bluuebunny/crossref_metadata_2025 huggingface dataset:
Education and income-based inequality in tooth loss among Brazilian adults: does the place you live make a difference?
Authors: Ferreira Raquel Conceição , Senna Maria Inês Barreiros , Rodrigues Lorrany Gabriela , Campos Fernanda Lamounier , Martins Andrea Eleuterio Barros Lima , Kawachi Ichiro
Published: September 2020

Background

Socioeconomic inequalities in tooth loss might be minimized or potentialized by the characteristics of the context where people live. We examined whether there is contextual variation in socioeconomic inequalities in tooth loss across Brazilian municipalities.

Methods

Data from the 2010 National Oral Health Survey of 9633 adults living in 157 Brazilian municipalities were used. The individual socioeconomic indicators were education and household income. At the municipal level, we used the Municipal Human Development Index (HDI) as our contextual indicator of socioeconomic status (low:< 0.699 versus high: > 0.70). The Relative (RII) and Slope (SII) Indexes of Inequality, Relative (RCI), and Absolute (ACI) Concentration Indexes were calculated to compare the magnitude of education and income-based inequalities among municipalities with low versus high HDI. Multilevel Poisson regression models with random intercepts and slopes were developed.

Results

At the individual level, adults with lower education & income reported more tooth loss. The mean number of missing teeth was 9.52 (95% CI: 7.93–11.13) and 6.95 (95% CI: 6.43–7.49) in municipalities with low and high HDI, respectively. Municipalities with high HDI showed higher relative and absolute education-based inequality. For income-based inequalities, higher SII and RCI was observed in municipalities with lower HDI. A significant cross-level interaction indicated that high-education adults reported fewer missing teeth when they lived in municipalities with high HDI compared to adults with the same education level living in low HDI municipalities. For individuals with the lowest education level, there was no difference in the number of teeth between those from municipalities with high and low HDI.

Conclusions

There was a social gradient in tooth loss by education and income. Living in disadvantaged municipalities cannot overcome the risk associated with low schooling. The protective effect of higher education can be reduced when people live in disadvantaged areas.
Envisioning the future of clinical analytics: a modified Delphi process in New South Wales, Australia
Authors: Sutherland Kim , Yeung Wilson , Mak Yoke , Levesque Jean-Frederic ,   the NSW Health Clinical Analytics Working Group
Published: September 2020

Background

Clinical analytics is a rapidly developing area of informatics and knowledge mobilisation which has huge potential to improve healthcare in the future. It is widely acknowledged to be a powerful mediator of clinical decision making, patient-centred care and organisational learning. As a result, healthcare systems require a strategic foundation for clinical analytics that is sufficiently directional to support meaningful change while flexible enough to allow for iteration and responsiveness to context as change occurs.

Methods

In New South Wales, the most populous state in Australia, the Clinical Analytics Working Group was charged with developing a five-year vision for the public health system. A modified Delphi process was undertaken to elicit expert views and to reach a consensus. The process included a combination of face-to-face workshops, traditional Delphi voting via email, and innovative, real-time iteration between text re-formulation and voting until consensus was reached. The six stage process engaged 35 experts — practising clinicians, patients and consumers, managers, policymakers, data scientists and academics.

Results

The process resulted in the production of 135 ideas that were subsequently synthesised into 23 agreed statements and encapsulated in a single page (456 word) narrative.

Conclusion

The visioning process highlighted three key perspectives (clinicians, patients and managers) and the need for synchronous (during the clinical encounter) and asynchronous (outside the clinical encounter) clinical decision support and reflective practice tools; the use of new and multiple data sources and communication formats; and the role of research and education.
CDE-1 suppresses the production of risiRNA by coupling polyuridylation and degradation of rRNA
Authors: Wang Yun , Weng Chenchun , Chen Xiangyang , Zhou Xufei , Huang Xinya , Yan Yonghong , Zhu Chengming
Published: September 2020

Background

Modification of RNAs, particularly at the terminals, is critical for various essential cell processes; for example, uridylation is implicated in tumorigenesis, proliferation, stem cell maintenance, and immune defense against viruses and retrotransposons. Ribosomal RNAs can be regulated by antisense ribosomal siRNAs (risiRNAs), which downregulate pre-rRNAs through the nuclear RNAi pathway in Caenorhabditis elegans. However, the biogenesis and regulation of risiRNAs remain obscure. Previously, we showed that 26S rRNAs are uridylated at the 3′-ends by an unknown terminal polyuridylation polymerase before the rRNAs are degraded by a 3′ to 5′ exoribonuclease SUSI-1(ceDIS3L2).

Results

Here, we found that CDE-1, one of the three C.elegans polyuridylation polymerases (PUPs), is specifically involved in suppressing risiRNA production. CDE-1 localizes to perinuclear granules in the germline and uridylates Argonaute-associated 22G-RNAs, 26S, and 5.8S rRNAs at the 3′-ends. Immunoprecipitation followed by mass spectrometry (IP-MS) revealed that CDE-1 interacts with SUSI-1(ceDIS3L2). Consistent with these results, both CDE-1 and SUSI-1(ceDIS3L2) are required for the inheritance of RNAi.

Conclusions

This work identified a rRNA surveillance machinery of rRNAs that couples terminal polyuridylation and degradation.
An ecological study of socioeconomic predictors in detection of COVID-19 cases across neighborhoods in New York City
Authors: Whittle Richard S. , Diaz-Artiles Ana
Published: September 2020

Background

New York City was the first major urban center of the COVID-19 pandemic in the USA. Cases are clustered in the city, with certain neighborhoods experiencing more cases than others. We investigate whether potential socioeconomic factors can explain between-neighborhood variation in the COVID-19 test positivity rate.

Methods

Data were collected from 177 Zip Code Tabulation Areas (ZCTA) in New York City (99.9% of the population). We fit multiple Bayesian Besag-York-Mollié (BYM) mixed models using positive COVID-19 tests as the outcome, a set of 11 representative demographic, economic, and health-care associated ZCTA-level parameters as potential predictors, and the total number of COVID-19 tests as the exposure. The BYM model includes both spatial and nonspatial random effects to account for clustering and overdispersion.

Results

Multiple regression approaches indicated a consistent, statistically significant association between detected COVID-19 cases and dependent children (under 18 years old), population density, median household income, and race. In the final model, we found that an increase of only 5% in young population is associated with a 2.3% increase in COVID-19 positivity rate (95% confidence interval (CI) 0.4 to 4.2%, p=0.021). An increase of 10,000 people per km2 is associated with a 2.4% (95% CI 0.6 to 4.2%, p=0.011) increase in positivity rate. A decrease of $10,000 median household income is associated with a 1.6% (95% CI 0.7 to 2.4%, p<0.001) increase in COVID-19 positivity rate. With respect to race, a decrease of 10% in White population is associated with a 1.8% (95% CI 0.8 to 2.8%, p<0.001) increase in positivity rate, while an increase of 10% in Black population is associated with a 1.1% (95% CI 0.3 to 1.8%, p<0.001) increase in positivity rate. The percentage of Hispanic (p=0.718), Asian (p=0.966), or Other (p=0.588) populations were not statistically significant factors.

Conclusions

Our findings indicate associations between neighborhoods with a large dependent youth population, densely populated, low-income, and predominantly black neighborhoods and COVID-19 test positivity rate. The study highlights the importance of public health management during and after the current COVID-19 pandemic. Further work is warranted to fully understand the mechanisms by which these factors may have affected the positivity rate, either in terms of the true number of cases or access to testing.
Exploring the use of leucine zippers for the generation of a new class of inclusion bodies for pharma and biotechnological applications
Authors: Roca-Pinilla Ramon , Fortuna Sara , Natalello Antonino , Sánchez-Chardi Alejandro , Ami Diletta , Arís Anna , Garcia-Fruitós Elena
Published: September 2020

Background

Inclusion bodies (IBs) are biologically active protein aggregates forming natural nanoparticles with a high stability and a slow-release behavior. Because of their nature, IBs have been explored to be used as biocatalysts, in tissue engineering, and also for human and animal therapies. To improve the production and biological efficiency of this nanomaterial, a wide range of aggregation tags have been evaluated. However, so far, the presence in the IBs of bacterial impurities such as lipids and other proteins coexisting with the recombinant product has been poorly studied. These impurities could strongly limit the potential of IB applications, being necessary to control the composition of these bacterial nanoparticles. Thus, we have explored the use of leucine zippers as alternative tags to promote not only aggregation but also the generation of a new type of IB-like protein nanoparticles with improved physicochemical properties.

Results

Three different protein constructs, named GFP, J-GFP-F and J/F-GFP were engineered. J-GFP-F corresponded to a GFP flanked by two leucine zippers (Jun and Fos); J/F-GFP was formed coexpressing a GFP fused to Jun leucine zipper (J-GFP) and a GFP fused to a Fos leucine zipper (F-GFP); and, finally, GFP was used as a control without any tag. All of them were expressed in Escherichia coli and formed IBs, where the aggregation tendency was especially high for J/F-GFP. Moreover, those IBs formed by J-GFP-F and J/F-GFP constructs were smaller, rougher, and more amorphous than GFP ones, increasing surface/mass ratio and, therefore, surface for protein release. Although the lipid and carbohydrate content were not reduced with the addition of leucine zippers, interesting differences were observed in the protein specific activity and conformation with the addition of Jun and Fos. Moreover, J-GFP-F and J/F-GFP nanoparticles were purer than GFP IBs in terms of protein content.

Conclusions

This study proved that the use of leucine zippers strategy allows the formation of IBs with an increased aggregation ratio and protein purity, as we observed with the J/F-GFP approach, and the formation of IBs with a higher specific activity, in the case of J-GFP-F IBs. Thus, overall, the use of leucine zippers seems to be a good system for the production of IBs with more promising characteristics useful for pharma or biotech applications.
Plasmodium falciparum gametocyte-induced volatiles enhance attraction of Anopheles mosquitoes in the field
Authors: Debebe Yared , Hill Sharon Rose , Birgersson Göran , Tekie Habte , Ignell Rickard
Published: September 2020

Background

Plasmodium parasites manipulate the interaction between their mosquito and human hosts. Patients infected with gametocytes attract anopheline mosquitoes differentially compared to healthy individuals, an effect associated with an increased release of attractive volatile cues. This odour-driven manipulation is partly mediated by the gametocyte-specific metabolite, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), which induces increased release of select aldehydes and terpenes from red blood cells and results in the enhanced attraction of host-seeking mosquitoes, which are vectors of malaria. This study investigates the effect of the HMBPP-induced volatiles on the attraction of wild Anopheles mosquitoes to humans under field conditions.

Methods

The efficacy of the HMBPP-induced odour blend to attract Anopheles was evaluated in a 4 × 6 Latin rectangular study design indoors using baited Suna traps. Furthermore, to assess the efficacy of the HMBPP-induced odour blend in (1) augmenting the attractiveness of human odour, and (2) attracting Anopheles mosquitoes in the absence of human odour, a two-choice assay using host decoy traps (HDTs) was used and evaluated using binomial generalized regression.

Results

Traps baited with the HMBPP-induced odour blend attracted and caught both Anopheles arabiensis and Anopheles pharoensis females in a dose-dependent manner in the presence of background human odour, up to 2.5 times that of an unbaited trap. Given a choice between human odour and human odour laden with the HMBPP-induced odour blend, mosquitoes differentially preferred traps augmented with the HMBPP-induced odour blend, which caught twice as many female An. arabiensis. Traps baited with the HMBPP-induced odour blend but lacking the background of human odour were not effective in attracting and catching mosquitoes.

Conclusion

The findings of the present study revealed that the HMBPP-induced odour blend, when augmented with human body odour, is attractive to anopheline mosquitoes and could be used as a complementary vector control tool along with existing strategies.
Trends in adolescent first births in sub-Saharan Africa: a tale of increasing inequity?
Authors: Neal Sarah , Channon Andrew Amos , Chandra-Mouli Venkatraman , Madise Nyovani
Published: September 2020

Background

Single aggregate figures for adolescent pregnancy may fail to demonstrate particular population groups where rates are very high, or where progress has been slow. In addition, most indicators fail to separate younger from older adolescents. As there is some evidence that the disadvantages faced by adolescent mothers are greatest for those at the younger end of the spectrum, this is an important omission. This paper provides information on levels and trends of adolescent first births in 22 countries (at national and regional level) disaggregated by age (< 16 years, 16/17 years and 18/19 years), socio-economic status and place of residence. It highlights differences and similarities between countries in the characteristics of women who experience first birth during adolescence, as well as providing information on trends to identify groups where progress in reducing adolescent first births is poor.

Methodology

In this descriptive and trend analysis study we used data from 22 low- and middle-income countries from sub-Saharan Africa that have at least three Demographic and Health Surveys (DHS) since 1990, with the most recent carried out after 2005. Adolescent first births from the most recent survey are analysed by age, wealth, and residence by country and region for women aged 20–24 years at time of survey. We also calculated annual percentage rates of change (using both short- and longer-term data) for adolescent first births disaggregated by age, family wealth and residence and examined changes in concentration indices (CI).

Findings

Overall percentages of adolescent first births vary considerably between countries for all disaggregated age groups. The burden of first birth among adolescents is significant, including in the youngest age group: in some countries over 20% of women gave birth before 16 years of age (e.g. Mali and Niger). Adolescent first births are more common among women who are poorer, and live in rural areas; early adolescent first births before 16 years of age are particularly concentrated in these disadvantaged groups. Progress in reducing adolescent first births has also been particularly poor amongst these vulnerable groups, leading to increasing inequity.

Conclusions

Findings from this study show that adolescent births are concentrated among vulnerable groups where progress is often poorest. Strategies and programmes need to be developed to reduce adolescent pregnancies in marginalised young women in low- and middle-income countries.
Internal cross-linked polymeric nanoparticles with dual sensitivity for combination therapy of muscle-invasive bladder cancer
Authors: Zhu Guanchen , Wang Kaikai , Qin Haixiang , Zhao Xiaozhi , Chen Wei , Xu Linfeng , Cao Wenmin , Guo Hongqian
Published: September 2020

Background

Chemotherapy is a standard cancer treatment which uses anti-cancer drugs to destroy or slow the growth of cancer cells. However, chemotherapy has limited therapeutic effects in bladder cancer. One of the reasons of this resistance to chemotherapy is that higher levels of glutathione in invasive bladder cancer cells. We have fabricated nanoparticles that respond to high concentrations of glutathione and near-infrared laser irradiation in order to increase the drug accumulation at the tumor sites and combine chemotherapy with photothermal therapy to overcome the challenges of bladder cancer treatment.

Methods

The DOX&IR780@PEG-PCL-SS NPs were prepared by co-precipitation method. We investigated the tumor targeting capability of NPs in vitro and in vivo. The orthotopic bladder cancer model in C57BL/6 mice was established for in vivo study and the photothermal effects and therapeutic efficacy of NPs were evaluated.

Results

The DOX&IR780@PEG-PCL-SS NPs were synthesized using internal cross-linking strategy to increase the stability of nanoparticles. Nanoparticles can be ingested by tumor cells in a short time. The DOX&IR780@PEG-PCL-SS NPs have dual sensitivity to high levels of glutathione in bladder cancer cells and near-infrared laser irradiation. Glutathione triggers chemical structural changes of nanoparticles and preliminarily releases drugs, Near-infrared laser irradiation can promote the complete release of the drugs from the nanoparticles and induce a photothermal effect, leading to destroying the tumor cells. Given the excellent tumor-targeting ability and negligible toxicity to normal tissue, DOX&IR780@PEG-PCL-SS NPs can greatly increase the concentration of the anti-cancer drugs in tumor cells. The mice treated with DOX&IR780@PEG-PCL-SS NPs have a significant reduction in tumor volume. The DOX&IR780@PEG-PCL-SS NPs can be tracked by in vivo imaging system and have good tumor targeting ability, to facilitate our assessment during the experiment.

Conclusion

A nanoparticle delivery system with dual sensitivity to glutathione and near-infrared laser irradiation was developed for delivering IR780 and DOX. Chemo-photothermal synergistic therapy of both primary bladder cancer and their metastases was achieved using this advanced delivery system.
Establishing a reasonable price for an orphan drug
Authors: Berdud Mikel , Drummond Michael , Towse Adrian
Published: September 2020

Background

This paper addresses the question of what a reasonable price for an orphan drug is. The research proposes a way to adjust an established payer/HTA body incremental cost-effectiveness threshold (CET) to take account of differences in patient populations and costs of research and development in order to sustain prices that generate rates of return from investments in developing orphan drugs that are no greater than the industry average.

Methods

We investigated the cost of conducting research for orphan drugs as compared to non-orphan drugs, as well as patient population sizes targeted by orphans and non-orphans. We provided an empirical illustration based on novel drug approvals of orphan and non-orphan drugs of the FDA between 2011 and 2015 (N = 182).

Results

Using, for illustration, the NICE incremental CET (£20 K per QALY) as an anchor and adjusting by R&D costs and expected market revenue, we estimated the adjusted reasonable CET for orphan drugs to be £39.1 K per QALY at the orphan population cut-off and £78.3 K per QALY at the orphan population mid-point. For ultra-orphan drugs the adjusted CET was £937.1 K.

Conclusions

We propose one general method for establishing a reasonable price for an orphan drug, based on the proposition that rates of return for investments in developing orphan drugs should not be greater than the industry average. More research is required on data and assumptions, but with the data and assumptions we use, we find that in order to secure such a reasonable price for an orphan drug, the CET for orphans would need to be higher. This could be one approach for establishing the maximum allowable price society should be willing to pay, although decision-makers may still wish to negotiate a lower price, or refuse to pay such a premium over the value-based price in order to treat these groups of patients.
Estimating completeness of national and subnational death reporting in Brazil: application of record linkage methods
Authors: Costa Luiz Fernando Lima , de Mesquita Silva Montenegro Marli , Rabello Neto Dacio de Lyra , de Oliveira Antonio Tadeu Ribeiro , Trindade Jose Eduardo de Oliveira , Adair Tim , Marinho Maria de Fatima
Published: September 2020

Background

In Brazil, both the Civil Registry (CR) and Ministry of Health (MoH) Mortality Information System (SIM) are sources of routine mortality data, but neither is 100% complete. Deaths from these two sources can be linked to facilitate estimation of completeness of mortality reporting and measurement of adjusted mortality indicators using generalized linear modeling (GLM).

Methods

The 2015 and 2016 CR and SIM data were linked using deterministic methods. GLM with covariates of the deceased’s sex, age, state of residence, cause of death and place of death, and municipality-level education decile and population density decile, was used to estimate total deaths and completeness nationally, subnationally and by population sub-group, and to identify the characteristics of unreported deaths. The empirical completeness method and Global Burden of Disease (GBD) 2017 estimates were comparators at the national and state level.

Results

Completeness was 98% for SIM and 95% for CR. The vast majority of deaths in Brazil were captured by either system and 94% were reported by both sources. For each source, completeness was lowest in the north. SIM completeness was consistently high across all sub-groups while CR completeness was lowest for deaths at younger ages, outside facilities, and in the lowest deciles of municipality education and population density. There was no clear municipality-level relationship in SIM and CR completeness, suggesting minimal dependence between sources. The empirical completeness method model 1 and GBD completeness estimates were each, on average, less than three percentage points different from GLM estimates at the state level. Life expectancy was lowest in the northeast and 7.5 years higher in females than males.

Conclusions

GLM using socio-economic and demographic covariates is a valuable tool to accurately estimate completeness from linked data sources. Close scrutiny of the quality of variables used to link deaths, targeted identification of unreported deaths in poorer, northern states, and closer coordination of the two systems will help Brazil achieve 100% death reporting completeness. The results also confirm the validity of the empirical completeness method.
Alpha-1 antitrypsin deficient individuals have circulating extracellular vesicles with profibrogenic cargo
Authors: Khodayari Nazli , Oshins Regina , Holliday L. Shannon , Clark Virginia , Xiao Qiang , Marek George , Mehrad Borna , Brantly Mark
Published: September 2020

Background

Alpha-1 antitrypsin deficiency (AATD)-mediated liver disease is a toxic “gain-of-function” inflammation in the liver associated with intracellular retention of mutant alpha-1 antitrypsin. The clinical presentation of the disease includes fibrosis, cirrhosis and liver failure. However, the pathogenic mechanism of AATD-mediated liver disease is not well understood. Here, we investigated the role of plasma extracellular vesicles (EVs) in progression of AATD-mediated liver disease.

Methods

EVs were isolated from plasma of AATD individuals with liver disease and healthy controls. Their cytokines and miRNA content were examined by multiplex assay and small RNA sequencing. The bioactivity of EVs was assessed by qPCR, western blot analysis and immunofluorescent experiments using human hepatic stellate cells (HSCs) treated with EVs isolated from control or AATD plasma samples.

Results

We have found that AATD individuals have a distinct population of EVs with pathological cytokine and miRNA contents. When HSCs were cultured with AATD plasma derived-EVs, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with healthy control plasma EVs.

Conclusion

AATD individuals have a distinct population of EVs with abnormal cytokine and miRNA contents and the capacity to activate HSCs and mediate fibrosis. Better understanding of the components which cause liver inflammation and fibrogenesis, leading to further liver injury, has the potential to lead to the development of new treatments or preventive strategies to prevent AATD-mediated liver disease.
Socioeconomic inequalities in effectiveness of and compliance to workplace health promotion programs: an individual participant data (IPD) meta-analysis
Authors: Coenen Pieter , Robroek Suzan J. W. , van der Beek Allard J. , Boot Cécile R. L. , van Lenthe Frank J. , Burdorf Alex , Oude Hengel Karen M.
Published: September 2020

Background

This individual patient data (IPD) meta-analysis aimed to investigate socioeconomic inequalities in effectiveness on healthy behavior of, and compliance to, workplace health promotion programs.

Methods

Dutch (randomized) controlled trials were identified and original IPD were retrieved and harmonized. A two-stage meta-analysis was conducted where linear mixed models were performed per study (stage 1), after which individual study effects were pooled (stage 2). All models were adjusted for baseline values of the outcomes, age and gender. Intervention effects were assessed on physical activity, diet, alcohol use, and smoking. Also, we assessed whether effects differed between participants with low and high program compliance and. All analyses were stratified by socioeconomic position.

Results

Data from 15 studies (n = 8709) were harmonized. Except for fruit intake (beta: 0·12 [95% CI 0·08 0·15]), no effects were found on health behaviors, nor did these effects differ across socioeconomic groups. Only participants with high compliance showed significant improvements in vigorous and moderate-to-vigorous physical activity, and in more fruit and less snack intake. There were no differences in compliance across socioeconomic groups.

Conclusions

Workplace health promotion programs were in general not effective. Neither effectiveness nor compliance differed across socioeconomic groups (operationalized by educational level). Even though stronger effects on health behavior were found for participations with high compliance, effects remained small. The results of the current study emphasize the need for new directions in health promotion programs to improve healthy behavior among workers, in particular for those in lower socioeconomic position.
Mass spectrometry-based analysis of formalin-fixed, paraffin-embedded distal cholangiocarcinoma identifies stromal thrombospondin-2 as a potential prognostic marker
Authors: Byrling Johannes , Kristl Theresa , Hu Dingyuan , Pla Indira , Sanchez Aniel , Sasor Agata , Andersson Roland , Marko-Varga György , Andersson Bodil
Published: September 2020

Background

Distal cholangiocarcinoma is an aggressive malignancy with a dismal prognosis. Diagnostic and prognostic biomarkers for distal cholangiocarcinoma are lacking. The aim of the present study was to identify differentially expressed proteins between distal cholangiocarcinoma and normal bile duct samples.

Methods

A workflow utilizing discovery mass spectrometry and verification by parallel reaction monitoring was used to analyze surgically resected formalin-fixed, paraffin-embedded samples from distal cholangiocarcinoma patients and normal bile duct samples. Bioinformatic analysis was used for functional annotation and pathway analysis. Immunohistochemistry was performed to validate the expression of thrombospondin-2 and investigate its association with survival.

Results

In the discovery study, a total of 3057 proteins were identified. Eighty-seven proteins were found to be differentially expressed (q < 0.05 and fold change ≥ 2 or ≤ 0.5); 31 proteins were upregulated and 56 were downregulated in the distal cholangiocarcinoma samples compared to controls. Bioinformatic analysis revealed an abundance of differentially expressed proteins associated with the tumor reactive stroma. Parallel reaction monitoring verified 28 proteins as upregulated and 18 as downregulated in distal cholangiocarcinoma samples compared to controls. Immunohistochemical validation revealed thrombospondin-2 to be upregulated in distal cholangiocarcinoma epithelial and stromal compartments. In paired lymph node metastases samples, thrombospondin-2 expression was significantly lower; however, stromal thrombospondin-2 expression was still frequent (72%). Stromal thrombospondin-2 was an independent predictor of poor disease-free survival (HR 3.95, 95% CI 1.09–14.3; P = 0.037).

Conclusion

Several proteins without prior association with distal cholangiocarcinoma biology were identified and verified as differentially expressed between distal cholangiocarcinoma and normal bile duct samples. These proteins can be further evaluated to elucidate their biomarker potential and role in distal cholangiocarcinoma carcinogenesis. Stromal thrombospondin-2 is a potential prognostic marker in distal cholangiocarcinoma.
Alterations of monocyte NF-κB p65/RelA signaling in a cohort of older medical patients, age-matched controls, and healthy young adults
Authors: Tavenier Juliette , Rasmussen Line Jee Hartmann , Houlind Morten Baltzer , Andersen Aino Leegaard , Panum Inge , Andersen Ove , Petersen Janne , Langkilde Anne , Nehlin Jan O.
Published: September 2020

Background

Altered monocyte NF-κB signaling is a possible cause of inflammaging and driver of aging, however, evidence from human aging studies is sparse. We assessed monocyte NF-κB signaling across different aging trajectories by comparing healthy older adults to older adults with a recent emergency department (ED) admission and to young adults.

Methods

We used data from: 52 older (≥65 years) Patients collected upon ED admission and at follow-up 30-days after discharge; 52 age- and sex-matched Older Controls without recent hospitalization; and 60 healthy Young Controls (20–35 years). Using flow cytometry, we assessed basal NF-κB phosphorylation (pNF-κB p65/RelA; Ser529) and induction of pNF-κB following stimulation with LPS or TNF-α in monocytes. We assessed frailty (FI-OutRef), physical and cognitive function, and plasma levels of IL-6, IL-18, TNF-α, and soluble urokinase plasminogen activator receptor.

Results

Patients at follow-up were frailer, had higher levels of inflammatory markers and decreased physical and cognitive function than Older Controls. Patients at follow-up had higher basal pNF-κB levels than Older Controls (median fluorescence intensity (MFI): 125, IQR: 105–153 vs. MFI: 80, IQR: 71–90,p < 0.0001), and reduced pNF-κB induction in response to LPS (mean pNF-κB MFI fold change calculated as the log10 ratio of LPS-stimulation to the PBS-control: 0.10, 95% CI: 0.08 to 0.12 vs. 0.13, 95% CI: 0.10 to 0.15,p = 0.05) and TNF-α stimulation (0.02, 95% CI: − 0.00 to 0.05 vs. 0.10, 95% CI: 0.08 to 0.12,p < 0.0001). Older Controls had higher levels of inflammatory markers than Young Controls, but basal pNF-κB MFI did not differ between Older and Young Controls (MFI: 81, IQR: 70–86;p = 0.72). Older Controls had reduced pNF-κB induction in response to LPS and TNF-α compared to Young Controls (LPS: 0.40, 95% CI: 0.35 to 0.44,p < 0.0001; and TNF-α: 0.33, 95% CI: 0.27 to 0.40,p < 0.0001). In Older Controls, basal pNF-κB MFI was associated with FI-OutRef (p = 0.02).

Conclusions

Increased basal pNF-κB activity in monocytes could be involved in the processes of frailty and accelerated aging. Furthermore, we show that monocyte NF-κB activation upon stimulation was impaired in frail older adults, which could result in reduced immune responses and vaccine effectiveness.
Prevalence of temporomandibular joint disorder in the Lebanese population, and its association with depression, anxiety, and stress
Authors: Kmeid Elio , Nacouzi Mansour , Hallit Souheil , Rohayem Ziad
Published: September 2020

Background

The objectives of this study were to study the prevalence of temporomandibular joint disorder (TMD) and its association with anxiety, depression, and stress among the general Lebanese population as well as in a sample of patients recruited from an otolaryngologist clinic.

Methods

A cross-sectional study was conducted between September 2018 and December 2019, which enrolled 459 participants from all districts of Lebanon (sample 1) and 37 patients from the otolaryngologist clinic at the Eye and Ear Hospital (sample 2). The temporomandibular disorder screening checklist was used to screen for temporomandibular joint disorder. The Fonseca’s anamnestic index was used to assess for temporomandibular joint disorder related signs and symptoms, as well as for symptoms severity.

Results

The results showed that 19.7% of the general Lebanese population had TMD, from which 55.9% were female. In contrast, 59.5% of patients in the sample recruited from the clinic were found to have TMD. Higher stress, anxiety, and depression scores were associated with higher temporomandibular disorder severity score (B = 0.23; B = 0.10 and B = 0.10 respectively). Patients in the sample recruited from the clinic had higher mean stress (20.75 vs 11.43), anxiety (12.46 vs 5.78), depression (13.24 vs 6.52), and temporomandibular disorder severity scores (59.5% vs 19.7%) than the general population.

Conclusion

Temporomandibular joint disorder appears to be associated significantly with depression, anxiety, and stress and remains largely underdiagnosed in the general population.
Changes in serum markers failed to predict persistent infection after two-stage exchange arthroplasty
Authors: Jiang Qiao , Fu Jun , Chai Wei , Hao Li-bo , Zhou Yong-Gang , Xu Chi , Chen Ji-Ying
Published: September 2020

Background

The proper timing of reimplantation is importation to treatment success in the two-stage exchange revision. The 2018 International Consensus Meeting suggested that a variation trend toward normalization in serum markers was useful for determining the proper timing of reimplantation. However, the opposite results were found by previous studies, and the normalization of serum markers was reported to fail to predict infection control. We investigated whether value changes and percent changes in four common serum markers (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-6 (IL-6), and fibrinogen) can predict persistent infection.

Methods

A retrospective review of 141 patients treated with the two-stage revision from 2014 to 2018 was conducted. The variation trend in serum indicators was evaluated by the percent changes (using values of serum markers pre-reimplantation divided by values pre-resection) and value changes (using values of serum markers pre-resection minus values pre-reimplantation). Treatment success was defined according to the Delphi-based consensus criteria with a minimum follow-up of 1 year, and the receiver operator characteristic (ROC) was used to examine the usefulness of changes in serum markers.

Results

Twenty-two patients (15.60%) were persistently infected. No significant difference was found in either the value change or percent change in serum markers between reinfection and non-reinfection patients. When predicting persistent infection, the area under the curves (AUC) demonstrated that both percent changes and value changes in serum markers were poor indicators. The AUC of value changes was 0.533 for the CRP, 0.504 for the IL-6, 0.508 for the ESR, and 0.586 for fibrinogen when predicted persistent PJI. In addition, the AUC indicated that percent changes in the CRP (0.464), the IL-6 (0.534), the ESR (0.527), and fibrinogen (0.586) were all poor markers.

Conclusions

We have shown that both value changes and percent changes in serum markers were not sufficiently rigorous to aid in persistent infection diagnosis. The proper timing of reimplantation must, therefore, take into account various clinical tests rather than the downward trend of serum markers only.
The potential of a constellation of low earth orbit satellite imagers to monitor worldwide fossil fuel CO2 emissions from large cities and point sources
Authors: Lespinas Franck , Wang Yilong , Broquet Grégoire , Bréon François-Marie , Buchwitz Michael , Reuter Maximilian , Meijer Yasjka , Loescher Armin , Janssens-Maenhout Greet , Zheng Bo , Ciais Philippe
Published: September 2020

Background

Satellite imagery will offer unparalleled global spatial coverage at high-resolution for long term cost-effective monitoring of CO2 concentration plumes generated by emission hotspots. CO2 emissions can then be estimated from the magnitude of these plumes. In this paper, we assimilate pseudo-observations in a global atmospheric inversion system to assess the performance of a constellation of one to four sun-synchronous low-Earth orbit (LEO) imagers to monitor anthropogenic CO2 emissions. The constellation of imagers follows the specifications from the European Spatial Agency (ESA) for the Copernicus Anthropogenic Carbon Dioxide Monitoring (CO2M) concept for a future operational mission dedicated to the monitoring of anthropogenic CO2 emissions. This study assesses the uncertainties in the inversion estimates of emissions (“posterior uncertainties”).

Results

The posterior uncertainties of emissions for individual cities and power plants are estimated for the 3 h before satellite overpasses, and extrapolated at annual scale assuming temporal auto-correlations in the uncertainties in the emission products that are used as a prior knowledge on the emissions by the Bayesian framework of the inversion. The results indicate that (i) the number of satellites has a proportional impact on the number of 3 h time windows for which emissions are constrained to better than 20%, but it has a small impact on the posterior uncertainties in annual emissions; (ii) having one satellite with wide swath would provide full images of the XCO2 plumes, and is more beneficial than having two satellites with half the width of reference swath; and (iii) an increase in the precision of XCO2 retrievals from 0.7 ppm to 0.35 ppm has a marginal impact on the emission monitoring performance.

Conclusions

For all constellation configurations, only the cities and power plants with an annual emission higher than 0.5 MtC per year can have at least one 8:30–11:30 time window during one year when the emissions can be constrained to better than 20%. The potential of satellite imagers to constrain annual emissions not only depend on the design of the imagers, but also strongly depend on the temporal error structure in the prior uncertainties, which is needed to be objectively assessed in the bottom-up emission maps.
Bone mineral density and bone microarchitecture in a cohort of patients with Erdheim-Chester Disease
Authors: He Tianhua , Cui Lijia , Niu Na , Wang Fengdan , Miao Huilei , Zhao Hao , Gao Xuemin , Liu Chang , Yu Fan , Jiang Yan , Wang Ou , Li Mei , Xing Xiaoping , Zhou Daobin , Li Jian , Cao Xinxin , Xia Weibo
Published: September 2020

Background

Erdheim-Chester Disease (ECD) is a rare type of non-Langerhans histiocytosis. Skeletal structures are affected in over 95% ECD patients. Due to the lack of proper imaging assessment tools, the alteration of bone microarchitecture in ECD has not been well studied. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a newly developed assessment of bone mineral density and bone microarchitecture.

Methods

We performed a cross-sectional study with 13 patients diagnosed with ECD in Peking Union Medical College Hospital between October 2018 and June 2019. The diagnosis of ECD was based on typical pathological findings in the context of appropriate clinical and radiological manifestations. Bone geometry, volumetric bone mineral density and bone microarchitecture of those ECD patients were assessed using HR-pQCT at the non-dominant distal radius and distal tibia. Those HR-pQCT parameters were then compared to an ongoing population-based database of HR-pQCT for Mainland Chinese.

Results

As a result, remarkable heterogeneity of osteosclerosis in the HR-pQCT images was found in ECD patients, ranging from apparent normal structure, scattered thickening of trabecula, to homogenous consolidation. In terms of quantitative measurements, total volumetric BMD (383.50 mg/cm3, 1.352 times of normal mean, p = 0.023) of the tibia differed significantly in ECD patients, due to the increased trabecular volumetric BMD (291 mg/cm3, 2.058 times of normal mean, p = 0.003). The increased trabecular volumetric BMD of tibia was associated with remarkably increased number of trabecula (1.7/mm, 1.455 times of normal mean, p = 0.002) and increased thickness of trabecula (0.37 mm, 1.466 times of normal mean, p = 0.003). These differences could be due to the existence of dense bone interposed in the trabecula.

Conclusion

This study is the first to assess the volumetric bone mineral density and bone microstructure with HR-pQCT in a cohort of ECD patients and indicated that the application of HR-pQCT may help to reveal the nature of bone lesions in the disease.
SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19
Authors: Zhang Si , Liu Yangyang , Wang Xiaofang , Yang Li , Li Haishan , Wang Yuyan , Liu Mengduan , Zhao Xiaoyan , Xie Youhua , Yang Yan , Zhang Shenghui , Fan Zhichao , Dong Jianzeng , Yuan Zhenghong , Ding Zhongren , Zhang Yi , Hu Liang
Published: September 2020

Background

Critically ill patients diagnosed with COVID-19 may develop a pro-thrombotic state that places them at a dramatically increased lethal risk. Although platelet activation is critical for thrombosis and is responsible for the thrombotic events and cardiovascular complications, the role of platelets in the pathogenesis of COVID-19 remains unclear.

Methods

Using platelets from healthy volunteers, non-COVID-19 and COVID-19 patients, as well as wild-type and hACE2 transgenic mice, we evaluated the changes in platelet and coagulation parameters in COVID-19 patients. We investigated ACE2 expression and direct effect of SARS-CoV-2 virus on platelets by RT-PCR, flow cytometry, Western blot, immunofluorescence, and platelet functional studies in vitro, FeCl3-induced thrombus formation in vivo, and thrombus formation under flow conditions ex vivo.

Results

We demonstrated that COVID-19 patients present with increased mean platelet volume (MPV) and platelet hyperactivity, which correlated with a decrease in overall platelet count. Detectable SARS-CoV-2 RNA in the blood stream was associated with platelet hyperactivity in critically ill patients. Platelets expressed ACE2, a host cell receptor for SARS-CoV-2, and TMPRSS2, a serine protease for Spike protein priming. SARS-CoV-2 and its Spike protein directly enhanced platelet activation such as platelet aggregation, PAC-1 binding, CD62P expression, α granule secretion, dense granule release, platelet spreading, and clot retraction in vitro, and thereby Spike protein enhanced thrombosis formation in wild-type mice transfused with hACE2 transgenic platelets, but this was not observed in animals transfused with wild-type platelets in vivo. Further, we provided evidence suggesting that the MAPK pathway, downstream of ACE2, mediates the potentiating role of SARS-CoV-2 on platelet activation, and that platelet ACE2 expression decreases following SARS-COV-2 stimulation. SARS-CoV-2 and its Spike protein directly stimulated platelets to facilitate the release of coagulation factors, the secretion of inflammatory factors, and the formation of leukocyte–platelet aggregates. Recombinant human ACE2 protein and anti-Spike monoclonal antibody could inhibit SARS-CoV-2 Spike protein-induced platelet activation.

Conclusions

Our findings uncovered a novel function of SARS-CoV-2 on platelet activation via binding of Spike to ACE2. SARS-CoV-2-induced platelet activation may participate in thrombus formation and inflammatory responses in COVID-19 patients.
Hydrocortisone treatment is associated with a longer duration of MODS in pediatric patients with severe sepsis and immunoparalysis
Authors: Bline Katherine E. , Moore-Clingenpeel Melissa , Hensley Josey , Steele Lisa , Greathouse Kristin , Anglim Larissa , Hanson-Huber Lisa , Nateri Jyotsna , Muszynski Jennifer A. , Ramilo Octavio , Hall Mark W.
Published: September 2020

Background

Severe critical illness-induced immune suppression, termed immunoparalysis, is associated with longer duration of organ dysfunction in septic children. mRNA studies have suggested differential benefit of hydrocortisone in septic children based on their immune phenotype, but this has not been shown using a functional readout of the immune response. This study represents a secondary analysis of a prospectively conducted immunophenotyping study of pediatric severe sepsis to test the hypothesis that hydrocortisone will be differentially associated with clinical outcomes in children with or without immunoparalysis.

Methods

Children with severe sepsis/septic shock underwent blood sampling within 48 h of sepsis onset. Immune function was measured by quantifying whole blood ex vivo LPS-induced TNFα production capacity, with a TNFα response < 200 pg/ml being diagnostic of immunoparalysis. The primary outcome measure was number of days in 14 with MODS. Univariate and multivariable negative binomial regression models were used to examine associations between hydrocortisone use, immune function, and duration of MODS.

Results

One hundred two children were enrolled (age 75 [6–160] months, 60% male). Thirty-one subjects received hydrocortisone and were more likely to be older (106 [52–184] vs 38 [3–153] months,p = 0.04), to have baseline immunocompromise (32 vs 8%,p = 0.006), to have higher PRISM III (13 [8–18] vs 7 [5–13],p = 0.0003) and vasoactive inotrope scores (20 [10–35] vs 10 [3–15],p = 0.0002) scores, and to have more MODS days (3 [1–9] vs 1 [0–3],p = 0.002). Thirty-three subjects had immunoparalysis (TNFα response 78 [52–141] vs 641 [418–1047] pg/ml,p < 0.0001). Hydrocortisone use was associated with longer duration of MODS in children with immunoparalysis after adjusting for covariables (aRR 3.7 [1.8–7.9],p = 0.0006) whereas no association with MODS duration was seen in children without immunoparalysis (aRR 1.2 [0.6–2.3],p = 0.67).

Conclusion

Hydrocortisone use was independently associated with longer duration of MODS in septic children with immunoparalysis but not in those with more robust immune function. Prospective clinical trials using a priori immunophenotyping are needed to understand optimal hydrocortisone strategies in this population.
Consistency of bootstrap approximation to the null distributions of local spatial statistics with application to house price analysis
Authors: Mei Chang-Lin , Xu Shou-Fang , Chen Feng
Published: September 2020

With the increasing availability of spatially extensive geo-referenced data, much attention has been paid to the use of local statistics to identify local patterns of spatial association, in which the null distributions of local statistics play an essential role in the related statistical inference. As a powerful tool to approximate the distribution of a statistic, the bootstrap method is used in this paper to derive null distributions of the commonly used local spatial statistics including local Getis and Ord’s$G_{i}$Gi, Moran’s$I_{i}$Iiand Geary’s$c_{i}$ci. Strong consistency of the bootstrap approximation to the null distributions of the statistics is proved under some mild conditions, and the Boston housing price data are analyzed to demonstrate the application of the theoretical results.