bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1, first-in-human study of TYRP1-TCB (RO7293583), a novel TYRP1-targeting CD3 T-cell engager, in metastatic melanoma: active drug monitoring to assess the impact of immune response on drug exposure
Authors: Spreafico Anna , Couselo Eva Muñoz , Irmisch Anja , Bessa Juliana , Au-Yeung George , Bechter Oliver , Svane Inge Marie , Sanmamed Miguel F. , Gambardella Valentina , McKean Meredith , Callahan Margaret , Dummer Reinhard , Klein Christian , Umaña Pablo , Justies Nicole , Heil Florian , Fahrni Linda , Opolka-Hoffmann Eugenia , Waldhauer Inja , Bleul Conrad , Staack Roland F. , Karanikas Vaios , Fowler Stephen 
Published: March 2024

IntroductionAlthough checkpoint inhibitors (CPIs) have improved outcomes for patients with metastatic melanoma, those progressing on CPIs have limited therapeutic options. To address this unmet need and overcome CPI resistance mechanisms, novel immunotherapies, such as T-cell engaging agents, are being developed. The use of these agents has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs), which is challenging to predict preclinically and can lead to neutralization of the drug and loss of efficacy.MethodsTYRP1-TCB (RO7293583; RG6232) is a T-cell engaging bispecific (TCB) antibody that targets tyrosinase-related protein 1 (TYRP1), which is expressed in many melanomas, thereby directing T cells to kill TYRP1-expressing tumor cells. Preclinical studies show TYRP1-TCB to have potent anti-tumor activity. This first-in-human (FIH) phase 1 dose-escalation study characterized the safety, tolerability, maximum tolerated dose/optimal biological dose, and pharmacokinetics (PK) of TYRP1-TCB in patients with metastatic melanoma (NCT04551352).ResultsTwenty participants with cutaneous, uveal, or mucosal TYRP1-positive melanoma received TYRP1-TCB in escalating doses (0.045 to 0.4 mg). All participants experienced ≥1 treatment-related adverse event (TRAE); two participants experienced grade 3 TRAEs. The most common toxicities were grade 1–2 cytokine release syndrome (CRS) and rash. Fractionated dosing mitigated CRS and was associated with lower levels of interleukin-6 and tumor necrosis factor-alpha. Measurement of active drug (dual TYPR1- and CD3-binding) PK rapidly identified loss of active drug exposure in all participants treated with 0.4 mg in a flat dosing schedule for ≥3 cycles. Loss of exposure was associated with development of ADAs towards both the TYRP1 and CD3 domains. A total drug PK assay, measuring free and ADA-bound forms, demonstrated that TYRP1-TCB-ADA immune complexes were present in participant samples, but showed no drug activity in vitro.DiscussionThis study provides important insights into how the use of active drug PK assays, coupled with mechanistic follow-up, can inform and enable ongoing benefit/risk assessment for individuals participating in FIH dose-escalation trials. Translational studies that lead to a better understanding of the underlying biology of cognate T- and B-cell interactions, ultimately resulting in ADA development to novel biotherapeutics, are needed.
The synergistic antibacterial activity and mechanism of colistin-oxethazaine combination against gram-negative pathogens
Authors: Li Jie , Han Ning , Li Yangyang , Zhao Feifei , Xiong Wenguang , Zeng Zhenling 
Published: March 2024

Background:The rapid spread of bacteria with plasmid-mediated resistance to antibiotics poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue.Methods:Synergistic activity of the FDA-approved agent oxethazine combined with colistin was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of their combination of oxethazine and colistin was explored by fluorescent dye, scanning electron microscopy (SEM) and LC-MS/MS. The synergistic efficacy was evaluated in vivo by the Galleria mellonella and mouse sepsis models.Results:In this study, we found that oxethazine could effectively enhance the antibacterial activity of colistin against both mcr-positive and -negative pathogens, and mechanistic assays revealed that oxethazine could improve the ability of colistin to destruct bacterial outer membrane and cytoplasmic membrane permeability. In addition, their combination triggered the accumulation of reactive oxygen species causing additional damage to the membrane structure resulting in cell death. Furthermore, oxethazine significantly enhanced the therapeutic efficacy of colistin in two animal models.Conclusion:These results suggested that oxethazine, as a promising antibiotic adjuvant, can effectively enhance colistin activity, providing a potential strategy for treating multidrug-resistant bacteria.
Addition of nimotuzumab to concurrent chemoradiotherapy after induction chemotherapy improves outcomes of patients with locally advanced nasopharyngeal carcinoma
Authors: Wang Run-Jie , Ke Rui-Quan , Yu Yi-Feng , Lu Guan-Zhong , Wu San-Gang 
Published: March 2024

Purpose:To investigate the survival outcomes and toxicities associated with the addition of nimotuzumab to concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal carcinoma (LANPC) patients who received induction chemotherapy (IC).Methods:Patients with stage III-IVA nasopharyngeal carcinoma who received IC and CCRT between January 2017 and October 2021 were retrospectively included. We aimed to compare the locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) between patients treated with CCRT+nimotuzumab and CCRT alone.Results:We included 411 patients in the analysis. Of these patients, 267 (65.0%) and 144 (35.0%) had CCRT+nimotuzumab and CCRT alone, respectively. Similar LRFS was found between those with and without nimotuzumab (92.9% vs. 92.6%, p = 0.855). The 3-year DMFS was 88.2% and 76.2% in those with and without nimotuzumab (p = 0.002). The 3-year DFS was 83.4% and 70.6% in those with and without nimotuzumab treatment (p = 0.003). The 3-year OS was 92.1% and 81.1% in those with and without nimotuzumab (p = 0.003). The multivariate Cox regression analysis indicated that the addition of nimotuzumab was independently associated with better DMFS (hazard ratio [HR] 0.606, p = 0.049), DFS (HR 0.613, p = 0.028), and OS (HR 0.497, p = 0.019). No significant differences in major toxicities were found between the two treatment arms, including hematologic toxicities, hepatoxicity, nephrotoxicity, gastrointestinal reactions, and mucositis (all p &gt; 0.05).Conclusion:The addition of nimotuzumab to CCRT after IC in LANPC has shown promising results in improving treatment outcomes and acceptable toxicities.
Data independent acquisition reveals in-depth serum proteome changes in uremic pruritus
Authors: Wen-Jing Zhao , Rui-Zhi Tan , Si-Yuan He , Xiao-Mei Du , Qiong-Dan Hu , Xiao-Qian Zhang , Wen-Hua Huang , Hong-Wei Su , Jian Liu , Qiong Zhang , Li Wang 
Published: March 2024

Introduction: Uremic pruritus (UP) is a prevalent symptom in patients suffering from uremia, yet its underlying etiology and mechanisms remain incompletely elucidated. Given the significant incidence of UP, identifying specific alterations in proteins present in the blood of UP patients could offer insights into the potential biological pathways associated with UP and facilitate the exploration of biomarkers.Methods: In this study, we employed LC-MS/MS-based data-independent acquisition (DIA) mode to analyze serum samples obtained from 54 UP patients categorized as DKD-UP, HN-UP, and GN-UP (n = 18 for each subgroup), along with 18 uremic patients without pruritus (Negative) and 18 CKD patients without pruritus (CKD). Through DIA mode analysis, a total of 7075 peptides and 959 proteins were quantified. Within these, we identified four upregulated and 13 downregulated Differentially Expressed Proteins (DEPs) in DKD-UP versus Negative, five upregulated and 22 downregulated DEPs in HN-UP versus Negative, and three upregulated and 23 downregulated DEPs in GN-UP versus Negative. Furthermore, we conducted an intersection analysis of the DEPs across these three comparison groups to derive a set of common DEPs (COMP). Subsequently, a total of 67 common DEPs were identified in the three UP groups when compared to the CKD group, with 40 DEPs showing upregulation and 27 DEPs displaying downregulation.Results: Following Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction (PPI) analyses, we observed that the DEPs distinguishing UP from CKD were primarily associated with mitochondrial function (MT-CYB, PRDX2, TOMM22), inflammation (CD59, CSF1), renal injury (WFDC2), and neural function (CAP1, VGF).Discussion: Our findings contribute to a potential molecular comprehension of UP pathogenesis, shedding light on the identification of these DEPs as plausible biomarkers for UP.
Changes of uterocervical angle and cervical length in early and mid-pregnancy and their value in predicting spontaneous preterm birth
Authors: Zhang Miaomiao , Li Shuilan , Tian Chao , Li Min , Zhang Baofang , Yu Hongkui 
Published: March 2024

Objective: To explore the feasibility of transvaginal ultrasound measurement of uterocervical angle (UCA) and cervical length (CL) in early and mid-pregnancy and evaluate their combined prediction of spontaneous preterm birth (sPTB) in singleton pregnancies.Patients and Methods: This retrospective study comprised 274 pregnant women who underwent transvaginal ultrasound measurement of CL in mid-pregnancy (15–23+6 weeks); in 75 among them, CL also had been measured in early-pregnancy (&lt;14 weeks). These 274 pregnant women were further divided into a preterm group (n = 149, &lt;37 weeks gestation) and a control group (n = 125, &gt;37 weeks gestation) according to delivery before or after 37 weeks, respectively. In the preterm group, 35 patients delivered before 34 weeks and the remaining 114 delivered between 34 and 37 weeks.Results: The optimal threshold of CL to predict preterm birth risk in women with &lt;37 weeks gestation was 3.38 cm, and the optimal threshold of the UCA to predict preterm birth risk in the same group of women was 96°. The optimal threshold of CL to predict preterm birth risk in women with &lt;34 weeks gestation was 2.54 cm, while that of the UCA in the same group of patients was 106°. The area under the curve for predicting preterm birth by combining the UCA and CL measurements was greater than that by using the UCA or CL alone (p &lt; 0.01). The sensitivity and specificity for predicting preterm birth at &lt;34 weeks gestation was 71.7% and 86.4%, respectively; and the sensitivity and specificity for predicting preterm birth at &lt;37 weeks gestation was 87.6% and 80.6%, respectively. The difference between the two groups in CL and UCA were not significant in early pregnancy (p &gt; 0.01), but only in mid-pregnancy (p &lt; 0.01). There was a negative correlation between UCA and gestational week at delivery (r = −0.361, p &lt; 0.001) and a positive correlation between CL and gestational week at delivery (r = 0.346, p &lt; 0.001) in mid-pregnancy. The proportion of deliveries at &lt;34 weeks was highest when the UCA was &gt;105°, and the proportion of deliveries between 35 and 37 weeks was highest when the UCA was between 95° and 105°. The proportion of deliveries at &lt;34 weeks was highest when the CL was &lt;2.5 cm.Conclusion: The combination of UCA and CL has a better ability to predict preterm birth than either measurement alone. A more obtuse UCA or a shorter CL is associated with an earlier spontaneous preterm birth. The UCA increases from early to mid-pregnancy, while the CL decreases from early to mid-pregnancy.
Inner speech in the daily lives of people with aphasia
Authors: Alexander Julianne M. , Hedrick Tessa , Stark Brielle C. 
Published: March 2024

IntroductionThis exploratory, preliminary, feasibility study evaluated the extent to which adults with chronic aphasia (N = 23) report experiencing inner speech in their daily lives by leveraging experience sampling and survey methodology.MethodsThe presence of inner speech was assessed at 30 time-points and themes of inner speech at three time-points, over the course of three weeks. The relationship of inner speech to aphasia severity, demographic information (age, sex, years post-stroke), and insight into language impairment was evaluated.ResultsThere was low attrition (&lt;8%) and high compliance (&gt;94%) for the study procedures, and inner speech was experienced in most sampled instances (&gt;78%). The most common themes of inner speech experience across the weeks were ‘when remembering’, ‘to plan’, and ‘to motivate oneself’. There was no significant relationship identified between inner speech and aphasia severity, insight into language impairment, or demographic information. In conclusion, adults with aphasia tend to report experiencing inner speech often, with some shared themes (e.g., remembering, planning), and use inner speech to explore themes that are uncommon in young adults in other studies (e.g., to talk to themselves about health).DiscussionHigh compliance and low attrition suggest design feasibility, and results emphasize the importance of collecting data in age-similar, non-brain-damaged peers as well as in adults with other neurogenic communication disorders to fully understand the experience and use of inner speech in daily life. Clinical implications and future directions are discussed.
Process evaluation of PsyCovidApp, a digital tool for mobile devices aimed at protecting the mental health of healthcare professionals during the COVID-19 pandemic: a mixed method study
Authors: Fiol-deRoque Maria A. , Serrano-Ripoll Maria J. , Mira-Martínez Sofia , Pastor-Moreno Guadalupe , Sitges Carolina , García-Buades M. Esther , Gervilla Elena , Garcia-Toro Mauro , Zamanillo-Campos Rocío , Ricci-Cabello Ignacio 
Published: March 2024

IntroductionPsyCovidApp, a digital intervention aimed at safeguarding the mental health of healthcare workers during the COVID-19 pandemic, demonstrated in a randomized clinical trial to yield significant improvements solely among healthcare workers undergoing psychotherapy or receiving psychotropic medication.Objectives(1) To identify contextual factors and mechanisms of action that influenced the impact of PsyCovidApp during the aforementioned trial; (2) To pinpoint enhancements for optimizing its efficacy.Materials and methodsFor the first objective, a process evaluation was conducted, amalgamating quantitative techniques (surveying 216 healthcare professionals who had utilized PsyCovidApp during the trial) and qualitative methods (in-depth interviews with 16 healthcare workers). The second objective involved a panel of seven experts, utilizing the RAND-UCLA methodology.ResultsThe quantitative study (response rate = 40%) revealed that 22% of respondents had not fully accessed the content of PsyCovidApp. The average usage time was 22.7 min/day, being higher (p &lt; 0.05) among consumers of psychotropic medications. Contents related to relaxation and mindfulness were most highly rated. Acceptability and usefulness scores ranged between 7.3–7.5/10 points, with higher ratings (p &lt; 0.05) among women and older healthcare workers. The qualitative study uncovered that the primary barriers to using PsyCovidApp were workload, lack of time, and exhaustion. Its primary mechanisms of action included emotion identification, mental health regulation (e.g., insomnia, intense emotions), and learning of techniques and skills. The expert panel reached a consensus on 29 proposals to optimize PsyCovidApp.ConclusionThe knowledge derived from this study could inform the design and implementation of future similar digital tools.
Consanguineous marriages, premarital screening, and genetic testing: a survey among Saudi university students
Authors: Jameel Tahir , Baig Mukhtiar , Murad Manal Abdulaziz , Gazzaz Zohair Jamil , Mal Youssof , Alyoubi Wedyan Eid , Alyoubi Ghadi Hamed , Alaslani Shoug Tawfiq , Alshuaibi Hanan Abdullah , Nawaz Ayesha , Alkaabi Turki 
Published: March 2024

BackgroundMarriage among cousins or close relatives, i.e., consanguinity, is prevalent in many parts of the world, especially the Muslim world. Across civilizations, cultural norms, religious beliefs, and economic factors affect consanguineous marriages (CMs); however, such marriages have social, genetic, and health repercussions. The present study investigated the university students’ attitudes regarding CMs and factors influencing their attitudes at King Abdulaziz University (KAU), Jeddah, Kingdom of Saudi Arabia (KSA).MethodsThis cross-sectional prospective study was conducted at KAU Jeddah in 2023. The questionnaire was distributed via electronic media (Emails, Facebook Messenger &amp; WhatsApp). The convenience sampling technique was used to select participants, and descriptive and inferential statistics were used to analyze the data on SPSS-26.ResultsA total of 1707 university students were part of the study (females, 1,198, 70.2%; males, 509, 29.8%). Almost half of the participants, 819 (48.0%), had parents with CMs. Most of the participants, 1,391 (81.5%), had CMs in the family. Half of the participants disagreed that parents consider marriage stable due to high compatibility and the same social relationship before and after marriage. About one-third of respondents said parents believe family marriage transmits cultural values and continuity and keeps wealth in the family. More than three-fourths of the participants stated that if marriage is arranged with first cousins, they will opt for genetic analysis (82.5%) and premarital counseling (85.2%). The personal attitudes of females (p &lt; 0.001), undergraduate (p = 0.02), and health sciences students (p = 0.02) were more positive than their counterparts. Males (OR = 0.41; p &lt; 0.001) and non-health sciences students (OR = 0.68; p = 0.01) were less likely to have significant positive attitudes than their counterparts. Among participants who had CM parents, males (OR = 0.397; p &lt; 0.001) and non-health sciences students (OR = 0.60; p = 0.01) and urban residents (OR = 0.59; p = 0.01) had significantly lower odds of having a positive attitude than their counterparts.ConclusionThe practice of CMs is still prevalent in Saudi culture, with almost half of the participants having CM parents and the majority reporting these marriages in their families. Personal attitudes toward CMs were extremely positive. Most students prefer genetic testing and premarital counseling if marrying first cousins. Gender, faculty, parental income, and educational background influenced participants’ attitudes.
A comprehensive analysis concerning eating behavior associated with chronic diseases among Romanian community nurses
Authors: Onofrei Lidia-Manuela , Puiu Maria , Chirita-Emandi Adela , Serban Costela Lacrimioara 
Published: March 2024

IntroductionLifestyle factors, including inadequate eating patterns, emerge as a critical determinant of chronic disease. Apart from caring for patients, nurses should also take an active role in monitoring and managing their own health. Understanding the intricate relationship between nurses’ eating behavior and managing their own health is crucial for fostering a holistic approach to healthcare, therefore our study aimed to evaluate eating behavior and demographic factors influencing chronic disease prevalence in a sample of community nurses from Romania.MethodsBetween October–November 2023, 1920 community nurses were invited to answer an online survey, using an advertisement in their professional network. Of them, 788 responded. In the survey, which included a semi-quantitative food frequency questionnaire with 53 food items, the Intuitive Eating Survey 2 (IES-2), and demographic items were used.ResultsA multivariate model was built for the prediction of the association between eating behavior and other factors associated with chronic diseases. The majority of participants were females (95.1%), with the largest age group falling between 40 and 49.9 years (48.2%). Regarding the EFSA criteria for adequate carbohydrate and fat intake, 20.2% of the group have a high intake of carbohydrates, respectively, 43.4% of the group have a high intake of fat. Analysis of chronic diseases indicated that 24.9% of individuals reported at least one diagnosis by a physician. The presence of chronic disease was associated with a low level of perceived health status, with an OR = 3.388, 95%CI (1.684–6.814), compared to those reporting excellent or very good perceived health status. High stress had an OR = 1.483, 95%CI (1.033–2.129). BMI had an OR = 1.069, 95%CI (1.032–1.108), while low carbohydrate diet score had an OR = 0.956, 95%CI (0.920–0.992). Gender and IES-2 did not significantly contribute to the model, but their effect was controlled.DiscussionBy unraveling the intricate interplay between nutrition, lifestyle, and health outcomes in this healthcare cohort, our findings contribute valuable insights for the development of targeted interventions and support programs tailored to enhance the well-being of community nurses and, by extension, the patients they support.
Unsupervised learning and natural language processing highlight research trends in a superbug
Authors: Méndez-Cruz Carlos-Francisco , Rodríguez-Herrera Joel , Varela-Vega Alfredo , Mateo-Estrada Valeria , Castillo-Ramírez Santiago 
Published: March 2024

IntroductionAntibiotic-resistant Acinetobacter baumannii is a very important nosocomial pathogen worldwide. Thousands of studies have been conducted about this pathogen. However, there has not been any attempt to use all this information to highlight the research trends concerning this pathogen.MethodsHere we use unsupervised learning and natural language processing (NLP), two areas of Artificial Intelligence, to analyse the most extensive database of articles created (5,500+ articles, from 851 different journals, published over 3 decades).ResultsK-means clustering found 113 theme clusters and these were defined with representative terms automatically obtained with topic modelling, summarising different research areas. The biggest clusters, all with over 100 articles, are biased toward multidrug resistance, carbapenem resistance, clinical treatment, and nosocomial infections. However, we also found that some research areas, such as ecology and non-human infections, have received very little attention. This approach allowed us to study research themes over time unveiling those of recent interest, such as the use of Cefiderocol (a recently approved antibiotic) against A. baumannii.DiscussionIn a broader context, our results show that unsupervised learning, NLP and topic modelling can be used to describe and analyse the research themes for important infectious diseases. This strategy should be very useful to analyse other ESKAPE pathogens or any other pathogens relevant to Public Health.