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Life expectancy with HIV: Better, but still decreased

2011-10-28T22:49:00.000+01:00

British Medical Journal

Life expectancy with HIV: Better, but still decreased

October 29, 2011

ST LOUIS (MD Consult) - Although life expectancy has increased for people with HIV in the United Kingdom, it remains significantly lower than in the general population, according to a study published in the October 29, 2011, issue of the British Medical Journal.

The cohort study included 17,661 adult patients enrolled in the U.K, Collaborative HIV Cohort study. All had a CD4 count of 350 cells/mm³ or less at the time they started antiretroviral therapy, between 1996 and 20078. During a total 91,203 person-years of follow-up, 1,248 of the patients died.

Cross-sectional age-specific mortality during follow-up was used to calculate life expectancy for a patient with HIV at the exact age of 20 years—ie, the average additional years of life after age 20. The analysis also estimated life expectancy for patients with late antiretroviral therapy: CD4 count of less than 200 cells/mm³.

Life expectancy after age 20 for people with HIV increased significantly during the period studied: from 30.0 years in 1996-99 to 45.8 years in 2006-08. However, life expectancy remained lower for people with HIV, compared to the general population: 39.5 versus 57.8 years for men and 50.2 versus 61.6 years for women.

Starting antiretroviral therapy late was associated with a significant reduction in life expectancy after age 20. Life expectancy values were 37.9 years for those starting treatment at a CD count of less than 100 cells/mm³ and 41.0 at 100 to 199 cells/mm³, compared to 53.4 years at 200 to 350 cells/mm³.

With early initiation of antiretroviral therapy, HIV infection now has a good prognosis. Although studies have documented decreased mortality, there are few data on estimated life expectancy for people with HIV. This information has important implications for patients, service providers, and policymakers.

This U.K. cohort study documents significant improvements in life expectancy for adult patients with HIV since the mid-1990s. However, life expectancy after age 20 remains about 13 years less than in the general population.

Starting antiretroviral therapy later than recommended by guidelines is associated with up to 15 years' loss of life. The investigators conclude, "Earlier diagnosis and subsequent timely treatment with antiretroviral therapy might increase life expectancy."

BMJ. 2011;343:d6016.

Molina CASTLE Presentation

2011-10-23T21:53:00.000+01:00

37 Molina CASTLE Presentation

Projected effects of tobacco smoking on worldwide tuberculosis control: mathematical modelling analysis

2011-10-09T16:23:00.002+01:00

BMJ

2011; 343:d5506 doi: 10.1136/bmj.d5506 (Published 4 October 2011)

Cite this as: BMJ 2011; 343:d5506

Research

Projected effects of tobacco smoking on worldwide tuberculosis control: mathematical modelling analysis

OPEN ACCESS

Sanjay Basu, physician1 2 3,

David Stuckler, university lecturer in sociology3 4,

Asaf Bitton, instructor in medicine5 6,

Stanton A Glantz, professor of medicine1

+Author Affiliations

¹Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA

²Division of General Internal Medicine, San Francisco General Hospital, San Francisco

³Department of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, UK

⁴Department of Sociology, Cambridge University, Cambridge, UK

⁵Department of Health Care Policy, Harvard Medical School, Boston, MA, USA

⁶Division of General Medicine, Brigham and Women’s Hospital, Boston

Correspondence to: S Basu, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA sanjay.basu@ucsf.edu

Accepted 28 July 2011

Abstract

Objectives Almost 20% of people smoke tobacco worldwide—a percentage projected to rise in many poor countries. Smoking has been linked to increased individual risk of tuberculosis infection and mortality, but it remains unclear how these risks affect population-wide tuberculosis rates.

Design We constructed a state transition, compartmental, mathematical model of tuberculosis epidemics to estimate the impact of alternative future smoking trends on tuberculosis control. We projected tuberculosis incidence, prevalence, and mortality in each World Health Organization region from 2010 to 2050, and incorporated changing trends in smoking, case detection, treatment success, and HIV prevalence.

Results The model predicted that smoking would produce an excess of 18 million tuberculosis cases (standard error 16-20) and 40 million deaths from tuberculosis (39-41) between 2010 and 2050, if smoking trends continued along current trajectories. The effect of smoking was anticipated to increase the number of tuberculosis cases by 7% (274 million v 256 million) and deaths by 66% (101 million v 61 million), compared with model predictions that did not account for smoking. Smoking was also expected to delay the millennium development goal target to reduce tuberculosis mortality by half from 1990 to 2015. The model estimated that aggressive tobacco control (achieving a 1% decrease in smoking prevalence per year down to eradication) would avert 27 million smoking attributable deaths from tuberculosis by 2050. However, if the prevalence of smoking increased to 50% of adults (as observed in countries with high tobacco use), the model estimated that 34 million additional deaths from tuberculosis would occur by 2050.

Conclusions Tobacco smoking could substantially increase tuberculosis cases and deaths worldwide in coming years, undermining progress towards tuberculosis mortality targets. Aggressive tobacco control could avert millions of deaths from tuberculosis.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See:http://creativecommons.org/licenses/by-nc/2.0/ andhttp://creativecommons.org/licenses/by-nc/2.0/legalcode.

Stenting versus Endarterectomy for Treatment of Carotid-Artery Stenosis

2011-10-07T01:39:00.000+01:00

Image via Wikipedia

You have a lot of articles to read !!! See the first page in schoolar google:

Stenting versus endarterectomy for treatment of carotid-artery stenosis

[HTML] de nih.govTG Brott, RW Hobson, G Howard… - … England Journal of …, 2010 - Mass Medical Soc
For 2502 patients over a median follow-up period of 2.5 years, there was no significant difference
in the estimated 4-year rates of the primary end point between the stenting group and the endarterectomy
group (7.2% and 6.8%, respectively; hazard ratio with stenting, 1.11; 95% confidence ...
Citado por 209 - Artículos relacionados - Las 10 versiones

Protected carotid-artery stenting versus endarterectomy in high-risk patients

[HTML] de shouxi.netJS Yadav, MH Wholey, RE Kuntz… - … England Journal of …, 2004 - Mass Medical Soc
... L. Nelson, Cutlip, Donald E., Cohen, David J., Popma, Jeffrey J., Ferguson, Robert D., Cohen,
Stanley N., Blackshear, Joseph L., Silver, Frank L., Mohr, JP, Lal, Brajesh K., Meschia, James
F., . (2010) Stenting versus Endarterectomy for Treatment of Carotid-Artery Stenosis. ...
Citado por 1265 - Artículos relacionados - Las 26 versiones

Safety and efficacy of endovascular treatment of carotid artery stenosis compared with carotidendarterectomy: a Cochrane systematic review of the randomized …

[HTML] de ahajournals.orgLJ Coward, RL Featherstone… - Stroke, 2005 - Am Heart Assoc
... insufficient evidence to support a widespread change in clinical practice away from recommending
carotid endarterectomy as the treatment of choice for suitable carotid artery stenosis. Patients
suitable for carotid endarterectomy should only be offered stenting within the ...
Citado por 216 - Artículos relacionados - Las 9 versiones

A comparison of angioplasty with stenting versus endarterectomy for the treatment of carotid artery stenosis

WD Jordan - Annals of vascular surgery, 1997 - Elsevier
Carotid endarterectomy has been established as the standard treatment for high-grade
carotid stenosis. The results of an ongoing prospective trial for the safety of percutaneous
angioplasty with stenting (PTAS) were compared to retrospectively reviewed patients ...
Citado por 109 - Artículos relacionados - Las 7 versiones

Immediate and late clinical outcomes of carotid artery stenting in patients with symptomatic and asymptomatic carotid artery stenosis: a 5-year prospective analysis

[HTML] de ahajournals.orgGS Roubin, G New, SS Iyer, JJ Vitek… - Circulation, 2001 - Am Heart Assoc
... 6. Hobson RW II, Brott T, Ferguson R, et al. CREST: Carotid Revascularization Endarterectomy
Versus Stent Trial. ... 8. Yadav JS, Roubin GS, Iyer S, et al. Elective stenting of the extracranial carotid
arteries. ... Interventional treatment of arteriosclerotic carotid stenosis [in German]. ...
Citado por 630 - Artículos relacionados - Las 9 versiones

Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis

[HTML] de shouxi.netJL Mas, G Chatellier, B Beyssen… - … England Journal of …, 2006 - Mass Medical Soc
... 5. &NA;. (2011) Stenting Versus Endarterectomy for Treatment of Carotid-Artery Stenosis. ... 82.
Larry B. Goldstein. (2009) New data about stenting versus endarterectomy for symptomatic carotid
artery stenosis. Current Treatment Options in Cardiovascular Medicine 11:3, 232-240. ...
Citado por 741 - Artículos relacionados - Las 20 versiones

International carotid stenting study: protocol for a randomised clinical trial comparing carotidstenting with endarterectomy in symptomatic carotid artery stenosis

[PDF] de ucl.ac.ukRL Featherstone, MM Brown… - Cerebrovascular …, 2004 - content.karger.com
... risk of causing stroke at the time of treatment [4]. Techniques for endovascular treatment for carotid ...
data are not sufficient to establish the safety and effectiveness of carotid stenting in comparison
with the well-established technique of carotid endarterectomy [5]. In ...
Citado por 100 - Artículos relacionados - Las 10 versiones

A cost comparison of balloon angioplasty and stenting versus endarterectomy for the treatment ofcarotid artery stenosis

WD Jordan Jr, GD Roye, WS Fisher III… - Journal of vascular …, 1998 - Elsevier
Purpose: Percutaneous transluminal angioplasty with stenting (PTAS) of the carotid artery
has been advocated as an alternative treatment for high-grade stenosis. Rationale for this
approach includes less morbidity, shorter recovery, and lower cost when compared with ...
Citado por 59 - Artículos relacionados - Las 5 versiones

Carotid angioplasty and stenting versus carotid endarterectomy for treatment of asymptomatic carotid stenosis: a randomized trial in a community hospital

WH Brooks, RR McClure, MR Jones… - …, 2004 - journals.lww.com
... Carotid angioplasty and stenting (CAS) represents a relatively new technique offering a theoretical ...
more than 80%, as determined by the North American Symptomatic Carotid Endarterectomy Trial
(45 ... not approved deployment of stents in the carotid artery for treatment of carotid ...
Citado por 134 - Artículos relacionados - Las 5 versiones

Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis

[PDF] de vanderbilt.eduHJM Barnett, DW Taylor, M Eliasziw… - … England Journal of …, 1998 - Mass Medical Soc
... outcomes of stenting versus endarterectomy: a subgroup analysis of the Carotid Revascularization
Endarterectomy versus Stenting Trial (CREST ... Angiographic Criteria for Measurement of Vertebral
Artery Origin Stenosis: The Vertebral Origin Treatment with Endovascular ...
Citado por 1507 - Artículos relacionados - Las 11 versiones

Búsqueda bibliográfica y Análisis de Datos

2011-10-05T05:14:00.000+01:00

Medline 2011

View more presentations from Marcelo Garcia Dieguez

Via: Slideshare. Autor: Marcelo Dieguez.

Prevalence and Clinical Significance of HIV Drug Resistance Mutations by Ultra-Deep Sequencing in Antiretroviral-Naïve Subjects in the CASTLE Study

2011-10-04T16:50:00.000+01:00

PDF | Citation | XML

Max Lataillade¹^,², Jennifer Chiarella², Rong Yang¹, Steven Schnittman¹, Victoria Wirtz¹, Jonathan Uy¹, Daniel Seekins¹, Mark Krystal¹, Marco Mancini¹, Donnie McGrath¹, Birgitte Simen³, Michael Egholm³, Michael Kozal²^*

1 Global Development and Medical Affairs, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America, 2 Yale University School of Medicine and Veterans Affairs Connecticut Healthcare System, New Haven, Connecticut, United States of America, 3 454 Life Sciences, a Roche company, Branford, Connecticut, United States of America

Abstract Top

Background

CASTLE compared the efficacy of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-naïve subjects from 5 continents.

Objectives

Determine the baseline rate and clinical significance of TDR mutations using ultra-deep sequencing (UDS) in ARV-naïve subjects in CASTLE.

Methods

A case control study was performed on baseline samples for all 53 subjects with virologic failures (VF) at Week 48 and 95 subjects with virologic successes (VS) randomly selected and matched by CD4 count and viral load. UDS was performed using 454 Life Sciences/Roche technology.

Results

Of 148 samples, 141 had successful UDS (86 subtype B, 55 non-B subtypes). Overall, 30.5% of subjects had a TDR mutation at baseline; 15.6% only had TDR(s) at <20% of the viral population. There was no difference in the rate of TDRs by B (30.2%) or non-B subtypes (30.9%). VF (51) and VS (90) had similar rates of any TDRs (25.5% vs. 33.3%), NNRTI TDRs (11.1% vs.11.8%) and NRTI TDRs (24.4% vs. 25.5%). Of 9 (6.4%) subjects with M184V/I (7 at <20% levels), 6 experienced VF. 16 (11.3%) subjects had multiple TAMs, and 7 experienced VF. 3 (2.1%) subjects had both multiple TAMs+M184V, and all experienced VF. Of 14 (9.9%) subjects with PI TDRs (11 at <20% levels): only 1 experienced virologic failure. The majority of PI TDRs were found in isolation (e.g. 46I) at <20% levels, and had low resistance algorithm scores.

Conclusion

Among a representative sample of ARV-naïve subjects in CASTLE, TDR mutations were common (30.5%); B and non-B subtypes had similar rates of TDRs. Subjects with multiple PI TDRs were infrequent. Overall, TDRs did not affect virologic response for subjects on a boosted PI by week 48; however, a small subset of subjects with extensive NRTI backbone TDR patterns experienced virologic failure.

Citation: Lataillade M, Chiarella J, Yang R, Schnittman S, Wirtz V, et al. (2010) Prevalence and Clinical Significance of HIV Drug Resistance Mutations by Ultra-Deep Sequencing in Antiretroviral-Naïve Subjects in the CASTLE Study. PLoS ONE 5(6): e10952. doi:10.1371/journal.pone.0010952

Editor: Lishomwa C. Ndhlovu, University of California San Francisco, United States of America

Received: March 30, 2010; Accepted: May 7, 2010; Published: June 3, 2010

This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

Funding: Bristol-Myers Squibb funded the study and Roche contributed to the funding of this study by the employment of Drs. Simen and Egholm. This study was a Bristol-Myers Squibb funded resistance study of the parent CASTLE study which was also funded by Bristol-Myers Squibb. Bristol-Myers Squibb had a role in the initial study design, data collection and analysis. The ultra-deep sequencing analysis was performed at Yale/VA under the direction of Dr. Kozal and the decision to prepare and publish the manuscript of the ultra-deep substudy was the decision of Dr. Kozal. Dr. Kozal was supported by a VA MERIT Award.

Competing interests: MJK is the local primary investigator on HIV therapy studies sponsored by Merck, Pfizer, Gilead, Abbott and Bristol-Myers Squibb. MJK receives laboratory research support from Virco and Bristol-Myers Squibb. MJK receives royalties from a patent owned by Stanford University for some HIV diagnostic tests. BS and ME are employees of 454 Life Sciences/Roche. ML, RY, SS, VW, JU, DS, MK, MM, and DM are employees of Bristol-Myers Squibb. The funding of this study by Bristol Myers Squibb does not alter adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors.

* E-mail: Michael.kozal@yale.edu

Full Article in PLOS Medicine

Abordaje integral de la enfermedad cardiovascular

2011-09-23T06:21:00.001+01:00

Abordaje Biopsicosocial de La Enf.cardiovascular

Busquedas en Pubmed usando Mesh

2011-08-17T07:12:00.001+01:00

Australian Prescriber - Augost 2011

2011-08-01T07:04:00.000+01:00

http://www.australianprescriber.com/upload/pdf/issues/159.pdf

Dear Australian Prescriber reader
The August issue of Australian Prescriber is out now

Treat the numbers or treat the patient? (editorial) Montori VM
Managing the metabolic adverse effects of antipsychotic drugs in patients with psychosis. Lambert T
Current management of atrial fibrillation. Samardhi H, Santos M, Denman R, Walters DL, Bett N
Securing the supply chain. De Somer E
Pharmaceutical excipients – where do we begin? Haywood A, Glass B
Managing aggressive and violent patients. Fulde G, Preisz P
Wallchart. Anaphylaxis: emergency management for health professionals

Plus features

New drug reviews
· fampridine for multiple sclerosis
· ferric carboxymaltose for iron deficiency
· palonosetron for prevention of nausea and vomiting
· vinflunine for bladder cancer

Medicines Safety Update
· Cramps, quinine and thrombocytopenia
· Venlafaxine and stress cardiomyopathy
· In utero antipsychotic exposure and neonatal extrapyramidal and withdrawal adverse effects
· Prescribing medicines in pregnancy – new TGA database
Book review – Therapeutic Guidelines: Rheumatology
Letters
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Controversies regarding long-acting B2 agonists

2011-07-21T04:50:00.000+01:00

Controversies Regarding Long-Acting b2-Agonists

Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis

2011-07-15T18:37:00.000+01:00

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Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis

Jeffrey A. Cohen, M.D., Frederik Barkhof, M.D., Giancarlo Comi, M.D., Hans-Peter Hartung, M.D., Bhupendra O. Khatri, M.D., Xavier Montalban, M.D., Jean Pelletier, M.D., Ruggero Capra, M.D., Paolo Gallo, M.D., Guillermo Izquierdo, M.D., Klaus Tiel-Wilck, M.D., Ana de Vera, M.D., James Jin, Ph.D., Tracy Stites, Ph.D., Stacy Wu, M.D., Shreeram Aradhye, M.D., and Ludwig Kappos, M.D. for the TRANSFORMS Study Group

N Engl J Med 2010; 362:402-415February 4, 2010

Abstract
Article
References
Citing Articles (96): Oral fingolimod (FTY720) is a sphingosine-1-phosphate–receptor modulator. After phosphorylation, fingolimod acts as a functional antagonist of the sphingosine-1-phosphate type 1 receptor, inducing receptor internalization and rendering T and B cells insensitive to a signal necessary for egress from secondary lymphoid tissues.1,2 The resulting redistribution to lymph nodes reduces recirculation of autoaggressive lymphocytes to the central nervous system.3-5 Also, fingolimod is lipophilic, readily crosses the blood–brain barrier, and is phosphorylated within the central nervous system.6 Through interaction with sphingosine-1-phosphate receptors on neural cells, fingolimod may have neuroprotective or reparative effects.6-9
Fingolimod effectively treats experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis.1,10,11 In a 6-month, phase 2 study involving patients with relapsing multiple sclerosis,12 daily oral fingolimod at a dose of 5.0 or 1.25 mg significantly reduced the number of gadolinium-enhancing lesions seen on magnetic resonance imaging (MRI) and the relapse rate, as compared with placebo. In an extension study, clinical and MRI benefits were maintained for up to 5 years, and no new safety issues were identified.13,14
In this 12-month, phase 3, multicenter, randomized, double-blind, double-dummy, parallel-group study, called the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS), we compared the efficacy and safety of fingolimod with that of intramuscular interferon beta-1a, an established therapy for multiple sclerosis.
METHODS
Patients
Patients were eligible to participate in the study if they were between 18 and 55 years of age, had received a diagnosis of multiple sclerosis that met the revised McDonald criteria,15 had disease with a relapsing–remitting course,16 had had at least one documented relapse during the previous year or at least two documented relapses during the previous 2 years, and had a score of 0 to 5.5 on the Expanded Disability Status Scale (EDSS) (ranging from 0 to 10, with higher scores indicating a greater degree of disability).17 Other exclusion criteria were a documented relapse or corticosteroid treatment within 30 days before randomization, active infection, macular edema, immunosuppression (either drug- or disease-induced), and clinically significant coexisting systemic disease. Previous recent therapy with either any type of interferon beta or glatiramer acetate was not a criterion for exclusion.
The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice18 and the principles of the Declaration of Helsinki.19 The protocol was approved by the institutional review board at each study site. All patients provided written informed consent before any study-related procedure was performed.
Study Oversight
A steering committee consisting of academic investigators collaborated with the sponsor (Novartis Pharma) to design the study and monitor its conduct. Data were collected by the site investigators and analyzed by the sponsor. All the authors had access to all data, participated in all analyses and their interpretation, wrote the manuscript, and decided to submit the manuscript for publication. The authors attest to the completeness and accuracy of the data and the analyses. During the study, the investigators, participating institutions, and sponsor agreed to maintain confidentiality of the data.
Study Design
Patients were randomly assigned to 12 months of treatment with oral fingolimod, at a daily dose of either 1.25 or 0.5 mg, or intramuscular interferon beta-1a (Avonex, Biogen Idec), at a weekly dose of 30 μg. Randomization was performed centrally in blocks of six within each site and was stratified according to site. Study-group assignments were performed with the use of an interactive voice-response system. At each site, a treating neurologist supervised medical management. A specially trained and certified20 examining neurologist determined EDSS scores at scheduled and unscheduled visits. The examining neurologist or a trained technician calculated Multiple Sclerosis Functional Composite (MSFC) scores, which included the average of scores on the timed 25-foot walk, the 9-hole peg test, and the paced auditory serial-addition test with a 3-second interstimulus interval. Each of these scores was converted to a z score on the basis of the combined study population at baseline as the reference population, with higher scores indicating improvement.21
During the trial, patients, study personnel, MRI evaluators, steering-committee members, and the study statistician were unaware of study-group assignments and leukocyte counts. Capsules, syringes, and packaging materials for active and placebo treatments were indistinguishable. Patients were instructed to cover injection sites at visits and not to discuss adverse events with clinical evaluators. An independent physician monitored patients after the first dose of the oral study drug was administered and was instructed not to discuss heart-rate changes with patients or study personnel. Employees of the sponsor working independently of the study team monitored first-dose safety data. An independent data and safety monitoring board evaluated overall safety in the fingolimod phase 3 program. No interim efficacy analysis was performed.
Study Procedures
Safety assessments were conducted during screening, at baseline, and at months 1, 2, 3, 6, 9, and 12. EDSS scores were determined every 3 months, and MSFC scores every 6 months. Standardized MRI scans were obtained at screening and at 12 months and were analyzed centrally by the Image Analysis Center in Amsterdam.
Relapse was defined as new, worsening, or recurrent neurologic symptoms that occurred at least 30 days after the onset of a preceding relapse, that lasted at least 24 hours without fever or infection, and that were accompanied by an increase of at least half a point on the EDSS or an increase of at least one point in two functional-systems scores or of at least two points in one functional-system score (excluding changes in bowel or bladder function and cognition). Potential relapses triggered an unscheduled visit and were confirmed by the treating neurologist on the basis of blinded examination by the examining neurologist. Progression of disability was defined as a one-point increase in the EDSS score (or a half-point increase for patients with a baseline score ≥5.5) that was confirmed 3 months later in the absence of relapse. Additional methodologic details are available in theSupplementary Appendix, available with the full text of this article at NEJM.org.
Study End Points
The primary efficacy end point was the annualized relapse rate, which was defined as the number of confirmed relapses during a 12-month period. The two key secondary end points were the number of new or enlarged hyperintense lesions on T₂-weighted MRI scans at 12 months and the time to confirmed disability progression.
Statistical Analysis
We based our sample-size estimates on a phase 2 trial of fingolimod12 and a phase 3 trial of interferon beta-1a,22 which showed an annualized relapse rate of 0.33 for a 1.25-mg dose of fingolimod and of 0.55 for interferon beta-1a, a common standard deviation of 0.9, and 57 study-drug discontinuations per year per group. Using the Wilcoxon–Mann–Whitney rank-sum test, we estimated that an enrollment of 425 patients per study group would be needed to provide a power of 90% at a two-sided significance level of 0.05.
To control for type I errors, multiplicity adjustment was applied to testing for comparisons between fingolimod and interferon beta-1a in a hierarchical order, according to the dose of fingolimod, for the study end points. Each test was performed at a significance level of 0.05. However, the lower-rank testing was performed only when every higher-rank test indicated statistical significance.
The modified intention-to-treat cohort, which consisted of all patients who underwent randomization and received at least one dose of a study drug, was the primary focus for efficacy and safety analyses. The study was designed to test the null hypothesis that there would be no significant differences in the annualized relapse rate between either of the fingolimod groups and the interferon group with the use of a negative binomial regression model with adjustment for study group, country, number of relapses in the previous 2 years, and baseline EDSS score. These prespecified covariates were based on exploratory analyses of the phase 2 study data.12 Heterogeneity in efficacy according to whether patients had undergone previous therapy was tested as a post hoc analysis with the use of the same negative binomial regression model, with the addition of the interaction term for therapy during the study and before baseline. Additional details concerning statistical methods are available in the Supplementary Appendix.
RESULTS
Study Population
From May 2006 through September 2007, a total of 1292 patients underwent randomization at 172 clinical centers in 18 countries. Of these patients, 12 were excluded before receiving any study drug or undergoing any safety or efficacy assessments because they did not meet eligibility criteria (Figure 1FIGURE 1Enrollment and Outcomes.). Baseline characteristics were similar across the study groups and were consistent with a population of patients with clinically active, relapsing–remitting multiple sclerosis (Table 1TABLE 1Baseline Characteristics of the Patients.). In all, 1153 patients (89%) completed the study, and 1123 (87%) continued to receive the assigned study drug. A slightly greater proportion of patients assigned to fingolimod at a dose of 1.25 mg discontinued treatment or study participation because of adverse events, as compared with the other two groups. Other reasons for discontinuation were equally distributed among the study groups.
Efficacy
Relapse
Table 2TABLE 2Clinical and MRI Results at 12 Months. summarizes the relapse rates, MRI outcomes, and results with respect to disability progression. There was a significantly greater reduction in the annualized relapse rates in both fingolimod groups than in the interferon group. Other relapse-related measures also significantly favored fingolimod, including the proportion of patients who were relapse-free, the proportion with multiple relapses, and the time to the first relapse (Figure 2FIGURE 2Annualized Relapse Rate at 12 Months and the Time to the First Relapse.). There was no significant difference in the magnitude of the treatment effect between patients who had previously undergone disease treatment and those who had not.
MRI Outcomes
Patients in the two fingolimod groups had significantly fewer new or enlarged hyperintense lesions on T₂-weighted images and gadolinium-enhancing lesions on T₁-weighted images at 12 months than did those in the interferon group. The mean percent reduction in brain volume from baseline to 12 months was significantly lower in the two fingolimod groups than in the interferon group. Changes in the volume of lesions on unenhanced T₂- or T₁-weighted images at 12 months did not differ significantly among the study groups.
Disability
Confirmed disability progression was infrequent in all the study groups. There were no significant differences in the time to the progression of disability or in the proportion of patients with confirmed progression among the study groups.
Adverse Events
Serious Events
Adverse events were reported for similar proportions of patients in the three study groups, ranging from 86 to 92% (Table 3TABLE 3Adverse Events and Serious Adverse Events (Safety Population).). Of these events, 87 to 90% were mild or moderate in severity. Serious adverse events and those leading to the discontinuation of a study drug were most frequent in the patients assigned to fingolimod at the 1.25-mg dose. The most common serious events in this group were bradycardia and atrioventricular block. All such events were observed after the first administration of fingolimod, and most were asymptomatic but were reported as serious adverse events because protocol-defined discharge criteria at 6 hours were not met, leading to mandatory hospitalization. All other serious adverse events occurred in fewer than four patients (<1%) in any study group.
There were two deaths during the trial, both in the group assigned to fingolimod at a dose of 1.25 mg. One of these deaths was caused by disseminated primary varicella zoster infection in a patient with no history of chicken pox and a negative baseline varicella zoster antibody titer who was exposed to a child with chicken pox during an 8-day course of corticosteroids (intravenous and then oral methylprednisolone) for a relapse of multiple sclerosis. Fingolimod was discontinued after 317 days of therapy, and intravenous antiviral therapy was started, but the patient died 3 days later. The second death was caused by herpes simplex encephalitis, which developed after 339 days of fingolimod therapy. A 3-day course of intravenous methylprednisolone was initially administered for suspected relapse of multiple sclerosis, followed by antiviral therapy starting 1 week after presentation. The patient died approximately 2 months later.
Two additional patients who received fingolimod at a dose of 1.25 mg died after the study ended. One patient, who had a baseline EDSS score of 5.0 at 3 years after the onset of disease, discontinued fingolimod after 11 months because of neurologic deterioration. Progressive multifocal leukoencephalopathy was ruled out. The patient's condition continued to decline, aspiration pneumonia developed, and the patient died 6 months after study discontinuation. The other patient died from metastatic breast cancer 10 months after discontinuing fingolimod.
Infections
The overall incidence of infection was similar across the study groups (ranging from 51 to 53%), whereas serious infections occurred in 0.2 to 1.7% of patients (Table 3). The only serious infections that were reported in more than one patient were appendicitis and herpesvirus infections. Among patients assigned to receive fingolimod, herpesvirus infections were diagnosed in 23 patients in the 1.25-mg group (5.5%) and 9 patients in the 0.5-mg group (2.1%), as well as in 12 patients in the interferon group (2.8%). In 41 of these 44 patients (93%), the infections were mild.
Cardiovascular Events
There was a transient, dose-dependent reduction in the heart rate that developed within 1 hour after the initial administration of fingolimod, which is consistent with the findings in previous clinical trials.12,13,23 Mean maximal decreases were reached after 4 to 5 hours of 12 beats per minute in the group that received the 1.25-mg dose and 8 beats per minute in the group that received the 0.5-mg dose, with the changes starting to attenuate within 6 hours after the first administration of the drug. Most patients had asymptomatic reductions in the heart rate of less than 20 beats per minute. Mild-to-moderate symptomatic bradycardia after the first dose of fingolimod was reported in four patients who received the 1.25-mg dose (0.9%) and in three patients who received the 0.5-mg dose (0.7%). Symptoms resolved within 24 hours without treatment. There were no cases of syncope. Second-degree atrioventricular block was reported during the first day of treatment in four patients receiving fingolimod — three in the 1.25-mg group (0.7%) and one in the 0.5-mg group (0.2%). Two patients in the 1.25-mg group had mild symptoms (intermittent dyspnea and dizziness in one patient and chest pain and palpitations in the other patient), which resolved within 24 hours without treatment. No significant effect on heart rate or atrioventricular conduction was observed with continued administration of the drug. Increases in mean arterial pressure occurred in both fingolimod groups (3 mm Hg in the 1.25-mg group and 2 mm Hg in the 0.5-mg group) during the first 6 months and remained stable between 6 and 12 months.
Ophthalmologic Events
Macular edema was confirmed on central review in six patients receiving fingolimod — four in the 1.25-mg group (1%) and two in the 0.5-mg group (0.5%). In three patients, the macular edema was asymptomatic and diagnosed by ophthalmologic examination. Five of the six cases were detected within 4 months after the start of therapy. The edema resolved within 3 months after discontinuation of fingolimod in four patients, was unchanged 1 month after discontinuation in one patient, and was reduced 8 months after discontinuation in one patient. Mean visual acuity and retinal thickness were similar across the study groups and remained stable over the 12-month study period.
Neoplasms
Ten localized skin cancers were reported, and all were successfully excised: five basal-cell carcinomas in the fingolimod groups (two in the 1.25-mg group and three in the 0.5-mg group) and one in the interferon group; three melanomas (all limited to the epidermis) in the group receiving the 0.5-mg dose of fingolimod; and one squamous-cell carcinoma in the interferon group. Of the 10 skin cancers, 8 were diagnosed at the first study examination by a dermatologist 4 to 12 months after enrollment. Breast cancer was reported in two patients in each of the fingolimod groups; three cases were diagnosed within 4 months after the initiation of the drug, and one was diagnosed 11 months after enrollment.
Pulmonary Events
A mild reduction (2 to 3%) in the mean forced expiratory volume in 1 second (FEV₁) was observed in both fingolimod groups at 1 month, with no further reductions thereafter. No changes in lung volumes or diffusion capacity were seen.
Laboratory Measurements
Reflecting fingolimod's mechanism of action, peripheral-blood lymphocyte counts were reduced after 1 month by 77% in the group that received the 1.25-mg dose of fingolimod and by 73% in the group that received the 0.5-mg dose and remained stable thereafter (for details, see the Supplementary Appendix). Alanine aminotransferase levels that were three times the upper limit of the normal range were more frequent in the fingolimod groups (occurring in 29 patients in the 1.25-mg group [7%] and 36 patients in the 0.5-mg group [8%]) than in the interferon group (10 patients [2%]). Alanine aminotransferase levels that were 10 times the upper limit of the normal range occurred in two patients in the interferon group.
DISCUSSION
This phase 3 study shows the superior efficacy of oral fingolimod over intramuscular interferon beta-1a. Fingolimod reduced the annualized relapse rate to a range of 0.16 to 0.20, as compared with 0.33 for interferon beta-1a, corresponding to a relative reduction of 38 to 52%. No differences were detected in the time to the confirmed progression of disability. The proportion of patients with progression was small in all the study groups, as would be expected in a 12-month study. Fingolimod treatment also more effectively reduced lesion activity and brain volume loss on MRI than did interferon beta-1a. The annualized relapse rate for patients receiving intramuscular interferon beta-1a in our study (0.33) was lower than that in several previous studies involving patients with relapsing–remitting multiple sclerosis, in which the rate ranged from 0.61 to 0.77.22,24-27 This observation suggests that the positive results of our study were not due to enrollment of a population with a large proportion of patients who did not have a response to interferon beta-1a.
The selection of the dose of fingolimod was based on pharmacokinetic and pharmacodynamic considerations from earlier studies,28 which suggested that a dose of 1.25 mg would be fully effective.12 The lower dose of 0.5 mg, which was expected to have a submaximal effect on lymphocyte recirculation, was at least as effective, although the 12-month study period may not have been sufficient to show real differences, particularly on disability outcomes.
The adverse events observed in patients receiving fingolimod were consistent with those in previous clinical studies.12,14,29 Key safety observations included transient bradyarrhythmias, macular edema, infections, and possibly cancers. Effects on the heart rate and atrioventricular conduction appear to be dose-related and result from the modulation of sphingosine-1-phosphate type 1 receptors in cardiac tissue.30 The mechanism by which macular edema occurs in patients receiving fingolimod requires further study. The onset of such events is early in the course of therapy, and most events improve or resolve after discontinuation of the drug.
Mild and moderate upper and lower respiratory tract infections were slightly more frequent among patients receiving fingolimod. Herpesvirus infections were most common in the 1.25-mg group and were fatal in two patients. The substantial decrease in peripheral-blood lymphocyte counts that is associated with fingolimod therapy reflects redistribution to lymph nodes, rather than destruction of lymphocytes. Thus, patients receiving fingolimod may have preservation of many aspects of immune function, including the total number of lymphocytes, the capacity for lymphocyte activation in lymph nodes and tissues, the capacity for generating antibodies, and innate immune responses.31Nevertheless, our findings suggest that fingolimod may be associated with an increased risk of certain viral infections, particularly herpesvirus infections.
After skin cancer was reported in the phase 2 study of fingolimod,12,29 regular dermatologic monitoring was included in our study. All of the 10 identified skin cancers were successfully excised. Four breast carcinomas were reported in patients in our study who were receiving fingolimod, two in each dose group. One patient died from metastatic disease, and the other three patients had ductal carcinomas diagnosed on routine examinations within 4 months after starting fingolimod. The overall number of cancers was too small to determine causality, and to date there has been no apparent relationship between the dose of fingolimod and the risk of cancer.
Although this is one of the largest studies involving patients with multiple sclerosis to date, a potential shortcoming is that rare or late-appearing adverse events may not have been detected because of their low incidence and the 1-year study duration. Integrated analyses of data from other phase 3 studies and from the extensions of the phase 2 and phase 3 studies will help refine the safety profile of fingolimod, including a possible increase in the risk of cancer.
An oral treatment option for relapsing–remitting multiple sclerosis is highly desirable to improve convenience, diminish side effects, and improve compliance.32-34 This study showed that once-daily oral fingolimod had superior efficacy to interferon beta-1a administered by weekly intramuscular injection. Fingolimod was associated with clearly identified adverse events, some of which may be dose-related. The absence of dose-related differences in efficacy in this study requires further evaluation in the 2-year, placebo-controlled phase 3 trials.
Presented in part at the annual meetings of the American Academy of Neurology, Seattle, in April 2009, and of the European Committee for Treatment and Research in Multiple Sclerosis, Dusseldorf, Germany, in September 2009.
Supported by Novartis Pharma.
Dr. Cohen reports receiving consulting fees from Biogen Idec, Novartis, EMD Serono, and Teva, lecture fees from Sanofi-Aventis and Waterfront Media, and research support from Genzyme, Novartis, and Teva; Dr. Barkhof, receiving consulting fees from Bayer Schering, Serono, Sanofi-Aventis, AstraZeneca, Genentech, Novartis, Biogen Idec, Lundbeck, Talecris, Roche, Wyeth, and MediciNova and lecture fees from Bayer Schering and Serono; Dr. Comi, receiving consulting fees from Merck Serono, Novartis, Sanofi-Aventis, and Teva and lecture fees from Bayer, Biogen-Dompé, Novartis, Merck Serono, Sanofi-Aventis, and Teva; Dr. Hartung, receiving consulting and lecture fees from Bayer Schering, Biogen Idec, Merck Serono, and Teva, consulting fees from Novartis, and grant support from Biogen Idec and Bayer Schering; Dr. Khatri, receiving consulting fees from Bayer, Biogen Idec, Medtronics, Pfizer, Teva, and Serono and lecture fees from Bayer, Biogen Idec, and Serono; Dr. Montalban, receiving consulting and lecture fees from Bayer Schering, Biogen Idec, Novartis, Sanofi-Aventis, and Teva; Dr. Pelletier, receiving consulting and lecture fees from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, and Sanofi-Aventis and grant support from Bayer and Sanofi-Aventis; Dr. Capra, receiving consulting fees from Novartis and lecture fees from Bayer, Biogen Dompé, and Sanofi-Aventis; Dr. Gallo, receiving lecture fees from Biogen Dompé, Merck Serono, and Bayer Schering and grant support from Biogen, Sanofi-Aventis, and Merck Serono; Dr. Izquierdo, receiving consulting fees from Biogen Idec, Merck Serono, Novartis, and Teva and lecture fees from Biogen and Merck Serono; Dr. Tiel-Wilck, receiving consulting fees from Novartis and lecture fees from Bayer Healthcare, Biogen Idec, Sanofi-Aventis, and Teva; Dr. de Vera, being an employee of Novartis Pharma; Drs. Jin, Stites, Wu, and Aradhye, being employees of Novartis Pharmaceuticals; and Dr. Kappos, serving as a consultant or a member or chair of a steering committee, data and safety monitoring board, or advisory board in clinical trials sponsored by Accorda, Actelion, Allergan, Allozyne, Bayer Schering, Biogen Idec, Biogen-Dompé, Boehringer Ingelheim, Genmab, GlaxoSmithKline, MediciNova, Merck Serono, Novartis, Roche, Sanofi-Aventis, Santhera, Teva Pharmaceuticals, UCB Pharma, and Wyeth, receiving lecture fees from Biogen Idec, Helvea, GlaxoSmithKline, Mediservice and Merck Serono, and receiving grant support from Bayer Schering, Biogen Idec, CSL Behring, Genmab, Genzyme, GlaxoSmithKline, MediciNova, Merck Serono, Novartis, Novartis Foundation, Roche, Santhera, Sanofi-Aventis, and UCB Pharma. No other potential conflict of interest relevant to this article was reported.
This article (10.1056/NEJMoa0907839) was published on January 20, 2010, at NEJM.org.
We thank Dave Anderson of Novartis Pharmaceuticals and Tom Potter and Rowena Hughes of Oxford PharmaGenesis for their editorial assistance.
SOURCE INFORMATION
The authors' affiliations are listed in the Appendix.
Address reprint requests to Dr. Cohen at Mellen Center U-10, Neurologic Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, or at cohenj@ccf.org.
The members of the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS) study group are listed in the Supplementary Appendix, available with the full text of this article at NEJM.org.
Appendix
The authors' affiliations are as follows: the Mellen Center, Cleveland Clinic, Cleveland (J.A.C.); Vrije Universiteit Medical Center, Amsterdam (F.B.); the Neurology Clinic, San Raffaele Hospital, University Vita e Salute, Milan (G.C.), the Regional Multiple Sclerosis Center, Presidio Ospedaliero di Montichiari, Montichiari (R.C.), and the Multiple Sclerosis Center of the Veneto Region, Department of Neuroscience, University Hospital of Padua, Padua (P.G.) — all in Italy; the Department of Neurology, Heinrich-Heine University, Düsseldorf (H.-P.H.), and Neurologisches Facharztzentrum Berlin, Klinisches Studienzentrum, Berlin (K.T.-W.) — both in Germany; Regional MS Center, Center for Neurological Disorders, Milwaukee (B.O.K.); the Neuroimmunology Unit, Hospital Vall d'Hebron, Barcelona (X.M.), and the MS Unit, Servicio de Neurologia, Hospital Universitario Virgen Macarena, Sevilla (G.I.) — both in Spain; the Departments of Neurology and Research (CRMBM), CHU Timone, Marseille, France (J.P.); Novartis Pharma (A.V.) and the Departments of Neurology and Research, University Hospital (L.K.) — both in Basel, Switzerland; and Novartis Pharmaceuticals, East Hanover, NJ (J.J., T.S., S.W., S.A.).

Hemoglobin Promotes Staphylococcus aureus Nasal Colonization

2011-07-09T01:11:00.001+01:00

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PLoS Pathogen
Source

Melissa Pynnonen¹^#, Rachel E. Stephenson²^#, Kelly Schwartz², Margarita Hernandez², Blaise R. Boles²^*

1 Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, United States of America, 2 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America

Abstract Top

Staphylococcus aureus nasal colonization is an important risk factor for community and nosocomial infection. Despite the importance of S. aureus to human health, molecular mechanisms and host factors influencing nasal colonization are not well understood. To identify host factors contributing to nasal colonization, we collected human nasal secretions and analyzed their ability to promote S. aureussurface colonization. Some individuals produced secretions possessing the ability to significantly promote S. aureus surface colonization. Nasal secretions pretreated with protease no longer promoted S. aureus surface colonization, suggesting the involvement of protein factors. The major protein components of secretions were identified and subsequent analysis revealed that hemoglobin possessed the ability to promote S. aureus surface colonization. Immunoprecipitation of hemoglobin from nasal secretions resulted in reduced S. aureus surface colonization. Furthermore, exogenously added hemoglobin significantly decreased the inoculum necessary for nasal colonization in a rodent model. Finally, we found that hemoglobin prevented expression of the agr quorum sensing system and that aberrant constitutive expression of the agr effector molecule, RNAIII, resulted in reduced nasal colonization of S. aureus. Collectively our results suggest that the presence of hemoglobin in nasal secretions contributes to S. aureus nasal colonization.

Author Summary Top

Staphylococcus aureus is a medically important human pathogen that is found in the nasal passages of approximately 1/3 of the population. The nose serves as a reservoir for spread of this pathogen and predisposes the host to potential infection. Factors contributing to S. aureus nasal colonization are only beginning to be elucidated. The collection and analysis of human nasal secretions provided evidence that the presence of hemoglobin in nasal secretions can promote S. aureus nasal colonization. Hemoglobin reduced expression of the S. aureus agr quorum sensing regulatory system known to be involved in surface colonization, and it was found that induction of the agr system reduced nasal colonization. These findings suggest that individuals experiencing frequent nosebleeds would be prone to S. aureus colonization and epidemiological data supports these findings. By understanding host factors and bacterial molecular mechanisms involved in nasal colonization we may one day be able to design novel decolonization strategies.

Citation: Pynnonen M, Stephenson RE, Schwartz K, Hernandez M, Boles BR (2011) Hemoglobin PromotesStaphylococcus aureus Nasal Colonization. PLoS Pathog 7(7): e1002104. doi:10.1371/journal.ppat.1002104

Editor: Frank R. DeLeo, National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States of America

Received: November 12, 2010; Accepted: April 19, 2011; Published: July 7, 2011

Copyright: © 2011 Pynnonen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was funded by a grant from the NIH NIAID #1K22AI081748. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: brboles@umich.edu

# These authors contributed equally to this work.

Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials

2011-07-08T04:16:00.001+01:00

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Singh S, Loke YK, Enright PL, et al. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. BMJ. 2011 Jun 14;342:d3215. doi: 10.1136/bmj.d3215. (Review) PMID: 21672999

OBJECTIVE: To systematically review the risk of mortality associated with long term use of tiotropium delivered using a mist inhaler for symptomatic improvement in chronic obstructive pulmonary disease.
DATA SOURCES: Medline, Embase, the pharmaceutical company clinical trials register, the US Food and Drug Administration website, and ClinicalTrials.gov for randomised controlled trials from inception to July 2010.
STUDY SELECTION: Trials were selected for inclusion if they were parallel group randomised controlled trials of tiotropium solution using a mist inhaler (Respimat Soft Mist Inhaler, Boehringer Ingelheim) versus placebo for chronic obstructive pulmonary disease; the treatment duration was more than 30 days, and they reported data on mortality. Relative risks of all cause mortality were estimated using a fixed effect meta-analysis, and heterogeneity was assessed with the I(2) statistic.
RESULTS: Five randomised controlled trials were eligible for inclusion. Tiotropium mist inhaler was associated with a significantly increased risk of mortality (90/3686 v 47/2836; relative risk 1.52, 95% confidence interval, 1.06 to 2.16; P=0.02; I(2)=0%). Both 10 microg (2.15, 1.03 to 4.51; P=0.04; I(2)=9%) and 5 microg (1.46, 1.01 to 2.10; P=0.04; I(2)=0%) doses of tiotropium mist inhaler were associated with an increased risk of mortality. The overall estimates were not substantially changed by sensitivity analysis of the fixed effect analysis of the five trials combined using the random effects model (1.45, 1.02 to 2.07; P=0.04), limiting the analysis to three trials of one year`s duration each (1.50, 1.05 to 2.15), or the inclusion of additional data on tiotropium mist inhaler from another investigational drug programme (1.42, 1.01 to 2.00). The number needed to treat for a year with the 5 microg dose to see one additional death was estimated to be 124 (95% confidence interval 52 to 5682) based on the average control event rate from the long term trials.
CONCLUSIONS: This meta-analysis explains safety concerns by regulatory agencies and indicates a 52% increased risk of mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease.

Adverse effects of Varenicicline

2011-07-08T02:25:00.000+01:00

Efectos adversos de Vareniciclina

Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening

2011-07-04T15:51:00.000+01:00

Lung cancer is an aggressive and heterogeneous disease.1,2 Advances in surgical, radiotherapeutic, and chemotherapeutic approaches have been made, but the long-term survival rate remains low.3After the Surgeon General's 1964 report on smoking and health, mortality from lung cancer among men peaked and then fell; among women, the peak occurred later and a slight decline has occurred more recently.4 Even though the rate of heavy smoking continues to decline in the United States,594 million current or former smokers remain at elevated risk for the disease,6 and lung cancer remains the leading cause of death from cancer in this country.3 The prevalence of smoking is substantially higher in developing countries than in the United States, and the worldwide burden of lung cancer is projected to rise considerably during the coming years.7

Although effective mass screening of high-risk groups could potentially be of benefit, randomized trials of screening with the use of chest radiography with or without cytologic analysis of sputum specimens have shown no reduction in lung-cancer mortality.8 Molecular markers in blood, sputum, and bronchial brushings have been studied but are currently unsuitable for clinical application.8Advances in multidetector computed tomography (CT), however, have made high-resolution volumetric imaging possible in a single breath hold at acceptable levels of radiation exposure,9allowing its use for certain lung-specific applications. Several observational studies have shown that low-dose helical CT of the lung detects more nodules and lung cancers, including early-stage cancers, than does chest radiography.8 Therefore, the National Cancer Institute (NCI) funded the National Lung Screening Trial (NLST), a randomized trial, to determine whether screening with low-dose CT, as compared with chest radiography, would reduce mortality from lung cancer among high-risk persons. The NLST was initiated in 2002.10 In October 2010, the available data showed that there was a significant reduction with low-dose CT screening in the rates of both death from lung cancer and death from any cause. We report here the findings of the NLST, including the performance characteristics of the screening techniques, the approaches used for and the results of diagnostic evaluation of positive screening results, the characteristics of the lung-cancer cases, and mortality. A comprehensive description of the design and operations of the trial, including the collection of the data and the acquisition variables of the screening techniques, has been published previously.10

Full Text in PDF

Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry

2011-06-28T17:52:00.000+01:00

The Lancet Neurology, Volume 10, Issue 7, Pages 609 - 617, July 2011

doi:10.1016/S1474-4422(11)70107-7 Cite or Link Using DOI

Published Online: 06 June 2011

Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry

Dr, Prof Torbjörn Tomson MD a , Dina Battino MD b, Erminio Bonizzoni PhD c, John Craig MD d, Prof Dick Lindhout MD e f, Anne Sabers MD g, Prof Emilio Perucca MD h, Prof Frank Vajda MD i, for the EURAP study group‡

Summary

Background

Prenatal exposure to antiepileptic drugs is associated with a greater risk of major congenital malformations, but there is inadequate information on the comparative teratogenicity of individual antiepileptic drugs and the association with dose. We aimed to establish the risks of major congenital malformations after monotherapy exposure to four major antiepileptic drugs at different doses.

Methods

The EURAP epilepsy and pregnancy registry is an observational cohort study representing a collaboration of physicians from 42 countries. We prospectively monitored pregnancies exposed to monotherapy with different doses of four common drugs: carbamazepine, lamotrigine, valproic acid, or phenobarbital. Our primary endpoint was the rate of major congenital malformations detected up to 12 months after birth. We assessed pregnancy outcomes according to dose at the time of conception irrespective of subsequent dose changes.

Findings

After excluding pregnancies that ended in spontaneous abortions or chromosomal or genetic abnormalities, those in which the women had treatment changes in the first trimester, and those involving other diseases or treatments that could affect fetal outcome, we assessed rates of major congenital malformations in 1402 pregnancies exposed to carbamazepine, 1280 on lamotrigine, 1010 on valproic acid, and 217 on phenobarbital. An increase in malformation rates with increasing dose at the time of conception was recorded for all drugs. Multivariable analysis including ten covariates in addition to treatment with antiepileptic drugs showed that the risk of malformations was greater with a parental history of major congenital malformations (odds ratio 4·4, 95% CI 2·06—9·23). We noted the lowest rates of malformation with less than 300 mg per day lamotrigine (2·0% [17 events], 95% CI 1·19—3·24) and less than 400 mg per day carbamazepine (3·4% [5 events], 95% CI 1·11—7·71). Compared with lamotrigine monotherapy at doses less than 300 mg per day, risks of malformation were significantly higher with valproic acid and phenobarbital at all investigated doses, and with carbamazepine at doses greater than 400 mg per day.

Interpretation

The risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential.

Funding

Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, Netherlands Epilepsy Foundation, Stockholm County Council, and ALF.

Estudio FREEDOM

2011-06-27T03:58:00.000+01:00

FREEDOM, an article from NEJM. It deals with 2 schemes of fingolimod (a new drug for Sclerosis Multiple) vs. placebo. Watching the Jadad´s scale could be considered as high quality. The authors received a grant from Novartis. This data is shown in the article.

This is the first oral treatment in Sclerosis Multiple so the relevant that this article show. Eventhough it seems to be safety and show efficacy, more trials are required, specially not founded by Novartis. Natalizumab is not an option, because its adverse effects. (leucoencephalopaty).

Nejm Freedoms

Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice

2011-06-24T22:00:00.000+01:00

The Lancet Oncology, Volume 12, Issue 7, Pages 663 - 672, July 2011

doi:10.1016/S1470-2045(11)70145-0

Cite or Link Using DOI

Published Online: 17 June 2011

Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice

Dr Hormuzd A Katki PhD a , Prof Walter K Kinney MD b, Barbara Fetterman SCT[ASCP] c, Thomas Lorey MD c, Nancy E Poitras ACS c, Li Cheung MS d, Franklin Demuth BS d, Prof Mark Schiffman MD a, Prof Sholom Wacholder PhD a, Philip E Castle PhD e

Summary

Background

Concurrent testing for human papillomavirus (HPV) and cervical cytology (co-testing) is an approved alternative to cytology alone in women aged 30 years and older. We aimed to assess the safety in routine clinical practice of 3-year screening intervals for women testing negative for HPV with normal cytology and to assess if co-testing can identify women at high risk of cervical cancer or cervical intraepithelial neoplasia grade 3 (CIN3) or worse over 5 years.

Methods

We assessed the 5-year cumulative incidence, starting in 2003—05, of cervical cancer and CIN3 or worse for 331 818 women aged 30 years and older who enrolled in co-testing at Kaiser Permanente Northern California (Berkeley, CA, USA) and had adequate enrolment co-test results. Follow-up continued until Dec 31, 2009. We defined cumulative incidence to include prevalence at enrolment and incidence after enrolment. Prevalence at enrolment was defined as the ratio of women diagnosed with each outcome on the biopsy visit immediately after their enrolment screening visit to the total enrolled women. At screening visits only HPV test and Pap smear samples were collected, and at biopsy visits colposcopically directed biopsies were taken. To estimate post-enrolment incidence, we used Weibull survival models.

Findings

In 315 061 women negative by HPV testing, the 5-year cumulative incidence of cancer was 3·8 per 100 000 women per year, slightly higher than for the 306 969 who were both negative by HPV and Pap testing (3·2 per 100 000), and half the cancer risk of the 319 177 who were negative by Pap testing (7·5 per 100 000). 313 465 (99·5%) women negative by HPV testing had either normal cytology or equivocal abnormalities. Abnormal cytology greatly increased cumulative incidence of CIN3 or worse over 5 years for the 16 757 positive by HPV testing (12·1% vs 5·9%; p<0·0001). By contrast, although statistically significant, abnormal cytology did not increase 5-year risk of CIN3 or worse for women negative by HPV testing to a substantial level (0·86% vs 0·16%; p=0·004). 12 208 (73%) of the women positive by HPV testing had no cytological abnormality, and these women had 258 (35%) of 747 CIN3 or worse, 25 (29%) of 87 cancers, and 17 (63%) of 27 adenocarcinomas.

Interpretation

For women aged 30 years and older in routine clinical practice who are negative by co-testing (both HPV and cytology), 3-year screening intervals were safe because a single negative test for HPV was sufficient to reassure against cervical cancer over 5 years. Incorporating HPV testing with cytology also resulted in earlier identification of women at high risk of cervical cancer, especially adenocarcinoma. Testing for HPV without adjunctive cytology might be sufficiently sensitive for primary screening for cervical cancer.

Funding

Intramural Research Program of the US National Cancer Institute/NIH/DHHS, and the American Cancer Society.

Journals on Line

Life expectancy with HIV: Better, but still decreased

Life expectancy with HIV: Better, but still decreased

Molina CASTLE Presentation

Projected effects of tobacco smoking on worldwide tuberculosis control: mathematical modelling analysis

Projected effects of tobacco smoking on worldwide tuberculosis control: mathematical modelling analysis

Abstract

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Prevalence and Clinical Significance of HIV Drug Resistance Mutations by Ultra-Deep Sequencing in Antiretroviral-Naïve Subjects in the CASTLE Study

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Background

Objectives

Methods

Results

Conclusion

Abordaje integral de la enfermedad cardiovascular

Busquedas en Pubmed usando Mesh

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CONTENTS

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Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis

Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis

METHODS

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Study Oversight

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Study Procedures

Study End Points

Statistical Analysis

RESULTS

Study Population

Efficacy

Relapse

MRI Outcomes

Disability

Adverse Events

Serious Events

Infections

Cardiovascular Events

Ophthalmologic Events

Neoplasms

Pulmonary Events

Laboratory Measurements

DISCUSSION

SOURCE INFORMATION

Appendix

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Hemoglobin Promotes Staphylococcus aureus Nasal Colonization

Abstract Top

Author Summary Top

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Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials

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Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry

Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry

Summary

Background

Methods

Findings

Interpretation

Funding

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Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice

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Summary

Background

Methods

Findings

Interpretation