bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy
Authors: Fabrizio Vanessa A. , Boelens Jaap Jan , Mauguen Audrey , Baggott Christina , Prabhu Snehit , Egeler Emily , Mavroukakis Sharon , Pacenta Holly , Phillips Christine L. , Rossoff Jenna , Stefanski Heather E. , Talano Julie-An , Moskop Amy , Margossian Steven P. , Verneris Michael R. , Myers Gary Douglas , Karras Nicole A. , Brown Patrick A. , Qayed Muna , Hermiston Michelle , Satwani Prakash , Krupski Christa , Keating Amy K. , Wilcox Rachel , Rabik Cara A. , Chinnabhandar Vasant , Kunicki Michael , Goksenin A. Yasemin , Mackall Crystal L. , Laetsch Theodore W. , Schultz Liora M. , Curran Kevin J.
Published: November 2021

Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range, <1 to 26), response rate of 86% (n = 131 of 152), 12-month OS of 75.1% (95% confidence interval [CI], 67.6% to 82.6%), and 12-month CIR of 36.4% (95% CI, 27.5% to 45.2%). Optimal fludarabine exposure was determined as AUC ≥13.8 mg × h/L. In multivariable analyses, patients with AUC <13.8 mg × h/L had a 2.5-fold higher CIR (hazard ratio [HR], 2.45; 95% CI, 1.34-4.48; P = .005) and twofold higher risk of relapse or loss of BCA (HR, 1.96; 95% CI, 1.19-3.23; P = .01) compared with those with optimal fludarabine exposure. High preinfusion disease burden was also associated with increased risk of relapse (HR, 2.66; 95% CI, 1.45-4.87; P = .001) and death (HR, 4.77; 95% CI, 2.10-10.9; P < .001). Personalized PK-directed dosing to achieve optimal fludarabine exposure should be tested in prospective trials and, based on this analysis, may reduce disease relapse after CAR T-cell therapy.
Effects of different exercise interventions on heart rate variability and cardiovascular health factors in older adults: a systematic review
Authors: Grässler Bernhard , Thielmann Beatrice , Böckelmann Irina , Hökelmann Anita
Published: November 2021

Background

Aging impairs physiological processes in the autonomic nervous, endocrine, and cardiovascular systems which are associated with increased risk of cardiovascular disease. Heart rate variability (HRV), the beat-to-beat variations of successive heartbeats, is an indicator of cardiac autonomic control and cardiovascular health. Physical activity has beneficial effects on cardiovascular health. However, no review has been conducted to summarize the effects of different exercise modalities on HRV in older adults. Therefore, the aim of this systematic review was to summarize the effects of endurance, resistance, coordinative, and multimodal exercise interventions on resting HRV and secondary health factors in healthy older adults aged 60 years in average and over.

Methods

Five databases (PubMed, Scopus, SPORTDiscus, Ovid, and Cochrane Library) were searched for eligible studies published between 2005 and September 8th, 2020. Two reviewers independently assessed the studies for potential inclusion. Outcome measures were changes in resting HRV indices, baroreflex sensitivity, blood pressure, body fat, body mass, body mass index, cardiac output, distance in the six-minute walking test, stroke volume, total peripheral resistance, and VO2 max or VO2 peak from pre to post intervention. The methodological quality of the final data set was assessed using two scales (TESTEX and STARDHRV). This review was registered in PROSPERO: CRD42020206606.

Results

The literature search retrieved 3991 articles, of which 13 were included in the review. Five studies used multimodal, three studies endurance, two studies resistance, two studies coordinative, and one study used an endurance and a resistance training intervention. The majority of the studies revealed significant positive effects on cardiac autonomic control, except for the resistance training interventions. All exercise modalities improved secondary health factors. The methodological quality assessment revealed a few criteria to improve the quality of and comparability between studies.

Conclusion

This systematic review revealed beneficial effects on cardiac autonomic control in healthy older adults through endurance, coordinative, and multimodal training but not through resistance training. Secondary health factors improved after all types of physical interventions. Future investigations should more thoroughly adhere to methodological standards of exercise interventions and ECG recording for the assessment of autonomic regulation.
Brain is modulated by neuronal plasticity during postnatal development
Authors: Kourosh-Arami Masoumeh , Hosseini Nasrin , Komaki Alireza
Published: November 2021

Neuroplasticity is referred to the ability of the nervous system to change its structure or functions as a result of former stimuli. It is a plausible mechanism underlying a dynamic brain through adaptation processes of neural structure and activity patterns. Nevertheless, it is still unclear how the plastic neural systems achieve and maintain their equilibrium. Additionally, the alterations of balanced brain dynamics under different plasticity rules have not been explored either. Therefore, the present article primarily aims to review recent research studies regarding homosynaptic and heterosynaptic neuroplasticity characterized by the manipulation of excitatory and inhibitory synaptic inputs. Moreover, it attempts to understand different mechanisms related to the main forms of synaptic plasticity at the excitatory and inhibitory synapses during the brain development processes. Hence, this study comprised surveying those articles published since 1988 and available through PubMed, Google Scholar and science direct databases on a keyword-based search paradigm. All in all, the study results presented extensive and corroborative pieces of evidence for the main types of plasticity, including the long-term potentiation (LTP) and long-term depression (LTD) of the excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs).
SCYN: single cell CNV profiling method using dynamic programming
Authors: Feng Xikang , Chen Lingxi , Qing Yuhao , Li Ruikang , Li Chaohui , Li Shuai Cheng
Published: November 2021

Background

Copy number variation is crucial in deciphering the mechanism and cure of complex disorders and cancers. The recent advancement of scDNA sequencing technology sheds light upon addressing intratumor heterogeneity, detecting rare subclones, and reconstructing tumor evolution lineages at single-cell resolution. Nevertheless, the current circular binary segmentation based approach proves to fail to efficiently and effectively identify copy number shifts on some exceptional trails.

Results

Here, we propose SCYN, a CNV segmentation method powered with dynamic programming. SCYN resolves the precise segmentation on in silico dataset. Then we verified SCYN manifested accurate copy number inferring on triple negative breast cancer scDNA data, with array comparative genomic hybridization results of purified bulk samples as ground truth validation. We tested SCYN on two datasets of the newly emerged 10x Genomics CNV solution. SCYN successfully recognizes gastric cancer cells from 1% and 10% spike-ins 10x datasets. Moreover, SCYN is about 150 times faster than state of the art tool when dealing with the datasets of approximately 2000 cells.

Conclusions

SCYN robustly and efficiently detects segmentations and infers copy number profiles on single cell DNA sequencing data. It serves to reveal the tumor intra-heterogeneity. The source code of SCYN can be accessed in https://github.com/xikanfeng2/SCYN.
Performance of rapid rk39 tests for the diagnosis of visceral leishmaniasis in Ethiopia: a systematic review and meta-analysis
Authors: Hagos Dawit Gebreegziabiher , Schallig Henk D. F. H. , Kiros Yazezew K. , Abdulkadir Mahmud , Wolday Dawit
Published: November 2021

Background

Visceral Leishmaniasis (VL) is a severely neglected disease affecting millions of people with high mortality if left untreated. In Ethiopia, the primary laboratory diagnosis of VL is by using an antigen from a 39-amino acid sequence repeat of a kinesin-related (rK39) of leishmania donovani complex (L. donovani), rapid diagnostic tests (RDT). Different rk39 RDT brands are available with very variable performance and studies from Ethiopia showed a very wide range of sensitivity and specificity. Therefore, a systematic review and meta-analysis were conducted to determine the pooled sensitivity and specificity of rk39 RDT in Ethiopia.

Method

PUBMED, EMBASE, and other sources were searched using predefined search terms to retrieve all relevant articles from 2007 to 2020. Heterogeneity was assessed by visually inspecting summary receiver operating curves (SROC), Spearman correlation coefficient (rs), Cochran Q test statistics, inconsistency square (I2) and subgroup analysis. The presence and statistical significance of publication bias were assessed by Egger's test at p < 0.05, and all the measurements showed the presence of considerable heterogeneity. Quality assessment of diagnostic accuracy studies (QUADAS-2) checklists was used to check the qualities of the study.

Results

A total of 664 articles were retrieved, and of this 12 articles were included in the meta-analysis. Overall pooled sensitivity and specificity of the rk39 RDT to diagnose VL in Ethiopia were 88.0% (95% CI 86.0% to 89.0%) and 84.0% (95% CI 82.0% to 86.0%), respectively. The sensitivity and specificity of the rk39 RDT commercial test kits were DiaMed: 86.9% (95% CI 84.3% to 89.1%) and 82.2% (95% CI 79.3% to 85.0%), and InBios: 80.0% (95% CI 77.0% to 82.8%) and 97.4% (95% CI 95.0% to 98.8%), respectively.

Conclusion

Referring to our result, rk39 RDT considered an essential rapid diagnostic test for VL diagnosis. Besides to the diagnostic accuracy, the features such as easy to perform, quick (10–20 min), cheap, equipment-free, electric and cold chain free, and result reproducibility, rk39 RDT is advisable to remains in practice as a diagnostic test at least in the remote VL endemic localities till a better test will come.
The “anti-vax” movement: a quantitative report on vaccine beliefs and knowledge across social media
Authors: Benoit Staci L , Mauldin Rachel F.
Published: November 2021

Background

Social media use has become a mainstay of communication and with that comes the exchange of factual and non-factual information. Social media has given many people the opportunity to speak their opinions without repercussions and create coalitionS of like-minded people. This also has led to the development of a community know as anti-vaxxers or vaccine deniers. This research explores the extent to which vaccine knowledge has reached on social media.

Methods

This cross sectional research explored the relationship between the spread of information regarding vaccines in relation to social media use. A sample of 2515 people over the age of 18 around the world completed the survey via a link distributed on Twitter, Facebook and Instagram. A series of questions on vaccine knowledge and beliefs were compounded to create an individual’s “knowledge score” and a “belief score”. Knowledge scores were ranked from low knowledge to high knowledge with increasing scores. Belief scores were ranked from belief in myths to disbelief in myths with higher scores. This score was then analysed, using a Welch test and post hoc testing when applicable, across demographics and questions relating to social media use.

Results

Significant relations were found in both the knowledge and belief categories, many of which were similar findings between the two. North Americans had significantly lower knowledge and belief scores compared to all other continents. While the majority of people primarily use Facebook, Twitter users were significantly more knowledgeable. It was also found that higher education was correlated with higher knowledge and belief scores.

Conclusions

Overall, these correlations are important in determining ways to intervene into the anti-vax movement through the use of social media. Cross demographics were not analysed in this study but could be in future studies. To better understand the social media exposures related to vaccine information a follow up structured interview research study would be beneficial. Note that due to the cross sectional nature of this study, causal relationships could not be made.
Public health implications of heavy metals in foods and drinking water in Ethiopia (2016 to 2020): systematic review
Authors: Mengistu Dechasa Adare
Published: November 2021

Background

Besides their benefits, heavy metals are toxic, persistent, and hazardous to human health, even at their lower concentrations. Consumption of unsafe concentrations of food contaminated with heavy metals may lead to the disruption of numerous biological and biochemical processes in the human body. In developing country including Ethiopia, where untreated or partially treated wastewater is used for agricultural purposes, the problems related to the consumption foods contaminated with heavy metals may poses highest risk to human health. Therefore, this review was aimed to determine the public health implications of heavy metals in foods and drinking water in Ethiopia.

Methods

The articles published from 2016 to 2020 were identified through systematic searches of electronic databases that include MEDLINE/PubMed, EMBASE, CINAH, Google Scholar, WHO, and FAO Libraries. The data was extracted using a predetermined data extraction form using Microsoft Excel, 2016. The methodological quality of the included studies was assessed using mixed methods appraisal tool (MMAT) version 2018 and Joanna Briggs Institute Critical Appraisal tools to determine the relevance of the studies. Finally, the results were evaluated based on the FAO/WHO guidelines for foods and drinking water.

Results

A total of 1019 articles published from 2016 to 2020 were searched from various electronic databases and by manual searching on Google. Following the initial screening, 317 articles were retrieved for evaluation and 49 articles were assessed for eligibility, of which 21 studies were included in the systematic review. The mean concentration of Cr, Cd, Pb, As, Hg, Zn, Cu, Ni, Co, Fe and Mn in fruits and vegetables ranged from 2.068–4.29, 0.86–1.37, 1.90–4.70, 1.01–3.56, 3.43–4.23, 19.18–98.15, 4.39–9.42, 1.037–5.27, 0.19–1.0, 199.5–370.4, 0.26–869 mg/kg, respectively. The mean concentration Cr, Cd, Pb, As, Zn, and Fe in meat and milk ranged from 1.032–2.72, 0.233–0.72, 1.32–3.15, 0.79–2.96, 78.37–467.7, and 505.61–3549.9 mg/kg, respectively. The mean concentration of Cr, Cd, Pb, Zn, and Cu in drinking water ranged 0.0089–0.054, 0.02–0.0237, 0.005–0.369, 0.625–2.137, and 0.176–1.176 ml/L, respectively. The mean concentration of Cr, Cd, Pb, Zn, Cu, Ni, Co, Fe, and Mn in other edible cereals ranged from 0.973–2.165, 0.424–0.55, 0.65–1.70, 70.51–81.58, 14.123–15.98, 1.89–13.8, 1.06–1.59, 67.866–110.3, and 13.686–15.4 mg/kg, respectively.

Conclusion

This systematic review identified heavy metals in foods and drinking water and determined their public health implications. The results of this finding imply that the majority of the studies reported high concentrations of toxic heavy metals in foods and drinking water that are hazardous to human health. Therefore, effective food safety and risk-based food quality assessment are essential to protect the public health.
Hounsfield unit value on CT as a predictor of cage subsidence following stand-alone oblique lumbar interbody fusion for the treatment of degenerative lumbar diseases
Authors: Zhou Jing , Yuan Chao , Liu Chao , Zhou Lei , Wang Jian
Published: November 2021

Background

To investigate the correlation between vertebral Hounsfield unit (HU) values and cage subsidence in patients treated with stand-alone (SA) OLIF.

Methods

A retrospective review of collected data was performed on 76 patients who underwent SA OLIF. We utilized the HU value for lumbar bone mineral density (BMD) obtained on preoperative CT. The vertebral HU values of patients with subsidence were compared to those without subsidence. The correlation between cage subsidence and clinical score was investigated.

Results

Sixteen patients (21.1%) had at least radiographic evidence of interbody cage subsidence. The average cage subsidence was 2.5 ± 1.3 mm (range 0.9-4.8 mm). There were no significant differences in sex, BMI, preoperative diagnoses, or fused level (p > 0.05); however, there were significant differences between the cage subsidence group and the nonsubsidence group in age, average of the lowest T-score, and average HU value, including for the L1 vertebrae, L1-L4 horizontal plane, and L1-L4 sagittal plane (p < 0.05). The average HU value of the L1-L4 horizontal plane showed a more predictable AUC of 0.909 (95% CI, 0.834–0.984; P < 0.001) compared with the average of the lowest T-score following an AUC of 0.791 (95% CI, 0.674–0.909; P < 0.001). Based on logistic regression analysis, the average HU value of the L1-L4 horizontal plane (OR, 0.912; 95% CI, 0.861–0.966; P = 0.002) was an independent factor influencing cage subsidence.

Conclusions

Patients with lower average HU values of the lumbar vertebrae are at a much higher risk of developing cage subsidence after SA OLIF. Measurement of preoperative HU values on preexisting CT scans could be rapid, simple and feasible.
Long-standing pubic-related groin pain in professional academy soccer players: a prospective cohort study on possible risk factors, rehabilitation and return to play
Authors: Eberbach Helge , Fürst-Meroth David , Kloos Ferdinand , Leible Magnus , Bohsung Valentin , Bode Lisa , Wenning Markus , Hagen Schmal , Bode Gerrit
Published: November 2021

Background

Despite being a common overuse entity in youth soccer, scientific data on risk factors, rehabilitation and return to play for long-standing pubic-related groin pain is still rare. The current prospective cohort study aims to evaluate potential risk-factors, propose a criteria-based conservative rehabilitation protocol and assess return-to-play outcomes among professional youth soccer players suffering from long-standing pubic-related groin pain.

Methods

Male soccer players with long-standing (> 6 weeks) pubic-related groin pain from a professional soccer club’s youth academy were analyzed for possible risk factors such as age, team (U12 - U23), younger/older age group within the team, position and preinjury Functional movement score. All injured players received a conservative, standardized, supervised, criteria-based, 6-level rehabilitation program. Outcome measures included time to return to play, recurrent groin pain in the follow-up period and clinical results at final follow-up two years after their return to play.

Results

A total of 14 out of 189 players developed long-standing pubic-related groin pain in the 2017/2018 season (incidence 7.4%). The average age of the players at the time of the injury was 16.1 ± 1.9 years. Risk factor analysis revealed a significant influence of the age group within the team (p = .007). Only players in the younger age group were affected by long-standing pubic-related groin pain, mainly in the first part of the season. Injured players successfully returned to play after an average period of 135.3 ± 83.9 days. Only one player experienced a recurrence of nonspecific symptoms (7.1%) within the follow-up period. The outcome at the 24-month follow-up was excellent for all 14 players.

Conclusions

Long-standing pubic-related groin pain is an overuse entity with a markedly high prevalence in youth soccer players, resulting in a relevant loss of time in training and match play. In particular, the youngest players in each team are at an elevated risk. Applying a criteria-based rehabilitation protocol resulted in an excellent return-to-play rate, with a very low probability of recurrence.

Trial registration

The trial was retrospectively registered under DRKS00016510 in the German Clinical Trials Register on 19.04.2021.
Screening for mild cognitive impairment in people with obesity: a systematic review
Authors: Karunathilaka Nimantha , Rathnayake Sarath
Published: November 2021

Objective

Recent evidence demonstrates that obesity is associated with developing cognitive impairment. However, evidence related to the assessment of mild cognitive impairment (MCI) in people with obesity is limited. Therefore, this systematic review aimed to examine evidence concerning the screening of MCI in people with obesity from the general population.

Method

We conducted a systematic search of CINHAL, EMBASE, MEDLINE, PsycINFO and PubMed electronic databases for observational studies to assess MCI in people with obesity from the general population. PRISMA guideline was followed. The articles published from January 2011 to July 2021 were included.

Results

Database search found 3104 sources. After the screening process, two articles from China and Egypt were included. The main age groups assessed were middle-aged adulthood and older adulthood. There were no studies undertaken in young adults or across the life span. Obesity was assessed by body mass index. MCI was assessed by cognitive screening tools; Mini-mental State Examination and Addenbrooke’s Cognitive Examination. The prevalence of MCI in people with obesity was 18.5 % and 42.9 % in Chinese and Egyptian studies, respectively. Only one study supported a positive association between MCI and obesity.

Conclusions

Limited studies were found on screening MCI in people with obesity in the general population. The available evidence was not adequate to explain the overall prevalence, possible associations, and the best tool for assessing MCI in people with obesity. Expanding screening studies for MCI in people with obesity in the general population is essential.
EOESGC: predicting miRNA-disease associations based on embedding of embedding and simplified graph convolutional network
Authors: Pang Shanchen , Zhuang Yu , Wang Xinzeng , Wang Fuyu , Qiao Sibo
Published: November 2021

Background

A large number of biological studies have shown that miRNAs are inextricably linked to many complex diseases. Studying the miRNA-disease associations could provide us a root cause understanding of the underlying pathogenesis in which promotes the progress of drug development. However, traditional biological experiments are very time-consuming and costly. Therefore, we come up with an efficient models to solve this challenge.

Results

In this work, we propose a deep learning model called EOESGC to predict potential miRNA-disease associations based on embedding of embedding and simplified convolutional network. Firstly, integrated disease similarity, integrated miRNA similarity, and miRNA-disease association network are used to construct a coupled heterogeneous graph, and the edges with low similarity are removed to simplify the graph structure and ensure the effectiveness of edges. Secondly, the Embedding of embedding model (EOE) is used to learn edge information in the coupled heterogeneous graph. The training rule of the model is that the associated nodes are close to each other and the unassociated nodes are far away from each other. Based on this rule, edge information learned is added into node embedding as supplementary information to enrich node information. Then, node embedding of EOE model training as a new feature of miRNA and disease, and information aggregation is performed by simplified graph convolution model, in which each level of convolution can aggregate multi-hop neighbor information. In this step, we only use the miRNA-disease association network to further simplify the graph structure, thus reducing the computational complexity. Finally, feature embeddings of both miRNA and disease are spliced into the MLP for prediction. On the EOESGC evaluation part, the AUC, AUPR, and F1-score of our model are 0.9658, 0.8543 and 0.8644 by 5-fold cross-validation respectively. Compared with the latest published models, our model shows better results. In addition, we predict the top 20 potential miRNAs for breast cancer and lung cancer, most of which are validated in the dbDEMC and HMDD3.2 databases.

Conclusion

The comprehensive experimental results show that EOESGC can effectively identify the potential miRNA-disease associations.
Cell type identification from single-cell transcriptomes in melanoma
Authors: Huo Qiuyan , Yin Yu , Liu Fangfang , Ma Yuying , Wang Liming , Qin Guimin
Published: November 2021

Background

Single-cell sequencing approaches allow gene expression to be measured at the single-cell level, providing opportunities and challenges to study the aetiology of complex diseases, including cancer.

Methods

Based on single-cell gene and lncRNA expression levels, we proposed a computational framework for cell type identification that fully considers cell dropout characteristics. First, we defined the dropout features of the cells and identified the dropout clusters. Second, we constructed a differential co-expression network and identified differential modules. Finally, we identified cell types based on the differential modules.

Results

The method was applied to single-cell melanoma data, and eight cell types were identified. Enrichment analysis of the candidate cell marker genes for the two key cell types showed that both key cell types were closely related to the physiological activities of the major histocompatibility complex (MHC); one key cell type was associated with mitosis-related activities, and the other with pathways related to ten diseases.

Conclusions

Through identification and analysis of key melanoma-related cell types, we explored the molecular mechanism of melanoma, providing insight into melanoma research. Moreover, the candidate cell markers for the two key cell types are potential therapeutic targets for melanoma.
Knockdown of circFOXO3 ameliorates cigarette smoke-induced lung injury in mice
Authors: Zhou Lei , Wu Bo , Yang Jun , Wang Bing , Pan Jing , Xu Donghui , Du Chunling
Published: November 2021

Background

Chronic obstructive pulmonary disease (COPD) remains a prevalent chronic airway inflammatory disease. Circular RNAs (circRNAs) are associated with inflammation regulation; therefore, we examined distinct effects of circRNA FOXO3 (circFOXO3) against pneumonic inflammatory processes in COPD.

Methods

We first quantified and localized circFOXO3 in mouse lung epithelial cell line MLE12 by quantitative reverse-transcription PCR and in situ hybridization. Next, circFOXO3 was suppressed by therapeutic administration of circFOXO3 knockdown lentivirus in mice exposed to air or cigarette smoke (CS) for 12 weeks, and several hallmarks of COPD were evaluated.

Results

We noticed that circFOXO3 is upregulated in CS-exposed lungs and cigarette smoke extract (CSE)-treated murine alveolar epithelial cells. Knockdown of circFOXO3 attenuated the release of CXCL1 and IL-6 as well as inflammatory processes in the lungs of CS-exposed mice. In addition, we identified miR-214-3p as a circFOXO3-targeted microRNA. MiR-214-3p overexpression exerted protective effects against pneumonic inflammation after CS exposure. Silencing of circFOXO3 downregulated IKK-β mRNA (miR-214-3p’s target), resulting in the dysfunction of the NF-κB signaling pathway and attenuation of CSE-induced inflammatory-cytokine expression.

Conclusions

Collectively, these findings reveal a crucial function of circFOXO3 in the pathological remodeling related to CS-induced inflammatory processes. Hence, circFOXO3 might be a good target for the treatment of inflammatory disorders similar to CS-induced lung inflammation.
Anticancer effects of mifepristone on human uveal melanoma cells
Authors: Alvarez Prisca Bustamante , Laskaris Alexander , Goyeneche Alicia A. , Chen Yunxi , Telleria Carlos M. , Burnier Julia V.
Published: November 2021

Background

Uveal melanoma (UM), the most prevalent intraocular tumor in adults, is a highly metastatic and drug resistant lesion. Recent studies have demonstrated cytotoxic and anti-metastatic effects of the antiprogestin and antiglucocorticoid mifepristone (MF) in vitro and in clinical trials involving meningioma, colon, breast, and ovarian cancers. Drug repurposing is a cost-effective approach to bring approved drugs with good safety profiles to the clinic. This current study assessed the cytotoxic effects of MF in human UM cell lines of different genetic backgrounds.

Methods

The effects of incremental concentrations of MF (0, 5, 10, 20, or 40 μM) on a panel of human UM primary (MEL270, 92.1, MP41, and MP46) and metastatic (OMM2.5) cells were evaluated. Cells were incubated with MF for up to 72 h before subsequent assays were conducted. Cellular functionality and viability were assessed by Cell Counting Kit-8, trypan blue exclusion assay, and quantitative label-free IncuCyte live-cell analysis. Cell death was analyzed by binding of Annexin V-FITC and/or PI, caspase-3/7 activity, and DNA fragmentation. Additionally, the release of cell-free DNA was assessed by droplet digital PCR, while the expression of progesterone and glucocorticoid receptors was determined by quantitative real-time reverse transcriptase PCR.

Results

MF treatment reduced cellular proliferation and viability of all UM cell lines studied in a concentration-dependent manner. A reduction in cell growth was observed at lower concentrations of MF, with evidence of cell death at higher concentrations. A significant increase in Annexin V-FITC and PI double positive cells, caspase-3/7 activity, DNA fragmentation, and cell-free DNA release suggests potent cytotoxicity of MF. None of the tested human UM cells expressed the classical progesterone receptor in the absence or presence of MF treatment, suggesting a mechanism independent of the modulation of the cognate nuclear progesterone receptor. In turn, all cells expressed non-classical progesterone receptors and the glucocorticoid receptor.

Conclusion

This study demonstrates that MF impedes the proliferation of UM cells in a concentration-dependent manner. We report that MF treatment at lower concentrations results in cell growth arrest, while increasing the concentration leads to lethality. MF, which has a good safety profile, could be a reliable adjuvant of a repurposing therapy against UM.
Analysis of the potential for a malaria vaccine to reduce gaps in malaria intervention coverage
Authors: Unwin H. Juliette T. , Mwandigha Lazaro , Winskill Peter , Ghani Azra C. , Hogan Alexandra B.
Published: November 2021

Background

The RTS,S/AS01 malaria vaccine is currently being evaluated in a cluster-randomized pilot implementation programme in three African countries. This study seeks to identify whether vaccination could reach additional children who are at risk from malaria but do not currently have access to, or use, core malaria interventions.

Methods

Using data from household surveys, the overlap between malaria intervention coverage and childhood vaccination (diphtheria-tetanus-pertussis dose 3, DTP3) uptake in 20 African countries with at least one first administrative level unit with Plasmodium falciparum parasite prevalence greater than 10% was calculated. Multilevel logistic regression was used to explore patterns of overlap by demographic and socioeconomic variables. The public health impact of delivering RTS,S/AS01 to those children who do not use an insecticide-treated net (ITN), but who received the DTP3 vaccine, was also estimated.

Results

Uptake of DTP3 was higher than malaria intervention coverage in most countries. Overall, 34% of children did not use ITNs and received DTP3, while 35% of children used ITNs and received DTP3, although this breakdown varied by country. It was estimated that there are 33 million children in these 20 countries who do not use an ITN. Of these, 23 million (70%) received the DTP3 vaccine. Vaccinating those 23 million children who receive DTP3 but do not use an ITN could avert up to an estimated 9.7 million (range 8.5–10.8 million) clinical malaria cases each year, assuming all children who receive DTP3 are administered all four RTS,S doses. An additional 10.8 million (9.5–12.0 million) cases could be averted by vaccinating those 24 million children who receive the DTP3 vaccine and use an ITN. Children who had access to or used an ITN were 9–13% more likely to reside in rural areas compared to those who had neither intervention regardless of vaccination status. Mothers’ education status was a strong predictor of intervention uptake and was positively associated with use of ITNs and vaccination uptake and negatively associated with having access to an ITN but not using it. Wealth was also a strong predictor of intervention coverage.

Conclusions

Childhood vaccination to prevent malaria has the potential to reduce inequity in access to existing malaria interventions and could substantially reduce the childhood malaria burden in sub-Saharan Africa, even in regions with lower existing DTP3 coverage.
Differential uptake of three clinically relevant allergens by human plasmacytoid dendritic cells
Authors: Zurmühl Noelle , Schmitt Anna , Formentini Ulrike , Weiss Johannes , Appel Heike , Debatin Klaus-Michael , Fabricius Dorit
Published: November 2021

Background

Human plasmacytoid dendritic cells (pDC) have a dual role as interferon-producing and antigen-presenting cells. Their relevance for allergic diseases is controversial. and the impact of pDC on allergic immune responses is poorly understood.

Methods

This in vitro study on human pDC isolated from peripheral blood was designed to compare side by side the uptake of three clinically relevant representative allergens: fluorochrome-labeled house dust mite Der p 1, Bee venom extract from Apis mellifera (Api) and the food allergen OVA analyzed flow cytometry and confocal microscopy.

Results

We found that the internalization and its regulation by TLR9 ligation was significantly different between allergens in terms of time course and strength of uptake. Api and OVA uptake in pDC of healthy subjects was faster and reached higher levels than Der p 1 uptake. CpG ODN 2006 suppressed OVA uptake and to a lesser extent Der p 1, while Api internalization was not affected. All allergens colocalized with LAMP1 and EEA1, with Api being internalized particularly fast and reaching highest intracellular levels in pDC. Of note, we could not determine any specific differences in antigen uptake in allergic compared with healthy subjects.

Conclusions

To our knowledge this is the first study that directly compares uptake regulation of clinically relevant inhalative, injective and food allergens in pDC. Our findings may help to explain differences in the onset and severity of allergic reactions as well as in the efficiency of AIT.
Quantitative assessment of AD markers using naked eyes: point-of-care testing with paper-based lateral flow immunoassay
Authors: Zhang Liding , Du Xuewei , Su Ying , Niu Shiqi , Li Yanqing , Liang Xiaohan , Luo Haiming
Published: November 2021

Aβ42is one of the most extensively studied blood and Cerebrospinal fluid (CSF) biomarkers for the diagnosis of symptomatic and prodromal Alzheimer’s disease (AD). Because of the heterogeneity and transient nature of Aβ42oligomers (Aβ42Os), the development of technologies for dynamically detecting changes in the blood or CSF levels of Aβ42monomers (Aβ42Ms) and Aβ42Os is essential for the accurate diagnosis of AD. The currently commonly used Aβ42ELISA test kits usually mis-detected the elevated Aβ42Os, leading to incomplete analysis and underestimation of soluble Aβ42, resulting in a comprised performance in AD diagnosis. Herein, we developed a dual-target lateral flow immunoassay (dLFI) using anti-Aβ42monoclonal antibodies 1F12 and 2C6 for the rapid and point-of-care detection of Aβ42Ms and Aβ42Os in blood samples within 30 min for AD diagnosis. By naked eye observation, the visual detection limit of Aβ42Ms or/and Aβ42Os in dLFI was 154 pg/mL. The test results for dLFI were similar to those observed in the enzyme-linked immunosorbent assay (ELISA). Therefore, this paper-based dLFI provides a practical and rapid method for the on-site detection of two biomarkers in blood or CSF samples without the need for additional expertise or equipment.

Graphical Abstract
Cardiovascular risk factors are associated with augmented thrombogenicity in healthy individuals: analysis using the Total Thrombus-formation Analysis System
Authors: Oda Yuu , Ito Takashi , Yamada Yoichiro , Koga Tadashi , Nagasato Tomoka , Ohnishi-Wada Tomoko , Hosokawa Kazuya , Fukase Hiroyuki , Hashiguchi Teruto , Maruyama Ikuro
Published: November 2021

Background

Rupture of an atherosclerotic plaque and subsequent exposure of the subendothelial prothrombotic matrix to blood cause arterial thrombosis. Circulating platelets play an indispensable role in the growth of arterial thrombi partially owing to their unique ability to adhere to the subendothelial matrix and to aggregate to each other under flow conditions. Recently, the Total Thrombus-formation Analysis System (T-TAS) was developed for ex vivo analysis of the thrombogenic potential of whole blood samples under flow conditions. Despite the potential clinical utility of the T-TAS in assessing the risk for thrombosis and bleeding, reference intervals for T-TAS analysis in healthy individuals have not been determined.

Methods

In total, 122 whole blood samples were collected from healthy volunteers ranging in age from 25 to 45 years. T-TAS analysis and hematological, physiological, and lifestyle assessments were conducted in these subjects. Whole blood samples anticoagulated with hirudin were perfused into a collagen-coated microchip (PL chip). The time to 10 kPa and the area under the flow pressure curve up to 10 min (AUC10) were analyzed as representative variables for thrombogenic potential. Reference intervals, which were defined as 2.5–97.5 percentiles, were determined. Additionally, univariate and multivariate analyses were performed to identify factors associated with the AUC10 in the T-TAS.

Results

The time to 10 kPa and the AUC10 widely varied, even in healthy volunteers. The reference intervals were 1.50–4.02 min and 223.4–456.8, respectively, at a shear rate of 1500 s− 1. Univariate and multivariate analyses showed that platelet counts were most significantly associated with the AUC10 of the T-TAS. The presence of one or more cardiovascular risk factors of a high body mass index, a high pulse pressure, high fasting serum glucose levels, high low-density lipoprotein-cholesterol levels, a history of smoking, and no habitual exercise, had the second largest effect on the AUC10 of the T-TAS.

Conclusions

Healthy volunteers who had any cardiovascular risk factors showed augmented thrombogenicity, even in artificial uniform capillaries, compared with those without any risk factors in the T-TAS.
Value of statistical life year in extreme poverty: a randomized experiment of measurement methods in rural Burkina Faso
Authors: Trautmann Stefan T. , Xu Yilong , König-Kersting Christian , Patenaude Bryan N. , Harling Guy , Sié Ali , Bärnighausen Till
Published: November 2021

Background

Value of a Statistical Life Year (VSLY) provides an important economic measure of an individual’s trade-off between health risks and other consumption, and is a widely used policy parameter. Measuring VSLY is complex though, especially in low-income and low-literacy communities.

Methods

Using a large randomized experiment (N = 3027), we study methodological aspects of stated-preference elicitation with payment cards (price lists) in an extreme poverty context. In a 2 × 2 design, we systematically vary whether buying or selling prices are measured, crossed with the range of the payment card.

Results

We find substantial effects of both the pricing method and the list range on elicited VSLY. Estimates of the gross domestic product per capita multiplier for VSLY range from 3.5 to 33.5 depending on the study design. Importantly, all estimates are economically and statistically significantly larger than the current World Health Organization threshold of 3.0 for cost-effectiveness analyses.

Conclusions

Our results inform design choice in VSLY measurements, and provide insight into the potential variability of these measurements and possibly robustness checks.
TRPV4-induced Müller cell gliosis and TNF-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2/STAT3/NF-κB pathway
Authors: Li Qian , Cheng Yun , Zhang Shenghai , Sun Xinghuai , Wu Jihong
Published: November 2021

Background

Glaucoma, the leading cause of irreversible blindness worldwide, is a type of retinal disease characterized by the selective death of retinal ganglion cells (RGCs). However, the pathogenesis of glaucoma has not been fully elucidated. Transient receptor potential vanilloid 4 (TRPV4) is a pressure-sensitive and calcium-permeable cation channel. TRPV4 is widely distributed in the retina and its sustained activation leads to RGC death; indicating that TRPV4 may be a possible target for glaucoma treatment. Here, we investigated the effects of TRPV4 on RGC apoptosis in a rat model of chronic ocular hypertension (COH), then examined the mechanism underlying these effects.

Methods

The COH model was established by injection of micro-magnetic beads into the anterior chamber of adult male rats. The expression levels of TRPV4, glial fibrillary acidic protein, and inflammatory factors were assessed by immunohistochemistry and immunoblotting. RGC apoptosis and visual dysfunction were evaluated by TUNEL assay and photopic negative response. Functional expression of TRPV4 was examined by electrophysiology and calcium imaging. Real-time polymerase chain reaction and immunoblotting were employed to investigate the molecular mechanism underlying the effects of TRPV4 on tumor necrosis factor-α (TNF-α) release.

Results

We found that TRPV4 played an essential role in glaucoma, such that high levels of TRPV4 expression were associated with elevated intraocular pressure. Furthermore, TRPV4 activation was involved in glaucoma-induced RGC apoptosis and RGC-related reductions in visual function. Mechanistic investigation demonstrated that TRPV4 activation led to enhanced Müller cell gliosis and TNF-α release via the JAK2/STAT3/NF-kB pathway, while TRPV4 inhibition could reverse these effects. Finally, TRPV4 activation could lead to elevated expression of TNF receptor 1 in RGCs, while inhibition of TNF-α could reduce TRPV4-mediated RGC apoptosis.

Conclusions

TRPV4 activation induces Müller cell gliosis and TNF-α elevation via the JAK2/STAT3/NF-κB pathway, which may exacerbate RGC apoptosis in glaucoma; these results suggest that TRPV4 can serve as a therapeutic target in glaucoma treatment.
Measuring the capacity to combat illicit tobacco trade in 160 countries
Authors: Ulep Valerie Gilbert , Lavares Monica Paula , Francisco Ariza
Published: November 2021

Background

Illicit trade of tobacco negatively affects countries’ tobacco control efforts. It leads to lower tobacco prices and makes tobacco products more accessible to vulnerable populations. In this study, we constructed an illicit tobacco trade index, which measures the structural and institutional capabilities of 160 countries in addressing illicit tobacco trade. We collected the most recent and best available data on general governance, tobacco control policies, and trade and customs practices.

Results

Singapore, New Zealand, Finland and Sweden lead countries with the most favorable illicit tobacco trade score. We observed a positive relationship between illicit tobacco trade scores and Gross National Income (GNI) per capita and a negative relationship with the share of illicit tobacco trade to total tobacco consumption.

Conclusions

The capability to combat illicit trade varies across countries. However, on average, low and middle-income countries (LMICs) are less capable of addressing illicit tobacco trade as suggested by the lower illicit tobacco trade index score. The lower index score in low and middle-income countries was mainly driven by low scores in tobacco control policies and trade and customs practices and conditions. Our study reinforces the importance for LMICs to adopt the WHO’s Protocol to Eliminate Illicit Tobacco Trade Products, particularly committing to treaty obligations and investing on track and trace system and other customs reforms.
The loneliness of the long-distance ethnobotanist: a constructive critique of methods used in an ethnoveterinary study in Mongolia
Authors: Seele Barbara C. , Dreyer Léanne , Esler Karen J. , Cunningham Anthony B.
Published: November 2021

Background

Fieldwork plays an important role in research projects across a variety of fields, especially in the multidisciplinary setting of natural and social science research. As is the nature of fieldwork, things do not always work out as planned, and yet this is not often written about. In response to the need for honest and transparent accounts of fieldwork, the purpose of this article is to review the methods used during fieldwork for the first author’s dissertation research on ethnoveterinary knowledge.

Methods

To critically review and reflect on the fieldwork methods used for an ethnoveterinary study in Mongolia, we compare the theory underpinning each method with the practical reality of implementing the method in the field. From this comparison, we draw out and discuss a number of key themes.

Results

Eighteen methods and approaches used for the research project are reviewed and compared. From this, we distil and further discuss the following five overarching themes: reflections on specific data collection methods (free listing, semi-structured interviews with interpreters, voucher specimen collection); assumptions around involving local people; power dynamics; gender relations; and researcher well-being.

Conclusion

By juxtaposing the theory and practical reality of the methods used, we highlight many potential fieldwork challenges and, within this context, offer general pointers, especially for novice female researchers doing fieldwork in foreign countries. A critical review of this type, where the experience and use of various methods, techniques, and approaches are openly shared and evaluated, is a contribution to selecting, adapting, and fine-tuning the methods best suited to a particular research context.