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1.  Hybrid Coronary Revascularization for the Treatment of Multivessel Coronary Artery Disease 
BACKGROUND
Hybrid coronary revascularization (HCR) combines minimally invasive surgical coronary artery bypass grafting of the left anterior descending artery with percutaneous coronary intervention (PCI) of non–left anterior descending vessels. HCR is increasingly used to treat multivessel coronary artery disease that includes stenoses in the proximal left anterior descending artery and at least 1 other vessel, but its effectiveness has not been rigorously evaluated.
OBJECTIVES
This National Institutes of Health–funded, multicenter, observational study was conducted to explore the characteristics and outcomes of patients undergoing clinically indicated HCR and multivessel PCI for hybrid-eligible coronary artery disease, to inform the design of a confirmatory comparative effectiveness trial.
METHODS
Over 18 months, 200 HCR and 98 multivessel PCI patients were enrolled at 11 sites. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE) (i.e., death, stroke, myocardial infarction, repeat revascularization) within 12 months post-intervention. Cox proportional hazards models were used to model time to first MACCE event. Propensity scores were used to balance the groups.
RESULTS
Mean age was 64.2 ± 11.5 years, 25.5% of patients were female, 38.6% were diabetic, and 4.7% had previous stroke. Thirty-eight percent had 3-vessel coronary artery disease, and the mean SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score was 19.7 ± 9.6. Adjusted for baseline risk, MACCE rates were similar between groups within 12 months post-intervention (hazard ratio [HR]: 1.063; p = 0.80) and during a median 17.6 months of follow-up (HR: 0.868; p = 0.53).
CONCLUSIONS
These observational data from this first multicenter study of HCR suggest that there is no significant difference in MACCE rates over 12 months between patients treated with multivessel PCI or HCR, an emerging modality. A randomized trial with long-term outcomes is needed to definitively compare the effectiveness of these 2 revascularization strategies. (Hybrid Revascularization Observational Study; NCT01121263)
doi:10.1016/j.jacc.2016.05.032
PMCID: PMC5142519  PMID: 27443431
coronary artery bypass; coronary vessels; drug-eluting stents; follow-up studies; percutaneous coronary intervention
2.  Low Adherence of HIV Providers to Practice Guidelines for Hepatocellular Carcinoma Screening in HIV/Hepatitis B Coinfection 
This study compared human immunodeficiency virus (HIV) provider and hepatologist awareness of and adherence to the American Association for the Study of Liver Diseases guidelines for chronic hepatitis B virus management, specifically hepatocellular carcinoma (HCC) screening. HIV providers ordered significantly fewer HCC screenings than hepatologists.
Background. In the era of combination therapy for human immunodeficiency virus (HIV), liver disease, and hepatocellular carcinoma (HCC) are major causes of death for patients coinfected with HIV and hepatitis B virus (HBV). This study compared HIV provider and hepatologist awareness of and adherence to the American Association for the Study of Liver Diseases (AASLD) practice guidelines for chronic HBV management. The primary endpoint of HIV provider adherence to HCC screening recommendations was compared to that of hepatologists at a large metropolitan academic medical center.
Methods. Medical record database searches by ICD-9 codes were used to identify HIV/HBV coinfected (n = 144) and HBV monoinfected (n = 225) patients who were seen at least twice over a 2-year period in outpatient clinics. Adherence to AASLD guidelines was assessed by chart review. Provider awareness was evaluated through a voluntary anonymous survey with knowledge-based questions.
Results. Over a 2-year period, only 36.0% of HIV/HBV coinfected patients seen in HIV practices completed HCC screening compared to 81.8% of HBV monoinfected patients in hepatology practices (P < .00001). Similarly, HIV providers less frequently monitored HBV viral load (P < .0001), HBeAg/anti-HBe (P < .00001), HBsAg/anti-HBs (P < .00001) than hepatologists but screened more often for hepatitis A immunity (P = .028). Self-reported adherence and knowledge scores were similar among 19 HIV providers and 16 hepatologists.
Conclusions. HIV providers ordered significantly fewer HCC screening and HBV monitoring tests than hepatologists within a single academic medical center. In the setting of increased reliance on quality indicators for care, both patients and providers will benefit from greater adherence to established guidelines.
doi:10.1093/cid/civ654
PMCID: PMC4809983  PMID: 26240206
hepatitis B virus; HIV/HBV coinfection; management guidelines; hepatocellular carcinoma
3.  Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial 
Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (AMCI) with the goal of collecting preliminary data on feasiblity, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with AMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective Reminding Test (SRT) and the score of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake (rCMRgl) in the posterior cingulate-precuneus in brain Fluorodeoxyglucose Positron Emission Tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty % of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7 ± 8.5 vs. 5.3 ± 8.5; p = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD.
doi:10.3233/JAD-150493
PMCID: PMC5079271  PMID: 26890736
Metformin; insulin; amnestic mild cognitive impairment; memory; ra
4.  Regression of Recurrent Malignant Gliomas With Convection-Enhanced Delivery of Topotecan 
Neurosurgery  2011;69(6):1272-1280.
BACKGROUND
Convection-enhanced delivery of chemotherapeutics for the treatment of malignant glioma is a technique that delivers drugs directly into a tumor and the surrounding interstitium through continuous, low-grade positive-pressure infusion. This allows high local concentrations of drug while overcoming the limitations imposed by toxicity and the blood-brain barrier in systemic therapies that prevent the use of many potentially effective drugs.
OBJECTIVE
To examine the safety profile of a conventional chemotherapeutic agent, topotecan, via convection-enhanced delivery in the treatment of recurrent malignant gliomas and secondarily to assess radiographic response and survival.
METHODS
We performed a prospective, dose-escalation phase Ib study of the topoisomerase-I inhibitor topotecan given by convection-enhanced delivery in patients with recurrent malignant gliomas.
RESULTS
Significant antitumor activity as described by radiographic changes and prolonged overall survival with minimal drug-associated toxicity was demonstrated. A maximum tolerated dose was established for future phase II studies.
CONCLUSION
Topotecan by convection-enhanced delivery has significant antitumor activity at concentrations that are nontoxic to normal brain. The potential for use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent phase II and III trials.
doi:10.1227/NEU.0b013e3182233e24
PMCID: PMC4940854  PMID: 21562434
Clinical trial; Glioblastoma; Glioma; Topotecan
5.  Effect of Functional Status on the Quality of Bowel Preparation in Elderly Patients Undergoing Screening and Surveillance Colonoscopy 
Gut and Liver  2016;10(4):569-573.
Background/Aims
Optimal bowel preparation is essential for successful screening or for surveillance colonoscopy (SC). Inadequate bowel preparation is associated with older age, the male gender, and the presence of certain comorbidities. However, the association between patients’ functional status and bowel preparation quality has not been studied. We prospectively examined the relationship between functional status, namely, the ability to perform activities of daily living (ADLs) and ambulate, and the quality of bowel preparation in elderly patients undergoing SC.
Methods
Before undergoing SC, 88 elderly patients were surveyed regarding their functional status, specifically regarding their ability to perform ADLs and ambulate a quarter of a mile. Gastroenterologists then determined the quality of the bowel preparation, which was classified as either adequate or inadequate. Then, the frequency of inadequate bowel preparation in patients who did or did not experience difficulty performing ADLs and ambulating was calculated.
Results
Difficulty ambulating (unadjusted odds ratio [OR], 4.83; p<0.001), difficulty performing ADLs (OR, 2.93; p=0.001), and history of diabetes (OR, 2.88; p=0.007) were significant univariate predictors of inadequate bowel preparation. After adjusting for the above variables, only difficulty ambulating (adjusted OR, 5.78; p=0.004) was an independent predictor of inadequate bowel preparation.
Conclusions
Difficulty with ambulation is a strong predictor of inadequate bowel preparation in elderly patients undergoing SC.
doi:10.5009/gnl15230
PMCID: PMC4933417  PMID: 27021501
Colonoscopy; Bowel preparation; Geriatric; Practice improvement
6.  Time to prerandomization monthly seizure count in perampanel trials 
Neurology  2015;84(20):2014-2020.
Objective:
To determine whether a novel endpoint of time to prerandomization monthly seizure count could be used to differentiate efficacious and nonefficacious therapies in clinical trials of new add-on antiepileptic drugs (AEDs).
Methods:
This analysis used data from 3 randomized, double-blind, placebo-controlled phase III trials of perampanel as an add-on therapy in patients with epilepsy who were experiencing refractory partial seizures: studies 304 (ClinicalTrials.gov identifier NCT00699972), 305 (NCT00699582), and 306 (NCT00700310). Time to prerandomization monthly seizure count was evaluated post hoc for each trial, and findings were compared with the original primary outcomes (median percent change in seizure frequency and 50% responder rate). Outcomes were assessed for all partial-onset seizures, secondarily generalized (SG) tonic-clonic seizures only, and complex partial plus SG (CP + SG) seizures.
Results:
Perampanel 4–12 mg significantly prolonged median time to prerandomization monthly seizure count, generally by more than 1 week, compared with placebo, across all 3 studies, consistent with the original primary outcomes. Analysis of SG seizures only, and CP + SG seizures, also indicated a significantly prolonged median time to prerandomization monthly seizure count with perampanel 8 mg and 12 mg compared with placebo.
Conclusions:
Time to prerandomization monthly seizure count is a promising novel alternative to the standard endpoints of median percent change in seizure frequency and 50% responder rates used in trials of add-on AEDs. Use of this endpoint could reduce exposure to placebo or ineffective treatments, thereby facilitating trial recruitment and improving safety.
doi:10.1212/WNL.0000000000001585
PMCID: PMC4442101  PMID: 25878175
7.  Interleukin-6 and Tumor Necrosis Factor-α Are Associated with Quality of Life–Related Symptoms in Pulmonary Arterial Hypertension 
Rationale: Inflammation is associated with symptoms in many chronic illnesses; however, this link has not been established in pulmonary arterial hypertension.
Objectives: The objective of this study was to investigate the association between inflammatory markers and quality of life–related symptoms in patients with pulmonary arterial hypertension. We hypothesized that higher circulating IL-6 and tumor necrosis factor-α levels would be associated with worse quality of life–related symptoms.
Methods: We performed a secondary analysis using baseline and 3-month assessments of 62 subjects in a clinical trial of aspirin and simvastatin to determine the association between plasma IL-6 and tumor necrosis factor-α levels and the Medical Outcomes Study Short Form-36 subscales (pain, vitality, mental health).
Measurements and Main Results: The mean age was 49.7 ± 13.4 years; 87% were female. Higher IL-6 levels were significantly associated with lower Medical Outcomes Study Short Form-36 subscale scores, indicating worse bodily pain, vitality, and mental health (all P < 0.01). Higher tumor necrosis factor-α levels were significantly associated with increased bodily pain, but better mental health scores.
Conclusions: IL-6 and tumor necrosis factor-α levels are associated with certain quality of life domains in patients with pulmonary arterial hypertension.
Clinical trial registered with www.clinicaltrials.gov (NCT00384865).
doi:10.1513/AnnalsATS.201410-463OC
PMCID: PMC4418312  PMID: 25615959
pulmonary arterial hypertension; interleukin-6; tumor necrosis factor-α; fatigue; pain
8.  Associated with Health Care-Associated Infections in Cardiac Surgery 
BACKGROUND
Health care-associated infections (HAIs) are the most common noncardiac complications after cardiac surgery and are associated with increased morbidity and mortality. Current information about their economic burden is limited.
OBJECTIVES
To determine the cost associated with major types of HAIs during the first 2 months after cardiac surgery.
METHODS
Prospectively collected data from a multicenter observational study of the Cardiothoracic Surgery Clinical Trials Network, in which patients were monitored for infections for 65 days after surgery, were merged with related financial data, routinely collected by the University HealthSystem Consortium. Incremental length of stay (LOS) and cost associated with HAIs were estimated using generalized linear models, adjusting for patient demographics, clinical history, baseline laboratory values, and surgery type.
RESULTS
Among 4,320 cardiac surgery patients, mean age of 64 ± 13 years, 119 (2.8%) experienced a major HAI during the index hospitalization. The most common HAIs were pneumonia (48%), sepsis (20%) and C. Difficile colitis (18%). On average, the estimated incremental cost associated with a major HAI was nearly $38,000, of which 47% was related to intensive care unit services. The incremental LOS was 14 days. Overall, there were 849 readmissions, among these, 8.7% were attributed to major HAIs. The cost of readmissions due to major HAI was on average nearly three times as much as readmissions not related to HAI.
CONCLUSIONS
Hospital cost, length of stay, and readmissions are strongly associated with HAIs. These associations suggest the potential for large reductions in costs if HAIs following cardiac surgery can be reduced.
doi:10.1016/j.jacc.2014.09.079
PMCID: PMC4293042  PMID: 25572505
9.  Surgical Ablation of Atrial Fibrillation during Mitral-Valve Surgery 
The New England journal of medicine  2015;372(15):1399-1409.
Background
Among patients undergoing mitral-valve surgery, 30 to 50% present with atrial fibrillation, which is associated with reduced survival and increased risk of stroke. Surgical ablation of atrial fibrillation has been widely adopted, but evidence regarding its safety and effectiveness is limited.
Methods
We randomly assigned 260 patients with persistent or long-standing persistent atrial fibrillation who required mitral-valve surgery to undergo either surgical ablation (ablation group) or no ablation (control group) during the mitral-valve operation. Patients in the ablation group underwent further randomization to pulmonary-vein isolation or a biatrial maze procedure. All patients underwent closure of the left atrial appendage. The primary end point was freedom from atrial fibrillation at both 6 months and 12 months (as assessed by means of 3-day Holter monitoring).
Results
More patients in the ablation group than in the control group were free from atrial fibrillation at both 6 and 12 months (63.2% vs. 29.4%, P<0.001). There was no significant difference in the rate of freedom from atrial fibrillation between patients who underwent pulmonary-vein isolation and those who underwent the biatrial maze procedure (61.0% and 66.0%, respectively; P = 0.60). One-year mortality was 6.8% in the ablation group and 8.7% in the control group (hazard ratio with ablation, 0.76; 95% confidence interval, 0.32 to 1.84; P = 0.55). Ablation was associated with more implantations of a permanent pacemaker than was no ablation (21.5 vs. 8.1 per 100 patient-years, P = 0.01). There were no significant between-group differences in major cardiac or cerebrovascular adverse events, overall serious adverse events, or hospital readmissions.
Conclusions
The addition of atrial fibrillation ablation to mitral-valve surgery significantly increased the rate of freedom from atrial fibrillation at 1 year among patients with persistent or long-standing persistent atrial fibrillation, but the risk of implantation of a permanent pacemaker was also increased. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00903370.)
doi:10.1056/NEJMoa1500528
PMCID: PMC4664179  PMID: 25853744
10.  Pulmonary Radiologic Findings in CVID: Clinical and Immunological Correlations 
doi:10.1016/j.anai.2014.04.024
PMCID: PMC4177442  PMID: 24880814
Bronchiectasis; Common variable immunodeficiency; Interstitial lung disease; Lymphoid hyperplasia; Pulmonary nodules
11.  Readmissions After Cardiac Surgery: Experience of the NIH / CIHR Cardiothoracic Surgical Trials Network 
The Annals of thoracic surgery  2014;98(4):1274-1280.
Background
Readmissions are a common problem in cardiac surgery. The goal of this study was to examine the frequency, timing, and associated risk factors for readmission after cardiac surgery.
Methods
5,158 adult cardiac surgery patients (5,059 included in analysis) were prospectively enrolled in a 10center cohort study to assess risk factors for infection following cardiac surgery. Data were also collected on all-cause readmissions occurring within 65 days after surgery. Major outcomes included readmission rate stratified by procedure type, cause of readmission, length of readmission stay, and discharge disposition after readmission. Multivariable Cox regression was used to determine risk factors for time to first readmission.
Results
The overall rate of readmission was 18.7% (number of readmissions=945). When stratified by the most common procedure type, readmission rates were: isolated CABG (14.9%, n=248), isolated valve (18.3%, n=337), CABG + valve (25.0%, n=169). The three most common causes of first readmission within 30 days were: infection (17.1%, n=115), arrhythmia (17.1%, n=115), and volume overload (13.5%, n=91). More first readmissions occurred within 30 days (80.6%, n=672) than after 30 days (19.4%, n=162), and 50% of patients were readmitted within 22 days from index surgery. The median length of stay during the first readmission was 5 days. 15.8% (n=128) of readmitted patients were discharged to a location other than home. Baseline patient characteristics associated with readmission included: female gender, diabetes mellitus on medication, COPD, elevated creatinine, lower hemoglobin, and longer surgery time. In addition, the more complex surgical procedures were associated with increased risk of readmission compared to the CABG group.
Conclusions
Nearly 1 out of 5 patients who undergo cardiac surgery require readmission, an outcome with significant health and economic implications. Management practices to avert in-hospital infections, reduce post-operative arrhythmias, and avoid volume overload offer important targets for quality improvement.
doi:10.1016/j.athoracsur.2014.06.059
PMCID: PMC4186890  PMID: 25173721
Hospital readmissions; length of stay; cardiac
12.  MANAGEMENT PRACTICES AND MAJOR INFECTIONS AFTER CARDIAC SURGERY 
Background
Infections are the most common non-cardiac complication after cardiac surgery, but their incidence across a broad range of operations, as well as the management factors that shape infection risk, remain unknown.
Objectives
This study prospectively examines the frequency of postoperative infections and associated mortality, and modifiable management practices predictive of infections within 65 days from cardiac surgery.
Methods
This study enrolled 5,158 patients and analyzed independently adjudicated infections using a competing risk model (with death as the competing event).
Results
Nearly 5% of patients experienced major infections. Baseline characteristics associated with increased infection risk included chronic lung disease (hazard ratio [HR] 1.66; CI 1.21–2.26), heart failure (HR 1.47; CI 1.11–1.95), and longer surgery (HR 1.31; CI 1.21–1.41). Practices associated with reduced infection risk included prophylaxis with second-generation cephalosporins (HR 0.70; CI 0.52–0.94), whereas postoperative antibiotic duration >48 hours (HR 1.92; CI 1.28–2.88), stress hyperglycemia (HR 1.32; CI 1.01–1.73); intubation time of 24–48 hours (HR 1.49; CI 1.04–2.14); and ventilation >48 hours (HR 2.45; CI 1.66–3.63) were associated with increased risk. HRs for infection were similar with either <24 hours or <48 hours of antibiotic prophylaxis. There was a significant but differential effect of transfusion by surgery type (excluding left ventricular assist device procedures/transplant) (HR 1.13; CI 1.07–1.20). Major infections substantially increased mortality (HR 10.02; CI 6.12, 16.39).
Conclusions
Major infections dramatically affect survival and readmissions. Second-generation cephalosporins were strongly associated with reduced major infection risk, but optimal duration of antibiotic prophylaxis requires further study. Given practice variations, considerable opportunities exist for improving outcomes and preventing readmissions.
doi:10.1016/j.jacc.2014.04.052
PMCID: PMC4222509  PMID: 25060372
Cardiac Surgery; Infection; Risk factors
13.  Mesenchymal Precursor Cells as Adjunctive Therapy in Recipients of Contemporary LVADs 
Circulation  2014;129(22):2287-2296.
Background
Allogeneic mesenchymal precursor cells (MPC) injected during left ventricular assist device (LVAD) implantation may contribute to myocardial recovery. This trial explores the safety and efficacy of this strategy.
Methods and Results
In this multi-center, double-blind, sham-procedure controlled trial, 30 patients were randomized (2:1) to intramyocardial injection of 25M MPCs or medium during LVAD implantation. The primary safety endpoint was incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization (90 days post-randomization). Key efficacy endpoints were functional status and ventricular function, while temporarily weaned from LVAD support (90 days post-randomization). Patients were followed until transplant or 12 months post-randomization, whichever came first. Mean age was 57.4 (±13.6) years, mean LVEF 18.1%, and 66.7% were destination therapy LVADs. No safety events were observed. Successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days (p=0.24); the posterior probability that MPCs increased the likelihood of successful weaning is 93%. At 90 days, 3 deaths occurred in control and none in MPC patients. Mean LVEF following successful wean was 24.0% (MPC=10) and 22.5% (Control=2) (p=0.56). At 12 months, 30% of MPC and 40% of control patients were successfully temporarily weaned from LVAD support (p=0.69) and 6 deaths occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months.
Conclusions
In this preliminary trial, administration of MPCs appeared to be safe and there was a potential signal of efficacy. Future studies will evaluate the potential for higher or additional doses to enhance the ability to wean LVAD recipients off support.
Clinical Trial Registration Information
ClinicalTrials.gov. Identifier: NCT01442129.
doi:10.1161/CIRCULATIONAHA.113.007412
PMCID: PMC4243683  PMID: 24682346
Left Ventricular Assist Device; Heart Failure; Mesenchymal precursor cell; Stem cells; Placebo; Randomized controlled trial
14.  Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis 
Fibrosis underlies the loss of renal function in patients with chronic kidney disease (CKD) and in kidney transplant recipients with chronic allograft nephropathy (CAN). Here, we studied the effect of an intronic SNP in SHROOM3, which has previously been linked to CKD, on the development of CAN in a prospective cohort of renal allograft recipients. The presence of the rs17319721 allele at the SHROOM3 locus in the donor correlated with increased SHROOM3 expression in the allograft. In vitro, we determined that the sequence containing the risk allele at rs17319721 is a transcription factor 7–like 2–dependent (TCF7L2-dependent) enhancer element that functions to increase SHROOM3 transcription. In renal tubular cells, TGF-β1 administration upregulated SHROOM3 expression in a β-catenin/TCF7L2–mediated manner, while SHROOM3 in turn facilitated canonical TGF-β1 signaling and increased α1 collagen (COL1A1) expression. Inducible and tubular cell–specific knockdown of Shroom3 markedly abrogated interstitial fibrosis in mice with unilateral ureteric obstruction. Moreover, SHROOM3 expression in allografts at 3 months after transplant and the presence of the SHROOM3 risk allele in the donor correlated with increased allograft fibrosis and with reduced estimated glomerular filtration rate at 12 months after transplant. Our findings suggest that rs17319721 functions as a cis-acting expression quantitative trait locus of SHROOM3 that facilitates TGF-β1 signaling and contributes to allograft injury.
doi:10.1172/JCI76902
PMCID: PMC4382250  PMID: 25437874
15.  Early Trajectory of Psychiatric Symptoms after Traumatic Brain Injury: Relationship to Patient and Injury Characteristics 
Journal of Neurotrauma  2014;31(7):610-617.
Abstract
Psychiatric disturbance is common and disabling after traumatic brain injury (TBI). Few studies have investigated the trajectory of psychiatric symptoms in the first 6 months postinjury, when monitoring and early treatment might prevent persistent difficulties. The aim of this study was to examine the trajectory of psychiatric symptoms 1–6 months post-TBI, the patient/injury characteristics associated with changes, and characteristics predictive of persisting symptoms. A secondary analysis was performed on data from a clinical trial with three data collection points. Across eight centers, 872 participants with complicated mild to severe TBI were administered the Brief Symptom Inventory (BSI) at 30, 90, and 180 days postinjury. Mixed-effects models were used to assess longitudinal changes in the BSI Global Severity Index (GSI). Multi-variate logistic regression was used to assess predictors of clinically significant GSI elevations persisting to 6 months post-TBI. In general, GSI scores improved over time. Women improved faster than men; race/ethnicity was also significantly associated with rate of change, with Hispanics showing the most and African Americans the least improvement. Clinically significant psychiatric symptoms (caseness) occurred in 42% of the sample at 6 months, and more than one type of symptom was common. Significant predictors of caseness included African American race, age from 30 to 60 years, longer post-traumatic amnesia (PTA) duration, pre-TBI unemployment, and pre-TBI risky alcohol use. Findings indicate that psychiatric symptoms are common in the first 6 months post-TBI and frequently extend beyond the depression and anxiety symptoms that may be most commonly screened. Patients with longer PTA and preinjury alcohol misuse may need more intensive monitoring for symptom persistence.
doi:10.1089/neu.2013.3041
PMCID: PMC3961785  PMID: 24237113
longitudinal studies; neurobehavioral signs and symptoms; psychological outcome; traumatic brain injury
16.  Effects of Marketed Antiepileptic Drugs and Placebo in the Human Photosensitivity Screening Protocol 
Neurotherapeutics  2013;11(2):412-418.
A study of epilepsy patients with a reproducible range of photoparoxysmal responses (PPR) (epileptiform discharges evoked by flashing lights) has been used as a “proof-of-concept” trial to determine if novel potential antiepileptic drugs (AEDs) should proceed in development. The standard design for this trial requires a 3-day inpatient stay and is single-blind. We evaluated two marketed and effective AEDs—one narrow-spectrum [carbamazepine (CBZ)], and one broad-spectrum [levetiracetam (LEV)]—using a novel double-blinded, cross-over outpatient version of the trial to detect acute drug effects of the two marketed AEDs on photosensitivity. We tested 6 patients with a known stable photosensitivity response, using single oral doses of CBZ 400 mg and LEV 1000 mg, compared to 2 test days with single placebo doses. Patients who received LEV had the lowest mean PPR (compared with placebo and CBZ). The mixed effect model showed a significant effect of LEV in all eye closure conditions (p < 0.001). There was no evidence of a significant change in PPR after CBZ or placebo treatment. In conclusion, LEV 1000 mg, but not CBZ 400 mg, was effective in suppressing photosensitivity within a 6-h period compared with placebo showing the ability of our novel photosensitivity trial design to demonstrate effects of broad-spectrum AEDs. We cannot confirm the ability of the photosensitivity trial to detect the narrow-spectrum AED CBZ in our design. The novel outpatient study design is feasible and is expected to reduce costs compared with previous methodology.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-013-0243-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s13311-013-0243-0
PMCID: PMC3996112  PMID: 24346821
Photosensitive epilepsy; clinical trial; antiepileptic drug; carbamazepine; levetiracetam
17.  Hippocampal Sclerosis After Febrile Status Epilepticus: The FEBSTAT Study 
Annals of neurology  2014;75(2):178-185.
Objective
Whether febrile status epilepticus (FSE) produces hippocampal sclerosis (HS) and temporal lobe epilepsy (TLE) has long been debated. Our objective is to determine if FSE produces acute hippocampal injury that evolves to HS.
Methods
FEBSTAT and two affiliated studies prospectively recruited 226 children aged 1 month to 6 years with FSE and controls with simple febrile seizures. All had acute MRIs and follow-up MRIs were obtained at approximately 1 year later in the majority. Visual interpretation by two neuroradiologists informed only of subject age was augmented by hippocampal volumetrics, analysis of the intra-hippocampal distribution of T2 signal, and apparent diffusion coefficients.
Results
Hippocampal T2 hyperintensity, maximum in Sommer's sector, occurred acutely after FSE in 22 of 226 children in association with increased volume. Follow-up MRIs obtained on 14 of the 22 with acute T2 hyperintensity showed HS in 10 and reduced hippocampal volume in 12. In contrast, follow-up of 116 children without acute hyperintensity showed abnormal T2 signal in only 1 (following another episode of FSE). Furthermore, compared to controls with simple febrile seizures, FSE subjects with normal acute MRIs had abnormally low right to left hippocampal volume ratios, smaller hippocampi initially and reduced hippocampal growth.
Interpretation
Hippocampal T2 hyperintensity after FSE represents acute injury often evolving to a radiological appearance of HS after one year. Furthermore, impaired growth of normal appearing hippocampi after FSE suggests subtle injury even in the absence of T2 hyperintensity. Longer follow-up is needed to determine the relationship of these findings to TLE.
doi:10.1002/ana.24081
PMCID: PMC3980500  PMID: 24318290
18.  Relationship of CRP, IL-6, and Fibrinogen with Right Ventricular Structure and Function: The MESA-Right Ventricle Study 
International journal of cardiology  2013;168(4):3818-3824.
Background/objectives
Inflammation contributes to the pathogenesis of disease associated with the left ventricle (LV); yet, our understanding of the effect of inflammation on the right ventricle (RV) is quite limited.
Methods and results
The relationships of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with RV morphology and function (from cardiac MRI) were examined in participants free of clinical cardiovascular disease (n=4,009) from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of CRP, IL-6 and fibrinogen with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF). Unadjusted and adjusted analyses revealed strong inverse associations between both CRP and IL-6 with RV mass, RVEDV, RVESV and RVSV (all p<0.01); there were no associations with RVEF. These relationships remained significant after adjustment for the respective LV parameters and lung function. However, GAM models suggested that extreme values of CRP and IL-6 might have positive associations with RV parameters. Fibrinogen showed significant associations in unadjusted models, but no associations after adjustment or in sensitivity analyses.
Conclusion
Levels of CRP and IL-6 are independently associated with RV morphology even after adjustment for the respective LV measure in this multi-ethnic population free of cardiovascular disease. Systemic inflammation may contribute to RV structural changes independent of effects on the LV.
doi:10.1016/j.ijcard.2013.06.028
PMCID: PMC3805818  PMID: 23932860
Systemic inflammation; right ventricle; heart failure; Multi-Ethnic Study of Atherosclerosis
19.  Mitral-Valve Repair versus Replacement for Severe Ischemic Mitral Regurgitation 
Background
Ischemic mitral regurgitation is associated with a substantial risk of death. Practice guidelines recommend surgery for patients with a severe form of this condition but acknowledge that the supporting evidence for repair or replacement is limited.
Methods
We randomly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral-valve repair or chordal-sparing replacement in order to evaluate efficacy and safety. The primary end point was the left ventricular end-systolic volume index (LVESVI) at 12 months, as assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized below the lowest LVESVI rank.
Results
At 12 months, the mean LVESVI among surviving patients was 54.6±25.0 ml per square meter of body-surface area in the repair group and 60.7±31.5 ml per square meter in the replacement group (mean change from baseline, −6.6 and −6.8 ml per square meter, respectively). The rate of death was 14.3% in the repair group and 17.6% in the replacement group (hazard ratio with repair, 0.79; 95% confidence interval, 0.42 to 1.47; P = 0.45 by the log-rank test). There was no significant between-group difference in LVESVI after adjustment for death (z score, 1.33; P = 0.18). The rate of moderate or severe recurrence of mitral regurgitation at 12 months was higher in the repair group than in the replacement group (32.6% vs. 2.3%, P<0.001). There were no significant between-group differences in the rate of a composite of major adverse cardiac or cerebrovascular events, in functional status, or in quality of life at 12 months.
Conclusions
We observed no significant difference in left ventricular reverse remodeling or survival at 12 months between patients who underwent mitral-valve repair and those who underwent mitral-valve replacement. Replacement provided a more durable correction of mitral regurgitation, but there was no significant between-group difference in clinical outcomes. (Funded by the National Institutes of Health and the Canadian Institutes of Health; ClinicalTrials.gov number, NCT00807040.)
doi:10.1056/NEJMoa1312808
PMCID: PMC4128011  PMID: 24245543
20.  Blood Transfusion and Infection After Cardiac Surgery 
The Annals of thoracic surgery  2013;95(6):2194-2201.
Cardiac surgery is the largest consumer of blood products in medicine; although believed life saving, transfusion carries substantial adverse risks. This study characterizes the relationship between transfusion and risk of major infection after cardiac surgery.
5,158 adults were prospectively enrolled to assess infections after cardiac surgery. The most common procedures were isolated coronary artery bypass grafting (31%) and isolated valve surgery (30%); 19% were reoperations. Infections were adjudicated by independent infectious disease experts. Multivariable Cox modeling was used to assess the independent effect of blood and platelet transfusions on major infections within 60±5 days of surgery.
Red blood cells (RBCs) and platelets were transfused in 48% and 31% of patients, respectively. Each RBC unit transfused was associated with a 29% increase in crude risk of major infection (P<0.001). Among RBC recipients, the most common infections were pneumonia (3.6%) and bloodstream infections (2%). Risk factors for infection included postoperative RBC units transfused, longer duration of surgery, and transplant or ventricular assist device implantation, in addition to chronic obstructive pulmonary disease, heart failure, and elevated preoperative creatinine. Platelet transfusion decreased the risk of infection (P=.02).
Greater attention to management practices that limit RBC use, including cell salvage, small priming volumes, vacuum-assisted venous return with rapid autologous priming, and ultrafiltration, and pre- and intraoperative measures to elevate hematocrit could potentially reduce occurrence of major postoperative infections.
doi:10.1016/j.athoracsur.2012.11.078
PMCID: PMC3992887  PMID: 23647857
Bleeding; reoperation; surgery; complications; cardiopulmonary bypass; CPB; CPB; cell saver; wound infection
21.  Risk Factors for Febrile Status Epilepticus: A Case-Control Study 
The Journal of pediatrics  2013;163(4):1147-51.e1.
Objective
To identify risk factors for developing a first febrile status epilepticus (FSE) among children with a first febrile seizure (FS).
Study design
Cases were children with a first FS that was FSE drawn from the Consequences of Prolonged Febrile Seizures in Childhood and Columbia cohorts. Controls were children with a first simple FS and separately, children with a first complex FS that was not FSE. Identical questionnaires were administered to family members of the 3 cohorts. Magnetic resonance imaging protocol and readings were consistent across cohorts, and seizure phenomenology was assessed by the same physicians. Risk factors were analyzed using logistic regression.
Results
Compared with children with simple FS, FSE was associated with younger age, lower temperature, longer duration (1-24 hours) of recognized temperature before FS, female sex, structural temporal lobe abnormalities, and first-degree family history of FS. Compared with children with other complex FS, FSE was associated with low temperature and longer duration (1-24 hours) of temperature recognition before FS. Risk factors for complex FS that was not FSE were similar in magnitude to those for FSE but only younger age was significant.
Conclusions
Among children with a first FS, FSE appears to be due to a combination of lower seizure threshold (younger age and lower temperatures) and impaired regulation of seizure duration. Clinicians evaluating FS should be aware of these factors as many episodes of FSE go unnoticed. Further work is needed to develop strategies to prevent FSE.
doi:10.1016/j.jpeds.2013.05.038
PMCID: PMC3989363  PMID: 23809042
22.  Postoperative Radiotherapy for Elderly Patients with Stage III Lung Cancer 
Cancer  2012;118(18):4478-4485.
Background
The potential role of postoperative radiation therapy (PORT) for patients with completely resected stage III non-small-cell lung cancer (NSCLC) with N2 disease remains controversial. Using population-based data, we compared survival of a concurrent cohort of elderly patients with N2 disease treated with and without PORT.
Methods
Using the Surveillance, Epidemiology and End Results (SEER) registry linked to Medicare records we identified 1,307 cases of stage III NSCLC with N2 lymph node involvement diagnosed between 1992 and 2005. We used propensity score methods and instrumental variable analysis to compare survival of patients treated with and without PORT after controlling for selection bias.
Results
Overall, 710 (54%) patients received PORT. Propensity score analysis showed that PORT was not associated with improved survival of patients with N2 disease (hazard ratio [HR]: 1.11; 95% confidence interval [CI]: 0.97–1.27). Analyses limited to patients treated with or without chemotherapy, intermediate or high complexity RT planning, or adjusting for time trends showed similar results. The instrumental variable estimator for the absolute improvement in 1- and 3-year survival with PORT was −0.04 (95% CI: −0.15 to 0.08) and −0.08 (95% CI:−0.24 to 0.15), respectively.
Conclusions
These data suggest that PORT is not associated with improved survival of elderly patients with N2 disease. These findings have important clinical implications given that SEER data shows that a large percentage of elderly patients are currently treated with PORT despite the lack of definitive evidence about its effectiveness. The potential effectiveness of PORT should be further evaluated in randomized control trials.
doi:10.1002/cncr.26585
PMCID: PMC3355220  PMID: 22331818
Postoperative radiotherapy; N2 disease; lung cancer; survival
23.  Design and Phenomenology of the FEBSTAT Study 
Epilepsia  2012;53(9):1471-1480.
Purpose
Febrile status epilepticus (FSE) has been associated with hippocampal injury and subsequent hipppocampal sclerosis (HS) and temporal lobe epilepsy. The FEBSTAT study was designed to prospectively examine the association between prolonged febrile seizures and development of HS and associated temporal lobe epilepsy, one of the most controversial issues in epilepsy. We report on the baseline phenomenology of the final cohorts as well as detailed aims and methodology.
Methods
The “Consequences of Prolonged Febrile Seizures in Childhood” (FEBSTAT) study is a prospective, multicenter study. Enrolled are children, aged 1 month to 6 years, presenting with a febrile seizure lasting 30 minutes or more based upon ambulance, emergency department, and hospital records, and parental interview. At baseline, procedures included an MRI and EEG done within 72 hours of FSE, and a detailed history and neurological examination. Baseline development and behavior are assessed at one month. The baseline assessment is repeated, with age- appropriate developmental testing at one and five years after enrollment as well as at the development of epilepsy and one year after that. Telephone calls every three months document further seizures. Two other groups of children are included: a ‘control’ group consisting of children with a first febrile seizure ascertained at Columbia University and with almost identical baseline and one year follow-up examinations and a pilot cohort of FSE from Duke University.
Key findings
The FEBSTAT cohort consists of 199 children with a median age at baseline of 16.0 months (Interquartile range (IQR)=12.0–24.0) and a median duration of FSE of 70.0 minutes (IQR=47.0–110.0). Seizures were continuous in 57.3% and behaviorally intermittent (without recovery in between) in 31.2%; most were partial (4;2.0%) or secondary generalized (65.8%), and almost all (98.0%) culminated in a generalized tonic clonic seizure. Of the 199 children, 86.4% had normal development and 20% had prior febrile seizures. In one third of cases, FSE was unrecognized in the emergency department.
The Duke existing cohort consists of 23 children with a median age of FSE onset of 18.0 months (IQR 14.0–28.0) and median duration of FSE of 90.0 minutes (IQR 50.0–170.0).
The Columbia control cohort consists of 159 children with a first febrile seizure who received almost the same work-up as the FEBSTAT cohort at baseline and at one-year. They were followed by telephone every 4 months for a median of 42 months. Among the control cohort, 64.2% had a first simple FS, 26.4% had a first complex FS that was not FSE, and 9.4% had FSE. Among the 15 with FSE, the median age at onset was 14.0 months (IQR 12.0–20.0) and the median duration of FSE was 43.0 minutes (IQR 35.0–75.0).
Significance
The FEBSTAT study presents an opportunity to prospectively study the relationship between FSE and acute hippocampal damage, the development of MTS, epilepsy (particularly TLE), and impaired hippocampal function in a large cohort. It is hoped that this study may illuminate a major mystery in clinical epilepsy today, and permit the development of interventions designed to prevent the sequelae of FSE.
doi:10.1111/j.1528-1167.2012.03567.x
PMCID: PMC3436982  PMID: 22742587
Febrile Seizures; Status Epilepticus; Epidemiology; Children
24.  Fetal Heart Rate Reactivity Differs by Women’s Psychiatric Status during Psychological Stress, but Not Paced Breathing 
Developmental psychobiology  2010;53(3):221-233.
Objective
Prenatal exposure to women’s mood dysregulation is associated with variation in neurobehavioral profiles in children. Few studies have assessed these relationships during the prenatal period.
Methods
In 113 women in the 36th – 38th gestational week (mean age 26.3 ± 5.4 years), electrocardiogram, blood pressure, respiration, salivary cortisol, and fetal heart rate (HR) were measured during baseline, a psychological challenge (Stroop color–word matching task), and a standardized paced breathing protocol. Subjects underwent the Structured Clinical Interview for DSM-IV prior to testing and were grouped as: depressed, co–morbid for depression and anxiety, anxiety disorder only, and control.
Results
There was a significant main effect of maternal diagnostic group on fetal HR only during the Stroop task: fetuses of women in the co–morbid group had a greater HR increase compared to controls (p < .05). Overall, fetuses showed robust increases in HR during paced breathing (p < .0001), but there was no significant difference by maternal diagnosis. For both tasks, changes in fetal HR were independent of women’s concurrent cardiorespiratory activity. Finally, although cortisol was higher in the co-morbid group (p <.05), independent of diagnosis, there was a trend for maternal baseline cortisol to be positively associated with average fetal HR (p = .08).
Conclusions
These findings indicate that variation in fetal HR reactivity — an index of emerging regulatory capacities — is likely influenced by multiple acute and chronic factors associated with women’s psychobiology.
doi:10.1002/dev.20513
PMCID: PMC3747960  PMID: 21400485
Fetal heart rate; fetal neurobehavioral development; antenatal depression; maternal stress; fetal programming
25.  Delayed Access and Survival in Idiopathic Pulmonary Fibrosis 
Rationale: Idiopathic pulmonary fibrosis is often initially misdiagnosed. Delays in accessing subspecialty care could lead to worse outcomes among those with idiopathic pulmonary fibrosis.
Objectives: To examine the association between delayed access to subspecialty care and survival time in idiopathic pulmonary fibrosis.
Methods: We performed a prospective cohort study of 129 adults who met American Thoracic Society criteria for idiopathic pulmonary fibrosis evaluated at a tertiary care center. Delay was defined as the time from the onset of dyspnea to the date of initial evaluation at a tertiary care center. We used competing risk survival methods to examine survival time and time to transplantation.
Measurements and Main Results: The mean age was 63 years and 76% were men. The median delay was 2.2 years (interquartile range 1.0–3.8 yr), and the median follow-up time was 1.1 years. Age and lung function at the time of evaluation did not vary by delay. A longer delay was associated with an increased risk of death independent of age, sex, forced vital capacity, third-party payer, and educational attainment (adjusted hazard ratio per doubling of delay was 1.3, 95% confidence interval 1.03 to 1.6). Longer delay was not associated with a lower likelihood of undergoing lung transplantation.
Conclusions: Delayed access to a tertiary care center is associated with a higher mortality rate in idiopathic pulmonary fibrosis independent of disease severity. Early referral to a specialty center should be considered for those with known or suspected interstitial lung disease.
doi:10.1164/rccm.201104-0668OC
PMCID: PMC3208648  PMID: 21719755
access to healthcare; healthcare disparities; idiopathic pulmonary fibrosis; interstitial lung disease; survival

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