bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prolonged course of brain edema and neurological recovery in a translational model of decompressive craniectomy after closed head injury in mice
Authors: Szczygielski Jacek , Hubertus Vanessa , Kruchten Eduard , Müller Andreas , Albrecht Lisa Franziska , Schwerdtfeger Karsten , Oertel Joachim 
Published: November 2023

BackgroundThe use of decompressive craniectomy in traumatic brain injury (TBI) remains a matter of debate. According to the DECRA trial, craniectomy may have a negative impact on functional outcome, while the RescueICP trial revealed a positive effect of surgical decompression, which is evolving over time. This ambivalence of craniectomy has not been studied extensively in controlled laboratory experiments.ObjectiveThe goal of the current study was to investigate the prolonged effects of decompressive craniectomy (both positive and negative) in an animal model.MethodsMale mice were assigned to the following groups: sham, decompressive craniectomy, TBI and TBI followed by craniectomy. The analysis of functional outcome was performed at time points 3d, 7d, 14d and 28d post trauma according to the Neurological Severity Score and Beam Balance Score. At the same time points, magnetic resonance imaging was performed, and brain edema was analyzed.ResultsAnimals subjected to both trauma and craniectomy presented the exacerbation of the neurological impairment that was apparent mostly in the early course (up to 7d) after injury. Decompressive craniectomy also caused a significant increase in brain edema volume (initially cytotoxic with a secondary shift to vasogenic edema and gliosis). Notably, delayed edema plus gliosis appeared also after decompression even without preceding trauma.ConclusionIn prolonged outcomes, craniectomy applied after closed head injury in mice aggravates posttraumatic brain edema, leading to additional functional impairment. This effect is, however, transient. Treatment options that reduce brain swelling after decompression may accelerate neurological recovery and should be explored in future experiments.
Identification of novel SHANK2 variants in two Chinese families via exome and RNA sequencing
Authors: Wu Yong , Li Wenzhou , Tan Bo , Luo Sanchuan 
Published: November 2023

BackgroundSHANK2 encodes a postsynaptic scaffolding protein involved in synapse formation, stabilization and homeostasis. Variations or microdeletions in the SHANK2 gene have been linked to a variety of neurodevelopmental disorders, including autism spectrum disorders (ASD) and mild to moderate intellectual disability (ID) in human. However, the number of reported cases with SHANK2 defects remains limited, with only 14 unrelated patients documented worldwide.MethodsIn this study, we investigated four patients from three families with ID. Whole-exome sequencing (WES) was performed to explore the genetic causes, while Sanger sequencing was used to confirm the identified variants. Furthermore, RNA sequencing and functional enrichment analysis were performed on patients with likely pathogenic variants to gain further insights into the molecular landscape associated with these variants.ResultsTwo novel variants in the SHANK2 gene: a heterozygous splicing substitution (NM_012309.5:c.2198-1G&gt;A p.Pro734Glyfs*22) in Family 1, and a heterozygous nonsense variant [NM_012309.5:c.2310dupT p.(Lys771*)] in Family 2 were identified by WES and confirmed by Sanger sequencing. RNA sequencing and cohort analysis identified a total of 1,196 genes exhibiting aberrant expression in three patients. Functional enrichment analysis revealed the involvement of these genes in protein binding and synaptic functions.ConclusionWe identified two novel loss of function variants that broadens the spectrum of SHANK2 variants. Furthermore, this study enhances our understanding of the molecular mechanisms underlying SHANK2-related disorders.
Novel combinatorial therapy of oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L with anti PD-1 exhibits enhanced anti-cancer efficacy through promotion of intratumoral T-cell infiltration and modulation of tumour microenvironment in mesothelioma mouse model
Authors: Garofalo Mariangela , Wieczorek Magdalena , Anders Ines , Staniszewska Monika , Lazniewski Michal , Prygiel Marta , Zasada Aleksandra Anna , Szczepińska Teresa , Plewczynski Dariusz , Salmaso Stefano , Caliceti Paolo , Cerullo Vincenzo , Alemany Ramon , Rinner Beate , Pancer Katarzyna , Kuryk Lukasz 
Published: November 2023

IntroductionMalignant mesothelioma is a rare and aggressive form of cancer. Despite improvements in cancer treatment, there are still no curative treatment modalities for advanced stage of the malignancy. The aim of this study was to evaluate the anti-tumor efficacy of a novel combinatorial therapy combining AdV5/3-D24-ICOSL-CD40L, an oncolytic vector, with an anti-PD-1 monoclonal antibody.MethodsThe efficacy of the vector was confirmed in vitro in three mesothelioma cell lines – H226, Mero-82, and MSTO-211H, and subsequently the antineoplastic properties in combination with anti-PD-1 was evaluated in xenograft H226 mesothelioma BALB/c and humanized NSG mouse models.Results and discussionAnticancer efficacy was attributed to reduced tumour volume and increased infiltration of tumour infiltrating lymphocytes, including activated cytotoxic T-cells (GrB+CD8+). Additionally, a correlation between tumour volume and activated CD8+ tumour infiltrating lymphocytes was observed. These findings were confirmed by transcriptomic analysis carried out on resected human tumour tissue, which also revealed upregulation of CD83 and CRTAM, as well as several chemokines (CXCL3, CXCL9, CXCL11) in the tumour microenvironment. Furthermore, according to observations, the combinatorial therapy had the strongest effect on reducing mesothelin and MUC16 levels. Gene set enrichment analysis suggested that the combinatorial therapy induced changes to the expression of genes belonging to the “adaptive immune response” gene ontology category. Combinatorial therapy with oncolytic adenovirus with checkpoint inhibitors may improve anticancer efficacy and survival by targeted cancer cell destruction and triggering of immunogenic cell death. Obtained results support further assessment of the AdV5/3-D24-ICOSL-CD40L in combination with checkpoint inhibitors as a novel therapeutic perspective for mesothelioma treatment.
Pancreatic cancer outcome—local treatment with radiation using MRI-LINAC
Authors: Almog Galit , Pfeffer Raphael M. , Zalmanov Svetlana , Grinberg Vladislav , Lipsky Yoav , Chernomordikov Elena , Levin Daphne , Apter Sara , Arsenault Orit , Epstein Dan , Tamimi Qusai , Hod Keren , Limon Dror , Golan Talia , Ben-Aharon Irit , Lawrence Yaacov Richard , Ben-David Merav Akiva 
Published: November 2023

IntroductionStereotactic MR-guided on-table adaptive radiotherapy (SMART) allows the precise delivery of high-dose radiation to tumors in great proximity to radiation-sensitive organs. The aim of this study is to evaluate the toxicity and clinical outcome in locally advanced or recurrent pancreatic tumors, with or without prior irradiation, treated with SMART.MethodsPatients were treated for pancreatic cancer (PC) using SMART technology to a prescribed dose of 50 Gy (BED10, 100 Gy) in five fractions, with daily on-table adaptation of treatment plan. Endpoints were acute and late toxicities, local control, local disease-free period, and overall survival.ResultsA total of 54 PC patients were treated between August 2019 and September 2022, with a median follow-up of 8.9 months from SMART. The median age was 70.4 (45.2–86.9) years. A total of 40 patients had upfront inoperable PC (55% were locally advanced and 45% metastatic), and 14 had local recurrence following prior pancreatectomy (six patients also had prior adjuvant RT). Of the patients, 87% received at least one chemotherapy regimen (Oxaliplatin based, 72.2%), and 25.9% received ≥2 regimens. Except from lower CA 19-9 serum level at the time of diagnosis and 6 weeks prior to SMART in previously operated patients, there were no significant differences in baseline parameters between prior pancreatectomy and the inoperable group. On-table adaptive replanning was performed for 100% of the fractions. No patient reported grade ≥2 acute GI toxicity. All previously irradiated patients reported only low-grade toxicities during RT. A total of 48 patients (88.9%) were available for evaluation. Complete local control was achieved in 21.7% (10 patients) for a median of 9 months (2.8–28.8); three had later local progression. Eight patients had regional or marginal recurrence. Six- and 12-month OS were 75.0% and 52.1%, respectively. Apart from mild diarrhea 1–3 months after SMART and general fatigue, there were no significant differences in toxicity and outcomes between post-pancreatectomy and inoperable groups.ConclusionSMART allows safe delivery of an ablative dose of radiotherapy, with minimal treatment-related toxicity, even in previously resected or irradiated patients. In this real-world cohort, local control with complete response was achieved by 20% of the patients. Further studies are needed to evaluate long-term outcome and late toxicity.
Case Report: Balancing immune responses – multiple sclerosis disease exacerbation under BRAF/MEK treatment for malignant melanoma
Authors: Pape Katrin , Protopapa Maria , Schraad Muriel , Steffen Falk , Zipp Frauke , Bittner Stefan 
Published: November 2023

BackgroundCombination treatment with BRAF/MEK inhibitors favorably impact progression-free survival in malignant melanoma. However, it may cause paradoxical activation of the MAPK/ERK pathway in immune cells without BRAF mutation, which may lead to over activation of the immune system, especially in patients with pre-existing autoimmune conditions. In this case report, treatment of malignant melanoma with BRAF/MEK inhibitors was associated with radiological disease exacerbation of pre-existing multiple sclerosis (MS).Case presentationA 47-year-old patient with pre-existing MS was diagnosed with malignant melanoma in June 2020. Anti-tumor treatment was initiated with a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. In February 2022, the patient presented at our neurological clinic after routine MRI revealed exacerbation of radiological MS disease activity with ten new and gadolinium-enhancing lesions, and concomitant high levels of neurofilament light chain (NfL) in serum, a marker for axonal damage. In-depth analysis of immune cells in both peripheral blood and cerebrospinal fluid was performed by multi-color flow cytometry. After treatment with the B cell-depleting antibody ocrelizumab, MS disease stability was obtained and anti-tumor medication could be continued.ConclusionsImmunomodulatory treatment in cancer patients is highly effective from an oncological point of view, but may be associated with autoimmune side effects. This is of special importance in patients with pre-existing autoimmune diseases, as reflected by our case of MS disease reactivation under treatment with BRAF/MEK inhibitors. In our case, sequential modulation of immune cell subsets by B cell depletion, associated with marked shifts in B and T cell subsets, allowed for stabilization of disease and continuation of anti-tumor treatment.
Tibetan mineral-herbal medicine Zuotai alleviates the depressive-like behaviors in chronic restraint-stressed mice while regulating stress hormone, inflammation and monoamine
Authors: Li Cen , Niu Cuiying , Bi Hongtao , Zhao Jing , Ivan Alvarez Jorge , Yuan Farong , Gai Xiangyun , Wei Lixin , Du Yuzhi , Qiao Yajun , Kebir Hania , Xiao Yuancan , Yang Hongxia 
Published: November 2023

Introduction:Zuotaiis an ancient mineral-herbal mixture containing β-HgS in Tibetan medicine. It is used to treat nervous system diseases, similar to Chinese medicine cinnabar and Indian Ayurveda medicineRasasindura. However, one of the key problems faced byZuotaiis that its indications are ambiguous. Our previous study found thatZuotaiexhibited the activity of ameliorating depressive-like behaviors in a chronic mild stress model. However, due to the inherent limitations of animal models in simulating human disease, clear results often require more than one model for confirmation.Methods:Therefore, another depression model, chronic restraint stressed (CRS) mice, was used to validate the antidepression effect ofZuotai. Prophylactic treatment was conducted for 21 consecutive days while mice were subjected to chronic restraint stress.Results:It was observed thatZuotaiand β-HgS alleviated anhedonia, behavioral despair, stereotype behavior, and reduced exploratory and spontaneous movement in CRS mice.Zuotaiand β-HgS also reversed the increases of stress hormone corticosterone (Cort) in serum and pro-inflammatory cytokines in serum and brain, and increased the serotonin in cortex in CRS mice, with positive dose-effect relationship. The number of Ki67-positive cells in the dentate gyrus and the level of brain-derived neurotrophic factor (BDNF) in the hippocampus were slightly elevated in CRS mice treated withZuotai; however, there was no statistically significant difference. AlthoughZuotaiincreased the total Hg concentration in main organs, the levels remained below those needed to result in observed adverse effect, at least for kidney and liver; andZuotaishowed no observed adverse effect on the brain histopathology, the cell proliferation in dentate gyrus, as well as the hippocampal and cortical organ coefficients.Conclusion:Zuotaiexhibited the alleviation of depressive-like behaviors in CRS mice, accompanying with ameliorating stress hormone, peripherical and cerebral inflammation, and monoamine neurotransmitter.
Population pharmacokinetics of everolimus in patients with seizures associated with focal cortical dysplasia
Authors: Park Jinha , Kim Se Hee , Hahn Jongsung , Kang Hoon-Chul , Lee Sang-Guk , Kim Heung Dong , Chang Min Jung 
Published: November 2023

Background: Everolimus is an inhibitor of mammalian target of rapamycin complex 1. As mutations in TSC1 and TSC2, which cause partial-onset seizures associated with TSC, were found in focal cortical dysplasia type Ⅱ (FCD Ⅱ) patients, a clinical trial has been performed to explore the efficacy and safety of everolimus in FCD patients. However, no dosage regimen was determined to treat FCD II. To recommend an optimal dose regimen for FCD patients, a population pharmacokinetic model of everolimus in FCD patients was developed.Methods: The data of everolimus were collected from September 2017 to May 2020 in a tertiary-level hospital in Korea. The model was developed using NONMEM® software version 7.4.1 (Icon Development Solutions, Ellicott City, MD, United States).Results: The population pharmacokinetics of everolimus was described as the one-compartment model with first-order absorption, with the effect of BSA on clearance. The final model was built as follows: TVCL = 12.5 + 9.71 × (BSA/1.5), TVV = 293, and TVKA = 0.585. As a result of simulation, a dose higher than 7 mg/m2 is needed in patients with BSA 0.5 m2, and a dose higher than 6 mg/m2 is needed in patients with BSA 0.7 m2. A dose of 4.5 mg/m2 is enough in the population with BSA higher than 1.5 m2 to meet the target trough range of 5–15 ng/mL.Conclusion: Based on the developed pharmacokinetics model, the optimal dose of everolimus in practice was recommended by considering the available strengths of Afinitor disperz®, 2 mg, 3 mg, and 5 mg.
An innovative tool to assess the functional resilience of a school system: learning from the COVID-19 pandemic
Authors: Kaim Arielle , Siman-Tov Maya , Adini Bruria , Lev-ari Shahar 
Published: November 2023

IntroductionPreparing the school system for a future crisis requires the ability to examine the effectiveness of schools’ functioning during distant learning and their level of preparedness for future crises. Functional resilience (FR) is defined as the ability to maintain vital operational continuity in the face of disturbance. The study objectives included to develop a FR index of schools and to evaluate and validate it.MethodsTo enable examination of the study objectives, the study design included tool development, followed by a validation process among 20 content experts. Concurrently, an eDelphi process for building an inclusive index, based on various components of resilience was conducted. The final study tool consists of four tailored questionnaires to examine perceptions of key stakeholders, i.e.- teachers, principals, parents, and highschool students regarding communication, psychosocial aspects, perceived stress, infrastructure, resources, pedagogic support, digital literacy, and perceived FR. Using an internet panel, the tool was disseminated cross-sectionally among the four groups of stakeholders.ResultsThe results showed high reliability of most of the scales developed. Furthermore, a high consensus level was reached on the relative importance of each component/ stakeholder to the schools FR. The findings further suggest that there were no significant differences in the composite FR score based on characteristics such as school type/ size/geographic location. However, the findings revealed interesting variations among stakeholders, with findings suggesting greater vulnerability among some.DiscussionTo increase resilience and preparedness for future adversities that school systems may face, it is recommended to periodically incorporate an assessment based on a structured tool.
Depression and perceived stress among perinatal women living with HIV in Nigeria
Authors: Akinsolu Folahanmi T. , Abodunrin Olunike R. , Lawale Abisola A. , Bankole Samuel A. , Adegbite Zaniab O. , Adewole Ifeoluwa E. , Olagunju Mobolaji T. , Ola Oluwabukola M. , Dabar Anita M. , Sanni-Adeniyi Rukayat A. , Gambari Aisha O. , Njuguna Diana Wangeshi , Salako Abideen O. , Ezechi Oliver C. 
Published: November 2023

BackgroundPregnancy and postpartum periods are crucial stages for women’s mental health, and women living with HIV are particularly susceptible to depression and psychological stress due to various factors. This study investigated the prevalence and associated factors of depression and perceived stress among women living with HIV during their perinatal period in Ibadan, Nigeria.MethodsA cross-sectional survey was conducted in three HIV treatment centers in Ibadan, Nigeria, among women living with HIV between the ages of 19 and 49 who were either pregnant or had given birth within the last 2 years. The study was conducted from September 2022 to December 2022. An interviewer-administered questionnaire was used to collect the data from the participants. Ethical approval and informed consent were obtained, and data were analyzed using the Statistical Package for Social Science version 26.ResultsThe study included 402 participants, of whom 69.0 and 78.0% reported symptoms of depression and perceived stress, respectively. However, 15.2% of the participants have comorbid depression and stress. Positive partner status was significantly associated with lower perceived depression, while gestational age between 29 and 40 weeks was significantly associated with lower perceived stress. The co-occurrence of depression and perceived stress was associated with partner status, income level, family support, gestational age, and years on antiretroviral therapy.ConclusionThe high prevalence of depression, perceived stress, and their co-occurrence among women living with HIV during the perinatal period call for incorporating mental health care into routine maternal healthcare for all women, particularly those living with HIV. This finding emphasizes the need for public health efforts to prioritize perinatal mental health and improve access to care and support for women and their partners.
Epidemiology and grade 2 disability of leprosy among migrant and resident patients in Guangdong: an unignorable continued transmission of leprosy
Authors: Chen Lei , Zheng Daocheng , Li Ming , Zeng Meiling , Yang Bin , Wang Xiaohua 
Published: November 2023

IntroductionLeprosy remains a major public health concern worldwide and one of the leading causes of disability. New cases of leprosy with grade 2 disability (G2D) often reflect delayed detection due to the limited capacity of the health system to recognize leprosy early. This study aimed to describe the epidemiology and G2D of leprosy among migrant and resident patients with leprosy in Guangdong province, China.MethodsData on newly diagnosed cases of leprosy were collected from the leprosy management information system in China. Descriptive statistical analysis was used to describe the status of G2D. Joinpoint regression model and logistic regression were performed to analyze the temporal trends and influencing factors for G2D.ResultsThe G2D rate among migrant, resident, and total patients with leprosy was 17.5%, 18.7%, and 18.4%, respectively. The total G2D rate increased significantly from 18.0% in 2001 to 25.7% in 2021 (average annual per cent change: 2.5%). Multivariate analysis revealed that factors that negatively influence G2D between migrant and resident patients included delayed discovery time (migrants: OR = 2.57; residents: OR = 4.99) and nerve damage when diagnosed (migrants: OR = 9.40; residents: OR = 21.28).DiscussionOur findings indicate that the targeted intervention measures implemented by our health system are urgently needed to improve the current situation, such as programs to promote early detection, strengthen awareness and skills of healthcare workers, and rehabilitation for disabled patients to improve their quality of life.
Prediction of progression from mild cognitive impairment to Alzheimer's disease with longitudinal and multimodal data
Authors: Ding Huitong , Wang Biqi , Hamel Alexander P. , Melkonyan Mark , Ang Ting F. A. , Au Rhoda , Lin Honghuang 
Published: November 2023

IntroductionAccurate prediction of the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) within a certain time frame is crucial for appropriate therapeutic interventions. However, it is challenging to capture the dynamic changes in cognitive and functional abilities over time, resulting in limited predictive performance. Our study aimed to investigate whether incorporating longitudinal multimodal data with advanced analytical methods could improve the capability to predict the risk of progressing to AD.MethodsThis study included participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a large-scale multi-center longitudinal study. Three data modalities, including demographic variables, neuropsychological tests, and neuroimaging measures were considered. A Long Short-Term Memory (LSTM) model using data collected at five-time points (baseline, 6, 12, 18, and 24-month) was developed to predict the risk of progression from MCI to AD within 2 years from the index exam (the exam at 24-month). In contrast, a random forest model was developed to predict the risk of progression just based on the data collected at the index exam.ResultsThe study included 347 participants with MCI at 24-month (age: mean 75, SD 7 years; 39.8% women) from ADNI, of whom 77 converted to AD over a 2-year follow-up period. The longitudinal LSTM model showed superior prediction performance of MCI-to-AD progression (AUC 0.93 ± 0.06) compared to the random forest model (AUC 0.90 ± 0.09). A similar pattern was also observed across different age groups.DiscussionOur study suggests that the incorporation of longitudinal data can provide better predictive performance for 2-year MCI-to-AD progression risk than relying solely on cross-sectional data. Therefore, repeated or multiple times routine health surveillance of MCI patients are essential in the early detection and intervention of AD.