Showing papers by "Medical University of South Carolina published in 2014"

2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8)

Abstract: Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.

A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis

Abstract: Background In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. Methods In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. Results In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P = 0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P = 0.16) or in rates of death from any cause (P = 0.10) or from idiopathic pulmonary fibrosis (P = 0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P = 0.01) and from idiopathic pulmonary fibrosis (P = 0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. Conclusions Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable sideeffect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.)

Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs

Abstract: Importance Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials. Objectives To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival. Design, Setting, and Participants From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival. Interventions Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies. Main Outcomes and Measures Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival. Results From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR , 122 (17%); ALK rearrangements, 57 (8%); other EGFR , 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2 ), 19 (3%); BRAF , 16 (2%); PIK3CA , 6 ( MET amplification, 5 ( NRAS , 5 ( MEK1 , 1 ( AKT1 , 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score–adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006). Conclusions and Relevance Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival. Trial Registration clinicaltrials.gov Identifier:NCT01014286.

The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update.

Abstract: This guideline is the result of a systematic literature review using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2) LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The life-time prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria do not only cause a decrease in quality of life, but also affect performance at work and school and, as such, are members of the group of severe allergic diseases. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS).

Fibroblasts in fibrosis: novel roles and mediators

Abstract: Fibroblasts are the most common cell type of the connective tissues found throughout the body and the principal source of the extensive extracellular matrix (ECM) characteristic of these tissues. They are also the central mediators of the pathological fibrotic accumulation of ECM and the cellular proliferation and differentiation that occurs in response to prolonged tissue injury and chronic inflammation. The transformation of the fibroblast cell lineage involves classical developmental signaling programs and includes a surprisingly diverse range of precursor cell types—most notably, myofibroblasts that are the apex of the fibrotic phenotype. Myofibroblasts display exaggerated ECM production; constitutively secrete and are hypersensitive to chemical signals such as cytokines, chemokines, and growth factors; and are endowed with a contractile apparatus allowing them to manipulate the ECM fibers physically to close open wounds. In addition to ECM production, fibroblasts have multiple concomitant biological roles, such as in wound healing, inflammation, and angiogenesis, which are each interwoven with the process of fibrosis. We now recognize many common fibroblast-related features across various physiological and pathological protracted processes. Indeed, a new appreciation has emerged for the role of noncancerous fibroblast interactions with tumors in cancer progression. Although the predominant current clinical treatments of fibrosis involve nonspecific immunosuppressive and anti-proliferative drugs, a variety of potential therapies under investigation specifically target fibroblast biology.

Temporal Relationship Between Subclinical Atrial Fibrillation and Embolic Events

Abstract: Background—Among patients with implantable pacemakers and defibrillators, subclinical atrial fibrillation (SCAF) is associated with an increased risk of stroke; however, there is limited understanding of their temporal relationship. Methods and Results—The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) enrolled 2580 pacemaker and defibrillator patients aged ≥65 years with a history of hypertension but without a history of atrial fibrillation. Pacemakers and implantable cardioverter-defibrillators precisely logged the time and duration of all episodes of SCAF and recorded electrograms that were adjudicated by experts. We examined the temporal relationship between SCAF >6 minutes in duration and stroke or systemic embolism. Of 51 patients who experienced stroke or systemic embolism during follow-up, 26 (51%) had SCAF. In 18 patients (35%), SCAF was detected before stroke or systemic embolism. However, only 4 pat...

Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group

Abstract: Angioedema is defined as localized and self-limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s). When angioedema recurs without significant wheals, the patient should be diagnosed to have angioedema as a distinct disease. In the absence of accepted classification, different types of angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying angioedema. Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of angioedema.

Two‐year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial

Abstract: SummaryObjective To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. Methods Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. Results All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was −37.9% in the active and −17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. Significance Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

Prophylaxis of post-ERCP pancreatitis: European society of gastrointestinal endoscopy (ESGE) guideline - Updated June 2014

Abstract: This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). It addresses the prophylaxis of post-endoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis. Main recommendations 1 ESGE recommends routine rectal administration of 100 mg of diclofenac or indomethacin immediately before or after ERCP in all patients without contraindication. In addition to this, in the case of high risk for post-ERCP pancreatitis (PEP), the placement of a 5-Fr prophylactic pancreatic stent should be strongly considered. Sublingually administered glyceryl trinitrate or 250 µg somatostatin given in bolus injection might be considered as an option in high risk cases if nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated and if prophylactic pancreatic stenting is not possible or successful. 2 ESGE recommends keeping the number of cannulation attempts as low as possible. 3 ESGE suggests restricting the use of a pancreatic guidewire as a backup technique for biliary cannulation to cases with repeated inadvertent cannulation of the pancreatic duct; if this method is used, deep biliary cannulation should be attempted using a guidewire rather than the contrast-assisted method and a prophylactic pancreatic stent should be placed. 4 ESGE suggests that needle-knife fistulotomy should be the preferred precut technique in patients with a bile duct dilated down to the papilla. Conventional precut and transpancreatic sphincterotomy present similar success and complication rates; if conventional precut is selected and pancreatic cannulation is easily obtained, ESGE suggests attempting to place a small-diameter (3-Fr or 5-Fr) pancreatic stent to guide the cut and leaving the pancreatic stent in place at the end of ERCP for a minimum of 12 – 24 hours. 4 ESGE does not recommend endoscopic papillary balloon dilation as an alternative to sphincterotomy in routine ERCP, but it may be advantageous in selected patients; if this technique is used, the duration of dilation should be longer than 1 minute.

Cost-Effectiveness of CT Screening in the National Lung Screening Trial

Abstract: We estimated mean life-years, quality-adjusted life-years (QALYs), costs per person, and incremental cost-effectiveness ratios (ICERs) for three alternative strategies: screening with low-dose CT, screening with radiography, and no screening. Estimations of life-years were based on the number of observed deaths that occurred during the trial and the projected survival of persons who were alive at the end of the trial. Quality adjustments were derived from a subgroup of participants who were selected to complete quality-of-life surveys. Costs were based on utilization rates and Medicare reimbursements. We also performed analyses of subgroups defined according to age, sex, smoking history, and risk of lung cancer and performed sensitivity analyses based on several assumptions. RESULTS As compared with no screening, screening with low-dose CT cost an additional $1,631 per person (95% confidence interval [CI], 1,557 to 1,709) and provided an additional 0.0316 life-years per person (95% CI, 0.0154 to 0.0478) and 0.0201 QALYs per person (95% CI, 0.0088 to 0.0314). The corresponding ICERs were $52,000 per life-year gained (95% CI, 34,000 to 106,000) and $81,000 per QALY gained (95% CI, 52,000 to 186,000). However, the ICERs varied widely in subgroup and sensitivity analyses. CONCLUSIONS We estimated that screening for lung cancer with low-dose CT would cost $81,000 per QALY gained, but we also determined that modest changes in our assumptions would greatly alter this figure. The determination of whether screening outside the trial will be cost-effective will depend on how screening is implemented. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.)

Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease The TEAM-AD VA Cooperative Randomized Trial

Abstract: Importance Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. Objective To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. Design, Setting, and Participants Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. Interventions Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). Main Outcomes and Measures Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. Results Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, −0.24 to 4.20; adjusted P = .40) than the placebo group’s decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of “infections or infestations,” with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). Conclusions and Relevance Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. Trial Registration clinicaltrials.gov Identifier:NCT00235716

Atenolol versus Losartan in Children and Young Adults with Marfan's Syndrome

Abstract: BACKGROUND Aortic-root dissection is the leading cause of death in Marfan’s syndrome Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers METHODS We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan’s syndrome The primary outcome was the rate of aorticroot enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events RESULTS From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] age, 115±65 years in the atenolol group and 110±62 years in the losartan group), who had an aorticroot z score greater than 30 The baseline-adjusted rate of change (±SE) in the aortic-root z score did not differ significantly between the atenolol group and the losartan group (−0139±0013 and −0107±0013 standard-deviation units per year, respectively; P = 008) Both slopes were significantly less than zero, indicating a decrease in the degree of aortic-root dilatation relative to body-surface area with either treatment The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups CONCLUSIONS Among children and young adults with Marfan’s syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aorticroot dilatation between the two treatment groups over a 3-year period (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrialsgov number, NCT00429364)

Very Early Administration of Progesterone for Acute Traumatic Brain Injury

Abstract: BACKGROUND Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI. METHODS We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score. RESULTS A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P = 0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. CONCLUSIONS This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.)

ADAPT FAST study: a direct aspiration first pass technique for acute stroke thrombectomy

Abstract: Background The development of new revascularization devices has improved recanalization rates and time, but not clinical outcomes. We report a prospectively collected clinical experience with a new technique utilizing a direct aspiration first pass technique with large bore aspiration catheter as the primary method for vessel recanalization. Methods 98 prospectively identified acute ischemic stroke patients with 100 occluded large cerebral vessels at six institutions were included in the study. The ADAPT technique was utilized in all patients. Procedural and clinical data were captured for analysis. Results The aspiration component of the ADAPT technique alone was successful in achieving Thrombolysis in Cerebral Infarction (TICI) 2b or 3 revascularization in 78% of cases. The additional use of stent retrievers improved the TICI 2b/3 revascularization rate to 95%. The average time from groin puncture to at least TICI 2b recanalization was 37 min. A 5MAX demonstrated similar success to a 5MAX ACE in achieving TICI 2b/3 revascularization alone (75% vs 82%, p=0.43). Patients presented with an admitting median National Institutes of Health Stroke Scale (NIHSS) score of 17.0 (12.0–21.0) and improved to a median NIHSS score at discharge of 7.3 (1.0–11.0). Ninety day functional outcomes were 40% (modified Rankin Scale (mRS) 0–2) and 20% (mRS 6). There were two procedural complications and no symptomatic intracerebral hemorrhages. Discussion The ADAPT technique is a fast, safe, simple, and effective method that has facilitated our approach to acute ischemic stroke thrombectomy by utilizing the latest generation of large bore aspiration catheters to achieve previously unparalleled angiographic outcomes.

mHealth: A Mechanism to Deliver More Accessible, More Effective Mental Health Care

Abstract: The increased popularity and functionality of mobile devices has a number of implications for the delivery of mental health services. Effective use of mobile applications has the potential to (a) increase access to evidence-based care; (b) better inform consumers of care and more actively engage them in treatment; (c) increase the use of evidence-based practices; and (d) enhance care after formal treatment has concluded. The current paper presents an overview of the many potential uses of mobile applications as a means to facilitate ongoing care at various stages of treatment. Examples of current mobileapplicationsinbehaviouraltreatmentandresearcharedescribed,andtheimplicationsofsuchuses are discussed. Finally, we provide recommendations for methods to include mobile applications into current treatment and outline future directions for evaluation. Copyright © 2013 John Wiley & Sons, Ltd. Key Practitioner Message:  Mobile devices are becoming increasingly common among the adult population and have tremendous potential to advance clinical care.  Mobile applications have the potential to enhance clinical care at stages of treatment—from engaging patients in clinical care to facilitating adherence to practices and in maintaining treatment gains.  Research is needed to validate the efficacy and effectiveness of mobile applications in clinical practice.  Research on such devices must incorporate assessments of usability and adherence in addition to their incremental benefit to treatment.

Time to angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial

Abstract: Summary Background The IMS III trial did not show a clinical benefit of endovascular treatment compared with intravenous alteplase (recombinant tissue plasminogen activator) alone for moderate or severe ischaemic strokes. Late reperfusion of tissue that was no longer salvageable could be one explanation, as suggested by previous exploratory studies that showed an association between time to reperfusion and good clinical outcome. We sought to validate this association in a preplanned analysis of data from the IMS III trial. Methods We used data for patients with complete proximal arterial occlusions in the anterior circulation who received endovascular treatment and achieved angiographic reperfusion (score on Thrombolysis in Cerebral Infarction scale of grade 2–3) during the endovascular procedure (within 7 h of symptom onset). We used logistic regression to model good clinical outcome (defined as a modified Rankin Scale score of 0–2 at 3 months) as a function of the time to reperfusion. We prespecified variables to be considered for adjustment, including age, baseline National Institutes of Health Stroke Scale score, sex, and baseline blood glucose concentration. Findings Of 240 patients who were otherwise eligible for inclusion in our analysis, 182 (76%) achieved angiographic reperfusion. Mean time from symptom onset to reperfusion (ie, procedure end) was 325 min (SD 52). Increased time to reperfusion was associated with a decreased likelihood of good clinical outcome (unadjusted relative risk for every 30-min delay 0·85 [95% CI 0·77–0·94]; adjusted relative risk 0·88 [0·80–0·98]). Interpretation Delays in time to angiographic reperfusion lead to a decreased likelihood of good clinical outcome in patients after moderate to severe stroke. Rapid reperfusion could be crucial for the success of future acute endovascular trials. Funding US National Institutes of Health and National Institute of Neurological Disorders and Stroke.

Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci

Abstract: We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus,showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P ¼ 1.17 � 10 � 31 ; AAs: Arg369Cys, P ¼ 6.33 � 10 � 17 ) and ADH1C in AAs (Thr151Thr, P ¼ 4.94 � 10 � 10 ), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P ¼ 2.63 � 10 � 11 ), PDLIM5 in EAs (P ¼ 2.01 � 10 � 8 ), and METAP in AAs (P ¼ 3.35 � 10 � 8 ). We also identified a novel GWS association (1.17 � 10 � 10 ) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19. Several of the novel associations implicate direct involvement of, or interaction with, genes previously identified as schizophrenia risk loci. Confirmation of known AD risk loci supports the overall validity of the study; the novel loci are worthy of genetic and biological follow-up. The findings support a convergence of risk genes (but not necessarily risk alleles) between populations, and, to a lesser extent, between psychiatric traits.

American Society of Clinical Oncology Perspective: Raising the Bar for Clinical Trials by Defining Clinically Meaningful Outcomes

Abstract: See accompanying editorial on page 1186 Lee M Ellis, University of Texas MD Anderson Cancer Center, Houston, TX; David S Bernstein and Richard L Schilsky, American Society of Clinical Oncology, Alexandria, VA; Emile E Voest, University Medical Center Utrecht, Utrecht, the Netherlands; Jordan D Berlin, Vanderbilt-Ingram Cancer Center, Nashville, TN; Daniel Sargent, Mayo Clinic, Rochester, MN; Patricia Cortazar, US Food and Drug Administration, Silver Spring, MD; Elizabeth Garrett-Mayer, Medical University of South Carolina, Charleston, SC; Roy S Herbst and Rogerio C Lilenbaum, Yale Cancer Center, New Haven, CT; Camelia Sima and Mithat Gonen, Memorial Sloan-Kettering Cancer Center, New York, NY; Alan P Venook, Helen Diller Family Comprehensive Cancer Center at University of California San Francisco, San Francisco, CA; Neal J Meropol, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH; Lowell E Schnipper, Beth Israel Deaconess Medical Center, Boston, MA

Guidelines for performing a comprehensive transesophageal echocardiographic examination: recommendations from the American Society of Echocardiography and the Society of Cardiovascular Anesthesiologists.

Abstract: TABLE OF CONTENTSIntroduction 921General Guidelines 922Training and Certification 922Indications for TEE 923Management of Patient Sedation 927Sedation and Anesthesia 929Probe Insertion Techniques 930Instrument Controls 930Instrument Manipulation 931Comprehensive Imaging Examination 932ME Views 932TG

Research capacity. Enabling the genomic revolution in Africa

Abstract: H3Africa is developing capacity for health-related genomics research in Africa Our understanding of genome biology, genomics, and disease, and even human history, has advanced tremendously with the completion of the Human Genome Project. Technological advances coupled with significant cost reductions in genomic research have yielded novel insights into disease etiology, diagnosis, and therapy for some of the world's most intractable and devastating diseases—including malaria, HIV/AIDS, tuberculosis, cancer, and diabetes. Yet, despite the burden of infectious diseases and, more recently, noncommunicable diseases (NCDs) in Africa, Africans have only participated minimally in genomics research. Of the thousands of genome-wide association studies (GWASs) that have been conducted globally, only seven (for HIV susceptibility, malaria, tuberculosis, and podoconiosis) have been conducted exclusively on African participants; four others (for prostate cancer, obsessive compulsive disorder, and anthropometry) included some African participants (www.genome.gov/gwastudies/). As discussed in 2011 (www.h3africa.org), if the dearth of genomics research involving Africans persists, the potential health and economic benefits emanating from genomic science may elude an entire continent.

Mindfulness-Oriented Recovery Enhancement for Chronic Pain and Prescription Opioid Misuse: Results from an Early Stage Randomized Controlled Trial

Abstract: Prescription opioid misuse is an emerging public health concern with significant health and psychological risks. Though opioid analgesic therapy for chronic pain is often efficacious, and most patients take medicine as prescribed, some individuals exhibit addictive tendencies toward opioids (Fishbain, Cole, Lewis, Rosomoff, & Rosomoff, 2007). Opioid addiction among chronic pain patients involves cognitive, affective, and behavioral dysregulation that, when coupled with persistent or worsening pain, may result in significant functional impairment and suffering (Hojsted, Nielsen, Guldstrand, Frich, & Sjogren, 2010). Opioid addiction may be presaged by the occurrence of opioid misuse behaviors, such as dose escalation or use of prescribed opioids to self-medicate negative emotions and stress (Butler et al., 2007); these medication-misusing behaviors are common, with more than one-in-ten chronic pain patients exhibiting signs of opioid misuse (Fishbain et al., 2007). Although opioid agents with lower addiction liability like buprenorphine can effectively substitute for unauthorized opioid use (Ling et al., 2002), extant treatments for opioid addiction are typically ineffective in the absence of ongoing maintenance pharmacotherapy (Weiss et al., 2011). Further, persons seeking treatment for chronic pain respond especially poorly to motivational and behavioral addiction treatments (Larson et al., 2007). Current best practices for persons with chronic pain who are at risk for prescription opioid misuse and addiction (e.g., Jamison, Serraillier, & Michner, 2011; Oliver et al., 2012) include frequent opioid adherence monitoring, opioid treatment agreements and compliance training, and cognitive-behavioral substance misuse counseling (Jamison et al., 2010). Yet, new interventions are needed to effectively address the maladaptive cognitive-affective processes and appetitive responses elicited by pain, stress, and drug-related cues that undergird the risk chain from chronic pain to opioid misuse and addiction. This risk chain initiates from prolonged use of opioids, which produces physical dependence via neuroadaptations resulting in tolerance, withdrawal, and, in some cases, opioid-induced hyperalgesia (Chu, Angst, & Clark, 2008). Heightened pain sensitivity, when coupled with tolerance to the analgesic effects of opioids, can result in increased opioid craving (Ren, Shi, Epstein, Wang, & Lu, 2009) and consumption (Martell et al., 2007), and can elicit negative emotions that feed back to magnify pain perception. This process may result in appraisal of pain sensations as threatening and perseveration on the affective components of pain (Garland, 2012). Consequently, opioids are often misused to self-medicate (Khantzian, 1997; Kirsh, Jass, Bennett, Hagen, & Passik, 2007) the negative affective states and autonomic arousal that cause, co-occur with, or result from pain (Janig, 1995; Martenson, Cetas, & Heinricher, 2009). As with pain, stress and negative affect can become internal cues associated with past opioid use episodes that elicit the habit of opioid use, particularly among opioid misusers who take opioids to cope with emotional distress. Concomitantly, the habitual drive to engage in prescription opioid misuse (including unauthorized dose escalation) involves implicit neurocognitive operations that promote craving and aberrant drug taking (Goldstein et al., 2009; Stacy & Wiers, 2010) by biasing attention towards opioid-related cues (e.g., the sight of a pill bottle) (Garland, Froeliger, Passik, & Howard, 2012). Theory suggests that addiction occurs when the appetitive motivation to obtain natural rewards is re-organized around seeking drug-induced reward and the desire to alleviate dysphoria stemming from withdrawal and aversive experiences (e.g., pain and stress) (Alcaro & Panksepp, 2011; Koob & Le Moal, 2008). In that regard, decreased responsiveness to natural reinforcers has been observed among opiate dependent individuals and is robustly predictive of future opiate consumption (Lubman et al., 2009; Lubman, Allen, Peters, & Deakin, 2007, 2008). Hence, the problem of co-occurring chronic pain and prescription opioid misuse may involve a cycle of behavioral escalation where nociception and stress amplify pain and provoke recurrent self-medication with opioids, which in turn biases attention towards opioid-related cues that come to elicit the habit of opioid use despite ever diminishing analgesia and increasing dysphoria (Garland, Froeliger, Zeidan, Partin, & Howard, 2013). Despite such risks, opioids remain medically necessary for many individuals experiencing prolonged and intractable pain. Thus, therapeutic interventions are needed to target comorbid pain and opioid misuse. Though cognitive-behavioral therapy (CBT) has been shown to produce therapeutic reductions in pain (Williams, Eccleston, & Morley, 2012) and opioid misuse (Jamison et al., 2010) in isolation, there is scant research on psychological treatments that simultaneously address symptoms of co-occurring chronic pain and opioid misuse. To that end, we conducted an early-stage randomized controlled trial of Mindfulness-Oriented Recovery Enhancement (MORE) (Garland, 2013), a novel multimodal intervention that integrates mindfulness training, cognitive reappraisal skills, and positive emotion regulation into a therapeutic approach designed to modify attentional biases, habit behavior, affective dysregulation, and autonomic stress responses underlying the feedback loop between chronic pain, craving, and opioid misuse behaviors. Each of these three intervention components has been shown to be beneficial in isolation. Mindfulness training leads to reductions in pain (Gaylord et al., 2011; Kabat-Zinn et al., 1992; Rosenzweig et al., 2010; Zeidan et al., 2011) that are mediated by increased nonreactivity to aversive mental experiences and reinterpretation of affectively-laden pain sensations as innocuous sensory signals (Garland, Gaylord, Palsson, Faurot, Mann, & Whitehead, 2012). Moreover, mindfulness training produces salutary effects on emotional distress (Grossman, Niemann, Schmidt, & Walach, 2004; Hofmann, Sawyer, Witt, & Oh, 2010) and addiction-related factors (Bowen et al., 2009; Garland, Froeliger, & Howard, 2013), including attentional bias and autonomic cue-reactivity (Garland, Gaylord, Boettiger, & Howard, 2010). Similarly, cognitive reappraisal has been shown to significantly decrease negative emotions and downregulate stress physiology (Ochsner & Gross, 2005), as well as reduce substance craving (Kober et al., 2011). In complementary fashion, positive emotion regulatory strategies (e.g., savoring pleasant events) may upregulate positive affect, reduce anhedonia, and promote psychological resilience (Garland, Fredrickson, Kring, Johnson, Meyer, & Penn, 2010). MORE, which was originally tested as a treatment for alcohol dependence (Garland, Gaylord et al., 2010), capitalizes on the synergy of these three treatment components by integrating them into a multimodal intervention. The aim of this study was to evaluate the feasibility of developing a clinical trial comparing acute (pre-post) and longer-term (3-month follow-up) efficacy of MORE with that of a conventional support group (SG) in reducing chronic pain and prescription opioid misuse. The study employed an active control condition which attempted to control for non-specific therapeutic factors such as social interaction and support. We hypothesized that participation in MORE would be associated with significantly greater reductions in pain severity, pain interference, stress symptoms, and desire for opioids than would participation in a SG. We also hypothesized that compared to SG participants, a significantly greater proportion of individuals completing MORE who met clinical criteria for prescription opioid use disorder before treatment would no longer meet opioid use disorder criteria following treatment. Insofar as clinicians in the field must often make dichotomous diagnostic judgments in practice and may need to ascertain the extent to which a disorder can be rendered subclinical following treatment (cf., Eftekhari et al., 2013), we were interested in whether MORE could reduce symptoms below the clinical threshold for opioid use disorder. Lastly, although MORE was designed to target a wide array of cognitive, affective, and autonomic mechanisms as detailed above, in the present study we tested the effects of the intervention on a focused set of mediators selected for their direct relevance to primary study outcomes. Because emotional reactivity and maladaptive appraisals of pain and stress undergird the risk chain linking chronic pain and opioid misuse, we hypothesized that the therapeutic effects of MORE on pain severity and opioid use disorder status would be associated with increased nonreactivity, cognitive reappraisal, and reinterpretation of pain sensations as innocuous sensory information.

Motivational activation: a unifying hypothesis of orexin/hypocretin function.

Abstract: Orexins (hypocretins) are involved in a large variety of behaviors and physiological processes including feeding, sleep/wake regulation, and reward. In this perspective, the authors propose a unifying function for orexins in translating motivational activation into sets of processes that support adaptive behaviors.

Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking

Abstract: The ventral pallidum is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to the ventral tegmental area (VTA) regulates neuronal activity there. However, the ventral pallidum is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear. We found that projections to VTA from the rostral ventral pallidum (RVP), but not the caudal ventral pallidum (CVP), were robustly Fos activated during cue-induced reinstatement of cocaine seeking--a rat model of relapse in addiction. Moreover, designer receptor-mediated transient inactivation of RVP neurons, their terminals in VTA or functional connectivity between RVP and VTA dopamine neurons blocked the ability of drug-associated cues (but not a cocaine prime) to reinstate cocaine seeking. In contrast, CVP neuronal inhibition blocked cocaine-primed, but not cue-induced, reinstatement. This double dissociation in ventral pallidum subregional roles in drug seeking is likely to be important for understanding the mesocorticolimbic circuits underlying reward seeking and addiction.

The role of periostin in tissue remodeling across health and disease.

Abstract: Periostin, also termed osteoblast-specific factor 2, is a matricellular protein with known functions in osteology, tissue repair, oncology, cardiovascular and respiratory systems, and in various inflammatory settings. However, most of the research to date has been conducted in divergent and circumscribed areas meaning that the overall understanding of this intriguing molecule remains fragmented. Here, we integrate the available evidence on periostin expression, its normal role in development, and whether it plays a similar function during pathologic repair, regeneration, and disease in order to bring together the different research fields in which periostin investigations are ongoing. In spite of the seemingly disparate roles of periostin in health and disease, tissue remodeling as a response to insult/injury is emerging as a common functional denominator of this matricellular molecule. Periostin is transiently upregulated during cell fate changes, either physiologic or pathologic. Combining observations from various conditions, a common pattern of events can be suggested, including periostin localization during development, insult and injury, epithelial–mesenchymal transition, extracellular matrix restructuring, and remodeling. We propose mesenchymal remodeling as an overarching role for the matricellular protein periostin, across physiology and disease. Periostin may be seen as an important structural mediator, balancing appropriate versus inappropriate tissue adaption in response to insult/injury.

Evidence Supporting a Systolic Blood Pressure Goal of Less Than 150 mm Hg in Patients Aged 60 Years or Older: The Minority View

Abstract: The 2014 guideline for the management of high blood pressure in adults from the panel appointed to the Eighth Joint National Committee includes a recommendation to increase the target systolic bloo...