Investigation of health inequities in maternal and neonatal outcomes of patients with placenta accreta spectrum: a multicenter study.

BACKGROUND: Placenta accreta spectrum is associated with significant maternal and neonatal morbidity and mortality. There is limited established data on healthcare inequities in the outcomes of patients with placenta accreta spectrum. OBJECTIVE: This study aimed to investigate health inequities in maternal and neonatal outcomes of pregnancies with placenta accreta spectrum. STUDY DESIGN: This multicentered retrospective cohort study included patients with a histopathological diagnosis of placenta accreta spectrum at 4 regional perinatal centers between January 1, 2013, and June 30, 2022. Maternal race and ethnicity were categorized as either Hispanic, non-Hispanic Black, non-Hispanic White, or Asian or Pacific Islander. The primary outcome was a composite adverse maternal outcome: transfusion of ≥4 units of packed red blood cells, vasopressor use, mechanical ventilation, bowel or bladder injury, or mortality. The secondary outcomes were a composite adverse neonatal outcome (Apgar score of <7 at 1 minute, morbidity, or mortality), gestational age at placenta accreta spectrum diagnosis, and planned delivery by a multidisciplinary team. Multivariable logistic regression was used to estimate the associations of race and ethnicity with maternal and neonatal outcomes. RESULTS: A total of 408 pregnancies with placenta accreta spectrum were included. In 218 patients (53.0%), the diagnosis of placenta accreta spectrum was made antenatally. Patients predominantly self-identified as non-Hispanic White (31.6%) or non-Hispanic Black (24.5%). After adjusting for institution, age, body mass index, income, and parity, there was no difference in composite adverse maternal outcomes among the racial and ethnic groups. Similarly, adverse neonatal outcomes, gestational age at prenatal diagnosis, rate of planned delivery by a multidisciplinary team, and cesarean hysterectomy were similar among groups. CONCLUSION: In our multicentered placenta accreta spectrum cohort, race and ethnicity were not associated with inequities in composite maternal or neonatal morbidity, timing of diagnosis, or planned multidisciplinary care. This study hypothesized that a comparable incidence of individual risk factors for perinatal morbidity and geographic proximity reduces potential inequities that may exist in a larger population.

Post-traumatic stress and future substance use outcomes: leveraging antecedent factors to stratify risk.

Background: Post-traumatic stress disorder (PTSD) and substance use (tobacco, alcohol, and cannabis) are highly comorbid. Many factors affect this relationship, including sociodemographic and psychosocial characteristics, other prior traumas, and physical health. However, few prior studies have investigated this prospectively, examining new substance use and the extent to which a wide range of factors may modify the relationship to PTSD. Methods: The Advancing Understanding of RecOvery afteR traumA (AURORA) study is a prospective cohort of adults presenting at emergency departments (N = 2,943). Participants self-reported PTSD symptoms and the frequency and quantity of tobacco, alcohol, and cannabis use at six total timepoints. We assessed the associations of PTSD and future substance use, lagged by one timepoint, using the Poisson generalized estimating equations. We also stratified by incident and prevalent substance use and generated causal forests to identify the most important effect modifiers of this relationship out of 128 potential variables. Results: At baseline, 37.3% (N = 1,099) of participants reported likely PTSD. PTSD was associated with tobacco frequency (incidence rate ratio (IRR): 1.003, 95% CI: 1.00, 1.01, p = 0.02) and quantity (IRR: 1.01, 95% CI: 1.001, 1.01, p = 0.01), and alcohol frequency (IRR: 1.002, 95% CI: 1.00, 1.004, p = 0.03) and quantity (IRR: 1.003, 95% CI: 1.001, 1.01, p = 0.001), but not with cannabis use. There were slight differences in incident compared to prevalent tobacco frequency and quantity of use; prevalent tobacco frequency and quantity were associated with PTSD symptoms, while incident tobacco frequency and quantity were not. Using causal forests, lifetime worst use of cigarettes, overall self-rated physical health, and prior childhood trauma were major moderators of the relationship between PTSD symptoms and the three substances investigated. Conclusion: PTSD symptoms were highly associated with tobacco and alcohol use, while the association with prospective cannabis use is not clear. Findings suggest that understanding the different risk stratification that occurs can aid in tailoring interventions to populations at greatest risk to best mitigate the comorbidity between PTSD symptoms and future substance use outcomes. We demonstrate that this is particularly salient for tobacco use and, to some extent, alcohol use, while cannabis is less likely to be impacted by PTSD symptoms across the strata.

Mid-trimester sonographic placenta previa thickness and persistence at delivery.

OBJECTIVE: Increasing placental thickness is associated with adverse outcomes including earlier gestational age at delivery, lower birthweight, and lower umbilical artery pH. We aim to determine whether mid-trimester placenta previa thickness is associated with persistence of previa at time of delivery. STUDY DESIGN: Single-center retrospective cohort study of singleton gestations with previa diagnosed at 18-24 weeks delivering between 2015 and 2019. The thickest portion of the placenta was measured in a longitudinal plane on transabdominal imaging to determine placental thickness. We defined three cohorts: 1) thick placenta (>1 standard deviation above the mean), 2) thin placenta (>1 standard deviation below the mean), and 3) average placenta (within 1 standard deviation above or below the mean). Primary outcome was previa persistence at time of delivery. Secondary outcomes included postpartum hemorrhage, cesarean delivery, placenta accreta spectrum, and maternal morbidity composite (use of Bakri balloon, B-lynch, or O'Leary, peripartum hysterectomy, blood transfusion, ICU admission, or death). In all analyses, average thickness was used as the base comparator. RESULTS: Of 239 pregnancies with mid-trimester previa there were 34 thin, 166 average, and 39 thick placentas. Patients with thick placenta were older, more likely to have prior cesarean delivery, fibroid uterus, and delivery at an earlier gestational age. After adjusting for confounders, thick placenta was associated with persistent previa (aOR 6.85 [3.13-15.00]) and cesarean delivery (aOR 2.76 [1.26-6.08]). CONCLUSION: At diagnosis of mid-trimester previa, thick placenta is associated with persistence at time of delivery and delivery by cesarean section. This suggests placental thickness may assist with risk stratification and coordination of care.

Current and potentially novel antithrombotic treatment in acute ischemic stroke.

Acute ischemic stroke (AIS) is the most common type of stroke and requires immediate reperfusion. Current acute reperfusion therapies comprise the administration of intravenous thrombolysis and/or endovascular thrombectomy. Although these acute reperfusion therapies are increasingly successful, optimized secondary antithrombotic treatment remains warranted, specifically to reduce the risk of major bleeding complications. In the development of AIS, coagulation and platelet activation play crucial roles by driving occlusive clot formation. Recent studies implicated that the intrinsic route of coagulation plays a more prominent role in this development, however, this is not fully understood yet. Next to the acute treatments, antithrombotic therapy, consisting of anticoagulants and/or antiplatelet therapy, is successfully used for primary and secondary prevention of AIS but at the cost of increased bleeding complications. Therefore, better understanding the interplay between the different pathways involved in the pathophysiology of AIS might provide new insights that could lead to novel treatment strategies. This narrative review focuses on the processes of platelet activation and coagulation in AIS, and the most common antithrombotic agents in primary and secondary prevention of AIS. Furthermore, we provide an overview of promising novel antithrombotic agents that could be used to improve in both acute treatment and stroke prevention.

The intrinsic coagulation pathway plays a dominant role in driving hypercoagulability in ANCA-associated vasculitis.

ABSTRACT: The risk of a venous thrombotic event (VTE) is increased in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV); however, a detailed understanding of the underlying mechanisms of hypercoagulability is limited. We assessed prospectively different coagulation parameters in 71 patients with active AAV at baseline and after 6 months of follow-up. D-dimers and fibrinogen were increased in most patients at presentation and remained elevated in half of the patients. Particularly, thrombin-antithrombin (T:AT) complex and activated coagulation factors in complex with their natural inhibitors of the intrinsic coagulation pathway (ie, activated FXII:C1 esterase inhibitor [FXIIa:C1Inh], FXIa:AT, and FXIa:alpha1-antitrypsin [FXIa:α1AT]) were profoundly elevated in patients at baseline. Thrombin formation was dominantly correlated with coagulation factors of the intrinsic pathway (ie, FXIIa:AT, FXIa:AT, FXIa:α1AT, and FXIa:C1Inh) compared to the extrinsic pathway (ie, FVIIa:AT). Hypercoagulability correlated with higher disease activity, ANCA levels, C-reactive protein, serum creatinine, and proteinuria. VTEs were observed in 5 out of 71 (7%) patients within 1 month (interquartile range, 1-5) after inclusion. Baseline T:AT levels were significantly higher in patients with VTE than in those without VTE (P = .044), but other clinical or laboratory markers were comparable between both groups. Hypercoagulability is dominantly characterized by activation of the intrinsic coagulation pathway and elevated D-dimers in active AAV. The driving factors of hypercoagulability are yet to be studied but are most likely related to an interplay of increased disease activity, vascular inflammation, and endothelial damage. Future targets for intervention could include inhibitors of the intrinsic coagulation pathway and compounds specifically reducing the hyperinflammatory state.

Platelet biology and function: plaque erosion vs. rupture.

The leading cause of heart disease in developed countries is coronary atherosclerosis, which is not simply a result of ageing but a chronic inflammatory process that can lead to acute clinical events upon atherosclerotic plaque rupture or erosion and arterial thrombus formation. The composition and location of atherosclerotic plaques determine the phenotype of the lesion and whether it is more likely to rupture or to erode. Although plaque rupture and erosion both initiate platelet activation on the exposed vascular surface, the contribution of platelets to thrombus formation differs between the two phenotypes. In this review, plaque phenotype is discussed in relation to thrombus composition, and an overview of important mediators (haemodynamics, matrix components, and soluble factors) in plaque-induced platelet activation is given. As thrombus formation on disrupted plaques does not necessarily result in complete vessel occlusion, plaque healing can occur. Therefore, the latest findings on plaque healing and the potential role of platelets in this process are summarized. Finally, the clinical need for more effective antithrombotic agents is highlighted.

Radiation and temperature drive diurnal variation of aerobic methane emissions from Scots pine canopy.

Methane emissions from plant foliage may play an important role in the global methane cycle, but their size and the underlying source processes remain poorly understood. Here, we quantify methane fluxes from the shoots of Scots pine trees, a dominant tree species in boreal forests, to identify source processes and environmental drivers, and we evaluate whether these fluxes can be constrained at the ecosystem-level by eddy covariance flux measurements. We show that shoot-level measurements conducted in forest, garden, or greenhouse settings; on mature trees and saplings; manually and with an automated CO2-, temperature-, and water-controlled chamber system; and with multiple methane analyzers all resulted in comparable daytime fluxes (0.144 ± 0.019 to 0.375 ± 0.074 nmol CH4 g-1 foliar d.w. h-1). We further find that these emissions exhibit a pronounced diurnal cycle that closely follows photosynthetically active radiation and is further modulated by temperature. These diurnal patterns indicate that methane production is associated with diurnal cycle of sunlight, indicating that this production is either a byproduct of photosynthesis-associated biochemical reactions (e.g., the methionine cycle) or produced through nonenzymatic photochemical reactions in plant biomass. Moreover, we identified a light-dependent component in stand-level methane fluxes, which showed order-of-magnitude agreement with shoot-level measurements (0.968 ± 0.031 nmol CH4 g-1 h-1) and which provides an upper limit for shoot methane emissions.

Higher levels of circulating desphospho-uncarboxylated matrix Gla protein over time are associated with worse survival: the prospective Maastricht Intensive Care COVID cohort.

BACKGROUND: Extra-hepatic vitamin K-status, measured by dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP), maintains vascular health, with high levels reflecting poor vitamin K status. The occurrence of extra-hepatic vitamin K deficiency throughout the disease of COVID-19 and possible associations with pulmonary embolism (PE), and mortality in intensive care unit (ICU) patients has not been studied. The aim of this study was to investigated the association between dp-ucMGP, at endotracheal intubation (ETI) and both ICU and six months mortality. Furthermore, we studied the associations between serially measured dp-ucMGP and both PE and mortality. METHODS: We included 112 ICU patients with confirmed COVID-19. Over the course of 4 weeks after ETI, dp-ucMGP was measured serially. All patients underwent computed tomography pulmonary angiography (CTPA) to rule out PE. Results were adjusted for patient characteristics, disease severity scores, inflammation, renal function, history of coumarin use, and coronary artery calcification (CAC) scores. RESULTS: Per 100 pmol/L dp-ucMGP, at ETI, the odds ratio (OR) was 1.056 (95% CI: 0.977 to 1.141, p = 0.172) for ICU mortality and 1.059 (95% CI: 0.976 to 1.059, p = 0.170) for six months mortality. After adjustments for age, gender, and APACHE II score, the mean difference in plasma dp-ucMGP over time of ICU admission was 167 pmol/L (95% CI: 4 to 332, p = 0.047). After additional adjustments for c-reactive protein, creatinine, and history of coumarin use, the difference was 199 pmol/L (95% CI: 50 to 346, p = 0.010). After additional adjustment for CAC score the difference was 213 pmol/L (95% CI: 3 to 422, p = 0.051) higher in ICU non-survivors compared to the ICU survivors. The regression slope, indicating changes over time, did not differ. Moreover, dp-ucMGP was not associated with PE. CONCLUSION: ICU mortality in COVID-19 patients was associated with higher dp-ucMGP levels over 4 weeks, independent of age, gender, and APACHE II score, and not explained by inflammation, renal function, history of coumarin use, and CAC score. No association with PE was observed. At ETI, higher levels of dp-ucMGP were associated with higher OR for both ICU and six month mortality in crude and adjusted modes, although not statistically significantly.

Biomarkers of sustained systemic inflammation and microvascular dysfunction associated with post-COVID-19 condition symptoms at 24 months after SARS-CoV-2-infection.

Introduction: Comprehensive studies investigating sustained hypercoagulability, endothelial function, and/or inflammation in relation to post-COVID-19 (PCC) symptoms with a prolonged follow-up are currently lacking. Therefore, the aim of this single-centre cohort study was to investigate serum biomarkers of coagulation activation, microvascular dysfunction, and inflammation in relation to persisting symptoms two years after acute COVID-19. Methods: Patients diagnosed with acute SARS-CoV-2 infection between February and June 2020 were recruited. Outcome measures included the CORona Follow-Up (CORFU) questionnaire, which is based on an internationally developed and partially validated basic questionnaire on persistent PCC symptoms. Additionally, plasma biomarkers reflecting coagulation activation, endothelial dysfunction and systemic inflammation were measured. Results: 167 individuals were approached of which 148 (89%) completed the CORFU questionnaire. At 24 months after acute infection, fatigue was the most prevalent PCC symptom (84.5%). Over 50% of the patients experienced symptoms related to breathing, cognition, sleep or mobility; 30.3% still experienced at least one severe or extreme (4 or 5 on a 5-point scale) PCC symptom. Multiple correlations were found between several PCC symptoms and markers of endothelial dysfunction (endothelin-1 and von Willebrand factor) and systemic inflammation (Interleukin-1 Receptor antagonist). No positive correlations were found between PCC symptoms and coagulation complexes. Discussion: In conclusion, this study shows that at 24 months after acute COVID-19 infection patients experience a high prevalence of PCC symptoms which correlate with inflammatory cytokine IL-1Ra and markers of endothelial dysfunction, especially endothelin-1. Our data may provide a rationale for the selection of treatment strategies for further clinical studies. Trial registration: This study was performed in collaboration with the CORona Follow-Up (CORFU) study (NCT05240742, https://clinicaltrials.gov/ct2/show/ NCT05240742).

Addressing the smoking-hypertension paradox in pregnancy: insight from a multiethnic US birth cohort.

Background: Smoking during pregnancy has been associated with reduced risk of a spectrum of hypertensive (HTN) disorders, known as the "smoking-hypertension paradox." Objective: We sought to test potential epidemiologic explanations for the smoking-hypertension paradox. Methods: We analyzed 8510 pregnant people in the Boston Birth Cohort, including 4027 non-Hispanic Black and 2428 Hispanic pregnancies. Study participants self-reported tobacco, alcohol, cannabis, opioids, or cocaine use during pregnancy. We used logistic regression to assess effect modification by race/ethnicity, and confounding of concurrent substances on hypertensive disorders or prior pregnancy. We also investigated early gestational age as a collider or competing risk for pre-eclampsia, using cause-specific Cox models and Fine-Gray models, respectively. Results: We replicated the paradox showing smoking to be protective against hypertensive disorders among Black participants who used other substances as well (aOR: 0.61, 95% CI: 0.41, 0.93), but observed null effects for Hispanic participants (aOR: 1.14, 95% CI: 0.55, 2.36). In our cause-specific Cox regression, the effects of tobacco use were reduced to null effects with pre-eclampsia (aOR: 0.81, 95% CI: 0.63, 1.04) after stratifying for preterm birth. For the Fine-Gray competing risk analysis, the paradoxical associations remained. The smoking paradox was either not observed or reversed after accounting for race/ethnicity, other substance use, and collider-stratification due to preterm birth. Conclusions: These findings offer new insights into this paradox and underscore the importance of considering multiple sources of bias in assessing the smoking-hypertension association in pregnancy.

A new species of the genus Brachytydeus Thor sensu André (Acari: Tydeidae) and a key to all known species from Peru.

Brachytydeus juanjosei sp. nov., a new species of Neotropical Tydeidae, is illustrated and described from females, males, and a tritonymph collected from the leaves of a native forest tree, Neltuma piurensis (Fabaceae), from Department of Piura in north-western Peru. The new tydeid mite was found all year long, but more frequently observed during spring in high populations (September/December). A key to the known Peruvian species of the subfamily Tydeinae is provided.

Tissue factor expression in monocyte subsets during human immunothrombosis, endotoxemia and sepsis.

INTRODUCTION: Tissue factor expression on monocytes is implicated in the pathophysiology of sepsis-induced coagulopathy. How tissue factor is expressed by monocyte subsets (classical, intermediate and non-classical) is unknown. METHODS: Monocytic tissue factor surface expression was investigated during three conditions. Primary human monocytes and microvascular endothelial cell co-cultures were used for in vitro studies. Volunteers received a bolus of lipopolysaccharide (2 ng/kg) to induce endotoxemia. Patients with sepsis, or controls with critical illness unrelated to sepsis, were recruited from four intensive care units. RESULTS: Contact with endothelium and stimulation with lipopolysaccharide reduced the proportion of intermediate monocytes. Lipopolysaccharide increased tissue factor surface expression on classical and non-classical monocytes. Endotoxemia induced profound, transient monocytopenia, along with activation of coagulation pathways. In the remaining circulating monocytes, tissue factor was up-regulated in intermediate monocytes, though approximately 60 % of individuals (responders) up-regulated tissue factor across all monocyte subsets. In critically ill patients, tissue factor expression on intermediate and non-classical monocytes was significantly higher in patients with established sepsis than among non-septic patients. Upon recovery of sepsis, expression of tissue factor increased significantly in classical monocytes. CONCLUSION: Tissue factor expression in monocyte subsets varies significantly during health, endotoxemia and sepsis.

Predictive value for increased activated factor XI activity in acute venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is associated with excessive coagulation activity, which in part can be attributed to activation of contact system. However, the knowledge regarding the impact of contact activation in acute VTE is limited. OBJECTIVE: To unravel the involvement of contact activation in acute VTE. METHODS: Contact activation was investigated in patients with acute VTE (n = 321) and population controls without a history of VTE (n = 300). For comparison, Factor XI(a) levels, activity, and plasma kallikrein (PKa) activity were determined in plasma samples with an activated partial thromboplastin time- or thrombin generation-based assay (free FXI concentration [FXI:c] and calibrated automated thrombogram:FXIa, respectively) and with enzyme-linked immunosorbent assays for enzyme-inhibitor complexes (FXIa:alpha-1-antitrypsin [α1AT], FXIa:antithrombin [AT], FXIa:C1-inhibitor [C1Inh], and PKa:C1-inh). RESULTS: In patients with VTE, higher FXI:c levels (124 ± 37% vs 114 ± 28%), but lower calibrated automated thrombogram:FXIa levels were apparent. This was accompanied by increased FXIa:α1AT, FXIa:AT, and PKa:C1-inh levels in patients compared with controls (312pM [238-424] vs 203pM [144-288]; 29pM [23-38] vs 23pM [20-30]; 1.9nM [1.2-4.7] vs 1.4nM [0.7-3.5], respectively), whereas FXIa:C1-inh levels did not differ. Logistic regression models showed good discriminatory values for FXI:c and FXIa:α1AT (area under the curve = 0.64 [0.6/0.69] and 0.73 [0.69/0.77], respectively). After a 2-year follow-up, 81 recurrent VTE events or deaths occurred in the patient cohort, for which the baseline levels of FXIa:α1AT and FXIa:C1Inh had a significant prognostic value (Hazard ratios per SD [95% CI], 1.26 [1.10-1.45]; p =.0012 and 1.19 [1.05-1.36]; p =.0082, respectively). CONCLUSION: Our study revealed elevated FXIa levels and activity in acute VTE, which was also associated with recurrent VTE, suggesting an important risk contribution of FXI activation to VTE. The evidence provided by this study supports the utility of FXIa inhibition in the setting of acute VTE.

Plasma Kallikrein as a Forgotten Clotting Factor.

For decades, it was considered that plasma kallikrein's (PKa) sole function within the coagulation cascade is the activation of factor (F)XII. Until recently, the two key known activators of FIX within the coagulation cascade were activated FXI(a) and the tissue factor-FVII(a) complex. Simultaneously, and using independent experimental approaches, three groups identified a new branch of the coagulation cascade, whereby PKa can directly activate FIX. These key studies identified that (1) FIX or FIXa can bind with high affinity to either prekallikrein (PK) or PKa; (2) in human plasma, PKa can dose dependently trigger thrombin generation and clot formation independent of FXI; (3) in FXI knockout murine models treated with intrinsic pathway agonists, PKa activity results in increased formation of FIXa:AT complexes, indicating direct activation of FIX by PKa in vivo. These findings suggest that there is both a canonical (FXIa-dependent) and non-canonical (PKa-dependent) pathway of FIX activation. These three recent studies are described within this review, alongside historical data that hinted at the existence of this novel role of PKa as a coagulation clotting factor. The implications of direct PKa cleavage of FIX remain to be determined physiologically, pathophysiologically, and in the context of next-generation anticoagulants in development.

Clinical utility of the 4S-AF scheme in predicting progression of atrial fibrillation: data from the RACE V study.

AIMS: The recent 4S-AF (scheme proposed by the 2020 ESC AF guidelines to address stroke risk, symptom severity, severity of AF burden and substrate of AF to provide a structured phenotyping of AF patients in clinical practice to guide therapy and assess prognosis) scheme has been proposed as a structured scheme to characterize patients with atrial fibrillation (AF). We aimed to assess whether the 4S-AF scheme predicts AF progression in patients with self-terminating AF. METHODS AND RESULTS: We analysed 341 patients with self-terminating AF included in the well-phenotyped Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical remodelling, and Vascular Destabilization in the Progression of AF (RACE V) study. Patients had continuous monitoring with implantable loop recorders or pacemakers. AF progression was defined as progression to persistent or permanent AF or progression of self-terminating AF with >3% burden increase. Progression of AF was observed in 42 patients (12.3%, 5.9% per year). Patients were given a score based on the components of the 4S-AF scheme. Mean age was 65 [interquartile range (IQR) 58-71] years, 149 (44%) were women, 103 (49%) had heart failure, 276 (81%) had hypertension, and 38 (11%) had coronary artery disease. Median CHA2DS2-VASc (the CHA2DS2-VASc score assesses thromboembolic risk. C, congestive heart failure/left ventricular dysfunction; H, hypertension; A2, age ≥ 75 years; D, diabetes mellitus; S2, stroke/transient ischaemic attack/systemic embolism; V, vascular disease; A, age 65-74 years; Sc, sex category (female sex)) score was 2 (IQR 2-3), and median follow-up was 2.1 (1.5-2.6) years. The average score of the 4S-AF scheme was 4.6 ± 1.4. The score points from the 4S-AF scheme did not predict the risk of AF progression [odds ratio (OR) 1.1 95% CI 0.88-1.41, C-statistic 0.53]. However, excluding the symptoms domain, resulting in the 3S-AF (4S-AF scheme without the domain symptom severity, only including stroke risk, severity of AF burden and substrate of AF) scheme, predicted the risk of progression (OR 1.59 95% CI 1.15-2.27, C-statistic 0.62) even after adjusting for sex and age. CONCLUSIONS: In self-terminating AF patients, the 4S-AF scheme does not predict AF progression. The 3S-AF scheme, excluding the symptom domain, may be a more appropriate score to predict AF progression. TRIAL REGISTRATION NUMBERS: Clinicaltrials.gov NCT02726698 for RACE V.

Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis.

The Fourth Maastricht Consensus Conference on Thrombosis included the following themes. Theme 1: The "coagulome" as a critical driver of cardiovascular disease. Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow, and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis. Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infection-associated coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies. This theme included state-of-the-art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: the value and limitations of ex vivo models. Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularized organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation-associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management. Plenary presentations addressed controversial areas, i.e., thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies, and clinically tested factor XI(a) inhibitors, both possibly with reduced bleeding risk. Finally, COVID-19-associated coagulopathy is revisited.

Activity and abundance of methanotrophic bacteria in a northern mountainous gradient of wetlands.

Methane uptake and diversity of methanotrophic bacteria was investigated across six hydrologically connected wetlands in a mountainous forest landscape upstream of lake Langtjern, southern Norway. From floodplain through shrubs, forest and sedges to a Sphagnum covered site, growing season CH4 production was insufficiently consumed to balance release into the atmosphere. Emission increased by soil moisture ranging 0.6-6.8 mg CH4 m-2  h-1 . Top soils of all sites consumed CH4 including at the lowest 78 ppmv CH4 supplied, thus potentially oxidizing 17-51 nmol CH4 g-1 dw h-1 , with highest Vmax 440 nmol g-1 dw h-1 under Sphagnum and lowest Km 559 nM under hummocked Carex. Nine genera and several less understood type I and type II methanotrophs were detected by the key functional gene pmoA involved in methane oxidation. Microarray signal intensities from all sites revealed Methylococcus, the affiliated Lake Washington cluster, Methylocaldum, a Japanese rice cluster, Methylosinus, Methylocystis and the affiliated Peat264 cluster. Notably enriched by site was a floodplain Methylomonas and a Methylocapsa-affiliated watershed cluster in the Sphagnum site. The climate sensitive water table was shown to be a strong controlling factor highlighting its link with the CH4 cycle in elevated wetlands.

Vascular Function, Systemic Inflammation, and Coagulation Activation 18 Months after COVID-19 Infection: An Observational Cohort Study.

INTRODUCTION: Among its effect on virtually all other organs, COVID-19 affects the cardiovascular system, potentially jeopardizing the cardiovascular health of millions. Previous research has shown no indication of macrovascular dysfunction as reflected by carotid artery reactivity, but has shown sustained microvascular dysfunction, systemic inflammation, and coagulation activation at 3 months after acute COVID-19. The long-term effects of COVID-19 on vascular function remain unknown. MATERIALS AND METHODS: This cohort study involved 167 patients who participated in the COVAS trial. At 3 months and 18 months after acute COVID-19, macrovascular dysfunction was evaluated by measuring the carotid artery diameter in response to cold pressor testing. Additionally, plasma endothelin-1, von Willebrand factor, Interleukin(IL)-1ra, IL-6, IL-18, and coagulation factor complexes were measured using ELISA techniques. RESULTS: The prevalence of macrovascular dysfunction did not differ between 3 months (14.5%) and 18 months (11.7%) after COVID-19 infection (p = 0.585). However, there was a significant decrease in absolute carotid artery diameter change, 3.5% ± 4.7 vs. 2.7% ± 2.5, p-0.001, respectively. Additionally, levels of vWF:Ag were persistently high in 80% of COVID-19 survivors, reflecting endothelial cell damage and possibly attenuated endothelial function. Furthermore, while levels of the inflammatory cytokines interleukin(IL)-1RA and IL-18 were normalized and evidence of contact pathway activation was no longer present, the concentrations of IL-6 and thrombin:antithrombin complexes were further increased at 18 months versus 3 months (2.5 pg/mL ± 2.6 vs. 4.0 pg/mL ± 4.6, p = 0.006 and 4.9 µg/L ± 4.4 vs. 18.2 µg/L ± 11.4, p < 0.001, respectively). DISCUSSION: This study shows that 18 months after COVID-19 infection, the incidence of macrovascular dysfunction as defined by a constrictive response during carotid artery reactivity testing is not increased. Nonetheless, plasma biomarkers indicate sustained endothelial cell activation (vWF), systemic inflammation (IL-6), and extrinsic/common pathway coagulation activation (FVII:AT, TAT) 18 months after COVID-19 infection.

Draft Genome Sequence of Bradyrhizobium denitrificans K2, Cultivated from an Air Ventilation Environment.

Bradyrhizobium denitrificans K2, isolated from an air circulation environment, has potential genes participating in inorganic nitrogen and carbon cycling. The draft genome comprises 8.31 Mb, with 7,982 coding sequences and 64.81% average G+C content. Genes related to carbon and inorganic nitrogen cycling were observed in the draft genome.