bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting the Mechanism of the Analgesic Property of Yanhusuo Based on Network Pharmacology
Authors: Xiao Wen-Ping , Yang Yan-Fang , Wu He-Zhen , Xiong Yi-yi
Published: October 2019

Yanhusuo (Corydalis Rhizoma) extracts are widely used for the treatment of pain and inflammation. The effects of Yanhusuo in pain assays were assessed in a few studies. However, there are few studies on its analgesic mechanism. In this paper, network pharmacology was used to explore the analgesic components of Yanhusuo and its analgesic mechanism. The active components of Yanhusuo were screened by TCMSP database, combined with literature data. PharmMapper and GeneCards databases were used for screening the analgesic targets of the components. The protein interaction network diagram was drawn by String database and Cytoscape software, the gene ontology and KEGG pathway analyses of the target were performed by DAVID database, and the component–target–pathway interaction network diagram was further drawn by Cytoscape3.6.1 software. System Dock Web Site verified the molecular docking among components and targets. Finally, an interaction network of the component–target–pathway of Yanhusuo was constructed, and the functions and pathways were analyzed for preliminarily investigating the mechanism of Yanhusuo in analgesia. The results showed that the active components of analgesic in Yanhusuo were Corynoline, 13-methylpalmatrubine, dehydrocorydaline, saulatine, 2,3,9,10-tetramethoxy-13-methyl-5,6-dihydroisoquinolino[2,1-b]isoquinolin-8-on-e, and Capaurine. The mechanisms were involved in metabolic pathways, PI3k-Akt signaling pathway, pathways in cancer, and so on. The top 3 targets were NOS3, glucose-6-phosphate dehydrogenase, and glucose-6-phosphate isomerase in components-target-pathways network, and they were all enriched in metabolic pathways. Meanwhile the molecular docking showed that there was a high binding activity between the 6 components and the important target proteins, as a further certification for the subsequent network analysis. This study reveals the relationship of the components, targets, and pathways of active components in Yanhusuo, and provides new ideas and methods for further research on the analgesic mechanism of Yanhusuo.
Vascular Epiphytic Diversity in a Neotropical Transition Zone Is Driven by Environmental and Structural Heterogeneity
Authors: de la Rosa-Manzano Edilia , Mendieta-Leiva Glenda , Guerra-Pérez Antonio , Aguilar-Dorantes Karla María , Arellano-Méndez Leonardo Uriel , Torres-Castillo Jorge Ariel
Published: October 2019

Vascular epiphytes contribute significantly to tropical diversity. Research on the factors that determine vascular epiphytic diversity and composition in tropical areas is flourishing. However, these factors are entirely unknown in tropical-temperate transition zones, which represent the distribution limit of several epiphytic species. We assessed the degree to which climatic and structural variables determine the diversity of vascular epiphytic assemblages (VEAs) in a transition zone in Mexico: the El Cielo Biosphere Reserve. We found 12,103 epiphytic individuals belonging to 30 species and 15 genera along a climatic gradient from 300 to 2,000 m a.s.l. Bromeliaceae and Orchidaceae were the most species-rich families. Forests along the windward slope of the Sierra Madre Oriental (semideciduous forest and tropical montane cloud forest) had higher species richness than forests along the leeward slope (pine-oak forest and submontane scrub). Species richness was largely determined by seasonality and, to a lesser degree, by forest structure, whereas abundance was mainly determined by host tree size. Variation in VEAs composition was largely explained by climatic variables, whereas forest structure was not as important. VEAs differed among forest types and slopes in terms of taxonomic and functional composition. For example, certain bromeliad indicator species reflected differences between slopes. Although within-tree epiphytic species richness (alpha diversity) was low in this transition zone relative to other habitats, species turnover among forest types (beta diversity) was high. These findings suggest that each forest type makes a unique and important contribution to epiphytic diversity in this transition zone.
Book review: K. Paddayya, Neolithic Ashmounds of the Deccan: Their Place in the Archaeology of Peninsular India
Authors: Habib Irfan
Published: October 2019

K. Paddayya, Neolithic Ashmounds of the Deccan: Their Place in the Archaeology of Peninsular India (New Delhi: Aryan Books International), 2019, 174 pp., ₹1500 (Hb).
Leading Organizational Change: Semester-Long Project
Authors: Trefalt Špela
Published: October 2019

For organizational change to happen, people have to change their behaviors. Leaders of organizational change therefore need to develop their abilities to influence others, sell issues, and overcome resistance to gain buy-in within organizations. This article describes the framework for a semester-long project in which MBA students practice these skills by planning and executing an organizational change project of their own design. In the process, they obtain developmental feedback on their growing change-management skills. The instructor does not need to arrange contact with organizations in which these change projects take place, as students are charged with developing their projects and negotiating necessary access if needed. The project works best with weekly feedback and is, therefore, more appropriate for smaller classes or classes with capable teaching assistants. Adjustments for use in larger classes are also provided.
A Novel Tool to Improve Shared Decision Making and Adherence in Multiple Sclerosis: Development and Preliminary Testing
Authors: Col Nananda , Alvarez Enrique , Springmann Vicky , Ionete Carolina , Berrios Morales Idanis , Solomon Andrew , Kutz Christen , Griffin Carolyn , Tierman Brenda , Livingston Terrie , Patel Michelle , van Leeuwen Danny , Ngo Long , Pbert Lori
Published: October 2019

Background. Most people with multiple sclerosis (MS) want to be involved in medical decision making about disease-modifying therapies (DMTs), but new approaches are needed to overcome barriers to participation. Objectives. We sought to develop a shared decision-making (SDM) tool for MS DMTs, evaluate patient and provider responses to the tool, and address challenges encountered during development to guide a future trial. Methods. We created a patient-centered design process informed by image theory to develop the MS-SUPPORT SDM tool. Development included semistructured interviews and alpha and beta testing with MS patients and providers. Beta testing assessed dissemination and clinical integration strategies, decision-making processes, communication, and adherence. Patients evaluated the tool before and after a clinic visit. Results. MS-SUPPORT combines self-assessment with tailored feedback to help patients identify their treatment goals and preferences, correct misperceptions, frame decisions, and promote adherence. MS-SUPPORT generates a personal summary of their responses that patients can share with their provider to facilitate communication. Alpha testing (14 patients) identified areas needing improvement, resulting in reorganization and shortening of the tool. MS-SUPPORT was highly rated in beta testing (15 patients, 4 providers) on patient-provider communication, patient preparation, adherence, and other endpoints. Dissemination through both patient and provider networks appeared feasible. All patient testers wanted to share the summary report with their provider, but only 60% did. Limitations. Small sample size, no comparison group. Conclusions. The development process resulted in a patient-centered SDM tool for MS that may facilitate patient involvement in decision making, help providers understand their patients’ preferences, and improve adherence, though further testing is needed. Beta testing in real-world conditions was critical to prepare the tool for future testing and inform the design of future studies.
Ethnographies of slow violence: Epistemological alliances in fieldwork and narrating ruins
Authors: Vorbrugg Alexander
Published: October 2019

This article explores the nexus of slow violence as a concept, research focus, and problem on the one hand, and the practices and politics of ethnographic fieldwork and writing on the other. I argue that paying more explicit attention to methodological challenges in conducting ethnographies of slow violence is both necessary and worthwhile. Ethnographies can animate the broader debates on slow violence, infuse them with new concepts and political urgencies, and relate them to new sites and problems. Conversely, the problem of slow violence can advance ethnographic debates and practices, even beyond ethnographies of slow violence in a narrower sense. I highlight two aspects. First, I explore epistemological alliances between researchers and research participants which confront forms of violence that at first remain partly elusive to both sides. Second, I argue for multi-temporal ethnographies which work through drawn-out and complex timescapes of violence and loss by tracing cross-temporal connections. Notions of fieldwork are still mainly defined in spatial terms, and so the problem of slow violence is an important reminder to pay more attention to temporal dimensions. I build this argument on ethnographic research conducted in rural Russia, and thus also show how the concept of slow violence helps to make sense of and to make visible those forms of loss and dispossession that often remain elusive in academic and public representations of the Russian countryside.
Transcriptional characterisation of human lung cells identifies novel mesenchymal lineage markers
Authors: Danopoulos Soula , Bhattacharya Soumyaroop , Mariani Thomas J. , Al Alam Denise
Published: October 2019

Rationale

The lung mesenchyme gives rise to multiple distinct lineages of cells in the mature respiratory system, including smooth muscle cells of the airway and vasculature. However, a thorough understanding of the specification and mesenchymal cell diversity in the human lung is lacking.

Methods

We completed single-cell RNA sequencing analysis of fetal human lung tissues. Canonical correlation analysis, clustering, cluster marker gene identification and t-distributed stochastic neighbour embedding representation was performed in Seurat. Cell populations were annotated using ToppFun. Immunohistochemistry and in situ hybridisation were used to validate spatiotemporal gene expression patterns for key marker genes.

Results

We identified molecularly distinct populations representing “committed” fetal human lung endothelial cells, pericytes and smooth muscle cells. Early endothelial lineages expressed “classic” endothelial cell markers (platelet endothelial cell adhesion molecule/CD31 and claudin 5), while pericytes expressed platelet-derived growth factor receptor-β, Thy-1 membrane glycoprotein and basement membrane molecules (collagen IV, laminin and proteoglycans). We observed a large population of “nonspecific” human lung mesenchymal progenitor cells characterised by expression of collagen I and multiple elastin fibre genes (ELN, MFAP2 and FBN1). We closely characterised the diversity of mesenchymal lineages defined by α2-smooth muscle actin (ACTA2) expression. Two cell populations, with the highest levels of ACTA2 transcriptional activity, expressed unique sets of markers associated with airway or vascular smooth muscle cells. Spatiotemporal analysis of these marker genes confirmed early and persistent spatial specification of airway (HHIP, MYLK and IGF1) and vascular (NTRK3 and MEF2C) smooth muscle cells in the developing human lung.

Conclusion

Our data suggest that specification of distinct airway and vascular smooth muscle cell phenotypes is established early in development and can be identified using the markers we provide.
A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug-resistant tuberculosis
Authors: Olayanju Olatunde , Esmail Aliasgar , Limberis Jason , Dheda Keertan
Published: October 2019

There are limited data on combining delamanid and bedaquiline in drug-resistant tuberculosis (DR-TB) regimens. Prospective long-term outcome data, including in HIV-infected persons, are unavailable.

We prospectively followed up 122 South African patients (52.5% HIV-infected) with DR-TB and poor prognostic features between 2014 and 2018. We examined outcomes and safety in those who received a bedaquiline-based regimen (n=82) compared to those who received a bedaquiline–delamanid combination regimen (n=40).

There was no significant difference in 6-month culture conversion (92.5%versus81.8%; p=0.26) and 18-month favourable outcome rate (63.4%versus67.5%; p=0.66) in the bedaquilineversusthe bedaquiline–delamanid combination group, despite the latter having more advanced drug resistance (3.7%versus22.5% resistant to at least five drugs; p=0.001) and higher pre-treatment failure rates (12.2%versus52.5% with pre-treatment multidrug-resistant TB therapy failure; p<0.001). Although the proportion of prolongation of the QT interval corrected using Fridericia's formula was higher in the combination group (>60 ms from baseline (p=0.001) or >450 ms during treatment (p=0.001)), there were no symptomatic cases or drug withdrawals in either group. Results were similar in HIV-infected patients.

A bedaquiline–delamanid combination regimen showed comparable long-term safety compared to a bedaquiline-based regimen in patients with DR-TB, irrespective of HIV status. These data inform regimen selection in patients with DR-TB from TB-endemic settings.
Shared genetics of asthma and mental health disorders: a large-scale genome-wide cross-trait analysis
Authors: Zhu Zhaozhong , Zhu Xi , Liu Cong-Lin , Shi Huwenbo , Shen Sipeng , Yang Yunqi , Hasegawa Kohei , Camargo Carlos A. , Liang Liming
Published: October 2019

Epidemiological studies demonstrate an association between asthma and mental health disorders, although little is known about the shared genetics and causality of this association. Thus, we aimed to investigate shared genetics and the causal link between asthma and mental health disorders.

We conducted a large-scale genome-wide cross-trait association study to investigate genetic overlap between asthma from the UK Biobank and eight mental health disorders from the Psychiatric Genomics Consortium: attention deficit hyperactivity disorder (ADHD), anxiety disorder (ANX), autism spectrum disorder, bipolar disorder, eating disorder, major depressive disorder (MDD), post-traumatic stress disorder and schizophrenia (sample size 9537–394 283).

In the single-trait genome-wide association analysis, we replicated 130 previously reported loci and discovered 31 novel independent loci that are associated with asthma. We identified that ADHD, ANX and MDD have a strong genetic correlation with asthma at the genome-wide level. Cross-trait meta-analysis identified seven loci jointly associated with asthma and ADHD, one locus with asthma and ANX, and 10 loci with asthma and MDD. Functional analysis revealed that the identified variants regulated gene expression in major tissues belonging to the exocrine/endocrine, digestive, respiratory and haemic/immune systems. Mendelian randomisation analyses suggested that ADHD and MDD (including 6.7% sample overlap with asthma) might increase the risk of asthma.

This large-scale genome-wide cross-trait analysis identified shared genetics and potential causal links between asthma and three mental health disorders (ADHD, ANX and MDD). Such shared genetics implicate potential new biological functions that are in common among them.
Geographic isolation and climatic variability contribute to genetic differentiation in fragmented populations of the long-lived subalpine conifer Pinus cembra L. in the western Alps
Authors: Tóth Endre Gy , Tremblay Francine , Housset Johann M. , Bergeron Yves , Carcaillet Christopher
Published: October 2019

Background

Genetic processes shape the modern-day distribution of genetic variation within and between populations and can provide important insights into the underlying mechanisms of evolution. The resulting genetic variation is often unequally partitioned within species’ distribution range and especially large differences can manifest at the range limit, where population fragmentation and isolation play a crucial role in species survival. Despite several molecular studies investigating the genetic diversity and differentiation of European Alpine mountain forests, the climatic and demographic constrains which influence the genetic processes are often unknown. Here, we apply non-coding microsatellite markers to evaluate the sporadic peripheral and continuous populations of cembra pine (Pinus cembraL.), a long-lived conifer species that inhabits the subalpine treeline ecotone in the western Alps to investigate how the genetic processes contribute to the modern-day spatial distribution. Moreover, we corroborate our findings with paleoecological records, micro and macro-remains, to infer the species’ possible glacial refugia and expansion scenarios.

Results

Four genetically distinct groups were identified, with Bayesian andFSTbased approaches, across the range of the species, situated in the northern, inner and south-western Alps. We found that genetic differentiation is substantially higher in marginal populations than at the center of the range, and marginal stands are characterized by geographic and genetic isolation due to spatial segregation and restricted gene flow. Moreover, multiple matrix regression approaches revealed effects of climatic heterogeneity in species’ spatial genetic pattern. Also, population stability tests indicated that all populations had experienced a severe historical bottleneck, no heterozygosity excess was detected, suggesting that more recently population sizes have remained relatively stable.

Conclusions

Our study demonstrated that cembra pine might have survived in multiple glacial refugia and subsequently recolonized the Alps by different routes. Modern-day marginal populations, at the edge of the species’ range, could maintain stable sizes over long periods without inbreeding depression and preserve high amounts of genetic variation. Moreover, our analyses indicate that climatic variability has played a major role in shaping differentiation, in addition to past historical events such as migration and demographic changes.
The recombination-cold region as an epidemiological marker of recombinogenic opportunistic pathogen Mycobacterium avium
Authors: Yano Hirokazu , Suzuki Haruo , Maruyama Fumito , Iwamoto Tomotada
Published: October 2019

Background

The rapid identification of lineage remains a challenge in the genotyping of clinical isolates of recombinogenic pathogens. The chromosome ofMycobacterium aviumsubsp.hominissuis(MAH), an agent ofMycobacterium aviumcomplex (MAC) lung disease, is often mosaic and is composed of chromosomal segments originating from different lineages. This makes it difficult to infer the MAH lineage in a simple experimental set-up. To overcome this difficulty, we sought to identify chromosomal marker genes containing lineage-specific alleles by genome data mining.

Results

We conducted genetic population structure analysis, phylogenetic analysis, and a survey of historical recombination using data from 125 global MAH isolates. Six MAH lineages (EA1, EA2, SC1, SC2, SC3, and SC4) were identified in the current dataset. One P-450 gene (locus_tag MAH_0788/MAV_0940) in the recombination-cold region was found to have multiple alleles that could discriminate five lineages. By combining the information about allele type from one additional gene, the six MAH lineages as well as otherM. aviumsubspecies were distinguishable. A recombination-cold region of 116 kb contains an insertion hotspot and is flanked by a mammalian cell-entry protein operon where allelic variants have previously been reported to occur. Hence, we speculate that the acquisition of lineage- or strain-specific insertions has introduced homology breaks in the chromosome, thereby reducing the chance of interlineage recombination.

Conclusions

The allele types of the newly identified marker genes can be used to predict major lineages ofM. avium.The single nucleotide polymorphism typing approach targeting multiallelic loci in recombination-cold regions will facilitate the epidemiological study of MAC, and may also be useful for equivalent studies of other nontuberculous mycobacteria potentially carrying mosaic genomes.
Use of patients’ unsolicited correspondence to a family doctor to describe and understand valued components of a doctor-patient relationship: A Hermeneutics approach
Authors: Yaffe Mark J. , Hovey Richard B. , Rodriguez Charo
Published: October 2019

Background

Communication and behavior within doctor - patient encounters have been examined using varied techniques; however the nature of unsolicited writings from patients to their family doctors has rarely been reported. This paper therefore aimed to explore the content of, and motivation for, such correspondence.

Methods

One hundred and seven writings to one family physician about care provided during a four decade period were considered. Univariate analyses were used to identify features of patients or family members who wrote personalized notes to the doctor, when, and in what fashion. A hermeneutic approach helped look at the content of the notes, the specific words or sentiments used to describe encounters or care received, and possible motivations for writing. Iterative review of words or phrases generated themes which summarized appreciated physician or relational attributes, as well as motivations for writing.

Results

Notes were mostly handwritten, predominantly by women, and frequently coinciding with holidays and life span events. Appreciated doctor characteristics and behaviors were (1) quality care; and physician (2) competence; (3) physical presence; (4) positive personal traits; (5) provision of emotional support; and (6) spiritual impact. Motivations for writing were grouped as desire to (1) express appreciation for an established relationship; (2) acknowledge value / benefit experienced from continuity of care; (3) seek catharsis, emotional relief or closure; (4) reflect on termination of care; (5) validate care that incorporates both Hippocratic tradition and Asklepian healing; and (6) share personal reflection, experience, or impact.

Conclusions

Unsolicited writings provide personalized links from patients to physicians, expressing thoughts perhaps difficult to share face to face. They offer potential as teaching tools about the content of doctor-patient relationships; for example, the writers studied expressed appreciation for quality continuity care that was competent, considerate, and supportive of emotional and spiritual needs.
Pulmonary Cryptococcus infections as a manifestation of idiopathic CD4 lymphocytopenia: case report and literature review
Authors: Thornton Christina S. , Larios Oscar , Grossman Jennifer , Griener Thomas P. , Vaughan Steven
Published: October 2019

Background

Idiopathic CD4 lymphocytopenia (ICL) is a rare clinical disease with relative CD4 deficiency in the absence of HIV infection. The pathogenicity of ICL is poorly understood with an unclear incidence rate in the general population. Sequelae of ICL includes AIDS-defining infections, which most commonly includes Cryptococcus neoformans. Typically, C. neoformans infections present with CNS involvement but rarely with extra-CNS manifestations. Here, we present a rare case of ICL with exclusively primary pulmonary cryptococcus and a review of the literature.

Case presentation

A 56-year-old female presented to our tertiary care hospital requiring a right hip open reduction intervention. The patient became febrile during admission, prompting a work-up that included a chest X-ray showing a peripheral pulmonary solitary nodule. Transthoracic biopsy revealed encapsulated yeast forms in keeping with C. neoformans. CD4 counts, repeated at least one month apart, were < 200 cells/mm3, with negative HIV testing. Flow cytometry and genetic testing were completed to elucidate the etiology of the immune deficiency, both of which were unremarkable. She was subsequently treated with 12 months of posaconazole with clinical resolution.

Conclusions

Our patient highlights a rare clinical disease, which a review of literature revealed only five cases in the literature with exclusive pulmonary Cryptococcus in ICL/ This case demonstrates the strong clinical acumen required to properly diagnose and ultimately manage the patient.
A case report on lipofuscin deposition in a graft biopsy two years after kidney transplantation: an insignificant bystander or a pathogenic benefactor?
Authors: Leung Vivian W. Y. , Pilon Sarah-Jeanne , Fiset Pierre O. , Sandal Shaifali
Published: October 2019

Background

Lipofuscin deposition is a characteristic manifestation of aging. There is very limited literature in humans and in animals describing these deposits in native kidneys. Overall, it is thought to be non-pathogenic and successful transplants from a donor with lipofuscin deposits have been reported. We present the case of a patient who underwent a kidney transplant and a for-cause biopsy post-transplantation incidentally revealed lipofuscin deposition.

Case presentation

A 48-year old gentleman with a past medical history of diabetes, hypertension, coronary artery disease, and ischemic and then hemorrhagic cardiovascular accident underwent a successful kidney transplant. His donor was an expanded criteria donor with no major past medical history. Post-transplant course was complicated by delayed graft function requiring one dialysis treatment for hyperkalemia. After that he had an uneventful course and achieved a baseline creatinine of 1.2 mg/dL, with no proteinuria. On a routine 19-month follow-up he was noted to have proteinuria and an antibody against the major-histocompatibility-complex class I-related chain A. A graft biopsy revealed acute antibody-mediated rejection and impressive lipofuscin deposition. He was subsequently treated with an antibody-mediated rejection protocol that included high dose steroids, Rituximab, plasmapheresis, and intravenous immunoglobulin, but responded poorly to this regimen. A 6-month follow up biopsy continued to show lipofuscin deposition, with similar microvascular injury scores and 12-months later his creatinine remained stable but his proteinuria worsened. Patient was struggling with recurrent infectious episodes requiring hospitalizations and thus no further diagnostic or therapeutic treatments were pursued.

Conclusions

Lipofuscin deposition has been reported in solid organ transplants but the significance and cause are not well understood. Several physiologic and some pathologic causes to these deposits have been reported including age, diabetes, medications and a genetic syndrome. We propose that immunologic causes such as rejection in the presence of other risk factors could potentiate the oxidative stress leading to excessive lipofuscin deposition in kidney transplants. In the case of our patient, we conclude that these deposits were likely recipient-derived, and postulate that the cumulative burden of inflammation from rejection, and underlying medical conditions led to increased lipofuscin deposition. We speculate them to be an innocent bystander.
Association between benign thyroid disease and breast cancer: a single center experience
Authors: Dobrinja Chiara , Scomersi Serena , Giudici Fabiola , Vallon Giulia , Lanzaro Alessio , Troian Marina , Bonazza Deborah , Romano Andrea , Zanconati Fabrizio , de Manzini Nicolò , Bortul Marina
Published: October 2019

Background

The relationship between breast cancer (BC) and thyroid disease (TD) is still controversial. The aim of the study was to investigate the possible coexistence of TD in patients with newly diagnosed BC and its correlation with BC clinical presentation with regard to menopausal status and stage of disease.

Methods

This is a retrospective cohort study of all patients treated for primary BC between 2014 and 2016 at the Breast Unit of Trieste University Hospital. Clinical charts and reports were reviewed for coexisting thyroid disorders (i.e. hyperthyroidism, hypothyroidism, benign TD, thyroid cancer, thyroid autoimmunity) and menopausal status at the time of BC diagnosis. Biomolecular profile, stage, and grading of BC were also evaluated.

Results

A total of 786 women and 7 men were included in the study. Co-presence of TD was found in 161(20.3%) cases: of these, 151(19.4%) patients presented benign TD and 10(1.3%) patients presented thyroid carcinoma. Thyroid autoimmunity was found in 51(32%) patients. Regarding thyroid function, 88(55%) patients had hypothyroidism, 19(12%) hyperthyroidism, and 54(33%) normal thyroid function. No statistically significant correlation was found between age and TD (p = 0.16), although TD was more common in women aged ≥60 years. Women with BC diagnosed at pre-menopausal age were more likely to have thyroid autoimmune diseases (45% vs. 29%, p = 0.05). No association was detected among BC molecular profiles with either thyroid autoimmunity (p = 0.26) or altered thyroid function (p = 0.63). High-grade BC was more frequent in women with hyperthyroidism (52.9%, p = 0.04), but the grading was independent from the presence of thyroid autoimmune disease (p = 0.87). BC stage was related to both thyroid autoimmunity (p = 0.04) and thyroid function (p < 0.001), with 55.2% of women affected by benign TD presenting with stage I BC and more aggressive BCs found in hypothyroid patients.

Conclusions

According our study results, patients with primary BC present a greater incidence of autoimmunity disorders, especially when diagnosed in the pre-menopausal setting. However, further prospective studies are required to definitively prove causality.
Assessing the validity of the clinician-rated distress thermometer in palliative care
Authors: Van Lander A. , Tarot A. , Savanovitch C. , Pereira B. , Vennat B. , Guastella V.
Published: October 2019

Background

The distress of patients suffering from a terminal illness can lead to a state of despair and requests for euthanasia and assisted suicide. It is a major challenge for palliative care workers. The Distress Thermometer (DT) is recommended by the National Comprehensive Cancer Network as a means of more easily assessing distress. It is available as a Self-assessment reported Distress Thermometer, but for a wider use in palliative care it should also be implemented in the form of a clinician-reported outcome (clinRO). Clinicians need to rate patient’s distress when the patient is not able to do so (subject that cannot be addressed, defensive patient…). The primary aim of the quantitative study was to assess the validity of the Clinician-Rated Distress Thermometer in palliative care.

Method

The assessments were performed by teams working in three palliative care centres. The primary endpoint was concordance between the patient and clinicians’ responses via Lin’s concordance coefficient. Eligible patients were aged 18 years or older, suffering from a severe disease in the palliative phase, and with a sufficient level of awareness to consent to participate in the study. A total of 51 patients were recruited, 55% were male, with a mean age of 65.8 years [39–90 years].

Results

Three hundred sixty-four clinician-Rated Distress Thermometer and 467 Self-Reported Distress Thermometer were performed. Only 364 of the 467 Self-Reported Distress Thermometer were used for the study, as investigators did not systematically ask the patient to give an account of his distress. Concordance between patient and clinician responses: The Lin’s concordance coefficient with a threshold (alpha) of 5% was 0.46 [0.38; 0.54]. At the first assessment, it was 0.61 [0.44; 0.79]. The Cohen’s kappa coefficient was 0.52, with a concordance rate of 79.6%. The sensitivity was 82.9% [66.4–93.4] and the specificity 71.4% [41.9–91.6].

Conclusion

The first assessment gave the best results in terms of concordance between Clinician-Rated DT and Self-Reported DT. In the next assessments, the Clinician-Rated DT were less consistent with the patients’ Self-Reported DT.
Impact of high drinking water nitrate levels on the endogenous formation of apparent N-nitroso compounds in combination with meat intake in healthy volunteers
Authors: van Breda Simone G. , Mathijs Karen , Sági-Kiss Virág , Kuhnle Gunter G. , van der Veer Ben , Jones Rena R. , Sinha Rashmi , Ward Mary H. , de Kok Theo M.
Published: October 2019

Background

Nitrate is converted to nitrite in the human body and subsequently can react with amines and amides in the gastrointestinal tract to form N-nitroso compounds (NOCs), which are known to be carcinogenic in animals. Humans can be exposed to nitrate via consumption of drinking water and diet, especially green leafy vegetables and cured meat. The contribution of nitrate from drinking water in combination with meat intake has not been investigated thoroughly. Therefore, in the present pilot study, we examined the effect of nitrate from drinking water, and its interaction with the consumption of white and processed red meat, on the endogenous formation of NOCs, taking into account the intake of vitamin C, a nitrosation inhibitor.

Methods

Twenty healthy subjects were randomly assigned to two groups consuming either 3.75 g/kg body weight (maximum 300 g per day) processed red meat or unprocessed white meat per day for two weeks. Drinking water nitrate levels were kept low during the first week (< 1.5 mg/L), whereas in week 2, nitrate levels in drinking water were adjusted to the acceptable daily intake level of 3.7 mg/kg bodyweight. At baseline, after 1 and 2 weeks, faeces and 24 h urine samples were collected for analyses of nitrate, apparent total N-nitroso compounds (ATNC), compliance markers, and genotoxic potential in human colonic Caco-2 cells.

Results

Urinary nitrate excretion was significantly increased during the high drinking water nitrate period for both meat types. Furthermore, levels of compliance markers for meat intake were significantly increased in urine from subjects consuming processed red meat (i.e. 1-Methylhistidine levels), or unprocessed white meat (i.e. 3-Methylhistidine). ATNC levels significantly increased during the high drinking water nitrate period, which was more pronounced in the processed red meat group. Genotoxicity in Caco-2 cells exposed to faecal water resulted in increased genotoxicity after the interventions, but results were only significant in the low drinking water nitrate period in subjects consuming processed red meat. Furthermore, a positive correlation was found between the ratio of nitrate/vitamin C intake (including drinking water) and the level of ATNC in faecal water of subjects in the processed red meat group, but this was not statistically significant.

Conclusions

Drinking water nitrate significantly contributed to the endogenous formation of NOC, independent of the meat type consumed. This implies that drinking water nitrate levels should be taken into account when evaluating the effect of meat consumption on endogenous formation of NOC.

Trial registration

Dutch Trialregister: 29707. Registered 19th of October 2018. Retrospectively registered.
Prevalence and risk factors of HIV infection among people who inject drugs in Cambodia: findings from a national survey
Authors: Mburu Gitau , Chhoun Pheak , Chann Navy , Tuot Sovannary , Mun Phalkun , Yi Siyan
Published: October 2019

Background

Globally, people who inject drugs (PWID) continue to be among the most vulnerable populations to acquire infection of human immunodeficiency virus (HIV). The most recent national survey found that nearly a quarter of PWID in Cambodia were infected with HIV in 2012. The aim of this study is to estimate the current prevalence of and factors associated with HIV infection among PWID in Cambodia.

Methods

This national integrated biological and behavioral survey was conducted from June to December 2017. Participants were recruited from the capital city and 11 major provinces using the respondent driven sampling method. Face-to-face interviews were conducted using a structured questionnaire, and blood samples were collected for HIV, syphilis, and hepatitis C virus (HCV) testing. Multiple logistic regression analysis was conducted to identify risk factors for HIV infection. All analyses were estimated with sampling weights that corrected for non-response and sample design.

Results

A total of 310 PWID participated in the study, and the mean age was 31.8 years (SD = 7.8). The prevalence of HIV was 15.2%. More than half (57.4%) of the HIV-positive participants were co-infected with HCV, and 44.7% were not aware of their HIV status prior to this study. After adjustment for other covariates, HIV infection remained positively associated with being female (AOR = 1.88, 95% CI = 1.03–4.04), being in the older age group of ≥35 (AOR = 2.99, 95% CI 1.33–9.22), being widowed, divorced or separated (AOR = 2.57, 95% CI = 1.04–6.67), living on the streets (AOR = 2.86, 95% CI 1.24–4.37), and HCV infection (AOR = 3.89, 95% CI 1.86–1.15). The HIV infection remained negatively associated with having higher level of formal education of ≥10 years (AOR = 0.44, 95% CI 0.13–0.83) and higher average income of ≥US$200 per month (AOR = 0.20, 95% CI = 0.05–0.74).

Conclusions

The prevalence of HIV among PWID in Cambodia remains high, but is reducing compared with the 24.8% reported in the 2012 national survey. Findings from this study provide critical information for tailoring interventions based on identified vulnerabilities and risk factors for HIV. Our findings underline the importance of socio-structural factors in HIV epidemiology among PWID in Cambodia, which require mitigation.
Cortical ensemble activity discriminates auditory attentional states
Authors: Yao Pan-tong , Shen Jia , Chen Liang , Ge Shaoyu , Xiong Qiaojie
Published: October 2019

Selective attention modulates sensory cortical activity. It remains unclear how auditory cortical activity represents stimuli that differ behaviorally. We designed a cross-modality task in which mice made decisions to obtain rewards based on attended visual or auditory stimuli. We recorded auditory cortical activity in behaving mice attending to, ignoring, or passively hearing auditory stimuli. Engaging in the task bidirectionally modulates neuronal responses to the auditory stimuli in both the attended and ignored conditions compared to passive hearing. Neuronal ensemble activity in response to stimuli under attended, ignored and passive conditions are readily distinguishable. Furthermore, ensemble activity under attended and ignored conditions are in closer states compared to passive condition, and they share a component of attentional modulation which drives them to the same direction in the population activity space. Our findings suggest that the ignored condition is very different from the passive condition, and the auditory cortical sensory processing under ignored, attended and passive conditions are modulated differently.
circRNA circAF4 functions as an oncogene to regulate MLL-AF4 fusion protein expression and inhibit MLL leukemia progression
Authors: Huang Wei , Fang Ke , Chen Tian-Qi , Zeng Zhan-Cheng , Sun Yu-Meng , Han Cai , Sun Lin-Yu , Chen Zhen-Hua , Yang Qian-Qian , Pan Qi , Luo Xue-Qun , Wang Wen-Tao , Chen Yue-Qin
Published: October 2019

Background

Circular RNAs (circRNAs) represent a type of endogenous noncoding RNAs that are generated by back-splicing events and favor repetitive sequences. Recent studies have reported that cancer-associated chromosomal translocations could juxtapose distant complementary repetitive intronic sequences, resulting in the aberrant formation of circRNAs. However, among the reported fusion genes, only a small number of circRNAs were found to originate from fusion regions during gene translocation. We question if circRNAs could also originate from fusion partners during gene translocation.

Methods

Firstly, we designed divergent primers for qRT-PCR to identify a circRNA circAF4 in AF4 gene and investigated the expression pattern in different types of leukemia samples. Secondly, we designed two small interfering RNAs specially targeting the back-spliced junction point of circAF4 for functional studies. CCK8 cell proliferation and cell cycle assay were performed, and a NOD-SCID mouse model was used to investigate the contribution of circAF4 in leukemogenesis. Finally, luciferase reporter assay, AGO2 RNA immunoprecipitation (RIP), and RNA Fluorescent in Situ Hybridization (FISH) were performed to confirm the relationship of miR-128-3p, circAF4, and MLL-AF4 expression.

Results

We discovered a circRNA, named circAF4, originating from the AF4 gene, a partner of the MLL fusion gene in MLL-AF4 leukemia. We showed that circAF4 plays an oncogenic role in MLL-AF4 leukemia and promotes leukemogenesis in vitro and in vivo. More importantly, knockdown of circAF4 increases the leukemic cell apoptosis rate in MLL-AF4 leukemia cells, while no effect was observed in leukemia cells that do not carry the MLL-AF4 translocation. Mechanically, circAF4 can act as a miR-128-3p sponge, thereby releasing its inhibition on MLL-AF4 expression. We finally analyzed most of the MLL fusion genes loci and found that a number of circRNAs could originate from these partners, suggesting the potential roles of fusion gene partner-originating circRNAs (named as FP-circRNAs) in leukemia with chromosomal translocations.

Conclusion

Our findings demonstrate that the abnormal elevated expression of circAF4 regulates the cell growth via the circAF4/miR-128-3p/MLL-AF4 axis, which could contribute to leukemogenesis, suggesting that circAF4 may be a novel therapeutic target of MLL-AF4 leukemia.
LINC00673 is activated by YY1 and promotes the proliferation of breast cancer cells via the miR-515-5p/MARK4/Hippo signaling pathway
Authors: Qiao Kun , Ning Shipeng , Wan Lin , Wu Hao , Wang Qin , Zhang Xingda , Xu Shouping , Pang Da
Published: October 2019

Background

An increasing number of studies have shown that long noncoding RNAs (lncRNAs) play essential roles in tumor initiation and progression. LncRNAs act as tumor promoters or suppressors by targeting specific genes via epigenetic modifications and competing endogenous RNA (ceRNA) mechanisms. In this study, we explored the function and detailed mechanisms of long intergenic nonprotein coding RNA 673 (LINC00673) in breast cancer progression.

Methods

Quantitative real-time PCR (qRT-PCR) was used to examine the expression of LINC00673 in breast cancer tissues and in adjacent normal tissues. Gain-of-function and loss-of function experiments were conducted to investigate the biological functions of LINC00673 in vitro and in vivo. We also explored the potential role of LINC00673 as a therapeutic target using antisense oligonucleotide (ASO) in vivo. RNA sequencing (RNA-seq), dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP) assay, and rescue experiments were performed to uncover the detailed mechanism of LINC00673 in promoting breast cancer progression.

Results

In the present study, LINC00673 displayed a trend of remarkably increased expression in breast cancer tissues and was associated with poor prognosis in breast cancer patients. Importantly, LINC00673 depletion inhibited breast cancer cell proliferation by inhibiting the cell cycle and increasing apoptosis. Furthermore, ASO therapy targeting LINC00673 substantially suppressed breast cancer cell proliferation in vivo. Mechanistically, LINC00673 was found to act as a ceRNA by sponging miR-515-5p to regulate MARK4 expression, thus inhibiting the Hippo signaling pathway. Finally, ChIP assay showed that the transcription factor Yin Yang 1 (YY1) could bind to the LINC00673 promoter and increase its transcription in cis.

Conclusions

YY1-activated LINC00673 may exert an oncogenic function by acting as a sponge for miR-515-5p to upregulate the MARK4 and then inhibit Hippo signaling pathway, and may serve as a potential therapeutic target.
Predicting acute coronary syndrome in males and females with chest pain who call an emergency medical communication centre
Authors: Reuter Paul-Georges , Pradeau Catherine , Huo Yung Kai Samantha , Lhermusier Thibault , Bourdé Arnaud , Tentillier Eric , Combes Xavier , Bongard Vanina , Ducassé Jean-Louis , Charpentier Sandrine
Published: October 2019

Background

Chest pain is a frequent reason for calls in emergency medical communication centre (EMCC). Detecting a coronary origin by phone is a challenge. This is especially so as the presentations differ according to gender. We aimed to establish and validate a sex-based model to predict a coronary origin of chest pain in patients calling an EMCC.

Methods

This prospective cohort study enrolled patients at 18 years of age or older who called the EMCC because of non-traumatic chest pain. The main outcome was the diagnosis of acute coronary syndrome (ACS) determined by expert evaluation of patient files.

Results

During 18 months, 3727 patients were enrolled: 2097 (56%) men and 1630 (44%) women. ACS was diagnosed in 508 (24%) men and 139 (9%) women. For men, independent factors associated with an ACS diagnosis were age, tobacco use, severe and permanent pain; retrosternal, breathing non-related and radiating pain; and additional symptoms. The area under the receiver operating characteristic curve (AUC) was 0.76 (95% confidence interval [CI] 0.73–0.79) for predicting ACS. The accuracy of the male model to predict ACS was validated in a validation dataset (Hosmer-Lemeshow test: p = 0.554); the AUC was 0.77 (95%CI 0.73–0.80). For women, independent factors associated with an ACS diagnosis were age ≥ 60 years, personal history of coronary artery disease, and breathing non-related and radiating pain. The AUC was 0.79 (95%CI 0.75–0.83). The accuracy of the female model to predict ACS was not validated in the validation dataset (Hosmer-Lemeshow test: p = 0.035); the AUC was 0.67 (95%CI 0.60–0.74).

Conclusions

Predictors of an ACS diagnosis in patients calling an EMCC for chest pain differ between men and women. We developed an accurate predictive model for men, but for women, the accuracy was poor.

Trial registration

This study is registered with ClinicalTrials.gov (NCT02042209).
A Delphi consensus study for teaching “Basic Trauma Management” to third-year medical students
Authors: Berger-Estilita Joana , Nabecker Sabine , Greif Robert
Published: October 2019

Background

The Basic-Trauma Management (BTM) course has been taught to third-year medical students in small groups for many years without substantial changes. With the introduction of a new curriculum for Swiss medical students, it was necessary to revise the BTM content and re-align it. Our aim was to identify core competencies for the revised BTM course.

Methods

We applied a three-round step-wise Delphi consensus. First, we asked open-ended questions on what were the most important competencies to be taught for BTM; the second round used Likert scales to ensure agreement on the competencies; and the final round reached out for consensus on these BTM competencies. Stakeholders were selected based on their long-standing experience in teaching BTM and in managing trauma patients.

Results

Consensus was found on 29 competencies out of an initial 130 proposals. “Human Factors”, which had not been taught previously, scored relatively high, at 22%. The sole specific trauma skill agreed upon was the use of tourniquets.

Conclusions

This is an example of curricular revision of a clinical skills course after the introduction of a regulatory framework for undergraduate medical education. The revised course curriculum tailors the concepts and skills in trauma that fulfill stakeholder needs, and are in agreement with the new Swiss learning outcomes.