Pericardial fenestration and thoracic duct ligation for treatment of chylopericardium as first symptom of underlying generalized lymphatic anomaly: a case report.

INTRODUCTION: Chylopericardium represents a rare condition of chyle accumulation within the pericardial sac, caused by abnormal thoracic duct anatomy or prolonged increased pressure. Nothing by mouth (NPO) policy and total parenteral nutrition (TPN), even in combination with pericardial drainage, render only a temporary solution. Surgical intervention with thoracic duct ligation and creation of a pericardial window is believed to be the most effective treatment. CASE PRESENTATION: An 18-year-old male was referred with a persisting idiopathic chylopericardium for five months. Various drainages and conservative treatment failed. To more permanently treat the chylopericardium, we created a pericardial window and ligated the thoracic duct by right-sided uniportal video-assisted thoracoscopic surgery. Postoperative NPO and TPN for 1 week were initiated, followed by medium-chain-triglycerides diet for 1 week. Clinical improvement occurred and the chest drain was removed two weeks after surgery. Magnetic resonance imaging of the whole body showed multiple cystic lesions in spleen and skeleton compatible with generalized lymphatic anomaly (GLA), proven by the anatomopathological examination of the thoracic duct and lung biopsy. Sirolimus was initiated for further treatment. CONCLUSION: In this case of idiopathic chylopericardium, we successfully performed thoracoscopic thoracic duct ligation and creation of a pericardial window, diagnosing a GLA.

Predicting intracranial bleeding during anticoagulation for venous thromboembolism within different time frames: Findings from the RIETE registry.

BACKGROUND: The risk of intracranial bleeding during anticoagulation for venous thromboembolism (VTE) is substantial and persists beyond the initial treatment phase. We aimed to refine risk-assessment through phase-specific prognostic scores. METHODS: We identified data from 77,786 VTE patients in the RIETE registry from March 2009 to October 2023 to develop two prognostic scores for intracranial bleeding. Multivariable Cox regression was used to analyze distinct variables for the early (≤90 days) and late (>90 days) phases, with comparative validation against existing scores (modified ACCP, RIETE, VTE-BLEED, and CHAP). RESULTS: Intracranial bleeding occurred in 411 patients (0.53 %), with 208 cases in the early phase and 203 in the late phase. The 30-day mortality was 45 % and 35 %, respectively. Shared significant predictors for both phases include baseline abnormal mental status, brain cancer, recent intracranial bleeding, and epilepsy. Unique to early-phase bleeding were body weight, non-brain cancer, hypertension, dementia, thrombocytopenia, renal insufficiency, and thrombolytic therapy. Advanced age, pulmonary embolism initially, prior stroke, depression, treatment with direct oral anticoagulants, and use of corticosteroids predicted late-phase bleeding. Both prognostic scores showed a c-statistic of 0.68, outperforming existing scores. CONCLUSIONS: The study introduces two temporal prognostic scores for intracranial bleeding during anticoagulation for VTE. By discerning specific risk factors pertinent to each treatment phase, these scores outperform traditional models, offering an advanced tool for clinical decision-making. They hold significant potential for optimizing anticoagulation management and reducing bleeding-related mortality.

Treating cancer-associated venous thromboembolism: A practical approach.

Venous thromboembolism (VTE) is a common and potentially life-threatening complication in patients with cancer. Both cancer and its treatments increase the risk of developing VTE. Specific cancer types and individual patient comorbidities increase the risk of developing cancer-associated VTE, and the risk of bleeding is increased with anticoagulation therapies. The aims of this article are to summarize the latest evidence for treating cancer-associated VTE, discuss the practical considerations involved, and share best practices for VTE treatment in patients with cancer. The article pays particular attention to challenging contexts including patients with brain, lung, gastrointestinal, and genitourinary tumors and those with hematological malignancies. Furthermore, the article summarizes specific clinical scenarios that require additional treatment considerations, including extremes of body weight, nausea and gastrointestinal disturbances, compromised renal function, and anemia, and touches upon the relevance of drug-drug interactions. Historically, vitamin K antagonists and low-molecular-weight heparins (LMWHs) have been used as therapy for cancer-associated VTE. The development of direct oral anticoagulants has provided additional treatment options, which, in certain instances, offer advantages over LMWHs. There are numerous factors that need to be considered when treating cancer-associated VTE, and although various treatment guidelines are helpful, they do not reflect each unique scenario that may arise in clinical practice. This article provides a summary of the latest evidence and a practical approach for treating cancer-associated VTE.

Osteoporosis in Relation to a Bone-Related Aging Biomarker Derived from the Urinary Proteomic Profile: A Population Study.

Screening for and prevention of osteoporosis and osteoporotic fractures is imperative, given the high burden on individuals and society. This study constructed and validated an aging-related biomarker derived from the urinary proteomic profile (UPP) indicative of osteoporosis (UPPost-age). In a prospective population study done in northern Belgium (1985-2019), participants were invited for a follow-up examination in 2005-2010 and participants in the 2005-2010 examination again invited in 2009-2013. Participants in both the 2005-2010 and 2009-2013 examinations (n = 519) constituted the derivation (2005-2016 data) and time-shifted validation (2009-2013 data) datasets; 187 participants with only 2005-2010 data formed the synchronous validation dataset. The UPP was assessed by capillary electrophoresis coupled with mass spectrometry. Analyses focused on 2372 sequenced urinary peptides (101 proteins) with key roles in maintaining the integrity of bone tissue. In multivariable analyses with correction for multiple testing, chronological age was associated with 99 urinary peptides (16 proteins). Peptides derived from IGF2 and MGP were upregulated in women compared to men, whereas COL1A2, COL3A1, COL5A2, COL10A1 and COL18A1 were downregulated. Via application of a 1000-fold bootstrapped elastic regression procedure, finally, 29 peptides (10 proteins) constituted the UPPost-age biomarker, replicated across datasets. In cross-sectional analyses of 2009-2013 data (n = 706), the body-height-to-arm-span ratio, an osteoporosis marker, was negatively associated with UPPost-age (p&;lt0.0001). Over 4.89 years (median), the 10-year risk of osteoporosis associated with chronological age and UPPost-age (53 cases including 37 fractures in 706 individuals) increased by 21% and 36% (p ≤ 0.044). Among 357 women, the corresponding estimates were 55% and 60% for incident osteoporosis (37 cases; p ≤ 0.0003) and 42% and 44% for osteoporotic fractures (25 cases; p ≤ 0.017). In conclusion, an aging-related UPP signature with focus on peptide fragments derived from bone-related proteins is associated with osteoporosis risk and available for clinical and trial research.

Corrigendum: Progression of functional and structural glaucomatous damage in relation to diurnal and nocturnal dips in mean arterial pressure.

[This corrects the article DOI: 10.3389/fcvm.2022.1024044.].

Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial.

OBJECTIVE: Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone. METHODS: In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in ≥30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform. RESULTS: Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) µg/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio. CONCLUSIONS: Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs. TRIAL REGISTRATION NUMBER: NCT02556450.

WITHDRAWN: Proteogenomic analyses identify coagulation factor XI as a thromboinflammatory mediator of long COVID.

The authors have withdrawn their manuscript due to analytical errors invalidating the main study findings. The authors of this work discovered the errors after submitting the initial version of the preprint. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Venous thromboembolism (VTE) developing after ankle sprain. Comparison with VTE after knee arthroplasty.

BACKGROUND: Venous thromboembolism (VTE) is a critical complication after non-major trauma or surgery. While the risk and severity of VTE following major orthopedic surgery is well-documented, there is significant knowledge gap regarding, non-major trauma such as ankle sprains. METHODS: We analyzed data from the RIETE registry to assess the clinical characteristics, VTE prophylaxis usage, and outcomes in patients with VTE following ankle sprain versus those post elective knee arthroplasty. We aimed to assess the risk and severity of VTE in a population traditionally considered at lower risk. Risk stratification was performed using the TRiP(cast) score. RESULTS: Among 1,250 patients with VTE, those with ankle sprain (n = 459) were much younger than those post knee arthroplasty (n = 791), less often female, had fewer comorbidities, and received VTE prophylaxis less often (27% vs. 93 %). During anticoagulation, 26 patients developed recurrent VTE, 31 had major bleeding, and 12 died (fatal PE 3, fatal bleeding 2). There were no differences between the two groups in the rates of VTE recurrences (rate ratio (RR): 1.65; 95%CI: 0.69-3.88) or death (RR: 1.12; 95%CI: 0.33-3.46), but patients with VTE after ankle sprain had a lower rate of major bleeding (RR: 0.39; 95%CI: 0.13-0.99). CONCLUSIONS: Ankle sprain patients are often undertreated for VTE prophylaxis and have similar severity of VTE than those undergoing elective knee surgery, indicating the need for a more customized approach to VTE management.

Lead-associated mortality in the US 1999-2020: a time-stratified analysis of a national cohort.

OBJECTIVES: We undertook time-stratified analyses of the National Health and Nutrition Examination Survey in the US to assess time trends (1999-2020) in the associations of blood lead (BL) with blood pressure, mortality, the BL-associated population attributable fraction (PAF). METHODS: Vital status of participants, 20-79 years old at enrolment, was ascertained via the National Death Index. Regressions, mediation analyses and PAF were multivariable adjusted and standardized to 2020 US Census data. RESULTS: In time-stratified analyses, BL decreased from 1.76 µg/dl in 1999-2004 to 0.93 µg/dl in 2017-2020, while the proportion of individuals with BL < 1 µg/dl increased from 19.2% to 63.0%. Total mortality was unrelated to BL (hazard ratio (HR) for a fourfold BL increment: 1.05 [95% confidence interval, CI: 0.93-1.17]). The HR for cardiovascular death was 1.44 (1.01-2.07) in the 1999-2000 cycle, but lost significance thereafter. BL was directly related to cardiovascular mortality, whereas the indirect BL pathway via BP was not significant. Low socioeconomic status (SES) was directly related to BL and cardiovascular mortality, but the indirect SES pathway via BL lost significance in 2007-2010. From 1999-2004 to 2017-2020, cardiovascular PAF decreased ( P  < 0.001) from 7.80% (0.17-14.4%) to 2.50% (0.05-4.68%) and number of lead-attributable cardiovascular deaths from 53 878 (1167-99 253) to 7539 (160-14 108). CONCLUSION: Due to implementation of strict environmental policies, lead exposure is no longer associated with total mortality, and the mildly increased cardiovascular mortality is not associated with blood lead via blood pressure in the United States.

OSTEO18, a novel urinary proteomic signature, associated with osteoporosis in heart transplant recipients.

Background: Immunosuppressive treatment in heart transplant (HTx) recipient causes osteoporosis. The urinary proteomic profile (UPP) includes peptide fragments derived from the bone extracellular matrix. Study aims were to develop and validate a multidimensional UPP biomarker for osteoporosis in HTx patients from single sequenced urinary peptides identifying the parent proteins. Methods: A single-center HTx cohort was analyzed. Urine samples were measured by capillary electrophoresis coupled with mass spectrometry. Cases with osteoporosis and matching controls were randomly selected from all available 389 patients. In derivation case-control dataset, 1576 sequenced peptides detectable in ≥30 % of patients. Applying statistical analysis on these, an 18-peptide multidimensional osteoporosis UPP biomarker (OSTEO18) was generated by support vector modeling. The 2 replication datasets included 118 and 94 patients. For further validation, the whole cohort was analyzed. Statistical methods included logistic regression and receiver operating characteristic curve (ROC) analysis. Results: In derivation dataset, the AUC, sensitivity and specificity of OSTEO18 were 0.83 (95 % CI: 0.76-0.90), 74.3 % and 87.1 %, respectively. In replication datasets, results were confirmatory. In the whole cohort (154 osteoporotic patients [39.6 %]), the ORs for osteoporosis increased (p < 0.0001) across OSTEO18 quartiles from 0.39 (95 % CI: 0.25-0.61) to 3.14 (2.08-4.75). With full adjustment for known osteoporosis risk factors, OSTEO18 improved AUC from 0.708 to 0.786 (p = 0.0003) for OSTEO18 categorized (optimized threshold: 0.095) and to 0.784 (p = 0.0004) for OSTEO18 as continuously distributed classifier. Conclusion: OSTEO18 is a clinically meaningful novel biomarker indicative of osteoporosis in HTx recipients and is being certified as in-vitro diagnostic.

Mortality and Cardiovascular End Points In Relation to the Aortic Pulse Wave Components: An Individual-Participant Meta-Analysis.

BACKGROUND: Wave separation analysis enables individualized evaluation of the aortic pulse wave components. Previous studies focused on the pressure height with overall positive but differing results. In the present analysis, we assessed the associations of the pressure of forward and backward (Pfor and Pref) pulse waves with prospective cardiovascular end points, with extended analysis for time to pressure peak (Tfor and Tref). METHODS: Participants in 3 IDCARS (International Database of Central Arterial Properties for Risk Stratification) cohorts (Argentina, Belgium, and Finland) aged ≥20 years with valid pulse wave analysis and follow-up data were included. Pulse wave analysis was done using the SphygmoCor device, and pulse wave separation was done using the triangular method. The primary end points consisted of cardiovascular mortality and nonfatal cardiovascular and cerebrovascular events. Multivariable-adjusted Cox regression was used to calculate hazard ratios. RESULTS: A total of 2206 participants (mean age, 57.0 years; 55.0% women) were analyzed. Mean±SDs for Pfor, Pref, Tfor, and Tfor/Tref were 31.0±9.1 mm Hg, 20.8±8.4 mm Hg, 130.8±35.5, and 0.51±0.11, respectively. Over a median follow-up of 4.4 years, 146 (6.6%) participants experienced a primary end point. Every 1 SD increment in Pfor, Tfor, and Tfor/Tref was associated with 27% (95% CI, 1.07-1.49), 25% (95% CI, 1.07-1.45), and 32% (95% CI, 1.12-1.56) higher risk, respectively. Adding Tfor and Tfor/Tref to existing risk models improved model prediction (∆Uno's C, 0.020; P<0.01). CONCLUSIONS: Pulse wave components were predictive of composite cardiovascular end points, with Tfor/Tref showing significant improvement in risk prediction. Pending further confirmation, the ratio of time to forward and backward pressure peak may be useful to evaluate increased afterload and signify increased cardiovascular risk.

Enoxaparin for Long-Term Therapy of Venous Thromboembolism in Patients with Cancer and Renal Insufficiency.

BACKGROUND: The optimal therapy of venous thromboembolism (VTE) in cancer patients with renal insufficiency (RI) is unknown. Current guidelines recommend to use low-molecular-weight heparin over direct oral anticoagulants to treat VTE in cancer patients at high risk of bleeding. METHODS: We used the Registro Informatizado Enfermedad Tromboemb00F3lica (RIETE) registry to compare the 6-month incidence rates of (1) VTE recurrences versus major bleeding and (2) fatal pulmonary embolism (PE) versus fatal bleeding in three subgroups (those with mild, moderate, or severe RI) of cancer patients receiving enoxaparin monotherapy. RESULTS: From January 2009 through June 2022, 2,844 patients with RI received enoxaparin for ≥6 months: 1,432 (50%) had mild RI, 1,168 (41%) moderate RI, and 244 (8.6%) had severe RI. Overall, 68, 62, and 12%, respectively, received the recommended doses. Among patients with mild RI, the rates of VTE recurrences versus major bleeding (4.6 vs. 5.4%) and fatal PE versus fatal bleeding (1.3 vs. 1.2%) were similar. Among patients with moderate RI, VTE recurrences were half as common as major bleeding (3.1 vs. 6.3%), but fatal PE and fatal bleeding were close (1.8 vs. 1.2%). Among patients with severe RI, VTE recurrences were threefold less common than major bleeding (4.1 vs. 13%), but fatal PE was threefold more frequent than fatal bleeding (2.5 vs. 0.8%). During the first 10 days, fatal PE was fivefold more common than fatal bleeding (2.1 vs. 0.4%). CONCLUSION: Among cancer patients with severe RI, fatal PE was fivefold more common than fatal bleeding. The recommended doses of enoxaparin in these patients should be revisited.

Incidence and predictors of post-thrombotic syndrome in patients with proximal DVT in a real-world setting: findings from the GARFIELD-VTE registry.

Although substantial progress has been made in the pathophysiology and management of the post-thrombotic syndrome (PTS), several aspects still need clarification. Among them, the incidence and severity of PTS in the real world, the risk factors for its development, the value of patient's self-evaluation, and the ability to identify patients at risk for severe PTS. Eligible participants (n = 1107) with proximal deep-vein thrombosis (DVT) from the global GARFIELD-VTE registry underwent conventional physician's evaluation for PTS 36 months after diagnosis of their DVT using the Villalta score. In addition, 856 patients completed a Villalta questionnaire at 24 months. Variable selection was performed using stepwise algorithm, and predictors of severe PTS were incorporated into a multivariable risk model. The optimistic adjusted c-index was calculated using bootstrapping techniques. Over 36-months, 27.8% of patients developed incident PTS (mild in 18.7%, moderate in 5.7%, severe in 3.4%). Patients with incident PTS were older, had a lower prevalence of transient risk factors of DVT and a higher prevalence of persistent risk factors of DVT. Self-assessment of overall PTS at 24 months showed an agreement of 63.4% with respect to physician's evaluations at 36 months. The severe PTS multivariable model provided an optimistic adjusted c-index of 0.68 (95% CI 0.59-0.77). Approximately a quarter of DVT patients experienced PTS over 36 months after VTE diagnosis. Patient's self-assessment after 24 months provided added value for estimating incident PTS over 36 months. Multivariable risk analysis allowed good discrimination for severe PTS.

Therapy and guideline adherence at a multidisciplinary hypertension clinic: A prospective, observational study.

BACKGROUND: Hypertension is highly prevalent and remains one of the most frequent and preventable causes of cardiovascular morbidity and mortality. Yet, suboptimal blood pressure control is common. Hypertension clinics might play an important role in improving target attainment, by targeting drug therapy adherence, improving guideline compliance and by involving pharmacists. OBJECTIVES: We aimed to characterize patient drug therapy adherence, prescriber guideline compliance and pharmacist interventions at the hypertension clinic. METHODS: A prospective observational study was performed at the hypertension clinic of a large, academic hospital. Adult Dutch-speaking patients were eligible for inclusion. Following data were collected: patient demographics, medication use, patient adherence to prescribed antihypertensive drug therapies according to the BAASIS tool and prescriber compliance to the 2018 European Society of Cardiology (ESC) hypertension guidelines. RESULTS: A cohort of 108 patients was included with 51.9% male and aged 65 (IQR: 52-75) years. In total, 104 patients took at least 1 antihypertensive drug and 46 patients (44.2%) were classified as non-adherent with regard to their antihypertensive treatment; 82 patients (78.8%) had suboptimal blood pressure control. Compliance with the ESC guidelines was 66.3% prior to the consultation at the clinic and significantly increased to 77.9% thereafter (p = 0.0015). The clinical pharmacist performed a medication review for 27 patients with a total of 44 recommendations and an acceptance rate of 59.1%. CONCLUSION: A visit to the multidisciplinary hypertension clinic improved prescriber guideline compliance and the use of single pill combinations. Involvement of a clinical pharmacist could be beneficial to further improve patient drug therapy adherence and guideline compliance.