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Background Pulmonary embolism (PE) is a common cause of death with an incidence of approximately 1–2 cases per 1000 inhabitants in Europe and the United States. Treatment for PE is the administration of anticoagulants for at least three months. Purpose To assess the feasibility of following the resolution rate of PE over time using repeated imaging with a non-contrast-enhanced magnetic resonance imaging (MRI) protocol. Material and Methods Patients (n = 18) diagnosed with acute PE via computed tomography pulmonary angiography (CTPA) underwent non-contrast-enhanced MRI at two tertiary hospitals. The first MRI was performed within 36 h of CTPA, with follow-up at one week, one, three, and six months. The MRI sequence used was a non-contrast-enhanced standard two-dimensional steady-state free precession under free-breathing and without respiratory or cardiac gating. All MRI scans were then compared to the initial CTPA. The emboli were assessed visually for location and size, and clot burden was calculated using the Qanadli score. Results MRI revealed complete resolution in seven cases at one week, in five cases at one month, and in three cases at three months. The most significant resolution of emboli occurred within the first few weeks, with only 10% of the diagnosed emboli persisting at the one-month examination. Conclusion The use of MRI imparts the ability to visualize PE without radiation and thus allows multiple examinations to be made, for example in studies investigating the resolution of PE or the evaluation of drug effect in clinical trials.

ObjectiveTo assess the efficacy of inhaled ciclesonide in reducing the duration of oxygen therapy (an indicator of time to clinical improvement) among adults hospitalised with COVID-19.DesignMulticentre, randomised, controlled, open-label trial.Setting9 hospitals (3 academic hospitals and 6 non-academic hospitals) in Sweden between 1 June 2020 and 17 May 2021.ParticipantsAdults hospitalised with COVID-19 and receiving oxygen therapy.InterventionInhaled ciclesonide 320 µg two times a day for 14 days versus standard care.Main outcome measuresPrimary outcome was duration of oxygen therapy, an indicator of time to clinical improvement. Key secondary outcome was a composite of invasive mechanical ventilation/death.ResultsData from 98 participants were analysed (48 receiving ciclesonide and 50 receiving standard care; median (IQR) age, 59.5 (49–67) years; 67 (68%) men). Median (IQR) duration of oxygen therapy was 5.5 (3–9) days in the ciclesonide group and 4 (2–7) days in the standard care group (HR for termination of oxygen therapy 0.73 (95% CI 0.47 to 1.11), with the upper 95% CI being compatible with a 10% relative reduction in oxygen therapy duration, corresponding to a ConclusionsIn patients hospitalised with COVID-19 receiving oxygen therapy, this trial ruled out, with 0.95 confidence, a treatment effect of ciclesonide corresponding to more than a 1 day reduction in duration of oxygen therapy. Ciclesonide is unlikely to improve this outcome meaningfully.Trial registration numberNCT04381364.

Pulmonary embolism (PE) is the third most common cause of cardiovascular death. Atrial fibrillation (AF) is the most common arrhythmia and is commonly detected in patients after embolic stroke. In this study, we set out to study if undiagnosed AF could be detected in patients with PE. In survivors of PE, persisting symptoms and exercise limitations are common. The disease burden of PE on quality of life (QoL) has received scarce attention. The primary aim was to study the prevalence of AF in patients with newly diagnosed PE. The secondary aim was to study QoL in PE patients.Patients with newly diagnosed acute PE were randomized 1:1 to long-term electrocardiogram (ECG) screening for AF (handheld ECG or ECG patch) or standard-of-care. The study participants were asked to complete RAND-36 questionnaires upon inclusion.In total 89 PE patients (mean age 74.6 years) were included, and 40 out of these patients were randomized to AF screening. The study was terminated early due to futility when analysis 1 year after inclusion did not find any patients with newly detected AF.RAND-36 showed that QoL was affected in PE patients. Interestingly, sex differences were found; women had a significantly lower QoL in the dimensions of vitality (P = .006), general health (P = .039), and mental health (P = .041).Screening for AF in PE patients did not yield a significant proportion of new cases. QoL is more affected in female patients with PE, and increased awareness of this is suggested.

The International Consortium for Health Outcomes Measurement assembled an international working group of venous thromboembolism experts and patient representatives to develop a standardised minimum set of outcomes and outcome measurements for integration into clinical practice and potentially research to support clinical decision making and benchmarking of quality of care. 15 core outcomes important to patients and health-care professionals were selected and categorised into four domains: patient-reported outcomes, long term consequences of the disease, disease-specific complications, and treatment-related complications. The outcomes and outcome measures were designed to apply to all patients with venous thromboembolism aged 16 years or older. A measurement tool package was selected for inclusion in the core standard set, with a minimum number of items to be measured at predefined timepoints, which capture all core outcomes. Additional measures can be introduced to the user by a cascade opt-in system that allows for further assessment if required. This set of outcomes and measurement tools will facilitate the implementation of the use of patient-centred outcomes in daily practice.

BackgroundChronic thromboembolic pulmonary hypertension (CTEPH), a complication of acute pulmonary embolism, is a potentially curable form of pulmonary hypertension (PH). CTEPH is under-diagnosed f...

The diagnostic workup of recurrent ipsilateral deep vein thrombosis (DVT) using compression ultrasonography (CUS) can be complicated by persistent intravascular abnormalities after a previous DVT. We showed that magnetic resonance direct thrombus imaging (MRDTI) can exclude recurrent ipsilateral DVT. However, it is unknown whether the application of MRDTI in daily clinical practice is cost effective. The aim of this study was to evaluate the cost effectiveness of MRDTI-based diagnosis for suspected recurrent ipsilateral DVT during first year of treatment and follow-up in the Dutch health care setting. Patient-level data of the Theia study (NCT02262052) were analyzed in 10 diagnostic scenarios, including a clinical decision rule and D-dimer test and imaging with CUS and/or MRDTI. The total costs of diagnostic tests and treatment during 1-year follow-up, including costs of false-positive and false-negative diagnoses, were compared and related to the associated mortality. The 1-year health care costs with MRDTI (range, €1219-1296) were generally lower than strategies without MRDTI (range, €1278-1529). This was because of superior specificity, despite higher initial diagnostic costs. Diagnostic strategies including CUS alone and CUS followed by MRDTI in case of an inconclusive CUS were potential optimal cost-effective strategies, with estimated average costs of €1529 and €1263 per patient and predicted mortality of 1 per 737 patients and 1 per 609 patients, respectively. Our model shows that diagnostic strategies with MRDTI for suspected recurrent ipsilateral DVT have generally lower 1-year health care costs than strategies without MRDTI. Therefore, compared with CUS alone, applying MRDTI did not increase health care costs.

The diagnosis of recurrent ipsilateral deep vein thrombosis (DVT) is challenging, because persistent intravascular abnormalities after previous DVT often hinder a diagnosis by compression ultrasonography. Magnetic resonance direct thrombus imaging (MRDTI), a technique without intravenous contrast and with a 10-minute acquisition time, has been shown to accurately distinguish acute recurrent DVT from chronic thrombotic remains. We have evaluated the safety of MRDTI as the sole test for excluding recurrent ipsilateral DVT. The Theia Study was a prospective, international, multicenter, diagnostic management study involving patients with clinically suspected acute recurrent ipsilateral DVT. Treatment of the patients was managed according to the result of the MRDTI, performed within 24 hours of study inclusion. The primary outcome was the 3-month incidence of venous thromboembolism (VTE) after a MRDTI negative for DVT. The secondary outcome was the interobserver agreement on the MRDTI readings. An independent committee adjudicated all end points. Three hundred five patients were included. The baseline prevalence of recurrent DVT was 38%; superficial thrombophlebitis was diagnosed in 4.6%. The primary outcome occurred in 2 of 119 (1.7%; 95% confidence interval [CI], 0.20-5.9) patients with MRDTI negative for DVT and thrombophlebitis, who were not treated with any anticoagulant during follow-up; neither of these recurrences was fatal. The incidence of recurrent VTE in all patients with MRDTI negative for DVT was 1.1% (95% CI, 0.13%-3.8%). The agreement between initial local and post hoc central reading of the MRDTI images was excellent (κ statistic, 0.91). The incidence of VTE recurrence after negative MRDTI was low, and MRDTI proved to be a feasible and reproducible diagnostic test. This trial was registered at www.clinicaltrials.gov as #NCT02262052.

Background The diagnostic accuracy of clinical probability assessment and D‐dimer testing for clinically suspected recurrent deep vein thrombosis (DVT) is largely unknown. Aim To evaluate the safety of ruling out acute recurrent DVT based on an unlikely Wells score for DVT and a normal D‐dimer test. Methods This was a predefined endpoint of the Theia study in which the diagnostic accuracy of magnetic resonance direct thrombus imaging in acute recurrent ipsilateral DVT was validated. The Wells rule and D‐dimer test, performed as part of the study protocol, were not used for management decisions. The primary outcome of this analysis was the incidence of recurrent DVT at baseline or during 3‐month follow‐up for patients with an unlikely Wells score and a normal D‐dimer test. Results Results of both Wells score and D‐dimer tests were available in 231 patients without anticoagulant treatment. The recurrent DVT prevalence was 45% (103/231). Forty‐nine patients had an unlikely Wells score and normal D‐dimer test, of whom 3 (6.1%, 95% confidence interval [CI] 1.3%‐18%) had recurrent DVT at baseline/follow‐up, yielding a sensitivity of 97% (95% CI 92%‐99%) and specificity of 36% (95% CI 28%‐45%). Thus, if clinical probability scoring and D‐dimer testing would have been applied, radiological imaging could have been omitted in 21% of patients with a diagnostic failure rate of 6.1%. Conclusion By applying clinical probability scoring and D‐dimer testing, radiological imaging could be spared in one fifth of patients with suspected recurrent ipsilateral DVT. However, the high failure rate does not support implementation of this strategy in daily practice.

The incidence of pulmonary and venous thromboembolism is increased during the first trimester of pregnancies after assisted reproductive technology (ART) compared to spontaneous conception. We previously found that haemostatic plasma variables changed but within normal limits during controlled ovarian hyperstimulation (COH) concomitant with a major increase in plasma microvesicles (MVs) and markers indicating cell activation. We now explored the proteome of these MVs. Thirty-one women undergoing ART were blood sampled at down-regulation (DR) of oestrogen and at high level stimulation (HLS) with its 10–100-fold increased oestrogen level. Samples were analysed by liquid chromatography and tandem mass spectrometry to identify and quantify the proteome. We identified 306 proteins in the MVs and 72 had changed significantly at HLS compared to DR and more than 20% of them were associated with haemostasis. Thus, proteins related to both haemostasis and complement activation altered in plasma MVs in parallel with MV activation during COH. This needs to be further explored in the clinical context.

Background The assisted reproductive technique in vitro fertilization (IVF) is associated with an increased risk of venous thromboembolism (VTE) and pulmonary embolism (PE) during the first trimester. Objectives To compare the incidence of VTE and PE during the first trimester of IVF pregnancies using fresh or frozen-thawed embryo transfer to that during natural pregnancies. Patient/methods Nationwide Swedish registry-based cohort study of women who gave birth (n = 902 891) at the age of 15-50 years to their first child from the 1st of January 1992 until the 31st of December 2012. Exposure groups were IVF with fresh respectively frozen-thawed embryo transfer. Incidences of VTE and PE were calculated, and time-varying hazard ratios estimated for all trimesters after fresh respectively frozen-thawed embryo transfer IVF and compared to natural conception. Results and conclusion Women giving birth after fresh embryo transfer IVF had a more than eightfold increased incidence of venous thromboembolism (hazard ratio [HR] 8.96, 95% CI 6.33 to 12.67) and pulmonary embolism during the first trimester, (HR 8.69, 95% CI 3.83 to 19.71) compared to women giving birth after natural conception. The incidence of VTE in women giving birth after frozen-thawed embryo transfer was not increased during the first trimester. To conclude, fresh embryo transfer IVF was associated with a significantly increased incidence of VTE and PE during the first trimester. These results suggest that frozen-thawed embryo transfer could be a preferred method of IVF with a minimised maternal risk.

Background Pulmonary embolism (PE) is a severe medical condition with non-specific clinical findings. Computed tomography angiography (CTA) using iodinated contrast agents is the golden standard for diagnosis, but many patients have contraindications for CTA. Purpose To investigate the diagnostic accuracy of repeated acquisitions of magnetic resonance imaging (MRI), without respiratory gating or breath holding, in diagnosing PE using CTA as the reference standard. Material and Methods Thirty-three patients with clinically suspected PE underwent MRI within 48 h after diagnostic CTA. A control group of 37 healthy participants underwent MRI and was matched with an equal number of negative CTA exams. The MRI protocol was based on free-breathing steady-state free precession producing 4.5 mm slices in axial, sagittal, and coronal planes. Instead of respiratory or cardiac gating five repetitive slices were obtained in each anatomical position to compensate for movement and artifacts. Clinical assessment including d-dimer and Well’s score was performed prior to imaging. One radiologist reviewed the CTA exams and two radiologists reviewed the MRI scans. Results All 70 MRI exams were of diagnostic quality and the total acquisition time for each MRI scan was 9 min 34 s. On CTA, 29 patients were diagnosed with PE and the MRI readers detected 26 and 27 of those, respectively. Specificity was 100% for both readers. Sensitivity was 90% and 93%, respectively. Inter-reader agreement using Cohen’s kappa was 0.97. Conclusion Our unenhanced MRI protocol shows a high sensitivity and specificity for PE, but further studies are required before considering it as a safe diagnostic test.

SummaryCell-derived microparticles (MPs) are known to be elevated in a number of diseases related to arterial and venous thromboembolism (VTE), such as acute myocardial infarction, VTE (deep-vein thrombosis and pulmonary embolism) and peripheral arterial disease. IVF-associated pregnancies have previously been shown to be associated with an increased incidence of VTE, mechanisms behind being unknown and sparsely studied. Our objective was to assess cell activation during IVF through analysis of MP levels and phenotype following ovarian stimulation. Thirty-one women undergoing IVF were included and blood samples were collected at down regulation of oestrogen and at high level stimulation with 10- to 100-fold increased endogenous oestrogen levels. MPs were analysed by flow cytometry and phenotyped according to size and protein expression. We found that overall phosphatidylserine positive platelet-, endothelial- and monocyte-derived MPs significantly increased following ovarian stimulation with increased levels of platelet activation markers CD40 ligand and P-selectin. Furthermore, there was an increase in endothelial-derived MPs exposing activation marker E-selectin and monocyte-derived MPs, while neutrophil-derived MPs decreased slightly. In conclusion we found a major increase in MPs and markers indicating cell activation in parallel with the profound oestrogen boost during IVF. To assess whether these changes in MPs are associated with thromboembolic events requires extended longitudinal studies.

Background Magnetic resonance imaging (MRI) can be an alternative method to computed tomography angiography (CTA) for pulmonary embolism. Purpose To evaluate the feasibility of diffusion-weighted imaging (DWI) detecting acute pulmonary embolism (PE) in free-breathing humans. Material and Methods Twenty patients with PE verified by CTA and 20 controls were investigated with MRI (1.5 Aera, Siemens Healthcare). All sequences were performed in the transversal plane using free-breathing without gating. The protocol consisted of a two-dimensional steady-state free precession (SSFP) and a single-shot DWI echo-planar imaging sequence with a voxel resolution of 2 × 2 × 5 mm. Three b values were used: 50, 400, and 800 s/mm2. Images were analyzed in two orders: an open source analysis (OSA); and a blinded only DWI analysis (BDA) simulating clinical work. Results OSA of corresponding images showed 370 findings on CTA (i.e. one elongated emboli could be represented in multiple images). SSFP identified 237 of those (64%). DWI with b values of 50, 400, and 800 identified 327 (88%), 245 (66%), and 138 (37%), respectively. In BDA we found 160 true emboli (according to CTA) on b50, 78 on b400, and 54 on b800. Fifty-two of these findings at the subsegmental level could be correlated to PE on CTA but were not visible on SSFP. Conclusions DWI has a high sensitivity for detecting PE but suffers from poor specificity. It could potentially be used as an eye catcher, i.e. where to look for PE in other MRI sequences.

Diagnosing upper extremity deep vein thrombosis (UEDVT) can be challenging. Compression ultrasonography is often inconclusive because of overlying anatomic structures that hamper compressing veins. Contrast venography is invasive and has a risk of contrast allergy. Magnetic Resonance Direct Thrombus Imaging (MRDTI) and Three Dimensional Turbo Spin-echo Spectral Attenuated Inversion Recovery (3D TSE-SPAIR) are both non-contrast-enhanced Magnetic Resonance Imaging (MRI) sequences that can visualize a thrombus directly by the visualization of methemoglobin, which is formed in a fresh blood clot. MRDTI has been proven to be accurate in diagnosing deep venous thrombosis (DVT) of the leg. The primary aim of this pilot study was to test the feasibility of diagnosing UEDVT with these MRI techniques. MRDTI and 3D TSE-SPAIR were performed in 3 pilot patients who were already diagnosed with UEDVT by ultrasonography or contrast venography. In all patients, UEDVT diagnosis could be confirmed by MRDTI and 3D TSE-SPAIR in all vein segments. In conclusion, this study showed that non-contrast MRDTI and 3D TSE-SPAIR sequences may be feasible tests to diagnose UEDVT. However diagnostic accuracy and management studies have to be performed before these techniques can be routinely used in clinical practice.

Objective To compare the incidence of hypertension, stroke, coronary heart disease, and diabetes in women who have delivered after in vitro fertilization (IVF) with those who delivered after natural conception. Design A cohort study in Sweden between 1990 and 2008. Setting Sweden. Patient(s) 23,498 women who had given birth to a child after IVF and 116,960 individually matched women. Intervention(s) None. Main Outcome Measure(s) Incidence rates of hypertension, diabetes, stroke, and coronary heart disease in both groups. Result(s) Inpatient and outpatient diagnoses of hypertension, stroke, coronary heart disease, and diabetes were identified by linkage to the Swedish National Patient Register. The mean time of follow-up was 8.6 years in both groups. Multivariable analysis showed that hypertension had a higher incidence in IVF mothers with a hazard ratio (HR) of 1.27, 95% confidence interval (CI) 1.13–1.41, as compared with mothers from the Medical Birth Register. There was a trend to a higher incidence of stroke (HR 1.27; 95% CI, 0.96–1.68), but the incidence of coronary heart disease and diabetes did not differ. Conclusion(s) Hypertension was more prevalent in the IVF group, which suggests that these women should be aware of their blood pressure and cardiovascular risk profile.

Controlled ovarian hyperstimulation during in vitro fertilization (IVF) causes profound increments in serum estradiol which may influence haemostasis and the ovarian hyperstimulation syndrome. In the present study we investigated the effect of the standard IVF-stimulation protocol on coagulation and fibrinolysis as assessed by different global haemostatic assays.Blood samples were drawn from 31 women during the down-regulation phase when estradiol secretion is inhibited, and before egg retrieval, i.e. when estradiol levels are at supraphysiological levels, in the following called high level stimulation phase. Haemostasis was assessed during both treatment phases with 1) the calibrated automated thrombogram which measures thrombin generation, 2) overall haemostasis potential which measures fibrin formation and degradation and 3) fibrin gel permeability measurements which measures the quality of the fibrin network.Estradiol increased from150pg/mL to 5889pg/mL (range 1620-19500pg/mL). We found both increased thrombin generation as measured by the calibrated automated thrombogram (p0.001) and an increase in overall haemostasis potential (p0.001) from time of down-regulation to high level stimulation.The assays used indicated procoagulable changes in haemostasis during in vitro fertilization. Further studies should evaluate their potential in the prediction of thrombosis and hyperstimulation.

Background In recent years, magnetic resonance imaging (MRI) has been suggested as an alternative to computed tomography angiography (CTA) to diagnose pulmonary embolism (PE). In previous studies, only senior radiologists have been evaluated as reviewers. Purpose To investigate if radiology residents can be trained to review MRI regarding PE and to determine the learning curve effects. Material and Methods Four residents independently went through a training program consisting of 70 participants that had undergone steady-state free precession MRI. The individuals were randomized into ten training sessions. For each exam, the review time and presence or absence of embolus was recorded. After completing each session, the residents received feedback on diagnostic accuracy compared to a consensus reading by two specialists. The residents were also presented with the corresponding CTA. Results The review time was nearly halved ( P = 0.0002) during the training program. Comparing the first three sessions with the last three sessions for all residents, the review time decreased from 5:22 min to 2:51 min. The inter-reader agreement improved for all residents during the training program reaching a clinically acceptable level after seven sessions. Conclusion Our study suggests that radiology residents can be trained to independently review MRI investigations regarding PE within a short training program. Similar training programs could be more extensively used as effective teaching method for residents.

Objective— Cholesterol and lipoprotein metabolism display pronounced gender differences. Premenopausal women have lower LDL and higher HDL cholesterol, whereas men display higher synthetic rates of bile acids and cholesterol. The effects of the administration of exogenous hormones to humans and animals indicate that these gender differences can often be explained by estrogens. We evaluated how increased levels of endogenous estrogens modulate cholesterol and lipoprotein metabolism in women. Methods and Results— We studied healthy women during initiation of in vitro fertilization using blood samples obtained when endogenous estrogens were low and high. Cholesterol in VLDL and LDL, but not in HDL, was reduced 20% when estrogens were high. Apolipoprotein B levels decreased 13%. Apolipoprotein A-I and triglyceride levels increased 8% and 37%, respectively, whereas lipoprotein(a) levels were unchanged. Circulating PCSK9, a suppressor of LDL receptors, was reduced 14% when estrogens were high. Serum markers of bile acid and cholesterol synthesis were unaltered. Growth hormone levels increased 3-fold when estrogens were high, whereas insulin-like growth factor-1 and fibroblast growth factor-21 concentrations were unaltered. Conclusion— In women, Apolipoprotein B-containing particles and circulating PCSK9 are reduced when endogenous estrogens are high, indicating that endogenous estrogens induce hepatic LDL receptors partly through a posttranscriptional mechanism. However, estrogens do not stimulate bile acid or cholesterol synthesis.

During IVF, circulating estradiol concentrations are strongly increased, and this may have direct effects on hemostasis. Elevated von Willebrand factor levels represent an important risk factor for arterial and venous thrombosis. ADAMTS13, also known as von Willebrand factor-cleaving protease, has an important regulatory function of von Willebrand factor but has not been studied during IVF. Blood was sampled from 31 women at maximal downregulation of estradiol synthesis using gonadotropin-releasing hormone analogues and during high-level stimulation of estradiol synthesis using follicle-stimulating hormone during the first phase of IVF. Von Willebrand factor antigen, von Willebrand factor ristocetin cofactor activity, factor VIII and ADAMTS13 antigen and activity levels in plasma were determined at the time of downregulation and at high-level stimulation. Estradiol increased from a mean of 154 pg/ml at downregulation to 5889 pg/ml at high-level stimulation (range 1620-19 500 pg/ml). Factor VIII increased from 0.96 ± 0.34 to 1.26 ± 0.41 kIU/l (P0.001). Von Willebrand factor antigen and activity increased from 0.75 ± 0.22 to 1.06 ± 0.40 kIU/l (P0.001) and from 0.83 ± 0.26 to 1.24 ± 0.48 kIU/l (P0.001), respectively. ADAMTS13 antigen decreased from 72.2 ± 13.5 to 67.9 ± 9.9% (P0.05, P = 0.01) and ADAMTS13 activity from 88.6 ± 18.3 to 80.8 ± 15.7% (P0.01). The increments in estradiol and factor VIII during IVF were paralleled by an increase in von Willebrand factor antigen and activity, and a decrease in circulating ADAMTS13 antigen and activity, respectively. This could in part explain why these patients have an increased risk of thrombotic events.

Objective To estimate the risk of pulmonary embolism and venous thromboembolism in pregnant women after in vitro fertilisation. Design Cross sectional study. Setting Sweden. Participants 23 498 women who had given birth after in vitro fertilisation between 1990 and 2008 and 116 960 individually matched women with natural pregnancies. Main outcome measures Risk of pulmonary embolism and venous thromboembolism (identified by linkage to the Swedish national patient register) during the whole pregnancy and by trimester. Results Venous thromboembolism occurred in 4.2/1000 women (n=99) after in vitro fertilisation compared with 2.5/1000 (n=291) in women with natural pregnancies (hazard ratio 1.77, 95% confidence interval 1.41 to 2.23). The risk of venous thromboembolism was increased during the whole pregnancy (P