COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Regulation von Pannexin1 durch Phosphorylierung

Pannexin1 gehört mit den Connexinen und Innexinen zur Gap junction-Proteinfamilie. Pannexin1 und Connexine weisen keine Sequenzhomologie auf, dennoch gleichen sich Sekundärstruktur und Aufbau. Da Connexine durch posttranslationale Phosphorylierung funktionell modifiziert werden und Pannexin1 ebenfalls ein Phosphoprotein ist, wurde untersucht, ob auch Pannexin1 durch Phosphorylierung reguliert wird. Mittels gezielter Mutagenese wurden potentielle Phosphorylierungstellen in Pannexin1 mutiert, mit eukaryotischen Expressionsvektoren in N2A-Zellen exprimiert und anhand von Western Blot-Analysen, konfokaler Fluoreszenzmikroskopie, sowie elektrophysiologisch untersucht. Mutationen einzelner Aminosäuren im Amino- und Carboxy-Terminus führen zur Ausbildung eines Kanals mit erhöhter Aktivität. Die veränderten Kanaleigenschaften durch die Mutation im Amino-Terminus sind auf strukturelle Veränderungen des Kanals zurückzuführen, die im Carboxy-Terminus auf geänderte Phosphorylierung

Moderator's View: Buttonhole cannulation of arteriovenous fistulae: great caution is warranted: Table 1.

Potential advantages of buttonhole (BH) cannulation over the standard rope-ladder technique have been claimed on the basis of small sized, potentially biased observational studies with a relatively short follow-up. On the contrary, randomized controlled trials (RCTs) show inconclusive or conflicting results. The uncertain benefit must thus be weighed against a definite increase in the infectious risk with the BH technique, which may not be completely abolished by preventative strategies. Awaiting the results of long-term studies (>2-3 years follow-up), the widespread use of the BH technique is not warranted, especially in busy in-centre haemodialysis (HD) settings with many rotating nurses. In our experience, the BH technique has been implemented safely in a self-care HD unit, presumably because of the limited number of cannulators and, in the case of self-cannulating patients, direct supervision by a small team of nurses. Units (and patients) willing to use the BH technique should be aware that BH is an extremely demanding technique and requires constant and strict adherence to the protocol. Regular monitoring of infection rates is recommended. Additional RCTs are clearly warranted, together with large-sized observational studies with multivariable adjustment

T cell-specific overexpression of TGFß1 fails to influence atherosclerosis in ApoE-deficient mice.

Clinical data have indicated a negative correlation between plasma TGFß1 concentrations and the extent of atherosclerosis and have thus led to the hypothesis that the pleiotropic cytokine may have anti-atherogenic properties. T-cells are currently discussed to significantly participate in atherogenesis, but the precise role of adaptive immunity in atherogenesis remains to be elucidated. TGFß1 is known to strongly modulate the function of T-cells, however, inhibition of TGFß1 signalling in T-cells of atherosclerosis-prone knock-out mice failed to unequivocally clarify the role of the cytokine for the development of atherosclerosis. In the present study, we thus tried to specify the role of TGFß1 in atherogenesis by using the murine CD2-TGFß1 transgenic strain which represents a well characterized model of T-cell specific TGFß1 overexpression. The CD2-TGFß1 transgenic mice were crossed to ApoE knock-out mice and quantity and quality of atherosclerosis regarding number of macrophages, smooth muscle cells, CD3 positive T-cells and collagen was analyzed in CD2-TGFß1 ApoE double mutants as well as non-transgenic ApoE controls on both normal and atherogenic diet of a duration of 8, 16 or 24 weeks, respectively. In all experimental groups investigated, we failed to detect any influence of TGFß1 overexpression on disease. Total number of CD3-positive T-lymphocytes was not significantly different in atherosclerotic lesions of CD2-TGFß1 ApoE(-/-) females and isogenic ApoE(-/-) controls, even after 24 weeks on the atherogenic diet. The synopsis of these data and our previous study on TGFß1 overexpressing macrophages suggests that potential effects of TGFß1 on atherosclerosis are most probably mediated by macrophages rather than T-cells

Combined B, T and NK Cell Deficiency Accelerates Atherosclerosis in BALB/c Mice

<div><p>This study focused on the unique properties of both the <i>Ldlr</i> knockout defect (closely mimicking the human situation) and the BALB/c (C) inbred mouse strain (Th-2 slanted immune response). We generated two immunodeficient strains with severe combined B- and T-cell immunodeficiency with or without a complete lack of natural killer cells to revisit the role of adaptive immune responses on atherogenesis. C-<i>Ldlr</i>^<i>-/-</i> <i>Rag1</i>^<i>-/-</i> mice, which show severe combined B- and T-cell immunodeficiency and C-<i>Ldlr</i>^<i>-/-</i> <i>Rag1</i>^<i>-/-</i> <i>Il2rg</i>^<i>-/-</i> mice, which combine the T- and B-cell defect with a complete lack of natural killer cells and inactivation of multiple cytokine signalling pathways were fed an atherogenic Western type diet (WTD). Both B6-<i>Ldlr</i>^<i>-/-</i> and C-<i>Ldlr</i>^<i>-/-</i> immunocompetent mice were used as controls. Body weights and serum cholesterol levels of both immunodeficient strains were significantly increased compared to C-<i>Ldlr</i>^<i>-/-</i> controls, except for cholesterol levels of C-<i>Ldlr</i>^<i>-/-</i> <i>Rag1</i>^<i>-/-</i> double mutants after 12 weeks on the WTD. Quantification of the aortic sinus plaque area revealed that both strains of immunodeficient mice developed significantly more atherosclerosis compared to C-<i>Ldlr</i>^<i>-/-</i> controls after 24 weeks on the WTD. Increased atherosclerotic lesion development in C-<i>Ldlr</i>^<i>-/-</i> <i>Rag1</i>^<i>-/-</i> <i>Il2rg</i>^<i>-/-</i> triple mutants was associated with significantly increased numbers of macrophages and significantly decreased numbers of smooth muscle cells compared to both C-<i>Ldlr</i>^<i>-/-</i> wild type and C-<i>Ldlr</i>^<i>-/-</i> <i>Rag1</i>^<i>-/-</i> double mutants pointing to a plaque destabilizing effect of NK cell loss. Collectively, the present study reveals a previously unappreciated complexity with regard to the impact of lymphocytes on lipoprotein metabolism and the role of lymphocyte subsets in plaque composition.</p></div

Lipoprotein analysis of murine sera.

<p>Group size, body weights, serum cholesterol and serum triglyceride concentrations of CD2-TGFß1 ApoE^−/− and ApoE^−/− mice on ND and WTD. Data are presented as means ± standard deviations.</p><p>*, ** indicate statistically significant differences (* p<0,05, ** p<0,01).</p

T-lymphocytes in atherosclerotic lesions.

<p><b>A</b>, Representative immunohistochemical staining of an atherosclerotic lesion located in the inner aortic arch intima (lesser curvature) of a CD2-TGFß1 ApoE^−/− mouse after 24 weeks on WTD. The slide was stained for T-lymphocytes with a monoclonal antibody against CD3 (clone CD3-12, AbD Serotec MorphoSys AbD GmbH, Düsseldorf, Germany) and the number of positively stained cells (asterisks) per mm² was counted (see <b>B</b>). The aortic lumen is to the upper left corner. The demarcation between intima and media is indicated by an arrowhead. <b>B</b>, Box and whiskers diagrams (median, interquartile range, minimum, and maximum) of the quantification of T-lymphocytes in atherosclerotic lesions of CD2-TGFß1 ApoE^−/− females and isogenic ApoE^−/− controls after 24 weeks on WTD (n.s.  =  not significant).</p

Quantification of atherosclerosis in the mouse model of TGFß1 overexpressing T cells.

<p><b>A</b>, Box and whisker diagrams (median, interquartile range, minimum, and maximum; n.s.  =  not significant) of the maximal area of the inner aortic arch intima (lesser curvature) of CD2-TGFß1 ApoE^−/− and ApoE^−/− mice on ND (upper panel) and WTD (lower panel). <b>B</b>, Representative Sudan-stained aortas <i>en face</i> of CD2-TGFß1 ApoE^−/− mice and ApoE^−/− controls on WTD.</p

Lipoprotein(a)-Associated Molecules Are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis

Summary: The LPA gene is the only monogenetic risk factor for calcific aortic valve stenosis (CAVS). Oxidized phospholipids (OxPL) and lysophosphatidic acid generated by autotaxin (ATX) from OxPL are pro-inflammatory. Aortic valve leaflets categorized pathologically from both ATXâapolipoprotein B and ATXâapolipoprotein(a) were measureable in plasma. Lipoprotein(a) (Lp[a]), ATX, OxPL, and malondialdehyde epitopes progressively increased in immunostaining (p < 0.001 for all). Six species of OxPL and lysophosphatidic acid were identified after extraction from valve leaflets. The presence of a constellation of pathologically linked, Lp(a)-associated molecules in plasma and in aortic valve leaflets of patients with CAVS suggest that Lp(a) is a key etiologic factor in CAVS. Key Words: aortic valve stenosis, autotaxin, inflammation, Lp(a), oxidation-specific epitope

Lipid and Lipoprotein analysis of murine sera.

<p><b>A,</b> Group size (n), body weights,serum cholesterol and serum triglyceride concentrations of C-Ldlr-/- controls, C-Ldlr-/- Rag1-/- and C-Ldlr-/- Rag1-/- Il2rg-/-mice after 12 and 24 weeks (w) on the WTD, respectively. Data are presented as means ± standard deviations. *, ** indicate statistically significant differences (*p < 0.05, ** p<0.01). <b>B,</b> Agarose gel electrophoresis of serum lipoproteins (left panel). Serum (2 μL) was electrophoresed on a 1% agarose gel and stained for neutral lipids (α- and ß-migrating lipoproteins) with Fat Red 7B. Representative lipoprotein profiles (right panel). Pooled plasma (n = 6) collected from mice fed a WTD for 12 weeks was used and analyzed by FPLC as described in the Materials and Methods.</p