bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing Multiple Statistical Software for Multiple-Indicator, Multiple-Cause Modeling: An Application of Gender Disparity in Adult Cognitive Functioning Using MIDUS II Dataset
Authors: Chang Chi , Gardiner Joseph , Houang Richard T , Yu Yan-Liang
Published: September 2020

Background The Multiple-indicator, multiple-cause model (MIMIC) incorporates covariates of interest in the factor analysis using latent variable framework, of which classical structural equation model is a special case. The MIMIC model provides rigorous results and becomes broadly available in multiple statistical software. The current study introduces the MIMIC model and how it can be implemented using statistical software SAS CALIS procedure, R lavaan package, and Mplus version 8.0. Methods In this paper, we first discussed the formulation of the MIMIC model with regard to model specification and identification. We then demonstrated the empirical application of the MIMIC model with the Midlife in the United States II (MIDUS II) Study (N=4,109) using SAS CALIS procedure, R lavaan package and Mplus version 8.0 to examine gender disparities in cognitive functioning. The input, output, and diagram syntaxes of the three statistical software programs were also presented.Results In terms of data structure, all three statistical programs can be conducted using both raw data and empirical covariance matrix. SAS and R are comprehensive statistical analytic packages and encompass numerous data manipulation capacities. Mplus is designed primarily for latent variable modeling and has far more modeling flexibility compared to SAS and R, but limited in data manipulation. Differences in model results from the three statistical programs are trivial. Overall, the results show that while men show better performance in executive function than women, women demonstrate better episodic memory than men.Conclusions Our study demonstrates the utility of the MIMIC model in its empirical application, fitted with three popular statistical software packages. Results from our models align with empirical findings from previous research. We provide coding procedures and examples with detailed explanations in the hopes of providing a concise tutorial for researchers and methodologists interested in incorporating latent constructs with multiple indicators and multiple covariates in their research projects. Future researchers are encouraged to adopt this flexible and rigorous modeling approach.
Association between long-term exposure to air pollutants and cardiopulmonary mortality rates in South Korea
Authors: Hwang Jeongeun , Kwon Jinhee , Yi Hahn , Bae Hyun-Jin , Jang Miso , Kim Namkug
Published: September 2020

Background: The association between long-term exposure to air pollutants, including nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2), ozone (O3), and particulate matter 10 μm or less in diameter (PM10), and mortality by ischemic heart disease (IHD), cerebrovascular disease (CVD), pneumonia (PN), and chronic lower respiratory disease (CLRD) is unclear. We investigated whether living in an administrative district with heavy air pollution is associated with an increased risk of mortality by the diseases through an ecological study using South Korean administrative data over 19 years. Methods: A total of 249 Si-Gun-Gus, unit of administrative districts in South Korea were studied. In each district, the daily concentrations of CO, SO2, NO2, O3, and PM10 were averaged over 19 years (2001–2018). Age-adjusted mortality rates by IHD, CVD, PN and CLRD for each district were averaged for the same study period. Multivariate beta-regression analysis was performed to estimate the associations between air pollutant concentrations and mortality rates, after adjusting for confounding factors including altitude, population density, higher education rate, smoking rate, obesity rate, and gross regional domestic product per capita. Associations were also estimated for two subgrouping schema: Capital and non-Capital areas (77:172 districts) and urban and rural areas (168:81 districts). Results: For IHD, higher SO2 concentrations were significantly associated with a higher mortality rate, whereas other air pollutants had null associations. For CVD, SO2 and PM10 concentrations were significantly associated with a higher mortality rate. For PN, O3 concentrations had significant positive associations with a higher mortality rate, while SO2, NO2, and PM10 concentrations had significant negative associations. For CLRD, O3 concentrations were associated with an increased mortality rate, while CO, NO2, and PM10 concentrations had negative associations. In the subgroup analysis, positive associations between SO2 concentrations and IHD mortality were consistently observed in all subgroups, while other pollutant-disease pairs showed null, or mixed associations.Conclusion: Long-term exposure to high SO2 concentration was significantly and consistently associated with a high mortality rate nationwide and in Capital and non-Capital areas, and in urban and rural areas. Associations between other air pollutants and disease-related mortalities need to be investigated in further studies.
The origin and spread of CRF85_BC, driven by heterosexual transmission among older people in Sichuan, China
Authors: Su Ling , Feng Yi , Liang Shu , Zeng Yali , Li Yiping , Yang Hong , Li Ye , Wang Qiushi , Wei Dongbin , Yuan Dan , Lai Wenhong , Zhang Linglin
Published: September 2020

Background：CRF_BC recombinants, including CRF07_BC and CRF08_BC, were considered the predominant subtypes in China. Since the discovery of HIV-1 circulating recombinant form CRF 85_BC in Southwest China in 2016, this BC recombinant forms had been reported in different regions of China. However, the history and magnitude of CRF85_BC transmission were still to be investigated. Method: We conducted the most recent molecular epidemiology of HIV-1 among newly reported HIV-1 infected patients in Sichuan in 2019 by sequencing and phylogenetic analysis of 1291 pol sequences. Then, we used maximum likelihood approach and the Bayesian Markov chain Monte Carlo (MCMC) sampling of pol sequences to reconstruct the phylogeographic and demographic dynamics of the CRF85_BC.Results: HIV-1 CRF85_BC (68/1291, 5.27%) became the fourth most prevalent strain revealing a significant increase in local population. CRF85_BC were only found in heterosexually infected individuals and the majority of CRF85_BC (95.45%) were circulating among the people living with HIV aged 50 years and over (PLHIV50+), suggesting a unique prevalent pattern. The founder lineages of CRF85_BC were likely to have first emerged in Yunnan, a province of Southwest China bordering Sichuan, in the early 2000s. It then spread exponentially to various places (including Guangxi, Sichuan, et al) and became endemic around 2008.6 (2006.7-2010.2) in Sichuan. Conclusion: Taken together, our ﬁndings on HIV-1 subtype CRF85_BC infections provided new insights into the spread of this virus and extended the understanding of the HIV epidemic in China.
Measuring parent proxy-reported quality of life of 11 rare diseases in children in Zhejiang, China
Authors: Gao Qisheng , Wang Shanshan , Ren Jianping , Wen Xin
Published: September 2020

Background: It has become increasingly important to measure the health-related quality of life (HRQoL) of rare diseases in children and adolescents in recent decades. Much attention has been paid to investigate the HROoL of a specific rare disease by self-report in previous studies. This study aimed to evaluate and compare the HROoL of 11 rare diseases in Chinese children by parent proxy-report, to explore the factors associated with HROoL of patients, and to understand the problems of most concern. Methods: A total of 651 children aged from 2 to 18 were enrolled from the Children’s Hospital Affiliated Zhejiang University in 2018. Their parents completed the parent proxy-report version of the Pediatric Quality of Life InventoryTM 4.0 (PedsQLTM 4.0). Independent samples t-test, one-way ANOVA, or Kruskal-Wallis H test was used to compare HROoL scores between groups. Multilevel linear regression models with random intercept were applied to analyze the relationship between socioeconomic variables and both the total score and subdomain scores.Results: The total PedsQL scores of Patent ductus arteriosus(PDA), Infantile agranulocytosis, Autoimmune thrombocytopenia(ITP), Polysyndactyly, Hirschsprung disease, Cleft lip and palate, Tetralogy of fallot, Myasthenia gravis, Guillain-barre syndrome, Glycogen storage disease(GSD), and Langerhans cell histiocytosis children were 79.65±5.46, 95.88±3.48, 71.39±3.27, 91.77±6.35, 76.18±6.92, 96.33±4.22, 77.85±8.90, 95.99±3.31, 85.77±4.56, 82.97±4.13 and 77.6±5.15, respectively. Age was significantly associated with physical functioning, school functioning, and psychosocial health scores. The household registration place was significantly related to the total score. The most urgent desire of patients was to reduce the overall medical costs.Conclusions: This study showed that patients with Patent ductus arteriosus(PDA) had the lowest physical functioning score, while patients with Autoimmune thrombocytopenia(ITP) scored the lowest in the emotional functioning, social functioning, school functioning, psychosocial health, and total scores. Incentive policies should be further adopted to improve orphan drug availability and reduce the economic burden of rare diseases.
The effects of changes in distance to nearest health facility on under-5 mortality and health care utilization in rural Malawi, 1980-1998
Authors: Quattrochi John Paul , Hill Kenneth , Salomon Joshua A , Castro Marcia C
Published: September 2020

Background: Despite important progress, the burden of under-5 mortality remains unacceptably high, with an estimated 5.3 million deaths in 2018. Lack of access to health care is a major risk factor for under-5 mortality, and distance to health care facilities has been shown to be associated with less access to care in multiple contexts, but few such studies have used a counterfactual approach to produce causal estimates.Methods: We combined retrospective reports on 18,714 births between 1980 and 1998 from the 2000 Malawi Demographic and Health Survey with a 1998 health facility census that includes the date of construction for each facility, including 335 maternity or maternity/dispensary facilities built in rural areas between 1980 and 1998. We estimated associations between distance to nearest health facility and (i) under-5 mortality, using Cox proportional hazards models, and (ii) maternal health care utilization (antenatal visits prior to delivery, place of delivery, receiving skilled assistance during delivery, and receiving a check-up following delivery), using linear probability models. We also estimated the causal effect of reducing the distance to nearest facility on those outcomes, using a two-way fixed effects approach.Findings: We found that greater distance was associated with higher mortality (hazard ratio 1.007 for one additional kilometer [95%CI 1.001 to 1.014]) and lower health care utilization (for one additional kilometer: 1.2 percentage point (pp) increase in homebirth [95%CI 0.8 to 1.5]; 0.8pp decrease in at least three antenatal visits [95% CI -1.4 to -0.2]; 1.2pp decrease in skilled assistance during delivery [95%CI -1.6 to -0.8]). However, we found no effects of a decrease in distance to the nearest health facility on the hazard of death before age five years, nor on antenatal visits prior to delivery, place of delivery, or receiving skilled assistance during delivery. We also found that reductions in distance decrease the probability that a woman receives a check-up following delivery (2.4pp decrease for a one kilometer decrease [95%CI 0.004 to 0.044]).Conclusion: Reducing under-5 mortality and increasing utilization of care in rural Malawi and similar settings may require more than the construction of new health infrastructure. Importantly, the effects estimated here likely depend on the quality of health care, the availability of transportation, the demand for health services, and the underlying causes of mortality, among other factors.
Psychometric Properties of a New Self-Report Measure of Medical Student Stress using Classic and Modern Test Theory Approaches
Authors: Mosquera Matthew Joseph , Kaat Aaron , Ring Melinda , Agarwal Gaurava , Glickson Sydney , Victorson David
Published: September 2020

Background. Medical students face significant stressors related to the intense rigors of their training and education. Accurate measurement of their stress is important to quickly identify, characterize and ameliorate these challenges. Existing measures have limitations that modern measurement approaches, such as item response theory (IRT), are able to address. This study presents the calibration and validation of a new IRT-based measure called the Medical Student Stress Scale (MSSS). Methods. Following rigorous measurement development procedures described elsewhere, the authors created and tested a pool of 35 items with 348 1st – 4th year medical students along with demographic and external validity measures. Psychometric analysis included exploratory and confirmatory factor analyses, IRT modeling, and correlations with legacy measures. Results. Of the original 35 items, 22 were retained based on their ability to discriminate, provide meaningful information, and perform well against legacy measures. The MSSS differentiated stress scores between male and female students, as well as between year in school. Conclusion. Developed with input from medical students, the MSSS represents a student-centered measurement tool that provides precise, relevant information about stress and holds potential for screening and outcomes-related applications.
Metabolic and transcriptome responses of RNAi-mediated AMPKα knockdown in Tribolium castaneum
Authors: Jiang Heng , Zhang Nan , Ji Caihong , Meng Xiangkun , Qian Kun , Zheng Yang , Wang Jianjun
Published: September 2020

Background The AMP-activated protein kinase (AMPK) is an intracellular fuel sensor for lipid and glucose metabolism. In addition to the short-term regulation of metabolic enzymes by phosphorylation, AMPK may also exert long-term effects on the transcription of downstream genes through the regulation of transcription factors and coactivators. In this study, RNA interference (RNAi) was conducted to investigate the effects of knockdown of TcAMPKα on lipid and carbohydrate metabolism in the red flour beetle, Tribolium castaneum, and the transcriptome profiles of dsTcAMPKα-injected and dsEGFP-injected beetles under normal conditions were compared by RNA-sequencing.Results RNAi-mediated suppression of TcAMPKα increased whole-body triglyceride (TG) level and the ratio between glucose and trehalose, as was confirmed by in vivo treatment with the AMPK-activating compound, 5-Aminoimidazole-4-carboxamide1-β-D-ribofuranoside (AICAR). A total of 1184 differentially expressed genes (DEGs) were identified between dsTcAMPKα-injected and dsEGFP-injected beetles. These include genes involved in lipid and carbohydrate metabolism as well as insulin/insulin-like growth factor signaling (IIS). Real-time quantitative polymerase chain reaction analysis confirmed the differential expression of selected genes. Interestingly, metabolism-related transcription factors such as sterol regulatory element-binding protein 1 (SREBP1) and carbohydrate response element-binding protein (ChREBP) were also significantly upregulated in dsTcAMPKα-injected beetles. Conclusions AMPK plays a critical role in the regulation of beetle metabolism. The findings of DEGs involved in lipid and carbohydrate metabolism provide valuable insight into the role of AMPK signaling in the transcriptional regulation of insect metabolism.
Peptidome analysis of cerebrospinal fluid in neonates with hypoxic-ischemic brain damage
Authors: Hou Xuewen , Yuan Zijun , Wang Xuan , Cheng Rui , Zhou Xiaoguang , Qiu Jie
Published: September 2020

Hypoxic-ischemic brain injury (HIBD) causes neonatal death and serious neurological disability; however, there are currently no promising therapies for it excepting cooling. Therefore, in this study, we used peptidome analysis to identify differentially expressed peptides in cerebrospinal fluid (CSF) of neonates with HIBD or controls, which may give a foundation for finding new promising drugs of neonatal HIBD. CSF samples were collected from neonates with HIBD (n=4) or controls (n=4). ITRAQ LC-MS/MS was used to identify differentially expressed peptides between two groups. Effects of the peptide from heat shock protein 90-alpha (HSP90α/HSP90AA1) on cell viability and pyroptosis under oxygen and glucose deprivation (OGD) were analyzed using cell counting kit-8 (CCK-8) assay and Annexin V-fluorescein isothiocyanate (FITC) Assay. Expressions of NLRP3, NLRP1, ASC and Caspase-1 were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Compared with the control group, one peptide significantly up-regulated and thirty-four peptides significantly down-regulated in the CSF of neonates with HIBD. A fragment of HSP90α/HSP90AA1 is the 2671.5Da peptide (HSQFIGYPITLFVEKER), one of the down-regulated peptides in neonatal HIBD. This peptide, we named it HIBDAP, inhibited pyroptosis of PC12 cells under OGD by suppressing expressions of NLRP3, ASC and Caspase-1 except NLRP1. The results of our study identified the characterization and expression profiles of peptides in CSF of neonatal HIBD. Several meaningful peptides such as HIBDAP may play significant roles in neonatal HIBD and provide new therapeutic targets for neonatal HIBD.
Human CD133-positive hematopoietic progenitor cells enhance the malignancy of breast cancer cells
Authors: Zhang Zhe , Zheng Qing Lian , Liu Yong Hui , Sun Lian Qing , Han Ping Ping , Wang Rui , Zhao Jiao , Hu Shan , Zhao Xin Han
Published: September 2020

BackgroundHuman CD133+ hematopoietic progenitor cells (HPCs) are a specific subset of cells that can regulate tumor malignancy. However, the mechanism by which CD133+ HPCs affect the malignancy of human breast cancer has not been reported.MethodsCD133+ HPCs were isolated and purified from human umbilical cord blood (UCB) .We used in vitro culture of MCF-7 and MDA-MB-231 cell lines, and MCF-7 and MDA-MB-231 cells in nude mice to evaluate whether CD133+ HPCs affected the apoptosis, proliferation, invasion and epithelial mesenchymal transition EMT of breast cancer cells.ResultsCo-culture with CD133+ HPCs, but not UCB CD133- cells, promoted the proliferation of human breast cancer MCF-7 and MDA-MB-231 cells, accompanied by reducing in vitro spontaneous apoptosis. Co-administration of these two lines with CD133+ HPCs significantly enhanced the growth of implanted breast cancer in vivo . Furthermore, co-culture with CD133+ HPCs, enhanced the invasion of breast cancer cells, N-cadherin and Vimentin expression, but reduced E-cadherin expression in breast cancer cells.ConclusionsOur study demonstrated that CD133+ HPCs enhance the malignancy of breast cancer cells by attenuating spontaneous apoptosis and promoting the process of epithelial mesenchymal transition. These findings may provide new insights into the role of human CD133+ HPCs in breast cancer pathogenesis. Therefore, CD133+ HPCs may be a new therapeutic target for inhibiting the progression of breast cancer.
Drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon: a systematic review and meta-analysis protocol
Authors: Niba Peter Thelma Ngwa , Nji Akindeh M. , Evehe Marie-Solange , Ali Innocent M. , Netongo Palmer Masumbe , Ngwafor Randolph , Moyeh Marcel N. , Ngum Lesley Ngum , Ndum Oliva Ebie , Acho Fon Abongwa , Mbu'u Cyrille Mbanwi , Fosah Dorothy A. , Atogho-Tiedeu Barbara , Achonduh-Atijegbe Olivia , Dadjeu Rosine , Chedjou Jean Paul Kengne , Bigoga Jude D. , Moukoko Carole Else Eboumbou , Ajua Anthony , Achidi Eric , Tallah Esther , Leke Rose G. F. , Tourgordi Alexis , Ringwald Pascal , Alifrangis Michael , Mbacham Wilfred F.
Published: September 2020

Background: Cameroon remains a country faced with high malaria burden despite enormous efforts made in the control of the disease. The rapid development and dispersal of mutations associated with anti-malarial drug resistance influenced policy changes from the use of chloroquine, amodiaquine and sulphadoxine-pyrimethamine to the adoption of artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated falciparum malaria. Different studies have identified the frequency of key markers in Plasmodium falciparum associated with drug resistance without a clear picture on the localisation of potential hotspots that may drive the emergence of resistance to the currently used ACTs. This systematic review and meta-analysis aims to determine the prevalence and distribution of P. falciparum drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon from 1990 to present. Methods: The PRISMA, PRISMA-P and STREGA statements will be adopted in the quality assessments of studies to be included in this review. The electronic databases of Medline via Pubmed, EMBASE, Google Scholar and Science Direct will be searched by two independent researchers using different MeSH terms and Boolean operators (AND, OR). More so, unpublished data that will be sourced from academic libraries will also be extracted. Quantitative syntheses will be done using the “metaphor” and “meta” commands in the R statistical software package version 3.5.2. Heterogeneity will be assessed using the Cochrane Q and I2 statistics. The random effects model will be used as benchmark in the determination of heterogeneity between studies. Discussion: The primary outcome of this review is to identify and describe molecular markers conferring drug resistance in Plasmodium falciparum parasites that have been circulating for a period of over 30 years in Cameroon. This review will be able to pool data from previously published and unpublished studies on anti-malarial drug resistance gene mutations. This will provide evidence to support the continuous use of ACTs in the treatment of uncomplicated P. falciparum malaria. Moreover, it is also hoped that potential hotspots driving the emergence and spread of anti-malarial resistance markers will be identified. Systematic review registration: PROSPERO CRD42020162620
Outcomes of tissue reconstruction in distal lower leg fractures: a retrospective cohort study
Authors: Aydogan Emrah , Langer Stefan , Josten Christoph , Fakler Johannes Maria Karl , Henkelmann Ralf
Published: September 2020

Background: Open and closed fractures can be associated with posttraumatic or postoperative soft tissue defects caused by initial trauma, operative procedures, or infections. This study evaluated the postoperative outcomes in patients with open or closed lower leg fractures, related soft tissue defects, and subsequent flap coverage.Methods: We performed a retrospective single-center cohort study in a level 1 trauma center. We analyzed the patients treated from January 2012 through December 2017 and recorded demographics, treatment, and outcome data. The outcome data were measured via patient-reported Foot and Ankle Outcomes Scores (FAOS) and EQ-5D-5L scores.Results: We included 22 patients with complicated fractures (11 open and 11 closed) and subsequent soft tissue defects and flap coverages. The mean follow-up time was 41.2 months. Twenty-one patients developed infections, and necrosis at the site of surgery manifested in all closed fractures. Therefore, all patients needed soft tissue reconstructions. Preoperatively, 16 patients underwent arterial examinations via angiography and six underwent ultrasound examinations of the venous system. Ten patients had complications involving the flaps due to ischemia and consequent necrosis. The mean EQ-5D index was 0.62 ± 0.27, and EQ-5D VAS score was 57.7 ± 20.2. The mean FAOS was 60.7 ± 22.2; in particular, quality of life was 32.3 ± 28.8. The rate of returning to work in our patient group was 37.5% after one year.Conclusions: Distal tibial fractures often require revisions and soft tissue reconstruction. The evaluated patient population had poor outcomes in terms of function, quality of life, and return to work. Furthermore, patients suffering from flap ischemia have worse outcomes than those without flap ischemia.
A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status
Authors: Wang Changpeng , Zhang Siwei , Zou Yuefei , Ma Hongzhao , Jiang Donglang , Sheng Lei , Sang Shaoming , Jin Lirong , Guan Yihui , Gui Yuan , Xu Zhihong , Zhong Chunjiu
Published: September 2020

Background: Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff-Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods: A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of 18F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 minutes after injection as represented by the area under the curve (AUC) and blood thiamine levels were investigated. Results: The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61±0.53 in the liver within 1 minute, 18.67±7.04 in the kidney within half a minute. The SUV dropped to 0.72±0.05 and 0.77±0.35 after 60 minutes of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 minutes after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 minutes was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = - 0.985, p = 0.015).Conclusion: The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.
Uncertainty analysis of tumour absorbed dose calculations in Molecular Radiotherapy
Authors: Finocchiaro Domenico , Gear Jonathan I , Fioroni Federica , Flux Glenn D , Murray Iain , Castellani Gastone , Versari Annibale , Iori Mauro , Grassi Elisa
Published: September 2020

Background: Internal dosimetry evaluation consists of a multi-step process ranging from imaging acquisition to absorbed dose calculations. Assessment of uncertainty is complicated and, for that reason, it is commonly ignored in clinical routine. However, it is essential for adequate interpretation of the results. Recently, the EANM published a practical guidance on uncertainty analysis for molecular radiotherapy based on the application of the law of propagation of uncertainty. In this study, we investigated the overall uncertainty on a sample of patient following the EANM guidelines. The aim of this study was to provide an indication of the typical uncertainties that may be expected from performing dosimetry, to determine parameters that have the greatest effect on the accuracy of calculations and to consider the potential improvements that could be made if these effects were reduced.Results: Absorbed doses and the relative uncertainties were calculated for a sample of 49 patients and a total of 154 tumours. A wide range of relative absorbed dose uncertainty values was observed (14 - 102%). Uncertainties associated with each quantity along the absorbed dose calculation chain (i.e. Volume, Recovery Coefficient, Calibration Factor, Activity, Time-Activity Curve Fitting, Time-Integrated Activity and Absorbed Dose) were estimated. An equation was derived to describe relationship between the uncertainty in the absorbed dose and the volume. The largest source of error was the VOI delineation. By postulating different values of FWHM, the impact of the imaging system spatial resolution on the uncertainties was investigated.Discussion: To the best of our knowledge, this is the first analysis of uncertainty in molecular radiotherapy based on a cohort of clinical cases. Wide inter-lesion variability of absorbed dose uncertainty was observed. Hence, a proper assessment of the uncertainties associated with the calculations should be considered as a basic scientific standard. A model for a quick estimate of uncertainty without implementing the entire error propagation schema, which may be useful in clinical practice, was presented. Ameliorating spatial resolution may be in future the key factor for accurate absorbed dose assessment.
Protective CD8+ T-cell response against Hantaan virus infection induced by immunization with designed linear multi-epitope peptides in HLA-A2.1/Kb transgenic mice
Authors: Ma Ying , Tang Kang , Zhang Yusi , Zhang Chunmei , Cheng Linfeng , Zhang Fanglin , Zhuang Ran , Jin Boquan , Zhang Yun
Published: September 2020

Background: An effective vaccine that prevents disease caused by hantaviruses is a global public health priority, but up to now, no vaccine has been approved for worldwide use. Therefore, novel vaccines with high prophylaxis efficacy are urgently needed.Methods: Herein, we designed and synthesized Hantaan virus (HTNV) linear multi-epitope peptide consisting of HLA-A*02-restricted HTNV cytotoxic T cell (CTL) epitope and pan HLA-DR-binding epitope (PADRE), and evaluated the immunogenicity, as well as effectiveness, of multi-epitope peptides in HLA-A2.1/Kb transgenic mice with interferon (IFN)-γ enzyme-linked immunospot assay, cytotoxic mediator detection, proliferation assay and HTNV-challenge test.Results: The results showed that a much higher frequency of specific IFN-γ-secreting CTLs, high levels of granzyme B production, and a strong proliferation capacity of specific CTLs were observed in splenocytes of mice immunized with multi-epitope peptide than in those of a single CTL epitope. Moreover, pre-immunization of multi-epitope peptide could reduce the levels of HTNV RNA loads in the liver, spleen and kidneys of mice, indicating that specific CTL responses induced by multi-epitope peptide could reduce HTNV RNA loads in vivo.Conclusions: This study may provide an important foundation for the development of novel peptide vaccines for HTNV prophylaxis.
Genetic diversity and complexity of Plasmodium falciparum infections in the microenvironment among siblings of the same household in North-Central Nigeria
Authors: Oyedeji Segun Isaac , Bassi Peter Usman , Oyedeji Samuel Adeola , Ojurongbe Olusola , Awobode Henrietta Oluwatoyin
Published: September 2020

Background Plasmodium falciparum parasites are known to exhibit extensive genetic diversity in areas of high transmission intensity and infected individuals in such communities often harbour several complex mixtures of parasite clones with different genetic characteristics. However, in the micro-environment, the extent of genetic diversity of P. falciparum parasites remain largely unknown. In this study therefore, the complexity of P. falciparum infections in households was investigated among symptomatic siblings, living under the same roof in north-central Nigeria.Methods Children were enrolled into the study if they were at least two from a household and presented with symptoms of uncomplicated malaria. Clinical malaria was confirmed by light microscopy of Giemsa-stained thick and thin blood films. Genomic DNA was isolated from blood spots on filter paper. Molecular characterization of P. falciparum isolates was done by allele-specific nested PCR of the highly polymorphic merozoite surface protein-2 (msp-2) gene.Results Ninety-three children from 43 households were enrolled into this study. A total of 26 different msp-2 alleles were identified from 215 fragments (range: 180-480 bp). Majority of the isolates (65.6% (n=61)) were polyclonal infections consisting of 2-6 clones and were significantly more common with the FC27 allelic family (p = 0.036). The multiplicity of infection (MOI) per household ranged from 1.0 to 4.5 while the overall MOI in the study population was 2.31. The pattern of distribution of msp-2 allele types among the households fell into two categories: households where both msp-2 allele types (FC27 and 3D7) were present; households where only one msp-2 allele type (FC27 or 3D7) was present. Majority of the households (88.4% (n=38)), had both msp-2 allele types but they were disproportionately distributed among the children while in a few households (11.6% (n=5)), all the children were infected with only one type of msp-2 allele.Conclusion These findings showed that P. falciparum isolates exhibit remarkable degree of genetic diversity in the micro-environment and are composed mainly of multiclonal infections, which is an indication of a high ongoing parasite transmission. This suggests that the micro-environment is an important area of focus for malaria control interventions and for evaluating intervention programmes.
Full Snapshot Reconstruction in Hybrid Architecture Antenna Arrays
Authors: Trigka Maria , Mavrokefalidis Christos , Berberidis Kostas
Published: September 2020

In the context of this research work, we study the so-called problem of full snapshot reconstruction in hybrid antenna array structures that are utilized in mmWave communication systems. It enables the recovery of the snapshots that would have been obtained if a conventional (non-hybrid) Uniform Linear Antenna (ULA) array was employed. The problem is considered at the receiver side where the hybrid architecture exploits in a novel way the antenna elements of a uniform linear array. To this end, the recommended scheme is properly designed so as to be applicable to overlapping and non-overlapping architectures. Moreover, the full snapshot recoverability is addressed for two cases, namely, for time-varying and constant signal sources. Simulation results are also presented to illustrate the consistency between the theoretically predicted behaviors and the simulated results, and the performance of the proposed scheme in terms Angle-of-Arrival (AoA) estimation, when compared to the conventional MUSIC algorithm and a recently proposed hybrid version of MUSIC (H-MUSIC).
Plasma Lipid Levels and Risk of Primary Open Angle Glaucoma: A Genetic Study Using Mendelian Randomization
Authors: Xu Mengqiao , Li Shengguo , Zhu Jundong , Luo Dawei , Song Weitao , Zhou Minwen
Published: September 2020

Background: The causal effects of plasma lipid concentrations and the risk of primary open angle glaucoma (POAG) are still unclear. Thus, the purpose of this study was to identify, applying a two-sample Mendelian randomization (MR) analysis, whether plasma lipid concentrations are causally associated with the risk of POAG.Methods Two-sample MR analysis of data from a genome-wide association study (GWAS) was performed to investigate the causal role of plasma lipid levels and POAG. A total of 185 independent single-nucleotide polymorphisms (SNPs) associated with plasma lipid levels were selected as instrumental variables (IVs). The SNPs were obtained from a meta-analysis of GWAS based on 188,577 European-ancestry individuals for MR analyses. Association with POAG for the SNPs was obtained from a GWAS conducted among the United Kingdom (UK) Biobank study participants with a total of 463,010 European-ancestry individuals. Four MR methods (inverse variance weighted [IVW], weighted mode, weighted median, and MR-Egger regression) were applied to obtain the overall causal estimate for multiple, instrumental SNPs.Results Using the IVW analysis method, no evidence was found to support a causal association between plasma LDL-C level and POAG risk (β=-0.00026; 95% CI=-0.00062, 0.00011; P=0.165) with no significant heterogeneity among SNPs. The overall causal estimate between plasma LDL-C level and POAG was consistent using the other three MR methods. Using the four MR methods, no evidence of an association between plasma HDL-C (β=0.00023; 95% CI=-0.00015, 0.00061; P=0.238; IVW method) or TG levels (β=-0.00028; 95% CI=-0.00071, 0.00015; P=0.206; IVW method) and POAG risk was found. Sensitivity analyses did not reveal any sign of directional pleiotropy.Conclusions The present study did not find any evidence for a causal association between plasma lipid levels and POAG risk. Further research is needed to elucidate the potential biological mechanisms to provide a reasonable interpretation for these results.
Expression of in vivo biotinylated recombinant antigens SAG1 and SAG2A from Toxoplasma gondii for improved seroepidemiological bead-based multiplex assays
Authors: Klein Sandra , Stern Daniel , Seeber Frank
Published: September 2020

BACKGROUND

Few bead-based multiplex assays have been described that detect antibodies against the protozoan parasite Toxoplasma gondii in large-scale seroepidemiological surveys. Moreover, each multiplex assay has specific variations or limitations, such as the use of truncated or fusion proteins as antigens, potentially masking important epitopes. Consequently, such an assay must be developed by interested groups as none are commercially available.

RESULTS

We report the bacterial expression and use of N-terminal fusion-free, soluble, in vivo biotinylated recombinant surface antigens SAG1 and SAG2A for the detection of anti-T. gondii IgG antibodies. The expression system relies on three compatible plasmids. An expression construct produces a fusion of maltose-binding protein with SAG1 (or SAG2A), separated by a TEV protease cleavage site, followed by a peptide sequence recognized by E. coli biotin ligase BirA (AviTag), and a terminal six histidine tag for affinity purification. TEV protease and BirA are encoded on a second plasmid, and their expression leads to proteolytic cleavage of the fusion protein and a single biotinylated lysine within the AviTag by BirA. Correct folding of the parasite proteins is dependent on proper disulfide bonding, which is facilitated by a sulfhydryl oxidase and a protein disulfide isomerase, encoded on the third plasmid. The C-terminal biotinylation allowed the oriented, reproducible coupling of the purified surface antigens to magnetic Luminex beads, requiring only minute amounts of protein per determination. We showed that an N-terminal fusion partner such as maltose-binding protein negatively influenced antibody binding, confirming that access to SAG1’s N-terminal epitopes is important for antibody recognition. We validated our bead-based multiplex assay with human sera previously tested with commercial diagnostic assays and found concordance of 98-100% regarding both, sensitivity and specificity, even when only biotinylated SAG1 was used as antigen.

CONCLUSIONS

Our recombinant in vivo-biotinylated T. gondii antigens offer distinct advantages compared to previously described proteins used in multiplex serological assays for T. gondii . They offer a cheap, specific and sensitive alternative to either parasite lysates or eukaryotic-cell expressed SAG1/SAG2A for BBMA and other formats. Our strategy can also be used for other antigens where oriented immobilization is key for sensitive recognition by antibodies.
No Support that Early Selective Dorsal Rhizotomy Increase Frequency of Scoliosis and Spinal Pain – a longitudinal population-based register study from four to 25 years of age
Authors: Josenby Annika Lundkvist , Westbom Lena
Published: September 2020

Spasticity interfering with gross motor development in cerebral palsy (CP) can be reduced with selective dorsal rhizotomy (SDR). Although reported, it is unknown if SDR surgery causes later spine problems. Using CP-registry data from a geographically defined population, the objectives were to compare frequency and time to scoliosis, and spinal pain up to adult age after SDR-surgery or not in all with same medical history, functional abilities, CP-subtype and level of spasticity at four years of age. Variables associated with scoliosis at 20 years of age were explored.MethodIn the total population with CP spastic diplegia in Skåne and Blekinge, born 1990-2006, 149 individuals had moderate to severe spasticity and no medical contraindications against SDR at four years of age and were included; 36 had undergone SDR at a median age of 4.0 years (range 2.5 – 6.6 years), and 113 had not. Frequency of scoliosis and age when scoliosis was identified, and frequency of spinal pain at 10, 15, 20 and 25 years of age were analysed using Kaplan-Meier survival curves and Fisher’s exact test. Multivariable logistic regression was performed to identify variables to explain scoliosis at 20 years of age. Gross Motor Function Classification System (GMFCS) levels at four years of age were used for stratification.ResultFrequency of scoliosis did not significantly differ between groups having had early SDR surgery or not. In GMFCS IV, the SDR group had later onset and lower occurrence of scoliosis (p=0.004). Frequency of spinal pain did not differ between the groups (p- levels >0.28). GMFCS level was the background variable that in the logistic regression explained scoliosis at 20 years of age.ConclusionFrequency of back pain and scoliosis in adulthood after early SDR are mainly part of the natural development with age, and not a surgery complication.
Clinical characteristics, risk factors and outcomes of mixed Candida albicans/bacterial bloodstream infections
Authors: Zhong Li , Zhang Shufang , Tang Kankai , Zhou Feifei , Zheng Cheng , Zhang Kai , Cai Jiachang , Zhou Hongwei , Wang Yesong , Tian Baoping , Zhang Zhaocai , Cui Wei , Dong Zhaohui , Zhang Gensheng
Published: September 2020

Purpose: The purpose of this study was to explore the clinical features, risk factors, and outcomes of the mixed Candida albicans/bacterial bloodstream infections (mixed-CA/B-BSIs) compared with monomicrobial Candida albicans bloodstream infection (mono-CA-BSI) in adult patients in China.Methods: All adult hospitalized cases ofadults with Candida albicans bloodstream infection (CA-BSI) were recruited in thefor this retrospective observational study from January 1, 2013, to December 31, 2018.Results: Of the 117 patients with CA-BSI, 24 patients (20.5%) werehad mixed-CA/B-BSIs. The most common co-pathogenscopathogens were Coagulasecoagulase-negative Staphylococcus (CNS) (24.0%), followed by Klebsiella pneumoniae (20.0%) and Staphylococcus aureus (16.0%). In the multivariable analysis, a prior ICU stay>2days >2 days (adjusted odds ratio [OR], 7.808445; 95% confidence interval [CI], 1.264152-48.233132) was an independent risk factor offor mixed-CA/B-BSIs. In comparisonCompared with patients with mono-CA-BSI, patients with mixed-CA/B-BSIs developed withhad a prolonged length of mechanical ventilation [17.5 (4.5, 34.8) vs. 3.0 (0.0, 24.5), Pp=0.019],] and prolonged length of ICU stay [22.0 (14.3, 42.2) vs. 8.0 (0.0, 31.5), Pp=0.010], whereas the ]; however, mortality was not significantly different. Conclusions: AThere was a high rate of mixed-CA/B-BSIs iscases among CA-BSI cases, and Coagulase-negative Staphylococcus isCNS was the predominant co-existedcoexisting species. PriorA prior ICU stay >2 days iswas an independent risk factor for mixed -CA/B-BSIs. Although there iswas no difference in mortality, the outcomes of patients with mixed -CA/B-BSIs, including prolonged length of mechanical ventilation and prolonged length of ICU stay, were worse than those with mono-CA-BSI, which; this deserves further attention offrom clinicians.
Plasma radio–metabolite analysis of PET tracers for dynamic PET imaging: TLC and autoradiography
Authors: Li Fiona , Hicks Justin W , Yu Lihai , Desjardin Lise , Morrison Laura , Hadway Jennifer , Lee Ting-Yim
Published: September 2020

Background

In molecular imaging with dynamic PET, the binding and dissociation of a targeted tracer is characterized by kinetics modeling which requires the arterial concentration of the tracer to be measured accurately. Once in the body the radiolabeled parent tracer may be subjected to hydrolysis, demethylation/dealkylation and other biochemical processes, resulting in the production and accumulation of different metabolites in blood which can be labeled with the same PET radionuclide as the parent. Since these radio-metabolites cannot be distinguished by PET scanning from the parent tracer, their contribution to the arterial concentration curve has to be removed for the accurate estimation of kinetic parameters from kinetic analysis of dynamic PET. High performance liquid chromatography has been used to separate and measure radio-metabolites in blood plasma, however, the method is labor intensive and remains a challenge to implement for each individual patient. The purpose of this study is to develop an alternate technique based on thin layer chromatography (TLC) and a sensitive commercial autoradiography system (Beaver, Ai4R, Nantes, France) to measure radio-metabolites in blood plasma of two targeted tracers - [ 18 F]FAZA and [ 18 F]FEPPA , for imaging hypoxia and inflammation respectively.

Results

Radioactivity as low as 17Bq in 2µL of pig’s plasma can be detected on the TLC plate using autoradiography. Peaks corresponding to the parent tracer and radio-metabolites could be distinguished in the line profile through each sample (n=8) in the autoradiographic image. Significant inter-subject and intra-subject variability in radio-metabolites production could be observed with both tracers. For [ 18 F]FEPPA, 50% of plasma activity was from radio-metabolites as early as 5 min post injection while for [ 18 F]FAZA, significant metabolites did not appear until 50 min post. Simulation study investigating the effect of radio-metabolite in the estimation of kinetic parameters indicated that 32-400% parameter error can result without radio-metabolites correction.

Conclusion

TLC coupled with autoradiography is a good alternative to high performance liquid chromatography for radio-metabolite correction. The advantages of requiring only small blood samples (~ 100 μL) and of analyzing multiple samples simultaneously, make the method suitable for individual dynamic PET studies.