bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large-scale in vitro microdosimetry via live cell microscopy imaging: implications for radiosensitivity and RBE evaluations in alpha-emitter radiopharmaceutical therapy
Authors: Bastiaannet Remco , Liatsou Ioanna , F Hobbs Robert , Sgouros George 
Published: February 2023

Abstract
Background
Alpha-emitter radiopharmaceutical therapy (αRPT) has shown promising outcomes in metastatic disease. However, the short range of the alpha particles necessitates dosimetry on a near-cellular spatial scale. Current knowledge on cellular dosimetry is primarily based on in vitro experiments using cell monolayers. The goal of such experiments is to establish cell sensitivity to absorbed dose (AD). However, AD cannot be measured directly and needs to be modeled. Current models, often idealize cells as spheroids in a regular grid (geometric model), simplify binding kinetics and ignore the stochastic nature of radioactive decay. It is unclear what the impact of such simplifications is, but oversimplification results in inaccurate and non-generalizable results, which hampers the rigorous study of the underlying radiobiology.

Methods
We systematically mapped out 3D cell geometries, clustering behavior, agent binding, internalization, and subcellular trafficking kinetics for a large cohort of live cells under representative experimental conditions using confocal microscopy. This allowed for realistic Monte Carlo-based (micro)dosimetry. Experimentally established surviving fractions of the HER2 + breast cancer cell line treated with a 212Pb-labelled anti-HER2 conjugate or external beam radiotherapy, anchored a rigorous statistical approach to cell sensitivity and relative biological effectiveness (RBE) estimation. All outcomes were compared to a reference geometric model, which allowed us to determine which aspects are crucial model components for the proper study of the underlying radiobiology.

Results
In total, 567 cells were measured up to 26 h post-incubation. Realistic cell clustering had a large (2x), and cell geometry a small (16.4% difference) impact on AD, compared to the geometric model. Microdosimetry revealed that more than half of the cells do not receive any dose for most of the tested conditions, greatly impacting cell sensitivity estimates. Including these stochastic effects in the model, resulted in significantly more accurate predictions of surviving fraction and RBE (permutation test; p < .01).

Conclusions
This comprehensive integration of the biological and physical aspects resulted in a more accurate method of cell survival modelling in αRPT experiments. Specifically, including realistic stochastic radiation effects and cell clustering behavior is crucial to obtaining generalizable radiobiological parameters.
Human umbilical cord-derived mesenchymal stem cell transplantation supplemented with curcumin improves the outcomes of ischemic stroke via AKT/GSK-3β/β-TrCP/Nrf2 axis
Authors: Li Yuan , Huang Jialu , Wang Jie , Xia Simin , Ran Hong , Gao Lenyu , Feng Chengjian , Gui Li , Zhou Zhenhua , Yuan Jichao 
Published: February 2023

Abstract
Background
Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) engraftment is a promising therapy for acute ischemic stroke (AIS). However, the harsh ischemic microenvironment limits the therapeutic efficacy of hUC-MSC therapy. Curcumin is an anti-inflammatory agent that could improve inflammatory microenvironment. However, whether it enhances the neuroprotective efficacy of hUC-MSC transplantation is still unknown. In the present study, we investigated the therapeutic efficacy and the possible mechanism of combined curcumin and hUC-MSC treatment in AIS.

Methods
Middle cerebral artery occlusion (MCAO) mice and oxygen glucose deprivation (OGD) microglia were administrated hUC-MSCs with or without curcumin. Neurological deficits assessment, brain water content and TTC were used to assess the therapeutic effects of combined treatment. To elucidate the mechanism, MCAO mice and OGD microglia were treated with AKT inhibitor MK2206, GSK3β activator sodium nitroprusside (SNP), GSK3β inhibitor TDZD-8 and Nrf2 gene knockout were used. Immunofluorescence, flow cytometric analysis, WB and RT-PCR were used to evaluate the microglia polarization and the expression of typical oxidative mediators, inflammatory cytokines and the AKT/GSK-3β/β-TrCP/Nrf2 pathway protein.

Results
Compared with the solo hUC-MSC-grafted or curcumin groups, combined curcumin-hUC-MSC therapy significantly improved the functional performance outcomes, diminished the infarct volumes and the cerebral edema. The combined treatment promoted anti-inflammatory microglia polarization via Nrf2 pathway and decreased the expression of ROS, oxidative mediators and pro-inflammatory cytokines, while elevating the expression of the anti-inflammatory cytokines. Nrf2 knockout abolished the antioxidant stress and anti-inflammation effects mediated with combined treatment. Moreover, the combined treatment enhanced the phosphorylation of AKT and GSK3β, inhibited the β-TrCP nucleus translocation, accompanied with Nrf2 activation in the nucleus. AKT inhibitor MK2206 activated GSK3β and β-TrCP and suppressed Nrf2 phosphorylation in nucleus, whereas MK2206 with the GSK3β inhibitor TDZD-8 reversed these phenomena. Furthermore, combined treatment followed by GSK3β inhibition with TDZD-8 restricted β-TrCP nucleus accumulation, which facilitated Nrf2 expression.

Conclusions
We have demonstrated that combined curcumin-hUC-MSC therapy exerts anti-inflammation and antioxidant stress efficacy mediated by anti-inflammatory microglia polarization via AKT/GSK-3β/β-TrCP/Nrf2 axis and an improved neurological function after AIS.
The presence of human respiratory syncytial virus in the cerebrospinal fluid of a child with Anti-N-methyl-D-aspartate receptor encephalitis of unknown trigger
Authors: Yu Siyan , Hua Ying , Qian Jun , Sun Mingxia , Kang Yan-Jun 
Published: February 2023

Abstract
Background
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an important type of brain inflammation caused by autoantibody. As one of the primary agents responsible for respiratory tract infection, the human respiratory syncytial virus (hRSV) has also been reported to be capable of causing extrapulmonary diseases. Here, we first describe a case of anti-NMDAR encephalitis when hRSV was shown to be present in the cerebrospinal fluid.

Case presentation
The child was noted to have ataxia and positive anti-NMDA receptors in the cerebrospinal fluid, diagnosed as anti-NMDA receptor encephalitis in combination with cranial MRI images. After high-dose hormone pulse therapy and medication, the disease improved, and he was discharged. However, a relapse occurred almost a year later, and the cranial MRI imaging showed progressive cerebellar atrophy. An hRSV strain from group B was detected in his cerebrospinal fluid, and the whole genome sequence was recovered using transcriptome sequencing.

Conclusions
To our knowledge, this is the first report of hRSV being found in the cerebrospinal fluid of a patient with anti-NMDAR encephalitis. Even though more clinical records and experimental evidence are needed for validation, this work expands the types of diseases linked to hRSV and the likely cause of anti-NMDAR encephalitis.
Implementation costs of hospital-based computerised decision support systems: a systematic review
Authors: Donovan Thomasina , Abell Bridget , Fernando Manasha , McPhail Steven M. , Carter Hannah E. 
Published: February 2023

Abstract
Background
The importance of accurately costing implementation strategies is increasingly recognised within the field of implementation science. However, there is a lack of methodological guidance for costing implementation, particularly within digital health settings. This study reports on a systematic review of costing analyses conducted alongside implementation of hospital-based computerised decision support systems.

Methods
PubMed, Embase, Scopus and CINAHL databases were searched between January 2010 and August 2021. Two reviewers independently screened and selected original research studies that were conducted in a hospital setting, examined the implementation of a computerised decision support systems and reported implementation costs. The Expert Recommendations for Implementing Change Framework was used to identify and categorise implementation strategies into clusters. A previously published costing framework was applied to describe the methods used to measure and value implementation costs. The reporting quality of included studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards checklist.

Results
Titles and abstracts of 1836 articles were screened, with nine articles eligible for inclusion in the review. Implementation costs were most frequently reported under the ‘evaluative and iterative strategies’ cluster, followed by ‘provide interactive assistance’. Labour was the largest implementation-related cost in the included papers, irrespective of implementation strategy. Other reported costs included consumables, durable assets and physical space, which was mostly associated with stakeholder training. The methods used to cost implementation were often unclear. There was variation across studies in the overall quality of reporting.

Conclusions
A relatively small number of papers have described computerised decision support systems implementation costs, and the methods used to measure and value these costs were not well reported. Priorities for future research should include establishing consistent terminology and appropriate methods for estimating and reporting on implementation costs.

Trial registration
The review protocol is registered with PROSPERO (ID: CRD42021272948).
Strategic discussion on funding and access to therapies targeting rare diseases in Spain: an expert consensus paper
Authors: Zozaya N. , Villaseca J. , Abdalla F. , Ancochea A. , Málaga I. , Trapero-Bertran M. , Martín-Sobrino N. , Delgado O. , Ferré P. , Hidalgo-Vega A. 
Published: February 2023

Abstract
Background
In recent years, significant advances have been made in the field of rare diseases (RDs). However, there is a large number of RDs without specific treatment and half of these treatments have public funding in Spain. The aim of the FINEERR project was to carry out a multidisciplinary strategic discussion on the challenge of funding and access to RD-targeted drugs in Spain, in order to agree on specific proposals for medium-term improvement and hence support decision-making in the Spanish National Healthcare System (SNHS).

Results
The FINEERR Project was organized around a CORE Advisory Committee, which provided an overview, agreed on the design and scope of the project, and selected the members within each of four working groups (WG). Overall, 40 experts discussed and reached a consensus on different relevant aspects, such as conditioning factors for initial funding and access, evaluation and access to RD-targeted therapies, funding of these therapies, and implementation of a new funding and access model. From these meetings, 50 proposals were defined and classified by their level of relevance according to the experts. A descriptive analysis of responses was performed for each proposal. Thereafter, experts completed another questionnaire where they ranked the 25 most relevant proposals according to their level of feasibility of being implemented in the SNHS. The most relevant and feasible proposals were to improve: process of referral of patients with RDs, control over monitoring mechanisms, and communication between healthcare professionals and patients.

Conclusions
The FINEERR project may provide a starting point for stakeholders involved in the process of funding and access to RD-targeted therapies in Spain to provide the necessary resources and implement measures to improve both the quality of life and life expectancy of patients with RDs.
Systems metabolic engineering of Escherichia coli for hyper-production of 5‑aminolevulinic acid
Authors: Pu Wei , Chen Jiuzhou , Zhou Yingyu , Qiu Huamin , Shi Tuo , Zhou Wenjuan , Guo Xuan , Cai Ningyun , Tan Zijian , Liu Jiao , Feng Jinhui , Wang Yu , Zheng Ping , Sun Jibin 
Published: February 2023

Abstract
Background
5-Aminolevulinic acid (5-ALA) is a promising biostimulant, feed nutrient, and photodynamic drug with wide applications in modern agriculture and therapy. Although microbial production of 5-ALA has been improved realized by using metabolic engineering strategies during the past few years, there is still a gap between the present production level and the requirement of industrialization.

Results
In this study, pathway, protein, and cellular engineering strategies were systematically employed to construct an industrially competitive 5-ALA producing Escherichia coli. Pathways involved in precursor supply and product degradation were regulated by gene overexpression and synthetic sRNA-based repression to channel metabolic flux to 5-ALA biosynthesis. 5-ALA synthase was rationally engineered to release the inhibition of heme and improve the catalytic activity. 5-ALA transport and antioxidant defense systems were targeted to enhance cellular tolerance to intra- and extra-cellular 5-ALA. The final engineered strain produced 30.7 g/L of 5-ALA in bioreactors with a productivity of 1.02 g/L/h and a yield of 0.532 mol/mol glucose, represent a new record of 5-ALA bioproduction.

Conclusions
An industrially competitive 5-ALA producing E. coli strain was constructed with the metabolic engineering strategies at multiple layers (protein, pathway, and cellular engineering), and the strategies here can be useful for developing industrial-strength strains for biomanufacturing.
Worldwide host associations of the tick genus Ixodes suggest relationships based on environmental sharing rather than on co-phylogenetic events
Authors: Estrada-Peña Agustín , Guglielmone Alberto A. , Nava Santiago 
Published: February 2023

AbstractBackgroundThis study aims to capture how ticks of the genusIxodesgained their hosts using network constructs. We propose two alternative hypotheses, namely, an ecological background (ticks and hosts sharing environmentally available conditions) and a phylogenetic one, in which both partners co-evolved, adapting to existing environmental conditions after the association took place.MethodsWe used network constructs linking all the known pairs of associations between each species and stage of ticks with families and orders of hosts. Faith’s phylogenetic diversity was used to evaluate the phylogenetic distance of the hosts of each species and changes occurring in the ontogenetic switch between consecutive stages of each species (or the extent of the changes in phylogenetic diversity of hosts for consecutive stages of the same species).ResultsWe report highly clustered associations amongIxodesticks and hosts, supporting the influence of the ecological adaptation and coexistence, demonstrating a lack of strict tick-host coevolution in most cases, except for a few species. Keystone hosts do not exist in the relationships betweenIxodesand vertebrates because of the high redundancy of the networks, further supporting an ecological relationship between both types of partners. The ontogenetic switch of hosts is high for species with enough data, which is another potential clue supporting the ecological hypothesis. Other results suggest that the networks displaying tick-host associations are different according to the biogeographical realms. Data for the Afrotropical region reveal a lack of extensive surveys, while results for the Australasian region are suggestive of a mass extinction of vertebrates. The Palearctic network is well developed, with many links demonstrating a highly modular set of relationships.ConclusionsWith the obvious exceptions ofIxodesspecies restricted to one or a few hosts, the results point to an ecological adaptation. Even results on species linked to groups of ticks (such asIxodes uriaeand the pelagic birds or the bat-tick species) are suggestive of a previous action of environmental forces.Graphical Abstract
Level of 25-hydroxyvitamin D and vitamin D receptor in diabetic foot ulcer and factor associated with diabetic foot ulcers
Authors: Tang Ying , Huang Yixuan , Luo Li , Xu Murong , Deng Datong , Fang Zhaohui , Zhao Xiaotong , Chen Mingwei 
Published: February 2023

Abstract
Background
At present, there is no clinical study to elucidate the correlation between vitamin D deficiency and the incidence of diabetic foot osteomyelitis (DFO).This study aims to clarify levels of 25-hydroxyvitamin D [25(OH)VD] in peripheral blood and vitamin D receptor (VDR) expression in wound margin tissues (T-VDR) of patients with type 2 diabetes mellitus (T2DM) with diabetic foot ulcer (DFU) and DFO, and to determine its correlation with treatment outcomes of DFU and DFO, and and its value as a potential biomarker for the diagnosis of DFU and DFO.

Methods
156 T2DM patients with DFU (DFU group), 100 T2DM patients without DFU (T2DM group), and 100 healthy controls (NC group). The DFU group patients were subdivided into DFO (n = 80) and NDFO groups (n = 76). The level of serum 25(OH)VD was measured via chemiluminescence immunoassay, and T-VDR expression level was determined by quantitative real-time PCR.

Results
The levels of serum 25(OH)VD in the DFU group were significantly lower than the T2DM group [(10.3 (5.8, 18.7) vs 15.7 (8.6, 24.6) ng/mL, P = 0.002)]. Similarly, the levels of serum 25(OH)VD and T-VDR expression in the DFO group were statistically lower than the NDFO group [9.2 (5.2, 20.5) vs 12.8 (6.9, 22.1) ng/mL, P = 0.006)], [1.96 (0.61, 3.97) vs 3.11 (1.36, 5.11), P = 0.004)], respectively. Furthermore, the levels of serum 25(OH)VD and T-VDR expression in DFU patients were positively correlated with the ulcer healing rate of foot ulcer after 8 weeks of treatment ( P = 0.031, P = 0.016, respectively). Multivariate logistic regression analysis showed that low level of serum 25(OH)VD was an independent risk factor for DFU and DFO (ORDFU = 2.42, ORDFO = 3.05, P = 0.008, 0.001, respectively), and decreased T-VDR expression level was an independent risk factor for DFO (OR = 2.83, P = 0.004). Meanwhile, the ROC curve analysis indicated that the AUC of serum 25(OH)VD level for the diagnosis of DFU and DFO was 0.821 (95% CI, 0.754–0.886, P < 0.001) and 0.786 (95%CI, 0.643–0.867, P < 0.001), respectively. When establishing a diagnosis of DFO, the AUC of T-VDR expression level was 0.703 (95%CI: 0.618–0.853, P < 0.001).

Conclusions
The levels of serum 25(OH)VD and T-VDR expression in DFU and DFO decreased. Serum 25(OH)VD and T-VDR are potentially valuable biomarkers for diagnosis and prognosis of DFU and DFO.
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Conjoined nerve root in a patient with lumbar disc herniation accompanied by a lumbosacral spine anomaly: a case report
Authors: Kuroki Hiroshi , Nagai Takuya 
Published: February 2023

Abstract
Background
A nerve root anomaly, typified by a conjoined nerve root, is a rare finding. Conjoined nerve root anomalies are easily missed even in preoperative advanced imaging modalities, which can be potentially troublesome during and after surgery. In this report, we present a case of conjoined right L5–S1 nerve root in a patient with lumbar disc herniation, accompanied by spina bifida occulta, which was undiagnosed on preoperative imaging studies.

Case report
A 55-year-old Asian (Japanese) woman presented with low back pain and right leg radiating pain due to lumbar disc herniation at the right L5/S1. Physical examination revealed a positive Lasègue sign and the range of the straight leg raising test was 20° on the right side. The right patellar tendon reflex was normal; however, the right ankle jerk reflex disappeared. Although no obvious hypoesthesia was noted, mild muscle weakness (4/5) was observed in the right leg on the manual muscle test. We planned the lumbar discectomy under a microscope. During surgery, the conjoined right L5–S1 nerve root, which was compressed by herniated nucleus pulposus, was encountered. Although it was very thick and less mobile, some pieces of herniated nucleus pulposus could be removed piece by piece from the axillary part. After sequential decompressive procedures, the tightness of the conjoined right L5–S1 nerve root decreased but its mobility did not improve much. The laterality of the thickness and exit angle of the conjoined right L5–S1 nerve root was retrospectively confirmed on T2 coronal magnetic resonance images and magnetic resonance neurography. Postoperatively, right leg pain was immediately alleviated and complete improvement of muscle weakness was achieved 1 week later (5/5).

Conclusions
Magnetic resonance neurography is extremely useful for the accurate diagnosis of anomalous nerve roots because of clear visualization of the neural tissue. Discectomy under a microscope, which enables magnified three-dimensional observation of the surgical field, must provide a valid and safe procedure to achieve not only secure resection of herniated discs but also adequate exposure of anomalous nerve roots.
Is cyberbullying perpetration associated with anxiety, depression and suicidal ideation among lebanese adolescents? Results from a cross-sectional study
Authors: Bitar Zeinab , Elias Marie-Belle , Malaeb Diana , Hallit Souheil , Obeid Sahar 
Published: February 2023

Abstract
Background
As cyberbullying is a new area of investigation, results worldwide point to the prevalence of cyberbullying perpetration. This study aimed to assess the association between cyberbullying perpetration, anxiety, depression and suicidal ideation among Lebanese adolescents.

Methods
This cross-sectional study was conducted between May and June 2021 and included a sample of adolescents aged between 13 and 16 years old, recruited from private schools chosen in a convenient way from all Lebanese districts. A total of 520 students accepted to participate in our study. To collect data, a questionnaire was shared by google form including: Cyber Bully/Cyber victim questionnaire; Lebanese Anxiety Scale; and Patient Health Questionnaire for Adolescents.

Results
The results of the linear regressions, taking anxiety and depression as dependent variables, showed that female gender, having kind of hard and very/extremely hard influence of problems on daily work, sexual cyberbullying in cyberspace, embarrassing and inserting malicious content in cyberspace and older age were significantly associated with more anxiety and depression. Having kind of hard influence of problems on daily work compared to not at all, higher anxiety, higher depression and higher household crowding index (lower socioeconomic status) were significantly associated with higher odds of having suicidal ideation in the last month.

Conclusion
Cyberbullying perpetration and its associated factors reported in this study are significant enough to call for early detection and prevention strategies for Lebanese adolescents. At the school level, effective programs implemented in the school years are needed, aiming to develop social/emotional control, and conflict resolution skills as they might decrease engagement in cyberbullying perpetration among adolescents. Preventive interventions are needed to reduce the engagement of Lebanese adolescents in cyberbullying perpetration.