bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

RationaleThe 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.MethodsWe 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.ResultsWe 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.ConclusionOur 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

AbstractBackgroundGenetic 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.ResultsFour 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.ConclusionsOur 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

AbstractBackgroundThe 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.ResultsWe 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.ConclusionsThe 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

AbstractBackgroundCommunication 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.MethodsOne 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.ResultsNotes 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.ConclusionsUnsolicited 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

Abstract

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

Abstract

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

Abstract

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

AbstractBackgroundThe 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.MethodThe 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].ResultsThree 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].ConclusionThe 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.