bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interpretation of in vitro concentration‐response data for risk assessment and regulatory decision‐making: Report from the 2022 IWGT quantitative analysis expert working group meeting
Authors: Beal Marc A. , Chen Guangchao , Dearfield Kerry L. , Gi Min , Gollapudi Bhaskar , Heflich Robert H. , Horibata Katsuyoshi , Long Alexandra S. , Lovell David P. , Parsons Barbara L. , Pfuhler Stefan , Wills John , Zeller Andreas , Johnson George , White Paul A. 
Published: December 2023

AbstractQuantitative risk assessments of chemicals are routinely performed using in vivo data from rodents; however, there is growing recognition that non‐animal approaches can be human‐relevant alternatives. There is an urgent need to build confidence in non‐animal alternatives given the international support to reduce the use of animals in toxicity testing where possible. In order for scientists and risk assessors to prepare for this paradigm shift in toxicity assessment, standardization and consensus on in vitro testing strategies and data interpretation will need to be established. To address this issue, an Expert Working Group (EWG) of the 8th International Workshop on Genotoxicity Testing (IWGT) evaluated the utility of quantitative in vitro genotoxicity concentration‐response data for risk assessment. The EWG first evaluated available in vitro methodologies and then examined the variability and maximal response of in vitro tests to estimate biologically relevant values for the critical effect sizes considered adverse or unacceptable. Next, the EWG reviewed the approaches and computational models employed to provide human‐relevant dose context to in vitro data. Lastly, the EWG evaluated risk assessment applications for which in vitro data are ready for use and applications where further work is required. The EWG concluded that in vitro genotoxicity concentration‐response data can be interpreted in a risk assessment context. However, prior to routine use in regulatory settings, further research will be required to address the remaining uncertainties and limitations.
Epileptogenic focal lesions in Dravet syndrome: A warning to investigators
Authors: Ventura Rita , Beltrán‐Corbellini Álvaro , Toledano Rafael , Román Irene Sánchez‐Miranda , García‐Morales Irene , Gil‐Nagel Antonio 
Published: December 2023

AbstractObjectiveMost patients with Dravet syndrome (DS) have unremarkable neuroimaging studies. However, a small number of patients exhibit focal abnormalities that may modify the epilepsy phenotype. We report a case series of DS patients carrying SCN1A variants concurrent with additional focal brain lesions, aiming to provide details regarding their clinical course, electrographic findings, and imaging features.MethodsWe reviewed the electronic medical records of patients with developmental and epileptic encephalopathies in our center, from January 2000 to December 2022, identifying 90 patients with DS resulting from SCN1A variants. Of these, patients displaying focal brain lesions were eligible.ResultsFive patients (4 males and 1 female), with median age of 26 years, were included. All exhibited clinical and electroencephalographic features consistent with the DS spectrum. Sequencing analysis of the SCN1A gene identified pathogenic variants. Magnetic resonance imaging (MRI) revealed focal cortical dysplasia (FCD) in two patients, while the remaining three had cystic lesions. Three patients had previously undergone resective epilepsy surgery in other centers, with no improvement in seizure frequency. Neuropathology studies revealed the presence of FCD type IIA, intracranial teratomas, and dysembryoplastic neuroepithelial tumor (DNET).SignificanceWhen an individual with an established diagnosis of genetic epilepsy and a focal lesion on MRI is undergoing preoperative evaluation, it is crucial to conduct a comprehensive analysis to understand the relevance of the focal finding for the patient's phenotype and thus anticipate potential surgical outcomes. In instances where epilepsy in DS patients is influenced by a specific focal structural lesion, resective surgery should be carefully considered after precise pharmacological treatment, acknowledging the persistent influence of an SCN1A variant on expected outcomes.
Effects of Tulp4 deficiency on murine embryonic development and adult phenotype
Authors: Jäger Roland , Geyer Stefan H. , Kavirayani Anoop , Kiss Máté G. , Waltenberger Elisabeth , Rülicke Thomas , Binder Christoph J. , Weninger Wolfgang J. , Kralovics Robert 
Published: December 2023

AbstractGenetically engineered mouse models have the potential to unravel fundamental biological processes and provide mechanistic insights into the pathogenesis of human diseases. We have previously observed that germline genetic variation at the TULP4 locus influences clinical characteristics in patients with myeloproliferative neoplasms. To elucidate the role of TULP4 in pathological and physiological processes in vivo, we generated a Tulp4 knockout mouse model. Systemic Tulp4 deficiency exerted a strong impact on embryonic development in both Tulp4 homozygous null (Tulp4−/−) and heterozygous (Tulp4+/−) knockout mice, the former exhibiting perinatal lethality. High‐resolution episcopic microscopy (HREM) of day 14.5 embryos allowed for the identification of multiple developmental defects in Tulp4−/− mice, including severe heart defects. Moreover, in Tulp4+/− embryos HREM revealed abnormalities of several organ systems, which per se do not affect prenatal or postnatal survival. In adult Tulp4+/− mice, extensive examinations of hematopoietic and cardiovascular features, involving histopathological surveys of multiple tissues as well as blood counts and immunophenotyping, did not provide evidence for anomalies as observed in corresponding embryos. Finally, evaluating a potential obesity‐related phenotype as reported for other TULP family members revealed a trend for increased body weight of Tulp4+/− mice.Research Highlights
To study the role of the TULP4 gene in vivo, we generated a Tulp4 knockout mouse model.
Correlative analyses involving HREM revealed a strong impact of Tulp4 deficiency on murine embryonic development.
Entrepreneur characteristics and financing patterns in SMES of MENA countries: Overcoming the burdens of liability of newness
Authors: Lassoued Naima , Khanchel Imen , Fakhfakh Imen , Etteyeb Mehdi 
Published: December 2023

AbstractThis study examines the impact of entrepreneur attributes on financing channels of small and medium‐sized enterprises (SMEs) as well as the moderating role of firm age on this relationship. It examines a comprehensive dataset of 4139 firm‐year observations operating in the Middle East and North Africa (MENA) region observed over the 2013–2019 period. The results are four‐fold. First, our overall findings reveal that experienced entrepreneurs tend to use internal funds. Second, the university education of entrepreneurs positively correlates with debt financing. Third, female entrepreneurs are more eager to use internal funds and less debt. Fourth, firm age is found to moderate these relationships. Indeed, in young SMEs, experienced entrepreneurs are shown to rely on debt, graduated entrepreneurs on internal funds, and in older SMEs, female entrepreneurs use debt. Our results bear on the proposals of upper echelons and organizational lifecycle theories.
Diagnostic delay in late‐onset Pompe disease among Chinese patients: A retrospective study
Authors: Yue Dongyue , Jiao Kexin , Xia Xingyu , Zhang Jialong , Zhu Bochen , Liu Lingchun , Du Kunzhao , Gao Mingshi , Cheng Nachuan , Wang Ningning , Luo Sushan , Xi Jianying , Lu Jiahong , Zhao Chongbo , Zhu Wenhua 
Published: December 2023

AbstractSurveys and retrospective studies have revealed considerable delays in diagnosing late‐onset Pompe disease (LOPD) in China, where the contributing factors remain poorly represented. Our study analyzed the diagnostic journey of 34 LOPD patients seen at our neuromuscular clinic from 2005 to 2022. We defined diagnostic delay as the time from the onset of the first relevant symptoms and laboratory findings suggestive of LOPD to the eventual diagnosis, and we constructed a correlation matrix to assess relationships among these variables. The cohort consisted of 34 patients with an equal male‐to‐female ratio, and the mean age at diagnosis was 27.68 ± 10.03 years. We found the median diagnostic delay to be 5 years, with a range of 0.3 to 20 years, with 97.1% having been misdiagnosed previously, most commonly with “Type II Respiratory insufficiency” (36.7%). Notably, patients at earlier onset (mean age, 18.19 years vs. 31 years; p < 0.005) tended to have higher creatine kinase (CK) levels. Furthermore, 92.6% reported difficulty in sitting up from a supine position since childhood. Our research emphasizes the role of early indicators like dyspnea and difficulty performing sit‐ups in adolescents for timely LOPD diagnosis and treatment initiation. The importance of early high‐risk screening using dried blood spot testing cannot be overstated.
Infusion reactions to adeno‐associated virus (AAV)‐based gene therapy: Mechanisms, diagnostics, treatment and review of the literature
Authors: Notarte Kin Israel , Catahay Jesus Alfonso , Macasaet Raymart , Liu Jin , Velasco Jacqueline Veronica , Peligro Princess Juneire , Vallo Jolaine , Goldrich Nathaniel , Lahoti Lokesh , Zhou Jiayan , Henry Brandon Michael 
Published: December 2023

AbstractThe use of adeno‐associated virus (AAV) vectors in gene therapy has demonstrated great potential in treating genetic disorders. However, infusion‐associated reactions (IARs) pose a significant challenge to the safety and efficacy of AAV‐based gene therapy. This review provides a comprehensive summary of the current understanding of IARs to AAV therapy, including their underlying mechanisms, clinical presentation, and treatment options. Toll‐like receptor activation and subsequent production of pro‐inflammatory cytokines are associated with IARs, stimulating neutralizing antibodies (Nabs) and T‐cell responses that interfere with gene therapy. Risk factors for IARs include high titers of pre‐existing Nabs, previous exposure to AAV, and specific comorbidities. Clinical presentation ranges from mild flu‐like symptoms to severe anaphylaxis and can occur during or after AAV administration. There are no established guidelines for pre‐ and postadministration tests for AAV therapies, and routine laboratory requests are not standardized. Treatment options include corticosteroids, plasmapheresis, and supportive medications such as antihistamines and acetaminophen, but there is no consensus on the route of administration, dosage, and duration. This review highlights the inadequacy of current treatment regimens for IARs and the need for further research to improve the safety and efficacy of AAV‐based gene therapy.
Clinical performance of the STANDARD M10 SARS‐CoV‐2 rapid RT‐PCR assay in patients visiting an emergency department
Authors: Lee Dong‐hyun , Han Eunhee , Ryu Soorack , Choi Hyuk joong , Kim Jieun , Kim Jinyeong , Bae Mi Hyun 
Published: December 2023

AbstractIn emergency departments, rapid screening of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was important for arranging limited isolation resources and patient care during the coronavirus disease 2019 (COVID‐19) pandemic. STANDARD M10 SARS‐CoV‐2 (SD Biosensor) is a recently developed cartridge‐based RT‐PCR that provides a turnaround time of 1 h, which is shorter than that for conventional RT‐PCR. This study evaluated the clinical performance of STANDARD M10 in patients visiting an emergency department. From March to June 2022, two specimens were collected from patients visiting an emergency department. Each specimen comprised one nasopharyngeal and one oropharyngeal swab. Respective specimens underwent rapid RT‐PCR using STANDARD M10 and conventional RT‐PCR using Allplex SARS‐CoV‐2 (Seegene). When discordant results occurred, specimens undergoing the STANDARD M10 were retested with the Allplex to exclude specimen variations. Retest results replaced initial results of the Allplex. Clinical performance of STANDARD M10 was compared with Allplex. The study enrolled 1971 patients. COVID‐19 prevalence was 6.2% based on the Allplex. Compared with the Allplex, overall agreement, positive percent agreement, and negative percent agreement of STANDARD M10 were 99.5% (95% CI: 99.1%–99.8%), 95.9% (95% CI: 90.8%–98.3%), and 99.8% (95% CI: 99.4%–99.9%), respectively. Nine discordant results were all positive on droplet digital PCR, except for one specimen that was positive with STANDARD M10. The STANDARD M10 showed reliable diagnostic performance for detecting SARS‐CoV‐2 from patients visiting in emergency departments and is a useful tool in emergency healthcare systems because of its easy‐to‐use cartridge‐based assay and short resulting time for detecting SARS‐CoV‐2.
The International Human Papillomavirus Reference Center: Standardization, collaboration, and quality assurance in HPV research and diagnostics
Authors: Arroyo Mühr Laila Sara , Lagheden Camilla , Hassan Sadaf S. , Eklund Carina , Dillner Joakim 
Published: December 2023

AbstractThe International Human Papillomavirus (HPV) Reference Center (IHRC) confirms and assigns type numbers to novel HPV types, maintains a reference clone repository, and issues international proficiency panels for HPV screening and genotyping. Furthermore, the Center coordinates the Global HPV Reference Laboratory Network that promotes collaboration and international exchange of experiences among national HPV reference laboratories, to further international standardization and quality assurance in the HPV field. The established HPV types (n = 225) belong to 5 different genera: alpha (n = 65), beta (n = 54), gamma (n = 102), mu (n = 3) and nu (n = 1). Since the last published IHRC overview in 2018, 6 novel types have been established, with 5/6 belonging to the gamma genus and 1/6 to beta genus. Also, 474 reference clones have been provided to 55 different research laboratories and the global proficiency program for HPV genotyping has seen an increasing proficiency (despite a decrease seen in 2019), from 68% proficiency in 2017 to 77.3% in 2022. The first proficiency study for HPV screening found an international proficiency of up to 77%. In summary, increasing complexity of the HPVs and demands on quality assurance in the era of cervical cancer elimination requires international efforts to support proficiency and recognized quality and order among HPV types.
Investigating the effects of zinc oxide and titanium dioxide nanoparticles on the formation of biofilm and persister cells in Klebsiella pneumoniae
Authors: Pourmehdiabadi Aisouda , Nobakht Mojgan Sarabi , Hajjam Balajorshari Behdad , Yazdi Mohammadreza Rezaei , Amini Kumarss 
Published: December 2023

AbstractThe biofilm formation in klebsiella pneumoniae isolates poses a significant problem as it can result in treatment failure and the development of chronic infections. These biofilms act as protective barriers, rendering the bacteria resistant to antibiotics. Additionally, persister cells, which make up a small fraction of the bacterial population, have the ability to enter a dormant state after treatment with high doses of antibiotics. These persister cells play a crucial role in the high level of biofilm‐mediated tolerance to antibiotics. The present study aimed to investigate the impact of Zinc oxide (ZnO) and titanium dioxide (TiO2) nanoparticles on the formation of biofilm and persister cells in K. pneumoniae. The minimum inhibitory concentration (MIC) of colistin in K. pneumoniae ATCC 13883 was determined using the microdilution method. The formation of persister cells was evaluated by introducing sub‐MIC of colistin. Subsequently, the MIC of ZnO NPs and TiO2 NPs in these persister cells was assessed using the microdilution method. Furthermore, the effects of nanoparticles on the expression levels of biofilm‐associated genes were analyzed using real‐time polymer chain reaction (PCR). The MIC values for colistin, ZnO, and TiO2 were determined at 2, 12.5, and 6.25 μg/mL, respectively. In the presence of nanoparticles, biofilm formation decreased. Real‐time PCR results showed the messenger RNA (mRNA) level of mrkH and fimH were decreased and the expression of luxS and mazF were increased. Biofilm formation of K. pneumoniae ATCC 1383 was inhibited in response to nanoparticles. According to the results of the present study use of nanoparticles may help control multidrug‐resistant (MDR) infections in hospitalized patients.
Creative Subprocess Frequencies and Their Relation to Personal Characteristics and Product Creativity: Insights from a Drawing Task Think Aloud Study
Authors: Boldt Gregory T. , Kaufman James C. 
Published: December 2023

ABSTRACTMost research on the creative process has focused on idea generation, and the prevalence and influence of many other creative subprocesses remain poorly understood. To clarify different subprocesses' respective roles in creative work, this study investigated their frequencies and associations with creativity‐related personal characteristics and product creativity. Undergraduate students (n = 266) articulated their creative thought processes via the think aloud method while completing an open‐ended drawing task and completed questionnaires assessing creativity‐relevant personal characteristics. Drawings were rated for creativity by quasi‐expert judges. Transcripts were coded using an a priori coding scheme informed by models of the creative process, including generation (14%), elaboration (26%), association (9%), selection (4%), evaluation (13%), anchoring (13%), metacognition (7%), and filler (14%). Subprocess frequencies correlated minimally with measures of personal characteristics, although several significant, albeit weak, relationships emerged. A hierarchical regression analysis indicated that the best predictors of drawing creativity were aesthetic fluency, the frequency of anchoring, time spent on task, and, marginally, the frequency of generation. Together, these results provide insight into how relevant personal characteristics and subprocess engagement contribute to drawing creativity and highlight the particular importance of anchoring, which involves monitoring and refining task‐related goals and constraints, throughout the creative process.
Rapid deglaciation of the La Vega gorge (Sierra de Gredos, Iberian Peninsula) at the end of the global Last Glacial Maximum
Authors: Alcalá‐Reygosa Jesús , Campos Néstor , Schimmelpfennig Irene , Sanjurjo‐Sánchez Jorge , Léanni Laetitia , Zamorano José Juan ,   ASTER Team
Published: December 2023

AbstractPrevious studies from the Iberian Central System and other mountains of the Iberian Peninsula and Europe suggest that deglaciation in this area occurred at the end or immediately after the global Last Glacial Maximum (LGM, 26.5–19 ka). In this research, we investigate the timing and speed of deglaciation of the palaeoglacier in La Vega gorge (Iberian Central system) since the global LGM, dating the outer moraines, glacially polished bedrock and glaciofluvial deposits by means of in situ cosmogenic 10Be and optically stimulated luminescence. The results show that one intermediate arc located at the outer frontal moraine system has an age of ~21 ka, being consistent with the global LGM. Deglaciation began at ~21–19 ka, speeding up at ~19 ka. We estimate that around 4–5 km of the palaeoglacier receded in ~1–2 kyrs since ~19 ka, leaving La Vega gorge probably ice‐free at ~18 ka. Therefore, our data confirm that deglaciation in Sierra de Gredos began at the end of the global LGM, characterised by a rapid and massive retreat of glaciers.
Can we let our patients sleep in the hospital? A randomized controlled trial of a pragmatic sleep protocol in surgical oncology patients
Authors: Kelly Kathrine , Kolbeinsson Hordur , Blanck Lauren M. , Khan Mariam , Kyriakakis Roxanne , Assifi M. Mura , Wright G. Paul , Chung Mathew 
Published: December 2023

AbstractBackgroundPostoperative inpatients experience increased stress due to pain and poor restorative sleep than non‐surgical inpatients.Objectives and MethodsA total of 101 patients, undergoing major oncologic surgery, were randomized to a postoperative sleep protocol (n = 50) or standard postoperative care (n = 51), between August 2020 and November 2021. The primary endpoint of the study was postoperative sleep time after major oncologic surgery. Sleep time and steps were measured using a Fitbit Charge 4®.ResultsThere was no statistically significant difference found in postoperative sleep time between the sleep protocol and standard group (median sleep time of 427 min vs. 402 min; p = 0.852, respectively). Major complication rates were similar in both groups (7.4% vs. 8.9%). Multivariate analysis found sex and Charlson Comorbidity Index to be significant factors affecting postoperative sleep time and step count. Postoperative delirium was only observed in the standard group, although this did not reach statistical significance. There were no in hospital mortalities.ConclusionThe use of a sleep protocol was found to be safe in our study population. There was no statistical difference in postoperative sleep time or major complications. Institution of a more humane sleep protocol for postoperative inpatients should be considered.
Controllable Wrinkling Inspired Multifunctional Metamaterial for Near‐Field and Holographic Displays
Authors: Han Donghai , Li Wenkang , Hou Yushan , Chen Xiaoming , Shi Hongyu , Meng Fanqi , Zhang Liuyang , Chen Xuefeng 
Published: December 2023

AbstractTunable electromagnetic (EM) metamaterials have received significant attention due to their compelling advantages of integration and minimization compared with conventional bulky devices. Meanwhile, mechanically reconfigurable metamaterials have witnessed a striving period over recent years due to their simplified structural composition and confined modulation capabilities. Here, a controllable‐wrinkling‐based reconfiguration method is proposed to design split‐ring resonant units with dynamic transmittance spectra by switching between planar and wrinkling morphologies. For the linear polarized incidence, the geometries of planar and wrinkled units are optimized to achieve on‐demanded manipulation of the phases and amplitudes, respectively. By simultaneously implementing the amplitude design and the phase gradient, the mechanically inspired metamaterial is engineered to display a near‐field and a holographic image. For circularly polarized incidences, the spin‐decoupled phases and chiral effects demonstrated in the planar and wrinkled state assist in designing a metamaterial to possess spin‐multiplexed and strain‐modulated fourfold displays. These results demonstrate the practical feasibility of the wrinkling method in engineering tunable metamaterials, and the design flexibility, as well as the mechanical strategy, can extend the potential toward the application scenarios such as information processing, sensing, imaging, flexible meta‐devices, etc.