bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk factors accounting for anal incontinence during the first year after vaginal delivery—A case control study in China
Authors: Jia Yang , Liu Qingao , Zeng Lin , Wang Yan
Published: May 2023

Introduction and hypothesis

Anal incontinence (AI) is a prevalent postpartum disorder. This study aims to investigate and quantify the risk factors for AI in the Chinese population during the first year following vaginal delivery.

Methods

The case control study was conducted at Peking University Third Hospital, including all women who delivered vaginally between January 1, 2014, and June 30, 2018. Participants were followed up by telephone interviews 1 year after delivery. AI was defined as the involuntary loss of flatus or feces using a retrospective Jorge and Wexner score above 0. Clinical data were retrieved from the medical record system. Univariate and multivariate analyses were applied to identify potential risk factors accounting for AI. Based on the logistic regression model, a nomogram was constructed to predict the probability of AI postpartum. Restricted cubic spline was utilized to explore potential non-linear relationships between birth weight and AI postpartum.

Results

Among the 140 AI and 421 none AI cases, we observed antepartum factors like every 100 g of birth weight gain (OR 1.39, 95% CI 1.30–1.49), while intrapartum factors like forceps-assisted vaginal delivery (OR 7.11, 95% CI 2.60–19.45), midline episiotomy (OR 13.11, 95% CI 1.71–100.89), second-degree perineal tear (OR 6.51, 95% CI 1.16–36.68), and third to fourth-degree perineal tear were independent risk factors for postpartum AI. Significantly, infant weighing over 3,400 g at birth increased the risk of AI postpartum. Based on logistic regression model, we constructed a nomogram to estimate the risk of AI 1 year after vaginal delivery.

Conclusion

Our findings indicated that during the first year following vaginal delivery, infant with birth weight of 3,400 g or more, forceps-assisted vaginal delivery, midline episiotomy, and second to fourth-degree perineal tear increased the risk of AI. As a result, it is essential to limit the routine use of forceps and midline episiotomy and to monitor fetal weight during prenatal care.
Diagnostic value of artificial intelligence-assisted endoscopy for chronic atrophic gastritis: a systematic review and meta-analysis
Authors: Shi Yanting , Wei Ning , Wang Kunhong , Tao Tao , Yu Feng , Lv Bing
Published: May 2023

Background and aims

The diagnosis of chronic atrophic gastritis (CAG) under normal white-light endoscopy depends on the endoscopist's experience and is not ideal. Artificial intelligence (AI) is increasingly used to diagnose diseases with good results. This review aimed to evaluate the accuracy of AI-assisted diagnosis of CAG through a meta-analysis.

Methods

We conducted a comprehensive literature search of four databases: PubMed, Embase, Web of Science, and the Cochrane Library. Studies published by November 21, 2022, on AI diagnosis CAG with endoscopic images or videos were included. We assessed the diagnostic performance of AI using meta-analysis, explored the sources of heterogeneity through subgroup analysis and meta-regression, and compared the accuracy of AI and endoscopists in diagnosing CAG.

Results

Eight studies that included a total of 25,216 patients of interest, 84,678 image training set images, and 10,937 test set images/videos were included. The results of the meta-analysis showed that the sensitivity of AI in identifying CAG was 94% (95% confidence interval [CI]: 0.88–0.97, I2 = 96.2%), the specificity was 96% (95% CI: 0.88–0.98, I2 = 98.04%), and the area under the summary receiver operating characteristic curve was 0.98 (95% CI: 0.96–0.99). The accuracy of AI in diagnosing CAG was significantly higher than that of endoscopists.

Conclusions

AI-assisted diagnosis of CAG in endoscopy has high accuracy and clinical diagnostic value.

Systematic review registration

http://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42023391853.
Whole genome sequence of Lactiplantibacillus plantarum MC5 and comparative analysis of eps gene clusters
Authors: Zhao Xuefang , Liang Qi , Song Xuemei , Zhang Yan
Published: May 2023

Introduction

Probiotic Lactiplantibacillus plantarum MC5 produces large amounts of exopolysaccharides (EPS), and its use as a compound fermentor can greatly improve the quality of fermented milk.

Methods

To gain insight into the genomic characteristics of probiotic MC5 and reveal the relationship between its EPS biosynthetic phenotype and genotype, we analyzed the carbohydrate metabolic capacity, nucleotide sugar formation pathways, and EPS biosynthesis-related gene clusters of strain MC5 based on its whole genome sequence. Finally, we performed validation tests on the monosaccharides and disaccharides that strain MC5 may metabolize.

Results

Genomic analysis showed that MC5 has seven nucleotide sugar biosynthesis pathways and 11 sugar-specific phosphate transport systems, suggesting that the strain can metabolize mannose, fructose, sucrose, cellobiose, glucose, lactose, and galactose. Validation results showed that strain MC5 can metabolize these seven sugars and produce significant amounts of EPS (> 250 mg/L). In addition, strain MC5 possesses two typical eps biosynthesis gene clusters, which include the conserved genes epsABCDE, wzx, and wzy, six key genes for polysaccharide biosynthesis, and one MC5-specific epsG gene.

Discussion

These insights into the mechanism of EPS-MC5 biosynthesis can be used to promote the production of EPS through genetic engineering.
Development and evaluation of a centrifugal disk system for the rapid detection of multiple pathogens and their antibiotic resistance genes in urinary tract infection
Authors: Chen Nianzhen , Li Gen , Si Yuying , Ye Yangqin , Zhang Tong , Chi Dali , Zhang Wenyan , Pan Lifeng , Qu Guoying , Lu Yun , Zong Ming , Sui Guodong , Fan Lieying
Published: May 2023

Background

Urinary tract infections (UTIs) are some of the most common bacterial infections in the world. Nevertheless, as uncomplicated UTIs are treated empirically without culturing the urine, adequate knowledge of the resistance pattern of uropathogens is essential. Conventional urine culture and identification take at least 2 days. Here, we developed a platform based on LAMP and centrifugal disk system (LCD) to simultaneously detect the main pathogens and antibiotic resistant genes (ARGs) of urgent concern multidrug-resistant among UTIs.

Methods

We designed specific primers to detect the target genes above and evaluated their sensitivity and specificity. We also assessed the result of our preload LCD platform on 645 urine specimens with a conventional culturing method and Sanger sequencing.

Results

The results obtained with the 645 clinical samples indicated that the platform has high specificity (0.988–1) and sensitivity (0.904–1) for the studied pathogens and ARGs. Moreover, the kappa value of all pathogens was more than 0.75, revealing an excellent agreement between the LCD and culture method. Compared to phenotypic tests, the LCD platform is a practical and fast detection approach for methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Acinetobacter, carbapenem-resistant Pseudomonas aeruginosa (kappa value of all >0.75), and non-extended-spectrum β-lactamase producers.

Conclusion

We developed a detection platform that has high accuracy and that meets the need for rapid diagnosis, which can be completed within 1.5 h from specimen collection. It may be a powerful tool for evidence-based UTIs diagnosis, which has essential support for the rational use of antibiotics. More high-quality clinical studies are required to prove the effectiveness of our platform.
In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers
Authors: Paul Argho Aninda , Szulc Natalia A. , Kobiela Adrian , Brown Sara J. , Pokrzywa Wojciech , Gutowska-Owsiak Danuta
Published: May 2023

Background: Loss of function mutation in FLG is the major genetic risk factor for atopic dermatitis (AD) and other allergic manifestations. Presently, little is known about the cellular turnover and stability of profilaggrin, the protein encoded by FLG. Since ubiquitination directly regulates the cellular fate of numerous proteins, their degradation and trafficking, this process could influence the concentration of filaggrin in the skin.

Objective: To determine the elements mediating the interaction of profilaggrin with the ubiquitin-proteasome system (i.e., degron motifs and ubiquitination sites), the features responsible for its stability, and the effect of nonsense and frameshift mutations on profilaggrin turnover.

Methods: The effect of inhibition of proteasome and deubiquitinases on the level and modifications of profilaggrin and processed products was assessed by immunoblotting. Wild-type profilaggrin sequence and its mutated variants were analysed in silico using the DEGRONOPEDIA and Clustal Omega tool.

Results: Inhibition of proteasome and deubiquitinases stabilizes profilaggrin and its high molecular weight of presumably ubiquitinated derivatives. In silico analysis of the sequence determined that profilaggrin contains 18 known degron motifs as well as multiple canonical and non-canonical ubiquitination-prone residues. FLG mutations generate products with increased stability scores, altered usage of the ubiquitination marks, and the frequent appearance of novel degrons, including those promoting C-terminus-mediated degradation routes.

Conclusion: The proteasome is involved in the turnover of profilaggrin, which contains multiple degrons and ubiquitination-prone residues. FLG mutations alter those key elements, affecting the degradation routes and the mutated products’ stability.
Multi-view image-based behavior classification of wet-dog shake in Kainate rat model
Authors: Negrete Salvador Blanco , Arai Hirofumi , Natsume Kiyohisa , Shibata Tomohiro
Published: May 2023

The wet-dog shake behavior (WDS) is a short-duration behavior relevant to the study of various animal disease models, including acute seizures, morphine abstinence, and nicotine withdrawal. However, no animal behavior detection system has included WDS. In this work, we present a multi-view animal behavior detection system based on image classification and use it to detect rats’ WDS behavior. Our system uses a novel time-multi-view fusion scheme that does not rely on artificial features (feature engineering) and is flexible to adapt to other animals and behaviors. It can use one or more views for higher accuracy. We tested our framework to classify WDS behavior in rats and compared the results using different amounts of cameras. Our results show that the use of additional views increases the performance of WDS behavioral classification. With three cameras, we achieved a precision of 0.91 and a recall of 0.86. Our multi-view animal behavior detection system represents the first system capable of detecting WDS and has potential applications in various animal disease models.
Efficacy and underlying mechanisms of acupuncture therapy for PTSD: evidence from animal and clinical studies
Authors: Tang Xiaorong , Lin Shumin , Fang Danwei , Lin Binjing , Yao Lulu , Wang Lin , Xu Qin , Lu Liming , Xu Nenggui
Published: May 2023

As a major public health problem, posttraumatic stress disorder (PTSD) has a substantial impact on individuals and society. The total excess economic burden of PTSD in the US is estimated to be more than $232.2 billion a year. Acupuncture is widely used in patients with PTSD, and an increasing number of studies have been undertaken to assess the efficacy and underlying mechanisms of acupuncture for the treatment of individuals with PTSD. However, there has not yet been a review that simultaneously elucidates the therapeutic efficacy and biological mechanisms of acupuncture. We wished to examine the efficacy and underlying mechanisms of acupuncture for the treatment of individuals with PTSD. We conducted this review in three sections as follows: a meta-analysis, an acupoint analysis, and mechanism research. PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure Database (CNKI), WanFang Database, China Biology Medicine Database (CBM), Chinese Science and Technology Journals Database (VIP), and other databases were searched from 1 January 2012 to 27 November 2022. Based on the included studies, we first determined whether acupuncture is more effective than psychological treatment or pharmacological treatment for treating and improving the quality of life of individuals with PTSD by meta-analysis. Second, the most commonly used acupoints and parameters of acupuncture were summarized based on animal and clinical studies. Third, we attempt to summarize the current mechanisms of acupuncture in the treatment of PTSD. Finally, 56 acupoint analyses, eight meta-analyses, and 33 mechanistic studies were included. Acupuncture outperformed pharmacotherapy treatment in improving symptom scores by CAPS, HAMA, HAMD, PCL-C, and SCL-90 somatization for PTSD and outperformed psychotherapy treatment in improving symptom scores by CAPS PCL-C and HAMD, according to the meta-analysis. GV20 was the most frequently used acupuncture point in clinical studies and animal studies, with a 78.6% application rate. Acupuncture may be effective in treating PTSD by regulating the structure and components of several brain areas, regulating the neuroendocrine system, and involving signaling pathways. In conclusion, this finding indicates that acupuncture has promising potential for treating PTSD.
An economic evaluation of a primary care-based technology-enabled intervention for stroke secondary prevention and management in rural China: a study protocol
Authors: Gong Enying , Yang Bolu , Chen Xingxing , Li Yuhan , Li Zixiao , Bettger Janet Prvu , Oldenburg Brian , Dong Dejin , Si Lei , Yan Lijing L.
Published: May 2023

Introduction

Secondary prevention of stroke is a leading challenge globally and only a few strategies have been tested to be effective in supporting stroke survivors. The system-integrated and technology-enabled model of care (SINEMA) intervention, a primary care-based and technology-enabled model of care, has been proven effective in strengthening the secondary prevention of stroke in rural China. The aim of this protocol is to outline the methods for the cost-effectiveness evaluation of the SINEMA intervention to better understand its potential economic benefits.

Methods

The economic evaluation will be a nested study based on the SINEMA trial; a cluster-randomized controlled trial implemented in 50 villages in rural China. The effectiveness of the intervention will be estimated using quality-adjusted life years for the cost-utility analysis and reduction in systolic blood pressure for the cost-effectiveness analysis. Health resource and service use and program costs will be identified, measured, and valued at the individual level based on medication use, hospital visits, and inpatients' records. The economic evaluation will be conducted from the perspective of the healthcare system.

Conclusion

The economic evaluation will be used to establish the value of the SINEMA intervention in the Chinese rural setting, which has great potential to be adapted and implemented in other resource-limited settings.
Noxious radiant heat evokes bi-component nociceptive withdrawal reflexes in spinal cord injured humans—A clinical tool to study neuroplastic changes of spinal neural circuits
Authors: Franz Steffen , Heutehaus Laura , Tappe-Theodor Anke , Weidner Norbert , Treede Rolf-Detlef , Schuh-Hofer Sigrid
Published: May 2023

Investigating nocifensive withdrawal reflexes as potential surrogate marker for the spinal excitation level may widen the understanding of maladaptive nociceptive processing after spinal cord injury (SCI). The aim of this prospective, explorative cross-sectional observational study was to investigate the response behavior of individuals with SCI to noxious radiant heat (laser) stimuli and to assess its relation to spasticity and neuropathic pain, two clinical consequences of spinal hyperexcitability/spinal disinhibition. Laser stimuli were applied at the sole and dorsum of the foot and below the fibula head. Corresponding reflexes were electromyography (EMG) recorded ipsilateral. Motor responses to laser stimuli were analyzed and related to clinical readouts (severity of injury/spasticity/pain), using established clinical assessment tools. Twenty-seven participants, 15 with SCI (age 18–63; 6.5 years post-injury; AIS-A through D) and 12 non-disabled controls, [non-disabled controls (NDC); age 19–63] were included. The percentage of individuals with SCI responding to stimuli (70–77%; p < 0.001), their response rates (16–21%; p < 0.05) and their reflex magnitude (p < 0.05) were significantly higher compared to NDC. SCI-related reflexes clustered in two time-windows, indicating involvement of both A-delta- and C-fibers. Spasticity was associated with facilitated reflexes in SCI (Kendall-tau-b p ≤ 0.05) and inversely associated with the occurrence/severity of neuropathic pain (Fisher’s exact p < 0.05; Eta-coefficient p < 0.05). However, neuropathic pain was not related to reflex behavior. Altogether, we found a bi-component motor hyperresponsiveness of SCI to noxious heat, which correlated with spasticity, but not neuropathic pain. Laser-evoked withdrawal reflexes may become a suitable outcome parameter to explore maladaptive spinal circuitries in SCI and to assess the effect of targeted treatment strategies. Registration: https://drks.de/search/de/trial/DRKS00006779.
Aesthetic experience models human learning
Authors: Starr G. Gabrielle
Published: May 2023

Aesthetic experiences have the potential to promote learning and creativity by enhancing the ability to understand complexity and to integrate novel or disparate information. Offering a theoretical framework for understanding the cognitive benefits of aesthetic experiences, this paper argues they are the necessary outcome of human learning, in which natural objects or artworks are evaluated in a multi-dimensional preference space shaped by Bayesian prediction. In addition, it contends that the brain-states underlying aesthetic experiences harness configurations of the apex three transmodal neural systems—the default mode network, the central executive network, and the salience network—that may offer information-processing advantages by recruiting the brain’s high-power communication hubs, thus enhancing potential for learning gain.
Compliance with a high-protein and energy-dense oral nutritional supplement in patients with disease-related malnutrition: a randomized open-label crossover trial
Authors: Leon-Sanz Miguel , Linares Francisca , Gonzalo Montserrat , Tapia María José , Maiz-Jimenez María , Ruiz Aguado Marta , Lizán Luis , Olveira Gabriel
Published: May 2023

Introduction

Patient compliance with oral nutritional supplements (ONS) is not optimal for meeting energy and nutritional requirements in a high proportion of patients with disease-related malnutrition (DRM). Energy density or prescribed volume of ONS may impact compliance.

Methods

A randomized, open-label crossover trial was conducted in outpatients with DRM to compare compliance with a high energy-dense ONS (edONS, 2.4 kcal/mL) and a reference ONS (heONS, 2.0 kcal/mL; NCT05609006). Patients were randomly assigned to two 8-week treatment sequences of four-weeks periods: edONS + heONS (sequence A) or heONS + edONS (sequence B). Patients daily reported the amount of product left over gastrointestinal tolerance and satisfaction with ONS. A non-inferiority analysis was performed to compare the compliance rate (percentage of consumed energy over the prescribed) for each period and sequence.

Results

Fifty-three patients were assigned to sequence A and 50 to sequence B (55.7 ± 13.9 years, 37.0% female, 67.1% oncology patients). In sequence A, the compliance rates were 88.6% ± 14.3% vs. 84.1 ± 21.8% (p = 0.183), while in sequence B, they were 78.9% ± 23.8% vs. 84.4% ± 21.4% (p < 0.01). In both sequences, the lower range of the confidence interval for compliance with edONS was greater than the non-inferiority threshold (for sequence A ΔCompA was 4.5% [95% CI, −2.0% to 10.0%], and for sequence, B ΔCompB was 5.6% [95% CI, −3.0% to 14.0%]). The total discarded cost for each ONS was higher for heONS than edONS, being the difference statistically significant in sequence B. BMI increased slightly and not significantly in both sequences, and the percentage of patients with severe malnutrition was reduced. The frequency of gastrointestinal symptoms was low for both sequences, and satisfaction with ONS was slightly higher for edONS.

Conclusion

Our findings highlight that edONS was non-inferior to heONS in terms of consumed energy over the prescribed, with a lower amount of edONS discarded, which suggests a higher efficiency of edONS.
Correlation between pathologic complete response, event-free survival/disease-free survival and overall survival in neoadjuvant and/or adjuvant HR+/HER2-breast cancer
Authors: Gogate Anagha , Ranjan Sandip , Kumar Amit , Bhandari Hitesh , Papademetriou Eros , Kim Inkyu , Potluri Ravi
Published: May 2023

Purpose

The study’s purpose was to evaluate the correlation between overall survival (OS) and its potential surrogate endpoints: pathologic complete response (pCR) and event-free survival (EFS)/disease-free survival (DFS) in neoadjuvant and/or adjuvant HR+/HER2- breast cancer.

Methods

Systematic search was performed in MEDLINE, EMBASE, Cochrane Library databases and other relevant sources to identify literature that have reported outcomes of interest in the target setting. The strength of correlation of EFS/DFS with OS, pCR with OS, and pCR with EFS/DFS was measured using Pearson’s correlation coefficient (r) based on weighted regression analysis. For Surrogate Endpoint-True Endpoint pairs where correlation was found to be moderate, surrogate threshold effect (STE) was estimated using a mixed-effects model. Sensitivity analyses were conducted on the scale and weights used and removing outlier data.

Results

Moderate correlation was observed of relative measures [log(HR)] of EFS/DFS and OS (r = 0.91; 95% CI: 0.83, 0.96, p < 0.0001). STE for HREFS/DFS was estimated to be 0.73. Association between EFS/DFS at 1, 2 and 3 years with OS at 4- and 5-year landmarks was moderate. Relative treatment effects of pCR and EFS/DFS were not strongly associated (r: 0.24; 95% CI: -0.63, 0.84, p = 0.6028). Correlation between pCR and OS was either not evaluated due to inadequate sample size (relative outcomes) or weak (absolute outcomes). Results obtained in the sensitivity analyses were similar to base scenario.

Conclusion

EFS/DFS were moderately correlated with OS in this trial-level analysis. They may be considered as valid surrogates for OS in HR+/HER2- breast cancer.
CD25 targeting with the afucosylated human IgG1 antibody RG6292 eliminates regulatory T cells and CD25+ blasts in acute myeloid leukemia
Authors: Pousse Laurène , Korfi Koorosh , Medeiros Bruno C. , Berrera Marco , Kumpesa Nadine , Eckmann Jan , Hutter Idil Karakoc , Griesser Vera , Karanikas Vaios , Klein Christian , Amann Maria
Published: May 2023

Background

Acute Myeloid leukemia is a heterogeneous disease that requires novel targeted treatment options tailored to the patients’ specific microenvironment and blast phenotype.

Methods

We characterized bone marrow and/or blood samples of 37 AML patients and healthy donors by high dimensional flow cytometry and RNA sequencing using computational analysis. In addition, we performed ex vivo ADCC assays using allogeneic NK cells isolated from healthy donors and AML patient material to test the cytotoxic potential of CD25 Mab (also referred to as RG6292 and RO7296682) or isotype control antibody on regulatory T cells and CD25+ AML cells.

Results

Bone marrow composition, in particular the abundance of regulatory T cells and CD25 expressing AML cells, correlated strongly with that of the blood in patients with time-matched samples. In addition, we observed a strong enrichment in the prevalence of CD25 expressing AML cells in patients bearing a FLT3-ITD mutation or treated with a hypomethylating agent in combination with venetoclax. We adopted a patient-centric approach to study AML clusters with CD25 expression and found it most highly expressed on immature phenotypes. Ex vivo treatment of primary AML patient samples with CD25 Mab, a human CD25 specific glycoengineered IgG1 antibody led to the specific killing of two different cell types, CD25+ AML cells and regulatory T cells, by allogeneic Natural Killer cells.

Conclusion

The in-depth characterization of patient samples by proteomic and genomic analyses supported the identification of a patient population that may benefit most by harnessing CD25 Mab’s dual mode of action. In this pre-selected patient population, CD25 Mab could lead to the specific depletion of regulatory T cells, in addition to leukemic stem cells and progenitor-like AML cells that are responsible for disease progression or relapse.
Interventions to improve neurocognitive late-effects in pediatric and adolescent CNS tumor patients and survivors - a systematic review
Authors: Kasteler Rahel , Fuchs Philipp , Otth Maria , Scheinemann Katrin
Published: May 2023

Introduction

Survival of children and adolescents diagnosed with central nervous system (CNS) tumors massively improved over the last decades due to better diagnostics, treatment, and supportive care. However, morbidity is still the highest of all cancer entities in this age group with neurocognitive late-effects being one of the most severe.

Aim

With this systematic review, we aim to summarize interventions designed to prevent or improve neurocognitive late-effects in CNS tumor patients.

Method

We searched PubMed on August 16th 2022 and included publications studying interventions for neurocognitive late-effects in pediatric and adolescent patients and survivors diagnosed with a CNS tumor. We included any form of neurocognitive intervention during treatment or following treatment completion. We considered all types of studies except for expert opinions and case reports.

Results

The literature search resulted in 735 publications. We included 43 publications in the full text screening and 14 met our inclusion criteria. Of those, two assessed the impact of pharmacological interventions, three of exercise interventions, five of online cognitive training, and four assessed behavioral interventions. Different neuropsychological test batteries and imaging were used to measure the impact of the respective interventions. Most studies showed a positive impact of the interventions in single to several of the subtests used.

Conclusion

We found several intervention studies indicating improvement of neurocognitive problems in children and adolescent CNS tumor survivors. In this population exercise interventions or online cognitive training might mitigate or improve neurocognitive late-effects.
Identification of novel molecular subtypes and a signature to predict prognosis and therapeutic response based on cuproptosis-related genes in prostate cancer
Authors: Zhang Jili , Jiang Shaoqin , Gu Di , Zhang Wenhui , Shen Xianqi , Qu Min , Yang Chenghua , Wang Yan , Gao Xu
Published: May 2023

Background

Prostate cancer (PCa) is the most common malignant tumor of the male urinary system. Cuproptosis, as a novel regulated cell death, remains unclear in PCa. This study aimed to investigate the role of cuproptosis-related genes (CRGs) in molecular stratification, prognostic prediction, and clinical decision-making in PCa.

Methods

Cuproptosis-related molecular subtypes were identified by consensus clustering analysis. A prognostic signature was constructed with LASSO cox regression analyses with 10-fold cross-validation. It was further validated in the internal validation cohort and eight external validation cohorts. The tumor microenvironment between the two risk groups was compared using the ssGSEA and ESTIMATE algorithms. Finally, qRT-PCR was used to explore the expression and regulation of these model genes at the cellular level. Furthermore, 4D Label-Free LC-MS/MS and RNAseq were used to investigate the changes in CRGs at protein and RNA levels after the knockdown of the key model gene B4GALNT4.

Results

Two cuproptosis-related molecular subtypes with significant differences in prognoses, clinical features, and the immune microenvironment were identified. Immunosuppressive microenvironments were associated with poor prognosis. A prognostic signature comprised of five genes (B4GALNT4, FAM83D, COL1A, CHRM3, and MYBPC1) was constructed. The performance and generalizability of the signature were validated in eight completely independent datasets from multiple centers. Patients in the high-risk group had a poorer prognosis, more immune cell infiltration, more active immune-related functions, higher expression of human leukocyte antigen and immune checkpoint molecules, and higher immune scores. In addition, anti-PDL-1 immunotherapy prediction, somatic mutation, chemotherapy response prediction, and potential drug prediction were also analyzed based on the risk signature. The validation of five model genes' expression and regulation in qPCR was consistent with the results of bioinformatics analysis. Transcriptomics and proteomics analyses revealed that the key model gene B4GALNT4 might regulate CRGs through protein modification after transcription.

Conclusion

The cuproptosis-related molecular subtypes and the prognostic signature identified in this study could be used to predict the prognosis and contribute to the clinical decision-making of PCa. Furthermore, we identified a potential cuproptosis-related oncogene B4GALNT4 in PCa, which could be used as a target to treat PCa in combination with cuproptosis.
A multiplexed assay for quantifying immunomodulatory proteins supports correlative studies in immunotherapy clinical trials
Authors: Whiteaker Jeffrey R. , Zhao Lei , Schoenherr Regine M. , Huang Dongqing , Lundeen Rachel A. , Voytovich Ulianna , Kennedy Jacob J. , Ivey Richard G. , Lin Chenwei , Murillo Oscar D. , Lorentzen Travis D. , Colantonio Simona , Caceres Tessa W. , Roberts Rhonda R. , Knotts Joseph G. , Reading Joshua J. , Perry Candice D. , Richardson Christopher W. , Garcia-Buntley Sandra S. , Bocik William , Hewitt Stephen M. , Chowdhury Shrabanti , Vandermeer Jackie , Smith Stephen D. , Gopal Ajay K. , Ramchurren Nirasha , Fling Steven P. , Wang Pei , Paulovich Amanda G.
Published: May 2023

Introduction

Immunotherapy is an effective treatment for a subset of cancer patients, and expanding the benefits of immunotherapy to all cancer patients will require predictive biomarkers of response and immune-related adverse events (irAEs). To support correlative studies in immunotherapy clinical trials, we are developing highly validated assays for quantifying immunomodulatory proteins in human biospecimens.

Methods

Here, we developed a panel of novel monoclonal antibodies and incorporated them into a novel, multiplexed, immuno-multiple reaction monitoring mass spectrometry (MRM-MS)-based proteomic assay targeting 49 proteotypic peptides representing 43 immunomodulatory proteins.

Results and discussion

The multiplex assay was validated in human tissue and plasma matrices, where the linearity of quantification was >3 orders of magnitude with median interday CVs of 8.7% (tissue) and 10.1% (plasma). Proof-of-principle demonstration of the assay was conducted in plasma samples collected in clinical trials from lymphoma patients receiving an immune checkpoint inhibitor. We provide the assays and novel monoclonal antibodies as a publicly available resource for the biomedical community.
Long-term outcomes of frontline imatinib therapy for chronic myeloid leukemia in China
Authors: Cheng Fang , Yuan Guolin , Li Qiang , Cui Zheng , Li Weiming
Published: May 2023

Background

Imatinib is the first-line therapy recommended for chronic myeloid leukemia (CML) patients in China. We reported a long-term follow-up study of patients on imatinib as first-line treatment for chronic phase (CP) CML to provide an important reference for the actual clinical treatment regimen of CML patients in China.

Methods

We evaluated the long-term efficacy, safety, low-dose attempt after years of treatment, and treatment-free remission (TFR) of 237 CML-CP patients receiving first-line imatinib therapy.

Results

The median age was 46 years (interquartile range: 33–55). After a median follow-up of 6.5 years, the cumulative complete cytogenetic response, major molecular response (MMR), and MR4.5 rates were 82.6%, 80.4%, and 69.3%, respectively. The 10-year transformation-free, event-free, and failure-free survival rates were 97.3%, 87.2% and 53.5%, respectively. Fifty-two (21.9%) patients with sustained deep molecular response (DMR) were treated with low-dose imatinib after years of imatinib treatment. No significant differences in the 1-year and 2-year molecular relapse-free survival in MMR and MR4 were observed between the standard-dose and low-dose groups. Twenty-eight (11.8%) patients discontinued imatinib, and the median time to maintain DMR before discontinuation was 8.43 years. Thirteen patients (5.5%) remained in TFR for a median of 43.33 months. No patients transformed to accelerate or blast phase or died. No new, late toxicity was observed, and the most frequent grade 3/4 adverse events were neutropenia (9.3%), anemia (7.6%), thrombocytopenia (6.3%), and rash (4.2%).

Conclusion

This study confirmed the long-term efficacy and safety of imatinib for treating Chinese CML patients. Additionally, it demonstrated the feasibility of imatinib dose reduction and TFR attempts in patients with sustained stable DMR after years of imatinib treatment in real-life settings.
Lipid metabolism in tumor immunology and immunotherapy
Authors: Duong Lisa K. , Corbali Halil Ibrahim , Riad Thomas S. , Ganjoo Shonik , Nanez Selene , Voss Tiffany , Barsoumian Hampartsoum B. , Welsh James , Cortez Maria Angelica
Published: May 2023

Lipids are a diverse class of biomolecules that have been implicated in cancer pathophysiology and in an array of immune responses, making them potential targets for improving immune responsiveness. Lipid and lipid oxidation also can affect tumor progression and response to treatment. Although their importance in cellular functions and their potential as cancer biomarkers have been explored, lipids have yet to be extensively investigated as a possible form of cancer therapy. This review explores the role of lipids in cancer pathophysiology and describes how further understanding of these macromolecules could prompt novel treatments for cancer.
Case report: Hepatotoxicity and nephrotoxicity induced by methotrexate in a paediatric patient, what is the role of precision medicine in 2023?
Authors: El Masri Ali El Rida , Tobler Caroline , Willemijn Breunis , Von Bueren Andre O. , Ansari Marc , Samer Caroline Flora
Published: May 2023

Methotrexate is an immunosuppressant and chemotherapeutic agent used in the treatment of a range of autoimmune disorders and cancers. Its main serious adverse effects, bone marrow suppression and gastrointestinal complications, arise from its antimetabolite effect. Nevertheless, hepatotoxicity and nephrotoxicity are two widely described adverse effects of methotrexate. Its hepatotoxicity has been studied mainly in the low-dose, chronic setting, where patients are at risk of fibrosis/cirrhosis. Studies of acute hepatoxicity of high dose methotrexate, such as during chemotherapy, are scarce. We present the case of a 14-year-old patient who received high-dose methotrexate and subsequently developed acute fulminant liver failure and acute kidney injury. Genotyping of MTHFR (Methylene tetrahydrofolate reductase gene), ABCB1 (codes for P-glycoprotein, intestinal transport and biliary excretion), ABCG2 (codes for BCRP, intestinal transporter and renal excretion) and SLCO1B1 (codes for OATP1B1, hepatic transporter) identified variants in all the genes analysed that predicted a reduced rate of methotrexate elimination and thus may have contributed to the clinical situation of the patient. Precision medicine involving pharmacogenomic testing could potentially avoid such adverse drug effects.
The human-initiated model of wolf domestication – An expansion based on human-dingo relations in Aboriginal Australia
Authors: Brumm Adam , Germonpré Mietje , Koungoulos Loukas
Published: May 2023

The historically known relationship of interspecies companionship between Aboriginal foraging communities in Australia and free-ranging dingoes provides a model for understanding the human-canid relations that gave rise to the first domesticated dogs. Here, we propose that a broadly similar relationship might have developed early in time between wild-living wolves and mobile groups of foragers in Late Pleistocene Eurasia, with hunter-gatherers routinely raiding wild wolf dens for pre-weaned pups, which were socialized to humans and kept in camp as tamed companions (“pets”). We outline a model in which captive wolf pups that reverted to the wild to breed when they were sexually mature established their territories in the vicinity of foraging communities — in a “liminal” ecological zone between humans and truly wild-living wolves. Many (or most) of the wolf pups humans took from the wilderness to rear in camp may have derived from these liminal dens where the breeding pairs had been under indirect human selection for tameness over many generations. This highlights the importance of the large seasonal hunting/aggregation camps associated with mammoth kill-sites in Gravettian/Epigravettian central Europe. Large numbers of foragers gathered regularly at these locations during the wild wolf birthing season. We infer that if a pattern of this kind occurred over long periods of time then there might have been a pronounced effect on genetic variation in free-ranging wolves that denned and whelped in the liminal zones in the vicinity of these human seasonal aggregation sites. The argument is not that wolves were domesticated in central Europe. Rather, it is this pattern of hunter-gatherers who caught and reared wild wolf pups gathering seasonally in large numbers that might have been the catalyst for the early changes leading to the first domesticated dogs — whether in western Eurasia or further afield.
Examining mental health knowledge, stigma, and service use intentions among Royal Canadian Mounted Police cadets
Authors: Andrews Katie L. , Jamshidi Laleh , Shields Robyn E. , Teckchandani Taylor A. , Afifi Tracie O. , Fletcher Amber J. , Sauer-Zavala Shannon , Brunet Alain , Krätzig Gregory P. , Carleton R. Nicholas
Published: May 2023

Background

Royal Canadian Mounted Police (RCMP) officers experience an elevated risk for mental health disorders due to inherent work-related exposures to potentially psychologically traumatic events and occupational stressors. RCMP officers also report high levels of stigma and low levels of intentions to seek mental health services. In contrast, very little is known about the levels of mental health knowledge and stigma of RCMP cadets starting the Cadet Training Program (CTP). The current study was designed to: (1) obtain baseline levels of mental health knowledge, stigma against peers in the workplace, and service use intentions in RCMP cadets; (2) determine the relationship among mental health knowledge, stigma against peers in the workplace, and service use intentions among RCMP cadets; (3) examine differences across sociodemographic characteristics; and (4) compare cadets to a sample of previously surveyed serving RCMP.

Methods

Participants were RCMP cadets (n = 772) starting the 26-week CTP. Cadets completed questionnaires assessing mental health knowledge, stigma against coworkers with mental health challenges, and mental health service use intentions.

Results

RCMP cadets reported statistically significantly lower levels of mental health knowledge (d = 0.233) and stigma (d = 0.127), and higher service use intentions (d = 0.148) than serving RCMP (all ps < 0.001). Female cadets reported statistically significantly higher scores on mental health knowledge and service use and lower scores on stigma compared to male cadets. Mental health knowledge and service use intentions were statistically significantly positively associated. For the total sample, stigma was inversely statistically significantly associated with mental health knowledge and service use intentions.

Conclusion

The current results indicate that higher levels of mental health knowledge were associated with lower stigma and higher intention to use professional mental health services. Differences between cadets and serving RCMP highlight the need for regular ongoing training starting from the CTP, designed to reduce stigma and increase mental health knowledge. Differences between male and female cadets suggest differential barriers to help-seeking behaviors. The current results provide a baseline to monitor cadet mental health knowledge and service use intentions and stigma as they progress throughout their careers.
Probing sociodemographic influence on code-switching and language choice in Quebec with geolocation of tweets
Authors: Kellert Olga
Published: May 2023

This paper investigates the influence of the relative size of speech communities on language use in multilingual regions and cities. Due to peoples’ everyday mobility inside a city, it is still unclear whether the size of a population matters for language use on a sub-city scale. By testing the correlation between the size of a population and language use on various spatial scales, this study will contribute to a better understanding of the extent to which sociodemographic factors influence language use. The present study investigates two particular phenomena that are common to multilingual speakers, namely language mixing or Code-Switching and using multiple languages without mixing. Demographic information from a Canadian census will make predictions about the intensity of Code-Switching and language use by multilinguals in cities of Quebec and neighborhoods of Montreal. Geolocated tweets will be used to identify where these linguistic phenomena occur the most and the least. My results show that the intensity of Code-Switching and the use of English by bilinguals is influenced by the size of anglophone and francophone populations on various spatial scales such as the city level, land use level (city center vs. periphery of Montreal), and large urban zones on the sub-city level, namely the western and eastern urban zones of Montreal. However, the correlation between population figures and language use is difficult to measure and evaluate on a much smaller sub-urban scale such as the city block scale due to factors such as population figures missing from the census and people’s mobility. A qualitative evaluation of language use on a small spatial scale seems to suggest that other social influences such as the location context or topic of discussion are much more important predictors for language use than population figures. Methods will be suggested for testing this hypothesis in future research. I conclude that geographic space can provide us information about the relation between language use in multilingual cities and sociodemographic factors such as a speech community’s size and that social media is a valuable alternative data source for sociolinguistic research that offers new insights into the mechanisms of language use such as Code-Switching.
More than just emotional intelligence online: introducing “digital emotional intelligence”
Authors: Audrin Catherine , Audrin Bertrand
Published: May 2023

The ubiquitous nature of emotional intelligence, as a central theme in every aspect of our lives—be it at work, school, or home—coupled with the growing prevalence of digital interactions, makes it fundamental to develop our understanding of emotional intelligence in a digital world. However, the digital world represents more than just a contextual factor to consider, as interactions in digital environments require digital competence. The objective of this paper is to conceptualize “digital emotional intelligence” as the integration of both emotional intelligence and digital competence. The model we propose posits that trait emotional intelligence predicts attitudes toward digital competence, while digital ability emotional intelligence is predicted by digital competence skills and digital competence knowledge. Using a self-reported questionnaire on 503 respondents, a structural equation model highlights a positive relationship between trait emotional intelligence and attitudes toward digital competence.
Association of adolescent self-esteem in 2014 and cognitive performance in 2014, 2016, and 2018: a longitudinal study
Authors: Wang Xue , Liu Yu , Zhao Zhe , Liu Wenting , Chen Yuqi , Chen Yu , Zang Shuang
Published: May 2023

Background

Cognition has long been regarded as a significant factor influencing individuals’ lives. Prior studies have underscored that self-esteem is associated with cognition, and there exists a knowledge gap regarding whether self-esteem remains associated with subsequent cognitive performance during adolescence, a crucial period for neurological development and influencing adult outcomes.

Methods

We conducted this population-based study using longitudinal data stretching three waves (2014, 2016, and 2018) of surveys from the nationally representative China Family Panel Studies (CFPS) to explore the association between adolescents’ self-esteem in 2014 and cognitive performance in 2014, 2016, and 2018.

Results

The results of the present study showed that self-esteem during adolescence in 2014 was significantly associated with cognitive performance in 2014, 2016, and 2018. This association remained robust after an extensive range of covariate adjustments (e.g., adolescents, parental, and family characteristics).

Conclusion

The findings in this study provide further insight into the understanding of the related factors for cognitive development across the life course and highlight the importance of improving individual self-esteem during adolescence.