The risk of venous thromboembolism (VTE) is increased in cancer patients. To improve prediction of VTE in cancer patients, we performed a prospective and observational cohort study of patients with newly diagnosed cancer or progression of disease after remission. A previously developed risk scoring model for prediction of VTE that included clinical (tumor entity and body mass index) and laboratory (hemoglobin level and thrombocyte and leukocyte count) parameters was expanded by incorporating <em>2</em> biomarkers, soluble P-selectin, and <em>D</em>-<em>Dimer</em>. Of 819 patients 61 (7.4%) experienced VTE during a median follow-up of 656 days. The cumulative VTE probability in the original risk model after 6 months was 17.7% in patients with the highest risk score (≥ 3, n = 93), 9.6% in those with score <em>2</em> (n = <em>2</em><em>2</em>1), 3.8% in those with score 1 (n = <em>2</em><em>2</em>9), and 1.5% in those with score 0 (n = <em>2</em>76). In the expanded risk model, the cumulative VTE probability after 6 months in patients with the highest score (≥ 5, n = 30) was 35.0% and 10.3% in those with an intermediate score (score 3, n = 130) as opposed to only 1.0% in patients with score 0 (n = <em>2</em>00); the hazard ratio of patients with the highest compared with those with the lowest score was <em>2</em>5.9 (8.0-84.6). Clinical and standard laboratory parameters with addition of biomarkers enable prediction of VTE and allow identification of cancer patients at high or low risk of VTE.

Introduction of TCR alpha transgene, TCR beta transgene, or both into RAG-<em>2</em>-/-mice differentially rescues T cell development. RAG-<em>2</em>-/- mice have small numbers of TCR-CD4-CD8-(double negative, DN) thymocytes that express CD3 gamma <em>delta</em> epsilon and zeta proteins intracellularly. Introduction of a TCR beta transgene, but not a TCR alpha transgene, into the RAG-<em>2</em>-/- background restored normal numbers of thymocytes. These cells were CD4+CD8+ (double positive, DP) and expressed small amounts of surface TCR beta chain <em>dimers</em> in association with CD3 gamma <em>delta</em> epsilon but not zeta. RAG-<em>2</em>-/- mice that expressed alpha and beta TCR transgenes developed both DP and single positive thymocytes. Thus, the TCR beta subunit, possibly in association with a novel CD3 complex, participates in the DN to the DP transition.

The introduction of the Musculoskeletal Infection Society (MSIS) criteria for periprosthetic joint infection (PJI) in <em>2</em>011 resulted in improvements in diagnostic confidence and research collaboration. The emergence of new diagnostic tests and the lessons we have learned from the past 7 years using the MSIS definition, prompted us to develop an evidence-based and validated updated version of the criteria.

This multi-institutional study of patients undergoing revision total joint arthroplasty was conducted at 3 academic centers. For the development of the new diagnostic criteria, PJI and aseptic patient cohorts were stringently defined: PJI cases were defined using only major criteria from the MSIS definition (n = 684) and aseptic cases underwent one-stage revision for a noninfective indication and did not fail within <em>2</em> years (n = 8<em>2</em>0). Serum C-reactive protein (CRP), <em>D</em>-<em>dimer</em>, erythrocyte sedimentation rate were investigated, as well as synovial white blood cell count, polymorphonuclear percentage, leukocyte esterase, alpha-defensin, and synovial CRP. Intraoperative findings included frozen section, presence of purulence, and isolation of a pathogen by culture. A stepwise approach using random forest analysis and multivariate regression was used to generate relative weights for each diagnostic marker. Preoperative and intraoperative definitions were created based on beta coefficients. The new definition was then validated on an external cohort of <em>2</em><em>2</em><em>2</em> patients with PJI who subsequently failed with reinfection and <em>2</em>00 aseptic patients. The performance of the new criteria was compared to the established MSIS and the prior International Consensus Meeting definitions.

Two positive cultures or the presence of a sinus tract were considered as major criteria and diagnostic of PJI. The calculated weights of an elevated serum CRP (>1 mg/dL), <em>D</em>-<em>dimer</em> (>860 ng/mL), and erythrocyte sedimentation rate (>30 mm/h) were <em>2</em>, <em>2</em>, and 1 points, respectively. Furthermore, elevated synovial fluid white blood cell count (>3000 cells/μL), alpha-defensin (signal-to-cutoff ratio >1), leukocyte esterase (++), polymorphonuclear percentage (>80%), and synovial CRP (>6.9 mg/L) received 3, 3, 3, <em>2</em>, and 1 points, respectively. Patients with an aggregate score of greater than or equal to 6 were considered infected, while a score between <em>2</em> and 5 required the inclusion of intraoperative findings for confirming or refuting the diagnosis. Intraoperative findings of positive histology, purulence, and single positive culture were assigned 3, 3, and <em>2</em> points, respectively. Combined with the preoperative score, a total of greater than or equal to 6 was considered infected, a score between 4 and 5 was inconclusive, and a score of 3 or less was not infected. The new criteria demonstrated a higher sensitivity of 97.7% compared to the MSIS (79.3%) and International Consensus Meeting definition (86.9%), with a similar specificity of 99.5%.

This study offers an evidence-based definition for diagnosing hip and knee PJI, which has shown excellent performance on formal external validation.

Coronavirus disease <em>2</em>019 (COVI<em>D</em>-19) is sweeping across the globe. Most patients have mild to moderate symptoms, but a subgroup will become severely ill. Sepsis, respiratory failure, and acute respiratory distress syndrome (AR<em>D</em>S) are common complications of the disease.(1) Factors associated with ICU admission and death include older age, comorbid conditions, elevated body mass index, lymphopenia, and elevated transaminases, L<em>D</em>H, <em>D</em>-<em>dimer</em>, ferritin, and soluble IL-<em>2</em> receptor (sIL-<em>2</em>R).(1-4).

BACKGROUND

High mobility group box nuclear protein 1 (HMGB1) is a DNA nuclear binding protein that has recently been shown to be an early trigger of sterile inflammation in animal models of trauma-hemorrhage via the activation of the Toll-like-receptor 4 (TLR4) and the receptor for the advanced glycation endproducts (RAGE). However, whether HMGB1 is released early after trauma hemorrhage in humans and is associated with the development of an inflammatory response and coagulopathy is not known and therefore constitutes the aim of the present study.

METHODS

One hundred sixty eight patients were studied as part of a prospective cohort study of severe trauma patients admitted to a single Level 1 Trauma center. Blood was drawn within 10 minutes of arrival to the emergency room before the administration of any fluid resuscitation. HMGB1, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, von Willebrand Factor (vWF), angiopoietin-<em>2</em> (Ang-<em>2</em>), Prothrombin time (PT), prothrombin fragments 1+<em>2</em> (PF1+<em>2</em>), soluble thrombomodulin (sTM), protein C (PC), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and <em>D</em>-<em>Dimers</em> were measured using standard techniques. Base deficit was used as a measure of tissue hypoperfusion. Measurements were compared to outcome measures obtained from the electronic medical record and trauma registry.

RESULTS

Plasma levels of HMGB1 were increased within 30 minutes after severe trauma in humans and correlated with the severity of injury, tissue hypoperfusion, early posttraumatic coagulopathy and hyperfibrinolysis as well with a systemic inflammatory response and activation of complement. Non-survivors had significantly higher plasma levels of HMGB1 than survivors. Finally, patients who later developed organ injury, (acute lung injury and acute renal failure) had also significantly higher plasma levels of HMGB1 early after trauma.

CONCLUSIONS

The results of this study demonstrate for the first time that HMGB1 is released into the bloodstream early after severe trauma in humans. The release of HMGB1 requires severe injury and tissue hypoperfusion, and is associated with posttraumatic coagulation abnormalities, activation of complement and severe systemic inflammatory response.

C-terminal bin<em>d</em>ing protein family members function pre<em>d</em>ominantly as transcriptional corepressors in association with sequence specific DNA-bin<em>d</em>ing transcriptional repressors. The vertebrates have two CtBP genes while the invertebrates contain a single gene. Genetic stu<em>d</em>ies in<em>d</em>icate that the CtBP genes play pivotal roles in animal <em>d</em>evelopment. The vertebrate C-terminal bin<em>d</em>ing proteins (CtBP1 an<em>d</em> CtBP<em>2</em>) are highly relate<em>d</em> an<em>d</em> are functionally re<em>d</em>un<em>d</em>ant for certain <em>d</em>evelopmental processes an<em>d</em> non-re<em>d</em>un<em>d</em>ant for others. The animal C-terminal bin<em>d</em>ing proteins exhibit structural an<em>d</em> functional similarity to <em>d</em>-isomer-specific <em>2</em>-hy<em>d</em>roxy aci<em>d</em> <em>d</em>ehy<em>d</em>rogenases (D<em>2</em>-HDH). They function as <em>dimers</em>, recruiting transcriptional regulators through two protein-bin<em>d</em>ing interfaces in each monomer. The corepressor complex of CtBP1 contains enzymatic constituents that me<em>d</em>iate coor<em>d</em>inate<em>d</em> histone mo<em>d</em>ification by <em>d</em>eacetylation an<em>d</em> methylation of histone H3-Lysine 9 an<em>d</em> <em>d</em>emethylation of histone H3-Lysine 4. CtBP also recruits the small ubiquitin-relate<em>d</em> mo<em>d</em>ifier (SUMO) conjugating E<em>2</em> enzyme UBC9 an<em>d</em> a SUMO E3 ligase (HPC<em>2</em>), suggesting that CtBP-me<em>d</em>iate<em>d</em> transcriptional regulation may also involve SUMOylation of transcription factors. In a<em>d</em><em>d</em>ition to gene-specific transcriptional repression, CtBP1 appears to antagonize the activity of the global transcriptional coactivators, p300/CBP. Genetic evi<em>d</em>ence also suggests that the fly CtBP (<em>d</em>CtBP) an<em>d</em> the vertebrate CtBP<em>2</em> might activate transcription in a context-<em>d</em>epen<em>d</em>ent manner. The transcriptional regulatory activity of CtBP is mo<em>d</em>ulate<em>d</em> by the nuclear NADH/NAD+ ratio an<em>d</em> hence appears to be influence<em>d</em> by the metabolic status of the cell. The nuclear <em>d</em>inucleoti<em>d</em>e ratio may <em>d</em>ifferentially influence the repression activities of factors that recruit CtBP through PLDLS-like motifs an<em>d</em> those through non-PLDLS-motifs.

The chemistry community now recognizes the cation-π interaction as a major force for molecular recognition, joining the hydrophobic effect, the hydrogen bond, and the ion pair in determining macromolecular structure and drug-receptor interactions. This Account provides the author's perspective on the intellectual origins and fundamental nature of the cation-π interaction. Early studies on cyclophanes established that water-soluble, cationic molecules would forego aqueous solvation to enter a hydrophobic cavity if that cavity was lined with π systems. Important gas phase studies established the fundamental nature of the cation-π interaction. The strength of the cation-π interaction (Li(+) binds to benzene with 38 kcal/mol of binding energy; NH4(+) with 19 kcal/mol) distinguishes it from the weaker polar-π interactions observed in the benzene <em>dimer</em> or water-benzene complexes. In addition to the substantial intrinsic strength of the cation-π interaction in gas phase studies, the cation-π interaction remains energetically significant in aqueous media and under biological conditions. Many studies have shown that cation-π interactions can enhance binding energies by <em>2</em>-5 kcal/mol, making them competitive with hydrogen bonds and ion pairs in drug-receptor and protein-protein interactions. As with other noncovalent interactions involving aromatic systems, the cation-π interaction includes a substantial electrostatic component. The six (four) C(<em>δ</em>-)-H(<em>δ</em>+) bond dipoles of a molecule like benzene (ethylene) combine to produce a region of negative electrostatic potential on the face of the π system. Simple electrostatics facilitate a natural attraction of cations to the surface. The trend for (gas phase) binding energies is Li(+)>> Na(+)>> K(+)>> Rb(+): as the ion gets larger the charge is dispersed over a larger sphere and binding interactions weaken, a classical electrostatic effect. On other hand, polarizability does not define these interactions. Cyclohexane is more polarizable than benzene but a decidedly poorer cation binder. Many studies have documented cation-π interactions in protein structures, where lysine or arginine side chains interact with phenylalanine, tyrosine, or tryptophan. In addition, countless studies have established the importance of the cation-π interaction in a range of biological processes. Our work has focused on molecular neurobiology, and we have shown that neurotransmitters generally use a cation-π interaction to bind to their receptors. We have also shown that many drug-receptor interactions involve cation-π interactions. A cation-π interaction plays a critical role in the binding of nicotine to ACh receptors in the brain, an especially significant case. Other researchers have established important cation-π interactions in the recognition of the "histone code," in terpene biosynthesis, in chemical catalysis, and in many other systems.

Background: The long-term pulmonary function and related physiological characteristics of COVID-19 survivors have not been studied in depth, thus many aspects are not understood.

<strong class="sub-title"> Methods: </strong> COVID-19 survivors were recruited for high resolution computed tomography (HRCT) of the thorax, lung function and serum levels of SARS-CoV-<em>2</em> IgG antibody tests 3 months after discharge. The relationship between the clinical characteristics and the pulmonary function or CT scores were investigated.

<strong class="sub-title"> Findings: </strong> Fifty-five recovered patients participated in this study. SARS-CoV-<em>2</em> infection related symptoms were detected in 35 of them and different degrees of radiological abnormalities were detected in 39 patients. Urea nitrogen concentration at admission was associated with the presence of CT abnormalities (<i>P</i> = 0.046, OR 7.149, 95% CI 1.038 to 49.<em>2</em>16). Lung function abnormalities were detected in 14 patients and the measurement of D-dimer levels at admission may be useful for prediction of impaired diffusion defect (<i>P</i> = 0.031, OR 1.066, 95% CI 1.006 to 1.1<em>2</em>9). Of all the subjects, 47 of 55 patients tested positive for SARS-CoV-<em>2</em> IgG in serum, among which the generation of Immunoglobulin G (IgG) antibody in female patients was stronger than male patients in infection rehabilitation phase.

Interpretation: Radiological and physiological abnormalities were still found in a considerable proportion of COVID-19 survivors without critical cases 3 months after discharge. Higher level of D-dimer on admission could effectively predict impaired DLCO after 3 months discharge. It is necessary to follow up the COVID-19 patients to appropriately manage any persistent or emerging long-term sequelae.

Funding: Key Scientific Research Projects of Henan Higher Education Institutions.

Keywords: Covid-19; Follow-up study; Pulmonary function; Recovered patients; Serum marker.

Genetic, molecular and cellular analyses of the HLA-<em>D</em> region of the major histocompatability complex (MHC) in man have led to the definition of three different products. Two of these, <em>D</em>R and MB (the latter also known as <em>D</em>C (ref. 1) and LB-E (ref. <em>2</em>)) are defined with serological reagents; the third, known as SB (ref. 3) and PL-3 (ref. 4) is defined with primed lymphocyte typing (PLT) cells. The classical features attributed to HLA-<em>D</em> region encoded (class II) molecules are that they are cell-surface <em>dimers</em> consisting of a structurally conserved alpha-chain noncovalently associated with a polymorphic beta-chain and that they are found primarily on B lymphocytes, some monocyte populations, endothelial and certain other cells. Using these criteria a monoclonal antibody, B7/<em>2</em>1, was described as reactive with HLA-<em>D</em>R (ref. 7). We have now re-evaluated B7/<em>2</em>1 antibody reactivity using mutant lymphoblastoid cell lines. It appears that this antibody does not react with the molecularly defined <em>D</em> region products described to date but instead, recognizes a class II antigen with distinctive molecular characteristics. We provisionally refer to this antigen as FA.

The role of thymine resi<em>d</em>ues in the formation of G-quartet structures for telomeric sequences has been investigate<em>d</em> using mo<em>d</em>el oligonucleoti<em>d</em>es of the type <em>d</em>(G4TnG4), with n = 1-4. Sequences <em>d</em>(G4T3G4) an<em>d</em> <em>d</em>(G4T4G4) a<em>d</em>opt a G-quartet structure forme<em>d</em> by hairpin <em>dimer</em>ization in 70 mM NaCl as ju<em>d</em>ge<em>d</em> by a characteristic circular <em>d</em>ichroism signature with a <em>2</em>95 nm positive an<em>d</em> <em>2</em>65 nm negative ban<em>d</em>s while <em>d</em>(G4TG4) a<em>d</em>opts a parallel G-quartet structure like <em>d</em>(G1<em>2</em>) which exhibits a strong positive ban<em>d</em> at <em>2</em>60 nm an<em>d</em> a negative ban<em>d</em> at <em>2</em>40 nm. The sequence <em>d</em>(G4T<em>2</em>G4) exhibits a mixture of both conformations. The stability of hairpin G-quartet structures <em>d</em>ecreases with <em>d</em>ecrease in the number of intervening thymine resi<em>d</em>ues. Potassium permanganate, a single stran<em>d</em> specific probe has been use<em>d</em> to establish the presence of loops compose<em>d</em> of T resi<em>d</em>ues in the hairpin G quartet structures forme<em>d</em> by the oligonucleoti<em>d</em>es <em>d</em>(G4TnG4) with n = <em>2</em>-4 in 70 mM NaCl. The formation of hairpin G quartet structure for the above sequences is further supporte<em>d</em> by the enhance<em>d</em> electrophoretic mobility observe<em>d</em> on non-<em>d</em>enaturing polyacrylami<em>d</em>e gels. Human telomeric sequence <em>d</em>(TTAGGG)4 which showe<em>d</em> enhance<em>d</em> electrophoretic mobility like Tetrahymena telomeric sequence <em>d</em>(T<em>2</em>G4)4 also exhibite<em>d</em> a characteristic CD spectrum for a fol<em>d</em>e<em>d</em>-back G-quartet structure. A <em>d</em>etaile<em>d</em> mo<em>d</em>el for G-quartet structure involving hairpin <em>dimer</em> with alternating syn-anti-syn-anti conformation for the guanine resi<em>d</em>ues both along the chain as well as aroun<em>d</em> the G tetra<em>d</em> with at least two thymine resi<em>d</em>ues in the loop is propose<em>d</em>. Intermolecular association of short telomeric sequences reporte<em>d</em> here provi<em>d</em>es a possible mo<em>d</em>el for chromosomal pairing.

Yeast DNA polymerase <em>delta</em> (Pol<em>delta</em>) has three subunits of 1<em>2</em>5, 58, and 55 kDa. The gene for the 1<em>2</em>5-kDa catalytic subunit (POL3) has been known for several years. Here we describe the cloning of the genes for the 58- and 55-kDa subunits using peptide sequence analysis and searching of the yeast genome data base. The 58-kDa subunit, encoded by the POL31 gene, shows <em>2</em>3-<em>2</em>8% sequence similarity to the 48-kDa subunit of human Pol<em>delta</em> and to S. pombe Cdc1. POL31 is allelic to HYS<em>2</em> and SDP5. The 55-kDa subunit is encoded by the POL3<em>2</em> gene (ORF YJR043c in the yeast data base). Very limited sequence similarity was observed between Pol3<em>2</em>p and Schizosaccharomyces pombe Cdc<em>2</em>7, the functionally analogous subunit in S. pombe Pol<em>delta</em>. The POL3<em>2</em> gene is not essential, but a deletion mutant shows cold sensitivity for growth and is sensitive to hydroxyurea and DNA damaging agents. In addition, lethality was observed when the POL3<em>2</em> deletion mutation was combined with conditional mutations in either the POL3 or POL31 gene. Pol3<em>2</em>Delta strains are weak antimutators and are defective for damage-induced mutagenesis. The POL3<em>2</em> gene product binds proliferating cell nuclear antigen. A gel filtration analysis showed that Pol3<em>2</em>p is a <em>dimer</em> in solution. When POL31 and POL3<em>2</em> were co-expressed in Escherichia coli, a tetrameric (Pol31p.Pol3<em>2</em>p)<em>2</em> species was detected by gel filtration, indicating that the two subunits form a complex.

This prospective, non-randomized, open-label, cohort study addresses the safety and efficacy of exosomes (ExoFlo™) derived from allogeneic bone marrow mesenchymal stem cells as treatment for severe COVI<em>D</em>-19. <em>D</em>uring April <em>2</em>0<em>2</em>0, ExoFlo was provided to <em>2</em>4 SARS-CoV-<em>2</em> PCR positive patients at a single hospital center, all of whom met criteria for severe COVI<em>D</em>-19 as well as moderate to severe Acute Respiratory <em>D</em>istress Syndrome (AR<em>D</em>S). Patients received a single 15 mL intravenous dose of ExoFlo and were evaluated for both safety and efficacy day 1-14 post-treatment. All safety endpoints were met with no adverse events observed within 7<em>2</em> hours of ExoFlo administration. A survival rate of 83% was observed. 17/<em>2</em>4 (71%) of the patients recovered; 3/<em>2</em>4 (13%) remained critically ill though stable; 4/<em>2</em>4 (16%) expired for reasons unrelated to the treatment. Overall, after one treatment, patients' clinical status and oxygenation improved with an average PaO<em>2</em>/FiO<em>2</em> ratio increase of 19<em>2</em>% (p < 0.001). Laboratory values revealed significant improvements in absolute neutrophil count [mean reduction 3<em>2</em>% [(p-value < 0.001)] and lymphopenia with average C<em>D</em>3+, C<em>D</em>4+ and C<em>D</em>8+ lymphocyte counts increasing by 46% (p < 0.05), 45% (p < 0.05), and 46% (p < 0.001), respectively. Likewise, acute phase reactants declined, with mean C-reactive protein (CRP), Ferritin, and <em>D</em>-<em>dimer</em> reduction of 77% (p < .001), 43% (p < .001), 4<em>2</em>% (p <0.05), respectively. In conclusion, due to its safety profile, capacity to restore oxygenation, downregulate cytokine storm, and reconstitute immunity, ExoFlo is a promising therapeutic candidate for severe COVI<em>D</em>-19. Future RCTs are needed to determine ExoFlo therapeutic potential.

Changes in the alveolar hemostatic balance in severe pneumonia were compared with those in the acute respiratory distress syndrome (AR<em>D</em>S). Analysis was performed in bronchoalveolar lavage fluids (BALF) of patients with AR<em>D</em>S triggered by nonpulmonary underlying events in the absence of lung infection (AR<em>D</em>S; n = <em>2</em>5), pneumonia demanding mechanical ventilation (PNEU-vent; n = 114), spontaneously breathing patients with pneumonia (PNEU-spon; n = 40), and AR<em>D</em>S in combination with lung infection (AR<em>D</em>S+PNEU; n = 43); comparison with healthy control subjects (n = 35) was performed. In all groups of patients, BALF total procoagulant activity was increased by nearly two orders of magnitude, being largely attributable to the tissue factor pathway of coagulation. Concomitantly, markedly reduced overall fibrinolytic capacity (fibrin plate assay) was noted in the lavage fluids of all patients. BALF levels of urokinase-type plasminogen activator were significantly reduced throughout, whereas the lavage concentrations of tissue-type plasminogen activator did not differ from those in control subjects. In addition, markedly enhanced levels of plasminogen activator- inhibitor I and alpha(<em>2</em>)-antiplasmin were noted in AR<em>D</em>S, AR<em>D</em>S+PNEU, and PNEU-vent, but not in PNEU-spon. In all groups of patients, the changes in the lavage enzymatic activities were paralleled by manifold increased BALF concentrations of fibrinopeptide A and <em>D</em>-<em>dimer</em>, reflecting in vivo coagulation processes. Within the overall number of patients with pneumonia, changes in the alveolar hemostatic balance were more prominent in alveolar and interstitial pneumonia than in bronchopneumonia. Acute inflammatory lung injury, whether triggered by nonpulmonary systemic events or primary lung infection, is thus consistently characterized by both enhanced procoagulant and depressed fibrinolytic activities in the alveolar lining layer, with the appearance of fibrin formation in this compartment. Profile and extent of changes in severe pneumonia demanding respirator therapy are virtually identical to those in AR<em>D</em>S, whereas somewhat less prominent alterations of the alveolar hemostatic balance are noted in spontaneously breathing patients with pneumonia.

This is the first evaluation of <em>d</em>abigatran, an oral <em>d</em>irect thrombin inhibitor, in patients with atrial fibrillation (AF). Patients (n = 50<em>2</em>) were ran<em>d</em>omize<em>d</em> to receive blin<em>d</em>e<em>d</em> <em>d</em>oses of 50-, 150-, or 300-mg <em>d</em>abigatran twice <em>d</em>aily alone or combine<em>d</em> with 81- or 3<em>2</em>5-mg aspirin or open-label warfarin a<em>d</em>ministere<em>d</em> to achieve an international normalize<em>d</em> ratio of <em>2</em> to 3 for 1<em>2</em> weeks. <em>D</em>abigatran plasma concentrations, activate<em>d</em> partial thromboplastin time, <em>D</em>-<em>dimer</em>, urinary 11-<em>d</em>ehy<em>d</em>rothromboxane B(<em>2</em>) (<em>D</em>TB<em>2</em>), an<em>d</em> liver function were measure<em>d</em> at baseline an<em>d</em> at 1, <em>2</em>, 4, 8, an<em>d</em> 1<em>2</em> weeks. Clinical en<em>d</em> points were assesse<em>d</em> accor<em>d</em>ing to the treatment receive<em>d</em> at the time of the event. Overall, 9<em>2</em>% of patients complete<em>d</em> the stu<em>d</em>y. Major hemorrhages were limite<em>d</em> to the group treate<em>d</em> with 300-mg <em>d</em>abigatran plus aspirin (4 of 64), an<em>d</em> the inci<em>d</em>ence was significant versus 300-mg <em>d</em>abigatran alone (0 of 105, p <0.0<em>2</em>). Total blee<em>d</em>ing events were more frequent in the 300-mg (39 of 169, <em>2</em>3%) an<em>d</em> 150-mg (30 of 169, 18%) <em>d</em>abigatran groups compare<em>d</em> with the 50-mg groups (7 of 107, 7%; p = 0.000<em>2</em> an<em>d</em> p = 0.01, respectively). Thromboembolic events were limite<em>d</em> to the 50-mg <em>d</em>abigatran <em>d</em>ose groups (<em>2</em> of 107, <em>2</em>%). The mean trough <em>d</em>-<em>dimer</em> measurements were suppresse<em>d</em> for the <em>2</em> highest <em>d</em>oses of <em>d</em>abigatran an<em>d</em> warfarin (international normalize<em>d</em> ratio of <em>2</em> to 3). Aminotransferase levels >3 times the upper limit of normal were observe<em>d</em> in 0.9% of the <em>d</em>abigatran recipients an<em>d</em> in none of the warfarin recipients. Two <em>d</em>abigatran recipients ha<em>d</em> aminotransferase levels >5 times the upper limit of normal as a result of gallstones, which resolve<em>d</em>. Trough activate<em>d</em> partial thromboplastin time values were 1.<em>2</em>, 1.5, an<em>d</em> 1.8 times the baseline level for the 50-, 150-, an<em>d</em> 300-mg <em>d</em>abigatran groups, respectively. <em>D</em>TB<em>2</em> concentrations after 1<em>2</em> weeks of 50-, 150-, an<em>d</em> 300-mg <em>d</em>abigatran treatment were increase<em>d</em> by 31%, 17%, an<em>d</em> <em>2</em>3%, respectively, versus baseline (p = 0.0<em>2</em>, p = 0.03, an<em>d</em> p = 0.0004). In conclusion, major blee<em>d</em>ing events were limite<em>d</em> to patients treate<em>d</em> with <em>d</em>abigatran 300 mg plus aspirin an<em>d</em> thromboembolic episo<em>d</em>es were limite<em>d</em> to the 50-mg <em>d</em>abigatran groups. The <em>2</em> highest <em>d</em>oses of <em>d</em>abigatran suppress <em>D</em>-<em>dimer</em> concentrations. Serious liver toxicity was not seen. The significance of the increase of <em>D</em>TB<em>2</em> concentrations in <em>d</em>abigatran-treate<em>d</em> patients nee<em>d</em>s resolution.

OBJECTIVE

Cardiovascular disease (CVD) contributes significantly to HIV-related morbidity and mortality. Chronic immune activation and inflammation are thought to augment the progression of atherosclerotic disease. In this retrospective, case-control study of HIV-infected individuals, we investigated the association of traditional cardiac risk factors, HIV-related disease, and inflammation with CVD events.

METHODS

HIV-infected individuals who experienced an incident CVD event while enrolled in National Institutes of Health clinical protocols from 1995 to <em>2</em>009 were matched <em>2</em>: 1 to HIV-infected individuals without known CVD. Markers of inflammation and cell activation were measured in serum or plasma using ELISA-based assays and peripheral mononuclear cells by four-color flow cytometry.

RESULTS

Fifty-two patients experienced an incident CVD event. Events were related to smoking, dyslipidemia, hyperglycemia, and family history as well as elevated D-dimer, soluble vascular cell adhesion molecule-1, tissue inhibitor of metalloproteinase-1, and soluble tissue factor, but not high-sensitivity C-reactive protein. No significant differences in antiviral therapy, CD4 T-cell count, or CD38 and human leukocyte antigen-DR expression were identified between patients and controls. In multivariable analysis, smoking, family history, D-dimer, and glucose were independently related to CVD risk.

CONCLUSIONS

In this cohort, CVD risk was related to traditional CVD risk factors and markers of thrombosis and endothelial damage, but not to high-sensitivity C-reactive protein or markers of T-cell activation such as CD38/human leukocyte antigen-DR coexpression. D-dimer may help identify HIV-infected patients at elevated CVD risk.

Severe acute respiratory syndrome coronavirus <em>2</em> (SARS-Cov-<em>2</em>) is an emergent pathogen responsible for the coronavirus disease <em>2</em>019 (COVI<em>D</em>-19). Since its emergence, the novel coronavirus has rapidly achieved pandemic proportions causing remarkably increased morbidity and mortality around the world. A hypercoagulability state has been reported as a major pathologic event in COVI<em>D</em>-19, and thromboembolic complications listed among life-threatening complications of the disease. Platelets are chief effector cells of hemostasis and pathological thrombosis. However, the participation of platelets in the pathogenesis of COVI<em>D</em>-19 remains elusive. This report demonstrates that increased platelet activation and platelet-monocyte aggregates formation is observed in severe COVI<em>D</em>-19 patients, but not in patients presenting mild COVI<em>D</em>-19 syndrome. In addition, exposure to plasma from severe COVI<em>D</em>-19 patients increased the activation of control platelets ex vivo. In our cohort of COVI<em>D</em>-19 patients admitted to the ICU, platelet-monocyte interaction was strongly associated with TF expression by the monocytes. Platelet activation and monocyte TF expression were associated with markers of coagulation dysfunction as fibrinogen and <em>D</em>-<em>dimers</em>, and were increased in patients requiring invasive mechanical ventilation or patients that evolved with in-hospital mortality. Finally, platelets from severe COVI<em>D</em>-19 patients were able to induce TF expression ex vivo in monocytes from healthy volunteers, a phenomenon that was inhibited by platelet P-selectin neutralization or integrin αIIb/β3 blocking with the aggregation inhibitor abciximab. Altogether, these data shed light on new pathological mechanisms involving platelet activation and platelet-dependent monocyte TF expression, which were associated with COVI<em>D</em>-19 severity and mortality.

<em>D</em>einococcus radiodurans and other members of the same genus share extraordinary resistance to the lethal and mutagenic effects of ionizing and u.v. radiation and to many other agents that damage <em>D</em>NA. While it is known that this resistance is due to exceedingly efficient <em>D</em>NA repair, the molecular mechanisms responsible remain poorly understood. Following very high exposures to u.v. irradiation (e.g. 500 J m-<em>2</em>, which is non-lethal to <em>D</em>. radiodurans), this organism carries out extremely efficient excision repair accomplished by two separate nucleotide excision repair pathways acting simultaneously. One pathway requires the uvrA gene and appears similar to the UvrABC excinuclease pathway defined in Escherichia coli. The other excision repair pathway is specific for u.v. <em>dimer</em>ic photoproducts, but is not mediated by a pyrimidine <em>dimer</em> <em>D</em>NA glycosylase. Instead, it is initiated by a second bona fide endonuclease that may recognize both pyrimidine <em>dimers</em> and pyrimidine-(6-4)pyrimidones. After high doses of ionizing-radiation (e.g. 1.5 Mrad), <em>D</em>. radiodurans can mend>> 100 double-strand breaks (dsb) per chromosome without lethality or mutagenesis. Both dsb mending and survival are recA-dependent, indicating that efficient dsb mending proceeds via homologous recombination. <em>D</em>. radiodurans contains multiple chromosomes per cell, and it is proposed that dsb mending requires extensive recombination amongst these chromosomes, a novel phenomenon in bacteria. Thus, <em>D</em>. radiodurans may serve as an easily accessible model system for the double-strand-break-initiated interchromosomal recombination that occurs in eukaryotic cells during mitosis and meiosis.

Between February and March <em>2</em>0<em>2</em>0, the Journal of Thrombosis and Hemosthasis has published four papers addressing the intricate, complex and still little understood relation between COVI<em>D</em>-19 and thrombogenesis (1-4). ARS-Cov-<em>2</em> induces in severe cases a cytokine storm that ultimately leads to the activation of the coagulation cascade, causing thrombotic phenomena (5). There is a further strong link between abnormal coagulation parameters (<em>D</em>-<em>dimer</em> and fibrin degradation products) and mortality. Tang et al. described that 71.4% of nonsurvivors and 0.6% of survivors showed evidence of disseminated intravascular coagulation (<em>D</em>IC), suggesting that <em>D</em>IC is a frequent occurrence in severe COVI<em>D</em>-19 (4). The frequency of <em>D</em>IC in these patients is much higher than that reported for severe SARS (6).

OBJECTIVE

D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients.

OBJECTIVE

To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE.

METHODS

A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013.

METHODS

All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period.

METHODS

The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result.

RESULTS

Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings.

CONCLUSIONS

Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism.

BACKGROUND

clinicaltrials.gov Identifier: NCT01134068.

BACKGROUND

Vascular complications are the leading cause of morbidity and mortality among patients with type 1 and type <em>2</em> diabetes mellitus. These vascular abnormalities result of a chronic hyperglycemic state, which leads to an increase in oxidative stress and inflammatory responses.

OBJECTIVE

This review addresses the relationships among endothelial dysfunction, hypercoagulability and inflammation and their biomarkers in the development of vascular complications in type 1 and type <em>2</em> diabetes.

RESULTS

Inflammation, endothelial dysfunction, and hypercoagulability are correlated to each other, playing an important role in the development of vascular complications in diabetic patients. Moreover, it has been observed that several endothelial, inflammatory and pro-coagulant biomarkers, such as VWF, IL-6, TNF-α, D-dimer and PAI-1, are increased in diabetic patients who have microvascular and macrovascular complications, including nephropathy or cardiovascular disease.

CONCLUSIONS

It is promising the clinical and laboratory use of endothelial, inflammatory and pro-coagulant biomarkers for predicting the risk of cardiovascular and renal complications in diabetic patients and for monitoring these patients.

The <em>D</em>-<em>dimer</em> antigen is a unique marker of fibrin degradation that is formed by the sequential action of 3 enzymes: thrombin, factor XIIIa, and plasmin. First, thrombin cleaves fibrinogen producing fibrin monomers, which polymerize and serve as a template for factor XIIIa and plasmin formation. Second, thrombin activates plasma factor XIII bound to fibrin polymers to produce the active transglutaminase, factor XIIIa. Factor XIIIa catalyzes the formation of covalent bonds between <em>D</em>-domains in the polymerized fibrin. Finally, plasmin degrades the crosslinked fibrin to release fibrin degradation products and expose the <em>D</em>-<em>dimer</em> antigen. <em>D</em>-<em>dimer</em> antigen can exist on fibrin degradation products derived from soluble fibrin before its incorporation into a fibrin gel, or after the fibrin clot has been degraded by plasmin. The clinical utility of <em>D</em>-<em>dimer</em> measurement has been established in some scenarios, most notably for the exclusion of VTE. This article consists of <em>2</em> sections: in the first, the dynamics of <em>D</em>-<em>dimer</em> antigen formation is discussed and an overview of commercially available <em>D</em>-<em>dimer</em> assays is provided. The second section reviews available evidence for the clinical utilization of <em>D</em>-<em>dimer</em> antigen measurement in VTE, as well as emerging areas of <em>D</em>-<em>dimer</em> utilization as a marker of coagulation activation in other clinical settings.

<AbstractText>This study explores the clinical characteristics of patients with diabetes with severe covid-19, and the association of diabetes with survival duration in patients with severe covid-19.</AbstractText><p><div><b>RESEARCH <em>D</em>ESIGN AN<em>D</em> METHO<em>D</em>S</b></div>In this single-center, retrospective, observational study, the clinical and laboratory characteristics of 193 patients with severe covid-19 were collected. 48 patients with severe covid-19 had diabetes, and 145 patients (ie, the controls) did not have diabetes. A severe case was defined as including at least one of the following criteria: (1) Respiratory rate >30/min. (<em>2</em>) Oxygen saturation ≤93%. (3) PaO_<em>2</em>/FiO_<em>2</em>≤300 mm Hg. (4) Patients, either with shock or respiratory failure, requiring mechanical ventilation, or combined with other organ failure, requiring admission to intensive care unit (ICU).</p><p><div><b>RESULTS</b></div>Of 193 patients with severe covid-19, 48 (<em>2</em>4.9%) had diabetes. Compared with patients with severe covid-19 without diabetes, patients with diabetes were older, susceptible to receiving mechanical ventilation and admission to ICU, and had higher mortality. In addition, patients with severe covid-19 with diabetes had higher levels of leukocyte count, neutrophil count, high-sensitivity C reaction protein, procalcitonin, ferritin, interleukin (IL) <em>2</em> receptor, IL-6, IL-8, tumor necrosis factor α, <em>D</em>-<em>dimer</em>, fibrinogen, lactic dehydrogenase and N-terminal pro-brain natriuretic peptide. Among patients with severe covid-19 with diabetes, more non-survivors were men (30 (76.9%) <i>vs</i> 9 (<em>2</em>3.1%)). Non-survivors had severe inflammatory response, and cardiac, hepatic, renal and coagulation impairment. Finally, the Kaplan-Meier survival curve showed a trend towards poorer survival in patients with severe covid-19 with diabetes than patients without diabetes. The HR was 1.53 (95% CI 1.0<em>2</em> to <em>2</em>.30; p=0.041) after adjustment for age, sex, hypertension, cardiovascular disease and cerebrovascular disease by Cox regression. The median survival durations from hospital admission in patients with severe covid-19 with and without diabetes were 10 days and 18 days, respectively.</p><AbstractText>The mortality rate in patients with severe covid-19 with diabetes is considerable. <em>D</em>iabetes may lead to an increase in the risk of death.</AbstractText>

Background: COVID-19 has spread globally. Epidemiological susceptibility to COVID-19 has been reported in patients with cancer. We aimed to systematically characterise clinical features and determine risk factors of COVID-19 disease severity for patients with cancer and COVID-19.

<strong class="sub-title">Methods:</strong> In this multicentre, retrospective, cohort study, we included all adult patients (aged ≥18 years) with any type of malignant solid tumours and haematological malignancy who were admitted to nine hospitals in Wuhan, China, with laboratory-confirmed COVID-19 between Jan 13 and March 18, <em>2</em>0<em>2</em>0. Enrolled patients were statistically matched (<em>2</em>:1) with patients admitted with COVID-19 who did not have cancer with propensity score on the basis of age, sex, and comorbidities. Demographic characteristics, laboratory examinations, illness severity, and clinical interventions were compared between patients with COVID-19 with or without cancer as well as between patients with cancer with non-severe or severe COVID-19. COVID-19 disease severity was defined on admission on the basis of the WHO guidelines. Univariable and multivariable logistic regression, adjusted for age, sex, comorbidities, cancer type, tumour stage, and antitumour treatments, were used to explore risk factors associated with COVID-19 disease severity. This study was registered in the Chinese Clinical Trial Register, ChiCTR<em>2</em>000030807.

<strong class="sub-title">Findings:</strong> Between Jan 13 and March 18, <em>2</em>0<em>2</em>0, 13 077 patients with COVID-19 were admitted to the nine hospitals in Wuhan and <em>2</em>3<em>2</em> patients with cancer and 519 statistically matched patients without cancer were enrolled. Median follow-up was <em>2</em>9 days (IQR <em>2</em><em>2</em>-38) in patients with cancer and <em>2</em>7 days (<em>2</em>0-35) in patients without cancer. Patients with cancer were more likely to have severe COVID-19 than patients without cancer (148 [64%] of <em>2</em>3<em>2</em> vs 166 [3<em>2</em>%] of 519; odds ratio [OR] 3·61 [95% CI <em>2</em>·59-5·04]; p<0·0001). Risk factors previously reported in patients without cancer, such as older age; elevated interleukin 6, procalcitonin, and D-dimer; and reduced lymphocytes were validated in patients with cancer. We also identified advanced tumour stage (OR <em>2</em>·60, 95% CI 1·05-6·43; p=0·039), elevated tumour necrosis factor α (1·<em>2</em><em>2</em>, 1·01-1·47; p=0·037), elevated N-terminal pro-B-type natriuretic peptide (1·65, 1·03-<em>2</em>·78; p=0·03<em>2</em>), reduced CD4+ T cells (0·84, 0·71-0·98; p=0·031), and reduced albumin-globulin ratio (0·1<em>2</em>, 0·0<em>2</em>-0·77; p=0·0<em>2</em>4) as risk factors of COVID-19 severity in patients with cancer.

Interpretation: Patients with cancer and COVID-19 were more likely to deteriorate into severe illness than those without cancer. The risk factors identified here could be helpful for early clinical surveillance of disease progression in patients with cancer who present with COVID-19.

Funding: China National Natural Science Foundation.

RANKL is a tumor necrosis factor (TNF)-like factor secreted by mesenchymal cells, osteoblast derivatives, and T cells that is essential for osteoclastogenesis. In osteoblasts, RANKL expression is regulated by two major calcemic hormones, 1,<em>2</em>5-dihydroxyvitamin <em>D</em>(3) [1,<em>2</em>5(OH)(<em>2</em>)<em>D</em>(3)] and parathyroid hormone (PTH), as well as by several inflammatory/osteoclastogenic cytokines; the molecular mechanisms for this regulation are unclear. To identify such mechanisms, we screened a <em>D</em>NA microarray which tiled across the entire mouse RankL gene locus at a 50-bp resolution using chromatin immunoprecipitation (ChIP)-derived <em>D</em>NA precipitated with antibodies to the vitamin <em>D</em> receptor (V<em>D</em>R) and the retinoid X receptor (RXR). Five sites of <em>dimer</em> interaction were observed on the RankL gene centered at 16, <em>2</em><em>2</em>, 60, 69, and 76 kb upstream of the TSS. These regions contained binding sites for not only V<em>D</em>R and RXR, but also the glucocorticoid receptor (GR). The most distant of these regions, termed the distal control region (RL-<em>D</em>CR), conferred both V<em>D</em>R-dependent 1,<em>2</em>5(OH)(<em>2</em>)<em>D</em>(3) and GR-dependent glucocorticoid (GC) responses. We mapped these activities to an unusual but functionally active vitamin <em>D</em> response element and to several potential GC response elements located over a more extensive region within the RL-<em>D</em>CR. An evolutionarily conserved region within the human RANKL gene contained a similar vitamin <em>D</em> response element and exhibited an equivalent behavior. Importantly, hormonal activation of the RankL gene was also associated with chromatin modification and RNA polymerase II recruitment. Our studies demonstrate that regulation of RankL gene expression by 1,<em>2</em>5(OH)(<em>2</em>)<em>D</em>(3) is complex and mediated by at least five distal regions, one of which contains a specific element capable of mediating direct transcriptional activation.