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There is limited information on the treatment trajectory and outcomes of patients with advanced cEGFRm NSCLC treated with osimertinib in routine clinical practice in Canada. By using and analyzing population-based administrative data and detailed chart abstraction in the province of Alberta, our objective was to capture Canadian-specific real-world treatment patterns, health outcomes, and healthcare resource utilization (HCRU) in advanced cEGFRm NSCLC patients who were (a) treated with osimertinib and (b) those receiving treatment after osimertinib. In our study cohort, we found that the overall survival rates for real-world patients receiving osimertinib were less favorable than those observed in clinical trials (24.0 versus 38.6 months). The attrition rate after osimertinib was substantial and high HCRU persisted across many years after diagnosis and treatment. This study provides important real-world evidence on contemporary survival, treatment patterns, and healthcare use among cEGFRm NSCLC patients treated with osimertinib and suggests that further research efforts are needed to improve therapeutic options in both the first and subsequent line settings.

Background: Remote monitoring has emerged as a complement to in-person care for patient with cardiac implantable electronic devices (CIEDs). It provides the care team with information about device integrity, programming issues, or other medical data (i.e. arrhythmias) and since 2015 has been recognized as a part of standard management by the Heart and Rhythm Society for all patients with CIEDs. However, while it can provide invaluable information to providers, the volume of generated data can increase the risk of oversight. We present a novel case of apparent device malfunction that on closer scrutiny was obvious, but provides a lesson in the mechanisms by which data can be artifactual., Case Summary: A 62-year-old male presented after his cardiac resynchronization therapy-defibrillator (CRT-D) alerted him that his device was at an elective replacement interval (ERI). He underwent an uncomplicated generator exchange; however, 2 weeks later, a remote alert showed that his device was at ERI and all impedances were above the upper limit. Device interrogation the following day demonstrated that the new device was functioning appropriately and his home monitor had in fact paired with his old generator. He obtained a new home monitor, and subsequent remote transmissions have demonstrated that his device is functioning appropriately., Discussion: This case demonstrates the importance of careful review of details from home-monitoring data. While concerning for device malfunction, there could be alternative causes when alerts are generated by remote monitoring. To our knowledge, this is the first report of this mechanism of alert via a home-monitoring device and should be considered when reviewing unusual remote download data., Competing Interests: There are no relationships relevant to the content of this paper to disclose. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Objectives: To review treatments for reducing the risk of recurrent stroke or death in patients with symptomatic intracranial atherosclerotic arterial stenosis (sICAS)., Methods: The development of this practice advisory followed the process outlined in the American Academy of Neurology Clinical Practice Guideline Process Manual, 2011 Edition, as amended. The systematic review included studies through November 2020. Recommendations were based on evidence, related evidence, principles of care, and inferences., Major Recommendations: Clinicians should recommend aspirin 325 mg/d for long-term prevention of stroke and death and should recommend adding clopidogrel 75 mg/d to aspirin for up to 90 days to further reduce stroke risk in patients with severe (70%-99%) sICAS who have low risk of hemorrhagic transformation. Clinicians should recommend high-intensity statin therapy to achieve a goal low-density lipoprotein cholesterol level <70 mg/dL, a long-term blood pressure target of <140/90 mm Hg, at least moderate physical activity, and treatment of other modifiable vascular risk factors for patients with sICAS. Clinicians should not recommend percutaneous transluminal angioplasty and stenting for stroke prevention in patients with moderate (50%-69%) sICAS or as the initial treatment for stroke prevention in patients with severe sICAS. Clinicians should not routinely recommend angioplasty alone or indirect bypass for stroke prevention in patients with sICAS outside clinical trials. Clinicians should not recommend direct bypass for stroke prevention in patients with sICAS. Clinicians should counsel patients about the risks of percutaneous transluminal angioplasty and stenting and alternative treatments if one of these procedures is being contemplated., (© 2022 American Academy of Neurology.)

Objectives: Hyperlipidemia is a strong risk factor for intracranial atherosclerotic disease (ICAD) and clinical stroke recurrence. We explored the effect of serum lipid levels on subclinical infarct recurrence in the Mechanisms of earlY Recurrence in Intracranial Atherosclerotic Disease (MYRIAD) study., Materials and Methods: We included enrolled MYRIAD patients with lipid measurements and brain MRI at baseline and brain MRI at 6-8 weeks. Infarct recurrence was defined as new infarcts in the territory of the symptomatic artery on brain MRI at 6-8 weeks compared to baseline brain MRI. We assessed the association between baseline total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels and recurrent infarct at 6-8 weeks using multivariable logistic regression., Results: Among 74 patients (mean age 64.2±12.9 years, 59.5% were white, 60.8% men), 20 (27.0%) had new or recurrent infarcts. Mean HDL-C (37.2 vs. 43.9 mg/dL, P=0.037) was lower and TG (113.5 vs. 91.3 mg/dL, P=0.008) was higher while TC (199.8 vs. 174.3 mg/dL, P=0.061) and LDL-C (124.3 vs. 101.2 mg/dL, P=0.053) were nominally higher among those with recurrent infarcts than those without. LDL-C (adj. OR 1.022, 95% CI 1.004-1.040, P=0.015) and TG (adj. OR 1.009, 95% CI 1.001-1.016, P=0.021) were predictors of recurrent infarct at 6-8 weeks adjusting for other clinical and imaging factors., Conclusions: Baseline cholesterol markers can predict early infarct recurrence in patients with symptomatic ICAD. More intensive and rapid lipid lowering drugs may be required to reduce risk of early recurrence., Competing Interests: Declaration of Competing Interest Dr. Prabhakaran reports grants from NIH during the conduct of the study; grants from AHRQ, personal fees from Abbvie, and personal fees from UpToDate outside the submitted work. Dr. Liebeskind reports grants from NIH during the conduct of the study; other from Cerenovus, other from Genentech, other from Medtronic, and other from Stryker outside the submitted work. Mr. Cotsonis reports grants from NIH during the conduct of the study. Mr. Nizam reports grants from NIH during the conduct of the study. Dr. Feldmann reports grants from NIH during the conduct of the study; and expert witness case reviews. Dr. Sangha reports no conflicts of interest. Ms. Campo-Bustillo reports grants from NIH during the conduct of the study. Dr. Romano reports grants from NIH during the conduct of the study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Purpose: While prior studies identified risk factors for recurrent stroke in patients with symptomatic intracranial atherosclerotic disease, few have assessed risk factors for early infarct recurrence., Methods: We performed a post hoc analysis of the MYRIAD study (Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease) of intracranial atherosclerotic disease patients with recent (<21 days) stroke/transient ischemic attack, 50% to 99% stenosis and who underwent 6- to 8-week magnetic resonance imaging (MRI) per protocol. Infarct recurrence was defined as new infarcts in the territory of the symptomatic artery on brain MRI at 6 to 8 weeks compared to index brain MRI. Qualifying events and clinical and imaging outcomes were centrally ascertained by 2 independent reviewers. We assessed the association between baseline clinical and imaging variables and recurrent infarct in bivariate models and multivariable logistic regression to identify independent predictors of infarct recurrence., Results: Of 105 enrolled patients in MYRIAD, 89 (84.8%) were included in this analysis (mean age, 64±12 years, 54 [60.7%] were male, and 53 [59.6%] were White). The median time from qualifying event to MRI was 51+16 days, on which 22 (24.7%) patients had new or recurrent infarcts. Younger age (57.7 versus 66.0 years; P <0.01), diabetes (32.6% versus 14.6%, P =0.05), index stroke (31.3% versus 4.6%, P =0.01), anterior circulation location of stenosis (29.7% versus 12.0%, P =0.08), number of diffusion-weighted imaging lesions (>1: 40.0%, 1: 26.9% versus 0: 4.4%, P <0.01), and borderzone infarct pattern (63.6% versus 25.0%, P =0.01) on baseline MRI were associated with new or recurrent infarcts. Age (adjusted odds ratio, 0.93 [95% CI, 0.89-0.98], P <0.01) and number of diffusion-weighted imaging lesions (adjusted odds ratio, 3.24 [95% CI, 1.36-7.71], P <0.01) were independently associated with recurrent infarct adjusting for hypertension, diabetes, and stenosis location (anterior versus posterior circulation)., Conclusions: An index multi-infarct pattern is associated with early recurrent infarcts, a finding that might be explained by plaque instability and artery-to-artery embolism. Further investigation of plaque vulnerability in intracranial atherosclerotic disease is needed. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02121028.

Introduction: While much is known about recurrent clinical events in patients with intracranial atherosclerotic disease (ICAD), there is limited data on characteristics of recurrent infarcts. Methods: The NIH-funded MyRIAD prospective, observational study was designed to identify mechanisms of ischemia and predictors of recurrence in ICAD. Recurrent infarction was assessed on MRI at 6-8 weeks. We reviewed the DWI/ADC and FLAIR sequences in patients with recurrent stroke and characterized the number of infarcts, infarct location, size, and patterns based on whether they were borderzone (BZ), perforator (SC/P), cortical or territorial (C/T), and mixed. Temporal characteristics were delineated by ADC/FLAIR correlation. Results: Of the 89 patients with 6-8 weeks MRI, 22 (24.7%) had recurrent infarcts in the territory of the symptomatic artery. Recurrent infarcts were evident on DWI in 63.6% and single infarcts in 54.5%. The median recurrent infarct volume was 2.0 cm 3 compared to median index infarct volumes of 2.5 cm 3 . A mixed infarct pattern was most common (40.9%), followed by borderzone (22.7%), cortical or territorial (27.3%), while only 9.1% were in a perforator artery distribution. Amongst those with a mixed pattern, 8/9 had a borderzone distribution infarct as part of their mixed infarct pattern. Conclusion: These findings provide novel data on the characteristics of early recurrent infarcts in patients with symptomatic ICAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sangha, Prabhakaran, Feldmann, Honda, Nizam, Cotsonis, Campo-Bustillo, Romano and Liebeskind.)

Purpose: This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors., Patients and Methods: The 3 + 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m 2 on days 1-3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity., Results: Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44%) and 16 of 25 (64%) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46%) and 5 of 6 (83%) of all enrolled and ED SCLC patients, respectively., Conclusions: Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC., (©2018 American Association for Cancer Research.)

Purpose: To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody-drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC). Patients and Methods: Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary-derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks. Results: The AGS-16M8F study ( n = 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7-83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study ( n = 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100-143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5-141 weeks). Conclusions: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks. Clin Cancer Res; 24(18); 4399-406. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Dofetilide is an antiarrhythmic drug with dosing based on the Cockcroft-Gault formula using total body weight (TBW). We investigated the impact of calculating dofetilide dose using adjusted body weight (ABW) or ideal body weight (IBW) on subsequent dose reduction or discontinuation. We conducted a retrospective review of 265 patients admitted to an academic medical center for initiation of dofetilide using TBW. Dosing was recalculated using ABW or IBW. Patients who would have received a reduced dose using ABW or IBW (reduced dose group) were compared with patients whose dose would not have changed (same dose group). Manual measurement of QT intervals was performed. We found that Forty-one of 265 patients (15%) would have received a lower initial dose of dofetilide based on ABW. Patients in this reduced dose group had 2.95 times greater odds of drug discontinuations or dose reductions due to QTc prolongation (95% confidence interval, 1.47-5.90; P < 0.01) compared with the same dose group. Seventy-seven of 265 patients (29%) would have received a lower initial dose of dofetilide based on IBW. Patients in this reduced dose group had 1.78 times greater odds of drug discontinuations or dose reductions due to QTc prolongation (95% confidence interval, 0.98-3.21; P = 0.056) compared with the same dose group. These data suggest that caution should be used when dosing dofetilide using TBW, as it may lead to a greater frequency of dose reduction or discontinuation compared with dosing using ABW or IBW.

Background: Traditionally the right ventricular (RV) pacing lead is placed in the RV apex in cardiac resynchronization therapy (CRT). It is not clear whether nonapical placement of the RV lead is associated with a better response to CRT. We aimed to perform a meta-analysis of all randomized controlled trials (RCTs) that compared apical and nonapical RV lead placement in CRT., Methods: We searched PubMed, EMBASE, Cochrane, Scopus, and relevant references for studies and performed meta-analysis using random effects model. Our main outcome measures were all-cause mortality, composite of death and heart failure hospitalization, improvement in ejection fraction (EF), left ventricle end-diastolic volume (LVEDV), left ventricle end-systolic volume (LVESV), and adverse events., Results: Seven RCTs with a total population of 1641 patients (1199 apical and 492 nonapical) were included in our meta-analysis. There was no difference in all-cause mortality (5% vs 4.3%, odds ratio (OR) = 0.86; 95% confidence interval (CI) 0.45-1.64; P  =   .65; I 2  = 11%) and a composite of death and heart failure hospitalization (14.2% vs 12.9%, OR   = 0.92; 95% CI: 0.61-1.38; P =  .68; I 2  = 0) between apical and nonapical groups. No difference in improvement in EF (Weighted mean difference (WMD)   = 0.37; 95% CI: -2.75-3.48; P =  .82; I 2  = 68%), change in LVEDV (WMD   = 3.67; 95% CI: -4.86-12.20; P  =   .40; I 2  = 89%) and LVESV (WMD   = -1.20; 95% CI: -4.32-1.91; P  =   .45; I 2  = 0) were noted between apical and nonapical groups. Proportion of patients achieving >15% improvement in EF was similar in both groups (OR   = 0.85; 95% CI: 0.62-1.16; P  =   .31; I 2  = 0)., Conclusion: In patients with CRT, nonapical RV pacing is not associated with improved clinical and echocardiographic outcomes compared with RV apical pacing.

Objectives: We sought to determine the effect of acute electrolyte and osmolar shifts on brain volume and neurologic function in patients with liver failure and severe hepatic encephalopathy., Design: Retrospective analysis of brain CT scans and clinical data., Setting: Tertiary care hospital ICUs., Patients: Patients with acute or acute-on-chronic liver failure and severe hepatic encephalopathy., Interventions: Clinically indicated CT scans and serum laboratory studies., Measurements and Main Results: Change in intracranial cerebrospinal fluid volume between sequential CT scans was measured as a biomarker of acute brain volume change. Corresponding changes in serum osmolality, chemistry measurements, and Glasgow Coma Scale were determined. Associations with cerebrospinal fluid volume change and Glasgow Coma Scale change for initial volume change assessments were identified by Spearman's correlations (rs) and regression models. Consistency of associations with repeated assessments was evaluated using generalized estimating equations. Forty patients were included. Median baseline osmolality was elevated (310 mOsm/Kg [296-321 mOsm/Kg]) whereas sodium was normal (137 mEq/L [134-142 mEq/L]). Median initial osmolality change was 9 mOsm/kg (5-17 mOsm/kg). Neuroimaging consistent with increased brain volume occurred in 27 initial assessments (68%). Cerebrospinal fluid volume change was more strongly correlated with osmolality (r = 0.70; p = 4 × 10) than sodium (r = 0.28; p = 0.08) change. Osmolality change was independently associated with Glasgow Coma Scale change (p = 1 × 10) and cerebrospinal fluid volume change (p = 2.7 × 10) in initial assessments and in generalized estimating equations using all 103 available assessments., Conclusions: Acute decline in osmolality was associated with brain swelling and neurologic deterioration in severe hepatic encephalopathy. Minimizing osmolality decline may avoid neurologic deterioration.

Objective: We tested the hypothesis that admission serum magnesium levels are associated with hematoma volume, hematoma growth, and functional outcomes in patients with intracerebral hemorrhage (ICH)., Methods: Patients presenting with spontaneous ICH were enrolled in an observational cohort study that prospectively collected demographic, clinical, laboratory, radiographic, and outcome data. We performed univariate and adjusted multivariate analyses to assess for associations between serum magnesium levels and initial hematoma volume, final hematoma volume, and in-hospital hematoma growth as radiographic measures of hemostasis, and functional outcome measured by the modified Rankin Scale (mRS) at 3 months., Results: We included 290 patients for analysis. Admission serum magnesium was 2.0 ± 0.3 mg/dL. Lower admission magnesium levels were associated with larger initial hematoma volumes on univariate ( p = 0.02), parsimoniously adjusted ( p = 0.002), and fully adjusted models ( p = 0.006), as well as greater hematoma growth ( p = 0.004, p = 0.005, and p = 0.008, respectively) and larger final hematoma volumes ( p = 0.02, p = 0.001, and p = 0.002, respectively). Lower admission magnesium level was associated with worse functional outcomes at 3 months (i.e., higher mRS; odds ratio 0.14, 95% confidence interval 0.03-0.64, p = 0.011) after adjustment for age, admission Glasgow Coma Scale score, initial hematoma volume, time from symptom onset to initial CT, and hematoma growth, with evidence that the effect of magnesium is mediated through hematoma growth., Conclusions: These data support the hypothesis that magnesium exerts a clinically meaningful influence on hemostasis in patients with ICH., (© 2017 American Academy of Neurology.)

Background and Purpose: Since the SAMMPRIS trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis), aggressive medical management (AMM), which includes dual antiplatelet therapy (DAPT) and high-dose statin (HDS) therapy, is recommended for patients with symptomatic intracranial atherosclerotic disease. However, limited data on the real-world application of this regimen exist. We hypothesized that recurrent stroke risk among patients treated with AMM is similar to the medical arm of the SAMMPRIS cohort., Methods: Using a prospective registry, we identified all patients admitted between August 2012 and March 2015 with (1) confirmed ischemic stroke or transient ischemic attack; (2) independently adjudicated symptomatic intracranial atherosclerotic disease; and (3) follow-up at 30 days. We analyzed 30-day risk of recurrent ischemic stroke stratified by treatment: (1) AMM: DAPT plus HDS therapy, (2) HDS alone, and (3) DAPT alone. We also assessed 30-day risk among patients who met prespecified SAMMPRIS eligibility criteria., Results: Among 99 patients who met study criteria (51.5% male, 54.5% black, mean age 68.2±11.2 years), 49 (48.5%) patients were treated with AMM, 69 (69.7%) with DAPT, and 73 (73.7%) with HDS therapy. At 30 days, 20 (20.2%) patients had recurrent strokes in the territory of stenosis. Compared with the risk in the medical arm of SAMMPRIS (4.4%), the 30-day risk of recurrent stroke was 20.4% in AMM patients, 21.5% in HDS patients, 22.4% in DAPT patients, and 23.2% in SAMMPRIS-eligible patients (all P <0.001)., Conclusions: Recurrent stroke risk within 30 days in patients with symptomatic intracranial atherosclerotic disease was higher than that observed in the medical arm of SAMMPRIS even in the subgroup receiving AMM. Replication of the SAMMPRIS findings requires further prospective study., (© 2017 American Heart Association, Inc.)

Background: Most literature for cryoablation of atrioventricular nodal reentry tachycardia (AVNRT) is based on -30 degree celsius cryomapping with 4 & 6 mm distal electrode catheters. The cryomapping mode is not available on the 6 mm cryocatheter in the United States. We describe a technique for 'pseudo' mapping at -80° using a 6 mm cryocatheter and report on short and long term outcomes., Methods: A retrospective analysis of all index cases (n = 253) of cryoablation of AVNRT at a single North American institution during the period of 2003-2010 was performed. The majority of cases utilized a 6 mm distal electrode tip catheter. Long term follow up (2.4 ± 1.8 years) was performed via review of the medical record and by questionnaire or telephone if necessary., Results: Acute ablation success was achieved in 93% of cases, with transient conduction defects noted in 39% of cases, and long term conduction defects in 1.6% of cases (4 patients with PR prolongation, 2 of which were permanent). General anesthesia, male gender and presence of structural heart disease were more common in the acute failure cohort. The recurrence rate for AVNRT was 8%. These patients tended to be younger and had more transient A-V conduction defects during the index procedure than those without a recurrence., Conclusions: In conclusion, anatomic cryoablation of AVNRT utilizing a 6 mm electrode catheter with mapping performed at -80° Celsius is a safe procedure with good long term efficacy. Transient A-V block during the index procedure increases the risk of late recurrence., (Copyright © 2017 Indian Heart Rhythm Society. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Prognostic assessments, which are crucial for decision-making in critical illnesses, have shown unsatisfactory reliability. We compared the accuracy of a widely used prognostic score against a model derived from clinical data obtained 5 days after admission for patients with intracerebral hemorrhage (ICH), a condition for which prognostication has proven notoriously challenging and prone to bias., Methods: Patients enrolled in a prospective observational cohort study of spontaneous ICH underwent hourly Glasgow Coma Scale (GCS) assessment. Outcome was measured at 3 months using the modified Rankin Scale (mRS). We analyzed the change in correlation between GCS and 3-month mRS scores from admission through day 5, and compared the performance of a parsimonious set of day 5 clinical variables against the ICH score., Results: Data was collected on 254 subjects. The ICH score and day 5 GCS score were both correlated with 3-month mRS score (p < 0.001), but the correlation was stronger with day 5 GCS score (p < 0.05 by Fisher z-transformation). Premorbid mRS score, intraventricular hemorrhage and day 5 GCS score were independent predictors of outcome (all p < 0.05 in ordinal regression model). While ICH score correctly classified good (mRS 0-3) vs. poor (mRS 4-6) outcome in 73% of cases, the day 5 model correctly classified 83% of cases., Conclusions: A simple reassessment after 5 days of care significantly improves the accuracy of prognosticating outcome in patients with ICH. These data confirm the feasibility and potential utility of early reassessments in refining prognosis for patients who survive early stabilization of a severe neurologic injury., (© 2017 S. Karger AG, Basel.)

Background: It is not clear whether additional empiric superior vena cava isolation (SVCI) to pulmonary vein isolation (PVI) results in low recurrences of atrial fibrillation. We aimed to perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) that evaluated role of empiric SVCI in atrial fibrillation ablation., Methods: We searched PubMed, EMBASE, Cochrane, Scopus, and relevant references for RCTs (inception April 15, 2016 without language restrictions) and performed meta-analysis using random effects model. Recurrence rates of atrial fibrillations, procedural times, fluoroscopic times, and adverse events were the measured outcomes., Results: Three RCTs with a total population of 526 were analyzed. There was no difference in the recurrence rate between PVI plus SVCI versus PVI alone when comparison was made across all types of AF (39 vs 60; odds ratio 0.68; 95 % CI 0.43-1.07; P = 0.73; I 2  = 0 %). When analysis was restricted only to paroxysmal AF, there was a trend towards low recurrence rate in combination group without statistical significance (19 vs 35, OR 0.54; 95 % CI 0.29-1.00; P = 0.05; I 2  = 0). Similarly, no difference was noted between two groups in procedural (weighted mean difference [WMD] 10.12; 95 % CI -9.84 to 30.08; P = 0.32; I 2  = 85 %) and fluoroscopic time (WMD 4.66; 95 % CI -0.92 to 10.25; P = 0.1; I 2  = 94). Adverse events were similar in both groups., Conclusion: Empiric SVCI does not provide additional benefit to PVI alone for atrial fibrillation ablation.

Importance: Cardiac arrhythmias are common causes of syncope. Brugada syndrome is an uncommon but serious genetic arrhythmia disorder that can be unmasked by medicines causing sodium channel blockade., Observations: This report documents a case of Brugada syndrome and polymorphic ventricular tachycardia-ventricular fibrillation not initially recognized in a patient taking nortriptyline and experiencing syncope. It also illustrates one of the longest episodes of ventricular fibrillation recorded on an ambulatory monitor (94 seconds). Although the baseline electrocardiogram did not demonstrate a typical appearance for Brugada syndrome, provocative testing with flecainide in this patient with documented polymorphic ventricular tachycardia revealed a Brugada electrocardiogram pattern., Conclusions and Relevance: Vigilance should be maintained for arrhythmia substrates such as Brugada syndrome in patients with typical symptoms when they are prescribed membrane-active medicines. Long-term ambulatory rhythm monitors can provide useful information in these cases, especially when symptoms are infrequent.

Objective: We investigated health-related quality of life (HRQOL) in patients with TIA and minor ischemic stroke (MIS) using Neuro-QOL, a validated, patient-reported outcome measurement system., Methods: Consecutive patients with TIA or MIS who had (1) modified Rankin Scale (mRS) score of 0 or 1 at baseline, (2) initial NIH Stroke Scale score of ≤5, (3) no acute reperfusion treatment, and (4) 3-month follow-up, were recruited. Recurrent stroke, disability by mRS and Barthel Index, and Neuro-QOL scores in 5 prespecified domains were prospectively recorded. We assessed the proportion of patients with impaired HRQOL, defined as T scores more than 0.5 SD worse than the general population average, and identified predictors of impaired HRQOL using logistic regression., Results: Among 332 patients who met study criteria (mean age 65.7 years, 52.4% male), 47 (14.2%) had recurrent stroke within 90 days and 41 (12.3%) were disabled (mRS >1 or Barthel Index <95) at 3 months. Any HRQOL impairment was noted in 119 patients (35.8%). In multivariate analysis, age (adjusted odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01-1.04), initial NIH Stroke Scale score (adjusted OR 1.39, 95% CI 1.17-1.64), recurrent stroke (adjusted OR 2.10, 95% CI 1.06-4.13), and proxy reporting (adjusted OR 3.94, 95% CI 1.54-10.10) were independent predictors of impaired HRQOL at 3 months., Conclusions: Impairment in HRQOL is common at 3 months after MIS and TIA. Predictors of impaired HRQOL include age, index stroke severity, and recurrent stroke. Future studies should include HRQOL measures in outcome assessment, as these may be more sensitive to mild deficits than traditional disability scales., (© 2015 American Academy of Neurology.)

Atrial fibrillation (AF) is a significant etiologic cause of acute ischemic stroke (AIS) that leads to disabling deficits as well as significant morbidity and mortality in this population. Approximately 25 % of AIS is considered to be cryptogenic with no etiology ascertained at the time of the index event. Recent advances from the EMBRACE and CRYSTAL-AF trial have improved detection and treatment of AF and subsequently lead to changes in guidelines. However, with improved detection rates, the duration and frequency cutoffs for treating AF are currently being investigated to ensure optimization of patient selection and subsequent treatment.

Cardiac electrophysiologic derangements often coexist with disorders of the circulatory system. Capturing and diagnosing arrhythmias and conduction system disease may lead to a change in diagnosis, clinical management and patient outcomes. Standard 12-lead electrocardiogram (ECG), Holter monitors and event recorders have served as useful diagnostic tools over the last few decades. However, their shortcomings are only recently being addressed by emerging technologies. With advances in device miniaturization and wireless technologies, and changing consumer expectations, wearable "on-body" ECG patch devices have evolved to meet contemporary needs. These devices are unobtrusive and easy to use, leading to increased device wear time and diagnostic yield. While becoming the standard for detecting arrhythmias and conduction system disorders in the outpatient setting where continuous ECG monitoring in the short to medium term (days to weeks) is indicated, these cardiac devices and related digital mobile health technologies are reshaping the clinician-patient interface with important implications for future healthcare delivery.

Background: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease., Methods: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025., Findings: Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%])., Interpretation: Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor., Funding: Canadian Cancer Society Research Institute and Pfizer., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background. Brugada syndrome is rare and has been a clinically diagnosable entity since 1992. Its clinical manifestations are highly variable, and while some patients remain asymptomatic, others endure sudden cardiac death. Initial presenting symptoms may include palpitations, seizures, syncope, and nocturnal agonal respiration. The diagnosis of Brugada syndrome relies on both clinical findings and characteristic ECG patterns that occur spontaneously or are induced by usage of sodium-channel blocking agents. Aims of Case Report. Many psychiatrists may be unaware of the possibility of medical cocontributing etiologies to physical symptoms of anxiety and depression. We present a case of a patient who was treated psychiatrically for anxiety and panic attacks and who was subsequently diagnosed with Brugada syndrome and treated medically with an implantable cardioverter defibrillator (ICD), the only treatment option demonstrated to be effective. Her psychiatric symptoms predated her diagnosis of Brugada syndrome by at least fifteen years. Conclusion. The patient's eventual diagnosis of Brugada syndrome altered the course of her psychopharmacologic medication management and illustrates the utility of a psychosomatic approach to psychiatric symptom management.

Background: Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in non-small cell lung cancer (NSCLC). Based on preclinical demonstration of additive cytotoxicity, we evaluated the safety and efficacy of combining pemetrexed and nanoparticle albumin bound (nab) paclitaxel with a focus on NSCLC for phase II expansion., Methods: A 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: pemetrexed 500 mg/m(2) day 1 and nab-paclitaxel day 1 at 180, 220, & 260 mg/m(2) every 21 days. Phase II eligibility included advanced NSCLC, ≤2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25%., Results: Planned dose escalation was completed without reaching the MTD. The RP2D was pemetrexed 500 mg/m(2) and nab-paclitaxel 260 mg/m(2). The phase II portion accrued 37 pts before early closure due to increasing first-line pemetrexed/platinum doublet use in non-squamous NSCLC. In 31 assessable phase II patients there were 5 partial responses, 12 stable disease, 14 progressive disease. The median overall survival was 8.8 months; progressive disease 4.4 months and disease control 15.6 months., Conclusions: Pemetrexed 500 mg/m(2) day 1 with nab-paclitaxel 260 mg/m(2) was feasible and well tolerated. The phase II component demonstrated activity in second/third-line therapy of advanced NSCLC; response rate 14% and disease control rate 46%. Treatment practice patterns of advanced NSCLC have evolved; further trials of this regimen are not planned.

A tropical marine bioassay was developed with juveniles of Pacific white shrimp, Litopenaeus vannamei, in order to test the acute and sublethal toxicity of Tilt, which is the commercial formulation of the fungicide propiconazole. A 10-d acute toxicity and a 32-d sublethal test were performed. A median lethal concentration (LC50) was determined for different exposure times, resulting in a 24-h LC50 of 1167 (1101-1386) microg/L (concentration based on active ingredient propiconazole), and reaching a threshold LC50 (72-h) at 1043 (1018-1068) microg/L. The sublethal exposure test was performed with propiconazole concentrations ranging from 367 to 825 microg/L. Animals in most treatments showed a significant increase in intermoult duration compared to those in the control treatment, although this did not seem to be concentration-dependent. However, the shrimps exposed to the sublethal concentrations of this fungicide showed morphological deformities, with a significant positive relationship between concentration and deformities of the rostrum, paraeopods, and uropods. Altogether, the results presented indicate the potential effects of Tilt on shrimp, particularly under long-term exposures, although these were found to occur at concentrations exceeding those reported in natural environments.

Decapod crustaceans have adopted a full range of reproductive strategies from the release of large numbers of small eggs (Penaeoidea) to the release of relatively low numbers of large advanced larvae (Nephropidae). As larval size determines trophic position in planktonic food webs, all food sources from phyto- to zooplankton are exploited, with many species changing trophic level during ontogenetic development. Comparative studies on digestive enzymes, levels of activity and changes during ontogeny, together with measurements of gastroevacuation rates and food energy values appear to reveal a general pattern. While herbivorous decapod larvae adapt to low food energy values with high enzyme activity levels, rapid food turnover and low assimilation efficiency, carnivorous larvae exhibit low levels of enzyme activity but compensate by extending retention time of high-energy food to maximise assimilation efficiency. New studies on digestive enzyme levels during development in the penaeid Litopenaeus vannamei, the caridean Lysmata debelius and the cirriped Elminius modestus, appear to agree with previous observations.