MBC) are limited. We have aimed to highlight the role of PLD in daily practice focusing on older patients and patients with comorbidities with MBC.MethodsWe analyzed electronic records of all patients with advanced/metastatic breast cancer treated with single‐agent PLD at the University Hospital Basel between 2003 and 2021. Primary endpoint was time to next chemotherapy or death (TTNC). Secondary endpoints were overall survival (OS), progression‐free survival (PFS), and overall response rate (ORR). We performed univariate and multivariate analysis for clinical variables.Results112 patients with MBC having received single‐agent PLD in any treatment line were analyzed, including 34 patient who were older than 70 years and 61 patients with relevant comorbidities. Median TTNC, OS, and PFS for treatment with PLD were 4.6, 11.9, and 4.4 months, respectively. ORR was 13.6%. Age >70 years predicted shorter OS (median 11.2 months) in multivariate analysis (hazard ratio [HR] 1.83, 95% CI 1.07–3.11, p = 0.026). Age and comorbidities did not significantly affect other endpoints. Unexpectedly, hypertension predicted longer TTNC (8.3 months, p = 0.04) in univariate analysis, maintained in multivariate analysis as a trend for both TTNC (HR 0.62, p = 0.07) and OS (HR 0.63, p = 0.1).ConclusionAge predicted shorter OS significantly but median OS was not relevantly shorter in older patients. PLD remains a treatment option in patients with comorbidities and older patients with MBC. However, our real‐world results of PLD appear underwhelming compared to relevant phase II trials through all age groups, pointing to an efficacy‐effectiveness gap, possibly due to sampling bias.
Development of skeletal muscle fibrosis in a rodent model of cancer cachexia
Authors: Washington Tyrone A. , Schrems Eleanor R. , Haynie Wesley S. , Rosa‐Caldwell Megan E. , Brown Jacob L. , Saling Landen , Lim Seongkyun , Perry Richard A. , Brown Lemuel A. , Lee David E. , Greene Nicholas P. 
Published: May 2023

AbstractCachexia is characterized by losses in lean body mass and its progression results in worsened quality of life and exacerbated outcomes in cancer patients. However, the role and impact of fibrosis during the early stages and development of cachexia in under‐investigated. The purpose of this study was to determine if fibrosis occurs during cachexia development, and to evaluate this in both sexes. Female and male C57BL6/J mice were injected with phosphate‐buffered saline or Lewis Lung Carcinoma (LLC) at 8‐week of age, and tumors were allowed to develop for 1, 2, 3, or 4 weeks. 3wk and 4wk female tumor‐bearing mice displayed a dichotomy in tumor growth and were reassigned to high tumor (HT) and low tumor (LT) groups. In vitro analyses were also performed on cocultured C2C12 and 3T3 cells exposed to LLC conditioned media. Immunohistochemistry and quantitative polymerase chain reaction (qPCR) analysis were used to investigate fibrosis and fibrosis‐related signaling in skeletal muscle. Collagen deposition in skeletal muscle was increased in the 1wk, LT, and HT groups in female mice. However, collagen deposition was only increased in the 4wk group in male mice. In general, female mice displayed earlier alterations in extracellular matrix (ECM)‐related genes beginning at 1wk post‐LLC injection. Whereas this was not seen in males. While overall tumor burden is tightly correlated to cachexia development in both sexes, fibrotic development is not. Male mice did not exhibit early‐stage alterations in ECM‐related genes contrary to what was noted in female mice.
Sulfonyl Diazaborine ‘Click’ Chemistry Enables Rapid and Efficient Bioorthogonal Labeling**
Authors: Chowdhury Arnab , Chatterjee Saurav , Kushwaha Apoorv , Nanda Sidhanta , Dhilip Kumar T. J. , Bandyopadhyay Anupam 
Published: May 2023

AbstractFinding an ideal bioorthogonal reaction that responds to a wide range of biological queries and applications is of great interest in biomedical applications. Rapid diazaborine (DAB) formation in water by the reactions of ortho‐carbonyl phenylboronic acid with α‐nucleophiles is an attractive conjugation module. Nevertheless, these conjugation reactions demand to satisfy stringent criteria for bioorthogonal applications. Here we show that widely used sulfonyl hydrazide (SHz) offers a stable DAB conjugate by combining with ortho‐carbonyl phenylboronic acid at physiological pH, competent for an optimal biorthogonal reaction. Remarkably, the reaction conversion is quantitative and rapid (k2>103 M−1 s−1) at low micromolar concentrations, and it preserves comparable efficacy in a complex biological milieu. DFT calculations support that SHz facilitates DAB formation via the most stable hydrazone intermediate and the lowest energy transition state compared to other biocompatible α‐nucleophiles. This conjugation is extremely efficient on living cell surfaces, enabling compelling pretargeted imaging and peptide delivery. We anticipate this work will permit addressing a wide range of cell biology queries and drug discovery platforms exploiting commercially available sulfonyl hydrazide fluorophores and derivatives.
Constructing pH‐Responsive and Tunable Azo‐Phenol‐Based o‐Nitrobenzyl Photocages
Authors: Wang Tsung‐Shing Andrew , Zhang Ya‐Wen , Chen Huai‐An , Lin Shiou‐Ting , Lee Hsien‐Ming 
Published: May 2023

AbstractMultiple triggered‐release strategies are widely utilized to control the release of caged target molecules. Among them, photocages with conditional triggers provide extra layers of control in photorelease. In this work, a series of pH‐responsive photocages was designed that could be triggered under irradiation and specific intracellular pH values. pH‐sensitive phenolic groups were conjugated with o‐nitrobenzyl (oNB) to form azo‐phenolic NPX photocages with tunable pKa. These azo‐phenol‐based oNB photocages showed differentiable photoreleasing profiles at pH 5.0, 7.2 and 9.0. By attaching fluorogenic cargos, it was shown that one of the photocages, NPdiCl, could be used to differentiate between acidic pH 5.0 and neutral pH 7.2 in cells under artificial pH conditions. Finally, NPdiCl was identified as a promising pH‐responsive photocage for photoreleasing cargo inside acidic tumor cells.