Whole-exome sequencing uncovers a novel EFEMP2 gene variant (c.C247T) associated with dominant nonsyndromic thoracic aortic aneurysm.

BACKGROUND: Thoracic aortic aneurysm (TAA) is a multifactorial disorder. Familial TAA, which is more clinically aggressive, is associated with a high risk of lethal dissection or rupture. Genetic evaluation can provide TAA patients with personalized treatment and help in predicting risk to family members. OBJECTIVE: The purpose of this investigation was to report a likely pathogenic variant in the EFEMP2 gene that may contribute to TAA in a family with a documented history of the condition. METHODS: In the index patient, the causative genetic predisposition was identified using whole-exome sequencing. The potential likely pathogenic effect of the candidate variant was further analyzed through bioinformatics analysis, homology modeling, and molecular docking. RESULTS: The results revealed a likely pathogenic heterozygous variant, c.247C>T p.Arg83Cys, in exon 4 of the EFEMP2 gene (NM_016938), which was predicted to have disease-causing effects by MutationTaster, PROVEAN, SIFT, and CADD (phred score = 27.6). CONCLUSION: In this study, a likely pathogenic variant in the EFEMP2 gene was identified in an Iranian family with a dominant pattern of autosomal inheritance of TAA. This finding underscores the importance of conducting molecular genetic evaluations in families with nonsyndromic TAA and the significance of early detection of at-risk family members.

In-silico investigations of haemodynamic parameters for a blunt thoracic aortic injury case.

Accounting for 1.5% of thoracic trauma, blunt thoracic aortic injury (BTAI) is a rare disease with a high mortality rate that nowadays is treated mostly via thoracic endovascular aortic repair (TEVAR). Personalised computational models based on fluid-solid interaction (FSI) principals not only support clinical researchers in studying virtual therapy response, but also are capable of predicting eventual outcomes. The present work studies the variation of key haemodynamic parameters in a clinical case of BTAI after successful TEVAR, using a two-way FSI model. The three-dimensional (3D) patient-specific geometries of the patient were coupled with three-element Windkessel model for both prior and post intervention cases, forcing a correct prediction of blood flow over each section. Results showed significant improvement in velocity and pressure distribution after stenting. High oscillatory, low magnitude shear (HOLMES) regions require careful examination in future follow-ups, since thrombus formation was confirmed in some previously clinically reported cases of BTAI treated with TEVAR. The strength of swirling flows along aorta was also damped after stent deployment. Highlighting the importance of haemodynamic parameters in case-specific therapies. In future studies, compromising motion of aortic wall due to excessive cost of FSI simulations can be considered and should be based on the objectives of studies to achieve a more clinical-friendly patient-specific CFD model.

Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

Spontaneous coronary artery dissection in a patient with recent COVID-19 infection: A case report.

We report a spontaneous coronary artery dissection (SCAD) case in a lady with a history of recent COVID-19 and without any known predisposing factors. We also highlight the value of CMR as a noninvasive tool for tissue characterization, which can also be more applicable during the COVID-19 pandemic.

Catheter-Directed Thrombolysis vs Anticoagulation in Patients With Acute Intermediate-High-risk Pulmonary Embolism: The CANARY Randomized Clinical Trial.

Importance: The optimal treatment of intermediate-high-risk pulmonary embolism (PE) remains unknown. Objective: To assess the effect of conventional catheter-directed thrombolysis (cCDT) plus anticoagulation vs anticoagulation monotherapy in improving echocardiographic measures of right ventricle (RV) to left ventricle (LV) ratio in acute intermediate-high-risk PE. Design, Setting, and Participants: The Catheter-Directed Thrombolysis vs Anticoagulation in Patients with Acute Intermediate-High-Risk Pulmonary Embolism (CANARY) trial was an open-label, randomized clinical trial of patients with intermediate-high-risk PE, conducted in 2 large cardiovascular centers in Tehran, Iran, between December 22, 2018, through February 2, 2020. Interventions: Patients were randomly assigned to cCDT (alteplase, 0.5 mg/catheter/h for 24 hours) plus heparin vs anticoagulation monotherapy. Main Outcomes and Measures: The proportion of patients with a 3-month echocardiographic RV/LV ratio greater than 0.9, assessed by a core laboratory, was the primary outcome. The proportion of patients with an RV/LV ratio greater than 0.9 at 72 hours after randomization and the 3-month all-cause mortality were among secondary outcomes. Major bleeding (Bleeding Academic Research Consortium type 3 or 5) was the main safety outcome. A clinical events committee, masked to the treatment assignment, adjudicated clinical outcomes. Results: The study was prematurely stopped due to the COVID-19 pandemic after recruiting 94 patients (mean [SD] age, 58.4 [2.5] years; 27 women [29%]), of whom 85 patients completed the 3-month echocardiographic follow-up. Overall, 2 of 46 patients (4.3%) in the cCDT group and 5 of 39 patients (12.8%) in the anticoagulation monotherapy group met the primary outcome (odds ratio [OR], 0.31; 95% CI, 0.06-1.69; P = .24). The median (IQR) 3-month RV/LV ratio was significantly lower with cCDT (0.7 [0.6-0.7]) than with anticoagulation (0.8 [0.7-0.9); P = .01). An RV/LV ratio greater than 0.9 at 72 hours after randomization was observed in fewer patients treated with cCDT (13 of 48 [27.0%]) than anticoagulation (24 of 46 [52.1%]; OR, 0.34; 95% CI, 0.14-0.80; P = .01). Fewer patients assigned to cCDT experienced a 3-month composite of death or RV/LV greater than 0.9 (2 of 48 [4.3%] vs 8 of 46 [17.3%]; OR, 0.20; 95% CI, 0.04-1.03; P = .048). One case of nonfatal major gastrointestinal bleeding occurred in the cCDT group. Conclusions and Relevance: This prematurely terminated randomized clinical trial of patients with intermediate-high-risk PE was hypothesis-generating for improvement in some efficacy outcomes and acceptable rate of major bleeding for cCDT compared with anticoagulation monotherapy and provided support for a definitive clinical outcomes trial. Trial Registration: ClinicalTrials.gov Identifier: NCT05172115.

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial.

BACKGROUND: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. METHODS: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. RESULTS: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). CONCLUSION: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

Fast vs. ultraslow thrombolytic infusion regimens in patients with obstructive mechanical prosthetic valve thrombosis: a pilot randomized clinical trial.

AIMS: Thrombolysis is an alternative to surgery for mechanical prosthetic valve thrombosis (MPVT). Randomized clinical trials have yet to test the safety and efficacy of a proposed ultraslow thrombolytic infusion regimen. METHODS AND RESULTS: This single-centre, open-label, pilot randomized clinical trial randomized adult patients with acute obstructive MPVT to an ultraslow thrombolytic regimen [25 mg of recombinant tissue-type plasminogen activator (rtPA) infused in 25 h] and a fast thrombolytic regimen (50 mg of rtPA infused in 6 h). If thrombolysis failed, a repeated dose of 25 mg of rtPA for 6 h was administered in both groups up to a cumulative dose of 150 mg or the occurrence of a complication. The primary outcome was a complete MPVT resolution (>75% fall in the obstructive gradient by transthoracic echocardiography, <10° limitation in opening and closing valve motion angles by fluoroscopy, and symptom improvement). The key safety outcome was a Bleeding Academic Research Consortium type III or V major bleeding. Overall, 120 patients, including 63 (52.5%) women, at a mean age of 36.3 ± 15.3 years, were randomized. Complete thrombolysis success was achieved in 51 patients (85.0%) in the ultraslow-regimen group and 47 patients (78.3%) in the fast-regimen group [odds ratio 1.58; 95% confidence interval (CI) 0.25-1.63; P = 0.34]. One case of transient ischaemic attack and three cases of intracranial haemorrhage (absolute risk difference -6.6%; 95%CI -12% -0.3%; P = 0.07) were observed only in the fast-regimen group. CONCLUSION: The ultraslow thrombolytic regimen conferred a high thrombosis resolution rate without major complications. Such findings should be replicated in more adequately powered trials.

Stressful life events and the risk of primary progressive multiple sclerosis: A population-based case-control study.

BACKGROUND: The onset and presentation of primary progressive multiple sclerosis (PPMS) like any other autoimmune diseases can be triggered by unexpected lifetime stressful events, which require to be assessed in order to minimize our exposure to such events as much as possible. OBJECTIVE: The aim of the present study was to determine the possible role of socioeconomic status (SES) and stressful events in PPMS development METHODS: The present population-based case-control study recruited PPMS cases and healthy controls from the general population during 2019-2020 in Tehran, Iran. Clinical diagnosis of cases was based on the 2017 McDonald criteria and confirmed by a neurologist. The selection of sex-matched controls from the same source population of cases was performed using the standard method of Random Digit Dialing (RDD). The study questionnaire was filled out over telephone interviews. Matched logistic regression was administered to estimate the adjusted and unadjusted odds ratio (OR) at 95% confidence intervals (CIs) adjusted for sex, age, and marital status using SPSS 23. RESULTS: This study examined 146 PPMS cases and 294 controls. Mean ages (SD) for cases and controls were 46.97 (9.4) and 37.67 (6.12), respectively (P < 0.001). No stressful events over five years prior to the disease onset were associated with an increased risk of PPMS. Marriage (OR: 0.04; 95% CI (0.01- 0.37), P = 0.004), close family members' serious disease (OR: 0.10; 95% CI (0.02-0.60), P = 0.01), and being in debt (OR: 0.03; 95% CI (0-0.37), P = 0.006) were found to have a negative association with the risk of disease occurrence. Death of a loved one, family disruption, jail term, homelessness period, Conquer(national university entrance exam), death of spouse, getting fired from a job, joblessness, divorce, migration, close family members' suicide, and retirement were not associated with the risk of PPMS (P > 0.05). History of depression before the PPMS presentation was considerably associated with the incidence of PPMS (P < 0.001). Self-rated health status was scored noticeably lower by cases as compared with controls (P < 0.001). Participants with the paternal educational degree of guidance school showed a higher risk of PPMS by 2.83 time (OR: 2.83; 95% CI (1.02 - 7.80), P = 0.04) than participants with university educated fathers. In total, SES during adolescence did not indicate any association with the risk of PPMS (with the exception of levels 2 (P = 0.02) and 7 (P = 0.05)). CONCLUSION: No stressful life events were identified as possible increasing risk factors for PPMS. Marriage, close family members' serious disease, and being in debt had a negative association with the disease risk. The history of depression may elevate the risk of PPMS. While the highest and lowest SES levels in adolescence were not remarkable determiners for PPMS, levels 2 and 7 had a positive association with the risk of PPMS. The maternal educational level was not an important factor; however, the paternal educational degree of guidance school as compared to university degree made individuals more susceptible to PPMS. Self-rated health status score was higher in controls.

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.

Stressful life events, socioeconomic status, and the risk of neuromyelitis optica spectrum disorder: A population-based case-control study.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a multifactorial autoimmune disease caused by genetic susceptibility and exposure to environmental factors. There is not sufficient evidence to estimate potential environmental risk factors for NMOSD; therefore, many predisposing factors may remain unknown. OBJECTIVE: The present study assessed the possible associations of ethnicity, socioeconomic status (SES), and stressful life events with NMOSD risk after adjustment for sex and age in an Iranian population. METHODS: This population-based case-control study included NMOSD cases and healthy controls in Tehran, Iran. Diagnosis of disease was confirmed by neurologists based on the 2015 International Consensus Criteria (ICC). Controls were sex-matched with cases and had no history of any neurological disorders. The telephone interviews were administered to gather pertinent data. Matched logistic regression was used to estimate unadjusted and adjusted odds ratio (ORs) and 95% confidence intervals (CIs) using SPSS. RESULTS: This study recruited 153 NMOSD cases and 400 controls with the case-control ratio of 1: 2.61 and mean ages (SD) of 37.11 (10.90) and 33.67 (8.37) years, respectively (p < 0.001). Depression history (OR = 3.79; 95% CI (1.50 - 9.58), p = 0.01) and stressful life events including death of first-degree relatives (OR = 5.10; 95% CI (1.78 - 14.61), p < 0.01), family disruption (OR = 12.68; 95% CI) 3.53 - 45.46), p < 0.001), homelessness periods(OR = 4.35; 95% CI (1.18 - 14.74), p = 0.02), joblessness (OR = 4.24; 95% CI (1.91 - 5.15), p = 0.01), and divorce (OR = 14.18; 95% CI (1.91 - 23.15), p = 0.01) were more common among NMOSD cases than matched controls and may play a role in increasing risk of disease occurrence. Marriage (OR = 0.10; 95% CI (0.03 - 0.35), p < 0.001) and Conquer (Iranian national exam for university entrance) (OR = 0.31; 95% CI (0.11 - 0.88), p = 0.02) had a negative association with NMOSD risk. Other stressful life events including jail term, close family members' serious disease or suicide, death of spouse, being in debt, getting fired from work, migration, and retirement had no relation with NMOSD risk (P > 0.05). The total stress number and load were not significantly associated with the risk of NMOSD (P > 0.05). Self-rated health status was significantly higher in controls (p < 0.001). Socioeconomic status (SES), parental ethnicity, and parental educational level during subjects' adolescence were not among the significant predictors of NMOSD risk (P > 0.05). CONCLUSION: No association was identified between ethnicity, SES, and parental educational levels as risk factors for developing NMOSD in an Iranian population. The obtained evidence showed the association of some individual stressful life events like death of first-degree relatives, family disruption, homelessness periods, joblessness, and divorce with the risk of developing NMOSD while marriage had a negative association. Depression history was more common among cases than healthy controls and may play a role in increasing risk of NMOSD.