bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cortical gray-white matter contrast abnormalities in male children with attention deficit hyperactivity disorder
Authors: Wang Changhao , Shen Yanyong , Cheng Meiying , Zhu Zitao , Lv Yuan , Zhang Xiaoxue , Feng Zhanqi , Yang Zhexuan , Zhao Xin 
Published: December 2023

PurposePresently, research concerning alterations in brain structure among individuals with attention deficit hyperactivity disorder (ADHD) predominantly focuses on entire brain volume and cortical thickness. In this study, we extend our examination to the cortical microstructure of male children with ADHD. To achieve this, we employ the gray-white matter tissue contrast (GWC) metric, allowing for an assessment of modifications in gray matter density and white matter microstructure. Furthermore, we explore the potential connection between GWC and the severity of disorder in male children by ADHD.MethodsWe acquired 3DT1 sequences from the public ADHD-200 database. In this study, we conducted a comparative analysis between 43 male children diagnosed with ADHD and 50 age-matched male controls exhibiting typical development trajectories. Our investigation entailed assessing differences in GWC and cortical thickness. Additionally, we explored the potential correlation between GWC and the severity of ADHD. To delineate the cerebral landscape, each hemisphere was subdivided into 34 cortical regions using freesurfer 7.2.0. For quantification, GWC was computed by evaluating the intensity contrast of non-normalized T1 images above and below the gray-white matter interface.ResultsOur findings unveiled elevated GWC within the bilateral lingual, bilateral insular, left transverse temporal, right parahippocampal and right pericalcarine regions in male children with ADHD when contrasted with their healthy counterparts. Moreover, the cortical thickness in the ADHD group no notable distinctions that of control group in all areas. Intriguingly, the GWC of left transverse temporal demonstrated a negative correlation with the extent of inattention experienced by male children with ADHD.ConclusionUtilizing GWC as a metric facilitates a more comprehensive assessment of microstructural brain changes in children with ADHD. The fluctuations in GWC observed in specific brain regions might serve as a neural biomarker, illuminating structural modifications in male children grappling with ADHD. This perspective enriches our comprehension of white matter microstructure and cortical density in these children. Notably, the inverse correlation between the GWC of the left transverse temporal and inattention severity underscores the potential role of structural and functional anomalies within this region in ADHD progression. Enhancing our insight into ADHD-related brain changes holds significant promise in deciphering potential neuropathological mechanisms.
Outcome differences in HPV-driven head and neck squamous cell carcinoma attributable to altered human leukocyte antigen frequencies
Authors: Wichmann Gunnar , Vetter Nathalie , Lehmann Claudia , Landgraf Ramona , Doxiadis Ilias , Großmann Rebecca , Vorobeva Ekaterina , Dietz Andreas , Zebralla Veit , Wiegand Susanne , Wald Theresa 
Published: December 2023

BackgroundEffective immune surveillance requires a functioning immune system and natural killer (NK) and T cells for adequate innate and antigen-specific immune responses critically depending on human leukocyte antigens (HLAs) and haplotypes representing advantageous combinations of HLA antigens. Recently, we reported a link between altered frequencies of HLA alleles and haplotypes and developing head and neck squamous cell carcinoma (HNSCC). Whereas the majority of HNSCCs seem to be related to classical risk factors alcohol and tobacco, a subset of HNSCC and especially oropharyngeal squamous cell carcinoma (OPSCC) were etiologically linked to human papillomavirus (HPV) recently. Here, we demonstrate in HPV-driven (p16-positive high risk-HPV DNA-positive) HNSCC a deviating distribution of HLA antigens and haplotypes and their relevance to outcome.MethodsLeukocyte DNA ofn= 94 HPV-driven HNSCC patients (n= 57 OPSCC,n= 37 outside oropharynx) underwent HLA SSO typing, allowing allele, antigen (allele group), and haplo-typing. Besides comparing these frequencies with those of German blood donors, we analyzed their impact on outcome using Kaplan–Meier plots and Cox proportional hazard regression.ResultsAntigen and haplotype frequencies demonstrate enrichment of rare antigens and haplotypes. The HLA score for unselected HNSCC patients was not predictive for outcome here. However, together with alcohol consumption, tobacco smoking, T category, and extranodal extension of locoregional metastases and treatment applied, eight HLA traits allow for predicting progression-free and tumor-specific survival.ConclusionPatients can be categorized into low, intermediate-low, intermediate-high, and high risk groups. Using a new PFS risk score for HPV-driven HNSCC may allow to improve prognostication.
Utilization of cancer immunotherapy in sub-Saharan Africa
Authors: Olatunji Elizabeth , Patel Saloni , Graef Katy , Joseph Adedayo , Lasebikan Nwamaka , Mallum Abba , Chigbo Chinelo , Jaffee Elizabeth , Ngwa Wil 
Published: December 2023

IntroductionThe Lancet Oncology Commission for sub-Saharan Africa (SSA) predicts that cancer deaths will double from 520,158 per year to more than 1 million per year by the year 2040. These striking figures indicate a need to urgently evaluate cancer treatment infrastructure and resources in the region. Studies have found immunotherapy to be effective for the treatment of advanced-stage cancer, which almost 70% of patients in SSA present with. Despite immunotherapy’s significant therapeutic potential, its utilization in SSA is not well documented. The purpose of this study was to evaluate the landscape of immunotherapy in SSA.MethodsA Qualtrics survey assessing the existing infrastructure and training for safe immunotherapy administration was developed and distributed online via email and WhatsApp to 3,231 healthcare providers across SSA, with a target audience of healthcare providers serving patients with cancer. The survey contained 22 questions evaluating the accessibility, use, knowledge, and training on immunotherapy in SSA. Responses were collected between January and February 2023. Microsoft Excel was used to summarize and visually present the distribution of responses as counts and proportions.Results292 responses were included from 28 countries in SSA. 29% of all respondents indicated their clinic has easy access to cancer immunotherapy and 46% indicated their clinic currently practices it. Of clinics that practiced immunotherapy (n = 133), 12% used genomic sequencing to assess the tumor mutational burden biomarker, and 44% assessed expression of the PD-L1 biomarker prior to immunotherapy administration. 46% of all respondents were familiar with immunotherapy. 11% indicated being adequately trained to administer it. Of these (n=33), 52% indicated also being trained to manage immune-related adverse events related to immunotherapy administration.ConclusionImmunotherapy utilization and training is low in SSA and insufficient for the rising cancer burden. Increased accessibility and usage of biomarker testing to predict immunotherapy response, incorporation of immunotherapy training into continuous medical education, and increased access to immunotherapy drugs may be prerequisites for expanded utilization of immunotherapy in SSA.
Hepatic arterial infusion chemotherapy and trastuzumab in gastric cancer with liver metastases: a case report
Authors: Li Hui-qin , Wang Qin , Zhang Liu-yan , Li Jia-yin , Wang Ying-jie , Wei Li , Yao Li-ge 
Published: December 2023

BackgroundGastric cancer is a common cancer worldwide and is responsible for over one million new cases in 2020 and an estimated 769,000 deaths, ranking fifth for incidence and fourth for mortality globally. Incidence rates are highest in Eastern Asia and Eastern Europe. Gastric cancer is highly heterogeneous and progresses rapidly. The prognosis of gastric cancer with liver metastases is poor, and clinical treatment remains challenging. Human epidermal growth factor receptor 2 (HER2) positivity is correlated to a bad prognosis for gastric cancer. Trastuzumab combined with systemic chemotherapy is the preferred treatment for HER2-positive advanced gastric cancer. However, intravenous chemotherapy has severe systemic toxicity, which reduces the local drug concentration and tumor uptake rate, and the effect is unsatisfactory.Case summaryWe reported a 66-year-old patient with HER2-positive advanced gastric cancer with jaundice due to multiple liver metastases, after 6 cycles of trastuzumab combined with hepatic arterial infusion chemotherapy (HAIC), the tumor retracted significantly, the jaundice subsided, and the patient recovered well. The patient achieved disease control with an intensive regimen followed by less toxic maintenance therapy. Trastuzumab combined with capecitabine maintenance therapy followed up for more than 16 months.ConclusionHAIC plus trastuzumab may be a tolerable treatment option for patients with severe liver metastases from HER2-positive gastric cancer to achieve local control and prolong survival.
Development and optimization of AI algorithms for wrist fracture detection in children using a freely available dataset
Authors: Till Tristan , Tschauner Sebastian , Singer Georg , Lichtenegger Klaus , Till Holger 
Published: December 2023

IntroductionIn the field of pediatric trauma computer-aided detection (CADe) and computer-aided diagnosis (CADx) systems have emerged offering a promising avenue for improved patient care. Especially children with wrist fractures may benefit from machine learning (ML) solutions, since some of these lesions may be overlooked on conventional X-ray due to minimal compression without dislocation or mistaken for cartilaginous growth plates. In this article, we describe the development and optimization of AI algorithms for wrist fracture detection in children.MethodsA team of IT-specialists, pediatric radiologists and pediatric surgeons used the freely available GRAZPEDWRI-DX dataset containing annotated pediatric trauma wrist radiographs of 6,091 patients, a total number of 10,643 studies (20,327 images). First, a basic object detection model, a You Only Look Once object detector of the seventh generation (YOLOv7) was trained and tested on these data. Then, team decisions were taken to adjust data preparation, image sizes used for training and testing, and configuration of the detection model. Furthermore, we investigated each of these models using an Explainable Artificial Intelligence (XAI) method called Gradient Class Activation Mapping (Grad-CAM). This method visualizes where a model directs its attention to before classifying and regressing a certain class through saliency maps.ResultsMean average precision (mAP) improved when applying optimizations pre-processing the dataset images (maximum increases of +25.51% mAP@0.5 and +39.78% mAP@[0.5:0.95]), as well as the object detection model itself (maximum increases of +13.36% mAP@0.5 and +27.01% mAP@[0.5:0.95]). Generally, when analyzing the resulting models using XAI methods, higher scoring model variations in terms of mAP paid more attention to broader regions of the image, prioritizing detection accuracy over precision compared to the less accurate models.DiscussionThis paper supports the implementation of ML solutions for pediatric trauma care. Optimization of a large X-ray dataset and the YOLOv7 model improve the model’s ability to detect objects and provide valid diagnostic support to health care specialists. Such optimization protocols must be understood and advocated, before comparing ML performances against health care specialists.
Development and performance of the c4c national clinical trial networks for optimizing pediatric trial facilitation
Authors: Degraeuwe Eva , van der Geest Tessa , Persijn Laura , Nuytinck Lieve , Raes Ann , Turner Mark , Fernandes Ricardo M. , Vande Walle Johan , de Wildt Saskia N. ,   IMI2 project conect4children (c4c) consortium, including National Hubs/Networks Belgian Pediatric Clinical Research Network (BPCRN) (Belgium) and Pedmed-NL (Netherlands)
Published: December 2023

IntroductionThe high failure rate of industry-driven pediatric clinical trials leads to insufficient timely labeling of drugs in children and a lack of scientific evidence, resulting in the persistently high off-label drug use. National clinical trial networks can facilitate collaboration between sites, investigators, and experts, increasing the likelihood of successful trials. Within the conect4children (c4c) network, an Innovative Medicines Initiative 2-funded project, National Hubs hosted by National Clinical Trials Networks were set up across 21 European countries to facilitate the setup and execution of pediatric clinical trials. In this paper, we aim to present the performance metrics of the trial feasibility process as well as learnings and challenges encountered by the Belgian and Dutch Networks in working within the European c4c project.MethodThe c4c National Hubs streamline pediatric clinical trials by initiating early country outreach, identifying overlapping studies, recommending quality trial sites, and supporting trial budgeting for both industry and academic settings. To show the impact of Pedmed-NL and Belgian Pediatric Clinical Research Network (BPCRN), internal metrics were collected from 2019 to 2022 on four industry-sponsored and three academic trials performed within the c4c network. Timelines and outcomes of the site identification were collected and analyzed for industry trials. A qualitative analysis was conducted through c4c platforms, sponsor interactions, and stakeholder engagement to evaluate the added value of a research network.ResultsIn industry-sponsored trials, full feasibility questionnaires were completed within 2 weeks (n = 48), and inclusion rates were up to 80% of clinical sites. Before committing to c4c, 14% of sites were contacted by industry, leading to communication burdens. Utilizing national infrastructure knowledge and therapeutic environment insights helped optimize trial timelines and address feasibility challenges. In addition, national adaptations, such as bilingual staff and site development, played a role in streamlining trial operations in both academic and industry settings. Performance and experiences were similar for both networks.ConclusionThe early-facilitation examples from the c4c trials demonstrated promising metrics for two National Hubs, including optimized start-up timelines and aiding site selection quality. The learnings and challenges of the Belgian and Dutch Networks provided insights for the development of clinical research networks.
Assessing the health literacy of caregivers in the pediatric intensive care unit: a mixed-methods study
Authors: Reddy Anireddy R. , Doshi Anushree K. , Mak Allison , Shea Judy A. , Fardad Joana T. , Moon Jiwon , Hu Paula , Garcia-Marcinkiewicz Annery G. 
Published: December 2023

BackgroundLimited health literacy is associated with increased hospitalizations, emergency visits, health care costs, and mortality. The health literacy levels of caregivers of critically ill children are unknown. This mixed-methods study aims to quantitatively assess the health literacy of caregivers of children admitted to the pediatric intensive care unit (PICU) and qualitatively describe facilitators and barriers to implementing health literacy screening from the provider perspective.MethodsCaregivers of patients admitted to our large, academic PICU (between August 12, 2022 and March 31, 2023) were approached to complete a survey with the Newest Vital Sign (NVS), which is a validated health literacy screener offered in English and Spanish. We additionally conducted focus groups of interdisciplinary PICU providers to identify factors which may influence implementation of health literacy screening using the Consolidated Framework for Implementation Research (CFIR) framework.ResultsAmong 48 surveyed caregivers, 79% demonstrated adequate health literacy using the Newest Vital Sign screener. The majority of caregivers spoke English (96%), were mothers (85%), and identified as White (75%). 83% of caregivers were able to attend rounds at least once and 98% believed attending rounds was helpful. Within the PICU provider focus groups, there were 11 participants (3 attendings, 3 fellows, 2 nurse practitioners, 1 hospitalist, 2 research assistants). Focus group participants described facilitators and barriers to implementation, which were mapped to CFIR domains. Timing of screening and person administering screening were identified as modifiable factors to improve future implementation.ConclusionWe found the health literacy levels of PICU caregivers in our setting is similar to prior assessments of parental health literacy. Participation in morning rounds was helpful for developing understanding of their child's illness, regardless of health literacy status. Qualitative feedback from providers identified barriers across all CFIR domains, with timing of screening and person administering screening as modifiable factors to improve future implementation.
Cenobamate as add-on therapy for drug resistant epilepsies: effectiveness, drug to drug interactions and neuropsychological impact. What have we learned from real word evidence?
Authors: Pietrafusa Nicola , Falcicchio Giovanni , Russo Emilio , Lattanzi Simona , Goffredo Bianca , Simeoli Raffaele , Cairoli Sara , Corsetti Tiziana , Roberti Roberta , De Tommaso Marina , Vigevano Federico , La Neve Angela , Specchio Nicola 
Published: December 2023

Background: Cenobamate (CNB) is an anti-seizure medication (ASM) approved in 2021 in Europe for adjunctive treatment of focal-onset seizures in adults who were not adequately controlled with at least two previous ASMs.Methods: seizure outcome, treatment-emergent adverse events, neuropsychological profile, and blood levels of CNB and concomitant ASM were analyzed in a real world setting in two different Italian epilepsy centers in the context of CNB early access program. All patients performed a general cognitive evaluation, while 32 patients underwent the administration of a battery of neuropsychological tests at baseline and 6 months after CNB treatment. We performed CNB quantification in plasma in 31 patients at different doses in the range of 100–400 mg/day (65 measures).Results: we enrolled 54 patients with a median age of 27.9 years. The mean follow-up was 10.7 months. Most (91%) completed the efficacy analysis. At last follow-up visit, a 69.5% median seizure reduction was registered. Thirty-two patients (59.2%) had a ≥50% reduction of seizures that was ≥75% in 20 (42.0%) cases, whilst 10 (20.2%) patients were seizure-free. The most common adverse events were somnolence (53.1%), dizziness (28.1%) and diplopia (12.5%). The correlation between CNB dose and plasma concentration, revealed a significant linear correlation (r = 0.86, p &lt; 0.0001), and there was a significant difference in mean plasma concentration/dose administered ratio (C/D ratio) between patients taking or not at least one inducer (0.10 ± 0.04 [(μg/mL)/(mg/day)]; n = 47 vs. 0.13 ± 0.05 [(μg/mL)/(mg/day)]; n = 18, p = 0.04). CNB dose was inversely correlated (r = −0.31, p = 0.02) to the C/D ratio of Carbamazepine blood levels. and positively correlated (r = 0.74, p &lt; 0.0001) with an increased plasma concentration of the active Clobazam metabolite N-desmethylclobazam. General Anxiety Disorder-7 showed a significant improvement of score from baseline evaluation of 6.82 to follow-up 6 months evaluation of 4.53 (p = 0.03).Conclusion: In this real-world study, we registered a clinically meaningful reduction in seizure frequency after CNB administration in most patients along with a good tolerability profile. CNB treatment is correlate to a reduction in symptom severity of anxiety score. Plasma levels measurements confirm that CNB acts both as “victim” and as “perpetrator” of drug-drug interactions.
Cholecystokinin-A signaling regulates automaticity of pacemaker cardiomyocytes
Authors: Ruan Hongmei , Mandla Ravi , Ravi Namita , Galang Giselle , Soe Amanda W. , Olgin Jeffrey E. , Lang Di , Vedantham Vasanth 
Published: December 2023

Aims: The behavior of pacemaker cardiomyocytes (PCs) in the sinoatrial node (SAN) is modulated by neurohormonal and paracrine factors, many of which signal through G-protein coupled receptors (GPCRs). The aims of the present study are to catalog GPCRs that are differentially expressed in the mammalian SAN and to define the acute physiological consequences of activating the cholecystokinin-A signaling system in isolated PCs.Methods and results: Using bulk and single cell RNA sequencing datasets, we identify a set of GPCRs that are differentially expressed between SAN and right atrial tissue, including several whose roles in PCs and in the SAN have not been thoroughly characterized. Focusing on one such GPCR, Cholecystokinin-A receptor (CCKAR), we demonstrate expression of Cckar mRNA specifically in mouse PCs, and further demonstrate that subsets of SAN fibroblasts and neurons within the cardiac intrinsic nervous system express cholecystokinin, the ligand for CCKAR. Using mouse models, we find that while baseline SAN function is not dramatically affected by loss of CCKAR, the firing rate of individual PCs is slowed by exposure to sulfated cholecystokinin-8 (sCCK-8), the high affinity ligand for CCKAR. The effect of sCCK-8 on firing rate is mediated by reduction in the rate of spontaneous phase 4 depolarization of PCs and is mitigated by activation of beta-adrenergic signaling.Conclusion: (1) PCs express many GPCRs whose specific roles in SAN function have not been characterized, (2) Activation of the cholecystokinin-A signaling pathway regulates PC automaticity.