Infarct-related structural disconnection and delirium in surgical aortic valve replacement patients.

OBJECTIVE: Although acute brain infarcts are common after surgical aortic valve replacement (SAVR), they are often unassociated with clinical stroke symptoms. The relationship between clinically "silent" infarcts and in-hospital delirium remains uncertain; obscured, in part, by how infarcts have been traditionally summarized as global metrics, independent of location or structural consequence. We sought to determine if infarct location and related structural connectivity changes were associated with postoperative delirium after SAVR. METHODS: A secondary analysis of a randomized multicenter SAVR trial of embolic protection devices (NCT02389894) was conducted, excluding participants with clinical stroke or incomplete neuroimaging (N = 298; 39% female, 7% non-White, 74 ± 7 years). Delirium during in-hospital recovery was serially screened using the Confusion Assessment Method. Parcellation and tractography atlas-based neuroimaging methods were used to determine infarct locations and cortical connectivity effects. Mixed-effect, zero-inflated gaussian modeling analyses, accounting for brain region-specific infarct characteristics, were conducted to examine for differences within and between groups by delirium status and perioperative neuroprotection device strategy. RESULTS: 23.5% participants experienced postoperative delirium. Delirium was associated with significantly increased lesion volumes in the right cerebellum and temporal lobe white matter, while diffusion weighted imaging infarct-related structural disconnection (DWI-ISD) was observed in frontal and temporal lobe regions (p-FDR < 0.05). Fewer brain regions demonstrated DWI-ISD loss in the suction-based neuroprotection device group, relative to filtration-based device or standard aortic cannula. INTERPRETATION: Structural disconnection from acute infarcts was greater in patients who experienced postoperative delirium, suggesting that the impact from covert perioperative infarcts may not be as clinically "silent" as commonly assumed.

Grand Multiparity and Obstetric Outcomes in a Contemporary Cohort: The Role of Increasing Parity.

OBJECTIVE: Evidence is inconsistent regarding grand multiparity and its association with adverse obstetric outcomes. Few large American cohorts of grand multiparas have been studied. We assessed if increasing parity among grand multiparas is associated with increased odds of adverse perinatal outcomes. STUDY DESIGN: Multicenter retrospective cohort of patients with parity ≥ 5 who delivered a singleton gestation in New York City from 2011 to 2019. Outcomes included postpartum hemorrhage, preterm delivery, hypertensive disorders of pregnancy, shoulder dystocia, birth weight > 4,000 and <2,500 g, and neonatal intensive care unit (NICU) admission. Parity was analyzed continuously, and multivariate analysis determined if increasing parity and other obstetric variables were associated with each adverse outcome. RESULTS: There were 2,496 patients who met inclusion criteria. Increasing parity among grand multiparas was not associated with any of the prespecified adverse outcomes. Odds of postpartum hemorrhage increased with history (adjusted odds ratio [aOR]: 2.65, 95% confidence interval [1.83, 3.84]) and current cesarean delivery (aOR: 4.59 [3.40, 6.18]). Preterm delivery was associated with history (aOR: 12.36 [8.70-17.58]) and non-White race (aOR: 1.90 [1.27, 2.84]). Odds of shoulder dystocia increased with history (aOR: 5.89 [3.22, 10.79]) and birth weight > 4,000 g (aOR: 9.94 [6.32, 15.65]). Birth weight > 4,000 g was associated with maternal obesity (aOR: 2.92 [2.22, 3.84]). Birth weight < 2,500 g was associated with advanced maternal age (aOR: 1.69 [1.15, 2.48]), chronic hypertension (aOR: 2.45 [1.32, 4.53]), and non-White race (aOR: 2.47 [1.66, 3.68]). Odds of hypertensive disorders of pregnancy increased with advanced maternal age (aOR: 1.79 [1.25, 2.56]), history (aOR: 10.09 [6.77-15.04]), and non-White race (aOR: 2.79 [1.95, 4.00]). NICU admission was associated with advanced maternal age (aOR: 1.47 [1.06, 2.02]) and non-White race (aOR: 2.57 [1.84, 3.58]). CONCLUSION: Among grand multiparous patients, the risk factor for adverse maternal, obstetric, and neonatal outcomes appears to be occurrence of those adverse events in a prior pregnancy and not increasing parity itself. KEY POINTS: · Increasing parity is not associated with adverse obstetric outcomes among grand multiparas.. · Prior adverse pregnancy outcome is a risk factor for the outcome among grand multiparas.. · Advanced maternal age is associated with adverse obstetric outcomes among grand multiparas..

Ledipasvir/Sofosbuvir Is Effective as Sole Treatment of Porphyria Cutanea Tarda with Chronic Hepatitis C.

BACKGROUND AND AIMS: Chronic hepatitis C [CHC] is a risk factor for porphyria cutanea tarda [PCT]. To assess whether ledipasvir/sofosbuvir is effective for treating both PCT and CHC, we treated patients with CHC + PCT solely with ledipasvir/sofosbuvir and followed them for at least 1 year to assess cure of CHC and remission of PCT. METHODS: Between September 2017 and May 2020, 15 of 23 screened PCT + CHC patients were eligible and enrolled. All were treated with ledipasvir/sofosbuvir at recommended doses and durations, according to their stage of liver disease. We measured plasma and urinary porphyrins at baseline and monthly for the first 12 months and at 16, 20, and 24 mos. We measured serum HCV RNA at baseline, 8-12, and 20-24 mos. Cure of HCV was defined as no detectable serum HCV RNA ≥ 12 weeks after the end of treatment (EOT). Remission of PCT was defined clinically as no new blisters or bullae and biochemically as urinary uro- plus hepta-carboxyl porphyrins ≤ 100 mcg/g creatinine. RESULTS: All 15 patients, 13 of whom were men, were infected with HCV genotype 1. 2/15 withdrew or were lost to follow-up. Of the remaining 13, 12 achieved cure of CHC; 1 had complete virological response, followed by relapse of HCV after ledipasvir/sofosbuvir but was subsequently cured by treatment with sofosbuvir/velpatasvir. Of the 12 cured of CHC, all achieved sustained clinical remission of PCT. CONCLUSIONS: Ledipasvir/sofosbuvir [and likely other direct-acting antivirals] is an effective treatment for HCV in the presence of PCT and leads to clinical remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03118674.

A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults.

Background: Stress exposure is a key risk factor for the development of major depressive disorder and posttraumatic stress disorder. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced disorders. The administration of ketamine one week prior to an acute stressor prevents the development of stress-induced depressive-like behavior in rodents. This study aimed to test if the prophylactic effect of ketamine against stress also applies to humans. Methods: We conducted a double-blind, placebo-controlled study wherein 24 healthy subjects (n = 11 males) were randomized to receive either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) intravenously one week prior to an acute stress [Trier Social Stress Test (TSST)]. The primary endpoint was the anxious-composed subscale of the Profile of Mood States Bipolar Scale (POMS-Bi) administered immediately after the TSST. Salivary and plasma cortisol and salivary alpha amylase were also measured at 15-min intervals for 60 min following the stressor, as proxies of hypothalamic pituitary adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axis activity, respectively. Results: Compared to the midazolam group (n = 12), the ketamine group (n = 12) showed a moderate to large (Cohen's d = 0.7) reduction in levels of anxiety immediately following stress, although this was not significant (p = 0.06). There was no effect of group on change in salivary cortisol or salivary alpha amylase following stress. We conducted a secondary analysis excluding one participant who did not show an expected correlation between plasma and salivary cortisol (n = 23, ketamine n = 11). In this subgroup, we observed a significant reduction in the level of salivary alpha amylase in the ketamine group compared to midazolam (Cohen's d = 0.7, p = 0.03). No formal adjustment for multiple testing was made as this is a pilot study and all secondary analyses are considered hypothesis-generating. Conclusions: Ketamine was associated with a numeric reduction in TSST-induced anxiety, equivalent to a medium-to-large effect size. However, this did not reach statistical significance . In a subset of subjects, ketamine appeared to blunt SAM reactivity following an acute stressor. Future studies with larger sample size are required to further investigate the pro-resilient effect of ketamine.

A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19.

Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P = 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.

A pilot study of oral iron therapy in erythropoietic protoporphyria and X-linked protoporphyria.

The use of iron supplementation for anemia in erythropoietic protoporphyria (EPP) is controversial with both benefit and deterioration reported in single case reports. There is no systematic study to evaluate the benefits or risks of iron supplementation in these patients. We assessed the potential efficacy of oral iron therapy in decreasing erythrocyte protoporphyrin (ePPIX) levels in patients with EPP or X-linked protoporphyria (XLP) and low ferritin in an open-label, single-arm, interventional study. Sixteen patients (≥18 years) with EPP or XLP confirmed by biochemical and/or genetic testing, and serum ferritin ≤30 ng/mL were enrolled. Baseline testing included iron studies, normal hepatic function, and elevated plasma porphyrins and ePPIX levels. Oral ferrous sulfate 325 mg twice daily was administered for 12 months. The primary efficacy outcome was the relative difference in total ePPIX level between baseline and 12 months after starting treatment with iron. Secondary measures included improvement in serum ferritin, plasma porphyrins, and clinical symptoms. Thirteen patients had EPP (8 females, 5 males) and 3 had XLP (all females) and the mean age of participants was 38.8 years (SD 14.5). Ten patients completed all study visits limiting interpretation of results. In EPP patients, a transient increase in ePPIX levels was observed at 3 months in 9 of 12 (75%) patients. Iron was discontinued in 2 of these patients after meeting the protocol stopping rule of a 35% increase in ePPIX. Seven patients withdrew before study end. Ferritin levels increased on iron replacement indicating an improvement in iron status. A decrease in ePPIX was seen in both XLP patients who completed the study (relative difference of 0.67 and 0.5 respectively). No substantial changes in ePPIX were seen in EPP patients at the end of the study (n = 8; median relative difference: -0.21 (IQR: -0.44, 0.05). The most common side effects of iron treatment were gastrointestinal symptoms. Hepatic function remained normal throughout the study. Our study showed that oral iron therapy repletes iron stores and transiently increases ePPIX in some EPP patients, perhaps due to a transient increase in erythropoiesis, and may decrease ePPIX in XLP patients. Further studies are needed to better define the role of iron repletion in EPP. Trial registration: NCT02979249.

Integrating non-concurrent controls in the analyses of late-entry experimental arms in multi-arm trials with a shared control group in the presence of parameter drift.

BACKGROUND: 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. METHODS: 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. RESULTS/CONCLUSIONS: 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.

The impact of perioperative stroke and delirium on outcomes after surgical aortic valve replacement.

OBJECTIVE: The effects of stroke and delirium on postdischarge cognition and patient-centered health outcomes after surgical aortic valve replacement (SAVR) are not well characterized. Here, we assess the impact of postoperative stroke and delirium on these health outcomes in SAVR patients at 90 days. METHODS: Patients (N = 383) undergoing SAVR (41% received concomitant coronary artery bypass graft) enrolled in a randomized trial of embolic protection devices underwent serial neurologic and delirium evaluations at postoperative days 1, 3, and 7 and magnetic resonance imaging at day 7. Outcomes included 90-day functional status, neurocognitive decline from presurgical baseline, and quality of life. RESULTS: By postoperative day 7, 25 (6.6%) patients experienced clinical stroke and 103 (28.5%) manifested delirium. During index hospitalization, time to discharge was longer in patients experiencing stroke (hazard ratio, 0.62; 95% confidence interval [CI], 0.42-0.94; P = .02) and patients experiencing delirium (hazard ratio, 0.68; 95% CI, 0.54-0.86; P = .001). At day 90, patients experiencing stroke were more likely to have a modified Rankin score >2 (odds ratio [OR], 5.9; 95% CI, 1.7-20.1; P = .01), depression (OR, 5.3; 95% CI, 1.6-17.3; P = .006), a lower 12-Item Short Form Survey physical health score (adjusted mean difference -3.3 ± 1.9; P = .08), and neurocognitive decline (OR, 7.8; 95% CI, 2.3-26.4; P = .001). Delirium was associated with depression (OR, 2.2; 95% CI, 0.9-5.3; P = .08), lower 12-Item Short Form Survey physical health (adjusted mean difference -2.3 ± 1.1; P = .03), and neurocognitive decline (OR, 2.2; 95% CI, 1.2-4.0; P = .01). CONCLUSIONS: Stroke and delirium occur more frequently after SAVR than is commonly recognized, and these events are associated with disability, depression, cognitive decline, and poorer quality of life at 90 days postoperatively. These findings support the need for new interventions to reduce these events and improve patient-centered outcomes.

Risk factors for surgical intervention in patients with primary spinal infection on initial presentation.

OBJECTIVE: Treatment of primary spinal infection includes medical management with or without surgical intervention. The objective of this study was to identify risk factors for the eventual need for surgery in patients with primary spinal infection on initial presentation. METHODS: From January 2010 to July 2019, 275 patients presented with primary spinal infection. Demographic, infectious, imaging, laboratory, treatment, and outcome data were retrospectively reviewed and collected. Thirty-three patients were excluded due to insufficient follow-up (≤ 90 days) or death prior to surgery. RESULTS: The mean age of the 242 patients was 58.8 ± 13.6 years. The majority of the patients were male (n = 130, 53.7%), White (n = 150, 62.0%), and never smokers (n = 132, 54.5%). Fifty-four patients (22.3%) were intravenous drug users. One hundred fifty-four patients (63.6%) ultimately required surgery while 88 (36.4%) never needed surgery during the duration of follow-up. There was no significant difference in age, gender, race, BMI, or comorbidities between the surgery and no-surgery groups. On univariate analysis, the presence of an epidural abscess (55.7% in the no-surgery group vs 82.5% in the surgery group, p < 0.0001), the median spinal levels involved (2 [interquartile range (IQR) 2-3] in the no-surgery group vs 3 [IQR 2-5] in the surgery group, p < 0.0001), and active bacteremia (20.5% in the no-surgery vs 35.1% in the surgery group, p = 0.02) were significantly different. The cultured organism and initial laboratory values (erythrocyte sedimentation rate, C-reactive protein, white blood cell count, creatinine, and albumin) were not significantly different between the groups. On multivariable analysis, the final model included epidural abscess, cervical or thoracic spine involvement, and number of involved levels. After adjusting for other variables, epidural abscess (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.64-5.63), cervical or thoracic spine involvement (OR 2.03, 95% CI 1.15-3.61), and increasing number of involved levels (OR 1.16, 95% CI 1.01-1.35) were associated with greater odds of surgery. Fifty-two surgical patients (33.8%) underwent decompression alone while 102 (66.2%) underwent decompression with fusion. Of those who underwent decompression alone, 2 (3.8%) of 52 required subsequent fusion due to kyphosis. No patient required hardware removal due to persistent infection. CONCLUSIONS: At time of initial presentation of primary spinal infection, the presence of epidural abscess, cervical or thoracic spine involvement, as well as an increasing number of involved spinal levels were potential risk factors for the eventual need for surgery in this study. Additional studies are needed to assess for risk factors for surgery and antibiotic treatment failure.

Concomitant Tricuspid Repair in Patients with Degenerative Mitral Regurgitation.

BACKGROUND: Tricuspid regurgitation is common in patients with severe degenerative mitral regurgitation. However, the evidence base is insufficient to inform a decision about whether to perform tricuspid-valve repair during mitral-valve surgery in patients who have moderate tricuspid regurgitation or less-than-moderate regurgitation with annular dilatation. METHODS: We randomly assigned 401 patients who were undergoing mitral-valve surgery for degenerative mitral regurgitation to receive a procedure with or without tricuspid annuloplasty (TA). The primary 2-year end point was a composite of reoperation for tricuspid regurgitation, progression of tricuspid regurgitation by two grades from baseline or the presence of severe tricuspid regurgitation, or death. RESULTS: Patients who underwent mitral-valve surgery plus TA had fewer primary-end-point events than those who underwent mitral-valve surgery alone (3.9% vs. 10.2%) (relative risk, 0.37; 95% confidence interval [CI], 0.16 to 0.86; P = 0.02). Two-year mortality was 3.2% in the surgery-plus-TA group and 4.5% in the surgery-alone group (relative risk, 0.69; 95% CI, 0.25 to 1.88). The 2-year prevalence of progression of tricuspid regurgitation was lower in the surgery-plus-TA group than in the surgery-alone group (0.6% vs. 6.1%; relative risk, 0.09; 95% CI, 0.01 to 0.69). The frequencies of major adverse cardiac and cerebrovascular events, functional status, and quality of life were similar in the two groups at 2 years, although the incidence of permanent pacemaker implantation was higher in the surgery-plus-TA group than in the surgery-alone group (14.1% vs. 2.5%; rate ratio, 5.75; 95% CI, 2.27 to 14.60). CONCLUSIONS: Among patients undergoing mitral-valve surgery, those who also received TA had a lower incidence of a primary-end-point event than those who underwent mitral-valve surgery alone at 2 years, a reduction that was driven by less frequent progression to severe tricuspid regurgitation. Tricuspid repair resulted in more frequent permanent pacemaker implantation. Whether reduced progression of tricuspid regurgitation results in long-term clinical benefit can be determined only with longer follow-up. (Funded by the National Heart, Lung, and Blood Institute and the German Center for Cardiovascular Research; ClinicalTrials.gov number, NCT02675244.).

Pacemaker implantation associated with tricuspid repair in the setting of mitral valve surgery: Insights from a Cardiothoracic Surgical Trials Network randomized trial.

OBJECTIVES: In a recent trial, tricuspid annuloplasty (TA) during mitral valve surgery (MVS) for degenerative mitral regurgitation and moderate or less tricuspid regurgitation (TR) reduced the composite rate of death, reoperation for TR, or TR progression at 2 years. However, this benefit was counterbalanced by an increase in implantation of permanent pacemakers (PPMs). In this study, we analyzed the timing, indications, and risk factors for these implantations. METHODS: We randomized 401 patients (MVS alone = 203; MVS + TA = 198). Potential risk factors for PPMs were assessed using multivariable time-to-event models with death and PPM implantation for heart failure indications as competing risks. RESULTS: A PPM was implanted in 36 patients (9.6; 95% CI, 6.8-13.0) within 2 years of randomization, with 30/187 (16.0%) in the MVS + TA and 6/188 (3.2%) in the MVS groups (rate ratio, 5.08; 95% CI, 2.16-11.94; P < .001). Most (29/36; 80.6%) implantations occurred within 30 days postoperatively. Independent risk factors for PPM implantation within 2 years were TA (hazard ratio [HR], 5.94; 95% CI, 2.27-15.53; P < .001), increasing age (5 years, HR, 1.23; 95% CI, 1.01-1.52; P = .04), and left ventricular ejection fraction (LVEF; HR, 0.96; 95% CI, 0.92-0.99; P = .02). In the subset of TA recipients (n = 197), age (5 years, HR, 1.05; 95% CI, 1.00-1.10; P = .04) and LVEF (HR, 0.95; 95% CI, 0.91-0.99; P = .01) were associated with PPM within 2 years. CONCLUSIONS: Concomitant TA, age, and baseline LVEF were risk factors for PPM implantation in patients who underwent MVS for degenerative mitral regurgitation. Although TA was effective in preventing progression of TR, innovation is needed to identify ways to decrease PPM implantation rates.

Accuracy of third trimester ultrasound in predicting neonatal birthweight in patients with inflammatory bowel disease.

OBJECTIVE: To evaluate the accuracy of third trimester ultrasound in predicting birthweight in patients with inflammatory bowel disease (IBD) using the gestation-adjusted projection (GAP) method. STUDY DESIGN: Retrospective cohort study including pregnant patients with IBD who had third trimester ultrasounds and delivered at a single institution from 2012 to 2017. Controls included pregnant patients without IBD seen during the study period with third trimester ultrasounds. Correlation plots of GAP birthweight and actual birthweight (AB) were created for IBD-positive cases, IBD-negative controls, and IBD-positive cases with and without prior abdominal surgery. GAP predicted birthweight error was calculated for cases and controls. Univariable linear regression models estimated the association between predicted birthweight and AB. Multivariable linear regression models estimated the association between GAP birthweight and AB adjusting for age, BMI, race, and IBD status. RESULTS: 320 patients were included (172 cases and 148 controls). Cases were more likely to be older (p < 0.001), white (p < 0.001), and have a lower BMI (p = 0.001). Correlation plots of GAP birthweight and AB showed linear correlations in cases (Spearman ρ = 0.81), controls (ρ = 0.74), cases with (p = 0.78) and without prior surgery (ρ = 0.83). GAP birthweight was significantly associated with AB in controls and cases in univariable linear regression models (ß = 0.85, standard error = 0.04, p < 0.001; ß = 0.90, standard error = 0.06, p < 0.001, respectively). No significant difference was found between the parameter estimates of the two models (p = 0.47). GAP birthweight remained significantly associated with AB in a multivariable linear regression model (ß = 0.86, standard error = 0.03, p < 0.001). There were no significant differences between GAP predicted birthweight error between controls and cases (APE 11% vs 10% respectively, p = 0.56) and between cases without and with prior surgery (APE 10% vs 11%, p = 0.7). CONCLUSION: The accuracy of fetal biometry in the third trimester for predicting actual birthweight was equivalent between patients with and without IBD and those with prior abdominal surgery.

Elective fetal reduction by radiofrequency ablation in monochorionic diamniotic twins decreases adverse outcomes compared to ongoing monochorionic diamniotic twins.

BACKGROUND: Multifetal pregnancy reduction is a technique used to reduce the fetal number to mitigate the risks of adverse outcomes associated with multiple gestations. Monochorionic diamniotic twin pregnancies are subject to unique complications, contributing to adverse pregnancy outcomes. Thus, patients have an option to electively reduce 1 fetus to improve outcomes. OBJECTIVE: This study aimed to compare outcomes of elective reduction of monochorionic diamniotic twins by radiofrequency ablation to planned ongoing monochorionic diamniotic twins. STUDY DESIGN: We performed a retrospective review of 315 monochorionic diamniotic twin gestations that underwent first-trimester ultrasound within 1 institution. Planned electively reduced twins were compared with ongoing monochorionic diamniotic twins. All reductions were performed via radiofrequency ablation of the cord insertion site into the fetal abdomen. The primary outcome was preterm birth at <36 weeks' gestation. Secondary outcomes included gestational age at delivery; preterm birth at less than 37-, 34-, 32-, and 28-weeks' gestation; unintended loss; and adverse perinatal outcomes. RESULTS: Among 315 monochorionic diamniotic pregnancies, 14 (4.4%) underwent elective multifetal pregnancy reduction, and 301 (95.6%) were planned ongoing twins. The mean gestational age of radiofrequency ablation in the elective multifetal pregnancy reduction group was 15.1±0.68 weeks. Patients who underwent elective multifetal pregnancy reduction had significantly higher maternal age (P<.01) and were more likely to be Asian (P<.01). Moreover, they were more likely to have undergone in vitro fertilization (P=.03) and chorionic villus sampling (P<.01). There was a significantly higher rate of term deliveries in the elective radiofrequency ablation group compared with ongoing twins (gestational age, 38 weeks [interquartile range, 36.1-39.1] vs 35.9 weeks [interquartile range, 34.0-36.9]; P<.01). Patients with ongoing pregnancies had a trend of increased rate of preterm birth at <36 weeks' gestation (odds ratio, 3.4; 95% confidence interval, 1.0-12.0; P=.06), a significantly increased risk of preterm birth at <37 weeks' gestation (odds ratio, 8.0; 95% confidence interval, 2.4-26.4; P<.01), and no difference at less than 34-, 32-, or 28- weeks' gestation. All patients who underwent elective radiofrequency ablation had successful pregnancies with no pregnancy losses or terminations. Of ongoing gestations, 36 required procedures, including 16 (5.3%) medically indicated radiofrequency ablation, 14 (4.6%) laser ablation, and 6 (1.9%) amnioreductions. Furthermore, 22 patients (7.3%) with planned ongoing twins had total pregnancy loss at <24 weeks' gestation. Notably, 12 patients (4.0%) had unintended loss of 1 fetus before 24 weeks' gestation in the ongoing pregnancy cohort, and 12 patients (4.0%) had unintended loss of both fetuses before 24 weeks' gestation. Moreover, 5 patients (1.7%) in the ongoing pregnancy group had intrauterine fetal demise at >24 weeks' gestation and 10 patients (3.3%) electively terminated both fetuses. There was no significant difference in loss rates between the 2 groups. CONCLUSION: In this study of monochorionic diamniotic twins, patients who elected to undergo multifetal pregnancy reduction had significantly lower rates of preterm birth at <37 weeks and a lower trend of preterm birth at <36 weeks' gestation without an increased risk of pregnancy loss. Median gestational age at delivery was significantly higher in the elective multifetal pregnancy reduction group (38 weeks) than in the ongoing pregnancy group (35.9 weeks). Further research is needed to clarify if multifetal pregnancy reduction improves long-term outcomes.

Progression of Tricuspid Regurgitation After Surgery for Ischemic Mitral Regurgitation.

BACKGROUND: Whether to repair nonsevere tricuspid regurgitation (TR) during surgery for ischemic mitral valve regurgitation (IMR) remains uncertain. OBJECTIVES: The goal of this study was to investigate the incidence, predictors, and clinical significance of TR progression and presence of ≥moderate TR after IMR surgery. METHODS: Patients (n = 492) with untreated nonsevere TR within 2 prospectively randomized IMR trials were included. Key outcomes were TR progression (either progression by ≥2 grades, surgery for TR, or severe TR at 2 years) and presence of ≥moderate TR at 2 years. RESULTS: Patients' mean age was 66 ± 10 years (67% male), and TR distribution was 60% ≤trace, 31% mild, and 9% moderate. Among 2-year survivors, TR progression occurred in 20 (6%) of 325 patients. Baseline tricuspid annular diameter (TAD) was not predictive of TR progression. At 2 years, 37 (11%) of 323 patients had ≥moderate TR. Baseline TR grade, indexed TAD, and surgical ablation for atrial fibrillation were independent predictors of ≥moderate TR. However, TAD alone had poor discrimination (area under the curve, ≤0.65). Presence of ≥moderate TR at 2 years was higher in patients with MR recurrence (20% vs. 9%; p = 0.02) and a permanent pacemaker/defibrillator (19% vs. 9%; p = 0.01). Clinical event rates (composite of ≥1 New York Heart Association functional class increase, heart failure hospitalization, mitral valve surgery, and stroke) were higher in patients with TR progression (55% vs. 23%; p = 0.003) and ≥moderate TR at 2 years (38% vs. 22%; p = 0.04). CONCLUSIONS: After IMR surgery, progression of unrepaired nonsevere TR is uncommon. Baseline TAD is not predictive of TR progression and is poorly discriminative of ≥moderate TR at 2 years. TR progression and presence of ≥moderate TR are associated with clinical events. (Comparing the Effectiveness of a Mitral Valve Repair Procedure in Combination With Coronary Artery Bypass Grafting [CABG] Versus CABG Alone in People With Moderate Ischemic Mitral Regurgitation, NCT00806988; Comparing the Effectiveness of Repairing Versus Replacing the Heart's Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation, NCT00807040).

Propranolol for Induction of Labor in Nulliparas trial a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Propranolol hydrochloride is a nonselective beta-adrenergic antagonist that has a known activity in the myometrium. Small trials have shown that propranolol decreases the duration of induced labor, although those studies are limited by methodological variability. OBJECTIVE: Our objective was to determine whether the addition of a single dose of propranolol to induce labor in nulliparous women would decrease total time to vaginal delivery. STUDY DESIGN: This study was a double-blind, randomized, placebo-controlled trial of nulliparous patients undergoing term induction of labor with a singleton, nonanomalous gestation. Subjects were randomized to 2 mg of intravenous propranolol hydrochloride or an identical-appearing saline placebo, administered 30 minutes after starting the induction of labor. Investigators, labor floor staff, and patients were blinded to the study drug allocation. The primary outcome was time to vaginal delivery. Secondary outcomes included mode of delivery, duration of the phases of labor, time to full dilation, composite maternal morbidity, and composite neonatal morbidity. Data were analyzed by intention-to-treat analysis with a P value of ≤.05 considered significant. RESULTS: In this study, 240 patients were enrolled from December 2017 to December 2018, with 121 patients randomized to the propranolol group and 119 to the placebo group. The 2 groups had similar baseline characteristics. Of the patients randomized, 154 (64.2%) delivered vaginally. There was no significant difference in time from the start of the induction of labor to vaginal delivery (13.8±5.4 hours for propranolol vs 14.3±5.3 hours for placebo; P=.58). There was also no difference in the rate of cesarean delivery (38% vs 33.6%; P=.48), time to active labor (11.0±5.0 vs 11.2±4.5 hours; P=.77), or time to full dilation (12.4±5.1 vs 12.8±5.2 hours; P=.60) in patients receiving propranolol compared with those receiving placebo. Subjects randomized to the propranolol group had a significantly lower rate of composite maternal morbidity (28.9% vs 41.2%; risk ratio, 0.70; 95% confidence interval, 0.49-1.00; P=.047). Rates of postpartum hemorrhage (12.4% vs 21.8%; P=.05) and transfusion (0% vs 4.2%; P=.03) were also lower in the treated group. There was no significant difference in neonatal outcomes or composite morbidity (risk ratio, 0.74; 95% confidence interval, 0.44-1.22). CONCLUSION: In this study, there is no evidence that the addition of a 1-time dose of propranolol to induce labor in nulliparous women decreases time to delivery or the rate of cesarean delivery. However, propranolol significantly reduced composite maternal morbidity without adverse neonatal effects.

What Is the Prevalence of Measles Immunity among Pregnant Women?

OBJECTIVE: This study aimed to estimate the prevalence of measles immunity in a cohort of pregnant women in New York City and determine if there is a positive correlation of measles immunity with patient demographics, rubella immunity, number of measles, mumps, and rubella vaccine (MMR) doses received, and age at last vaccination. STUDY DESIGN: This is a cross-sectional study of pregnant patients seen at a single institution from January 2019 to May 2019. Patients were classified as measles and rubella immune or nonimmune using commercial immunoglobulin G (IgG) tests. Patient characteristics were compared using t-tests, Chi-square tests, or Fisher's exact tests as appropriate. The association of age at last vaccination with immunity status was assessed using multivariable logistic regression adjusted for age at presentation. The utility of rubella IgG for distinguishing measles immunity was assessed using receiver operating characteristic curve analysis. RESULTS: Serologic immunity for measles and rubella was obtained for 1,366 patients. Of these, 1,047 (77%) were measles immune and 1,291 (95%) were rubella immune. Patients born after 1989 were less likely to be immune to measles, while multiparity and private insurance were associated with increased measles immunity. Documentation of MMR vaccination was available for 140 (10%) patients. Of these, 44 (31%) were serologically nonimmune to measles and 9 (6.4%) were nonimmune to rubella. In patients known to have received one dose of MMR, 62% (24/39) were immune to measles with an improvement to 72% (69/96) among those who received two or more doses. Age at last vaccination was not associated with measles immunity. Rubella IgG level was a poor predictor of positive measles titer (area under the curve = 0.59). CONCLUSION: Approximately one of every four pregnant patients is serologically measles nonimmune, even among women with documented MMR vaccination or documented rubella immunity. These findings raise concerns that relying on vaccination history or rubella immune status may not be sufficient to assure protection from infection with measles. If further suggests that measles serology should be added to routine prenatal laboratory testing to identify nonimmune patients that may benefit from postpartum vaccination. KEY POINTS: · Approximately one of every four pregnant patients were serologically measles nonimmune.. · Rubella immunoglobulin G was a poor predictor of measles immunity status.. · Measles serology should be added to routine prenatal laboratory testing..

Hepatocellular Carcinoma in Acute Hepatic Porphyrias: Results from the Longitudinal Study of the U.S. Porphyrias Consortium.

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.

Pregnant women with severe or critical coronavirus disease 2019 have increased composite morbidity compared with nonpregnant matched controls.

BACKGROUND: 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. OBJECTIVE: We aimed to describe the outcomes of severe and critical cases of coronavirus disease 2019 in pregnant vs nonpregnant, reproductive-aged women. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: National Institute of Neurological Disorders and Stroke for the randomisation phase and Vital Projects Fund for the follow-up phase.

Impact of Aortic Atherosclerosis Burden on Outcomes of Surgical Aortic Valve Replacement.

BACKGROUND: Epiaortic ultrasound detects and localizes ascending aortic atherosclerosis. In this analysis we investigated the association between epiaortic ultrasound-based atheroma grade during surgical aortic valve replacement (SAVR) and perioperative adverse outcomes. METHODS: SAVR patients in a randomized trial of 2 embolic protection devices underwent a protocol-defined 5-view epiaortic ultrasound read at a core laboratory. Aortic atherosclerosis was quantified with the Katz atheroma grade, and patients were categorized as mild (grade I-II) or moderate/severe (grade III-V). Multivariable logistic regression was used to estimate associations between atheroma grade and adverse outcomes, including death, clinically apparent stroke, cerebral infarction on diffusion-weighted magnetic resonance imaging, delirium, and acute kidney injury (AKI) by 7 and 30 days. RESULTS: Precannulation epiaortic ultrasound data were available for 326 of 383 randomized patients (85.1%). Of these, 106 (32.5%) had moderate/severe Katz atheroma grade at any segment of the ascending aorta. Although differences in the composite of death, stroke, or cerebral infarction on diffusion-weighted magnetic resonance imaging by 7 days were not statistically significant, moderate/severe atheroma grade was associated with a greater risk of AKI by 7 days (adjusted odds ratio, 2.63; 95% confidence interval, 1.24-5.58; P = .01). At 30 days, patients with moderate/severe atheroma grade had a greater risk of death, stroke, or AKI (adjusted odds ratio, 1.97; 95% confidence interval, 1.04-3.71; P = .04). CONCLUSIONS: Moderate/severe aortic atherosclerosis was associated with an increased risk of adverse events after SAVR. Epiaortic ultrasound may serve as a useful adjunct for identifying patients who may benefit from strategies to reduce atheroembolic complications during SAVR.