Previously, we showed that truncated soluble forms of herpes simplex virus (HSV) glycoprotein <em>D</em> (g<em>D</em>t) bound directly to a truncated soluble form of the herpesvirus entry mediator (HveAt, formerly HVEMt), a cellular receptor for HSV. The purpose of the present study was to determine the affinity of g<em>D</em>t for HveAt by surface plasmon resonance and to compare and contrast the kinetics of an expanded panel of g<em>D</em>t variants in binding to HveAt in an effort to better understand the mechanism of receptor binding and virus entry. Both HveAt and g<em>D</em>t are <em>dimers</em> in solution and interact with a <em>2</em>:1 stoichiometry. With HveAt, g<em>D</em>1(306t) (from the KOS strain of HSV-1) had a dissociation constant (K<em>D</em>) of 3.<em>2</em> x 10(-6) M and g<em>D</em><em>2</em>(306t) had a K<em>D</em> of 1.5 x 10(-6) M. The interaction between g<em>D</em>t and HveAt fits a 1:1 Langmuir binding model, i.e., two <em>dimers</em> of HveAt may act as one binding unit to interact with one <em>dimer</em> of g<em>D</em>t as the second binding unit. A g<em>D</em> variant lacking all signals for N-linked oligosaccharides had an affinity for HveAt similar to that of g<em>D</em>1(306t). A variant lacking the bond from cysteine 1 to cysteine 5 had an affinity for HveAt that did not differ from that of the wild type. However, variants with double cysteine mutations that eliminated either of the other two disulfide bonds showed decreased affinity for HveAt. This result suggests that two of the three disulfide bonds of g<em>D</em> are important for receptor binding. Four nonfunctional g<em>D</em>t variants, each representing one functional domain of g<em>D</em>, were also studied. Mutations in functional regions I and II drastically decreased the affinity of g<em>D</em>t for HveAt. Surprisingly, a variant with an insertion in functional region III had a wild-type level of affinity for HveAt, suggesting that this domain may function in virus entry at a step other than receptor binding. A variant with a deletion in functional region IV [g<em>D</em>1(<em>D</em>elta<em>2</em>90-<em>2</em>99t)] exhibited a 100-fold enhancement in affinity for HveAt (K<em>D</em> = 3.3 x 10(-8) M) due mainly to a 40-fold increase in its kinetic on rate. This agrees with the results of other studies showing the enhanced ability of g<em>D</em>1(<em>D</em>elta<em>2</em>90-<em>2</em>99t) to block infection. Interestingly, all the variants with decreased affinities for HveAt exhibited decreased kinetic on rates but only minor changes in their kinetic off rates. The results suggest that once the complex between g<em>D</em>t and HveAt forms, its stability is unaffected by a variety of changes in g<em>D</em>.

<AbstractText>No agent has yet been proven to be effective for the treatment of severe patients with COVI<em>D</em>-19.</AbstractText><AbstractText>We conducted a pilot prospective open, single-arm multicentre study on off-label use of tocilizumab (TCZ) involving 63 hospitalised adult patients (56 males, age 6<em>2</em>.6±1<em>2</em>.5) with severe COVI<em>D</em>-19. Clinical and laboratory parameters were prospectively collected at baseline, day 1, <em>2</em>, 7 and 14. No moderate-to severe adverse events attributable to TCZ were recorded.</AbstractText><AbstractText>We observed a significant improvement in the levels of ferritin, C-reactive protein, <em>D</em>-<em>dimer</em>. The ratio of the partial pressure of oxygen (Pa0<em>2</em>) to the fraction of inspired oxygen (Fi0<em>2</em>) improved (mean±S<em>D</em> Pa0<em>2</em>/Fi0<em>2</em> at admission: 15<em>2</em>±53; at day 7: <em>2</em>83.73 ± 115.9, at day 14: 30<em>2</em>.<em>2</em> ± 1<em>2</em>6, p<0.05). The overall mortality was 11%; <em>D</em>-<em>dimer</em> level at baseline, but not IL-6 levels were predictors of mortality. TCZ administration within 6 days from admission in the hospital was associated with an increased likelihood of survival (HR <em>2</em>.<em>2</em> 95%CI 1.3-6.7, p<0.05).</AbstractText><AbstractText>In hospitalised adult patients with severe COVI<em>D</em>-19, TCZ could be a safe option. An improvement in respiratory and laboratory parameters was observed. Future controlled trials in patients with severe illness are urgently needed to confirm the definite benefit with IL-6 target therapy.</AbstractText>

Recombinant DNA technology has been use<em>d</em> to analyze the first step in keratin interme<em>d</em>iate filament (IF) assembly; i.e., the formation of the <em>d</em>ouble stran<em>d</em>e<em>d</em> coile<em>d</em> coil. Keratins 8 an<em>d</em> 18, lacking cysteine, were subjecte<em>d</em> to site specific in vitro mutagenesis to change one amino aci<em>d</em> in the same relative position of the alpha-helical ro<em>d</em> <em>d</em>omain of both keratins to a cysteine. The mutations lie at position -36 of the ro<em>d</em> in a "<em>d</em>" position of the hepta<em>d</em> repeat pattern, an<em>d</em> thus air oxi<em>d</em>ation can intro<em>d</em>uce a zero-length cystine cross-link. Mutant keratins 8 an<em>d</em> 18 purifie<em>d</em> separately from Escherichia coli rea<em>d</em>ily forme<em>d</em> cystine homo<em>dimer</em>s in <em>2</em> M guani<em>d</em>ine-HCl, an<em>d</em> coul<em>d</em> be separate<em>d</em> from the monomers by gel filtration. Hetero<em>dimer</em>s with a cystine cross-link were obtaine<em>d</em> when filaments forme<em>d</em> by the two re<em>d</em>uce<em>d</em> monomers were allowe<em>d</em> to oxi<em>d</em>ize. Subsequent ion exchange chromatography in 8.5 M urea showe<em>d</em> that only a single <em>dimer</em> species ha<em>d</em> forme<em>d</em>. Diagonal electrophoresis an<em>d</em> reverse phase HPLC i<em>d</em>entifie<em>d</em> the <em>dimer</em> as the cystine containing hetero<em>dimer</em>. This hetero<em>dimer</em> rea<em>d</em>ily assemble<em>d</em> again into IF in<em>d</em>istinguishable from those obtaine<em>d</em> from the nonmutant counterparts or from authentic keratins. In contrast, the mixture of cystine-stabilize<em>d</em> homo<em>dimer</em>s forme<em>d</em> only large aberrant aggregates. However, when a re<em>d</em>ucing agent was a<em>d</em><em>d</em>e<em>d</em>, filaments forme<em>d</em> again an<em>d</em> yiel<em>d</em>e<em>d</em> the hetero<em>dimer</em> after oxi<em>d</em>ation. Thus, the obligatory heteropolymer step in keratin IF assembly seems to occur preferentially at the <em>dimer</em> level an<em>d</em> not <em>d</em>uring tetramer formation. Our results also suggest that keratin I an<em>d</em> II homo<em>dimer</em>s, once forme<em>d</em>, are at least in <em>2</em> M guani<em>d</em>ine-HCl a metastable species as their mixtures convert spontaneously into hetero<em>dimer</em>s unless the homo<em>dimer</em>s are stabilize<em>d</em> by the cystine cross-link. This previously unexpecte<em>d</em> property of homo<em>dimer</em>s explains major <em>d</em>iscrepancies in the literature on the keratin <em>dimer</em>.

Background: Elevated serum C-reactive protein (CRP) level was observed in most patients with COVID-19.

Methods: Data of COVID-19 patients with clinical outcome in a designated hospital in Wuhan, China, were retrospectively collected and analyzed from Jan 30 to Feb 20, 2020. The prognostic value of admission CRP was evaluated in patients with COVID-19.

Results: Out of 298 patients enrolled, 84 died and 214 recovered. Most non-survivors tended to be males, old aged, or with chronic diseases. Compared to survivors, non-survivors showed significantly elevated white blood cell and neutrophil count, neutrophil to lymphocyte ratio (NLR), systemic immune-inflammation index (SII, defined by platelet count multiply by NLR), CRP, procalcitonin, and D-dimer, and decreased red blood cell, lymphocyte, and platelet count. Age, neutrophil count, platelet count, and CRP were identified as independent predictors of adverse outcome. The area under the receiver operating characteristic (ROC) curve (AUC) of CRP (0.896) was significantly higher than that of age (0.833), neutrophil count (0.820), and platelet count (0.678) in outcome prediction (all p<0.05). With a cut-off value of 41.4, CRP exhibited sensitivity 90.5%, specificity 77.6%, positive predictive value 61.3%, and negative predictive value 95.4%. Subgroup analysis revealed that CRP remained robust accuracy in adverse outcome prediction in patients with different disease severity (AUC 0.832, z=10.23, p<0.001; AUC 0.989, z=44.04, p<0.001). CRP was also an independent discriminator of severe/critical illness on admission (AUC 0.783, z=10.69, p<0.001).

Conclusions: In patients with COVID-19, admission CRP correlated with disease severity and tended to be a good predictor of adverse outcome.

Keywords: C-reactive protein; COVID-2019; SARS-CoV-2; prognosis.

BACKGROUND

Subjective sleep disturbances have been associated with increased risk of coronary artery disease (CAD). We hypothesized that disrupted sleep as verified by polysomnography is associated with increased levels of prothrombotic hemostasis factors previously shown to predict CAD risk.

METHODS

Full-night polysomnography was performed in 135 unmedicated men and women (mean age +/- SD, 36.8 +/- 7.8 years) without a history of sleep disorders. Morning fasting plasma levels of von Willebrand Factor (VWF) antigen, soluble tissue factor (sTF) antigen, d-dimer, and plasminogen activator inhibitor (PAI)-1 antigen were determined. Statistical analyses were adjusted for age, gender, ethnicity, body mass index, BP, and smoking history.

RESULTS

Higher total arousal index (ArI) was associated with higher levels of VWF (beta = 0.25, p = 0.011, DeltaR(2) = 0.045), and longer wake after sleep onset was associated with higher levels of sTF (beta = 0.23, p = 0.023, DeltaR(2) = 0.038). More nighttime spent at mean oxygen saturation < 90% (beta = 0.20, p = 0.020, DeltaR(2) = 0.029) and higher apnea-hypopnea index (AHI) [beta = 0.19, p = 0.034, DeltaR(2) = 0.024] were associated with higher PAI-1. There was a trend for a relationship between mean oxygen desaturation < 90% and PAI-1 (p = 0.053), even after controlling for AHI. Total ArI (beta = 0.28, p = 0.005, DeltaR(2) = 0.056) and WASO (beta = 0.25, p = 0.017, DeltaR(2) = 0.042) continued to predict VWF and sTF, respectively, even after controlling for AHI.

CONCLUSIONS

Polysomnographically verified sleep disruptions were associated with prothrombotic changes. Measures of sleep fragmentation and sleep efficiency were related to VWF and sTF, respectively. Apnea-related measures were related to PAI-1. Our findings suggest that sleep disruptions, even in a relatively healthy population, are associated with potential markers of prothrombotic cardiovascular risk.

Oligomerization of members of the p53 family of transcription factors (p53, p63, and p73) is essential for their distinct functions in cell-cycle control and development. To elucidate the molecular basis for tetramer formation of the various family members, we solved the crystal structure of the human p73 tetramerization domain (residues 351-399). Similarly to the canonical p53 tetramer, p73 forms a tetramer with <em>D</em>(<em>2</em>) symmetry that can be described as a <em>dimer</em> of <em>dimers</em>. The most striking difference between the p53 and p73 tetramerization domain is the presence of an additional C-terminal helix in p73. This helix, which is conserved in p63, is essential for stabilizing the overall architecture of the tetramer, as evidenced by the different oligomeric structures observed for a shortened variant lacking this helix. The helices act as clamps, wrapping around the neighboring <em>dimer</em> and holding it in place. In addition, we show by mass spectrometry that the tetramerization domains of p63 and p73, but not p53, fully exchange, with different mixed tetramers present at equilibrium, albeit at a relatively slow rate. Taken together, these data provide intriguing insights into the divergent evolution of the oligomerization domain within the p53 family, from the ancestral p63/p73-like protein toward smaller, less promiscuous monomeric building blocks in human p53, allowing functional separation of the p53 pathway from that of its family members.

OBJECTIVE

To investigate the association between optimism/pessimism and concentrations of seven inflammation and hemostasis markers. Optimism and pessimism are associated with cardiovascular disease mortality and progression; however, the biological mechanism remains unclear.

METHODS

This cross-sectional study used data from the Multi-Ethnic Study of Atherosclerosis (MESA), a study of 6814 persons aged 45 to 84 years with no history of clinical cardiovascular disease. The Life-Orientation Test-Revised (LOT-R) was used to measure dispositional optimism and pessimism. Regression analyses were used to estimate associations of optimism and pessimism with interleukin (IL)-6, C-reactive protein (CRP), fibrinogen, homocysteine, Factor VIII, D-dimer, and plasmin-antiplasmin, before and after adjustment for sociodemographics, depression, cynicism, health behaviors, body mass index (BMI), hypertension, and diabetes.

RESULTS

Higher scores on the LOT-R (positive disposition) were related to lower concentrations of IL-6 (p = .001), fibrinogen (p < .001), and homocysteine (p = .031). Associations were stronger for the pessimism subscale. After adjustment for demographics, the percentage differences in inflammatory markers corresponding to a 2-standard deviation increase in pessimism were 6.01% (p = .001) for IL-6, 10.31% (p = .001) for CRP, 2.47% (p < .0001) for fibrinogen, and 1.36% (p = .07) for homocysteine. Associations were attenuated but significant after adjustment for sociodemographics, depression, cynical distrust, and behaviors. Further adjustment for hypertension, BMI, and diabetes reduced associations for CRP and IL-6. Pessimism remained associated with a 1.36% (p = .02) increase in fibrinogen in the fully adjusted model. Factor VIII, D-dimer, and plasmin-antiplasmin were not associated with the LOT-R or subscales.

CONCLUSIONS

Pessimism is related to higher levels of inflammation. Health behaviors, BMI, hypertension, and diabetes seem to play a mediating role.

BACKGROUND

Outpatients with suspected deep vein thrombosis (DVT) have nonspecific signs and symptoms. Missed DVT diagnosis may result in fatal pulmonary embolism. Since many patients may have DVT, a selective and efficient diagnostic process is needed.

OBJECTIVE

To systematically review trials that determined the prevalence of DVT using clinical prediction rules either with or without D-dimer, for the diagnosis of DVT.

METHODS

English- and French-language studies were identified from MEDLINE from 1990 to July 2004 and supplemented by a review of all relevant bibliographies.

METHODS

We included studies that prospectively enrolled consecutive, unselected outpatients with suspected DVT and applied clinical prediction rules before D-dimer testing or diagnostic imaging. All studies included sufficient information to allow the calculation of the prevalence of DVT for at least 1 of the 3 clinical probability estimates (low, moderate, or high). We required that patients be followed up for a minimum 3-month period. Unless the clinical model incorporated prior DVT, studies were excluded if patients with a history of prior DVT were enrolled.

METHODS

Two reviewers independently reviewed and abstracted data for estimating the prevalence of DVT, sensitivity, specificity, and likelihood ratios (LRs) of D-dimer in each of the 3 clinical probability estimates. Data for the D-dimer in all studies were pooled and analyzed as high-sensitivity/low-specificity test or a moderate-sensitivity/moderate-specificity test.

RESULTS

Fourteen studies involving more than 8000 patients used 1 clinical prediction rule for diagnosing DVT, of which 11 incorporated D-dimer testing in the diagnostic algorithm. The prevalence of DVT in the low, moderate, and high clinical probability groups was 5.0% (95% CI, 4.0%-8.0%), 17% (95% CI, 13%-23%), and 53% (95% CI, 44%-61%), respectively. The overall prevalence of DVT was 19% (95% CI, 16%-23%). Pooling all studies, the sensitivity, specificity, and negative LRs of D-dimer testing in the low probability group were 88% (95% CI, 81%-92%), 72% (95% CI, 65%-78%), and 0.18% (95% CI, 0.12-0.18); in the moderate probability group: 90% (95% CI, 80%-95%), 58% (95% CI, 49%-67%), and 0.19% (95% CI, 0.11-0.32); and in the high probability group: 92% (95% CI, 85%-96%), 45% (95% CI, 37%-52%), and 0.16% (95% CI, 0.09-0.30). The LRs for a normal result on a high or moderately sensitive D-dimer assay among patients with: (1) low clinical suspicion were 0.10 (95% CI, 0.03-0.37) and 0.20 (95% CI, 0.12-0.31); (2) moderate clinical suspicion were 0.05 (95% CI, 0.01-0.21) and 0.23 (95% CI, 0.13-0.39); and (3) high clinical suspicion were 0.07 (95% CI, 0.03-0.18) and 0.15 (95% CI, 0.10-0.38).

CONCLUSIONS

Diagnostic accuracy for DVT improves when clinical probability is estimated before diagnostic tests. Patients with low clinical probability on the predictive rule have prevalence of DVT of less than 5%. In low-probability patients with negative D-dimer results, diagnosis of DVT can be excluded without ultrasound; in patients with high clinical suspicion for DVT, results should not affect clinical decisions.

1. Potato lectin is a glycoprotein that contains about 47% (by weight) l-arabinose, 3% <em>d</em>-galactose an<em>d</em> 11% hy<em>d</em>roxyproline. It has a monomeric molecular weight of about 50000 an<em>d</em> probably exists as a monomer-<em>dimer</em> system in aqueous solution, with the monomer pre<em>d</em>ominating. It has a very high viscosity, which woul<em>d</em> in<em>d</em>icate either that the molecule is very expan<em>d</em>e<em>d</em> or that it is an elongate<em>d</em> ellipsoi<em>d</em>. <em>2</em>. After prolonge<em>d</em> proteolytic <em>d</em>igestion of a re<em>d</em>uce<em>d</em> an<em>d</em> carboxymethylate<em>d</em> <em>d</em>erivative of the lectin, a glycopepti<em>d</em>e was isolate<em>d</em> (of mol.wt. 3<em>2</em>000-34000) that inclu<em>d</em>e<em>d</em> all the carbohy<em>d</em>rate an<em>d</em> hy<em>d</em>roxyproline of the original glycoprotein but less than 30% of the total original amino aci<em>d</em> resi<em>d</em>ues. 3. The arabinose of the glycoprotein is present exclusively as the beta-arabinofuranosi<em>d</em>e an<em>d</em> this inclu<em>d</em>es those resi<em>d</em>ues that are <em>d</em>irectly linke<em>d</em> to the hy<em>d</em>roxyproline resi<em>d</em>ues of the polypepti<em>d</em>e chain. All the arabinose of the glycoprotein is linke<em>d</em> to the polypepti<em>d</em>e chain through the hy<em>d</em>roxyproline resi<em>d</em>ues; the ratio of arabinose to hy<em>d</em>roxyproline is 3.4:1. Although alpha-arabinofuranosi<em>d</em>es are known to be present in arabinans an<em>d</em> arabinogalactans, the natural occurrence of beta-arabinofuranosi<em>d</em>es has not previously been reporte<em>d</em>. 4. Nine or ten serine resi<em>d</em>ues of the polypepti<em>d</em>e chain are substitute<em>d</em> with single alpha-galactopyranosi<em>d</em>e resi<em>d</em>ues that can be remove<em>d</em> by the action of alpha-galactosi<em>d</em>ase from coffee beans but not by a beta-galactosi<em>d</em>ase. This is the first report of an alpha-galactosi<em>d</em>e linkage to serine. The effect of alpha-galactosi<em>d</em>ase is much greater on a glycopepti<em>d</em>e from which the arabinose has been alrea<em>d</em>y remove<em>d</em>, which in<em>d</em>icates a steric hin<em>d</em>rance of the galactosi<em>d</em>ase action by a<em>d</em>jacent chains of arabinosi<em>d</em>es. 5. In 0.5m-NaOH (pH13.7), galactose resi<em>d</em>ues were remove<em>d</em> from the serine resi<em>d</em>ues of the glycopepti<em>d</em>e by a process of beta-elimination. This reaction took place very slowly in the intact glycopepti<em>d</em>e but much more rapi<em>d</em>ly when the arabinofuranosi<em>d</em>e resi<em>d</em>ues ha<em>d</em> been remove<em>d</em>. This inhibitory effect of the arabinofuranosi<em>d</em>e resi<em>d</em>ues on the beta-elimination reaction is likely to be <em>d</em>ue to a negative charge on the hy<em>d</em>roxy groups of the a<em>d</em>jacent arabinofuranosi<em>d</em>e resi<em>d</em>ues, which woul<em>d</em> be ionize<em>d</em> at this high pH value. 6. It is suggeste<em>d</em> that potato lectin may be representative of a class of soluble plant glycoproteins that woul<em>d</em> inclu<em>d</em>e precursors of the cell-wall glycoprotein extensin. If this is the case, extensin shoul<em>d</em> also contain beta-l-arabinofuranosi<em>d</em>es linke<em>d</em> to hy<em>d</em>roxyproline an<em>d</em> alpha-<em>d</em>-galactopyranosi<em>d</em>es linke<em>d</em> to serine resi<em>d</em>ues of the polypepti<em>d</em>e chain.

In mammals, male sex is determined by the Y-chromosomal gene Sry (sex-determining region of Y chromosome). The expression of Sry and subsequently Sox9 (SRY box containing gene 9) in precursors of the supporting cell lineage results in the differentiation of these cells into Sertoli cells. Sertoli cells in turn orchestrate the development of all other male-specific cell types. To ensure that Sertoli cells differentiate in sufficient numbers to induce normal testis development, the early testis produces prostaglandin <em>D</em>(<em>2</em>) (PG<em>D</em>(<em>2</em>)), which recruits cells of the supporting cell lineage to a Sertoli cell fate. Here we show that the gene encoding prostaglandin <em>D</em> synthase (Pgds), the enzyme that produces PG<em>D</em>(<em>2</em>), is expressed in Sertoli cells immediately after the onset of Sox9 expression. Promoter analysis in silico and in vitro identified a paired SOX/SRY binding site. Interestingly, only SOX9, and not SRY, was able to bind as a <em>dimer</em> to this site and transactivate the Pgds promoter. In line with this, a transgenic mouse model showed that Pgds expression is not affected by ectopic Sry expression. Finally, chromatin immunoprecipitation proved that SOX9 but not SRY binds to the Pgds promoter in vivo.

BACKGROUND

Ventilation-perfusion (V(dot)Q(dot) lung scanning and computed tomographic pulmonary angiography (CTPA) are widely used imaging procedures for the evaluation of patients with suspected pulmonary embolism. Ventilation-perfusion scanning has been largely replaced by CTPA in many centers despite limited comparative formal evaluations and concerns about CTPA's low sensitivity (ie, chance of missing clinically important pulmonary embuli).

OBJECTIVE

To determine whether CTPA may be relied upon as a safe alternative to V(dot)Q(dot scanning as the initial pulmonary imaging procedure for excluding the diagnosis of pulmonary embolism in acutely symptomatic patients.

METHODS

Randomized, single-blinded noninferiority clinical trial performed at 4 Canadian and 1 US tertiary care centers between May 2001 and April 2005 and involving 1417 patients considered likely to have acute pulmonary embolism based on a Wells clinical model score of 4.5 or greater or a positive D-dimer assay result.

METHODS

Patients were randomized to undergo either V(dot)Q(dot scanning or CTPA. Patients in whom pulmonary embolism was considered excluded did not receive antithrombotic therapy and were followed up for a 3-month period.

METHODS

The primary outcome was the subsequent development of symptomatic pulmonary embolism or proximal deep vein thrombosis in patients in whom pulmonary embolism had initially been excluded.

RESULTS

Seven hundred one patients were randomized to CTPA and 716 to V(dot)Q(dot scanning. Of these, 133 patients (19.2%) in the CTPA group vs 101 (14.2%) in the V(dot)Q(dot scan group were diagnosed as having pulmonary embolism in the initial evaluation period (difference, 5.0%; 95% confidence interval [CI], 1.1% to 8.9%) and were treated with anticoagulant therapy. Of those in whom pulmonary embolism was considered excluded, 2 of 561 patients (0.4%) randomized to CTPA vs 6 of 611 patients (1.0%) undergoing V(dot)Q(dot scanning developed venous thromboembolism in follow-up (difference, -0.6%; 95% CI, -1.6% to 0.3%) including one patient with fatal pulmonary embolism in the V(dot)Q(dot group.

CONCLUSIONS

In this study, CTPA was not inferior to V(dot)Q(dot scanning in ruling out pulmonary embolism. However, significantly more patients were diagnosed with pulmonary embolism using the CTPA approach. Further research is required to determine whether all pulmonary emboli detected by CTPA should be managed with anticoagulant therapy.

BACKGROUND

isrctn.org Identifier: ISRCTN65486961.

Background: Studies summarizing the clinical picture of COVID-19 in children are lacking. This review characterizes clinical symptoms, laboratory, and imaging findings, as well as therapies provided to confirmed pediatric cases of COVID-19.

<strong class="sub-title"> Methods: </strong> Adhering to PRISMA guidelines, we searched four medical databases (PubMed, LitCovid, Scopus, WHO COVID-19 database) between December 1, <em>2</em>019 to May 14, <em>2</em>0<em>2</em>0 using the keywords "novel coronavirus", "COVID-19" or "SARS-CoV-<em>2</em>". We included published or in press peer-reviewed cross-sectional, case series, and case reports providing clinical signs, imaging findings, and/or laboratory results of pediatric patients who were positive for COVID-19. Risk of bias was appraised through the quality assessment tool published by the National Institutes of Health. PROSPERO registration # CRD4<em>2</em>0<em>2</em>018<em>2</em><em>2</em>61.

<strong class="sub-title"> Findings: </strong> We identified 131 studies across <em>2</em>6 countries comprising 7780 pediatric patients. Although fever (59·1%) and cough (55·9%) were the most frequent symptoms 19·3% of children were asymptomatic. Patchy lesions (<em>2</em>1·0%) and ground-glass opacities (3<em>2</em>·9%) depicted lung radiograph and computed tomography findings, respectively. Immunocompromised children or those with respiratory/cardiac disease comprised the largest subset of COVID-19 children with underlying medical conditions (15<em>2</em> of <em>2</em>33 individuals). Coinfections were observed in 5.6% of children and abnormal laboratory markers included serum D-dimer, procalcitonin, creatine kinase, and interleukin-6. Seven deaths were reported (0·09%) and 11 children (0·14%) met inclusion for multisystem inflammatory syndrome in children.

Interpretation: This review provides evidence that children diagnosed with COVID-19 have an overall excellent prognosis. Future longitudinal studies are needed to confirm our findings and better understand which patients are at increased risk for developing severe inflammation and multiorgan failure.

<strong class="sub-title"> Funding: </strong> Parker B. Francis and pilot grant from <em>2</em>R<em>2</em>5-HL1<em>2</em>6140. Funding agencies had no involvement in the study.

OBJECTIVE

To determine whether objective measures of sleep correlate with plasma levels of the proinflammatory cytokine interleukin (IL)-6 and the procoagulant marker fibrin D-dimer in caregivers of patients with dementia.

METHODS

Cross-sectional study.

METHODS

Subjects' homes.

METHODS

Sixty-four community-dwelling spousal caregivers (69% women, mean age+/-standard deviation 72+/-9) and 36 sex-matched noncaregiving controls.

METHODS

All participants underwent in-home full-night polysomnography. Demographic and lifestyle factors, depression, diseases, and medication that could affect inflammation, coagulation, and sleep were controlled for in analyses regressing sleep variables and caregiver status and their interaction on plasma levels of IL-6 and D-dimer.

RESULTS

Caregivers had higher levels of D-dimer (781+/-591 vs 463+/-214 ng/mL, P=.001) and IL-6 (1.42+/-1.52 vs 0.99+/-0.86 pg/mL, P<.06) and lower levels of total sleep time (369+/-70 vs 393+/-51 minutes, P=.049) and sleep efficiency (77+/-11 vs 82+/-9%, P=.04) than controls. After controlling for age and body mass index, longer wake time after sleep onset (change in coefficient of determination (DeltaR2)=0.039, P=.04) and the interaction between caregiver status and higher apnea-hypopnea index (DeltaR2=0.054, P=.01) were predictors of IL-6. Controlling for age, caregiver status independently predicted D-dimer levels (DeltaR2=0.047, P=.01). Controlling for age and caregiver status, lower sleep efficiency (DeltaR2=0.032, P=.03) and the interaction between caregiver status and more Stage 2 sleep (DeltaR2=0.037, P=.02) independently predicted plasma D-dimer levels.

CONCLUSIONS

Poor sleep was associated with higher plasma IL-6 and D-dimer levels. These effects were most pronounced in caregivers of subjects with Alzheimer's disease. The findings suggest a mechanism that may explain how disturbed sleep might be associated downstream with cardiovascular risk, particularly in older people under chronic stress.

Plasma <em>D</em>-<em>dimer</em> concentration rises more than 100-fold during acute deep vein thrombosis, but there are no prospective data concerning <em>D</em>-<em>dimer</em> as a risk factor for incident venous thrombosis in a general population. Incident venous thrombosis was ascertained in <em>2</em> prospective observational studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Of <em>2</em>1 690 participants enrolled between 1987 and 1993, after 8 years of follow-up, <em>D</em>-<em>dimer</em> was measured using baseline stored plasma of 307 participants who developed venous thrombosis and 616 who did not. Relative to the first quintile of the distribution of <em>D</em>-<em>dimer</em>, the age-adjusted odds ratios for future venous thrombosis for the second to fifth quintiles of <em>D</em>-<em>dimer</em> were 1.6, <em>2</em>.3, <em>2</em>.3, and 4.<em>2</em>, respectively (P for trend <.0001). Following added adjustment for sex, race, body mass index, factor V Leiden, prothrombin <em>2</em>0<em>2</em>10A, and elevated factor VIII coagulant activity (factor VIII:c), these odds ratios were 1.5, <em>2</em>.1, 1.9, and 3.0, respectively (P for trend <.0001). Among those with idiopathic thrombosis or secondary thrombosis unrelated to cancer, the adjusted fifth quintile odds ratios were 3.5 and 4.8, respectively. By contrast, <em>D</em>-<em>dimer</em> in the fifth versus first quintile was not related to occurrence of cancer-associated thrombosis (odds ratio, 1.1). Odds ratios for elevated <em>D</em>-<em>dimer</em> were consistently elevated in subgroups defined by age, sex, race, duration of follow-up, and thrombosis type (deep vein thrombosis or pulmonary embolus). <em>D</em>-<em>dimer</em> is strongly and positively related to the occurrence of future venous thrombosis.

Background and purpose: The objective of our systematic review is to identify prognostic factors that may be used in decision-making related to the care of patients infected with COVID-19.

<strong class="sub-title"> Data sources: </strong> We conducted highly sensitive searches in PubMed/MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) and Embase. The searches covered the period from the inception date of each database until April <em>2</em>8, <em>2</em>0<em>2</em>0. No study design, publication status or language restriction were applied.

<strong class="sub-title"> Study selection and data extraction: </strong> We included studies that assessed patients with confirmed or suspected SARS-CoV-<em>2</em> infectious disease and examined one or more prognostic factors for mortality or disease severity. Reviewers working in pairs independently screened studies for eligibility, extracted data and assessed the risk of bias. We performed meta-analyses and used GRADE to assess the certainty of the evidence for each prognostic factor and outcome.

<strong class="sub-title"> Results: </strong> We included <em>2</em>07 studies and found high or moderate certainty that the following 49 variables provide valuable prognostic information on mortality and/or severe disease in patients with COVID-19 infectious disease: Demographic factors (age, male sex, smoking), patient history factors (comorbidities, cerebrovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, cardiovascular disease, cardiac arrhythmia, arterial hypertension, diabetes, dementia, cancer and dyslipidemia), physical examination factors (respiratory failure, low blood pressure, hypoxemia, tachycardia, dyspnea, anorexia, tachypnea, haemoptysis, abdominal pain, fatigue, fever and myalgia or arthralgia), laboratory factors (high blood procalcitonin, myocardial injury markers, high blood White Blood Cell count (WBC), high blood lactate, low blood platelet count, plasma creatinine increase, high blood D-dimer, high blood lactate dehydrogenase (LDH), high blood C-reactive protein (CRP), decrease in lymphocyte count, high blood aspartate aminotransferase (AST), decrease in blood albumin, high blood interleukin-6 (IL-6), high blood neutrophil count, high blood B-type natriuretic peptide (BNP), high blood urea nitrogen (BUN), high blood creatine kinase (CK), high blood bilirubin and high erythrocyte sedimentation rate (ESR)), radiological factors (consolidative infiltrate and pleural effusion) and high SOFA score (sequential organ failure assessment score).

Conclusion: Identified prognostic factors can help clinicians and policy makers in tailoring management strategies for patients with COVID-19 infectious disease while researchers can utilise our findings to develop multivariable prognostic models that could eventually facilitate decision-making and improve patient important outcomes.

<strong class="sub-title"> Systematic review registration: </strong> Prospero registration number: CRD4<em>2</em>0<em>2</em>017880<em>2</em>. Protocol available at: https://www.medrxiv.org/content/10.1101/<em>2</em>0<em>2</em>0.04.08.<em>2</em>0056598v1.

BACKGROUND

We designed a simple and integrated diagnostic algorithm for acute venous thromboembolism based on clinical probability assessment of deep-vein thrombosis (DVT) or pulmonary embolism (PE), plasma D-dimer measurement, lower-limb venous compression ultrasonography, and lung scan to reduce the need for phlebography and pulmonary angiography.

METHODS

918 consecutive patients presenting at the emergency ward of the Geneva University Hospital, Geneva, Switzerland, and Hôpital Saint-Luc, Montreal, Canada, with clinically suspected venous thromboembolism were entered into a sequential diagnostic protocol. Patients in whom venous thromboembolism was deemed absent were not given anticoagulants and were followed up for 3 months.

RESULTS

A normal D-dimer concentration (<500 microg/L by a rapid ELISA) ruled out venous thromboembolism in 286 (31%) members of the study cohort, whereas DVT by ultrasonography established the diagnosis in 157 (17%). Lung scan was diagnostic in 80 (9%) of the remaining patients. Venous thromboembolism was also deemed absent in patients with low to intermediate clinical probability of DVT and a normal venous ultrasonography (236 [26%] patients), and in patients with a low clinical probability of PE and a non-diagnostic result on lung scan (107 [12%] patients). Pulmonary angiography and phlebography were done in only 50 (5%) and 2 (<1%) of the patients, respectively. Hence, a non-invasive diagnosis was possible in 866 (94%) members of the entire cohort. The 3-month thromboembolic risk in patients not given anticoagulants, based on the results of the diagnostic protocol, was 1.8% (95% CI 0.9-3.1).

CONCLUSIONS

A diagnostic strategy combining clinical assessment, D-dimer, ultrasonography, and lung scan gave a non-invasive diagnosis in the vast majority of outpatients with suspected venous thromboembolism, and appeared to be safe.

The mammalian cytosolic/nuclear thioredoxin system, comprising thioredoxin (Trx), selenoenzyme thioredoxin reductase (TrxR), and NA<em>D</em>PH, is the major protein-disulfide reductase of the cell and has numerous functions. The active site of reduced Trx comprises Cys(3<em>2</em>)-Gly-Pro-Cys(35) thiols that catalyze target disulfide reduction, generating a disulfide. Human Trx1 has also three structural Cys residues in positions 6<em>2</em>, 69, and 73 that upon diamide oxidation induce a second Cys(6<em>2</em>)-Cys(69) disulfide as well as <em>dimers</em> and multimers. We have discovered that after incubation with H(<em>2</em>)O(<em>2</em>) only monomeric two-disulfide molecules are generated, and they are inactive but able to regain full activity in an autocatalytic process in the presence of NA<em>D</em>PH and TrxR. There are conflicting results regarding the effects of S-nitrosylation on Trx antioxidant functions and which residues are involved. We found that S-nitrosoglutathione-mediated S-nitrosylation at physiological pH is critically dependent on the redox state of Trx. Starting from fully reduced human Trx, both Cys(69) and Cys(73) were nitrosylated, and the active site formed a disulfide; the nitrosylated Trx was not a substrate for TrxR but regained activity after a lag phase consistent with autoactivation. Treatment of a two-disulfide form of Trx1 with S-nitrosoglutathione resulted in nitrosylation of Cys(73), which can act as a trans-nitrosylating agent as observed by others to control caspase 3 activity (Mitchell, <em>D</em>. A., and Marletta, M. A. (<em>2</em>005) Nat. Chem. Biol. 1, 154-158). The reversible inhibition of human Trx1 activity by H(<em>2</em>)O(<em>2</em>) and NO donors is suggested to act in cell signaling via temporal control of reduction for the transmission of oxidative and/or nitrosative signals in thiol redox control.

Background: COVID-19 is an ongoing global pandemic. Changes in haematological characteristics in patients with COVID-19 are emerging as important features of the disease. We aimed to explore the haematological characteristics and related risk factors in patients with COVID-19.

Methods: This retrospective cohort study included patients with COVID-19 admitted to three designated sites of Wuhan Union Hospital (Wuhan, China). Demographic, clinical, laboratory, treatment, and outcome data were extracted from electronic medical records and compared between patients with moderate, severe, and critical disease (defined according to the diagnosis and treatment protocol for novel coronavirus pneumonia, trial version 7, published by the National Health Commission of China). We assessed the risk factors associated with critical illness and poor prognosis. Dynamic haematological and coagulation parameters were investigated with a linear mixed model, and coagulopathy screening with sepsis-induced coagulopathy and International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation scoring systems was applied.

<strong class="sub-title"> Findings: </strong> Of 466 patients admitted to hospital from Jan <em>2</em>3 to Feb <em>2</em>3, <em>2</em>0<em>2</em>0, 380 patients with COVI<em>D</em>-19 were included in our study. The incidence of thrombocytopenia (platelet count <100 × 10⁹ cells per L) in patients with critical disease (4<em>2</em> [49%] of 86) was significantly higher than in those with severe (<em>2</em>0 [14%] of 145) or moderate (nine [6%] of 149) disease (p<0·0001). The numbers of lymphocytes and eosinophils were significantly lower in patients with critical disease than those with severe or moderate disease (p<0·0001), and prothrombin time, <em>D</em>-<em>dimer</em>, and fibrin degradation products significantly increased with increasing disease severity (p<0·0001). In multivariate analyses, death was associated with increased neutrophil to lymphocyte ratio (≥9·13; odds ratio [OR] 5·39 [95% CI 1·70-17·13], p=0·004<em>2</em>), thrombocytopenia (platelet count <100 × 10⁹ per L; OR 8·33 [<em>2</em>·56-<em>2</em>7·15], p=0·00045), prolonged prothrombin time (>16 s; OR 4·94 [1·50-16·<em>2</em>5], p=0·0094), and increased <em>D</em>-<em>dimer</em> (><em>2</em> mg/L; OR 4·41 [1·06-18·30], p=0·041). Thrombotic and haemorrhagic events were common complications in patients who died (19 [35%] of 55). Sepsis-induced coagulopathy and International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation scores (assessed in 1<em>2</em> patients who survived and eight patients who died) increased over time in patients who died. The onset of sepsis-induced coagulopathy was typically before overt disseminated intravascular coagulation.

Interpretation: Rapid blood tests, including platelet count, prothrombin time, D-dimer, and neutrophil to lymphocyte ratio can help clinicians to assess severity and prognosis of patients with COVID-19. The sepsis-induced coagulopathy scoring system can be used for early assessment and management of patients with critical disease.

Funding: National Key Research and Development Program of China.

OBJECTIVE

To investigate the time course and the relation to prognosis of coagulation and fibrinolytic abnormalities in patients with septic shock.

METHODS

Forty-eight consecutive patients admitted to the medical ICU with the diagnosis of septic shock (diagnosed by defined criteria) were studied. Mortality was <em>2</em>5 of 48. Mean age was 57 +/- 7.3 years. Blood samples were obtained on days 1, 4, and 7 after hospital admission to measure tissue-type plasminogen activator antigen (t-PA), urokinase-type plasminogen activator (u-PA), plasminogen activator inhibitor antigen (PAI-1), plasminogen, alpha <em>2</em>-antiplasmin, fibrinogen, antithrombin III, protein C, protein S, thrombin-antithrombin complexes (TAT), <em>D</em>-<em>dimer</em>, and von Willebrand factor-related antigen (vWF:Ag).

RESULTS

All patients showed marked abnormalities in both the coagulation and fibrinolytic systems. There were signs of coagulation activation and elevation of both activators and inhibitors of fibrinolysis. Nonsurvivors showed lower levels of protein C and antithrombin III and higher concentration of TAT than survivors. While both t-PA and PAI-1 concentrations were high in survivors and nonsurvivors, only survivors showed a progressive normalization of both parameters during the study period. Low plasminogen levels and plasminogen/alpha <em>2</em>-antiplasmin ratio were found in both groups, presenting a trend toward normalization only in survivors. The differences reported were not apparent at the time of hospital admission.

CONCLUSIONS

Septic shock is characterized by coagulation activation and fibrinolysis activation and inhibition. Nonsurvivors present a particular hemostatic profile characterized by a more marked activation of coagulation and a more intense inhibition of fibrinolysis. None of the abnormalities studied was significantly different between survivors and nonsurvivors at the time of hospital admission. In the presence of fibrin formation, nonsurvivors present a maintained imbalance in the fibrinolytic response determined by higher PAI-1 plasma concentration, probably contributing to their poor outcome.

OBJECTIVE

The purpose of this study was to: 1) determine the significance and magnitude of associations between novel cardiovascular disease (CVD) risk factors and peripheral arterial disease (PAD) after adjustment for traditional risk factors; and <em>2</em>) ascertain the extent to which novel risk factors explain the excess or lower risk for PAD in different ethnic groups.

BACKGROUND

Previous reports have found a significant difference in the risk of PAD by ethnic group, with some of the risk difference attributed to different levels of traditional CVD risk factors.

METHODS

A total of 6,814 individuals free of clinically apparent CVD were enrolled in the MESA (Multiethnic Study of Atherosclerosis) and underwent standardized testing for the presence of PAD by the ankle-brachial index. These subjects also had fasting blood drawn for serum cholesterol, glucose, and a number of novel biomarkers for CVD. Non-Hispanic whites were the largest ethnic group (38%), followed by African Americans (<em>2</em>8%), Hispanics (<em>2</em><em>2</em>%), and Chinese (1<em>2</em>%).

RESULTS

In this cross-sectional analysis, 6,653 subjects with an ankle brachial index <1.40 were analyzed. The mean (SD) age was 6<em>2</em>.<em>2</em> (10.<em>2</em>) years, and 5<em>2</em>.9% were women. Interleukin-6, fibrinogen, D-dimer, and homocysteine were significantly associated with PAD after adjustment for traditional CVD risk factors. Compared with non-Hispanic whites and after adjustment for traditional and "novel" risk factors, the odds for PAD were 1.47 (95% confidence interval [CI]: 1.07 to <em>2</em>.0<em>2</em>) times higher in African Americans, while being 0.45 (95% CI: 0.<em>2</em>9 to 0.70) and 0.44 (95% CI: 0.<em>2</em>4 to 0.78) in Hispanics and Chinese, respectively.

CONCLUSIONS

Ethnic associations with PAD remained significant even after adjustment for traditional and novel risk factors. This suggests that unknown factors may account for the residual ethnic differences in PAD.

Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown.

Patients who were hospitalize<em>d</em> for acute me<em>d</em>ical illnesses were ran<em>d</em>omly assigne<em>d</em> to receive subcutaneous enoxaparin (at a <em>d</em>ose of 40 mg once <em>d</em>aily) for 10±4 <em>d</em>ays plus oral betrixaban placebo for 35 to 4<em>2</em> <em>d</em>ays or subcutaneous enoxaparin placebo for 10±4 <em>d</em>ays plus oral betrixaban (at a <em>d</em>ose of 80 mg once <em>d</em>aily) for 35 to 4<em>2</em> <em>d</em>ays. We performe<em>d</em> sequential analyses in three prespecifie<em>d</em>, progressively inclusive cohorts: patients with an elevate<em>d</em> <em>d</em>-<em>dimer</em> level (cohort 1), patients with an elevate<em>d</em> <em>d</em>-<em>dimer</em> level or an age of at least 75 years (cohort <em>2</em>), an<em>d</em> all the enrolle<em>d</em> patients (overall population cohort). The statistical analysis plan specifie<em>d</em> that if the between-group <em>d</em>ifference in any analysis in this sequence was not significant, the other analyses woul<em>d</em> be consi<em>d</em>ere<em>d</em> exploratory. The primary efficacy outcome was a composite of asymptomatic proximal <em>d</em>eep-vein thrombosis an<em>d</em> symptomatic venous thromboembolism. The principal safety outcome was major blee<em>d</em>ing.

A total of 7513 patients un<em>d</em>erwent ran<em>d</em>omization. In cohort 1, the primary efficacy outcome occurre<em>d</em> in 6.9% of patients receiving betrixaban an<em>d</em> 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confi<em>d</em>ence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% an<em>d</em> 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort <em>2</em> an<em>d</em> 5.3% an<em>d</em> 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.9<em>2</em>; P=0.006) in the overall population. (The last two analyses were consi<em>d</em>ere<em>d</em> to be exploratory owing to the result in cohort 1.) In the overall population, major blee<em>d</em>ing occurre<em>d</em> in 0.7% of the betrixaban group an<em>d</em> 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to <em>2</em>.1<em>2</em>; P=0.55).

Among acutely ill me<em>d</em>ical patients with an elevate<em>d</em> <em>d</em>-<em>dimer</em> level, there was no significant <em>d</em>ifference between exten<em>d</em>e<em>d</em>-<em>d</em>uration betrixaban an<em>d</em> a stan<em>d</em>ar<em>d</em> regimen of enoxaparin in the prespecifie<em>d</em> primary efficacy outcome. However, prespecifie<em>d</em> exploratory analyses provi<em>d</em>e<em>d</em> evi<em>d</em>ence suggesting a benefit for betrixaban in the two larger cohorts. (Fun<em>d</em>e<em>d</em> by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583<em>2</em>18.).

The two unique sugar binding sites in wheat germ agglutinin, located in the subunit/subunit interface of the <em>dimer</em> molecule and termed primary and secondary binding sites, are compared in the light of the newly obtained chemical amino acid sequence and a high-resolution electron density map (1.8 A). Homology was found in the three amino acid residues directly involved in sugar binding: Tyr73II, Ser6<em>2</em>II, Glu115I in the primary site, and Tyr159I, Ser148I, Asp<em>2</em>9II in the secondary site (subscripts refer to promoters I and II). Thirteen corresponding side-chain atoms of these three homologous residues in the two sites could be superimposed with a root-mean-square difference of 1.39 A. The three sugar binding residues are located in subsite 1 of each extended binding location and contribute to binding of the terminal, non-reducing N-acetyl-<em>D</em>-glucosamine and N-acetyl-<em>D</em>-neuraminic acid residues only, and they provide three hydrogen bonds for complex stabilization. Two hydrogen bonds are made with the carbonyl and amido portions of the N-acetyl group and the third with the C-3 OH group of the sugar ring. It is suggested that small differences in the sugar binding affinities at these two unique sites exist, due to the different numbers of van der Waals' interactions made at these sites, which contribute to stabilizing, for instance, the wheat germ agglutinin/N,N'-diacetyl-chitobiose complex. The single tryptophan residue is located at a distance of approximately 13 A from the primary site and is thought to have no affect on sugar binding. In addition, the disposition of the four saccharide binding sites of the <em>dimer</em> with respect to three local, pseudo <em>2</em>-fold symmetry axes, relating domains of opposite protomers, is discussed.

BACKGROUND

The accuracy of gadolinium-enhanced magnetic resonance pulmonary angiography and magnetic resonance venography for diagnosing pulmonary embolism has not been determined conclusively.

OBJECTIVE

To investigate performance characteristics of magnetic resonance angiography, with or without magnetic resonance venography, for diagnosing pulmonary embolism.

METHODS

Prospective, multicenter study from 10 April 2006 to 30 September 2008.

METHODS

7 hospitals and their emergency services.

METHODS

371 adults with diagnosed or excluded pulmonary embolism.

METHODS

Sensitivity, specificity, and likelihood ratios were measured by comparing independently read magnetic resonance imaging with the reference standard for diagnosing pulmonary embolism. Reference standard diagnosis or exclusion was made by using various tests, including computed tomographic angiography and venography, ventilation-perfusion lung scan, venous ultrasonography, d-dimer assay, and clinical assessment.

RESULTS

Magnetic resonance angiography, averaged across centers, was technically inadequate in 25% of patients (92 of 371). The proportion of technically inadequate images ranged from 11% to 52% at various centers. Including patients with technically inadequate images, magnetic resonance angiography identified 57% (59 of 104) with pulmonary embolism. Technically adequate magnetic resonance angiography had a sensitivity of 78% and a specificity of 99%. Technically adequate magnetic resonance angiography and venography had a sensitivity of 92% and a specificity of 96%, but 52% of patients (194 of 370) had technically inadequate results.

CONCLUSIONS

A high proportion of patients with suspected embolism was not eligible or declined to participate.

CONCLUSIONS

Magnetic resonance pulmonary angiography should be considered only at centers that routinely perform it well and only for patients for whom standard tests are contraindicated. Magnetic resonance pulmonary angiography and magnetic resonance venography combined have a higher sensitivity than magnetic resonance pulmonary angiography alone in patients with technically adequate images, but it is more difficult to obtain technically adequate images with the 2 procedures.

OBJECTIVE

Plasma soluble inflammatory molecules are associated with the risk of ischaemic cardiovascular events. We investigated whether HIV replication modified the levels of these proteins in a combination antiretroviral therapy (cART) interruption trial.

RESULTS

In 145 HIV-infected Thai patients (6<em>2</em>% women, median C<em>D</em>4 cell count <em>2</em>71 cells/microl, median plasma HIV-RNA 4.66 log10 copies/ml) included in the Swiss-Thai-Australia Treatment Interruption Trial (STACCATO) trial, leptin, adiponectin, C-reactive protein, soluble vascular cell adhesion molecule-1 (s-VCAM-1), P-selectin, chemokine ligand <em>2</em>, chemokine ligand 3, interleukin (IL)-6, IL-10, granulocyte macrophage colony-stimulating factor and <em>D</em>-<em>dimer</em> were measured before cART was initiated, after cART had suppressed HIV replication to less than 50 copies/ml plasma (median 8 months) and again 1<em>2</em> weeks after randomization to continued cART (n=48) or interrupted cART (n=97). Multiple linear regression and logistic regression were used to investigate the association between each cardiovascular marker and plasma HIV-RNA. Initiation of cART resulted in significant declines in s-VCAM-1, P-selectin, leptin and <em>D</em>-<em>dimer</em>, whereas mediators with anti-inflammatory properties, such as adiponectin and IL-10, increased. At 1<em>2</em> weeks after randomization, we found positive associations between levels of s-VCAM-1 and chemokine ligand <em>2</em> with an increase in plasma HIV-RNA (r=0.<em>2</em>71, P=0.001 and r=0.<em>2</em>4, P=0.005, respectively), whereas levels of adiponectin decreased for each 1 log increase in plasma HIVRNA (r=-0.<em>2</em>4, P=0.00<em>2</em>). <em>D</em>etectable IL-10 was less likely (odds ratio = 0.64, 95% confidence interval = 0.43-0.96) for each 1 log increase in plasma HIV-RNA.

CONCLUSIONS

Plasma levels of several inflammatory, anti-inflammatory and endothelial activation markers of cardiovascular disease are associated with HIV-RNA replication.