An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19-associated coagulopathy, characterised by increased thrombotic and microvascular complications. ...Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy. To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19.
In this single-centre cross-sectional study, hospitalised adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the medical intensive care unit (ICU) or a specialised non-ICU COVID-19 floor in our hospital. Asymptomatic, non-hospitalised controls were recruited as a comparator group for biomarkers that did not have a reference range. We assessed markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes. We compared the level of each marker in ICU patients, non-ICU patients, and controls, where applicable. We assessed correlations between these laboratory results with clinical outcomes, including hospital discharge and mortality. Kaplan-Meier analysis was used to further explore the association between biochemical markers and survival.
68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls. Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% SD 199 in ICU patients vs 278% 133 in non-ICU patients; p<0·0001) and soluble P-selectin (15·9 ng/mL 4·8 vs 11·2 ng/mL 3·1; p=0·0014). VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients. We found mortality to be significantly correlated with VWF antigen (r = 0·38; p=0·0022) and soluble thrombomodulin (r = 0·38; p=0·0078) among all patients. In all patients, soluble thrombomodulin concentrations greater than 3·26 ng/mL were associated with lower rates of hospital discharge (22 88% of 25 patients with low concentrations vs 13 52% of 25 patients with high concentrations; p=0·0050) and lower likelihood of survival on Kaplan-Meier analysis (hazard ratio 5·9, 95% CI 1·9-18·4; p=0·0087).
Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death. Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19.
This work was supported by a gift donation from Jack Levin to the Benign Hematology programme at Yale, and the National Institutes of Health.
To describe the characteristics and outcome of patients with giant-cell arteritis (GCA)-related ophthalmologic involvement at diagnosis.
In a retrospective single-center cohort of 409 consecutive ...patients with GCA, we retrieved 104 patients with visual symptoms at GCA diagnosis and we compared them to 104 age- and sex-matched controls without ophthalmologic involvement. Each visual symptom was associated to an ophthalmologic diagnosis that was centrally re-assessed by an ophthalmologist.
Compared to controls, patients with visual symptoms showed less fever (p = 0.0006), less polymyalgia rheumatica (p = 0.02) and lower acute phase reactants (p = 0.004). Blurred vision (in 60% of patients), amaurosis fugax (in 18%), diplopia (in 13%) and permanent visual loss (in 9%) were the four visual symptoms described by patients before GCA diagnosis. Anterior ischemic optic neuropathy (AION) was found in 47 (45%) patients, followed by central retinal artery occlusion (CRAO) in 15 (15%). Two patients had both involvements. The delay of glucocorticoids initiation was not different between patients with and without visual symptoms (p = 0.06). Among the 60 patients with initial AION and/or CRAO, 39 (65%) kept definite blindness or important visual damage, although 45 (75%) had received intravenous (IV) pulses of methylprednisolone. A new ischemic event (AION in all cases) occurred in 4% of patients with visual symptoms despite the initiation of treatment.
Ophthalmologic involvement was observed in one-quarter of our GCA patients. AION is still associated with the worst visual prognosis, and IV methylprednisolone pulses did not reduce the risk of blindness in our study.
Studies report a growing tendency for students to experience state anxiety in schools. However, the combination of individual susceptibilities likely to trigger students' anxious states remains ...unclear.
This study examined whether distinct profiles of students emerge regarding their susceptibility to anxiety sensitivity and/or test anxiety and evaluated whether students' profile predicted anxious states. We also verified whether susceptibility profiles varied across gender, school level, and school type.
In total, 1,404 Canadian students in Grades 5 and 10 (589 boys;
= 15.2,
= 2.1) from 13 public and private schools completed self-reported measures of state/trait anxiety, anxiety sensitivity, and test anxiety.
Latent profile analyses identified four susceptibility profiles: (1) Double-susceptibility: highest anxiety sensitivity and test anxiety scores; (2) Unique-susceptibility to test anxiety: high test anxiety score and low anxiety sensitivity score; (3) Unique-susceptibility to anxiety sensitivity: high anxiety sensitivity score and low test anxiety score; and (4) No-susceptibility: lowest anxiety sensitivity and test anxiety scores. The profiles comprised 12, 9, 6, and 73% of the sample, respectively, and their membership varied across gender and school type, but not across school levels. A linear mixed-effect model showed that state anxiety varied significantly between profiles, where the Double-susceptibility profile predicted the highest state anxiety scores, followed by the two Unique-susceptibility profiles (indifferently), and the No-susceptibility profile.
Beyond their theoretical contribution to the state-trait anxiety literature, these findings suggest that selective interventions designed more specifically for students with the Double-susceptibility profile may be worthwhile. Results also highlight the high proportion of students with the No-susceptibility profile and shed light on the reassuring portrait regarding students' anxiety.
Oesophageal atresia-tracheoesophageal fistula (EA-TEF) is a common congenital digestive disease. Patients with EA-TEF face gastrointestinal, surgical, respiratory, otolaryngological, nutritional, ...psychological and quality of life issues in childhood, adolescence and adulthood. Although consensus guidelines exist for the management of gastrointestinal, nutritional, surgical and respiratory problems in childhood, a systematic approach to the care of these patients in adolescence, during transition to adulthood and in adulthood is currently lacking. The Transition Working Group of the International Network on Oesophageal Atresia (INoEA) was charged with the task of developing uniform evidence-based guidelines for the management of complications through the transition from adolescence into adulthood. Forty-two questions addressing the diagnosis, treatment and prognosis of gastrointestinal, surgical, respiratory, otolaryngological, nutritional, psychological and quality of life complications that patients with EA-TEF face during adolescence and after the transition to adulthood were formulated. A systematic literature search was performed based on which recommendations were made. All recommendations were discussed and finalized during consensus meetings, and the group members voted on each recommendation. Expert opinion was used when no randomized controlled trials were available to support the recommendation. The list of the 42 statements, all based on expert opinion, was voted on and agreed upon.
Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast ...cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10
. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
The PI3K-AKT-mTOR pathway may be involved in the development of central nervous system (CNS) metastasis from breast cancer. Accordingly, herein we explored whether single nucleotide polymorphisms ...(SNPs) of this pathway are associated with altered risk of CNS metastasis formation in metastatic breast cancer patients.
The GENEOM study (NCT00959556) included blood sample collection from breast cancer patients treated in the neoadjuvant, adjuvant or metastatic setting. We identified patients with CNS metastases for comparison with patients without CNS metastasis, defined as either absence of neurological symptoms or normal brain magnetic resonance imaging (MRI) before death or during 5-year follow-up. Eighty-eight SNPs of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian (or mechanistic) target of rapamycin (mTOR) pathway genes were selected for analysis: AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6).
Of 342 patients with metastases, 207 fulfilled the inclusion criteria: One-hundred-and-seven patients remained free of CNS metastases at last follow-up or date of death whereas 100 patients developed CNS metastases. Among clinical parameters, hormonal and human epidermal growth factor receptor-2 (HER2) status as well as vascular tumour emboli was associated with risk of CNS metastasis. Only PI3KR1-rs706716 was associated with CNS metastasis in univariate analysis after Bonferroni correction (p < 0.00085). Multivariate analysis showed associations between AKT1-rs3803304, AKT2-rs3730050, PDK1-rs11686903 and PI3KR1-rs706716 and CNS metastasis .
PI3KR1-rs706716 may be associated with CNS metastasis in metastatic breast cancer patients and could be included in a predictive composite score to detect early CNS metastasis irrespective of breast cancer subtype.
•Early diagnosis of central nervous system (CNS) metastasis may improve outcome of breast cancer patients.•Identification of CNS metastasis risk may influence imaging follow-up and help to design prevention strategies.•PI3K-AKT-mTOR pathway single nucleotide polymorphisms (SNPs) may identify metastatic breast cancer patients at risk of CNS metastasis.
Large-vessel involvement (LVI) can occur in giant-cell arteritis (GCA) and may represent a distinct disease subgroup with a higher risk for aortic dilation. This study aimed to better characterize ...the presentation and evolution of LVI in patients with GCA.
A retrospective multicenter study enrolled 248 GCA patients with LVI and 301 GCA patients without LVI on imaging. Factors associated with aortic dilation were identified in a multivariable model.
The patients with LVI were younger (p<0.0001), more likely to be women (p=0.01), and showed fewer cephalic symptoms (p<0.0001) and polymyalgia rheumatica (p=0.001) but more extracranial vascular symptoms (p=0.05) than the patients without LVI. Glucocorticoids (GC) management did not differ between the two groups, but the GC discontinuation rate was lower in the patients with LVI (p=0.0003). Repeated aortic imaging procedures were performed at 19months range: 5–162months and 17months range: 6–168months after diagnosis in 154 patients with LVI and 123 patients without LVI, respectively, of whom 21% and 7%, respectively, presented new aortic dilations (p=0.0008). In the patients with LVI, aortic dilation occurred on an aorta segment shown to be inflammatory on previous imaging in 94% of patients. In the multivariate analysis, LVI was the strongest predictor of aortic dilation (hazard ratio: 3.16 range: 1.34–7.48, p=0.009).
LVI represents a distinct disease pattern of GCA with an increased risk of aortic dilation. Control of the aortic morphology during follow-up is required.
•Patients with GCA-related large-vessel involvement showed distinct features.•Aortic dilation more likely occurs on inflammatory aorta segment.•Patients with GCA-related large-vessel involvement have to control aorta morphology.
To identify characteristics and factors associated with relapse and glucocorticoid (GC) dependence in patients with giant cell arteritis (GCA).
We retrospectively analyzed 326 consecutive patients ...with GCA followed for at least 12 months. Factors associated with relapse and GC dependence were identified in multivariable analyses.
The 326 patients (73% women) were followed up for 62 (12-262) months. During followup, 171 (52%) patients relapsed, including 113 (35%) who developed GC dependence. Relapsing patients had less history of stroke (p = 0.01) and presented large-vessel vasculitis (LVV) more frequently on imaging (p = 0.01) than patients without relapse. During the first months, therapeutic strategy did not differ among relapsing and nonrelapsing patients. GC-dependent patients were less likely to have a history of stroke (p = 0.004) and presented LVV on imaging more frequently (p = 0.005) than patients without GC-dependent disease. In multivariable analyses, LVV was an independent predictive factor of relapse (HR 1.49, 95% CI 1.002-2.12; p = 0.04) and GC dependence (OR 2.19, 95% CI 1.19-4.05; p = 0.01). Conversely, stroke was a protective factor against relapse (HR 0.21, 95% CI 0.03-0.68; p = 0.005) and GC-dependent disease (OR 0.10, 95% CI 0.001-0.31; p = 0.0005). Patients with a GC-dependent disease who received a GC-sparing agent had a shorter GC treatment duration than those without (p = 0.008).
In this study, LVV was an independent predictor of relapse and GC dependence. Further prospective studies are needed to confirm these findings and to determine whether patients with LVV require a different treatment approach.
•We model plant–herbivore interactions taking into account plant defences (tolerance and resistance).•We highlight two indices that summarize the dynamics of the system.•We show that antagonistic and ...mutualistic patterns exist and, sometimes, can co-exist.•We show under which conditions plants can benefit from herbivory.•We discuss implications of the mutualistic pattern in ecosystems ecology and in agricultural pest management.
The potential positive effects of herbivores on plants have been the subject of debates for decades. While traditionally, herbivory was considered to have a negative impact on plants, some studies also reported possible mutualism between plants and herbivores. Plant defences, and in particular tolerance and resistance, seem to play an important role in shaping plant–herbivore interactions. The aim of this study is to show how a direct plant compensation mechanism translates into apparent compensation, i.e. the long-term biomass response to herbivory, in simple plant–herbivore models. A special emphasis is then put on how it interacts with resistance mechanisms. A qualitative study of the proposed models shows that they can exhibit different plant–herbivore patterns, including neutral, antagonistic (negative apparent compensation) and mutualistic (positive apparent compensation) interactions. Moreover, it is shown that density dependence plays a crucial role since, for a given system, the realized plant–herbivore pattern critically depends on the initial plant and herbivore levels. Our study shows the importance of direct compensation for the presence of plant–herbivore mutualism, a finding which we show, has significant implications both in ecosystems ecology and in agricultural pest management.
PDF
