Summary Background The clinical benefit of preventive eradication of unruptured brain arteriovenous malformations remains uncertain. A Randomised trial of Unruptured Brain Arteriovenous malformations ...(ARUBA) aims to compare the risk of death and symptomatic stroke in patients with an unruptured brain arteriovenous malformation who are allocated to either medical management alone or medical management with interventional therapy. Methods Adult patients (≥18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1:1 ratio, with random permuted block design block size 2, 4, or 6, stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00389181. Findings Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4·10, exceeding the prespecified stopping boundary value of 2·87). At this point, outcome data were available for 223 patients (mean follow-up 33·3 months SD 19·7), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10·1%) patients in the medical management group compared with 35 (30·7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0·27, 95% CI 0·14–0·54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy compared with medical management. Interpretation The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up. Funding National Institutes of Health, National Institute of Neurological Disorders and Stroke.
In March 2020, as community spread of severe acute respiratory syndrome coronavirus 2 became increasingly prevalent, pregnant women seemed to be equally susceptible to developing coronavirus disease ...2019. Although the disease course usually appears mild, severe and critical cases of coronavirus disease 2019 seem to lead to substantial morbidity, including intensive care unit admission with prolonged hospital stay, intubation, mechanical ventilation, and even death. Although there are recent reports regarding the impact of coronavirus disease 2019 on pregnancy, there is a lack of information regarding the severity of coronavirus disease 2019 in pregnant vs nonpregnant women.
We aimed to describe the outcomes of severe and critical cases of coronavirus disease 2019 in pregnant vs nonpregnant, reproductive-aged women.
This is a multicenter, retrospective, case-control study of women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection hospitalized with severe or critical coronavirus disease 2019 in 4 academic medical centers in New York City and 1 in Philadelphia between March 12, 2020, and May 5, 2020. The cases consisted of pregnant women admitted specifically for severe or critical coronavirus disease 2019 and not for obstetrical indications. The controls consisted of reproductive-aged, nonpregnant women admitted for severe or critical coronavirus disease 2019. The primary outcome was a composite morbidity that includes the following: death, a need for intubation, extracorporeal membrane oxygenation, noninvasive positive pressure ventilation, or a need for high-flow nasal cannula O2 supplementation. The secondary outcomes included intensive care unit admission, length of stay, a need for discharge to long-term acute care facilities, and discharge with a home O2 requirement.
A total of 38 pregnant women with severe acute respiratory syndrome coronavirus 2 polymerase chain reaction-confirmed infections were admitted to 5 institutions specifically for coronavirus disease 2019, 29 (76.3%) meeting the criteria for severe disease status and 9 (23.7%) meeting the criteria for critical disease status. The mean age and body mass index were markedly higher in the nonpregnant control group. The nonpregnant cohort also had an increased frequency of preexisting medical comorbidities, including diabetes, hypertension, and coronary artery disease. The pregnant women were more likely to experience the primary outcome when compared with the nonpregnant control group (34.2% vs 14.9%; P=.03; adjusted odds ratio, 4.6; 95% confidence interval, 1.2–18.2). The pregnant patients experienced higher rates of intensive care unit admission (39.5% vs 17.0%; P<.01; adjusted odds ratio, 5.2; 95% confidence interval, 1.5–17.5). Among the pregnant women who underwent delivery, 72.7% occurred through cesarean delivery and the mean gestational age at delivery was 33.8±5.5 weeks in patients with severe disease status and 35±3.5 weeks in patients with critical coronavirus disease 2019 status.
Pregnant women with severe and critical coronavirus disease 2019 are at an increased risk for certain morbidities when compared with nonpregnant controls. Despite the higher comorbidities of diabetes and hypertension in the nonpregnant controls, the pregnant cases were at an increased risk for composite morbidity, intubation, mechanical ventilation, and intensive care unit admission. These findings suggest that pregnancy may be associated with a worse outcome in women with severe and critical cases of coronavirus disease 2019. Our study suggests that similar to other viral infections such as severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, pregnant women may be at risk for greater morbidity and disease severity.
Among patients with severe ischemic mitral regurgitation who were assigned to mitral-valve repair or replacement, there were no significant between-group differences in left ventricular remodeling or ...mortality at 2 years. Mitral regurgitation recurred more frequently in the repair group.
Ischemic mitral regurgitation is a serious consequence of coronary artery disease that carries a substantial risk of death from cardiovascular causes in proportion to its severity.
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Ischemic mitral regurgitation is anatomically characterized by remodeling or distortion of left ventricular geometry that ultimately results in papillary-muscle displacement, leaflet tethering, and impaired coaptation. For the subgroup of patients with severe ischemic mitral regurgitation, the prognosis is grave, with rates of death ranging from 15 to 40% at 1 year.
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For patients with severe ischemic mitral regurgitation, the benefit of surgical revascularization is undisputed, provided that the patient has suitable coronary . . .
After 2 years of follow-up in a randomized trial involving 301 patients with moderate ischemic mitral regurgitation undergoing CABG, the addition of mitral-valve repair did not improve left ...ventricular function or remodeling.
Ischemic mitral regurgitation of moderate severity develops in approximately 10% of patients after myocardial infarction.
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Mitral regurgitation is caused by the displacement of papillary muscle, leaflet tethering, reduced closing forces, and annular dilatation. Over time, the condition has an adverse effect on the rate of survival free of heart failure.
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Because most patients with ischemic mitral regurgitation have multivessel coronary artery disease requiring revascularization, surgeons have to consider whether to add mitral-valve repair to coronary-artery bypass grafting (CABG).
The appropriate surgical management of moderate ischemic mitral regurgitation at the time of CABG remains controversial. Some experts advocate revascularization alone . . .
This trial compared coronary-artery bypass grafting alone with CABG plus mitral-valve repair in patients with coronary artery disease and moderate ischemic mitral regurgitation. Mitral-valve repair ...provided no apparent benefit and was associated with more neurologic complications.
Each year, approximately 1 million Americans have a myocardial infarction, and nearly 8 million Americans have a history of myocardial infarction.
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Ischemic mitral regurgitation, which results from functional-valve incompetence due to myocardial injury and adverse left ventricular remodeling, develops in approximately 50% of patients after an infarction, and moderate regurgitation occurs in more than 10% of patients.
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Ischemic mitral regurgitation is associated with excess mortality regardless of management.
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The valve leaflets and chordal structures in affected patients are “innocent bystanders”; mitral regurgitation results from papillary muscle displacement, leaflet tethering, reduced closing forces, and annular dilatation.
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Many patients . . .
In A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA), randomisation was halted at a mean follow-up of 33·3 months after a prespecified interim analysis showed that medical ...management alone was superior to the combination of medical management and interventional therapy in preventing symptomatic stroke or death. We aimed to study whether these differences persisted through 5-years' follow-up.
ARUBA was a non-blinded, randomised trial done at 39 clinical centres in nine countries. Adults (age ≥18 years) diagnosed with an unruptured brain arteriovenous malformation, who had never undergone interventional therapy, and were considered by participating clinical centres to be suitable for intervention to eradicate the lesion, were eligible for inclusion. Patients were randomly assigned (1:1) by a web-based data collection system, stratified by clinical centre in a random permuted block design with block sizes of two, four, and six, to medical management alone or with interventional therapy (neurosurgery, embolisation, or stereotactic radiotherapy, alone or in any combination, sequence, or number). Although patients and investigators at a given centre were not masked to treatment assignment, investigators at other centres and those in the clinical coordinating centre were not informed of assignment or outcomes at any of the centres. The primary outcome was time to death or symptomatic stroke confirmed by imaging, assessed by a neurologist at each centre not involved in the management of participants' care, and monitored by an independent committee using an adaptive approach with interim analyses. Enrolment began on April 4, 2007, and was halted on April 15, 2013, after which follow-up continued until July 15, 2015. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00389181.
Of 1740 patients screened, 226 were randomly assigned to medical management alone (n=110) or medical management plus interventional therapy (n=116). During a mean follow-up of 50·4 months (SD 22·9), the incidence of death or symptomatic stroke was lower with medical management alone (15 of 110, 3·39 per 100 patient-years) than with medical management with interventional therapy (41 of 116, 12·32 per 100 patient-years; hazard ratio 0·31, 95% CI 0·17 to 0·56). Two patients in the medical management group and four in the interventional therapy group (two attributed to intervention) died during follow-up. Adverse events were observed less often in patients allocated to medical management compared with interventional therapy (283 vs 369; 58·97 vs 78·73 per 100 patient-years; risk difference −19·76, 95% CI −30·33 to −9·19).
After extended follow-up, ARUBA showed that medical management alone remained superior to interventional therapy for the prevention of death or symptomatic stroke in patients with an unruptured brain arteriovenous malformation. The data concerning the disparity in outcomes should affect standard specialist practice and the information presented to patients. The even longer-term risks and differences between the two therapeutic approaches remains uncertain.
National Institute of Neurological Disorders and Stroke for the randomisation phase and Vital Projects Fund for the follow-up phase.
It remains unclear whether interstitial lung disease (ILD) in common variable immunodeficiency (CVID) is a consequence of chronic infection or a manifestation of dysregulated lymphoid proliferation ...found in those with this condition.
To increase understanding of CVID-associated lung disease by comparing clinical and immunologic associations in those with bronchiectasis, ILD, or no lung disease observed on chest computerized tomography (CT).
Retrospective review of electronic medical records of 61 patients with CVID was used to identify clinical and laboratory correlates of bronchiectasis, ground glass opacity, and pulmonary nodules on CT scan.
Significant clinical and immunologic associations were identified for common CT scan findings in CVID. Bronchiectasis was strongly correlated with a CD4+ T-cell count lower than 700 cells/μL and was associated with a history of pneumonia and older age. Pulmonary nodular disease was correlated with increased CD4+:CD8+ T-cell ratios, a history of autoimmune hemolytic anemia or immune thrombocytopenic purpura, elevated IgM, and younger age. Ground glass opacity had similar clinical and laboratory characteristics as those for nodular lung disease but was associated with elevated monocyte counts and the presence of liver disease.
CT findings of bronchiectasis or ILD, including ground glass opacity and extensive pulmonary nodules, were correlated with selected clinical and laboratory characteristics. These results suggest divergent processes of CVID lung disease, with bronchiectasis more strongly associated with infection and T-cell lymphopenia and ILD more strongly linked with autoimmunity and lymphoproliferation.
Under a master protocol, open platform trials allow new experimental treatments to enter an existing clinical trial. Whether late-entry experimental treatments should be compared to all available or ...concurrently randomized controls is not well established. Using all available data can increase power and precision; however, drift in population parameters can yield biased estimates and impact type I error rate.
We explored the application of methods developed to incorporate historical controls in two-arm trials to the analysis of a late-entry arm in a simulated open platform trial under varying scenarios of parameter drift. Methods explored include test-then-pool, fixed power prior, dynamic power prior, and multi-source exchangeability model approaches.
Simulated trial results confirm that in the presence of no drift, naively pooling all controls increases power and produces more precise, unbiased estimates when compared to using concurrent controls only. However, under drift, pooling can result in type I error rate inflation or deflation and biased estimates. In the presence of parameter drift, methods that partially borrow non-concurrent data, either through a static weighting mechanism or through methods that allow the heterogeneity between non-concurrent and concurrent data to determine the degree of borrowing, are superior to naively pooling the data. However, compared to using concurrent controls only, these approaches cannot guarantee type I error control or unbiased estimates. Thus, concurrent controls should be used as comparators in confirmatory studies.
BACKGROUND:In ischemic mitral regurgitation (IMR), ring annuloplasty is associated with a significant rate of recurrent MR. Ring size is based on intertrigonal distance without consideration of left ...ventricular (LV) size. However, LV size is an important determinant of mitral valve (MV) leaflet tethering before and after repair. We aimed to determine whether LV-MV ring mismatch (mismatch of LV size relative to ring size) is associated with recurrent MR in patients with IMR after restrictive ring annuloplasty.
METHODS:Patients with moderate or severe IMR from the 2 Cardiothoracic Surgical Trials Network IMR trials who received MV repair were examined at 1 year after surgery. Baseline LV size was assessed by LV end-diastolic dimension and LV end-systolic dimension (LVESd). LV-MV ring mismatch was calculated as the ratio of LV to ring size (LV end-diastolic dimension/ring size and LVESd/ring size).
RESULTS:At 1 year after ring annuloplasty, 45 of 214 patients with MV repair (21%) had moderate or greater MR. In univariable logistic regression analysis, larger LVESd (P=0.02) and LVESd/ring size (P=0.007) were associated with recurrent MR. In multivariable models adjusted for age, sex, baseline LV ejection fraction, and severe IMR, only LVESd/ring size (odd ratio per 0.5 increase, 2.20; 95% confidence interval, 1.05–4.62; P=0.038) remained significantly associated with 1-year MR recurrence.
CONCLUSIONS:LV-MV ring size mismatch is associated with increased risk of MR recurrence. This finding may be helpful in guiding choice of ring size to prevent recurrent MR in patients undergoing MV repair and in identifying patients who may benefit from MV repair with additional subvalvular intervention or MV replacement rather than repair alone.
CLINICAL TRIAL REGISTRATION:URL:http://clinicaltrials.gov. Unique identifiersNCT00806988 and NCT00807040.
Background and Aims
The risk for hepatocellular carcinoma (HCC) is increased in acute hepatic porphyrias (AHP). The aim of this study was to explore the clinicopathologic characteristics, outcomes, ...and frequency of HCC in patients with AHP in the United States.
Approach and Results
This cross‐sectional analysis evaluated patients with HCC in a multicenter, longitudinal study of AHP. Among 327 patients with AHP, 5 (1.5%) were diagnosed with HCC. Of the 5 HCC cases, 4 had acute intermittent porphyria and 1 had variegate porphyria, confirmed by biochemical and/or genetic testing. All patients were white females, with a median age of 27 years (range 21‐75) at diagnosis. The median age at HCC diagnosis was 69 years (range 61‐74). AHP was asymptomatic in 2 patients; 2 reported sporadic attacks; and 1 reported recurrent attacks (>4 attacks/year). All patients had a single HCC lesion on liver imaging that was 1.8‐6.5 centimeters in diameter. Serum alpha fetoprotein levels were below 10 ng/mL in all 4 patients with available results. Four patients underwent liver resection, and 1 was treated with radioembolization. No significant inflammation or fibrosis was found in adjacent liver tissues of 3 patients who underwent liver resection. Two patients developed recurrence of HCC at 22 and 26 months following liver resection. All patients are alive with survival times from HCC diagnosis ranging from 26‐153 months.
Conclusion
In this U.S. study, 1.5% of patients with AHP had HCC. HCC in AHP occurred in the absence of cirrhosis, which contrasts with other chronic liver diseases. Patients with AHP, regardless of clinical attacks, should be screened for HCC, beginning at age 50. The pathogenesis of hepatocarcinogenesis in AHP is unknown and needs further investigation.
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