bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 2 trial of montelukast for prevention of pain in sickle cell disease
Authors: Field Joshua J. , Kassim Adetola , Brandow Amanda , Embury Stephen H. , Matsui Neil , Wilkerson Karina , Bryant Valencia , Zhang Liyun , Simpson Pippa , DeBaun Michael R.
Published: March 2020

Cysteinyl leukotrienes (CysLTs) are lipid mediators of inflammation. In patients with sickle cell disease (SCD), levels of CysLTs are increased compared with controls and associated with a higher rate of hospitalization for pain. We tested the hypothesis that administration of the CysLT receptor antagonist montelukast would improve SCD-related comorbidities, including pain, in adolescents and adults with SCD. In a phase 2 randomized trial, we administered montelukast or placebo for 8 weeks. The primary outcome measure was a >30% reduction in soluble vascular cell adhesion molecule 1 (sVCAM), a marker of vascular injury. Secondary outcome measures were reduction in daily pain, improvement in pulmonary function, and improvement in microvascular blood flow, as measured by laser Doppler velocimetry. Forty-two participants with SCD were randomized to receive montelukast or placebo for 8 weeks. We found no difference between the montelukast and placebo groups with regard to the levels of sVCAM, reported pain, pulmonary function, or microvascular blood flow. Although montelukast is an effective treatment for asthma, we did not find benefit for SCD-related outcomes. This clinical trial was registered at www.clinicaltrials.gov as #NCT01960413.
Interferon-complement loop in transplant-associated thrombotic microangiopathy
Authors: Jodele Sonata , Medvedovic Mario , Luebbering Nathan , Chen Jenny , Dandoy Christopher E. , Laskin Benjamin L. , Davies Stella M.
Published: March 2020

Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an “interferon-complement loop” that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.
Reducing turnover intention: perceived organizational support for frontline employees
Authors: Wang Qiang , Wang Chao
Published: March 2020

Frontline employees are generally under great pressure, and carry out repetitive and mundane daily tasks, leading to burnout and a high turnover intention among them. To identify ways to reduce this turnover intention, this study examines the effect of perceived organizational support (POS) on burnout and turnover intention in the Chinese context and adds to the literature on frontline employee burnout. Using data from a survey of the frontline employees of a gas station in Beijing, we examine the mediating effects of frontline employee burnout on their POS and turnover intention. This study shows that POS has a significant negative impact on burnout and turnover intention, and that job resources cannot substitute POS.
The energy impact of adaptive cruise control in real-world highway multiple-car-following scenarios
Authors: He Yinglong , Makridis Michail , Fontaras Georgios , Mattas Konstantinos , Xu Hongming , Ciuffo Biagio
Published: March 2020

Background

Surging acceptance of adaptive cruise control (ACC) across the globe is further escalating concerns over its energy impact. Two questions have directed much of this project: how to distinguish ACC driving behaviour from that of the human driver and how to identify the ACC energy impact. As opposed to simulations or test-track experiments as described in previous studies, this work is unique because it was performed in real-world car-following scenarios with a variety of vehicle specifications, propulsion systems, drivers, and road and traffic conditions.

Methods

Tractive energy consumption serves as the energy impact indicator, ruling out the effect of the propulsion system. To further isolate the driving behaviour as the only possible contributor to tractive energy differences, two techniques are offered to normalize heterogeneous vehicle specifications and road and traffic conditions. Finally, ACC driving behaviour is compared with that of the human driver from transient and statistical perspectives. Its impact on tractive energy consumption is then evaluated from individual and platoon perspectives.

Results

Our data suggest that unlike human drivers, ACC followers lead to string instability. Their inability to absorb the speed overshoots may partly be explained by their high responsiveness from a control theory perspective. Statistical results might imply the followers in the automated or mixed traffic flow generally perform worse in reproducing the driving style of the preceding vehicle. On the individual level, ACC followers have tractive energy consumption 2.7–20.5% higher than those of human counterparts. On the platoon level, the tractive energy values of ACC followers tend to consecutively increase (11.2–17.3%).

Conclusions

In general, therefore, ACC impacts negatively on tractive energy efficiency. This research provides a feasible path for evaluating the energy impact of ACC in real-world applications. Moreover, the findings have significant implications for ACC safety design when handling the stability-responsiveness trade-off.
Internal versus external European air market realities: the competitive divide
Authors: Ellis Darren
Published: March 2020

Background

This paper looks at how ongoing attempts to improve air market competitiveness in Europe are challenged by the differing internal and external realities that exist. Europe’s internal multilateral single air market has encouraged the proliferation of pan-European airlines unhindered by national borders, which have stimulated increased competition and driven down airfare prices. Meanwhile, externally the bilateral system continues to dominate the wider global airline industry and a number of countries still prefer to negotiate air access with individual European countries.

Methods

Data from a five stage mixed-method Delphi study underpin the paper. Qualitative data, collected at a first stage brainstorming workshop and during final stage in-depth interviews, were thematically analysed to locate key and sub-themes. Quantitative survey data were collected across the remaining stages and were statistically analysed with mostly t-tests and chi-square tests of association to a 95% confidence level.

Results

The key themetransferabilityof the European regional single air market emerged from the study data; supported by the three sub-themesEU regional model, extraterritorialityandNorth Atlantic single air market.

Conclusions

Europe remains the multilateral exception to the general rule in international aviation that bilateralism is the norm. Despite efforts to address this competitive divide, aeropowers like China and Russia are reluctant to embrace extensive change, while major European flag carriers resist unfettered competition from outside the bloc.
Infectious pseudo-aneurysm of the left ventricle: a case report and a review of the literature
Authors: Juliana Amadu E. , van ’t Kruys Kevin H. , Voigt Pieter G. , Blom Nico A.
Published: March 2020

Background

In the workup of a pediatric patient with pericarditis we found evidence of a pseudo-aneurysm of the left ventricle, which is a rare complication of purulent pericarditis.

Case presentation

We present a case of a six-year-old girl who was diagnosed with pericarditis and a fistula between the pericardial and the intra-luminal space of the left ventricle of the heart. She was successfully treated with antibiotics and cardio-thoracic surgery. We found 23 published cases (21 with follow-up) of infectious pseudo-aneurysm of the heart, of which 19 underwent surgery, 5 had fatal outcome, and 2 who refused surgery survived. The majority of cases were associated with Staphylococcus aureus. The exact mechanisms of this rare complication remain unknown.

Conclusions

A pseudo-aneurysm of the left ventricle is a rare and not well understood complication of a purulent pericarditis most commonly caused by Staphylococcus aureus infection. Because of risk of rupture, surgical intervention is advised.
Novel variants underlying autosomal recessive intellectual disability in Pakistani consanguineous families
Authors: Ilyas Muhammad , Efthymiou Stephanie , Salpietro Vincenzo , Noureen Nuzhat , Zafar Faisal , Rauf Sobiah , Mir Asif , Houlden Henry
Published: March 2020

Background

Intellectual disability (ID) is both a clinically diverse and genetically heterogeneous group of disorder, with an onset of cognitive impairment before the age of 18 years. ID is characterized by significant limitations in intellectual functioning and adaptive behaviour. The identification of genetic variants causing ID and neurodevelopmental disorders using whole-exome sequencing (WES) has proven to be successful. So far more than 1222 primary and 1127 candidate genes are associated with ID.

Methods

To determine pathogenic variants causative of ID in three unrelated consanguineous Pakistani families, we used a combination of WES, homozygosity-by-descent mapping, de-deoxy sequencing and bioinformatics analysis.

Results

Rare pathogenic single nucleotide variants identified by WES which passed our filtering strategy were confirmed by traditional Sanger sequencing and segregation analysis. Novel and deleterious variants in VPS53, GLB1, and MLC1, genes previously associated with variable neurodevelopmental anomalies, were found to segregate with the disease in the three families.

Conclusions

This study expands our knowledge on the molecular basis of ID as well as the clinical heterogeneity associated to different rare genetic causes of neurodevelopmental disorders. This genetic study could also provide additional knowledge to help genetic assessment as well as clinical and social management of ID in Pakistani families.
A novel variant of IHH in a Chinese family with brachydactyly type 1
Authors: Yang Qi , Wang Jin , Tian Xiaoxian , Shen Fei , Lan Jing , Zhang Qiang , Fan Xin , Yi Shang , Li Mengting , Shen Yiping
Published: March 2020

Background

Brachydactyly type A1(BDA-1) is an autosomal dominant disorder which is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog (IHH). The disorder is mainly characterized by shortening or missing of the middle phalanges. In this study, Our purpose is to identify the pathogenic variations associated with BDA-1 involved in a five-generation Chinese family.

Methods

A BDA-1 family with 8 affected and 14 unaffected family members was recruited. Whole exome sequencing (WES) was performed to identify the pathogenic variant in the proband, and which was later confirmed and segregated by Sanger sequencing. The significance of variants were assessed using several molecular and bioinformatics analysis methods.

Results

We uncovered a novel heterozygous missense variant c.299A > G (p.D100G) at the mutational hotspot ofIHHgene following whole-exome sequencing of a Chinese family with BDA-1. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity.

Conclusions

In conclusion, this study reports a five-generation Chinese family with BDA-1 due to a novel pathogenic variant (c.299A > G (p.D100G)) of IHH and expands the clinical and genetic spectrum of BDA-1.
Correction to: Chloride content of solutions used for regional citrate anticoagulation might be responsible for blunting correction of metabolic acidosis during continuous venovenous hemofiltration
Authors: Jacobs Rita , Honore Patrick M. , Diltoer Marc , Spapen Herbert D.
Published: March 2020

Following publication of the original article [1], we have been notified that the approved number by the Ethical Committee was given incorrectly. In the section “Methods” stated that: The Central Ethical Committee of the University Hospital approved the study protocol (B.U.N. 143201318818), this number is incorrect and should be expressed as follows: B.U.N. 143201318819.”
Isolated thrombotic microangiopathy of the small intestine in a patient with atypical hemolytic uremic syndrome – a case report
Authors: Nunius Christoph , Büttner-Herold Maike , Bertz Simone , Schiffer Mario , Buchholz Bjoern
Published: March 2020

Background

Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by systemic thrombotic microangiopathy (TMA) reflected by hemolysis, anemia, thrombocytopenia and systemic organ injury. The optimal management of aHUS-patients when undergoing kidney transplantation to prevent recurrence in the allograft is eculizumab, an approved recombinant antibody targeting human complement component C5.

Case presentation

A 39 year-old woman presented with severe abdominal pain, diarrhea and emesis for 3 days. In her past medical history she had experienced an episode of aHUS leading to end stage renal disease (ESRD) in 2007 and a genetic workup revealed a heterozygous mutation in the membrane cofactor protein gene. In 2014 she underwent cadaveric kidney transplantation. Four years later she had to go back on hemodialysis due to allograft failure following a severe systemic cytomegalovirus infection resulting in transplant failure. At presentation she still received calcineurin-inhibitor therapy and reported subfebrile temperatures and pain projecting over the transplant prior to the current symptoms. A contrast enhanced CT-scan of the abdomen revealed inflammatory wall thickening of the small intestine. Diagnostic endoscopy discovered fresh blood in the small intestine without a clear source of bleeding. Histopathology of the small intestine biopsies showed severe thrombotic microangiopathy. Of note, the patient persistently had no signs of systemic hemolysis. Since the TMA of the small intestine was most likely due to aHUS, eculizumab treatment was initiated which abolished the symptoms.

Conclusion

Here we report a patient with thrombotic microangiopathy with predominant manifestation in a single organ, the small intestine, due to aHUS with absence of systemic signs and symptoms. aHUS patients usually require a secondary trigger for the disease to manifest. In this case, the trigger may be attributed to the dysfunctional renal transplant, which was subsequently explanted. Histology of the explanted kidney showed severe inflammation due to purulent nephritis and signs of cellular rejection. After nephrectomy, we continued eculizumab therapy until the patient completely recovered. No signs of TMA recurred after discontinuation of eculizumab, further supporting the concept of the renal transplant as the main trigger of TMA of the small intestine in our patient.
RNAseq expression patterns of canine invasive urothelial carcinoma reveal two distinct tumor clusters and shared regions of dysregulation with human bladder tumors
Authors: Parker Heidi G. , Dhawan Deepika , Harris Alex C. , Ramos-Vara Jose A. , Davis Brian W. , Knapp Deborah W. , Ostrander Elaine A.
Published: March 2020

Background

Invasive urothelial carcinoma (iUC) is highly similar between dogs and humans in terms of pathologic presentation, molecular subtypes, response to treatment and age at onset. Thus, the dog is an established and relevant model for testing and development of targeted drugs benefiting both canine and human patients. We sought to identify gene expression patterns associated with two primary types of canine iUC tumors: those that express a common somatic mutation in the BRAF gene, and those that do not.

Methods

We performed RNAseq on tumor and normal tissues from pet dogs. Analysis of differential expression and clustering, and positional and individual expression was used to develop gene set enrichment profiles distinguishing iUC tumors with and without BRAFV595E mutations, as well as genomic regions harboring excessive numbers of dysregulated genes.

Results

We identified two expression clusters that are defined by the presence/absence of a BRAFV595E (BRAFV600E in humans) somatic mutation. BRAFV595E tumors shared significantly more dysregulated genes than BRAF wild-type tumors, and vice versa, with 398 genes differentiating the two clusters. Key genes fall into clades of limited function: tissue development, cell cycle regulation, immune response, and membrane transport. The genomic site with highest number of dysregulated genes overall lies in a locus corresponding to human chromosome 8q24, a region frequently amplified in human urothelial cancers.

Conclusions

These data identify critical sets of genes that are differently regulated in association with an activating mutation in the MAPK/ERK pathway in canine iUC tumors. The experiments also highlight the value of the canine system in identifying expression patterns associated with a common, shared cancer.
Clinicopathologic features and genomic analysis of pulmonary blastomatoid carcinosarcoma
Authors: Zhao Jikai , Xiang Chan , Zhao Ruiying , Guo Ping , Zheng Jingjing , Han-Zhang Han , Yu Keke , Zhang Jie , Han Yuchen
Published: March 2020

Background

This study was designed to investigate the clinicopathologic features of pulmonary blastomatoid carcinosarcoma and explore the genomic profiles of epithelial and mesenchymal components in this tumor.

Methods

Three cases of pulmonary blastomatoid carcinosarcoma were enrolled in this study. Clinicopathologic information and prognostic data were retrospectively reviewed. Diagnostic immunohistochemistry was performed. The epithelial and mesenchymal components were microdissected to investigate the genomic profiles by performing capture-based targeted next generation sequencing.

Results

The epithelial components in patient one consisted of low-grade and high-grade fetal lung adenocarcinoma. Low-grade epithelial cells showed nuclear expression of β-catenin and missense mutation of CTNNB1. The epithelial components in another two patients consisted of high-grade fetal lung adenocarcinoma/enteric adenocarcinoma. The epithelial cells showed membrane staining of β-catenin and harbored no mutation of CTNNB1. The mesenchymal components in all three tumors were composed of primitive round/spindle cells without definite differentiation and showed cytoplasmic dot positive of β-catenin and no corresponding mutation. Within a tumor, both components exhibited relatively comparable molecular profile. In patient one, 4 mutations: RB1, FAT3, PTCH1 and LRP1B were shared by both epithelial and mesenchymal components. Epithelial component had additional mutations in BCOR, CTNNB1, CTCF, FAT1 and DICER1. In patient two, 12 mutations were shared. The epithelial component had BRCA2 mutation and the mesenchymal had mutations in CREBBP, ALK, DNMT3A, ASXL2, MYCN and RICTOR. Patient three had 6 shared mutations. The epithelial component had an additional mutation in KAT6A and the mesenchymal had an additional mutation in APC. Collectively, we observed heterogeneity between epithelial and mesenchymal components of the same tumor.

Conclusions

Blastomatoid carcinosarcoma showed characteristic morphology and immunophenotype. Parallel detection of genetic abnormalities in epithelial and mesenchymal components could provide further evidence for tumor differentiation, molecular targeting and differential diagnosis.
Integrated bioinformatics analysis of aberrantly-methylated differentially-expressed genes and pathways in age-related macular degeneration
Authors: Shen Yinchen , Li Mo , Liu Kun , Xu Xiaoyin , Zhu Shaopin , Wang Ning , Guo Wenke , Zhao Qianqian , Lu Ping , Yu Fudong , Xu Xun
Published: March 2020

Background

Age-related macular degeneration (AMD) represents the leading cause of visual impairment in the aging population. The goal of this study was to identify aberrantly-methylated, differentially-expressed genes (MDEGs) in AMD and explore the involved pathways via integrated bioinformatics analysis.

Methods

Data from expression profile GSE29801 and methylation profile GSE102952 were obtained from the Gene Expression Omnibus database. We analyzed differentially-methylated genes and differentially-expressed genes using R software. Functional enrichment and protein–protein interaction (PPI) network analysis were performed using the R package and Search Tool for the Retrieval of Interacting Genes online database. Hub genes were identified using Cytoscape.

Results

In total, 827 and 592 genes showed high and low expression, respectively, in GSE29801; 4117 hyper-methylated genes and 511 hypo-methylated genes were detected in GSE102952. Based on overlap, we categorized 153 genes as hyper-methylated, low-expression genes (Hyper-LGs) and 24 genes as hypo-methylated, high-expression genes (Hypo-HGs). Four Hyper-LGs (CKB, PPP3CA, TGFB2, SOCS2) overlapped with AMD risk genes in the Public Health Genomics and Precision Health Knowledge Base. KEGG pathway enrichment analysis indicated that Hypo-HGs were enriched in the calcium signaling pathway, whereas Hyper-LGs were enriched in sphingolipid metabolism. In GO analysis, Hypo-HGs were enriched in fibroblast migration, membrane raft, and coenzyme binding, among others. Hyper-LGs were enriched in mRNA transport, nuclear speck, and DNA binding, among others. In PPI network analysis, 23 nodes and two edges were established from Hypo-HGs, and 151 nodes and 73 edges were established from Hyper-LGs. Hub genes (DHX9, MAPT, PAX6) showed the greatest overlap.

Conclusion

This study revealed potentially aberrantly MDEGs and pathways in AMD, which might improve the understanding of this disease.
Cross-cultural adaptation and validation of the 3D-CAM Chinese version in surgical ICU patients
Authors: Mu Dong-Liang , Ding Pan-Pan , Zhou Shu-Zhe , Liu Mei-Jing , Sun Xin-Yu , Li Xue-Ying , Wang Dong-Xin
Published: March 2020

Background

Accurate diagnosis of delirium is very important for prevention and treatment. Present study was designed to validate the 3-Minute Diagnostic Interview for CAM-defined Delirium Chinese version (3D-CAM-CN) in surgical ICU patients.

Methods

In this prospective diagnostic study, the 3D-CAM was translated into Chinese with culture adaption. Two interviewers (Roles A and B) independently administrated 3D-CAM-CN assessment in adult patients from postoperative days 1 to day 3. At the meantime, a panel of psychiatrists diagnosed delirium according to the Diagnostic and Statistical Manual of Mental Disorders-fifth edition as the reference standard. The sensitivity and specificity were calculated to analyze the diagnostic character of the 3D-CAM-CN.Kappacoefficient was used to evaluate interrater reliability.

Results

Two hundred forty-five adult patients were assessed for at least 2 days, resulting a total of 647 paired-assessments. When compared with the reference standard, the sensitivity and specificity of the 3D-CAM-CN assessment were 87.2 and 96.7%, respectively, by Role A and 84.6 and 97.4%, respectively, by Role B, with good interrater reliability (Kappacoefficient = 0.82,P < 0.001). It also performed well in patients with mild cognitive impairment, with the sensitivity from 85.7 to 100% and the specificity from 95.7 to 96.4%.

Conclusion

Our results showed that the 3D-CAM-CN can be used as a reliable and accurate instrument for delirium assessment in surgical patients.

Trial registration

This trail was approved by the Clinical Research Ethic Committee of Peking University First Hospital (No. 2017–1321) and registered on Chinese clinical trial registry on July 6, 2017 (ChiCTR-OOC-17011887).
Height predict incident non-alcoholic fatty liver disease among general adult population in Tianjin, China, independent of body mass index, waist circumference, waist-to-height ratio, and metabolic syndrome
Authors: Kumari Shubham , Wang Xuena , Liu Yunyun , Gu Yeqing , Huang Yuhan , Zhang Qing , Liu Li , Meng Ge , Wu Hongmei , Sun Shaomei , Wang Xing , Zhou Ming , Jia Qiyu , Wang Guolin , Song Kun , Niu Kaijun
Published: March 2020

Background

Early-life hormonal and nutritional factors can greatly influence the risk of non-alcoholic fatty liver disease (NAFLD). Adult height is a simple marker for these factors. This study aimed to investigate the association between adult height and NAFLD.

Methods

We performed a prospective cohort study of 35,994 participants aged 25 years or over with measured height at baseline. NAFLD was diagnosed by abdominal ultrasound and self-reported history of alcohol intake. Multivariable Cox proportional hazards regression models were conducted to assess the gender-specific association between height and the risk of NAFLD.

Results

During a follow-up period of 5.5 years, 6245 of 35,994 subjects developed NAFLD. The adjusted hazard ratios (95% confidence interval) of NAFLD for increasing quintiles of height were 1.00 (reference), 0.82 (0.73, 0.92), 0.84 (0.73, 0.97), 0.72 (0.61, 0.85) and 0.63 (0.50, 0.79) (P for trend < 0.0001) in males, and 1.00 (reference), 1.00 (reference), 0.80 (0.69, 0.91), 0.72 (0.61, 0.85), 0.60 (0.49, 0.74) and 0.45 (0.35, 0.59) (P for trend < 0.0001) in females, respectively.

Conclusions

A higher adult height was associated with lower risk of NAFLD among males and females in Tianjin, China.
Nutritional quality of foods and non-alcoholic beverages advertised on Brazilian free-to-air television: a cross-sectional study
Authors: Leite Fernanda Helena Marrocos , Mais Laís Amaral , Ricardo Camila Zancheta , Andrade Giovanna Calixto , Guimarães Julia Soares , Claro Rafael Moreira , Duran Ana Clara da Fonseca Leitão , Martins Ana Paula Bortoletto
Published: March 2020

Background

Evidence shows that foods marketed on television are often low-nutrient-dense foods associated with poor nutritional diet quality, obesity and non-communicable diseases. However, little research has been undertaken in Brazil around this issue. This study assessed the nutritional profile of foods and non-alcoholic beverages advertised on Brazilian television by applying the Pan American Health Organization (PAHO) and the World Health Organization (WHO/Europe) nutrient profiling models.

Methods

Cross-sectional study based on the International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support (INFORMAS) protocol. A total of 432 h on the three major Brazilian free-to-air TV channels was recorded from April 1st to 30th 2018. Recordings were done for eight non-consecutive and randomly selected days from 6 am to 12 am (midnight). All food-related ads were coded using a systematic approach and classified according to the PAHO and the WHO/Europe nutrient profile models as “eligible”/“not eligible” for marketing restrictions. Absolute and relative frequencies were used to describe absolute numbers and proportions of food and beverage advertisements. The nutritional profile of foods was compared by day, time of the day and types of TV program. For each advertisement, the parent company of promoted food products, supermarkets and restaurants was identified.

Results

A total of 1610 food and beverage ads were broadcast, representing 18.1% of the total ads shown on selected channels. Over 80.0% of all foods and beverages advertised on Brazilian TV channels did not meet the PAHO and the WHO/Europe nutritional quality standards and were considered eligible for marketing restrictions. The proportion of unhealthy food ads was significantly higher on weekends, in the afternoon, and during soap operas programming. Altogether, 10 transnational and local food and beverage companies, two large international fast food chains and two of Brazil’s largest supermarket retailers accounted for almost 90% of all unhealthy food ads shown.

Conclusions

The findings of the present study indicate a high exposure of the Brazilian population to unhealthy food marketing and an inefficient enforcement of existing regulations. Further research to monitor population exposure to unhealthy food marketing and understand the policy inertia that is preventing policy progress, is highly recommended.
A natural experiment of state-level physical activity and screen-time policy changes early childhood education (ECE) centers and child physical activity
Authors: Kracht Chelsea L. , Webster E. Kipling , Staiano Amanda E.
Published: March 2020

Background

Early childhood education (ECE) centers are an important place for preschool-aged children to obtain physical activity (PA). A U.S. state government (Louisiana) recently updated requirements for licensed centers’ PA and screen-time policies, which allowed for assessment of 1) ECE center practices, environment, staff behaviors, and policies changes on child-level PA and 2) state level changes on the ECE center.

Methods

ECE centers were assessed at the beginning of state licensing changes and 1-year later. The ECE centers were assessed via the Environmental Policy Assessment and Observation (EPAO) tool. The EPAO Sedentary Opportunities score, which primarily assesses television viewing time, was revised to reflect viewing non-television devices (e.g. tablets). Child-level PA was measured using accelerometry. For Aim 1, mixed models assessed ECE center changes and child PA with adjustment for demographic characteristics (fixed effects), baseline EPAO score (random effects), and clustering for center. For Aim 2, paired t-tests assessed ECE center environment differences between baseline and follow-up.

Results

Nine ECE centers participated and 49 preschoolers provided complete measures at both time points. For Aim 1, increases in the EPAO revised-Sedentary Opportunities score (as in less non-television screen-time) resulted in increased child PA (p = 0.02). For Aim 2, ECE centers improved their EPAO Active Opportunities and Staff Behaviors score (p = 0.04 and p = 0.02 respectively).

Conclusions

ECE centers improved their environment after 1-year, resulting in additional child PA. Changes in ECE centers environment, possibly through policy, can positively influence children’s PA.
The impact of the duration of the palliative care period on cancer patients with regard to the use of hospital services and the place of death: a retrospective cohort study
Authors: Hirvonen Outi M. , Leskelä Riikka-Leena , Grönholm Lotta , Haltia Olli , Voltti Samuli , Tyynelä-Korhonen Kristiina , Rahko Eeva K. , Lehto Juho T. , Saarto Tiina
Published: March 2020

Background

In order to avoid unnecessary use of hospital services at the end-of-life, palliative care should be initiated early enough in order to have sufficient time to initiate and carry out good quality advance care planning (ACP). This single center study assesses the impact of the PC decision and its timing on the use of hospital services at EOL and the place of death.

Methods

A randomly chosen cohort of 992 cancer patients treated in a tertiary hospital between Jan 2013 –Dec 2014, who were deceased by the end of 2014, were selected from the total number of 2737 identified from the hospital database. The PC decision (the decision to terminate life-prolonging anticancer treatments and focus on symptom centered palliative care) and use of PC unit services were studied in relation to emergency department (ED) visits, hospital inpatient days and place of death.

Results

A PC decision was defined for 82% of the patients and 37% visited a PC unit. The earlier the PC decision was made, the more often patients had an appointment at the PC unit (> 180 days prior to death 72% and < 14 days 10%). The number of ED visits and inpatient days were highest for patients with no PC decision and lowest for patients with both a PC decision and an PC unit appointment (60 days before death ED visits 1.3 vs 0.8 and inpatient days 9.9 vs 2.9 respectively, p < 0.01). Patients with no PC decision died more often in secondary/tertiary hospitals (28% vs. 19% with a PC decision, and 6% with a decision and an appointment to a PC unit).

Conclusions

The PC decision to initiate a palliative goal for the treatment had a distinct impact on the use of hospital services at the EOL. Contact with a PC unit further increased the likelihood of EOL care at primary care.
Quality of youth friendly sexual and reproductive health Services in West Gojjam Zone, north West Ethiopia: with special reference to the application of the Donabedian model
Authors: Munea Alemtsehay Mekonnen , Alene Getu Degu , Debelew Gurmesa Tura
Published: March 2020

Background

Although there has been momentum in implementing sexual and reproductive health services in Ethiopia, young people remain underserved despite their demonstrated needs. Quality care improves utilization of health service and increases the likelihood of obtaining ongoing care. However, little is known about the quality of youth-friendly sexual and reproductive health service in Ethiopia. Therefore, this study sought to investigate the quality of youth-friendly sexual and reproductive health service in West Gojjam Zone, North West Ethiopia.

Methods

Health facility-based cross-sectional study was conducted in West Gojjam zone in 2018 to assess the quality of the service using the Donabedian model. The assessment was done through the triangulation of multiple methods: simulated client study; structured interviews with service providers; observations; and key informant interview with providers and expertise. Fifty-four visits were made to 18 randomly selected health facilities by three simulated clients trained to present three different scenarios (i.e., adolescent with sexually transmitted infection, pregnancy test request and a lady with dry cough). Data were entered and analyzed using SPSS version 21. Facility visit score of ≥ 75% in all quality component categorized as “good quality” otherwise classified as performing below the standard. Thematic analysis was done to analyze qualitative data.

Results

In this study, none of the health facilities achieved ≥ 75% in the three components of quality measurement. From 18 health facilities, 6(33.3%) provided low quality in all domains. Process component, which measures client-provider interaction and privacy/confidentiality, was the most compromised one. However, a promising result was reported in the input quality that measured the availability of trained providers, drugs, and supplies. The presence of community-based health insurance and age driven comprehensive youth-friendly service delivery approach were identified as challenges to deliver quality services.

Conclusions

The quality of the service ranges from low to medium, with adolescent related elements performing poorly. Minor renovations of health facilities, training on client handling, and contextual modifying the age driven youth-friendly service approach may improve the quality of the services.
Disruption or reduced expression of the orotidine-5′-decarboxylase gene pyrG increases citric acid production: a new discovery during recyclable genome editing in Aspergillus niger
Authors: Zhang Lihui , Zheng Xiaomei , Cairns Timothy C. , Zhang Zhidan , Wang Depei , Zheng Ping , Sun Jibin
Published: March 2020

Background

Aspergillus niger is a filamentous fungus used for the majority of global citric acid production. Recent developments in genome editing now enable biotechnologists to engineer and optimize A. niger. Currently, however, genetic-leads for maximizing citric acid titers in industrial A. niger isolates is limited.

Results

In this study, we try to engineer two citric acid A. niger production isolates, WT-D and D353, to serve as platform strains for future high-throughput genome engineering. Consequently, we used genome editing to simultaneously disrupt genes encoding the orotidine-5′-decarboxylase (pyrG) and non-homologous end-joining component (kusA) to enable use of the pyrG selection/counter selection system, and to elevate homologous recombination rates, respectively. During routine screening of these pyrG mutant strains, we unexpectedly observed a 2.17-fold increase in citric acid production when compared to the progenitor controls, indicating that inhibition of uridine/pyrimidine synthesis may increase citric acid titers. In order to further test this hypothesis, the pyrG gene was placed under the control of a tetracycline titratable cassette, which confirmed that reduced expression of this gene elevated citric acid titers in both shake flask and bioreactor fermentation. Subsequently, we conducted intracellular metabolomics analysis, which demonstrated that pyrG disruption enhanced the glycolysis flux and significantly improved abundance of citrate and its precursors.

Conclusions

In this study, we deliver two citric acid producing isolates which are amenable to high throughput genetic manipulation due to pyrG/kusA deletion. Strikingly, we demonstrate for the first time that A. niger pyrG is a promising genetic lead for generating citric acid hyper-producing strains. Our data support the hypothesis that uridine/pyrimidine biosynthetic pathway offer future avenues for strain engineering efforts.
Effect of nicastrin on hepatocellular carcinoma proliferation and apoptosis through PI3K/AKT signalling pathway modulation
Authors: Wang Xicheng , Wang Xining , Xu Yunxiuxiu , Yan Maolin , Li Wenxin , Chen Jie , Chen Tao
Published: March 2020

Background

Increasing evidence has proven that the γ-secretase complex plays significant roles in the carcinogenesis of malignancies. However, the independent effect of nicastrin (NCSTN), the largest constituent of the γ-secretase complex, on the progression of hepatocellular carcinoma (HCC) remains to be discovered.

Methods

In our study, we used open online databases, including the Oncomine database, GEPIA and KMPlotter, to analyse the expression of 4 genes and their correlation with prognosis in HCC. NCSTN expression in 60 HCC patients from our centre was determined by immunohistochemical staining and qRT-PCR. The clinical and prognostic significance of NCSTN expression were analysed statistically. Stable Sk-hep1 cell lines with NCSTN overexpression were established using lentivirus-based vectors, and RNAi technology was used to transiently downregulate NCSTN expression in HepG2 cell lines. Cell growth and apoptosis were assessed by using EdU, clone formation, flow cytometry and Western blotting assays.

Results

Bioinformatics analysis showed that NCSTN mRNA expression was generally higher in HCC tissues than in normal tissues according to a meta-analysis of 9 HCC datasets, excluding PS-1, PEN-2 and APH-1. Moreover, NCSTN was associated with a poor prognosis in HCC patients from The Cancer Genome Atlas (TCGA). Although the relationship between NCSTN levels and the clinicopathological features of HCC patients was not significant, a survival analysis of HCC patients from TCGA indicated that overall and disease-free survival were significantly associated with NCSTN expression. NCSTN expression in HCC cell lines regulated cell growth and apoptosis in vitro. NCSTN downregulation in HepG2 cells inhibited tumour growth ability in vivo. In addition, NCSTN downregulation in HepG2 cell lines decreased p-PI3K and p-Akt expression, and IGF1, a PI3K/Akt activator, neutralized the effects on PI3K and Akt phosphorylation. Moreover, NCSTN overexpression in Sk-hep1 cells activated the PI3K/Akt signalling pathway, and MK-2206, a PI3K/Akt inhibitor, reversed this activation according to Western blotting analysis.

Conclusions

We suggest that NCSTN serves as an oncogene in HCC by promoting growth and inhibiting apoptosis via the PI3K/Akt pathway, providing a potential novel therapeutic target for HCC treatment.
Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer
Authors: Ren Qianqian , Zhu Peng , Zhang Hui , Ye Tianhe , Liu Dehan , Gong Zhao , Xia Xiangwen
Published: March 2020

Background

Immunotherapies targeting programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) have been approved for gastric cancer (GC) patients. However, a large proportion of patients with T-cell-inflamed tumor microenvironment do not respond to the PD-1/PD-L1 blockade. The stromal component of the tumor microenvironment has been associated with immunotherapy. This study aims to explore the clinical significance of the non-immune cells in the tumor microenvironment and their potential as biomarkers for immunotherapy.

Methods

A total of 383 patients with GC from the Cancer Genome Atlas (TCGA) cohort, 300 patients with GC from the GSE62254 cohort in Gene Expression Omnibus (GEO) were included in the study. A stromal score was generated using the ESTIMATE algorithm, and the likelihood of response to PD-1/PD-L1 immunotherapy of GC patients was predicted using the TIDE algorithm. The prognostic value of the stromal score from GC cases was evaluated by the Kaplan–Meier method and Cox regression analysis. Gene set enrichment analysis (GSEA) was also conducted.

Results

The stromal score showed significant differences in different molecular subtypes and T stages. Multivariate analyses further confirmed that the stromal score was an independent indicator of overall survival (OS) in the two cohorts. The low stromal score group showed higher tumor mutation burden (TMB) and micro-satellite instability (MSI), and was more sensitive to immune checkpoint inhibitor according to the TIDE algorithm. Activation of the transforming growth factor and epithelial–mesenchymal transition were observed in the high stromal score subtype, which is associated with T-cell suppression, and may be responsible for resistance to PD-1/PD-L1 therapy. BPIFB2 was confirmed as a hub gene relevant to immunotherapy.

Conclusion

The stromal score was associated with cancer progression and molecular subtypes, and may serve as a novel biomarker for predicting the prognosis and response to immunotherapy in patients with GC.
Prevalence and risk factors associated with HIV-1 infection among people who inject drugs in Dar es Salaam, Tanzania: a sign of successful intervention?
Authors: Likindikoki Samuel Lazarus , Mmbaga Elia John , Leyna Germana Henry , Moen Kåre , Makyao Neema , Mizinduko Mucho , Mwijage Alex Ishungisa , Faini Diana , Leshabari Melkizedeck Thomas , Meyrowitsch Dan Wolf
Published: March 2020

Background

Prevalence of HIV infection among people who inject drugs (PWID) has been reported to be higher than that of the general population. The present study aimed to estimate the prevalence of HIV infection and associated risk factors among PWID in Dar es Salaam, Tanzania, following the introduction of a comprehensive HIV intervention package (CHIP) for PWID in the country in 2014.

Methods

We conducted an integrated bio-behavioral survey (IBBS) among PWID using respondent-driven sampling (RDS) in Dar es Salaam, Tanzania, between October and December 2017. Data on socio-demographic characteristics and risky behaviors were collected through face-to-face interviews. Blood samples were collected and tested for HIV infection. We accounted for weighting in the analyses, and logistic regression was performed to assess risk factors for HIV infection.

Results

A total of 611 PWID (94.4% males and 5.6% females) with a median age of 34 years (IQR 29–38) were recruited. The overall prevalence of HIV infection was 8.7% (95% CI 6.5–10.9). The prevalence of HIV infections for males and females were 6.8% (95% CI 4.7–8.9%) and 41.2% (95% CI 23.7–58.6%) respectively. Adjusted weighted logistic regression analysis (WLRA) showed that being a female (aOR 19.1; 95% CI 5.9–61.8), injecting drugs for more than 10 years (aOR = 7.32; 95% CI 2.1–25.5) compared to 1 year or less and being 45 years or older (aOR = 34.22; 95% CI 2.4–489.5) compared to being 25 years or younger were associated with increased odds of HIV infection. Use of a sterile needle at last injection decreased odds of HIV infection (aOR = 0.3; 95% CI 0.1–0.8).

Conclusions

The present study observed a decline in prevalence of HIV infections among PWID in Dar es Salaam (8.7%) compared to a previous estimate of 15.5% from an IBBS conducted in 2013. Despite the decrease, HIV prevalence remains high among PWID compared to the general population, and women are disproportionally affected. The decline may be possibly attributed to the on-going implementation of CHIP for PWID, highlighting the need for strengthening the existing harm reduction interventions by incorporating access to sterile needle/syringe and addressing the layered risks for women.
Transcriptomic analysis of long noncoding RNAs and mRNAs expression profiles in the spinal cord of bone cancer pain rats
Authors: Hou Xinran , Weng Yingqi , Guo Qulian , Ding Zhuofeng , Wang Jian , Dai Jiajia , Wei Anqi , Song Zongbin
Published: March 2020

Bone cancer pain (BCP) is one of the most common types of chronic cancer pain and its pathogenesis has not been fully understood. Long non-coding RNAs (lncRNAs) are new promising targets in the field of pain research, however, their involvements in BCP have not been reported. In the present study, we established the BCP model by implantation of Walker 256 carcinoma cells into rats’ tibial medullary cavity and performed transcriptome sequencing of the ipsilateral lumbar spinal cord to explore changes in expression profiles of lncRNA and mRNA. We identified 1220 differently expressed mRNAs (DEmRNAs) (1171 up-regulated and 49 down-regulated) and 323 differently expressed lncRNAs (DElncRNAs) (246 up-regulated and 77 down-regulated) in BCP model, among which 10 DEmRNAs (5 up-regulated and 5 down-regulated) and 10 DElncRNAs (5 up-regulated and 5 down-regulated) were validated the expression by RT-qPCR. Then, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on the expression of DEmRNAs and DElncRNAs, showing that they were mainly enriched in inflammatory and immunologic processes/pathways. Finally, we constructed a co-expression network and a ceRNA network of DEmRNAs and DElncRNAs to exhibit a potential regulatory mechanism of DElncRNAs, directly regulating protein coding gene expression in cis or in trans and indirectly regulating protein coding gene expression by sponging miRNA. In conclusion, our study provided a landscape of dysregulated lncRNA and mRNA in spinal cord of bone cancer pain and detected novel potential targets for treatment in the future.
ARDS Subphenotypes: Understanding a Heterogeneous Syndrome
Authors: Wilson Jennifer G. , Calfee Carolyn S.
Published: March 2020

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2020. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.